WO2023083210A1 - Dérivé de naphtyridinone substitué, composition pharmaceutique de celui-ci et utilisation de celui-ci - Google Patents

Dérivé de naphtyridinone substitué, composition pharmaceutique de celui-ci et utilisation de celui-ci 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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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/fr

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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.

Abstract

La divulgation concerne un dérivé de naphtyridinone substitué, qui a une structure telle que représentée dans la formule (I). La divulgation concerne en outre un sel pharmaceutiquement acceptable, un stéréoisomère et une composition pharmaceutique du dérivé et l'utilisation médicinale de celui-ci.
PCT/CN2022/130850 2021-11-09 2022-11-09 Dérivé de naphtyridinone substitué, composition pharmaceutique de celui-ci et utilisation de celui-ci WO2023083210A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018039972A1 (fr) * 2016-08-31 2018-03-08 Agios Pharmaceuticals, Inc. Inhibiteurs de processus métaboliques cellulaires
CN109890822A (zh) * 2016-08-31 2019-06-14 安吉奥斯医药品有限公司 细胞代谢过程的抑制剂
CN111936499A (zh) * 2018-03-30 2020-11-13 安吉奥斯医药品有限公司 Mat2a的杂二环抑制剂和用于治疗癌症的方法
WO2020243376A1 (fr) * 2019-05-31 2020-12-03 Agios Pharmaceuticals, Inc. Inhibiteurs hétérobicycliques de mat2a et procédés d'utilisation pour le traitement du cancer
CN113166078A (zh) * 2018-12-10 2021-07-23 伊迪亚生物科学有限公司 2-氧代喹唑啉衍生物作为甲硫氨酸腺苷转移酶2a抑制剂

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018039972A1 (fr) * 2016-08-31 2018-03-08 Agios Pharmaceuticals, Inc. Inhibiteurs de processus métaboliques cellulaires
CN109890822A (zh) * 2016-08-31 2019-06-14 安吉奥斯医药品有限公司 细胞代谢过程的抑制剂
CN111936499A (zh) * 2018-03-30 2020-11-13 安吉奥斯医药品有限公司 Mat2a的杂二环抑制剂和用于治疗癌症的方法
CN113166078A (zh) * 2018-12-10 2021-07-23 伊迪亚生物科学有限公司 2-氧代喹唑啉衍生物作为甲硫氨酸腺苷转移酶2a抑制剂
WO2020243376A1 (fr) * 2019-05-31 2020-12-03 Agios Pharmaceuticals, Inc. Inhibiteurs hétérobicycliques de mat2a et procédés d'utilisation pour le traitement du cancer

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