WO2023083210A1 - Substituted naphthyridinone derivative, and pharmaceutical composition thereof and use thereof - Google Patents

Substituted naphthyridinone derivative, and pharmaceutical composition thereof and use thereof Download PDF

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WO2023083210A1
WO2023083210A1 PCT/CN2022/130850 CN2022130850W WO2023083210A1 WO 2023083210 A1 WO2023083210 A1 WO 2023083210A1 CN 2022130850 W CN2022130850 W CN 2022130850W WO 2023083210 A1 WO2023083210 A1 WO 2023083210A1
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alkyl
alkoxy
ring
halogenated
compound
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PCT/CN2022/130850
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French (fr)
Chinese (zh)
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杨赛
胡斌
赵志明
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上海海雁医药科技有限公司
扬子江药业集团有限公司
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Publication of WO2023083210A1 publication Critical patent/WO2023083210A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present application relates to the technical field of medicine, in particular to a substituted naphthyridone derivative, its pharmaceutically acceptable salt, stereoisomer, pharmaceutical composition and application.
  • Methionine adenosyltransferase also known as S-adenosylmethionine synthetase
  • MAT is a kind of enzyme that catalyzes the reaction between methionine (Met) and ATP to generate S-adenosylmethionine (SAM ) enzymes.
  • SAM S-adenosylmethionine
  • MATI methionine
  • MATII methionine
  • MATIII encoded by MAT1A
  • MAT2A MAT2A
  • MAT2B genes respectively.
  • MAT1A mainly exists in mature liver tissue
  • MAT2A is widely distributed in extrahepatic cells, and its high expression can also be detected in various tumor tissues.
  • MTAP methylthioadenosine phosphorylase
  • MTA has a significant inhibitory effect on arginine methyltransferase (PRMT5), which makes MTAP-deficient cells more dependent on the activity of MAT2A, and ultimately increases the sensitivity of cancer cells to MAT2A inhibition.
  • PRMT5 arginine methyltransferase
  • tumors with high frequency of MTAP deletion include glioma, mesothelioma, melanoma, gastric cancer, esophageal cancer, bladder cancer, pancreatic cancer, non-small cell lung cancer, astrocytoma, osteosarcoma, head and neck cancer, mucinous Chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, non-Hodgkin's lymphoma, etc.
  • MAT2A Due to the loss of MTAP, the level of MAT2A is abnormally increased in many types of tumors, including gastric cancer, colon cancer, liver cancer and pancreatic cancer.
  • MTAP-deficient cells selective inhibition of MAT2A can reduce the proliferation activity of MTAP-deficient cancer cells and cause "synthetic lethality" of tumor cells. Therefore, selective inhibition of MAT2A can be used as an effective tumor therapy.
  • the first aspect of the present application provides a compound represented by formula (I), its pharmaceutically acceptable salt or its stereoisomer:
  • S 1 and S 2 represent ring atoms on ring A; S 1 is N or C; and S 2 is N or C;
  • Z 1 is N or CR Z1 ;
  • Z 2 is N or CR Z2 ;
  • Z 3 is N or CR Z3 ;
  • Z 4 is N or CR Z4 ;
  • R Z1 , R Z2 , R Z3 , and R Z4 are each independently Hydrogen, cyano, nitro, hydroxyl, carboxyl, halogen (preferably fluorine or chlorine), C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 3 -8 cycloalkyl (preferably C 3-6 cycloalkyl), halogenated C 1-8 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy ) , halogenated C 1-8 alkoxy (preferably halogenated C 1-6 alkoxy group, more preferably halogenated C 1-3 alkoxy),
  • R 1 , and R 2 are each independently hydrogen, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), -C(O)OC 1-8 alkyl (preferably -C(O)OC 1-6 alkyl, more preferably -C(O)OC 1-3 alkyl), -C(O)C 1-8 alkyl (preferably -C(O) C 1-6 alkyl, more preferably -C(O)C 1-3 alkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl) or 3 to 6 membered heterocycloalkyl ; or R 1 , R 2 and the connected ring atoms jointly form a 4 to 7 membered saturated or partially unsaturated monocyclic ring (preferably a 5 to 7 membered saturated or partially unsaturated monocyclic ring) or a 4 to 7 membered saturated or partially unsaturated monocyclic ring Monoheterocycle (preferably 5 to 7 membered saturated or partially uns
  • Ring A is a benzene ring or a 5- to 6-membered heteroaromatic ring; said ring A is unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of cyano, nitro, hydroxyl, Carboxyl, halogen (preferably fluorine or chlorine), C 1-8 alkyl ( preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 3-8 cycloalkyl (preferably C 3 -6 cycloalkyl), C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), -C (O) C 1-8 alkyl (preferably -C(O)C 1-6 alkyl, more preferably -C(O)C 1-3 alkyl), -C(O)OC 1-8 alkyl (preferably -C(O)OC 1 -6 alkyl, more preferably -C(O)OC 1-3 alkyl), -OC(O)C 1-8
  • R 3 , and R 4 are each independently hydrogen, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 3-6 cycloalkyl, -C( O)OC 1-8 alkyl (preferably -C(O)OC 1-6 alkyl, more preferably -C(O) OC 1-3 alkyl) or -C(O)C 1-8 alkyl (preferably -C(O)C 1-6 alkyl, more preferably -C(O)C 1-3 alkyl); or R 3 , R 4 and the connected nitrogen atom together form a 3- to 7-membered saturated or partially unsaturated monoheterocycle; wherein said C 1-8 alkyl, C 3-6 cycloalkyl, 3 to 7 membered saturated or partially unsaturated monoheterocycle is unsubstituted or replaced by 1, 2 or 3 Each substituent independently selected from the following group is substituted: deuterium, halogen, cyano, nitro, hydroxyl,
  • R a0 , and R b0 are each independently hydrogen, C 1-3 alkyl or acetyl; or R a0 , R b0 and the connected nitrogen atom together form a 4 to 6-membered saturated monoheterocyclic ring; the 4 to 6-membered
  • the saturated monoheterocycle is unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen, cyano, nitro, hydroxyl, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, -SO 2 C 1-3 alkyl, -S(O)C 1-3 alkyl, -C(O)NH 2 , -C(O)NH(C 1-3 alkyl), -C(O)N(C 1-3 alkyl) 2 , -
  • R a1 , and R b1 are each independently hydrogen, C 1-3 alkyl, halogenated C 1-3 alkyl or acetyl; or R a1 , R b1 and the connected nitrogen atom together form a 4 to 6-membered saturated unit Heterocycle; the 4- to 6-membered saturated monoheterocycle is unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen, cyano, nitro, hydroxyl, carboxyl , C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, - SO 2 C 1-3 alkyl, -S(O)C 1-3 alkyl, -C(O)NH 2 , -C(O)NH(C 1-3 alkyl), -C(O)N (C 1-3 alkyl
  • S 1 is C; and S 2 is C.
  • S 1 is N or C; and S 2 is C.
  • S 1 is C; and S 2 is N or C.
  • Z 1 is N or CR Z1 ;
  • Z 2 is CR Z2 ;
  • Z 3 is N or CR Z3 ; and
  • Z 4 is CR Z4 .
  • Z 1 is CR Z1 ;
  • Z 2 is CR Z2 ;
  • Z 3 is CR Z3 ; and
  • Z 4 is CR Z4 .
  • Z 1 is N;
  • Z 2 is CR Z2 ;
  • Z 3 is CR Z3 ; and
  • Z 4 is CR Z4 .
  • Z 1 is CR Z1 ;
  • Z 2 is CR Z2 ;
  • Z 3 is N; and
  • Z 4 is CR Z4 .
  • Z 1 is N;
  • Z 2 is CR Z2 ;
  • Z 3 is N; and
  • Z 4 is CR Z4 .
  • Z4 is CH.
  • Z 1 is N or CH
  • Z 2 is CR Z2
  • Z 3 is N or CH
  • Z 4 is CH.
  • Z 1 is N or CH;
  • Z 2 is CR Z2 ;
  • Z 3 is CH; and
  • Z 4 is CH.
  • Z 1 is N
  • Z 2 is CR Z2
  • Z 3 is CR Z3
  • Z 4 is CR Z4
  • Z 1 is CR Z1
  • Z 2 is CR Z2
  • Z 3 is CR Z3
  • Z 4 is CR Z4
  • Z 1 is N
  • Z 2 is CR Z2
  • Z 3 is N
  • Z 4 is CR Z4
  • Z 1 is CH
  • Z 2 is CR Z2
  • Z 3 is N
  • Z 4 for CR Z4 .
  • Z 1 is N, Z 2 is CR Z2 , Z 3 is CH, and Z 4 is CH; or Z 1 is CH, Z 2 is CR Z2 , Z 3 is CR Z3 , and Z 4 is CR Z4 ; or Z 1 is N, Z 2 is CR Z2 , Z 3 is N, and Z 4 is CH; or Z 1 is CH, Z 2 is CR Z2 , Z 3 is N, and Z 4 is CH.
  • R Z1 , R Z2 , R Z3 , and R Z4 are each independently hydrogen, cyano, halogen (preferably fluorine or chlorine), C 1-8 alkyl (preferably C 1-6 alkane group, more preferably C 1-3 alkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), halogenated C 1-8 alkyl (preferably halogenated C 1-6 alkane group, more preferably halogenated C 1-3 alkyl), C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), halogenated C 1- 8 alkoxy (preferably halogenated C 1-6 alkoxy, more preferably halogenated C 1-3 alkoxy) or -NR a1 R b1 ; wherein the C 1-8 alkyl, C 3- 8 Cycloalkyl groups are each independently unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of deuterium
  • R Z1 is hydrogen
  • R Z2 is cyano, halogen (preferably fluorine or chlorine), C 1-3 alkyl (preferably methyl), C 3-6 cycloalkyl (preferably cyclopropyl), halogen C 1-3 alkyl (preferably fluoro C 1-3 alkyl, more preferably monofluoromethyl, monofluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl or pentafluoroethyl), C 1-3 alkoxy (preferably methoxy or ethoxy), halogenated C 1-3 alkoxy (preferably difluoromethoxy or trifluoromethoxy ), halogen-substituted C 3-6 cycloalkyl or -NR a1 R b1 ; and R a1 , R b1 are each independently hydrogen, C 1-3 alkyl, halogenated C 1-3 alkyl or acetyl.
  • R Z3 is hydrogen, cyano, or halo (preferably fluoro or chloro). Further, R Z3 is hydrogen.
  • R Z4 is hydrogen or halo (preferably fluoro or chloro). Further, R Z4 is hydrogen.
  • R Z1 , R Z2 , R Z3 , R Z4 are each independently selected from the group consisting of hydrogen, methyl, ethyl, methoxy, ethoxy, -NH-CH 2 -CF 3 and cyclopropyl.
  • Z 1 is CH; Z 2 is CR Z2 ; Z 3 is CH; Z 4 is CH; and R Z2 is trifluoromethyl.
  • the 3-7 membered saturated or partially unsaturated monoheterocyclic ring formed by R 3 , R 4 and the connected nitrogen atom is selected from: azetidine, tetrahydropyrrole ring, piperidine ring, Piperazine ring, morpholine ring, thiomorpholine ring, azetidin-2-one ring, pyrrolidin-2-one ring, pyrrolidine-2,5-dione ring, piperidin-2-one ring, piperazin-2-one ring and morpholin-3-one ring.
  • R 4 is hydrogen or methyl;
  • R 3 is hydrogen, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 3-6 Cycloalkyl, -C(O)OC 1-8 alkyl (preferably -C(O)OC 1-6 alkyl, more preferably -C(O)OC 1-3 alkyl) or -C(O )C 1-8 alkyl (preferably -C(O)C 1-6 alkyl, more preferably -C(O)C 1-3 alkyl); wherein the C 1-8 alkyl, C 3 -6 cycloalkyl is unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen (preferably fluorine), cyano, nitro, hydroxyl, carboxyl, C -3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 1-3 alky
  • R 4 is hydrogen;
  • R 3 is C 1-3 alkyl (preferably methyl or ethyl); wherein said C 1-3 alkyl (preferably methyl or ethyl) is Substituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen (preferably fluorine).
  • R 4 is hydrogen or methyl;
  • R 3 is methyl, -CD 3 , or is selected from the following groups:
  • the ring A is a benzene ring or a 5-6 membered heteroaryl ring
  • the 5-6 membered heteroaryl ring is selected from the group consisting of a thiophene ring, a furan ring, a thiazole ring, Isothiazole ring, imidazole ring, oxazole ring, pyrrole ring, pyrazole ring, triazole ring, 1,2,3-triazole ring, 1,2,4-triazole ring, 1,2,5-triazole ring ring, 1,3,4-triazole ring, tetrazole ring, isoxazole ring, oxadiazole ring, 1,2,3-oxadiazole ring, 1,2,4-oxadiazole ring, 1, 2,5-oxadiazole ring, 1,3,4-oxadiazole ring, thiadiazole ring, pyridine ring, pyri
  • Ring A is unsubstituted.
  • L is -(CR q1 R q2 ) m -, -(CR q3 R q4 ) t1 -O-(CR q5 R q6 ) t2 -, or -(CR q7 R q8 ) t3 -NR q0 -(CR q9 R q10 ) t4 -;
  • n 1, 2, 3 or 4;
  • t1, t2, t3, and t4 are each independently 0, 1, 2 or 3; wherein t1, and t2 are not 0 at the same time; and t3, and t4 are not 0 at the same time;
  • R q1 and R q2 are each independently hydrogen, halogen (preferably fluorine or chlorine), cyano, nitro, hydroxyl, carboxyl, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), halogenated C 1-8 alkyl (preferably halogenated C 1-6 alkyl, more preferably Halogenated C 1-3 alkyl), C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), halogenated C 1-8 alkoxy ( Preferred is halogenated C 1-6 alkoxy, more preferably halogenated C 1-3 alkoxy), -C(O)NR a0 R b0 , -C(O)C 1-8 alkyl (preferably -C(O)C 1-6 alkyl, more preferably -C(O)C 1-3 alkyl) or -C(O)OC 1
  • R q3 , R q4 , R q5 , R q6 , R q7 , R q8 , R q9 , and R q10 are each independently hydrogen, halogen (preferably fluorine or chlorine), cyano, nitro, hydroxyl, carboxyl, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), halogenated C 1- 8 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), halogenated C 1-8 alkoxy (preferably halogenated C 1-6 alkoxy, more preferably halogenated C 1-3 alkoxy), -C(O ) NR a0 R b0 , -C(O)C 1- 8 alkyl (
  • R q0 is hydrogen, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl) , -C(O)NR a0 R b0 , -C(O)C 1-8 alkyl (preferably -C(O)C 1-6 alkyl, more preferably -C(O)C 1-3 alkane base) or -SO 2 C 1-8 alkyl (preferably -SO 2 C 1-6 alkyl, more preferably -SO 2 C 1-3 alkyl); wherein the C 1-8 alkyl, C 3-8 cycloalkyl is unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen, cyano, nitro, hydroxyl, carboxyl, C 1-3 alkyl , C 1-3 alkoxy, C 2- 4 alkenyl, C 2-4 alkynyl,
  • Z 1 , Z 2 , Z 3 , Z 4 , R 3 , R 4 , S 1 , S 2 , and ring A groups are as defined in the above specification.
  • t1 is 0; and t2 is 1, 2 or 3.
  • t3 is 0; and t4 is 1, 2 or 3.
  • R q1 , and R q2 are each independently hydrogen; and m is 2, 3, or 4.
  • the 3-7 membered saturated or partially unsaturated monocyclic ring formed by R q1 , R q2 and the connected carbon atoms is a 3-6 membered saturated monocyclic ring; and may be selected from the group consisting of: Propyl ring, cyclobutyl ring, cyclopentyl ring and cyclohexyl ring.
  • the 3-7 membered saturated or partially unsaturated monoheterocyclic ring formed by R q1 , R q2 and the connected carbon atoms is a 4-6 membered saturated or partially unsaturated monoheterocyclic ring; and may be selected from The group consisting of: azetidine, oxetane, tetrahydrofuran ring, tetrahydrothiophene ring, tetrahydropyrrole ring, piperidine ring, piperazine ring, morpholine ring, thiomorpholine ring, thio Morpholine-1,1-dioxide and tetrahydropyran ring.
  • L is -(CH 2 ) m - and m is 2 or 3.
  • the structure of the compound is shown in formula (I-1a) or formula (I-1b):
  • Z 5 is N or CR Z5 ;
  • Z 6 is N or CR Z6 ;
  • Z 7 is N or CR Z7 ; and
  • Z 8 is N or CR Z8 ;
  • R Z5 , R Z6 , R Z7 and R Z8 are each independently hydrogen, cyano, nitro, hydroxyl, carboxyl, halogen (preferably fluorine or chlorine), C 1-8 alkyl (preferably C 1-6 alkane group, more preferably C 1-3 alkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), halogenated C 1-8 alkyl (preferably halogenated C 1-6 alkane group, more preferably halogenated C 1-3 alkyl), C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), halogenated C 1- 8 alkoxy (preferably halogenated C 1-6 alkoxy, more preferably halogenated C 1-3 alkoxy), -C (O) C 1-8 alkyl (preferably -C (O) C 1-6 alkyl, more preferably -C(O)C 1-3 alkyl), -C(O)OC 1-8 alkyl (preferably -
  • the Z 1 , Z 2 , Z 3 , Z 4 , R 3 , R 4 , and L groups are as defined in the above specification.
  • Z 5 is N or CR Z5 ;
  • Z 6 is CR Z6 ;
  • Z 7 is CR Z7 ; and
  • Z 8 is CR Z8 .
  • Z 5 is CR Z5 ;
  • Z 6 is CR Z6 ;
  • Z 7 is CR Z7 ; and
  • Z 8 is CR Z8 .
  • Z 5 is CR Z5 ;
  • Z 6 is CR Z6 ;
  • Z 7 is CR Z7 ; and
  • Z 8 is N.
  • Z7 is CH.
  • R Z5 , R Z6 , R Z7 , and R Z8 are each independently hydrogen or halogen. Further, R Z5 , R Z6 , R Z7 and R Z8 are all hydrogen.
  • Z5 is N; Z6 is CH; Z7 is CH; and Z8 is CH.
  • the structure of the compound is shown in formula (I-2a) or formula (I-2b):
  • the compound is selected from the group consisting of:
  • the compound is selected from the group consisting of:
  • the second aspect of the present application provides a compound represented by formula (II), its pharmaceutically acceptable salt or its stereoisomer:
  • S 1' and S 2' represent ring atoms on ring A'; S 1' is N or C; and S 2' is N or C;
  • Z 1' is N or CR Z1' ;
  • Z 2' is N or CR Z2' ;
  • Z 3' is N or CR Z3' ;
  • Z 4' is N or CR Z4' ;
  • R Z1' , R Z2' , R Z3' and R Z4' are each independently hydrogen, cyano, nitro, hydroxyl, carboxyl, halogen (preferably fluorine or chlorine), C 1-8 alkyl (preferably C 1-6 alkyl, more preferably is C 1-3 alkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), halogenated C 1-8 alkyl (preferably halogenated C 1-6 alkyl, more preferably is halogenated C 1-3 alkyl), C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), halogenated C 1-8 alkoxy (preferably halogenated C 1-6 alkoxy, more preferably halogenated C
  • L' is -(CR q1' R q2' ) m' -, -(CR q3' R q4' ) t1' -O-(CR q5' R q6' ) t2' -, or -(CR q7' R q8 ' ) t3' -NR q0' -(CR q9' R q10' ) t4' -;
  • n' is 1, 2, 3 or 4;
  • t1', t2', t3', and t4' are each independently 0, 1, 2 or 3; wherein t1' and t2' are not 0 at the same time; and t3' and t4' are not 0 at the same time;
  • R q1' and R q2' are each independently hydrogen, halogen (preferably fluorine or chlorine), cyano, nitro, hydroxyl, carboxyl, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), halogenated C 1-8 alkyl (preferably halogenated C 1-6 alkyl, more Preferably halogenated C 1-3 alkyl), C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), halogenated C 1-8 alkoxy group (preferably halogenated C 1-6 alkoxy, more preferably halogenated C 1-3 alkoxy), -C(O)NR a0' R b0' , -C(O)C 1-8 alkoxy group (preferably -C(O)C 1-6 alkyl, more preferably -C(O)C 1-3 alkyl) or -
  • R q3' , R q4' , R q5' , R q6' , R q7' , R q8' , R q9' , and R q10' are each independently hydrogen, halogen (preferably fluorine or chlorine), cyano, Nitro, hydroxyl, carboxyl, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkane base), halogenated C 1-8 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), C 1-8 alkoxy (preferably C 1-6 Alkoxy, more preferably C 1-3 alkoxy), halogenated C 1-8 alkoxy (preferably halogenated C 1-6 alkoxy, more preferably halogenated C 1-3 alkoxy ), -C(O)NR a0' R b0' , -C(
  • R q0' is hydrogen, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl ), -C(O)NR a0' R b0' , -C(O)C 1-8 alkyl (preferably -C(O)C 1-6 alkyl, more preferably -C(O)C 1 -3 alkyl) or -SO 2 C 1-8 alkyl (preferably -SO 2 C 1-6 alkyl, more preferably -SO 2 C 1-3 alkyl); wherein the C 1-8 alkyl Group, C 3-8 cycloalkyl is unsubstituted or substituted by 1, 2 or 3 substituents independently selected from the group consisting of deuterium, halogen, cyano, nitro, hydroxyl, carboxyl, C 1- 3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl
  • Ring A' is a benzene ring or a 5- to 6-membered heteroaromatic ring; Ring A' is unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of cyano, nitro, hydroxyl, Carboxyl, halogen (preferably fluorine or chlorine), C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 3-8 cycloalkyl (preferably C 3 -6 cycloalkyl), C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), -C (O) C 1- 8 alkyl (preferably -C(O)C 1-6 alkyl, more preferably -C(O)C 1-3 alkyl), -C(O)OC 1-8 alkyl (preferably -C(O)OC 1 -6 alkyl, more preferably -C(O)OC 1-3 alkyl), -OC(O)C 1-8 al
  • R a0' and R b0' are each independently hydrogen, C 1-3 alkyl or acetyl; or R a0' and R b0' together with the connected nitrogen atom form a 4 to 6-membered saturated monoheterocyclic ring; said The 4 to 6 membered saturated monoheterocycle is unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen, cyano, nitro, hydroxyl, carboxyl, C 1-3 Alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, -SO 2 C 1- 3 alkyl, -S(O)C 1-3 alkyl, -C(O)NH 2 , -C(O)NH(C 1-3 alkyl), -C(O)N(C 1-3 Alkyl) 2 , -C
  • R a1' , and R b1' are each independently hydrogen, C 1-3 alkyl, halogenated C 1-3 alkyl or acetyl; or R a1' , R b1' and the connected nitrogen atom together form 4 to 6-membered saturated monoheterocycle; the 4-6 membered saturated monoheterocycle is unsubstituted or substituted by 1, 2 or 3 substituents independently selected from the group consisting of deuterium, halogen, cyano, nitro , hydroxyl, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkane Oxygen, -SO 2 C 1-3 alkyl, -S(O)C 1-3 alkyl, -C(O)NH 2 , -C(O)NH(C 1-3 alkyl), -C (O)N(C 1-3
  • Z 1' is N or CR Z1' ;
  • Z 2' is CR Z2' ;
  • Z 3' is N or CR Z3' ; and
  • Z 4' is CR Z4' .
  • Z 1' is CR Z1' ;
  • Z 2' is CR Z2' ;
  • Z 3' is CR Z3' ;
  • Z 4' is CR Z4' .
  • Z 1' is N;
  • Z 2' is CR Z2' ;
  • Z 3' is CR Z3' ;
  • Z 4' is CR Z4' .
  • Z 1' is CR Z1' ;
  • Z 2' is CR Z2' ;
  • Z 3' is N; and
  • Z 4' is CR Z4' .
  • Z 1' is N; Z 2' is CR Z2' ; Z 3' is N; and Z 4' is CR Z4' .
  • Z 4' is CH.
  • Z 1' is N or CH
  • Z 2' is CR Z2'
  • Z 3' is N or CH
  • Z 4' is CH.
  • Z 1' is N or CH
  • Z 2' is CR Z2'
  • Z 3' is CH
  • Z 4' is CH.
  • Z 1' is N
  • Z 2' is CR Z2'
  • Z 3' is CR Z3'
  • Z 4' is CR Z4'
  • Z 1' is CR Z1' and Z 2' is CR Z2'
  • Z 3' is CR Z3'
  • Z 4' is CR Z4'
  • Z 1' is N
  • Z 2' is CR Z2'
  • Z 3' is N
  • Z 4' is CR Z4'
  • Z 1' is CH
  • Z 2' is CR Z2'
  • Z 3' is N
  • Z 4' is CR Z4' .
  • Z 1' is N, Z 2' is CR Z2' , Z 3' is CH, and Z 4' is CH; or Z 1' is CH, Z 2' is CR Z2' , Z 3 ' is CR Z3' , and Z 4' is CR Z4' ; or Z 1' is N, Z 2' is CR Z2' , Z 3' is N, and Z 4' is CH; or Z 1' is CH, Z 2' is CR Z2' , Z 3' is N, and Z 4' is CH.
  • R Z1' , R Z2' , R Z3' , and R Z4' are each independently hydrogen, cyano, halogen (preferably fluorine or chlorine), C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), halogenated C 1-8 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), halogen Substituted C 1-8 alkoxy (preferably halogenated C 1-6 alkoxy, more preferably halogenated C 1-3 alkoxy) or -NR a1' R b1' ; wherein the C 1-8 Alkyl, C 3-8 cycloalkyl are each independently unsubstituted or substituted by 1, 2 or 3 substituents independently selected from the
  • R Z1' is hydrogen
  • R Z2' is cyano, halogen (preferably fluorine or chlorine), C 1-3 alkyl (preferably methyl), C 3-6 cycloalkyl (preferably cyclopropyl), Halogenated C 1-3 alkyl (preferably fluoro C 1-3 alkyl, more preferably monofluoromethyl, monofluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoro ethyl, pentafluoroethyl), C 1-3 alkoxy (preferably methoxy or ethoxy), halogenated C 1-3 alkoxy (preferably difluoromethoxy, trifluoromethoxy base), halogen-substituted C 3-6 cycloalkyl or -NR a1' R b1' ; R a1' and R b1' are each independently hydrogen, C 1-3 alkyl, halogenated C 1-3 alkyl or acetyl.
  • R Z3' is hydrogen, cyano, or halo (preferably fluoro or chloro). Further, R Z3' is hydrogen.
  • R Z4' is hydrogen or halo (preferably fluoro or chloro). Further, R Z4' is hydrogen.
  • R Z1' , R Z2' , R Z3' , and R Z4' are each independently selected from the group consisting of hydrogen, methyl, ethyl, methoxy, ethoxy, -NH -CH2 - CF3 and cyclopropyl.
  • Z 1' is CH; Z 2' is CR Z2' ; Z 3' is CH; Z 4' is CH; and R Z2' is trifluoromethyl.
  • the ring A' is a benzene ring or a 5-6 membered heteroaryl ring
  • the 5-6 membered heteroaryl ring is selected from the group consisting of a thiophene ring, a furan ring, a thiazole ring , isothiazole ring, imidazole ring, oxazole ring, pyrrole ring, pyrazole ring, triazole ring, 1,2,3-triazole ring, 1,2,4-triazole ring, 1,2,5-triazole ring Azole ring, 1,3,4-triazole ring, tetrazole ring, isoxazole ring, oxadiazole ring, 1,2,3-oxadiazole ring, 1,2,4-oxadiazole ring, 1 , 2,5-oxadiazole ring, 1,3,4-oxadiazole ring, thiadiazole ring, pyridine
  • Ring A' is unsubstituted.
  • t1' is 0; and t2' is 1, 2 or 3.
  • t3' is 0; and t4' is 1, 2 or 3.
  • R q1′ , R q2′ are each independently hydrogen; and m′ is 2, 3, or 4.
  • the 3-7 membered saturated or partially unsaturated monocyclic ring formed by R q1' , R q2' and the connected carbon atoms is a 3-6 membered saturated monocyclic ring; and may be selected from the group consisting of : Cyclopropyl ring, cyclobutyl ring, cyclopentyl ring and cyclohexyl ring.
  • the 3-7 membered saturated or partially unsaturated monoheterocyclic ring formed by R q1' , R q2' and the connected carbon atoms is a 4-6 membered saturated or partially unsaturated monoheterocyclic ring; and may selected from the group consisting of: azetidine, oxetane, tetrahydrofuran ring, tetrahydrothiophene ring, tetrahydropyrrole ring, piperidine ring, piperazine ring, morpholine ring, thiomorpholine ring, Thiomorpholine-1,1-dioxide and tetrahydropyran ring.
  • L' is -(CH 2 ) m' -; and m' is 2 or 3.
  • Z 5' is N or CR Z5' ;
  • Z 6' is N or CR Z6' ;
  • Z 7' is N or CR Z7' ;
  • Z 8' is N or CR Z8' ;
  • R Z5' , R Z6' , R Z7' and R Z8' are each independently hydrogen, cyano, nitro, hydroxyl, carboxyl, halogen (preferably fluorine or chlorine), C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), halogenated C 1-8 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), halogen Substituted C 1-8 alkoxy (preferably halogenated C 1-6 alkoxy, more preferably halogenated C 1-3 alkoxy ) , -C (O) C 1-8 alkyl (preferably - C(O)C 1-6 alkyl, more preferably -C(O)C 1-3 alkyl), -C(O)OC
  • the Z 1' , Z 2' , Z 3' , Z 4' , and L ' groups are as defined in the above specification.
  • Z 5' is N or CR Z5' ;
  • Z 6' is CR Z6' ;
  • Z 7' is CR Z7' ; and
  • Z 8' is CR Z8' .
  • Z 5' is N; Z 6' is CR Z6' ; Z 7' is CR Z7' ; and Z 8' is CR Z8' .
  • Z 5' is CR Z5' ;
  • Z 6' is CR Z6' ;
  • Z 7' is CR Z7' ; and
  • Z 8' is CR Z8' .
  • Z 7' is CH.
  • R Z5' , R Z6' , R Z7' , and R Z8' are each independently hydrogen or halogen. Further, R Z5' , R Z6' , R Z7' , and R Z8' are all hydrogen.
  • Z 5' is N; Z 6' is CH; Z 7' is CH; and Z 8' is CH.
  • the structure of the compound is shown in formula (II-1a) or formula (II-1b):
  • the compound is selected from the group consisting of:
  • the present invention provides a compound represented by formula (II-c), or a salt thereof, or a stereoisomer thereof:
  • R a is cyano or C(O)NH 2
  • S 1' , S 2' , ring A', Z 1' , Z 2' , Z 3' , Z 4' , and L' groups are as The S 1' , S 2' , ring A', Z 1' , Z 2' , Z 3' , Z 4' , and L' groups in the second aspect of the invention are defined.
  • the fourth aspect of the present application provides a pharmaceutical composition, which includes: the compound described in the first aspect of the present application, its pharmaceutically acceptable salt or its stereoisomer; and a pharmaceutically acceptable carrier.
  • the fifth aspect of the application provides the compound described in the first aspect of the application, its pharmaceutically acceptable salt or its stereoisomer and the pharmaceutical composition described in the fourth aspect of the application in the preparation of a drug for inhibiting MAT2A in the application.
  • the sixth aspect of the present application provides the compound described in the first aspect of the present application, its pharmaceutically acceptable salt or its stereoisomer or The pharmaceutical composition described in the fourth aspect of the application.
  • the disease associated with or mediated by MAT2A activity is cancer.
  • the seventh aspect of the present application provides the compound described in the first aspect of the present application, its pharmaceutically acceptable salt or its stereoisomer, or the pharmaceutical composition described in the fourth aspect of the present application for use as a medicine.
  • the eighth aspect of the present application provides a method for treating MAT2A-mediated diseases, the method comprising administering to patients an effective amount of the compound described in the first aspect of the present application, its pharmaceutically acceptable salt or its stereoisomer , or the pharmaceutical composition as described in the fourth aspect of the present application.
  • the MAT2A-mediated disease is cancer, such as solid tumors and hematological tumors.
  • Alkyl refers to straight and branched chain saturated aliphatic hydrocarbon groups.
  • C 1-8 alkyl refers to an alkyl group having 1 to 8 carbon atoms, which may be C 1-6 alkyl, further C 1-3 alkyl; non-limiting examples of alkyl include: Base, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethyl Propyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1 ,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl , 2-eth
  • C2-6 alkenyl such as C2-4 alkenyl, which is similarly defined; non-limiting examples include vinyl, propenyl, isopropenyl, n-butenyl, isobutenyl, pentenyl base, hexenyl, etc.
  • Alkynyl refers to straight-chain and branched unsaturated aliphatic hydrocarbon groups with one or more carbon-carbon triple bonds
  • C 2-8 alkynyl refers to alkynyl groups with 2 to 8 carbon atoms, which can be C 2-6 alkynyl, such as C2-4 alkynyl, is similarly defined; non-limiting examples include ethynyl, propynyl, n-butynyl, isobutynyl, pentynyl, hexynyl, and the like.
  • Cycloalkyl and “cycloalkyl ring” are used interchangeably and both refer to a saturated monocyclic, bicyclic or polycyclic cyclic hydrocarbon group, which may be fused with an aryl or heteroaryl group. Cycloalkyl rings can be optionally substituted. In certain embodiments, cycloalkyl rings contain one or more carbonyl groups, such as oxo groups.
  • C 3-8 cycloalkyl refers to a monocyclic cycloalkyl group with 3 to 8 carbon atoms
  • cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Cycloheptyl, cyclooctyl, cyclobutanone, cyclopentanone, cyclopentane-1,3-dione, etc.
  • Cycloalkyl may be C 3-6 cycloalkyl, including cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • Heterocycloalkyl and “heterocycloalkyl ring” are used interchangeably and both refer to a cycloalkyl group containing at least one heteroatom selected from nitrogen, oxygen and sulfur, which may be combined with an aryl or heteroaryl fused. Heterocycloalkyl rings can be optionally substituted. In certain embodiments, heterocycloalkyl rings contain one or more carbonyl or thiocarbonyl groups, eg, groups comprising oxo and thioxo.
  • 3 to 8 membered heterocycloalkyl refers to a monocyclic cyclic hydrocarbon group having 3 to 8 ring atoms, wherein 1, 2 or 3 ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, which can be 4 to 8-membered heterocycloalkyl, further 3 to 6-membered heterocycloalkyl, which has 3 to 6 ring atoms, wherein 1 or 2 ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, for example, 4 to 6-membered heterocycloalkyl having 4 to 6 ring atoms, of which 1 or 2 ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur.
  • Non-limiting examples of monocyclic heterocycloalkyl groups include aziridine, oxiranyl, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyrrolyl , oxazolidinyl, dioxolanyl, piperidinyl, piperazinyl, morpholinyl, dioxanyl, thiomorpholinyl, thiomorpholine-1,1-dioxide, tetra Hydropyranyl, azetidin-2-one, oxetane-2-one, dihydrofuran-2(3H)-one, pyrrolidin-2-one, pyrrolidin- 2,5-diketone, dihydrofuran-2,5-diketone, piperidin-2-one, tetrahydro-2H-pyran-2-one, piperazin-2-one, morphine Lin-3-
  • Aryl and “aromatic ring” are used interchangeably and both refer to an all-carbon monocyclic or fused polycyclic (that is, rings sharing adjacent pairs of carbon atoms) group having a conjugated pi-electron system, which Can be fused to a cycloalkyl ring, heterocycloalkyl ring, cycloalkenyl ring, heterocycloalkenyl ring or heteroaryl.
  • C 6-10 aryl refers to a monocyclic or bicyclic aryl group having 6 to 10 carbon atoms, and non-limiting examples of the aryl group include phenyl, naphthyl, and the like.
  • Heteroaryl and “heteroaryl ring” are used interchangeably and both refer to a monocyclic, bicyclic or polycyclic 4n+2 aromatic ring system having ring carbon atoms and ring heteroatoms (e.g., having A group of shared 6 or 10 ⁇ electrons) where each heteroatom is independently selected from nitrogen, oxygen and sulfur.
  • heteroaryl also includes ring systems in which the aforementioned heteroaryl ring is fused to one or more cycloalkyl rings, heterocycloalkyl rings, cycloalkenyl rings, heterocycloalkenyl rings or aromatic rings. Heteroaryl rings can be optionally substituted.
  • “5 to 10 membered heteroaryl” refers to a monocyclic or bicyclic heteroaryl group having 5 to 10 ring atoms, of which 1, 2, 3 or 4 ring atoms are heteroatoms.
  • “5 to 6 membered heteroaryl” means a monocyclic heteroaryl group having 5 to 6 ring atoms, of which 1, 2, 3 or 4 ring atoms are heteroatoms, non-limiting examples include thienyl, furan base, thiazolyl, isothiazolyl, imidazolyl, oxazolyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2 ,5-triazolyl, 1,3,4-triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadi Azolyl, 1,2,5-ox
  • 8 to 10 membered heteroaryl refers to a bicyclic heteroaryl group having 8 to 10 ring atoms in which 1, 2, 3 or 4 ring atoms are heteroatoms, non-limiting examples of which include indolyl, Isoindolyl, indazolyl, benzotriazolyl, benzothienyl, isobenzothienyl, benzofuryl, benzisofuryl, benzimidazole, benzoxazolyl, benzo Isoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indenazinyl, purinyl, pyrido[3,2-d]pyrimidinyl, pyridine A[2,3-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrido[4,3-d]pyrimidinyl, 1,8-naphth
  • Heteroatom means nitrogen, oxygen or sulfur. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valence permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings.
  • “Fused” refers to a structure in which two or more rings share one or more bonds.
  • Alkoxy refers to -O-alkyl, wherein the definition of alkyl is as above, it can be C 1-8 alkoxy, further C 1-6 alkoxy, such as C 1-3 alkoxy base.
  • Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, t-butoxy, isobutoxy, pentyloxy, and the like.
  • Cycloalkyloxy refers to -O - cycloalkyl, wherein the definition of cycloalkyl is as above, which can be C 3-8 cycloalkyloxy, and further C 3-6 cycloalkyloxy.
  • Non-limiting examples include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • a bond means that the two groups connected by it are connected by a covalent bond.
  • Halogen means fluorine, chlorine, bromine or iodine.
  • Halo refers to a group in which one or more (eg 1, 2, 3, 4 or 5) hydrogens are replaced by a halogen.
  • Amino means NH 2
  • cyano means CN
  • nitro means NO 2
  • benzyl means -CH 2 -phenyl
  • oxo O
  • carboxy means -C (O)OH
  • acetyl refers to -C(O)CH 3
  • hydroxymethyl refers to -CH 2 OH
  • hydroxyethyl refers to -CH 2 CH 2 OH or -CHOHCH 3
  • hydroxyl refers to -OH
  • mercapto refers to -SH
  • the structure of "cyclopropylene” is:
  • saturated or partially unsaturated monocyclic ring means a saturated or partially unsaturated all-carbon monocyclic ring system, where "partially unsaturated” means a ring portion that includes at least one double or triple bond, and “partially unsaturated” is intended to encompass Rings with multiple sites of unsaturation, but are not intended to include aryl or heteroaryl moieties as defined herein.
  • saturated or partially unsaturated monocyclic rings contain one or more carbonyl groups, such as oxo groups.
  • a "3 to 7 membered saturated or partially unsaturated monocyclic ring” has 3 to 7 ring carbon atoms, may be a saturated or partially unsaturated monocyclic ring having 3 to 6 ring carbon atoms, for example has 3 to 6 ring carbon atoms atoms of a saturated monocyclic ring.
  • Non-limiting examples of saturated or partially unsaturated monocyclic rings include cyclopropyl rings, cyclobutyl rings, cyclopentyl rings, cyclopentenyl rings, cyclohexyl rings, cyclohexenyl rings, cyclohexadienyl rings, Cycloheptyl ring, cycloheptatrienyl ring, cyclopentanone ring, cyclopentane-1,3-dione ring, etc.
  • “Saturated or partially unsaturated monoheterocyclic ring” means that 1, 2 or 3 ring carbon atoms in a saturated or partially unsaturated monocyclic ring are selected from nitrogen, oxygen or S(O) t (where t is an integer from 0 to 2 ), but excluding ring portions of -OO-, -OS- or -SS-, the remaining ring atoms are carbon.
  • the "3- to 7-membered saturated or partially unsaturated monoheterocyclic ring” has 3 to 7 ring atoms, of which 1, 2 or 3 ring atoms are the above-mentioned heteroatoms.
  • a "3- to 7-membered saturated or partially unsaturated monoheterocycle” is a 3- to 6-membered saturated or partially unsaturated ring atom having 3 to 6 ring atoms, of which 1 or 2 ring atoms are the aforementioned heteroatoms. single heterocycle.
  • a "3- to 7-membered saturated or partially unsaturated monoheterocycle” is a 5- to 6-membered saturated or partially unsaturated ring atom having 5 to 6 ring atoms, of which 1 or 2 ring atoms are heteroatoms as described above. single heterocycle.
  • the "3- to 7-membered saturated or partially unsaturated monoheterocycle” is a 5- or 6-membered saturated monoheterocycle.
  • saturated monoheterocyclic rings include propylene oxide rings, azetidine rings, oxetane rings, tetrahydrofuran rings, tetrahydrothiophene rings, tetrahydropyrrole rings, piperidine rings, pyrroline rings , oxazolidine ring, piperazine ring, dioxolane, dioxane, morpholine ring, thiomorpholine ring, thiomorpholine-1,1-dioxide, tetrahydropyran ring, nitrogen Heterocyclobutane-2-one ring, oxetane-2-one ring, pyrrolidin-2-one ring, pyrrolidine-2,5-dione ring, piperidin-2-one ring, di
  • Non-limiting examples of partially unsaturated monoheterocyclic rings include 1,2-dihydroazetidinium rings, 1,2-dihydrooxetidine rings, 2,5-dihydro-1H- Pyrrole ring, 2,5-dihydrofuran ring, 2,3-dihydrofuran ring, 2,3-dihydro-1H-pyrrole ring, 3,4-dihydro-2H-pyran ring, 1,2, 3,4-tetrahydropyridine ring, 3,6-dihydro-2H-pyran ring, 1,2,3,6-tetrahydropyridine ring, 4,5-dihydro-1H-imidazole ring, 1,4 ,5,6-tetrahydropyrimidine ring, 3,4,7,8-tetrahydro-2H-1,4,6-oxadiazosin ring, 1,6-dihydropyrimidine ring, 4,5,6, 7-tetrahydro-1H-1,3-
  • Substituted means that one or more hydrogen atoms in a group, such as 1-5, 1-3, or 1 hydrogen atom, are independently substituted by the corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions and that a person skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when bonded to a carbon atom with an unsaturated (eg, ethylenic) bond.
  • substituted substituents independently selected from " described in this application means that when more than one hydrogen on the group is replaced by a substituent, the types of substituents may be the same or different, so The selected substituents are each independent species.
  • X 1 is (CR q1 R q2 ) m , when m is 2, that is, X 1 is CR q1 R q2 -CR q1 R q2 , where the two R q1 can be the same or different from each other, and the two R q2 can be The same or different, for each independent category.
  • any group herein may be substituted or unsubstituted.
  • the substituents can be 1 to 5 following groups, independently selected from cyano, nitro, halogen (such as fluorine or chlorine), C 1-8 alkyl (can be C 1-6 Alkyl, such as C 1-3 alkyl), C 1-8 alkoxy (can be C 1-6 alkoxy, such as C 1-3 alkoxy), halogenated C 1-8 alkyl (can is halogenated C 1-6 alkyl, such as halogenated C 1-3 alkyl), C 3-8 cycloalkyl (may be C 3-6 cycloalkyl), halogenated C 1-8 alkoxy ( Can be halogenated C 1-6 alkoxy, such as halogenated C 1-3 alkoxy), C 1-8 alkyl substituted amino, halogenated C 1-8 alkyl substituted amino, acetyl, hydroxyl , hydroxymethyl, hydroxy
  • any two substituents may be the same or different.
  • groups on the compounds of the present application may be substituted by two identical or different halogens or may be substituted by one halogen and one hydroxyl.
  • the compound of the present application can be administered in a suitable dosage form with one or more pharmaceutically acceptable carriers.
  • These dosage forms are suitable for oral, rectal, topical, oral and other parenteral administration (eg, subcutaneous, intramuscular, intravenous, etc.).
  • dosage forms suitable for oral administration include capsules, tablets, granules, syrups and the like.
  • the compound of the present application contained in these formulations may be: solid powder or granule; solution or suspension in aqueous or non-aqueous liquid; and water-in-oil or oil-in-water emulsion and the like.
  • the above-mentioned dosage forms can be made from the active compound and one or more carriers or excipients through common pharmaceutical methods.
  • the aforementioned carriers need to be compatible with the active compound or other excipients.
  • commonly used non-toxic carriers include, but are not limited to, mannitol, lactose, starch, magnesium stearate, cellulose, glucose, sucrose, and the like.
  • Carriers for liquid preparations include water, physiological saline, aqueous dextrose, ethylene glycol, polyethylene glycol, and the like.
  • the active compounds can form solutions or suspensions with the above-mentioned carriers.
  • “Pharmaceutically acceptable carrier” means a non-toxic, inert, solid, semi-solid substance or liquid filler, diluent, encapsulating material or auxiliary preparation or excipient of any type, which is compatible with the patient, who may be breastfeeding In animals, such as humans, the pharmaceutically acceptable carrier is suitable for delivering the active agent to the target site of interest without terminating the activity of the agent.
  • the active substance of the present application or “the active compound of the present application” refers to the compound of formula (I) of the present application, its pharmaceutically acceptable salt or its stereoisomer, which has a higher MAT2A selective inhibitory activity.
  • compositions of the present application are formulated, dosed and administered in a manner consistent with medical practice.
  • the "therapeutically effective amount" of a compound to be administered is determined by factors such as the particular condition to be treated, the individual being treated, the cause of the condition, the target of the drug, and the mode of administration.
  • “Therapeutically effective amount” refers to the amount of the compound of the present application that will cause the individual's biological or medical response, such as reducing or inhibiting enzyme or protein activity or improving symptoms, alleviating symptoms, slowing down or delaying disease progression or preventing diseases, etc.
  • the therapeutically effective amount of the compound of the present application contained in the pharmaceutical composition of the present application or the pharmaceutical composition, its pharmaceutically acceptable salt or its stereoisomer can be 0.1mg-5000mg/kg (body weight) .
  • Patient refers to an animal, which may be a mammal, such as a human.
  • mammal refers to warm-blooded vertebrate mammals including, for example, cats, dogs, rabbits, bears, foxes, wolves, monkeys, deer, mice, pigs and humans.
  • Treating means alleviating, delaying progression, attenuating, preventing or maintaining an existing disease or condition (eg, cancer). Treatment also includes curing, preventing its development, or alleviating to some extent one or more symptoms of a disease or disorder.
  • the "pharmaceutically acceptable salt” includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • a pharmaceutically acceptable acid addition salt refers to a salt formed with an inorganic or organic acid that retains the biological effectiveness of the free base without other side effects. These salts can be prepared by methods known in the art.
  • “Pharmaceutically acceptable base addition salts” include, but are not limited to, salts with inorganic bases and salts with organic bases. These salts can be prepared by methods known in the art.
  • the compound represented by formula (I) of the present application contains one or more chiral centers, it can exist in different optically active forms.
  • a compound of formula (I) contains a chiral center, the compound comprises a pair of enantiomers, unless otherwise stated, separated by a wedge bond Indicates the absolute configuration of a stereocenter.
  • the two enantiomers of the compound and the mixture of the pair of enantiomers, such as the racemic mixture are also within the protection scope of the present application. Enantiomers may be resolved by methods known in the art, such as crystallization and chiral chromatography.
  • the compound includes enantiomers and diastereomers.
  • Enantiomers and diastereomers of the compound and mixtures of enantiomers, mixtures of diastereomers, and mixtures of enantiomers and diastereomers Also within the protection scope of the present application.
  • Enantiomers and diastereomers may be resolved by methods known in the art, such as crystallization and preparative chromatography.
  • the absolute configurations of the isomers resolved in the Examples of the present application are arbitrarily assigned.
  • the present application provides the preparation method of the compound of formula (I), and the compound of formula (I) can be synthesized by using the standard synthetic technique known to those skilled in the art or using the method known in the art in combination with the method described in the present application. Solvents, temperatures and other reaction conditions given in this application can be varied according to the skill in the art. The reactions can be used in sequence to provide the compounds of the application, or they can be used to synthesize fragments which are subsequently added by methods described herein and/or methods known in the art.
  • a chlorinating reagent such as phosphorus oxychloride or thionyl chloride
  • a base such as triethylamine or N,N-diisopropylethylamine
  • a suitable solvent React with the corresponding amine to obtain the compound of formula (I-1).
  • the compound of formula (II), chlorination reagent and base are reacted at 80-100°C in the presence of a solvent to obtain a reaction solution, and then the reaction solution is reacted with the corresponding amine at 0°C to room temperature , to obtain the compound of formula (I-1).
  • a class of general synthetic methods for compounds of formula (II) of the present invention are as follows:
  • the compound of formula (II-a) is reacted with the compound of formula (II-b) in the presence of a base and a solvent to obtain a compound of formula (II-c), and the compound of formula (II-c) is subjected to a ring-closing reaction in the presence of an acid and a solvent A compound of formula (II) is obtained.
  • R a is cyano or C(O)NH 2
  • R b is a leaving group such as halogen, and other groups are as defined in the description.
  • LC-MS Agilent 1290 HPLC System/6130/6150 MS liquid mass spectrometry (manufacturer: Agilent), column Waters BEH/CHS, 50 ⁇ 2.1mm, 1.7 ⁇ m.
  • Adopt ISCO Combiflash-Rf75 or Rf200 automatic column passing instrument Agela 4g, 12g, 20g, 40g, 80g, 120g disposable silica gel column.
  • the monitoring of the reaction progress can be carried out by thin layer chromatography (TLC), and the purification of the compound can be carried out by column chromatography.
  • TLC thin layer chromatography
  • the developer system used in column chromatography or TLC can be selected from: dichloromethane and methanol system, n-hexane and ethyl acetate system, petroleum ether and ethyl acetate system and acetone system, etc., the volume ratio of the solvent is based on the polarity of the compound Adjust differently.
  • DMF N,N-dimethylformamide
  • DMSO dimethylsulfoxide
  • THF tetrahydrofuran
  • DIEA N,N-diisopropylethylamine
  • EA ethyl acetate
  • PE petroleum Ether
  • KHMDS potassium bis(trimethylsilyl)amide
  • BINAP (2R,3S)-2,2'-bisdiphenylphosphino-1,1'-binaphthyl
  • NBS N-bromobutanedi imide
  • NCS N-chlorosuccinimide
  • Pd 2 (dba) 3 tris(dibenzylideneacetone) dipalladium
  • Pd(dppf)Cl 2 [1,1'-bis( Diphenylphospho)ferrocene]palladium dichloride
  • Pd(PPh 3 ) 4 tetrakis(triphenylphosphine)palladium dichloride
  • room temperature means about 20-30°C.
  • Step 1 Dissolve 2,3-dihydro-1H-indene-1-carbonitrile (3.03g, 21.25mmol) in toluene (60mL), add 1M KHMDS solution in THF (24mL, 23.94 mmol), stirred at 0°C for 1 h.
  • Step 1 Sodium hydrogen (666 mg, 16.64 mmol) was added to a solution of 6,7-dihydro-5H-cyclopentadiene[b]pyridine-5-carbonitrile (393 mg, 2.08 mmol) in DMF (10 mL), in Stir under nitrogen protection in an ice-water bath for 1 h, and then add a solution of 2-fluoro-4-trifluoromethylbenzonitrile (300 mg, 2.08 mmol) in DMF (2 mL) to the reaction solution. And react in ice water bath for 1h.
  • Step 1 Starting from 4-hydroxy-2-(trifluoromethyl)pyrimidine-5-carboxylic acid, compound v9-1 was obtained by reacting with thionyl chloride and ammonia in THF. LCMS: m/z 223.9 [MH] - .
  • Step 2-3 Using compound v9-1 and 2,3-dihydro-1H-indene-1-carbonitrile as raw materials, refer to the preparation method of intermediate v1 to obtain intermediate compound v9.
  • LCMS m/z 332.0 [MH] - .
  • Step 1 2,3-dihydro-1H-indene-1-carbonitrile (1.56g, 10.9mmol) was dissolved in THF (15mL), the reaction solution was cooled to -70°C, and 2M dihydrogen was added to the reaction solution Lithium isopropylamide (5.5 mL, 11.0 mmol). The reaction solution was stirred at -70°C for 30 min. Then 4-chloro-2-(methylmercapto)pyrimidine-5-carboxamide (0.50 g, 2.48 mmol) was added to the reaction solution, and the reaction solution was stirred at -70°C for 20 min. Diluted with ice water/EA (40mL/20mL), extracted with EA (30mL x 2).
  • Step 2 Using compound v10-1 as a raw material, refer to the preparation method in step 2 of intermediate v1 to obtain intermediate compound v10.
  • LCMS m/z 310.1 [MH] - .
  • EA:PE 80:
  • Step 2-3 Using compound v11-1 and 2,3-dihydro-1H-indene-1-carbonitrile as raw materials, refer to the preparation method of intermediate v1 to obtain intermediate compound v11.
  • Step 1 Combine 2,6-dichloronicotinonitrile (8.0g, 0.047mol) and cyclopropylboronic acid (4.8g, 0.056mol), palladium acetate (522mg, 2.32mmol), tricyclohexylphosphine (1.3g, 4.64 mmol), potassium phosphate (34.5g, 0.162mol) was dissolved in toluene/water (180mL/30mL), and the reaction solution was raised to 100°C under nitrogen atmosphere and stirred overnight. The reaction solution was filtered, and the filtrate was concentrated. The filtrate was added with EA (700ml) and washed with saturated brine (700ml*2).
  • Step 2-3 Using compound v12-1 and 2,3-dihydro-1H-indene-1-carbonitrile as raw materials, refer to the preparation method of intermediate v1 to obtain intermediate compound v12.
  • Step 1 The compound 3,3-dimethyl-1H-1-indanone (1g, 6.25mmol) and p-toluenesulfonylmethylisonitrile (1.83g, 9.38mmol) were dissolved in dry ethylene di Alcohol dimethyl ether (5 mL), sodium ethoxide (2.7M, 4.2 mL, 11.25 mmol) was added to the above solution at 0°C, and stirred at room temperature for 3 hours. EA (50 mL) was extracted twice, the organic phase was dried over sodium sulfate, concentrated, and passed through the column to obtain compound v17-1 (1.07 g, 58%).
  • Step 2-3 Refer to the preparation method of intermediate v1 to obtain intermediate compound v17.
  • LCMS m/z 359.1 [MH] - .
  • Step 1 Dissolve sodium hydrogen (1.41g, 35.2mmol) in xylene (150mL), add ethanol (1.47g, 32.0mmol) in xylene (50mL) to the above solution, stir at room temperature for 20 minutes, and then add A xylene solution (150 mL) of 2,6-dichloro-3-cyanopyridine (5.5 g, 32.0 mmol) was added to the above solution, and the reaction solution was stirred at 140° C. for 16 hours. Concentrate, extract three times with EA (50 mL), dry the organic phase over sodium sulfate, concentrate, and pass through the column to obtain compound v20-1.
  • Step 2 Compound v20-1 (2.0g), K 2 CO 3 (4.55g, 32.7mmol) was dissolved in DMSO (10ml), and 30% H 2 O 2 (5mL) was added dropwise at room temperature. Stir for 2 hours. The reaction solution was poured into saturated brine (40ml), extracted with EA (20mL x 3), the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to remove the solvent under reduced pressure to obtain compound v20-2 (260mg, yield : 11.9%).
  • Step 3-4 Refer to the preparation method of intermediate v1 to obtain intermediate compound v20.
  • Step 2-3 Refer to the preparation method of intermediate v3 to obtain intermediate compound v24.
  • Step 1 Dissolve 2-chloro-5H,6H,7H-cyclopenta[B]pyridin-5-one (CAS NO.1092301-56-8) (200mg, 1.2mmol) in methanol (10mL), Sodium borohydride (136.5 mg, 3.60 mmol) was added to the above solution at 0°C, and the reaction was stirred at room temperature for 16 hours. Concentrate, extract with EA (50mL x 3), combine the organic layers, wash with water (8mL) and saturated brine (8mL) successively, dry over anhydrous sodium sulfate, filter, evaporate the filtrate to remove the solvent under reduced pressure, and pass through the column to obtain compound v25 -1 (190 mg, yield 94%).
  • LCMS m/z 170.2 [M+H] + .
  • Step 2 Thionyl chloride (267mg, 2.24mmol) was added dropwise to a solution of compound v25-1 (190mg, 1.12mmol) in dichloromethane (10ml). Stir at room temperature for 3 hours. 100 ml of ice water was added to the reaction solution. The pH of the reaction solution was adjusted to 8-9 with NaHCO 3 saturated solution. Extracted with DCM (200ml) and twice with EA (200ml). The organic phase was dried over anhydrous sodium sulfate. Compound v25-2 was obtained by filtration and concentration, which was directly used in the next step.
  • Step 3 Compound v25-2 (200 mg) and sodium cyanide (219.5 mg, 4.48 mmol) were dissolved in dimethyl sulfoxide (5 mL), and reacted at 60° C. for 2 hours. Extracted with EA (50mL x 3), combined the organic layers, washed with water (8mL) and saturated brine (8mL) successively, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to remove the solvent under reduced pressure, and the compound v25- 3 (120 mg, yield 60.9%).
  • Step 4-5 Refer to the preparation method of intermediate v3 to obtain intermediate compound v25.
  • Step 1 Under nitrogen protection, 0-5 ° C, NaH (5.2g, 60%, 130mmol) was added in portions to 6,7-dihydro-5H-cyclopentadiene[b]pyridine-5-carbonitrile ( 4.7g, 32.6mmol) in tetrahydrofuran (90mL) solution, keep warm for 0.5-1h. A solution of 4-bromo-2-fluorobenzonitrile (7.1 g, 35.86 mmol) in THF (10 mL) was added dropwise to the reaction solution. The ice bath was removed, and then reacted at room temperature for 16 hours.
  • Step 2 Compound v49-1 (6g, 18.5mmol), Pd(PPh 3 )Cl 2 (1.2g, 1.85mmole), triethylamine (4.67g, 46.25mmole) and tributyl (1-ethoxy Vinyl) stannane (8 g, 22.2 mmole) was added into N,N-dimethylformamide (100 mL), and after nitrogen replacement three times, it was heated to 100° C., and the reaction was stirred for 16 hours.
  • Step 3 Compound v49-2 (4 g, 12.7 mmol) was added into concentrated hydrochloric acid (50 mL, 33%) at room temperature, heated to 100° C., and stirred overnight. Concentrate the reaction solution to remove concentrated hydrochloric acid to obtain a crude product, then add ethyl acetate (200mL) and saturated aqueous sodium carbonate solution (200mL) for extraction, the aqueous phase is extracted once more with ethyl acetate (200mL), combine the organic phases, and then use saturated brine ( 500 mL) was washed, dried over anhydrous sodium sulfate, the organic phase was passed through a short silica gel column once, and concentrated to obtain compound v24 (3 g, yield 77%).
  • LCMS: ESI [M+H] + 307.
  • Step 4 DAST (63 mL) was added to a solution of compound v24 (1.5 g, 4.9 mmol) in dichloromethane (7 mL) at room temperature, and the reaction solution was heated to 50° C. and stirred overnight. The reaction solution was slowly added dropwise to an ice solution of saturated sodium carbonate and ethyl acetate to quench, extracted with ethyl acetate (200mL X 3), the organic phases were combined, and then washed with saturated brine (500mL), and the organic phase was washed with Dry over sodium sulfate and concentrate the organic phase to obtain a crude product, which is purified by column chromatography to obtain intermediate v49 (800 mg, yield 50%).
  • LCMS: ESI [M+H] + 328.9.
  • Step 1 Dissolve 4-bromo-2,5-difluorobenzonitrile (5g, 22.94mmol) and tributyl(1-ethoxyethylene)tin (10.77g, 29.82mmol, 10.06mL) in DMF (60mL ), bistriphenylphosphinepalladium dichloride (1.61g, 2.29mmol) and TEA (6.96g, 68.81mmol, 9.60mL) were added. Argon was replaced three times, and the temperature was raised to 100° C. and stirred for 3 hours.
  • Step 2 Dissolve 4-(1-ethoxyvinyl)-2,5-difluorobenzonitrile (4.5 g, 21.51 mmol) in HCl/dioxane (1M) (50 mL), and stir at room temperature for 0.5 hour. Concentrate under reduced pressure to remove the solvent, adjust the pH value to greater than 7 with saturated aqueous sodium bicarbonate solution, then extract three times with ethyl acetate, combine the organic phases, wash with brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a crude product.
  • Step 3 Dissolve 4-acetyl-2,5-difluorobenzonitrile (1 g, 5.52 mmol) in DAST (10 mL), replace with argon three times, heat up to 45°C and stir for 4 hours. Cool to room temperature, slowly drop the reaction solution into an ice bath to quench the reaction, then use saturated aqueous sodium bicarbonate to adjust the pH value to greater than 7, then extract three times with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, and reduce Concentrate under reduced pressure to obtain the crude product.
  • Step 4 Dissolve 6,7-dihydro-5H-cyclopentadiene[b]pyridine-5-carbonitrile (0.45g, 3.12mmol) in THF (15mL), cool down to 0°C under the protection of argon, and separate NaH (499.40 mg, 12.49 mmol, 60% purity) was added in batches, then stirred at 0 °C for 0.5 h, then compound v50-1 (634.04 mg, 3.12 mmol) and THF (3 mL) were added. Slowly return to room temperature and stir overnight.
  • Step 1 Compound 2-fluoro-4-iodobenzonitrile (1.0g, 4.06mmol, 1.0eq), potassium fluoride (445mg, 7.7mmol, 1.9eq), cuprous iodide (1.9g, 10.16mmol, 2.5eq), trimethyl(perfluoroethyl)silane (1.7g, 8.12mmol, 2.0eq) were added into anhydrous DMF (14mL), purged with argon for 10 seconds and then sealed. Microwave reaction at 80°C for 6 hours.
  • Step 2 Under nitrogen protection, the compound 6,7-dihydro-5H-cyclopentyl[b]pyridine-5-carbonitrile (1.19g, 8.26mmol, 1.0eq) was added to anhydrous tetrahydrofuran (50mL), Cool down to 0°C, add 60wt% sodium hydrogen (1.32g, 33mmol, 4.0eq), keep warm for 30min, then dropwise add 2-fluoro-4-(perfluoroethyl)benzonitrile (1.98g, 8.26mol, 1.0eq ) in tetrahydrofuran (5 mL), stirred overnight at room temperature.
  • LCMS: ESI [M+H] + 383.5.
  • Embodiment 1 the preparation of compound Y1 and its isomers
  • Compound Y1 was purified and separated by chiral high performance liquid chromatography (chiral analysis method: SFC: IB N5( 250mm*4.6mm particle size: 5um)-Hex-EtOH(70:30)-30min; flow rate: 1.00(ml/min); temperature: 30°C; wavelength: 254nm; elution time: 30min), respectively get the retention time
  • the single-configuration compound Y1-1 is 4.698min and the single-configuration compound Y1-2 is 5.484min.
  • Embodiment 2 the preparation of compound Y2
  • Embodiment 3 the preparation of compound Y3
  • Embodiment 4 the preparation of compound Y-4 and its isomer
  • Example 2 Referring to the preparation method of Example 1, the difference is that methylamine is replaced with (R)-3-pyrrolidinol to obtain compound Y4.
  • Compound Y4 was separated by LCMS [mobile phase: from 60% water (0.02% NH 4 Ac) and 40% acetonitrile to 5% water (0.02% NH 4 Ac) and 95% acetonitrile within 15 min, finally under this condition],
  • the single-configuration compound Y4-1 with a retention time of 5.697min and the single-configuration compound Y4-2 with a retention time of 6.209min were obtained respectively.
  • Embodiment 5 the preparation of compound Y5
  • Embodiment 6 the preparation of compound Y6
  • Embodiment 7 the preparation of compound Y7
  • Embodiment 8 the preparation of compound Y8
  • Embodiment 9 the preparation of compound Y9
  • Embodiment 10 Preparation of compound Y10
  • Embodiment 11 Preparation of compound Y11
  • Embodiment 12 Preparation of compound Y12 and its isomers
  • Compound Y12 was purified and separated by chiral high performance liquid chromatography (chiral analysis method: SFC:SFC:IA3.0cm( 250mm*4.6mm particle size: 5um)-CO2-EtOH(80:20)-30min; flow rate: 60(g/min); temperature: 30°C; wavelength: 230nm; elution time: 30min), respectively get the retention time
  • Embodiment 13 Preparation of Compound Y13
  • Embodiment 14 Preparation of compound Y14
  • Embodiment 15 Preparation of compound Y15 and its isomers
  • Compound Y15 was purified and separated by chiral high performance liquid chromatography (chiral analysis method: SFC:IC( 250mm*4.6mm particle size: 5um)-Hex-EtOH(40:60)-30min; flow rate: 1(ml/min); temperature: 30°C; wavelength: 214nm; elution time: 30min), respectively get the retention time
  • the single-configuration compound Y15-1 was 4.258min and the single-configuration compound Y15-2 was 5.231min.
  • Embodiment 16 Preparation of compound Y16
  • Embodiment 17 Preparation of compound Y17
  • Embodiment 18 Preparation of Compound Y18
  • Embodiment 19 Preparation of Compound Y19
  • Step 2 Dissolve compound 19-1 (100mg, 0.25mmol), cuprous chloride (5mg, 0.05mmol) in dimethyl sulfoxide (15mL), stir the reaction solution at 80°C for 3h under an oxygen atmosphere, and depressurize The solvent was distilled off to obtain compound 19-2 (90 mg).
  • ESI-MS m/z 377.0 [MH] - .
  • Step 3 Compound 19-2 (90mg, 0.24mmol), silver nitrate (90mg, 0.53mmol), methylamine THF solution (2M) (2mL, 4.00mmol) were dissolved in toluene (10mL), and the reaction solution was heated at 110°C After stirring for 2h, the product was detected by LCMS. Diluted with water (20mL), extracted with EA (30mL x 3), combined the organic layers, washed with water (50mL) and saturated brine (50mL) successively, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to remove the solvent under reduced pressure.
  • Embodiment 20 Preparation of Compound Y20
  • Embodiment 22 Preparation of compound Y22
  • Embodiment 23 Preparation of Compound Y23
  • Embodiment 24 Preparation of compound Y24
  • Embodiment 26 Preparation of compound Y26
  • Embodiment 27 Preparation of compound Y27
  • Embodiment 28 Preparation of Compound Y28
  • Embodiment 30 Preparation of compound Y30
  • Step 1 Refer to the preparation method of Example 1, the difference is that compound v1 is replaced by compound v19 to obtain compound 38-1, LCMS: m/z 422.0 [MH] - .
  • Step 2 Compound 38-1 (110 mg, 0.26 mmol), zinc cyanide (152 mg, 1.30 mmol) and xphos (24.7 mg, 0.052 mmol) were dissolved in dry DMF (2 mL), and Pd 2 (dba ) 3 (23.7mg, 0.026mmol), microwave heated to 110°C under nitrogen protection and stirred for 2.5 hours. Extracted twice with EA (50 mL), the organic phase was dried over sodium sulfate and concentrated to prepare compound Y38 (16.9 mg, yield 19%).
  • Example 2 Referring to the preparation method of Example 1, the difference is that compound v1 is replaced by compound v30 to obtain compound Y45.
  • Compound Y45 (200 mg) was subjected to chiral resolution ( OJ-250*25mm 10mm-CO2-MEOH (methanol+0.1% 7.0mol/l ammonia water)-(75:25)-5.0min; flow rate: 80ml/min; T: RT; wavelength: 214nm; elution time: 5.0min. ) to get:
  • Example 2 Referring to the preparation method of Example 1, the difference is that compound v1 is replaced by compound v30, and methylamine is replaced by deuterated methylamine hydrochloride to obtain compound Y46.
  • Compound Y46 160 mg was subjected to chiral resolution ( OJ-250*25mm 10mm-CO2-MeOH (methanol+0.1% 7.0mol/l ammonia)-(75:25)-5.0min; flow rate: 80ml/min; T: RT; wavelength: 214nm; elution time: 5.0min. ), respectively get:
  • Step 1 Referring to the preparation method of Example 1, the difference is that compound v1 is replaced by compound v19 to obtain compound 53-1.
  • Step 2 Compound 53-1 (120mg, 0.28mmol), copper trifluoromethanesulfonate (15.1mg, 0.042mmol) and N,N'-dimethylethylenediamine (7.4mg, 0.084mmol) were dissolved in dry Dimethyl sulfoxide (5 mL), sodium methanesulfinate (107 mg, 1.05 mmol) was added to the above solution, heated to 120° C. and stirred for 2 hours under nitrogen protection. Extracted twice with EA (50 mL), the organic phase was dried over sodium sulfate and concentrated to prepare compound Y53 (29.1 mg, yield 24.2%).
  • Step 1 Referring to the preparation method of Example 1, the difference is that compound v1 is replaced by compound v27 to obtain compound 54-1.
  • Example 1 Referring to the preparation method of Example 1, the difference is that compound v1 is replaced by compound v29, and methylamine is replaced by ammonia to obtain compound Y55.
  • Compound Y55 was further purified and separated by chiral high performance liquid chromatography (chiral separation method: SFC:IG 3.0cm( 250mm*4.6mm particle size: 5um)-Hex-EtOH(90:10)-30min; flow rate: 25mL/min; T: 30°C; wavelength: 214nm; elution time: 30min), the retention time is 4.491min
  • SFC:IG 3.0cm( 250mm*4.6mm particle size: 5um)-Hex-EtOH(90:10)-30min; flow rate: 25mL/min; T: 30°C; wavelength: 214nm; elution time: 30min the retention time is 4.491min
  • the single configuration compound Y55-1 and the single configuration compound Y55-2 with a retention time of 5.150min.
  • Step 1 Compound v26 (35mg, 0.1mmol) and phosphorus pentasulfide (60mg, 0.3mmol) were dissolved in pyridine (2mL), and the reaction solution was raised to 150°C in microwave and stirred for 3 hours. The reaction solution was concentrated to obtain compound 26-1, which was directly used in the next step.
  • Step 2 The above compound 26-1 (40mg) was dissolved in ethanol (2ml), and a THF solution (2M, 3mL) of methylamine was added dropwise at room temperature, and the reaction solution was stirred at room temperature for 16 hours. Extracted with EA (10mL x 3), the organic layers were combined, washed with water (50mL) and saturated brine (50mL) successively, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to remove the solvent. The prepared compound Y56 (3.4mg , yield: 13%).
  • Example 1 Referring to the preparation method of Example 1, the difference is that compound v1 is replaced by compound v3, and methylamine is replaced by 2,2-difluoroethylamine to obtain compound Y60.
  • Compound Y60 was further purified and separated by chiral high performance liquid chromatography (chiral separation method: SFC: IC 3.0cm ( 250mm*4.6mm particle size: 5um)-Hex-EtOH(50:50)-30min; flow rate: 25ml/min; temperature: 30°C; wavelength: 214nm; elution time: 30min), respectively, the retention time is 4.767min
  • SFC IC 3.0cm ( 250mm*4.6mm particle size: 5um)-Hex-EtOH(50:50)-30min; flow rate: 25ml/min; temperature: 30°C; wavelength: 214nm; elution time: 30min)
  • Step 1 Referring to the preparation method of Example 1, the difference is that compound v1 is replaced by compound v23 to obtain compound Y63.
  • Step 2 Compound Y63 (200mg) was subjected to chiral resolution ( OJ-250*25mm 10 ⁇ m-CO 2,- MeOH (methanol+0.1% 7.0mol/l ammonia water)-(60:40)-5.0min; flow rate: 80ml/min; T: RT; wavelength: 214nm; elution Duration: 5.0min) to obtain the compound:
  • Embodiment 64 Preparation of Compound Y64
  • Step 1 Referring to the preparation method of Example 1, the difference is that compound v1 is replaced by compound v24 to obtain compound 65-1.
  • Step 3 Compound Y65 (100mg) was subjected to chiral resolution ( OJ-250*25mm 10 ⁇ m-CO 2, -MeOH(+0.1%7.0mol/l ammonia methanol)-(85:15)-6.0min; Flow rate: 70ml/min; T: RT; Wavelength: 214nm; Elution Duration: 6.0min. ),get:
  • Embodiment 67 Preparation of Compound Y67
  • Step 1 Referring to the preparation method of Example 1, the difference is that compound v1 is replaced by compound v22 to obtain compound 67-1.
  • Embodiment 68 Preparation of Compound Y68
  • compound Y70 was synthesized by referring to the preparation method of the above examples.
  • Compound Y70 (100 mg) was subjected to chiral resolution ( AS-250*25mm 10 ⁇ m-CO 2 -MEOH (+0.1% 7.0mol/l methanol containing ammonia)-(60:40)-2.0min; flow rate: 70ml/min; T: RT; wavelength: 214nm; elution Duration: 2.0min. ), respectively get:
  • compound Y72 was synthesized by referring to the preparation method of the above examples.
  • Compound Y72 (73 mg) was subjected to chiral resolution ( OJ-250*25mm 10mm-CO 2 -MeOH (methanol+0.1% 7.0mol/l ammonia water)-(75:25)-2.5min; flow rate: 70ml/min; T: RT; wavelength: 214nm; elution time : 2.5min.
  • compound Y73 was synthesized by referring to the preparation method of the above example; compound Y73 (100 mg) was subjected to chiral resolution (Dr.maish Reprosil Chiral-MIC ( IC)-250*25mm 10mm-CO 2 -MeOH (methanol+0.1% 7.0mol/l ammonia water)-(50:50)-7.0min; flow rate: 70ml/min; T: RT; wavelength: 214nm; elution Duration: 7.0min.
  • chiral resolution Dr.maish Reprosil Chiral-MIC ( IC)-250*25mm 10mm-CO 2 -MeOH (methanol+0.1% 7.0mol/l ammonia water)-(50:50)-7.0min; flow rate: 70ml/min; T: RT; wavelength: 214nm; elution Duration: 7.0min.
  • compound Y74 was synthesized by referring to the preparation method of the above examples.
  • Compound Y74 (100mg) was subjected to chiral resolution (Dr.maish Reprosil Chiral-MIC ( IC)-250*25mm 10mm-CO 2 -MeOH (methanol+0.1% 7.0mol/l ammonia water)-(50:50)-7.0min; flow rate: 70ml/min; T: RT; wavelength: 214nm; elution Duration: 7.0min.
  • chiral resolution Dr.maish Reprosil Chiral-MIC ( IC)-250*25mm 10mm-CO 2 -MeOH (methanol+0.1% 7.0mol/l ammonia water)-(50:50)-7.0min; flow rate: 70ml/min; T: RT; wavelength: 214nm; elution Duration: 7.0min.
  • Step 1 Compound v23 (600mg, 1.86mmol, 1.0eq) was dissolved in anhydrous acetonitrile (10mL), and DIEA (2.4g, 18.6mmol, 10eq) and POCl 3 (1.4g, 9.3mmol, 5.0eq) were added at room temperature ), stirred at 100°C for 6 minutes. Cool the reaction solution to room temperature, add deuterated methylamine aqueous solution (30mL, 2mol/L), continue to react at room temperature for 2 hours, add 100mL ethyl acetate and 100mL water to dilute and extract, wash the organic phase three times with water, and separate the layers. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated.
  • Step 2 Compound Y75 (100mg) was subjected to chiral resolution ( IG-250*25mm 10 ⁇ m-CO 2 ,-MeOH(methanol+0.1%7.0mol/l ammonia water)-(50:50)-5.0min; flow rate: 70ml/min; T: RT; wavelength: 214nm; elution Duration: 5.0min. )get:
  • Step 1 Compound v23 (600mg, 1.86mmol, 1.0eq) was dissolved in anhydrous acetonitrile (10mL), and DIEA (2.4g, 18.6mmol, 10eq) and POCl 3 (1.4g, 9.3mmol, 5.0eq) were added at room temperature ), stirred at 100°C for 6 minutes.
  • Step 2 Compound Y76 (60mg) was subjected to chiral resolution ( OJ-250*25mm 10 ⁇ m-CO 2 -MeOH (methanol+0.1% 7.0mol/l ammonia water)-(70:30)-3.0min; flow rate: 80ml/min; T: RT; wavelength: 214nm; elution time : 3.0min), get:
  • Step 1 Phosphorus oxychloride (1 g, 6.63 mmol, 5.0 eq) and diisopropylethylamine (1.7 g, 13.2 mmol, 10.0 eq) were added to compound v49 (435 mg, 1.32 mmol, 1.0 eq) at room temperature ) in anhydrous acetonitrile (10mL) solution, put the reaction system in an oil bath at 100°C, react for five minutes, cool down to 0-5°C after five minutes, slowly add an aqueous solution of deuterated methylamine dropwise to the reaction solution (30mL, 2mole/L), the temperature of the reaction system was controlled at 5-15°C.
  • Step 2 Compound Y77 (120mg) was subjected to chiral resolution (( IC)-250*25mm 10 ⁇ m-CO 2 -MeOH (methanol+0.1% 7.0mol/l ammonia water)-(50:50)-8.0min; flow rate: 100ml/min; T: RT; wavelength: 214nm; elution Duration: 8.0min. ),get:
  • Step 1 Add phosphorus oxychloride (1.4g, 9.14mmol, 5.0eq) and diisopropylethylamine (2.3g, 18.3mmol, 10.0eq) to compound v49 (600mg, 1.83mmol, 1.0 eq) in anhydrous acetonitrile (10mL) solution, put the reaction system in an oil bath at 100°C, react for five minutes, cool down to 0-5°C after five minutes, slowly add difluoroethylamine dropwise to the reaction solution Acetonitrile solution (30mL, 2mole/L), the temperature of the reaction system was controlled at 0-5°C.
  • Step 2 Compound Y80 (140mg) was subjected to chiral resolution ( AD-250*25mm 10 ⁇ m-CO 2 -MEOH (methanol+0.1% 7.0mol/l ammonia water)-(80:20)-3.5min; flow rate: 70ml/min; T: RT; wavelength: 214nm; elution time : 3.5min. ),get:
  • Step 1 Add phosphorus oxychloride (1.4g, 9.14mmol, 5.0eq) and diisopropylethylamine (2.3g, 18.3mmol, 10.0eq) to compound v49 (600mg, 1.83mmol, 1.0 eq) in anhydrous acetonitrile (10mL) solution, put the reaction system in an oil bath at 100°C, react for five minutes, cool down to 0-5°C after five minutes, slowly add trifluoroethylamine dropwise to the reaction solution Acetonitrile solution (30mL, 2mole/L), the temperature of the reaction system was controlled at 0-5°C.
  • Step 2 Compound Y81 (60mg) was subjected to chiral resolution ( IB-250*25mm 10 ⁇ m-CO 2 -MeOH (methanol+0.1% 7.0mol/l ammonia water)-(80:20)-4.5min; flow rate: 70ml/min; T: RT; wavelength: 214nm; elution time : 4.5min. ),get:
  • Step 1 Compound v50 (0.25g, 721.91 ⁇ mol) was dissolved in MeCN (10mL), and POCl3 (553.45mg, 3.61mmol, 336.45 ⁇ L) and DIEA (933.00mg, 7.22mmol, 1.26mL) were added under argon protection. Stir at 100° C. for 10 min, then concentrate under reduced pressure to remove the solvent (to obtain sample A). Deuteromethylamine hydrochloride (509.21 mg, 7.22 mmol, HCl) and DIEA (1.40 g, 10.83 mmol, 1.89 mL) were dissolved in THF (5 mL) and stirred for 0.5 h (obtaining sample B).
  • Step 2 Compound Y82 (130mg) was subjected to chiral resolution ( AD-250*25mm 10 ⁇ m-CO 2 -MeOH (methanol+0.1% 7.0mol/l ammonia water)-(70:30)-3.0min; flow rate: 70ml/min; T: RT; wavelength: 214nm; elution time : 3.0min. ),get:
  • Step 1 Add compound v3 (800mg, 2.4mmol, 1.0eq) to anhydrous acetonitrile (10mL), then add DIEA (3.1g, 24mmol, 10.0eq), phosphorus oxychloride (1.8g, 12mmol, 5.0eq) . Place it in a pre-heated 100°C oil bath for 10 minutes, and then start to cool down to about 0°C. And the reaction solution was added dropwise to a solution of trifluoropropylethylamine (1.3g, 12mmol, 20eq) in 10mL of acetonitrile, after the addition was complete, the reaction was carried out at room temperature for 10min.
  • DIEA 3.g, 24mmol, 10.0eq
  • phosphorus oxychloride 1.8g, 12mmol, 5.0eq
  • Prep-HPLC was prepared by reverse phase HPLC (Waters 2767 Column: Xbridge Xbridge C18, 19*250mm, 10um; mobile phase A: 10mmol NH 4 HCO 3 /H 2 O, B: ACN; flow rate: 20ml/min; gradient: 52 -52% Time: 9.4-10.6 min of 16min) to obtain compound Y83 (120 mg, yield 11.71%).
  • Step 2 Compound Y83 (120mg) is subjected to chiral resolution ( OD-250*25mm 10 ⁇ m-CO 2,- MEOH (+0.1%7.0mol/l methanol containing ammonia)-(90:10)-3.0min; flow rate: 100ml/min; T: RT; wavelength: 214nm; washing Take off time length: 3.0min) obtain:
  • Step 1 Add anhydrous acetonitrile (20mL) to compound v51 (1g, 2.62mmol, 1.0eq), then add DIPEA (3.3g, 26.2mmol, 10.0eq), phosphorus oxychloride (2.0g, 13mmol, 5.0 eq). Place it in a pre-heated 100°C oil bath for 5 minutes, and then start to cool down to about 0°C. And the reaction solution was added dropwise into an aqueous solution of methylamine (50 mL, 2.0 mol/L), and after the addition was complete, the reaction was carried out at room temperature for 10 min.
  • DIPEA 3.3g, 26.2mmol, 10.0eq
  • phosphorus oxychloride 2.0g, 13mmol, 5.0 eq
  • Step 2 Compound Y84 (200mg) was subjected to chiral resolution (Dr.maish Reprosil Chiral-MIC ( IC)-250*25mm 10 ⁇ m-CO 2 -MeOH (+0.1%7.0mol/l methanol containing ammonia)-(55:45)-2.0min; flow rate: 100ml/min; T: RT; wavelength: 214nm; washing Desorption time: 2.0 min) to obtain compound Y84-1 (83 mg, yield 41.5%, retention time: 1.295 min).
  • LCMS: ESI [M+H] + 396.1.
  • Step 1 Add anhydrous acetonitrile (20mL) to compound v51 (1g, 2.62mmol, 1.0eq), then add DIPEA (3.3g, 26.2mmol, 10.0eq), phosphorus oxychloride (2.0g, 13mmol, 5.0 eq). Place it in a pre-heated 100°C oil bath for five minutes, and then start to cool down to about 0°C. And the reaction liquid was added dropwise to deuterated methylamine aqueous solution (30mL, 20.0eq), after the dropwise addition was completed, the reaction was carried out at room temperature for 10min.
  • Step 2 Compound Y85 (300mg) was subjected to chiral resolution (Dr.maish Reprosil Chiral-MIC ( IC)-250*25mm 10 ⁇ m-CO 2 -MEOH (+0.1%7.0mol/l methanol containing ammonia)-(55:45)-2.0min; flow rate: 100ml/min; T: RT; wavelength: 214nm; washing Take off time length: 2.0min) obtain:
  • Step 1 Add anhydrous acetonitrile (30mL) to compound v50 (1g, 2.9mmol, 1.0eq), then add DIEA (3.7g, 29mmol, 10.0eq), phosphorus oxychloride (2.2g, 14.5mmol, 5.0 eq). Place it in a pre-heated 100°C oil bath for 10 minutes, and then start to cool down to about 0°C. And the reaction solution was added dropwise into 30ml of methylamine aqueous solution, after the dropwise addition was completed, the reaction was carried out at room temperature for 10 minutes.
  • Step 2 Compound Y86 (150mg) is subjected to chiral resolution ( OD-250*25mm 10 ⁇ m-CO 2,- MeOH (+0.1%7.0mol/l methanol containing ammonia)-(80:20)-3.6min; flow rate: 100ml/min; T: RT; wavelength: 214nm; washing Take off time length: 3.6min) obtain:
  • Test Example 1 MAT2A Enzyme Activity Inhibition
  • DMSO DMSO to prepare 100 times the final concentration of the compound to be tested, and then use 1 ⁇ buffer to dilute to 5 times the final concentration of the compound to be tested.
  • the DMSO content is 5%, and save it for later use;
  • Max Positive control well, namely the maximum value well
  • Min Negative control well, namely the minimum value well.
  • the XLFIT 5.0 software (IDBS, UK) was used for fitting, with the logarithm of the compound concentration as the X-axis and the inhibition rate as the Y-axis, using a four-parameter model to calculate the half-maximum inhibitory concentration IC 50 of the compound. The results are shown in Table 1.
  • Test example 2 HCT 116 (MTAP-/-) cell activity inhibition experiment
  • HCT116 cells Inoculate MTAP-deficient HCT116 cells in the logarithmic phase in 384 cell culture plates, the medium is 30 ⁇ L of MCCOYS 5A containing 10% FBS and 1x penicillin and streptomycin, and the cell density is 300/well;
  • the Max well is the positive control well, that is, the maximum value well tested on the 5th day
  • the Min well is the negative control well, that is, the minimum value well tested on the 5th day
  • the BL well is the blank control well, that is, the test well on the 0th day .
  • the compounds of the embodiments of the present application have higher inhibitory activity on HCT 116 (MTAP-/-) cells.
  • Test example 3 HCT 116WT cell activity inhibition experiment
  • HCT116 cells in the logarithmic phase in 384 cell culture plates, the medium is 30 ⁇ L MCCOYS 5A containing 10% FBS and 1x penicillin and streptomycin, and the cell density is 300/well;
  • the Max well is the positive control well, that is, the maximum value well tested on the 5th day
  • the Min well is the negative control well, that is, the minimum value well tested on the 5th day
  • the BL well is the blank control well, that is, the test well on the 0th day .
  • the LC/MS/MS method was used to determine the drug concentration in plasma of the compound at different time points after intravenous injection and intragastric administration in mice, and to evaluate the pharmacokinetic behavior of the compound in mice.
  • the test compound will be formulated into a clear solution or a homogeneous suspension with a solvent according to the dose and concentration of the drug, and administered to the ICR mice.
  • Single intravenous injection and oral administration ICR mice (male, 30-40 g, 7-9 weeks old, Beijing Weitong Lihua Experimental Animal Co., Ltd.) were randomly divided into 6 mice/group.
  • the intravenous group had free access to food and water before administration; the gavage group fasted overnight before administration, and resumed food four hours after administration (except in special cases), and had free access to water.
  • the vehicle of the intravenous injection group and the oral group was a mixed solution of a certain proportion of dimethyl sulfoxide, polyethylene glycol-15 hydroxystearate and sulfobutyl ether-beta-cyclodextrin, vortexed, and ultrasonicated to make it Dissolve to prepare a 0.4 mg/mL or 1 mg/mL solution.
  • the intravenous injection group requires the solution to be clear, and the oral group requires the solution to be homogeneously suspended or a clear solution for later use. After intravenous administration of 2 mg/kg or oral administration of 10 mg/kg to rats, a certain amount of whole blood sample.
  • the whole blood sample was centrifuged at 3700 rpm for 15 minutes, and the supernatant was separated to obtain a plasma sample.
  • diluent such as pure water, methanol/water solution, etc., which can be adjusted according to the situation
  • the blood drug concentration was quantitatively analyzed, and the pharmacokinetic parameters were calculated with Data Analysie System software (Shanghai Bojia Pharmaceutical Technology Co., Ltd., version 3.0). The results are shown in Table 4.
  • Test Example 5 Drug efficacy evaluation of the test substance on the subcutaneous xenograft tumor model of human colon cancer HCT116MTAP-/- nude mice
  • Human colon cancer HCT116MTAP -/- cells were implanted subcutaneously in nude mice to construct a xenograft tumor-bearing mouse model for in vivo drug efficacy experiments.
  • mice Female, 6-8 weeks old, purchased from Zhejiang Weitong Lihua Experimental Animal Technology Co., Ltd.
  • mice were bred in a specific pathogen-free environment. The mice were kept in transparent resin plastic cages (260mm ⁇ 160mm ⁇ 127mm), with 5 mice per cage. Cage litter was autoclaved wood chips and corncob litter, which was changed twice a week.
  • Experimental mice can obtain unlimited amount of special mouse food (sterilized by irradiation, purchased from Shanghai Slack Experimental Animal Co., Ltd.). Experimental mice had unlimited access to internally treated drinking water throughout the experiment.
  • Tumor cells (5 ⁇ 10 6 cells/100 ⁇ L+50% Matrigel) were inoculated into the right axilla of the mice, which was defined as day 0.
  • the tumor volume reached 100mm 3 -200mm 3 , they were randomly divided into groups according to tumor size and body weight, with 8 rats in each group. Administration was carried out on the day of grouping, which was recorded as P0.
  • the body weight and tumor volume of the animals were measured twice a week, and the clinical symptoms of the animals were observed every day.
  • Relative tumor proliferation rate T/C (%): the calculation formula is T/C (%) (T RTV /C RTV ) ⁇ 100%.
  • the structure of the positive product is shown below, which can be prepared by referring to J.Med.Chem.2021, 64, 8, 4430–4449.

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Abstract

Disclosed is a substituted naphthyridinone derivative, which has a structure as shown in formula (I). Further provided are a pharmaceutically acceptable salt, stereoisomer and pharmaceutical composition of the derivative and the medicinal use thereof.

Description

取代的萘啶酮衍生物、其药物组合物及应用Substituted naphthyridone derivatives, pharmaceutical compositions and applications thereof
相关申请related application
本申请要求以下中国专利申请的优先权：2021年11月9日提交的，申请号为202111319902.8，名称为“取代的萘啶酮衍生物、其药物组合物及应用”的中国专利申请；2022年4月15日提交的，申请号为202210395699.0，名称为“取代的萘啶酮衍生物、其药物组合物及应用”的中国专利申请；以及2022年9月29日提交的，申请号为202211200661.X，名称为“取代的萘啶酮衍生物、其药物组合物及应用”的中国专利申请，在此将其全文引入作为参考。This application claims the priority of the following Chinese patent application: a Chinese patent application filed on November 9, 2021, with application number 202111319902.8, entitled "Substituted naphthyridone derivatives, pharmaceutical compositions and applications thereof"; 2022 Submitted on April 15, with application number 202210395699.0, a Chinese patent application titled "Substituted naphthyridinone derivatives, pharmaceutical compositions and applications thereof"; and submitted on September 29, 2022, with application number 202211200661. X, a Chinese patent application entitled "Substituted Nalidinone Derivatives, Pharmaceutical Compositions and Applications thereof", the entirety of which is hereby incorporated by reference.
技术领域technical field
本申请涉及医药技术领域，特别涉及一种取代的萘啶酮衍生物、其药学上可接受的盐、立体异构体、药物组合物以及应用。The present application relates to the technical field of medicine, in particular to a substituted naphthyridone derivative, its pharmaceutically acceptable salt, stereoisomer, pharmaceutical composition and application.
背景技术Background technique
甲硫氨酸腺苷转移酶(MAT)，又称S-腺苷甲硫氨酸合成酶，是一种催化甲硫氨酸(Met)与ATP反应生成S-腺苷甲硫氨酸(SAM)的酶。MAT酶有三种亚型，包括分别由MAT1A，MAT2A及MAT2B基因编码的MATI，MATII及MATIII。其中，MAT1A主要存在于成熟肝脏组织中，而MAT2A广泛分布于肝外细胞，在多种肿瘤组织中也能检测到其高表达。Methionine adenosyltransferase (MAT), also known as S-adenosylmethionine synthetase, is a kind of enzyme that catalyzes the reaction between methionine (Met) and ATP to generate S-adenosylmethionine (SAM ) enzymes. There are three isoforms of MAT enzymes, including MATI, MATII and MATIII encoded by MAT1A, MAT2A and MAT2B genes, respectively. Among them, MAT1A mainly exists in mature liver tissue, while MAT2A is widely distributed in extrahepatic cells, and its high expression can also be detected in various tumor tissues.
在甲硫腺苷磷酸化酶(MTAP)缺失的肿瘤细胞系中，抑制MAT2A活性能显著影响肿瘤细胞增殖。MTAP是嘌呤和甲硫氨酸合成补偿途径中的一种关键的酶，其能催化甲硫腺苷(MTA)转化为5-甲基硫代核糖-1-磷酸及腺嘌呤，这一过程是人体内甲硫氨酸补偿途径中的重要环节。当MTAP缺失后，MTA的代谢途径受到抑制，进而导致体内MTA大量蓄积。而MTA对精氨酸甲基转移酶(PRMT5)有显著的抑制效果，这种抑制效果使MTAP缺失细胞更依赖于MAT2A的活性，最终造成癌细胞对MAT2A抑制的敏感性增强。In tumor cell lines deficient in methylthioadenosine phosphorylase (MTAP), inhibition of MAT2A activity significantly affects tumor cell proliferation. MTAP is a key enzyme in the compensatory pathway of purine and methionine synthesis, which can catalyze the conversion of methylthio adenosine (MTA) into 5-methylthioribose-1-phosphate and adenine. This process is An important link in the methionine compensation pathway in the human body. When MTAP is missing, the metabolic pathway of MTA is inhibited, which leads to a large accumulation of MTA in the body. However, MTA has a significant inhibitory effect on arginine methyltransferase (PRMT5), which makes MTAP-deficient cells more dependent on the activity of MAT2A, and ultimately increases the sensitivity of cancer cells to MAT2A inhibition.
有研究表明，MTAP在所有肿瘤中纯合性缺失的频率约为15％，且在不同肿瘤中的缺失频率有所不同。其中MTAP缺失频率较高的瘤种包括胶质瘤、间皮瘤、黑色素瘤、胃癌、食管癌、膀胱癌、胰腺癌、非小细胞肺癌、星形细胞瘤、骨肉瘤、头颈癌、粘液性软骨肉瘤、卵巢癌、子宫内膜癌、乳腺癌、软组织肉瘤、非霍奇金淋巴瘤等。因MTAP的缺失，MAT2A在多类肿瘤中的水平异常升高，这些肿瘤包括胃癌、结肠癌、肝癌和胰腺癌等。在MTAP缺失的细胞中，选择性抑制MAT2A能够降低MTAP缺失癌细胞的增殖活性，引起肿瘤细胞的“合成致死”。因此，选择性抑制MAT2A能够作为一种有效的肿瘤治疗手段。Studies have shown that the frequency of homozygous deletion of MTAP in all tumors is about 15%, and the frequency of deletion varies in different tumors. Among them, tumors with high frequency of MTAP deletion include glioma, mesothelioma, melanoma, gastric cancer, esophageal cancer, bladder cancer, pancreatic cancer, non-small cell lung cancer, astrocytoma, osteosarcoma, head and neck cancer, mucinous Chondrosarcoma, ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma, non-Hodgkin's lymphoma, etc. Due to the loss of MTAP, the level of MAT2A is abnormally increased in many types of tumors, including gastric cancer, colon cancer, liver cancer and pancreatic cancer. In MTAP-deficient cells, selective inhibition of MAT2A can reduce the proliferation activity of MTAP-deficient cancer cells and cause "synthetic lethality" of tumor cells. Therefore, selective inhibition of MAT2A can be used as an effective tumor therapy.
然而目前选择性MAT2A抑制剂大多还处于临床早期开发阶段，因此开发新的高活性和高选择性的MAT2A抑制剂具有重要的临床意义。However, most of the current selective MAT2A inhibitors are still in the early stage of clinical development, so the development of new highly active and highly selective MAT2A inhibitors has important clinical significance.
发明内容Contents of the invention
本申请第一方面提供了一种式(I)所示的化合物、其药学上可接受的盐或其立体异构体：The first aspect of the present application provides a compound represented by formula (I), its pharmaceutically acceptable salt or its stereoisomer:
Figure PCTCN2022130850-appb-000001
Figure PCTCN2022130850-appb-000001
其中，S 1和S 2代表环A上的环原子；S 1为N或C；且S 2为N或C； Wherein, S 1 and S 2 represent ring atoms on ring A; S 1 is N or C; and S 2 is N or C;
Z 1为N或CR Z1；Z 2为N或CR Z2；Z 3为N或CR Z3；且Z 4为N或CR Z4；其中R Z1、R Z2、R Z3、和R Z4各自独立地为氢、氰基、硝基、羟基、羧基、卤素(优选为氟或氯)、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、C 3-8环烷基(优选为C 3-6环烷基)、卤代C 1-8烷基(优选为卤代C 1-6烷基，更优选为卤代C 1-3烷基)、C 1-8烷氧基(优选为C 1-6烷氧基，更优选为C 1-3烷氧基)、卤代C 1-8烷氧基(优选为卤代C 1- 6烷氧基，更优选为卤代C 1-3烷氧基)、-C(O)C 1-8烷基(优选为-C(O)C 1-6烷基，更优选为-C(O)C 1-3烷基)、-C(O)OC 1-8烷基(优选为-C(O)OC 1-6烷基，更优选为-C(O)OC 1-3烷基)、-C(O)NR a0R b0或-NR a1R b1；其中 所述C 1-8烷基、C 3-8环烷基、卤代C 1-8烷基、C 1-8烷氧基、卤代C 1-8烷氧基各自独立地为未取代的或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素、氰基、硝基、羟基、羧基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-NR a1R b1、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR a0R b0、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基和3至6元杂环烷基； Z 1 is N or CR Z1 ; Z 2 is N or CR Z2 ; Z 3 is N or CR Z3 ; and Z 4 is N or CR Z4 ; wherein R Z1 , R Z2 , R Z3 , and R Z4 are each independently Hydrogen, cyano, nitro, hydroxyl, carboxyl, halogen (preferably fluorine or chlorine), C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 3 -8 cycloalkyl (preferably C 3-6 cycloalkyl), halogenated C 1-8 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy ) , halogenated C 1-8 alkoxy (preferably halogenated C 1-6 alkoxy group, more preferably halogenated C 1-3 alkoxy), -C(O)C 1-8 alkyl (preferably -C(O)C 1-6 alkyl, more preferably -C(O) C 1-3 alkyl), -C(O)OC 1-8 alkyl (preferably -C(O)OC 1-6 alkyl, more preferably -C(O)OC 1-3 alkyl), -C(O)NR a0 R b0 or -NR a1 R b1 ; wherein the C 1-8 alkyl, C 3-8 cycloalkyl, halogenated C 1-8 alkyl, C 1-8 alkoxy , Halogenated C 1-8 alkoxy groups are each independently unsubstituted or substituted by 1, 2 or 3 substituents independently selected from the group consisting of deuterium, halogen, cyano, nitro, hydroxyl, carboxyl , C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, - NR a1 R b1 , -SO 2 C 1-3 alkyl, -S(O)C 1-3 alkyl, -C(O)NR a0 R b0 , -C(O)OC 1-3 alkyl, - OC(O)C 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy and 3 to 6 membered heterocycloalkyl;
R 1、和R 2各自独立地为氢、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、-C(O)OC 1-8烷基(优选为-C(O)OC 1-6烷基，更优选为-C(O)OC 1-3烷基)、-C(O)C 1-8烷基(优选为-C(O)C 1-6烷基，更优选为-C(O)C 1-3烷基)、C 3-8环烷基(优选为C 3-6环烷基)或3至6元杂环烷基；或者R 1、R 2与相连接的环原子共同形成4至7元饱和或部分不饱和单环(优选5至7元饱和或部分不饱和单环)或4至7元饱和或部分不饱和单杂环(优选5至7元饱和或部分不饱和单杂环)；其中所述C 1-8烷基、C 3-6环烷基、4至7元饱和或部分不饱和单环、4至7元饱和或部分不饱和单杂环为未取代的或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素、氰基、硝基、羟基、羧基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2- 4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-NR a1R b1、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR a0R b0、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基和3至6元杂环烷基； R 1 , and R 2 are each independently hydrogen, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), -C(O)OC 1-8 alkyl (preferably -C(O)OC 1-6 alkyl, more preferably -C(O)OC 1-3 alkyl), -C(O)C 1-8 alkyl (preferably -C(O) C 1-6 alkyl, more preferably -C(O)C 1-3 alkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl) or 3 to 6 membered heterocycloalkyl ; or R 1 , R 2 and the connected ring atoms jointly form a 4 to 7 membered saturated or partially unsaturated monocyclic ring (preferably a 5 to 7 membered saturated or partially unsaturated monocyclic ring) or a 4 to 7 membered saturated or partially unsaturated monocyclic ring Monoheterocycle (preferably 5 to 7 membered saturated or partially unsaturated monoheterocycle); wherein said C 1-8 alkyl, C 3-6 cycloalkyl, 4 to 7 membered saturated or partially unsaturated monocycle, 4 Up to 7 membered saturated or partially unsaturated monoheterocycles are unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen, cyano, nitro, hydroxyl, carboxyl, C 1-3 alkyl, C 1-3 alkoxy , C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, -NR a1 R b1 , -SO 2 C 1-3 alkyl, -S(O)C 1-3 alkyl, -C(O)NR a0 R b0 , -C(O)OC 1-3 alkyl, -OC( O) C 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy and 3 to 6 membered heterocycloalkyl;
化学键
Figure PCTCN2022130850-appb-000002
代表单键或双键； chemical bond
Figure PCTCN2022130850-appb-000002
represents a single or double bond;
环A为苯环或5至6元杂芳环；所述环A为未取代的或被1、2或3个各自独立地选自下组的取代基取代：氰基、硝基、羟基、羧基、卤素(优选为氟或氯)、C 1-8烷基(优选为C 1-6烷基，更优选为C 1- 3烷基)、C 3-8环烷基(优选为C 3-6环烷基)、C 1-8烷氧基(优选为C 1-6烷氧基，更优选为C 1-3烷氧基)、-C(O)C 1-8烷基(优选为-C(O)C 1-6烷基，更优选为-C(O)C 1-3烷基)、-C(O)OC 1-8烷基(优选为-C(O)OC 1-6烷基，更优选为-C(O)OC 1-3烷基)、-OC(O)C 1-8烷基(优选为-OC(O)C 1-6烷基，更优选为-OC(O)C 1-3烷基)、-SO 2C 1-8烷基(优选为-SO 2C 1-6烷基，更优选为-SO 2C 1-3烷基)和-C(O)NR a0R b0；其中所述C 1-8烷基、C 3- 6环烷基、C 1-8烷氧基为未取代的或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素、氰基、硝基、羟基、羧基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-NR a1R b1、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR a0R b0、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基和3至6元杂环烷基； Ring A is a benzene ring or a 5- to 6-membered heteroaromatic ring; said ring A is unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of cyano, nitro, hydroxyl, Carboxyl, halogen (preferably fluorine or chlorine), C 1-8 alkyl ( preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 3-8 cycloalkyl (preferably C 3 -6 cycloalkyl), C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), -C (O) C 1-8 alkyl (preferably -C(O)C 1-6 alkyl, more preferably -C(O)C 1-3 alkyl), -C(O)OC 1-8 alkyl (preferably -C(O)OC 1 -6 alkyl, more preferably -C(O)OC 1-3 alkyl), -OC(O)C 1-8 alkyl (preferably -OC(O)C 1-6 alkyl, more preferably -OC(O)C 1-3 alkyl), -SO 2 C 1-8 alkyl (preferably -SO 2 C 1-6 alkyl, more preferably -SO 2 C 1-3 alkyl) and - C(O) NR a0 R b0 ; wherein the C 1-8 alkyl, C 3-6 cycloalkyl, C 1-8 alkoxy are unsubstituted or independently selected by 1, 2 or 3 Substituents from the following group: deuterium, halogen, cyano, nitro, hydroxyl, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl , Halogenated C 1-3 alkyl, Halogenated C 1-3 alkoxy, -NR a1 R b1 , -SO 2 C 1-3 alkyl, -S(O)C 1-3 alkyl, -C (O)NR a0 R b0 , -C(O)OC 1-3 alkyl, -OC(O)C 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy and 3 to 6 membered heterocycloalkyl;
R 3、和R 4各自独立地为氢、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、C 3-6环烷基、-C(O)OC 1- 8烷基(优选为-C(O)OC 1-6烷基，更优选为-C(O)OC 1-3烷基)或-C(O)C 1-8烷基(优选为-C(O)C 1-6烷基，更优选为-C(O)C 1-3烷基)；或者R 3、R 4与相连接的氮原子共同形成3至7元饱和或部分不饱和单杂环；其中所述C 1-8烷基、C 3-6环烷基、3至7元饱和或部分不饱和单杂环为未取代的或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素、氰基、硝基、羟基、羧基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-NR a1R b1、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR a0R b0、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基和3至6元杂环烷基； R 3 , and R 4 are each independently hydrogen, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 3-6 cycloalkyl, -C( O)OC 1-8 alkyl (preferably -C(O)OC 1-6 alkyl, more preferably -C(O) OC 1-3 alkyl) or -C(O)C 1-8 alkyl (preferably -C(O)C 1-6 alkyl, more preferably -C(O)C 1-3 alkyl); or R 3 , R 4 and the connected nitrogen atom together form a 3- to 7-membered saturated or partially unsaturated monoheterocycle; wherein said C 1-8 alkyl, C 3-6 cycloalkyl, 3 to 7 membered saturated or partially unsaturated monoheterocycle is unsubstituted or replaced by 1, 2 or 3 Each substituent independently selected from the following group is substituted: deuterium, halogen, cyano, nitro, hydroxyl, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2 -4 alkynyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, -NR a1 R b1 , -SO 2 C 1-3 alkyl, -S(O)C 1-3 alkane group, -C(O)NR a0 R b0 , -C(O)OC 1-3 alkyl, -OC(O)C 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkane Baseoxy and 3 to 6 membered heterocycloalkyl;
R a0、和R b0各自独立地为氢、C 1-3烷基或乙酰基；或者R a0、R b0与相连的氮原子共同形成4至6元饱和单杂环；所述4至6元饱和单杂环为未取代的或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素、氰基、硝基、羟基、羧基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NH 2、-C(O)NH(C 1-3烷基)、-C(O)N(C 1-3烷基) 2、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基和3至6元杂环烷基；以及 R a0 , and R b0 are each independently hydrogen, C 1-3 alkyl or acetyl; or R a0 , R b0 and the connected nitrogen atom together form a 4 to 6-membered saturated monoheterocyclic ring; the 4 to 6-membered The saturated monoheterocycle is unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen, cyano, nitro, hydroxyl, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, -SO 2 C 1-3 alkyl, -S(O)C 1-3 alkyl, -C(O)NH 2 , -C(O)NH(C 1-3 alkyl), -C(O)N(C 1-3 alkyl) 2 , -C(O)OC 1-3 alkyl, -OC(O)C 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy and 3 to 6 membered heterocycloalkane base; and
R a1、和R b1各自独立地为氢、C 1-3烷基、卤代C 1-3烷基或乙酰基；或者R a1、R b1与相连的氮原子共同形成4至6元饱和单杂环；所述4至6元饱和单杂环为未取代的或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素、氰基、硝基、羟基、羧基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NH 2、-C(O)NH(C 1-3烷基)、-C(O)N(C 1-3烷基) 2、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基和3至6元杂环烷基。 R a1 , and R b1 are each independently hydrogen, C 1-3 alkyl, halogenated C 1-3 alkyl or acetyl; or R a1 , R b1 and the connected nitrogen atom together form a 4 to 6-membered saturated unit Heterocycle; the 4- to 6-membered saturated monoheterocycle is unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen, cyano, nitro, hydroxyl, carboxyl , C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, - SO 2 C 1-3 alkyl, -S(O)C 1-3 alkyl, -C(O)NH 2 , -C(O)NH(C 1-3 alkyl), -C(O)N (C 1-3 alkyl) 2 , -C(O)OC 1-3 alkyl, -OC(O)C 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy and 3 to 6 membered heterocycloalkyl groups.
在一些实施例中，S 1为C；以及S 2为C。 In some embodiments, S 1 is C; and S 2 is C.
在一些实施例中，S 1为N或C；以及S 2为C。 In some embodiments, S 1 is N or C; and S 2 is C.
在一些实施例中，S 1为C；以及S 2为N或C。 In some embodiments, S 1 is C; and S 2 is N or C.
在一些实施例中，Z 1为N或CR Z1；Z 2为CR Z2；Z 3为N或CR Z3；以及Z 4为CR Z4。 In some embodiments, Z 1 is N or CR Z1 ; Z 2 is CR Z2 ; Z 3 is N or CR Z3 ; and Z 4 is CR Z4 .
在一些实施例中，Z 1为CR Z1；Z 2为CR Z2；Z 3为CR Z3；以及Z 4为CR Z4。 In some embodiments, Z 1 is CR Z1 ; Z 2 is CR Z2 ; Z 3 is CR Z3 ; and Z 4 is CR Z4 .
在一些实施例中，Z 1为N；Z 2为CR Z2；Z 3为CR Z3；以及Z 4为CR Z4。 In some embodiments, Z 1 is N; Z 2 is CR Z2 ; Z 3 is CR Z3 ; and Z 4 is CR Z4 .
在一些实施例中，Z 1为CR Z1；Z 2为CR Z2；Z 3为N；以及Z 4为CR Z4。 In some embodiments, Z 1 is CR Z1 ; Z 2 is CR Z2 ; Z 3 is N; and Z 4 is CR Z4 .
在一些实施例中，Z 1为N；Z 2为CR Z2；Z 3为N；以及Z 4为CR Z4。 In some embodiments, Z 1 is N; Z 2 is CR Z2 ; Z 3 is N; and Z 4 is CR Z4 .
在一些实施例中，Z 4为CH。 In some embodiments, Z4 is CH.
进一步地，Z 1为N或CH；Z 2为CR Z2；Z 3为N或CH；以及Z 4为CH。 Further, Z 1 is N or CH; Z 2 is CR Z2 ; Z 3 is N or CH; and Z 4 is CH.
更进一步地，Z 1为N或CH；Z 2为CR Z2；Z 3为CH；以及Z 4为CH。 Further, Z 1 is N or CH; Z 2 is CR Z2 ; Z 3 is CH; and Z 4 is CH.
在一些实施例中，Z 1为N，Z 2为CR Z2，Z 3为CR Z3，以及Z 4为CR Z4；或者Z 1为CR Z1，Z 2为CR Z2，Z 3为CR Z3，以及Z 4为CR Z4；或者Z 1为N，Z 2为CR Z2，Z 3为N，以及Z 4为CR Z4；或者Z 1为CH，Z 2为CR Z2，Z 3为N，以及Z 4为CR Z4。 In some embodiments, Z 1 is N, Z 2 is CR Z2 , Z 3 is CR Z3 , and Z 4 is CR Z4 ; or Z 1 is CR Z1 , Z 2 is CR Z2 , Z 3 is CR Z3 , and Z 4 is CR Z4 ; or Z 1 is N, Z 2 is CR Z2 , Z 3 is N, and Z 4 is CR Z4 ; or Z 1 is CH, Z 2 is CR Z2 , Z 3 is N, and Z 4 for CR Z4 .
在一些实施例中，Z 1为N，Z 2为CR Z2，Z 3为CH，以及Z 4为CH；或者Z 1为CH，Z 2为CR Z2，Z 3为CR Z3，以及Z 4为CR Z4；或者Z 1为N，Z 2为CR Z2，Z 3为N，以及Z 4为CH；或者Z 1为CH，Z 2为CR Z2，Z 3为N，以及Z 4为CH。 In some embodiments, Z 1 is N, Z 2 is CR Z2 , Z 3 is CH, and Z 4 is CH; or Z 1 is CH, Z 2 is CR Z2 , Z 3 is CR Z3 , and Z 4 is CR Z4 ; or Z 1 is N, Z 2 is CR Z2 , Z 3 is N, and Z 4 is CH; or Z 1 is CH, Z 2 is CR Z2 , Z 3 is N, and Z 4 is CH.
在一些实施例中，R Z1、R Z2、R Z3、和R Z4各自独立地为氢、氰基、卤素(优选为氟或氯)、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、C 3-8环烷基(优选为C 3-6环烷基)、卤代C 1-8烷基(优选为卤代C 1-6烷基，更优选为卤代C 1-3烷基)、C 1-8烷氧基(优选为C 1-6烷氧基，更优选为C 1-3烷氧基)、卤代C 1- 8烷氧基(优选为卤代C 1-6烷氧基，更优选为卤代C 1-3烷氧基)或-NR a1R b1；其中所述C 1-8烷基、C 3-8环烷基各自独立地为未取代的或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素、氰基、硝基、羟基、羧基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-NR a1R b1、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR a0R b0、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基和3至6元杂环烷基。 In some embodiments, R Z1 , R Z2 , R Z3 , and R Z4 are each independently hydrogen, cyano, halogen (preferably fluorine or chlorine), C 1-8 alkyl (preferably C 1-6 alkane group, more preferably C 1-3 alkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), halogenated C 1-8 alkyl (preferably halogenated C 1-6 alkane group, more preferably halogenated C 1-3 alkyl), C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), halogenated C 1- 8 alkoxy (preferably halogenated C 1-6 alkoxy, more preferably halogenated C 1-3 alkoxy) or -NR a1 R b1 ; wherein the C 1-8 alkyl, C 3- 8 Cycloalkyl groups are each independently unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen, cyano, nitro, hydroxyl, carboxyl, C 1-3 alkane Base, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, -NR a1 R b1 , - SO 2 C 1-3 alkyl, -S(O)C 1-3 alkyl, -C(O)NR a0 R b0 , -C(O)OC 1-3 alkyl, -OC(O)C 1 -3 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy and 3 to 6 membered heterocycloalkyl.
在一些实施例中，R Z1为氢。 In some embodiments, R Z1 is hydrogen.
在一些实施例中，R Z2为氰基、卤素(优选为氟或氯)、C 1-3烷基(优选为甲基)、C 3-6环烷基(优选为环丙基)、卤代C 1-3烷基(优选为氟代C 1-3烷基，更优选为一氟甲基、一氟乙基、二氟甲基、二氟乙基、三氟甲基、三氟乙基或五氟乙基)、C 1-3烷氧基(优选为甲氧基或乙氧基)、卤代C 1-3烷氧基(优选为二氟甲氧基或三氟甲氧基)、卤素取代的C 3-6环烷基或-NR a1R b1；以及R a1、R b1各自独立地为氢、C 1-3烷基、卤代C 1-3烷基或乙酰基。 In some embodiments, R Z2 is cyano, halogen (preferably fluorine or chlorine), C 1-3 alkyl (preferably methyl), C 3-6 cycloalkyl (preferably cyclopropyl), halogen C 1-3 alkyl (preferably fluoro C 1-3 alkyl, more preferably monofluoromethyl, monofluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl or pentafluoroethyl), C 1-3 alkoxy (preferably methoxy or ethoxy), halogenated C 1-3 alkoxy (preferably difluoromethoxy or trifluoromethoxy ), halogen-substituted C 3-6 cycloalkyl or -NR a1 R b1 ; and R a1 , R b1 are each independently hydrogen, C 1-3 alkyl, halogenated C 1-3 alkyl or acetyl.
在一些实施例中，R Z3为氢、氰基或卤素(优选为氟或氯)。进一步地，R Z3为氢。 In some embodiments, R Z3 is hydrogen, cyano, or halo (preferably fluoro or chloro). Further, R Z3 is hydrogen.
在一些实施例中，R Z4为氢或卤素(优选为氟或氯)。进一步地，R Z4为氢。 In some embodiments, R Z4 is hydrogen or halo (preferably fluoro or chloro). Further, R Z4 is hydrogen.
在一些实施例中，R Z1、R Z2、R Z3、R Z4各自独立地选自由以下组成的组：氢、甲基、乙基、甲氧基、乙氧基、-NH-CH 2-CF 3和环丙基。 In some embodiments, R Z1 , R Z2 , R Z3 , R Z4 are each independently selected from the group consisting of hydrogen, methyl, ethyl, methoxy, ethoxy, -NH-CH 2 -CF 3 and cyclopropyl.
在一些实施例中，Z 1为CH；Z 2为CR Z2；Z 3为CH；Z 4为CH；以及R Z2为三氟甲基。 In some embodiments, Z 1 is CH; Z 2 is CR Z2 ; Z 3 is CH; Z 4 is CH; and R Z2 is trifluoromethyl.
在一些实施例中，R 3、R 4与相连接的氮原子共同形成的3至7元饱和或部分不饱和单杂环选自：氮杂环丁烷、四氢吡咯环、哌啶环、哌嗪环、吗啉环、硫代吗啉环、氮杂环丁烷-2-酮环、吡咯烷-2-酮环、吡咯烷-2,5-二酮环、哌啶-2-酮环、哌嗪-2-酮环和吗啉-3-酮环。 In some embodiments, the 3-7 membered saturated or partially unsaturated monoheterocyclic ring formed by R 3 , R 4 and the connected nitrogen atom is selected from: azetidine, tetrahydropyrrole ring, piperidine ring, Piperazine ring, morpholine ring, thiomorpholine ring, azetidin-2-one ring, pyrrolidin-2-one ring, pyrrolidine-2,5-dione ring, piperidin-2-one ring, piperazin-2-one ring and morpholin-3-one ring.
在一些实施例中，R 4为氢或甲基；R 3为氢、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、C 3-6环烷基、-C(O)OC 1-8烷基(优选为-C(O)OC 1-6烷基，更优选为-C(O)OC 1-3烷基)或-C(O)C 1-8烷基(优选为-C(O)C 1-6烷基，更优选为-C(O)C 1-3烷基)；其中所述C 1-8烷基、C 3-6环烷基为未取代的或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素(优选为氟)、氰基、硝基、羟基、羧基、C 1-3烷基、C 1- 3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-NR a1R b1、-SO2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR a0R b0、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基和3至6元杂环烷基。 In some embodiments, R 4 is hydrogen or methyl; R 3 is hydrogen, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 3-6 Cycloalkyl, -C(O)OC 1-8 alkyl (preferably -C(O)OC 1-6 alkyl, more preferably -C(O)OC 1-3 alkyl) or -C(O )C 1-8 alkyl (preferably -C(O)C 1-6 alkyl, more preferably -C(O)C 1-3 alkyl); wherein the C 1-8 alkyl, C 3 -6 cycloalkyl is unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen (preferably fluorine), cyano, nitro, hydroxyl, carboxyl, C -3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, -NR a1 R b1 , -SO2C 1-3 alkyl, -S(O)C 1-3 alkyl, -C(O)NR a0 R b0 , -C(O)OC 1-3 alkyl, -OC(O)C 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy and 3 to 6 membered heterocycloalkyl.
在一些实施例中，R 4为氢；R 3为C 1-3烷基(优选为甲基或乙基)；其中所述C 1-3烷基(优选为甲基或乙基)为未取代的或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素(优选为氟)。 In some embodiments, R 4 is hydrogen; R 3 is C 1-3 alkyl (preferably methyl or ethyl); wherein said C 1-3 alkyl (preferably methyl or ethyl) is Substituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen (preferably fluorine).
在一些实施例中，R 4为氢或甲基；R 3为甲基、-CD 3、或选自以下基团： In some embodiments, R 4 is hydrogen or methyl; R 3 is methyl, -CD 3 , or is selected from the following groups:
Figure PCTCN2022130850-appb-000003
Figure PCTCN2022130850-appb-000003
在一些实施例中，所述环A是苯环或5至6元杂芳基环，且所述5至6元杂芳基环选自以下组成的组：噻吩环、呋喃环、噻唑环、异噻唑环、咪唑环、噁唑环、吡咯环、吡唑环、三唑环、1,2,3-三唑环、1,2,4-三唑环、1,2,5-三唑环、1,3,4-三唑环、四唑环、异噁唑环、噁二唑环、1,2,3-噁二唑环、1,2,4-噁二唑环、1,2,5-噁二唑环、1,3,4-噁二唑环、噻二唑环、吡啶环、哒嗪环、嘧啶环、吡嗪环、三嗪环和四嗪环。In some embodiments, the ring A is a benzene ring or a 5-6 membered heteroaryl ring, and the 5-6 membered heteroaryl ring is selected from the group consisting of a thiophene ring, a furan ring, a thiazole ring, Isothiazole ring, imidazole ring, oxazole ring, pyrrole ring, pyrazole ring, triazole ring, 1,2,3-triazole ring, 1,2,4-triazole ring, 1,2,5-triazole ring ring, 1,3,4-triazole ring, tetrazole ring, isoxazole ring, oxadiazole ring, 1,2,3-oxadiazole ring, 1,2,4-oxadiazole ring, 1, 2,5-oxadiazole ring, 1,3,4-oxadiazole ring, thiadiazole ring, pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring, triazine ring, and tetrazine ring.
在一些实施例中，环A为未取代的。In some embodiments, Ring A is unsubstituted.
在一些实施例中，
Figure PCTCN2022130850-appb-000004
为
Figure PCTCN2022130850-appb-000005
In some embodiments,
Figure PCTCN2022130850-appb-000004
for
Figure PCTCN2022130850-appb-000005
在一些实施例中，所述化合物结构如式(Ia)或式(Ib)所示：In some embodiments, the structure of the compound is shown in formula (Ia) or formula (Ib):
Figure PCTCN2022130850-appb-000006
Figure PCTCN2022130850-appb-000006
在一些实施例中，所述化合物结构如式(I-1)所示：In some embodiments, the structure of the compound is shown in formula (I-1):
Figure PCTCN2022130850-appb-000007
Figure PCTCN2022130850-appb-000007
其中，L为-(CR q1R q2) m-、-(CR q3R q4) t1-O-(CR q5R q6) t2-、或-(CR q7R q8) t3-NR q0-(CR q9R q10) t4-； Among them, L is -(CR q1 R q2 ) m -, -(CR q3 R q4 ) t1 -O-(CR q5 R q6 ) t2 -, or -(CR q7 R q8 ) t3 -NR q0 -(CR q9 R q10 ) t4 -;
m为1、2、3或4；m is 1, 2, 3 or 4;
t1、t2、t3、和t4各自独立地为0、1、2或3；其中t1、和t2不同时为0；且t3、和t4不同时为0；t1, t2, t3, and t4 are each independently 0, 1, 2 or 3; wherein t1, and t2 are not 0 at the same time; and t3, and t4 are not 0 at the same time;
R q1、和R q2各自独立地为氢、卤素(优选为氟或氯)、氰基、硝基、羟基、羧基、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、C 3-8环烷基(优选为C 3-6环烷基)、卤代C 1-8烷基(优选为卤代C 1-6烷基，更优选为卤代C 1-3烷基)、C 1-8烷氧基(优选为C 1-6烷氧基，更优选为C 1-3烷氧基)、卤代C 1-8烷氧基(优选为卤代C 1-6烷氧基，更优选为卤代C 1-3烷氧基)、-C(O)NR a0R b0、-C(O)C 1-8烷基(优选为-C(O)C 1-6烷基，更优选为-C(O)C 1-3烷基)或-C(O)OC 1-8烷基(优选为-C(O)OC 1-6烷基，更优选为-C(O)OC 1-3烷基)；或者R q1、R q2与相连接的碳原子共同形成3至7元饱和或部分不饱和单环或3至7元饱和或部分不饱和单杂环；其中所述C 1-8烷基、C 3-6环烷基、卤代C 1-8烷基、C 1-8烷氧基、卤代C 1-8烷氧基、3至7元饱和或部分不饱和单环、3至7元饱和或部分不饱和单杂环为未取代的或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素、氰基、硝基、羟基、羧基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-NR a1R b1、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR a0R b0、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基和3至6元杂环烷基； R q1 and R q2 are each independently hydrogen, halogen (preferably fluorine or chlorine), cyano, nitro, hydroxyl, carboxyl, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), halogenated C 1-8 alkyl (preferably halogenated C 1-6 alkyl, more preferably Halogenated C 1-3 alkyl), C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), halogenated C 1-8 alkoxy ( Preferred is halogenated C 1-6 alkoxy, more preferably halogenated C 1-3 alkoxy), -C(O)NR a0 R b0 , -C(O)C 1-8 alkyl (preferably -C(O)C 1-6 alkyl, more preferably -C(O)C 1-3 alkyl) or -C(O)OC 1-8 alkyl (preferably -C(O)OC 1- 6 alkyl, more preferably -C(O)OC 1-3 alkyl); or R q1 , R q2 together with the connected carbon atoms form a 3-7 membered saturated or partially unsaturated monocyclic ring or a 3-7 membered Saturated or partially unsaturated monoheterocycle; wherein said C 1-8 alkyl, C 3-6 cycloalkyl, halogenated C 1-8 alkyl, C 1-8 alkoxy, halogenated C 1-8 Alkoxy, 3 to 7-membered saturated or partially unsaturated monocyclic ring, 3 to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring are unsubstituted or 1, 2 or 3 substituents independently selected from the following group Substitution: deuterium, halogen, cyano, nitro, hydroxyl, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 1- 3 alkyl, halogenated C 1-3 alkoxy, -NR a1 R b1 , -SO 2 C 1-3 alkyl, -S(O)C 1-3 alkyl, -C(O)NR a0 R b0 , -C(O)OC 1-3 alkyl, -OC(O)C 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy and 3 to 6 membered heterocycle alkyl;
R q3、R q4、R q5、R q6、R q7、R q8、R q9、和R q10各自独立地为氢、卤素(优选为氟或氯)、氰基、硝基、羟基、羧基、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、C 3-8环烷基(优选为C 3-6环烷基)、卤代C 1-8烷基(优选为卤代C 1-6烷基，更优选为卤代C 1-3烷基)、C 1-8烷氧基(优选为C 1-6烷氧基，更优选为C 1- 3烷氧基)、卤代C 1-8烷氧基(优选为卤代C 1-6烷氧基，更优选为卤代C 1-3烷氧基)、-C(O)NR a0R b0、-C(O)C 1- 8烷基(优选为-C(O)C 1-6烷基，更优选为-C(O)C 1-3烷基)或-C(O)OC 1-8烷基(优选为-C(O)OC 1-6烷基，更优选为-C(O)OC 1-3烷基)；以及 R q3 , R q4 , R q5 , R q6 , R q7 , R q8 , R q9 , and R q10 are each independently hydrogen, halogen (preferably fluorine or chlorine), cyano, nitro, hydroxyl, carboxyl, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), halogenated C 1- 8 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), halogenated C 1-8 alkoxy (preferably halogenated C 1-6 alkoxy, more preferably halogenated C 1-3 alkoxy), -C(O ) NR a0 R b0 , -C(O)C 1- 8 alkyl (preferably -C(O)C 1-6 alkyl, more preferably -C(O)C 1-3 alkyl) or -C(O ) OC1-8alkyl (preferably -C(O) OC1-6alkyl , more preferably -C(O) OC1-3alkyl ); and
R q0为氢、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、C 3-8环烷基(优选为C 3-6环烷基)、-C(O)NR a0R b0、-C(O)C 1-8烷基(优选为-C(O)C 1-6烷基，更优选为-C(O)C 1-3烷基)或-SO 2C 1-8烷基(优选为-SO 2C 1-6烷基，更优选为-SO 2C 1-3烷基)；其中所述C 1-8烷基、C 3-8环烷基为未取代的或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素、氰基、硝基、羟基、羧基、C 1-3烷基、C 1-3烷氧基、C 2- 4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-NR a1R b1、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR a0R b0、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基和3至6元杂环烷基；以及 R q0 is hydrogen, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl) , -C(O)NR a0 R b0 , -C(O)C 1-8 alkyl (preferably -C(O)C 1-6 alkyl, more preferably -C(O)C 1-3 alkane base) or -SO 2 C 1-8 alkyl (preferably -SO 2 C 1-6 alkyl, more preferably -SO 2 C 1-3 alkyl); wherein the C 1-8 alkyl, C 3-8 cycloalkyl is unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen, cyano, nitro, hydroxyl, carboxyl, C 1-3 alkyl , C 1-3 alkoxy, C 2- 4 alkenyl, C 2-4 alkynyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, -NR a1 R b1 , -SO 2 C 1-3 alkyl, -S(O)C 1-3 alkyl, -C(O)NR a0 R b0 , -C(O)OC 1-3 alkyl, -OC(O)C 1- 3 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy and 3 to 6 membered heterocycloalkyl; and
Z 1、Z 2、Z 3、Z 4、R 3、R 4、S 1、S 2、和环A基团如上述说明书中所定义。 Z 1 , Z 2 , Z 3 , Z 4 , R 3 , R 4 , S 1 , S 2 , and ring A groups are as defined in the above specification.
在一些实施例中，t1为0；且t2为1、2或3。In some embodiments, t1 is 0; and t2 is 1, 2 or 3.
在一些实施例中，t3为0；且t4为1、2或3。In some embodiments, t3 is 0; and t4 is 1, 2 or 3.
在一些实施例中，R q1、和R q2各自独立地为氢；且m为2、3或4。 In some embodiments, R q1 , and R q2 are each independently hydrogen; and m is 2, 3, or 4.
在一些实施例中，R q1、R q2与相连接的碳原子共同形成的3至7元饱和或部分不饱和单环为3至6元饱和单环；并且可以选自由以下组成的组：环丙基环、环丁基环、环戊基环和环己基环。 In some embodiments, the 3-7 membered saturated or partially unsaturated monocyclic ring formed by R q1 , R q2 and the connected carbon atoms is a 3-6 membered saturated monocyclic ring; and may be selected from the group consisting of: Propyl ring, cyclobutyl ring, cyclopentyl ring and cyclohexyl ring.
在一些实施例中，R q1、R q2与相连接的碳原子共同形成的3至7元饱和或部分不饱和单杂环为4至6元饱和或部分不饱和单杂环；并且可以选自由以下组成的组：氮杂环丁烷、氧杂环丁烷、四氢呋喃环、四氢噻吩环、四氢吡咯环、哌啶环、哌嗪环、吗啉环、硫代吗啉环、硫代吗啉-1,1-二氧化物和四氢吡喃环。 In some embodiments, the 3-7 membered saturated or partially unsaturated monoheterocyclic ring formed by R q1 , R q2 and the connected carbon atoms is a 4-6 membered saturated or partially unsaturated monoheterocyclic ring; and may be selected from The group consisting of: azetidine, oxetane, tetrahydrofuran ring, tetrahydrothiophene ring, tetrahydropyrrole ring, piperidine ring, piperazine ring, morpholine ring, thiomorpholine ring, thio Morpholine-1,1-dioxide and tetrahydropyran ring.
在一些实施例中，L为-(CH 2) m-，并且m为2或3。 In some embodiments, L is -(CH 2 ) m - and m is 2 or 3.
在一些实施例中，基团
Figure PCTCN2022130850-appb-000008
选自由以下组成的组： In some embodiments, the group
Figure PCTCN2022130850-appb-000008
Selected from the group consisting of:
Figure PCTCN2022130850-appb-000009
Figure PCTCN2022130850-appb-000009
在一些实施例中，基团
Figure PCTCN2022130850-appb-000010
选自由以下组成的组： In some embodiments, the group
Figure PCTCN2022130850-appb-000010
Selected from the group consisting of:
Figure PCTCN2022130850-appb-000011
Figure PCTCN2022130850-appb-000011
Figure PCTCN2022130850-appb-000012
Figure PCTCN2022130850-appb-000012
在一些实施例中，所述化合物结构如式(I-1a)或式(I-1b)所示：In some embodiments, the structure of the compound is shown in formula (I-1a) or formula (I-1b):
Figure PCTCN2022130850-appb-000013
Figure PCTCN2022130850-appb-000013
在一些实施例中，所述化合物结构如式(I-2)所示：In some embodiments, the structure of the compound is shown in formula (I-2):
Figure PCTCN2022130850-appb-000014
Figure PCTCN2022130850-appb-000014
其中，Z 5为N或CR Z5；Z 6为N或CR Z6；Z 7为N或CR Z7；且Z 8为N或CR Z8； Wherein, Z 5 is N or CR Z5 ; Z 6 is N or CR Z6 ; Z 7 is N or CR Z7 ; and Z 8 is N or CR Z8 ;
R Z5、R Z6、R Z7和R Z8各自独立地为氢、氰基、硝基、羟基、羧基、卤素(优选为氟或氯)、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、C 3-8环烷基(优选为C 3-6环烷基)、卤代C 1-8烷基(优选为卤代C 1-6烷基，更优选为卤代C 1-3烷基)、C 1-8烷氧基(优选为C 1-6烷氧基，更优选为C 1-3烷氧基)、卤代C 1- 8烷氧基(优选为卤代C 1-6烷氧基，更优选为卤代C 1-3烷氧基)、-C(O)C 1-8烷基(优选为-C(O)C 1-6烷基，更优选为-C(O)C 1-3烷基)、-C(O)OC 1-8烷基(优选为-C(O)OC 1-6烷基，更优选为-C(O)OC 1-3烷基)、-SO 2C 1- 8烷基(优选为-SO 2C 1-6烷基，更优选为-SO 2C 1-3烷基)、-C(O)NR a0R b0、-NR a1R b1、5至6元杂芳基或8至10元杂芳基；其中所述C 1-8烷基、C 3-8环烷基、卤代C 1-8烷基、C 1-8烷氧基、卤代C 1-8烷氧基为未取代的或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素、氰基、硝基、羟基、羧基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-NR a1R b1、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR a0R b0、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基、3至6元杂环烷基、苯基和5至6元杂芳基；以及 R Z5 , R Z6 , R Z7 and R Z8 are each independently hydrogen, cyano, nitro, hydroxyl, carboxyl, halogen (preferably fluorine or chlorine), C 1-8 alkyl (preferably C 1-6 alkane group, more preferably C 1-3 alkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), halogenated C 1-8 alkyl (preferably halogenated C 1-6 alkane group, more preferably halogenated C 1-3 alkyl), C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), halogenated C 1- 8 alkoxy (preferably halogenated C 1-6 alkoxy, more preferably halogenated C 1-3 alkoxy), -C (O) C 1-8 alkyl (preferably -C (O) C 1-6 alkyl, more preferably -C(O)C 1-3 alkyl), -C(O)OC 1-8 alkyl (preferably -C(O)OC 1-6 alkyl, more preferably Preferably -C(O)OC 1-3 alkyl), -SO 2 C 1-8 alkyl (preferably -SO 2 C 1-6 alkyl, more preferably -SO 2 C 1-3 alkyl) , -C(O)NR a0 R b0 , -NR a1 R b1 , 5 to 6-membered heteroaryl or 8 to 10-membered heteroaryl; wherein the C 1-8 alkyl, C 3-8 cycloalkyl , halogenated C 1-8 alkyl, C 1-8 alkoxy, halogenated C 1-8 alkoxy are unsubstituted or substituted by 1, 2 or 3 substituents independently selected from the following group : Deuterium, halogen, cyano, nitro, hydroxyl, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 1-3 Alkyl, halogenated C 1-3 alkoxy, -NR a1 R b1 , -SO 2 C 1-3 alkyl, -S(O)C 1-3 alkyl, -C(O)NR a0 R b0 , -C(O)OC 1-3 alkyl, -OC(O)C 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy, 3 to 6 membered heterocycloalkane radical, phenyl and 5 to 6 membered heteroaryl; and
Z 1、Z 2、Z 3、Z 4、R 3、R 4、和L基团如上述说明书中所定义。 The Z 1 , Z 2 , Z 3 , Z 4 , R 3 , R 4 , and L groups are as defined in the above specification.
在一些实施例中，Z 5为N或CR Z5；Z 6为CR Z6；Z 7为CR Z7；且Z 8为CR Z8。 In some embodiments, Z 5 is N or CR Z5 ; Z 6 is CR Z6 ; Z 7 is CR Z7 ; and Z 8 is CR Z8 .
在一些实施例中，Z 5为N；Z 6为CR Z6；Z 7为CR Z7；且Z 8为CR Z8。 In some embodiments, Z 5 is N; Z 6 is CR Z6 ; Z 7 is CR Z7 ; and Z 8 is CR Z8 .
在一些实施例中，Z 5为CR Z5；Z 6为CR Z6；Z 7为CR Z7；且Z 8为CR Z8。 In some embodiments, Z 5 is CR Z5 ; Z 6 is CR Z6 ; Z 7 is CR Z7 ; and Z 8 is CR Z8 .
在一些实施例中，Z 5为CR Z5；Z 6为CR Z6；Z 7为CR Z7；且Z 8为N。 In some embodiments, Z 5 is CR Z5 ; Z 6 is CR Z6 ; Z 7 is CR Z7 ; and Z 8 is N.
在一些实施例中，Z 7为CH。 In some embodiments, Z7 is CH.
在一些实施例中，R Z5、R Z6、R Z7和R Z8各自独立地为氢或卤素。进一步地，R Z5、R Z6、R Z7和R Z8均为氢。 In some embodiments, R Z5 , R Z6 , R Z7 , and R Z8 are each independently hydrogen or halogen. Further, R Z5 , R Z6 , R Z7 and R Z8 are all hydrogen.
在一些实施例中，Z 5为N；Z 6为CH；Z 7为CH；且Z 8为CH。 In some embodiments, Z5 is N; Z6 is CH; Z7 is CH; and Z8 is CH.
在一些实施例中，所述化合物结构如式(I-2a)或式(I-2b)所示：In some embodiments, the structure of the compound is shown in formula (I-2a) or formula (I-2b):
Figure PCTCN2022130850-appb-000015
Figure PCTCN2022130850-appb-000015
在一些实施例中，所述化合物选自由以下组成的组：In some embodiments, the compound is selected from the group consisting of:
Figure PCTCN2022130850-appb-000016
Figure PCTCN2022130850-appb-000016
Figure PCTCN2022130850-appb-000017
Figure PCTCN2022130850-appb-000017
Figure PCTCN2022130850-appb-000018
Figure PCTCN2022130850-appb-000018
Figure PCTCN2022130850-appb-000019
Figure PCTCN2022130850-appb-000019
在一些实施例中，所述化合物选自由以下组成的组：In some embodiments, the compound is selected from the group consisting of:
Figure PCTCN2022130850-appb-000020
Figure PCTCN2022130850-appb-000020
Figure PCTCN2022130850-appb-000021
Figure PCTCN2022130850-appb-000021
Figure PCTCN2022130850-appb-000022
Figure PCTCN2022130850-appb-000022
Figure PCTCN2022130850-appb-000023
Figure PCTCN2022130850-appb-000023
Figure PCTCN2022130850-appb-000024
Figure PCTCN2022130850-appb-000024
Figure PCTCN2022130850-appb-000025
Figure PCTCN2022130850-appb-000025
本申请第二方面提供一种式(II)所示的化合物、其药学上可接受的盐或其立体异构体：The second aspect of the present application provides a compound represented by formula (II), its pharmaceutically acceptable salt or its stereoisomer:
Figure PCTCN2022130850-appb-000026
Figure PCTCN2022130850-appb-000026
其中，S 1’和S 2’代表环A’上的环原子；S 1’为N或C；且S 2’为N或C； Wherein, S 1' and S 2' represent ring atoms on ring A'; S 1' is N or C; and S 2' is N or C;
Z 1’为N或CR Z1’；Z 2’为N或CR Z2’；Z 3’为N或CR Z3’；且Z 4’为N或CR Z4’；其中R Z1’、R Z2’、R Z3’、R Z4’各自独立地为氢、氰基、硝基、羟基、羧基、卤素(优选为氟或氯)、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、C 3-8环烷基(优选为C 3-6环烷基)、卤代C 1-8烷基(优选为卤代C 1-6烷基，更优选为卤代C 1-3烷基)、C 1-8烷氧基(优选为C 1-6烷氧基，更优选为C 1-3烷氧基)、卤代C 1-8烷氧基(优选为卤代C 1- 6烷氧基，更优选为卤代C 1-3烷氧基)、-C(O)C 1-8烷基(优选为-C(O)C 1-6烷基，更优选为-C(O)C 1-3烷基)、-C(O)OC 1-8烷基(优选为-C(O)OC 1-6烷基，更优选为-C(O)OC 1-3烷基)、-C(O)NR a0’R b0’或-NR a1’R b1’；其中所述C 1-8烷基、C 3-8环烷基、卤代C 1-8烷基、C 1-8烷氧基、卤代C 1-8烷氧基各自独立地为未取代的或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素、氰基、硝基、羟基、羧基、C 1-3烷基、C 1- 3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-NR a1’R b1’、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR a0’R b0’、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基和3至6元杂 环烷基； Z 1' is N or CR Z1' ; Z 2' is N or CR Z2' ; Z 3' is N or CR Z3' ; and Z 4' is N or CR Z4' ; wherein R Z1' , R Z2' , R Z3' and R Z4' are each independently hydrogen, cyano, nitro, hydroxyl, carboxyl, halogen (preferably fluorine or chlorine), C 1-8 alkyl (preferably C 1-6 alkyl, more preferably is C 1-3 alkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), halogenated C 1-8 alkyl (preferably halogenated C 1-6 alkyl, more preferably is halogenated C 1-3 alkyl), C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), halogenated C 1-8 alkoxy (preferably halogenated C 1-6 alkoxy, more preferably halogenated C 1-3 alkoxy), -C (O)C 1-8 alkyl (preferably -C(O)C 1-6 Alkyl, more preferably -C (O) C 1-3 alkyl), -C (O) OC 1-8 alkyl (preferably -C (O) OC 1-6 alkyl, more preferably -C (O)OC 1-3 alkyl), -C(O)NR a0' R b0' or -NR a1' R b1' ; wherein the C 1-8 alkyl, C 3-8 cycloalkyl, halogen Substituted C 1-8 alkyl, C 1-8 alkoxy, halogenated C 1-8 alkoxy are each independently unsubstituted or replaced by 1, 2 or 3 substituents independently selected from the following group Substitution : deuterium, halogen, cyano, nitro, hydroxyl, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 1- 3 alkyl, halogenated C 1-3 alkoxy, -NR a1' R b1' , -SO 2 C 1-3 alkyl, -S(O)C 1-3 alkyl, -C(O)NR a0' R b0' , -C(O)OC 1-3 alkyl, -OC(O)C 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy and 3 to 6-membered heterocycloalkyl;
L’为-(CR q1’R q2’) m’-、-(CR q3’R q4’) t1’-O-(CR q5’R q6’) t2’-、或-(CR q7’R q8’) t3’-NR q0’-(CR q9’R q10’) t4’-； L' is -(CR q1' R q2' ) m' -, -(CR q3' R q4' ) t1' -O-(CR q5' R q6' ) t2' -, or -(CR q7' R q8 ' ) t3' -NR q0' -(CR q9' R q10' ) t4' -;
m’为1、2、3或4；m' is 1, 2, 3 or 4;
t1’、t2’、t3’、和t4’各自独立地为0、1、2或3；其中t1’、和t2’不同时为0；且t3’、和t4’不同时为0；t1', t2', t3', and t4' are each independently 0, 1, 2 or 3; wherein t1' and t2' are not 0 at the same time; and t3' and t4' are not 0 at the same time;
R q1’、和R q2’各自独立地为氢、卤素(优选为氟或氯)、氰基、硝基、羟基、羧基、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、C 3-8环烷基(优选为C 3-6环烷基)、卤代C 1-8烷基(优选为卤代C 1-6烷基，更优选为卤代C 1-3烷基)、C 1-8烷氧基(优选为C 1-6烷氧基，更优选为C 1-3烷氧基)、卤代C 1-8烷氧基(优选为卤代C 1-6烷氧基，更优选为卤代C 1-3烷氧基)、-C(O)NR a0’R b0’、-C(O)C 1-8烷基(优选为-C(O)C 1-6烷基，更优选为-C(O)C 1-3烷基)或-C(O)OC 1-8烷基(优选为-C(O)OC 1-6烷基，更优选为-C(O)OC 1-3烷基)；或者R q1’、R q2’与相连接的碳原子共同形成3至7元饱和或部分不饱和单环或3至7元饱和或部分不饱和单杂环；其中所述C 1-8烷基、C 3-6环烷基、卤代C 1-8烷基、C 1-8烷氧基、卤代C 1-8烷氧基、3至7元饱和或部分不饱和单环、3至7元饱和或部分不饱和单杂环为未取代的或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素、氰基、硝基、羟基、羧基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-NR a1’R b1’、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR a0’R b0’、-C(O)OC 1- 3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基和3至6元杂环烷基； R q1' and R q2' are each independently hydrogen, halogen (preferably fluorine or chlorine), cyano, nitro, hydroxyl, carboxyl, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), halogenated C 1-8 alkyl (preferably halogenated C 1-6 alkyl, more Preferably halogenated C 1-3 alkyl), C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), halogenated C 1-8 alkoxy group (preferably halogenated C 1-6 alkoxy, more preferably halogenated C 1-3 alkoxy), -C(O)NR a0' R b0' , -C(O)C 1-8 alkoxy group (preferably -C(O)C 1-6 alkyl, more preferably -C(O)C 1-3 alkyl) or -C(O)OC 1-8 alkyl (preferably -C(O) )OC 1-6 alkyl, more preferably -C(O)OC 1-3 alkyl); or R q1' , R q2' and the connected carbon atoms together form a 3 to 7-membered saturated or partially unsaturated unit Ring or 3 to 7 membered saturated or partially unsaturated monoheterocycle; wherein said C 1-8 alkyl, C 3-6 cycloalkyl, halogenated C 1-8 alkyl, C 1-8 alkoxy, Halogenated C 1-8 alkoxy, 3 to 7 membered saturated or partially unsaturated monocyclic ring, 3 to 7 membered saturated or partially unsaturated monoheterocyclic ring are unsubstituted or are independently selected from 1, 2 or 3 Substituents from the following group: deuterium, halogen, cyano, nitro, hydroxyl, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl , Halogenated C 1-3 alkyl, Halogenated C 1-3 alkoxy, -NR a1' R b1' , -SO 2 C 1-3 alkyl, -S(O)C 1-3 alkyl, -C(O)NR a0' R b0' , -C(O)OC 1- 3 alkyl, -OC(O)C 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkane Baseoxy and 3 to 6 membered heterocycloalkyl;
R q3’、R q4’、R q5’、R q6’、R q7’、R q8’、R q9’、和R q10’各自独立地为氢、卤素(优选为氟或氯)、氰基、硝基、羟基、羧基、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、C 3-8环烷基(优选为C 3-6环烷基)、卤代C 1-8烷基(优选为卤代C 1-6烷基，更优选为卤代C 1-3烷基)、C 1-8烷氧基(优选为C 1-6烷氧基，更优选为C 1-3烷氧基)、卤代C 1-8烷氧基(优选为卤代C 1-6烷氧基，更优选为卤代C 1-3烷氧基)、-C(O)NR a0’R b0’、-C(O)C 1-8烷基(优选为-C(O)C 1-6烷基，更优选为-C(O)C 1-3烷基)或-C(O)OC 1-8烷基(优选为-C(O)OC 1- 6烷基，更优选为-C(O)OC 1-3烷基)； R q3' , R q4' , R q5' , R q6' , R q7' , R q8' , R q9' , and R q10' are each independently hydrogen, halogen (preferably fluorine or chlorine), cyano, Nitro, hydroxyl, carboxyl, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkane base), halogenated C 1-8 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), C 1-8 alkoxy (preferably C 1-6 Alkoxy, more preferably C 1-3 alkoxy), halogenated C 1-8 alkoxy (preferably halogenated C 1-6 alkoxy, more preferably halogenated C 1-3 alkoxy ), -C(O)NR a0' R b0' , -C(O)C 1-8 alkyl (preferably -C(O)C 1-6 alkyl, more preferably -C(O)C 1 -3 alkyl) or -C(O ) OC 1-8 alkyl (preferably -C(O)OC 1-6 alkyl, more preferably -C(O)OC 1-3 alkyl);
R q0’为氢、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、C 3-8环烷基(优选为C 3-6环烷基)、-C(O)NR a0’R b0’、-C(O)C 1-8烷基(优选为-C(O)C 1-6烷基，更优选为-C(O)C 1-3烷基)或-SO 2C 1-8烷基(优选为-SO 2C 1-6烷基，更优选为-SO 2C 1-3烷基)；其中所述C 1-8烷基、C 3-8环烷基为未取代的或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素、氰基、硝基、羟基、羧基、C 1-3烷基、C 1-3烷氧基、C 2- 4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-NR a1’R b1’、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR a0’R b0’、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基和3至6元杂环烷基； R q0' is hydrogen, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl ), -C(O)NR a0' R b0' , -C(O)C 1-8 alkyl (preferably -C(O)C 1-6 alkyl, more preferably -C(O)C 1 -3 alkyl) or -SO 2 C 1-8 alkyl (preferably -SO 2 C 1-6 alkyl, more preferably -SO 2 C 1-3 alkyl); wherein the C 1-8 alkyl Group, C 3-8 cycloalkyl is unsubstituted or substituted by 1, 2 or 3 substituents independently selected from the group consisting of deuterium, halogen, cyano, nitro, hydroxyl, carboxyl, C 1- 3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, -NR a1' R b1' , -SO 2 C 1-3 alkyl, -S(O)C 1-3 alkyl, -C(O)NR a0' R b0' , -C(O)OC 1-3 alkyl, - OC(O)C 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy and 3 to 6 membered heterocycloalkyl;
化学键
Figure PCTCN2022130850-appb-000027
代表单键或双键； chemical bond
Figure PCTCN2022130850-appb-000027
represents a single or double bond;
环A’为苯环或5至6元杂芳环；环A’为未取代的或被1、2或3个各自独立地选自下组的取代基取代：氰基、硝基、羟基、羧基、卤素(优选为氟或氯)、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、C 3-8环烷基(优选为C 3-6环烷基)、C 1-8烷氧基(优选为C 1-6烷氧基，更优选为C 1-3烷氧基)、-C(O)C 1- 8烷基(优选为-C(O)C 1-6烷基，更优选为-C(O)C 1-3烷基)、-C(O)OC 1-8烷基(优选为-C(O)OC 1-6烷基，更优选为-C(O)OC 1-3烷基)、-OC(O)C 1-8烷基(优选为-OC(O)C 1-6烷基，更优选为-OC(O)C 1-3烷基)、-SO 2C 1- 8烷基(优选为-SO 2C 1-6烷基，更优选为-SO 2C 1-3烷基)和-C(O)NR a0’R b0’；其中所述C 1-8烷基、C 3-6环烷基、C 1-8烷氧基为未取代的或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素、氰基、硝基、羟基、羧基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-NR a1’R b1’、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR a0’R b0’、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基和3至6元杂环烷基； Ring A' is a benzene ring or a 5- to 6-membered heteroaromatic ring; Ring A' is unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of cyano, nitro, hydroxyl, Carboxyl, halogen (preferably fluorine or chlorine), C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 3-8 cycloalkyl (preferably C 3 -6 cycloalkyl), C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), -C (O) C 1- 8 alkyl (preferably -C(O)C 1-6 alkyl, more preferably -C(O)C 1-3 alkyl), -C(O)OC 1-8 alkyl (preferably -C(O)OC 1 -6 alkyl, more preferably -C(O)OC 1-3 alkyl), -OC(O)C 1-8 alkyl (preferably -OC(O)C 1-6 alkyl, more preferably -OC(O) C 1-3 alkyl), -SO 2 C 1-8 alkyl (preferably -SO 2 C 1-6 alkyl, more preferably -SO 2 C 1-3 alkyl) and - C(O)NR a0' R b0' ; wherein the C 1-8 alkyl, C 3-6 cycloalkyl, C 1-8 alkoxy are unsubstituted or are independently replaced by 1, 2 or 3 Substituents selected from the group consisting of deuterium, halogen, cyano, nitro, hydroxyl, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 Alkynyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, -NR a1' R b1' , -SO 2 C 1-3 alkyl, -S(O)C 1-3 alkane radical, -C(O)NR a0' R b0' , -C(O)OC 1-3 alkyl, -OC(O)C 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 Cycloalkyloxy and 3 to 6 membered heterocycloalkyl;
R a0’、和R b0’各自独立地为氢、C 1-3烷基或乙酰基；或者R a0’、R b0’与相连的氮原子共同形成4至6元饱和单杂环；所述4至6元饱和单杂环为未取代的或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素、氰基、硝基、羟基、羧基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NH 2、-C(O)NH(C 1-3烷基)、-C(O)N(C 1-3烷基) 2、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基和3至6元杂环烷基；以及 R a0' and R b0' are each independently hydrogen, C 1-3 alkyl or acetyl; or R a0' and R b0' together with the connected nitrogen atom form a 4 to 6-membered saturated monoheterocyclic ring; said The 4 to 6 membered saturated monoheterocycle is unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen, cyano, nitro, hydroxyl, carboxyl, C 1-3 Alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, -SO 2 C 1- 3 alkyl, -S(O)C 1-3 alkyl, -C(O)NH 2 , -C(O)NH(C 1-3 alkyl), -C(O)N(C 1-3 Alkyl) 2 , -C(O)OC 1-3 alkyl, -OC(O)C 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy and 3 to 6 membered heterocycloalkyl; and
R a1’、和R b1’各自独立地为氢、C 1-3烷基、卤代C 1-3烷基或乙酰基；或者R a1’、R b1’与相连的氮原子共同形成4至6元饱和单杂环；所述4至6元饱和单杂环为未取代的或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素、氰基、硝基、羟基、羧基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NH 2、-C(O)NH(C 1-3烷基)、-C(O)N(C 1-3烷基) 2、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基和3至6元杂环烷基。 R a1' , and R b1' are each independently hydrogen, C 1-3 alkyl, halogenated C 1-3 alkyl or acetyl; or R a1' , R b1' and the connected nitrogen atom together form 4 to 6-membered saturated monoheterocycle; the 4-6 membered saturated monoheterocycle is unsubstituted or substituted by 1, 2 or 3 substituents independently selected from the group consisting of deuterium, halogen, cyano, nitro , hydroxyl, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkane Oxygen, -SO 2 C 1-3 alkyl, -S(O)C 1-3 alkyl, -C(O)NH 2 , -C(O)NH(C 1-3 alkyl), -C (O)N(C 1-3 alkyl) 2 , -C(O)OC 1-3 alkyl, -OC(O)C 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 Cycloalkyloxy and 3 to 6 membered heterocycloalkyl.
在一些实施例中，Z 1’为N或CR Z1’；Z 2’为CR Z2’；Z 3’为N或CR Z3’；以及Z 4’为CR Z4’。 In some embodiments, Z 1' is N or CR Z1' ; Z 2' is CR Z2' ; Z 3' is N or CR Z3' ; and Z 4' is CR Z4' .
在一些实施例中，Z 1’为CR Z1’；Z 2’为CR Z2’；Z 3’为CR Z3’；以及Z 4’为CR Z4’。 In some embodiments, Z 1' is CR Z1' ; Z 2' is CR Z2' ; Z 3' is CR Z3' ; and Z 4' is CR Z4' .
在一些实施例中，Z 1’为N；Z 2’为CR Z2’；Z 3’为CR Z3’；以及Z 4’为CR Z4’。 In some embodiments, Z 1' is N; Z 2' is CR Z2' ; Z 3' is CR Z3' ; and Z 4' is CR Z4' .
在一些实施例中，Z 1’为CR Z1’；Z 2’为CR Z2’；Z 3’为N；以及Z 4`为CR Z4’。 In some embodiments, Z 1' is CR Z1' ; Z 2' is CR Z2' ; Z 3' is N; and Z 4' is CR Z4' .
在一些实施例中，Z 1’为N；Z 2’为CR Z2’；Z 3’为N；以及Z 4’为CR Z4’。 In some embodiments, Z 1' is N; Z 2' is CR Z2' ; Z 3' is N; and Z 4' is CR Z4' .
在一些实施例中，Z 4’为CH。 In some embodiments, Z 4' is CH.
进一步地，Z 1’为N或CH；Z 2’为CR Z2’；Z 3’为N或CH；以及Z 4’为CH。 Further, Z 1' is N or CH; Z 2' is CR Z2' ; Z 3' is N or CH; and Z 4' is CH.
更进一步地，Z 1’为N或CH；Z 2’为CR Z2’；Z 3’为CH；以及Z 4’为CH。 Further, Z 1' is N or CH; Z 2' is CR Z2' ; Z 3' is CH; and Z 4' is CH.
在一些实施例中，Z 1’为N，Z 2’为CR Z2’，Z 3’为CR Z3’，以及Z 4’为CR Z4’；或者Z 1’为CR Z1’，Z 2’为CR Z2’，Z 3’为CR Z3’，以及Z 4’为CR Z4’；或者Z 1’为N，Z 2’为CR Z2’，Z 3’为N，以及Z 4’为CR Z4’；或者Z 1’为CH，Z 2’为CR Z2’，Z 3’为N，以及Z 4’为CR Z4’。 In some embodiments, Z 1' is N, Z 2' is CR Z2' , Z 3' is CR Z3' , and Z 4' is CR Z4' ; or Z 1' is CR Z1' and Z 2' is CR Z2' , Z 3' is CR Z3' , and Z 4' is CR Z4' ; or Z 1' is N, Z 2' is CR Z2' , Z 3' is N, and Z 4' is CR Z4' ; or Z 1' is CH, Z 2' is CR Z2' , Z 3' is N, and Z 4' is CR Z4' .
在一些实施例中，Z 1’为N，Z 2’为CR Z2’，Z 3’为CH，以及Z 4’为CH；或者Z 1’为CH，Z 2’为CR Z2’，Z 3’为CR Z3’，以及Z 4’为CR Z4’；或者Z 1’为N，Z 2’为CR Z2’，Z 3’为N，以及Z 4’为CH；或者Z 1’为CH，Z 2’为CR Z2’，Z 3’为N，以及Z 4’为CH。 In some embodiments, Z 1' is N, Z 2' is CR Z2' , Z 3' is CH, and Z 4' is CH; or Z 1' is CH, Z 2' is CR Z2' , Z 3 ' is CR Z3' , and Z 4' is CR Z4' ; or Z 1' is N, Z 2' is CR Z2' , Z 3' is N, and Z 4' is CH; or Z 1' is CH, Z 2' is CR Z2' , Z 3' is N, and Z 4' is CH.
在一些实施例中，R Z1’、R Z2’、R Z3’、和R Z4’各自独立地为氢、氰基、卤素(优选为氟或氯)、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、C 3-8环烷基(优选为C 3-6环烷基)、卤代C 1-8烷基(优选为卤代C 1-6烷基，更优选为卤代C 1-3烷基)、C 1-8烷氧基(优选为C 1-6烷氧基，更优选为C 1-3烷氧基)、卤代C 1- 8烷氧基(优选为卤代C 1-6烷氧基，更优选为卤代C 1-3烷氧基)或-NR a1’R b1’；其中所述C 1-8烷基、C 3-8环烷基各自独立地为未取代的或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素、氰基、硝基、羟基、羧基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-NR a1’R b1’、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR a0’R b0’、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基和3至6元杂环烷基。 In some embodiments, R Z1' , R Z2' , R Z3' , and R Z4' are each independently hydrogen, cyano, halogen (preferably fluorine or chlorine), C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), halogenated C 1-8 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), halogen Substituted C 1-8 alkoxy (preferably halogenated C 1-6 alkoxy, more preferably halogenated C 1-3 alkoxy) or -NR a1' R b1' ; wherein the C 1-8 Alkyl, C 3-8 cycloalkyl are each independently unsubstituted or substituted by 1, 2 or 3 substituents independently selected from the group consisting of deuterium, halogen, cyano, nitro, hydroxyl, carboxyl , C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, - NR a1' R b1' , -SO 2 C 1-3 alkyl, -S(O)C 1-3 alkyl, -C(O)NR a0' R b0' , -C(O)OC 1-3 Alkyl, -OC(O)C 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy and 3 to 6 membered heterocycloalkyl.
在一些实施例中，R Z1’为氢。 In some embodiments, R Z1' is hydrogen.
在一些实施例中，R Z2’为氰基、卤素(优选为氟或氯)、C 1-3烷基(优选为甲基)、C 3-6环烷基(优选为环丙基)、卤代C 1-3烷基(优选为氟代C 1-3烷基，更优选为一氟甲基、一氟乙基、二氟甲基、二氟乙基、三氟甲基、三氟乙基、五氟乙基)、C 1-3烷氧基(优选为甲氧基或乙氧基)、卤代C 1-3烷氧基(优选为二氟甲氧基、三氟甲氧基)、卤素取代的C 3-6环烷基或-NR a1’R b1’；R a1’、R b1’各自独立地为氢、C 1-3烷基、卤代C 1-3烷基或乙酰基。 In some embodiments, R Z2' is cyano, halogen (preferably fluorine or chlorine), C 1-3 alkyl (preferably methyl), C 3-6 cycloalkyl (preferably cyclopropyl), Halogenated C 1-3 alkyl (preferably fluoro C 1-3 alkyl, more preferably monofluoromethyl, monofluoroethyl, difluoromethyl, difluoroethyl, trifluoromethyl, trifluoro ethyl, pentafluoroethyl), C 1-3 alkoxy (preferably methoxy or ethoxy), halogenated C 1-3 alkoxy (preferably difluoromethoxy, trifluoromethoxy base), halogen-substituted C 3-6 cycloalkyl or -NR a1' R b1' ; R a1' and R b1' are each independently hydrogen, C 1-3 alkyl, halogenated C 1-3 alkyl or acetyl.
在一些实施例中，R Z3’为氢、氰基或卤素(优选为氟或氯)。进一步地，R Z3’为氢。 In some embodiments, R Z3' is hydrogen, cyano, or halo (preferably fluoro or chloro). Further, R Z3' is hydrogen.
在一些实施例中，R Z4’为氢或卤素(优选为氟或氯)。进一步地，R Z4`为氢。 In some embodiments, R Z4' is hydrogen or halo (preferably fluoro or chloro). Further, R Z4' is hydrogen.
在一些实施例中，R Z1’、R Z2’、R Z3’、和R Z4’各自独立地选自由以下组成的组：氢、甲基、乙基、甲氧基、乙氧基、-NH-CH 2-CF 3和环丙基。 In some embodiments, R Z1' , R Z2' , R Z3' , and R Z4' are each independently selected from the group consisting of hydrogen, methyl, ethyl, methoxy, ethoxy, -NH -CH2 - CF3 and cyclopropyl.
在一些实施例中，Z 1’为CH；Z 2’为CR Z2’；Z 3’为CH；Z 4’为CH；以及R Z2’为三氟甲基。 In some embodiments, Z 1' is CH; Z 2' is CR Z2' ; Z 3' is CH; Z 4' is CH; and R Z2' is trifluoromethyl.
在一些实施例中，所述环A’是苯环或5至6元杂芳基环，且所述5至6元杂芳基环选自由以下组成的组：噻吩环、呋喃环、噻唑环、异噻唑环、咪唑环、噁唑环、吡咯环、吡唑环、三唑环、1,2,3-三唑环、1,2,4-三唑环、1,2,5-三唑环、1,3,4-三唑环、四唑环、异噁唑环、噁二唑环、1,2,3-噁二唑环、1,2,4-噁二唑环、1,2,5-噁二唑环、1,3,4-噁二唑环、噻二唑环、吡啶环、哒嗪环、嘧啶环、吡嗪环、三嗪环和四嗪环。In some embodiments, the ring A' is a benzene ring or a 5-6 membered heteroaryl ring, and the 5-6 membered heteroaryl ring is selected from the group consisting of a thiophene ring, a furan ring, a thiazole ring , isothiazole ring, imidazole ring, oxazole ring, pyrrole ring, pyrazole ring, triazole ring, 1,2,3-triazole ring, 1,2,4-triazole ring, 1,2,5-triazole ring Azole ring, 1,3,4-triazole ring, tetrazole ring, isoxazole ring, oxadiazole ring, 1,2,3-oxadiazole ring, 1,2,4-oxadiazole ring, 1 , 2,5-oxadiazole ring, 1,3,4-oxadiazole ring, thiadiazole ring, pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring, triazine ring and tetrazine ring.
在一些实施例中，环A’为未取代的。In some embodiments, Ring A' is unsubstituted.
在一些实施例中，
Figure PCTCN2022130850-appb-000028
为
Figure PCTCN2022130850-appb-000029
In some embodiments,
Figure PCTCN2022130850-appb-000028
for
Figure PCTCN2022130850-appb-000029
在一些实施例中，t1’为0；以及t2’为1、2或3。In some embodiments, t1' is 0; and t2' is 1, 2 or 3.
在一些实施例中，t3’为0；以及t4’为1、2或3。In some embodiments, t3' is 0; and t4' is 1, 2 or 3.
在一些实施例中，R q1’、R q2’各自独立地为氢；并且m’为2、3或4。 In some embodiments, R q1′ , R q2′ are each independently hydrogen; and m′ is 2, 3, or 4.
在一些实施例中，R q1’、R q2’与相连接的碳原子共同形成的3至7元饱和或部分不饱和单环为3至6元饱和单环；并且可以选自由以下组成的组：环丙基环、环丁基环、环戊基环和环己基环。 In some embodiments, the 3-7 membered saturated or partially unsaturated monocyclic ring formed by R q1' , R q2' and the connected carbon atoms is a 3-6 membered saturated monocyclic ring; and may be selected from the group consisting of : Cyclopropyl ring, cyclobutyl ring, cyclopentyl ring and cyclohexyl ring.
在一些实施例中，R q1’、R q2’与相连接的碳原子共同形成的3至7元饱和或部分不饱和单杂环为4至6元饱和或部分不饱和单杂环；并且可以选自由以下组成的组：氮杂环丁烷、氧杂环丁烷、四氢呋喃环、四氢噻吩环、四氢吡咯环、哌啶环、哌嗪环、吗啉环、硫代吗啉环、硫代吗啉-1,1-二氧化物和四氢吡喃环。 In some embodiments, the 3-7 membered saturated or partially unsaturated monoheterocyclic ring formed by R q1' , R q2' and the connected carbon atoms is a 4-6 membered saturated or partially unsaturated monoheterocyclic ring; and may selected from the group consisting of: azetidine, oxetane, tetrahydrofuran ring, tetrahydrothiophene ring, tetrahydropyrrole ring, piperidine ring, piperazine ring, morpholine ring, thiomorpholine ring, Thiomorpholine-1,1-dioxide and tetrahydropyran ring.
在一些实施例中，L’为-(CH 2) m’-；并且m’为2或3。 In some embodiments, L' is -(CH 2 ) m' -; and m' is 2 or 3.
在一些实施例中，基团
Figure PCTCN2022130850-appb-000030
选自由以下组成的组： In some embodiments, the group
Figure PCTCN2022130850-appb-000030
Selected from the group consisting of:
Figure PCTCN2022130850-appb-000031
Figure PCTCN2022130850-appb-000031
在一些实施例中，基团
Figure PCTCN2022130850-appb-000032
选自由以下组成的组： In some embodiments, the group
Figure PCTCN2022130850-appb-000032
Selected from the group consisting of:
Figure PCTCN2022130850-appb-000033
Figure PCTCN2022130850-appb-000034
Figure PCTCN2022130850-appb-000033
Figure PCTCN2022130850-appb-000034
在一些实施例中，所述化合物结构如式(IIa)或式(IIb)所示：In some embodiments, the structure of the compound is shown in formula (IIa) or formula (IIb):
Figure PCTCN2022130850-appb-000035
Figure PCTCN2022130850-appb-000035
在一些实施例中，所述化合物结构如式(II-1)所示：In some embodiments, the structure of the compound is shown in formula (II-1):
Figure PCTCN2022130850-appb-000036
Figure PCTCN2022130850-appb-000036
其中，Z 5’为N或CR Z5’；Z 6’为N或CR Z6’；Z 7’为N或CR Z7’；且Z 8’为N或CR Z8’； Wherein, Z 5' is N or CR Z5' ; Z 6' is N or CR Z6' ; Z 7' is N or CR Z7' ; and Z 8' is N or CR Z8' ;
R Z5’、R Z6’、R Z7’和R Z8’各自独立地为氢、氰基、硝基、羟基、羧基、卤素(优选为氟或氯)、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、C 3-8环烷基(优选为C 3-6环烷基)、卤代C 1-8烷基(优选为卤代C 1-6烷基，更优选为卤代C 1-3烷基)、C 1-8烷氧基(优选为C 1-6烷氧基，更优选为C 1-3烷氧基)、卤代C 1- 8烷氧基(优选为卤代C 1-6烷氧基，更优选为卤代C 1-3烷氧基)、-C(O)C 1-8烷基(优选为-C(O)C 1-6烷基，更优选为-C(O)C 1-3烷基)、-C(O)OC 1-8烷基(优选为-C(O)OC 1-6烷基，更优选为-C(O)OC 1-3烷基)、-SO 2C 1- 8烷基(优选为-SO 2C 1-6烷基，更优选为-SO 2C 1-3烷基)、-C(O)NR a0’R b0’、-NR a1’R b1’、5至6元杂芳基或8至10元杂芳基；其中所述C 1-8烷基、C 3-8环烷基、卤代C 1-8烷基、C 1-8烷氧基、卤代C 1-8烷氧基为未取代的或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素、氰基、硝基、羟基、羧基、C 1- 3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-NR a1’R b1’、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR a0’R b0’、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基、3至6元杂环烷基、苯基和5至6元杂芳基；以及 R Z5' , R Z6' , R Z7' and R Z8' are each independently hydrogen, cyano, nitro, hydroxyl, carboxyl, halogen (preferably fluorine or chlorine), C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), halogenated C 1-8 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), halogen Substituted C 1-8 alkoxy (preferably halogenated C 1-6 alkoxy, more preferably halogenated C 1-3 alkoxy ) , -C (O) C 1-8 alkyl (preferably - C(O)C 1-6 alkyl, more preferably -C(O)C 1-3 alkyl), -C(O)OC 1-8 alkyl (preferably -C(O)OC 1-6 Alkyl, more preferably -C(O)OC 1-3 alkyl) , -SO 2 C 1-8 alkyl (preferably -SO 2 C 1-6 alkyl, more preferably -SO 2 C 1- 3 alkyl), -C(O)NR a0' R b0' , -NR a1' R b1' , 5 to 6 membered heteroaryl or 8 to 10 membered heteroaryl; wherein the C 1-8 alkyl , C 3-8 cycloalkyl, halogenated C 1-8 alkyl, C 1-8 alkoxy, halogenated C 1-8 alkoxy are unsubstituted or replaced by 1, 2 or 3 independently Substituents selected from the group consisting of: deuterium, halogen, cyano, nitro, hydroxyl, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkyne group, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, -NR a1' R b1' , -SO 2 C 1-3 alkyl, -S(O)C 1-3 alkyl , -C(O)NR a0' R b0' , -C(O)OC 1-3 alkyl, -OC(O)C 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 ring Alkyloxy, 3 to 6 membered heterocycloalkyl, phenyl and 5 to 6 membered heteroaryl; and
Z 1’、Z 2’、Z 3’、Z 4’、和L ’基团如上述说明书中所定义。 The Z 1' , Z 2' , Z 3' , Z 4' , and L ' groups are as defined in the above specification.
在一些实施例中，Z 5’为N或CR Z5’；Z 6’为CR Z6’；Z 7’为CR Z7’；以及Z 8’为CR Z8’。 In some embodiments, Z 5' is N or CR Z5' ; Z 6' is CR Z6' ; Z 7' is CR Z7' ; and Z 8' is CR Z8' .
在一些实施例中，Z 5’为N；Z 6’为CR Z6’；Z 7’为CR Z7’；以及Z 8’为CR Z8’。 In some embodiments, Z 5' is N; Z 6' is CR Z6' ; Z 7' is CR Z7' ; and Z 8' is CR Z8' .
在一些实施例中，Z 5’为CR Z5’；Z 6’为CR Z6’；Z 7’为CR Z7’；以及Z 8’为CR Z8’。 In some embodiments, Z 5' is CR Z5' ; Z 6' is CR Z6' ; Z 7' is CR Z7' ; and Z 8' is CR Z8' .
在一些实施例中，Z 7’为CH。 In some embodiments, Z 7' is CH.
在一些实施例中，R Z5’、R Z6’、R Z7’、和R Z8’各自独立地为氢或卤素。进一步地，R Z5’、R Z6’、R Z7’、以及R Z8’均为氢。 In some embodiments, R Z5' , R Z6' , R Z7' , and R Z8' are each independently hydrogen or halogen. Further, R Z5' , R Z6' , R Z7' , and R Z8' are all hydrogen.
在一些实施例中，Z 5’为N；Z 6’为CH；Z 7’为CH；以及Z 8’为CH。 In some embodiments, Z 5' is N; Z 6' is CH; Z 7' is CH; and Z 8' is CH.
在一些实施例中，所述化合物结构如式(II-1a)或式(II-1b)所示：In some embodiments, the structure of the compound is shown in formula (II-1a) or formula (II-1b):
Figure PCTCN2022130850-appb-000037
Figure PCTCN2022130850-appb-000037
在一些实施例中，所述化合物选自由以下组成的组：In some embodiments, the compound is selected from the group consisting of:
Figure PCTCN2022130850-appb-000038
Figure PCTCN2022130850-appb-000038
Figure PCTCN2022130850-appb-000039
Figure PCTCN2022130850-appb-000039
在第三方面，本发明提供一种式(II-c)所示的化合物、或其盐、或其立体异构体：In a third aspect, the present invention provides a compound represented by formula (II-c), or a salt thereof, or a stereoisomer thereof:
Figure PCTCN2022130850-appb-000040
Figure PCTCN2022130850-appb-000040
其中R a为氰基或C(O)NH 2，并且S 1’、S 2’、环A’、Z 1’、Z 2’、Z 3’、Z 4’、和L’基团分别如本发明第二方面中的S 1’、S 2’、环A’、Z 1’、Z 2’、Z 3’、Z 4’、和L’基团所定义。 wherein R a is cyano or C(O)NH 2 , and the S 1' , S 2' , ring A', Z 1' , Z 2' , Z 3' , Z 4' , and L' groups are as The S 1' , S 2' , ring A', Z 1' , Z 2' , Z 3' , Z 4' , and L' groups in the second aspect of the invention are defined.
在一些实施例中，所述式(II-c)化合物结构如式(II-c-1)所示：In some embodiments, the structure of the compound of formula (II-c) is shown in formula (II-c-1):
Figure PCTCN2022130850-appb-000041
Figure PCTCN2022130850-appb-000041
本申请第四方面提供了一种药物组合物，其包括：本申请第一方面所述的化合物、其药学上可接受的盐或其立体异构体；以及药学上可接受的载体。The fourth aspect of the present application provides a pharmaceutical composition, which includes: the compound described in the first aspect of the present application, its pharmaceutically acceptable salt or its stereoisomer; and a pharmaceutically acceptable carrier.
本申请第五方面提供了本申请第一方面所述的化合物、其药学上可接受的盐或其立体异构体以及本申请第四方面所述的药物组合物在制备用于抑制MAT2A的药物中的应用。The fifth aspect of the application provides the compound described in the first aspect of the application, its pharmaceutically acceptable salt or its stereoisomer and the pharmaceutical composition described in the fourth aspect of the application in the preparation of a drug for inhibiting MAT2A in the application.
本申请第六方面提供了用于治疗或预防与MAT2A活性相关的或由MAT2A活性介导的疾病的本申请第一方面所述的化合物、其药学上可接受的盐或其立体异构体或本申请第四方面所述的药物组合物。The sixth aspect of the present application provides the compound described in the first aspect of the present application, its pharmaceutically acceptable salt or its stereoisomer or The pharmaceutical composition described in the fourth aspect of the application.
在一些实施例中，与MAT2A活性相关的或由MAT2A活性介导的疾病为癌症。In some embodiments, the disease associated with or mediated by MAT2A activity is cancer.
本申请第七方面提供了用作药物的本申请第一方面所述的化合物、其药学上可接受的盐或其立体异构体或本申请第四方面所述的药物组合物。The seventh aspect of the present application provides the compound described in the first aspect of the present application, its pharmaceutically acceptable salt or its stereoisomer, or the pharmaceutical composition described in the fourth aspect of the present application for use as a medicine.
本申请第八方面提供了一种治疗MAT2A介导的疾病的方法，所述方法包括给予患者有效量的本申请第一方面所述的化合物、其药学上可接受的盐或其立体异构体，或如本申请第四方面所述药物组合物。在某些实施方式中，MAT2A介导的疾病是癌症，例如实体瘤和血液瘤。The eighth aspect of the present application provides a method for treating MAT2A-mediated diseases, the method comprising administering to patients an effective amount of the compound described in the first aspect of the present application, its pharmaceutically acceptable salt or its stereoisomer , or the pharmaceutical composition as described in the fourth aspect of the present application. In certain embodiments, the MAT2A-mediated disease is cancer, such as solid tumors and hematological tumors.
应理解，在本申请范围内中，本申请的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的技术方案。限于篇幅，在此不再一一累述。It should be understood that within the scope of the present application, the above-mentioned technical features of the present application and the technical features specifically described in the following (such as the embodiments) can be combined with each other to form a new technical solution. Due to space limitations, we will not repeat them here.
具体实施方式Detailed ways
下面将对本申请实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例仅仅是本申请一部分实施例，而不是全部的实施例。基于本申请中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例，都属于本申请保护的范围。The following will clearly and completely describe the technical solutions in the embodiments of the present application. Obviously, the described embodiments are only some of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in this application, all other embodiments obtained by persons of ordinary skill in the art without making creative efforts belong to the scope of protection of this application.
本申请人经过广泛而深入的研究，意外地发现了这类取代的萘啶酮衍生物，其具有较高的MAT2A酶抑制活性，并且对HCT-116 MTAP LOSS细胞具有较高的抑制活性，对HCT-116 WT细胞抑制活性低，具有显著的选择抑制活性。因此该系列化合物有望开发成为用于治疗和/或预防MAT2A介导的疾病的药物。在此基础上，发明人完成了本申请。After extensive and in-depth research, the applicant unexpectedly discovered this kind of substituted naphthyridone derivatives, which have higher MAT2A enzyme inhibitory activity, and have higher inhibitory activity on HCT-116 MTAP LOSS cells, and have higher inhibitory activity on HCT-116 MTAP LOSS cells. HCT-116 WT cells have low inhibitory activity and significant selective inhibitory activity. Therefore, this series of compounds is expected to be developed into drugs for treating and/or preventing diseases mediated by MAT2A. On this basis, the inventor has completed the present application.
术语定义Definition of Terms
为了能够更清楚地理解本申请的技术内容，下面对本申请的术语作进一步说明。In order to understand the technical content of the present application more clearly, the terms of the present application will be further explained below.
“烷基”指直链和支链的饱和的脂族烃基。“C 1-8烷基”是指具有1至8个碳原子的烷基，可以为C 1-6烷基，进一步为C 1-3烷基；烷基的非限制性的例子包括：甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基，及其各种支链异构体等。 "Alkyl" refers to straight and branched chain saturated aliphatic hydrocarbon groups. "C 1-8 alkyl" refers to an alkyl group having 1 to 8 carbon atoms, which may be C 1-6 alkyl, further C 1-3 alkyl; non-limiting examples of alkyl include: Base, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethyl Propyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1 ,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl , 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3 -Methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3 -Dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethyl Hexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methylhexyl Base-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2 -Diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof.
“烯基”指直链或支链的具有一个或多个碳碳双键(C＝C)的不饱和脂族烃基，“C 2-8烯基”指具有2至8个碳原子的烯基，可以为C 2-6烯基，例如为C 2-4烯基，其定义类似；非限制性实施例包括乙烯基、丙烯基、异丙烯基、正丁烯基、异丁烯基、戊烯基、己烯基等。 "Alkenyl" refers to a straight-chain or branched unsaturated aliphatic hydrocarbon group having one or more carbon-carbon double bonds (C=C), and "C 2-8 alkenyl" refers to an alkenyl group having 2 to 8 carbon atoms. C2-6 alkenyl, such as C2-4 alkenyl, which is similarly defined; non-limiting examples include vinyl, propenyl, isopropenyl, n-butenyl, isobutenyl, pentenyl base, hexenyl, etc.
“炔基”指直链和支链的具有一个或多个碳碳三键的不饱和脂族烃基，“C 2-8炔基”指具有2至8个碳原子的炔基，可以为C 2-6炔基，例如为C 2-4炔基，定义类似；非限制性实施例包括乙炔基、丙炔基、正丁炔基、异丁炔基、戊炔基、己炔基等。 "Alkynyl" refers to straight-chain and branched unsaturated aliphatic hydrocarbon groups with one or more carbon-carbon triple bonds, and "C 2-8 alkynyl" refers to alkynyl groups with 2 to 8 carbon atoms, which can be C 2-6 alkynyl, such as C2-4 alkynyl, is similarly defined; non-limiting examples include ethynyl, propynyl, n-butynyl, isobutynyl, pentynyl, hexynyl, and the like.
“环烷基”和“环烷基环”可互换使用，均指饱和单环、双环或多环环状烃基，该基团可以与芳基或杂芳基稠合。环烷基环可以任选地被取代。在某些实施方式中，环烷基环含有一个或多个羰基，例如氧代的基团。“C 3-8环烷基”是指具有3至8个碳原子的单环环烷基，环烷基的非限制性实施例包括环丙基、 环丁基、环戊基、环己基、环庚基、环辛基、环丁酮、环戊酮、环戊烷-1,3-二酮等。环烷基可以为C 3-6环烷基，包括环丙基、环丁基、环戊基和环己基。 "Cycloalkyl" and "cycloalkyl ring" are used interchangeably and both refer to a saturated monocyclic, bicyclic or polycyclic cyclic hydrocarbon group, which may be fused with an aryl or heteroaryl group. Cycloalkyl rings can be optionally substituted. In certain embodiments, cycloalkyl rings contain one or more carbonyl groups, such as oxo groups. "C 3-8 cycloalkyl" refers to a monocyclic cycloalkyl group with 3 to 8 carbon atoms, non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Cycloheptyl, cyclooctyl, cyclobutanone, cyclopentanone, cyclopentane-1,3-dione, etc. Cycloalkyl may be C 3-6 cycloalkyl, including cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
“杂环烷基”和“杂环烷基环”可互换使用，均指包含至少一个选自氮、氧和硫的杂原子的环烷基，该基团可以与芳基或杂芳基稠合。杂环烷基环可以任选地被取代。在某些实施方式中，杂环烷基环含有一个或多个羰基或硫代羰基，例如包含氧代和硫代的基团。“3至8元杂环烷基”是指具有3至8个环原子，其中1、2或3个环原子为选自氮、氧和硫的杂原子的单环环状烃基，可以为4至8元杂环烷基，进一步为3至6元杂环烷基，其具有3至6个环原子，其中1或2个环原子为选自氮、氧和硫的杂原子，例如为4至6元杂环烷基，其具有4至6个环原子，其中1或2个环原子为选自氮、氧和硫的杂原子。单环杂环烷基的非限制性实施例包括氮丙环基、环氧乙烷基、氮杂环丁烷基、氧杂环丁烷基、四氢呋喃基、四氢噻吩基、四氢吡咯基、噁唑烷基、二氧戊环基、哌啶基、哌嗪基、吗啉基、二氧六环基、硫代吗啉基、硫代吗啉-1,1-二氧化物、四氢吡喃基、氮杂环丁烷-2-酮基、氧杂环丁烷-2-酮基、二氢呋喃-2(3H)-酮基、吡咯烷-2-酮基、吡咯烷-2,5-二酮基、二氢呋喃-2,5-二酮基、哌啶-2-酮基、四氢-2H-吡喃-2-酮基、哌嗪-2-酮基、吗啉-3-酮基等。"Heterocycloalkyl" and "heterocycloalkyl ring" are used interchangeably and both refer to a cycloalkyl group containing at least one heteroatom selected from nitrogen, oxygen and sulfur, which may be combined with an aryl or heteroaryl fused. Heterocycloalkyl rings can be optionally substituted. In certain embodiments, heterocycloalkyl rings contain one or more carbonyl or thiocarbonyl groups, eg, groups comprising oxo and thioxo. "3 to 8 membered heterocycloalkyl" refers to a monocyclic cyclic hydrocarbon group having 3 to 8 ring atoms, wherein 1, 2 or 3 ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, which can be 4 to 8-membered heterocycloalkyl, further 3 to 6-membered heterocycloalkyl, which has 3 to 6 ring atoms, wherein 1 or 2 ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, for example, 4 to 6-membered heterocycloalkyl having 4 to 6 ring atoms, of which 1 or 2 ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur. Non-limiting examples of monocyclic heterocycloalkyl groups include aziridine, oxiranyl, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyrrolyl , oxazolidinyl, dioxolanyl, piperidinyl, piperazinyl, morpholinyl, dioxanyl, thiomorpholinyl, thiomorpholine-1,1-dioxide, tetra Hydropyranyl, azetidin-2-one, oxetane-2-one, dihydrofuran-2(3H)-one, pyrrolidin-2-one, pyrrolidin- 2,5-diketone, dihydrofuran-2,5-diketone, piperidin-2-one, tetrahydro-2H-pyran-2-one, piperazin-2-one, morphine Lin-3-one group and so on.
“芳基”和“芳环”可互换使用，均指具有共轭的π电子体系的全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，该基团可以与环烷基环、杂环烷基环、环烯基环、杂环烯基环或杂芳基稠合。“C 6- 10芳基”指具有6至10个碳原子的单环或双环芳基，芳基的非限制性实施例包括苯基、萘基等。 "Aryl" and "aromatic ring" are used interchangeably and both refer to an all-carbon monocyclic or fused polycyclic (that is, rings sharing adjacent pairs of carbon atoms) group having a conjugated pi-electron system, which Can be fused to a cycloalkyl ring, heterocycloalkyl ring, cycloalkenyl ring, heterocycloalkenyl ring or heteroaryl. "C 6-10 aryl" refers to a monocyclic or bicyclic aryl group having 6 to 10 carbon atoms, and non-limiting examples of the aryl group include phenyl, naphthyl, and the like.
“杂芳基”和“杂芳基环”可互换使用，均指具有环碳原子和环杂原子的单环、双环或多环的4n+2芳族环体系(例如，具有以环状排列共享的6或10个π电子)的基团，其中每个杂原子独立地选自氮、氧和硫。本申请中，杂芳基还包括其中上述杂芳基环与一个或多个环烷基环、杂环烷基环、环烯基环、杂环烯基环或芳环稠合的环系统。杂芳基环可以任选地被取代。“5至10元杂芳基”是指具有5至10个环原子，其中1、2、3或4个环原子为杂原子的单环或双环杂芳基。“5至6元杂芳基”是指具有5至6个环原子，其中1、2、3或4个环原子为杂原子的单环杂芳基，非限制性实施例包括噻吩基、呋喃基、噻唑基、异噻唑基、咪唑基、噁唑基、吡咯基、吡唑基、三唑基、1,2,3-三唑基、1,2,4-三唑基、1,2,5-三唑基、1,3,4-三唑基、四唑基、异噁唑基、噁二唑基、1,2,3-噁二唑基、1,2,4-噁二唑基、1,2,5-噁二唑基、1,3,4-噁二唑基、噻二唑基、吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基、四嗪基。“8至10元杂芳基”是指具有8至10个环原子并且其中1、2、3或4个环原子为杂原子的双环杂芳基，其非限制性实施例包括吲哚基、异吲哚基、吲唑基、苯并三唑基、苯并噻吩基、异苯并噻吩基、苯并呋喃基、苯并异呋喃基、苯并咪唑基、苯并噁唑基、苯并异噁唑基、苯并噁二唑基、苯并噻唑基、苯并异噻唑基、苯并噻二唑基、茚嗪基、嘌呤基、吡啶并[3,2-d]嘧啶基、吡啶并[2,3-d]嘧啶基、吡啶并[3,4-d]嘧啶基、吡啶并[4,3-d]嘧啶基、1,8-萘啶基、1,7-萘啶基、1,6-萘啶基、1,5-萘啶基、喋啶基、喹啉基、异喹啉基、噌琳基、喹喔啉基、酞嗪基和喹唑啉基。“杂原子”是指氮、氧或硫。在含有一个或多个氮原子的杂芳基中，只要化合价允许，连接点可以是碳或氮原子。杂芳基双环系统在一个或两个环中可以包括一个或多个杂原子。"Heteroaryl" and "heteroaryl ring" are used interchangeably and both refer to a monocyclic, bicyclic or polycyclic 4n+2 aromatic ring system having ring carbon atoms and ring heteroatoms (e.g., having A group of shared 6 or 10 π electrons) where each heteroatom is independently selected from nitrogen, oxygen and sulfur. In this application, heteroaryl also includes ring systems in which the aforementioned heteroaryl ring is fused to one or more cycloalkyl rings, heterocycloalkyl rings, cycloalkenyl rings, heterocycloalkenyl rings or aromatic rings. Heteroaryl rings can be optionally substituted. "5 to 10 membered heteroaryl" refers to a monocyclic or bicyclic heteroaryl group having 5 to 10 ring atoms, of which 1, 2, 3 or 4 ring atoms are heteroatoms. "5 to 6 membered heteroaryl" means a monocyclic heteroaryl group having 5 to 6 ring atoms, of which 1, 2, 3 or 4 ring atoms are heteroatoms, non-limiting examples include thienyl, furan base, thiazolyl, isothiazolyl, imidazolyl, oxazolyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2 ,5-triazolyl, 1,3,4-triazolyl, tetrazolyl, isoxazolyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadi Azolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazine base. "8 to 10 membered heteroaryl" refers to a bicyclic heteroaryl group having 8 to 10 ring atoms in which 1, 2, 3 or 4 ring atoms are heteroatoms, non-limiting examples of which include indolyl, Isoindolyl, indazolyl, benzotriazolyl, benzothienyl, isobenzothienyl, benzofuryl, benzisofuryl, benzimidazole, benzoxazolyl, benzo Isoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indenazinyl, purinyl, pyrido[3,2-d]pyrimidinyl, pyridine A[2,3-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrido[4,3-d]pyrimidinyl, 1,8-naphthyridinyl, 1,7-naphthyridinyl , 1,6-naphthyridinyl, 1,5-naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cincinyl, quinoxalinyl, phthalazinyl and quinazolinyl. "Heteroatom" means nitrogen, oxygen or sulfur. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valence permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings.
“稠合”是指两个或多个环共用一个或多个键的结构。"Fused" refers to a structure in which two or more rings share one or more bonds.
“烷氧基”指-O-烷基，其中烷基的定义如上所述，其可以为C 1-8烷氧基，进一步为C 1-6烷氧基，例如为C 1-3烷氧基。非限制性实施例包含甲氧基、乙氧基、正丙氧基、异丙氧基、丁氧基、叔丁氧基、异丁氧基、戊氧基等。 "Alkoxy" refers to -O-alkyl, wherein the definition of alkyl is as above, it can be C 1-8 alkoxy, further C 1-6 alkoxy, such as C 1-3 alkoxy base. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, t-butoxy, isobutoxy, pentyloxy, and the like.
“环烷基氧基”指-O-环烷基，其中环烷基的定义如上所述，其可以为C 3-8环烷基氧基，进一步为C 3- 6环烷基氧基。非限制性实施例包含环丙基氧基、环丁基氧基、环戊基氧基、环己基氧基等。 "Cycloalkyloxy" refers to -O - cycloalkyl, wherein the definition of cycloalkyl is as above, which can be C 3-8 cycloalkyloxy, and further C 3-6 cycloalkyloxy. Non-limiting examples include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.
“一个键”指由其连接的两个基团通过一个共价键连接。"A bond" means that the two groups connected by it are connected by a covalent bond.
“卤素”指氟、氯、溴或碘。"Halogen" means fluorine, chlorine, bromine or iodine.
“卤代”指基团中一个或多个(如1、2、3、4或5个)氢被卤素所取代。"Halo" refers to a group in which one or more (eg 1, 2, 3, 4 or 5) hydrogens are replaced by a halogen.
“氨基”指NH 2，“氰基”指CN，“硝基”指NO 2，“苯甲基”指-CH 2-苯基，“氧代基”指＝O，“羧基”指-C(O)OH，“乙酰基”指-C(O)CH 3，“羟甲基”指-CH 2OH，“羟乙基”指-CH 2CH 2OH或-CHOHCH 3，“羟基”指-OH，“巯基”指-SH，“亚环丙基”结构为：
Figure PCTCN2022130850-appb-000042
"Amino" means NH 2 , "cyano" means CN, "nitro" means NO 2 , "benzyl" means -CH 2 -phenyl, "oxo" means =O, "carboxy" means -C (O)OH, "acetyl" refers to -C(O)CH 3 , "hydroxymethyl" refers to -CH 2 OH, "hydroxyethyl" refers to -CH 2 CH 2 OH or -CHOHCH 3 , "hydroxyl" refers to -OH, "mercapto" refers to -SH, and the structure of "cyclopropylene" is:
Figure PCTCN2022130850-appb-000042
“饱和或部分不饱和单环”是指饱和或部分不饱和的全碳单环系统，其中“部分不饱和”是指包括至少一个双键或三键的环部分，“部分不饱和”意图涵盖具有多个不饱和位点的环，但并不意图包括如本文所定义的芳基或杂芳基部分。在某些实施方式中，饱和或部分不饱和单环含有一个或多个羰基，例如氧代的基团。“3至7元饱和或部分不饱和单环”具有3到7个环碳原子，可以为具有3到6个环碳原子的饱和或部分不饱和单环，例如为具有3到6个环碳原子的饱和单环。饱和或部分不饱和单环的非限制性实施例包括环丙基环、环丁基环、环戊基环、环戊烯基环、环己基环、环己烯基环、环己二烯基环、环庚基环、环庚三烯基环、环戊酮环、环戊烷-1,3-二酮环等。对于“R 1、R 2与相连接的环原子共同形成4至7元饱和或部分不饱和单环”中的“单环”，可以理解的是，若化学键
Figure PCTCN2022130850-appb-000043
代表双键，由于与环A稠 合，则形成的环系为“不饱和单环”。 "Saturated or partially unsaturated monocyclic ring" means a saturated or partially unsaturated all-carbon monocyclic ring system, where "partially unsaturated" means a ring portion that includes at least one double or triple bond, and "partially unsaturated" is intended to encompass Rings with multiple sites of unsaturation, but are not intended to include aryl or heteroaryl moieties as defined herein. In certain embodiments, saturated or partially unsaturated monocyclic rings contain one or more carbonyl groups, such as oxo groups. A "3 to 7 membered saturated or partially unsaturated monocyclic ring" has 3 to 7 ring carbon atoms, may be a saturated or partially unsaturated monocyclic ring having 3 to 6 ring carbon atoms, for example has 3 to 6 ring carbon atoms atoms of a saturated monocyclic ring. Non-limiting examples of saturated or partially unsaturated monocyclic rings include cyclopropyl rings, cyclobutyl rings, cyclopentyl rings, cyclopentenyl rings, cyclohexyl rings, cyclohexenyl rings, cyclohexadienyl rings, Cycloheptyl ring, cycloheptatrienyl ring, cyclopentanone ring, cyclopentane-1,3-dione ring, etc. Regarding the "monocyclic ring" in "R 1 , R 2 and the connected ring atoms together form a 4- to 7-membered saturated or partially unsaturated monocyclic ring", it can be understood that if the chemical bond
Figure PCTCN2022130850-appb-000043
Represents a double bond. Since it is fused with ring A, the ring system formed is an "unsaturated monocyclic ring".
“饱和或部分不饱和单杂环”是指饱和或部分不饱和单环中的1、2或3个环碳原子被选自氮、氧或S(O) t(其中t是整数0至2)的杂原子所取代，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。“3至7元饱和或部分不饱和单杂环”具有3到7个环原子，其中1、2或3个环原子为上述杂原子。在一个实施例中，“3至7元饱和或部分不饱和单杂环”为具有3到6个环原子，其中1或2个环原子为上述杂原子的3至6元饱和或部分不饱和单杂环。在一个实施例中，“3至7元饱和或部分不饱和单杂环”为具有5到6个环原子，其中1或2个环原子为上述杂原子的5至6元饱和或部分不饱和单杂环。在一个实施例中，“3至7元饱和或部分不饱和单杂环”为5或6元饱和单杂环。饱和单杂环的非限制性实施例包括环氧丙烷环、氮杂环丁烷环、氧杂环丁烷环、四氢呋喃环、四氢噻吩环、四氢吡咯环、哌啶环、吡咯啉环、噁唑烷环、哌嗪环、二氧戊环、二氧六环、吗啉环、硫代吗啉环、硫代吗啉-1,1-二氧化物、四氢吡喃环、氮杂环丁烷-2-酮环、氧杂环丁烷-2-酮环、吡咯烷-2-酮环、吡咯烷-2,5-二酮环、哌啶-2-酮环、二氢呋喃-2(3H)-酮环、二氢呋喃-2,5-二酮环、四氢-2H-吡喃-2-酮环、哌嗪-2-酮环、和吗啉-3-酮环。部分不饱和单杂环的非限制性实施例包括1,2-二氢氮杂环丁二烯环、1,2-二氢氧杂环丁二烯环、2,5-二氢-1H-吡咯环、2,5-二氢呋喃环、2,3-二氢呋喃环、2,3-二氢-1H-吡咯环、3,4-二氢-2H-吡喃环、1,2,3,4-四氢吡啶环、3,6-二氢-2H-吡喃环、1,2,3,6-四氢吡啶环、4,5-二氢-1H-咪唑环、1,4,5,6-四氢嘧啶环、3,4,7,8-四氢-2H-1,4,6-噁二唑嗪环、1,6-二氢嘧啶环、4,5,6,7-四氢-1H-1,3-二氮杂
Figure PCTCN2022130850-appb-000044
环、和2,5,6,7-四氢-1,3,5-噁二氮杂
Figure PCTCN2022130850-appb-000045
环等。对于“R 1、R 2与相连接的环原子共同形成4至7元饱和或部分不饱和单杂环”中的“单杂环”，可以理解的是，当化学键
Figure PCTCN2022130850-appb-000046
代表双键时，由于与环A稠合，则形成的环系为“不饱和单杂环”。 "Saturated or partially unsaturated monoheterocyclic ring" means that 1, 2 or 3 ring carbon atoms in a saturated or partially unsaturated monocyclic ring are selected from nitrogen, oxygen or S(O) t (where t is an integer from 0 to 2 ), but excluding ring portions of -OO-, -OS- or -SS-, the remaining ring atoms are carbon. The "3- to 7-membered saturated or partially unsaturated monoheterocyclic ring" has 3 to 7 ring atoms, of which 1, 2 or 3 ring atoms are the above-mentioned heteroatoms. In one embodiment, a "3- to 7-membered saturated or partially unsaturated monoheterocycle" is a 3- to 6-membered saturated or partially unsaturated ring atom having 3 to 6 ring atoms, of which 1 or 2 ring atoms are the aforementioned heteroatoms. single heterocycle. In one embodiment, a "3- to 7-membered saturated or partially unsaturated monoheterocycle" is a 5- to 6-membered saturated or partially unsaturated ring atom having 5 to 6 ring atoms, of which 1 or 2 ring atoms are heteroatoms as described above. single heterocycle. In one embodiment, the "3- to 7-membered saturated or partially unsaturated monoheterocycle" is a 5- or 6-membered saturated monoheterocycle. Non-limiting examples of saturated monoheterocyclic rings include propylene oxide rings, azetidine rings, oxetane rings, tetrahydrofuran rings, tetrahydrothiophene rings, tetrahydropyrrole rings, piperidine rings, pyrroline rings , oxazolidine ring, piperazine ring, dioxolane, dioxane, morpholine ring, thiomorpholine ring, thiomorpholine-1,1-dioxide, tetrahydropyran ring, nitrogen Heterocyclobutane-2-one ring, oxetane-2-one ring, pyrrolidin-2-one ring, pyrrolidine-2,5-dione ring, piperidin-2-one ring, dihydro Furan-2(3H)-one ring, dihydrofuran-2,5-dione ring, tetrahydro-2H-pyran-2-one ring, piperazin-2-one ring, and morpholin-3-one ring ring. Non-limiting examples of partially unsaturated monoheterocyclic rings include 1,2-dihydroazetidinium rings, 1,2-dihydrooxetidine rings, 2,5-dihydro-1H- Pyrrole ring, 2,5-dihydrofuran ring, 2,3-dihydrofuran ring, 2,3-dihydro-1H-pyrrole ring, 3,4-dihydro-2H-pyran ring, 1,2, 3,4-tetrahydropyridine ring, 3,6-dihydro-2H-pyran ring, 1,2,3,6-tetrahydropyridine ring, 4,5-dihydro-1H-imidazole ring, 1,4 ,5,6-tetrahydropyrimidine ring, 3,4,7,8-tetrahydro-2H-1,4,6-oxadiazosin ring, 1,6-dihydropyrimidine ring, 4,5,6, 7-tetrahydro-1H-1,3-diazepine
Figure PCTCN2022130850-appb-000044
Cyclo, and 2,5,6,7-tetrahydro-1,3,5-oxadiazepine
Figure PCTCN2022130850-appb-000045
Ring etc. As for the "monoheterocycle" in "R 1 , R 2 and the connected ring atoms together form a 4 to 7 membered saturated or partially unsaturated monoheterocycle", it can be understood that when the chemical bond
Figure PCTCN2022130850-appb-000046
When representing a double bond, since it is fused with ring A, the formed ring system is an "unsaturated monoheterocyclic ring".
“取代的”指基团中的一个或多个氢原子，例如1～5，1～3，或1个氢原子，彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。"Substituted" means that one or more hydrogen atoms in a group, such as 1-5, 1-3, or 1 hydrogen atom, are independently substituted by the corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions and that a person skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when bonded to a carbon atom with an unsaturated (eg, ethylenic) bond.
除非另有定义，本申请所述“各自独立地选自……的取代基”是指当基团上的一个以上的氢被取代基取代时，所述的取代基种类可以相同或不同，所选自的取代基为各自独立的种类。Unless otherwise defined, the "substituents independently selected from ..." described in this application means that when more than one hydrogen on the group is replaced by a substituent, the types of substituents may be the same or different, so The selected substituents are each independent species.
除非另有定义，本申请所述“……相同或不同，且各自独立地为……”是指当通式中存在一个以上的相同取代基团时，该基团可以相同或不同，为各自独立的种类。例如X 1为(CR q1R q2) m，当m为2时，即X 1为CR q1R q2-CR q1R q2，其中的两个R q1彼此可以相同或不同，两个R q2彼此可以相同或不同，为各自独立的种类。 Unless otherwise defined, "...the same or different, and each independently being..." in this application means that when there are more than one identical substituent groups in the general formula, the groups may be the same or different, and are each separate species. For example, X 1 is (CR q1 R q2 ) m , when m is 2, that is, X 1 is CR q1 R q2 -CR q1 R q2 , where the two R q1 can be the same or different from each other, and the two R q2 can be The same or different, for each independent category.
除非另有定义，本文任一基团可以是取代的或未取代的。上述基团被取代时，取代基可以为1至5个以下基团，独立地选自氰基、硝基、卤素(例如氟或氯)、C 1-8烷基(可以为C 1-6烷基，例如C 1-3烷基)、C 1-8烷氧基(可以为C 1-6烷氧基，例如C 1-3烷氧基)、卤代C 1-8烷基(可以为卤代C 1-6烷基，例如卤代C 1-3烷基)、C 3-8环烷基(可以为C 3-6环烷基)、卤代C 1-8烷氧基(可以为卤代C 1-6烷氧基，例如卤代C 1-3烷氧基)、C 1-8烷基取代的氨基、卤代C 1-8烷基取代的氨基、乙酰基、羟基、羟甲基、羟乙基、羧基、硝基、C 6-10芳基(可以为苯基)、C 3-8环烷基氧基(可以为C 3-6环烷基氧基)、C 2-8烯基(可以为C 2-6烯基，例如C 2- 4烯基)、C 2-8炔基(可以为C 2-6炔基，例如C 2-4炔基)、-CONR a0R b0、-C(O)OC 1-10烷基(可以为-C(O)OC 1-6烷基，例如-C(O)OC 1-3烷基)、-CHO、-OC(O)C 1-10烷基(可以为-OC(O)C 1-6烷基，例如-OC(O)C 1-3烷基)、-SO 2C 1-10烷基(可以为-SO 2C 1-6烷基，例如-SO 2C 1-3烷基)、-SO 2C 6-10芳基(可以为-SO 2C 6芳基，如-SO 2-苯基)、-COC 6-10芳基(可以为-COC 6芳基，如-CO-苯基)、4至6元饱和或不饱和单杂环、4至6元饱和或不饱和单环、5至6元单环杂芳基环、8至10元双环杂芳基环、螺环、螺杂环、桥环和桥杂环，其中R a0、R b0各自独立地为氢或C 1-3烷基。 Unless otherwise defined, any group herein may be substituted or unsubstituted. When the above-mentioned groups are substituted, the substituents can be 1 to 5 following groups, independently selected from cyano, nitro, halogen (such as fluorine or chlorine), C 1-8 alkyl (can be C 1-6 Alkyl, such as C 1-3 alkyl), C 1-8 alkoxy (can be C 1-6 alkoxy, such as C 1-3 alkoxy), halogenated C 1-8 alkyl (can is halogenated C 1-6 alkyl, such as halogenated C 1-3 alkyl), C 3-8 cycloalkyl (may be C 3-6 cycloalkyl), halogenated C 1-8 alkoxy ( Can be halogenated C 1-6 alkoxy, such as halogenated C 1-3 alkoxy), C 1-8 alkyl substituted amino, halogenated C 1-8 alkyl substituted amino, acetyl, hydroxyl , hydroxymethyl, hydroxyethyl, carboxyl, nitro, C 6-10 aryl (can be phenyl), C 3-8 cycloalkyloxy (can be C 3-6 cycloalkyloxy), C 2-8 alkenyl (can be C 2-6 alkenyl, such as C 2-4 alkenyl), C 2-8 alkynyl (can be C 2-6 alkynyl, such as C 2-4 alkynyl), -CONR a0 R b0 , -C(O)OC 1-10 alkyl (can be -C(O)OC 1-6 alkyl, such as -C(O)OC 1-3 alkyl), -CHO, - OC(O)C 1-10 alkyl (can be -OC(O)C 1-6 alkyl, such as -OC(O)C 1-3 alkyl), -SO 2 C 1-10 alkyl (can be -SO 2 C 1-6 alkyl, such as -SO 2 C 1-3 alkyl), -SO 2 C 6-10 aryl (can be -SO 2 C 6 aryl, such as -SO 2 -phenyl ), -COC 6-10 aryl (can be -COC 6 aryl, such as -CO-phenyl), 4 to 6 membered saturated or unsaturated monoheterocyclic ring, 4 to 6 membered saturated or unsaturated monocyclic ring, 5 to 6-membered monocyclic heteroaryl ring, 8- to 10-membered bicyclic heteroaryl ring, spiro ring, spiro heterocyclic ring, bridged ring and bridged heterocyclic ring, wherein R a0 and R b0 are each independently hydrogen or C 1-3 alkyl.
本申请中，当取代基的数量大于1时，任意的两个取代基可以相同或不同。例如，本申请化合物上的基团可以为二个相同或不同的卤素取代或者可以为一个卤素和一个羟基取代。In the present application, when the number of substituents is greater than 1, any two substituents may be the same or different. For example, groups on the compounds of the present application may be substituted by two identical or different halogens or may be substituted by one halogen and one hydroxyl.
本文以上所述的各类取代基团其自身也是可以被本文所描述的基团取代。The various substituent groups described herein above may themselves be substituted by groups described herein.
本文所述的饱和单杂环被取代时，取代基的位置可处在它们可能的化学位置，示例性的单杂环的代表性的取代情况如下所示：When the saturated monoheterocycle described herein is substituted, the positions of the substituents can be in their possible chemical positions, and the representative substitution situation of the exemplary monoheterocycle is as follows:
Figure PCTCN2022130850-appb-000047
Figure PCTCN2022130850-appb-000047
Figure PCTCN2022130850-appb-000048
Figure PCTCN2022130850-appb-000049
其中“Sub”表示本文所述的各类取代基；
Figure PCTCN2022130850-appb-000050
表示与其他原子的连接位置。
Figure PCTCN2022130850-appb-000048
Figure PCTCN2022130850-appb-000049
Where "Sub" represents various substituents described herein;
Figure PCTCN2022130850-appb-000050
Indicates the position of attachment to other atoms.
药物组合物pharmaceutical composition
通常本申请化合物、其药学上可接受的盐或其立体异构体可以与一种或多种药学上可接受的载体形成适合的剂型施用。这些剂型适用于口服、直肠施用、局部施用、口内施用以及其他非胃肠道施用(例如，皮下、肌肉、静脉等)。例如，适合口服施用的剂型包括胶囊、片剂、颗粒剂以及糖浆等。这些制剂中包含的本申请的化合物可以是：固体粉末或颗粒；水性或非水性液体中的溶液或是混悬液；以及油包水或水包油的乳剂等。上述剂型可由活性化合物与一种或多种载体或辅料经由通用的药剂学方法制成。上述的载体需要与活性化合物或其他辅料兼容。对于固体制剂，常用的无毒载体包括但不限于甘露醇、乳糖、淀粉、硬脂酸镁、纤维素、葡萄糖、蔗糖等。用于液体制剂的载体包括水、生理盐水、葡萄糖水溶液、乙二醇和聚乙二醇等。活性化合物可与上述载体形成溶液或是混悬液。Usually, the compound of the present application, its pharmaceutically acceptable salt or its stereoisomer can be administered in a suitable dosage form with one or more pharmaceutically acceptable carriers. These dosage forms are suitable for oral, rectal, topical, oral and other parenteral administration (eg, subcutaneous, intramuscular, intravenous, etc.). For example, dosage forms suitable for oral administration include capsules, tablets, granules, syrups and the like. The compound of the present application contained in these formulations may be: solid powder or granule; solution or suspension in aqueous or non-aqueous liquid; and water-in-oil or oil-in-water emulsion and the like. The above-mentioned dosage forms can be made from the active compound and one or more carriers or excipients through common pharmaceutical methods. The aforementioned carriers need to be compatible with the active compound or other excipients. For solid preparations, commonly used non-toxic carriers include, but are not limited to, mannitol, lactose, starch, magnesium stearate, cellulose, glucose, sucrose, and the like. Carriers for liquid preparations include water, physiological saline, aqueous dextrose, ethylene glycol, polyethylene glycol, and the like. The active compounds can form solutions or suspensions with the above-mentioned carriers.
“药学上可接受的载体”是指无毒、惰性、固态、半固态的物质或液体灌装机、稀释剂、封装材料或辅助制剂或任何类型辅料，其与患者相兼容，患者可以为哺乳动物，例如为人，药学上可接受的载体适合将活性试剂输送到目标靶点而不终止试剂的活性。"Pharmaceutically acceptable carrier" means a non-toxic, inert, solid, semi-solid substance or liquid filler, diluent, encapsulating material or auxiliary preparation or excipient of any type, which is compatible with the patient, who may be breastfeeding In animals, such as humans, the pharmaceutically acceptable carrier is suitable for delivering the active agent to the target site of interest without terminating the activity of the agent.
“本申请的活性物质”或“本申请的活性化合物”是指本申请的式(I)化合物、其药学上可接受的盐或其立体异构体，其具有较高的MAT2A选择抑制活性。"The active substance of the present application" or "the active compound of the present application" refers to the compound of formula (I) of the present application, its pharmaceutically acceptable salt or its stereoisomer, which has a higher MAT2A selective inhibitory activity.
本申请的组合物以符合医学实践规范的方式配制、定量和施用。给予化合物的“治疗有效量”由要治疗的具体病症、治疗的个体、病症的起因、药物的靶点以及施用方式等因素决定。The compositions of the present application are formulated, dosed and administered in a manner consistent with medical practice. The "therapeutically effective amount" of a compound to be administered is determined by factors such as the particular condition to be treated, the individual being treated, the cause of the condition, the target of the drug, and the mode of administration.
“治疗有效量”是指将引起个体的生物学或医学响应，例如降低或抑制酶或蛋白质活性或改善症状、缓解病症、减缓或延迟疾病进程或预防疾病等的本申请化合物的量。"Therapeutically effective amount" refers to the amount of the compound of the present application that will cause the individual's biological or medical response, such as reducing or inhibiting enzyme or protein activity or improving symptoms, alleviating symptoms, slowing down or delaying disease progression or preventing diseases, etc.
本申请的所述药物组合物或所述药用组合物中含有的本申请化合物、其药学上可接受的盐或其立体异构体的治疗有效量可以为0.1mg-5000mg/kg(体重)。The therapeutically effective amount of the compound of the present application contained in the pharmaceutical composition of the present application or the pharmaceutical composition, its pharmaceutically acceptable salt or its stereoisomer can be 0.1mg-5000mg/kg (body weight) .
“患者”是指动物，可以为哺乳动物，例如为人。术语“哺乳动物”是指温血脊椎类哺乳动物，包括如猫、狗、兔、熊、狐狸、狼、猴子、鹿、鼠、猪和人。"Patient" refers to an animal, which may be a mammal, such as a human. The term "mammal" refers to warm-blooded vertebrate mammals including, for example, cats, dogs, rabbits, bears, foxes, wolves, monkeys, deer, mice, pigs and humans.
“治疗”是指减轻、延缓进展、衰减、预防或维持现有疾病或病症(例如癌症)。治疗还包括将疾病或病症的一个或多个症状治愈、预防其发展或减轻到某种程度。"Treating" means alleviating, delaying progression, attenuating, preventing or maintaining an existing disease or condition (eg, cancer). Treatment also includes curing, preventing its development, or alleviating to some extent one or more symptoms of a disease or disorder.
所述“药学上可接受的盐”包括药学上可接受的酸加成盐和药学上可接受的碱加成盐。药学上可接受的酸加成盐是指能够保留游离碱的生物有效性而无其他副作用的、与无机酸或有机酸所形成的盐。这些盐可通过本专业已知的方法制备。The "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. A pharmaceutically acceptable acid addition salt refers to a salt formed with an inorganic or organic acid that retains the biological effectiveness of the free base without other side effects. These salts can be prepared by methods known in the art.
“药学上可接受的碱加成盐”，包括但不限于无机碱的盐、有机碱的盐。这些盐可通过本专业已知的 方法制备。"Pharmaceutically acceptable base addition salts" include, but are not limited to, salts with inorganic bases and salts with organic bases. These salts can be prepared by methods known in the art.
当本申请式(I)所示的化合物含有一个或多个手性中心时，能够以不同的光学活性形式存在。当式(I)化合物含有一个手性中心时，该化合物包含一对对映异构体，除非另有说明，用楔形键
Figure PCTCN2022130850-appb-000051
表示一个立体中心的绝对构型。该化合物的两个对映异构体以及该一对对映异构体的混合物，如外消旋混合物也在本申请的保护范围内。对映异构体可以通过本专业已知的方法拆分，例如结晶以及手性色谱等方法。当式(I)化合物含有多于一个手性中心时，该化合物包含对映异构体和非对映异构体。该化合物的所有对映异构体和非对映异构体，以及对映异构体的混合物，非对映异构体的混合物，以及对映异构体和非对映异构体的混合物也在本申请的保护范围内。对映异构体、非对映异构体可由本专业已知方法拆分，比如结晶以及制备色谱。本申请实施例中拆分得到的异构体的绝对构型为任意指定的。 When the compound represented by formula (I) of the present application contains one or more chiral centers, it can exist in different optically active forms. When a compound of formula (I) contains a chiral center, the compound comprises a pair of enantiomers, unless otherwise stated, separated by a wedge bond
Figure PCTCN2022130850-appb-000051
Indicates the absolute configuration of a stereocenter. The two enantiomers of the compound and the mixture of the pair of enantiomers, such as the racemic mixture, are also within the protection scope of the present application. Enantiomers may be resolved by methods known in the art, such as crystallization and chiral chromatography. When a compound of formula (I) contains more than one chiral center, the compound includes enantiomers and diastereomers. All enantiomers and diastereomers of the compound, and mixtures of enantiomers, mixtures of diastereomers, and mixtures of enantiomers and diastereomers Also within the protection scope of the present application. Enantiomers and diastereomers may be resolved by methods known in the art, such as crystallization and preparative chromatography. The absolute configurations of the isomers resolved in the Examples of the present application are arbitrarily assigned.
制备方法Preparation
本申请提供了式(I)化合物的制备方法，使用本领域技术人员已知的标准合成技术或使用本领域已知的方法与本申请描述的方法组合可以合成式(I)化合物。本申请给出的溶剂、温度和其它反应条件可以根据本领域技术而改变。所述反应可以按顺序使用，以提供本申请的化合物，或者它们可以用于合成片段，所述片段通过本申请所描述的方法和/或本领域已知的方法随后加入。The present application provides the preparation method of the compound of formula (I), and the compound of formula (I) can be synthesized by using the standard synthetic technique known to those skilled in the art or using the method known in the art in combination with the method described in the present application. Solvents, temperatures and other reaction conditions given in this application can be varied according to the skill in the art. The reactions can be used in sequence to provide the compounds of the application, or they can be used to synthesize fragments which are subsequently added by methods described herein and/or methods known in the art.
本申请描述的化合物可以使用与下述类似的方法或实施例中所述的示例性方法或本领域技术人员所用的相关公开文献、通过使用适当的可选择的起始原料来合成。本申请式(I-1)化合物的一类通用合成方法如下所示：The compounds described in this application can be synthesized using methods analogous to those described below or the exemplary methods described in the Examples or relevant publications available to those skilled in the art by using appropriate alternative starting materials. A general synthetic method of the application formula (I-1) compound is as follows:
Figure PCTCN2022130850-appb-000052
Figure PCTCN2022130850-appb-000052
以式(II)化合物为原料，在氯化试剂(例如三氯氧磷或二氯亚砜)、碱(例如三乙胺或N,N-二异丙基乙胺)以及合适的溶剂的存在下与相应的胺进行反应，得到式(I-1)化合物。在一些实施方式中，将式(II)化合物、氯化试剂和碱在溶剂存在下在80-100℃下反应，得到反应液，然后将该反应液与相应的胺在0℃至室温下反应，得到式(I-1)化合物。Using the compound of formula (II) as a raw material, in the presence of a chlorinating reagent (such as phosphorus oxychloride or thionyl chloride), a base (such as triethylamine or N,N-diisopropylethylamine) and a suitable solvent React with the corresponding amine to obtain the compound of formula (I-1). In some embodiments, the compound of formula (II), chlorination reagent and base are reacted at 80-100°C in the presence of a solvent to obtain a reaction solution, and then the reaction solution is reacted with the corresponding amine at 0°C to room temperature , to obtain the compound of formula (I-1).
本发明式(II)化合物的一类通用合成方法如下所示：A class of general synthetic methods for compounds of formula (II) of the present invention are as follows:
Figure PCTCN2022130850-appb-000053
Figure PCTCN2022130850-appb-000053
使式(II-a)化合物与式(II-b)化合物在碱和溶剂存在下反应得到式(II-c)化合物，使式(II-c)化合物在酸和溶剂存在下发生关环反应得到式(II)化合物。其中R a为氰基或C(O)NH 2；R b为卤素等离去基团，其他基团如说明书中所定义。 The compound of formula (II-a) is reacted with the compound of formula (II-b) in the presence of a base and a solvent to obtain a compound of formula (II-c), and the compound of formula (II-c) is subjected to a ring-closing reaction in the presence of an acid and a solvent A compound of formula (II) is obtained. Wherein R a is cyano or C(O)NH 2 ; R b is a leaving group such as halogen, and other groups are as defined in the description.
用于合成本申请所描述的化合物的起始原料可以被合成或可以从商业来源获得。本申请描述的化合物和其它相关具有不同取代基的化合物可以使用本领域技术人员已知的技术和原料合成。制备本申请公开的化合物的一般方法可以来自本领域已知的反应，并且该反应可以通过由本领域技术人员所认 为适当的试剂和条件修改，以引入本申请提供的分子中的各种部分。Starting materials for the synthesis of compounds described herein can be synthesized or can be obtained from commercial sources. The compounds described herein and other related compounds having various substituents can be synthesized using techniques and starting materials known to those skilled in the art. General methods for preparing compounds disclosed herein can be derived from reactions known in the art, and the reactions can be modified by reagents and conditions deemed appropriate by those skilled in the art to introduce various moieties in the molecules provided herein.
本申请的主要优点在于：The main advantages of this application are:
提供了一系列结构新颖的取代的萘啶酮衍生物，其对MAT2A酶具有较高的抑制活性，并且对细胞具有较高的选择抑制活性，因此可用作治疗和/或预防MAT2A介导的疾病的药物。Provides a series of structurally novel substituted naphthyridinone derivatives, which have high inhibitory activity on MAT2A enzymes and high selective inhibitory activity on cells, so they can be used for the treatment and/or prevention of MAT2A-mediated Medicines for diseases.
下面结合具体实施例，进一步阐述本申请。应理解，这些实施例仅用于说明本申请而不用于限制本申请的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件如Sambrook等人，分子克隆：实验室手册(New York:Cold Spring Harbor Laboratory Press，1989)中所述的条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。除非另行定义，本文所用的术语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或同等的方法及材料皆可应用于本申请中。试剂与仪器The present application will be further elaborated below in conjunction with specific embodiments. It should be understood that these examples are only used to illustrate the present application and are not intended to limit the scope of the present application. The experimental method that does not indicate specific conditions in the following examples, usually according to conventional conditions such as people such as Sambrook, molecular cloning: the conditions described in the laboratory manual (New York: Cold Spring Harbor Laboratory Press, 1989), or according to the manufacturer suggested conditions. Percentages and parts are by weight unless otherwise indicated. Unless otherwise defined, terms used herein have the same meanings as those skilled in the art are familiar with. In addition, any methods and materials similar or equivalent to those described can be applied to this application. Reagents and Instruments
1HNMR：Bruker AVANCE-400核磁仪，内标为四甲基硅烷(TMS)。 1 HNMR: Bruker AVANCE-400 nuclear magnetic analyzer, the internal standard is tetramethylsilane (TMS).
LC-MS：Agilent 1290 HPLC System/6130/6150 MS液质联用质谱仪(生产商：安捷伦)，柱子Waters BEH/CHS，50×2.1mm，1.7μm。LC-MS: Agilent 1290 HPLC System/6130/6150 MS liquid mass spectrometry (manufacturer: Agilent), column Waters BEH/CHS, 50×2.1mm, 1.7μm.
制备高效液相色谱(pre-HPLC)：GX-281(生产商：吉尔森)。Preparative high performance liquid chromatography (pre-HPLC): GX-281 (manufacturer: Gilson).
采用ISCO Combiflash-Rf75或Rf200型自动过柱仪，Agela 4g、12g、20g、40g、80g、120g一次性硅胶柱。Adopt ISCO Combiflash-Rf75 or Rf200 automatic column passing instrument, Agela 4g, 12g, 20g, 40g, 80g, 120g disposable silica gel column.
已知的起始原料可以采用或按照本领域已知的方法来合成，或可以购自ABCR GmbH&Co.KG，Acros Organics，Aldrich Chemical Company，韶远化学科技(Accela ChemBio Inc)和达瑞化学品等公司。Known starting materials can be adopted or synthesized according to methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Chemical Technology (Accela ChemBio Inc) and Darui Chemicals, etc. company.
在实施例中，反应进程的监测可采用薄层色谱法(TLC)，化合物纯化可采用柱层析。柱层析或TLC所用的展开剂体系可选自：二氯甲烷和甲醇体系、正己烷和乙酸乙酯体系、石油醚和乙酸乙酯体系和丙酮体系等，溶剂的体积比根据化合物的极性不同而进行调节。In the embodiments, the monitoring of the reaction progress can be carried out by thin layer chromatography (TLC), and the purification of the compound can be carried out by column chromatography. The developer system used in column chromatography or TLC can be selected from: dichloromethane and methanol system, n-hexane and ethyl acetate system, petroleum ether and ethyl acetate system and acetone system, etc., the volume ratio of the solvent is based on the polarity of the compound Adjust differently.
如本文所用，DMF：N,N-二甲基甲酰胺；DMSO：二甲基亚砜；THF：四氢呋喃；DIEA：N,N-二异丙基乙胺，EA：乙酸乙酯，PE：石油醚，KHMDS：双(三甲基硅烷基)氨基钾，BINAP：(2R,3S)-2,2’-双二苯膦基-1,1’-联萘，NBS：N-溴代丁二酰亚胺，NCS：N-氯代丁二酰亚胺，Pd 2(dba) 3：三(二亚苯甲基丙酮)二钯，Pd(dppf)Cl 2：[1,1’-双(二苯基磷)二茂铁]二氯化钯，Pd(PPh 3) 4：四(三苯基膦)钯，PdCl 2(CH 3CN) 2：二氯二(乙腈)钯，DPPA：叠氮磷酸二苯酯，DBU：1,8-二氮杂二环十一碳-7-烯，TBAF：四丁基氟化铵，DAST：二乙胺基三氟化硫，Na Ascorbate：抗坏血酸钠，t-BuXPhosPd-G3：甲磺酸(2-二叔丁基膦基-2’，4’，6’-三异丙基-1,1’-联苯)(2’-氨基-1,1’-联苯-2-基)钯(II)，X-PHOS：2-二环己基膦-2’,4’,6’-三异丙基联苯，XantPhos：4,5-双二苯基膦-9,9-二甲基氧杂蒽，DCM：二氯甲烷，NaH：氢化钠，TEA：三乙胺，HCl/dioxane：盐酸/二氧六环，CombiFlash：快速制备色谱分离仪，Hex-EtOH：正己烷-乙醇，NH 4Ac：醋酸铵，POCl 3：三氯氧磷，MeCN：乙腈，DIPEA：N,N-二异丙基乙胺。 As used herein, DMF: N,N-dimethylformamide; DMSO: dimethylsulfoxide; THF: tetrahydrofuran; DIEA: N,N-diisopropylethylamine, EA: ethyl acetate, PE: petroleum Ether, KHMDS: potassium bis(trimethylsilyl)amide, BINAP: (2R,3S)-2,2'-bisdiphenylphosphino-1,1'-binaphthyl, NBS: N-bromobutanedi imide, NCS: N-chlorosuccinimide, Pd 2 (dba) 3 : tris(dibenzylideneacetone) dipalladium, Pd(dppf)Cl 2 : [1,1'-bis( Diphenylphospho)ferrocene]palladium dichloride, Pd(PPh 3 ) 4 : tetrakis(triphenylphosphine)palladium, PdCl 2 (CH 3 CN) 2 : bis(acetonitrile)palladium dichloride, DPPA: azide Diphenyl Nitrophosphate, DBU: 1,8-Diazabicycloundec-7-ene, TBAF: Tetrabutylammonium Fluoride, DAST: Diethylaminosulfur Trifluoride, Na Ascorbate: Sodium Ascorbate , t-BuXPhosPd-G3: Methanesulfonic acid (2-di-tert-butylphosphino-2', 4', 6'-triisopropyl-1,1'-biphenyl) (2'-amino-1, 1'-biphenyl-2-yl)palladium(II), X-PHOS: 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl, XantPhos: 4,5-dibis Phenylphosphine-9,9-dimethylxanthene, DCM: dichloromethane, NaH: sodium hydride, TEA: triethylamine, HCl/dioxane: hydrochloric acid/dioxane, CombiFlash: flash preparative chromatography , Hex-EtOH: n-hexane-ethanol, NH 4 Ac: ammonium acetate, POCl 3 : phosphorus oxychloride, MeCN: acetonitrile, DIPEA: N,N-diisopropylethylamine.
如本文所用，室温是指约20-30℃。As used herein, room temperature means about 20-30°C.
中间体v1intermediate v1
Figure PCTCN2022130850-appb-000054
Figure PCTCN2022130850-appb-000054
步骤1：将2,3-二氢-1H-茚-1-甲腈(3.03g，21.25mmol)溶于甲苯(60mL)中，于0℃左右滴加1M的KHMDS的THF溶液(24mL,23.94mmol)，0℃搅拌1h。随后滴加化合物2-氯-6-(三氟甲基)烟酰胺(1.19g，5.32mmol)的THF溶液(10mL)，于0℃搅拌1h,将反应液倒入碳酸氢钠水溶液(50mL)中，用EA(100mL×2)萃取，合并有机层，依次用水(50mL)、饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，滤液减压下蒸除溶剂，残留物打浆(乙醚:石油醚＝1:2)得到化合物v1-1(1.5g)。LCMS：m/z 332.2[M+H] +。 Step 1: Dissolve 2,3-dihydro-1H-indene-1-carbonitrile (3.03g, 21.25mmol) in toluene (60mL), add 1M KHMDS solution in THF (24mL, 23.94 mmol), stirred at 0°C for 1 h. Then a THF solution (10 mL) of compound 2-chloro-6-(trifluoromethyl)nicotinamide (1.19 g, 5.32 mmol) was added dropwise, stirred at 0°C for 1 h, and the reaction solution was poured into aqueous sodium bicarbonate solution (50 mL) , extracted with EA (100mL×2), combined the organic layers, washed with water (50mL) and saturated brine (50mL) successively, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to remove the solvent under reduced pressure, and the residue was beaten (ether : Petroleum ether=1:2) to obtain compound v1-1 (1.5g). LCMS: m/z 332.2 [M+H] + .
步骤2：将化合物v1-1(1.5g，4.53mmol)溶于浓盐酸(20mL)中，在70℃搅拌过夜。将反应液浓缩后倒入冰水(20mL)中，用5N的氢氧化钠调至pH＝7，用二氯甲烷(50mL×2)萃取，合并有机层，依次用水(8mL)、饱和食盐水(8mL)洗涤，无水硫酸钠干燥，过滤，滤液减压下蒸除溶剂，得到化合物v1(1.1g)。LCMS：m/z 333.2[M+H] +。 Step 2: Compound v1-1 (1.5 g, 4.53 mmol) was dissolved in concentrated hydrochloric acid (20 mL), and stirred at 70° C. overnight. The reaction solution was concentrated and poured into ice water (20 mL), adjusted to pH=7 with 5N sodium hydroxide, extracted with dichloromethane (50 mL×2), combined organic layers, followed by water (8 mL), saturated saline (8 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to remove the solvent under reduced pressure to obtain compound v1 (1.1 g). LCMS: m/z 333.2 [M+H] + .
中间体v2intermediate v2
Figure PCTCN2022130850-appb-000055
Figure PCTCN2022130850-appb-000055
以6,7-二氢-5H-环戊二烯[b]吡啶-5-腈和2-氯-6-(三氟甲基)烟腈为原料，参考中间体v1的制备方法，得到化合物v2(0.16g)。LCMS：m/z 334.1[M+H] +。 Using 6,7-dihydro-5H-cyclopentadiene[b]pyridine-5-carbonitrile and 2-chloro-6-(trifluoromethyl)nicotinonitrile as raw materials, refer to the preparation method of intermediate v1 to obtain the compound v2 (0.16g). LCMS: m/z 334.1 [M+H] + .
中间体v3intermediate v3
Figure PCTCN2022130850-appb-000056
Figure PCTCN2022130850-appb-000056
步骤1：将钠氢(666mg，16.64mmol)加入到6,7-二氢-5H-环戊二烯[b]吡啶-5-腈(393mg,2.08mmol)的DMF(10mL)溶液中，在冰水浴中氮气保护下搅拌1h，然后往反应液加入2-氟-4-三氟甲基苯腈(300mg，2.08mmol)的DMF(2mL)溶液。并在冰水浴反应1h。往溶液中加入饱和的氯化铵(70mL)并用EA(100mL×2)萃取，有机相用饱和食盐水(50mL)洗涤，用无水硫酸钠干燥，过滤浓缩，用柱层析纯化得到化合物v3-1(550mg，收率：84.3％)。ESI-MS m/z＝314[M+H] +。 Step 1: Sodium hydrogen (666 mg, 16.64 mmol) was added to a solution of 6,7-dihydro-5H-cyclopentadiene[b]pyridine-5-carbonitrile (393 mg, 2.08 mmol) in DMF (10 mL), in Stir under nitrogen protection in an ice-water bath for 1 h, and then add a solution of 2-fluoro-4-trifluoromethylbenzonitrile (300 mg, 2.08 mmol) in DMF (2 mL) to the reaction solution. And react in ice water bath for 1h. Saturated ammonium chloride (70mL) was added to the solution and extracted with EA (100mL×2), the organic phase was washed with saturated brine (50mL), dried over anhydrous sodium sulfate, concentrated by filtration, and purified by column chromatography to obtain compound v3 -1 (550 mg, yield: 84.3%). ESI-MS m/z = 314 [M+H] + .
步骤2：将化合物v3-1(545mg,1.7mmol)溶于浓硫酸(4mL)并在60℃搅拌6个小时。把反应液温度降到室温并加入到200ml的冰水中。再用5M的氢氧化钠溶液把反应液的pH调到8。用100mL EA萃取两次。有机相用饱和食盐水(100mL)洗涤。并用无水硫酸钠干燥，浓缩，重结晶得到化合物v3(340mg,收率：58.8％)。ESI-MS m/z＝333[M+H] +。 Step 2: Compound v3-1 (545mg, 1.7mmol) was dissolved in concentrated sulfuric acid (4mL) and stirred at 60°C for 6 hours. The temperature of the reaction solution was lowered to room temperature and added to 200 ml of ice water. The pH of the reaction solution was then adjusted to 8 with 5M sodium hydroxide solution. Extracted twice with 100 mL EA. The organic phase was washed with saturated brine (100 mL). It was dried with anhydrous sodium sulfate, concentrated, and recrystallized to obtain compound v3 (340 mg, yield: 58.8%). ESI-MS m/z = 333 [M+H] + .
中间体v4intermediate v4
Figure PCTCN2022130850-appb-000057
Figure PCTCN2022130850-appb-000057
以1,2,3,4-四氢萘-1-腈和2-氯-6-(三氟甲基)烟酰胺为原料，参考中间体v1的制备方法，得到化合物v4。LCMS：m/z 345.0[M-H] -。 Using 1,2,3,4-tetrahydronaphthalene-1-carbonitrile and 2-chloro-6-(trifluoromethyl)nicotinamide as raw materials, refer to the preparation method of intermediate v1 to obtain compound v4. LCMS: m/z 345.0 [MH] - .
中间体v5intermediate v5
Figure PCTCN2022130850-appb-000058
Figure PCTCN2022130850-appb-000058
以2,3-二氢-苯并呋喃-3-腈和2-氯-6-(三氟甲基)烟腈为原料，，参照参考中间体v3的制备方法，得到化合物v5(308mg)。LCMS：m/z 332.9[M-H] -。 Using 2,3-dihydro-benzofuran-3-carbonitrile and 2-chloro-6-(trifluoromethyl)nicotinonitrile as raw materials, according to the preparation method of reference intermediate v3, compound v5 (308 mg) was obtained. LCMS: m/z 332.9 [MH] - .
中间体v6intermediate v6
Figure PCTCN2022130850-appb-000059
Figure PCTCN2022130850-appb-000059
以2,3-二氢-1H-茚-1-甲腈和2-氟-4-(三氟甲基)苄腈为原料，参照参考中间体v3的制备方法，得到化合物v6。LCMS：m/z 330.0[M-H] -。 Using 2,3-dihydro-1H-indene-1-carbonitrile and 2-fluoro-4-(trifluoromethyl)benzonitrile as raw materials, according to the preparation method of reference intermediate v3, compound v6 was obtained. LCMS: m/z 330.0 [MH] - .
中间体v7intermediate v7
Figure PCTCN2022130850-appb-000060
Figure PCTCN2022130850-appb-000060
以6,7-二氢-5H-环戊二烯[b]吡啶-7-腈和2-氯-6-三氟甲基烟腈为原料，参考中间体v3的制备方法，得到中间体化合物v7。LCMS：m/z 334.1[M+H] +。 Using 6,7-dihydro-5H-cyclopentadiene[b]pyridine-7-carbonitrile and 2-chloro-6-trifluoromethylnicotinonitrile as raw materials, refer to the preparation method of intermediate v3 to obtain the intermediate compound v7. LCMS: m/z 334.1 [M+H] + .
中间体v8intermediate v8
Figure PCTCN2022130850-appb-000061
Figure PCTCN2022130850-appb-000061
以3,4-二氢-2H-1-苯并吡喃-4-甲腈(CAS NO:109543-00-2)和2-氯-6-(三氟甲基)烟酰胺为原料，参考中间体v1的制备方法，得到中间体化合物v8。LCMS：m/z 347.1[M-H] -。 Using 3,4-dihydro-2H-1-benzopyran-4-carbonitrile (CAS NO:109543-00-2) and 2-chloro-6-(trifluoromethyl)nicotinamide as raw materials, refer to The preparation method of the intermediate v1, the intermediate compound v8 is obtained. LCMS: m/z 347.1 [MH] - .
中间体v9intermediate v9
Figure PCTCN2022130850-appb-000062
Figure PCTCN2022130850-appb-000062
步骤1：以4-羟基-2-(三氟甲基)嘧啶-5-甲酸为原料，在通过与二氯亚砜和氨的THF溶液反应得到化合物v9-1。LCMS：m/z 223.9[M-H] -。 Step 1: Starting from 4-hydroxy-2-(trifluoromethyl)pyrimidine-5-carboxylic acid, compound v9-1 was obtained by reacting with thionyl chloride and ammonia in THF. LCMS: m/z 223.9 [MH] - .
步骤2-3：以化合物v9-1和2,3-二氢-1H-茚-1-甲腈为原料，参考中间体v1的制备方法，得到中间体化合物v9。LCMS：m/z 332.0[M-H] -。 Step 2-3: Using compound v9-1 and 2,3-dihydro-1H-indene-1-carbonitrile as raw materials, refer to the preparation method of intermediate v1 to obtain intermediate compound v9. LCMS: m/z 332.0 [MH] - .
中间体v10Intermediate v10
Figure PCTCN2022130850-appb-000063
Figure PCTCN2022130850-appb-000063
步骤1：将2,3-二氢-1H-茚-1-甲腈(1.56g,10.9mmol)溶于THF(15mL)中，反应液冷却至-70℃，向反应液中加入2M的二异丙基氨基锂(5.5mL,11.0mmol)。反应液在-70℃搅拌30min。再向反应液中加入4-氯-2-(甲巯基)嘧啶-5-甲酰胺(0.50g,2.48mmol)，反应液在-70℃搅拌20min。以冰水/EA(40mL/20mL)稀释，EA(30mL x 2)萃取。干燥，过滤，旋干，用甲基叔丁基醚(15mL)打浆，过滤，得到化合物v10-1(0.50g,收率65％)。LCMS：m/z 309.0[M-H] -。 Step 1: 2,3-dihydro-1H-indene-1-carbonitrile (1.56g, 10.9mmol) was dissolved in THF (15mL), the reaction solution was cooled to -70°C, and 2M dihydrogen was added to the reaction solution Lithium isopropylamide (5.5 mL, 11.0 mmol). The reaction solution was stirred at -70°C for 30 min. Then 4-chloro-2-(methylmercapto)pyrimidine-5-carboxamide (0.50 g, 2.48 mmol) was added to the reaction solution, and the reaction solution was stirred at -70°C for 20 min. Diluted with ice water/EA (40mL/20mL), extracted with EA (30mL x 2). Dried, filtered, spin-dried, slurried with methyl tert-butyl ether (15 mL), and filtered to obtain compound v10-1 (0.50 g, yield 65%). LCMS: m/z 309.0 [MH] - .
步骤2：以化合物v10-1为原料，参考中间体v1步骤2的制备方法，得到中间体化合物v10。LCMS：m/z 310.1[M-H] -。 Step 2: Using compound v10-1 as a raw material, refer to the preparation method in step 2 of intermediate v1 to obtain intermediate compound v10. LCMS: m/z 310.1 [MH] - .
中间体v11intermediate v11
Figure PCTCN2022130850-appb-000064
Figure PCTCN2022130850-appb-000064
步骤1：将4,6-二氯烟腈(6.0g,0.034mol)和环丙基硼酸(3.3g,0.038mol),Pd(dppf)Cl 2(1.14g,1.15mmol),Cs 2CO3(34.0g,0.10mmol)溶于1,4-二氧六环/水(180mL/30mL)中，反应液在氮气氛围中升至100℃并搅拌过夜。反应液过滤，滤液浓缩。滤液加入EA(700ml)并且用饱和食盐水(700ml*2)洗涤。有机相用无水硫酸钠干燥过滤，减压下蒸除溶剂，粗品用正相过柱纯化(EA：PE＝80:1)得到黄色固体， 再将黄色固体通过反向过柱纯化，得到化合物v11-1(300mg,收率4.8％)。 Step 1: 4,6-dichloronicotinonitrile (6.0g, 0.034mol) and cyclopropylboronic acid (3.3g, 0.038mol), Pd(dppf)Cl 2 (1.14g, 1.15mmol), Cs 2 CO3 ( 34.0g, 0.10mmol) was dissolved in 1,4-dioxane/water (180mL/30mL), and the reaction solution was raised to 100°C under nitrogen atmosphere and stirred overnight. The reaction solution was filtered, and the filtrate was concentrated. The filtrate was added with EA (700ml) and washed with saturated brine (700ml*2). The organic phase was dried and filtered with anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The crude product was purified by normal phase column purification (EA:PE=80:1) to obtain a yellow solid, and then the yellow solid was purified by reverse column to obtain the compound v11-1 (300mg, yield 4.8%).
步骤2-3：以化合物v11-1和2,3-二氢-1H-茚-1-甲腈为原料，参考中间体v1的制备方法，得到中间体化合物v11。LCMS：m/z 303.6[M-H] -。 Step 2-3: Using compound v11-1 and 2,3-dihydro-1H-indene-1-carbonitrile as raw materials, refer to the preparation method of intermediate v1 to obtain intermediate compound v11. LCMS: m/z 303.6 [MH] - .
中间体v12intermediate v12
Figure PCTCN2022130850-appb-000065
Figure PCTCN2022130850-appb-000065
步骤1：将2,6-二氯烟腈(8.0g,0.047mol)和环丙基硼酸(4.8g,0.056mol),醋酸钯(522mg,2.32mmol),三环己基膦(1.3g,4.64mmol)，磷酸钾(34.5g,0.162mol)溶于甲苯/水(180mL/30mL)中，反应液在氮气氛围中升至100℃并搅拌过夜。反应液过滤，滤液浓缩。滤液加入EA(700ml)并且用饱和食盐水(700ml*2)洗涤。有机相用无水硫酸钠干燥过滤，减压下蒸除溶剂，粗品用正相过柱纯化(EA：PE＝80:1)，再通过反向纯化得到化合物v12-1。LCMS：m/z＝179[M+H] +。 Step 1: Combine 2,6-dichloronicotinonitrile (8.0g, 0.047mol) and cyclopropylboronic acid (4.8g, 0.056mol), palladium acetate (522mg, 2.32mmol), tricyclohexylphosphine (1.3g, 4.64 mmol), potassium phosphate (34.5g, 0.162mol) was dissolved in toluene/water (180mL/30mL), and the reaction solution was raised to 100°C under nitrogen atmosphere and stirred overnight. The reaction solution was filtered, and the filtrate was concentrated. The filtrate was added with EA (700ml) and washed with saturated brine (700ml*2). The organic phase was dried and filtered with anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The crude product was purified by normal phase column (EA:PE=80:1), and compound v12-1 was obtained by reverse purification. LCMS: m/z = 179 [M+H] + .
步骤2-3：以化合物v12-1和2,3-二氢-1H-茚-1-甲腈为原料，参考中间体v1的制备方法，得到中间体化合物v12。LCMS：m/z 303[M-H] -。 Step 2-3: Using compound v12-1 and 2,3-dihydro-1H-indene-1-carbonitrile as raw materials, refer to the preparation method of intermediate v1 to obtain intermediate compound v12. LCMS: m/z 303 [MH] - .
中间体v13intermediate v13
Figure PCTCN2022130850-appb-000066
Figure PCTCN2022130850-appb-000066
以5-氟-2,3-二氢-1H-茚-1-腈(CAS NO:915030-25-0)和2-氯-6-(三氟甲基)烟腈为原料，参考中间体v2的制备方法，得到中间体化合物v13。LCMS：m/z 349.1[M-H] -。 Use 5-fluoro-2,3-dihydro-1H-indene-1-carbonitrile (CAS NO:915030-25-0) and 2-chloro-6-(trifluoromethyl)nicotinonitrile as raw materials, refer to intermediates The preparation method of v2, obtains intermediate compound v13. LCMS: m/z 349.1 [MH] - .
中间体v14intermediate v14
Figure PCTCN2022130850-appb-000067
Figure PCTCN2022130850-appb-000067
以2-苯基丙腈和2-氯-6-(三氟甲基)烟腈为原料，参考中间体v2的制备方法，得到中间体化合物v14。LCMS：m/z 319.5[M-H] -。 Using 2-phenylpropionitrile and 2-chloro-6-(trifluoromethyl)nicotinonitrile as raw materials, refer to the preparation method of intermediate v2 to obtain intermediate compound v14. LCMS: m/z 319.5 [MH] - .
中间体v15intermediate v15
Figure PCTCN2022130850-appb-000068
Figure PCTCN2022130850-appb-000068
将化合物v10(200mg,0.64mmol)，乙醇钠(0.94mL,2.56mmol)溶于乙醇(8mL)和DMF(12mL)中，反应液在70℃搅拌15h。用水(20mL)稀释，用EA(30mL x 3)萃取，合并有机层，依次用水(50mL)、饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，滤液减压下蒸除溶剂，粗品用柱层析纯化(PE/EA＝3:1)，得到化合物v15(120mg，收率：60％)。ESI-MS：m/z 309.8[M+H] +。 Compound v10 (200mg, 0.64mmol), sodium ethoxide (0.94mL, 2.56mmol) was dissolved in ethanol (8mL) and DMF (12mL), and the reaction solution was stirred at 70°C for 15h. Diluted with water (20mL), extracted with EA (30mL x 3), combined the organic layers, washed with water (50mL) and saturated brine (50mL) successively, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to remove the solvent under reduced pressure, the crude product Purification by column chromatography (PE/EA=3:1) gave compound v15 (120 mg, yield: 60%). ESI-MS: m/z 309.8 [M+H] + .
中间体v16intermediate v16
Figure PCTCN2022130850-appb-000069
Figure PCTCN2022130850-appb-000069
将化合物v10(200mg,0.64mmol)，间氯过氧苯甲酸(277mg,1.60mmol)溶于二氯甲烷(15mL)中， 反应液在室温下搅拌3h，然后加入三氟乙胺(316.80mg,3.20mmol)，反应液在室温下搅拌16h。用水(20mL)稀释，用EA(30mL x 3)萃取，合并有机层，依次用水(50mL)、饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，滤液减压下蒸除溶剂，粗品用柱层析纯化(PE/EA＝3:1)得到中间体化合物v16(150mg,收率：65％)。ESI-MS：m/z＝363.2[M+H] +。 Compound v10 (200mg, 0.64mmol), m-chloroperbenzoic acid (277mg, 1.60mmol) were dissolved in dichloromethane (15mL), the reaction solution was stirred at room temperature for 3h, and then trifluoroethylamine (316.80mg, 3.20mmol), the reaction solution was stirred at room temperature for 16h. Diluted with water (20mL), extracted with EA (30mL x 3), combined the organic layers, washed with water (50mL) and saturated brine (50mL) successively, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to remove the solvent under reduced pressure, the crude product Purification by column chromatography (PE/EA=3:1) gave intermediate compound v16 (150 mg, yield: 65%). ESI-MS: m/z = 363.2 [M+H] + .
中间体v17intermediate v17
Figure PCTCN2022130850-appb-000070
Figure PCTCN2022130850-appb-000070
步骤1：将化合物3,3-二甲基-1H-1-茚满酮(1g,6.25mmol)和对甲基苯磺酰甲基异腈(1.83g,9.38mmol)溶于干燥的乙二醇二甲醚(5mL)中，0℃向上述溶液中加入乙醇钠(2.7M,4.2mL,11.25mmol),室温搅拌3小时。EA(50mL)萃取两次，有机相用硫酸钠干燥后浓缩，过柱得化合物v17-1(1.07g,58％)。Step 1: The compound 3,3-dimethyl-1H-1-indanone (1g, 6.25mmol) and p-toluenesulfonylmethylisonitrile (1.83g, 9.38mmol) were dissolved in dry ethylene di Alcohol dimethyl ether (5 mL), sodium ethoxide (2.7M, 4.2 mL, 11.25 mmol) was added to the above solution at 0°C, and stirred at room temperature for 3 hours. EA (50 mL) was extracted twice, the organic phase was dried over sodium sulfate, concentrated, and passed through the column to obtain compound v17-1 (1.07 g, 58%).
步骤2-3：参考中间体v1的制备方法，得到中间体化合物v17。LCMS m/z＝359.1[M-H] -。 Step 2-3: Refer to the preparation method of intermediate v1 to obtain intermediate compound v17. LCMS m/z = 359.1 [MH] - .
中间体v18intermediate v18
Figure PCTCN2022130850-appb-000071
Figure PCTCN2022130850-appb-000071
参考中间体v11的制备方法，区别在于用6,7-二氢-5H-环戊二烯[b]吡啶-7-腈替换2,3-二氢-1H-茚-1-甲腈，得到中间体化合物v18。LCMS：m/z 306.1[M+H] +。 Referring to the preparation method of intermediate v11, the difference is that 2,3-dihydro-1H-indene-1-carbonitrile is replaced by 6,7-dihydro-5H-cyclopentadiene[b]pyridine-7-carbonitrile to obtain Intermediate compound v18. LCMS: m/z 306.1 [M+H] + .
中间体v19intermediate v19
Figure PCTCN2022130850-appb-000072
Figure PCTCN2022130850-appb-000072
以4-溴-2,3-二氢-1H-茚-1-腈(CAS NO:1033811-54-9)和2-氯-6-(三氟甲基)烟腈为原料，参考中间体v3的制备方法，得到中间体化合物v19。Using 4-bromo-2,3-dihydro-1H-indene-1-carbonitrile (CAS NO:1033811-54-9) and 2-chloro-6-(trifluoromethyl)nicotinonitrile as raw materials, refer to intermediates The preparation method of v3 obtains the intermediate compound v19.
中间体v20Intermediate v20
Figure PCTCN2022130850-appb-000073
Figure PCTCN2022130850-appb-000073
步骤1：将钠氢(1.41g,35.2mmol)溶于二甲苯(150mL)中,向上述溶液中加入乙醇(1.47g，32.0mmol)的二甲苯溶液(50mL)，室温搅拌20分钟，然后向上述溶液中加入2,6-二氯-3-氰基吡啶(5.5g，32.0mmol)的二甲苯溶液(150mL)，反应液140℃搅拌16小时。浓缩，用EA(50mL)萃取三次，有机相用硫酸钠干燥后浓缩，过柱得到化合物v20-1。Step 1: Dissolve sodium hydrogen (1.41g, 35.2mmol) in xylene (150mL), add ethanol (1.47g, 32.0mmol) in xylene (50mL) to the above solution, stir at room temperature for 20 minutes, and then add A xylene solution (150 mL) of 2,6-dichloro-3-cyanopyridine (5.5 g, 32.0 mmol) was added to the above solution, and the reaction solution was stirred at 140° C. for 16 hours. Concentrate, extract three times with EA (50 mL), dry the organic phase over sodium sulfate, concentrate, and pass through the column to obtain compound v20-1.
步骤2：将化合物v20-1(2.0g)，K 2CO 3(4.55g,32.7mmol)溶于DMSO(10ml)中，于室温滴加入30％H 2O 2(5mL)，反应液在室温搅拌2小时。反应液倒入饱和食盐水(40ml),用EA(20mL x 3)萃取，合并有机层，无水硫酸钠干燥，过滤，滤液减压下蒸除溶剂，得到化合物v20-2(260mg,收率：11.9％)。 Step 2: Compound v20-1 (2.0g), K 2 CO 3 (4.55g, 32.7mmol) was dissolved in DMSO (10ml), and 30% H 2 O 2 (5mL) was added dropwise at room temperature. Stir for 2 hours. The reaction solution was poured into saturated brine (40ml), extracted with EA (20mL x 3), the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to remove the solvent under reduced pressure to obtain compound v20-2 (260mg, yield : 11.9%).
步骤3-4：参考中间体v1的制备方法，得到中间体化合物v20。LCMS：m/z 309.2[M+H] +。 Step 3-4: Refer to the preparation method of intermediate v1 to obtain intermediate compound v20. LCMS: m/z 309.2 [M+H] + .
中间体v21intermediate v21
Figure PCTCN2022130850-appb-000074
Figure PCTCN2022130850-appb-000074
参考中间体v12的制备方法，区别在于用6,7-二氢-5H-环戊二烯[b]吡啶-7-腈替换2,3-二氢-1H-茚-1-甲腈，得到中间体化合物v21。LCMS：m/z 306.0[M+H] +。 Referring to the preparation method of intermediate v12, the difference is that 2,3-dihydro-1H-indene-1-carbonitrile is replaced by 6,7-dihydro-5H-cyclopentadiene[b]pyridine-7-carbonitrile to obtain Intermediate compound v21. LCMS: m/z 306.0 [M+H] + .
中间体v22intermediate v22
Figure PCTCN2022130850-appb-000075
Figure PCTCN2022130850-appb-000075
参考中间体v3的制备方法，区别在于用4,6-二溴间苯二甲腈替换2-氟-4-三氟甲基苯腈，得到中间体化合物v22。LCMS：m/z 368.0[M+H] +。 Referring to the preparation method of intermediate v3, the difference is that 2-fluoro-4-trifluoromethylbenzonitrile is replaced by 4,6-dibromoisophthalonitrile to obtain intermediate compound v22. LCMS: m/z 368.0 [M+H] + .
中间体v23intermediate v23
Figure PCTCN2022130850-appb-000076
Figure PCTCN2022130850-appb-000076
参考中间体v12的制备方法，区别在于用4-溴-2,5-二氟苯腈替换2,6-二氯烟腈，用6,7-二氢-5H-环戊二烯[b]吡啶-7-腈替换2,3-二氢-1H-茚-1-甲腈，得到中间体化合物v23。LCMS：m/z 323.0[M+H] +。 Refer to the preparation method of intermediate v12, the difference is that 2,6-dichloronicotinonitrile is replaced by 4-bromo-2,5-difluorobenzonitrile, and 6,7-dihydro-5H-cyclopentadiene[b] Substitution of pyridine-7-carbonitrile for 2,3-dihydro-1H-indene-1-carbonitrile affords intermediate compound v23. LCMS: m/z 323.0 [M+H] + .
中间体v24intermediate v24
Figure PCTCN2022130850-appb-000077
Figure PCTCN2022130850-appb-000077
步骤1：将4-乙酰基-2-氟苯甲腈(900mg,5.5mmol)溶于干燥的DAST(6mL)中，45℃搅拌48小时。将反应液冷却至室温，缓慢的滴加到冰/碳酸钠水溶液中，保持体系成碱性，用EA(50mL)萃取三次，有机相用硫酸钠干燥后浓缩，过柱(PE：EA＝50:1)得到化合物v24-1(810mg,产率79％)。Step 1: 4-acetyl-2-fluorobenzonitrile (900mg, 5.5mmol) was dissolved in dry DAST (6mL), stirred at 45°C for 48 hours. The reaction solution was cooled to room temperature, slowly added dropwise to ice/sodium carbonate aqueous solution to keep the system alkaline, extracted three times with EA (50 mL), the organic phase was dried over sodium sulfate and concentrated, passed through a column (PE:EA=50 : 1) Compound v24-1 (810 mg, yield 79%) was obtained.
步骤2-3：参考中间体v3的制备方法，得到中间体化合物v24。LCMS：m/z 307.0[M+H] +。 Step 2-3: Refer to the preparation method of intermediate v3 to obtain intermediate compound v24. LCMS: m/z 307.0 [M+H] + .
中间体v25intermediate v25
Figure PCTCN2022130850-appb-000078
Figure PCTCN2022130850-appb-000078
步骤1：将2-氯-5H,6H,7H-环戊二烯并[B]吡啶-5-酮(CAS NO.1092301-56-8)(200mg,1.2mmol)溶于甲醇(10mL),0℃向上述溶液中加入硼氢化钠(136.5mg,3.60mmol)，反应室温搅拌16小时。浓缩，用EA(50mL x 3)萃取，合并有机层，依次用水(8mL)、饱和食盐水(8mL)洗涤，无水硫酸钠干燥，过滤，滤液减压下蒸除溶剂，过柱得到化合物v25-1(190mg,产率94％)。LCMS：m/z 170.2[M+H] +。 Step 1: Dissolve 2-chloro-5H,6H,7H-cyclopenta[B]pyridin-5-one (CAS NO.1092301-56-8) (200mg, 1.2mmol) in methanol (10mL), Sodium borohydride (136.5 mg, 3.60 mmol) was added to the above solution at 0°C, and the reaction was stirred at room temperature for 16 hours. Concentrate, extract with EA (50mL x 3), combine the organic layers, wash with water (8mL) and saturated brine (8mL) successively, dry over anhydrous sodium sulfate, filter, evaporate the filtrate to remove the solvent under reduced pressure, and pass through the column to obtain compound v25 -1 (190 mg, yield 94%). LCMS: m/z 170.2 [M+H] + .
步骤2：将二氯亚砜(267mg，2.24mmol)滴加到化合物v25-1(190mg,1.12mmol)的二氯甲烷(10ml)的溶液中。室温搅拌3个小时。往反应液加入100ml的冰水。再用NaHCO 3饱和溶液把反应液的pH调到8-9。用DCM(200ml)萃取，再用EA(200ml)萃取两次。有机相用无水硫酸钠干燥。过滤浓缩得到化合物v25-2，直接用于下一步。 Step 2: Thionyl chloride (267mg, 2.24mmol) was added dropwise to a solution of compound v25-1 (190mg, 1.12mmol) in dichloromethane (10ml). Stir at room temperature for 3 hours. 100 ml of ice water was added to the reaction solution. The pH of the reaction solution was adjusted to 8-9 with NaHCO 3 saturated solution. Extracted with DCM (200ml) and twice with EA (200ml). The organic phase was dried over anhydrous sodium sulfate. Compound v25-2 was obtained by filtration and concentration, which was directly used in the next step.
步骤3：将化合物v25-2(200mg)和氰化钠(219.5mg，4.48mmol)溶于二甲亚砜(5mL),60℃反应2小时。用EA(50mL x 3)萃取，合并有机层，依次用水(8mL)、饱和食盐水(8mL)洗涤，无水硫酸钠干燥，过滤，滤液减压下蒸除溶剂，过柱得到的化合物v25-3(120mg,产率60.9％)。Step 3: Compound v25-2 (200 mg) and sodium cyanide (219.5 mg, 4.48 mmol) were dissolved in dimethyl sulfoxide (5 mL), and reacted at 60° C. for 2 hours. Extracted with EA (50mL x 3), combined the organic layers, washed with water (8mL) and saturated brine (8mL) successively, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to remove the solvent under reduced pressure, and the compound v25- 3 (120 mg, yield 60.9%).
步骤4-5：参考中间体v3的制备方法，得到中间体化合物v25。LCMS：m/z 367.1[M+H] +。 Step 4-5: Refer to the preparation method of intermediate v3 to obtain intermediate compound v25. LCMS: m/z 367.1 [M+H] + .
中间体v26intermediate v26
Figure PCTCN2022130850-appb-000079
Figure PCTCN2022130850-appb-000079
参考中间体v1的制备方法，区别在于用1,3-二氢异苯并呋喃-1-甲腈替换2,3-二氢-1H-茚-1-甲腈，得到中间体化合物v26。LCMS：m/z 335.3[M+H] +。 Referring to the preparation method of intermediate v1, the difference is that 2,3-dihydro-1H-indene-1-carbonitrile is replaced by 1,3-dihydroisobenzofuran-1-carbonitrile to obtain intermediate compound v26. LCMS: m/z 335.3 [M+H] + .
中间体v27intermediate v27
Figure PCTCN2022130850-appb-000080
Figure PCTCN2022130850-appb-000080
参考中间体v3的制备方法，区别在于用4-溴-2,6-二氟苯腈替换2-氟-4-三氟甲基苯腈，得到中间体化合物v27。Referring to the preparation method of intermediate v3, the difference is that 2-fluoro-4-trifluoromethylbenzonitrile is replaced by 4-bromo-2,6-difluorobenzonitrile to obtain intermediate compound v27.
中间体v28intermediate v28
Figure PCTCN2022130850-appb-000081
Figure PCTCN2022130850-appb-000081
参考中间体v3的制备方法，区别在于用5,6,7,8-四氢喹啉-5-甲腈替换2-氟-4-三氟甲基苯腈，得到中间体化合物v28。LCMS：m/z 348.3[M+H] +。 Referring to the preparation method of intermediate v3, the difference is that 2-fluoro-4-trifluoromethylbenzonitrile is replaced by 5,6,7,8-tetrahydroquinoline-5-carbonitrile to obtain intermediate compound v28. LCMS: m/z 348.3 [M+H] + .
中间体v29intermediate v29
Figure PCTCN2022130850-appb-000082
Figure PCTCN2022130850-appb-000082
参考中间体v3的制备方法，区别在于用3,4-二氢-2H-1-苯并吡喃-4-甲腈替换6,7-二氢-5H-环戊二烯[b]吡啶-5-腈，得到中间体化合物v29。LCMS：m/z 347.1[M-H] -。 Refer to the preparation method of intermediate v3, the difference is that 6,7-dihydro-5H-cyclopentadiene[b]pyridine is replaced by 3,4-dihydro-2H-1-chromene-4-carbonitrile- 5-carbonitrile to obtain intermediate compound v29. LCMS: m/z 347.1 [MH] - .
中间体v30intermediate v30
Figure PCTCN2022130850-appb-000083
Figure PCTCN2022130850-appb-000083
参考中间体v3的制备方法，区别在于用5,6,7,8-四氢喹啉-5-甲腈替换6,7-二氢-5H-环戊二烯[b]吡啶-5-腈，得到中间体化合物v30。Refer to the preparation method of intermediate v3, the difference is that 6,7-dihydro-5H-cyclopentadiene[b]pyridine-5-carbonitrile is replaced by 5,6,7,8-tetrahydroquinoline-5-carbonitrile , to obtain the intermediate compound v30.
参照上述中间体的制备方法，合成以下中间体化合物。以3,3-二氟-2,2-二氢-1H-茚-1-酮(CAS NO:1510778-04-7)和2-氯-6-(三氟甲基)烟酰胺为原料，得到中间体化合物v31；以2-环丙基-2-苯基乙睛和2-氯-6-(三氟甲基)烟腈为原料，得到中间体化合物v32；以3,4-二氢-2H-1-苯并吡喃-4-甲腈和2-氯-6-(三氟甲基)烟腈为原料，得到中间体化合物v33；以6,7-二氢-5H-环戊二烯[b]吡啶-5-腈和2-氯-4-环丙基苄 腈为原料，得到中间体化合物v34；以6,7,8,9-四氢-5H-苯并环庚烯-5-甲腈(CAS NO:62248-67-3)和2-氯-6-(三氟甲基)烟酰胺为原料，得到中间体化合物v35；以5,6-二氢-7H-吡咯并[1,2-A]咪唑-7-酮(CAS NO:112513-82-3)和2-氯-6-(三氟甲基)烟腈为原料，得到中间体化合物v36；以4,6-二氟-2,3-二氢-1H-茚-1-腈和2-氯-6-(三氟甲基)烟腈为原料，得到中间体化合物v37；以6,7-二氢-5H-吡咯并[1,2-a]咪唑-5-酮和2-氯-6-(三氟甲基)烟腈为原料，得到中间体化合物v38；以5,6-二氢-4H-吡咯并[1,2-b]吡唑-4-酮和2-氯-6-(三氟甲基)烟腈为原料，得到中间体化合物v39；以3,4-二氢-2H-1-苯并吡喃-4-甲腈和化合物v11-1，得到中间体化合物v40；以7-氟-2,3-二氢-1H-茚-1-腈和2-氯-6-(三氟甲基)烟腈为原料，得到中间体化合物v41；以4-氟-2,3-二氢-1H-茚-1-腈和2-氯-6-(三氟甲基)烟腈为原料，得到中间体化合物v42；以6-氟-2,3-二氢-1H-茚-1-腈和2-氯-6-(三氟甲基)烟腈为原料，得到中间体化合物v43；以3,4-二氢-2H-1-苯并吡喃-4-甲腈和4-(1-氯乙基)-2,5-二氟苄腈(CAS NO:1823439-95-7)为原料，得到中间体化合物v44；以4-氰基-2,3-二氢-1H-茚-1-腈和化合物v11-1为原料，得到中间体化合物v45；以4-溴-2,3-二氢-1H-茚-1-腈和化合物v11-1为原料，得到中间体化合物v46；以3,4-二氢-2H-1-苯并吡喃-4-甲腈和2-氯-4-环丙基-5-氟苯腈为原料，得到中间体化合物v47；以3,4-二氢-2H-1-苯并吡喃-4-甲腈和2-氯-4-环丙基苄腈为原料，得到中间体化合物v48。Referring to the preparation method of the above-mentioned intermediates, the following intermediate compounds were synthesized. Using 3,3-difluoro-2,2-dihydro-1H-inden-1-one (CAS NO:1510778-04-7) and 2-chloro-6-(trifluoromethyl)nicotinamide as raw materials, The intermediate compound v31 was obtained; with 2-cyclopropyl-2-phenylacetonitrile and 2-chloro-6-(trifluoromethyl)nicotinonitrile as raw materials, the intermediate compound v32 was obtained; with 3,4-dihydro -2H-1-benzopyran-4-carbonitrile and 2-chloro-6-(trifluoromethyl)nicotinonitrile are raw materials to obtain intermediate compound v33; 6,7-dihydro-5H-cyclopentadiene Starting from diene[b]pyridine-5-carbonitrile and 2-chloro-4-cyclopropylbenzonitrile, intermediate compound v34 was obtained; 6,7,8,9-tetrahydro-5H-benzocycloheptene -5-carbonitrile (CAS NO:62248-67-3) and 2-chloro-6-(trifluoromethyl)nicotinamide were used as raw materials to obtain intermediate compound v35; 5,6-dihydro-7H-pyrrole [1,2-A]imidazol-7-one (CAS NO:112513-82-3) and 2-chloro-6-(trifluoromethyl)nicotinonitrile were used as raw materials to obtain intermediate compound v36; with 4, 6-Difluoro-2,3-dihydro-1H-indene-1-carbonitrile and 2-chloro-6-(trifluoromethyl)nicotinonitrile were starting materials to obtain intermediate compound v37; 6,7-dihydro -5H-pyrrolo[1,2-a]imidazol-5-one and 2-chloro-6-(trifluoromethyl)nicotinonitrile as raw materials to obtain intermediate compound v38; 5,6-dihydro-4H -Pyrrolo[1,2-b]pyrazol-4-one and 2-chloro-6-(trifluoromethyl)nicotinonitrile as raw materials to obtain intermediate compound v39; 3,4-dihydro-2H- 1-benzopyran-4-carbonitrile and compound v11-1, to obtain intermediate compound v40; Trifluoromethyl) nicotinonitrile as starting material to obtain intermediate compound v41; 4-fluoro-2,3-dihydro-1H-indene-1-carbonitrile and 2-chloro-6-(trifluoromethyl) nicotinonitrile As raw material, intermediate compound v42 is obtained; with 6-fluoro-2,3-dihydro-1H-indene-1-carbonitrile and 2-chloro-6-(trifluoromethyl)nicotinonitrile as raw material, intermediate compound is obtained v43; with 3,4-dihydro-2H-1-benzopyran-4-carbonitrile and 4-(1-chloroethyl)-2,5-difluorobenzonitrile (CAS NO:1823439-95- 7) as raw material, to obtain intermediate compound v44; to 4-cyano-2,3-dihydro-1H-indene-1-carbonitrile and compound v11-1 as raw materials to obtain intermediate compound v45; to 4-bromo- 2,3-dihydro-1H-indene-1-carbonitrile and compound v11-1 were used as raw materials to obtain intermediate compound v46; 3,4-dihydro-2H-1-benzopyran-4-carbonitrile and 2-Chloro-4-cyclopropyl-5-fluorobenzonitrile was used as starting material to obtain intermediate compound v47; 3,4-dihydro-2H-1-benzopyran-4-carbonitrile and 2-chloro- Using 4-cyclopropylbenzonitrile as starting material, the intermediate compound v48 was obtained.
Figure PCTCN2022130850-appb-000084
Figure PCTCN2022130850-appb-000084
Figure PCTCN2022130850-appb-000085
Figure PCTCN2022130850-appb-000085
中间体v49intermediate v49
Figure PCTCN2022130850-appb-000086
Figure PCTCN2022130850-appb-000086
步骤1：在氮气保护下，0-5℃，将NaH(5.2g，60％,130mmol)分批加入到6,7-二氢-5H-环戊二烯[b]吡啶-5-腈(4.7g，32.6mmol)的四氢呋喃(90mL)溶液，保温反应0.5-1h。再把4-溴-2-氟苯腈(7.1g，35.86mmol)的THF(10mL)溶液滴加到反应液中。撤掉冰浴，然后室温反应16小时。将反应液缓慢加入水(200mL)和乙酸乙酯(200mL)猝灭反应，分层后，再用EA(100mL*2)萃取，有机相合并后用饱和食盐水(30ml)洗涤并用无水硫酸钠干燥，过滤，滤液浓缩用Flash纯化得到棕色油状化合物v49-1(6g,产率57％)。Step 1: Under nitrogen protection, 0-5 ° C, NaH (5.2g, 60%, 130mmol) was added in portions to 6,7-dihydro-5H-cyclopentadiene[b]pyridine-5-carbonitrile ( 4.7g, 32.6mmol) in tetrahydrofuran (90mL) solution, keep warm for 0.5-1h. A solution of 4-bromo-2-fluorobenzonitrile (7.1 g, 35.86 mmol) in THF (10 mL) was added dropwise to the reaction solution. The ice bath was removed, and then reacted at room temperature for 16 hours. Slowly add water (200mL) and ethyl acetate (200mL) to the reaction solution to quench the reaction, separate the layers, then extract with EA (100mL*2), combine the organic phases, wash with saturated brine (30ml) and wash with anhydrous sulfuric acid It was dried over sodium, filtered, and the filtrate was concentrated and purified by Flash to obtain compound v49-1 (6 g, yield 57%) as a brown oil.
步骤2：将化合物v49-1(6g，18.5mmol)，Pd(PPh 3)Cl 2(1.2g,，1.85mmole)，三乙胺(4.67g,46.25mmole)和三丁基(1-乙氧基乙烯基)锡烷(8g,22.2mmole)加入到N,N-二甲基甲酰胺(100mL)中，氮气置换三次后，加热到100℃，反应搅拌16小时。往反应液加入水(200mL)和乙酸乙酯(200mL),分层并用乙酸乙酯(200mL)萃取两次，合并有机相，饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤，滤液浓缩，粗品经Flash纯化得到棕色固体v49-2(4g,产率68.3％)。LCMS:ESI[M+H] +＝316。 Step 2: Compound v49-1 (6g, 18.5mmol), Pd(PPh 3 )Cl 2 (1.2g, 1.85mmole), triethylamine (4.67g, 46.25mmole) and tributyl (1-ethoxy Vinyl) stannane (8 g, 22.2 mmole) was added into N,N-dimethylformamide (100 mL), and after nitrogen replacement three times, it was heated to 100° C., and the reaction was stirred for 16 hours. Add water (200mL) and ethyl acetate (200mL) to the reaction solution, separate the layers and extract twice with ethyl acetate (200mL), combine the organic phases, wash with saturated brine (100mL), dry over anhydrous sodium sulfate, filter, and the filtrate After concentration, the crude product was purified by Flash to obtain a brown solid v49-2 (4 g, yield 68.3%). LCMS: ESI [M+H] + = 316.
步骤3：在室温下将到化合物v49-2(4g，12.7mmol)加入浓盐酸(50mL，33％)中,加热到100℃，搅拌过夜。浓缩反应液除去浓盐酸得到粗品，然后加入乙酸乙酯(200mL)和饱和碳酸钠水溶液(200mL)萃取，水相再用乙酸乙酯(200mL)萃取一次，合并有机相，然后用饱和食盐水(500mL)洗涤，无水硫酸钠干燥，有机相用短硅胶柱过柱一次，浓缩得到化合物v24(3g,产率77％)。LCMS:ESI[M+H] +＝307。 Step 3: Compound v49-2 (4 g, 12.7 mmol) was added into concentrated hydrochloric acid (50 mL, 33%) at room temperature, heated to 100° C., and stirred overnight. Concentrate the reaction solution to remove concentrated hydrochloric acid to obtain a crude product, then add ethyl acetate (200mL) and saturated aqueous sodium carbonate solution (200mL) for extraction, the aqueous phase is extracted once more with ethyl acetate (200mL), combine the organic phases, and then use saturated brine ( 500 mL) was washed, dried over anhydrous sodium sulfate, the organic phase was passed through a short silica gel column once, and concentrated to obtain compound v24 (3 g, yield 77%). LCMS: ESI [M+H] + = 307.
步骤4：在室温下将DAST(63mL)加入到化合物v24(1.5g，4.9mmol)的二氯甲烷(7mL)溶液中，反应液加热到50℃，搅拌过夜。将反应液缓慢滴加到冰的饱和碳酸钠和乙酸乙酯的溶液中淬灭，乙酸乙酯萃取(200mL X 3)，合并有机相，然后用饱和食盐水(500mL)洗涤，有机相用无水硫酸钠干燥，浓缩有机相得粗品，粗品经柱层析纯化得到中间体v49(800mg,产率50％)。LCMS:ESI[M+H] +＝328.9。 Step 4: DAST (63 mL) was added to a solution of compound v24 (1.5 g, 4.9 mmol) in dichloromethane (7 mL) at room temperature, and the reaction solution was heated to 50° C. and stirred overnight. The reaction solution was slowly added dropwise to an ice solution of saturated sodium carbonate and ethyl acetate to quench, extracted with ethyl acetate (200mL X 3), the organic phases were combined, and then washed with saturated brine (500mL), and the organic phase was washed with Dry over sodium sulfate and concentrate the organic phase to obtain a crude product, which is purified by column chromatography to obtain intermediate v49 (800 mg, yield 50%). LCMS: ESI [M+H] + = 328.9.
中间体v50intermediate v50
Figure PCTCN2022130850-appb-000087
Figure PCTCN2022130850-appb-000087
步骤1：将4-溴-2,5-二氟苯腈(5g,22.94mmol)和三丁基(1-乙氧基乙烯)锡(10.77g,29.82mmol,10.06mL)溶于DMF(60mL)中，加入双三苯基磷二氯化钯(1.61g,2.29mmol)和TEA(6.96g,68.81mmol,9.60mL)。氩气置换三次，升温至100℃搅拌3小时。加入饱和氟化钾水溶液搅拌10小时，然后用乙酸乙酯萃取三次，食盐水洗涤，无水硫酸钠干燥，减压浓缩得到粗产品4-(1-乙氧基乙烯基)-2,5-二氟苯腈(4.5g,crude)。不纯化直接进行下一步。Step 1: Dissolve 4-bromo-2,5-difluorobenzonitrile (5g, 22.94mmol) and tributyl(1-ethoxyethylene)tin (10.77g, 29.82mmol, 10.06mL) in DMF (60mL ), bistriphenylphosphinepalladium dichloride (1.61g, 2.29mmol) and TEA (6.96g, 68.81mmol, 9.60mL) were added. Argon was replaced three times, and the temperature was raised to 100° C. and stirred for 3 hours. Add saturated potassium fluoride aqueous solution and stir for 10 hours, then extract three times with ethyl acetate, wash with brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product 4-(1-ethoxyvinyl)-2,5- Difluorobenzonitrile (4.5 g, crude). Proceed directly to the next step without purification.
步骤2：将4-(1-乙氧基乙烯基)-2,5-二氟苯腈(4.5g,21.51mmol)溶于HCl/dioxane(1M)(50mL)中，室温搅拌0.5小时。减压浓缩除去溶剂，用饱和碳酸氢钠水溶液调pH值大于7，然后用乙酸乙酯萃取三次，合并有机相，食盐水洗涤，无水硫酸钠干燥，减压浓缩得到粗产品。残留物经CombiFlash过柱分离(40g，0～20％EA/PE)得到目标产物4-乙酰基-2,5-二氟苯腈(3.3g,收率：84.69％)淡黄色固体。Step 2: Dissolve 4-(1-ethoxyvinyl)-2,5-difluorobenzonitrile (4.5 g, 21.51 mmol) in HCl/dioxane (1M) (50 mL), and stir at room temperature for 0.5 hour. Concentrate under reduced pressure to remove the solvent, adjust the pH value to greater than 7 with saturated aqueous sodium bicarbonate solution, then extract three times with ethyl acetate, combine the organic phases, wash with brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a crude product. The residue was separated by CombiFlash column (40g, 0-20% EA/PE) to obtain the target product 4-acetyl-2,5-difluorobenzonitrile (3.3g, yield: 84.69%) as a pale yellow solid.
步骤3：将4-乙酰基-2,5-二氟苯腈(1g,5.52mmol)溶于DAST(10mL)中，氩气置换三次，升温至45℃搅拌4小时。冷却至室温，把反应液缓慢滴加到冰浴中淬灭反应，然后用饱和碳酸氢钠水溶液调pH值大于7，然后用乙酸乙酯萃取三次，合并有机相，无水硫酸钠干燥，减压浓缩得到粗产品。残留物经CombiFlash过柱分离(12g，0～10％EA/PE)得到目标产物v50-1(0.7g,收率：62.42％)淡黄色油状物。 1H NMR(400MHz,DMSO-d 6)δ8.18(dd,J＝10.0,5.2Hz,1H),7.79(dd,J＝9.2,6.0Hz,1H),2.01(td,J＝19.2,0.8Hz,3H)。 Step 3: Dissolve 4-acetyl-2,5-difluorobenzonitrile (1 g, 5.52 mmol) in DAST (10 mL), replace with argon three times, heat up to 45°C and stir for 4 hours. Cool to room temperature, slowly drop the reaction solution into an ice bath to quench the reaction, then use saturated aqueous sodium bicarbonate to adjust the pH value to greater than 7, then extract three times with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, and reduce Concentrate under reduced pressure to obtain the crude product. The residue was separated by CombiFlash column (12 g, 0-10% EA/PE) to obtain the target product v50-1 (0.7 g, yield: 62.42%) as a pale yellow oil. 1 H NMR (400MHz, DMSO-d 6 )δ8.18(dd, J=10.0,5.2Hz,1H),7.79(dd,J=9.2,6.0Hz,1H),2.01(td,J=19.2,0.8 Hz, 3H).
步骤4：将6,7-二氢-5H-环戊二烯[b]吡啶-5-腈(0.45g,3.12mmol)溶于THF(15mL)中，氩气保护下降温至0℃，分批次加入NaH(499.40mg,12.49mmol,60％纯度)，然后0℃搅拌0.5小时，然后加入化合物v50-1(634.04mg,3.12mmol)和THF(3mL)。缓慢恢复到室温搅拌过夜。用水淬灭反应，乙酸乙酯萃取三次，合并有机相，食盐水洗涤，无水硫酸钠干燥，减压浓缩得到粗产品。残留物经Combiflash过柱分离(12g，0～40％EA/PE)得到目标产物v50-2(0.7g,收率：68.52％)淡黄色固体。LCMS:ESI[M+H] +＝328.0。 Step 4: Dissolve 6,7-dihydro-5H-cyclopentadiene[b]pyridine-5-carbonitrile (0.45g, 3.12mmol) in THF (15mL), cool down to 0°C under the protection of argon, and separate NaH (499.40 mg, 12.49 mmol, 60% purity) was added in batches, then stirred at 0 °C for 0.5 h, then compound v50-1 (634.04 mg, 3.12 mmol) and THF (3 mL) were added. Slowly return to room temperature and stir overnight. The reaction was quenched with water, extracted three times with ethyl acetate, the organic phases were combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The residue was separated by Combiflash column (12 g, 0-40% EA/PE) to obtain the target product v50-2 (0.7 g, yield: 68.52%) as a pale yellow solid. LCMS: ESI [M+H] + = 328.0.
步骤5：将化合物v50-2(0.7g,2.14mmol)溶于浓HCl(10mL)，升温至60℃搅拌20小时。减压浓缩除去溶剂，然后溶于水，用饱和碳酸氢钠溶液调pH值大于7，再用乙酸乙酯萃取三次，合并有机相，食盐水洗涤，无水硫酸钠干燥，减压浓缩得到粗产品。残留物经Combiflash过柱分离(12g，0～60％EA/PE)得到目标化合物v50(0.5g,收率：67.51％)淡黄色固体。LCMS:ESI[M+H] +＝347.0。 Step 5: Compound v50-2 (0.7 g, 2.14 mmol) was dissolved in concentrated HCl (10 mL), heated to 60° C. and stirred for 20 hours. Concentrate under reduced pressure to remove the solvent, then dissolve in water, use saturated sodium bicarbonate solution to adjust the pH value to greater than 7, then extract three times with ethyl acetate, combine the organic phases, wash with brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain crude product. The residue was separated by Combiflash column (12 g, 0-60% EA/PE) to obtain the target compound v50 (0.5 g, yield: 67.51%) as a pale yellow solid. LCMS: ESI [M+H] + = 347.0.
中间体v51intermediate v51
Figure PCTCN2022130850-appb-000088
Figure PCTCN2022130850-appb-000088
步骤一：将化合物2-氟-4-碘苯甲腈(1.0g，4.06mmol,1.0eq)，氟化钾(445mg,7.7mmol,1.9eq)，碘化亚铜(1.9g,10.16mmol,2.5eq)，三甲基(全氟乙基)硅烷(1.7g,8.12mmol,2.0eq)加入到无水DMF(14mL)中，氩气吹扫10秒后密封。80℃下微波反应6小时。将反应液倒入水中，用乙酸乙酯(500mL*2)萃取，有机相用饱和食盐水(100mL)洗涤，用无水硫酸钠干燥，过滤浓缩，用Flash纯化(石油醚:乙酸乙酯＝0-20:1)得到化合物2-氟-4-(全氟乙基)苯甲腈(300mg，收率：30.9％)。 1H NMR(400MHz,DMSO-d 6)δ8.25(t,J＝7.4Hz,1H),8.08(d,J＝9.6Hz,1H),7.81(d,J＝8.0Hz,1H)。 Step 1: Compound 2-fluoro-4-iodobenzonitrile (1.0g, 4.06mmol, 1.0eq), potassium fluoride (445mg, 7.7mmol, 1.9eq), cuprous iodide (1.9g, 10.16mmol, 2.5eq), trimethyl(perfluoroethyl)silane (1.7g, 8.12mmol, 2.0eq) were added into anhydrous DMF (14mL), purged with argon for 10 seconds and then sealed. Microwave reaction at 80°C for 6 hours. The reaction solution was poured into water, extracted with ethyl acetate (500 mL*2), the organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, concentrated by filtration, and purified by Flash (petroleum ether: ethyl acetate = 0-20:1) The compound 2-fluoro-4-(perfluoroethyl)benzonitrile (300 mg, yield: 30.9%) was obtained. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.25 (t, J=7.4 Hz, 1H), 8.08 (d, J=9.6 Hz, 1H), 7.81 (d, J=8.0 Hz, 1H).
步骤二：氮气保护下，将化合物6,7-二氢-5H-环戊基[b]吡啶-5-碳腈(1.19g，8.26mmol,1.0eq)加入到无水四氢呋喃(50mL)中，降温至0℃，加入60wt％钠氢(1.32g,33mmol,4.0eq)，保温30min,随后滴加2-氟-4-(全氟乙基)苯甲腈(1.98g,8.26mol,1.0eq)的四氢呋喃溶液(5mL)，室温搅拌过夜。将反应液倒入饱和氯化铵溶液中，用乙酸乙酯(100mL*2)萃取，有机相并用饱和食盐水(100mL)洗涤，用无水硫酸钠干燥，过滤浓缩，用Flash纯化(EA：PE＝50:1-2:1)得到化合物v51-1(3g，收率：100％)。LCMS:ESI[M+H] +＝364.1。 Step 2: Under nitrogen protection, the compound 6,7-dihydro-5H-cyclopentyl[b]pyridine-5-carbonitrile (1.19g, 8.26mmol, 1.0eq) was added to anhydrous tetrahydrofuran (50mL), Cool down to 0°C, add 60wt% sodium hydrogen (1.32g, 33mmol, 4.0eq), keep warm for 30min, then dropwise add 2-fluoro-4-(perfluoroethyl)benzonitrile (1.98g, 8.26mol, 1.0eq ) in tetrahydrofuran (5 mL), stirred overnight at room temperature. The reaction solution was poured into saturated ammonium chloride solution, extracted with ethyl acetate (100mL*2), the organic phase was washed with saturated brine (100mL), dried over anhydrous sodium sulfate, concentrated by filtration, and purified by Flash (EA: PE=50:1-2:1) to obtain compound v51-1 (3 g, yield: 100%). LCMS: ESI [M+H] + = 364.1.
步骤三：将化合物v51-1(2.8g,7.7mmol,1eq)加入到33wt％盐酸(30mL)，加热到80℃，保温搅拌过夜。将反应液缓慢加入饱和碳酸钠水溶液中，调节溶液的PH值为～8，用乙酸乙酯(300mL*2)萃取，有机相用饱和食盐水(200mL)洗涤，用无水硫酸钠干燥，过滤浓缩，用Flash纯化(EA：PE＝50:1-1:1)得到化合物v51(2.5g，收率：85％)。LCMS:ESI[M+H] +＝383.5。 Step 3: Compound v51-1 (2.8g, 7.7mmol, 1eq) was added to 33wt% hydrochloric acid (30mL), heated to 80°C, and kept stirring overnight. Slowly add the reaction solution into saturated aqueous sodium carbonate solution, adjust the pH of the solution to ~8, extract with ethyl acetate (300mL*2), wash the organic phase with saturated brine (200mL), dry over anhydrous sodium sulfate, and filter Concentrated and purified by Flash (EA:PE=50:1-1:1) to obtain compound v51 (2.5 g, yield: 85%). LCMS: ESI [M+H] + = 383.5.
实施例1：化合物Y1及其异构体的制备Embodiment 1: the preparation of compound Y1 and its isomers
Figure PCTCN2022130850-appb-000089
Figure PCTCN2022130850-appb-000089
将化合物v1(80mg,0.241mmol)，DIEA(0.54mL,3.014mmol)溶于乙腈(10mL)中,加入三氯氧磷(0.18mL,1.76mmol)，反应液加热至95℃搅拌2h。将反应液滴入到甲胺的THF溶液(2M,40mL)中， 室温搅拌2h，倒入冰中，用EA(150mL×3)萃取，合并有机层，无水硫酸钠干燥，过滤，滤液减压下蒸除溶剂，制备纯化得到化合物Y1(21.2mg,收率：25％)。LCMS：m/z 346.1[M+H] +； 1H NMR(DMSO-d 6,400MHz):δ8.65(brs,1H),8.26(brs,1H),7.62(d,J＝8.4Hz,1H),7.32(d,J＝7.2Hz,1H),7.20(t,J＝7.2Hz,1H),7.03(t,J＝7.6Hz,1H),6.69(d,J＝8Hz,1H),3.50-3.38(m,2H),3.29(s,3H),3.17-3.13(m,1H),3.06-3.00(m,1H)。 Compound v1 (80mg, 0.241mmol), DIEA (0.54mL, 3.014mmol) were dissolved in acetonitrile (10mL), phosphorus oxychloride (0.18mL, 1.76mmol) was added, and the reaction solution was heated to 95°C and stirred for 2h. The reaction solution was dropped into a THF solution of methylamine (2M, 40mL), stirred at room temperature for 2h, poured into ice, extracted with EA (150mL×3), combined the organic layers, dried over anhydrous sodium sulfate, filtered, and the filtrate was reduced to The solvent was distilled off under reduced pressure, and compound Y1 (21.2 mg, yield: 25%) was prepared and purified. LCMS: m/z 346.1[M+H] + ; 1 H NMR (DMSO-d 6 , 400MHz): δ8.65(brs, 1H), 8.26(brs, 1H), 7.62(d, J=8.4Hz, 1H), 7.32(d, J=7.2Hz, 1H), 7.20(t, J=7.2Hz, 1H), 7.03(t, J=7.6Hz, 1H), 6.69(d, J=8Hz, 1H), 3.50-3.38 (m, 2H), 3.29 (s, 3H), 3.17-3.13 (m, 1H), 3.06-3.00 (m, 1H).
将化合物Y1通过手性高效液相色谱纯化分离(手性分析方法:SFC:IB N5(
Figure PCTCN2022130850-appb-000090
250mm*4.6mm粒径:5um)-Hex-EtOH(70:30)-30min；流速：1.00(ml/min)；温度:30℃；波长：254nm；洗脱时长：30min)，分别得到保留时间为4.698min的单一构型化合物Y1-1和保留时间为5.484min的单一构型化合物Y1-2。 Compound Y1 was purified and separated by chiral high performance liquid chromatography (chiral analysis method: SFC: IB N5(
Figure PCTCN2022130850-appb-000090
250mm*4.6mm particle size: 5um)-Hex-EtOH(70:30)-30min; flow rate: 1.00(ml/min); temperature: 30°C; wavelength: 254nm; elution time: 30min), respectively get the retention time The single-configuration compound Y1-1 is 4.698min and the single-configuration compound Y1-2 is 5.484min.
实施例2：化合物Y2的制备Embodiment 2: the preparation of compound Y2
Figure PCTCN2022130850-appb-000091
Figure PCTCN2022130850-appb-000091
参考实施例1的制备方法，区别在于用环丙基甲基胺替换甲胺，参考实施例1的制备方法，得到化合物Y2。LCMS：m/z 386.1[M+H] +； 1H NMR(DMSO-d 6,400MHz):δ9.41(s,1H),8.79(d,J＝8.0Hz,1H),8.09(d,J＝8.0Hz,1H),7.31(d,J＝6.8Hz,1H),7.17(t,J＝7.4Hz,1H),7.02(t,J＝7.2Hz,1H),6.63(d,J＝7.6,1H),3.52-3.38(m,2H),3.27-3.24(m,2H),2.98-2.84(m,2H),1.19(brs,1H),0.53(d,J＝7.2Hz,2H),0.34(d,J＝3.2Hz,2H)。 Referring to the preparation method of Example 1, the difference is that methylamine is replaced by cyclopropylmethylamine, and referring to the preparation method of Example 1, compound Y2 is obtained. LCMS: m/z 386.1[M+H] + ; 1 H NMR (DMSO-d 6 , 400MHz): δ9.41(s, 1H), 8.79(d, J=8.0Hz, 1H), 8.09(d, J＝8.0Hz, 1H), 7.31(d, J＝6.8Hz, 1H), 7.17(t, J＝7.4Hz, 1H), 7.02(t, J＝7.2Hz, 1H), 6.63(d, J＝ 7.6,1H),3.52-3.38(m,2H),3.27-3.24(m,2H),2.98-2.84(m,2H),1.19(brs,1H),0.53(d,J=7.2Hz,2H) , 0.34 (d, J=3.2Hz, 2H).
实施例3：化合物Y3的制备Embodiment 3: the preparation of compound Y3
Figure PCTCN2022130850-appb-000092
Figure PCTCN2022130850-appb-000092
将化合物v1(65mg,0.196mmol)，DIEA(0.54mL,3.014mmol)溶于乙腈(10mL)中,加入三氯氧磷(0.18mL,1.76mmol)，反应液加热至95℃搅拌2h，反应液待用(第一份反应液)。将3-羟基氮杂环丁烷盐酸盐(82.5mg,0.75mmol)溶于乙腈(2mL)中，加入DIEA(0.54mL,3.014mmol)，反应液于室温并搅拌30min，滴加第一份反应液，滴完，反应液于室温并搅拌1.5h,LCMS检测反应结束后，倒入冰中，用二氯甲烷(20mL×3)萃取，合并有机层，无水硫酸钠干燥，过滤，减压下蒸除溶剂，粗品制备纯化得到化合物Y3(11.9mg,收率：16％)。LCMS：m/z 388.1[M+H] +； 1H NMR(400MHz,DMSO-d 6):δ8.48(d,J＝8Hz,1H),7.91(d,J＝8Hz,1H),7.30(d,J＝6.8Hz,1H),7.18(t,J＝7.6Hz,1H),7.04(q,J＝6.4Hz,1H),6.71(t,J＝7.2Hz,1H),6.02(dd,J 1＝16.8Hz,J 2＝5.6Hz,1H),5.185-4.97(m,1H),4.79-4.50(m,3H),4.08(t,J＝15.6Hz,1H),3.28-3.24(m,2H),2.97-2.79(m,2H)。 Compound v1 (65mg, 0.196mmol), DIEA (0.54mL, 3.014mmol) were dissolved in acetonitrile (10mL), phosphorus oxychloride (0.18mL, 1.76mmol) was added, the reaction solution was heated to 95°C and stirred for 2h, the reaction solution Stand-by (the first reaction solution). 3-Hydroxyazetidine hydrochloride (82.5mg, 0.75mmol) was dissolved in acetonitrile (2mL), DIEA (0.54mL, 3.014mmol) was added, the reaction solution was stirred at room temperature for 30min, and the first portion was added dropwise The reaction solution was dropped, and the reaction solution was stirred at room temperature for 1.5h. After the reaction was detected by LCMS, it was poured into ice, extracted with dichloromethane (20mL×3), the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and reduced The solvent was evaporated under reduced pressure, and the crude product was prepared and purified to obtain compound Y3 (11.9 mg, yield: 16%). LCMS: m/z 388.1 [M+H] + ; 1 H NMR (400MHz, DMSO-d 6 ): δ8.48 (d, J = 8Hz, 1H), 7.91 (d, J = 8Hz, 1H), 7.30 (d, J=6.8Hz, 1H), 7.18(t, J=7.6Hz, 1H), 7.04(q, J=6.4Hz, 1H), 6.71(t, J=7.2Hz, 1H), 6.02(dd , J 1 =16.8Hz, J 2 =5.6Hz, 1H), 5.185-4.97(m, 1H), 4.79-4.50(m, 3H), 4.08(t, J=15.6Hz, 1H), 3.28-3.24( m,2H), 2.97-2.79(m,2H).
实施例4：化合物Y-4及其异构体的制备Embodiment 4: the preparation of compound Y-4 and its isomer
Figure PCTCN2022130850-appb-000093
Figure PCTCN2022130850-appb-000093
参考实施例1的制备方法，区别在于用(R)-3-吡咯烷醇替换甲胺，得到化合物Y4。将化合物Y4通过LCMS[流动相:15min内从60％水(0.02％NH 4Ac)和40％乙腈至5％水(0.02％NH 4Ac)和95％乙腈,最终在此条件下]分离，分别得到保留时间为5.697min的单一构型化合物Y4-1和保留时间为6.209min的单一构型化合物Y4-2。 Referring to the preparation method of Example 1, the difference is that methylamine is replaced with (R)-3-pyrrolidinol to obtain compound Y4. Compound Y4 was separated by LCMS [mobile phase: from 60% water (0.02% NH 4 Ac) and 40% acetonitrile to 5% water (0.02% NH 4 Ac) and 95% acetonitrile within 15 min, finally under this condition], The single-configuration compound Y4-1 with a retention time of 5.697min and the single-configuration compound Y4-2 with a retention time of 6.209min were obtained respectively.
化合物Y4-1：LCMS：m/z 402.1[M+H] +. 1H NMR(DMSO-d 6,400MHz):δ8.883-8.619(m,1H),7.969-7.940(m,1H),7.29(d,J＝7.6Hz,1H),7.18(t,J＝7.6Hz,1H),7.075-7.009(m,1H),6.75(d,J＝7.6Hz,1H),5.400-5.251(d,J＝59.6Hz,1H),4.43(d,J＝4,1H),4.232-4.047(m,1H),3.909-3.827(m,1H),3.792(m, 1H),3.17(t,J＝7.2Hz,2H),2.896-2.752(m,2H),2.218-2.122(m,1H),2.023-1.882(m,1H)。 Compound Y4-1: LCMS: m/z 402.1[M+H] + . 1 H NMR (DMSO-d 6 , 400MHz): δ8.883-8.619 (m, 1H), 7.969-7.940 (m, 1H), 7.29(d, J=7.6Hz, 1H), 7.18(t, J=7.6Hz, 1H), 7.075-7.009(m, 1H), 6.75(d, J=7.6Hz, 1H), 5.400-5.251(d ,J=59.6Hz,1H),4.43(d,J=4,1H),4.232-4.047(m,1H),3.909-3.827(m,1H),3.792(m,1H),3.17(t,J =7.2Hz, 2H), 2.896-2.752(m, 2H), 2.218-2.122(m, 1H), 2.023-1.882(m, 1H).
化合物Y4-2：LCMS：m/z 402.1[M+H] +. 1H NMR(DMSO-d 6,400MHz):δ8.883-8.619(m,1H),7.969-7.940(m,1H),7.29(d,J＝7.6Hz,1H),7.18(t,J＝7.6Hz,1H),7.075-7.009(m,1H),6.75(d,J＝7.6Hz,1H),5.400-5.251(d,J＝59.6Hz,1H),4.43(d,J＝4,1H),4.232-4.047(m,1H),3.909-3.827(m,1H),3.792(s,1H),3.17(t,J＝7.2Hz,2H),2.896-2.752(m,2H),2.218-2.122(m,1H),2.023-1.882(m,1H)。 Compound Y4-2: LCMS: m/z 402.1[M+H] + . 1 H NMR (DMSO-d 6 , 400MHz): δ8.883-8.619 (m, 1H), 7.969-7.940 (m, 1H), 7.29(d, J=7.6Hz, 1H), 7.18(t, J=7.6Hz, 1H), 7.075-7.009(m, 1H), 6.75(d, J=7.6Hz, 1H), 5.400-5.251(d ,J=59.6Hz,1H),4.43(d,J=4,1H),4.232-4.047(m,1H),3.909-3.827(m,1H),3.792(s,1H),3.17(t,J =7.2Hz, 2H), 2.896-2.752(m, 2H), 2.218-2.122(m, 1H), 2.023-1.882(m, 1H).
实施例5：化合物Y5的制备Embodiment 5: the preparation of compound Y5
Figure PCTCN2022130850-appb-000094
Figure PCTCN2022130850-appb-000094
参考实施例1的制备方法，区别在于用顺式-2-氟环丙胺替换甲胺，得到化合物Y5。LCMS MS:390.1[M+H] +。 1H NMR(CDCl 3,400MHz):δ9.15(s,1H),8.75(d,J＝9.6Hz,1H),7.61(d,J＝8.0Hz,1H),7.35-7.32(m,1H),7.22(t,J＝8.0Hz,1H),7.05(t,J＝8.0Hz,1H),6.75-6.70(m,1H),4.85-4.64(m,1H),3.49-3.32(m,2H),3.18-3.10(m,1H),3.00-2.89(m,2H),1.29-1.24(m,2H)。 Referring to the preparation method of Example 1, the difference is that methylamine is replaced by cis-2-fluorocyclopropylamine to obtain compound Y5. LCMS MS: 390.1 [M+H] + . 1 H NMR (CDCl 3 , 400MHz): δ9.15(s, 1H), 8.75(d, J=9.6Hz, 1H), 7.61(d, J=8.0Hz, 1H), 7.35-7.32(m, 1H ),7.22(t,J=8.0Hz,1H),7.05(t,J=8.0Hz,1H),6.75-6.70(m,1H),4.85-4.64(m,1H),3.49-3.32(m, 2H), 3.18-3.10(m, 1H), 3.00-2.89(m, 2H), 1.29-1.24(m, 2H).
实施例6：化合物Y6的制备Embodiment 6: the preparation of compound Y6
Figure PCTCN2022130850-appb-000095
Figure PCTCN2022130850-appb-000095
参考实施例1的制备方法，区别在于用2-甲氧基乙胺替换甲胺，得到化合物Y6。LCMS：m/z 390.1[M+H] +； 1H NMR(CDCl 3,400MHz):δ8.90(brs,1H),8.72(d,J＝7.6Hz,1H),7.61(d,J＝8Hz,1H),7.31(d,J＝7.2Hz,1H),7.20(t,J＝7.2Hz,1H),7.03(t,J＝7.2Hz,1H),6.72(d,J＝8Hz,1H),3.79-3.71(m,4H),3.49-3.41(m,2H),3.46(s,3H),3.18-3.01(m,2H)。 Referring to the preparation method of Example 1, the difference is that methylamine is replaced with 2-methoxyethylamine to obtain compound Y6. LCMS: m/z 390.1[M+H] + ; 1 H NMR (CDCl 3 , 400MHz): δ8.90(brs, 1H), 8.72(d, J=7.6Hz, 1H), 7.61(d, J= 8Hz, 1H), 7.31(d, J=7.2Hz, 1H), 7.20(t, J=7.2Hz, 1H), 7.03(t, J=7.2Hz, 1H), 6.72(d, J=8Hz, 1H ), 3.79-3.71(m, 4H), 3.49-3.41(m, 2H), 3.46(s, 3H), 3.18-3.01(m, 2H).
实施例7：化合物Y7的制备Embodiment 7: the preparation of compound Y7
Figure PCTCN2022130850-appb-000096
Figure PCTCN2022130850-appb-000096
参考实施例1的制备方法，区别在于用2–2-二氟乙胺替换甲胺，得到化合物Y7。LCMS：m/z 396.1[M+H] +； 1H NMR(CDCl 3,400MHz).δ8.76(d,J＝8Hz,2H),7.63(d,J＝8.4Hz,1H),7.34(d,J＝7.6Hz,1H),7.22(t,J＝8.4Hz,1H),7.04(t,J＝7.6Hz,1H),6.66(t,J＝7.6Hz,1H),6.16(tt,J 1＝56Hz,J 2＝4.4Hz,1H),3.75(tt,J 1＝14.8Hz,J 2＝4Hz,2H),3.44(t,J＝8Hz,2H),3.21-3.14(m,1H),3.02-2.95(m,1H)。 Referring to the preparation method of Example 1, the difference is that methylamine is replaced with 2-2-difluoroethylamine to obtain compound Y7. LCMS: m/z 396.1 [M+H] + ; 1 H NMR (CDCl 3 , 400 MHz). δ8.76 (d, J = 8 Hz, 2H), 7.63 (d, J = 8.4 Hz, 1 H), 7.34 ( d, J=7.6Hz, 1H), 7.22(t, J=8.4Hz, 1H), 7.04(t, J=7.6Hz, 1H), 6.66(t, J=7.6Hz, 1H), 6.16(tt, J 1 =56Hz, J 2 =4.4Hz, 1H), 3.75(tt, J 1 =14.8Hz, J 2 =4Hz, 2H), 3.44(t, J=8Hz, 2H), 3.21-3.14(m, 1H ),3.02-2.95(m,1H).
实施例8：化合物Y8的制备Embodiment 8: the preparation of compound Y8
Figure PCTCN2022130850-appb-000097
Figure PCTCN2022130850-appb-000097
参考实施例1的制备方法，区别在于用L-氨基丙醇替换甲胺，得到化合物Y8。LCMS：m/z 390 [M+H] +； 1H NMR(DMSO-d 6,400MHz):δ8.97-8.71(m,2H),8.09-7.90(m,1H),7.39-7.27(m,1H),7.27-7.13(m,1H),7.10-6.96(m,1H),6.77-6.56(m,1H),4.94(s,1H),4.57-4.41(m,1H),3.66-3.43(m,2H),3.30-3.17(m,2H),3.02-2.75(m,2H),1.33-1.20(m,3H)。 Referring to the preparation method of Example 1, the difference is that methylamine is replaced by L-aminopropanol to obtain compound Y8. LCMS: m/z 390 [M+H] + ; 1 H NMR (DMSO-d 6 , 400MHz): δ8.97-8.71(m, 2H), 8.09-7.90(m, 1H), 7.39-7.27(m ,1H),7.27-7.13(m,1H),7.10-6.96(m,1H),6.77-6.56(m,1H),4.94(s,1H),4.57-4.41(m,1H),3.66-3.43 (m,2H),3.30-3.17(m,2H),3.02-2.75(m,2H),1.33-1.20(m,3H).
实施例9：化合物Y9的制备Embodiment 9: the preparation of compound Y9
Figure PCTCN2022130850-appb-000098
Figure PCTCN2022130850-appb-000098
参考实施例1的制备方法，区别在于D-氨基丙醇替换甲胺，得到化合物Y9。LCMS：m/z 390[M+H] +； 1H NMR(DMSO-d 6,400MHz):δ8.83(d,J＝8.4Hz,1H),8.04(brs,1H),7.34-7.31(m,1H),7.20-7.17(m,1H),7.07-7.00(m,1H),6.75(d,J＝6.8Hz,1H),6.64(d,J＝7.2Hz,1H),4.98(brs,1H),4.48(brs,1H),3.69-3.47(m,2H),3.29-3.26(m,2H),3.01-2.84(m,2H),1.24(s,3H)。 Referring to the preparation method of Example 1, the difference is that D-aminopropanol is substituted for methylamine to obtain compound Y9. LCMS: m/z 390[M+H] + ; 1 H NMR (DMSO-d 6 , 400MHz): δ8.83(d, J=8.4Hz, 1H), 8.04(brs, 1H), 7.34-7.31( m,1H),7.20-7.17(m,1H),7.07-7.00(m,1H),6.75(d,J=6.8Hz,1H),6.64(d,J=7.2Hz,1H),4.98(brs ,1H), 4.48(brs,1H), 3.69-3.47(m,2H), 3.29-3.26(m,2H), 3.01-2.84(m,2H), 1.24(s,3H).
实施例10：化合物Y10的制备Embodiment 10: Preparation of compound Y10
Figure PCTCN2022130850-appb-000099
Figure PCTCN2022130850-appb-000099
参考实施例1的制备方法，区别在于化合物v2替换化合物v1，得到化合物Y10。LCMS：m/z 347.1[M+H] +； 1H NMR(DMSO-d 6,400MHz)：δ9.35(s,1H),8.73(d,J＝8.0Hz,1H),8.36(dd,J 1＝2.4Hz,J 2＝4.4Hz,1H),8.07(d,J＝3.2Hz,1H),7.07-7.04(m,2H),3.34-3.17(m,2H),3.11(s,3H)，2.80-2.73(m,2H)。 Referring to the preparation method of Example 1, the difference is that compound v2 replaces compound v1 to obtain compound Y10. LCMS: m/z 347.1[M+H] + ; 1 H NMR (DMSO-d 6 , 400MHz): δ9.35(s, 1H), 8.73(d, J=8.0Hz, 1H), 8.36(dd, J 1 =2.4Hz, J 2 =4.4Hz,1H), 8.07(d,J=3.2Hz,1H),7.07-7.04(m,2H),3.34-3.17(m,2H),3.11(s,3H ), 2.80-2.73(m,2H).
实施例11：化合物Y11的制备Embodiment 11: Preparation of compound Y11
Figure PCTCN2022130850-appb-000100
Figure PCTCN2022130850-appb-000100
参考实施例1的制备方法，区别在于用化合物v2替换化合物v1，用环丙基甲胺替换甲胺，得到化合物Y11。LCMS：m/z 387.2[M+H] +； 1H NMR(DMSO-d 6,400MHz):δ9.43(s)1H),8.81(d,J＝8.4Hz,1H),8.37(s,1H),8.10(d,J＝8.0Hz,1H),7.07(d,J＝2.4Hz,2H),3.49-3.41(m,2H),3.28-3.25(m,2H),2.82-2.78(m,2H),1.19(brs,1H)，0.53(d,J＝7.2Hz,2H)，0.34(m，d,J＝4.0Hz,2H)。 Referring to the preparation method of Example 1, the difference is that compound v1 is replaced by compound v2, and methylamine is replaced by cyclopropylmethylamine to obtain compound Y11. LCMS: m/z 387.2[M+H] + ; 1 H NMR (DMSO-d 6 , 400MHz): δ9.43(s)1H), 8.81(d, J=8.4Hz, 1H), 8.37(s, 1H), 8.10(d, J=8.0Hz, 1H), 7.07(d, J=2.4Hz, 2H), 3.49-3.41(m, 2H), 3.28-3.25(m, 2H), 2.82-2.78(m , 2H), 1.19 (brs, 1H), 0.53 (d, J=7.2Hz, 2H), 0.34 (m, d, J=4.0Hz, 2H).
实施例12：化合物Y12及其异构体的制备Embodiment 12: Preparation of compound Y12 and its isomers
Figure PCTCN2022130850-appb-000101
Figure PCTCN2022130850-appb-000101
参考实施例1的制备方法，区别在于用化合物v3替换化合物v1，得到化合物Y12。LCMS：m/z 346.1[M+H] +； 1H NMR(DMSO-d 6,400MHz):δ9.19(s,1H),8.43(s,1H),8.28(d,J＝7.6Hz,1H),7.90(d,J＝3.2Hz,1H),7.32(s,1H),7.17-7.14(m,2H),3.23-3.09(m,2H).3.06(s,3H),3.28-3.26(m，1H),2.44-2.39(m,1H)。 Referring to the preparation method of Example 1, the difference is that compound v1 is replaced by compound v3 to obtain compound Y12. LCMS: m/z 346.1[M+H] + ; 1 H NMR (DMSO-d 6 , 400MHz): δ9.19(s, 1H), 8.43(s, 1H), 8.28(d, J=7.6Hz, 1H),7.90(d,J=3.2Hz,1H),7.32(s,1H),7.17-7.14(m,2H),3.23-3.09(m,2H).3.06(s,3H),3.28-3.26 (m, 1H), 2.44-2.39 (m, 1H).
将化合物Y12通过手性高效液相色谱纯化分离(手性分析方法:SFC:SFC:IA3.0cm(
Figure PCTCN2022130850-appb-000102
250mm*4.6mm粒径:5um)-CO2-EtOH(80:20)-30min；流速：60(g/min)；温度:30℃；波长：230nm；洗脱时长：30min)，分别得到保留时间为4.698min的单一构型化合物Y12-1， 1H NMR(DMSO-d 6,400MHz):δ9.18(s,1H),8.42(dd，J 1＝2.0Hz,J 2＝4.0Hz,1H),8.27(d,J＝8.0Hz,1H),7.90 (dd，J 1＝7.2Hz,J 2＝8.4Hz,1H),7.33(s,1H),7.16-7.12(m,2H),3.24-3.13(m,2H).3.05(d，J＝8.8Hz,3H)，2.75-2.26(m，1H),2.43-2.36(m,1H)。 Compound Y12 was purified and separated by chiral high performance liquid chromatography (chiral analysis method: SFC:SFC:IA3.0cm(
Figure PCTCN2022130850-appb-000102
250mm*4.6mm particle size: 5um)-CO2-EtOH(80:20)-30min; flow rate: 60(g/min); temperature: 30°C; wavelength: 230nm; elution time: 30min), respectively get the retention time Compound Y12-1 with a single configuration of 4.698min, 1 H NMR (DMSO-d 6 , 400MHz): δ9.18(s,1H), 8.42(dd, J 1 =2.0Hz, J 2 =4.0Hz,1H ), 8.27 (d, J = 8.0Hz, 1H), 7.90 (dd, J 1 = 7.2Hz, J 2 = 8.4Hz, 1H), 7.33 (s, 1H), 7.16-7.12 (m, 2H), 3.24 -3.13(m, 2H). 3.05(d, J=8.8Hz, 3H), 2.75-2.26(m, 1H), 2.43-2.36(m, 1H).
和保留时间为5.484min的单一构型化合物Y12-2， 1H NMR(DMSO-d 6,400MHz):δ9.18(s,1H),8.42(dd，J 1＝2.0Hz,J 2＝4.0Hz,1H),8.27(d,J＝8.0Hz,1H),7.90(dd，J 1＝7.2Hz,J 2＝8.4Hz,1H),7.33(s,1H),7.16-7.11(m,2H),3.24-3.13(m,2H).3.05(d，J＝3.2Hz,3H)，2.75-2.26(m，1H),2.43-2.36(m,1H)。 And the single-configuration compound Y12-2 with a retention time of 5.484min, 1 H NMR (DMSO-d 6 , 400MHz): δ9.18(s, 1H), 8.42(dd, J 1 =2.0Hz, J 2 =4.0 Hz, 1H), 8.27(d, J=8.0Hz, 1H), 7.90(dd, J 1 =7.2Hz, J 2 =8.4Hz, 1H), 7.33(s, 1H), 7.16-7.11(m, 2H ), 3.24-3.13(m, 2H). 3.05(d, J=3.2Hz, 3H), 2.75-2.26(m, 1H), 2.43-2.36(m, 1H).
实施例13：化合物Y13的制备Embodiment 13: Preparation of Compound Y13
Figure PCTCN2022130850-appb-000103
Figure PCTCN2022130850-appb-000103
步骤1：将中间体v7(100mg,0.30mmol)和五硫化二磷(200mg,0.9mmol)溶于吡啶(8mL)中，反应液在微波中升至150℃并搅拌8小时。反应液浓缩，粗品用正相过柱纯化(EA：PE＝20:1)，得到化合物13-1(45mg)。LCMS：m/z:350.1[M+H] +。 Step 1: Intermediate v7 (100mg, 0.30mmol) and phosphorus pentasulfide (200mg, 0.9mmol) were dissolved in pyridine (8mL), and the reaction solution was raised to 150°C in microwave and stirred for 8 hours. The reaction solution was concentrated, and the crude product was purified by normal phase column (EA:PE=20:1) to obtain compound 13-1 (45 mg). LCMS: m/z: 350.1 [M+H] + .
步骤2：将化合物13-1(40mg，0.115mmol)溶于乙醇(5ml)中，于室温滴加甲胺的THF溶液(2M,3mL)，反应液于0℃搅拌1h,反应液于室温搅拌0.5h,将反应液倒入冰水(10ml)中，用EA(10mL x 3)萃取，合并有机层，依次用水(50mL)、饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，滤液减压下蒸除溶剂，粗品用正相过柱纯化(EA：PE＝4:1)，得到化合物Y13(24.8mg,，收率：62％)。LCMS:m/z 347.1[M+H] +。 1H NMR(CD 3OD-d 4,400MHz):δ8.47(d,J＝8.4Hz,1H),8.02(d,J＝4.4Hz,1H),7.77(d,J＝8Hz,1H),7.69(d,J＝7.6Hz,1H),7.13-7.10(m,1H),3.34-3.25(m,2H),3.12(s,3H),2.99-2.92(m,1H),2.85-2.80(m,1H)。 Step 2: Dissolve compound 13-1 (40mg, 0.115mmol) in ethanol (5ml), add a solution of methylamine in THF (2M, 3mL) dropwise at room temperature, stir the reaction solution at 0°C for 1h, and stir the reaction solution at room temperature 0.5h, the reaction solution was poured into ice water (10ml), extracted with EA (10mL x 3), the organic layers were combined, washed with water (50mL), saturated brine (50mL) successively, dried over anhydrous sodium sulfate, filtered, The solvent was evaporated from the filtrate under reduced pressure, and the crude product was purified by normal phase column (EA:PE=4:1) to obtain compound Y13 (24.8 mg, yield: 62%). LCMS: m/z 347.1 [M+H] + . 1 H NMR (CD 3 OD-d 4 , 400MHz): δ8.47(d, J=8.4Hz, 1H), 8.02(d, J=4.4Hz, 1H), 7.77(d, J=8Hz, 1H) ,7.69(d,J＝7.6Hz,1H),7.13-7.10(m,1H),3.34-3.25(m,2H),3.12(s,3H),2.99-2.92(m,1H),2.85-2.80 (m,1H).
实施例14：化合物Y14的制备Embodiment 14: Preparation of compound Y14
Figure PCTCN2022130850-appb-000104
Figure PCTCN2022130850-appb-000104
参考实施例1的制备方法，区别在于用化合物v4替换化合物v1，得到化合物Y14。LCMS：m/z 360.1[M+H] +； 1H NMR(CDCl 3,400MHz):δ8.70(d,J＝8.0Hz,1H),8.25(s,1H),7.60(d,J＝8.4Hz,1H),7.20(d,J＝8.0Hz,1H),7.14(t,J＝6.8Hz,1H),6.98(t,J＝8.0Hz,1H),6.51(d,J＝7.6Hz,1H),3.26(s,3H),3.02-2.94(m,2H),2.42(t,J＝5.6Hz,2H),2.25-2.16(m,2H)。 Referring to the preparation method of Example 1, the difference is that compound v1 is replaced by compound v4 to obtain compound Y14. LCMS: m/z 360.1[M+H] + ; 1 H NMR (CDCl 3 , 400MHz): δ8.70(d, J=8.0Hz, 1H), 8.25(s, 1H), 7.60(d, J= 8.4Hz, 1H), 7.20(d, J=8.0Hz, 1H), 7.14(t, J=6.8Hz, 1H), 6.98(t, J=8.0Hz, 1H), 6.51(d, J=7.6Hz , 1H), 3.26(s, 3H), 3.02-2.94(m, 2H), 2.42(t, J=5.6Hz, 2H), 2.25-2.16(m, 2H).
实施例15：化合物Y15及其异构体的制备Embodiment 15: Preparation of compound Y15 and its isomers
Figure PCTCN2022130850-appb-000105
Figure PCTCN2022130850-appb-000105
参考实施例1的制备方法，区别在于用化合物v8替换化合物v1，得到化合物Y15。LCMS MS:362.1[M+H] +。 1H NMR(DMSO-d 6,400MHz):δ9.33(s,1H),8.76(d,J＝8.0Hz,1H),8.08(s,1H),7.56-7.48(m,1H),6.84(d,J＝8.0Hz,1H),6.69-6.65(m,1H),6.40(s,1H),4.53-4.51(m,2H),3.09(s,3H),2.42-2.33(m,2H)。 Referring to the preparation method of Example 1, the difference is that compound v1 is replaced by compound v8 to obtain compound Y15. LCMS MS: 362.1 [M+H] + . 1 H NMR (DMSO-d 6 , 400MHz): δ9.33(s, 1H), 8.76(d, J=8.0Hz, 1H), 8.08(s, 1H), 7.56-7.48(m, 1H), 6.84 (d,J=8.0Hz,1H),6.69-6.65(m,1H),6.40(s,1H),4.53-4.51(m,2H),3.09(s,3H),2.42-2.33(m,2H ).
将化合物Y15通过手性高效液相色谱纯化分离(手性分析方法:SFC:IC(
Figure PCTCN2022130850-appb-000106
250mm*4.6mm粒径:5um)-Hex-EtOH(40:60)-30min；流速：1(ml/min)；温度:30℃；波长：214nm；洗脱时长：30min)，分别得到保留时间为4.258min的单一构型化合物Y15-1和保留时间为5.231min的单一构型化合物Y15-2。 Compound Y15 was purified and separated by chiral high performance liquid chromatography (chiral analysis method: SFC:IC(
Figure PCTCN2022130850-appb-000106
250mm*4.6mm particle size: 5um)-Hex-EtOH(40:60)-30min; flow rate: 1(ml/min); temperature: 30°C; wavelength: 214nm; elution time: 30min), respectively get the retention time The single-configuration compound Y15-1 was 4.258min and the single-configuration compound Y15-2 was 5.231min.
实施例16：化合物Y16的制备Embodiment 16: Preparation of compound Y16
Figure PCTCN2022130850-appb-000107
Figure PCTCN2022130850-appb-000107
参考实施例1的制备方法，区别在于用化合物v5替换化合物v1，得到化合物Y16。LCMS：m/z 347.90[M+H] +； 1H NMR(DMSO-d 6,400MHz):δ8.45(d,J＝4.0Hz,1H),8.74(d,J＝8.4Hz,1H),8.12(d,J＝8.0Hz,1H),7.15-7.11(m,1H),6.88(d,J＝8.0Hz,1H),6.71-6.66(m,2H),5.30(d,J＝1.2Hz,2H),3.11(d,J＝4.4Hz,3H)。 Referring to the preparation method of Example 1, the difference is that compound v1 is replaced by compound v5 to obtain compound Y16. LCMS: m/z 347.90[M+H] + ; 1 H NMR (DMSO-d 6 , 400MHz): δ8.45 (d, J=4.0Hz, 1H), 8.74 (d, J=8.4Hz, 1H) ,8.12(d,J=8.0Hz,1H),7.15-7.11(m,1H),6.88(d,J=8.0Hz,1H),6.71-6.66(m,2H),5.30(d,J=1.2 Hz, 2H), 3.11 (d, J=4.4Hz, 3H).
实施例17：化合物Y17的制备Embodiment 17: Preparation of compound Y17
Figure PCTCN2022130850-appb-000108
Figure PCTCN2022130850-appb-000108
参考实施例1的制备方法，区别在于用化合物v9替换化合物v1，得到化合物Y17。LCMS:347.1[M+H] +。 1H NMR(DMSO-d 6,400MHz):δ9.59(s,1H),9.46(br,1H),7.34(d,J＝7.6Hz,1H),7.21(t,J＝7.2Hz,1H),7.05(d,J＝7.2Hz,1H),6.69(br,1H),3.26-3.19(m,2H),3.13(s,3H),2.87-2.85(m,2H)。 Referring to the preparation method of Example 1, the difference is that compound v1 is replaced by compound v9 to obtain compound Y17. LCMS: 347.1 [M+H] + . 1 H NMR (DMSO-d 6 , 400MHz): δ9.59(s, 1H), 9.46(br, 1H), 7.34(d, J=7.6Hz, 1H), 7.21(t, J=7.2Hz, 1H ), 7.05 (d, J=7.2Hz, 1H), 6.69 (br, 1H), 3.26-3.19 (m, 2H), 3.13 (s, 3H), 2.87-2.85 (m, 2H).
实施例18：化合物Y18的制备Embodiment 18: Preparation of Compound Y18
Figure PCTCN2022130850-appb-000109
Figure PCTCN2022130850-appb-000109
参考实施例1的制备方法，区别在于用化合物v15替换化合物v1，得到化合物Y18。LCMS:323.1[M+H] +。 1H NMR(CDCl 3,400MHz):δ9.28(s,1H),7.33-7.21(m,2H),7.18-6.97(m,1H),7.08-6.97(m,1H),6.78-6.72(m,1H),4.39-4.31(m,2H),3.43-3.37(m,3H),3.13-3.08(m,2H),3.03-2.96(m,2H),1.37-1.32(m,3H)。 Referring to the preparation method of Example 1, the difference is that compound v1 is replaced by compound v15 to obtain compound Y18. LCMS: 323.1 [M+H] + . 1 H NMR (CDCl 3 , 400MHz): δ9.28(s,1H),7.33-7.21(m,2H),7.18-6.97(m,1H),7.08-6.97(m,1H),6.78-6.72( m, 1H), 4.39-4.31(m, 2H), 3.43-3.37(m, 3H), 3.13-3.08(m, 2H), 3.03-2.96(m, 2H), 1.37-1.32(m, 3H).
实施例19：化合物Y19的制备Embodiment 19: Preparation of Compound Y19
Figure PCTCN2022130850-appb-000110
Figure PCTCN2022130850-appb-000110
步骤1：将v16(150mg,0.41mmol)，劳森试剂(331mg,0.82mmol)溶于甲苯(15mL)中，反应液在110℃下搅拌16h，用水(20mL)稀释，用EA(30mL x 3)萃取，合并有机层，依次用水(50mL)、饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，滤液减压下蒸除溶剂，粗品用柱层析纯化(石油醚/二氯甲烷＝3:1)得到化合物19-1(100mg)。ESI-MS m/z＝392.9[M-H] -。 Step 1: Dissolve v16 (150mg, 0.41mmol), Lawson's reagent (331mg, 0.82mmol) in toluene (15mL), stir the reaction solution at 110°C for 16h, dilute with water (20mL), wash with EA (30mL x 3 ) extraction, the combined organic layers were washed with water (50mL) and saturated brine (50mL) successively, dried over anhydrous sodium sulfate, filtered, the filtrate was evaporated to remove solvent under reduced pressure, and the crude product was purified by column chromatography (petroleum ether/dichloromethane =3:1) Compound 19-1 (100 mg) was obtained. ESI-MS m/z = 392.9 [MH] - .
步骤2：将化合物19-1(100mg,0.25mmol)，氯化亚铜(5mg,0.05mmol)溶于二甲基亚砜(15mL)中，反应液在氧气氛围下80℃搅拌3h，减压下蒸除溶剂，得到化合物19-2(90mg)。ESI-MS m/z＝377.0[M-H] -。 Step 2: Dissolve compound 19-1 (100mg, 0.25mmol), cuprous chloride (5mg, 0.05mmol) in dimethyl sulfoxide (15mL), stir the reaction solution at 80°C for 3h under an oxygen atmosphere, and depressurize The solvent was distilled off to obtain compound 19-2 (90 mg). ESI-MS m/z = 377.0 [MH] - .
步骤3：将化合物19-2(90mg,0.24mmol)，硝酸银(90mg,0.53mmol)，甲胺THF溶液(2M)(2mL,4.00mmol)溶于甲苯(10mL)中，反应液在110℃搅拌2h，LCMS检测到产物。以水(20mL)稀释，用EA(30mL x 3)萃取，合并有机层，依次用水(50mL)、饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，滤液减压下蒸除溶剂，粗品用柱层析纯化(PE/EA＝1:1)得到的化合物Y19(14mg)，MS:376.1[M+H] +。 1H NMR(DMSO-d 6,400MHz):δ9.01(d,J＝14.4Hz,1H),8.85(s,1H),8.52-8.42(m,1H),7.28(d,J＝7.2Hz,1H),7.16(t,J＝7.6Hz,1H),7.02(t,J＝7.2Hz,1H),6.68-6.61(m,1H),4.19-3.98(m,2H),3.32-3.20(m,2H),3.03(s,3H),2.82-2.69(m,2H)。 Step 3: Compound 19-2 (90mg, 0.24mmol), silver nitrate (90mg, 0.53mmol), methylamine THF solution (2M) (2mL, 4.00mmol) were dissolved in toluene (10mL), and the reaction solution was heated at 110°C After stirring for 2h, the product was detected by LCMS. Diluted with water (20mL), extracted with EA (30mL x 3), combined the organic layers, washed with water (50mL) and saturated brine (50mL) successively, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to remove the solvent under reduced pressure. The crude product was purified by column chromatography (PE/EA=1:1) to obtain compound Y19 (14 mg), MS: 376.1 [M+H] + . 1 H NMR (DMSO-d 6 , 400MHz): δ9.01(d, J=14.4Hz, 1H), 8.85(s, 1H), 8.52-8.42(m, 1H), 7.28(d, J=7.2Hz ,1H),7.16(t,J=7.6Hz,1H),7.02(t,J=7.2Hz,1H),6.68-6.61(m,1H),4.19-3.98(m,2H),3.32-3.20( m,2H), 3.03(s,3H), 2.82-2.69(m,2H).
实施例20：化合物Y20的制备Embodiment 20: Preparation of Compound Y20
Figure PCTCN2022130850-appb-000111
Figure PCTCN2022130850-appb-000111
参考实施例1的制备方法，区别在于用化合物v6替换化合物v1，得到化合物Y20。LCMS：m/z 345.1[M+H] +； 1H NMR(CDCl 3,400MHz):δ8.41-8.36(m,1H),8.10(s,1H),7.58(d,J＝8.0Hz,1H),7.42-7.35(m,1H),7.34-7.28(m,1H),7.22(s,1H),7.16(t,J＝7.2Hz,1H),6.80(d,J＝7.6Hz,1H),3.45-3.35(m,1H),3.25(s,3H),3.18-3.13(m,1H),2.98-2.92(m,1H),2.49-2.34(m,1H)。 Referring to the preparation method of Example 1, the difference is that compound v1 is replaced by compound v6 to obtain compound Y20. LCMS: m/z 345.1[M+H] + ; 1 H NMR (CDCl 3 , 400MHz): δ8.41-8.36 (m, 1H), 8.10 (s, 1H), 7.58 (d, J=8.0Hz, 1H),7.42-7.35(m,1H),7.34-7.28(m,1H),7.22(s,1H),7.16(t,J=7.2Hz,1H),6.80(d,J=7.6Hz,1H ), 3.45-3.35(m,1H), 3.25(s,3H), 3.18-3.13(m,1H), 2.98-2.92(m,1H), 2.49-2.34(m,1H).
实施例21：化合物Y21的制备Example 21: Preparation of Compound Y21
Figure PCTCN2022130850-appb-000112
Figure PCTCN2022130850-appb-000112
参考实施例1的制备方法，区别在于用化合物v11替换化合物v1，得到化合物Y21。LCMS:m/z:318.1[M+H] +. 1H NMR(DMSO-d 6,400MHz):δ9.02(s,1H),8.97(d,J＝4Hz,1H)),7.33(d,J＝7.6Hz,1H),7.21(t,J＝7.2Hz,1H),7.09(d,J＝7.6Hz,1H),7.07(s,1H),6.63(d,J＝7.2Hz,1H),3.23-3.18(m,2H),3.03(d,J＝4.8Hz,3H),2.79-2.77(m,1H),2.50-2.39(m,1H),2.10-2.07(m,1H),0.95-0.91(m,4H)。 Referring to the preparation method of Example 1, the difference is that compound v1 is replaced by compound v11 to obtain compound Y21. LCMS: m/z: 318.1[M+H] + . 1 H NMR (DMSO-d 6 , 400MHz): δ9.02(s, 1H), 8.97(d, J=4Hz, 1H)), 7.33(d ,J=7.6Hz,1H),7.21(t,J=7.2Hz,1H),7.09(d,J=7.6Hz,1H),7.07(s,1H),6.63(d,J=7.2Hz,1H ),3.23-3.18(m,2H),3.03(d,J＝4.8Hz,3H),2.79-2.77(m,1H),2.50-2.39(m,1H),2.10-2.07(m,1H), 0.95-0.91 (m, 4H).
实施例22：化合物Y22的制备Embodiment 22: Preparation of compound Y22
Figure PCTCN2022130850-appb-000113
Figure PCTCN2022130850-appb-000113
参考实施例1的制备方法，区别在于用化合物v12替换化合物v1，得到化合物Y22。LCMS:m/z 318.1[M+H] +。 1H NMR(DMSO-d 6,400MHz):δ8.92(s,1H),8.23(d,J＝8.4Hz,1H),7.34(d,J＝8.4Hz,1H),7.28(d,J＝7.2Hz,1H),7.12(t,J＝7.2Hz,1H),6.98(t,J＝7.2Hz,1H),6.57(d,J＝7.6Hz,1H),3.25-3.19(m,2H),3.05(s,3H),2.83-2.76(m,2H),2.10-2.06(m,1H),1.00-0.95(m,1H),0.88-0.87(m,2H),0.72-0.69(m,1H)。 Referring to the preparation method of Example 1, the difference is that compound v1 is replaced by compound v12 to obtain compound Y22. LCMS: m/z 318.1 [M+H] + . 1 H NMR (DMSO-d 6 , 400MHz): δ8.92(s, 1H), 8.23(d, J=8.4Hz, 1H), 7.34(d, J=8.4Hz, 1H), 7.28(d, J =7.2Hz, 1H), 7.12(t, J=7.2Hz, 1H), 6.98(t, J=7.2Hz, 1H), 6.57(d, J=7.6Hz, 1H), 3.25-3.19(m, 2H ),3.05(s,3H),2.83-2.76(m,2H),2.10-2.06(m,1H),1.00-0.95(m,1H),0.88-0.87(m,2H),0.72-0.69(m ,1H).
实施例23：化合物Y23的制备Embodiment 23: Preparation of Compound Y23
Figure PCTCN2022130850-appb-000114
Figure PCTCN2022130850-appb-000114
参考实施例1的制备方法，区别在于用化合物v13替换化合物v1，得到化合物Y23。LCMS：m/z 363.3[M+H] +。 1H NMR(DMSO-d 6,400MHz):δ9.33-9.31(br,1H),8.71(d,J＝8.4Hz,1H),8.05(s,1H)7.16-7.13(m,1H),6.87-6.82(m,1H),6.63(s,1H),3.29-3.19(m,2H),3.11(s,3H),2.93-2.82(m,2H)。 Referring to the preparation method of Example 1, the difference is that compound v1 is replaced by compound v13 to obtain compound Y23. LCMS: m/z 363.3 [M+H] + . 1 H NMR (DMSO-d 6 , 400MHz): δ9.33-9.31(br, 1H), 8.71(d, J=8.4Hz, 1H), 8.05(s, 1H), 7.16-7.13(m, 1H), 6.87-6.82 (m, 1H), 6.63 (s, 1H), 3.29-3.19 (m, 2H), 3.11 (s, 3H), 2.93-2.82 (m, 2H).
实施例24：化合物Y24的制备Embodiment 24: Preparation of compound Y24
Figure PCTCN2022130850-appb-000115
Figure PCTCN2022130850-appb-000115
参考实施例1的制备方法，区别在于用化合物v17替换化合物v1，得到化合物Y24。LCMS：m/z 374.1[M+H] +； 1H NMR(DMSO-d 6,400MHz):δ9.34(s,1H),8.72-8.70(d,J＝8.0Hz,1H),8.02-8.00(d,J＝8.0Hz,1H),7.26-7.20(m,2H),7.05-7.03(t,J＝8.0Hz,1H),6.61-6.59(d,J＝8.0Hz,1H),3.14(s,3H),2.92-2.89(d,J＝12.0Hz,1H),2.80-2.77(d,J＝12.0Hz,1H),1.50(s,3H),1.48(s,3H)。 Referring to the preparation method of Example 1, the difference is that compound v1 is replaced by compound v17 to obtain compound Y24. LCMS: m/z 374.1[M+H] + ; 1 H NMR (DMSO-d 6 , 400MHz): δ9.34(s, 1H), 8.72-8.70(d, J=8.0Hz, 1H), 8.02- 8.00(d,J=8.0Hz,1H),7.26-7.20(m,2H),7.05-7.03(t,J=8.0Hz,1H),6.61-6.59(d,J=8.0Hz,1H),3.14 (s, 3H), 2.92-2.89 (d, J = 12.0Hz, 1H), 2.80-2.77 (d, J = 12.0Hz, 1H), 1.50 (s, 3H), 1.48 (s, 3H).
实施例26：化合物Y26的制备Embodiment 26: Preparation of compound Y26
Figure PCTCN2022130850-appb-000116
Figure PCTCN2022130850-appb-000116
参考实施例1的制备方法，区别在于用化合物v14替换化合物v1，得到化合物Y26。LCMS:m/z 334.1[M+H] +。 1H NMR(DMSO-d 6,400MHz):δ9.17(br,1H),8.67(d,J＝8.0Hz,1H),8.11(br,1H),7.27-7.17(m,3H),7.01(s,2H),2.99(s,3H),1.88(s,3H)。 Referring to the preparation method of Example 1, the difference is that compound v1 is replaced by compound v14 to obtain compound Y26. LCMS: m/z 334.1 [M+H] + . 1 H NMR (DMSO-d 6 , 400MHz): δ9.17 (br, 1H), 8.67 (d, J=8.0Hz, 1H), 8.11 (br, 1H), 7.27-7.17 (m, 3H), 7.01 (s,2H),2.99(s,3H),1.88(s,3H).
实施例27：化合物Y27的制备Embodiment 27: Preparation of compound Y27
Figure PCTCN2022130850-appb-000117
Figure PCTCN2022130850-appb-000117
参考实施例1的制备方法，区别在于用化合物v8替换化合物v1，用环丙胺替换甲胺，得到化合物Y27。LCMS:m/z 388.1[M+H] +。 1H NMR(DMSO-d 6,400MHz):δ11.07(s,1H),8.66-8.64(d,J＝8.0Hz,1H),7.88-7.86(d,J＝8.0Hz,1H),7.14-7.10(t,J＝16.0Hz,1H),6.89-6.87(d,J＝8.0Hz,1H),6.75-6.71(t,J＝16.0Hz,1H),6.59-6.57(d,J＝8.0Hz,1H),4.56-4.55(m,1H),4.49-4.48(m,1H),3.55(s,1H),2.56(s,2H),0.96-0.94(m,2H),0.82-0.80(m,2H)。 Referring to the preparation method of Example 1, the difference is that compound v1 is replaced by compound v8, and methylamine is replaced by cyclopropylamine to obtain compound Y27. LCMS: m/z 388.1 [M+H] + . 1 H NMR (DMSO-d 6 , 400MHz): δ11.07(s, 1H), 8.66-8.64(d, J=8.0Hz, 1H), 7.88-7.86(d, J=8.0Hz, 1H), 7.14 -7.10(t, J=16.0Hz, 1H), 6.89-6.87(d, J=8.0Hz, 1H), 6.75-6.71(t, J=16.0Hz, 1H), 6.59-6.57(d, J=8.0 Hz,1H),4.56-4.55(m,1H),4.49-4.48(m,1H),3.55(s,1H),2.56(s,2H),0.96-0.94(m,2H),0.82-0.80( m,2H).
实施例28：化合物Y28的制备Embodiment 28: Preparation of Compound Y28
Figure PCTCN2022130850-appb-000118
Figure PCTCN2022130850-appb-000118
参考实施例1的制备方法，区别在于用化合物v8替换化合物v1，用吡咯烷替换甲胺，得到化合物Y28。LCMS:m/z 402.2[M+H] +。 1H NMR(DMSO-d 6,400MHz):δ8.66-8.64(d,J＝8.0Hz,1H),7.96-7.94(d,J＝8.0Hz,1H),7.11-7.07(m,1H),6.83-6.81(dd,J 1＝0.8Hz,d,J 2＝8.0Hz,,1H),6.72-6.68(m,1H),6.42-6.40(dd,J 1＝1.6Hz,d,J 2＝8.0Hz,,1H,1H),4.38-4.36(t,J＝8.0Hz,1H),4.31-4.29(t,J＝8.0Hz,1H),4.12-4.02(m,1H),4.00-3.90(m,1H),3.77(s,2H),2.51-2.49(m,1H),2.46-2.35(m,1H),2.01-1.95(m,4H)。 Referring to the preparation method of Example 1, the difference is that compound v1 is replaced by compound v8, and methylamine is replaced by pyrrolidine to obtain compound Y28. LCMS: m/z 402.2 [M+H] + . 1 H NMR (DMSO-d 6 , 400MHz): δ8.66-8.64(d, J=8.0Hz, 1H), 7.96-7.94(d, J=8.0Hz, 1H), 7.11-7.07(m, 1H) ,6.83-6.81(dd,J 1 =0.8Hz,d,J 2 =8.0Hz,,1H),6.72-6.68(m,1H),6.42-6.40(dd,J 1 =1.6Hz,d,J 2 =8.0Hz,,1H,1H),4.38-4.36(t,J=8.0Hz,1H),4.31-4.29(t,J=8.0Hz,1H),4.12-4.02(m,1H),4.00-3.90 (m,1H), 3.77(s,2H), 2.51-2.49(m,1H), 2.46-2.35(m,1H), 2.01-1.95(m,4H).
实施例29：化合物Y29及其异构体的制备Example 29: Preparation of compound Y29 and its isomers
Figure PCTCN2022130850-appb-000119
Figure PCTCN2022130850-appb-000119
参考实施例1的制备方法，区别在于用化合物v8替换化合物v1，用氘代甲胺盐酸盐替换甲胺，得到化合物Y29。LCMS:m/z 365.1[M+H] +。 1H NMR(DMSO-d 6,400MHz):δ9.33(s,1H),8.78-8.76(d,J＝8.0Hz,1H),8.10-8.08(d,J＝8.0Hz,1H),7.10-7.06(m,1H),6.85-6.83(dd,J 1＝1.2Hz,J 2＝8.0Hz,1H),6.68-6.64(m,1H),6.40-6.38(dd,J 1＝1.6Hz,J 2＝8.0Hz,1H),4.52-4.48(m,1H),4.42-4.38(m,1H),2.42-2.39(m,1H),2.36-2.34(m,1H)。 Referring to the preparation method of Example 1, the difference is that compound v1 is replaced by compound v8, and methylamine is replaced by deuterated methylamine hydrochloride to obtain compound Y29. LCMS: m/z 365.1 [M+H] + . 1 H NMR (DMSO-d 6 , 400MHz): δ9.33(s, 1H), 8.78-8.76(d, J=8.0Hz, 1H), 8.10-8.08(d, J=8.0Hz, 1H), 7.10 -7.06(m,1H),6.85-6.83(dd,J 1 =1.2Hz,J 2 =8.0Hz,1H),6.68-6.64(m,1H),6.40-6.38(dd,J 1 =1.6Hz, J 2 =8.0Hz, 1H), 4.52-4.48(m, 1H), 4.42-4.38(m, 1H), 2.42-2.39(m, 1H), 2.36-2.34(m, 1H).
将化合物Y29通过手性高效液相色谱纯化分离(手性分离方法:SFC:IC 3.0cm(
Figure PCTCN2022130850-appb-000120
250mm*4.6mm粒径:5um)-Hex-EtOH-DEA(70:30:0.2)-15min；流速：(1mL/min)；T:30℃；波长：214nm；洗脱时长：15min)分别得到保留时间为5.978min的单一构型化合物Y29-1和保留时间为8.277min的单一构型化合物Y29-2。 Compound Y29 was purified and separated by chiral high performance liquid chromatography (chiral separation method: SFC: IC 3.0cm (
Figure PCTCN2022130850-appb-000120
250mm*4.6mm particle size: 5um)-Hex-EtOH-DEA(70:30:0.2)-15min; flow rate: (1mL/min); T: 30°C; wavelength: 214nm; elution time: 15min) respectively The single configuration compound Y29-1 with a retention time of 5.978 min and the single configuration compound Y29-2 with a retention time of 8.277 min.
实施例30：化合物Y30的制备Embodiment 30: Preparation of compound Y30
Figure PCTCN2022130850-appb-000121
Figure PCTCN2022130850-appb-000121
参考实施例1的制备方法，区别在于用化合物v2替换化合物v1，用二甲胺替换甲胺，得到化合物Y30。LCMS:m/z 376.1[M+H] +。 1H NMR(DMSO-d 6,400MHz):δ8.55(d,J＝8.0Hz,1H),7.93(d,J＝8.0Hz,1H),7.12-7.08(m,1H),6.83-6.81(dd,J 1＝1.2Hz,J 2＝8.0Hz,1H),6.73-6.68(m,1H),6.40-6.42(dd,J 1＝1.6Hz,J 2＝8.0Hz,1H),4.38-4.26(m,2H),3.31(s,6H),2.47-2.42(m,1H),2.36-2.30(m,1H)。 Referring to the preparation method of Example 1, the difference is that compound v1 is replaced by compound v2, and methylamine is replaced by dimethylamine to obtain compound Y30. LCMS: m/z 376.1 [M+H] + . 1 H NMR (DMSO-d 6 , 400MHz): δ8.55 (d, J = 8.0Hz, 1H), 7.93 (d, J = 8.0Hz, 1H), 7.12-7.08 (m, 1H), 6.83-6.81 (dd, J 1 =1.2Hz, J 2 =8.0Hz, 1H), 6.73-6.68(m, 1H), 6.40-6.42(dd, J 1 =1.6Hz, J 2 =8.0Hz, 1H), 4.38- 4.26 (m, 2H), 3.31 (s, 6H), 2.47-2.42 (m, 1H), 2.36-2.30 (m, 1H).
实施例31：化合物Y31的制备Example 31: Preparation of Compound Y31
Figure PCTCN2022130850-appb-000122
Figure PCTCN2022130850-appb-000122
参考实施例1的制备方法，区别在于用化合物v2替换化合物v1，用环丙胺替换甲胺，得到化合物Y31。LCMS：m/z 373.1[M+H] +； 1H NMR(DMSO-d 6,400MHz):δ11.01(s,1H),8.62(d,J＝8.4Hz,1H),8.41(d,J＝4.0Hz,1H),7.89(s,1H),7.22(s,1H),7.22-7.01(m,1H),3.51(s,1H),3.31-3.23(m,2H),2.91-2.75(m,2H),0.95(d,J＝4.8Hz,2H),0.87-0.78(m,2H)。 Referring to the preparation method of Example 1, the difference is that compound v1 is replaced by compound v2, and methylamine is replaced by cyclopropylamine to obtain compound Y31. LCMS: m/z 373.1[M+H] + ; 1 H NMR (DMSO-d 6 , 400MHz): δ11.01(s, 1H), 8.62(d, J=8.4Hz, 1H), 8.41(d, J＝4.0Hz,1H),7.89(s,1H),7.22(s,1H),7.22-7.01(m,1H),3.51(s,1H),3.31-3.23(m,2H),2.91-2.75 (m, 2H), 0.95 (d, J=4.8Hz, 2H), 0.87-0.78 (m, 2H).
实施例34：化合物Y34的异构体的制备Example 34: Preparation of Isomers of Compound Y34
Figure PCTCN2022130850-appb-000123
Figure PCTCN2022130850-appb-000123
将化合物Y34(200mg)进行手性拆分(
Figure PCTCN2022130850-appb-000124
IG-250*25mm 10μm-CO 2,-MEOH(+0.1％7.0mol/l含氨水的甲醇)-(50:50)-5.0min；流速：70ml/min；T：RT；波长：214nm；洗脱时长：5.0min。)得到： Compound Y34 (200 mg) was subjected to chiral resolution (
Figure PCTCN2022130850-appb-000124
IG-250*25mm 10μm-CO 2,- MEOH (+0.1%7.0mol/l methanol containing ammonia)-(50:50)-5.0min; flow rate: 70ml/min; T: RT; wavelength: 214nm; washing Take off time: 5.0min. )get:
化合物Y34-1(70mg，产率35％，保留时间：1.054min)，LCMS:ESI[M+H] +＝318.0， 1H NMR(400MHz,DMSO-d 6)δ8.82(d,J＝4.2Hz,1H),8.38(d,J＝4.4Hz,1H),7.91(d,J＝8.0Hz,1H),7.11-7.01(m,3H),6.79(s,1H),3.27–3.07(m,2H),3.01(d,J＝4.4Hz,3H),2.80–2.64(m,1H),2.39-2.24(m,1H),1.95–1.82(m,1H),1.03–0.85(m,2H),0.75-0.58(m,2H)；以及 Compound Y34-1 (70 mg, yield 35%, retention time: 1.054 min), LCMS: ESI [M+H] + = 318.0, 1 H NMR (400 MHz, DMSO-d 6 ) δ8.82 (d, J = 4.2Hz, 1H), 8.38(d, J＝4.4Hz, 1H), 7.91(d, J＝8.0Hz, 1H), 7.11-7.01(m, 3H), 6.79(s, 1H), 3.27–3.07( m,2H),3.01(d,J＝4.4Hz,3H),2.80–2.64(m,1H),2.39-2.24(m,1H),1.95–1.82(m,1H),1.03–0.85(m, 2H), 0.75-0.58(m, 2H); and
化合物Y34-2(96mg，产率48％，保留时间：1.699min)。LCMS:ESI[M+H] +＝318.1， 1H NMR(400MHz,DMSO-d 6)δ8.82(d,J＝4.2Hz,1H),8.38(d,J＝4.4Hz,1H),7.91(d,J＝8.0Hz,1H),7.11-7.01(m,3H),6.79(s,1H),3.27–3.07(m,2H),3.01(d,J＝4.4Hz,3H),2.80–2.64(m,1H),2.39-2.24(m,1H),1.95–1.82(m,1H),1.03–0.85(m,2H),0.75-0.58(m,2H)。 Compound Y34-2 (96 mg, yield 48%, retention time: 1.699 min). LCMS: ESI [M+H] + =318.1, 1 H NMR (400MHz, DMSO-d 6 ) δ8.82 (d, J = 4.2Hz, 1H), 8.38 (d, J = 4.4Hz, 1H), 7.91 (d,J=8.0Hz,1H),7.11-7.01(m,3H),6.79(s,1H),3.27–3.07(m,2H),3.01(d,J=4.4Hz,3H),2.80– 2.64 (m, 1H), 2.39-2.24 (m, 1H), 1.95-1.82 (m, 1H), 1.03-0.85 (m, 2H), 0.75-0.58 (m, 2H).
实施例35：化合物Y35的制备Example 35: Preparation of Compound Y35
Figure PCTCN2022130850-appb-000125
Figure PCTCN2022130850-appb-000125
参考实施例1的制备方法，区别在于用化合物v18替换化合物v1，得到化合物Y35。LCMS：m/z 319.1[M+H] +； 1H NMR(DMSO-d 6,400MHz):δ9.03(m,2H),8.41(dd,J 1＝4Hz,J 2＝2.4Hz,1H),7.12(t,J ＝2.4Hz,2H),7.05(s,1H),3.23-3.18(m,2H),3.03(d,J＝4.8Hz,3H),2.77-2.72(m,1H),2.41-2.35(m,1H),2.33-2.07(m,1H),0.97-0.95(m,4H)。 Referring to the preparation method of Example 1, the difference is that compound v1 is replaced by compound v18 to obtain compound Y35. LCMS: m/z 319.1 [M+H] + ; 1 H NMR (DMSO-d 6 , 400 MHz): δ9.03 (m, 2H), 8.41 (dd, J 1 = 4Hz, J 2 = 2.4Hz, 1H ),7.12(t,J＝2.4Hz,2H),7.05(s,1H),3.23-3.18(m,2H),3.03(d,J＝4.8Hz,3H),2.77-2.72(m,1H) ,2.41-2.35(m,1H),2.33-2.07(m,1H),0.97-0.95(m,4H).
实施例36：化合物Y36及其异构体的制备Example 36: Preparation of compound Y36 and its isomers
Figure PCTCN2022130850-appb-000126
Figure PCTCN2022130850-appb-000126
在冰水浴氮气保护下将三氯氧磷(0.3ml)加入到化合物v3(150mg，0.45mmol)和N,N-二异丙基乙胺(0.9ml)的乙腈(30ml)溶液中并在90℃下反应1.5h。冷却到50℃左右，把反应液直接加入到氘代甲胺盐酸盐(150mg，0.45mmol)的N,N-二异丙基乙胺溶液(2ml)中搅拌10分钟，然后加EA(100ml)并用饱和食盐水(50ml)洗涤三次，有机相用无水硫酸钠干燥，过滤，滤液浓缩用柱层析纯化得到化合物Y36(25.8mg,产率16.4％).LCMS：m/z 349.1[M+H] +. 1H NMR(DMSO-d 6,400MHz):δ9.16(s,1H),8.42(d,J 1＝2.0Hz,J 2＝4.4Hz,1H),8.27(d,J＝8.2Hz,1H),7.91-7.89(m,1H),7.32(s,1H),7.16-7.11(m,2H),3.32-3.10(m,2H),2.75-2.68(m,1H),2.43-2.36(m,1H)。 Under nitrogen protection in an ice-water bath, phosphorus oxychloride (0.3ml) was added to compound v3 (150mg, 0.45mmol) and N,N-diisopropylethylamine (0.9ml) in acetonitrile (30ml) solution and heated at 90 Reaction at ℃ for 1.5h. Cool to about 50°C, add the reaction solution directly into N,N-diisopropylethylamine solution (2ml) of deuterated methylamine hydrochloride (150mg, 0.45mmol) and stir for 10 minutes, then add EA (100ml ) and washed three times with saturated brine (50ml), the organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography to obtain compound Y36 (25.8mg, yield 16.4%). LCMS: m/z 349.1[M +H] + . 1 H NMR (DMSO-d 6 , 400MHz): δ9.16(s, 1H), 8.42(d, J 1 = 2.0Hz, J 2 = 4.4Hz, 1H), 8.27(d, J ＝8.2Hz,1H),7.91-7.89(m,1H),7.32(s,1H),7.16-7.11(m,2H),3.32-3.10(m,2H),2.75-2.68(m,1H), 2.43-2.36(m,1H).
取化合物Y36进一步通过手性高效液相色谱纯化分离(手性分析方法:SFC:IA3.0cm(
Figure PCTCN2022130850-appb-000127
250mm*4.6mm粒径:5um)-Hex-EtOH(60:40)-30min；流速：60g/min；T:30℃；波长：230nm；洗脱时长：30min)，分别得到保留时间为7.973min的单一构型化合物Y36-1和保留时间为7.973min的单一构型化合物Y36-2。 Compound Y36 was further purified and separated by chiral high performance liquid chromatography (chiral analysis method: SFC: IA3.0cm (
Figure PCTCN2022130850-appb-000127
250mm*4.6mm particle size: 5um)-Hex-EtOH(60:40)-30min; flow rate: 60g/min; T: 30℃; wavelength: 230nm; elution time: 30min), the retention time is 7.973min The single configuration compound Y36-1 and the single configuration compound Y36-2 with a retention time of 7.973min.
化合物Y36-1: 1H NMR(DMSO-d 6,400MHz):δ9.17(s,1H),8.43(d,J＝2.4Hz,1H),8.27(d,J＝8.4Hz,1H),7.90(d,J＝8.0Hz,1H),7.33(s,1H),7.17-7.11(m,2H),3.54-3.01(m,2H),2.75-2.68(m,1H),2.43-2.33(m,1H)。 Compound Y36-1: 1 H NMR (DMSO-d 6 , 400MHz): δ9.17(s, 1H), 8.43(d, J=2.4Hz, 1H), 8.27(d, J=8.4Hz, 1H), 7.90(d,J＝8.0Hz,1H),7.33(s,1H),7.17-7.11(m,2H),3.54-3.01(m,2H),2.75-2.68(m,1H),2.43-2.33( m, 1H).
化合物Y36-2: 1H NMR(DMSO-d 6,400MHz):δ9.19(s,1H),8.44(dd,J 1＝2.0Hz,J 2＝4.0Hz 1H),,8.28(d,J＝8.0Hz,1H),7.92(d,J＝8.0Hz,1H),7.34(s,1H),7.16-7.13(m,2H),3.24-3.10(m,2H),2.75-2.70(m,1H),2.45-2.39(m,1H)。 Compound Y36-2: 1 H NMR (DMSO-d 6 , 400MHz): δ9.19(s,1H),8.44(dd,J 1 =2.0Hz,J 2 =4.0Hz 1H),,8.28(d,J =8.0Hz,1H),7.92(d,J=8.0Hz,1H),7.34(s,1H),7.16-7.13(m,2H),3.24-3.10(m,2H),2.75-2.70(m, 1H), 2.45-2.39 (m, 1H).
实施例38：化合物Y38的制备Example 38: Preparation of Compound Y38
Figure PCTCN2022130850-appb-000128
Figure PCTCN2022130850-appb-000128
步骤1：参考实施例1的制备方法，区别在于用化合物v19替换化合物v1，得到化合物38-1，LCMS：m/z 422.0[M-H] -。 Step 1: Refer to the preparation method of Example 1, the difference is that compound v1 is replaced by compound v19 to obtain compound 38-1, LCMS: m/z 422.0 [MH] - .
步骤2：将化合物38-1(110mg,0.26mmol),氰化锌(152mg,1.30mmol)和xphos(24.7mg,0.052mmol)溶于干燥DMF(2mL),向上述溶液中加入Pd 2(dba) 3(23.7mg,0.026mmol)，氮气保护下微波加热到110℃搅拌2.5小时。用EA(50mL)萃取两次，有机相用硫酸钠干燥后浓缩,制备得到化合物Y38(16.9mg,产率19％)。LCMS：m/z 371.0[M+H] +； 1H NMR(CD 3OD-d 4,400MHz):δ9.39(s,br,1H),8.74(d,J＝8.0Hz,1H),8.11(d,J＝6.0Hz,1H),7.68(d,J＝7.6Hz,1H),7.27(t,J＝8.0Hz,1H),6.99(d,J＝4.8Hz，1H),3.41-3.32(m,2H),3.09(s,3H),2.84(t,J＝7.6Hz,2H)。 Step 2: Compound 38-1 (110 mg, 0.26 mmol), zinc cyanide (152 mg, 1.30 mmol) and xphos (24.7 mg, 0.052 mmol) were dissolved in dry DMF (2 mL), and Pd 2 (dba ) 3 (23.7mg, 0.026mmol), microwave heated to 110°C under nitrogen protection and stirred for 2.5 hours. Extracted twice with EA (50 mL), the organic phase was dried over sodium sulfate and concentrated to prepare compound Y38 (16.9 mg, yield 19%). LCMS: m/z 371.0[M+H] + ; 1 H NMR (CD 3 OD-d 4 , 400MHz): δ9.39 (s, br, 1H), 8.74 (d, J=8.0Hz, 1H), 8.11(d, J=6.0Hz, 1H), 7.68(d, J=7.6Hz, 1H), 7.27(t, J=8.0Hz, 1H), 6.99(d, J=4.8Hz, 1H), 3.41- 3.32 (m, 2H), 3.09 (s, 3H), 2.84 (t, J=7.6Hz, 2H).
实施例43：化合物Y43的制备Example 43: Preparation of Compound Y43
Figure PCTCN2022130850-appb-000129
Figure PCTCN2022130850-appb-000129
参考实施例1的制备方法，区别在于用化合物v20替换化合物v1，得到化合物Y43。LCMS：m/z 322.1[M+H] +； 1H NMR(DMSO-d 6,400MHz):δ8.84(br,1H),8.30(d,J＝8.0Hz,1H),7.28(d,J＝7.6Hz,1H),7.13(t,J＝7.6Hz,1H),6.99(t,J＝7.6Hz,1H)，6.83(d,J＝8.8Hz,1H)，6.60(d,J＝7.6Hz,1H),4.26- 4.13(m,2H),3.28-3.20(m,2H),3.04(d,J＝4.4Hz,3H)，2.85-2.76(m,2H),1.18(t,J＝7.2Hz,3H)。 Referring to the preparation method of Example 1, the difference is that compound v1 is replaced by compound v20 to obtain compound Y43. LCMS: m/z 322.1[M+H] + ; 1 H NMR (DMSO-d 6 , 400MHz): δ8.84(br, 1H), 8.30(d, J=8.0Hz, 1H), 7.28(d, J=7.6Hz, 1H), 7.13(t, J=7.6Hz, 1H), 6.99(t, J=7.6Hz, 1H), 6.83(d, J=8.8Hz, 1H), 6.60(d, J= 7.6Hz, 1H), 4.26- 4.13(m, 2H), 3.28-3.20(m, 2H), 3.04(d, J=4.4Hz, 3H), 2.85-2.76(m, 2H), 1.18(t, J =7.2Hz, 3H).
实施例44：化合物Y44的制备Example 44: Preparation of Compound Y44
Figure PCTCN2022130850-appb-000130
Figure PCTCN2022130850-appb-000130
参考实施例1的制备方法，区别在于用化合物v21替换化合物v1，得到化合物Y44。LCMS：m/z 319.1[M+H] +； 1H NMR(CDCl 3,400MHz):8.42-8.42(t,J＝8Hz,1H),8.15-8.13(d,J＝8Hz,1H),7.16-7.14(d,J＝8Hz,1H),7.09-7.07((dd,J 1＝1.6Hz,J 2＝7.6Hz,1H),6.99-6.96(dd,J 1＝4.8Hz,J 2＝7.6Hz 1H),3.45-3.41(t,J＝16Hz,2H),3.27(s,3H),2.98-2.94(m,1H),2.82-2.78(m,1H),1.97-1.93(m,1H),0.99-0.95(m,2H),0.92-0.88(m,1H),0.75-0.71(m,1H)。 Referring to the preparation method of Example 1, the difference is that compound v1 is replaced by compound v21 to obtain compound Y44. LCMS: m/z 319.1 [M+H] + ; 1 H NMR (CDCl 3 , 400 MHz): 8.42-8.42 (t, J=8Hz, 1H), 8.15-8.13 (d, J=8Hz, 1H), 7.16 -7.14 (d, J = 8Hz, 1H), 7.09-7.07 ((dd, J 1 = 1.6Hz, J 2 = 7.6Hz, 1H), 6.99-6.96 (dd, J 1 = 4.8Hz, J 2 = 7.6 Hz 1H), 3.45-3.41(t, J=16Hz, 2H), 3.27(s, 3H), 2.98-2.94(m, 1H), 2.82-2.78(m, 1H), 1.97-1.93(m, 1H) ,0.99-0.95(m,2H),0.92-0.88(m,1H),0.75-0.71(m,1H).
实施例45：化合物Y45及其异构体的制备Example 45: Preparation of compound Y45 and its isomers
Figure PCTCN2022130850-appb-000131
Figure PCTCN2022130850-appb-000131
参考实施例1的制备方法，区别在于用化合物v30替换化合物v1，得到化合物Y45。将化合物Y45(200mg)进行手性拆分(
Figure PCTCN2022130850-appb-000132
OJ-250*25mm 10mm-CO2-MEOH(+0.1％7.0mol/l氨水的甲醇)-(75:25)-5.0min；流速：80ml/min；T：RT；波长：214nm；洗脱时长：5.0min。)分别得到： Referring to the preparation method of Example 1, the difference is that compound v1 is replaced by compound v30 to obtain compound Y45. Compound Y45 (200 mg) was subjected to chiral resolution (
Figure PCTCN2022130850-appb-000132
OJ-250*25mm 10mm-CO2-MEOH (methanol+0.1% 7.0mol/l ammonia water)-(75:25)-5.0min; flow rate: 80ml/min; T: RT; wavelength: 214nm; elution time: 5.0min. ) to get:
保留时间为2.63min的单一构型化合物Y45-1(30mg)，chiral-LCMS:ESI[M+H]+＝360.34，1H NMR(400MHz,DMSO-d 6)δ9.15(s,1H),8.42(dd,J＝4.6,1.6Hz,1H),8.26(d,J＝8.1Hz,1H),7.86(d,J＝7.9Hz,1H),7.08(dt,J＝24.9,12.5Hz,1H),6.97(d,J＝13.5Hz,2H),3.15–2.96(m,5H),2.90(dd,J＝17.6,5.4Hz,1H),2.10(t,J＝10.3Hz,2H),1.82–1.64(m,1H)；以及 Single-configuration compound Y45-1 (30mg) with a retention time of 2.63min, chiral-LCMS:ESI[M+H]+=360.34, 1H NMR(400MHz,DMSO-d 6 )δ9.15(s,1H), 8.42(dd, J=4.6,1.6Hz,1H),8.26(d,J=8.1Hz,1H),7.86(d,J=7.9Hz,1H),7.08(dt,J=24.9,12.5Hz,1H ), 6.97(d, J=13.5Hz, 2H), 3.15–2.96(m, 5H), 2.90(dd, J=17.6, 5.4Hz, 1H), 2.10(t, J=10.3Hz, 2H), 1.82 –1.64(m,1H); and
保留时间为2.84min的单一构型化合物Y45-2(20.4mg)，chiral-LCMS:ESI[M+H]+＝360.36。1H NMR(400MHz,DMSO-d 6)δ9.13(s,1H),8.42(dd,J＝4.6,1.6Hz,1H),8.26(d,J＝8.1Hz,1H),7.86(d,J＝7.7Hz,1H),7.09(dd,J＝7.8,4.6Hz,1H),7.07–6.83(m,3H),3.17–2.99(m,4H),2.90(dd,J＝17.3,5.3Hz,1H),2.18(s,1H),2.17–2.06(m,2H),1.75(dd,J＝13.4,5.9Hz,1H)。 Single-configuration compound Y45-2 (20.4mg) with a retention time of 2.84min, chiral-LCMS:ESI[M+H]+=360.36.1H NMR(400MHz,DMSO-d 6 )δ9.13(s,1H) ,8.42(dd,J=4.6,1.6Hz,1H),8.26(d,J=8.1Hz,1H),7.86(d,J=7.7Hz,1H),7.09(dd,J=7.8,4.6Hz, 1H),7.07–6.83(m,3H),3.17–2.99(m,4H),2.90(dd,J＝17.3,5.3Hz,1H),2.18(s,1H),2.17–2.06(m,2H) , 1.75 (dd, J = 13.4, 5.9 Hz, 1H).
实施例46：化合物Y46及其异构体的制备Example 46: Preparation of compound Y46 and its isomers
Figure PCTCN2022130850-appb-000133
Figure PCTCN2022130850-appb-000133
参考实施例1的制备方法，区别在于用化合物v30替换化合物v1，用氘代甲胺盐酸盐替换甲胺，得到化合物Y46。将化合物Y46(160mg)进行手性拆分(
Figure PCTCN2022130850-appb-000134
OJ-250*25mm 10mm-CO2-MeOH(+0.1％7.0mol/l氨水的甲醇)-(75:25)-5.0min；流速：80ml/min；T：RT；波长：214nm；洗脱时长：5.0min。)，分别得到： Referring to the preparation method of Example 1, the difference is that compound v1 is replaced by compound v30, and methylamine is replaced by deuterated methylamine hydrochloride to obtain compound Y46. Compound Y46 (160 mg) was subjected to chiral resolution (
Figure PCTCN2022130850-appb-000134
OJ-250*25mm 10mm-CO2-MeOH (methanol+0.1% 7.0mol/l ammonia)-(75:25)-5.0min; flow rate: 80ml/min; T: RT; wavelength: 214nm; elution time: 5.0min. ), respectively get:
保留时间为2.613min的单一构型化合物Y46-1(32.4mg)，chiral-LCMS:ESI[M+H]+＝363.37，1H NMR(400MHz,DMSO-d 6)δ9.16(s,1H),8.56–8.36(m,1H),8.31(d,J＝8.2Hz,1H),7.92(d,J＝7.9Hz,1H),7.16(dd,J＝7.8,4.7Hz,1H),7.04(d,J＝12.3Hz,2H),3.10(dd,J＝15.1,9.7Hz,1H),2.96(dd,J＝17.5,5.4Hz,1H),2.17(d,J＝11.3Hz,1H),2.10–1.92(m,2H),1.87–1.68(m,1H)；以及 Single-configuration compound Y46-1 (32.4mg) with a retention time of 2.613min, chiral-LCMS:ESI[M+H]+=363.37, 1H NMR(400MHz,DMSO-d 6 )δ9.16(s,1H) ,8.56–8.36(m,1H),8.31(d,J=8.2Hz,1H),7.92(d,J=7.9Hz,1H),7.16(dd,J=7.8,4.7Hz,1H),7.04( d,J=12.3Hz,2H),3.10(dd,J=15.1,9.7Hz,1H),2.96(dd,J=17.5,5.4Hz,1H),2.17(d,J=11.3Hz,1H), 2.10–1.92(m,2H), 1.87–1.68(m,1H); and
保留时间为2.835min的单一构型化合物Y46-2(34mg)，chiral-LCMS:ESI[M+H]+＝363.37。1H NMR(400MHz,DMSO-d 6)δ9.12(s,1H),8.61–8.13(m,2H),7.88(s,1H),7.01(t,J＝29.3Hz,3H),2.98(dd,J＝55.1,16.9Hz,2H),2.37–1.61(m,4H)。 Single-configuration compound Y46-2 (34mg) with a retention time of 2.835min, chiral-LCMS:ESI[M+H]+=363.37.1H NMR(400MHz,DMSO-d 6 )δ9.12(s,1H), 8.61–8.13(m,2H),7.88(s,1H),7.01(t,J=29.3Hz,3H),2.98(dd,J=55.1,16.9Hz,2H),2.37–1.61(m,4H) .
实施例47：化合物Y47的异构体的制备Example 47: Preparation of Isomers of Compound Y47
Figure PCTCN2022130850-appb-000135
Figure PCTCN2022130850-appb-000135
将化合物Y47(160mg)进行手性拆分(
Figure PCTCN2022130850-appb-000136
AS-250*25mm 10μm-CO2-MeOH(+0.1％7.0mol/l含氨水的甲醇)-(70:30)-2.5min；流速：70ml/min；T：RT；波长：214nm；洗脱时长：2.0min。)，分别得到： Compound Y47 (160 mg) was subjected to chiral resolution (
Figure PCTCN2022130850-appb-000136
AS-250*25mm 10μm-CO2-MeOH (+0.1%7.0mol/l methanol containing ammonia)-(70:30)-2.5min; flow rate: 70ml/min; T: RT; wavelength: 214nm; elution time : 2.0min. ), respectively get:
化合物Y47-1(29.45mg，保留时间：3.225min，产率18.4％)。LCMS:ESI[M+H]+＝321.1，1H NMR(400MHz,DMSO-d 6)δ8.82(s,1H),8.39(d,J＝3.6Hz,1H),7.92(d,J＝8.4Hz,1H),7.18–6.99(m,3H),6.80(s,1H),3.24–3.02(m,2H),2.80-2.65(m,1H),2.40-2.23(m,1H),1.95-1.79(m,1H),1.02–0.91(m,2H),0.78-0.5(m,2H)；以及 Compound Y47-1 (29.45 mg, retention time: 3.225 min, yield 18.4%). LCMS: ESI[M+H]+=321.1, 1H NMR (400MHz, DMSO-d 6 )δ8.82(s, 1H), 8.39(d, J=3.6Hz, 1H), 7.92(d, J=8.4 Hz,1H),7.18–6.99(m,3H),6.80(s,1H),3.24–3.02(m,2H),2.80-2.65(m,1H),2.40-2.23(m,1H),1.95- 1.79(m,1H), 1.02–0.91(m,2H), 0.78-0.5(m,2H); and
化合物Y47-2(28.7mg，保留时间：3.561min，产率17.9％)。LCMS:ESI[M+H]+＝321.1，1H NMR(400MHz,DMSO-d 6)δ8.82(s,1H),8.39(d,J＝3.6Hz,1H),7.92(d,J＝8.4Hz,1H),7.18–6.99(m,3H),6.80(s,1H),3.24–3.02(m,2H),2.80-2.65(m,1H),2.40-2.23(m,1H),1.95-1.79(m,1H),1.02–0.91(m,2H),0.78-0.5(m,2H)。 Compound Y47-2 (28.7 mg, retention time: 3.561 min, yield 17.9%). LCMS: ESI[M+H]+=321.1, 1H NMR (400MHz, DMSO-d 6 )δ8.82(s, 1H), 8.39(d, J=3.6Hz, 1H), 7.92(d, J=8.4 Hz,1H),7.18–6.99(m,3H),6.80(s,1H),3.24–3.02(m,2H),2.80-2.65(m,1H),2.40-2.23(m,1H),1.95- 1.79 (m, 1H), 1.02–0.91 (m, 2H), 0.78-0.5 (m, 2H).
实施例53：化合物Y53的制备Example 53: Preparation of Compound Y53
Figure PCTCN2022130850-appb-000137
Figure PCTCN2022130850-appb-000137
步骤1：参考实施例1的制备方法，区别在于用化合物v19替换化合物v1，得到化合物53-1。LCMS：m/z 425.0[M+H] +。 Step 1: Referring to the preparation method of Example 1, the difference is that compound v1 is replaced by compound v19 to obtain compound 53-1. LCMS: m/z 425.0 [M+H] + .
步骤2：将化合物53-1(120mg,0.28mmol),三氟甲烷磺酸铜(15.1mg,0.042mmol)和N,N'-二甲基乙二胺(7.4mg,0.084mmol)溶于干燥的二甲亚砜(5mL),向上述溶液中加入甲烷亚磺酸钠(107mg,1.05mmol)，氮气保护下加热到120℃搅拌2小时。用EA(50mL)萃取两次，有机相用硫酸钠干燥后浓缩,制备得到化合物Y53(29.1mg,产率24.2％)。LCMS：m/z＝424.4[M+H] +； 1H NMR(CD 3OD-d 4,400MHz):δ8.51(d,J＝8.4Hz,1H),7.79(d,J＝8.4Hz,1H),7.72(d,J＝8.0Hz,1H),7.24(t,J＝8.0Hz,1H),6.93(d,J＝7.6Hz,1H),3.64-3.58(m,2H),3.14(s,3H),3.06(s,3H),2.86(t,J＝7.6Hz,2H)。 Step 2: Compound 53-1 (120mg, 0.28mmol), copper trifluoromethanesulfonate (15.1mg, 0.042mmol) and N,N'-dimethylethylenediamine (7.4mg, 0.084mmol) were dissolved in dry Dimethyl sulfoxide (5 mL), sodium methanesulfinate (107 mg, 1.05 mmol) was added to the above solution, heated to 120° C. and stirred for 2 hours under nitrogen protection. Extracted twice with EA (50 mL), the organic phase was dried over sodium sulfate and concentrated to prepare compound Y53 (29.1 mg, yield 24.2%). LCMS: m/z=424.4[M+H] + ; 1 H NMR (CD 3 OD-d 4 , 400MHz): δ8.51(d, J=8.4Hz, 1H), 7.79(d, J=8.4Hz ,1H),7.72(d,J=8.0Hz,1H),7.24(t,J=8.0Hz,1H),6.93(d,J=7.6Hz,1H),3.64-3.58(m,2H),3.14 (s, 3H), 3.06 (s, 3H), 2.86 (t, J=7.6Hz, 2H).
实施例54：化合物Y54的制备Example 54: Preparation of compound Y54
Figure PCTCN2022130850-appb-000138
Figure PCTCN2022130850-appb-000138
步骤1：参考实施例1的制备方法，区别在于用化合物v27替换化合物v1，得到化合物54-1。LCMS：m/z 374.0[M+H] +。 Step 1: Referring to the preparation method of Example 1, the difference is that compound v1 is replaced by compound v27 to obtain compound 54-1. LCMS: m/z 374.0 [M+H] + .
步骤2：以化合物54-1(30mg,0.08mmol)和环丙基硼酸(314g,0.16mol)为原料，参考中间体v12步骤1的制备方法，用正相过柱纯化(甲醇：二氯甲烷＝1:20)，再通过制备纯化得到化合物Y54(5.1mg,收率18.8％).LCMS：m/z＝336.0[M+H] +； 1H NMR(CD 3OD-d 4,400MHz):δ8.45(s,1H),7.33(d,J＝6.8Hz,1H),7.29-7.2(m,1H),6.91(d,J＝12.8Hz,1H),6.61(S,1H),3.36-3.29(m,3H),3.26-3.21(m,1H),2.85-2.80(m,1H),2.46-2.41(m,1H),1.92-1.90(m,1H),1.33(d,J＝16.4Hz,1H),1.06(d,J1＝8.4Hz,J2＝1.6Hz,2H),0.73-0.70(m,2H)。 Step 2: Using compound 54-1 (30mg, 0.08mmol) and cyclopropylboronic acid (314g, 0.16mol) as raw materials, refer to the preparation method of intermediate v12 step 1, and use normal phase column purification (methanol: dichloromethane =1:20), and then purified by preparation to obtain compound Y54 (5.1 mg, yield 18.8%). LCMS: m/z=336.0[M+H] + ; 1 H NMR (CD 3 OD-d 4 , 400MHz) :δ8.45(s,1H),7.33(d,J＝6.8Hz,1H),7.29-7.2(m,1H),6.91(d,J＝12.8Hz,1H),6.61(S,1H), 3.36-3.29(m,3H),3.26-3.21(m,1H),2.85-2.80(m,1H),2.46-2.41(m,1H),1.92-1.90(m,1H),1.33(d,J =16.4Hz, 1H), 1.06(d, J1=8.4Hz, J2=1.6Hz, 2H), 0.73-0.70(m, 2H).
实施例55：化合物Y55及其异构体的制备Example 55: Preparation of compound Y55 and its isomers
Figure PCTCN2022130850-appb-000139
Figure PCTCN2022130850-appb-000139
参考实施例1的制备方法，区别在于用化合物v29替换化合物v1，用氨气替换甲胺，得到化合物Y55。将化合物Y55进一步通过手性高效液相色谱纯化分离(手性分离方法:SFC:IG 3.0cm(
Figure PCTCN2022130850-appb-000140
250mm*4.6mm粒径:5um)-Hex-EtOH(90:10)-30min；流速：25mL/min；T:30℃；波长：214nm；洗脱时长：30min)，分别得到保留时间为4.491min的单一构型化合物Y55-1和保留时间为5.150min的单一构型化合物Y55-2。 Referring to the preparation method of Example 1, the difference is that compound v1 is replaced by compound v29, and methylamine is replaced by ammonia to obtain compound Y55. Compound Y55 was further purified and separated by chiral high performance liquid chromatography (chiral separation method: SFC:IG 3.0cm(
Figure PCTCN2022130850-appb-000140
250mm*4.6mm particle size: 5um)-Hex-EtOH(90:10)-30min; flow rate: 25mL/min; T: 30℃; wavelength: 214nm; elution time: 30min), the retention time is 4.491min The single configuration compound Y55-1 and the single configuration compound Y55-2 with a retention time of 5.150min.
化合物Y55-1:LCMS：m/z 348.0[M+H] +。 1H NMR(DMSO-d 6,400MHz):δ8.85-8.83(d,J＝8Hz,1H),8.09-8.07(d,J＝8Hz,1H),7.10-7.06(t,J＝16Hz,1H),6.85-6.83(d,J＝8Hz,1H),6.69-6.66(t,J＝12Hz,1H)，6.42-6.41(d,J＝3.6Hz,1H),4.56-4.52(m,1H),4.43-4.41(m,1H),2.45-2.43(m,1H),2.42-2.38(m,1H)。 Compound Y55-1: LCMS: m/z 348.0 [M+H] + . 1 H NMR (DMSO-d 6 , 400MHz): δ8.85-8.83(d, J=8Hz, 1H), 8.09-8.07(d, J=8Hz, 1H), 7.10-7.06(t, J=16Hz, 1H), 6.85-6.83(d, J=8Hz, 1H), 6.69-6.66(t, J=12Hz, 1H), 6.42-6.41(d, J=3.6Hz, 1H), 4.56-4.52(m, 1H ), 4.43-4.41(m,1H), 2.45-2.43(m,1H), 2.42-2.38(m,1H).
化合物Y55-2:LCMS：m/z 348.0[M+H] +。 1H NMR(DMSO-d 6,400MHz):δ8.85-8.83(d,J＝8Hz,1H),8.09-8.07(d,J＝8Hz,1H),7.10-7.06(t,J＝16Hz,1H),6.85-6.83(d,J＝8Hz,1H),6.69-6.66(t,J＝12Hz,1H)，6.42-6.40(d,J＝3.6Hz,1H).4.56-4.52(m,1H),4.43-4.41(m,1H),2.45-2.43(m,1H),2.42-2.38(m,1H)。 Compound Y55-2: LCMS: m/z 348.0 [M+H] + . 1 H NMR (DMSO-d 6 , 400MHz): δ8.85-8.83(d, J=8Hz, 1H), 8.09-8.07(d, J=8Hz, 1H), 7.10-7.06(t, J=16Hz, 1H), 6.85-6.83(d, J=8Hz, 1H), 6.69-6.66(t, J=12Hz, 1H), 6.42-6.40(d, J=3.6Hz, 1H). 4.56-4.52(m, 1H ), 4.43-4.41(m,1H), 2.45-2.43(m,1H), 2.42-2.38(m,1H).
实施例56：化合物Y56的制备Example 56: Preparation of compound Y56
Figure PCTCN2022130850-appb-000141
Figure PCTCN2022130850-appb-000141
步骤1：将化合物v26(35mg,0.1mmol)和五硫化二磷(60mg,0.3mmol)溶于吡啶(2mL)中，反应液在微波升至150℃并搅拌3小时。反应液浓缩得到化合物26-1，直接用于下一步。Step 1: Compound v26 (35mg, 0.1mmol) and phosphorus pentasulfide (60mg, 0.3mmol) were dissolved in pyridine (2mL), and the reaction solution was raised to 150°C in microwave and stirred for 3 hours. The reaction solution was concentrated to obtain compound 26-1, which was directly used in the next step.
步骤2：将上述化合物26-1(40mg)溶于乙醇(2ml)中，于室温加滴加甲胺的THF溶液(2M,3mL)，反应液于室温搅拌16小时。用EA(10mL x 3)萃取，合并有机层，依次用水(50mL)、饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤，滤液减压下蒸除溶剂制备得到的化合物Y56(3.4mg，收率：13％)。LCMS：m/z 348.0[M+H] +； 1H NMR(CD 3Cl,400MHz):δ8.29(d,J＝8.0Hz,1H),8.21(d,J＝8.8Hz,1H),7.63(d,J＝8.4Hz,1H),7.36-7.33(m,1H),7.28-7.26(m,2H),5.48(d,J＝3.6Hz,1H),3.94(s,2H),3.21(d,J＝4.4Hz,3H)。 Step 2: The above compound 26-1 (40mg) was dissolved in ethanol (2ml), and a THF solution (2M, 3mL) of methylamine was added dropwise at room temperature, and the reaction solution was stirred at room temperature for 16 hours. Extracted with EA (10mL x 3), the organic layers were combined, washed with water (50mL) and saturated brine (50mL) successively, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated under reduced pressure to remove the solvent. The prepared compound Y56 (3.4mg , yield: 13%). LCMS: m/z 348.0[M+H] + ; 1 H NMR (CD 3 Cl, 400MHz): δ8.29(d, J=8.0Hz, 1H), 8.21(d, J=8.8Hz, 1H), 7.63(d,J=8.4Hz,1H),7.36-7.33(m,1H),7.28-7.26(m,2H),5.48(d,J=3.6Hz,1H),3.94(s,2H),3.21 (d, J=4.4Hz, 3H).
实施例57：化合物Y57的制备Example 57: Preparation of compound Y57
Figure PCTCN2022130850-appb-000142
Figure PCTCN2022130850-appb-000142
参考实施例1的制备方法，区别在于用化合物v28替换化合物v1，用氘代甲氨盐酸盐替换甲胺，得到化合物Y57。LCMS：m/z＝364.1[M+1] +； 1H NMR(DMSO-d 6,400MHz):δ9.22(s,1H),8.71(d,J＝8Hz,1H)，8.33(d,J＝3.6Hz,1H),8.06(d,J＝8.4Hz,1H),7.01-6.98(dd,J 1＝5.2Hz,J 2＝8Hz 1H),6.83(d,J＝7.6Hz,1H),2.93(s,2H),2.18-2.12(m,1H),2.03-1.95(m,3H)。 Referring to the preparation method of Example 1, the difference is that compound v1 is replaced by compound v28, and methylamine is replaced by deuterated methylamine hydrochloride to obtain compound Y57. LCMS: m/z=364.1[M+1] + ; 1 H NMR (DMSO-d 6 , 400MHz): δ9.22(s, 1H), 8.71(d, J=8Hz, 1H), 8.33(d, J＝3.6Hz, 1H), 8.06(d, J＝8.4Hz, 1H), 7.01-6.98(dd, J 1 ＝5.2Hz, J 2 ＝8Hz 1H), 6.83(d, J＝7.6Hz, 1H) ,2.93(s,2H),2.18-2.12(m,1H),2.03-1.95(m,3H).
实施例58：化合物Y58的制备Example 58: Preparation of Compound Y58
Figure PCTCN2022130850-appb-000143
Figure PCTCN2022130850-appb-000143
参考实施例1的制备方法，区别在于用化合物v3替换化合物v1，用2，2，2-三氟乙胺替换甲胺，得到化合物Y58。LCMS：m/z＝413.9[M+H] +； 1H NMR(DMSO-d 6,400MHz):δ10.78(s,1H),8.48(dd,J 1＝3.2Hz,J 2＝1.6Hz,1H)，8.41(d,J＝8.4Hz,1H),7.81(d,J＝8.0Hz,1H),7.31-7.29(m,2H),7.20-7.17(dd,J 1＝8Hz,J 2＝4.8Hz,,1H),4.29-4.24(m,2H),3.29-3.16(m,2H),2.87-2.81(m,1H),2.50-2.44(m,1H)。 Referring to the preparation method of Example 1, the difference is that compound v1 is replaced by compound v3, and methylamine is replaced by 2,2,2-trifluoroethylamine to obtain compound Y58. LCMS: m/z = 413.9 [M+H] + ; 1 H NMR (DMSO-d 6 , 400 MHz): δ10.78 (s, 1H), 8.48 (dd, J 1 = 3.2 Hz, J 2 = 1.6 Hz ,1H), 8.41(d,J=8.4Hz,1H),7.81(d,J=8.0Hz,1H),7.31-7.29(m,2H),7.20-7.17(dd,J 1 =8Hz,J 2 =4.8Hz,, 1H), 4.29-4.24(m, 2H), 3.29-3.16(m, 2H), 2.87-2.81(m, 1H), 2.50-2.44(m, 1H).
实施例59：化合物Y59及其异构体的制备Example 59: Preparation of compound Y59 and its isomers
Figure PCTCN2022130850-appb-000144
Figure PCTCN2022130850-appb-000144
参考实施例1的制备方法，区别在于用化合物v3替换化合物v1，得到化合物Y59，LCMS：m/z＝332.2[M+H] +。将化合物Y59(100mg,0.30mmol)进一步通过手性高效液相色谱纯化分离(手性分离方法:SFC:IB N5(
Figure PCTCN2022130850-appb-000145
250mm*4.6mm粒径:5um)-Hex-EtOH(70:30)-30min；流速：1.00(ml/min)；T:30℃；波长：254nm；洗脱时长：30min)，分别得到保留时间为4.698min的单一构型化合物Y59-1和保留时间为5.484min的单一构型化合物Y59-2。 Referring to the preparation method of Example 1, the difference is that compound v1 is replaced by compound v3 to obtain compound Y59, LCMS: m/z=332.2[M+H] +. Compound Y59 (100mg, 0.30mmol) was further purified and separated by chiral high performance liquid chromatography (chiral separation method: SFC: IB N5(
Figure PCTCN2022130850-appb-000145
250mm*4.6mm particle size: 5um)-Hex-EtOH(70:30)-30min; flow rate: 1.00(ml/min); T: 30°C; wavelength: 254nm; elution time: 30min), respectively get the retention time The single-configuration compound Y59-1 is 4.698min and the single-configuration compound Y59-2 is 5.484min.
化合物Y59-1：LCMS：m/z＝332.2[M+H] +. 1H NMR(DMSO-d 6,400MHz):δ8.43(t,J＝3.2Hz,1H)，8.38(d,J＝8.0Hz,1H),7.86(d,J＝8.4Hz,1H),7.34(s,1H),7.15(d,J＝3.6Hz,2H),3.29-3.12(m,2H),2.77-2.72(m,1H),2.51-2.33(m,1H)。 Compound Y59-1: LCMS: m/z=332.2[M+H] + . 1 H NMR (DMSO-d 6 , 400MHz): δ8.43(t,J=3.2Hz,1H), 8.38(d,J =8.0Hz,1H),7.86(d,J=8.4Hz,1H),7.34(s,1H),7.15(d,J=3.6Hz,2H),3.29-3.12(m,2H),2.77-2.72 (m,1H),2.51-2.33(m,1H).
化合物Y59-2：LCMS：m/z＝332.2[M+H] +. 1H NMR(DMSO-d 6,400MHz):δ8.43(t,J＝3.2Hz,1H)，8.38(d,J＝8.0Hz,1H),7.86(d,J＝8.4Hz,1H),7.34(s,1H),7.15(d,J＝3.6Hz,2H),3.29-3.12(m,2H),2.77-2.72(m,1H),2.51-2.33(m,1H)。 Compound Y59-2: LCMS: m/z=332.2[M+H] + . 1 H NMR (DMSO-d 6 , 400MHz): δ8.43(t,J=3.2Hz,1H), 8.38(d,J =8.0Hz,1H),7.86(d,J=8.4Hz,1H),7.34(s,1H),7.15(d,J=3.6Hz,2H),3.29-3.12(m,2H),2.77-2.72 (m,1H),2.51-2.33(m,1H).
实施例60：化合物Y60及其异构体的制备Example 60: Preparation of compound Y60 and its isomers
Figure PCTCN2022130850-appb-000146
Figure PCTCN2022130850-appb-000146
参考实施例1的制备方法，区别在于用化合物v3替换化合物v1，用2，2-二氟乙胺替换甲胺，得到化合物Y60。将化合物Y60进一步通过手性高效液相色谱纯化分离(手性分离方法:SFC:IC 3.0cm(
Figure PCTCN2022130850-appb-000147
250mm*4.6mm粒径:5um)-Hex-EtOH(50:50)-30min；流速：25ml/min；温度:30℃；波长：214nm；洗脱时长：30min)，分别得到保留时间为4.767min的单一构型化合物Y60-1和保留时间为6.745min的单一构型化合物Y60-2。 Referring to the preparation method of Example 1, the difference is that compound v1 is replaced by compound v3, and methylamine is replaced by 2,2-difluoroethylamine to obtain compound Y60. Compound Y60 was further purified and separated by chiral high performance liquid chromatography (chiral separation method: SFC: IC 3.0cm (
Figure PCTCN2022130850-appb-000147
250mm*4.6mm particle size: 5um)-Hex-EtOH(50:50)-30min; flow rate: 25ml/min; temperature: 30°C; wavelength: 214nm; elution time: 30min), respectively, the retention time is 4.767min The single configuration compound Y60-1 and the single configuration compound Y60-2 with a retention time of 6.745min.
化合物Y60-1:LCMS：m/z＝396.0[M+H] +； 1H NMR(DMSO-d 6,400MHz):δ10.73(s,1H),8.47-8.38(m,2H),7.93-7.80(m 1H),7.29 7.29-7.16(m,3H),6.33(t,J＝16Hz，1H),3.95-3.80(m,2H),3.30-3.10(m,2H).2.70-2.40(m,1H)，2.50-2.30(m，1H)。 Compound Y60-1: LCMS: m/z=396.0[M+H] + ; 1 H NMR (DMSO-d 6 , 400MHz): δ10.73(s,1H),8.47-8.38(m,2H),7.93 -7.80(m 1H),7.29 7.29-7.16(m,3H),6.33(t,J=16Hz,1H),3.95-3.80(m,2H),3.30-3.10(m,2H).2.70-2.40( m, 1H), 2.50-2.30 (m, 1H).
化合物Y60-2:LCMS：m/z＝396.0[M+H] +； 1H NMR(DMSO-d 6,400MHz):δ10.64(s,1H),8.49-8.31(m,2H),7.89-7.80(m 1H),7.50-7.10(m,3H),6.33(t,J＝16Hz，1H),3.96-3.80(m,2H),3.32-3.10(m,2H).2.90-2.40(m,1H)，2.50-2.30(m，1H). Compound Y60-2: LCMS: m/z=396.0[M+H] + ; 1 H NMR (DMSO-d 6 , 400MHz): δ10.64(s,1H),8.49-8.31(m,2H),7.89 -7.80(m 1H),7.50-7.10(m,3H),6.33(t,J=16Hz,1H),3.96-3.80(m,2H),3.32-3.10(m,2H).2.90-2.40(m ,1H), 2.50-2.30(m,1H).
实施例63：化合物Y63及其异构体的制备Example 63: Preparation of compound Y63 and its isomers
Figure PCTCN2022130850-appb-000148
Figure PCTCN2022130850-appb-000148
步骤1：参考实施例1的制备方法，区别在于用化合物v23替换化合物v1，得到化合物Y63。LCMS：m/z＝336.1[M+H] +； 1H NMR(DMSO-d 6,400MHz):δ8.87(s,1H),8.39-8.38(d,J＝4.0Hz,1H),7.89-7.86(d,J＝11.2Hz,1H),7.12-7.09(m,1H),7.03-7.01(d,J＝8.0Hz,1H),6.62-6.60(d,J＝8.0Hz,1H),3.19-3.09(m,2H),3.01(s,3H),2.67-2.64(m,1H),2.35-2.32(m,1H),2.04-2.01(m,1H),0.97-0.94(m,2H),0.72-0.68(m,1H),0.58-0.56(m,1H)。 Step 1: Referring to the preparation method of Example 1, the difference is that compound v1 is replaced by compound v23 to obtain compound Y63. LCMS: m/z=336.1[M+H] + ; 1 H NMR (DMSO-d 6 , 400MHz): δ8.87(s, 1H), 8.39-8.38(d, J=4.0Hz, 1H), 7.89 -7.86(d,J=11.2Hz,1H),7.12-7.09(m,1H),7.03-7.01(d,J=8.0Hz,1H),6.62-6.60(d,J=8.0Hz,1H), 3.19-3.09(m,2H),3.01(s,3H),2.67-2.64(m,1H),2.35-2.32(m,1H),2.04-2.01(m,1H),0.97-0.94(m,2H ),0.72-0.68(m,1H),0.58-0.56(m,1H).
步骤2：将化合物Y63(200mg)进行手性拆分(
Figure PCTCN2022130850-appb-000149
OJ-250*25mm 10μm-CO 2,-MeOH(+0.1％7.0mol/l氨水的甲醇)-(60:40)-5.0min；流速：80ml/min；T：RT；波长：214nm；洗脱时长：5.0min)得到化合物： Step 2: Compound Y63 (200mg) was subjected to chiral resolution (
Figure PCTCN2022130850-appb-000149
OJ-250*25mm 10μm-CO 2,- MeOH (methanol+0.1% 7.0mol/l ammonia water)-(60:40)-5.0min; flow rate: 80ml/min; T: RT; wavelength: 214nm; elution Duration: 5.0min) to obtain the compound:
化合物Y63-1(62mg，产率31％，保留时间：3.164min)，LCMS:ESI[M+H] +＝336.1, 1H NMR(400MHz,DMSO-d 6)δ8.88(s,1H),8.39(d,J＝3.8Hz,1H),7.86(d,J＝11.2Hz,1H),7.17–6.99(m,2H),6.61(d,J＝7.6Hz,1H),3.22–3.10(m,2H),3.02(s,3H),2.72–2.61(m,1H),2.41-2.26(m,1H),2.11-1.88(m,1H),1.0-0.88(m,2H),0.74–0.52(m,2H)；以及 Compound Y63-1 (62 mg, yield 31%, retention time: 3.164 min), LCMS: ESI [M+H] + =336.1, 1 H NMR (400 MHz, DMSO-d 6 ) δ8.88 (s, 1H) ,8.39(d,J=3.8Hz,1H),7.86(d,J=11.2Hz,1H),7.17–6.99(m,2H),6.61(d,J=7.6Hz,1H),3.22–3.10( m,2H),3.02(s,3H),2.72–2.61(m,1H),2.41-2.26(m,1H),2.11-1.88(m,1H),1.0-0.88(m,2H),0.74– 0.52(m,2H); and
化合物Y63-2(61mg，产率30.5％，保留时间：4.202min)。LCMS:ESI[M+H] +＝336.1, 1H NMR(400MHz,DMSO-d 6)δ8.88(s,1H),8.39(d,J＝3.8Hz,1H),7.86(d,J＝11.2Hz,1H),7.17–6.99(m,2H),6.61(d,J＝7.6Hz,1H),3.22–3.10(m,2H),3.02(s,3H),2.72–2.61(m,1H),2.41-2.26(m,1H),2.11-1.88(m,1H),1.0-0.88(m,2H),0.74–0.52(m,2H)。 Compound Y63-2 (61 mg, yield 30.5%, retention time: 4.202 min). LCMS: ESI[M+H] + =336.1, 1 H NMR (400MHz, DMSO-d 6 )δ8.88(s, 1H), 8.39(d, J=3.8Hz, 1H), 7.86(d, J= 11.2Hz, 1H), 7.17–6.99(m, 2H), 6.61(d, J＝7.6Hz, 1H), 3.22–3.10(m, 2H), 3.02(s, 3H), 2.72–2.61(m, 1H ), 2.41-2.26(m,1H), 2.11-1.88(m,1H), 1.0-0.88(m,2H), 0.74–0.52(m,2H).
实施例64：化合物Y64的制备Embodiment 64: Preparation of Compound Y64
Figure PCTCN2022130850-appb-000150
Figure PCTCN2022130850-appb-000150
参考实施例1的制备方法，区别在于用化合物v28替换化合物v1，得到化合物Y64。LCMS：m/z＝361.0[M+H] +； 1H NMR(DMSO-d 6,400MHz):δ9.27(s,1H),8.71(d,J＝8.4Hz,1H)，8.32(d,J＝4Hz,1H),8.07(d,J＝7.6Hz,1H),7.01-6.99(m,1H),6.84(d,J＝7.6Hz,1H),3.08(s,3H),2.89(m,2H),2.03-2.01(m,1H),1.99-1.90(m,3H)。 Referring to the preparation method of Example 1, the difference is that compound v1 is replaced by compound v28 to obtain compound Y64. LCMS: m/z=361.0[M+H] + ; 1 H NMR (DMSO-d 6 , 400MHz): δ9.27(s, 1H), 8.71(d, J=8.4Hz, 1H), 8.32(d ,J=4Hz,1H),8.07(d,J=7.6Hz,1H),7.01-6.99(m,1H),6.84(d,J=7.6Hz,1H),3.08(s,3H),2.89( m,2H), 2.03-2.01(m,1H), 1.99-1.90(m,3H).
实施例65：化合物Y65及其异构体的制备Example 65: Preparation of compound Y65 and its isomers
Figure PCTCN2022130850-appb-000151
Figure PCTCN2022130850-appb-000151
步骤1：参考实施例1的制备方法，区别在于用化合物v24替换化合物v1，得到化合物65-1。LCMS：m/z 318.1[M-H] -。 Step 1: Referring to the preparation method of Example 1, the difference is that compound v1 is replaced by compound v24 to obtain compound 65-1. LCMS: m/z 318.1 [MH] - .
步骤2：将化合物65-1(155mg,0.485mmol)溶于干燥的DAST(3mL)中，室温搅拌过夜，缓慢的滴加到冰/碳酸钠水溶液中，保持体系成碱性，用EA(50mL)萃取三次，有机相用硫酸钠干燥后浓缩，过柱(二氯甲烷：甲醇＝20:1)后得到化合物Y65(5.7mg,产率79％)。LCMS：m/z＝342.0[M+H] +； 1H NMR(CD 3OD-d 4,400MHz):δ8.34(s,1H),7.96(d,J＝8.4Hz,1H),7.54(d,J＝8.4Hz,1H),7.18-7.16(m,2H),7.06(s,1H),3.29-3.21(m,1H),3.16-3.11(m,1H),3.09(s,3H),2.77-2.71(m,1H),2.37-2.30(m,1H),1.75 (t,J＝18.8Hz,3H)。 Step 2: Dissolve compound 65-1 (155mg, 0.485mmol) in dry DAST (3mL), stir overnight at room temperature, slowly add it dropwise to ice/sodium carbonate aqueous solution, keep the system alkaline, wash with EA (50mL ) was extracted three times, the organic phase was dried over sodium sulfate, concentrated, and passed through a column (dichloromethane:methanol=20:1) to obtain compound Y65 (5.7 mg, yield 79%). LCMS: m/z=342.0[M+H] + ; 1 H NMR (CD 3 OD-d 4 , 400MHz): δ8.34(s, 1H), 7.96 (d, J=8.4Hz, 1H), 7.54 (d,J=8.4Hz,1H),7.18-7.16(m,2H),7.06(s,1H),3.29-3.21(m,1H),3.16-3.11(m,1H),3.09(s,3H ), 2.77-2.71 (m, 1H), 2.37-2.30 (m, 1H), 1.75 (t, J=18.8Hz, 3H).
步骤3：将化合物Y65(100mg)进行手性拆分(
Figure PCTCN2022130850-appb-000152
OJ-250*25mm 10μm-CO 2,-MeOH(+0.1％7.0mol/l氨水的甲醇)-(85:15)-6.0min；流速：70ml/min；T：RT；波长：214nm；洗脱时长：6.0min。)，得到： Step 3: Compound Y65 (100mg) was subjected to chiral resolution (
Figure PCTCN2022130850-appb-000152
OJ-250*25mm 10μm-CO 2, -MeOH(+0.1%7.0mol/l ammonia methanol)-(85:15)-6.0min; Flow rate: 70ml/min; T: RT; Wavelength: 214nm; Elution Duration: 6.0min. ),get:
化合物Y65-1(28.39mg，产率28％，保留时间：2.025min)。LCMS:ESI[M+H] +＝342.2， 1H NMR(400MHz,DMSO-d 6)δ9.08(s,1H),8.41(d,J＝4.2Hz,1H),8.17(d,J＝8.0Hz,1H),7.68(d,J＝7.6Hz,1H),7.22-7.03(m,3H),3.26-3.11(m,2H),3.05(s,3H),2.72(s,1H),2.42–2.29(m,1H),2.00–1.84(m,3H)；以及 Compound Y65-1 (28.39 mg, yield 28%, retention time: 2.025 min). LCMS: ESI[M+H] + =342.2, 1 H NMR (400MHz, DMSO-d 6 ) δ9.08(s, 1H), 8.41(d, J=4.2Hz, 1H), 8.17(d, J= 8.0Hz,1H),7.68(d,J＝7.6Hz,1H),7.22-7.03(m,3H),3.26-3.11(m,2H),3.05(s,3H),2.72(s,1H), 2.42–2.29(m,1H), 2.00–1.84(m,3H); and
化合物Y65-2(20.69mg，产率20％，保留时间：2.384min)。LCMS:ESI[M+H] +＝342.2， 1H NMR(400MHz,DMSO-d 6)δ9.08(s,1H),8.41(d,J＝4.2Hz,1H),8.17(d,J＝8.0Hz,1H),7.68(d,J＝7.6Hz,1H),7.22-7.03(m,3H),3.26-3.11(m,2H),3.05(s,3H),2.72(s,1H),2.42–2.29(m,1H),2.00–1.84(m,3H)。 Compound Y65-2 (20.69 mg, yield 20%, retention time: 2.384 min). LCMS: ESI[M+H] + =342.2, 1 H NMR (400MHz, DMSO-d 6 ) δ9.08(s, 1H), 8.41(d, J=4.2Hz, 1H), 8.17(d, J= 8.0Hz,1H),7.68(d,J＝7.6Hz,1H),7.22-7.03(m,3H),3.26-3.11(m,2H),3.05(s,3H),2.72(s,1H), 2.42–2.29(m,1H), 2.00–1.84(m,3H).
实施例67：化合物Y67的制备Embodiment 67: Preparation of Compound Y67
Figure PCTCN2022130850-appb-000153
Figure PCTCN2022130850-appb-000153
步骤1：参考实施例1的制备方法，区别在于用化合物v22替换化合物v1，得到化合物67-1。LCMS：m/z 381.0[M+H] +。 Step 1: Referring to the preparation method of Example 1, the difference is that compound v1 is replaced by compound v22 to obtain compound 67-1. LCMS: m/z 381.0 [M+H] + .
步骤2：以化合物67-1(30mg,0.052mmol)和环丙基硼酸(5.4g,0.063mol)为原料，参考中间体v12步骤1的制备方法，用正相过柱纯化(甲醇：二氯甲烷＝1:20)，再通过制备纯化得到化合物Y67(10.5mg,收率38％).。LCMS：m/z＝343.1[M+H] +； 1H NMR(DMSO-d 6,400MHz):δ9.02(s,1H),8.47(s,1H),8.40(d,J＝4.0Hz,1H),7.13-7.06(m,2H),6.65(s,1H),3.20-3.15(m,2H),3.02(d,J＝4.0Hz,3H),2.68-2.63(m,1H),2.38-2.35(m,1H),2.18-2.07(m,1H),1.11(d,J＝8.0Hz,2H),0.81-0.79(m,1H),0.81-0.79(m,1H)。 Step 2: Using compound 67-1 (30mg, 0.052mmol) and cyclopropylboronic acid (5.4g, 0.063mol) as raw materials, refer to the preparation method of intermediate v12 step 1, and use normal phase column purification (methanol: dichloro Methane=1:20), and then purified by preparation to obtain compound Y67 (10.5 mg, yield 38%). LCMS: m/z=343.1[M+H] + ; 1 H NMR (DMSO-d 6 , 400MHz): δ9.02(s, 1H), 8.47(s, 1H), 8.40(d, J=4.0Hz ,1H),7.13-7.06(m,2H),6.65(s,1H),3.20-3.15(m,2H),3.02(d,J=4.0Hz,3H),2.68-2.63(m,1H), 2.38-2.35 (m, 1H), 2.18-2.07 (m, 1H), 1.11 (d, J=8.0Hz, 2H), 0.81-0.79 (m, 1H), 0.81-0.79 (m, 1H).
实施例68：化合物Y68的制备Embodiment 68: Preparation of Compound Y68
Figure PCTCN2022130850-appb-000154
Figure PCTCN2022130850-appb-000154
参考实施例1的制备方法，区别在于用化合物v25替换化合物v1，得到化合物Y68。LCMS：m/z 380.0[M+H] +； 1H NMR(DMSO-d 6,400MHz):δ9.23(br,1H),8.27(d,J＝8.0Hz,1H),7.92(d,J＝8.0Hz,1H),7.37(s,1H),7.25(q,J＝8.0Hz,2H),3.32-3.10(m,2H),3.11(d,J＝4.0Hz,3H),2.69-2.66(m,1H),2.40-2.37(m,1H)。 Referring to the preparation method of Example 1, the difference is that compound v1 is replaced by compound v25 to obtain compound Y68. LCMS: m/z 380.0[M+H] + ; 1 H NMR (DMSO-d 6 , 400MHz): δ9.23(br, 1H), 8.27(d, J=8.0Hz, 1H), 7.92(d, J＝8.0Hz, 1H), 7.37(s, 1H), 7.25(q, J＝8.0Hz, 2H), 3.32-3.10(m, 2H), 3.11(d, J＝4.0Hz, 3H), 2.69- 2.66(m,1H),2.40-2.37(m,1H).
参照上述实施例的制备方法合成以下化合物。以中间体v31和甲胺为原料，得到化合物Y25；以中间体v32和甲胺为原料，得到化合物Y32；以中间体v33和2，2，2-三氟乙胺为原料，得到化合物Y33；以中间体v34和甲胺为原料，得到化合物Y34；以中间体v35和甲胺为原料，得到化合物Y37；以中间体v36和甲胺为原料，得到化合物Y39；以中间体v37和甲胺为原料，得到化合物Y40；以中间体v38和甲胺为原料，得到化合物Y41；以中间体v39和甲胺为原料，得到化合物Y42；以中间体v34和氘代甲氨盐酸盐为原料，得到化合物Y47；以中间体v2和氘代甲氨盐酸盐为原料，得到化合物Y48；以中间体v40和氘代甲氨盐酸盐为原料，得到化合物Y49；以中间体v40和甲胺为原料，得到化合物Y50；以中间体v18和氘代甲氨盐酸盐为原料，得到化合物Y51；以中间体v18和甲胺为原料，得到化合物Y52；以中间体v41和甲胺为原料，得到化合物Y61；以中间体v42和甲胺为原料，得到化合物Y62；以中间体v43和甲胺为原料，得到化合物Y66；以中间体v44和甲胺为原料，得到化合物Y69；以中间体v46和甲胺为原料，得到化合物Y71。The following compounds were synthesized with reference to the preparation methods of the above examples. Using intermediate v31 and methylamine as raw materials to obtain compound Y25; using intermediate v32 and methylamine as raw materials to obtain compound Y32; using intermediate v33 and 2,2,2-trifluoroethylamine as raw materials to obtain compound Y33; Using intermediate v34 and methylamine as raw materials, compound Y34 was obtained; intermediate v35 and methylamine were used as raw materials to obtain compound Y37; intermediate v36 and methylamine were used as raw materials to obtain compound Y39; intermediate v37 and methylamine were used as As raw materials, compound Y40 is obtained; intermediate v38 and methylamine are used as raw materials to obtain compound Y41; intermediate v39 and methylamine are used as raw materials to obtain compound Y42; intermediate v34 and deuterated methylamine hydrochloride are used as raw materials to obtain Compound Y47; using intermediate v2 and deuterated methylamine hydrochloride as raw materials to obtain compound Y48; using intermediate v40 and deuterated methylamine hydrochloride as raw materials to obtain compound Y49; using intermediate v40 and methylamine as raw materials , to obtain compound Y50; taking intermediate v18 and deuterated methylamine hydrochloride as raw materials to obtain compound Y51; taking intermediate v18 and methylamine as raw materials to obtain compound Y52; taking intermediate v41 and methylamine as raw materials to obtain compound Y61; use intermediate v42 and methylamine as raw materials to obtain compound Y62; use intermediate v43 and methylamine as raw materials to obtain compound Y66; use intermediate v44 and methylamine as raw materials to obtain compound Y69; use intermediate v46 and formazan Starting from an amine, compound Y71 is obtained.
Figure PCTCN2022130850-appb-000155
Figure PCTCN2022130850-appb-000155
Figure PCTCN2022130850-appb-000156
Figure PCTCN2022130850-appb-000156
实施例70：化合物Y70及其异构体的制备Example 70: Preparation of compound Y70 and its isomers
Figure PCTCN2022130850-appb-000157
Figure PCTCN2022130850-appb-000157
以中间体v45和甲胺为原料，参照上述实施例的制备方法合成得到化合物Y70。将化合物Y70(100mg)进行手性拆分(
Figure PCTCN2022130850-appb-000158
AS-250*25mm 10μm-CO 2-MEOH(+0.1％7.0mol/l含氨水的甲醇)-(60:40)-2.0min；流速：70ml/min；T：RT；波长：214nm；洗脱时长：2.0min。)，分别得到： Using intermediate v45 and methylamine as raw materials, compound Y70 was synthesized by referring to the preparation method of the above examples. Compound Y70 (100 mg) was subjected to chiral resolution (
Figure PCTCN2022130850-appb-000158
AS-250*25mm 10μm-CO 2 -MEOH (+0.1% 7.0mol/l methanol containing ammonia)-(60:40)-2.0min; flow rate: 70ml/min; T: RT; wavelength: 214nm; elution Duration: 2.0min. ), respectively get:
化合物Y70-1(31mg，保留时间：3.524min)。LCMS:ESI[M+H]+＝343.2；1H NMR(400MHz,DMSO-d 6)δ9.15–8.93(m,2H),7.72(d,J＝7.2Hz,1H),7.33(t,J＝7.8Hz,1H),7.10–6.98(m,2H),3.34(s,1H),3.29(s,1H),3.04(d,J＝4.8Hz,3H),2.85–2.72(m,1H),2.46–2.36(m,1H),2.16–2.09(m,1H),1.00–0.93(m,4H)；以及 Compound Y70-1 (31 mg, retention time: 3.524 min). LCMS:ESI[M+H]+=343.2; 1H NMR(400MHz,DMSO-d 6 )δ9.15–8.93(m,2H),7.72(d,J=7.2Hz,1H),7.33(t,J ＝7.8Hz,1H),7.10–6.98(m,2H),3.34(s,1H),3.29(s,1H),3.04(d,J＝4.8Hz,3H),2.85–2.72(m,1H) ,2.46–2.36(m,1H),2.16–2.09(m,1H),1.00–0.93(m,4H); and
化合物Y70-2(38mg，保留时间：4.002min)。LCMS:ESI[M+H]+＝343.2；1H NMR(400MHz,DMSO-d 6)δ9.15–8.93(m,2H),7.72(d,J＝7.2Hz,1H),7.33(t,J＝7.8Hz,1H),7.10–6.98(m,2H),3.34(s,1H),3.29(s,1H),3.04(d,J＝4.8Hz,3H),2.85–2.72(m,1H),2.46–2.36(m,1H),2.16–2.09(m,1H),1.00–0.93(m,4H)。 Compound Y70-2 (38 mg, retention time: 4.002 min). LCMS:ESI[M+H]+=343.2; 1H NMR(400MHz,DMSO-d 6 )δ9.15–8.93(m,2H),7.72(d,J=7.2Hz,1H),7.33(t,J ＝7.8Hz,1H),7.10–6.98(m,2H),3.34(s,1H),3.29(s,1H),3.04(d,J＝4.8Hz,3H),2.85–2.72(m,1H) ,2.46–2.36(m,1H),2.16–2.09(m,1H),1.00–0.93(m,4H).
实施例72：化合物Y72及其异构体的制备Example 72: Preparation of compound Y72 and its isomers
Figure PCTCN2022130850-appb-000159
Figure PCTCN2022130850-appb-000159
以中间体v47和甲胺为原料，参照上述实施例的制备方法合成得到化合物Y72。将化合物Y72(73mg)进行手性拆分(
Figure PCTCN2022130850-appb-000160
OJ-250*25mm 10mm-CO 2-MeOH(+0.1％7.0mol/l氨水的甲醇)-(75:25)-2.5min；流速：70ml/min；T：RT；波长：214nm；洗脱时长：2.5min。)得到化合物Y72-1(30mg，保留时间：2.669min)，LCMS:ESI[M+H]+＝351.1；和化合物Y72-2(30mg，保留时间：3.415min)，LCMS:ESI[M+H]+＝351.1。 Using intermediate v47 and methylamine as raw materials, compound Y72 was synthesized by referring to the preparation method of the above examples. Compound Y72 (73 mg) was subjected to chiral resolution (
Figure PCTCN2022130850-appb-000160
OJ-250*25mm 10mm-CO 2 -MeOH (methanol+0.1% 7.0mol/l ammonia water)-(75:25)-2.5min; flow rate: 70ml/min; T: RT; wavelength: 214nm; elution time : 2.5min. ) to obtain compound Y72-1 (30mg, retention time: 2.669min), LCMS:ESI[M+H]+=351.1; and compound Y72-2 (30mg, retention time: 3.415min), LCMS:ESI[M+H] ]+=351.1.
实施例73：化合物Y73及其异构体的制备Example 73: Preparation of compound Y73 and its isomers
Figure PCTCN2022130850-appb-000161
Figure PCTCN2022130850-appb-000161
以中间体v48和氘代甲氨盐酸盐为原料，参照上述实施例的制备方法合成得到化合物Y73；将化合物Y73(100mg)进行手性拆分(Dr.maish Reprosil Chiral-MIC(
Figure PCTCN2022130850-appb-000162
IC)-250*25mm 10mm-CO 2-MeOH(+0.1％7.0mol/l氨水的甲醇)-(50:50)-7.0min；流速：70ml/min；T：RT；波长：214nm；洗脱时长：7.0min。)得到化合物Y73-1(32mg，保留时间：RT 1.944min)，LCMS:ESI[M+H]+＝336.2；和化合物Y73-2(35mg，保留时间：4.249min)，LCMS:ESI[M+H]+＝336.2。 Using intermediate v48 and deuterated methylamine hydrochloride as raw materials, compound Y73 was synthesized by referring to the preparation method of the above example; compound Y73 (100 mg) was subjected to chiral resolution (Dr.maish Reprosil Chiral-MIC (
Figure PCTCN2022130850-appb-000162
IC)-250*25mm 10mm-CO 2 -MeOH (methanol+0.1% 7.0mol/l ammonia water)-(50:50)-7.0min; flow rate: 70ml/min; T: RT; wavelength: 214nm; elution Duration: 7.0min. ) to obtain compound Y73-1 (32mg, retention time: RT 1.944min), LCMS:ESI[M+H]+=336.2; and compound Y73-2 (35mg, retention time: 4.249min), LCMS:ESI[M+ H]+=336.2.
实施例74：化合物Y74及其异构体的制备Example 74: Preparation of compound Y74 and its isomers
Figure PCTCN2022130850-appb-000163
Figure PCTCN2022130850-appb-000163
以中间体v48和甲胺为原料，参照上述实施例的制备方法合成得到化合物Y74。将化合物 Y74(100mg)进行手性拆分(Dr.maish Reprosil Chiral-MIC(
Figure PCTCN2022130850-appb-000164
IC)-250*25mm 10mm-CO 2-MeOH(+0.1％7.0mol/l氨水的甲醇)-(50:50)-7.0min；流速：70ml/min；T：RT；波长：214nm；洗脱时长：7.0min。)得到化合物Y74-1(30mg，保留时间：1.925min)，LCMS:ESI[M+H]+＝333.2；和化合物Y74-2(28mg，保留时间：4.298min)，LCMS:ESI[M+H]+＝333.2。 Using intermediate v48 and methylamine as raw materials, compound Y74 was synthesized by referring to the preparation method of the above examples. Compound Y74 (100mg) was subjected to chiral resolution (Dr.maish Reprosil Chiral-MIC (
Figure PCTCN2022130850-appb-000164
IC)-250*25mm 10mm-CO 2 -MeOH (methanol+0.1% 7.0mol/l ammonia water)-(50:50)-7.0min; flow rate: 70ml/min; T: RT; wavelength: 214nm; elution Duration: 7.0min. ) to obtain compound Y74-1 (30mg, retention time: 1.925min), LCMS:ESI[M+H]+=333.2; and compound Y74-2 (28mg, retention time: 4.298min), LCMS:ESI[M+H] ]+=333.2.
实施例75：化合物Y75及其异构体的制备Example 75: Preparation of compound Y75 and its isomers
Figure PCTCN2022130850-appb-000165
Figure PCTCN2022130850-appb-000165
步骤1：将化合物v23(600mg，1.86mmol,1.0eq)加入无水乙腈(10mL)溶解,室温下分别加入DIEA(2.4g,18.6mmol,10eq)和POCl 3(1.4g,9.3mmol,5.0eq)后，100℃搅拌6分钟。将反应液冷却到室温后加入氘代甲胺水溶液(30mL,2mol/L)，室温继续反应2小时后，加入100mL乙酸乙酯和100mL水稀释后萃取，有机相用清水洗三次，分液，有机相用无水硫酸钠干燥，过滤浓缩。经薄层色谱硅胶纯化(石油醚：乙酸乙酯＝1：1)得到化合物Y75(100mg,产率15.8％)。LCMS:ESI[M+H] +＝339.1。 Step 1: Compound v23 (600mg, 1.86mmol, 1.0eq) was dissolved in anhydrous acetonitrile (10mL), and DIEA (2.4g, 18.6mmol, 10eq) and POCl 3 (1.4g, 9.3mmol, 5.0eq) were added at room temperature ), stirred at 100°C for 6 minutes. Cool the reaction solution to room temperature, add deuterated methylamine aqueous solution (30mL, 2mol/L), continue to react at room temperature for 2 hours, add 100mL ethyl acetate and 100mL water to dilute and extract, wash the organic phase three times with water, and separate the layers. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. Purified by thin layer chromatography on silica gel (petroleum ether: ethyl acetate = 1:1) to obtain compound Y75 (100 mg, yield 15.8%). LCMS: ESI [M+H] + = 339.1.
步骤2：将化合物Y75(100mg)进行手性拆分(
Figure PCTCN2022130850-appb-000166
IG-250*25mm 10μm-CO 2,-MeOH(+0.1％7.0mol/l氨水的甲醇)-(50:50)-5.0min；流速：70ml/min；T：RT；波长：214nm；洗脱时长：5.0min。)得到： Step 2: Compound Y75 (100mg) was subjected to chiral resolution (
Figure PCTCN2022130850-appb-000166
IG-250*25mm 10μm-CO 2 ,-MeOH(methanol+0.1%7.0mol/l ammonia water)-(50:50)-5.0min; flow rate: 70ml/min; T: RT; wavelength: 214nm; elution Duration: 5.0min. )get:
化合物Y75-1(41mg，收率41％，保留时间：3.088min)。LCMS:ESI[M+H] +＝339.2， 1H NMR(400MHz,DMSO-d 6)δ8.85(s,1H),8.43–8.27(m,1H),7.87(d,J＝11.4Hz,1H),7.13-7.07(m,1H),7.02(d,J＝7.6Hz,1H),6.61(d,J＝7.4Hz,1H),3.23–3.07(m,2H),2.70-2.62(m,1H),2.37–2.24(m,1H),2.11–2.01(m,1H),1.03–0.90(m,2H),0.75-0.48(m,2H)；以及 Compound Y75-1 (41 mg, yield 41%, retention time: 3.088 min). LCMS: ESI [M+H] + =339.2, 1 H NMR (400MHz, DMSO-d 6 ) δ8.85 (s, 1H), 8.43–8.27 (m, 1H), 7.87 (d, J = 11.4Hz, 1H), 7.13-7.07(m, 1H), 7.02(d, J＝7.6Hz, 1H), 6.61(d, J＝7.4Hz, 1H), 3.23–3.07(m, 2H), 2.70-2.62(m ,1H),2.37–2.24(m,1H),2.11–2.01(m,1H),1.03–0.90(m,2H),0.75–0.48(m,2H); and
化合物Y75-2(38mg，收率38％，保留时间：4.122min)。LCMS:ESI[M+H]+＝339.2，1H NMR(400MHz,DMSO-d 6)δ8.85(s,1H),8.43–8.27(m,1H),7.87(d,J＝11.4Hz,1H),7.13-7.07(m,1H),7.02(d,J＝7.6Hz,1H),6.61(d,J＝7.4Hz,1H),3.23–3.07(m,2H),2.70-2.62(m,1H),2.37–2.24(m,1H),2.11–2.01(m,1H),1.03–0.90(m,2H),0.75-0.48(m,2H)。 Compound Y75-2 (38 mg, yield 38%, retention time: 4.122 min). LCMS: ESI[M+H]+=339.2, 1H NMR (400MHz, DMSO-d 6 )δ8.85(s, 1H), 8.43–8.27(m, 1H), 7.87(d, J=11.4Hz, 1H ),7.13-7.07(m,1H),7.02(d,J＝7.6Hz,1H),6.61(d,J＝7.4Hz,1H),3.23–3.07(m,2H),2.70-2.62(m, 1H), 2.37–2.24(m,1H), 2.11–2.01(m,1H), 1.03–0.90(m,2H), 0.75–0.48(m,2H).
实施例76：化合物Y76及其异构体的制备Example 76: Preparation of compound Y76 and its isomers
Figure PCTCN2022130850-appb-000167
Figure PCTCN2022130850-appb-000167
步骤1：将化合物v23(600mg，1.86mmol,1.0eq)加入无水乙腈(10mL)溶解,室温下分别加入DIEA(2.4g,18.6mmol,10eq)和POCl 3(1.4g,9.3mmol,5.0eq)后，100℃搅拌6分钟。将反应液冷却到室温后加入2,2-二氟乙胺水溶液(30mL,2mole/L)，室温继续反应2小时后，加入100mL乙酸乙酯和100mL水稀释后萃取，有机相用清水洗三次，分液，有机相用无水硫酸钠干燥，过滤浓缩。经薄层色谱硅胶纯化(石油醚：乙酸乙酯＝1：1)得到化合物Y76(60mg,产率8.3％)。LCMS:ESI[M+H] +＝386.1。 Step 1: Compound v23 (600mg, 1.86mmol, 1.0eq) was dissolved in anhydrous acetonitrile (10mL), and DIEA (2.4g, 18.6mmol, 10eq) and POCl 3 (1.4g, 9.3mmol, 5.0eq) were added at room temperature ), stirred at 100°C for 6 minutes. After cooling the reaction solution to room temperature, add 2,2-difluoroethylamine aqueous solution (30mL, 2mole/L), continue the reaction at room temperature for 2 hours, add 100mL ethyl acetate and 100mL water to dilute and extract, and wash the organic phase three times with water , separated, and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. Purified by thin layer chromatography on silica gel (petroleum ether: ethyl acetate = 1:1) to obtain compound Y76 (60 mg, yield 8.3%). LCMS: ESI [M+H] + = 386.1.
步骤2：将化合物Y76(60mg)进行手性拆分(
Figure PCTCN2022130850-appb-000168
OJ-250*25mm 10μm-CO 2-MeOH(+0.1％7.0mol/l氨水的甲醇)-(70:30)-3.0min；流速：80ml/min；T：RT；波长：214nm；洗脱时长：3.0min)，得到： Step 2: Compound Y76 (60mg) was subjected to chiral resolution (
Figure PCTCN2022130850-appb-000168
OJ-250*25mm 10μm-CO 2 -MeOH (methanol+0.1% 7.0mol/l ammonia water)-(70:30)-3.0min; flow rate: 80ml/min; T: RT; wavelength: 214nm; elution time : 3.0min), get:
化合物Y76-1(27mg，产率45％，保留时间：2.887min)。LCMS:ESI[M+H] +＝386.1, 1H NMR(400MHz,DMSO-d 6)δ10.61(s,1H),8.43(dd,J＝21.6,3.2Hz,1H),7.87(dd,J＝71.2,11.2Hz,1H),7.28–7.00(m,2H),6.64(dd,J＝39.6,7.6Hz,1H),6.48–6.08(m,1H),4.0-3.77(m,2H),3.24–3.11(m,2H),2.83-2.65(m,1H),2.40–2.34(m,1H),2.09–1.96(m,1H),1.0-0.88(m,2H),0.76-0.49(m,2H)；以及 Compound Y76-1 (27 mg, yield 45%, retention time: 2.887 min). LCMS: ESI [M+H] + =386.1, 1 H NMR (400MHz, DMSO-d 6 ) δ10.61 (s, 1H), 8.43 (dd, J = 21.6, 3.2Hz, 1H), 7.87 (dd, J=71.2,11.2Hz,1H),7.28–7.00(m,2H),6.64(dd,J=39.6,7.6Hz,1H),6.48–6.08(m,1H),4.0-3.77(m,2H) ,3.24–3.11(m,2H),2.83-2.65(m,1H),2.40–2.34(m,1H),2.09–1.96(m,1H),1.0-0.88(m,2H),0.76-0.49( m,2H); and
化合物Y76-2(26mg，产率43％，保留时间：2.581min)。LCMS:ESI[M+H] +＝386.1， 1H NMR(400MHz,DMSO-d 6)δ10.61(s,1H),8.43(dd,J＝21.6,3.2Hz,1H),7.87(dd,J＝71.2,11.2Hz,1H),7.28–7.00(m,2H),6.64(dd,J＝39.6,7.6Hz,1H),6.48–6.08(m,1H),4.0-3.77(m,2H),3.24–3.11(m,2H),2.83-2.65(m,1H),2.40–2.34(m,1H),2.09–1.96(m,1H),1.0-0.88(m,2H),0.76-0.49(m,2H),0.74–0.52(m,2H)。 Compound Y76-2 (26 mg, yield 43%, retention time: 2.581 min). LCMS: ESI [M+H] + = 386.1, 1 H NMR (400MHz, DMSO-d 6 ) δ 10.61 (s, 1H), 8.43 (dd, J = 21.6, 3.2Hz, 1H), 7.87 (dd, J=71.2,11.2Hz,1H),7.28–7.00(m,2H),6.64(dd,J=39.6,7.6Hz,1H),6.48–6.08(m,1H),4.0-3.77(m,2H) ,3.24–3.11(m,2H),2.83-2.65(m,1H),2.40–2.34(m,1H),2.09–1.96(m,1H),1.0-0.88(m,2H),0.76-0.49( m,2H), 0.74–0.52(m,2H).
实施例77：化合物Y77及其异构体的制备Example 77: Preparation of compound Y77 and its isomers
Figure PCTCN2022130850-appb-000169
Figure PCTCN2022130850-appb-000169
步骤1：在室温下将三氯氧磷(1g，6.63mmol,5.0eq)和二异丙基乙基胺(1.7g，13.2mmol,10.0eq)加入到化合物v49(435mg，1.32mmol,1.0eq)的无水乙腈(10mL)溶液中，将反应体系放到100℃的油浴中，反应五分钟，五分钟后降温到0-5℃，向反应液中缓慢滴加氘代甲胺的水溶液(30mL，2mole/L)，反应体系温度控制在5-15℃。室温搅拌10min后，向体系中加入水(100mL)和乙酸乙酯(100mL)，分层后，水相再用乙酸乙酯萃取(100mL X 2)，合并有机相，然后用饱和食盐水(500mL)洗涤，有机相用无水硫酸钠干燥，浓缩有机相得粗品，粗品经薄层色谱硅胶(乙酸乙酯：甲醇＝10：1)纯化得到化合物Y77(120mg,产率26.3％)。LCMS:ESI[M+H] +＝345.3。 Step 1: Phosphorus oxychloride (1 g, 6.63 mmol, 5.0 eq) and diisopropylethylamine (1.7 g, 13.2 mmol, 10.0 eq) were added to compound v49 (435 mg, 1.32 mmol, 1.0 eq) at room temperature ) in anhydrous acetonitrile (10mL) solution, put the reaction system in an oil bath at 100°C, react for five minutes, cool down to 0-5°C after five minutes, slowly add an aqueous solution of deuterated methylamine dropwise to the reaction solution (30mL, 2mole/L), the temperature of the reaction system was controlled at 5-15°C. After stirring at room temperature for 10min, water (100mL) and ethyl acetate (100mL) were added to the system. ), the organic phase was dried with anhydrous sodium sulfate, and the organic phase was concentrated to obtain a crude product, which was purified by thin-layer chromatography on silica gel (ethyl acetate:methanol=10:1) to obtain compound Y77 (120 mg, yield 26.3%). LCMS: ESI [M+H] + = 345.3.
步骤2：将化合物Y77(120mg)进行手性拆分((
Figure PCTCN2022130850-appb-000170
IC)-250*25mm 10μm-CO 2-MeOH(+0.1％7.0mol/l氨水的甲醇)-(50:50)-8.0min；流速：100ml/min；T：RT；波长：214nm；洗脱时长：8.0min。)，得到： Step 2: Compound Y77 (120mg) was subjected to chiral resolution ((
Figure PCTCN2022130850-appb-000170
IC)-250*25mm 10μm-CO 2 -MeOH (methanol+0.1% 7.0mol/l ammonia water)-(50:50)-8.0min; flow rate: 100ml/min; T: RT; wavelength: 214nm; elution Duration: 8.0min. ),get:
化合物Y77-1(42mg，产率35％，保留时间：1.033min)。LCMS:ESI[M+H] +＝345.2， 1H NMR(400MHz,DMSO-d 6)δ9.06(s,1H),8.41(d,J＝4.8Hz,1H),8.16(d,J＝8.0Hz,1H),7.68(d,J＝8.0Hz,1H),7.26–7.01(m,3H),3.26–3.03(m,2H),2.78–2.66(m,1H),2.45–2.27(m,1H),2.04–1.71(m,3H)；以及 Compound Y77-1 (42 mg, yield 35%, retention time: 1.033 min). LCMS: ESI[M+H] + =345.2, 1 H NMR (400MHz, DMSO-d 6 )δ9.06(s, 1H), 8.41(d, J=4.8Hz, 1H), 8.16(d, J= 8.0Hz,1H),7.68(d,J＝8.0Hz,1H),7.26–7.01(m,3H),3.26–3.03(m,2H),2.78–2.66(m,1H),2.45–2.27(m ,1H),2.04–1.71(m,3H); and
化合物Y77-2(32mg，产率26％，保留时间：1.944min)。LCMS:ESI[M+H] +＝345.2， 1H NMR(400MHz,DMSO-d 6)δ9.06(s,1H),8.41(d,J＝4.8Hz,1H),8.16(d,J＝8.0Hz,1H),7.68(d,J＝8.0Hz,1H),7.26–7.01(m,3H),3.26–3.03(m,2H),2.78–2.66(m,1H),2.45–2.27(m,1H),2.04–1.71(m,3H)。 Compound Y77-2 (32 mg, yield 26%, retention time: 1.944 min). LCMS: ESI[M+H] + =345.2, 1 H NMR (400MHz, DMSO-d 6 )δ9.06(s, 1H), 8.41(d, J=4.8Hz, 1H), 8.16(d, J= 8.0Hz,1H),7.68(d,J＝8.0Hz,1H),7.26–7.01(m,3H),3.26–3.03(m,2H),2.78–2.66(m,1H),2.45–2.27(m ,1H), 2.04–1.71(m,3H).
实施例78：化合物Y78的制备Example 78: Preparation of compound Y78
Figure PCTCN2022130850-appb-000171
Figure PCTCN2022130850-appb-000171
将化合物v49(500mg,1.52mmol)溶于MeCN(15mL)中，氩气保护下加入POCl 3(1.17g,7.61mmol,709.77μL)和DIEA(1.97g,15.23mmol,2.65mL).100℃搅拌10min，然后降温至0℃，缓慢滴加2,2,2-三氟乙胺(754.27mg,7.61mmol)和THF(2mL)。室温搅拌10min。加入水和乙酸乙酯，用乙酸乙酯萃取三次，合并有机相，用食盐水和饱和碳酸氢钠水溶液洗涤，无水硫酸钠干燥，减压浓缩得到粗产品。用制备液相色谱(制备柱：21.2X250mm C18柱；体系：10mM NH 4HCO 3H 2O；波长：254/214nm；梯度：5％-95％乙腈变化)纯化所得粗产品，得到目标化合物Y78(64.97mg,收率：9.94％,纯度：95.39％)。LCMS:ESI[M+H] +＝410.1。 1H NMR(400MHz,DMSO-d 6)δ10.61(s,1H),8.45(dd,J＝4.8,1.6Hz,1H),8.28(d,J＝8.4Hz,1H),7.61(d,J＝8.4Hz,1H),7.29–7.22(m,1H),7.16(dd,J＝7.6,4.8Hz,1H),7.10(s,1H),4.24(s,2H),3.27–3.11(m,2H),2.80(s,1H),2.46–2.37(m,1H),1.87(t,J＝20.0Hz,3H)。 Compound v49 (500mg, 1.52mmol) was dissolved in MeCN (15mL), POCl 3 (1.17g, 7.61mmol, 709.77μL) and DIEA (1.97g, 15.23mmol, 2.65mL) were added under argon protection. Stir at 100°C After 10 min, the temperature was lowered to 0° C., and 2,2,2-trifluoroethylamine (754.27 mg, 7.61 mmol) and THF (2 mL) were slowly added dropwise. Stir at room temperature for 10 min. Add water and ethyl acetate, extract three times with ethyl acetate, combine the organic phases, wash with brine and saturated aqueous sodium bicarbonate solution, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a crude product. The obtained crude product was purified by preparative liquid chromatography (preparative column: 21.2X250mm C18 column; system: 10mM NH 4 HCO 3 H 2 O; wavelength: 254/214nm; gradient: 5%-95% change in acetonitrile) to obtain the target compound Y78 (64.97mg, yield: 9.94%, purity: 95.39%). LCMS: ESI [M+H] + = 410.1. 1 H NMR (400MHz, DMSO-d 6 )δ10.61(s, 1H), 8.45(dd, J=4.8, 1.6Hz, 1H), 8.28(d, J=8.4Hz, 1H), 7.61(d, J=8.4Hz,1H),7.29–7.22(m,1H),7.16(dd,J=7.6,4.8Hz,1H),7.10(s,1H),4.24(s,2H),3.27–3.11(m ,2H), 2.80(s,1H), 2.46–2.37(m,1H), 1.87(t,J=20.0Hz,3H).
实施例79：化合物Y79的制备Example 79: Preparation of Compound Y79
Figure PCTCN2022130850-appb-000172
Figure PCTCN2022130850-appb-000172
将化合物v49(100mg，0.305mmol,1.0eq)加入无水乙腈(3mL)溶解,室温下分别加入DIEA(393.66mg,3.05mmol,10eq)和POCl 3(233.52mg,1.52mmol,5.0eq)后，100℃搅拌15分钟。将反应液冷却到室温后，加入二甲胺的乙腈溶液(3mL,2Ml,10eq)，回到室温搅拌20分钟，加入10mL乙酸乙酯和10mL水稀释后萃取，有机相用清水洗三次，分液，有机相用无水硫酸钠干燥，过滤浓缩。经Prep-HPLC制备纯化(EA:MeOH＝10:1)得到化合物Y79(41.70mg,产率36.71％)。LCMS:ESI[M+H] +＝356.2。 1H NMR(400MHz,DMSO-d 6)δ8.44(dd,J＝4.8,1.6Hz,1H),7.98(d,J＝8.0Hz,1H),7.62(dd,J＝8.0,1.6Hz,1H),7.26–7.19(m,2H),7.09(d,J＝1.2Hz,1H),3.39(s,6H),3.07(t,J＝7.2Hz,2H),2.78–2.68(m,1H),2.45(d,J＝12.8Hz,1H),1.91(t,J＝19.2Hz,3H)。 Compound v49 (100mg, 0.305mmol, 1.0eq) was dissolved in anhydrous acetonitrile (3mL), and DIEA (393.66mg, 3.05mmol, 10eq) and POCl 3 (233.52mg, 1.52mmol, 5.0eq) were added at room temperature, Stir at 100°C for 15 minutes. After cooling the reaction solution to room temperature, add dimethylamine in acetonitrile solution (3mL, 2Ml, 10eq), return to room temperature and stir for 20 minutes, add 10mL ethyl acetate and 10mL water to dilute and extract, wash the organic phase three times with water, separate liquid, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. Purified by Prep-HPLC (EA:MeOH=10:1) to obtain compound Y79 (41.70 mg, yield 36.71%). LCMS: ESI [M+H] + = 356.2. 1 H NMR (400MHz, DMSO-d 6 )δ8.44(dd, J=4.8,1.6Hz,1H),7.98(d,J=8.0Hz,1H),7.62(dd,J=8.0,1.6Hz, 1H),7.26–7.19(m,2H),7.09(d,J＝1.2Hz,1H),3.39(s,6H),3.07(t,J＝7.2Hz,2H),2.78–2.68(m,1H ), 2.45 (d, J=12.8Hz, 1H), 1.91 (t, J=19.2Hz, 3H).
实施例80：化合物Y80及其异构体的制备Example 80: Preparation of compound Y80 and its isomers
Figure PCTCN2022130850-appb-000173
Figure PCTCN2022130850-appb-000173
步骤1：在室温下将三氯氧磷(1.4g，9.14mmol,5.0eq)和二异丙基乙基胺(2.3g，18.3mmol,10.0eq)加入到化合物v49(600mg，1.83mmol,1.0eq)的无水乙腈(10mL)溶液中，将反应体系放到100℃的油浴中，反应五分钟，五分钟后降温到0-5℃，向反应液中缓慢滴加二氟乙胺的乙腈溶液(30mL，2mole/L)，反应体系温度控制在0-5℃。室温搅拌10min后，向体系中加入水(100mL)和乙酸乙酯(100mL)，分层后，水相再用乙酸乙酯萃取(100mL×2)，合并有机相，然后用饱和食盐水(500mL)洗涤，有机相用无水硫酸钠干燥，浓缩有机相得粗品，粗品经反相HPLC(Prep-HPLC(Waters 2767 Column:Xbridge C18,19*250mm,10μm；流动相A:0.05％NH 3H 2O/H 2O,B:ACN；流速:20ml/min；梯度:36-36％；Time:9.1-10.1min of 16min)纯化得到化合物Y80(140mg,产率19.5％)。LCMS:ESI[M+H] +＝392.1。 Step 1: Add phosphorus oxychloride (1.4g, 9.14mmol, 5.0eq) and diisopropylethylamine (2.3g, 18.3mmol, 10.0eq) to compound v49 (600mg, 1.83mmol, 1.0 eq) in anhydrous acetonitrile (10mL) solution, put the reaction system in an oil bath at 100°C, react for five minutes, cool down to 0-5°C after five minutes, slowly add difluoroethylamine dropwise to the reaction solution Acetonitrile solution (30mL, 2mole/L), the temperature of the reaction system was controlled at 0-5°C. After stirring at room temperature for 10min, water (100mL) and ethyl acetate (100mL) were added to the system. After the layers were separated, the aqueous phase was extracted with ethyl acetate (100mL×2). ), the organic phase was dried with anhydrous sodium sulfate, and the organic phase was concentrated to obtain a crude product, which was subjected to reverse phase HPLC (Prep-HPLC (Waters 2767 Column: Xbridge C18, 19*250mm, 10 μm; mobile phase A: 0.05% NH 3 H 2 O/H 2 O, B: ACN; Flow rate: 20ml/min; Gradient: 36-36%; Time: 9.1-10.1min of 16min) was purified to obtain compound Y80 (140mg, yield 19.5%).LCMS:ESI[ M+H] + = 392.1.
步骤2：将化合物Y80(140mg)进行手性拆分(
Figure PCTCN2022130850-appb-000174
AD-250*25mm 10μm-CO 2-MEOH(+0.1％7.0mol/l氨水的甲醇)-(80:20)-3.5min；流速：70ml/min；T：RT；波长：214nm；洗脱时长：3.5min。)，得到： Step 2: Compound Y80 (140mg) was subjected to chiral resolution (
Figure PCTCN2022130850-appb-000174
AD-250*25mm 10μm-CO 2 -MEOH (methanol+0.1% 7.0mol/l ammonia water)-(80:20)-3.5min; flow rate: 70ml/min; T: RT; wavelength: 214nm; elution time : 3.5min. ),get:
化合物Y80-1(27mg，产率19.2％，保留时间：2.134min)。LCMS:ESI[M+H] +＝392.4， 1H NMR(400MHz,DMSO-d 6)δ10.66(s,0.5H),9.33(s,0.5H),8.47(s,1H),8.29(s,1H),7.76-7.55(m,1H),7.33–7.04(m,3H),6.31(t,J＝57.2Hz,1H),4.07–3.75(m,2H),3.22(s,2H),2.83(s,1H),2.46–2.36(m,1H),1.90(t,J＝18.8Hz,3H)；以及 Compound Y80-1 (27 mg, yield 19.2%, retention time: 2.134 min). LCMS: ESI [M+H] + = 392.4, 1 H NMR (400MHz, DMSO-d 6 ) δ 10.66 (s, 0.5H), 9.33 (s, 0.5H), 8.47 (s, 1H), 8.29 ( s,1H),7.76-7.55(m,1H),7.33–7.04(m,3H),6.31(t,J＝57.2Hz,1H),4.07–3.75(m,2H),3.22(s,2H) ,2.83(s,1H),2.46–2.36(m,1H),1.90(t,J=18.8Hz,3H); and
化合物Y80-2(29mg，产率20.7％，保留时间：2.771min)。LCMS:ESI[M+H] +＝392.4， 1H NMR(400MHz,DMSO-d 6)δ10.66(s,0.5H),9.33(s,0.5H),8.47(s,1H),8.29(s,1H),7.76-7.55(m,1H),7.33–7.04(m,3H),6.31(t,J＝57.2Hz,1H),4.07–3.75(m,2H),3.22(s,2H),2.83(s,1H),2.46–2.36(m,1H),1.90(t,J＝18.8Hz,3H)。 Compound Y80-2 (29 mg, yield 20.7%, retention time: 2.771 min). LCMS: ESI [M+H] + = 392.4, 1 H NMR (400MHz, DMSO-d 6 ) δ 10.66 (s, 0.5H), 9.33 (s, 0.5H), 8.47 (s, 1H), 8.29 ( s,1H),7.76-7.55(m,1H),7.33–7.04(m,3H),6.31(t,J＝57.2Hz,1H),4.07–3.75(m,2H),3.22(s,2H) , 2.83 (s, 1H), 2.46–2.36 (m, 1H), 1.90 (t, J=18.8Hz, 3H).
实施例81：化合物Y81及其异构体的制备Example 81: Preparation of compound Y81 and its isomers
Figure PCTCN2022130850-appb-000175
Figure PCTCN2022130850-appb-000175
步骤1：在室温下将三氯氧磷(1.4g，9.14mmol,5.0eq)和二异丙基乙基胺(2.3g，18.3mmol,10.0eq)加入到化合物v49(600mg，1.83mmol,1.0eq)的无水乙腈(10mL)溶液中，将反应体系放到100℃的油浴中，反应五分钟，五分钟后降温到0-5℃，向反应液中缓慢滴加三氟乙胺的乙腈溶液(30mL，2mole/L)，反应体系温度控制在0-5℃。室温搅拌10min后，向体系中加入水(100mL)和乙酸乙酯(100mL)，分层后，水相再用乙酸乙酯萃取(100mL×2)，合并有机相，然后用饱和食盐水(500mL)洗涤，有机相用无水硫酸钠干燥，浓缩有机相得粗品，粗品经反相HPLC((Waters 2767 Column:Xbridge C18,19*250mm,10μm；流动相A:10mmolNH 4HCO 3/H 2O,B:ACN；流速:20ml/min；梯度:47-47％；时间:8.2-9.3min of 16min)纯化得到化合物Y81(60mg,产率8％)。LCMS:ESI[M+H] +＝410。 Step 1: Add phosphorus oxychloride (1.4g, 9.14mmol, 5.0eq) and diisopropylethylamine (2.3g, 18.3mmol, 10.0eq) to compound v49 (600mg, 1.83mmol, 1.0 eq) in anhydrous acetonitrile (10mL) solution, put the reaction system in an oil bath at 100°C, react for five minutes, cool down to 0-5°C after five minutes, slowly add trifluoroethylamine dropwise to the reaction solution Acetonitrile solution (30mL, 2mole/L), the temperature of the reaction system was controlled at 0-5°C. After stirring at room temperature for 10min, water (100mL) and ethyl acetate (100mL) were added to the system. After the layers were separated, the aqueous phase was extracted with ethyl acetate (100mL×2). ), the organic phase was dried with anhydrous sodium sulfate, and the organic phase was concentrated to obtain a crude product, which was subjected to reverse-phase HPLC ((Waters 2767 Column: Xbridge C18, 19*250mm, 10 μm; mobile phase A: 10mmolNH 4 HCO 3 /H 2 O , B: ACN; flow rate: 20ml/min; gradient: 47-47%; time: 8.2-9.3min of 16min) was purified to obtain compound Y81 (60mg, yield 8%).LCMS:ESI[M+H] + = 410.
步骤2：将化合物Y81(60mg)进行手性拆分(
Figure PCTCN2022130850-appb-000176
IB-250*25mm 10μm-CO 2-MeOH(+0.1％7.0mol/l氨水的甲醇)-(80:20)-4.5min；流速：70ml/min；T：RT；波长：214nm；洗脱时长：4.5min。)，得到： Step 2: Compound Y81 (60mg) was subjected to chiral resolution (
Figure PCTCN2022130850-appb-000176
IB-250*25mm 10μm-CO 2 -MeOH (methanol+0.1% 7.0mol/l ammonia water)-(80:20)-4.5min; flow rate: 70ml/min; T: RT; wavelength: 214nm; elution time : 4.5min. ),get:
化合物Y81-1(25mg，产率41％，保留时间：2.430min)。P1:LCMS:ESI[M+H] +＝410.1， 1H NMR(400MHz,DMSO-d 6)δ10.74(s,1H),8.48(d,J＝4.4Hz,1H),8.30(d,J＝8.8Hz,1H),7.62(d,J＝8.0Hz,1H),7.42–7.05(m,3H),4.25(s,2H),3.23(s,2H),2.84(s,1H),2.44(s,1H),1.89(t,J＝18.8Hz,3H)；以及 Compound Y81-1 (25 mg, yield 41%, retention time: 2.430 min). P1: LCMS: ESI[M+H] + =410.1, 1 H NMR (400MHz, DMSO-d 6 )δ10.74(s, 1H), 8.48(d, J=4.4Hz, 1H), 8.30(d, J=8.8Hz,1H),7.62(d,J=8.0Hz,1H),7.42–7.05(m,3H),4.25(s,2H),3.23(s,2H),2.84(s,1H), 2.44(s, 1H), 1.89(t, J=18.8Hz, 3H); and
化合物Y81-2(23mg，产率38％，保留时间：2.697min)。LCMS:ESI[M+H] +＝410.1， 1H NMR(400 MHz,DMSO-d 6)δ10.74(s,1H),8.48(d,J＝4.4Hz,1H),8.30(d,J＝8.8Hz,1H),7.62(d,J＝8.0Hz,1H),7.42–7.05(m,3H),4.25(s,2H),3.23(s,2H),2.84(s,1H),2.44(s,1H),1.89(t,J＝18.8Hz,3H)。 Compound Y81-2 (23 mg, yield 38%, retention time: 2.697 min). LCMS: ESI [M+H] + = 410.1, 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.74 (s, 1H), 8.48 (d, J = 4.4Hz, 1H), 8.30 (d, J =8.8Hz,1H),7.62(d,J=8.0Hz,1H),7.42–7.05(m,3H),4.25(s,2H),3.23(s,2H),2.84(s,1H),2.44 (s, 1H), 1.89 (t, J = 18.8Hz, 3H).
实施例82：化合物Y82及其异构体的制备Example 82: Preparation of compound Y82 and its isomers
Figure PCTCN2022130850-appb-000177
Figure PCTCN2022130850-appb-000177
步骤1：将化合物v50(0.25g,721.91μmol)溶于MeCN(10mL)中，氩气保护下加入POCl3(553.45mg,3.61mmol,336.45μL)和DIEA(933.00mg,7.22mmol,1.26mL).100℃搅拌10min，然后减压浓缩除去溶剂(得到样品A)。把氘代甲胺盐酸盐(509.21mg,7.22mmol,HCl)和DIEA(1.40g,10.83mmol,1.89mL)溶于THF(5mL)中，搅拌0.5小时(得到样品B)。把样品A溶于THF(10mL)中，加入样品B中，室温搅拌10min。减压浓缩除去溶剂。再用制备液相色谱碱法(制备柱：21.2×250mm C18柱；体系：10mM NH 4HCO 3H 2O；波长：254/214nm；梯度：5％-95％乙腈变化)纯化所得粗产品，得到目标化合物Y82(4.29mg,收率：1.63％,纯度：99.32％)。LCMS:ESI[M+H] +＝363.1。 1H NMR(400MHz,DMSO-d 6)δ9.03(s,1H),8.40(t,J＝3.2Hz,1H),8.08(d,J＝12.0Hz,1H),7.15–7.09(m,3H),3.24–3.04(m,2H),2.71-2.62(m,1H),2.37-2.28(m,1H),1.94(t,J＝19.2Hz,3H)。 Step 1: Compound v50 (0.25g, 721.91μmol) was dissolved in MeCN (10mL), and POCl3 (553.45mg, 3.61mmol, 336.45μL) and DIEA (933.00mg, 7.22mmol, 1.26mL) were added under argon protection. Stir at 100° C. for 10 min, then concentrate under reduced pressure to remove the solvent (to obtain sample A). Deuteromethylamine hydrochloride (509.21 mg, 7.22 mmol, HCl) and DIEA (1.40 g, 10.83 mmol, 1.89 mL) were dissolved in THF (5 mL) and stirred for 0.5 h (obtaining sample B). Dissolve sample A in THF (10 mL), add to sample B, and stir at room temperature for 10 min. Concentrate under reduced pressure to remove the solvent. The obtained crude product was purified by preparative liquid chromatography alkali method (preparative column: 21.2×250mm C18 column; system: 10mM NH 4 HCO 3 H 2 O; wavelength: 254/214nm; gradient: 5%-95% change in acetonitrile), The target compound Y82 (4.29 mg, yield: 1.63%, purity: 99.32%) was obtained. LCMS: ESI [M+H] + = 363.1. 1 H NMR (400MHz, DMSO-d 6 )δ9.03(s, 1H), 8.40(t, J=3.2Hz, 1H), 8.08(d, J=12.0Hz, 1H), 7.15–7.09(m, 3H), 3.24–3.04(m, 2H), 2.71-2.62(m, 1H), 2.37-2.28(m, 1H), 1.94(t, J=19.2Hz, 3H).
步骤2：将化合物Y82(130mg)进行手性拆分(
Figure PCTCN2022130850-appb-000178
AD-250*25mm 10μm-CO 2-MeOH(+0.1％7.0mol/l氨水的甲醇)-(70:30)-3.0min；流速：70ml/min；T：RT；波长：214nm；洗脱时长：3.0min。)，得到： Step 2: Compound Y82 (130mg) was subjected to chiral resolution (
Figure PCTCN2022130850-appb-000178
AD-250*25mm 10μm-CO 2 -MeOH (methanol+0.1% 7.0mol/l ammonia water)-(70:30)-3.0min; flow rate: 70ml/min; T: RT; wavelength: 214nm; elution time : 3.0min. ),get:
化合物Y82-1(53mg，产率40％，保留时间：2.602min)。LCMS:ESI[M+H] +＝363.1， 1H NMR(400MHz,DMSO-d 6)δ9.05(s,1H),8.42(s,1H),8.09(d,J＝11.2Hz,1H),7.22–7.02(m,3H),3.26–3.05(m,2H),2.69(s,1H),2.44–2.26(m,1H),1.96(t,J＝19.2Hz,3H)；以及 Compound Y82-1 (53 mg, yield 40%, retention time: 2.602 min). LCMS: ESI [M+H] + =363.1, 1 H NMR (400MHz, DMSO-d 6 ) δ9.05(s, 1H), 8.42(s, 1H), 8.09 (d, J = 11.2Hz, 1H) , 7.22–7.02(m,3H), 3.26–3.05(m,2H), 2.69(s,1H), 2.44–2.26(m,1H), 1.96(t,J=19.2Hz,3H); and
化合物Y82-2(47mg，产率36％，保留时间：3.463min)，LCMS:ESI[M+H] +＝363.1， 1H NMR(400MHz,DMSO-d 6)δ9.05(s,1H),8.42(s,1H),8.09(d,J＝11.2Hz,1H),7.22–7.02(m,3H),3.26–3.05(m,2H),2.69(s,1H),2.44–2.26(m,1H),1.96(t,J＝19.2Hz,3H)。 Compound Y82-2 (47 mg, yield 36%, retention time: 3.463 min), LCMS: ESI [M+H] + =363.1, 1 H NMR (400 MHz, DMSO-d 6 ) δ9.05 (s, 1H) ,8.42(s,1H),8.09(d,J＝11.2Hz,1H),7.22–7.02(m,3H),3.26–3.05(m,2H),2.69(s,1H),2.44–2.26(m , 1H), 1.96 (t, J = 19.2Hz, 3H).
实施例83：化合物Y83及其异构体的制备Example 83: Preparation of compound Y83 and its isomers
Figure PCTCN2022130850-appb-000179
Figure PCTCN2022130850-appb-000179
步骤一：将化合物v3(800mg,2.4mmol,1.0eq)加入无水乙腈(10mL)，而后依次加入DIEA(3.1g,24mmol,10.0eq)，三氯氧磷(1.8g,12mmol,5.0eq)。放置于提前加热好的100℃的油浴锅中反应10min，然后开始降温至0℃左右。并将反应液滴加到三氟丙乙胺(1.3g,12mmol,20eq)的10mL乙腈溶液中，滴加完毕，室温反应10min。用乙酸乙酯(100mL*2)萃取，有机相用饱和食盐水(100mL)洗涤，用无水硫酸钠干燥，过滤浓缩。经反相HPLC制备prep-HPLC(Waters 2767 Column:Xbridge Xbridge C18,19*250mm,10um；流动相A:10mmol NH 4HCO 3/H 2O,B:ACN；流速:20ml/min；梯度:52-52％Time:9.4-10.6 min of 16min)后得到化合物Y83(120mg,收率11.71％)。 1H NMR(400MHz,DMSO-d 6)δ10.90(s,1H),8.49(d,J＝4.0Hz,1H),8.42(d,J＝8.0Hz,1H),7.80(d,J＝8.0Hz,1H),7.33(d,J＝6.8Hz,1H),7.28–7.14(m,2H),4.78(s,1H),3.28–3.15(m,2H),2.91–2.74(m,1H),2.48–2.39(m,1H),1.31(d,J＝5.2Hz,3H). Step 1: Add compound v3 (800mg, 2.4mmol, 1.0eq) to anhydrous acetonitrile (10mL), then add DIEA (3.1g, 24mmol, 10.0eq), phosphorus oxychloride (1.8g, 12mmol, 5.0eq) . Place it in a pre-heated 100°C oil bath for 10 minutes, and then start to cool down to about 0°C. And the reaction solution was added dropwise to a solution of trifluoropropylethylamine (1.3g, 12mmol, 20eq) in 10mL of acetonitrile, after the addition was complete, the reaction was carried out at room temperature for 10min. Extracted with ethyl acetate (100 mL*2), the organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated. Prep-HPLC was prepared by reverse phase HPLC (Waters 2767 Column: Xbridge Xbridge C18, 19*250mm, 10um; mobile phase A: 10mmol NH 4 HCO 3 /H 2 O, B: ACN; flow rate: 20ml/min; gradient: 52 -52% Time: 9.4-10.6 min of 16min) to obtain compound Y83 (120 mg, yield 11.71%). 1 H NMR (400MHz, DMSO-d 6 ) δ10.90(s, 1H), 8.49(d, J=4.0Hz, 1H), 8.42(d, J=8.0Hz, 1H), 7.80(d, J= 8.0Hz,1H),7.33(d,J＝6.8Hz,1H),7.28–7.14(m,2H),4.78(s,1H),3.28–3.15(m,2H),2.91–2.74(m,1H ),2.48–2.39(m,1H),1.31(d,J＝5.2Hz,3H).
步骤二：将化合物Y83(120mg)进行手性拆分(
Figure PCTCN2022130850-appb-000180
OD-250*25mm 10μm-CO 2,-MEOH(+0.1％7.0mol/l含氨水的甲醇)-(90:10)-3.0min；流速：100ml/min；T：RT；波长：214nm；洗脱时长：3.0min)得到： Step 2: Compound Y83 (120mg) is subjected to chiral resolution (
Figure PCTCN2022130850-appb-000180
OD-250*25mm 10μm-CO 2,- MEOH (+0.1%7.0mol/l methanol containing ammonia)-(90:10)-3.0min; flow rate: 100ml/min; T: RT; wavelength: 214nm; washing Take off time length: 3.0min) obtain:
化合物Y83-1(9.73mg，产率8.11％，保留时间：1.924min)。LCMS:ESI[M+H] +＝428.1。 1H NMR(400MHz,DMSO-d 6)δ10.90(s,1H),8.49(d,J＝4.0Hz,1H),8.42(d,J＝8.0Hz,1H),7.80(d,J＝8.0Hz,1H),7.33(d,J＝6.8Hz,1H),7.28–7.14(m,2H),4.78(s,1H),3.28–3.15(m,2H),2.91–2.74(m,1H),2.48–2.39(m,1H),1.31(d,J＝5.2Hz,3H)；和 Compound Y83-1 (9.73 mg, yield 8.11%, retention time: 1.924 min). LCMS: ESI [M+H] + = 428.1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.90(s, 1H), 8.49(d, J=4.0Hz, 1H), 8.42(d, J=8.0Hz, 1H), 7.80(d, J= 8.0Hz,1H),7.33(d,J＝6.8Hz,1H),7.28–7.14(m,2H),4.78(s,1H),3.28–3.15(m,2H),2.91–2.74(m,1H ), 2.48–2.39(m,1H), 1.31(d,J=5.2Hz,3H); and
化合物Y83-4(13.13mg，产率10.94％，保留时间：1.575min).LCMS:ESI[M+H] +＝428.1。 1H NMR(400MHz,DMSO-d 6)δ10.90(s,1H),8.49(d,J＝4.0Hz,1H),8.42(d,J＝8.0Hz,1H),7.80(d,J＝8.0Hz,1H),7.33(d,J＝6.8Hz,1H),7.28–7.14(m,2H),4.78(s,1H),3.28–3.15(m,2H),2.91–2.74(m,1H),2.48–2.39(m,1H),1.31(d,J＝5.2Hz,3H)。 Compound Y83-4 (13.13 mg, yield 10.94%, retention time: 1.575 min). LCMS: ESI [M+H] + =428.1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.90(s, 1H), 8.49(d, J=4.0Hz, 1H), 8.42(d, J=8.0Hz, 1H), 7.80(d, J= 8.0Hz,1H),7.33(d,J＝6.8Hz,1H),7.28–7.14(m,2H),4.78(s,1H),3.28–3.15(m,2H),2.91–2.74(m,1H ), 2.48–2.39 (m, 1H), 1.31 (d, J=5.2Hz, 3H).
将化合物Y83(35mg)进行手性拆分(
Figure PCTCN2022130850-appb-000181
IB-250*25mm 10μm-CO 2,-MEOH(+0.1％7.0mol/l含氨水的甲醇)-(80:20)-2.88min；流速：100ml/min；T：RT；波长：214nm；洗脱时长：2.88min)得到： Compound Y83 (35 mg) was subjected to chiral resolution (
Figure PCTCN2022130850-appb-000181
IB-250*25mm 10μm-CO 2,- MEOH (+0.1%7.0mol/l methanol containing ammonia)-(80:20)-2.88min; flow rate: 100ml/min; T: RT; wavelength: 214nm; washing Take off time length: 2.88min) obtain:
化合物Y83-2(9.16mg，产率26.2％，保留时间：1.942min)。LCMS:ESI[M+H] +＝428.1。 1H NMR(400MHz,DMSO-d 6)δ10.90(s,1H),8.49(d,J＝4.0Hz,1H),8.42(d,J＝8.0Hz,1H),7.80(d,J＝8.0Hz,1H),7.33(d,J＝6.8Hz,1H),7.28–7.14(m,2H),4.78(s,1H),3.28–3.15(m,2H),2.91–2.74(m,1H),2.48–2.39(m,1H),1.31(d,J＝5.2Hz,3H)；和 Compound Y83-2 (9.16 mg, yield 26.2%, retention time: 1.942 min). LCMS: ESI [M+H] + = 428.1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.90(s, 1H), 8.49(d, J=4.0Hz, 1H), 8.42(d, J=8.0Hz, 1H), 7.80(d, J= 8.0Hz,1H),7.33(d,J＝6.8Hz,1H),7.28–7.14(m,2H),4.78(s,1H),3.28–3.15(m,2H),2.91–2.74(m,1H ), 2.48–2.39(m,1H), 1.31(d,J=5.2Hz,3H); and
化合物Y83-3(12.11mg，产率34.6％，保留时间：1.554min)。LCMS:ESI[M+H] +＝428.1。 1H NMR(400MHz,DMSO-d 6)δ10.90(s,1H),8.49(d,J＝4.0Hz,1H),8.42(d,J＝8.0Hz,1H),7.80(d,J＝8.0Hz,1H),7.33(d,J＝6.8Hz,1H),7.28–7.14(m,2H),4.78(s,1H),3.28–3.15(m,2H),2.91–2.74(m,1H),2.48–2.39(m,1H),1.31(d,J＝5.2Hz,3H)。 Compound Y83-3 (12.11 mg, yield 34.6%, retention time: 1.554 min). LCMS: ESI [M+H] + = 428.1. 1 H NMR (400MHz, DMSO-d 6 ) δ10.90(s, 1H), 8.49(d, J=4.0Hz, 1H), 8.42(d, J=8.0Hz, 1H), 7.80(d, J= 8.0Hz,1H),7.33(d,J＝6.8Hz,1H),7.28–7.14(m,2H),4.78(s,1H),3.28–3.15(m,2H),2.91–2.74(m,1H ), 2.48–2.39 (m, 1H), 1.31 (d, J=5.2Hz, 3H).
实施例84：化合物Y84及其异构体的制备Example 84: Preparation of compound Y84 and its isomers
Figure PCTCN2022130850-appb-000182
Figure PCTCN2022130850-appb-000182
步骤一：将化合物v51(1g,2.62mmol,1.0eq)，加入无水乙腈(20mL)，而后依次加入DIPEA(3.3g,26.2mmol,10.0eq)，三氯氧磷(2.0g,13mmol,5.0eq)。放置于提前加热好的100℃的油浴锅中反应5分钟，然后开始降温至0℃左右。并将反应液滴加到甲胺水溶液(50mL,2.0mol/L)中，滴加完毕，室温反应10min。用乙酸乙酯(100mL*2)萃取，有机相用饱和食盐水(100mL)洗涤，用无水硫酸钠干燥，过滤浓缩，粗品经快速色谱硅胶(乙酸乙酯：甲醇＝10：1)纯化得到化合物Y84(200mg,产率19.4％)。LCMS:ESI[M+H] +＝396.4。 Step 1: Add anhydrous acetonitrile (20mL) to compound v51 (1g, 2.62mmol, 1.0eq), then add DIPEA (3.3g, 26.2mmol, 10.0eq), phosphorus oxychloride (2.0g, 13mmol, 5.0 eq). Place it in a pre-heated 100°C oil bath for 5 minutes, and then start to cool down to about 0°C. And the reaction solution was added dropwise into an aqueous solution of methylamine (50 mL, 2.0 mol/L), and after the addition was complete, the reaction was carried out at room temperature for 10 min. Extracted with ethyl acetate (100mL*2), washed the organic phase with saturated brine (100mL), dried over anhydrous sodium sulfate, filtered and concentrated, the crude product was purified by flash chromatography on silica gel (ethyl acetate:methanol=10:1) to obtain Compound Y84 (200 mg, yield 19.4%). LCMS: ESI [M+H] + = 396.4.
步骤二：将化合物Y84(200mg)进行手性拆分(Dr.maish Reprosil Chiral-MIC(
Figure PCTCN2022130850-appb-000183
IC)-250*25mm 10μm-CO 2-MeOH(+0.1％7.0mol/l含氨水的甲醇)-(55:45)-2.0min；流速：100ml/min；T：RT；波长：214nm；洗脱时长：2.0min)得到化合物Y84-1(83mg，产率41.5％，保留时间：1.295min)。LCMS:ESI[M+H] +＝396.1。 1H NMR(400MHz,DMSO-d 6)δ9.21(s,1H),8.44(s,1H),8.30(d,J＝8.0Hz,1H),7.87(d,J＝7.6Hz,1H),7.35–6.99(m,3H),3.23–3.01(m,5H),2.71(s,1H),2.41–2.28(m,1H)。 Step 2: Compound Y84 (200mg) was subjected to chiral resolution (Dr.maish Reprosil Chiral-MIC (
Figure PCTCN2022130850-appb-000183
IC)-250*25mm 10μm-CO 2 -MeOH (+0.1%7.0mol/l methanol containing ammonia)-(55:45)-2.0min; flow rate: 100ml/min; T: RT; wavelength: 214nm; washing Desorption time: 2.0 min) to obtain compound Y84-1 (83 mg, yield 41.5%, retention time: 1.295 min). LCMS: ESI [M+H] + = 396.1. 1 H NMR (400MHz,DMSO-d 6 )δ9.21(s,1H),8.44(s,1H),8.30(d,J=8.0Hz,1H),7.87(d,J=7.6Hz,1H) ,7.35–6.99(m,3H),3.23–3.01(m,5H),2.71(s,1H),2.41–2.28(m,1H).
和化合物Y84-2(84mg，产率42％，保留时间：2.137min).LCMS:ESI[M+H] +＝396.1。 1H NMR(400MHz,DMSO-d 6)δ9.21(s,1H),8.44(s,1H),8.30(d,J＝8.0Hz,1H),7.87(d,J＝7.6Hz,1H),7.35–6.99(m,3H),3.23–3.01(m,5H),2.71(s,1H),2.41–2.28(m,1H)。 And compound Y84-2 (84 mg, yield 42%, retention time: 2.137 min). LCMS: ESI [M+H] + =396.1. 1 H NMR (400MHz,DMSO-d 6 )δ9.21(s,1H),8.44(s,1H),8.30(d,J=8.0Hz,1H),7.87(d,J=7.6Hz,1H) ,7.35–6.99(m,3H),3.23–3.01(m,5H),2.71(s,1H),2.41–2.28(m,1H).
实施例85：化合物Y85及其异构体的制备Example 85: Preparation of compound Y85 and its isomers
Figure PCTCN2022130850-appb-000184
Figure PCTCN2022130850-appb-000184
步骤一：将化合物v51(1g,2.62mmol,1.0eq)，加入无水乙腈(20mL)，而后依次加入DIPEA(3.3 g,26.2mmol,10.0eq)，三氯氧磷(2.0g,13mmol,5.0eq)。放置于提前加热好的100℃的油浴锅中反应五分钟，然后开始降温至0℃左右。并将反应液滴加到氘代甲胺水溶液(30mL,20.0eq)中，滴加完毕，室温反应10min。用乙酸乙酯(100mL*2)萃取，有机相用饱和食盐水(100mL)洗涤，用无水硫酸钠干燥，过滤浓缩，粗品经快速色谱硅胶(乙酸乙酯：甲醇＝10：1)纯化得到产物(300mg,产率28.8％)。LCMS:ESI[M+H] +＝399.2。 Step 1: Add anhydrous acetonitrile (20mL) to compound v51 (1g, 2.62mmol, 1.0eq), then add DIPEA (3.3g, 26.2mmol, 10.0eq), phosphorus oxychloride (2.0g, 13mmol, 5.0 eq). Place it in a pre-heated 100°C oil bath for five minutes, and then start to cool down to about 0°C. And the reaction liquid was added dropwise to deuterated methylamine aqueous solution (30mL, 20.0eq), after the dropwise addition was completed, the reaction was carried out at room temperature for 10min. Extracted with ethyl acetate (100mL*2), washed the organic phase with saturated brine (100mL), dried over anhydrous sodium sulfate, filtered and concentrated, the crude product was purified by flash chromatography on silica gel (ethyl acetate:methanol=10:1) to obtain Product (300 mg, yield 28.8%). LCMS: ESI [M+H] + = 399.2.
步骤二：将化合物Y85(300mg)进行手性拆分(Dr.maish Reprosil Chiral-MIC(
Figure PCTCN2022130850-appb-000185
IC)-250*25mm 10μm-CO 2-MEOH(+0.1％7.0mol/l含氨水的甲醇)-(55:45)-2.0min；流速：100ml/min；T：RT；波长：214nm；洗脱时长：2.0min)得到： Step 2: Compound Y85 (300mg) was subjected to chiral resolution (Dr.maish Reprosil Chiral-MIC (
Figure PCTCN2022130850-appb-000185
IC)-250*25mm 10μm-CO 2 -MEOH (+0.1%7.0mol/l methanol containing ammonia)-(55:45)-2.0min; flow rate: 100ml/min; T: RT; wavelength: 214nm; washing Take off time length: 2.0min) obtain:
化合物Y85-1(114mg，产率38％，保留时间：1.297min)。LCMS:ESI[M+H] +＝399.1。 1H NMR(400MHz,DMSO-d 6)δ9.18(s,1H),8.43(dd,J＝4.4,2.0Hz,1H),8.29(d,J＝8.4Hz,1H),7.87(d,J＝8.0Hz,1H),7.22(s,1H),7.19–7.07(m,2H),3.25–3.04(m,2H),2.73–2.65(m,1H),2.40–2.29(m,1H)；和 Compound Y85-1 (114 mg, yield 38%, retention time: 1.297 min). LCMS: ESI [M+H] + = 399.1. 1 H NMR (400MHz, DMSO-d 6 )δ9.18(s, 1H), 8.43(dd, J=4.4, 2.0Hz, 1H), 8.29(d, J=8.4Hz, 1H), 7.87(d, J＝8.0Hz,1H),7.22(s,1H),7.19–7.07(m,2H),3.25–3.04(m,2H),2.73–2.65(m,1H),2.40–2.29(m,1H) ;and
化合物Y85-2(106mg，产率35％，保留时间：2.127min)。LCMS:ESI[M+H] +＝399.1。 1H NMR(400MHz,DMSO-d 6)δ9.18(s,1H),8.43(dd,J＝4.4,2.0Hz,1H),8.29(d,J＝8.4Hz,1H),7.87(d,J＝8.0Hz,1H),7.22(s,1H),7.19–7.07(m,2H),3.25–3.04(m,2H),2.73–2.65(m,1H),2.40–2.29(m,1H)。 Compound Y85-2 (106 mg, yield 35%, retention time: 2.127 min). LCMS: ESI [M+H] + = 399.1. 1 H NMR (400MHz, DMSO-d 6 )δ9.18(s, 1H), 8.43(dd, J=4.4, 2.0Hz, 1H), 8.29(d, J=8.4Hz, 1H), 7.87(d, J＝8.0Hz,1H),7.22(s,1H),7.19–7.07(m,2H),3.25–3.04(m,2H),2.73–2.65(m,1H),2.40–2.29(m,1H) .
实施例86：化合物Y86及其异构体的制备Example 86: Preparation of compound Y86 and its isomers
Figure PCTCN2022130850-appb-000186
Figure PCTCN2022130850-appb-000186
步骤一：将化合物v50(1g,2.9mmol,1.0eq)，加入无水乙腈(30mL)，而后依次加入DIEA(3.7g,29mmol,10.0eq)，三氯氧磷(2.2g,14.5mmol,5.0eq)。放置于提前加热好的100℃的油浴锅中反应10min，然后开始降温至0℃左右。并将反应液滴加到30ml甲胺水溶液中，滴加完毕，室温反应10min。用乙酸乙酯(100mL*2)萃取，有机相用饱和食盐水(100mL)洗涤，用无水硫酸钠干燥，过滤浓缩，用Flash纯化(石油醚:乙酸乙酯＝0-1:1)后得到化合物Y86(360mg,收率34.58％)。LCMS:ESI[M+H] +＝360.0。 Step 1: Add anhydrous acetonitrile (30mL) to compound v50 (1g, 2.9mmol, 1.0eq), then add DIEA (3.7g, 29mmol, 10.0eq), phosphorus oxychloride (2.2g, 14.5mmol, 5.0 eq). Place it in a pre-heated 100°C oil bath for 10 minutes, and then start to cool down to about 0°C. And the reaction solution was added dropwise into 30ml of methylamine aqueous solution, after the dropwise addition was completed, the reaction was carried out at room temperature for 10 minutes. Extracted with ethyl acetate (100mL*2), washed the organic phase with saturated brine (100mL), dried over anhydrous sodium sulfate, concentrated by filtration, and purified by Flash (petroleum ether:ethyl acetate=0-1:1) Compound Y86 (360 mg, yield 34.58%) was obtained. LCMS: ESI [M+H] + = 360.0.
步骤二：将化合物Y86(150mg)进行手性拆分(
Figure PCTCN2022130850-appb-000187
OD-250*25mm 10μm-CO 2,-MeOH(+0.1％7.0mol/l含氨水的甲醇)-(80:20)-3.6min；流速：100ml/min；T：RT；波长：214nm；洗脱时长：3.6min)得到： Step 2: Compound Y86 (150mg) is subjected to chiral resolution (
Figure PCTCN2022130850-appb-000187
OD-250*25mm 10μm-CO 2,- MeOH (+0.1%7.0mol/l methanol containing ammonia)-(80:20)-3.6min; flow rate: 100ml/min; T: RT; wavelength: 214nm; washing Take off time length: 3.6min) obtain:
化合物Y86-1(60.69mg，产率40.46％，保留时间：0.618min)。LCMS:ESI[M+H] +＝360.1。 1H NMR(400MHz,DMSO-d 6)δ9.07(s,1H),8.42(t,J＝6.4Hz,1H),8.10(d,J＝12.0Hz,1H),7.14(t,J＝11.6Hz,3H),3.24–3.12(m,2H),3.04(d,J＝4.0Hz,3H),2.73–2.63(m,1H),2.41–2.28(m,1H),1.98(d,J＝19.6Hz,3H)；和 Compound Y86-1 (60.69 mg, yield 40.46%, retention time: 0.618 min). LCMS: ESI [M+H] + = 360.1. 1 H NMR (400MHz, DMSO-d 6 )δ9.07(s, 1H), 8.42(t, J=6.4Hz, 1H), 8.10(d, J=12.0Hz, 1H), 7.14(t, J= 11.6Hz, 3H), 3.24–3.12(m, 2H), 3.04(d, J＝4.0Hz, 3H), 2.73–2.63(m, 1H), 2.41–2.28(m, 1H), 1.98(d, J = 19.6Hz, 3H); and
化合物Y86-2(61.77mg，产率41.18％，保留时间：1.230min).LCMS:ESI[M+H] +＝360.1。 1H NMR(400MHz,DMSO-d 6)δ9.07(s,1H),8.42(t,J＝6.4Hz,1H),8.10(d,J＝12.0Hz,1H),7.14(t,J＝11.6Hz,3H),3.24–3.12(m,2H),3.04(d,J＝4.0Hz,3H),2.73–2.63(m,1H),2.41–2.28(m,1H),1.98(d,J＝19.6Hz,3H)。 Compound Y86-2 (61.77 mg, yield 41.18%, retention time: 1.230 min). LCMS: ESI [M+H] + =360.1. 1 H NMR (400MHz, DMSO-d 6 )δ9.07(s, 1H), 8.42(t, J=6.4Hz, 1H), 8.10(d, J=12.0Hz, 1H), 7.14(t, J= 11.6Hz, 3H), 3.24–3.12(m, 2H), 3.04(d, J＝4.0Hz, 3H), 2.73–2.63(m, 1H), 2.41–2.28(m, 1H), 1.98(d, J =19.6Hz, 3H).
测试例1：MAT2A酶活性抑制Test Example 1: MAT2A Enzyme Activity Inhibition
一、实验所需试剂1. Reagents required for the experiment
试剂及板Reagents and Plates 厂商manufacturers 货号Item No.
MAT2A proteinMAT2A protein BPS BioscienceBPS Bioscience 7140171401
ATP Solution(10mM)ATP Solution(10mM) Thermo FisherThermo Fisher PV3227PV3227
L-甲硫氨酸L-methionine adamas-betaadamas-beta 73108A73108A
CD73比色检测试剂CD73 Colorimetric Detection Reagent BPS BioscienceBPS Bioscience 7400174001
Tris盐酸Tris hydrochloric acid SigmaSigma RES3098T-B701XRES3098T-B701X
氯化镁magnesium chloride InvitrogenInvitrogen AM9530GAM9530G
DMSODMSO SigmaSigma D5879D5879
DTTDTT MilliporeMillipore 20-26520-265
Brij TM-35 BrijTM -35 Thermo FisherThermo Fisher 8511785117
0.5M EDTA,pH 8.00.5M EDTA, pH 8.0 Thermo FisherThermo Fisher 1557515575
氯化钾potassium chloride sigmasigma 7447-40-77447-40-7
二、实验所需板及仪器2. Plates and instruments required for the experiment
试剂Reagent 厂商manufacturers S/NS/N
384 well with lid flat bottom384 well with lid flat bottom corningcorning 37653765
M1000proM1000pro iControl 1.10iControl 1.10 14110045831411004583
三、实验过程3. Experimental process
1、配置酶学反应1×buffer：Tris(PH8.0)50mM，MgCl 2 15mM，KCl 50mM，EDTA 0.3mM，0.005％(v/v)BSA，0.01％Brij TM-35，DTT 1mM； 1. Configure enzymatic reaction 1×buffer: Tris (PH8.0) 50mM, MgCl 2 15mM, KCl 50mM, EDTA 0.3mM, 0.005% (v/v) BSA, 0.01% Brij TM -35, DTT 1mM;
2、用DMSO配置100倍化合物测试终浓度，之后用1×buffer稀释至5倍的待测化合物终浓度，DMSO含量为5％，保存备用；2. Use DMSO to prepare 100 times the final concentration of the compound to be tested, and then use 1× buffer to dilute to 5 times the final concentration of the compound to be tested. The DMSO content is 5%, and save it for later use;
3、加入5μL配置好的化合物，1000rpm离心1min，阳性及阴性对照孔均加入1×buffer配置的5％DMSO；3. Add 5 μL of prepared compound, centrifuge at 1000 rpm for 1 min, add 5% DMSO in 1×buffer to both positive and negative control wells;
4、用1×buffer配置MAT2A酶溶液，使其反应终浓度为12.5nM，之后反应板中阳性对照孔及化合物孔加入10μL酶溶液至反应板中，阴性对照孔加入10uL的1×buffer；4. Prepare the MAT2A enzyme solution with 1× buffer so that the final reaction concentration is 12.5nM, then add 10 μL of enzyme solution to the positive control well and compound well in the reaction plate, and add 10 μL of 1× buffer to the negative control well;
5、1000rpm离心1min，室温放置30min；5. Centrifuge at 1000rpm for 1min, and place at room temperature for 30min;
6、用1×buffer配置反应终浓度均为200μM的ATP和L-methionine混合溶液，往反应板中加入10μL此混合溶液；6. Prepare a mixed solution of ATP and L-methionine with a final concentration of 200 μM in 1× buffer, and add 10 μL of the mixed solution to the reaction plate;
7、1000rpm离心1min，室温放置2.5h反应；7. Centrifuge at 1000rpm for 1min, place at room temperature for 2.5h to react;
8、加入50μL的Detection reagent；8. Add 50 μL of Detection reagent;
9、1000rpm离心1min，室温放置1h后用M1000pro读取OD630。9. Centrifuge at 1000rpm for 1min, and read OD630 with M1000pro after standing at room temperature for 1h.
四、数据计算4. Data calculation
1、化合物抑制率的计算1. Calculation of compound inhibition rate
Figure PCTCN2022130850-appb-000188
Figure PCTCN2022130850-appb-000188
Max：阳性对照孔，即最大值孔；Min：阴性对照孔，即最小值孔。Max: Positive control well, namely the maximum value well; Min: Negative control well, namely the minimum value well.
2、用XLFIT 5.0软件(英国IDBS公司)进行拟合，以化合物浓度的对数值作为X轴，以抑制率作为Y轴，使用四参数模型计算化合物的半数抑制浓度IC 50。结果如表1所示。 2. The XLFIT 5.0 software (IDBS, UK) was used for fitting, with the logarithm of the compound concentration as the X-axis and the inhibition rate as the Y-axis, using a four-parameter model to calculate the half-maximum inhibitory concentration IC 50 of the compound. The results are shown in Table 1.
表1化合物对MAT2A的抑制活性The inhibitory activity of the compound of table 1 to MAT2A
Figure PCTCN2022130850-appb-000189
Figure PCTCN2022130850-appb-000189
Figure PCTCN2022130850-appb-000190
Figure PCTCN2022130850-appb-000190
由表1可知，本申请实施例化合物对MAT2A具有较高的抑制活性。It can be seen from Table 1 that the compounds of the examples of the present application have higher inhibitory activity on MAT2A.
测试例2：HCT 116(MTAP-/-)细胞活性抑制实验Test example 2: HCT 116 (MTAP-/-) cell activity inhibition experiment
一、实验所需试剂1. Reagents required for the experiment
Figure PCTCN2022130850-appb-000191
Figure PCTCN2022130850-appb-000191
二、实验所需板及仪器2. Plates and instruments required for the experiment
Figure PCTCN2022130850-appb-000192
Figure PCTCN2022130850-appb-000192
三、实验过程3. Experimental process
1.将处于对数期的MTAP缺失的HCT116细胞接种于384细胞培养板中，培养基为30μL含10％FBS和1x青链霉素的MCCOYS 5A，细胞密度为300/孔；1. Inoculate MTAP-deficient HCT116 cells in the logarithmic phase in 384 cell culture plates, the medium is 30 μL of MCCOYS 5A containing 10% FBS and 1x penicillin and streptomycin, and the cell density is 300/well;
2.用100％DMSO配置1000倍所需的化合物测试终浓度，保存备用；2. Use 100% DMSO to prepare 1000 times the required compound test final concentration, and save it for later use;
3.用Echo 655向化合物测试孔加如30nL的配置好的化合物，阴性对照孔加入30nL的最高浓度阳性药溶液，阳性对照孔和空白对照孔加入30nL的100％DMSO溶液；3. Add 30nL of the prepared compound to the compound test well with Echo 655, add 30nL of the highest concentration positive drug solution to the negative control well, add 30nL of 100% DMSO solution to the positive control well and blank control well;
4.空白对照孔板直接加入30μL的CTG试剂，用Envision读取Luminescence值；4. Add 30 μL of CTG reagent directly to the blank control plate, and read the Luminescence value with Envision;
5.化合物测试板放置于37℃，5％CO 2细胞培养箱中培养5天； 5. Place the compound test plate in a 37°C, 5% CO 2 cell incubator for 5 days;
6.每孔加入30μL的CTG试剂；6. Add 30 μL of CTG reagent to each well;
7.37℃，5％CO 2细胞培养箱中孵育1.5h； Incubate at 7.37°C, 5% CO 2 cell incubator for 1.5h;
8.用Envision读取Luminescence值。8. Read the Luminescence value with Envision.
四、数据计算4. Data calculation
1.Max孔为阳性对照孔，即第5天测试的最大值孔，Min孔为阴性对照孔，即第5天测试的最小值孔，BL孔为空白对照孔，即第0天的测试孔。1. The Max well is the positive control well, that is, the maximum value well tested on the 5th day, the Min well is the negative control well, that is, the minimum value well tested on the 5th day, and the BL well is the blank control well, that is, the test well on the 0th day .
2.化合物抑制率的计算2. Calculation of compound inhibition rate
Figure PCTCN2022130850-appb-000193
Figure PCTCN2022130850-appb-000193
结果如表2所示。The results are shown in Table 2.
表2化合物对HCT 116(MTAP-/-)细胞的抑制活性The inhibitory activity of table 2 compound to HCT 116 (MTAP-/-) cell
Figure PCTCN2022130850-appb-000194
Figure PCTCN2022130850-appb-000194
由表2可知，本申请实施例化合物对HCT 116(MTAP-/-)细胞具有较高的抑制活性。As can be seen from Table 2, the compounds of the embodiments of the present application have higher inhibitory activity on HCT 116 (MTAP-/-) cells.
测试例3：HCT 116WT细胞活性抑制实验Test example 3: HCT 116WT cell activity inhibition experiment
一、实验所需试剂1. Reagents required for the experiment
试剂及板Reagents and Plates 厂商manufacturers 货号Item No.
HCT116HCT116 ATCCATCC CCL-247CCL-247
青霉素-链霉素(10000U/ml,100ml)Penicillin-streptomycin (10000U/ml, 100ml) GibicoGibico 15140-12215140-122
MCCOYS 5A MED MODMCCOYS 5A MED MOD invitrogenInvitrogen 16600-08216600-082
胎牛血清FBSFetal bovine serum FBS GibcoGibco 10099-14110099-141
CelltiterGlo assay kit(CTG)Celltiter Glo assay kit(CTG) PromegaPromega G7573G7573
二、实验所需板及仪器2. Plates and instruments required for the experiment
Figure PCTCN2022130850-appb-000195
Figure PCTCN2022130850-appb-000195
三、实验过程3. Experimental process
1.将处于对数期的HCT116细胞接种于384细胞培养板中，培养基为30μL含10％FBS和1x青链霉素的MCCOYS 5A，细胞密度为300/孔；1. Inoculate HCT116 cells in the logarithmic phase in 384 cell culture plates, the medium is 30 μL MCCOYS 5A containing 10% FBS and 1x penicillin and streptomycin, and the cell density is 300/well;
2.用100％DMSO配置1000倍所需的化合物测试终浓度，保存备用；2. Use 100% DMSO to prepare 1000 times the required compound test final concentration, and save it for later use;
3.用Echo 655向化合物测试孔加30nL的配置好的化合物，阴性对照孔加入30nL的最高浓度阳性药溶液，阳性对照孔和空白对照孔加入30nL的100％DMSO溶液；3. Add 30nL of the prepared compound to the compound test well with Echo 655, add 30nL of the highest concentration positive drug solution to the negative control well, add 30nL of 100% DMSO solution to the positive control well and blank control well;
4.空白对照孔板直接加入30μL的CTG试剂，用Envision读取Luminescence值；4. Add 30 μL of CTG reagent directly to the blank control plate, and read the Luminescence value with Envision;
5.化合物测试板放置于37℃，5％CO 2细胞培养箱中培养5天； 5. Place the compound test plate in a 37°C, 5% CO 2 cell incubator for 5 days;
6.每孔加入30μL的CTG试剂；6. Add 30 μL of CTG reagent to each well;
7.37℃，5％CO 2细胞培养箱中孵育1.5h； Incubate at 7.37°C, 5% CO 2 cell incubator for 1.5h;
8.用Envision读取Luminescence值。8. Read the Luminescence value with Envision.
四、数据计算4. Data calculation
1.Max孔为阳性对照孔，即第5天测试的最大值孔，Min孔为阴性对照孔，即第5天测试的最小值孔，BL孔为空白对照孔，即第0天的测试孔。1. The Max well is the positive control well, that is, the maximum value well tested on the 5th day, the Min well is the negative control well, that is, the minimum value well tested on the 5th day, and the BL well is the blank control well, that is, the test well on the 0th day .
2.化合物抑制率的计算2. Calculation of compound inhibition rate
Figure PCTCN2022130850-appb-000196
Figure PCTCN2022130850-appb-000196
实验结果如表3所示。The experimental results are shown in Table 3.
表3化合物对HCT-116WT细胞的抑制活性The inhibitory activity of table 3 compound to HCT-116WT cell
Figure PCTCN2022130850-appb-000197
Figure PCTCN2022130850-appb-000197
由表3可知，本申请实施例化合物对HCT 116野生型细胞具有较低的抑制活性。It can be seen from Table 3 that the compounds of the examples of the present application have lower inhibitory activity on HCT 116 wild-type cells.
测试例4：小鼠体内药代动力学研究Test Example 4: Pharmacokinetic study in mice
应用LC/MS/MS法测定小鼠静脉注射和灌胃给药后化合物不同时间点血浆中的药物浓度，评价化合物在小鼠体内的药代动力学行为。The LC/MS/MS method was used to determine the drug concentration in plasma of the compound at different time points after intravenous injection and intragastric administration in mice, and to evaluate the pharmacokinetic behavior of the compound in mice.
实验操作步骤：Experimental operation steps:
以标准方案测试待测化合物静脉注射及口服给药后的啮齿类动物药代特征，实验中待测化合物将根据给药剂量和浓度用溶媒配成澄清溶液或均一混悬液，给予ICR小鼠单次静脉注射及口服给药。将ICR小鼠(雄性，30-40g，7～9周龄，北京维通利华实验动物有限公司)随机分组为6只/组。静脉组给药前自由进食饮水；灌胃组给药前禁食过夜，给药后四小时恢复给食(特殊情况除外)，自由饮水。Test the pharmacokinetic characteristics of rodents after intravenous injection and oral administration of the test compound according to the standard protocol. In the experiment, the test compound will be formulated into a clear solution or a homogeneous suspension with a solvent according to the dose and concentration of the drug, and administered to the ICR mice. Single intravenous injection and oral administration. ICR mice (male, 30-40 g, 7-9 weeks old, Beijing Weitong Lihua Experimental Animal Co., Ltd.) were randomly divided into 6 mice/group. The intravenous group had free access to food and water before administration; the gavage group fasted overnight before administration, and resumed food four hours after administration (except in special cases), and had free access to water.
静脉注射组和口服组溶媒为一定比例的二甲基亚砜、聚乙二醇-15羟基硬脂酸酯和磺丁醚-beta-环糊精的混合溶液，涡旋搅拌，超声后使其溶解，制备得到0.4mg/mL或1mg/mL的溶液。静脉注射组要求溶液为澄清，口服组要求溶液均一混悬或澄清溶液，备用。大鼠2mg/kg静脉给药或10mg/kg口 服给药后，分别于给药后0.083，0.25，0.5，1，2，4，7，24小时用含有K 2EDTA的采血管收集一定量的全血样品。全血样品3700rpm离心15分钟，分离上清得血浆样品。血浆样品加入一定体积含内标的乙腈溶液沉淀蛋白，离心取上清液加入一定体积的稀释液(如纯水、甲醇/水溶液等，可根据情况调整)，混匀后以LC-MS/MS分析方法定量分析血药浓度，并用Data Analysie System软件(上海博佳医药科技有限公司，版本号3.0)计算药代参数。结果如表4所示。 The vehicle of the intravenous injection group and the oral group was a mixed solution of a certain proportion of dimethyl sulfoxide, polyethylene glycol-15 hydroxystearate and sulfobutyl ether-beta-cyclodextrin, vortexed, and ultrasonicated to make it Dissolve to prepare a 0.4 mg/mL or 1 mg/mL solution. The intravenous injection group requires the solution to be clear, and the oral group requires the solution to be homogeneously suspended or a clear solution for later use. After intravenous administration of 2 mg/kg or oral administration of 10 mg/kg to rats, a certain amount of whole blood sample. The whole blood sample was centrifuged at 3700 rpm for 15 minutes, and the supernatant was separated to obtain a plasma sample. Add a certain volume of acetonitrile solution containing an internal standard to precipitate the protein, centrifuge the supernatant and add a certain volume of diluent (such as pure water, methanol/water solution, etc., which can be adjusted according to the situation), mix well and analyze by LC-MS/MS Methods The blood drug concentration was quantitatively analyzed, and the pharmacokinetic parameters were calculated with Data Analysie System software (Shanghai Bojia Pharmaceutical Technology Co., Ltd., version 3.0). The results are shown in Table 4.
表4化合物在小鼠体内药代动力学参数Table 4 Compound pharmacokinetic parameters in mice
Figure PCTCN2022130850-appb-000198
Figure PCTCN2022130850-appb-000198
测试例5：受试物在人结肠癌HCT116MTAP-/-裸鼠皮下异种移植瘤模型上的药效评价Test Example 5: Drug efficacy evaluation of the test substance on the subcutaneous xenograft tumor model of human colon cancer HCT116MTAP-/- nude mice
在裸小鼠皮下植入人结肠癌HCT116MTAP -/-细胞，构建异种移植荷瘤小鼠模型，进行体内药效实验。 Human colon cancer HCT116MTAP -/- cells were implanted subcutaneously in nude mice to construct a xenograft tumor-bearing mouse model for in vivo drug efficacy experiments.
实验方案：BALB/c Nude小鼠(雌性，6-8周龄，购自浙江维通利华实验动物技术有限公司)饲养于无特定病原体的环境中。小鼠饲养笼为透明树脂塑料笼(260mm×160mm×127mm)中，每笼5只。鼠笼垫料为经高压灭菌的木屑和玉米芯垫料，每星期更换两次。实验用小鼠可无限量获取专用鼠粮(经辐照消毒，购自上海斯莱克实验动物责任有限公司)。整个实验期间，实验用小鼠可无限量获取经内部处理的饮用水。于小鼠右侧腋下，接种肿瘤细胞(5×10 6个细胞/100μL+50％基质胶)，定为第0天。当肿瘤体积达到100mm 3-200mm 3时，根据肿瘤大小和体重进行随机分组，每组8只。分组当天进行给药，记为P0。实验期间每周2次测定动物体重和肿瘤体积，每日进行观察动物的临床症状。肿瘤体积用mm 3表示，公式为:V＝0.5×a×b 2，其中a和b分别为肿瘤的长径和短径。相对肿瘤体积(relative tumor volume,RTV)：计算公式为RTV＝Vt/V initial×100(％)，其中，V initial为分组给药时测量所得肿瘤体积，Vt为每一次测量时的肿瘤体积。相对肿瘤增殖率T/C(％)：计算公式为T/C(％)＝(T RTV/C RTV)×100％。 Experimental protocol: BALB/c Nude mice (female, 6-8 weeks old, purchased from Zhejiang Weitong Lihua Experimental Animal Technology Co., Ltd.) were bred in a specific pathogen-free environment. The mice were kept in transparent resin plastic cages (260mm×160mm×127mm), with 5 mice per cage. Cage litter was autoclaved wood chips and corncob litter, which was changed twice a week. Experimental mice can obtain unlimited amount of special mouse food (sterilized by irradiation, purchased from Shanghai Slack Experimental Animal Co., Ltd.). Experimental mice had unlimited access to internally treated drinking water throughout the experiment. Tumor cells (5×10 6 cells/100 μL+50% Matrigel) were inoculated into the right axilla of the mice, which was defined as day 0. When the tumor volume reached 100mm 3 -200mm 3 , they were randomly divided into groups according to tumor size and body weight, with 8 rats in each group. Administration was carried out on the day of grouping, which was recorded as P0. During the experiment, the body weight and tumor volume of the animals were measured twice a week, and the clinical symptoms of the animals were observed every day. The tumor volume is expressed in mm 3 , and the formula is: V=0.5×a×b 2 , where a and b are the long and short diameters of the tumor, respectively. Relative tumor volume (relative tumor volume, RTV): the calculation formula is RTV = Vt/V initial × 100 (%), wherein, V initial is the tumor volume measured during group administration, and Vt is the tumor volume at each measurement. Relative tumor proliferation rate T/C (%): the calculation formula is T/C (%)=(T RTV /C RTV )×100%.
表5.化合物在小鼠体内的肿瘤抑制效果Table 5. Tumor inhibitory effect of compounds in mice
Figure PCTCN2022130850-appb-000199
Figure PCTCN2022130850-appb-000199
阳性物的结构如下所示，可参考J.Med.Chem.2021,64,8,4430–4449制备。The structure of the positive product is shown below, which can be prepared by referring to J.Med.Chem.2021, 64, 8, 4430–4449.
Figure PCTCN2022130850-appb-000200
Figure PCTCN2022130850-appb-000200
以上所述实施例的各技术特征可以进行任意的组合，为使描述简洁，未对上述实施例中的各个技术特征所有可能的组合都进行描述，然而，只要这些技术特征的组合不存在矛盾，都应当认为是本说明书记载的范围。The technical features of the above-mentioned embodiments can be combined arbitrarily. To make the description concise, all possible combinations of the technical features in the above-mentioned embodiments are not described. However, as long as there is no contradiction in the combination of these technical features, should be considered as within the scope of this specification.
以上所述实施例仅表达了本申请的几种实施方式，其描述较为具体和详细，但并不能因此而理解为对申请专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本申请构思的前提下，还可以做出若干变形和改进，这些都属于本申请的保护范围。因此，本申请专利的保护范围应以所附权利要求为准。。The above-mentioned embodiments only express several implementation modes of the present application, and the description thereof is relatively specific and detailed, but should not be construed as limiting the scope of the patent application. It should be noted that those skilled in the art can make several modifications and improvements without departing from the concept of the present application, and these all belong to the protection scope of the present application. Therefore, the scope of protection of the patent application should be based on the appended claims. .

Claims (42)

  1. 一种式(I)所示的化合物、其药学上可接受的盐或其立体异构体：A compound represented by formula (I), its pharmaceutically acceptable salt or its stereoisomer:
    Figure PCTCN2022130850-appb-100001
    Figure PCTCN2022130850-appb-100001
    其中，S 1和S 2代表环A上的环原子；S 1为N或C；且S 2为N或C； Wherein, S 1 and S 2 represent ring atoms on ring A; S 1 is N or C; and S 2 is N or C;
    Z 1为N或CR Z1；Z 2为N或CR Z2；Z 3为N或CR Z3；且Z 4为N或CR Z4；其中R Z1、R Z2、R Z3、和R Z4各自独立地为氢、氰基、硝基、羟基、羧基、卤素(优选为氟或氯)、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、C 3-8环烷基(优选为C 3-6环烷基)、卤代C 1-8烷基(优选为卤代C 1-6烷基，更优选为卤代C 1-3烷基)、C 1-8烷氧基(优选为C 1-6烷氧基，更优选为C 1-3烷氧基)、卤代C 1-8烷氧基(优选为卤代C 1- 6烷氧基，更优选为卤代C 1-3烷氧基)、-C(O)C 1-8烷基(优选为-C(O)C 1-6烷基，更优选为-C(O)C 1-3烷基)、-C(O)OC 1-8烷基(优选为-C(O)OC 1-6烷基，更优选为-C(O)OC 1-3烷基)、-C(O)NR a0R b0或-NR a1R b1；其中所述C 1-8烷基、C 3-8环烷基、卤代C 1-8烷基、C 1-8烷氧基、卤代C 1-8烷氧基各自独立地为未取代的或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素、氰基、硝基、羟基、羧基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-NR a1R b1、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR a0R b0、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基和3至6元杂环烷基； Z 1 is N or CR Z1 ; Z 2 is N or CR Z2 ; Z 3 is N or CR Z3 ; and Z 4 is N or CR Z4 ; wherein R Z1 , R Z2 , R Z3 , and R Z4 are each independently Hydrogen, cyano, nitro, hydroxyl, carboxyl, halogen (preferably fluorine or chlorine), C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 3 -8 cycloalkyl (preferably C 3-6 cycloalkyl), halogenated C 1-8 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy ) , halogenated C 1-8 alkoxy (preferably halogenated C 1-6 alkoxy group, more preferably halogenated C 1-3 alkoxy), -C(O)C 1-8 alkyl (preferably -C(O)C 1-6 alkyl, more preferably -C(O) C 1-3 alkyl), -C(O)OC 1-8 alkyl (preferably -C(O)OC 1-6 alkyl, more preferably -C(O)OC 1-3 alkyl), -C(O)NR a0 R b0 or -NR a1 R b1 ; wherein the C 1-8 alkyl, C 3-8 cycloalkyl, halogenated C 1-8 alkyl, C 1-8 alkoxy , Halogenated C 1-8 alkoxy groups are each independently unsubstituted or substituted by 1, 2 or 3 substituents independently selected from the group consisting of deuterium, halogen, cyano, nitro, hydroxyl, carboxyl , C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, - NR a1 R b1 , -SO 2 C 1-3 alkyl, -S(O)C 1-3 alkyl, -C(O)NR a0 R b0 , -C(O)OC 1-3 alkyl, - OC(O)C 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy and 3 to 6 membered heterocycloalkyl;
    R 1和R 2各自独立地为氢、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、-C(O)OC 1-8烷基(优选为-C(O)OC 1-6烷基，更优选为-C(O)OC 1-3烷基)、-C(O)C 1-8烷基(优选为-C(O)C 1-6烷基，更优选为-C(O)C 1- 3烷基)、C 3-8环烷基(优选为C 3-6环烷基)或3至6元杂环烷基；或者R 1、R 2与相连接的环原子共同形成4至7元饱和或部分不饱和单环(优选5至7元饱和或部分不饱和单环)或4至7元饱和或部分不饱和单杂环(优选5至7元饱和或部分不饱和单杂环)；其中所述C 1-8烷基、C 3-6环烷基、4至7元饱和或部分不饱和单环、4至7元饱和或部分不饱和单杂环为未取代的或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素、氰基、硝基、羟基、羧基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-NR a1R b1、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR a0R b0、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基和3至6元杂环烷基； R 1 and R 2 are each independently hydrogen, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), -C(O)OC 1-8 alkyl ( Preferably -C(O)OC 1-6 alkyl, more preferably -C(O)OC 1-3 alkyl), -C(O)C 1-8 alkyl (preferably -C(O)C 1-6 alkyl, more preferably -C(O)C 1-3 alkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl ) or 3 to 6 membered heterocycloalkyl; Or R 1 , R 2 and the connected ring atoms together form a 4 to 7 membered saturated or partially unsaturated monocyclic ring (preferably a 5 to 7 membered saturated or partially unsaturated monocyclic ring) or a 4 to 7 membered saturated or partially unsaturated monocyclic ring Heterocyclic ring (preferably 5 to 7 membered saturated or partially unsaturated monoheterocyclic ring); wherein said C 1-8 alkyl, C 3-6 cycloalkyl, 4 to 7 membered saturated or partially unsaturated monocyclic ring, 4 to The 7-membered saturated or partially unsaturated monoheterocycle is unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen, cyano, nitro, hydroxyl, carboxyl, C -3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, -NR a1 R b1 , -SO 2 C 1-3 alkyl, -S(O)C 1-3 alkyl, -C(O)NR a0 R b0 , -C(O)OC 1-3 alkyl, -OC(O ) C 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy and 3 to 6 membered heterocycloalkyl;
    化学键
    Figure PCTCN2022130850-appb-100002
    代表单键或双键；     chemical bond
    Figure PCTCN2022130850-appb-100002
    represents a single or double bond;
    所述环A为苯环或5至6元杂芳环；所述环A为未取代的或被1、2或3个各自独立地选自下组的取代基取代：氰基、硝基、羟基、羧基、卤素(优选为氟或氯)、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、C 3-8环烷基(优选为C 3-6环烷基)、C 1-8烷氧基(优选为C 1-6烷氧基，更优选为C 1-3烷氧基)、-C(O)C 1-8烷基(优选为-C(O)C 1-6烷基，更优选为-C(O)C 1-3烷基)、-C(O)OC 1-8烷基(优选为-C(O)OC 1-6烷基更优选为-C(O)OC 1-3烷基)、-OC(O)C 1-8烷基(优选为-OC(O)C 1-6烷基更优选为-OC(O)C 1-3烷基)、-SO 2C 1-8烷基(优选为-SO 2C 1-6烷基，更优选为-SO 2C 1-3烷基)和-C(O)NR a0R b0；其中所述C 1-8烷基、C 3- 6环烷基、C 1-8烷氧基为未取代的或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素、氰基、硝基、羟基、羧基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-NR a1R b1、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR a0R b0、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基和3至6元杂环烷基； The ring A is a benzene ring or a 5- to 6-membered heteroaromatic ring; the ring A is unsubstituted or substituted by 1, 2 or 3 substituents independently selected from the following group: cyano, nitro, Hydroxy, carboxyl, halogen (preferably fluorine or chlorine), C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), -C (O) C 1-8 alkyl (preferably -C(O)C 1-6 alkyl, more preferably -C(O)C 1-3 alkyl), -C(O)OC 1-8 alkyl (preferably -C(O) OC 1-6 alkyl is more preferably -C (O) OC 1-3 alkyl), -OC (O) C 1-8 alkyl (preferably -OC (O) C 1-6 alkyl is more preferably -OC(O)C 1-3 alkyl), -SO 2 C 1-8 alkyl (preferably -SO 2 C 1-6 alkyl, more preferably -SO 2 C 1-3 alkyl) and - C(O) NR a0 R b0 ; wherein the C 1-8 alkyl, C 3-6 cycloalkyl, C 1-8 alkoxy are unsubstituted or independently selected by 1, 2 or 3 Substituents from the following group: deuterium, halogen, cyano, nitro, hydroxyl, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl , Halogenated C 1-3 alkyl, Halogenated C 1-3 alkoxy, -NR a1 R b1 , -SO 2 C 1-3 alkyl, -S(O)C 1-3 alkyl, -C (O)NR a0 R b0 , -C(O)OC 1-3 alkyl, -OC(O)C 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy and 3 to 6 membered heterocycloalkyl;
    R 3和R 4各自独立地为氢、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、C 3-6环烷基、-C(O)OC 1- 8烷基(优选为-C(O)OC 1-6烷基，更优选为-C(O)OC 1-3烷基)或-C(O)C 1-8烷基(优选为-C(O)C 1-6烷基，更优选为-C(O)C 1-3烷基)；或者R 3、R 4与相连接的氮原子共同形成3至7元饱和或部分不饱和单杂环；其中所述C 1-8烷基、C 3-6环烷基、3至7元饱和或部分不饱和单杂环为未取代的或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素、氰基、硝基、羟基、羧基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-NR a1R b1、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR a0R b0、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基和3至6元杂环烷基； R 3 and R 4 are each independently hydrogen, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 3-6 cycloalkyl, -C(O )OC 1-8 alkyl (preferably -C (O) OC 1-6 alkyl, more preferably -C (O) OC 1-3 alkyl) or -C (O) C 1-8 alkyl ( It is preferably -C(O)C 1-6 alkyl, more preferably -C(O)C 1-3 alkyl); or R 3 , R 4 and the connected nitrogen atom together form a 3-7 membered saturated or Partially unsaturated monoheterocycle; wherein said C 1-8 alkyl, C 3-6 cycloalkyl, 3 to 7 membered saturated or partly unsaturated monoheterocycle is unsubstituted or replaced by 1, 2 or 3 each Substituents independently selected from the group consisting of: deuterium, halogen, cyano, nitro, hydroxyl, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2- 4 alkynyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, -NR a1 R b1 , -SO 2 C 1-3 alkyl, -S(O)C 1-3 alkyl , -C(O)NR a0 R b0 , -C(O)OC 1-3 alkyl, -OC(O)C 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl Oxygen and 3 to 6 membered heterocycloalkyl;
    R a0和R b0各自独立地为氢、C 1-3烷基或乙酰基；或者R a0、R b0与相连的氮原子共同形成4至6元饱和单杂环；所述4至6元饱和单杂环为未取代的或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素、氰基、硝基、羟基、羧基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NH 2、-C(O)NH(C 1-3烷基)、-C(O)N(C 1-3烷基) 2、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基和3至6元杂环烷基；以及 R a0 and R b0 are each independently hydrogen, C 1-3 alkyl or acetyl; or R a0 , R b0 and the connected nitrogen atom together form a 4-6 membered saturated monoheterocycle; the 4-6 membered saturated The single heterocycle is unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen, cyano, nitro, hydroxyl, carboxyl, C 1-3 alkyl, C 1 -3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, -SO 2 C 1-3 alkyl, - S(O)C 1-3 alkyl, -C(O)NH 2 , -C(O)NH(C 1-3 alkyl), -C(O)N(C 1-3 alkyl) 2 , -C(O)OC 1-3 alkyl, -OC(O)C 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy and 3 to 6 membered heterocycloalkyl ;as well as
    R a1和R b1各自独立地为氢、C 1-3烷基、卤代C 1-3烷基或乙酰基；或者R a1、R b1与相连的氮原子共同形成4至6元饱和单杂环；所述4至6元饱和单杂环为未取代的或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素、氰基、硝基、羟基、羧基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NH 2、-C(O)NH(C 1-3烷基)、-C(O)N(C 1- 3烷基) 2、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基和3至6元杂环烷基。 R a1 and R b1 are each independently hydrogen, C 1-3 alkyl, halogenated C 1-3 alkyl or acetyl; or R a1 , R b1 together with the connected nitrogen atom form a 4 to 6-membered saturated monohetero ring; the 4 to 6 membered saturated monoheterocycle is unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen, cyano, nitro, hydroxyl, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, -SO 2 C 1-3 alkyl, -S(O)C 1-3 alkyl, -C(O)NH 2 , -C(O)NH(C 1-3 alkyl), -C(O)N( C 1- 3 alkyl) 2 , -C(O)OC 1-3 alkyl, -OC(O)C 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy and 3 to 6 membered heterocycloalkyl.
  2. 如权利要求1所述的化合物、其药学上可接受的盐或其立体异构体，其中，Z 1为N或CR Z1；Z 2为CR Z2；Z 3为N或CR Z3；且Z 4为CR Z4。 The compound as claimed in claim 1, its pharmaceutically acceptable salt or its stereoisomer, wherein, Z 1 is N or CR Z1 ; Z 2 is CR Z2 ; Z 3 is N or CR Z3 ; and Z 4 for CR Z4 .
  3. 如权利要求1所述的化合物、其药学上可接受的盐或其立体异构体，其中，Z 1为CR Z1；Z 2为CR Z2；Z 3为CR Z3；且Z 4为CR Z4。 The compound as claimed in claim 1 , its pharmaceutically acceptable salt or its stereoisomer, wherein, Z 1 is CR Z1 ; Z 2 is CR Z2 ; Z 3 is CR Z3 ; and Z 4 is CR Z4 .
  4. 如权利要求1所述的化合物、其药学上可接受的盐或其立体异构体，其中，R Z1、R Z2、R Z3、和R Z4各自独立地为氢、氰基、卤素(优选为氟或氯)、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、C 3-8环烷基(优选为C 3-6环烷基)、卤代C 1-8烷基(优选为卤代C 1-6烷基，更优选为卤代C 1-3烷基)、C 1-8烷氧基(优选为C 1-6烷氧基，更优选为C 1-3烷氧基)、卤代C 1-8烷氧基(优选为卤代C 1-6烷氧基，更优选为卤代C 1-3烷氧基)或-NR a1R b1；其中所述C 1-8烷基、C 3-8环烷基各自独立地为未取代的或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素、氰基、硝基、羟基、羧基、C 1-3烷基、C 1-3烷氧基、C 2- 4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-NR a1R b1、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR a0R b0、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基和3至6元杂环烷基。 The compound as claimed in claim 1, its pharmaceutically acceptable salt or its stereoisomer, wherein, R Z1 , R Z2 , R Z3 , and R Z4 are each independently hydrogen, cyano, halogen (preferably Fluorine or chlorine), C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl) , halogenated C 1-8 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), C 1-8 alkoxy (preferably C 1-6 alkoxy group, more preferably C 1-3 alkoxy), halogenated C 1-8 alkoxy (preferably halogenated C 1-6 alkoxy, more preferably halogenated C 1-3 alkoxy) or -NR a1 R b1 ; wherein the C 1-8 alkyl and C 3-8 cycloalkyl are each independently unsubstituted or substituted by 1, 2 or 3 substituents independently selected from the following group: Deuterium, halogen, cyano, nitro, hydroxyl, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 1-3 alkane group, halogenated C 1-3 alkoxy group, -NR a1 R b1 , -SO 2 C 1-3 alkyl group, -S(O)C 1-3 alkyl group, -C(O)NR a0 R b0 , -C(O)OC 1-3 alkyl, -OC(O)C 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy and 3 to 6 membered heterocycloalkyl .
  5. 如权利要求1所述的化合物、其药学上可接受的盐或其立体异构体，其中，R Z1为氢。 The compound, its pharmaceutically acceptable salt or its stereoisomer as claimed in claim 1, wherein, R Z1 is hydrogen.
  6. 如权利要求1所述的化合物、其药学上可接受的盐或其立体异构体，其中，R Z2为氰基、卤素(优选为氟或氯)、C 1-3烷基(优选为甲基)、C 3-6环烷基(优选为环丙基)、卤代C 1-3烷基(优选为氟代C 1- 3烷基，更优选为一氟甲基、一氟乙基、二氟甲基、二氟乙基、三氟甲基、三氟乙基或五氟乙基)、C 1-3烷氧基(优选为甲氧基或乙氧基)、卤代C 1-3烷氧基(优选为二氟甲氧基或三氟甲氧基)、卤素取代的C 3- 6环烷基或-NR a1R b1；以及R a1、R b1各自独立地为氢、C 1-3烷基、卤代C 1-3烷基或乙酰基。 The compound as claimed in claim 1, its pharmaceutically acceptable salt or its stereoisomer, wherein, R Z2 is cyano, halogen (preferably fluorine or chlorine), C 1-3 alkyl (preferably methyl base), C 3-6 cycloalkyl (preferably cyclopropyl), halogenated C 1-3 alkyl (preferably fluoro C 1-3 alkyl, more preferably monofluoromethyl, monofluoroethyl , difluoromethyl, difluoroethyl, trifluoromethyl, trifluoroethyl or pentafluoroethyl), C 1-3 alkoxy (preferably methoxy or ethoxy), halogenated C 1 -3 alkoxy (preferably difluoromethoxy or trifluoromethoxy), halogen-substituted C 3-6 cycloalkyl or -NR a1 R b1 ; and R a1 and R b1 are each independently hydrogen, C 1-3 alkyl, halogenated C 1-3 alkyl or acetyl.
  7. 如权利要求1所述的化合物、其药学上可接受的盐或其立体异构体，其中，R Z3为氢、氰基或卤素(优选为氟或氯)。 The compound as claimed in claim 1, its pharmaceutically acceptable salt or its stereoisomer, wherein, R Z3 is hydrogen, cyano or halogen (preferably fluorine or chlorine).
  8. 如权利要求1所述的化合物、其药学上可接受的盐或其立体异构体，其中，R Z4为氢或卤素(优选为氟或氯)。 The compound as claimed in claim 1, its pharmaceutically acceptable salt or its stereoisomer, wherein, R Z4 is hydrogen or halogen (preferably fluorine or chlorine).
  9. 如权利要求1所述的化合物、其药学上可接受的盐或其立体异构体，其中，R 3、R 4与相连接的氮原子共同形成的3至7元饱和或部分不饱和单杂环选自：氮杂环丁烷、四氢吡咯环、哌啶环、哌嗪环、吗啉环、硫代吗啉环、氮杂环丁烷-2-酮环、吡咯烷-2-酮环、吡咯烷-2，5-二酮环、哌啶-2-酮环、哌嗪-2-酮环和吗啉-3-酮环。 The compound according to claim 1, its pharmaceutically acceptable salt or its stereoisomer, wherein R 3 , R 4 and the connected nitrogen atom jointly form a 3-7 membered saturated or partially unsaturated monohetero The ring is selected from: azetidine, tetrahydropyrrole ring, piperidine ring, piperazine ring, morpholine ring, thiomorpholine ring, azetidin-2-one ring, pyrrolidin-2-one ring, pyrrolidine-2,5-dione ring, piperidin-2-one ring, piperazin-2-one ring and morpholin-3-one ring.
  10. 如权利要求1所述的化合物、其药学上可接受的盐或其立体异构体，其中，S 1为C；以及S 2为C。 The compound as claimed in claim 1, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein S 1 is C; and S 2 is C.
  11. 如权利要求1所述的化合物、其药学上可接受的盐或其立体异构体，其中，所述环A是苯环或5至6元杂芳基环，且所述5至6元杂芳环选自：噻吩环、呋喃环、噻唑环、异噻唑环、咪唑环、噁唑环、吡咯环、吡唑环、三唑环、1，2，3-三唑环、1，2，4-三唑环、1，2，5-三唑环、1，3，4-三唑环、四唑环、异噁唑环、噁二唑环、1，2，3-噁二唑环、1，2，4-噁二唑环、1，2，5-噁二唑环、1，3，4-噁二唑环、噻二唑环、吡啶环、哒嗪环、嘧啶环、吡嗪环、三嗪环和四嗪环。The compound according to claim 1, its pharmaceutically acceptable salt or its stereoisomer, wherein, said ring A is a benzene ring or a 5-6 membered heteroaryl ring, and said 5-6 membered heteroaryl ring The aromatic ring is selected from: thiophene ring, furan ring, thiazole ring, isothiazole ring, imidazole ring, oxazole ring, pyrrole ring, pyrazole ring, triazole ring, 1,2,3-triazole ring, 1,2, 4-triazole ring, 1,2,5-triazole ring, 1,3,4-triazole ring, tetrazole ring, isoxazole ring, oxadiazole ring, 1,2,3-oxadiazole ring , 1,2,4-oxadiazole ring, 1,2,5-oxadiazole ring, 1,3,4-oxadiazole ring, thiadiazole ring, pyridine ring, pyridazine ring, pyrimidine ring, pyrimidine ring, oxazine, triazine and tetrazine rings.
  12. 如权利要求1所述的化合物、其药学上可接受的盐或其立体异构体，其中，所述环A为未取代的。The compound according to claim 1, its pharmaceutically acceptable salt or its stereoisomer, wherein the ring A is unsubstituted.
  13. 如权利要求1所述的化合物、其药学上可接受的盐或其立体异构体，其中，R 4为氢或甲基；R 3为氢、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、C 3-6环烷基、-C(O)OC 1-8烷基(优选为-C(O)OC 1- 6烷基，更优选为-C(O)OC 1-3烷基)或-C(O)C 1-8烷基(优选为-C(O)C 1-6烷基，更优选为-C(O)C 1-3烷基)；其中所述C 1-8烷基、C 3-6环烷基为未取代的或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素、氰基、硝基、羟基、羧基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1- 3烷氧基、-NR a1R b1、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR a0R b0、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基和3至6元杂环烷基。 The compound as claimed in claim 1, its pharmaceutically acceptable salt or its stereoisomer, wherein, R 4 is hydrogen or methyl; R 3 is hydrogen, C 1-8 alkyl (preferably C 1-8 6 alkyl, more preferably C 1-3 alkyl), C 3-6 cycloalkyl, -C( O )OC 1-8 alkyl (preferably -C(O)OC 1-6 alkyl, more Preferably -C(O)OC 1-3 alkyl) or -C(O)C 1-8 alkyl (preferably -C(O)C 1-6 alkyl, more preferably -C(O)C 1-3 alkyl); wherein the C 1-8 alkyl, C 3-6 cycloalkyl are unsubstituted or substituted by 1, 2 or 3 substituents independently selected from the following group: deuterium, Halogen, cyano, nitro, hydroxyl, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 1-3 alkyl, Halogenated C 1-3 alkoxy, -NR a1 R b1 , -SO 2 C 1-3 alkyl, -S(O)C 1-3 alkyl, -C(O)NR a0 R b0 , -C (O)OC 1-3 alkyl, -OC(O)C 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy and 3 to 6-membered heterocycloalkyl.
  14. 如权利要求1所述的化合物、其药学上可接受的盐或其立体异构体，其中，R 4为氢或甲基；以 及R 3为甲基、-CD 3、
    Figure PCTCN2022130850-appb-100003
    Figure PCTCN2022130850-appb-100004
    The compound as claimed in claim 1, its pharmaceutically acceptable salt or its stereoisomer, wherein, R 4 is hydrogen or methyl; and R 3 is methyl, -CD 3 ,
    Figure PCTCN2022130850-appb-100003
    Figure PCTCN2022130850-appb-100004
  15. 如权利要求1所述的化合物、其药学上可接受的盐或其立体异构体，其中，所述化合物结构如式(Ia)或式(Ib)所示：The compound as claimed in claim 1, its pharmaceutically acceptable salt or its stereoisomer, wherein, said compound structure is as shown in formula (Ia) or formula (Ib):
    Figure PCTCN2022130850-appb-100005
    Figure PCTCN2022130850-appb-100005
  16. 如权利要求1所述的化合物、其药学上可接受的盐或其立体异构体，其中，所述化合物结构如式(I-1)所示：The compound as claimed in claim 1, its pharmaceutically acceptable salt or its stereoisomer, wherein, the compound structure is as shown in formula (I-1):
    Figure PCTCN2022130850-appb-100006
    Figure PCTCN2022130850-appb-100006
    其中，in,
    L为-(CR q1R q2) m-、-(CR q3R q4) t1-O-(CR q5R q6) t2-、或-(CR q7R q8) t3-NR q0-(CR q9R q10) t4-； L is -(CR q1 R q2 ) m -, -(CR q3 R q4 ) t1 -O-(CR q5 R q6 ) t2 -, or -(CR q7 R q8 ) t3 -NR q0 -(CR q9 R q10 ) t4 -;
    m为1、2、3或4；m is 1, 2, 3 or 4;
    t1、t2、t3、和t4各自独立地为0、1、2或3；其中t1和t2不同时为0；且t3和t4不同时为0；t1, t2, t3, and t4 are each independently 0, 1, 2 or 3; wherein t1 and t2 are not 0 at the same time; and t3 and t4 are not 0 at the same time;
    R q1和R q2各自独立地为氢、卤素(优选为氟或氯)、氰基、硝基、羟基、羧基、C 1-8烷基(优选为C 1- 6烷基，更优选为C 1-3烷基)、C 3-8环烷基(优选为C 3-6环烷基)、卤代C 1-8烷基(优选为卤代C 1-6烷基，更优选为卤代C 1-3烷基)、C 1-8烷氧基(优选为C 1-6烷氧基，更优选为C 1-3烷氧基)、卤代C 1-8烷氧基(优选为卤代C 1-6烷氧基，更优选为卤代C 1-3烷氧基)、-C(O)NR a0R b0、-C(O)C 1-8烷基(优选为-C(O)C 1-6烷基，更优选为-C(O)C 1-3烷基)或-C(O)OC 1-8烷基(优选为-C(O)OC 1-6烷基，更优选为-C(O)OC 1-3烷基)；或者R q1、R q2与相连接的碳原子共同形成3至7元饱和或部分不饱和单环或3至7元饱和或部分不饱和单杂环；其中所述C 1-8烷基、C 3-6环烷基、卤代C 1-8烷基、C 1-8烷氧基、卤代C 1-8烷氧基、3至7元饱和或部分不饱和单环、3至7元饱和或部分不饱和单杂环为未取代的或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素、氰基、硝基、羟基、羧基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-NR a1R b1、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR a0R b0、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基和3至6元杂环烷基； R q1 and R q2 are each independently hydrogen, halogen (preferably fluorine or chlorine) , cyano, nitro, hydroxyl, carboxyl, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), halogenated C 1-8 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogen C 1-3 alkyl), C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), halogenated C 1-8 alkoxy (preferably is halogenated C 1-6 alkoxy, more preferably halogenated C 1-3 alkoxy), -C(O)NR a0 R b0 , -C(O)C 1-8 alkyl (preferably - C(O)C 1-6 alkyl, more preferably -C(O)C 1-3 alkyl) or -C(O)OC 1-8 alkyl (preferably -C(O)OC 1-6 Alkyl, more preferably -C(O)OC 1-3 alkyl); or R q1 , R q2 and the connected carbon atoms together form a 3-7 membered saturated or partially unsaturated monocyclic ring or a 3-7 membered saturated Or partially unsaturated monoheterocycle; wherein said C 1-8 alkyl, C 3-6 cycloalkyl, halogenated C 1-8 alkyl, C 1-8 alkoxy, halogenated C 1-8 alkane Oxygen, 3 to 7-membered saturated or partially unsaturated monocyclic ring, 3 to 7-membered saturated or partially unsaturated monocyclic heterocyclic ring is unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the following group : Deuterium, halogen, cyano, nitro, hydroxyl, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 1-3 Alkyl, halogenated C 1-3 alkoxy, -NR a1 R b1 , -SO 2 C 1-3 alkyl, -S(O)C 1-3 alkyl, -C(O)NR a0 R b0 , -C(O)OC 1-3 alkyl, -OC(O)C 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy and 3 to 6 membered heterocycloalkane base;
    R q3、R q4、R q5、R q6、R q7、R q8、R q9、和R q10各自独立地为氢、卤素(优选为氟或氯)、氰基、硝基、羟基、羧基、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、C 3-8环烷基(优选为C 3-6环烷基)、卤代C 1-8烷基(优选为卤代C 1-6烷基，更优选为卤代C 1-3烷基)、C 1-8烷氧基(优选为C 1-6烷氧基，更优选为C 1- 3烷氧基)、卤代C 1-8烷氧基(优选为卤代C 1-6烷氧基，更优选为卤代C 1-3烷氧基)、-C(O)NR a0R b0、-C(O)C 1- 8烷基(优选为-C(O)C 1-6烷基，更优选为-C(O)C 1-3烷基)或-C(O)OC 1-8烷基(优选为-C(O)OC 1-6烷基，更优选为-C(O)OC 1-3烷基)；以及 R q3 , R q4 , R q5 , R q6 , R q7 , R q8 , R q9 , and R q10 are each independently hydrogen, halogen (preferably fluorine or chlorine), cyano, nitro, hydroxyl, carboxyl, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), halogenated C 1- 8 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), halogenated C 1-8 alkoxy (preferably halogenated C 1-6 alkoxy, more preferably halogenated C 1-3 alkoxy), -C(O ) NR a0 R b0 , -C(O)C 1- 8 alkyl (preferably -C(O)C 1-6 alkyl, more preferably -C(O)C 1-3 alkyl) or -C(O ) OC1-8alkyl (preferably -C(O) OC1-6alkyl , more preferably -C(O) OC1-3alkyl ); and
    R q0为氢、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、C 3-8环烷基(优选为C 3-6环烷基)、- C(O)NR a0R b0、-C(O)C 1-8烷基(优选为-C(O)C 1-6烷基，更优选为-C(O)C 1-3烷基)或-SO 2C 1-8烷基(优选为-SO 2C 1-6烷基，更优选为-SO 2C 1-3烷基)；其中所述C 1-8烷基、C 3-8环烷基为未取代的或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素、氰基、硝基、羟基、羧基、C 1-3烷基、C 1-3烷氧基、C 2- 4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-NR a1R b1、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR a0R b0、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基和3至6元杂环烷基。 R q0 is hydrogen, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl) , -C(O)NR a0 R b0 , -C(O)C 1-8 alkyl (preferably -C(O)C 1-6 alkyl, more preferably -C(O)C 1-3 alkane base) or -SO 2 C 1-8 alkyl (preferably -SO 2 C 1-6 alkyl, more preferably -SO 2 C 1-3 alkyl); wherein the C 1-8 alkyl, C 3-8 cycloalkyl is unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen, cyano, nitro, hydroxyl, carboxyl, C 1-3 alkyl , C 1-3 alkoxy, C 2- 4 alkenyl, C 2-4 alkynyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, -NR a1 R b1 , -SO 2 C 1-3 alkyl, -S(O)C 1-3 alkyl, -C(O)NR a0 R b0 , -C(O)OC 1-3 alkyl, -OC(O)C 1- 3 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy and 3 to 6 membered heterocycloalkyl.
  17. 如权利要求16所述的化合物、其药学上可接受的盐或其立体异构体，其中，所述化合物结构如式(I-1a)或式(I-1b)所示：The compound according to claim 16, its pharmaceutically acceptable salt or its stereoisomer, wherein, the structure of the compound is shown in formula (I-1a) or formula (I-1b):
    Figure PCTCN2022130850-appb-100007
    Figure PCTCN2022130850-appb-100007
  18. 如权利要求16所述的化合物、其药学上可接受的盐或其立体异构体，其中，R q1、R q2与相连接的碳原子共同形成的3至7元饱和或部分不饱和单环为3至6元饱和单环；并且优选选自由以下组成的组：环丙基环、环丁基环、环戊基环和环己基环。 The compound as claimed in claim 16, its pharmaceutically acceptable salt or its stereoisomer, wherein, R q1 , R q2 and the connected carbon atoms form a 3-7 membered saturated or partially unsaturated monocyclic ring is a 3- to 6-membered saturated monocyclic ring; and is preferably selected from the group consisting of a cyclopropyl ring, a cyclobutyl ring, a cyclopentyl ring and a cyclohexyl ring.
  19. 如权利要求16所述的化合物、其药学上可接受的盐或其立体异构体，其中，R q1、R q2与相连接的碳原子共同形成的3至7元饱和或部分不饱和单杂环为4至6元饱和或部分不饱和单杂环；并且优选选自由以下组成的组：氮杂环丁烷、氧杂环丁烷、四氢呋喃环、四氢噻吩环、四氢吡咯环、哌啶环、哌嗪环、吗啉环、硫代吗啉环、硫代吗啉-1，1-二氧化物和四氢吡喃环。 The compound as claimed in claim 16, its pharmaceutically acceptable salt or its stereoisomer, wherein, R q1 , R q2 and the connected carbon atom together form a 3-7 membered saturated or partially unsaturated monohetero The ring is a 4 to 6 membered saturated or partially unsaturated monoheterocyclic ring; and is preferably selected from the group consisting of azetidine, oxetane, tetrahydrofuran ring, tetrahydrothiophene ring, tetrahydropyrrole ring, piperine Pyridine ring, piperazine ring, morpholine ring, thiomorpholine ring, thiomorpholine-1,1-dioxide and tetrahydropyran ring.
  20. 如权利要求16所述的化合物、其药学上可接受的盐或其立体异构体，其中，所述化合物结构如式(I-2)所示：The compound according to claim 16, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein the structure of the compound is shown in formula (I-2):
    Figure PCTCN2022130850-appb-100008
    Figure PCTCN2022130850-appb-100008
    其中，Z 5为N或CR Z5；Z 6为N或CR Z6；Z 7为N或CR Z7；且Z 8为N或CR Z8； Wherein, Z 5 is N or CR Z5 ; Z 6 is N or CR Z6 ; Z 7 is N or CR Z7 ; and Z 8 is N or CR Z8 ;
    R Z5、R Z6、R Z7和R Z8各自独立地为氢、氰基、硝基、羟基、羧基、卤素(优选为氟或氯)、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、C 3-8环烷基(优选为C 3-6环烷基)、卤代C 1-8烷基(优选为卤代C 1-6烷基，更优选为卤代C 1-3烷基)、C 1-8烷氧基(优选为C 1-6烷氧基，更优选为C 1-3烷氧基)、卤代C 1- 8烷氧基(优选为卤代C 1-6烷氧基，更优选为卤代C 1-3烷氧基)、-C(O)C 1-8烷基(优选为-C(O)C 1-6烷基，更优选为-C(O)C 1-3烷基)、-C(O)OC 1-8烷基(优选为-C(O)OC 1-6烷基，更优选为-C(O)OC 1-3烷基)、-SO 2C 1- 8烷基(优选为-SO 2C 1-6烷基，更优选为-SO 2C 1-3烷基)、-C(O)NR a0R b0、-NR a1R b1、5至6元杂芳基或8至10元杂芳基；其中所述C 1-8烷基、C 3-8环烷基、卤代C 1-8烷基、C 1-8烷氧基、卤代C 1-8烷氧基为未取代的或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素、氰基、硝基、羟基、羧基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-NR a1R b1、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR a0R b0、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基、3至6元杂环烷基、苯基和5至6元杂芳基。 R Z5 , R Z6 , R Z7 and R Z8 are each independently hydrogen, cyano, nitro, hydroxyl, carboxyl, halogen (preferably fluorine or chlorine), C 1-8 alkyl (preferably C 1-6 alkane group, more preferably C 1-3 alkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), halogenated C 1-8 alkyl (preferably halogenated C 1-6 alkane group, more preferably halogenated C 1-3 alkyl), C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), halogenated C 1- 8 alkoxy (preferably halogenated C 1-6 alkoxy, more preferably halogenated C 1-3 alkoxy), -C (O) C 1-8 alkyl (preferably -C (O) C 1-6 alkyl, more preferably -C(O)C 1-3 alkyl), -C(O)OC 1-8 alkyl (preferably -C(O)OC 1-6 alkyl, more preferably Preferably -C(O)OC 1-3 alkyl), -SO 2 C 1-8 alkyl (preferably -SO 2 C 1-6 alkyl, more preferably -SO 2 C 1-3 alkyl) , -C(O)NR a0 R b0 , -NR a1 R b1 , 5 to 6-membered heteroaryl or 8 to 10-membered heteroaryl; wherein the C 1-8 alkyl, C 3-8 cycloalkyl , halogenated C 1-8 alkyl, C 1-8 alkoxy, halogenated C 1-8 alkoxy are unsubstituted or substituted by 1, 2 or 3 substituents independently selected from the following group : Deuterium, halogen, cyano, nitro, hydroxyl, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 1-3 Alkyl, halogenated C 1-3 alkoxy, -NR a1 R b1 , -SO 2 C 1-3 alkyl, -S(O)C 1-3 alkyl, -C(O)NR a0 R b0 , -C(O)OC 1-3 alkyl, -OC(O)C 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy, 3 to 6 membered heterocycloalkane radical, phenyl and 5 to 6 membered heteroaryl.
  21. 如权利要求20所述的化合物、其药学上可接受的盐或其立体异构体，其中，Z 5为N或CR Z5；Z 6为CR Z6；Z 7为CR Z7；以及Z 8为CR Z8。 The compound of claim 20, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein Z 5 is N or CR Z5 ; Z 6 is CR Z6 ; Z 7 is CR Z7 ; and Z 8 is CR Z8 .
  22. 如权利要求20所述的化合物、或其药学上可接受的盐或其立体异构体，其中，所述化合物结构如式(I-2a)或式(I-2b)所示：The compound according to claim 20, or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein the structure of the compound is shown in formula (I-2a) or formula (I-2b):
    Figure PCTCN2022130850-appb-100009
    Figure PCTCN2022130850-appb-100009
  23. 如权利要求16所述的化合物、其药学上可接受的盐或其立体异构体，其中，基团
    Figure PCTCN2022130850-appb-100010
    选自由以下组成的组：     The compound as claimed in claim 16, its pharmaceutically acceptable salt or its stereoisomer, wherein, the group
    Figure PCTCN2022130850-appb-100010
    Selected from the group consisting of:
    Figure PCTCN2022130850-appb-100011
    Figure PCTCN2022130850-appb-100011
  24. 如权利要求1所述的化合物、其药学上可接受的盐或其立体异构体，其中，所述化合物选自由以下组成的组：The compound according to claim 1, its pharmaceutically acceptable salt or its stereoisomer, wherein said compound is selected from the group consisting of:
    Figure PCTCN2022130850-appb-100012
    Figure PCTCN2022130850-appb-100012
    Figure PCTCN2022130850-appb-100013
    Figure PCTCN2022130850-appb-100013
    Figure PCTCN2022130850-appb-100014
    Figure PCTCN2022130850-appb-100014
    Figure PCTCN2022130850-appb-100015
    Figure PCTCN2022130850-appb-100015
    Figure PCTCN2022130850-appb-100016
    Figure PCTCN2022130850-appb-100016
  25. 如权利要求1所述的化合物、其药学上可接受的盐或其立体异构体，其中，所述化合物选自由以下组成的组：The compound according to claim 1, its pharmaceutically acceptable salt or its stereoisomer, wherein said compound is selected from the group consisting of:
    Figure PCTCN2022130850-appb-100017
    Figure PCTCN2022130850-appb-100017
    Figure PCTCN2022130850-appb-100018
    Figure PCTCN2022130850-appb-100018
    Figure PCTCN2022130850-appb-100019
    Figure PCTCN2022130850-appb-100019
    Figure PCTCN2022130850-appb-100020
    Figure PCTCN2022130850-appb-100020
    Figure PCTCN2022130850-appb-100021
    Figure PCTCN2022130850-appb-100021
    Figure PCTCN2022130850-appb-100022
    Figure PCTCN2022130850-appb-100022
  26. 一种式(II)所示的化合物、其药学上可接受的盐或其立体异构体：A compound represented by formula (II), its pharmaceutically acceptable salt or its stereoisomer:
    Figure PCTCN2022130850-appb-100023
    Figure PCTCN2022130850-appb-100023
    其中，S 1’和S 2’代表环A’上的环原子；S 1’为N或C；且S 2’为N或C； Wherein, S 1' and S 2' represent ring atoms on ring A'; S 1' is N or C; and S 2' is N or C;
    Z 1’为N或CR Z1’；Z 2’为N或CR Z2’；Z 3’为N或CR Z3’；且Z 4’为N或CR Z4’；其中R Z1’、R Z2’、R Z3’、R Z4’各自独立地为氢、氰基、硝基、羟基、羧基、卤素(优选为氟或氯)、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、C 3-8环烷基(优选为C 3-6环烷基)、卤代C 1-8烷基(优选为卤代C 1-6烷基，更优选为卤代C 1-3烷基)、C 1-8烷氧基(优选为C 1-6烷氧基，更优选为C 1-3烷氧基)、卤代C 1-8烷氧基(优选为卤代C 1- 6烷氧基，更优选为卤代C 1-3烷氧基)、-C(O)C 1-8烷基(优选为-C(O)C 1-6烷基，更优选为-C(O)C 1-3烷基)、-C(O)OC 1-8烷基(优选为-C(O)OC 1-6烷基，更优选为-C(O)OC 1-3烷基)、-C(O)NR a0’R b0’或-NR a1’R b1’；其中所述C 1-8烷基、C 3-8环烷基、卤代C 1-8烷基、C 1-8烷氧基、卤代C 1-8烷氧基各自独立地为未取代的或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素、氰基、硝基、羟基、羧基、C 1-3烷基、C 1- 3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-NR a1’R b1’、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR a0’R b0’、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基和3至6元杂环烷基； Z 1' is N or CR Z1' ; Z 2' is N or CR Z2' ; Z 3' is N or CR Z3' ; and Z 4' is N or CR Z4' ; wherein R Z1' , R Z2' , R Z3' and R Z4' are each independently hydrogen, cyano, nitro, hydroxyl, carboxyl, halogen (preferably fluorine or chlorine), C 1-8 alkyl (preferably C 1-6 alkyl, more preferably is C 1-3 alkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), halogenated C 1-8 alkyl (preferably halogenated C 1-6 alkyl, more preferably is halogenated C 1-3 alkyl), C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), halogenated C 1-8 alkoxy (preferably halogenated C 1-6 alkoxy, more preferably halogenated C 1-3 alkoxy), -C (O)C 1-8 alkyl (preferably -C(O)C 1-6 Alkyl, more preferably -C (O) C 1-3 alkyl), -C (O) OC 1-8 alkyl (preferably -C (O) OC 1-6 alkyl, more preferably -C (O)OC 1-3 alkyl), -C(O)NR a0' R b0' or -NR a1' R b1' ; wherein the C 1-8 alkyl, C 3-8 cycloalkyl, halogen Substituted C 1-8 alkyl, C 1-8 alkoxy, halogenated C 1-8 alkoxy are each independently unsubstituted or replaced by 1, 2 or 3 substituents independently selected from the following group Substitution : deuterium, halogen, cyano, nitro, hydroxyl, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 1- 3 alkyl, halogenated C 1-3 alkoxy, -NR a1' R b1' , -SO 2 C 1-3 alkyl, -S(O)C 1-3 alkyl, -C(O)NR a0' R b0' , -C(O)OC 1-3 alkyl, -OC(O)C 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy and 3 to 6-membered heterocycloalkyl;
    L’为-(CR q1’R q2’) m’-、-(CR q3’R q4’) t1’-O-(CR q5’R q6’) t2’-、或-(CR q7’R q8’) t3’-NR q0’-(CR q9’R q10’) t4’-； L' is -(CR q1' R q2' ) m' -, -(CR q3' R q4' ) t1' -O-(CR q5' R q6' ) t2' -, or -(CR q7' R q8 ' ) t3' -NR q0' -(CR q9' R q10' ) t4' -;
    m’为1、2、3或4；m' is 1, 2, 3 or 4;
    t1’、t2’、t3’、和t4’各自独立地为0、1、2或3；其中t1’和t2’不同时为0；且t3’和t4’不同时为0；t1', t2', t3', and t4' are each independently 0, 1, 2 or 3; wherein t1' and t2' are not 0 at the same time; and t3' and t4' are not 0 at the same time;
    R q1’和R q2’各自独立地为氢、卤素(优选为氟或氯)、氰基、硝基、羟基、羧基、C 1-8烷基(优选为C 1- 6烷基，更优选为C 1-3烷基)、C 3-8环烷基(优选为C 3-6环烷基)、卤代C 1-8烷基(优选为卤代C 1-6烷基，更优选为卤代C 1-3烷基)、C 1-8烷氧基(优选为C 1-6烷氧基，更优选为C 1-3烷氧基)、卤代C 1-8烷氧基(优选为卤代C 1-6烷氧基，更优选为卤代C 1-3烷氧基)、-C(O)NR a0’R b0’、-C(O)C 1-8烷基(优选为-C(O)C 1-6烷基，更优选为-C(O)C 1-3烷基)或-C(O)OC 1-8烷基(优选为-C(O)OC 1-6烷基，更优选为-C(O)OC 1-3烷基)；或者R q1’、R q2’与相连接的碳原子共同形成3至7元饱和或部分不饱和单环或3至7元饱和或部分不饱 和单杂环；其中所述C 1-8烷基、C 3-6环烷基、卤代C 1-8烷基、C 1-8烷氧基、卤代C 1-8烷氧基、3至7元饱和或部分不饱和单环、3至7元饱和或部分不饱和单杂环为未取代的或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素、氰基、硝基、羟基、羧基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-NR a1’R b1’、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR a0’R b0’、-C(O)OC 1- 3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基和3至6元杂环烷基； R q1' and R q2' are each independently hydrogen, halogen (preferably fluorine or chlorine ) , cyano, nitro, hydroxyl, carboxyl, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably is C 1-3 alkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), halogenated C 1-8 alkyl (preferably halogenated C 1-6 alkyl, more preferably is halogenated C 1-3 alkyl), C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), halogenated C 1-8 alkoxy (preferably halogenated C 1-6 alkoxy, more preferably halogenated C 1-3 alkoxy), -C(O)NR a0' R b0' , -C(O)C 1-8 alkyl (preferably -C(O)C 1-6 alkyl, more preferably -C(O)C 1-3 alkyl) or -C(O)OC 1-8 alkyl (preferably -C(O) OC 1-6 alkyl, more preferably -C(O)OC 1-3 alkyl); or R q1' , R q2' and the connected carbon atoms together form a 3-7 membered saturated or partially unsaturated monocyclic ring Or 3 to 7 membered saturated or partially unsaturated monoheterocycle; wherein said C 1-8 alkyl, C 3-6 cycloalkyl, halogenated C 1-8 alkyl, C 1-8 alkoxy, halogen C 1-8 alkoxy, 3 to 7 membered saturated or partially unsaturated monocyclic ring, 3 to 7 membered saturated or partially unsaturated monoheterocyclic ring are unsubstituted or are independently selected from 1, 2 or 3 The following substituents are substituted: deuterium, halogen, cyano, nitro, hydroxyl, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, Halogenated C 1-3 alkyl, Halogenated C 1-3 alkoxy, -NR a1' R b1' , -SO 2 C 1-3 alkyl, -S(O)C 1-3 alkyl, - C(O)NR a0' R b0' , -C(O)OC 1- 3 alkyl, -OC(O)C 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl Oxygen and 3 to 6 membered heterocycloalkyl;
    R q3’、R q4’、R q5’、R q6’、R q7’、R q8’、R q9’、和R q10’各自独立地为氢、卤素(优选为氟或氯)、氰基、硝基、羟基、羧基、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、C 3-8环烷基(优选为C 3-6环烷基)、卤代C 1-8烷基(优选为卤代C 1-6烷基，更优选为卤代C 1-3烷基)、C 1-8烷氧基(优选为C 1-6烷氧基，更优选为C 1-3烷氧基)、卤代C 1-8烷氧基(优选为卤代C 1-6烷氧基，更优选为卤代C 1-3烷氧基)、-C(O)NR a0’R b0’、-C(O)C 1-8烷基(优选为-C(O)C 1-6烷基，更优选为-C(O)C 1-3烷基)或-C(O)OC 1-8烷基(优选为-C(O)OC 1- 6烷基，更优选为-C(O)OC 1-3烷基)； R q3' , R q4' , R q5' , R q6' , R q7' , R q8' , R q9' , and R q10' are each independently hydrogen, halogen (preferably fluorine or chlorine), cyano, Nitro, hydroxyl, carboxyl, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkane base), halogenated C 1-8 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), C 1-8 alkoxy (preferably C 1-6 Alkoxy, more preferably C 1-3 alkoxy), halogenated C 1-8 alkoxy (preferably halogenated C 1-6 alkoxy, more preferably halogenated C 1-3 alkoxy ), -C(O)NR a0' R b0' , -C(O)C 1-8 alkyl (preferably -C(O)C 1-6 alkyl, more preferably -C(O)C 1 -3 alkyl) or -C(O ) OC 1-8 alkyl (preferably -C(O)OC 1-6 alkyl, more preferably -C(O)OC 1-3 alkyl);
    R q0’为氢、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、C 3-8环烷基(优选为C 3-6环烷基)、-C(O)NR a0’R b0’、-C(O)C 1-8烷基(优选为-C(O)C 1-6烷基，更优选为-C(O)C 1-3烷基)或-SO 2C 1-8烷基(优选为-SO 2C 1-6烷基，更优选为-SO 2C 1-3烷基)；其中所述C 1-8烷基、C 3-8环烷基为未取代的或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素、氰基、硝基、羟基、羧基、C 1-3烷基、C 1-3烷氧基、C 2- 4烯基C 2-4炔基卤代C 1-3烷基卤代C 1-3烷氧基-NR a1’R b1’、-SO 2C 1-3烷基-S(O)C 1-3烷基-C(O)NR a0’R b0’、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基和3至6元杂环烷基； R q0' is hydrogen, C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl ), -C(O)NR a0' R b0' , -C(O)C 1-8 alkyl (preferably -C(O)C 1-6 alkyl, more preferably -C(O)C 1 -3 alkyl) or -SO 2 C 1-8 alkyl (preferably -SO 2 C 1-6 alkyl, more preferably -SO 2 C 1-3 alkyl); wherein the C 1-8 alkyl Group, C 3-8 cycloalkyl is unsubstituted or substituted by 1, 2 or 3 substituents independently selected from the group consisting of deuterium, halogen, cyano, nitro, hydroxyl, carboxyl, C 1- 3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl C 2-4 alkynyl halo C 1-3 alkyl halo C 1-3 alkoxy -NR a1' R b1' , - SO 2 C 1-3 Alkyl-S(O)C 1-3 Alkyl-C(O)NR a0' R b0' , -C(O)OC 1-3 Alkyl, -OC(O)C 1 -3 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy and 3 to 6 membered heterocycloalkyl;
    化学键
    Figure PCTCN2022130850-appb-100024
    代表单键或双键；     chemical bond
    Figure PCTCN2022130850-appb-100024
    represents a single or double bond;
    所述环A’为苯环或5至6元杂芳环；所述环A’为未取代的或被1、2或3个各自独立地选自下组的取代基取代：氰基、硝基、羟基、羧基、卤素(优选为氟或氯)、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、C 3-8环烷基(优选为C 3-6环烷基)、C 1-8烷氧基(优选为C 1-6烷氧基，更优选为C 1-3烷氧基)、-C(O)C 1-8烷基(优选为-C(O)C 1-6烷基，更优选为-C(O)C 1-3烷基)、-C(O)OC 1-8烷基(优选为-C(O)OC 1-6烷基更优选为-C(O)OC 1-3烷基)、-OC(O)C 1-8烷基(优选为-OC(O)C 1-6烷基更优选为-OC(O)C 1-3烷基)、-SO 2C 1-8烷基(优选为-SO 2C 1-6烷基，更优选为-SO 2C 1-3烷基)和-C(O)NR a0’R b0’；其中所述C 1-8烷基、C 3- 6环烷基、C 1-8烷氧基为未取代的或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素、氰基、硝基、羟基、羧基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-NR a1’R b1’、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR a0’R b0’、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基和3至6元杂环烷基； The ring A' is a benzene ring or a 5- to 6-membered heteroaromatic ring; the ring A' is unsubstituted or substituted by 1, 2 or 3 substituents independently selected from the following group: cyano, nitro radical, hydroxyl, carboxyl, halogen (preferably fluorine or chlorine), C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 3-8 cycloalkyl ( preferably C 3-6 cycloalkyl), C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), -C(O)C 1-8 Alkyl (preferably -C (O) C 1-6 alkyl, more preferably -C (O) C 1-3 alkyl), -C (O) OC 1-8 alkyl (preferably -C ( O) OC 1-6 alkyl is more preferably -C (O) OC 1-3 alkyl), -OC (O) C 1-8 alkyl (preferably -OC (O) C 1-6 alkyl is more Preferably -OC(O)C 1-3 alkyl), -SO 2 C 1-8 alkyl (preferably -SO 2 C 1-6 alkyl, more preferably -SO 2 C 1-3 alkyl) And -C(O ) NR a0' R b0' ; wherein the C 1-8 alkyl, C 3-6 cycloalkyl, C 1-8 alkoxy are unsubstituted or replaced by 1, 2 or 3 Each substituent independently selected from the following group is substituted: deuterium, halogen, cyano, nitro, hydroxyl, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2 -4 alkynyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, -NR a1' R b1' , -SO 2 C 1-3 alkyl, -S(O)C 1- 3 Alkyl, -C(O)NR a0' R b0' , -C(O)OC 1-3 Alkyl, -OC(O)C 1-3 Alkyl, C 3-6 Cycloalkyl, C 3 -6 cycloalkyloxy and 3 to 6 membered heterocycloalkyl;
    R a0’、和R b0’各自独立地为氢、C 1-3烷基或乙酰基；或者R a0’、R b0’与相连的氮原子共同形成4至6元饱和单杂环；所述4至6元饱和单杂环为未取代的或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素、氰基、硝基、羟基、羧基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NH 2、-C(O)NH(C 1-3烷基)、-C(O)N(C 1-3烷基) 2、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基和3至6元杂环烷基；以及 R a0' and R b0' are each independently hydrogen, C 1-3 alkyl or acetyl; or R a0' and R b0' together with the connected nitrogen atom form a 4 to 6-membered saturated monoheterocyclic ring; said The 4 to 6 membered saturated monoheterocycle is unsubstituted or substituted by 1, 2 or 3 substituents each independently selected from the group consisting of deuterium, halogen, cyano, nitro, hydroxyl, carboxyl, C 1-3 Alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, -SO 2 C 1- 3 alkyl, -S(O)C 1-3 alkyl, -C(O)NH 2 , -C(O)NH(C 1-3 alkyl), -C(O)N(C 1-3 Alkyl) 2 , -C(O)OC 1-3 alkyl, -OC(O)C 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy and 3 to 6 membered heterocycloalkyl; and
    R a1’、和R b1’各自独立地为氢、C 1-3烷基、卤代C 1-3烷基或乙酰基；或者R a1’、R b1’与相连的氮原子共同形成4至6元饱和单杂环；所述4至6元饱和单杂环为未取代的或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素、氰基、硝基、羟基、羧基、C 1-3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NH 2、-C(O)NH(C 1-3烷基)、-C(O)N(C 1-3烷基) 2、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基和3至6元杂环烷基。 R a1' , and R b1' are each independently hydrogen, C 1-3 alkyl, halogenated C 1-3 alkyl or acetyl; or R a1' , R b1' and the connected nitrogen atom together form 4 to 6-membered saturated monoheterocycle; the 4-6 membered saturated monoheterocycle is unsubstituted or substituted by 1, 2 or 3 substituents independently selected from the group consisting of deuterium, halogen, cyano, nitro , hydroxyl, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkane Oxygen, -SO 2 C 1-3 alkyl, -S(O)C 1-3 alkyl, -C(O)NH 2 , -C(O)NH(C 1-3 alkyl), -C (O)N(C 1-3 alkyl) 2 , -C(O)OC 1-3 alkyl, -OC(O)C 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 Cycloalkyloxy and 3 to 6 membered heterocycloalkyl.
  27. 如权利要求26所述的化合物、其药学上可接受的盐或其立体异构体，其中，Z 1’为N或CR Z1’；Z 2’为CR Z2’；Z 3’为N或CR Z3’；以及Z 4’为CR Z4’。 The compound as claimed in claim 26, its pharmaceutically acceptable salt or its stereoisomer, wherein, Z 1' is N or CR Z1' ; Z 2' is CR Z2' ; Z 3' is N or CR Z3' ; and Z4' is CR Z4' .
  28. 如权利要求26所述的化合物、其药学上可接受的盐或其立体异构体，其中，Z 1’为CR Z1’；Z 2’为CR Z2’；Z 3’为CR Z3’；以及Z 4’为CR Z4’。 The compound as claimed in claim 26, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein Z 1' is CR Z1' ; Z 2' is CR Z2' ; Z 3' is CR Z3' ; and Z 4' is CR Z4' .
  29. 如权利要求26所述的化合物、其药学上可接受的盐或其立体异构体，其中，R Z1’、R Z2’、R Z3’、和R Z4’各自独立地为氢、氰基、卤素(优选为氟或氯)、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、C 3-8环烷基(优选为C 3-6环烷基)、卤代C 1-8烷基(优选为卤代C 1-6烷基，更优选为卤代C 1-3烷基)、C 1-8烷氧基(优选为C 1-6烷氧基，更优选为C 1-3烷氧基)、卤代C 1-8烷氧基(优选为卤代C 1-6烷氧基，更优选为卤代C 1-3烷氧基)或-NR a1’R b1’；其中所述C 1-8烷基、C 3-8环烷基各自独立地为未取代的或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素、氰基、硝基、羟基、羧基、C 1-3烷基、C 1-3烷氧基、C 2- 4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-NR a1’R b1’、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR a0’R b0’、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基和3至6元杂环烷基。 The compound as claimed in claim 26, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein R Z1' , R Z2' , R Z3' , and R Z4' are each independently hydrogen, cyano, Halogen (preferably fluorine or chlorine), C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), halogenated C 1-8 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), C 1-8 alkoxy (preferably C 1 -6 alkoxy, more preferably C 1-3 alkoxy), halogenated C 1-8 alkoxy (preferably halogenated C 1-6 alkoxy, more preferably halogenated C 1-3 alkoxy Oxygen) or -NR a1' R b1' ; wherein said C 1-8 alkyl, C 3-8 cycloalkyl are each independently unsubstituted or are independently selected from the following by 1, 2 or 3 Group substituent substitution: deuterium, halogen, cyano , nitro, hydroxyl, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halogen Substituted C 1-3 alkyl, halogenated C 1-3 alkoxy, -NR a1' R b1' , -SO 2 C 1-3 alkyl, -S(O)C 1-3 alkyl, -C (O)NR a0' R b0' , -C(O)OC 1-3 alkyl, -OC(O)C 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy and 3 to 6 membered heterocycloalkyl groups.
  30. 如权利要求26所述的化合物、其药学上可接受的盐或其立体异构体，其中，R Z1’为氢。 The compound according to claim 26, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein R Z1' is hydrogen.
  31. 如权利要求26所述的化合物、其药学上可接受的盐或其立体异构体，其中，R Z2’为氰基、卤 素(优选为氟或氯)、C 1-3烷基(优选为甲基)、C 3-6环烷基(优选为环丙基)、卤代C 1-3烷基(优选为氟代C 1-3烷基，更优选为一氟甲基、一氟乙基、二氟甲基、二氟乙基、三氟甲基、三氟乙基、五氟乙基)、C 1- 3烷氧基(优选为甲氧基或乙氧基)、卤代C 1-3烷氧基(优选为二氟甲氧基、三氟甲氧基)、卤素取代的C 3- 6环烷基或-NR a1’R b1’；并且R a1’、R b1’各自独立地为氢、C 1-3烷基、卤代C 1-3烷基或乙酰基。 The compound as claimed in claim 26, its pharmaceutically acceptable salt or its stereoisomer, wherein, R Z2' is cyano, halogen (preferably fluorine or chlorine), C 1-3 alkyl (preferably methyl), C 3-6 cycloalkyl (preferably cyclopropyl), halogenated C 1-3 alkyl (preferably fluoro C 1-3 alkyl, more preferably monofluoromethyl, monofluoroethyl radical, difluoromethyl, difluoroethyl, trifluoromethyl , trifluoroethyl, pentafluoroethyl), C 1-3 alkoxy (preferably methoxy or ethoxy), halogenated C 1-3 alkoxy (preferably difluoromethoxy, trifluoromethoxy), halogen-substituted C 3- 6 cycloalkyl or -NR a1' R b1' ; and R a1' , R b1' each independently hydrogen, C 1-3 alkyl, halogenated C 1-3 alkyl or acetyl.
  32. 如权利要求26所述的化合物、其药学上可接受的盐或其立体异构体，其中，R Z3’为氢、氰基或卤素(优选为氟或氯)。 The compound as claimed in claim 26, its pharmaceutically acceptable salt or its stereoisomer, wherein, R Z3' is hydrogen, cyano or halogen (preferably fluorine or chlorine).
  33. 如权利要求26所述的化合物、其药学上可接受的盐或其立体异构体，其中，R Z4’为氢或卤素(优选为氟或氯)。 The compound as claimed in claim 26, its pharmaceutically acceptable salt or its stereoisomer, wherein, R Z4' is hydrogen or halogen (preferably fluorine or chlorine).
  34. 如权利要求26所述的化合物、其药学上可接受的盐或其立体异构体，其中，所述环A’是苯环或5至6元杂芳基环，且所述5至6元杂芳基环选自由以下组成的组：噻吩环、呋喃环、噻唑环、异噻唑环、咪唑环、噁唑环、吡咯环、吡唑环、三唑环、1，2，3-三唑环、1，2，4-三唑环、1，2，5-三唑环、1，3，4-三唑环、四唑环、异噁唑环、噁二唑环、1，2，3-噁二唑环、1，2，4-噁二唑环、1，2，5-噁二唑环、1，3，4-噁二唑环、噻二唑环、吡啶环、哒嗪环、嘧啶环、吡嗪环、三嗪环和四嗪环。The compound as claimed in claim 26, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein the ring A' is a benzene ring or a 5-6 membered heteroaryl ring, and the 5-6 membered The heteroaryl ring is selected from the group consisting of thiophene ring, furan ring, thiazole ring, isothiazole ring, imidazole ring, oxazole ring, pyrrole ring, pyrazole ring, triazole ring, 1,2,3-triazole ring Ring, 1,2,4-triazole ring, 1,2,5-triazole ring, 1,3,4-triazole ring, tetrazole ring, isoxazole ring, oxadiazole ring, 1,2, 3-oxadiazole ring, 1,2,4-oxadiazole ring, 1,2,5-oxadiazole ring, 1,3,4-oxadiazole ring, thiadiazole ring, pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring, triazine ring and tetrazine ring.
  35. 如权利要求26所述的化合物、其药学上可接受的盐或其立体异构体，其中，所述环A’为未取代的。The compound according to claim 26, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein the ring A' is unsubstituted.
  36. 如权利要求26所述的化合物、其药学上可接受的盐或其立体异构体，其中，所述化合物结构如式(II-1)所示：The compound according to claim 26, its pharmaceutically acceptable salt or its stereoisomer, wherein, the structure of the compound is shown in formula (II-1):
    Figure PCTCN2022130850-appb-100025
    Figure PCTCN2022130850-appb-100025
    其中，Z 5’为N或CR Z5’；Z 6’为N或CR Z6’；Z 7’为N或CR Z7’；以及Z 8’为N或CR Z8’； Wherein, Z 5' is N or CR Z5' ; Z 6' is N or CR Z6' ; Z 7' is N or CR Z7' ; and Z 8' is N or CR Z8' ;
    R Z5’、R Z6’、R Z7’、和R Z8’各自独立地为氢、氰基、硝基、羟基、羧基、卤素(优选为氟或氯)、C 1-8烷基(优选为C 1-6烷基，更优选为C 1-3烷基)、C 3-8环烷基(优选为C 3-6环烷基)、卤代C 1-8烷基(优选为卤代C 1-6烷基，更优选为卤代C 1-3烷基)、C 1-8烷氧基(优选为C 1-6烷氧基，更优选为C 1-3烷氧基)、卤代C 1-8烷氧基(优选为卤代C 1-6烷氧基，更优选为卤代C 1-3烷氧基)、-C(O)C 1-8烷基(优选为-C(O)C 1-6烷基，更优选为-C(O)C 1-3烷基)、-C(O)OC 1-8烷基(优选为-C(O)OC 1-6烷基，更优选为-C(O)OC 1-3烷基)、-SO 2C 1- 8烷基(优选为-SO 2C 1-6烷基，更优选为-SO 2C 1-3烷基)、-C(O)NR a0’R b0’、-NR a1’R b1’、5至6元杂芳基或8至10元杂芳基；其中所述C 1-8烷基、C 3-8环烷基、卤代C 1-8烷基、C 1-8烷氧基、卤代C 1-8烷氧基为未取代的或被1、2或3个各自独立地选自下组的取代基取代：氘、卤素、氰基、硝基、羟基、羧基、C 1- 3烷基、C 1-3烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-3烷基、卤代C 1-3烷氧基、-NR a1’R b1’、-SO 2C 1-3烷基、-S(O)C 1-3烷基、-C(O)NR a0’R b0’、-C(O)OC 1-3烷基、-OC(O)C 1-3烷基、C 3-6环烷基、C 3-6环烷基氧基、3至6元杂环烷基、苯基和5至6元杂芳基。 R Z5' , R Z6' , R Z7' , and R Z8' are each independently hydrogen, cyano, nitro, hydroxyl, carboxyl, halogen (preferably fluorine or chlorine), C 1-8 alkyl (preferably C 1-6 alkyl, more preferably C 1-3 alkyl), C 3-8 cycloalkyl (preferably C 3-6 cycloalkyl), halogenated C 1-8 alkyl (preferably halogenated C 1-6 alkyl, more preferably halogenated C 1-3 alkyl), C 1-8 alkoxy (preferably C 1-6 alkoxy, more preferably C 1-3 alkoxy), Halogenated C 1-8 alkoxy (preferably halogenated C 1-6 alkoxy, more preferably halogenated C 1-3 alkoxy), -C (O) C 1-8 alkyl (preferably -C(O)C 1-6 alkyl, more preferably -C(O)C 1-3 alkyl), -C(O)OC 1-8 alkyl (preferably -C(O)OC 1- 6 alkyl, more preferably -C(O)OC 1-3 alkyl), -SO 2 C 1-8 alkyl (preferably -SO 2 C 1-6 alkyl, more preferably -SO 2 C 1 -3 alkyl), -C(O)NR a0' R b0' , -NR a1' R b1' , 5 to 6 membered heteroaryl or 8 to 10 membered heteroaryl; wherein the C 1-8 alkane Base, C 3-8 cycloalkyl, halogenated C 1-8 alkyl, C 1-8 alkoxy, halogenated C 1-8 alkoxy are unsubstituted or are independently replaced by 1, 2 or 3 Substituents selected from the group consisting of deuterium, halogen, cyano, nitro, hydroxyl, carboxyl, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkenyl, C 2-4 Alkynyl, halogenated C 1-3 alkyl, halogenated C 1-3 alkoxy, -NR a1' R b1' , -SO 2 C 1-3 alkyl, -S(O)C 1-3 alkane radical, -C(O)NR a0' R b0' , -C(O)OC 1-3 alkyl, -OC(O)C 1-3 alkyl, C 3-6 cycloalkyl, C 3-6 Cycloalkyloxy, 3- to 6-membered heterocycloalkyl, phenyl, and 5- to 6-membered heteroaryl.
  37. 如权利要求36所述的化合物、其药学上可接受的盐或其立体异构体，其中，Z 5’为N或CR Z5’；Z 6’为CR Z6’；Z 7’为CR Z7’；以及Z 8’为CR Z8’。 The compound as claimed in claim 36, its pharmaceutically acceptable salt or its stereoisomer, wherein, Z 5' is N or CR Z5' ; Z 6' is CR Z6' ; Z 7' is CR Z7' ; and Z 8' is CR Z8' .
  38. 如权利要求26所述的化合物、其药学上可接受的盐或其立体异构体，其中，所述化合物选自由以下组成的组：The compound according to claim 26, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein the compound is selected from the group consisting of:
    Figure PCTCN2022130850-appb-100026
    Figure PCTCN2022130850-appb-100026
    Figure PCTCN2022130850-appb-100027
    Figure PCTCN2022130850-appb-100027
    Figure PCTCN2022130850-appb-100028
    Figure PCTCN2022130850-appb-100028
  39. 一种药物组合物，包括：权利要求1-25中任一项所述的化合物、其药学上可接受的盐或其立体异构体；以及药学上可接受的载体。A pharmaceutical composition, comprising: the compound according to any one of claims 1-25, its pharmaceutically acceptable salt or its stereoisomer; and a pharmaceutically acceptable carrier.
  40. 用于治疗或预防与MAT2A活性相关的或由MAT2A活性介导的疾病的权利要求1-25中任一所述的化合物、其药学上可接受的盐或其立体异构体，或权利要求39所述的药物组合物。A compound according to any one of claims 1-25, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, or claim 39 for treating or preventing a disease associated with MAT2A activity or mediated by MAT2A activity The pharmaceutical composition.
  41. 根据权利要求40所述的权利要求1-25中任一所述的化合物、其药学上可接受的盐或其立体异构体，或权利要求39所述的药物组合物的用途，其中，与MAT2A活性相关的或由MAT2A活性介导的疾病为癌症。According to claim 40, the compound according to any one of claims 1-25, its pharmaceutically acceptable salt or its stereoisomer, or the purposes of the pharmaceutical composition described in claim 39, wherein, with A disease associated with or mediated by MAT2A activity is cancer.
  42. 用作药物的权利要求1-25任一所述的化合物、其药学上可接受的盐或其立体异构体，或权利要求39所述的药物组合物。A compound according to any one of claims 1-25, a pharmaceutically acceptable salt thereof or a stereoisomer thereof, or a pharmaceutical composition according to claim 39 for use as a medicament.
PCT/CN2022/130850 2021-11-09 2022-11-09 Substituted naphthyridinone derivative, and pharmaceutical composition thereof and use thereof WO2023083210A1 (en)

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