WO2022223022A1 - Dérivé hétérocyclique à cycles fusionnés et son application médicale - Google Patents

Dérivé hétérocyclique à cycles fusionnés et son application médicale Download PDF

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Publication number
WO2022223022A1
WO2022223022A1 PCT/CN2022/088446 CN2022088446W WO2022223022A1 WO 2022223022 A1 WO2022223022 A1 WO 2022223022A1 CN 2022088446 W CN2022088446 W CN 2022088446W WO 2022223022 A1 WO2022223022 A1 WO 2022223022A1
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Prior art keywords
alkyl
halogen
substituted
cyano
trifluoromethyl
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PCT/CN2022/088446
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English (en)
Chinese (zh)
Inventor
张晨
赵明亮
杨定菊
邓华
刘含波
余彦
叶飞
李瑶
倪佳
严庞科
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四川海思科制药有限公司
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Priority to CN202280013780.6A priority Critical patent/CN117083274A/zh
Publication of WO2022223022A1 publication Critical patent/WO2022223022A1/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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines 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
    • 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
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 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
    • C07D471/12—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 three hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings

Definitions

  • the present invention relates to a compound of general formula (I) or its stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, and intermediate and preparation method thereof , and the application in the preparation of medicines for treating diseases related to the activity or expression of PARP7.
  • the full name of PARP is poly-ADP-ribose polymerase, that is, poly-ADP-ribose polymerase, which is involved in a series of cellular processes including DNA repair and genome stability.
  • the protein family consists of 17 members, divided into polyPARPs and monoPARPs.
  • the MonoPARP protein family plays a role in a variety of stress responses associated with the development of cancer, inflammatory and neurodegenerative diseases, and its member PARP7 has been shown to be overactive in tumors and plays a key role in cancer cell survival.
  • PARP7 for intrinsic cell survival, and PARP7 enables cancer cells to "hide” from the immune system. Inhibition of PARP7 effectively inhibits the growth of cancer cells and restores interferon signaling, effectively releasing the "brakes” that cancer uses to evade the immune system and suppress innate and adaptive immune mechanisms.
  • PARP7 inhibitors exhibit durable tumor growth inhibition, potent antiproliferative activity, and restoration of interferon signaling in several cancer models, making PARP7 inhibitors promising targets for the development of novel anticancer drugs.
  • the object of the present invention is to provide a class of heterocyclic compounds or pharmaceutically acceptable salts thereof, which can be applied to PARP7 inhibitors.
  • the compounds in the present invention can effectively inhibit PARP7 and can be used to treat tumors and other diseases.
  • the present invention provides a compound of general formula (I) or a stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein
  • R y are each independently selected from H, C 1-6 alkyl or C 3-6 cycloalkyl, optionally further 0 to 4 (eg 0 , 1, 2, 3 or 4) is selected from H, deuterium, halogen, CF 3 , OH, cyano, NH 2 , C 1-6 alkyl, C 1-6 alkoxy, 3- to 8-membered heterocyclyl or C 3-6 cycloalkyl substituent, the heterocyclic group contains 1 to 3 heteroatoms selected from O, S, N;
  • R y are each independently selected from H, C 1-4 alkyl or C 3-6 cycloalkyl, optionally further substituted by 0 to 4 (eg 0 , 1, 2, 3 or 4) is selected from H, deuterium, halogen, CF 3 , OH, cyano, NH 2 , C 1-4 alkyl, C 1-4 alkoxy, 3- to 8-membered heterocyclyl or C 3-6 cycloalkyl substituent, the heterocyclic group contains 1 to 3 heteroatoms selected from O, S, N;
  • R y are each independently selected from H, C 1-4 alkyl, optionally further 0 to 4 (eg 0, 1, 2, 3, or 4 alkyl or cycloalkyl) ) is selected from H, deuterium, halogen, CF 3 , OH, cyano, NH 2 , C 1-4 alkyl, C 1-4 alkoxy, 3- to 8-membered heterocyclyl or C 3-6 cycloalkyl substituted by the substituent, the heterocyclic group contains 1 to 3 heteroatoms selected from O, S, N;
  • each R y is independently selected from H, C 1-4 alkyl
  • each R y is independently selected from deuterated C 1-4 alkyl
  • each Ry is independently selected from CD3 ;
  • each R is independently selected from H, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl, isobutyl, cyclopropyl, cyclobutyl , cyclopentyl, cyclohexyl, the methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl , cyclohexyl is optionally further selected from H, deuterium, halogen, CF3 , OH, cyano, NH2 , C1-4 alkyl, C 1-4 alkoxy, 3- to 8-membered heterocyclic group or C 3-6 cycloalkyl substituent, the heterocyclic group contains 1 to 3 heteroatoms selected from O, S, N;
  • each R is independently selected from H, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl, isobutyl, cyclopropyl, cyclobutyl , cyclopentyl, cyclohexyl, the methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl , cyclohexyl is optionally further selected by 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, deuterium, F, Cl, Br, CF3 , OH, cyano, NH2 , methyl, ethyl radical, propyl, butyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopent
  • each Ry is independently selected from H, methyl, ethyl
  • Ring A is selected from C 6-10 aryl, 5-10 membered heteroaryl, or 5-10 membered heterocyclyl containing 1 to 5 (eg 1, 2, 3, 4 or 5) heteroatoms selected from O, S, N;
  • Ring A is selected from 3(2H)-pyridazinone or 2(1H)-pyridinone;
  • X 1 , X 2 , X 3 , X 4 are each independently selected from N, CR x , X 1 , X 2 , X 3 , X 4 contain up to 2 N;
  • X 1 is selected from N
  • X 2 is selected from CH
  • X 3 is selected from CH, CF, CCl, CCN or CCF 3
  • X 4 is selected from CH or N;
  • Ring X is selected from C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 carbocycle or 5-10 membered heterocyclyl, said heteroaryl or heterocyclyl contains 1 to 5 (eg 1, 2, 3, 4 or 5) heteroatoms selected from O, S, N;
  • Ring X is selected from phenyl, 5-6 membered heteroaryl, or 5-6 membered heterocyclyl containing 1 to 5 (eg 1, 2, 3, 4 or 5) heteroatoms selected from O, S, N;
  • Ring X is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, thiazolyl, furyl, oxazolyl, pyrrolyl, pyrazolyl, or imidazolyl;
  • Wi is selected from N or C(R a4 );
  • W is selected from N or CH;
  • Wi is selected from N;
  • R a1 , R a2 , R a4 are each independently selected from R a ;
  • R a3 is selected from H, C 1-6 alkyl, -(CH 2 ) q -C 3-10 carbocycle or -(CH 2 ) q -3 to 12 membered heterocycle, said -CH2- , alkyl, carbocyclic or heterocycle optionally further selected from 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, C1-6 alkyl , halogen-substituted C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl or substituents of 3- to 10-membered heterocyclic rings containing 1 to 3 ( For example 1, 2 or 3) heteroatoms selected from O, S, N;
  • R a3 is selected from H, C 1-4 alkyl optionally further selected from 0 to 4 (eg, 0, 1, 2, 3 or 4) from H, halogen, OH, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl substituent;
  • R a3 is selected from H, methyl, ethyl, propyl, isopropyl, optionally further 0 to 4 (eg, 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 substituted by the substituents of cycloalkyl;
  • R a2 is selected from the group consisting of H, F, Cl, Br, I, cyano, CF3 , CHF2 , CH2F , methyl, methoxy, cyclopropyl;
  • R a3 is selected from H or methyl
  • each Rx is independently selected from H, F, Cl, Br, I, cyano, OH, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, ethynyl , methoxy, ethoxy, -SCH 3 , -SCH 2 CH 3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, the methyl, ethyl, propyl, isopropyl, Ethynyl, methoxy, ethoxy, -SCH 3 , -SCH 2 CH 3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl are optionally further substituted by 0 to 4 (eg 0, 1, 2 , 3 or 4) is substituted with a substituent selected from H, F, OH, cyano, methyl, ethyl, methoxy
  • R a1 is selected from H, F, Cl, Br, I, cyano, CF3 , CHF2 , CH2F , methyl, ethyl, propyl, isopropyl, ethynyl, methyl oxy, ethoxy, -SCH 3 , -SCH 2 CH 3 , cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;
  • R a1 is selected from H, F, Cl, Br, I, cyano, CF3 , methyl;
  • R a2 is selected from H
  • Ring B is selected from 4 to 11 membered nitrogen-containing heterocycles, C4-10 carbocycles;
  • Ring B is selected from the group consisting of a 4- to 7-membered monocyclic nitrogen-containing heterocycle, a 5-11 membered spirocyclic nitrogen-containing heterocycle, a 5-11 membered cyclic nitrogen-containing heterocycle, a 5-11 membered bridged ring containing nitrogen heterocycle or C 4-7 monocyclic carbocycle;
  • Ring B is selected from cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl,
  • selected from The left side is connected with L;
  • W is selected from a bond, a C1-3 alkylene group, or Q2, and said alkylene group is optionally further selected from 0 to 4 (eg, 0, 1, 2, 3, or 4) from H, Substituted by substituents of halogen, CF 3 , OH, cyano, NH 2 , C 1-6 alkyl or C 1-6 alkoxy;
  • W is selected from a bond
  • L is selected from L1, L2 or L3;
  • L1 is selected from -Q1-Ak1-Q2-Ak2-Q3-, and the right side is attached to ring B;
  • L1 is selected from The right side is connected with ring B;
  • L1 is selected from The right side is connected with ring B;
  • L2 is selected from The right side is connected with ring B;
  • L2 is selected from The right side is connected with ring B;
  • L2 is selected from The right side is connected with ring B;
  • L3 is selected from The right side is connected with ring B;
  • L3 is selected from The right side is connected with ring B;
  • L4 is selected from -Ak3-Q4-Ak4-K1-Q5-K2-Ak5-Q6- or -Ak3-Q4-Ak4-K1-Q5-, and the right side is attached to loop B;
  • Ak1, Ak2 are each independently selected from C 1-4 alkylene, C 2-4 alkenylene, C 2-4 alkynylene, and Ak1 is optionally further selected from 0 to 4 ( For example, 0, 1, 2, 3 or 4) R k1 substitutions, the Ak2 is optionally further substituted with 0 to 4 (e.g. 0, 1, 2, 3 or 4) R k2 ;
  • Ak1, Ak2 are each independently selected from C 1-3 alkylene, C 2-3 alkenylene, C 2-3 alkynylene, and Ak1 is optionally further selected from 0 to 4 ( For example, 0, 1, 2, 3 or 4) R k1 substitutions, the Ak2 is optionally further substituted with 0 to 4 (e.g. 0, 1, 2, 3 or 4) R k2 ;
  • Ak1, Ak2 are each independently selected from methylene, ethylene, propylene, vinylene, propenylene, ethynylene, propynylene, and Ak1 is optionally further 0 to 4 (eg 0, 1, 2, 3 or 4) R k1 substitutions, the Ak2 is optionally further substituted with 0 to 4 (eg 0, 1, 2, 3 or 4) R k2 ;
  • Ak3, Ak4, Ak5 are each independently selected from bond, C 1-4 alkylene, C 2-4 alkenylene, C 2-4 alkynylene, and Ak3 is optionally further modified by O to 4 (eg 0, 1, 2, 3 or 4) R k3 substitutions, the Ak4 is optionally further substituted with 0 to 4 (eg 0, 1, 2, 3 or 4) R k4 , the Ak5 any Select is further substituted with 0 to 4 R k5 ;
  • Ak3, Ak4, Ak5 are each independently selected from a bond, a C1-3 alkylene group, a C2-3 alkenylene group, a C2-3 alkynylene group, and the Ak3 is optionally further modified by O to 4 (eg 0, 1, 2, 3 or 4) R k3 substitutions, the Ak4 is optionally further substituted with 0 to 4 (eg 0, 1, 2, 3 or 4) R k4 , the Ak5 any is further substituted with 0 to 4 R k5 (eg 0, 1, 2, 3 or 4);
  • Ak3, Ak4, Ak5 are each independently selected from bond, methylene group, ethylene group, propylene group, vinylidene group, propenylene group, ethynylene group, propynylene group, the Ak3 optionally further substituted with 0 to 4 (eg 0, 1, 2, 3 or 4) R k3 , said Ak4 optionally further substituted with 0 to 4 (eg 0, 1, 2, 3 or 4) R k4 , the Ak5 is optionally further substituted by 0 to 4 R k5 ;
  • K1 or K2 is selected from C 1-2 alkylene, C 3-10 carbocycle, or 3-12 membered heterocycle, and said alkylene is optionally further substituted by 0 to 4 (eg, 0 , 1, 2, 3 or 4) R k6 substituted, the carbocycle or heterocycle is optionally further 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano base, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen substituted C 1-6 alkyl, C 1-6 alkoxy, -C 1-6 alkane Substituents of base-OC 1-6 alkyl, -OC 1-6 alkyl-OC 1-6 alkyl, -OC 3-8 carbocycle, C 3-8 carbocycle, 4- to 10-membered heterocycle , the heterocycle contains 1 to 3 (eg 1, 2 or 3) heteroatoms selected from O, S, N;
  • K1 or K2 is selected from C 1-2 alkylene, C 3-6 carbocycle, or 3- to 7-membered heterocycle, and said alkylene is optionally further substituted by 0 to 4 (eg, 0 , 1, 2, 3 or 4) R k6 substituted, the carbocycle or heterocycle is optionally further 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano base, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen substituted C 1-4 alkyl, C 1-4 alkoxy, -C 1-4 alkane Substituents of base-OC 1-4 alkyl, -OC 1-4 alkyl-OC 1-4 alkyl, -OC 3-6 carbocycle, C 3-6 carbocycle, 4- to 7-membered heterocycle , the heterocycle contains 1 to 3 (eg 1, 2 or 3) heteroatoms selected from O, S,
  • K1 or K2 is selected from methylene, ethylene, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azacyclopentyl, azacyclohexyl , piperazine, morpholine, oxetanyl, oxacyclopentyl, oxetanyl, benzene ring, pyridine, pyrazine, pyrimidine, pyridazine, the methylene, ethylene optionally further Substituted by 0 to 4 (eg 0, 1, 2, 3 or 4) R k6 , said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azetidine , azacyclohexyl, piperazine, morpholine, oxetanyl, oxolane,
  • Q2, Q3, Q4, Q6 are each independently selected from a bond or Q1;
  • Ring E is selected from C 3-6 carbocycles or 4 to 7 membered heterocycles containing 1 to 3 (eg 1, 2 or 3) selected from O, S, N of heteroatoms;
  • Ring E is selected from C 3-6 carbocycles or 4 to 6 membered heterocycles containing 1 to 3 (eg 1, 2 or 3) selected from O, S, N of heteroatoms;
  • Ring E is selected from phenyl or 5-6 membered heteroaryl containing 1 to 3 (eg 1, 2 or 3) heteroaryls selected from O, S, N atom;
  • Ring E is selected from a benzene ring or a pyridine
  • R q is each independently selected from H, C 1-6 alkyl, or C 3-6 cycloalkyl, optionally further substituted by 0 to 4 (eg, 0 , 1, 2, 3 or 4) is substituted with a substituent selected from H, halogen, CF 3 , OH, cyano, NH 2 , C 1-6 alkyl or C 1-6 alkoxy;
  • each R q is independently selected from H, C 1-4 alkyl optionally further selected from 0 to 4 (eg, 0, 1, 2, 3, or 4) from H , halogen, CF 3 , OH, cyano, NH 2 , C 1-4 alkyl or C 1-4 alkoxy substituents;
  • each R q is independently selected from H, methyl, ethyl
  • the heterocycle contains 1 to 3 (eg 1, 2 or 3) heteroatoms selected from O, S, N;
  • L1 is selected from
  • the right side is connected with ring B;
  • L1 is selected from The right side is connected with ring B;
  • L1 is selected from or L1 is selected from The right side is connected with ring B;
  • L is selected from The right side is connected with ring B;
  • L is selected from The right side is connected with ring B;
  • L2 is selected from The right side is connected with ring B;
  • L3 is selected from The right side is connected with ring B;
  • each q is independently selected from 0, 1, 2, 3, or 4;
  • a is selected from 0, 1, 2, 3, or 4;
  • b is selected from 0, 1, 2, 3, or 4;
  • x is selected from 0, 1, 2, 3, or 4;
  • s1 is selected from 0, 1, 2, 3, or 4;
  • s2 is selected from 0, 1, 2, 3, or 4;
  • s3 is selected from 0, 1, 2, 3, or 4.
  • R y are each independently selected from H, C 1-6 alkyl or C 3-6 cycloalkyl, and said alkyl or cycloalkyl is optionally further substituted by 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, deuterium, halogen, CF 3 , OH, cyano, NH 2 , C 1-6 alkyl, C 1-6 alkoxy, 3- to 8-membered heterocyclyl or C 3-6 ring substituted by the substituent of the alkyl group, the heterocyclic group contains 1 to 3 heteroatoms selected from O, S, N;
  • Ring A is selected from C 6-10 aryl, 5-10-membered heteroaryl or 5-10-membered heterocyclic group, and the heteroaryl or heterocyclic group contains 1 to 5 selected from O, S, N heteroatom;
  • Ring X is selected from C 6-10 aryl, 5-10-membered heteroaryl, C 3-10 carbocyclic or 5-10-membered heterocyclic group, and the heteroaryl or heterocyclic group contains 1 to 5 heteroatoms from O, S, N;
  • Ring B is selected from 4- to 11-membered nitrogen-containing heterocycles, C 4-10 carbocycles;
  • W is selected from a bond, a C1-3 alkylene group or Q2, the alkylene group is optionally further selected from 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, halogen, CF3 , OH , cyano, NH 2 , C 1-6 alkyl or C 1-6 alkoxy substituent;
  • L is selected from L1, L2 or L3;
  • L1 is selected from -Q1-Ak1-Q2-Ak2-Q3-, and the right side is connected to ring B;
  • L2 is selected from The right side is connected with ring B;
  • L3 is selected from The right side is connected with ring B;
  • L4 is selected from -Ak3-Q4-Ak4-K1-Q5-K2-Ak5-Q6- or -Ak3-Q4-Ak4-K1-Q5-, and the right side is connected to ring B;
  • Ak1, Ak2 are each independently selected from C 1-4 alkylene, C 2-4 alkenylene, C 2-4 alkynylene, said Ak1 is optionally further substituted by 0 to 4 R k1 , said Ak2 optionally further substituted with 0 to 4 R k2 ;
  • Ak3, Ak4, Ak5 are each independently selected from bond, C 1-4 alkylene group, C 2-4 alkenylene group, C 2-4 alkynylene group, and said Ak3 is optionally further replaced by 0 to 4 (for example, 0 , 1, 2, 3 or 4) R k3 substituted, the Ak4 optionally further substituted with 0 to 4 (eg 0, 1, 2, 3 or 4) R k4 , the Ak5 optionally further 0 to 4 (e.g. 0, 1, 2, 3 or 4) R k5 substitutions;
  • K1 or K2 is selected from C 1-2 alkylene, C 3-10 carbocycle or 3- to 12-membered heterocycle, and the alkylene is optionally further substituted by 0 to 4 (eg 0, 1, 2, 3 or 4) R k6 substituted, the carbocycle or heterocycle is optionally further 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen substituted C 1-6 alkyl, C 1-6 alkoxy, -C 1-6 alkyl-OC 1-6 Alkyl, -OC 1-6 alkyl, -OC 1-6 alkyl, -OC 3-8 carbocycle, C 3-8 carbocycle, 4- to 10-membered heterocycle substituents, the heterocycle contains 1 to 3 (eg 1, 2 or 3) heteroatoms selected from O, S, N;
  • Q2, Q3, Q4, Q6 are each independently selected from the key or Q1;
  • Ring E is selected from C 3-6 carbocycles or 4- to 7-membered heterocycles containing 1 to 3 (eg 1, 2 or 3) heteroatoms selected from O, S, N;
  • R q are each independently selected from H, C 1-6 alkyl or C 3-6 cycloalkyl, and said alkyl or cycloalkyl is optionally further substituted by 0 to 4 (eg 0, 1, 2, 3 or 4) substituted with a substituent selected from H, halogen, CF 3 , OH, cyano, NH 2 , C 1-6 alkyl or C 1-6 alkoxy ;
  • the heterocycle contains 1 to 3 (eg 1, 2 or 3) heteroatoms selected from O, S, N;
  • q is independently selected from 0, 1, 2, 3 or 4;
  • a is selected from 0, 1, 2, 3 or 4;
  • b is selected from 0, 1, 2, 3 or 4;
  • x is selected from 0, 1, 2, 3 or 4;
  • s1 is selected from 0, 1, 2, 3 or 4;
  • s2 is selected from 0, 1, 2, 3 or 4;
  • s3 is selected from 0, 1, 2, 3 or 4.
  • W 1 is selected from N or C(R a4 );
  • Ring X is selected from phenyl, 5-6 membered heteroaryl or 5-6 membered heterocyclyl, and said heteroaryl or heterocyclyl contains 1 to 5 heteroatoms selected from O, S, N;
  • R a3 is selected from H, C 1-6 alkyl, -(CH 2 ) q -C 3-10 carbocycle or -(CH 2 ) q -3- to 12-membered heterocycle, said -CH 2 -, alkane radical, carbocycle or heterocycle optionally further substituted by 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, C1-6 alkyl, halogen substituted C1 -6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl or substituents of 3- to 10-membered heterocycles containing 1 to 3 (eg 1, 2 or 3 heterocycles) a) heteroatoms selected from O, S, N;
  • R y are each independently selected from H, C 1-4 alkyl or C 3-6 cycloalkyl, and said alkyl or cycloalkyl is optionally further substituted by 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, deuterium, halogen, CF 3 , OH, cyano, NH 2 , C 1-4 alkyl, C 1-4 alkoxy, 3- to 8-membered heterocyclyl or C 3-6 ring substituted by the substituent of the alkyl group, the heterocyclic group contains 1 to 3 heteroatoms selected from O, S, N;
  • R a3 is selected from H, C 1-4 alkyl, said alkyl is optionally further selected from 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl substituent;
  • Ring B is selected from 4- to 7-membered monocyclic nitrogen-containing heterocycles, 5-11-membered spirocyclic nitrogen-containing heterocycles, 5-11-membered parallel nitrogen-containing heterocycles, 5-11-membered bridged nitrogen-containing heterocycles or C 4 -7 monocyclic carbocycle;
  • Ak1, Ak2 are each independently selected from C 1-3 alkylene group, C 2-3 alkenylene group, C 2-3 alkynylene group, and said Ak1 is optionally further replaced by 0 to 4 (eg 0, 1, 2 , 3 or 4) Rk1 substitution, the Ak2 is optionally further substituted with 0 to 4 (eg 0, 1, 2, 3 or 4) Rk2 ;
  • Ak3, Ak4, Ak5 are each independently selected from bond, C 1-3 alkylene group, C 2-3 alkenylene group, C 2-3 alkynylene group, and said Ak3 is optionally further replaced by 0 to 4 (eg, 0 , 1, 2, 3 or 4) R k3 substituted, the Ak4 optionally further substituted with 0 to 4 (eg 0, 1, 2, 3 or 4) R k4 , the Ak5 optionally further 0 to 4 (e.g. 0, 1, 2, 3 or 4) R k5 substitutions;
  • K1 or K2 is selected from C 1-2 alkylene, C 3-6 carbocycle or 3 to 7 membered heterocycle, and said alkylene is optionally further substituted by 0 to 4 (eg 0, 1, 2, 3 or 4) R k6 substituted, the carbocycle or heterocycle is optionally further 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen substituted C 1-4 alkyl, C 1-4 alkoxy, -C 1-4 alkyl-OC 1-4 Substituents of alkyl, -OC 1-4 alkyl, -OC 1-4 alkyl, -OC 3-6 carbocycle, C 3-6 carbocycle, 4 to 7-membered heterocycle, the heterocycle contains 1 to 3 (eg 1, 2 or 3) heteroatoms selected from O, S, N;
  • Q2, Q3, Q4, Q6 are each independently selected from the key or Q1;
  • Ring E is selected from C 3-6 carbocycles or 4- to 6-membered heterocycles containing 1 to 3 (eg 1, 2 or 3) heteroatoms selected from O, S, N;
  • R q is each independently selected from H, C 1-4 alkyl, and said alkyl is optionally further selected from 0 to 4 (eg 0, 1, 2, 3 or 4) from H, halogen, CF 3 , substituted by substituents of OH, cyano, NH 2 , C 1-4 alkyl or C 1-4 alkoxy;
  • R q and R k1 , and R q and R k2 are directly linked to form a 4- to 7-membered heterocycle, optionally further 0 to 4 (eg, 0, 1, 2, 3, or 4)
  • Substituents selected from H, halogen, O, OH, cyano, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl
  • the heterocycle contains 1 to 3 (eg 1, 2 or 3) heteroatoms selected from O, S, N;
  • W 1 is selected from N or CH;
  • Ring X is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, thiazolyl, furyl, oxazolyl, pyrrolyl, pyrazolyl or imidazolyl;
  • R a3 is selected from H, methyl, ethyl, propyl, isopropyl, and said methyl, ethyl, propyl or isopropyl is optionally further substituted by 0 to 4 (eg 0, 1, 2, 3 or 4) a substituent selected from H, halogen, OH, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl replaced;
  • R y are each independently selected from H, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclobutyl Hexyl, the methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl are optionally further by 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, deuterium, halogen, CF3 , OH, cyano, NH2 , C1-4alkyl , C1-4alkoxy , 3- to 8-membered heterocyclic group or C 3-6 cycloalkyl substituent, the heterocyclic group contains 1 to 3 heteroatom
  • Ring B is selected from cyclobutyl, cyclopentyl, cyclohexyl, azetidine, pyrrolidinyl, piperidinyl, piperazinyl,
  • Ak1 and Ak2 are each independently selected from methylene, ethylene, propylene, vinylene, propenylene, ethynylene, and propynylene, and said Ak1 is optionally further substituted by 0 to 4 (for example, 0, 1, 2, 3 or 4) R k1 substitution, the Ak2 is optionally further substituted with 0 to 4 R k2 ;
  • Ak3, Ak4, Ak5 are each independently selected from bond, methylene group, ethylene group, propylene group, vinylidene group, propenylene group, ethynylene group, propynylene group, and said Ak3 is optionally further selected from 0 to 4 (eg 0, 1, 2, 3 or 4) R k3 substitutions, said Ak4 optionally further substituted with 0 to 4 (eg 0, 1, 2, 3 or 4) R k4 , said Ak5 optionally is further substituted with 0 to 4 (eg 0, 1, 2, 3 or 4) R k5 ;
  • K1 or K2 is selected from the group consisting of methylene, ethylene, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidine, azacyclopentyl, azacyclohexyl, piperazine, morpholine , oxetanyl, oxolane, oxanyl, benzene ring, pyridine, pyrazine, pyrimidine, pyridazine, the methylene group and ethylene group are optionally further replaced by 0 to 4 ( For example, 0, 1, 2, 3 or 4) R k6 is substituted, the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azacyclopentyl, azacyclohexyl, Piperazine, morpholine, oxetanyl, oxolane, oxet
  • Q2, Q3, Q4, Q6 are each independently selected from the key or Q1;
  • Ring E is selected from phenyl or 5-6 membered heteroaryl, and the heteroaryl contains 1 to 3 (eg 1, 2 or 3) heteroatoms selected from O, S, N;
  • R q are each independently selected from H, methyl, ethyl
  • R q and R k1 , and R q and R k2 are directly linked to form a 4- to 7-membered heterocycle, optionally further 0 to 4 (eg, 0, 1, 2, 3, or 4)
  • Substituents selected from H, halogen, O, OH, cyano, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl
  • the heterocycle contains 1 to 3 (eg 1, 2 or 3) heteroatoms selected from O, S, N;
  • Ring E is selected from benzene ring or pyridine
  • R a2 is selected from H
  • W 1 is selected from N;
  • L1 is selected from
  • the right side is connected with ring B;
  • L2 is selected from The right side is connected with ring B;
  • L3 is selected from The right side is connected with ring B;
  • R x is each independently selected from H, F, Cl, Br, I, cyano, OH, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, ethynyl, methoxy, ethynyl Oxygen, -SCH 3 , -SCH 2 CH 3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, the methyl, ethyl, propyl, isopropyl, ethynyl, methoxy , ethoxy, -SCH 3 , -SCH 2 CH 3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl are optionally further selected from 0 to 4 (eg 0, 1, 2, 3 or 4) Substituted from H, F, OH, cyano, methyl, ethyl, methoxy or e
  • R a1 is selected from H, F, Cl, Br, I, cyano, CF3 , CHF2 , CH2F , methyl, ethyl, propyl, isopropyl, ethynyl, methoxy, ethoxy , -SCH 3 , -SCH 2 CH 3 , cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;
  • R a3 is selected from H or methyl
  • X 1 , X 2 , X 3 , and X 4 are each independently selected from N, CR x , and X 1 , X 2 , X 3 , and X 4 contain at most 2 N;
  • L is selected from or The right side is connected with ring B;
  • L is selected from The right side is connected with ring B;
  • X 1 is selected from N
  • X 2 is selected from CH
  • X 3 is selected from CH, CF, CCl, CCN or CCF 3
  • X 4 is selected from CH or N;
  • the present invention relates to a compound shown below or a stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein the compound is selected from one of the following structures:
  • R y are each independently selected from H, C 1-6 alkanes or C 3-6 cycloalkyl, said alkyl or cycloalkyl is optionally further selected from 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, deuterium, halogen, CF 3 , OH, cyano, NH 2 , C 1-6 alkyl, C 1-6 alkoxy, 3- to 8-membered heterocyclyl or C 3-6 cycloalkyl substituents, the heterocyclyl Contains 1 to 3 heteroatoms selected from O, S, N.
  • R y is each independently selected from H, C 1-4 alkanes or C 3-6 cycloalkyl, said alkyl or cycloalkyl is optionally further selected from 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, deuterium, halogen, CF 3 , OH, cyano, NH 2 , C 1-4 alkyl, C 1-4 alkoxy, 3- to 8-membered heterocyclyl or C 3-6 cycloalkyl substituents, the heterocyclyl Contains 1 to 3 heteroatoms selected from O, S, N.
  • R y are each independently selected from H, methyl, ethyl , propyl, isopropyl, butyl, tert-butyl, sec-butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, the methyl, ethyl, propyl, Isopropyl, butyl, tert-butyl, sec-butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl are optionally further 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, deuterium, halogen, CF 3 , OH, cyano, NH 2 , C 1-4 alkyl, C 1-4 alkoxy
  • R y are each independently selected from H, methyl, ethyl , propyl, isopropyl, butyl, tert-butyl, sec-butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, the methyl, ethyl, propyl, Isopropyl, butyl, tert-butyl, sec-butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl are optionally further 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, deuterium, F, Cl, Br, CF3 , OH, cyano, NH2 , methyl, ethyl, propy
  • R y is each independently selected from H, C 1-4 alkanes base.
  • R y are each independently selected from H, methyl, ethyl .
  • each Ry is independently selected from CD3 ;
  • ring A is selected from C 6-10 aryl, 5-10 membered heteroaryl or 5-10 membered heterocyclyl, said heteroaryl or heterocycle A radical contains 1 to 5 (eg 1, 2, 3, 4 or 5) heteroatoms selected from O, S, N.
  • Ring A is selected from 3(2H)-pyridazinone or 2(1H)-pyridinone.
  • the present invention relates to some embodiments of general formula (I), selected from
  • the present invention relates to some embodiments of general formula (I), selected from
  • the present invention relates to some embodiments of general formula (I), selected from
  • the present invention relates to some embodiments of general formula (I), selected from
  • the present invention relates to some embodiments of general formula (I), selected from
  • the present invention relates to some embodiments of general formula (II-a), (II-b) or (II-c), X 1 , X 2 , X 3 , X 4 are each independently selected from N, CR x , X 1 , X 2 , X 3 , and X 4 contain at most two Ns (at most two of X 1 , X 2 , X 3 , and X 4 are N).
  • ring X is selected from C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 carbocycle or 5-10 membered heterocycle
  • the heteroaryl or heterocyclic group contains 1 to 5 (eg 1, 2, 3, 4 or 5) heteroatoms selected from O, S, N.
  • the present invention relates to some embodiments of general formula (II-a), (II-b) or (II-c), X 1 is selected from N, X 2 is selected from CH, X 3 is selected from CH, CF, CCl, CCN or CCF 3 , X 4 is selected from CH or N.
  • ring X is selected from phenyl, 5-6 membered heteroaryl or 5-6 membered heterocyclyl, said heteroaryl or heterocycle A radical contains 1 to 5 (eg 1, 2, 3, 4 or 5) heteroatoms selected from O, S, N.
  • ring X is selected from the group consisting of phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, thiazolyl, furyl, oxazole group, pyrrolyl, pyrazolyl or imidazolyl.
  • W 1 is selected from N or C(R a4 ).
  • W 1 is selected from N or CH.
  • W 1 is selected from N.
  • R a1 , R a2 , R a4 are each independently selected from R a .
  • R a3 is selected from H, C 1-6 alkyl, -(CH 2 ) q -C 3-10 carbocyclic or -(CH 2 ) q -3 to 12-membered heterocycle
  • said -CH2- , alkyl, carbocycle or heterocycle is optionally further selected from H, halogen, OH, cyano by 0 to 4 (eg 0, 1, 2, 3 or 4) base, C 1-6 alkyl, halogen-substituted C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl or 3- to 10-membered heterocyclic substituents
  • the said Heterocycles contain 1 to 3 (eg 1, 2 or 3) heteroatoms selected from O, S, N.
  • R a3 is selected from H, C 1-4 alkyl, optionally further 0 to 4 (eg 0, 1, 2, 3 or 4) Replaced by a substituent selected from H, halogen, OH, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl .
  • R a3 is selected from H, methyl, ethyl, propyl, isopropyl, and said methyl, ethyl, propyl or isopropyl is optionally further 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, C1-4 alkyl, halogen substituted C1-4 alkyl, C1-4 Substituents of alkoxy and C 3-6 cycloalkyl.
  • R a2 is selected from the group consisting of H, F, Cl, Br, I, cyano, CF3 , CHF2 , CH2F , methyl, methoxy, Cyclopropyl.
  • R a3 is selected from H or methyl.
  • each R x is independently selected from H, F, Cl, Br , I, cyano, OH, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, ethynyl, methoxy, ethoxy, -SCH 3 , -SCH 2 CH 3 , ring Propyl, cyclobutyl, cyclopentyl, cyclohexyl, the methyl, ethyl, propyl, isopropyl, ethynyl, methoxy, ethoxy, -SCH 3 , -SCH 2 CH 3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl optionally further selected by 0 to 4 (eg 0, 1, 2, 3 or 4) selected from
  • R a1 is selected from H, F, Cl, Br, I, cyano, CF 3 , CHF 2 , CH 2 F, methyl, ethyl, propyl, isopropyl, ethynyl, methoxy, ethoxy, -SCH 3 , -SCH 2 CH 3 , cyclopropyl, cyclobutyl , cyclopentyl or cyclohexyl.
  • R a1 is selected from H, F, Cl, Br, I, cyano, CF 3. Methyl.
  • R a2 is selected from H.
  • Ring B is selected from the group consisting of 4 to 11 membered nitrogen-containing heterocycles, C 4-10 carbon rings.
  • Ring B is selected from 4 to 7 membered monocyclic nitrogen-containing heterocycles , 5-11-membered spirocyclic nitrogen-containing heterocycle, 5-11-membered parallel nitrogen-containing heterocycle, 5-11-membered bridged nitrogen-containing heterocycle or C 4-7 monocyclic carbocycle.
  • ring B is selected from the group consisting of cyclobutyl, cyclopentyl, cyclohexyl, azetidine, pyrrolidinyl, piperidinyl, piperazinyl ,
  • the present invention relates to some embodiments of general formula (I), (II), selected from The left side is connected to L.
  • W is selected from a bond, a C 1-3 alkylene group or Q2, and the indicated alkylene group is optionally further substituted by 0 to 4 (eg 0, 1, 2, 3 or 4) is substituted with a substituent selected from H, halogen, CF 3 , OH, cyano, NH 2 , C 1-6 alkyl or C 1-6 alkoxy.
  • W is selected from a bond.
  • the present invention relates to some embodiments of general formula (I), (II), (II-a), (II-b) or (II-c), L is selected from L1, L2 or L3.
  • L1 is selected from -Q1-Ak1-Q2-Ak2-Q3- , the right side is connected to ring B.
  • L1 is selected from The right side is connected to ring B.
  • L2 is selected from The right side is connected to ring B.
  • L2 is selected from The right side is connected to ring B.
  • L2 is selected from The right side is connected to ring B.
  • L3 is selected from The right side is connected to ring B.
  • L3 is selected from The right side is connected to ring B.
  • L4 is selected from -Ak3-Q4-Ak4-K1-Q5- K2-Ak5-Q6- or -Ak3-Q4-Ak4-K1-Q5-, connected to ring B on the right side.
  • the present invention relates to some embodiments of formula (I), (II), (II-a), (II-b) or (II-c), Ak1, Ak2 are each independently selected from C 1-4 alkylene group, C 2-4 alkenylene, C 2-4 alkynylene, the Ak1 is optionally further substituted with 0 to 4 (eg 0, 1, 2, 3 or 4) R k1 , the Ak2 is optionally is further substituted with 0 to 4 (eg 0, 1, 2, 3 or 4) R k2 .
  • the present invention relates to some embodiments of general formula (I), (II), (II-a), (II-b) or (II-c), Ak1, Ak2 are each independently selected from C 1-3 alkylene group, C 2-3 alkenylene, C 2-3 alkynylene, the Ak1 is optionally further substituted with 0 to 4 (eg 0, 1, 2, 3 or 4) R k1 , the Ak2 is optionally is further substituted with 0 to 4 (eg 0, 1, 2, 3 or 4) R k2 .
  • Ak1 and Ak2 are each independently selected from methylene, ethylene group, propylene, vinylene, propenylene, ethynylene, propynylene, said Ak1 is optionally further substituted with 0 to 4 (eg 0, 1, 2, 3 or 4) Rk1 , The Ak2 is optionally further substituted with 0 to 4 (eg 0, 1, 2, 3 or 4) R k2 .
  • the present invention relates to some embodiments of general formula (I), (II), (II-a), (II-b) or (II-c), Ak3, Ak4, Ak5 are each independently selected from the bond, C 1 -4 alkylene, C 2-4 alkenylene, C 2-4 alkynylene, the Ak3 is optionally further substituted by 0 to 4 (eg 0, 1, 2, 3 or 4) R k3 , the The Ak4 is optionally further substituted with 0 to 4 (eg 0, 1, 2, 3 or 4) R k4 , and the Ak5 is optionally further substituted with 0 to 4 (eg 0, 1, 2, 3 or 4) R Replaced by k5 .
  • the present invention relates to some embodiments of general formula (I), (II), (II-a), (II-b) or (II-c), Ak3, Ak4, Ak5 are each independently selected from the bond, C 1 -3 alkylene, C 2-3 alkenylene, C 2-3 alkynylene, the Ak3 is optionally further substituted by 0 to 4 (eg 0, 1, 2, 3 or 4) R k3 , the The Ak4 is optionally further substituted with 0 to 4 (eg 0, 1, 2, 3 or 4) R k4 , and the Ak5 is optionally further substituted with 0 to 4 (eg 0, 1, 2, 3 or 4) R Replaced by k5 .
  • the present invention relates to some embodiments of formula (I), (II), (II-a), (II-b) or (II-c), Ak3, Ak4, Ak5 are each independently selected from the group consisting of bond, methylene group, ethylene group, propylene group, vinylidene group, propenylene group, ethynylene group, propynylene group, said Ak3 is optionally further 0 to 4 (eg 0, 1, 2, 3 or 4) R k3 is substituted, the Ak4 is optionally further substituted with 0 to 4 (eg 0, 1, 2, 3 or 4) R k4 , the Ak5 is optionally further substituted with 0 to 4 (eg 0, 1, 2, 3 or 4) R k5 substitution.
  • K1 or K2 is selected from C 1-2 alkylene, C 3-10 carbocycle or 3 to 12 membered heterocycle, the alkylene is optionally further substituted by 0 to 4 (eg 0, 1, 2, 3 or 4) R k6 , the carbocycle or heterocycle
  • the ring is optionally further 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, NH2 , C1-6 alkyl, C2-6 alkenyl, C 2-6 alkynyl, halogen-substituted C 1-6 alkyl, C 1-6 alkoxy, -C 1-6 alkyl-OC 1-6 alkyl, -OC 1-6 alkyl-OC 1- 6 alkyl, -OC 3-8 carbocycle, C 3-8 carbocycle, 4- to 10-membered heterocycle substituents,
  • K1 or K2 is selected from C 1-2 alkylene, C 3-6 carbon ring or 3 to 7 membered heterocycle, said alkylene is optionally further substituted by 0 to 4 (eg 0, 1, 2, 3 or 4) R k6 , said carbocycle or heterocycle
  • the ring is optionally further 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, NH2 , C1-4alkyl , C2-4alkenyl , C 2-4 alkynyl, halogen-substituted C 1-4 alkyl, C 1-4 alkoxy, -C 1-4 alkyl-OC 1-4 alkyl, -OC 1-4 alkyl-OC 1- 4 alkyl, -OC 3-6 carbocycle, C 3-6 carbocycle, 4- to 7-membered heterocycle substituent
  • K1 or K2 is selected from methylene, ethylene, cyclic Propyl, Cyclobutyl, Cyclopentyl, Cyclohexyl, Azacyclobutyl, Azacyclopentyl, Azacyclohexyl, Piperazine, Morpholine, Oxetanyl, Oxacyclopentyl, Oxygen Heterocyclohexyl, benzene ring, pyridine, pyrazine, pyrimidine, pyridazine, said methylene, ethylene are optionally further substituted by 0 to 4 (eg 0, 1, 2, 3 or 4) R k6 , the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidine, azetidine, azetidine, piperaz
  • the present invention relates to some embodiments of general formula (I), (II), (II-a), (II-b) or (II-c), Q2, Q3, Q4, Q6 are each independently selected from the bond or Q1.
  • Ring E is selected from C 3-6 carbocycles or 4 to 7 A membered heterocycle containing 1 to 3 (eg 1, 2 or 3) heteroatoms selected from O, S, N.
  • Ring E is selected from C 3-6 carbocycles or 4 to 6 A membered heterocycle containing 1 to 3 (eg 1, 2 or 3) heteroatoms selected from O, S, N.
  • Ring E is selected from phenyl or 5-6 membered heteroaryl , the heteroaryl group contains 1 to 3 (eg 1, 2 or 3) heteroatoms selected from O, S, N.
  • Ring E is selected from a benzene ring or a pyridine.
  • R q is each independently selected from H, C 1-6 alkanes or C 3-6 cycloalkyl, said alkyl or cycloalkyl is optionally further selected from 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, halogen, CF 3 , OH, Substituents of cyano, NH 2 , C 1-6 alkyl or C 1-6 alkoxy.
  • R q are each independently selected from H, C 1-4 alkyl, and the alkyl is optionally further O up to 4 (eg 0, 1, 2, 3 or 4) substituents selected from H, halogen, CF3 , OH, cyano, NH2 , C1-4alkyl or C1-4alkoxy replace.
  • each Rq is independently selected from H, methyl, ethyl .
  • 0 to 4 eg 0, 1, 2, 3 or 4
  • the heterocycle contains 1 to 3 (for example, 1, 2 or 3 ) heteroatoms selected from O, S, N.
  • 0 to 4 eg 0, 1, 2, 3 or 4
  • the heterocycle contains 1 to 3 (for example, 1, 2 or 3) heteroatoms selected from O, S, N.
  • L1 is selected from
  • the right side is connected to ring B.
  • L1 is selected from The right side is connected to ring B.
  • L is selected from or The right side is connected to ring B.
  • L is selected from The right side is connected to ring B.
  • L is selected from The right side is connected to ring B.
  • L2 is selected from The right side is connected to ring B.
  • L3 is selected from The right side is connected to ring B.
  • each q is independently selected from 0, 1, 2, 3 or 4.
  • a is selected from 0, 1, 2, 3 or 4.
  • b is selected from 0, 1, 2, 3 or 4.
  • x is selected from 0, 1, 2, 3 or 4.
  • s1 is selected from 0, 1, 2, 3 or 4.
  • s2 is selected from 0, 1, 2, 3 or 4.
  • s3 is selected from 0, 1, 2, 3 or 4.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising any of the above compounds or their stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals, and a pharmaceutically acceptable carrier .
  • the present invention relates to any of the above-mentioned compounds or their stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals for the preparation of medicines for the treatment of diseases related to the activity or expression of PARP7
  • the disease is selected from tumors.
  • the carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds of the present invention all include their isotopic conditions, and the carbons involved in the groups and compounds of the present invention , hydrogen, oxygen, sulfur or nitrogen are optionally further replaced by one or more of their corresponding isotopes, wherein isotopes of carbon include 12 C, 13 C and 14 C, and isotopes of hydrogen include protium (H), deuterium (D, Also known as heavy hydrogen), tritium (T, also known as super-heavy hydrogen), the isotopes of oxygen include 16 O, 17 O and 18 O, the isotopes of sulfur include 32 S, 33 S, 34 S and 36 S, and the isotopes of nitrogen include 14 N and 15 N, fluorine isotopes include 17 F and 19 F, chlorine isotopes include 35 Cl and 37 Cl, and bromine isotopes include 79 Br and 81 Br.
  • isotopes of carbon include 12 C, 13 C
  • Halogen means F, Cl, Br or I.
  • Halogen-substituted refers to substitution with F, Cl, Br or I, including but not limited to 1 to 10 substituents selected from F, Cl, Br or I, 1 to 6 selected from F, Cl, Br or substituted by the substituent of I, substituted by 1 to 4 substituents selected from F, Cl, Br or I.
  • Halogen-substituted is abbreviated as "halo”.
  • Alkyl refers to a substituted or unsubstituted straight or branched chain saturated aliphatic hydrocarbon group, including but not limited to alkyl groups of 1 to 20 carbon atoms, alkyl groups of 1 to 8 carbon atoms, alkyl groups of 1 to 6 carbon atoms Alkyl of carbon atoms, alkyl of 1 to 4 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and its various branched chain isomers; alkyl groups appearing herein are defined in accordance with this definition. Alkyl groups can be monovalent, divalent, trivalent or tetravalent.
  • Heteroalkyl refers to a substituted or unsubstituted alkyl where one or more (including but not limited to 2, 3, 4, 5 or 6) carbon atoms are replaced by heteroatoms (including but not limited to N, O or S) to replace.
  • Non-limiting examples include -X( CH2 )vX( CH2 )vX( CH2 )vH (v is an integer from 1 to 5, each X is independently selected from a bond or a heteroatom, including but not limited to N , O or S, and at least one X is selected from heteroatoms, and N or S in the heteroatoms can be oxidized to various oxidation states).
  • Heteroalkyl groups can be monovalent, divalent, trivalent or tetravalent.
  • Alkylene refers to substituted or unsubstituted linear and branched divalent saturated hydrocarbon groups, including -(CH 2 ) v - (v is an integer from 1 to 10), examples of alkylene include but not Limited to methylene, ethylene, propylene and butylene etc.
  • Heteroalkylene refers to a substituted or unsubstituted alkylene where one or more (including but not limited to 2, 3, 4, 5 or 6) carbon atoms are replaced by heteroatoms (including but not limited to N, O or S) replacement.
  • Non-limiting examples include -X(CH 2 )vX(CH 2 )vX(CH 2 )v-, where v is an integer from 1 to 5, each X is independently selected from a bond, N, O, or S, and at least 1 X is selected from N, O or S.
  • Cycloalkyl means a substituted or unsubstituted saturated carbocyclic hydrocarbon group, usually having 3 to 10 carbon atoms, non-limiting examples including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cyclohexyl Heptyl et al. Cycloalkyl groups appearing herein are as defined above. Cycloalkyl groups can be monovalent, divalent, trivalent or tetravalent.
  • Heterocycloalkyl refers to a substituted or unsubstituted saturated heteroatom-containing cyclic hydrocarbon group, including but not limited to 3 to 10 atoms, 3 to 8 atoms, including 1 to 3 atoms selected from N, O or
  • the heteroatom of S, N and S selectively substituted in the ring of heterocycloalkyl can be oxidized to various oxidation states.
  • Heterocycloalkyl can be attached to a heteroatom or carbon atom, heterocycloalkyl can be attached to an aromatic ring or a non-aromatic ring, heterocycloalkyl can be attached to a bridged ring or a spiro ring, non-limiting examples include ring Oxyethyl, azetidine, oxetanyl, azetidine, tetrahydrofuranyl, tetrahydro-2H-pyranyl, dioxolane, dioxane, pyrrolidinyl, Piperidinyl, imidazolidinyl, oxazolidinyl, oxazinyl, morpholinyl, hexahydropyrimidinyl, piperazinyl. Heterocycloalkyl can be monovalent, divalent, trivalent or tetravalent
  • alkenyl refers to substituted or unsubstituted linear and branched unsaturated hydrocarbon groups having at least 1, usually 1, 2 or 3 carbon-carbon double bonds, and the main chain includes, but is not limited to, 2 to 10 1, 2 to 6, or 2 to 4 carbon atoms
  • alkenyl groups include, but are not limited to, vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl , 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl Alkenyl, 2-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1 - Pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl,
  • Alkynyl refers to substituted or unsubstituted linear and branched monovalent unsaturated hydrocarbon groups having at least 1, usually 1, 2 or 3 carbon-carbon triple bonds, including but not limited to, in the main chain Including 2 to 10 carbon atoms, 2 to 6 carbon atoms, 2 to 4 carbon atoms, and examples of alkynyl groups include, but are not limited to, ethynyl, propargyl, 1-propynyl, 2-propynyl, 1 -butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-1-butynyl base, 2-methyl-1-butynyl, 2-methyl-3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl Hex
  • Alkoxy refers to a substituted or unsubstituted -O-alkyl group. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexyloxy, cyclopropyl oxy and cyclobutoxy.
  • Carbocyclyl or “carbocycle” refers to a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring, which may be a 3- to 8-membered monocyclic, 4- to 12-membered A bicyclic or 10- to 15-membered tricyclic ring system, the carbocyclic group can be attached to an aromatic ring or a non-aromatic ring, and the aromatic or non-aromatic ring is optionally monocyclic, bridged or spirocyclic.
  • Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl Pentyl-3-enyl, cyclohexyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexenyl, benzene ring, naphthalene ring,
  • a "carbocyclyl” or “carbocycle” can be monovalent, divalent, trivalent or tetravalent.
  • Heterocyclyl or “heterocycle” refers to a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring, the aromatic or non-aromatic ring may be a 3- to 8-membered monocyclic, 4- to 12-membered Bicyclic or 10- to 15-membered tricyclic ring system, and contains 1 or more (including but not limited to 2, 3, 4 or 5) heteroatoms selected from N, O or S, the ring selectivity of heterocyclyl Substituted N, S can be oxidized to various oxidation states.
  • the heterocyclic group can be attached to a heteroatom or a carbon atom, the heterocyclic group can be attached to an aromatic ring or a non-aromatic ring, and the heterocyclic group can be a single ring, a ring, a bridged ring or a spiro ring, non-limiting examples Including oxirane, azetidinyl, oxetanyl, azetidinyl, 1,3-dioxolane, 1,4-dioxolane, 1,3-dioxolan Hexacyclyl, azepanyl, pyridyl, furanyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholine base, thiomorpholinyl, 1,3-dithiyl, dihydrofurany
  • Spirocycle or “spirocyclyl” refers to a polycyclic group in which substituted or unsubstituted monocyclic rings share one atom (called a spiro atom).
  • Non-limiting examples include:
  • a “spiro” or “spirocyclyl” can be monovalent, divalent, trivalent or tetravalent.
  • the number of ring atoms in the paracyclic system includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, and 5 to 10.
  • Non-limiting examples include:
  • a "cyclo-cyclo" or "cyclo-cyclo group” can be monovalent, divalent, trivalent or tetravalent.
  • the number of ring atoms includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, or 5 to 10.
  • Non-limiting examples include Cubicane, Adamantane.
  • a "bridged ring” or “bridged ring group” can be monovalent, divalent, trivalent or tetravalent.
  • Carbospiro refers to a “spirocycle” in which the ring system consists of only carbon atoms.
  • Carbospiro refers to a "spirocycle” in which the ring system consists of only carbon atoms.
  • Carbospiro refers to a "spirocycle” in which the ring system consists of only carbon atoms.
  • Carbospiro refers to a "spirocycle” in which the ring system consists of only carbon atoms.
  • Carbospiro refers to a "spirocycle” in which the ring system consists of only carbon atoms.
  • Carbocyclyl refers to a “carbocyclyl” in which the ring system consists of only carbon atoms.
  • “carbocyclyl”, “carbocyclyl”, “carbocyclyl” or “carbocyclyl” are defined in the same way as for cyclocarbocyclyl.
  • Carbon-bridged ring refers to a “bridged ring” in which the ring system consists only of carbon atoms.
  • carbon-bridged ring refers to a "bridged ring” in which the ring system consists only of carbon atoms.
  • Heterocyclyl refers to a “heterocyclyl” or “heterocycle” of a monocyclic ring system, heterocyclyl, “monocyclic heterocyclyl” appearing herein group” or “heteromonocyclyl” as defined in heterocycle.
  • Heterocyclyl refers to a “heterocyclyl” containing a heteroatom. Heterocyclyl, “heterocyclyl”, “bicycloheterocyclyl” or “heterocyclyl” appearing herein have the same definitions as for bicyclyl.
  • Heterospirocycle refers to a “spirocycle” containing a heteroatom.
  • heterospirocycle refers to a "spirocycle” containing a heteroatom.
  • heterospirocycle refers to a "spirocycle” containing a heteroatom.
  • Heterobridged ring refers to a “bridged ring” containing a heteroatom.
  • a heterobridged ring refers to a “bridged ring” containing a heteroatom.
  • a heterobridged ring refers to a “bridged ring” containing a heteroatom.
  • a heterobridged ring refers to a “bridged ring” containing a heteroatom.
  • Aryl or “aromatic ring” refers to a substituted or unsubstituted aromatic hydrocarbon group with a single ring or a condensed ring, and the number of ring atoms in the aromatic ring includes but is not limited to 6 to 18, 6 to 12 or 6 to 10 carbon atoms.
  • the aryl ring can be fused to a saturated or unsaturated carbocyclic or heterocyclic ring, wherein the ring connected to the parent structure is an aryl ring, and non-limiting examples include benzene ring, naphthalene ring, "Aryl” or “aromatic ring” can be monovalent, divalent, trivalent or tetravalent. When divalent, trivalent or tetravalent, the site of attachment is on the aryl ring.
  • heteroaryl groups include, but are not limited to, pyridyl, furyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, Benzopyrazole, benzimidazole, benzopyridine, pyrrolopyridine, etc.
  • the heteroaryl ring can be fused to a saturated or unsaturated carbocyclic or heterocyclic ring, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples include Heteroaryl groups appearing herein are defined in accordance with this definition. Heteroaryl groups can be monovalent, divalent, trivalent or tetravalent. When divalent, trivalent or tetravalent, the site of attachment is on the heteroaryl ring.
  • 5-membered ring and 5-membered heteroaromatic ring refers to a 5-membered and 5-membered fused heteroaromatic ring, at least one of the two rings contains more than one heteroatom (including but not limited to O, S or N), the whole group is aromatic, non-limiting examples include pyrrolopyrrole ring, pyrazolopyrrole ring, pyrazolopyrazole ring, pyrrolofuran ring, pyrazolofuran ring, pyrrolothiophene ring, Pyrazolothiophene ring.
  • 5 and 6-membered heteroaromatic ring refers to a 5- and 6-membered condensed heteroaromatic ring, at least one of the two rings contains more than one heteroatom (including but not limited to O, S or N) , the whole group is aromatic, non-limiting examples include benzo 5-membered heteroaromatic ring, 6-membered heteroaromatic ring and 5-membered heteroaromatic ring.
  • Constants 1 to 5 heteroatoms selected from O, S, N means containing 1, 2, 3, 4 or 5 heteroatoms selected from O, S, N.
  • Substituted with 0 to X substituents means substituted with 0, 1, 2, 3 . . . X substituents, and X is selected from any integer between 1 and 10.
  • substituted with 0 to 4 substituents means substituted with 0, 1, 2, 3 or 4 substituents.
  • substituted with 0 to 5 substituents means substituted with 0, 1, 2, 3, 4 or 5 substituents.
  • heterobridged ring is optionally further substituted with 0 to 4 substituents selected from H or F” means that the heterobridged ring is optionally further substituted with 0, 1, 2, 3 or 4 substituents selected from H or F base substituted.
  • the ring of X-Y members (X is selected from an integer less than Y and greater than or equal to 3, and Y is selected from any integer between 4 and 12) includes X+1, X+2, X+3, X+4....Y-membered rings ring.
  • Rings include heterocycles, carbocycles, aromatic rings, aryl, heteroaryl, cycloalkyl, heteromonocycles, heterocycles, heterospirocycles, or heterobridged rings.
  • 4--7 membered heteromonocycle refers to a 4-membered, 5-membered, 6-membered or 7-membered heteromonocycle
  • 5--10 membered heterocyclic ring refers to 5-membered, 6-membered, 7-membered, 8-membered , 9- or 10-membered heterocyclic ring.
  • alkyl optionally substituted by F means that the alkyl group may but not necessarily be substituted by F, and the description includes the case where the alkyl group is substituted by F and the case where the alkyl group is not substituted by F.
  • “Pharmaceutically acceptable salt” or “a pharmaceutically acceptable salt thereof” means that a compound of the present invention retains the biological effectiveness and properties of a free acid or free base that is treated with a non-toxic inorganic base or Organic bases, said free bases are salts obtained by reacting with non-toxic inorganic or organic acids.
  • “Pharmaceutical composition” refers to one or more of the compounds described herein, or a stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or A mixture of co-crystals and other chemical components, where "other chemical components” refers to a pharmaceutically acceptable carrier, excipient, and/or one or more other therapeutic agents.
  • the pharmaceutical composition is administered in a manner appropriate to the disease to be treated (or prevented). Appropriate dosages and appropriate duration and frequency of administration will be determined by factors such as the patient's condition, the type and severity of the patient's disease, the particular form of active ingredient, and the method of administration. Optimal dosages can be determined using experimental models and/or clinical trials.
  • the methods involve administering from about 0.1 ⁇ g to about 500 mg of at least one compound of the invention per kg of body weight of the subject. More generally, doses of from about 10 ⁇ g to about 200 mg of the compounds disclosed herein are used, depending on the physiological response of the subject.
  • the dosage of a compound described herein for the treatment and/or prevention of a disease as described herein is about 0.001 to about 1 mg/kg subject body weight/day, eg, about 0.001 mg, about 0.002 mg, about 0.005 mg , about 0.010 mg, about 0.015 mg, about 0.020 mg, about 0.025 mg, about 0.050 mg, about 0.075 mg, about 0.1 mg, about 0.15 mg, about 0.2 mg, about 0.25 mg, about 0.5 mg, about 0.75 mg, or about 1 mg /kg body weight/day.
  • the dosage of a compound described herein for use in the described methods is about 1 to about 1000 mg/kg of body weight of the subject treated/day, about 1 mg, about 2 mg, about 5 mg, about 10 mg, About 15 mg, about 20 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 500 mg, about 750 mg, or about 1000 mg per day.
  • Carrier refers to a material that is not appreciably irritating to the organism and that does not abrogate the biological activity and properties of the administered compound.
  • Excipient refers to an inert substance added to a pharmaceutical composition to facilitate administration of a compound.
  • Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binding agents agent and disintegrant.
  • a “prodrug” refers to a compound of the present invention that can be metabolized in vivo into a biologically active compound.
  • the prodrugs of the present invention are prepared by modifying the amino or carboxyl groups in the compounds of the present invention, and the modification can be removed by conventional operations or in vivo to obtain the parent compound.
  • the prodrugs of the present invention are administered to a mammalian subject, the prodrugs are cleaved to form free amino or carboxyl groups.
  • Co-crystal refers to a crystal formed by the combination of an active pharmaceutical ingredient (API) and a co-crystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds, wherein the pure states of API and CCF are both at room temperature solid, and there is a fixed stoichiometric ratio between the components.
  • a co-crystal is a multicomponent crystal that includes both binary co-crystals formed between two neutral solids and multi-component co-crystals formed between neutral solids and salts or solvates.
  • Animal is meant to include mammals such as humans, companion animals, zoo animals and domestic animals, preferably humans, horses or dogs.
  • Steps refer to isomers resulting from different arrangements of atoms in a molecule in space, including cis-trans isomers, enantiomers and conformational isomers.
  • Tautomer refers to a functional group isomer produced by the rapid movement of an atom in two positions in a molecule, such as keto-enol isomerism and amide-imino alcohol isomerism.
  • heterocyclyl optionally substituted with an alkyl group means that the alkyl group may, but need not, be present, and the description includes instances where the heterocyclyl group is substituted with an alkyl group, as well as where the heterocyclyl group is not substituted with an alkyl group happening.
  • IC50 is the concentration of drug or inhibitor required to inhibit by half a given biological process (or some component of the process such as an enzyme, receptor, cell, etc.).
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • HPLC used Agilent 1260DAD high performance liquid chromatograph (Zorbax SB-C18 100 ⁇ 4.6mm, 3.5 ⁇ M);
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used for thin layer chromatography (TLC) is 0.15mm-0.20mm, and the specification used for TLC separation and purification products is 0.4mm -0.5mm;
  • DMSO dimethyl sulfoxide
  • DMA dimethylacetamide
  • Solutol polyethylene glycol-15-hydroxystearate
  • PEG400 polyethylene glycol 400
  • 20% SBE- ⁇ -CD sulfobutyl - ⁇ -cyclodextrin
  • Saline physiological saline
  • MC methylcellulose solution
  • CO2 carbon dioxide
  • MeOH methanol
  • DEA diethylamine
  • DIPEA N,N-diisopropylethylamine: DMF: N,N-dimethylformamide
  • DIPEA N,N-diisopropylethylamine
  • DMF N,N-dimethylformamide
  • HATU CAS 148893-10-1;
  • Example 1 5-(((S)-1-(3-oxo-3-((R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[ 1,2-d]pyrido[3,2-b][1,4]oxazin-8(6H)-yl)propoxy)prop-2-yl)amino)-4-(trifluoromethyl) ) Pyridazin-3(2H)-one (Compound 1)
  • the fifth step ((S)-1-(3-oxo-3-((R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2 -d]pyrido[3,2-b][1,4]oxazin-8(6H)-yl)propoxy)prop-2-yl)carbamate tert-butyl ester (1 g)
  • the seventh step 2-(4-methoxybenzyl)-5-(((S)-1-(3-oxo-3-((R)-3-(trifluoromethyl)-6a, 7,9,10-Tetrahydropyrazino[1,2-d]pyrido[3,2-b][1,4]oxazin-8(6H)-yl)propoxy)propan-2- yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (1j)
  • the eighth step 5-(((S)-1-(3-oxo-3-((R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[ 1,2-d]pyrido[3,2-b][1,4]oxazin-8(6H)-yl)propoxy)prop-2-yl)amino)-4-(trifluoromethyl) ) Pyridazin-3(2H)-one (Compound 1)
  • Example 2 5-(((S)-1-(3-oxo-3-((S)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[ 1,2-d]pyrido[3,2-b][1,4]oxazin-8(6H)-yl)propoxy)prop-2-yl)amino)-4-(trifluoromethyl) ) pyridazin-3(2H)-one (compound 2)
  • the seventh step 2-(4-methoxybenzyl)-5-(((S)-1-(3-oxo-3-((S)-3-(trifluoromethyl)-6a, 7,9,10-Tetrahydropyrazino[1,2-d]pyrido[3,2-b][1,4]oxazin-8(6H)-yl)propoxy)propan-2- yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (2j)
  • the eighth step 5-(((S)-1-(3-oxo-3-((S)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[ 1,2-d]pyrido[3,2-b][1,4]oxazin-8(6H)-yl)propoxy)prop-2-yl)amino)-4-(trifluoromethyl) ) pyridazin-3(2H)-one (compound 2)
  • Example 3 5-(((2S)-1-(3-oxo-3-(3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyridine Azino[1,2-d]pyrido[3,2-b][1,4]oxazepin-9-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl) yl)pyridazin-3(2H)-one (compound 3)
  • tert-butyl 3-(2-methoxy-2-oxoethyl)piperazine-1-carboxylate (3a) (1.00 g, 3.87 mmol) was added to THF ( 10 mL), LiAlH was added (0.11 g, 2.90 mmol). The mixture was stirred under an ice bath for 2 h.
  • the fourth step 3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-6H-pyrazino[1,2-d]pyrido[3,2-b][ 1,4]oxazepine(3e) trifluoroacetate salt
  • the seventh step 3-((S)-2-aminopropoxy)-1-(3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyrazine Hydrochloride salt of do[1,2-d]pyridin[3,2-b][1,4]oxazepin-9-yl)propan-1-one (3h)
  • the eighth step 2-(4-methoxybenzyl)-5-(((2S)-1-(3-oxo-3-(3-(trifluoromethyl)-6,7,7a, 8,10,11-Hexahydro-9Hpyrazino[1,2-d]pyrido[3,2-b][1,4]oxazepin-9-yl)propoxy)propan-2- yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (3I)
  • Step 9 5-(((2S)-1-(3-oxo-3-(3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyridine Azino[1,2-d]pyrido[3,2-b][1,4]oxazepin-9-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl) yl)pyridazin-3(2H)-one (compound 3)
  • tert-butyl-(R)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2 -a]pyrido[3,2-e]pyrazine-8-carboxylate (100 mg, 0.27 mmol) was dissolved in 1,4-dioxane (5 mL), followed by hydrogen chloride-1 , 4-dioxane solution (4.0 M, 10 mL, 40 mmol) was reacted at room temperature for 4 hours.
  • Step 7 3-[(2S)-2-[(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino]propoxy]propionic acid (4j)
  • Preparation method The reaction solution was filtered with a 0.45 ⁇ m filter membrane to prepare a sample solution.
  • Mobile phase system acetonitrile/water (containing 0.05% ammonia water).
  • Gradient elution method Gradient elution of acetonitrile from 5% to 50% (elution time 15 min).
  • Example 5 5-Methyl-8-(3-((S)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrole Alk-2-yl)methoxy)propionyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazine[1,2-a]pyridine[3,2 -e]pyrazin-6(6aH)-one (compound 5)
  • Step 2 5-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl) -2,3-Dihydropyridazin-3-one (5c)
  • the fifth step 3- ⁇ [(2S)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl]methane Oxy ⁇ propionic acid (5f)
  • Methyl propionate (5e) was dissolved in a mixed solution of methanol (60 mL) and water (60 mL), the pH was adjusted to 7-8 with lithium hydroxide monohydrate, and then lithium hydroxide monohydrate (1.70 g, 40.41 mmol), and reacted at room temperature for 16h.
  • tert-butyl-(R)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2 -a]pyrido[3,2-e]pyrazine-8-carboxylate (200 mg, 0.54 mmol) was dissolved in anhydrous tetrahydrofuran (10 mL), cooled to 0 °C, and sodium hydride (60 mL) was added slowly. %, 93 mg, 2.32 mmol). After stirring at 0°C for 10 minutes, iodomethane (232 mg, 1.62 mmol) was added and the reaction was stirred at room temperature for 16 hours.
  • Step 7 5-Methyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazine[1,2-a]pyridine[3,2-e]pyrazine -6(6aH)-ketone (5h) hydrochloride
  • tert-butyl-5-methyl-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1, 2-a]pyrido[3,2-e]pyrazine-8-carboxylate 5g (155mg, 0.40mmol) was dissolved in 1,4-dioxane (5mL) solution, and hydrogen chloride- 1,4-dioxane solution (4.0 M, 10 mL, 40 mmol) was reacted at room temperature for 4 hours.
  • the eighth step 5-methyl-8-(3-((S)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrole Alk-2-yl)methoxy)propionyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazine[1,2-a]pyridine[3,2 -e]pyrazin-6(6aH)-one (compound 5)
  • Preparation method The reaction solution was filtered with a 0.45 ⁇ m filter membrane to prepare a sample solution.
  • Mobile phase system acetonitrile/water (containing 0.05% ammonia water).
  • Gradient elution method Gradient elution of acetonitrile from 5% to 50% (elution time 15 min).
  • Preparation method The reaction solution was filtered with a 0.45 ⁇ m filter membrane to prepare a sample solution.
  • Mobile phase system acetonitrile/water (containing 0.05% ammonia water).
  • Gradient elution method Gradient elution of acetonitrile from 5% to 50% (elution time 15 min).
  • Example 7 5-(((S)-1-(3-oxo-3-((R)-3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro -9H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazepin-9-yl)propoxy)prop-2-yl)amino)-4- (Trifluoromethyl)pyridazin-3(2H)-one (Compound 7-1)
  • Compound 3 was purified by SFC on AD column (instrument and preparative column: Waters 150 mgm, preparative column model: DAICEL CHIRALPAK AD (250 mm ⁇ 30 mm, 10 ⁇ m)).
  • Preparation method Compound 3 was dissolved in ethanol, and filtered through a 0.45 ⁇ m filter to prepare a sample solution.
  • Mobile phase system A for CO 2 and B for EtOH (0.1% NH 3 ⁇ H 2 O).
  • Gradient elution method 30% phase B (flow rate: 120 mL/min; elution time 2.5 min) to obtain compound 7-1 and compound 7-2 after lyophilization.
  • Example 7-A (Example 7-A is one of the structures of compound 7-1 and compound 7-2).
  • Example 7-B is one of the structures of compound 7-1 and compound 7-2).
  • Example 8 5-((S)-2-((3-oxo-3-((S)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazine[1 ,2-d]pyridin[3,2-b][1,4]oxazin-8(6H)-yl)propoxy)methyl)pyrrolidin-1-yl)-4-(trifluoromethyl) )pyrazin-3(2H)-one (compound 8)
  • Preparation method the crude product is dissolved in DMF, And filter with a 0.45 ⁇ m filter membrane to prepare a sample solution.
  • Mobile phase system acetonitrile/water (containing 0.05% ammonia water).
  • Gradient elution method acetonitrile gradient elution from 10% to 55% (flow rate: 12mL/min; wash (S)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl) Amino)propoxy)propionyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e ] Pyrazin-6(6aH)-one (Compound 10) (10 mg, 11%).
  • Preparation method the crude product is dissolved in DMF, and filtered with a 0.45 ⁇ m filter membrane to prepare a sample solution.
  • Mobile phase system acetonitrile/water (containing 0.05% ammonia water).
  • Gradient elution method Gradient elution of acetonitrile from 10% to 55% (flow rate: 12 mL/min; elution time 17 min) to obtain ((S)-5-methyl-8-(3-((S)-2- ((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionyl)-3-(trifluoromethyl)-7, 8,9,10-Tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6-(6aH)-one (Compound 11) (10 mg, 11%) .
  • Example 12 (S)-8-(3-(((S)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrole Alk-2-yl)methoxy)propionyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3 ,2-e]pyrazin-6(6aH)-one (compound 12) trifluoroacetate salt
  • Preparation method the crude product was dissolved in DMF, and filtered with a 0.45 ⁇ m filter membrane to prepare a sample solution.
  • Mobile phase system acetonitrile/water (containing 1% trifluoroacetic acid).
  • Example 13 (S)-5-Methyl-8-(3-(((S)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine- 4-yl)pyrrolidin-2-yl)methoxy)propionyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a ]pyrido[3,2-e]pyrazin-6(6aH)-one (compound 13) trifluoroacetate salt
  • Preparation method the crude product is dissolved in DMF, and filtered with a 0.45 ⁇ m filter membrane to prepare a sample solution.
  • Mobile phase system acetonitrile/water (containing 1% trifluoroacetic acid).
  • Example 14 5-((S)-2-((3-oxo-3-((R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[ 1,2-d]pyrido[3,2-b][1,4]oxazin-8(6H)-yl)propoxy)methyl)pyrrolidin-1-yl)-4-(trifluoro Methyl)pyridazin-3(2H)-one (compound 14) trifluoroacetate salt
  • Compound 14 was identified as (S)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2-b][1,4] Oxazine-8(6H)-carboxylate tert-butyl ester (1d) and 3- ⁇ [(2S)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine- 4-yl)pyrrolidin-2-yl]methoxy ⁇ propionic acid (5f) is the starting material.
  • Example 10 Refer to the synthetic method of Example 10 to obtain 5-((S)-2-((3-oxo-3 -((R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2-b][1,4]oxa Azin-8(6H)-yl)propoxy)methyl)pyrrolidin-1-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one (compound 14) in trifluoroacetic acid Salt.
  • Example 15 (5-((2S)-2-((3-oxo-3-(3-(trifluoromethyl)-6,7,7a,8,10,11hexahydro-9H-pyridine) Azino[1,2-d]pyrido[3,2-b][1,4]oxazepin-9-yl)propoxy)methyl)pyrrolidin-1-yl)-4-(tris Fluoromethyl)pyridazin-3(2H)-one (compound 15) trifluoroacetate salt
  • Example 16 9-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy )propionyl)-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydropyrazino[1,2-d]pyrido[3,2-b][1, 4] Diaza-6(5H)-one (Compound 16)
  • the reaction was quenched by adding water (40 mL), extracted with ethyl acetate (40 mL x 2), the organic phases were combined, the organic phases were washed with saturated brine (40 mL x 3), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product .
  • the reaction was quenched by adding water (40 mL), extracted with ethyl acetate (40 mL x 3), the organic phases were combined, the organic phases were washed with saturated brine (40 mL x 3), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product .
  • Step 5 9-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy )propionyl)-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydropyrazino[1,2-d]pyrido[3,2-b][1, 4] Diaza-6(5H)-one (Compound 16)
  • Example 17 9-(3-(((S)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidine-2- yl)methoxy)propionyl)-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydropyrazino[1,2-d]pyrido[3,2- b][1,4]diaza-6(5H)-one (Compound 17)
  • Preparation method The reaction solution was filtered with a 0.45 ⁇ m filter membrane to prepare a sample solution.
  • Mobile phase system acetonitrile/water (containing 0.1% ammonia water).
  • Example 18 5-Methyl-9-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl) Amino)propoxy)propionyl)-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydropyrazino[1,2-d]pyrido[3,2- b][1,4]diaza-6(5H)-one (Compound 18)
  • tert-butyl-6-oxo-3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydropyrazino[1,2-d]pyrido[3, 2-B][1,4]diaza-9-(5H)-carboxylate (16e) (300 mg, 0.78 mmol) was added to DMF (5 mL), K 2 CO 3 (321 mg, 2.33 mmol) and CH3I (133 gm, 0.93 mmol). The mixture was stirred at room temperature overnight.
  • Step 2 5-Methyl-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydropyrazino[1,2-d]pyrido[3,2-B ][1,4]diaza-6(5H)-one (18b) hydrochloride
  • the third step 5-methyl-9-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl) Amino)propoxy)propionyl)-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydropyrazino[1,2-d]pyrido[3,2- b][1,4]diaza-6(5H)-one (Compound 18)
  • Preparation method The reaction solution was filtered with a 0.45 ⁇ m filter membrane to prepare a sample solution.
  • Mobile phase system acetonitrile/water (containing 0.1% ammonia).
  • Example 19 5-Methyl-9-(3-(((S)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl) Pyrrolidin-2-yl)methoxy)propionyl)-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydropyrazino[1,2-d]pyrido [3,2-b][1,4]diaza-6(5H)-one (Compound 19)
  • Preparation method The reaction solution was filtered with a 0.45 ⁇ m filter membrane to prepare a sample solution.
  • Mobile phase system acetonitrile/water (containing 0.1% ammonia).
  • Example 20 9-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy )propionyl)-7,7a,9,10,11-hexahydro-6H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazepine-3- Formonitrile (Compound 20)
  • 6-Chloro-5-nitropyridine-3-carbonitrile (20a) (1 g, 5.45 mmol) was dissolved in DMF (10 mL) at room temperature and 3-(2-hydroxyethyl)piperazine-1- tert-Butyl formate (3b) (1.26 g, 5.45 mmol) and DIPEA (2.11 g, 16.35 mmol). The mixture was stirred at room temperature overnight. Water (20 mL) was added to quench the reaction, ethyl acetate (20 mL ⁇ 2) was used for extraction, the organic phases were combined, the organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product.
  • the fourth step 9-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy )propionyl)-7,7a,9,10,11-hexahydro-6H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazepine-3- Formonitrile (Compound 20)
  • Preparation method The crude product is dissolved in DMF and filtered with a 0.45 ⁇ m filter membrane. , prepared into a sample solution.
  • Mobile phase system acetonitrile/water (containing 0.05% ammonia water).
  • Example 21 9-(3-(((S)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidine-2- yl)methoxy)propionyl)-7,7a,8,9,10,11-hexahydro-6H-pyrazino[1,2-d]pyrido[3,2-b][1,4 ]oxazepine-3-carbonitrile (Compound 21)
  • Preparation method the crude product is dissolved in DMF, And filter with a 0.45 ⁇ m filter membrane to prepare a sample solution.
  • Mobile phase system acetonitrile/water (containing 0.05% ammonia water).
  • tert-butyl-(R)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2 -a]Pyridin[3,2-e]pyrazine-8-carboxylate (16.0 g, 43.0 mmol) was dissolved in DMF (150 mL) followed by potassium carbonate (17.82 g, 128.9 mmol), iodine Methane (18.43 g, 128.9 mmol) was reacted at room temperature for 16 hours. After the reaction, 300 mL of water was added, followed by extraction with ethyl acetate (300 mL x 3).
  • the third step (R)-5-methyl-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine- 4-yl)amino)propoxy)propionyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyridine[3, 2-e]pyrazin-6(6aH)-one (Compound 22)
  • reaction solution was poured into water (50 mL), and ethyl acetate ( 20mL ⁇ 3) extraction, the organic phases were combined, the organic phase was backwashed with saturated brine (20mL ⁇ 3), dried over anhydrous sodium sulfate, suction filtered, and the filtrate was concentrated under reduced pressure to obtain a residue.
  • the fourth step 5-methyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-dipyrazine[1,2-a:2',3'-e]pyridine
  • the fifth step 5-methyl-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl) Amino)propoxy)propionyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-dipyrazine[1,2-a:2',3'-e] Pyrazin-6(6aH)-one (Compound 23)
  • Preparation method The reaction solution was filtered with a 0.45 ⁇ m filter membrane to prepare a sample solution.
  • Mobile phase system acetonitrile/water (containing 0.1% ammonia).
  • Example 24 5-Methyl-8-(3-(((S)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl) Pyrrolidin-2-yl)methoxy)propionyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-dipyrazine[1,2-a:2', 3'-e]pyrazin-6(6aH)-one (Compound 24)
  • Example 25 5-(((S)-1-(3-oxo-3-((R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydrodipyrazine[ 2,3-b:1',2'-d][1,4]oxazin-8(6H)-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl) Pyridazin-3(2H)-one (Compound 25)
  • reaction solution was poured into water (20 mL), and ethyl acetate (20 mL ⁇ 3) Extract, combine the organic phases, backwash the organic phase with saturated brine (20 mL x 3), dry over anhydrous sodium sulfate, filter with suction, and concentrate the filtrate under reduced pressure to obtain a residue.

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Abstract

L'invention concerne un composé représenté par la formule générale (I), ou un stéréoisomère, un produit deutéré, un solvate, un promédicament, un métabolite, un sel pharmaceutiquement acceptable ou un cocristal de celui-ci, un intermédiaire de celui-ci et un procédé pour leur préparation, ainsi qu'une application dans la préparation d'un médicament pour le traitement de maladies liées à l'activité ou au niveau d'expression de PAR P7.
PCT/CN2022/088446 2021-04-23 2022-04-22 Dérivé hétérocyclique à cycles fusionnés et son application médicale WO2022223022A1 (fr)

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Citations (9)

* Cited by examiner, † Cited by third party
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WO1996023789A1 (fr) * 1995-02-03 1996-08-08 Sankyo Company, Limited Derives d'hexahydropyrazinoquinoline
WO2001090077A1 (fr) * 2000-05-19 2001-11-29 Guilford Pharmaceuticals, Inc. Derives de sulfonamide et de carbamide de 6(5h) phenanthridinones et utilisations de ceux-ci
US20050171101A1 (en) * 2002-03-26 2005-08-04 Fujisawa Pharmaceutical Co. Ltd. Phenanthridinones as parp inhibitors
CN1948298A (zh) * 2006-11-09 2007-04-18 东南大学 一种多巴胺d3受体部分激动剂及其应用
CN1976931A (zh) * 2004-04-09 2007-06-06 千禧药品公司 用以治疗炎症的β－咔啉
CN101501006A (zh) * 2006-05-31 2009-08-05 P.安杰莱蒂分子生物学研究所 作为聚(adp-核糖)聚合酶(parp)抑制剂的吡啶酮和哒嗪酮衍生物
CN102341394A (zh) * 2009-01-23 2012-02-01 武田药品工业株式会社 聚(adp-核糖)聚合酶(parp)抑制剂
CN104884435A (zh) * 2012-12-06 2015-09-02 协和发酵麒麟株式会社 吡啶酮化合物
CN112424188A (zh) * 2018-04-30 2021-02-26 里邦医疗公司 作为parp7抑制剂的哒嗪酮

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996023789A1 (fr) * 1995-02-03 1996-08-08 Sankyo Company, Limited Derives d'hexahydropyrazinoquinoline
WO2001090077A1 (fr) * 2000-05-19 2001-11-29 Guilford Pharmaceuticals, Inc. Derives de sulfonamide et de carbamide de 6(5h) phenanthridinones et utilisations de ceux-ci
US20050171101A1 (en) * 2002-03-26 2005-08-04 Fujisawa Pharmaceutical Co. Ltd. Phenanthridinones as parp inhibitors
CN1976931A (zh) * 2004-04-09 2007-06-06 千禧药品公司 用以治疗炎症的β－咔啉
CN101501006A (zh) * 2006-05-31 2009-08-05 P.安杰莱蒂分子生物学研究所 作为聚(adp-核糖)聚合酶(parp)抑制剂的吡啶酮和哒嗪酮衍生物
CN1948298A (zh) * 2006-11-09 2007-04-18 东南大学 一种多巴胺d3受体部分激动剂及其应用
CN102341394A (zh) * 2009-01-23 2012-02-01 武田药品工业株式会社 聚(adp-核糖)聚合酶(parp)抑制剂
CN104884435A (zh) * 2012-12-06 2015-09-02 协和发酵麒麟株式会社 吡啶酮化合物
CN112424188A (zh) * 2018-04-30 2021-02-26 里邦医疗公司 作为parp7抑制剂的哒嗪酮

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