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WO2022223022A1 - Fused-ring heterocycle derivative and medical application thereof - Google Patents

Fused-ring heterocycle derivative and medical application thereof 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
Prior art date
Application number
PCT/CN2022/088446
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French (fr)
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
Original Assignee
四川海思科制药有限公司
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Publication date
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Priority to CN202280013780.6A priority Critical patent/CN117083274A/en
Publication of WO2022223022A1 publication Critical patent/WO2022223022A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—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

Provided are a compound represented by general formula (I), or a stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, an intermediate thereof, and a preparation method therefor, as well as an application in the preparation of a drug for treating diseases related to PAR P7 activity or expression level.

Description

一种并环杂环衍生物及其在医药上的应用A kind of heterocyclic heterocyclic derivative and its application in medicine 技术领域technical field
本发明涉及一种通式(I)所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，及其中间体和制备方法，以及在制备治疗与PARP7活性或表达量相关疾病的药物中的应用。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.
背景技术Background technique
PARP全称为poly-ADP-ribose polymerase，即多聚ADP核糖聚合酶，参与了包括DNA修复、基因组稳定性等在内的一系列细胞过程。该蛋白家族由17个成员组成，分为polyPARPs和monoPARPs。MonoPARP蛋白家族在与癌症、炎性疾病和神经退行性疾病发展相关的多种应激反应中起作用，其成员PARP7被证明在肿瘤中过度活跃，且在癌细胞生存中起着关键作用。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.
研究发现，许多癌细胞都依赖PARP7来实现内在的细胞存活，而PARP7则使癌细胞能够“躲藏”在免疫系统之外。抑制PARP7可有效抑制癌细胞的生长并恢复干扰素信号传导，有效释放癌症用于躲避免疫系统，抑制先天和适应性免疫机制的“刹车”。在几种癌症模型中，PARP7抑制剂表现出持久的肿瘤生长抑制作用、有效的抗增殖活性以及干扰素信号传导恢复作用，PARP7抑制剂有望成为新型抗癌药物研发的靶点。The study found that many cancer cells depend on 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.
发明内容SUMMARY OF THE INVENTION
本发明的目的就是提供一类杂环类化合物或其药学上可接受的盐，将其应用于PARP7抑制剂。本发明中的化合物能有效抑制PARP7并可用于治疗肿瘤等疾病。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.
本发明提供一种通式(I)所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中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
Figure PCTCN2022088446-appb-000001
Figure PCTCN2022088446-appb-000001
在一些实施方案中，Y选自O、S、S(＝O)、S(＝O) 2、S(＝O) 2N(R y)、N(R y)、C 1-4亚烷基、-OC 1-3亚烷基-、-C 1-3亚烷基O-、-C 1-3亚烷基S-、-C 1-3亚烷基S(＝O)-、-C 1-3亚烷基 S(＝O) 2-、-N(R y)C 1-3亚烷基-、-C 1-3亚烷基N(R y)-，所述的亚烷基任选进一步被0至4个(例如0、1、2、3或4)选自H、卤素、＝O、＝S、OH、氰基、C 1-6烷基、卤素取代的C 1-6烷基、C 1-6烷氧基、C 3-6环烷基的取代基所取代； In some embodiments, Y is selected from O, S, S(=O), S(=O) 2 , S(=O) 2 N(R y ), N(R y ), C 1-4 alkylene base, -OC 1-3 alkylene-, -C 1-3 alkylene O-, -C 1-3 alkylene S-, -C 1-3 alkylene S(=O)-, - C 1-3 alkylene S(=O) 2 -, -N(R y )C 1-3 alkylene-, -C 1-3 alkylene N(R y )-, the alkylene C 1 optionally further substituted by 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, halogen, =O, =S, OH, cyano, C1-6 alkyl, halogen -6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl substituents;
在一些实施方案中，Y选自O、N(R y)、C 1-3亚烷基、-OC 1-2亚烷基-、-C 1-2亚烷基O-、-C 1-2亚烷基S-、-C 1-2亚烷基S(＝O) 2-、-N(R y)C 1-2亚烷基-、-C 1-2亚烷基N(R y)-，所述的亚烷基任选进一步被0至4个(例如0、1、2、3或4)选自H、卤素、＝O、＝S、OH、氰基、C 1-4烷基、卤素取代的C 1-4烷基、C 1-4烷氧基、C 3-6环烷基的取代基所取代； In some embodiments, Y is selected from O, N(R y ), C 1-3 alkylene, -OC 1-2 alkylene-, -C 1-2 alkylene O-, -C 1- 2 alkylene S-, -C 1-2 alkylene S(=O) 2 -, -N(R y )C 1-2 alkylene-, -C 1-2 alkylene N(R y )-, the alkylene group is optionally further selected by 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, halogen, =O, =S, OH, cyano, C 1-4 Substituted by substituents of alkyl, halogen-substituted C 1-4 alkyl, C 1-4 alkoxy, and C 3-6 cycloalkyl;
在一些实施方案中，Y选自O、N(R y)、-N(R y)C(＝O)-、-C(＝O)N(R y)-、-CH 2-、-CH 2CH 2-、-CH 2CH 2CH 2-、-OCH 2-、-OCH 2CH 2-、-CH 2O-、-CH 2CH 2O-、-CH 2S-、-CH 2CH 2S-、-CH 2S(＝O) 2-、-CH 2CH 2S(＝O) 2-、-N(R y)CH 2-、-N(R y)CH 2CH 2-、-CH 2N(R y)-、-CH 2CH 2N(R y)-、-N(R y)C(＝O)CH 2-、-CH 2C(＝O)N(R y)-，所述CH 2任选进一步被0至2个(例如0、1或2个)选自H、＝O、＝S、OH、氰基、C 1-4烷基、卤素取代的C 1-4烷基、C 1-4烷氧基、C 3-6环烷基的取代基所取代； In some embodiments, Y is selected from O, N( Ry ), -N( Ry )C(=O)-, -C(=O)N( Ry )-, -CH2- , -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -OCH 2 -, -OCH 2 CH 2 -, -CH 2 O-, -CH 2 CH 2 O-, -CH 2 S-, -CH 2 CH 2 S-, -CH 2 S(=O) 2 -, -CH 2 CH 2 S(=O) 2 -, -N(R y )CH 2 -, -N(R y )CH 2 CH 2 -, -CH 2 N(R y )-, -CH 2 CH 2 N(R y )-, -N(R y )C(=O)CH 2 -, -CH 2 C(=O)N(R y ) -, said CH 2 is optionally further C 1 substituted by 0 to 2 (eg 0, 1 or 2) selected from H, =O, =S, OH, cyano, C 1-4 alkyl, halogen -4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl substituents;
在一些实施方案中，Y选自O、-NHC(＝O)-、-C(＝O)NH-、-CH 2-、-CH 2CH 2-、-CH 2CH 2CH 2-、-OCH 2-、-OCH 2CH 2-、-CH 2O-、-CH 2CH 2O-、-NHCH 2-、-NHCH 2CH 2-、-CH 2NH-、-CH 2CH 2NH-、-NHC(＝O)CH 2-、-CH 2C(＝O)NH-； In some embodiments, Y is selected from O, -NHC(=O) - , -C (=O)NH-, -CH2- , -CH2CH2- , -CH2CH2CH2- , - OCH 2 -, -OCH 2 CH 2 -, -CH 2 O-, -CH 2 CH 2 O-, -NHCH 2 -, -NHCH 2 CH 2 -, -CH 2 NH-, -CH 2 CH 2 NH- , -NHC(=O)CH 2 -, -CH 2 C(=O)NH-;
在一些实施方案中，Y选自-NHC(＝O)-、-C(＝O)NH-、-CH 2CH 2CH 2-、-OCH 2-、-CH 2CH 2-、-CH 2O-、-CH 2CH 2O-、-OCH 2CH 2-； In some embodiments, Y is selected from -NHC(=O) - , -C (=O)NH-, -CH2CH2CH2- , -OCH2- , -CH2CH2- , -CH2 O-, -CH 2 CH 2 O-, -OCH 2 CH 2 -;
在一些实施方案中，Y选自O、-N(CH 3)C(＝O)-、-C(＝O)N(CH 3)-、-CH 2C(＝O)NH-、-CH 2C(＝O)N(CH 3)-； In some embodiments, Y is selected from O, -N( CH3 )C(=O)-, -C(=O)N( CH3 )-, -CH2C (=O)NH-, -CH 2 C(=O)N(CH 3 )-;
在一些实施方案中，Y选自-CH 2S(＝O) 2-； In some embodiments, Y is selected from -CH2S(=O) 2- ;
在一些实施方案中，Y选自-N(CH 2CH 3)C(＝O)-、-N(CH(CH 3) 2)C(＝O)-、-N(CH 2CH(CH 3) 2)C(＝O)-、-N(环丙基)C(＝O)-、-N(CH 2-环丙基)C(＝O)-、-C(＝O)N(CH 2CH 3)-、-C(＝O)N(CH(CH 3) 2)-、-C(＝O)N(CH 2CH(CH 3) 2)-、-C(＝O)N(环丙基)-、-C(＝O)N(CH 2-环丙基)-； In some embodiments, Y is selected from -N( CH2CH3 )C(=O)-, -N( CH(CH3)2 ) C (=O)-, -N(CH2CH ( CH3 ) 2 )C(=O)-, -N(cyclopropyl)C(=O)-, -N(CH 2 -cyclopropyl)C(=O)-, -C(=O)N(CH 2 CH 3 )-, -C(=O)N(CH(CH 3 ) 2 )-, -C(=O)N(CH 2 CH(CH 3 ) 2 )-, -C(=O)N( cyclopropyl)-, -C(=O)N(CH 2 -cyclopropyl)-;
在一些实施方案中，Y各自独立的选自-C(＝O)N(CD 3)-、-C(＝O)N(CH 2-氧杂环丁基)-、-C(＝O)N(CH 2-氧杂环戊基)-、-C(＝O)N(CH 2-氮杂环丁基)-、-C(＝O)N(CH 2-吡咯烷基)-、-C(＝O)N(CH 2-环戊基)-、-C(＝O)N(CH 2CH 2CH 3)-、-C(＝O)N(CH 2CH(CH 2CH 3) 2)-、-C(＝O)N(CH 2CH 2CH 2CH 3)-、-C(＝O)N(CH 2CH 2CH(CH 3) 2)-、-C(＝O)N(CH 2CH(CH 3)CH 2CH 3)-、-C(＝O)N(正辛基)-、-C(＝S)N(CH 3)-、-C(＝S)N(CH 2CH 3)-、 -C(＝S)N(CH 2-环丙基)-、
Figure PCTCN2022088446-appb-000002
In some embodiments, each Y is independently selected from -C(=O)N( CD3 )-, -C(=O)N( CH2 -oxetanyl)-, -C(=O) N(CH 2 -oxolane)-, -C(=O)N(CH 2 -azetidinyl)-, -C(=O)N(CH 2 -pyrrolidinyl)-, - C(=O)N(CH 2 -cyclopentyl)-, -C(=O)N(CH 2 CH 2 CH 3 )-, -C(=O)N(CH 2 CH(CH 2 CH 3 ) 2 )-, -C(=O)N(CH 2 CH 2 CH 2 CH 3 )-, -C(=O)N(CH 2 CH 2 CH(CH 3 ) 2 )-, -C(=O) N(CH 2 CH(CH 3 )CH 2 CH 3 )-, -C(=O)N(n-octyl)-, -C(=S)N(CH 3 )-, -C(=S)N (CH 2 CH 3 )-, -C(=S)N(CH 2 -cyclopropyl)-,
Figure PCTCN2022088446-appb-000002
在一些实施方案中，R y各自独立的选自H、C 1-6烷基或C 3-6环烷基，所述的烷基或环烷基任选进一步被0至4个(例如0、1、2、3或4)选自H、氘、卤素、CF 3、OH、氰基、NH 2、C 1-6烷基、C 1-6烷氧基、3至8元杂环基或C 3-6环烷基的取代基所取代，所述的杂环基含有1至3个选自O、S、N的杂原子； In some embodiments, 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;
在一些实施方案中，R y各自独立的选自H、C 1-4烷基或C 3-6环烷基，所述的烷基或环烷基任选进一步被0至4个(例如0、1、2、3或4)选自H、氘、卤素、CF 3、OH、氰基、NH 2、C 1-4烷基、C 1-4烷氧基、3至8元杂环基或C 3-6环烷基的取代基所取代，所述的杂环基含有1至3个选自O、S、N的杂原子； In some embodiments, 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;
在一些实施方案中，R y各自独立的选自H、C 1-4烷基，所述的烷基或环烷基任选进一步被0至4个(例如0、1、2、3或4)选自H、氘、卤素、CF 3、OH、氰基、NH 2、C 1-4烷基、C 1-4烷氧基、3至8元杂环基或C 3-6环烷基的取代基所取代，所述的杂环基含有1至3个选自O、S、N的杂原子； In some embodiments, 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;
在一些实施方案中，R y各自独立的选自H、C 1-4烷基； In some embodiments, each R y is independently selected from H, C 1-4 alkyl;
在一些实施方案中，R y各自独立的选自氘代C 1-4烷基； In some embodiments, each R y is independently selected from deuterated C 1-4 alkyl;
在一些实施方案中，R y各自独立的选自CD 3； In some embodiments, each Ry is independently selected from CD3 ;
在一些实施方案中，R y各自独立的选自H、甲基、乙基、丙基、异丙基、丁基、叔丁基、仲丁基、异丁基、环丙基、环丁基、环戊基、环己基，所述的甲基、乙基、丙基、异丙基、丁基、叔丁基、仲丁基、异丁基、环丙基、环丁基、环戊基、环己基任选进一步被0至4个(例如0、1、2、3或4)选自H、氘、卤素、CF 3、OH、氰基、NH 2、C 1-4烷基、C 1-4烷氧基、3至8元杂环基或C 3-6环烷基的取代基所取代，所述的杂环基含有1至3个选自O、S、N的杂原子； In some embodiments, 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;
在一些实施方案中，R y各自独立的选自H、甲基、乙基、丙基、异丙基、丁基、叔丁基、仲丁基、异丁基、环丙基、环丁基、环戊基、环己基，所述的甲基、乙基、丙基、异丙基、丁基、叔丁基、仲丁基、异丁基、环丙基、环丁基、环戊基、环己基任选进一步被0至4个(例如0、1、2、3或4)选自H、氘、F、Cl、Br、CF 3、OH、氰基、NH 2、甲基、乙基、丙基、丁基、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基、氧杂环丁基、氧杂环丁基、氧杂环戊基、氮杂环丁基、吡咯烷基的取代基所取代； In some embodiments, 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, cyclopentyl, cyclohexyl, oxetanyl, oxetanyl, oxolane, nitrogen Substituents of heterocyclobutyl and pyrrolidinyl;
在一些实施方案中，R y各自独立的选自H、甲基、乙基； In some embodiments, each Ry is independently selected from H, methyl, ethyl;
在一些实施方案中，环A选自C 6-10芳基、5-10元杂芳基或5-10元杂环基，所述的杂芳基或者杂环基含有1至5个(例如1、2、3、4或5个)选自O、S、N的杂原子； In some embodiments, 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;
在一些实施方案中，环A选自3(2H)-哒嗪酮或2(1H)-吡啶酮；In some embodiments, Ring A is selected from 3(2H)-pyridazinone or 2(1H)-pyridinone;
在一些实施方案中，
Figure PCTCN2022088446-appb-000003
选自
Figure PCTCN2022088446-appb-000004
In some embodiments,
Figure PCTCN2022088446-appb-000003
selected from
Figure PCTCN2022088446-appb-000004
在一些实施方案中，
Figure PCTCN2022088446-appb-000005
选自
Figure PCTCN2022088446-appb-000006
In some embodiments,
Figure PCTCN2022088446-appb-000005
selected from
Figure PCTCN2022088446-appb-000006
在一些实施方案中，
Figure PCTCN2022088446-appb-000007
选自
Figure PCTCN2022088446-appb-000008
In some embodiments,
Figure PCTCN2022088446-appb-000007
selected from
Figure PCTCN2022088446-appb-000008
在一些实施方案中，
Figure PCTCN2022088446-appb-000009
选自
Figure PCTCN2022088446-appb-000010
In some embodiments,
Figure PCTCN2022088446-appb-000009
selected from
Figure PCTCN2022088446-appb-000010
在一些实施方案中，
Figure PCTCN2022088446-appb-000011
选自
Figure PCTCN2022088446-appb-000012
In some embodiments,
Figure PCTCN2022088446-appb-000011
selected from
Figure PCTCN2022088446-appb-000012
在一些实施方案中，
Figure PCTCN2022088446-appb-000013
选自
Figure PCTCN2022088446-appb-000014
Figure PCTCN2022088446-appb-000015
In some embodiments,
Figure PCTCN2022088446-appb-000013
selected from
Figure PCTCN2022088446-appb-000014
Figure PCTCN2022088446-appb-000015
Figure PCTCN2022088446-appb-000016
Figure PCTCN2022088446-appb-000016
在一些实施方案中，X 1、X 2、X 3、X 4各自独立的选自N、CR x，X 1、X 2、X 3、X 4至多含有2个N； In some embodiments, 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;
在一些实施方案中，X 1选自N，X 2选自CH，X 3选自CH、CF、CCl、CCN或CCF 3，X 4选自CH或N； In some embodiments, 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;
在一些实施方案中，环X选自C 6-10芳基、5-10元杂芳基、C 3-10碳环或5-10元杂环基，所述的杂芳基或者杂环基含有1至5个(例如1、2、3、4或5个)选自O、S、N的杂原子； In some embodiments, 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;
在一些实施方案中，环X选自苯基、5-6元杂芳基或5-6元杂环基，所述的杂芳基或杂环基含有1至5个(例如1、2、3、4或5个)选自O、S、N的杂原子；In some embodiments, 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;
在一些实施方案中，环X选自苯基、吡啶基、嘧啶基、吡嗪基、哒嗪基、噻吩基、噻唑基、呋喃基、噁唑基、吡咯基、吡唑基或咪唑基；In some embodiments, Ring X is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, thiazolyl, furyl, oxazolyl, pyrrolyl, pyrazolyl, or imidazolyl;
在一些实施方案中，W 1选自N或C(R a4)； In some embodiments, Wi is selected from N or C(R a4 );
在一些实施方案中，W 1选自N或CH； In some embodiments, W is selected from N or CH;
在一些实施方案中，W 1选自N； In some embodiments, Wi is selected from N;
在一些实施方案中，R x、R a各自独立的选自H、卤素、氰基、OH、＝O、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6烷硫基、-SO 2-C 1-6烷基、-C(＝O)C 1-6烷基、-(CH 2) q-C 3-10碳环或-(CH 2) q-3至12元杂环，所述的-CH 2-、烷基、烯基、炔基、烷氧基、烷硫基、碳环或杂环任选进一步被0至4个(例如0、1、2、3或4)选自H、卤素、OH、氰基、＝O、NH 2、NH(C 1-6烷基)、N(C 1-6烷基) 2、C 1-6烷基、卤素取代的C 1-6烷基、C 1-6烷氧基、C 3-6环烷基或3至10元杂环的取代基所取代，所述的杂环含有1至3个(例如1、2或3个)选自O、S、N的杂原子； In some embodiments, R x , Ra are each independently selected from H, halogen, cyano, OH, =O, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthio, -SO 2 -C 1-6 alkyl, -C(=O)C 1-6 alkyl, -(CH 2 ) q -C 3-10 Carbocycle or -(CH 2 ) q -3- to 12-membered heterocycle, said -CH 2 -, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, carbocycle or heterocycle optionally further by 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, =O, NH2 , NH( C1-6 alkyl), N( C1-6 Alkyl) 2 , 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 heterocycle contains 1 to 3 (eg 1, 2 or 3) heteroatoms selected from O, S, N;
在一些实施方案中，R a1、R a2、R a4各自独立的选自R a； In some embodiments, R a1 , R a2 , R a4 are each independently selected from R a ;
在一些实施方案中，R a1、R a2、R a4各自独立的选自H、卤素、氰基、OH、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6烷硫基、-SO 2-C 1-6烷基、-C(＝O)C 1-6烷基、-(CH 2) q-C 3-10碳环或-(CH 2) q-3至12元杂环，所述的-CH 2-、烷基、烯基、炔基、烷氧基、烷硫基、碳环或杂环任选进一步被0至4个(例如0、1、2、3或4)选自H、卤素、OH、氰基、＝O、C 1-6烷基、卤素取代的C 1-6烷基、C 1-6烷氧基、C 3-6环烷基或3至10元杂环的取代基所取代，所述的杂环含有1至3个(例如1、2或3个)选自O、S、N的杂原子； In some embodiments, R a1 , R a2 , R a4 are each independently selected from H, halogen, cyano, OH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthio, -SO 2 -C 1-6 alkyl, -C(=O)C 1-6 alkyl, -(CH 2 ) q -C 3-10 Carbocycle or -(CH 2 ) q -3- to 12-membered heterocycle, said -CH 2 -, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, carbocycle or heterocycle optionally further C1-6 alkyl substituted with 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, =O, C1-6 alkyl, halogen, C1 -6 alkoxy, C 3-6 cycloalkyl or 3- to 10-membered heterocycle substituents, the heterocycle contains 1 to 3 (eg 1, 2 or 3) selected from O, S , N heteroatoms;
在一些实施方案中，R a3选自H、C 1-6烷基、-(CH 2) q-C 3-10碳环或-(CH 2) q-3至12元杂环，所述的-CH 2-、烷基、碳环或杂环任选进一步被0至4个(例如0、1、2、3或4)选自H、卤素、OH、氰基、C 1-6烷基、卤素取代的C 1-6烷基、C 1-6烷氧基、C 3-6环烷基或3至10元杂环的取代基所取代，所述的杂环含有1至3个(例如1、2或3个)选自O、S、N的杂原子； In some embodiments, 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;
在一些实施方案中，R a3选自H、C 1-4烷基，所述的烷基任选进一步被0至4个(例如0、1、2、3或4)选自H、卤素、OH、氰基、C 1-4烷基、卤素取代的C 1-4烷基、C 1-4烷氧基、C 3-6环烷基的取代基所取代； In some embodiments, 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;
在一些实施方案中，R a3选自H、甲基、乙基、丙基、异丙基，所述的甲基、乙基、丙基或异丙基任选进一步被0至4个(例如0、1、2、3或4)选自H、卤素、OH、氰基、C 1-4烷基、卤素取代的C 1-4烷基、C 1-4烷氧基、C 3-6环烷基的取代基所取代； In some embodiments, 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;
在一些实施方案中，R a2选自选自H、F、Cl、Br、I、氰基、CF 3、CHF 2、CH 2F、甲基、甲氧基、环丙基； In some embodiments, R a2 is selected from the group consisting of H, F, Cl, Br, I, cyano, CF3 , CHF2 , CH2F , methyl, methoxy, cyclopropyl;
在一些实施方案中，R a3选自H或甲基； In some embodiments, R a3 is selected from H or methyl;
在一些实施方案中，R x、R a1、R a2、R a4各自独立的选自H、卤素、氰基、OH、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4烷氧基、C 1-4烷硫基、-SO 2-C 1-4烷基、-C(＝O)C 1-4烷基、-(CH 2) q-C 3-6碳环或-(CH 2) q-3至6元杂环，所述的-CH 2-、烷基、烯基、炔基、烷氧基、烷硫基、碳环或杂环任选进一步被0至4个(例如0、1、2、3或4)选自H、卤素、OH、氰基、＝O、C 1-4烷基、卤素取代的C 1-4烷基、C 1-4烷氧基、C 3-6环烷基或3至6元杂环的取代基所取代，所述的杂环含有1至3个(例如1、2或3个)选自O、S、N的杂原子； In some embodiments, R x , R a1 , R a2 , R a4 are each independently selected from H, halogen, cyano, OH, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkyne base, C 1-4 alkoxy, C 1-4 alkylthio, -SO 2 -C 1-4 alkyl, -C(=O)C 1-4 alkyl, -(CH 2 ) q -C 3-6 carbocycle or -( CH2 ) q -3 to 6 membered heterocycle, said -CH2- , alkyl, alkenyl, alkynyl, alkoxy, alkylthio, carbocycle or heterocycle optionally further C1-4alkyl substituted with 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, =0, C1-4alkyl , halogen , C 1-4 alkoxy, C 3-6 cycloalkyl or 3- to 6-membered heterocyclic substituents, and the heterocyclic ring contains 1 to 3 (eg 1, 2 or 3) selected from Heteroatoms of O, S, N;
在一些实施方案中，R x、R a1、R a2各自独立的选自H、F、Cl、Br、I、氰基、OH、甲基、乙基、丙基、异丙基、丁基、叔丁基、乙烯基、乙炔基、甲氧基、乙氧基、-SCH 3、-SCH 2CH 3、-SO 2CH 3、-SO 2CH 2CH 3、-C(＝O)CH 3、-C(＝O)CH 2CH 3、环丙基、环丁基、环戊基、环己基，所述的甲基、乙基、丙基、异丙基、丁基、叔丁基、乙烯基、乙炔基、甲氧基、乙氧基、-SCH 3、-SCH 2CH 3、-SO 2CH 3、-SO 2CH 2CH 3、-C(＝O)CH 3、-C(＝O)CH 2CH 3、环丙基、环丁基、环戊基、环己基任选进一步被0至4个(例如0、1、2、3或4)选自H、卤素、OH、氰基、C 1-4烷基、卤素取代的C 1-4烷基、C 1-4烷氧基、C 3-6环烷基的取代基所取代； In some embodiments, R x , R a1 , R a2 are each independently selected from H, F, Cl, Br, I, cyano, OH, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, vinyl, ethynyl, methoxy, ethoxy, -SCH 3 , -SCH 2 CH 3 , -SO 2 CH 3 , -SO 2 CH 2 CH 3 , -C(=O)CH 3 , -C(=O)CH 2 CH 3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, the methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, vinyl, ethynyl, methoxy, ethoxy, -SCH 3 , -SCH 2 CH 3 , -SO 2 CH 3 , -SO 2 CH 2 CH 3 , -C(=O)CH 3 , -C( =O) CH2CH3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl optionally further selected from 0 to 4 (eg 0, 1 , 2, 3 or 4) from H, halogen, OH, Substituted by substituents of cyano, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, C 1-4 alkoxy, and C 3-6 cycloalkyl;
在一些实施方案中，R x各自独立的选自H、F、Cl、Br、I、氰基、OH、甲基、乙基、丙基、异丙基、丁基、叔丁基、乙炔基、甲氧基、乙氧基、-SCH 3、-SCH 2CH 3、环丙基、环丁基、环戊基、环己基，所述的甲基、乙基、丙基、异丙基、乙炔基、甲氧基、乙氧基、-SCH 3、-SCH 2CH 3、环丙基、环丁基、环戊基、环己基任选进一步被0至4个(例如0、1、2、3或4)选自H、F、OH、氰基、甲基、乙基、甲氧基或乙氧基的取代基所取代； In some embodiments, 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 or ethoxy;
在一些实施方案中，R x各自独立的选自H、F、Cl、氰基、甲基、乙基、异丙基、三氟甲基、甲氧基、乙氧基、-SO 2CH 3、-SO 2CH 2CH 3、-C(＝O)CH 3、-C(＝O)CH 2CH 3、环丙基； In some embodiments, each Rx is independently selected from H, F, Cl , cyano, methyl, ethyl, isopropyl, trifluoromethyl, methoxy, ethoxy, -SO2CH3 , -SO 2 CH 2 CH 3 , -C(=O)CH 3 , -C(=O)CH 2 CH 3 , cyclopropyl;
在一些实施方案中，R a1选自H、F、Cl、Br、I、氰基、CF 3、CHF 2、CH 2F、甲基、乙基、丙基、异丙基、乙炔基、甲氧基、乙氧基、-SCH 3、-SCH 2CH 3、环丙基、环丁基、环戊基或环己基； In some embodiments, 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;
在一些实施方案中，R a1选自H、F、Cl、Br、I、氰基、CF 3、甲基； In some embodiments, R a1 is selected from H, F, Cl, Br, I, cyano, CF3 , methyl;
在一些实施方案中，R a2选自H； In some embodiments, R a2 is selected from H;
在一些实施方案中，环B选自4至11元含氮杂环、C 4-10碳环； In some embodiments, Ring B is selected from 4 to 11 membered nitrogen-containing heterocycles, C4-10 carbocycles;
在一些实施方案中，环B选自4至7元单环含氮杂环、5-11元螺环含氮杂环、5-11 元并环含氮杂环、5-11元桥环含氮杂环或C 4-7单环碳环； In some embodiments, 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;
在一些实施方案中，环B选自环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、哌啶基、哌嗪基、
Figure PCTCN2022088446-appb-000017
Figure PCTCN2022088446-appb-000018
In some embodiments, Ring B is selected from cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl,
Figure PCTCN2022088446-appb-000017
Figure PCTCN2022088446-appb-000018
在一些实施方案中，
Figure PCTCN2022088446-appb-000019
选自
Figure PCTCN2022088446-appb-000020
Figure PCTCN2022088446-appb-000021
Figure PCTCN2022088446-appb-000022
左侧与L连接； In some embodiments,
Figure PCTCN2022088446-appb-000019
selected from
Figure PCTCN2022088446-appb-000020
Figure PCTCN2022088446-appb-000021
Figure PCTCN2022088446-appb-000022
The left side is connected with L;
在一些实施方案中，R b各自独立的选自H、卤素、氰基、OH、＝O、C 1-6烷基、C 1-6烷氧基、-(CH 2) q-C 3-6环烷基，所述的-CH 2-、烷基、烷氧基或环烷基任选进一步被0至4个(例如0、1、2、3或4)选自H、卤素、OH、氰基、NH 2、C 1-6烷基、卤素取代的C 1-6烷基、C 1-6烷氧基或C 3-6环烷基的取代基所取代； In some embodiments, each R b is independently selected from H, halogen, cyano, OH, =O, C 1-6 alkyl, C 1-6 alkoxy, -(CH 2 ) q -C 3- 6 cycloalkyl, said -CH2- , alkyl, alkoxy or cycloalkyl is optionally further selected by 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, halogen, OH , cyano, NH 2 , C 1-6 alkyl, halogen substituted C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl substituent;
在一些实施方案中，R b各自独立的选自H、卤素、氰基、OH、＝O、C 1-4烷基、C 1-4烷氧基、-(CH 2) q-C 3-6环烷基，所述的-CH 2-、烷基、烷氧基或环烷基任选进一步被0至4个(例如0、1、2、3或4)选自H、卤素、OH、氰基、NH 2、C 1-4烷基、卤素取代的C 1-4烷基、C 1-4烷氧基或C 3-6环烷基的取代基所取代； In some embodiments, each R b is independently selected from H, halogen, cyano, OH, =O, C 1-4 alkyl, C 1-4 alkoxy, -(CH 2 ) q -C 3- 6 cycloalkyl, said -CH2- , alkyl, alkoxy or cycloalkyl is optionally further selected by 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, halogen, OH , cyano, NH 2 , C 1-4 alkyl, halogen substituted C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl substituent;
在一些实施方案中，R b各自独立的选自H、F、Cl、Br、I、氰基、OH、＝O、甲基、乙基、丙基或异丙基，所述的甲基、乙基、丙基或异丙基任选进一步被0至4个(例如 0、1、2、3或4)选自H、卤素、OH、氰基、NH 2、C 1-4烷基、卤素取代的C 1-4烷基、C 1-4烷氧基或C 3-6环烷基的取代基所取代； In some embodiments, each R b is independently selected from H, F, Cl, Br, I, cyano, OH, =O, methyl, ethyl, propyl, or isopropyl, the methyl, Ethyl, propyl or isopropyl are optionally further 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, NH2 , C1-4 alkyl, substituted by halogen-substituted C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl substituents;
在一些实施方案中，R b各自独立的选自H、F、Cl、Br、I、氰基、OH、＝O、甲基、乙基、丙基或异丙基； In some embodiments, each R b is independently selected from H, F, Cl, Br, I, cyano, OH, =O, methyl, ethyl, propyl, or isopropyl;
在一些实施方案中，W选自键、C 1-3亚烷基或者Q2，所示亚烷基任选进一步被0至4个(例如0、1、2、3或4)选自H、卤素、CF 3、OH、氰基、NH 2、C 1-6烷基或C 1-6烷氧基的取代基所取代； In some embodiments, 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;
在一些实施方案中，W选自键；In some embodiments, W is selected from a bond;
在一些实施方案中，L选自L1、L2或L3；In some embodiments, L is selected from L1, L2 or L3;
在一些实施方案中，L1选自-Q1-Ak1-Q2-Ak2-Q3-，右侧与环B连接；In some embodiments, L1 is selected from -Q1-Ak1-Q2-Ak2-Q3-, and the right side is attached to ring B;
在一些实施方案中，L1选自-N(R q)-Ak1-O-Ak2-C(＝O)-、-O-Ak1-O-Ak2-C(＝O)-、-O-Ak1-N(R q)-Ak2-C(＝O)-、-N(R q)-Ak1-N(R q)-Ak2-C(＝O)-、-N(R q)-Ak1-O-Ak2-N(R q)C(＝O)-、-O-Ak1-O-Ak2-N(R q)C(＝O)-、-N(R q)-Ak1-Ak2-C(＝O)-、-N(R q)-Ak1-Ak2-N(R q)C(＝O)-、-O-Ak1-N(R q)-Ak2-N(R q)C(＝O)-、-S-Ak1-O-Ak2-C(＝O)-、-O-Ak1-S-Ak2-C(＝O)-、-N(R q)-Ak1-O-Ak2-S(＝O) 2-、-O-Ak1-O-Ak2-S(＝O) 2-、-N(R q)-Ak1-O-Ak2-、-O-Ak1-O-Ak2-，右侧与环B连接； In some embodiments, L1 is selected from -N( Rq )-Ak1-O-Ak2-C(=O)-, -O-Ak1-O-Ak2-C(=O)-, -O-Ak1- N(R q )-Ak2-C(=O)-, -N(R q )-Ak1-N(R q )-Ak2-C(=O)-, -N(R q )-Ak1-O- Ak2-N( Rq )C(=O)-, -O-Ak1-O-Ak2-N( Rq )C(=O)-, -N( Rq )-Ak1-Ak2-C(=O )-, -N(R q )-Ak1-Ak2-N(R q )C(=O)-, -O-Ak1-N(R q )-Ak2-N(R q )C(=O)- , -S-Ak1-O-Ak2-C(=O)-, -O-Ak1-S-Ak2-C(=O)-, -N(R q )-Ak1-O-Ak2-S(=O ) 2 -, -O-Ak1-O-Ak2-S(=O) 2 -, -N(R q )-Ak1-O-Ak2-, -O-Ak1-O-Ak2-, right side with ring B connect;
在一些实施方案中，L1选自-N(R q)-Ak1-O-Ak2-C(＝O)N(R q)-、-O-Ak1-N(R q)-Ak2-C(＝O)N(R q)-、-O-Ak1-O-C(＝O)N(R q)-，右侧与环B连接； In some embodiments, L1 is selected from -N( Rq )-Ak1-O-Ak2-C(=O)N( Rq )-, -O-Ak1-N( Rq )-Ak2-C(= O)N(R q )-, -O-Ak1-OC(=O)N(R q )-, the right side is connected to ring B;
在一些实施方案中，L1选自
Figure PCTCN2022088446-appb-000023
右侧与环B连接； In some embodiments, L1 is selected from
Figure PCTCN2022088446-appb-000023
The right side is connected with ring B;
在一些实施方案中，L1选自
Figure PCTCN2022088446-appb-000024
Figure PCTCN2022088446-appb-000025
右侧与环B连接； In some embodiments, L1 is selected from
Figure PCTCN2022088446-appb-000024
Figure PCTCN2022088446-appb-000025
The right side is connected with ring B;
在一些实施方案中，L1选自-NH-Ak1-O-Ak2-C(＝O)-、-O-Ak1-O-Ak2-C(＝O)-、-N(CH 3)-Ak1-O-Ak2-C(＝O)-、-O-Ak1-NH-Ak2-C(＝O)-、-O-Ak1-N(CH 3)-Ak2-C(＝O)-、-N(CH 3)-Ak1-NH-Ak2-C(＝O)-、-NH-Ak1-NH-Ak2-C(＝O)-、-S-Ak1-O-Ak2-C(＝O)-、 -O-Ak1-S-Ak2-C(＝O)-、-NH-Ak1-O-Ak2-S(＝O) 2-、-O-Ak1-O-Ak2-S(＝O) 2-、-NH-Ak1-O-Ak2-、-O-Ak1-O-Ak2-，右侧与环B连接； In some embodiments, L1 is selected from -NH-Ak1-O-Ak2-C(=O)-, -O-Ak1-O-Ak2-C(=O)-, -N( CH3 )-Ak1- O-Ak2-C(=O)-, -O-Ak1-NH-Ak2-C(=O)-, -O-Ak1-N(CH 3 )-Ak2-C(=O)-, -N( CH 3 )-Ak1-NH-Ak2-C(=O)-, -NH-Ak1-NH-Ak2-C(=O)-, -S-Ak1-O-Ak2-C(=O)-, - O-Ak1-S-Ak2-C(=O)-, -NH-Ak1-O-Ak2-S(=O) 2 -, -O-Ak1-O-Ak2-S(=O) 2 -, - NH-Ak1-O-Ak2-, -O-Ak1-O-Ak2-, the right side is connected to ring B;
在一些实施方案中，L2选自
Figure PCTCN2022088446-appb-000026
右侧与环B连接； In some embodiments, L2 is selected from
Figure PCTCN2022088446-appb-000026
The right side is connected with ring B;
在一些实施方案中，L2选自
Figure PCTCN2022088446-appb-000027
右侧与环B连接； In some embodiments, L2 is selected from
Figure PCTCN2022088446-appb-000027
The right side is connected with ring B;
在一些实施方案中，L2选自
Figure PCTCN2022088446-appb-000028
右侧与环B连接； In some embodiments, L2 is selected from
Figure PCTCN2022088446-appb-000028
The right side is connected with ring B;
在一些实施方案中，L3选自
Figure PCTCN2022088446-appb-000029
右侧与环B连接； In some embodiments, L3 is selected from
Figure PCTCN2022088446-appb-000029
The right side is connected with ring B;
在一些实施方案中，L3选自
Figure PCTCN2022088446-appb-000030
Figure PCTCN2022088446-appb-000031
右侧与环B连接； In some embodiments, L3 is selected from
Figure PCTCN2022088446-appb-000030
Figure PCTCN2022088446-appb-000031
The right side is connected with ring B;
在一些实施方案中，L4选自-Ak3-Q4-Ak4-K1-Q5-K2-Ak5-Q6-或-Ak3-Q4-Ak4-K1-Q5-，右侧与环B连接；In some embodiments, 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;
在一些实施方案中，L4选自-Ak3-O-K1-C(＝O)-、-Ak3-N(R q)-K1-C(＝O)-、-Ak3-N(R q)-K1-C(＝O)-，右侧与环B连接； In some embodiments, L4 is selected from -Ak3-O-K1-C(=O)-, -Ak3-N( Rq )-K1-C(=O)-, -Ak3-N( Rq )- K1-C(=O)-, the right side is connected with ring B;
在一些实施方案中，L4选自-Ak3-O-K1-C(＝O)-、-Ak3-NH-K1-C(＝O)-、-Ak3-N(CH 3)-K1-C(＝O)-，右侧与环B连接； In some embodiments, L4 is selected from -Ak3-O-K1-C(=O)-, -Ak3-NH-K1-C(=O)-, -Ak3-N( CH3 )-K1-C( =O)-, the right side is connected with ring B;
在一些实施方案中，Ak1、Ak2各自独立的选自C 1-4亚烷基、C 2-4亚烯基、C 2-4亚炔基，所述Ak1任选进一步被0至4个(例如0、1、2、3或4)R k1取代，所述Ak2任选进一步被0至4个(例如0、1、2、3或4)R k2取代； In some embodiments, 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 ;
在一些实施方案中，Ak1、Ak2各自独立的选自C 1-3亚烷基、C 2-3亚烯基、C 2-3亚炔基，所述Ak1任选进一步被0至4个(例如0、1、2、3或4)R k1取代，所述Ak2任选 进一步被0至4个(例如0、1、2、3或4)R k2取代； In some embodiments, 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 ;
在一些实施方案中，Ak1、Ak2各自独立的选自亚甲基、亚乙基、亚丙基、亚乙烯基、亚丙烯基、亚乙炔基、亚丙炔基，所述Ak1任选进一步被0至4个(例如0、1、2、3或4)R k1取代，所述Ak2任选进一步被0至4个(例如0、1、2、3或4)R k2取代； In some embodiments, 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 ;
在一些实施方案中，Ak3、Ak4、Ak5各自独立的选自键、C 1-4亚烷基、C 2-4亚烯基、C 2-4亚炔基，所述Ak3任选进一步被0至4个(例如0、1、2、3或4)R k3取代，所述Ak4任选进一步被0至4个(例如0、1、2、3或4)R k4取代，所述Ak5任选进一步被0至4个R k5取代； In some embodiments, 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 ;
在一些实施方案中，Ak3、Ak4、Ak5各自独立的选自键、C 1-3亚烷基、C 2-3亚烯基、C 2-3亚炔基，所述Ak3任选进一步被0至4个(例如0、1、2、3或4)R k3取代，所述Ak4任选进一步被0至4个(例如0、1、2、3或4)R k4取代，所述Ak5任选进一步被0至4个R k5(例如0、1、2、3或4)取代； In some embodiments, 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);
在一些实施方案中，Ak3、Ak4、Ak5各自独立的选自键、亚甲基、亚乙基、亚丙基、亚乙烯基、亚丙烯基、亚乙炔基、亚丙炔基，所述Ak3任选进一步被0至4个(例如0、1、2、3或4)R k3取代，所述Ak4任选进一步被0至4个(例如0、1、2、3或4)R k4取代，所述Ak5任选进一步被0至4个R k5取代； In some embodiments, 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 ;
在一些实施方案中，K1或K2选自C 1-2亚烷基、C 3-10碳环或3至12元杂环，所述的亚烷基任选进一步被0至4个(例如0、1、2、3或4)R k6取代，所述的碳环或杂环任选进一步被0至4个(例如0、1、2、3或4)选自H、卤素、OH、氰基、NH 2、C 1-6烷基、C 2-6烯基、C 2-6炔基、卤素取代的C 1-6烷基、C 1-6烷氧基、-C 1-6烷基-OC 1-6烷基、-O-C 1-6烷基-OC 1-6烷基、-O-C 3-8碳环、C 3-8碳环、4至10元杂环的取代基所取代，所述的杂环含有1至3个(例如1、2或3个)选自O、S、N的杂原子； In some embodiments, 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;
在一些实施方案中，K1或K2选自C 1-2亚烷基、C 3-6碳环或3至7元杂环，所述的亚烷基任选进一步被0至4个(例如0、1、2、3或4)R k6取代，所述的碳环或杂环任选进一步被0至4个(例如0、1、2、3或4)选自H、卤素、OH、氰基、NH 2、C 1-4烷基、C 2-4烯基、C 2-4炔基、卤素取代的C 1-4烷基、C 1-4烷氧基、-C 1-4烷基-OC 1-4烷基、-O-C 1-4烷基-OC 1-4烷基、-O-C 3-6碳环、C 3-6碳环、4至7元杂环的取代基所取代，所述的杂环含有1至3个(例如1、2或3个)选自O、S、N的杂原子； In some embodiments, 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, N;
在一些实施方案中，K1或K2选自亚甲基、亚乙基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氮杂环戊基、氮杂环己基、哌嗪、吗啉、氧杂环丁基、氧杂环戊基、 氧杂环己基、苯环、吡啶、吡嗪、嘧啶、哒嗪，所述的亚甲基、亚乙基任选进一步被0至4个(例如0、1、2、3或4)R k6取代，所述的环丙基、环丁基、环戊基、环己基、氮杂环丁基、氮杂环戊基、氮杂环己基、哌嗪、吗啉、氧杂环丁基、氧杂环戊基、氧杂环己基、苯环、吡啶、吡嗪、嘧啶、哒嗪任选进一步被0至4个(例如0、1、2、3或4)选自H、卤素、OH、氰基、NH 2、C 1-4烷基、C 2-4烯基、C 2-4炔基、卤素取代的C 1-4烷基、C 1-4烷氧基、-C 1-4烷基-OC 1-4烷基、-O-C 1-4烷基-OC 1-4烷基、-O-C 3-6碳环、C 3-6碳环、4至7元杂环的取代基所取代，所述的杂环含有1至3个(例如1、2或3个)选自O、S、N的杂原子； In some embodiments, 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, oxanyl, benzene ring, pyridine, pyrazine, pyrimidine, pyridazine are optionally further substituted by 0 to 4 ( For example 0, 1, 2, 3 or 4) is 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 alkyl, -OC 1-4 alkyl-OC 1-4 alkyl, -OC 3-6 carbon substituted by substituents of ring, C 3-6 carbocycle, 4- to 7-membered heterocycle containing 1 to 3 (eg 1, 2 or 3) heteroatoms selected from O, S, N ;
在一些实施方案中，R k1、R k2、R k3、R k4、R k5、R k6、R L1、R L2各自独立的选自H、卤素、氰基、OH、＝O、NH 2、NHC 1-6烷基、N(C 1-6烷基) 2、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、-OC 3-6碳环、C 3-6碳环或4至7元杂环，所述的烷基、烯基、炔基、烷氧基、碳环或杂环任选进一步被0至4个(例如0、1、2、3或4)选自H、卤素、OH、氰基、NH 2、C 1-6烷基、C 2-6烯基、C 2-6炔基、卤素取代的C 1-6烷基、C 1-6烷氧基、-O-C 3-8碳环、C 3-8碳环、4至10元杂环的取代基所取代，所述的杂环含有1至3个(例如1、2或3个)选自O、S、N的杂原子； In some embodiments, R k1 , R k2 , R k3 , R k4 , R k5 , R k6 , R L1 , R L2 are each independently selected from H, halogen, cyano, OH, =O, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, -OC 3- 6 -carbocycle, C 3-6 carbocycle or 4- to 7-membered heterocycle, said alkyl, alkenyl, alkynyl, alkoxy, carbocycle or heterocycle is optionally further substituted by 0 to 4 (eg 0 , 1, 2, 3 or 4) is 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, -OC 3-8 carbocycle, C 3-8 carbocycle, 4- to 10-membered heterocycle substituents, and the heterocycle contains 1 to 3 ( For example 1, 2 or 3) heteroatoms selected from O, S, N;
在一些实施方案中，R k1、R k2、R k3、R k4、R k5、R k6、R L1、R L2各自独立的选自H、卤素、氰基、OH、＝O、NH 2、NHC 1-4烷基、N(C 1-4烷基) 2、C 1-4烷基、C 1-4烷氧基、C 3-6碳环或4至7元杂环，所述的烷基、烷氧基、碳环或杂环任选进一步被0至4个(例如0、1、2、3或4)选自H、卤素、OH、氰基、NH 2、C 1-4烷基、卤素取代的C 1-4烷基、C 1-4烷氧基、C 3-6碳环(例如C 3、C 4、C 5或C 6)、4至6元(例如4、5或6元)杂环的取代基所取代，所述的杂环含有1至3个(例如1、2或3个)选自O、S、N的杂原子； In some embodiments, R k1 , R k2 , R k3 , R k4 , R k5 , R k6 , R L1 , R L2 are each independently selected from H, halogen, cyano, OH, =O, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 alkoxy, C 3-6 carbocycle or 4- to 7-membered heterocycle, the alkane radical, alkoxy, carbocycle or heterocycle optionally further selected from 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, NH2 , C1-4alkane base, halogen-substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 carbocyclic (eg C 3 , C 4 , C 5 or C 6 ), 4 to 6 membered (eg 4, 5 or 6-membered) substituents of heterocycles containing 1 to 3 (eg 1, 2 or 3) heteroatoms selected from O, S, N;
在一些实施方案中，R k1、R k2、R k3、R k4、R k5、R k6、R L1、R L2各自独立的选自H、F、Cl、Br、I、氰基、OH、＝O、NH 2、NH(CH 3)、N(CH 3) 2、甲基、乙基、丙基、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氮杂环戊基、氮杂环己基、氧杂环丁基、氧杂环戊基、氧杂环己基、吡啶、苯基，所述甲基、乙基、丙基、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氮杂环戊基、氮杂环己基、氧杂环丁基、氧杂环戊基、氧杂环己基、吡啶、苯基任选进一步被0至4个(例如0、1、2、3或4)选自H、卤素、OH、氰基、NH 2、C 1-4烷基、卤素取代的C 1-4烷基、C 1-4烷氧基、C 3-6碳环(例如C 3、C 4、C 5或C 6)、4至6元(例如4、5或6元)杂环的取代基所取代，所述的杂环含有1至3个(例如1、2或3个)选自O、S、N的杂原子； In some embodiments, R k1 , R k2 , R k3 , R k4 , R k5 , R k6 , R L1 , R L2 are each independently selected from H, F, Cl, Br, I, cyano, OH, = O, NH2 , NH( CH3 ), N( CH3 ) 2 , methyl, ethyl, propyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Azacyclobutyl, azacyclopentyl, azacyclohexyl, oxetanyl, oxolane, oxanyl, pyridine, phenyl, the methyl, ethyl, propyl, Methoxy, Ethoxy, Cyclopropyl, Cyclobutyl, Cyclopentyl, Cyclohexyl, Azacyclobutyl, Azacyclopentyl, Azacyclohexyl, Oxetanyl, Oxolane group, oxanyl, pyridine, phenyl optionally further selected by 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, NH2 , C1-4alkane base, halogen-substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 carbocyclic (eg C 3 , C 4 , C 5 or C 6 ), 4 to 6 membered (eg 4, 5 or 6-membered) substituents of heterocycles containing 1 to 3 (eg 1, 2 or 3) heteroatoms selected from O, S, N;
在一些实施方案中，R k1与R k1、R k2与R k2、R k1与R k2、R k3与R k3、R k4与R k4、R k5与R k5、R k6与R k6直接连接形成C 3-6碳环(例如C 3、C 4、C 5或C 6)或者4至7元(例如4、5、6或7元)的杂环，所述的碳环或杂环任选进一步被0至4个(例如0、1、2、3或4)选自H、卤素、＝O、OH、氰基、C 1-6烷基、卤素取代的C 1-6烷基、C 1-6烷氧基、C 3-6环烷基的取代基所取代，所述的杂环含有1至3个(例如1、2或3个)选自O、S、N的杂原子； In some embodiments, R k1 and R k1 , R k2 and R k2 , R k1 and R k2 , R k3 and R k3 , R k4 and R k4 , R k5 and R k5 , and R k6 and R k6 are directly linked to form C 3-6 carbocycle (eg C 3 , C 4 , C 5 or C 6 ) or 4 to 7 membered (eg 4, 5, 6 or 7 membered) heterocycle, said carbocycle or heterocycle optionally further 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, halogen, =O, OH, cyano, C1-6 alkyl, halogen substituted C1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl substituent, the heterocycle contains 1 to 3 (eg 1, 2 or 3) heteroatoms selected from O, S, N;
在一些实施方案中，R k1与R k1、R k2与R k2、R k1与R k2、R k3与R k3、R k4与R k4、R k5与R k5、R k6与R k6直接连接形成C 3-6碳环(例如C 3、C 4、C 5或C 6)或者4至7元(例如4、5、6或7元)的杂环，所述的碳环或杂环任选进一步被0至4个(例如0、1、2、3或4)选自H、卤素、＝O、OH、氰基、C 1-4烷基、卤素取代的C 1-4烷基、C 1-4烷氧基、C 3-6环烷基的取代基所取代，所述的杂环含有1至3个(例如1、2或3个)选自O、S、N的杂原子； In some embodiments, R k1 and R k1 , R k2 and R k2 , R k1 and R k2 , R k3 and R k3 , R k4 and R k4 , R k5 and R k5 , and R k6 and R k6 are directly linked to form C 3-6 carbocycle (eg C 3 , C 4 , C 5 or C 6 ) or 4 to 7 membered (eg 4, 5, 6 or 7 membered) heterocycle, said carbocycle or heterocycle optionally further 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, halogen, =O, OH, cyano, C1-4alkyl , halogen substituted C1-4alkyl , C 1-4 alkoxy, C 3-6 cycloalkyl substituent, the heterocycle contains 1 to 3 (eg 1, 2 or 3) heteroatoms selected from O, S, N;
在一些实施方案中，Q1、Q5各自独立的选自O、S、N(R q)、C(＝O)、C(＝O)N(R q)、N(R q)C(＝O)、C(＝O)O、OC(＝O)、S(＝O)、S(＝O) 2、S(＝O) 2N(R q)、N(R q)S(＝O) 2、N(R q)C(＝O)N(R q)、N(R q)C(＝O)N(R q)； In some embodiments, Q1, Q5 are each independently selected from O, S, N( Rq ), C(=O), C(=O)N( Rq ), N( Rq )C(=O ), C(=O)O, OC(=O), S(=O), S(=O) 2 , S(=O) 2 N(R q ), N(R q )S(=O) 2. N(R q )C(=O)N(R q ), N(R q )C(=O)N(R q );
在一些实施方案中，Q1、Q5各自独立的选自O、S、N(R q)、C(＝O)、C(＝O)N(R q)、N(R q)C(＝O)、S(＝O) 2； In some embodiments, Q1, Q5 are each independently selected from O, S, N( Rq ), C(=O), C(=O)N( Rq ), N( Rq )C(=O ), S(=O) 2 ;
在一些实施方案中，Q2、Q3、Q4、Q6各自独立的选自键或者Q1；In some embodiments, Q2, Q3, Q4, Q6 are each independently selected from a bond or Q1;
在一些实施方案中，环E选自C 3-6碳环或4至7元杂环，所述的杂环含有1至3个(例如1、2或3个)选自O、S、N的杂原子； In some embodiments, 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;
在一些实施方案中，环E选自C 3-6碳环或4至6元杂环，所述的杂环含有1至3个(例如1、2或3个)选自O、S、N的杂原子； In some embodiments, 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;
在一些实施方案中，环E选自苯基或5-6元杂芳基，所述的杂芳基含有1至3个(例如1、2或3个)选自O、S、N的杂原子；In some embodiments, 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;
在一些实施方案中，环E选自苯环或吡啶；In some embodiments, Ring E is selected from a benzene ring or a pyridine;
在一些实施方案中，R q各自独立的选自H、C 1-6烷基或C 3-6环烷基，所述的烷基或环烷基任选进一步被0至4个(例如0、1、2、3或4)选自H、卤素、CF 3、OH、氰基、NH 2、C 1-6烷基或C 1-6烷氧基的取代基所取代； In some embodiments, 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;
在一些实施方案中，R q各自独立的选自H、C 1-4烷基，所述的烷基任选进一步被0至4个(例如0、1、2、3或4)选自H、卤素、CF 3、OH、氰基、NH 2、C 1-4烷基或C 1-4 烷氧基的取代基所取代； In some embodiments, 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;
在一些实施方案中，R q各自独立的选自H、甲基、乙基； In some embodiments, each R q is independently selected from H, methyl, ethyl;
在一些实施方案中，R q与R k1或R k2直接连接，形成4至7元的杂环，所述的杂环任选进一步被0至4个(例如0、1、2、3或4)选自H、卤素、＝O、OH、氰基、C 1-6烷基、卤素取代的C 1-6烷基、C 1-6烷氧基、C 3-6环烷基的取代基所取代，所述的杂环含有1至3个(例如1、2或3个)选自O、S、N的杂原子； In some embodiments, R q is directly linked to R k1 or R k2 to form a 4- to 7-membered heterocycle optionally further substituted by 0 to 4 (eg, 0, 1, 2, 3, or 4 ) is a substituent selected from H, halogen, =O, OH, cyano, C 1-6 alkyl, halogen substituted C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl substituted, the heterocycle contains 1 to 3 (eg 1, 2 or 3) heteroatoms selected from O, S, N;
在一些实施方案中，R q与R k1、R q与R k2直接连接形成4至7元的杂环，所述的杂环任选进一步被0至4个(例如0、1、2、3或4)选自H、卤素、＝O、OH、氰基、C 1-4烷基、卤素取代的C 1-4烷基、C 1-4烷氧基、C 3-6环烷基的取代基所取代，所述的杂环含有1至3个(例如1、2或3个)选自O、S、N的杂原子； In some embodiments, R q and R k1 , and R q and R k2 are directly linked to form a 4- to 7-membered heterocycle optionally further substituted by 0 to 4 (eg, 0, 1, 2, 3 or 4) 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 Substituents are substituted, and the heterocycle contains 1 to 3 (eg 1, 2 or 3) heteroatoms selected from O, S, N;
在一些实施方案中，R q与R k1、R q与R k2直接连接形成4至7元的杂环，所述的杂环任选进一步被0至4个(例如0、1、2、3或4)选自H、卤素、＝O、OH、氰基、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、环丙基的取代基所取代，所述的杂环含有1至3个(例如1、2或3个)选自O、S、N的杂原子； In some embodiments, R q and R k1 , and R q and R k2 are directly linked to form a 4- to 7-membered heterocycle optionally further substituted by 0 to 4 (eg, 0, 1, 2, 3 or 4) substituted with a substituent selected from H, halogen, =O, OH, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, and cyclopropyl, said The heterocycle contains 1 to 3 (eg 1, 2 or 3) heteroatoms selected from O, S, N;
在一些实施方案中，L1选自
Figure PCTCN2022088446-appb-000032
In some embodiments, L1 is selected from
Figure PCTCN2022088446-appb-000032
Figure PCTCN2022088446-appb-000033
Figure PCTCN2022088446-appb-000033
Figure PCTCN2022088446-appb-000034
Figure PCTCN2022088446-appb-000034
Figure PCTCN2022088446-appb-000035
Figure PCTCN2022088446-appb-000036
右侧与环B连接；
Figure PCTCN2022088446-appb-000035
Figure PCTCN2022088446-appb-000036
The right side is connected with ring B;
在一些实施方案中，L1选自
Figure PCTCN2022088446-appb-000037
右侧与环B连接； In some embodiments, L1 is selected from
Figure PCTCN2022088446-appb-000037
The right side is connected with ring B;
在一些实施方案中，L1选自或者L1选自
Figure PCTCN2022088446-appb-000038
Figure PCTCN2022088446-appb-000039
Figure PCTCN2022088446-appb-000040
右侧与环B连接； In some embodiments, L1 is selected from or L1 is selected from
Figure PCTCN2022088446-appb-000038
Figure PCTCN2022088446-appb-000039
Figure PCTCN2022088446-appb-000040
The right side is connected with ring B;
在一些实施方案中，L选自
Figure PCTCN2022088446-appb-000041
或者
Figure PCTCN2022088446-appb-000042
或者Y选自-CH 2S(＝O) 2-； In some embodiments, L is selected from
Figure PCTCN2022088446-appb-000041
or
Figure PCTCN2022088446-appb-000042
or Y is selected from -CH 2 S(=O) 2 -;
在一些实施方案中，L选自
Figure PCTCN2022088446-appb-000043
Figure PCTCN2022088446-appb-000044
右侧与环B连接； In some embodiments, L is selected from
Figure PCTCN2022088446-appb-000043
Figure PCTCN2022088446-appb-000044
The right side is connected with ring B;
在一些实施方案中，L选自
Figure PCTCN2022088446-appb-000045
Figure PCTCN2022088446-appb-000046
右侧与环B连接； In some embodiments, L is selected from
Figure PCTCN2022088446-appb-000045
Figure PCTCN2022088446-appb-000046
The right side is connected with ring B;
在一些实施方案中，L2选自
Figure PCTCN2022088446-appb-000047
Figure PCTCN2022088446-appb-000048
Figure PCTCN2022088446-appb-000049
右侧与环B连接； In some embodiments, L2 is selected from
Figure PCTCN2022088446-appb-000047
Figure PCTCN2022088446-appb-000048
Figure PCTCN2022088446-appb-000049
The right side is connected with ring B;
在一些实施方案中，L3选自
Figure PCTCN2022088446-appb-000050
右侧与环B连接； In some embodiments, L3 is selected from
Figure PCTCN2022088446-appb-000050
The right side is connected with ring B;
在一些实施方案中，q各自独立的选自0、1、2、3或4；In some embodiments, each q is independently selected from 0, 1, 2, 3, or 4;
在一些实施方案中，a选自0、1、2、3或4；In some embodiments, a is selected from 0, 1, 2, 3, or 4;
在一些实施方案中，b选自0、1、2、3或4；In some embodiments, b is selected from 0, 1, 2, 3, or 4;
在一些实施方案中，x选自0、1、2、3或4；In some embodiments, x is selected from 0, 1, 2, 3, or 4;
在一些实施方案中，s1选自0、1、2、3或4；In some embodiments, s1 is selected from 0, 1, 2, 3, or 4;
在一些实施方案中，s2选自0、1、2、3或4；In some embodiments, s2 is selected from 0, 1, 2, 3, or 4;
在一些实施方案中，s3选自0、1、2、3或4。In some embodiments, s3 is selected from 0, 1, 2, 3, or 4.
作为本发明的第一种实施方案，上述通式(I)所示化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，As the first embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,
Y选自O、S、S(＝O)、S(＝O) 2、S(＝O) 2N(R y)、N(R y)、C 1-4亚烷基、-OC 1-3亚烷基-、-C 1-3亚烷基O-、-C 1-3亚烷基S-、-C 1-3亚烷基S(＝O)-、-C 1-3亚烷基S(＝O) 2-、-N(R y)C 1-3亚烷基-、-C 1-3亚烷基N(R y)-，所述的亚烷基任选进一步被0至4个(例如0、1、2、3或4)选自H、卤素、＝O、＝S、OH、氰基、C 1-6烷基、卤素取代的C 1-6烷基、C 1-6烷氧基、C 3-6环烷基的取代基所取代； Y is selected from O, S, S(=O), S(=O) 2 , S(=O) 2 N(R y ), N(R y ), C 1-4 alkylene, -OC 1- 3 alkylene-, -C 1-3 alkylene O-, -C 1-3 alkylene S-, -C 1-3 alkylene S(=O)-, -C 1-3 alkylene Base S(=O) 2 -, -N(R y )C 1-3 alkylene-, -C 1-3 alkylene N(R y )-, the alkylene group is optionally further modified by O to 4 (eg 0, 1, 2, 3 or 4) selected from H, halogen, =O, =S, OH, cyano, C1-6 alkyl, halogen substituted C1-6 alkyl, C Substituents of 1-6 alkoxy and C 3-6 cycloalkyl;
R y各自独立的选自H、C 1-6烷基或C 3-6环烷基，所述的烷基或环烷基任选进一步被0至4个(例如0、1、2、3或4)选自H、氘、卤素、CF 3、OH、氰基、NH 2、C 1-6烷基、C 1-6烷氧基、3至8元杂环基或C 3-6环烷基的取代基所取代，所述的杂环基含有1至3个选自O、S、N的杂原子； 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;
环A选自C 6-10芳基、5-10元杂芳基或5-10元杂环基,所述的杂芳基或者杂环基含有1至5个选自O、S、N的杂原子； 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;
环X选自C 6-10芳基、5-10元杂芳基、C 3-10碳环或5-10元杂环基，所述的杂芳基或者杂环基含有1至5个选自O、S、N的杂原子； 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;
R x、R a各自独立的选自H、卤素、氰基、OH、＝O、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6烷硫基、-SO 2-C 1-6烷基、-C(＝O)C 1-6烷基、-(CH 2) q-C 3-10碳环或-(CH 2) q-3至12元杂环，所述的-CH 2-、烷基、烯基、炔基、烷氧基、烷硫基、碳环或杂环任选进一步被0至4个(例如0、1、2、3或4)选自H、卤素、OH、氰基、＝O、NH 2、NH(C 1-6烷基)、N(C 1-6烷基) 2、C 1-6烷基、卤素取代的C 1-6烷基、C 1-6烷氧基、C 3-6环烷基或3至10元杂环的取代基所取代，所述的杂环含有1至3个(例如1、2或3个)选自O、S、N的杂原子； R x and Ra are independently selected from H, halogen, cyano, OH, =O, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy , C 1-6 alkylthio, -SO 2 -C 1-6 alkyl, -C(=O)C 1-6 alkyl, -(CH 2 ) q -C 3-10 carbocyclic or -(CH 2 ) q -3- to 12-membered heterocycle, the -CH 2 -, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, carbocycle or heterocycle are optionally further replaced by 0 to 4 ( For example 0, 1, 2, 3 or 4) is selected from H, halogen, OH, cyano, =O, NH 2 , NH(C 1-6 alkyl), N(C 1-6 alkyl) 2 , C 1-6 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 (eg 1, 2 or 3) heteroatoms selected from O, S, N;
环B选自4至11元含氮杂环、C 4-10碳环； Ring B is selected from 4- to 11-membered nitrogen-containing heterocycles, C 4-10 carbocycles;
R b各自独立的选自H、卤素、氰基、OH、＝O、C 1-6烷基、C 1-6烷氧基、-(CH 2) q-C 3-6环烷基，所述的-CH 2-、烷基、烷氧基或环烷基任选进一步被0至4个(例如0、1、2、3或4)选自H、卤素、OH、氰基、NH 2、C 1-6烷基、卤素取代的C 1-6烷基、C 1-6烷氧基或C 3-6环烷基的取代基所取代； R b is each independently selected from H, halogen, cyano, OH, =O, C 1-6 alkyl, C 1-6 alkoxy, -(CH 2 ) q -C 3-6 cycloalkyl, so Said -CH2- , alkyl, alkoxy or cycloalkyl is optionally further selected from 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, NH2 , C 1-6 alkyl, halogen substituted C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl substituent;
W选自键、C 1-3亚烷基或者Q2，所示亚烷基任选进一步被0至4个(例如0、1、2、3或4)选自H、卤素、CF 3、OH、氰基、NH 2、C 1-6烷基或C 1-6烷氧基的取代基所取代； 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选自L1、L2或L3；L is selected from L1, L2 or L3;
L1选自-Q1-Ak1-Q2-Ak2-Q3-，右侧与环B连接；L1 is selected from -Q1-Ak1-Q2-Ak2-Q3-, and the right side is connected to ring B;
L2选自
Figure PCTCN2022088446-appb-000051
右侧与环B连接； L2 is selected from
Figure PCTCN2022088446-appb-000051
The right side is connected with ring B;
L3选自
Figure PCTCN2022088446-appb-000052
右侧与环B连接； L3 is selected from
Figure PCTCN2022088446-appb-000052
The right side is connected with ring B;
L4选自-Ak3-Q4-Ak4-K1-Q5-K2-Ak5-Q6-或-Ak3-Q4-Ak4-K1-Q5-，右侧与环B连接；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各自独立的选自C 1-4亚烷基、C 2-4亚烯基、C 2-4亚炔基，所述Ak1任选进一步被0至4个R k1取代，所述Ak2任选进一步被0至4个R k2取代； 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各自独立的选自键、C 1-4亚烷基、C 2-4亚烯基、C 2-4亚炔基，所述Ak3任选进一步被0至4个(例如0、1、2、3或4)R k3取代，所述Ak4任选进一步被0至4个(例如0、1、2、3或4)R k4取代，所述Ak5任选进一步被0至4个(例如0、1、2、3或4)R k5取代； 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或K2选自C 1-2亚烷基、C 3-10碳环或3至12元杂环，所述的亚烷基任选进一步被0至4个(例如0、1、2、3或4)R k6取代，所述的碳环或杂环任选进一步被0至4个(例如0、1、2、3或4)选自H、卤素、OH、氰基、NH 2、C 1-6烷基、C 2-6烯基、C 2-6炔基、卤素取代的C 1-6烷基、C 1-6烷氧基、-C 1-6烷基-OC 1-6烷基、-O-C 1-6烷基-OC 1-6烷基、-O-C 3-8碳环、C 3-8碳环、4至10元杂环的取代基所取代，所述的杂环含有1至3个(例如1、2或3个)选自O、S、N的杂原子； 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;
R k1、R k2、R k3、R k4、R k5、R k6、R L1、R L2各自独立的选自H、卤素、氰基、OH、＝O、NH 2、NHC 1-6烷基、N(C 1-6烷基) 2、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、-OC 3-6碳环、C 3-6碳环或4至7元杂环，所述的烷基、烯基、炔基、烷氧基、碳环或杂环任选进一步被0至4个(例如0、1、2、3或4)选自H、卤素、OH、氰基、NH 2、C 1-6烷基、C 2-6烯基、C 2-6炔基、卤素取代的C 1-6烷基、C 1-6烷氧基、-O-C 3-8碳环、C 3-8碳环、4至10元杂环的取代基所取代，所述的杂环含有1至3个(例如1、2或3个)选自O、S、N的杂原子； R k1 , R k2 , R k3 , R k4 , R k5 , R k6 , R L1 , R L2 are each independently selected from H, halogen, cyano, OH, =O, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, -OC 3-6 carbocycle, C 3 -6 -carbocycle or 4- to 7-membered heterocycle, said alkyl, alkenyl, alkynyl, alkoxy, carbocycle or heterocycle optionally further substituted by 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, -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 a) heteroatoms selected from O, S, N;
作为选择，R k1与R k1、R k2与R k2、R k1与R k2、R k3与R k3、R k4与R k4、R k5与R k5、R k6与R k6直接连接形成C 3-6碳环或者4至7元的杂环，所述的碳环或杂环任选进一步被0至4个(例如0、1、2、3或4)选自H、卤素、＝O、OH、氰基、C 1-6烷基、卤素取代的 C 1-6烷基、C 1-6烷氧基、C 3-6环烷基的取代基所取代，所述的杂环含有1至3个(例如1、2或3个)选自O、S、N的杂原子； Alternatively, Rk1 and Rk1 , Rk2 and Rk2 , Rk1 and Rk2 , Rk3 and Rk3, Rk4 and Rk4, Rk5 and Rk5 , Rk6 and Rk6 are directly linked to form C3- 6 -carbocycle or 4- to 7-membered heterocycle optionally further selected from H, halogen, =O, OH by 0 to 4 (eg 0, 1, 2, 3 or 4) , cyano, C 1-6 alkyl, halogen-substituted C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl substituents, the heterocycle contains 1 to 3 (eg 1, 2 or 3) heteroatoms selected from O, S, N;
Q1、Q5各自独立的选自O、S、N(R q)、C(＝O)、C(＝O)N(R q)、N(R q)C(＝O)、C(＝O)O、OC(＝O)、S(＝O)、S(＝O) 2、S(＝O) 2N(R q)、N(R q)S(＝O) 2、N(R q)C(＝O)N(R q)、N(R q)C(＝O)N(R q)； Q1 and Q5 are independently selected from O, S, N(R q ), C(=O), C(=O) N(R q ), N(R q ), C(=O), C(=O )O, OC(=O), S(=O), S(=O) 2 , S(=O) 2 N(R q ), N(R q )S(=O) 2 , N(R q ) )C(=O)N( Rq ), N( Rq )C(=O)N( Rq );
Q2、Q3、Q4、Q6各自独立的选自键或者Q1；Q2, Q3, Q4, Q6 are each independently selected from the key or Q1;
环E选自C 3-6碳环或4至7元杂环，所述的杂环含有1至3个(例如1、2或3个)选自O、S、N的杂原子； 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各自独立的选自H、C 1-6烷基或C 3-6环烷基，所述的烷基或环烷基任选进一步被0至4个(例如0、1、2、3或4)选自H、卤素、CF 3、OH、氰基、NH 2、C 1-6烷基或C 1- 6烷氧基的取代基所取代； 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 ;
作为选择，R q与R k1或R k2直接连接，形成4至7元的杂环，所述的杂环任选进一步被0至4个(例如0、1、2、3或4)选自H、卤素、＝O、OH、氰基、C 1-6烷基、卤素取代的C 1-6烷基、C 1-6烷氧基、C 3-6环烷基的取代基所取代，所述的杂环含有1至3个(例如1、2或3个)选自O、S、N的杂原子； Alternatively, R q is directly linked to R k1 or R k2 to form a 4 to 7 membered heterocycle optionally further selected from 0 to 4 (eg 0, 1, 2, 3 or 4) H, halogen, =O, OH, cyano, C 1-6 alkyl, halogen-substituted C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl substituents, The heterocycle contains 1 to 3 (eg 1, 2 or 3) heteroatoms selected from O, S, N;
q各自独立的选自0、1、2、3或4；q is independently selected from 0, 1, 2, 3 or 4;
a选自0、1、2、3或4；a is selected from 0, 1, 2, 3 or 4;
b选自0、1、2、3或4；b is selected from 0, 1, 2, 3 or 4;
x选自0、1、2、3或4；x is selected from 0, 1, 2, 3 or 4;
s1选自0、1、2、3或4；s1 is selected from 0, 1, 2, 3 or 4;
s2选自0、1、2、3或4；s2 is selected from 0, 1, 2, 3 or 4;
s3选自0、1、2、3或4。s3 is selected from 0, 1, 2, 3 or 4.
作为本发明的第二种实施方案，下述通式(II)所示化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，As the second embodiment of the present invention, the compound represented by the following general formula (II) or its stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,
Figure PCTCN2022088446-appb-000053
Figure PCTCN2022088446-appb-000053
W 1选自N或C(R a4)； W 1 is selected from N or C(R a4 );
环X选自苯基、5-6元杂芳基或5-6元杂环基，所述的杂芳基或杂环基含有1至5 个选自O、S、N的杂原子；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 a1、R a2、R a4各自独立的选自H、卤素、氰基、OH、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6烷硫基、-SO 2-C 1-6烷基、-C(＝O)C 1-6烷基、-(CH 2) q-C 3-10碳环或-(CH 2) q-3至12元杂环，所述的-CH 2-、烷基、烯基、炔基、烷氧基、烷硫基、碳环或杂环任选进一步被0至4个(例如0、1、2、3或4)选自H、卤素、OH、氰基、＝O、C 1-6烷基、卤素取代的C 1-6烷基、C 1-6烷氧基、C 3-6环烷基或3至10元杂环的取代基所取代，所述的杂环含有1至3个(例如1、2或3个)选自O、S、N的杂原子； R a1 , R a2 and R a4 are each independently selected from H, halogen, cyano, OH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy , C 1-6 alkylthio, -SO 2 -C 1-6 alkyl, -C(=O)C 1-6 alkyl, -(CH 2 ) q -C 3-10 carbocyclic or -(CH 2 ) q -3- to 12-membered heterocycle, the -CH 2 -, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, carbocycle or heterocycle are optionally further replaced by 0 to 4 ( For example 0, 1, 2, 3 or 4) is selected from H, halogen, OH, cyano, =O, C1-6 alkyl, halogen substituted C1-6 alkyl, C1-6 alkoxy, C 3-6 cycloalkyl or 3- to 10-membered heterocycle substituents, the heterocycle contains 1 to 3 (eg 1, 2 or 3) heteroatoms selected from O, S, N;
R a3选自H、C 1-6烷基、-(CH 2) q-C 3-10碳环或-(CH 2) q-3至12元杂环，所述的-CH 2-、烷基、碳环或杂环任选进一步被0至4个(例如0、1、2、3或4)选自H、卤素、OH、氰基、C 1-6烷基、卤素取代的C 1-6烷基、C 1-6烷氧基、C 3-6环烷基或3至10元杂环的取代基所取代，所述的杂环含有1至3个(例如1、2或3个)选自O、S、N的杂原子； 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;
其余基团的定义与本发明第一种实施方案相同。The definitions of the remaining groups are the same as in the first embodiment of the present invention.
作为本发明的第三种实施方案，前述通式(II)所示化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，As the third embodiment of the present invention, the compound represented by the aforementioned general formula (II) or its stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,
Y选自O、N(R y)、C 1-3亚烷基、-OC 1-2亚烷基-、-C 1-2亚烷基O-、-C 1-2亚烷基S-、-C 1-2亚烷基S(＝O) 2-、-N(R y)C 1-2亚烷基-、-C 1-2亚烷基N(R y)-，所述的亚烷基任选进一步被0至4个(例如0、1、2、3或4)选自H、卤素、＝O、＝S、OH、氰基、C 1-4烷基、卤素取代的C 1-4烷基、C 1-4烷氧基、C 3-6环烷基的取代基所取代； Y is selected from O, N(R y ), C 1-3 alkylene, -OC 1-2 alkylene-, -C 1-2 alkylene O-, -C 1-2 alkylene S- , -C 1-2 alkylene S(=O) 2 -, -N(R y )C 1-2 alkylene-, -C 1-2 alkylene N(R y )-, the described Alkylene is optionally further substituted with 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, halogen, =O, =S, OH, cyano, C1-4 alkyl, halogen Substituted by the substituents of C 1-4 alkyl, C 1-4 alkoxy and C 3-6 cycloalkyl;
R y各自独立的选自H、C 1-4烷基或C 3-6环烷基，所述的烷基或环烷基任选进一步被0至4个(例如0、1、2、3或4)选自H、氘、卤素、CF 3、OH、氰基、NH 2、C 1-4烷基、C 1-4烷氧基、3至8元杂环基或C 3-6环烷基的取代基所取代，所述的杂环基含有1至3个选自O、S、N的杂原子； 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 x、R a1、R a2、R a4各自独立的选自H、卤素、氰基、OH、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4烷氧基、C 1-4烷硫基、-SO 2-C 1-4烷基、-C(＝O)C 1-4烷基、-(CH 2) q-C 3-6碳环或-(CH 2) q-3至6元杂环，所述的-CH 2-、烷基、烯基、炔基、烷氧基、烷硫基、碳环或杂环任选进一步被0至4个(例如0、1、2、3或4)选自H、卤素、OH、氰基、＝O、C 1-4烷基、卤素取代的C 1-4烷基、C 1-4烷氧基、C 3-6环烷基或3至6元杂环的取代基所取代，所述的杂环含有1至3个(例如1、2或3个)选自O、S、N的杂原子； R x , R a1 , R a2 , R a4 are each independently selected from H, halogen, cyano, OH, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 Alkoxy, C 1-4 alkylthio, -SO 2 -C 1-4 alkyl, -C(=O)C 1-4 alkyl, -(CH 2 ) q -C 3-6 carbocyclic or -(CH 2 ) q -3- to 6-membered heterocycle, said -CH 2 -, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, carbocycle or heterocycle is optionally further substituted by 0 to 6 4 (eg 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, =O, C1-4alkyl , halogen-substituted C1-4alkyl , C1-4alkane Oxygen, C 3-6 cycloalkyl or substituents of 3- to 6-membered heterocyclic rings containing 1 to 3 (eg 1, 2 or 3) selected from O, S, N heteroatom;
R a3选自H、C 1-4烷基，所述的烷基任选进一步被0至4个(例如0、1、2、3或4)选自H、卤素、OH、氰基、C 1-4烷基、卤素取代的C 1-4烷基、C 1-4烷氧基、C 3-6环烷基的 取代基所取代； 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;
环B选自4至7元单环含氮杂环、5-11元螺环含氮杂环、5-11元并环含氮杂环、5-11元桥环含氮杂环或C 4-7单环碳环； 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;
R b各自独立的选自H、卤素、氰基、OH、＝O、C 1-4烷基、C 1-4烷氧基、-(CH 2) q-C 3-6环烷基，所述的-CH 2-、烷基、烷氧基或环烷基任选进一步被0至4个(例如0、1、2、3或4)选自H、卤素、OH、氰基、NH 2、C 1-4烷基、卤素取代的C 1-4烷基、C 1-4烷氧基或C 3-6环烷基的取代基所取代； R b is each independently selected from H, halogen, cyano, OH, =O, C 1-4 alkyl, C 1-4 alkoxy, -(CH 2 ) q -C 3-6 cycloalkyl, so Said -CH2- , alkyl, alkoxy or cycloalkyl is optionally further selected from 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, NH2 , C 1-4 alkyl, halogen substituted C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl substituent;
Ak1、Ak2各自独立的选自C 1-3亚烷基、C 2-3亚烯基、C 2-3亚炔基，所述Ak1任选进一步被0至4个(例如0、1、2、3或4)R k1取代，所述Ak2任选进一步被0至4个(例如0、1、2、3或4)R k2取代； 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各自独立的选自键、C 1-3亚烷基、C 2-3亚烯基、C 2-3亚炔基，所述Ak3任选进一步被0至4个(例如0、1、2、3或4)R k3取代，所述Ak4任选进一步被0至4个(例如0、1、2、3或4)R k4取代，所述Ak5任选进一步被0至4个(例如0、1、2、3或4)R k5取代； 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或K2选自C 1-2亚烷基、C 3-6碳环或3至7元杂环，所述的亚烷基任选进一步被0至4个(例如0、1、2、3或4)R k6取代，所述的碳环或杂环任选进一步被0至4个(例如0、1、2、3或4)选自H、卤素、OH、氰基、NH 2、C 1-4烷基、C 2-4烯基、C 2-4炔基、卤素取代的C 1-4烷基、C 1-4烷氧基、-C 1-4烷基-OC 1-4烷基、-O-C 1-4烷基-OC 1-4烷基、-O-C 3-6碳环、C 3-6碳环、4至7元杂环的取代基所取代，所述的杂环含有1至3个(例如1、2或3个)选自O、S、N的杂原子； 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;
R k1、R k2、R k3、R k4、R k5、R k6、R L1、R L2各自独立的选自H、卤素、氰基、OH、＝O、NH 2、NHC 1-4烷基、N(C 1-4烷基) 2、C 1-4烷基、C 1-4烷氧基、C 3-6碳环或4至7元杂环，所述的烷基、烷氧基、碳环或杂环任选进一步被0至4个(例如0、1、2、3或4)选自H、卤素、OH、氰基、NH 2、C 1-4烷基、卤素取代的C 1-4烷基、C 1-4烷氧基、C 3-6碳环(例如C 3、C 4、C 5或C 6)、4至6元(例如4、5或6元)杂环的取代基所取代，所述的杂环含有1至3个(例如1、2或3个)选自O、S、N的杂原子； R k1 , R k2 , R k3 , R k4 , R k5 , R k6 , R L1 , R L2 are each independently selected from H, halogen, cyano, OH, =O, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 alkoxy, C 3-6 carbocycle or 4- to 7-membered heterocycle, the alkyl, alkoxy, Carbocycle or heterocycle optionally further C substituted with 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, NH2 , C1-4alkyl , halogen 1-4 alkyl, C 1-4 alkoxy, C 3-6 carbocycle (eg C 3 , C 4 , C 5 or C 6 ), 4 to 6 membered (eg 4, 5 or 6 membered) heterocycle substituted by the substituent, the heterocycle contains 1 to 3 (eg 1, 2 or 3) heteroatoms selected from O, S, N;
作为选择，R k1与R k1、R k2与R k2、R k1与R k2、R k3与R k3、R k4与R k4、R k5与R k5、R k6与R k6直接连接形成C 3-6碳环(例如C 3、C 4、C 5或C 6)或者4至7元(例如4、5、6或7元)的杂环，所述的碳环或杂环任选进一步被0至4个(例如0、1、2、3或4)选自H、卤素、＝O、OH、氰基、C 1-4烷基、卤素取代的C 1-4烷基、C 1-4烷氧基、C 3-6环烷基的 取代基所取代，所述的杂环含有1至3个(例如1、2或3个)选自O、S、N的杂原子； Alternatively, Rk1 and Rk1 , Rk2 and Rk2 , Rk1 and Rk2 , Rk3 and Rk3, Rk4 and Rk4, Rk5 and Rk5 , Rk6 and Rk6 are directly linked to form C3- 6 - carbocycle (eg C3, C4 , C5 or C6 ) or 4- to 7-membered (eg 4, 5, 6 or 7 membered) heterocycle optionally further substituted by O to 4 (eg 0, 1, 2, 3 or 4) selected from H, halogen, =O, OH, cyano, C1-4 alkyl, halogen substituted C1-4 alkyl, C1-4 substituted by the substituents of alkoxy and C 3-6 cycloalkyl, and the heterocycle contains 1 to 3 (eg 1, 2 or 3) heteroatoms selected from O, S, N;
Q1、Q5各自独立的选自O、S、N(R q)、C(＝O)、C(＝O)N(R q)、N(R q)C(＝O)、S(＝O) 2； Q1 and Q5 are independently selected from O, S, N( Rq ), C(=O), C(=O)N( Rq ), N( Rq )C(=O), S(=O ) 2 ;
Q2、Q3、Q4、Q6各自独立的选自键或者Q1；Q2, Q3, Q4, Q6 are each independently selected from the key or Q1;
环E选自C 3-6碳环或4至6元杂环，所述的杂环含有1至3个(例如1、2或3个)选自O、S、N的杂原子； 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各自独立的选自H、C 1-4烷基，所述的烷基任选进一步被0至4个(例如0、1、2、3或4)选自H、卤素、CF 3、OH、氰基、NH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代； 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;
作为选择，R q与R k1、R q与R k2直接连接形成4至7元的杂环，所述的杂环任选进一步被0至4个(例如0、1、2、3或4)选自H、卤素、＝O、OH、氰基、C 1-4烷基、卤素取代的C 1-4烷基、C 1-4烷氧基、C 3-6环烷基的取代基所取代，所述的杂环含有1至3个(例如1、2或3个)选自O、S、N的杂原子； Alternatively, 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 Substituted, the heterocycle contains 1 to 3 (eg 1, 2 or 3) heteroatoms selected from O, S, N;
其余基团定义与本发明第二种实施方案相同。The rest of the group definitions are the same as in the second embodiment of the present invention.
作为本发明的第四种实施方案，前述通式(II)所示化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，As the fourth embodiment of the present invention, the compound represented by the aforementioned general formula (II) or its stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,
W 1选自N或CH； W 1 is selected from N or CH;
环X选自苯基基、吡啶基、嘧啶基、吡嗪基、哒嗪基、噻吩基、噻唑基、呋喃基、噁唑基、吡咯基、吡唑基或咪唑基；Ring X is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, thiazolyl, furyl, oxazolyl, pyrrolyl, pyrazolyl or imidazolyl;
R x、R a1、R a2各自独立的选自H、F、Cl、Br、I、氰基、OH、甲基、乙基、丙基、异丙基、丁基、叔丁基、乙烯基、乙炔基、甲氧基、乙氧基、-SCH 3、-SCH 2CH 3、-SO 2CH 3、-S O 2CH 2CH 3、-C(＝O)CH 3、-C(＝O)CH 2CH 3、环丙基、环丁基、环戊基、环己基，所述的甲基、乙基、丙基、异丙基、丁基、叔丁基、乙烯基、乙炔基、甲氧基、乙氧基、-SCH 3、-SCH 2CH 3、-SO 2CH 3、-SO 2CH 2CH 3、-C(＝O)CH 3、-C(＝O)CH 2CH 3、环丙基、环丁基、环戊基、环己基任选进一步被0至4个(例如0、1、2、3或4)选自H、卤素、OH、氰基、C 1-4烷基、卤素取代的C 1-4烷基、C 1-4烷氧基、C 3-6环烷基的取代基所取代； R x , R a1 , R a2 are each independently selected from H, F, Cl, Br, I, cyano, OH, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, vinyl , ethynyl, methoxy, ethoxy, -SCH 3 , -SCH 2 CH 3 , -SO 2 CH 3 , -SO 2 CH 2 CH 3 , -C(=O)CH 3 , -C(=O ) CH 2 CH 3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, the methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, vinyl, ethynyl, Methoxy, ethoxy, -SCH 3 , -SCH 2 CH 3 , -SO 2 CH 3 , -SO 2 CH 2 CH 3 , -C(=O)CH 3 , -C(=O)CH 2 CH 3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl optionally further selected from 0 to 4 (eg 0, 1 , 2, 3 or 4) selected from H, halogen, OH, cyano, C1- 4 alkyl, halogen substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl substituent;
R a3选自H、甲基、乙基、丙基、异丙基，所述的甲基、乙基、丙基或异丙基任选进一步被0至4个(例如0、1、2、3或4)选自H、卤素、OH、氰基、C 1-4烷基、卤素取代的C 1-4烷基、C 1-4烷氧基、C 3-6环烷基的取代基所取代； 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;
Y选自O、N(R y)、-N(R y)C(＝O)-、-C(＝O)N(R y)-、-CH 2-、-CH 2CH 2-、-CH 2CH 2CH 2-、-OCH 2-、-OCH 2CH 2-、-CH 2O-、-CH 2CH 2O-、-CH 2S-、-CH 2CH 2S-、-CH 2S(＝O) 2-、-CH 2CH 2S(＝O) 2-、-N(R y)CH 2-、-N(R y)CH 2CH 2-、-CH 2N(R y)-、-CH 2CH 2N(R y)-、-N(R y)C(＝O)CH 2-、-CH 2C(＝O)N(R y)-，所述CH 2任选进一步被0至2个(例如0、1或2)选自H、＝O、＝S、OH、氰基、C 1-4烷基、卤素取代的C 1-4烷基、C 1-4烷氧基、C 3-6环烷基的取代基所取代； Y is selected from O, N( Ry ), -N( Ry )C(=O)-, -C(=O)N( Ry )-, -CH2- , -CH2CH2- , - CH 2 CH 2 CH 2 -, -OCH 2 -, -OCH 2 CH 2 -, -CH 2 O-, -CH 2 CH 2 O-, -CH 2 S-, -CH 2 CH 2 S-, -CH 2 S(=O) 2 -, -CH 2 CH 2 S(=O) 2 -, -N(R y )CH 2 -, -N(R y )CH 2 CH 2 -, -CH 2 N(R y )-, -CH 2 CH 2 N(R y )-, -N(R y )C(=O)CH 2 -, -CH 2 C(=O)N(R y )-, the CH 2 optionally further 0 to 2 (eg 0, 1 or 2) selected from H, =O, =S, OH, cyano, C1-4alkyl , halogen substituted C1-4alkyl , C1 -4 alkoxy, C 3-6 cycloalkyl substituents;
R y各自独立的选自H、甲基、乙基、丙基、异丙基、丁基、叔丁基、仲丁基、异丁基、环丙基、环丁基、环戊基、环己基，所述的甲基、乙基、丙基、异丙基、丁基、叔丁基、仲丁基、异丁基、环丙基、环丁基、环戊基、环己基任选进一步被0至4个(例如0、1、2、3或4)选自H、氘、卤素、CF 3、OH、氰基、NH 2、C 1-4烷基、C 1-4烷氧基、3至8元杂环基或C 3-6环烷基的取代基所取代，所述的杂环基含有1至3个选自O、S、N的杂原子； 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 heteroatoms selected from O, S, N;
环B选自环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、哌啶基、哌嗪基、
Figure PCTCN2022088446-appb-000054
Ring B is selected from cyclobutyl, cyclopentyl, cyclohexyl, azetidine, pyrrolidinyl, piperidinyl, piperazinyl,
Figure PCTCN2022088446-appb-000054
R b各自独立的选自H、F、Cl、Br、I、氰基、OH、＝O、甲基、乙基、丙基或异丙基，所述的甲基、乙基、丙基或异丙基任选进一步被0至4个(例如0、1、2、3或4)选自H、卤素、OH、氰基、NH 2、C 1-4烷基、卤素取代的C 1-4烷基、C 1-4烷氧基或C 3-6环烷基的取代基所取代； R b is each independently selected from H, F, Cl, Br, I, cyano, OH, =O, methyl, ethyl, propyl or isopropyl, said methyl, ethyl, propyl or Isopropyl is optionally further C1- substituted with 0 to 4 (eg 0, 1 , 2, 3 or 4) selected from H, halogen, OH, cyano, NH2 , C1-4 alkyl, halogen 4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl substituent;
Ak1、Ak2各自独立的选自亚甲基、亚乙基、亚丙基、亚乙烯基、亚丙烯基、亚乙炔基、亚丙炔基，所述Ak1任选进一步被0至4个(例如0、1、2、3或4)R k1取代，所述Ak2任选进一步被0至4个R k2取代； 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各自独立的选自键、亚甲基、亚乙基、亚丙基、亚乙烯基、亚丙烯基、亚乙炔基、亚丙炔基，所述Ak3任选进一步被0至4个(例如0、1、2、3或4)R k3取代，所述Ak4任选进一步被0至4个(例如0、1、2、3或4)R k4取代，所述Ak5任选进一步被0至4个(例如0、1、2、3或4)R k5取代； 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或K2选自亚甲基、亚乙基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氮杂环戊基、氮杂环己基、哌嗪、吗啉、氧杂环丁基、氧杂环戊基、氧杂环己基、苯环、吡啶、吡嗪、嘧啶、哒嗪，所述的亚甲基、亚乙基任选进一步被0至4个(例如0、1、2、3或4)R k6取代，所述的环丙基、环丁基、环戊基、环己基、氮杂环丁基、氮杂环戊基、氮杂环己基、哌嗪、吗啉、氧杂环丁基、氧杂环戊基、氧杂环己基、苯环、吡啶、吡嗪、嘧啶、哒嗪任选进一步被0至4个(例如0、1、2、3或4)选自H、卤素、OH、氰基、NH 2、C 1-4烷基、C 2-4烯基、C 2-4炔基、卤素取代的C 1-4烷基、C 1-4烷氧基、-C 1-4烷基-OC 1-4烷基、-O-C 1-4烷基-OC 1-4烷基、-O-C 3-6碳环、C 3-6碳环、4至7元杂环的取代基所取代，所述的杂环含有1至3个(例如1、2或3个)选自O、S、N的杂原子； 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, oxetanyl, benzene ring, pyridine, pyrazine, pyrimidine, pyridazine are optionally further substituted by 0 to 4 (eg 0, 1, 2 , 3 or 4) is 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 alkyl, -OC 1-4 alkyl-OC 1-4 alkyl, -OC 3-6 carbocyclic, C 3-6 Substituents of carbocyclic, 4- to 7-membered heterocycles containing 1 to 3 (eg 1, 2 or 3) heteroatoms selected from O, S, N;
R k1、R k2、R k3、R k4、R k5、R k6、R L1、R L2各自独立的选自H、F、Cl、Br、I、氰基、OH、＝O、NH 2、NH(CH 3)、N(CH 3) 2、甲基、乙基、丙基、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氮杂环戊基、氮杂环己基、氧杂环丁基、氧杂环戊基、氧杂环己基、吡啶、苯基，所述甲基、乙基、丙基、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氮杂环戊基、氮杂环己基、氧杂环丁基、氧杂环戊基、氧杂环己基、吡啶、苯基任选进一步被0至4个(例如0、1、2、3或4)选自H、卤素、OH、氰基、NH 2、C 1-4烷基、卤素取代的C 1-4烷基、C 1-4烷氧基、C 3-6碳环、4至6元杂环的取代基所取代，所述的杂环含有1至3个(例如1、2或3个)选自O、S、N的杂原子； R k1 , R k2 , R k3 , R k4 , R k5 , R k6 , R L1 , R L2 are each independently selected from H, F, Cl, Br, I, cyano, OH, =O, NH 2 , NH (CH 3 ), N(CH 3 ) 2 , methyl, ethyl, propyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidine, Azacyclopentyl, azacyclohexyl, oxetanyl, oxolane, oxanyl, pyridine, phenyl, the methyl, ethyl, propyl, methoxy, ethoxy cyclopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidine, azacyclopentyl, azacyclohexyl, oxetanyl, oxolane, oxetyl , pyridine, phenyl optionally further C substituted with 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, NH 2 , C 1-4 alkyl, halogen 1-4 alkyl, C 1-4 alkoxy, C 3-6 carbocycle, 4- to 6-membered heterocycle substituents, and the heterocycle contains 1 to 3 (for example, 1, 2 or 3 a) heteroatoms selected from O, S, N;
作为选择，R k1与R k1、R k2与R k2、R k1与R k2、R k3与R k3、R k4与R k4、R k5与R k5、R k6与R k6直接连接形成C 3-6碳环(例如C 3、C 4、C 5或C 6)或者4至7元(例如0、1、2、3或4)的杂环，所述的碳环或杂环任选进一步被0至4个(例如0、1、2、3或4)选自H、卤素、＝O、OH、氰基、C 1-4烷基、卤素取代的C 1-4烷基、C 1-4烷氧基、C 3-6环烷基的取代基所取代，所述的杂环含有1至3个(例如1、2或3个)选自O、S、N的杂原子； Alternatively, Rk1 and Rk1 , Rk2 and Rk2 , Rk1 and Rk2 , Rk3 and Rk3, Rk4 and Rk4, Rk5 and Rk5 , Rk6 and Rk6 are directly linked to form C3- 6 -carbocycle (eg C3, C4 , C5 or C6 ) or 4- to 7-membered (eg 0, 1, 2, 3 or 4) heterocycle optionally further 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, halogen, =O, OH, cyano, C1-4 alkyl, halogen substituted C1-4 alkyl, C1- 4 alkoxy, C 3-6 cycloalkyl substituents, the heterocycle contains 1 to 3 (for example 1, 2 or 3) heteroatoms selected from O, S, N;
Q1、Q5各自独立的选自O、S、N(R q)、C(＝O)、C(＝O)N(R q)、N(R q)C(＝O)、S(＝O) 2； Q1 and Q5 are independently selected from O, S, N( Rq ), C(=O), C(=O)N( Rq ), N( Rq )C(=O), S(=O ) 2 ;
Q2、Q3、Q4、Q6各自独立的选自键或者Q1；Q2, Q3, Q4, Q6 are each independently selected from the key or Q1;
环E选自苯基或5-6元杂芳基，所述的杂芳基含有1至3个(例如1、2或3个)选自O、S、N的杂原子；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各自独立的选自H、甲基、乙基； R q are each independently selected from H, methyl, ethyl;
作为选择，R q与R k1、R q与R k2直接连接形成4至7元的杂环，所述的杂环任选进一步被0至4个(例如0、1、2、3或4)选自H、卤素、＝O、OH、氰基、C 1-4烷基、卤素 取代的C 1-4烷基、C 1-4烷氧基、C 3-6环烷基的取代基所取代，所述的杂环含有1至3个(例如1、2或3个)选自O、S、N的杂原子； Alternatively, 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 Substituted, the heterocycle contains 1 to 3 (eg 1, 2 or 3) heteroatoms selected from O, S, N;
其余基团定义与本发明第二或三种实施方案中任意一种相同。The remaining group definitions are the same as in any of the second or third embodiments of the present invention.
作为本发明的第五种实施方案，前述通式(II)所示化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，As the fifth embodiment of the present invention, the compound represented by the aforementioned general formula (II) or its stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,
Figure PCTCN2022088446-appb-000055
选自
Figure PCTCN2022088446-appb-000056
Figure PCTCN2022088446-appb-000057
左侧与L连接；
Figure PCTCN2022088446-appb-000055
selected from
Figure PCTCN2022088446-appb-000056
Figure PCTCN2022088446-appb-000057
The left side is connected with L;
L1选自-N(R q)-Ak1-O-Ak2-C(＝O)-、-O-Ak1-O-Ak2-C(＝O)-、-O-Ak1-N(R q)-Ak2-C(＝O)-、-N(R q)-Ak1-N(R q)-Ak2-C(＝O)-、-N(R q)-Ak1-O-Ak2-N(R q)C(＝O)-、-O-Ak1-O-Ak2-N(R q)C(＝O)-、-N(R q)-Ak1-Ak2-C(＝O)-、-N(R q)-Ak1-Ak2-N(R q)C(＝O)-、-O-Ak1-N(R q)-Ak2-N(R q)C(＝O)-、-S-Ak1-O-Ak2-C(＝O)-、-O-Ak1-S-Ak2-C(＝O)-、-N(R q)-Ak1-O-Ak2-S(＝O) 2-、-O-Ak1-O-Ak2-S(＝O) 2-、-N(R q)-Ak1-O-Ak2-、-O-Ak1-O-Ak2-，右侧与环B连接； L1 is selected from -N( Rq )-Ak1-O-Ak2-C(=O)-, -O-Ak1-O-Ak2-C(=O)-, -O-Ak1-N( Rq )- Ak2-C(=O)-, -N( Rq )-Ak1-N( Rq )-Ak2-C(=O)-, -N( Rq )-Ak1-O-Ak2-N( Rq )C(=O)-,-O-Ak1-O-Ak2-N( Rq )C(=O)-,-N( Rq )-Ak1-Ak2-C(=O)-,-N( R q )-Ak1-Ak2-N(R q )C(=O)-, -O-Ak1-N(R q )-Ak2-N(R q )C(=O)-, -S-Ak1- O-Ak2-C(=O)-, -O-Ak1-S-Ak2-C(=O)-, -N(R q )-Ak1-O-Ak2-S(=O) 2 -, -O -Ak1-O-Ak2-S(=O) 2 -, -N(R q )-Ak1-O-Ak2-, -O-Ak1-O-Ak2-, the right side is connected to ring B;
或者L1选自-N(R q)-Ak1-O-Ak2-C(＝O)N(R q)-、-O-Ak1-N(R q)-Ak2-C(＝O)N(R q)-、-O-Ak1-O-C(＝O)N(R q)-，右侧与环B连接； Or L1 is selected from -N( Rq )-Ak1-O-Ak2-C(=O)N( Rq )-, -O-Ak1-N( Rq )-Ak2-C(=O)N(R q )-, -O-Ak1-OC(=O)N(R q )-, the right side is connected with ring B;
L4选自-Ak3-O-K1-C(＝O)-、-Ak3-N(R q)-K1-C(＝O)-、-Ak3-N(R q)-K1-C(＝O)-，右侧与环B连接； L4 is selected from -Ak3-O-K1-C(=O)-, -Ak3-N( Rq )-K1-C(=O)-, -Ak3-N( Rq )-K1-C(=O )-, the right side is connected with ring B;
环E选自苯环或吡啶；Ring E is selected from benzene ring or pyridine;
Y选自-NHC(＝O)-、-C(＝O)NH-、-CH 2-、-CH 2CH 2-、-CH 2CH 2CH 2-、-OCH 2-、-OCH 2CH 2-、-CH 2O-、-CH 2CH 2O-、-NHCH 2-、-NHCH 2CH 2-、-CH 2NH-、-CH 2CH 2NH-、-NHC(＝O)CH 2-、-CH 2C(＝O)NH-； Y is selected from -NHC(=O) - , -C (=O) NH- , -CH2- , -CH2CH2- , -CH2CH2CH2- , -OCH2- , -OCH2CH 2- , -CH2O- , -CH2CH2O- , -NHCH2- , -NHCH2CH2- , -CH2NH- , -CH2CH2NH- , -NHC ( =O) CH 2 -, -CH 2 C(=O)NH-;
或者Y选自O、-N(CH 3)C(＝O)-、-C(＝O)N(CH 3)-、-CH 2C(＝O)NH-、-CH 2C(＝O)N(CH 3)-； Or Y is selected from O, -N( CH3 )C(=O)-, -C(=O)N( CH3 )-, -CH2C (=O)NH-, -CH2C (=O )N( CH3 )-;
或者Y选自-N(CH 2CH 3)C(＝O)-、-N(CH(CH 3) 2)C(＝O)-、-N(CH 2CH(CH 3) 2)C(＝O)-、-N(环丙基)C(＝O)-、-N(CH 2-环丙基)C(＝O)-、-C(＝O)N(CH 2CH 3)-、-C(＝O)N(CH(CH 3) 2)-、-C(＝O)N(CH 2CH(CH 3) 2)-、-C(＝O)N(环丙基)-、-C(＝O)N(CH 2-环丙基)-； Or Y is selected from -N( CH2CH3 )C(=O)-, -N(CH( CH3 ) 2 )C(=O)-, -N(CH2CH( CH3 ) 2 ) C( =O)-, -N(cyclopropyl)C(=O)-, -N( CH2 -cyclopropyl)C(=O)-, -C(=O)N( CH2CH3 ) - , -C(=O)N(CH(CH 3 ) 2 )-, -C(=O)N(CH 2 CH(CH 3 ) 2 )-, -C(=O)N(cyclopropyl)- , -C(=O)N(CH 2 -cyclopropyl)-;
或者Y各自独立的选自-C(＝O)N(CD 3)-、-C(＝O)N(CH 2-氧杂环丁基)-、-C(＝O)N(CH 2-氧杂环戊基)-、-C(＝O)N(CH 2-氮杂环丁基)-、-C(＝O)N(CH 2-吡咯烷基)-、-C(＝O)N(CH 2-环 戊基)-、-C(＝O)N(CH 2CH 2CH 3)-、-C(＝O)N(CH 2CH(CH 2CH 3) 2)-、-C(＝O)N(CH 2CH 2CH 2CH 3)-、-C(＝O)N(CH 2CH 2CH(CH 3) 2)-、-C(＝O)N(CH 2CH(CH 3)CH 2CH 3)-、-C(＝O)N(正辛基)-、-C(＝S)N(CH 3)-、-C(＝S)N(CH 2CH 3)-、-C(＝S)N(CH 2-环丙基)-、
Figure PCTCN2022088446-appb-000058
Or each Y is independently selected from -C(=O)N(CD 3 )-, -C(=O)N(CH 2 -oxetanyl)-, -C(=O)N(CH 2 - oxolane)-, -C(=O)N(CH 2 -azetidinyl)-, -C(=O)N(CH 2 -pyrrolidinyl)-, -C(=O) N(CH 2 -cyclopentyl)-, -C(=O)N(CH 2 CH 2 CH 3 )-, -C(=O)N(CH 2 CH(CH 2 CH 3 ) 2 )-,- C(=O)N(CH 2 CH 2 CH 2 CH 3 )-, -C(=O)N(CH 2 CH 2 CH(CH 3 ) 2 )-, -C(=O)N(CH 2 CH (CH 3 )CH 2 CH 3 )-, -C(=O)N(n-octyl)-, -C(=S)N(CH 3 )-, -C(=S)N(CH 2 CH 3 )-, -C(=S)N(CH 2 -cyclopropyl)-,
Figure PCTCN2022088446-appb-000058
或者Y选自-CH 2S(＝O) 2-； or Y is selected from -CH 2 S(=O) 2 -;
R a2选自H； R a2 is selected from H;
W 1选自N； W 1 is selected from N;
其余基团定义与本发明第二、三或四种实施方案中任意一种相同。The remaining group definitions are the same as in any of the second, third or fourth embodiments of the present invention.
作为本发明的第六种实施方案，前述通式(II)所示化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，As the sixth embodiment of the present invention, the compound represented by the aforementioned general formula (II) or its stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,
L1选自
Figure PCTCN2022088446-appb-000059
Figure PCTCN2022088446-appb-000060
L1 is selected from
Figure PCTCN2022088446-appb-000059
Figure PCTCN2022088446-appb-000060
Figure PCTCN2022088446-appb-000061
Figure PCTCN2022088446-appb-000061
Figure PCTCN2022088446-appb-000062
Figure PCTCN2022088446-appb-000063
右侧与环B连接；
Figure PCTCN2022088446-appb-000062
Figure PCTCN2022088446-appb-000063
The right side is connected with ring B;
或者L1选自
Figure PCTCN2022088446-appb-000064
Figure PCTCN2022088446-appb-000065
Figure PCTCN2022088446-appb-000066
右侧与环B连接； or L1 is selected from
Figure PCTCN2022088446-appb-000064
Figure PCTCN2022088446-appb-000065
Figure PCTCN2022088446-appb-000066
The right side is connected with ring B;
L2选自
Figure PCTCN2022088446-appb-000067
Figure PCTCN2022088446-appb-000068
Figure PCTCN2022088446-appb-000069
右侧与环B连接； L2 is selected from
Figure PCTCN2022088446-appb-000067
Figure PCTCN2022088446-appb-000068
Figure PCTCN2022088446-appb-000069
The right side is connected with ring B;
L3选自
Figure PCTCN2022088446-appb-000070
右侧与环B连接； L3 is selected from
Figure PCTCN2022088446-appb-000070
The right side is connected with ring B;
R x各自独立的选自H、F、Cl、Br、I、氰基、OH、甲基、乙基、丙基、异丙基、丁基、叔丁基、乙炔基、甲氧基、乙氧基、-SCH 3、-SCH 2CH 3、环丙基、环丁基、环戊基、环己基，所述的甲基、乙基、丙基、异丙基、乙炔基、甲氧基、乙氧基、-SCH 3、-SCH 2CH 3、环丙基、环丁基、环戊基、环己基任选进一步被0至4个(例如0、1、2、3或4)选自H、F、OH、氰基、甲基、乙基、甲氧基或乙氧基的取代基所取代； 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 ethoxy substituents;
R a1选自H、F、Cl、Br、I、氰基、CF 3、CHF 2、CH 2F、甲基、乙基、丙基、异丙基、乙炔基、甲氧基、乙氧基、-SCH 3、-SCH 2CH 3、环丙基、环丁基、环戊基或环己基； 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选自H或甲基； R a3 is selected from H or methyl;
R b各自独立的选自H、F、Cl、Br、I、氰基、OH、＝O、甲基、乙基、丙基或异丙基； R b is each independently selected from H, F, Cl, Br, I, cyano, OH, =O, methyl, ethyl, propyl or isopropyl;
其余基团定义与本发明第二、三、四或五种实施方案中任意一种相同。The remaining group definitions are the same as in any of the second, third, fourth or fifth embodiments of the present invention.
作为本发明的第七种实施方案，下述通式(II-a)、(II-b)、(II-c)所示化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，As the seventh embodiment of the present invention, the compounds represented by the following general formulae (II-a), (II-b), (II-c) or their stereoisomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals,
Figure PCTCN2022088446-appb-000071
Figure PCTCN2022088446-appb-000071
Y选自-NHC(＝O)-、-C(＝O)NH-、-CH 2CH 2CH 2-、-OCH 2-、-CH 2CH 2-、-CH 2O-、-CH 2CH 2O-、-OCH 2CH 2-； Y is selected from -NHC(=O) - , -C (=O) NH- , -CH2CH2CH2- , -OCH2- , -CH2CH2- , -CH2O- , -CH2 CH 2 O-, -OCH 2 CH 2 -;
或者Y选自O、-N(CH 3)C(＝O)-、-C(＝O)N(CH 3)-、-CH 2C(＝O)NH-、-CH 2C(＝O)N(CH 3)-； Or Y is selected from O, -N( CH3 )C(=O)-, -C(=O)N( CH3 )-, -CH2C (=O)NH-, -CH2C (=O )N( CH3 )-;
或者Y选自-N(CH 2CH 3)C(＝O)-、-N(CH(CH 3) 2)C(＝O)-、-N(CH 2CH(CH 3) 2)C(＝O)-、-N(环丙基)C(＝O)-、-N(CH 2-环丙基)C(＝O)-、-C(＝O)N(CH 2CH 3)-、-C(＝O)N(CH(CH 3) 2)-、 -C(＝O)N(CH 2CH(CH 3) 2)-、-C(＝O)N(环丙基)-、-C(＝O)N(CH 2-环丙基)-； Or Y is selected from -N( CH2CH3 )C(=O)-, -N(CH( CH3 ) 2 )C(=O)-, -N(CH2CH( CH3 ) 2 ) C( =O)-, -N(cyclopropyl)C(=O)-, -N( CH2 -cyclopropyl)C(=O)-, -C(=O)N( CH2CH3 ) - , -C(=O)N(CH(CH 3 ) 2 )-, -C(=O)N(CH 2 CH(CH 3 ) 2 )-, -C(=O)N(cyclopropyl)- , -C(=O)N(CH 2 -cyclopropyl)-;
或者Y各自独立的选自-C(＝O)N(CD 3)-、-C(＝O)N(CH 2-氧杂环丁基)-、-C(＝O)N(CH 2-氧杂环戊基)-、-C(＝O)N(CH 2-氮杂环丁基)-、-C(＝O)N(CH 2-吡咯烷基)-、-C(＝O)N(CH 2-环戊基)-、-C(＝O)N(CH 2CH 2CH 3)-、-C(＝O)N(CH 2CH(CH 2CH 3) 2)-、-C(＝O)N(CH 2CH 2CH 2CH 3)-、-C(＝O)N(CH 2CH 2CH(CH 3) 2)-、-C(＝O)N(CH 2CH(CH 3)CH 2CH 3)-、-C(＝O)N(正辛基)-、-C(＝S)N(CH 3)-、-C(＝S)N(CH 2CH 3)-、-C(＝S)N(CH 2-环丙基)-、
Figure PCTCN2022088446-appb-000072
Or each Y is independently selected from -C(=O)N(CD 3 )-, -C(=O)N(CH 2 -oxetanyl)-, -C(=O)N(CH 2 - oxolane)-, -C(=O)N(CH 2 -azetidinyl)-, -C(=O)N(CH 2 -pyrrolidinyl)-, -C(=O) N(CH 2 -cyclopentyl)-, -C(=O)N(CH 2 CH 2 CH 3 )-, -C(=O)N(CH 2 CH(CH 2 CH 3 ) 2 )-,- C(=O)N(CH 2 CH 2 CH 2 CH 3 )-, -C(=O)N(CH 2 CH 2 CH(CH 3 ) 2 )-, -C(=O)N(CH 2 CH (CH 3 )CH 2 CH 3 )-, -C(=O)N(n-octyl)-, -C(=S)N(CH 3 )-, -C(=S)N(CH 2 CH 3 )-, -C(=S)N(CH 2 -cyclopropyl)-,
Figure PCTCN2022088446-appb-000072
或者Y选自-CH 2S(＝O) 2-； or Y is selected from -CH 2 S(=O) 2 -;
X 1、X 2、X 3、X 4各自独立的选自N、CR x，X 1、X 2、X 3、X 4至多含有2个N； 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;
R x各自独立的选自H、F、Cl、氰基、甲基、乙基、异丙基、三氟甲基、甲氧基、乙氧基、-SO 2CH 3、-SO 2CH 2CH 3、-C(＝O)CH 3、-C(＝O)CH 2CH 3、环丙基； R x is each independently selected from H, F, Cl, cyano, methyl, ethyl, isopropyl, trifluoromethyl, methoxy, ethoxy, -SO 2 CH 3 , -SO 2 CH 2 CH 3 , -C(=O)CH 3 , -C(=O)CH 2 CH 3 , cyclopropyl;
其余基团的定义与本发明第二、三、四、五或六种实施方案中任意一种相同。The definitions of the remaining groups are the same as in any of the second, third, fourth, fifth or sixth embodiments of the present invention.
作为本发明的第八种实施方案，上述通式(II-a)、(II-b)、(II-c)所示化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，As the eighth embodiment of the present invention, the compounds represented by the above general formulas (II-a), (II-b), (II-c) or their stereoisomers, deuterated compounds, solvates, prodrugs, metabolites product, pharmaceutically acceptable salt or co-crystal,
L选自
Figure PCTCN2022088446-appb-000073
或者
Figure PCTCN2022088446-appb-000074
右侧与环B连接； L is selected from
Figure PCTCN2022088446-appb-000073
or
Figure PCTCN2022088446-appb-000074
The right side is connected with ring B;
或者L选自
Figure PCTCN2022088446-appb-000075
Figure PCTCN2022088446-appb-000076
右侧与环B连接； or L is selected from
Figure PCTCN2022088446-appb-000075
Figure PCTCN2022088446-appb-000076
The right side is connected with ring B;
L选自
Figure PCTCN2022088446-appb-000077
Figure PCTCN2022088446-appb-000078
右侧与环B连接； L is selected from
Figure PCTCN2022088446-appb-000077
Figure PCTCN2022088446-appb-000078
The right side is connected with ring B;
优选地，X 1选自N，X 2选自CH，X 3选自CH、CF、CCl、CCN或CCF 3，X 4选自CH或N； Preferably, 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;
其余基团的定义与本发明第七种实施方案中任意一种相同。The definitions of the remaining groups are the same as in any of the seventh embodiments of the present invention.
本发明涉及如下所示的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中该化合物选自如下结构之一：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:
Figure PCTCN2022088446-appb-000079
Figure PCTCN2022088446-appb-000079
Figure PCTCN2022088446-appb-000080
Figure PCTCN2022088446-appb-000080
Figure PCTCN2022088446-appb-000081
Figure PCTCN2022088446-appb-000081
Figure PCTCN2022088446-appb-000082
Figure PCTCN2022088446-appb-000082
Figure PCTCN2022088446-appb-000083
Figure PCTCN2022088446-appb-000083
Figure PCTCN2022088446-appb-000084
Figure PCTCN2022088446-appb-000084
Figure PCTCN2022088446-appb-000085
Figure PCTCN2022088446-appb-000085
Figure PCTCN2022088446-appb-000086
Figure PCTCN2022088446-appb-000086
Figure PCTCN2022088446-appb-000087
Figure PCTCN2022088446-appb-000087
Figure PCTCN2022088446-appb-000088
Figure PCTCN2022088446-appb-000088
Figure PCTCN2022088446-appb-000089
Figure PCTCN2022088446-appb-000089
Figure PCTCN2022088446-appb-000090
Figure PCTCN2022088446-appb-000090
Figure PCTCN2022088446-appb-000091
Figure PCTCN2022088446-appb-000091
Figure PCTCN2022088446-appb-000092
Figure PCTCN2022088446-appb-000092
Figure PCTCN2022088446-appb-000093
Figure PCTCN2022088446-appb-000093
Figure PCTCN2022088446-appb-000094
Figure PCTCN2022088446-appb-000094
Figure PCTCN2022088446-appb-000095
Figure PCTCN2022088446-appb-000095
本发明涉及通式(I)、(II)、(II-a)、(II-b)或(II-c)的一些实施方案中，Y选自O、S、S(＝O)、 S(＝O) 2、S(＝O) 2N(R y)、N(R y)、C 1-4亚烷基、-OC 1-3亚烷基-、-C 1-3亚烷基O-、-C 1-3亚烷基S-、-C 1-3亚烷基S(＝O)-、-C 1-3亚烷基S(＝O) 2-、-N(R y)C 1-3亚烷基-、-C 1-3亚烷基N(R y)-，所述的亚烷基任选进一步被0至4个(例如0、1、2、3或4)选自H、卤素、＝O、＝S、OH、氰基、C 1-6烷基、卤素取代的C 1-6烷基、C 1-6烷氧基、C 3-6环烷基的取代基所取代。 In some embodiments of the present invention relating to general formula (I), (II), (II-a), (II-b) or (II-c), Y is selected from O, S, S(=O), S (=O) 2 , S(=O) 2 N(R y ), N(R y ), C 1-4 alkylene, -OC 1-3 alkylene-, -C 1-3 alkylene O-, -C 1-3 alkylene S-, -C 1-3 alkylene S(=O)-, -C 1-3 alkylene S(=O) 2 -, -N(R y ) C 1-3 alkylene-, -C 1-3 alkylene N(R y )-, the alkylene is optionally further replaced by 0 to 4 (eg 0, 1, 2, 3 or 4 ) is selected from H, halogen, =O, =S, OH, cyano, C 1-6 alkyl, halogen-substituted C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl substituted by the substituents.
本发明涉及通式(I)、(II)、(II-a)、(II-b)或(II-c)的一些实施方案中，Y选自O、N(R y)、C 1-3亚烷基、-OC 1-2亚烷基-、-C 1-2亚烷基O-、-C 1-2亚烷基S-、-C 1-2亚烷基S(＝O) 2-、-N(R y)C 1-2亚烷基-、-C 1-2亚烷基N(R y)-，所述的亚烷基任选进一步被0至4个(例如0、1、2、3或4)选自H、卤素、＝O、＝S、OH、氰基、C 1-4烷基、卤素取代的C 1-4烷基、C 1-4烷氧基、C 3-6环烷基的取代基所取代。 In some embodiments of the present invention relating to general formula (I), (II), (II-a), (II-b) or (II-c), Y is selected from O, N( Ry ), C1- 3 alkylene, -OC 1-2 alkylene-, -C 1-2 alkylene O-, -C 1-2 alkylene S-, -C 1-2 alkylene S (=O) 2- , -N(R y )C 1-2 alkylene-, -C 1-2 alkylene N(R y )-, the alkylene group is optionally further replaced by 0 to 4 (eg 0 , 1, 2, 3 or 4) is selected from H, halogen, =O, =S, OH, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, C 1-4 alkoxy , C 3-6 cycloalkyl substituents are substituted.
本发明涉及通式(I)、(II)、(II-a)、(II-b)或(II-c)的一些实施方案中，Y选自O、N(R y)、-N(R y)C(＝O)-、-C(＝O)N(R y)-、-CH 2-、-CH 2CH 2-、-CH 2CH 2CH 2-、-OCH 2-、-OCH 2CH 2-、-CH 2O-、-CH 2CH 2O-、-CH 2S-、-CH 2CH 2S-、-CH 2S(＝O) 2-、-CH 2CH 2S(＝O) 2-、-N(R y)CH 2-、-N(R y)CH 2CH 2-、-CH 2N(R y)-、-CH 2CH 2N(R y)-、-N(R y)C(＝O)CH 2-、-CH 2C(＝O)N(R y)-，所述CH 2任选进一步被0至2个(例如0、1或2)选自H、＝O、＝S、OH、氰基、C 1-4烷基、卤素取代的C 1-4烷基、C 1-4烷氧基、C 3-6环烷基的取代基所取代。 In some embodiments of the present invention relating to general formula (I), (II), (II-a), (II-b) or (II-c), Y is selected from O, N( Ry ), -N( R y )C(=O)-, -C(=O)N(R y )-, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -OCH 2 -, - OCH 2 CH 2 -, -CH 2 O-, -CH 2 CH 2 O-, -CH 2 S-, -CH 2 CH 2 S-, -CH 2 S(=O) 2 -, -CH 2 CH 2 S(=O) 2 -, -N(R y )CH 2 -, -N(R y )CH 2 CH 2 -, -CH 2 N(R y )-, -CH 2 CH 2 N(R y ) -, -N(R y )C(=O)CH 2 -, -CH 2 C(=O)N(R y )-, said CH 2 optionally further separated by 0 to 2 (eg 0, 1 or 2) selected from H, =O, =S, OH, cyano, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl Substituents are substituted.
本发明涉及通式(I)、(II)、(II-a)、(II-b)或(II-c)的一些实施方案中，Y选自O、-NHC(＝O)-、-C(＝O)NH-、-CH 2-、-CH 2CH 2-、-CH 2CH 2CH 2-、-OCH 2-、-OCH 2CH 2-、-CH 2O-、-CH 2CH 2O-、-NHCH 2-、-NHCH 2CH 2-、-CH 2NH-、-CH 2CH 2NH-、-NHC(＝O)CH 2-、-CH 2C(＝O)NH-。 In some embodiments of the present invention relating to general formula (I), (II), (II-a), (II-b) or (II-c), Y is selected from O, -NHC(=O)-, - C( = O) NH- , -CH2- , -CH2CH2- , -CH2CH2CH2- , -OCH2- , -OCH2CH2- , -CH2O- , -CH2 CH2O- , -NHCH2- , -NHCH2CH2- , -CH2NH- , -CH2CH2NH- , -NHC(=O ) CH2-, -CH2C ( =O ) NH -.
本发明涉及通式(I)、(II)、(II-a)、(II-b)或(II-c)的一些实施方案中，Y选自O、-NHC(＝O)-、-C(＝O)NH-、-CH 2CH 2CH 2-、-OCH 2-、-CH 2CH 2-、-CH 2O-、-CH 2CH 2O-、-OCH 2CH 2-。 In some embodiments of the present invention relating to general formula (I), (II), (II-a), (II-b) or (II-c), Y is selected from O, -NHC(=O)-, - C( = O ) NH- , -CH2CH2CH2- , -OCH2- , -CH2CH2- , -CH2O- , -CH2CH2O- , -OCH2CH2- .
本发明涉及通式(I)、(II)、(II-a)、(II-b)或(II-c)的一些实施方案中，Y选自O、-N(CH 3)C(＝O)-、-C(＝O)N(CH 3)-、-CH 2C(＝O)NH-、-CH 2C(＝O)N(CH 3)-。 In some embodiments of the present invention relating to general formula (I), (II), (II-a), (II-b) or (II-c), Y is selected from O, -N( CH3 )C (= O)-, -C(=O)N( CH3 )-, -CH2C (=O)NH-, -CH2C (=O)N( CH3 )-.
本发明涉及通式(I)、(II)、(II-a)、(II-b)或(II-c)的一些实施方案中，Y选自-N(CH 2CH 3)C(＝O)-、-N(CH(CH 3) 2)C(＝O)-、-N(CH 2CH(CH 3) 2)C(＝O)-、-N(环丙基)C(＝O)-、-N(CH 2-环丙基)C(＝O)-、-C(＝O)N(CH 2CH 3)-、-C(＝O)N(CH(CH 3) 2)-、-C(＝O)N(CH 2CH(CH 3) 2)-、-C(＝O)N(环丙基)-、-C(＝O)N(CH 2-环丙基)-。 In some embodiments of the present invention relating to general formula (I), (II), (II-a), (II-b) or (II-c), Y is selected from -N( CH2CH3 ) C(= O)-, -N(CH( CH3 ) 2 )C(=O)-, -N(CH2CH( CH3 )2 ) C(=O)-, -N(cyclopropyl)C(= O)-, -N(CH 2 -cyclopropyl)C(=O)-, -C(=O)N(CH 2 CH 3 )-, -C(=O)N(CH(CH 3 ) 2 )-, -C(=O)N(CH 2 CH(CH 3 ) 2 )-, -C(=O)N(cyclopropyl)-, -C(=O)N(CH 2 -cyclopropyl )-.
本发明涉及通式(I)、(II)、(II-a)、(II-b)或(II-c)的一些实施方案中，Y各自独立的选自-C(＝O)N(CD 3)-、-C(＝O)N(CH 2-氧杂环丁基)-、-C(＝O)N(CH 2-氧杂环戊基)-、-C(＝O)N(CH 2-氮杂环丁基)-、-C(＝O)N(CH 2-吡咯烷基)-、-C(＝O)N(CH 2-环戊基)-、-C(＝O)N(CH 2CH 2CH 3)-、-C(＝O)N(CH 2CH(CH 2CH 3) 2)-、-C(＝O)N(CH 2CH 2CH 2CH 3)-、-C(＝O)N(CH 2CH 2CH(CH 3) 2)-、 -C(＝O)N(CH 2CH(CH 3)CH 2CH 3)-、-C(＝O)N(正辛基)-、-C(＝S)N(CH 3)-、-C(＝S)N(CH 2CH 3)-、-C(＝S)N(CH 2-环丙基)-、
Figure PCTCN2022088446-appb-000096
In some embodiments of the present invention relating to general formula (I), (II), (II-a), (II-b) or (II-c), each Y is independently selected from -C(=O)N( CD 3 )-, -C(=O)N(CH 2 -oxetanyl)-, -C(=O)N(CH 2 -oxolane)-, -C(=O)N (CH 2 -azetidinyl)-, -C(=O)N(CH 2 -pyrrolidinyl)-, -C(=O)N(CH 2 -cyclopentyl)-, -C(= O)N(CH 2 CH 2 CH 3 )-, -C(=O)N(CH 2 CH(CH 2 CH 3 ) 2 )-, -C(=O)N(CH 2 CH 2 CH 2 CH 3 )-, -C(=O)N(CH 2 CH 2 CH(CH 3 ) 2 )-, -C(=O)N(CH 2 CH(CH 3 )CH 2 CH 3 )-, -C(= O)N(n-octyl)-, -C(=S)N( CH3 )-, -C(=S)N( CH2CH3 ) -, -C(=S)N( CH2 -ring propyl)-,
Figure PCTCN2022088446-appb-000096
本发明涉及通式(I)、(II)、(II-a)、(II-b)或(II-c)的一些实施方案中，Y各自独立的选自Y选自-CH 2S(＝O) 2-。 In some embodiments of the present invention relating to general formula (I), (II), (II-a), (II-b) or (II-c), each Y is independently selected from Y is selected from -CH2S ( =O) 2 -.
本发明涉及通式(I)、(II)、(II-a)、(II-b)或(II-c)的一些实施方案中，R y各自独立的选自H、C 1-6烷基或C 3-6环烷基，所述的烷基或环烷基任选进一步被0至4个(例如0、1、2、3或4)选自H、氘、卤素、CF 3、OH、氰基、NH 2、C 1-6烷基、C 1-6烷氧基、3至8元杂环基或C 3-6环烷基的取代基所取代，所述的杂环基含有1至3个选自O、S、N的杂原子。 In some embodiments of the present invention relating to general formula (I), (II), (II-a), (II-b) or (II-c), 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.
本发明涉及通式(I)、(II)、(II-a)、(II-b)或(II-c)的一些实施方案中，R y各自独立的选自H、C 1-4烷基或C 3-6环烷基，所述的烷基或环烷基任选进一步被0至4个(例如0、1、2、3或4)选自H、氘、卤素、CF 3、OH、氰基、NH 2、C 1-4烷基、C 1-4烷氧基、3至8元杂环基或C 3-6环烷基的取代基所取代，所述的杂环基含有1至3个选自O、S、N的杂原子。 In some embodiments of the present invention relating to general formula (I), (II), (II-a), (II-b) or (II-c), 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.
本发明涉及通式(I)、(II)、(II-a)、(II-b)或(II-c)的一些实施方案中，R y各自独立的选自H、甲基、乙基、丙基、异丙基、丁基、叔丁基、仲丁基、异丁基、环丙基、环丁基、环戊基、环己基，所述的甲基、乙基、丙基、异丙基、丁基、叔丁基、仲丁基、异丁基、环丙基、环丁基、环戊基、环己基任选进一步被0至4个(例如0、1、2、3或4)选自H、氘、卤素、CF 3、OH、氰基、NH 2、C 1-4烷基、C 1-4烷氧基、3至8元杂环基或C 3-6环烷基的取代基所取代，所述的杂环基含有1至3个选自O、S、N的杂原子。 In some embodiments of the present invention relating to general formula (I), (II), (II-a), (II-b) or (II-c), 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, 3- to 8-membered heterocyclyl or C 3-6 ring The heterocyclic group is substituted by the substituent of the alkyl group, and the heterocyclic group contains 1 to 3 heteroatoms selected from O, S and N.
本发明涉及通式(I)、(II)、(II-a)、(II-b)或(II-c)的一些实施方案中，R y各自独立的选自H、甲基、乙基、丙基、异丙基、丁基、叔丁基、仲丁基、异丁基、环丙基、环丁基、环戊基、环己基，所述的甲基、乙基、丙基、异丙基、丁基、叔丁基、仲丁基、异丁基、环丙基、环丁基、环戊基、环己基任选进一步被0至4个(例如0、1、2、3或4)选自H、氘、F、Cl、Br、CF 3、OH、氰基、NH 2、甲基、乙基、丙基、丁基、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基、氧杂环丁基、氧杂环戊基、氮杂环丁基、吡咯烷基的取代基所取代。 In some embodiments of the present invention relating to general formula (I), (II), (II-a), (II-b) or (II-c), 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, propyl, butyl, methoxy, ethoxy, cyclopropyl, Substituents of cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, oxolanyl, azetidinyl, and pyrrolidinyl are substituted.
本发明涉及通式(I)、(II)、(II-a)、(II-b)或(II-c)的一些实施方案中，R y各自独立的选自H、C 1-4烷基。 In some embodiments of the present invention relating to general formula (I), (II), (II-a), (II-b) or (II-c), R y is each independently selected from H, C 1-4 alkanes base.
本发明涉及通式(I)、(II)、(II-a)、(II-b)或(II-c)的一些实施方案中，R y各自独立的选自H、甲基、乙基。 In some embodiments of the present invention relating to general formula (I), (II), (II-a), (II-b) or (II-c), R y are each independently selected from H, methyl, ethyl .
本发明涉及通式(I)、(II)、(II-a)、(II-b)或(II-c)的一些实施方案中，R y各自独立的选自CD 3； In some embodiments of the present invention relating to general formula (I), (II), (II-a), (II-b) or (II-c), each Ry is independently selected from CD3 ;
本发明涉及通式(I)的一些实施方案中，环A选自C 6-10芳基、5-10元杂芳基或5-10元杂环基，所述的杂芳基或者杂环基含有1至5个(例如1、2、3、4或5个)选自O、S、N的杂原子。 In some embodiments of the present invention relating to general formula (I), 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.
本发明涉及通式(I)的一些实施方案中，环A选自3(2H)-哒嗪酮或2(1H)-吡啶酮。In some embodiments of the present invention relating to general formula (I), Ring A is selected from 3(2H)-pyridazinone or 2(1H)-pyridinone.
本发明涉及通式(I)的一些实施方案中，
Figure PCTCN2022088446-appb-000097
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The present invention relates to some embodiments of general formula (I),
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The present invention relates to some embodiments of general formula (I),
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本发明涉及通式(II-a)、(II-b)或(II-c)的一些实施方案中，X 1、X 2、X 3、X 4各自独立的选自N、CR x，X 1、X 2、X 3、X 4至多含有2个N(X 1、X 2、X 3、X 4中的至多2个为N)。 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).
本发明涉及通式(I)、(II)的一些实施方案中，环X选自C 6-10芳基、5-10元杂芳基、C 3-10碳环或5-10元杂环基，所述的杂芳基或者杂环基含有1至5个(例如1、2、3、4或5个)选自O、S、N的杂原子。 In some embodiments of the present invention relating to general formulae (I) and (II), 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.
本发明涉及通式(II-a)、(II-b)或(II-c)的一些实施方案中，X 1选自N，X 2选自CH，X 3选自CH、CF、CCl、CCN或CCF 3，X 4选自CH或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.
本发明涉及通式(I)、(II)的一些实施方案中，环X选自苯基、5-6元杂芳基或5-6元杂环基，所述的杂芳基或杂环基含有1至5个(例如1、2、3、4或5个)选自O、S、N的杂原子。The present invention relates to some embodiments of general formula (I), (II), 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.
本发明涉及通式(I)、(II)的一些实施方案中，环X选自苯基、吡啶基、嘧啶基、吡嗪基、哒嗪基、噻吩基、噻唑基、呋喃基、噁唑基、吡咯基、吡唑基或咪唑基。In some embodiments of the present invention relating to formulae (I) and (II), ring X is selected from the group consisting of phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, thiazolyl, furyl, oxazole group, pyrrolyl, pyrazolyl or imidazolyl.
本发明涉及通式(II)的一些实施方案中，W 1选自N或C(R a4)。 In some embodiments of the present invention relating to general formula (II), W 1 is selected from N or C(R a4 ).
本发明涉及通式(II)的一些实施方案中，W 1选自N或CH。 In some embodiments of the present invention relating to general formula (II), W 1 is selected from N or CH.
本发明涉及通式(II)的一些实施方案中，W 1选自N。 In some embodiments of the present invention relating to general formula (II), W 1 is selected from N.
本发明涉及通式(I)、(II)、(II-a)、(II-b)或(II-c)的一些实施方案中，R x、R a各自独立的选自H、卤素、氰基、OH、＝O、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6烷硫基、-SO 2-C 1-6烷基、-C(＝O)C 1-6烷基、-(CH 2) q-C 3-10碳环或-(CH 2) q-3至12元杂环，所述的-CH 2-、烷基、烯基、炔基、烷氧基、烷硫基、碳环或杂环任选进一步被0至4个(例如0、1、2、3或4)选自H、卤素、OH、氰基、＝O、NH 2、NH(C 1-6烷基)、N(C 1-6烷基) 2、C 1-6烷基、卤素取代的C 1-6烷基、C 1-6烷氧基、C 3-6环烷基或3至10元杂环的取代基所取代，所述的杂环含有1至3个(例如1、2或3个)选自O、S、N的杂原子。 The present invention relates to some embodiments of general formula (I), (II), (II-a), (II-b) or (II-c), R x and R a are each independently selected from H, halogen, Cyano, OH, =O, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthio, -SO 2 -C 1-6 alkyl, -C(=O)C 1-6 alkyl, -(CH 2 ) q -C 3-10 carbocycle or -(CH 2 ) q -3- to 12-membered heterocycle, said -CH2- , alkyl, alkenyl, alkynyl, alkoxy, alkylthio, carbocyclic or heterocycle optionally further selected from H by 0 to 4 (eg 0, 1, 2, 3 or 4) , halogen, OH, cyano, =O, NH 2 , NH(C 1-6 alkyl), N(C 1-6 alkyl) 2 , C 1-6 alkyl, halogen substituted C 1-6 alkane base, C 1-6 alkoxy, C 3-6 cycloalkyl or substituents of a 3- to 10-membered heterocyclic ring containing 1 to 3 (for example, 1, 2 or 3) Heteroatoms from O, S, N.
本发明涉及通式(II)、(II-a)、(II-b)或(II-c)的一些实施方案中，R a1、R a2、R a4各自独立的选自R a。 In some embodiments of the present invention relating to general formula (II), (II-a), (II-b) or (II-c), R a1 , R a2 , R a4 are each independently selected from R a .
本发明涉及通式(II)、(II-a)、(II-b)或(II-c)的一些实施方案中，R a1、R a2、R a4各自独立的选自H、卤素、氰基、OH、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6烷硫基、-SO 2-C 1-6烷基、-C(＝O)C 1-6烷基、-(CH 2) q-C 3-10碳环或-(CH 2) q-3至12元杂环，所述的-CH 2-、烷基、烯基、炔基、烷氧基、烷硫基、碳环或杂环任选进一步被0至4个(例如 0、1、2、3或4)选自H、卤素、OH、氰基、＝O、C 1-6烷基、卤素取代的C 1-6烷基、C 1-6烷氧基、C 3-6环烷基或3至10元杂环的取代基所取代，所述的杂环含有1至3个(例如1、2或3个)选自O、S、N的杂原子。 In some embodiments of the present invention relating to general formula (II), (II-a), (II-b) or (II-c), R a1 , R a2 , R a4 are each independently selected from H, halogen, cyano base, OH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylthio, -SO 2 -C 1-6 alkane base, -C(=O)C 1-6 alkyl, -(CH 2 ) q -C 3-10 carbocycle or -(CH 2 ) q -3- to 12-membered heterocycle, the -CH 2 - , alkyl, alkenyl, alkynyl, alkoxy, alkylthio, carbocyclic or heterocycle optionally further selected from H, halogen, OH by 0 to 4 (eg 0, 1, 2, 3 or 4) , cyano, =O, 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 Alternatively, the heterocycle contains 1 to 3 (eg 1, 2 or 3) heteroatoms selected from O, S, N.
本发明涉及通式(II)的一些实施方案中，R a3选自H、C 1-6烷基、-(CH 2) q-C 3-10碳环或-(CH 2) q-3至12元杂环，所述的-CH 2-、烷基、碳环或杂环任选进一步被0至4个(例如0、1、2、3或4)选自H、卤素、OH、氰基、C 1-6烷基、卤素取代的C 1-6烷基、C 1-6烷氧基、C 3-6环烷基或3至10元杂环的取代基所取代，所述的杂环含有1至3个(例如1、2或3个)选自O、S、N的杂原子。 In some embodiments of the present invention relating to general formula (II), 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.
本发明涉及通式(II)的一些实施方案中，R a3选自H、C 1-4烷基，所述的烷基任选进一步被0至4个(例如0、1、2、3或4)选自H、卤素、OH、氰基、C 1-4烷基、卤素取代的C 1-4烷基、C 1-4烷氧基、C 3-6环烷基的取代基所取代。 In some embodiments of the present invention relating to general formula (II), 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 .
本发明涉及通式(II)的一些实施方案中，R a3选自H、甲基、乙基、丙基、异丙基，所述的甲基、乙基、丙基或异丙基任选进一步被0至4个(例如0、1、2、3或4)选自H、卤素、OH、氰基、C 1-4烷基、卤素取代的C 1-4烷基、C 1-4烷氧基、C 3-6环烷基的取代基所取代。 In some embodiments of the present invention relating to general formula (II), 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.
本发明涉及通式(II)的一些实施方案中，R a2选自选自H、F、Cl、Br、I、氰基、CF 3、CHF 2、CH 2F、甲基、甲氧基、环丙基。 In some embodiments of the present invention relating to general formula (II), R a2 is selected from the group consisting of H, F, Cl, Br, I, cyano, CF3 , CHF2 , CH2F , methyl, methoxy, Cyclopropyl.
本发明涉及通式(II)的一些实施方案中，R a3选自H或甲基。 In some embodiments of the present invention relating to general formula (II), R a3 is selected from H or methyl.
本发明涉及通式(I)、(II)、(II-a)、(II-b)或(II-c)的一些实施方案中，R x、R a1、R a2、R a4各自独立的选自H、卤素、氰基、OH、C 1-4烷基、C 2-4烯基、C 2-4炔基、C 1-4烷氧基、C 1-4烷硫基、-SO 2-C 1-4烷基、-C(＝O)C 1-4烷基、-(CH 2) q-C 3-6碳环或-(CH 2) q-3至6元杂环，所述的-CH 2-、烷基、烯基、炔基、烷氧基、烷硫基、碳环或杂环任选进一步被0至4个(例如0、1、2、3或4)选自H、卤素、OH、氰基、＝O、C 1-4烷基、卤素取代的C 1-4烷基、C 1-4烷氧基、C 3-6环烷基或3至6元杂环的取代基所取代，所述的杂环含有1至3个(例如1、2或3个)选自O、S、N的杂原子。 In some embodiments of the present invention relating to general formula (I), (II), (II-a), (II-b) or (II-c), R x , R a1 , R a2 , R a4 are each independently Selected from H, halogen, cyano, OH, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 alkylthio, -SO 2 -C 1-4 alkyl, -C(=O)C 1-4 alkyl, -(CH 2 ) q -C 3-6 carbocycle or -(CH 2 ) q -3- to 6-membered heterocycle, Said -CH2- , alkyl, alkenyl, alkynyl, alkoxy, alkylthio, carbocyclic or heterocycle is optionally further substituted by 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano, =O, C 1-4 alkyl, halogen substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl or 3 to 6 Substituents of a membered heterocyclic ring containing 1 to 3 (eg 1, 2 or 3) heteroatoms selected from O, S, N.
本发明涉及通式(I)、(II)、(II-a)、(II-b)或(II-c)的一些实施方案中，R x、R a1、R a2各自独立的选自H、F、Cl、Br、I、氰基、OH、甲基、乙基、丙基、异丙基、丁基、叔丁基、乙烯基、乙炔基、甲氧基、乙氧基、-SCH 3、-SCH 2CH 3、-SO 2CH 3、-SO 2CH 2CH 3、-C(＝O)CH 3、-C(＝O)CH 2CH 3、环丙基、环丁基、环戊基、环己基，所述的甲基、乙基、丙基、异丙基、丁基、叔丁基、乙烯基、乙炔基、甲氧基、乙氧基、-SCH 3、-SCH 2CH 3、-SO 2CH 3、-SO 2CH 2CH 3、 -C(＝O)CH 3、-C(＝O)CH 2CH 3、环丙基、环丁基、环戊基、环己基任选进一步被0至4个(例如0、1、2、3或4)选自H、卤素、OH、氰基、C 1-4烷基、卤素取代的C 1-4烷基、C 1-4烷氧基、C 3-6环烷基的取代基所取代。 The present invention relates to some embodiments of general formula (I), (II), (II-a), (II-b) or (II-c), R x , R a1 , R a2 are each independently selected from H , F, Cl, Br, I, cyano, OH, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, vinyl, ethynyl, methoxy, ethoxy, -SCH 3 , -SCH 2 CH 3 , -SO 2 CH 3 , -SO 2 CH 2 CH 3 , -C(=O)CH 3 , -C(=O)CH 2 CH 3 , cyclopropyl, cyclobutyl, Cyclopentyl, cyclohexyl, the methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, vinyl, ethynyl, methoxy, ethoxy, -SCH 3 , -SCH 2 CH 3 , -SO 2 CH 3 , -SO 2 CH 2 CH 3 , -C(=O)CH 3 , -C(=O)CH 2 CH 3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl 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, Substituents of C 1-4 alkoxy and C 3-6 cycloalkyl.
本发明涉及通式(I)、(II)、(II-a)、(II-b)或(II-c)的一些实施方案中，R x各自独立的选自H、F、Cl、Br、I、氰基、OH、甲基、乙基、丙基、异丙基、丁基、叔丁基、乙炔基、甲氧基、乙氧基、-SCH 3、-SCH 2CH 3、环丙基、环丁基、环戊基、环己基，所述的甲基、乙基、丙基、异丙基、乙炔基、甲氧基、乙氧基、-SCH 3、-SCH 2CH 3、环丙基、环丁基、环戊基、环己基任选进一步被0至4个(例如0、1、2、3或4)选自H、F、OH、氰基、甲基、乙基、甲氧基或乙氧基的取代基所取代。 In some embodiments of the present invention relating to general formula (I), (II), (II-a), (II-b) or (II-c), 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 H, F, OH, cyano, methyl, ethyl substituted by substituents of methoxy, methoxy or ethoxy.
本发明涉及通式(I)、(II)、(II-a)、(II-b)或(II-c)的一些实施方案中，R x各自独立的选自H、F、Cl、氰基、甲基、乙基、异丙基、三氟甲基、甲氧基、乙氧基、-SO 2CH 3、-SO 2CH 2CH 3、-C(＝O)CH 3、-C(＝O)CH 2CH 3、环丙基。 In some embodiments of the present invention relating to general formula (I), (II), (II-a), (II-b) or (II-c), each R x is independently selected from H, F, Cl, cyanogen radical, methyl, ethyl, isopropyl, trifluoromethyl, methoxy, ethoxy, -SO 2 CH 3 , -SO 2 CH 2 CH 3 , -C(=O)CH 3 , -C ( = O) CH2CH3 , cyclopropyl.
本发明涉及通式(II)、(II-a)、(II-b)或(II-c)的一些实施方案中，R a1选自H、F、Cl、Br、I、氰基、CF 3、CHF 2、CH 2F、甲基、乙基、丙基、异丙基、乙炔基、甲氧基、乙氧基、-SCH 3、-SCH 2CH 3、环丙基、环丁基、环戊基或环己基。 In some embodiments of the present invention relating to general formula (II), (II-a), (II-b) or (II-c), 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.
本发明涉及通式(II)、(II-a)、(II-b)或(II-c)的一些实施方案中，R a1选自H、F、Cl、Br、I、氰基、CF 3、甲基。 In some embodiments of the present invention relating to general formula (II), (II-a), (II-b) or (II-c), R a1 is selected from H, F, Cl, Br, I, cyano, CF 3. Methyl.
本发明涉及通式(II)的一些实施方案中，R a2选自H。 In some embodiments of the present invention relating to general formula (II), R a2 is selected from H.
本发明涉及通式(I)、(II)、(II-a)、(II-b)或(II-c)的一些实施方案中，环B选自4至11元含氮杂环、C 4-10碳环。 In some embodiments of the present invention relating to general formula (I), (II), (II-a), (II-b) or (II-c), Ring B is selected from the group consisting of 4 to 11 membered nitrogen-containing heterocycles, C 4-10 carbon rings.
本发明涉及通式(I)、(II)、(II-a)、(II-b)或(II-c)的一些实施方案中，环B选自4至7元单环含氮杂环、5-11元螺环含氮杂环、5-11元并环含氮杂环、5-11元桥环含氮杂环或C 4-7单环碳环。 In some embodiments of the present invention relating to general formula (I), (II), (II-a), (II-b) or (II-c), 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.
本发明涉及通式(I)、(II)的一些实施方案中，环B选自环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、哌啶基、哌嗪基、
Figure PCTCN2022088446-appb-000109
Figure PCTCN2022088446-appb-000110
Figure PCTCN2022088446-appb-000111
In some embodiments of the present invention relating to general formulae (I) and (II), ring B is selected from the group consisting of cyclobutyl, cyclopentyl, cyclohexyl, azetidine, pyrrolidinyl, piperidinyl, piperazinyl ,
Figure PCTCN2022088446-appb-000109
Figure PCTCN2022088446-appb-000110
Figure PCTCN2022088446-appb-000111
本发明涉及通式(I)、(II)的一些实施方案中，
Figure PCTCN2022088446-appb-000112
选自
Figure PCTCN2022088446-appb-000113
Figure PCTCN2022088446-appb-000114
Figure PCTCN2022088446-appb-000115
左侧与L连接。 The present invention relates to some embodiments of general formula (I), (II),
Figure PCTCN2022088446-appb-000112
selected from
Figure PCTCN2022088446-appb-000113
Figure PCTCN2022088446-appb-000114
Figure PCTCN2022088446-appb-000115
The left side is connected to L.
本发明涉及通式(I)、(II)的一些实施方案中，R b各自独立的选自H、卤素、氰基、OH、＝O、C 1-6烷基、C 1-6烷氧基、-(CH 2) q-C 3-6环烷基，所述的-CH 2-、烷基、烷氧基或环烷基任选进一步被0至4个(例如0、1、2、3或4)选自H、卤素、OH、氰基、NH 2、C 1-6烷基、卤素取代的C 1-6烷基、C 1-6烷氧基或C 3-6环烷基的取代基所取代。 The present invention relates to some embodiments of general formula (I), (II), R b is each independently selected from H, halogen, cyano, OH, =O, C 1-6 alkyl, C 1-6 alkoxy base, -(CH 2 ) q -C 3-6 cycloalkyl, said -CH 2 -, alkyl, alkoxy or cycloalkyl is optionally further substituted by 0 to 4 (eg 0, 1, 2 , 3 or 4) is selected from H, halogen, OH, cyano, NH 2 , C 1-6 alkyl, halogen substituted C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkane substituted by the substituents of the base.
本发明涉及通式(I)、(II)的一些实施方案中，R b各自独立的选自H、卤素、氰基、OH、＝O、C 1-4烷基、C 1-4烷氧基、-(CH 2) q-C 3-6环烷基，所述的-CH 2-、烷基、烷氧基或环烷基任选进一步被0至4个(例如0、1、2、3或4)选自H、卤素、OH、氰基、NH 2、C 1-4烷基、卤素取代的C 1-4烷基、C 1-4烷氧基或C 3-6环烷基的取代基所取代。 The present invention relates to some embodiments of general formula (I), (II), each R b is independently selected from H, halogen, cyano, OH, =O, C 1-4 alkyl, C 1-4 alkoxy base, -(CH 2 ) q -C 3-6 cycloalkyl, said -CH 2 -, alkyl, alkoxy or cycloalkyl is optionally further substituted by 0 to 4 (eg 0, 1, 2 , 3 or 4) is selected from H, halogen, OH, cyano, NH 2 , C 1-4 alkyl, halogen substituted C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkane substituted by the substituents of the base.
本发明涉及通式(I)、(II)的一些实施方案中，R b各自独立的选自H、F、Cl、Br、I、氰基、OH、＝O、甲基、乙基、丙基或异丙基，所述的甲基、乙基、丙基或异丙基任选进一步被0至4个(例如0、1、2、3或4)选自H、卤素、OH、氰基、NH 2、C 1-4烷基、卤素取代的C 1-4烷基、C 1-4烷氧基或C 3-6环烷基的取代基所取代。 The present invention relates to some embodiments of formulae (I) and (II), wherein each R b is independently selected from H, F, Cl, Br, I, cyano, OH, =O, methyl, ethyl, propyl or isopropyl, the methyl, ethyl, propyl or isopropyl optionally further selected from 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, halogen, OH, cyano substituted with substituents of C 1-4 alkyl, NH 2 , C 1-4 alkyl, halogen-substituted C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl.
本发明涉及通式(I)、(II)的一些实施方案中，R b各自独立的选自H、F、Cl、Br、I、氰基、OH、＝O、甲基、乙基、丙基或异丙基。 The present invention relates to some embodiments of formulae (I) and (II), wherein each R b is independently selected from H, F, Cl, Br, I, cyano, OH, =O, methyl, ethyl, propyl radical or isopropyl.
本发明涉及通式(I)的一些实施方案中，W选自键、C 1-3亚烷基或者Q2，所示亚烷基任选进一步被0至4个(例如0、1、2、3或4)选自H、卤素、CF 3、OH、氰基、NH 2、C 1-6烷基或C 1-6烷氧基的取代基所取代。 In some embodiments of the present invention relating to general formula (I), 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.
本发明涉及通式(I)的一些实施方案中，W选自键。In some embodiments of the present invention relating to general formula (I), W is selected from a bond.
本发明涉及通式(I)、(II)、(II-a)、(II-b)或(II-c)的一些实施方案中，L选自L1、L2或L3。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.
本发明涉及通式(I)、(II)、(II-a)、(II-b)或(II-c)的一些实施方案中，L1选自-Q1-Ak1-Q2-Ak2-Q3-，右侧与环B连接。In some embodiments of the present invention relating to general formula (I), (II), (II-a), (II-b) or (II-c), L1 is selected from -Q1-Ak1-Q2-Ak2-Q3- , the right side is connected to ring B.
本发明涉及通式(I)、(II)、(II-a)、(II-b)或(II-c)的一些实施方案中，L1选自-N(R q)-Ak1-O-Ak2-C(＝O)-、-O-Ak1-O-Ak2-C(＝O)-、-O-Ak1-N(R q)-Ak2-C(＝O)-、-N(R q)-Ak1-N(R q)-Ak2-C(＝O)-、-N(R q)-Ak1-O-Ak2-N(R q)C(＝O)-、-O-Ak1-O-Ak2-N(R q)C(＝O)-、-N(R q)-Ak1-Ak2-C(＝O)-、-N(R q)-Ak1-Ak2-N(R q)C(＝O)-、-O-Ak1-N(R q)-Ak2-N(R q)C(＝O)-、-S-Ak1-O-Ak2-C(＝O)-、-O-Ak1-S-Ak2-C(＝O)-、-N(R q)-Ak1-O-Ak2-S(＝O) 2-、-O-Ak1-O-Ak2-S(＝O) 2-、-N(R q)-Ak1-O-Ak2-、-O-Ak1-O-Ak2-，右侧与环B连接。 In some embodiments of the present invention relating to general formula (I), (II), (II-a), (II-b) or (II-c), L1 is selected from -N( Rq )-Ak1-O- Ak2-C(=O)-, -O-Ak1-O-Ak2-C(=O)-, -O-Ak1-N(R q )-Ak2-C(=O)-, -N(R q )-Ak1-N(R q )-Ak2-C(=O)-, -N(R q )-Ak1-O-Ak2-N(R q )C(=O)-, -O-Ak1-O -Ak2-N( Rq )C(=O)-, -N( Rq )-Ak1-Ak2-C(=O)-, -N( Rq )-Ak1-Ak2-N( Rq )C (=O)-, -O-Ak1-N(R q )-Ak2-N(R q )C(=O)-, -S-Ak1-O-Ak2-C(=O)-, -O- Ak1-S-Ak2-C(=O)-, -N(R q )-Ak1-O-Ak2-S(=O) 2 -, -O-Ak1-O-Ak2-S(=O) 2 - , -N(R q )-Ak1-O-Ak2-, -O-Ak1-O-Ak2-, and the right side is connected to ring B.
本发明涉及通式(I)、(II)、(II-a)、(II-b)或(II-c)的一些实施方案中，或者L1选自-N(R q)-Ak1-O-Ak2-C(＝O)N(R q)-、-O-Ak1-N(R q)-Ak2-C(＝O)N(R q)-、-O-Ak1-O-C(＝O)N(R q)-，右侧与环B连接。 The present invention relates to some embodiments of general formula (I), (II), (II-a), (II-b) or (II-c), or L1 is selected from -N( Rq )-Ak1-O -Ak2-C(=O)N( Rq )-, -O-Ak1-N( Rq )-Ak2-C(=O)N( Rq )-, -O-Ak1-OC(=O) N(R q )-, connected to ring B on the right side.
本发明涉及通式(I)、(II)、(II-a)、(II-b)或(II-c)的一些实施方案中，L1选自
Figure PCTCN2022088446-appb-000116
右侧与环B连接。 In some embodiments of the present invention relating to general formula (I), (II), (II-a), (II-b) or (II-c), L1 is selected from
Figure PCTCN2022088446-appb-000116
The right side is connected to ring B.
本发明涉及通式(I)、(II)、(II-a)、(II-b)或(II-c)的一些实施方案中，L1选自-NH-Ak1-O-Ak2-C(＝O)-、-O-Ak1-O-Ak2-C(＝O)-、-N(CH 3)-Ak1-O-Ak2-C(＝O)-、-O-Ak1-NH-Ak2-C(＝O)-、-O-Ak1-N(CH 3)-Ak2-C(＝O)-、-N(CH 3)-Ak1-NH-Ak2-C(＝O)-、-NH-Ak1-NH-Ak2-C(＝O)-、-S-Ak1-O-Ak2-C(＝O)-、-O-Ak1-S-Ak2-C(＝O)-、-NH-Ak1-O-Ak2-S(＝O) 2-、-O-Ak1-O-Ak2-S(＝O) 2-、-NH-Ak1-O-Ak2-、-O-Ak1-O-Ak2-，右侧与环B连接。 In some embodiments of the present invention relating to general formula (I), (II), (II-a), (II-b) or (II-c), L1 is selected from -NH-Ak1-O-Ak2-C( =O)-, -O-Ak1-O-Ak2-C(=O)-, -N(CH 3 )-Ak1-O-Ak2-C(=O)-, -O-Ak1-NH-Ak2- C(=O)-, -O-Ak1-N(CH 3 )-Ak2-C(=O)-, -N(CH 3 )-Ak1-NH-Ak2-C(=O)-, -NH- Ak1-NH-Ak2-C(=O)-, -S-Ak1-O-Ak2-C(=O)-, -O-Ak1-S-Ak2-C(=O)-, -NH-Ak1- O-Ak2-S(=O) 2 -, -O-Ak1-O-Ak2-S(=O) 2 -, -NH-Ak1-O-Ak2-, -O-Ak1-O-Ak2-, right side is connected to ring B.
本发明涉及通式(I)、(II)、(II-a)、(II-b)或(II-c)的一些实施方案中，L2选自
Figure PCTCN2022088446-appb-000117
右侧与环B连接。 In some embodiments of the present invention relating to general formula (I), (II), (II-a), (II-b) or (II-c), L2 is selected from
Figure PCTCN2022088446-appb-000117
The right side is connected to ring B.
本发明涉及通式(I)、(II)、(II-a)、(II-b)或(II-c)的一些实施方案中，L2选自
Figure PCTCN2022088446-appb-000118
右侧与环B连接。 In some embodiments of the present invention relating to general formula (I), (II), (II-a), (II-b) or (II-c), L2 is selected from
Figure PCTCN2022088446-appb-000118
The right side is connected to ring B.
本发明涉及通式(I)、(II)、(II-a)、(II-b)或(II-c)的一些实施方案中，L2选自
Figure PCTCN2022088446-appb-000119
Figure PCTCN2022088446-appb-000120
右侧与环B连接。 In some embodiments of the present invention relating to general formula (I), (II), (II-a), (II-b) or (II-c), L2 is selected from
Figure PCTCN2022088446-appb-000119
Figure PCTCN2022088446-appb-000120
The right side is connected to ring B.
本发明涉及通式(I)、(II)、(II-a)、(II-b)或(II-c)的一些实施方案中，L3选自
Figure PCTCN2022088446-appb-000121
右侧与环B连接。 In some embodiments of the present invention relating to general formula (I), (II), (II-a), (II-b) or (II-c), L3 is selected from
Figure PCTCN2022088446-appb-000121
The right side is connected to ring B.
本发明涉及通式(I)、(II)、(II-a)、(II-b)或(II-c)的一些实施方案中，L3选自
Figure PCTCN2022088446-appb-000122
Figure PCTCN2022088446-appb-000123
Figure PCTCN2022088446-appb-000124
右侧与环B连接。 In some embodiments of the present invention relating to general formula (I), (II), (II-a), (II-b) or (II-c), L3 is selected from
Figure PCTCN2022088446-appb-000122
Figure PCTCN2022088446-appb-000123
Figure PCTCN2022088446-appb-000124
The right side is connected to ring B.
本发明涉及通式(I)、(II)、(II-a)、(II-b)或(II-c)的一些实施方案中，L4选自-Ak3-Q4-Ak4-K1-Q5-K2-Ak5-Q6-或-Ak3-Q4-Ak4-K1-Q5-，右侧与环B连接。In some embodiments of the present invention relating to general formula (I), (II), (II-a), (II-b) or (II-c), 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.
本发明涉及通式(I)、(II)、(II-a)、(II-b)或(II-c)的一些实施方案中，L4选自-Ak3-O-K1-C(＝O)-、-Ak3-N(R q)-K1-C(＝O)-、-Ak3-N(R q)-K1-C(＝O)-，右侧与环B连接。 In some embodiments of the present invention relating to general formula (I), (II), (II-a), (II-b) or (II-c), L4 is selected from -Ak3-O-K1-C(=O )-, -Ak3-N(R q )-K1-C(=O)-, -Ak3-N(R q )-K1-C(=O)-, and the right side is connected to ring B.
本发明涉及通式(I)、(II)、(II-a)、(II-b)或(II-c)的一些实施方案中，L4选自-Ak3-O-K1-C(＝O)-、-Ak3-NH-K1-C(＝O)-、-Ak3-N(CH 3)-K1-C(＝O)-，右侧与环B连接。 In some embodiments of the present invention relating to general formula (I), (II), (II-a), (II-b) or (II-c), L4 is selected from -Ak3-O-K1-C(=O )-, -Ak3-NH-K1-C(=O)-, -Ak3-N(CH 3 )-K1-C(=O)-, and the right side is connected to ring B.
本发明涉及通式(I)、(II)、(II-a)、(II-b)或(II-c)的一些实施方案中，Ak1、Ak2各自独立的选自C 1-4亚烷基、C 2-4亚烯基、C 2-4亚炔基，所述Ak1任选进一步被0至4个(例如0、1、2、3或4)R k1取代，所述Ak2任选进一步被0至4个(例如0、1、2、3或4)R k2取代。 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 .
本发明涉及通式(I)、(II)、(II-a)、(II-b)或(II-c)的一些实施方案中，Ak1、Ak2各自独立的选自C 1-3亚烷基、C 2-3亚烯基、C 2-3亚炔基，所述Ak1任选进一步被0至4个(例如 0、1、2、3或4)R k1取代，所述Ak2任选进一步被0至4个(例如0、1、2、3或4)R k2取代。 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 .
本发明涉及通式(I)、(II)、(II-a)、(II-b)或(II-c)的一些实施方案中，Ak1、Ak2各自独立的选自亚甲基、亚乙基、亚丙基、亚乙烯基、亚丙烯基、亚乙炔基、亚丙炔基，所述Ak1任选进一步被0至4个(例如0、1、2、3或4)R k1取代，所述Ak2任选进一步被0至4个(例如0、1、2、3或4)R k2取代。 In some embodiments of the present invention relating to general formula (I), (II), (II-a), (II-b) or (II-c), 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 .
本发明涉及通式(I)、(II)、(II-a)、(II-b)或(II-c)的一些实施方案中，Ak3、Ak4、Ak5各自独立的选自键、C 1-4亚烷基、C 2-4亚烯基、C 2-4亚炔基，所述Ak3任选进一步被0至4个(例如0、1、2、3或4)R k3取代，所述Ak4任选进一步被0至4个(例如0、1、2、3或4)R k4取代，所述Ak5任选进一步被0至4个(例如0、1、2、3或4)R k5取代。 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 .
本发明涉及通式(I)、(II)、(II-a)、(II-b)或(II-c)的一些实施方案中，Ak3、Ak4、Ak5各自独立的选自键、C 1-3亚烷基、C 2-3亚烯基、C 2-3亚炔基，所述Ak3任选进一步被0至4个(例如0、1、2、3或4)R k3取代，所述Ak4任选进一步被0至4个(例如0、1、2、3或4)R k4取代，所述Ak5任选进一步被0至4个(例如0、1、2、3或4)R k5取代。 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 .
本发明涉及通式(I)、(II)、(II-a)、(II-b)或(II-c)的一些实施方案中，Ak3、Ak4、Ak5各自独立的选自键、亚甲基、亚乙基、亚丙基、亚乙烯基、亚丙烯基、亚乙炔基、亚丙炔基，所述Ak3任选进一步被0至4个(例如0、1、2、3或4)R k3取代，所述Ak4任选进一步被0至4个(例如0、1、2、3或4)R k4取代，所述Ak5任选进一步被0至4个(例如0、1、2、3或4)R k5取代。 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.
本发明涉及通式(I)、(II)、(II-a)、(II-b)或(II-c)的一些实施方案中，K1或K2选自C 1-2亚烷基、C 3-10碳环或3至12元杂环，所述的亚烷基任选进一步被0至4个(例如0、1、2、3或4)R k6取代，所述的碳环或杂环任选进一步被0至4个(例如0、1、2、3或4)选自H、卤素、OH、氰基、NH 2、C 1-6烷基、C 2-6烯基、C 2-6炔基、卤素取代的C 1-6烷基、C 1-6烷氧基、-C 1-6烷基-OC 1-6烷基、-O-C 1-6烷基-OC 1-6烷基、-O-C 3-8碳环、C 3-8碳环、4至10元杂环的取代基所取代，所述的杂环含有1至3个(例如1、2或3个)选自O、S、N的杂原子。 In some embodiments of the present invention relating to general formula (I), (II), (II-a), (II-b) or (II-c), 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, the heterocycle contains 1 to 3 (eg 1, 2 or 3) Heteroatoms selected from O, S, N.
本发明涉及通式(I)、(II)、(II-a)、(II-b)或(II-c)的一些实施方案中，K1或K2选自C 1-2亚烷基、C 3-6碳环或3至7元杂环，所述的亚烷基任选进一步被0至4个(例如0、1、2、3或4)R k6取代，所述的碳环或杂环任选进一步被0至4个(例如0、1、2、3或4)选自H、卤素、OH、氰基、NH 2、C 1-4烷基、C 2-4烯基、C 2-4炔基、卤素取代的C 1-4烷基、 C 1-4烷氧基、-C 1-4烷基-OC 1-4烷基、-O-C 1-4烷基-OC 1-4烷基、-O-C 3-6碳环、C 3-6碳环、4至7元杂环的取代基所取代，所述的杂环含有1至3个(例如1、2或3个)选自O、S、N的杂原子。 In some embodiments of the present invention relating to general formula (I), (II), (II-a), (II-b) or (II-c), 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 substituents, the heterocycle contains 1 to 3 (eg 1, 2 or 3) Heteroatoms selected from O, S, N.
本发明涉及通式(I)、(II)、(II-a)、(II-b)或(II-c)的一些实施方案中，K1或K2选自亚甲基、亚乙基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氮杂环戊基、氮杂环己基、哌嗪、吗啉、氧杂环丁基、氧杂环戊基、氧杂环己基、苯环、吡啶、吡嗪、嘧啶、哒嗪，所述的亚甲基、亚乙基任选进一步被0至4个(例如0、1、2、3或4)R k6取代，所述的环丙基、环丁基、环戊基、环己基、氮杂环丁基、氮杂环戊基、氮杂环己基、哌嗪、吗啉、氧杂环丁基、氧杂环戊基、氧杂环己基、苯环、吡啶、吡嗪、嘧啶、哒嗪任选进一步被0至4个(例如0、1、2、3或4)选自H、卤素、OH、氰基、NH 2、C 1-4烷基、C 2-4烯基、C 2-4炔基、卤素取代的C 1-4烷基、C 1-4烷氧基、-C 1-4烷基-OC 1-4烷基、-O-C 1-4烷基-OC 1-4烷基、-O-C 3-6碳环、C 3-6碳环、4至7元杂环的取代基所取代，所述的杂环含有1至3个(例如1、2或3个)选自O、S、N的杂原子。 In some embodiments of the present invention relating to general formula (I), (II), (II-a), (II-b) or (II-c), 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, piperazine, morpholine, oxetanyl, oxa Cyclopentyl, oxanyl, benzene ring, pyridine, pyrazine, pyrimidine, pyridazine optionally further selected from 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, N.
本发明涉及通式(I)、(II)、(II-a)、(II-b)或(II-c)的一些实施方案中，R k1、R k2、R k3、R k4、R k5、R k6、R L1、R L2各自独立的选自H、卤素、氰基、OH、＝O、NH 2、NHC 1-6烷基、N(C 1-6烷基) 2、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、-OC 3-6碳环、C 3-6碳环或4至7元杂环，所述的烷基、烯基、炔基、烷氧基、碳环或杂环任选进一步被0至4个(例如0、1、2、3或4)选自H、卤素、OH、氰基、NH 2、C 1-6烷基、C 2-6烯基、C 2-6炔基、卤素取代的C 1-6烷基、C 1-6烷氧基、-O-C 3-8碳环、C 3-8碳环、4至10元杂环的取代基所取代，所述的杂环含有1至3个(例如1、2或3个)选自O、S、N的杂原子。 The present invention relates to some embodiments of formula (I), (II), (II-a), (II-b) or (II-c), R k1 , R k2 , R k3 , R k4 , R k5 , R k6 , R L1 , and R L2 are each independently selected from H, halogen, cyano, OH, =O, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , C 1- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, -OC 3-6 carbocycle, C 3-6 carbocycle or 4- to 7-membered heterocycle, the The alkyl, alkenyl, alkynyl, alkoxy, carbocycle or heterocycle is optionally further selected from 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, -OC 3-8 carbocycle, C 3-8 carbocyclic ring, 4- to 10-membered heterocyclic ring containing 1 to 3 (eg 1, 2 or 3) heteroatoms selected from O, S, N.
本发明涉及通式(I)、(II)、(II-a)、(II-b)或(II-c)的一些实施方案中，R k1、R k2、R k3、R k4、R k5、R k6、R L1、R L2各自独立的选自H、卤素、氰基、OH、＝O、NH 2、NHC 1-4烷基、N(C 1-4烷基) 2、C 1-4烷基、C 1-4烷氧基、C 3-6碳环或4至7元杂环，所述的烷基、烷氧基、碳环或杂环任选进一步被0至4个(例如0、1、2、3或4)选自H、卤素、OH、氰基、NH 2、C 1-4烷基、卤素取代的C 1-4烷基、C 1-4烷氧基、C 3-6碳环、4至6元杂环的取代基所取代，所述的杂环含有1至3个(例如1、2或3个)选自O、S、N的杂原子。 The present invention relates to some embodiments of formula (I), (II), (II-a), (II-b) or (II-c), R k1 , R k2 , R k3 , R k4 , R k5 , R k6 , R L1 , and R L2 are each independently selected from H, halogen, cyano, OH, =O, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , C 1- 4 alkyl, C 1-4 alkoxy, C 3-6 carbocycle or 4 to 7-membered heterocycle, the alkyl, alkoxy, carbocycle or heterocycle is optionally further replaced by 0 to 4 ( For example 0, 1, 2, 3 or 4) is selected from H, halogen, OH, cyano, NH 2 , C 1-4 alkyl, halogen substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 carbocyclic ring, 4- to 6-membered heterocyclic ring containing 1 to 3 (eg 1, 2 or 3) heteroatoms selected from O, S, N.
本发明涉及通式(I)、(II)、(II-a)、(II-b)或(II-c)的一些实施方案中，R k1、R k2、R k3、R k4、R k5、R k6、R L1、R L2各自独立的选自H、F、Cl、Br、I、氰基、OH、＝O、NH 2、NH(CH 3)、N(CH 3) 2、甲基、乙基、丙基、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氮杂环戊基、氮杂环己基、氧杂环丁基、氧杂环戊基、氧杂环己基、吡啶、 苯基，所述甲基、乙基、丙基、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氮杂环戊基、氮杂环己基、氧杂环丁基、氧杂环戊基、氧杂环己基、吡啶、苯基任选进一步被0至4个(例如0、1、2、3或4)选自H、卤素、OH、氰基、NH 2、C 1-4烷基、卤素取代的C 1-4烷基、C 1-4烷氧基、C 3-6碳环、4至6元杂环的取代基所取代，所述的杂环含有1至3个(例如1、2或3个)选自O、S、N的杂原子。 The present invention relates to some embodiments of formula (I), (II), (II-a), (II-b) or (II-c), R k1 , R k2 , R k3 , R k4 , R k5 , R k6 , R L1 , R L2 are each independently selected from H, F, Cl, Br, I, cyano, OH, =O, NH 2 , NH(CH 3 ), N(CH 3 ) 2 , methyl , ethyl, propyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, azacyclopentyl, azacyclohexyl, oxane Butyl, oxolane, oxhexyl, pyridine, phenyl, the methyl, ethyl, propyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl, azetidine, azepanyl, azetidine, oxetanyl, oxolane, oxanyl, pyridine, phenyl are optionally further substituted by 0 to 4 ( For example 0, 1, 2, 3 or 4) is selected from H, halogen, OH, cyano, NH 2 , C 1-4 alkyl, halogen substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 carbocyclic ring, 4- to 6-membered heterocyclic ring containing 1 to 3 (eg 1, 2 or 3) heteroatoms selected from O, S, N.
本发明涉及通式(I)、(II)、(II-a)、(II-b)或(II-c)的一些实施方案中，R k1与R k1、R k2与R k2、R k1与R k2、R k3与R k3、R k4与R k4、R k5与R k5、R k6与R k6直接连接形成C 3-6碳环或者4至7元的杂环，所述的碳环或杂环任选进一步被0至4个(例如0、1、2、3或4)选自H、卤素、＝O、OH、氰基、C 1-6烷基、卤素取代的C 1-6烷基、C 1-6烷氧基、C 3-6环烷基的取代基所取代，所述的杂环含有1至3个(例如1、2或3个)选自O、S、N的杂原子。 The present invention relates to some embodiments of formula (I), (II), (II-a), (II-b) or (II-c), R k1 and R k1 , R k2 and R k2 , R k1 and R k2 , R k3 and R k3 , R k4 and R k4 , R k5 and R k5 , R k6 and R k6 are directly connected to form a C 3-6 carbocycle or a 4- to 7-membered heterocycle, the carbocycle or heterocycle optionally further 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, halogen, =O, OH, cyano, C 1-6 alkyl, halogen substituted C 1- 6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl substituents, the heterocycle contains 1 to 3 (for example 1, 2 or 3) selected from O, S, heteroatom of N.
本发明涉及通式(I)、(II)、(II-a)的一些实施方案中，R k1与R k1、R k2与R k2、R k1与R k2、R k3与R k3、R k4与R k4、R k5与R k5、R k6与R k6直接连接形成C 3-6碳环(例如C 3、C 4、C 5或C 6)或者4至7元(例如4、5、6或7元)的杂环，所述的碳环或杂环任选进一步被0至4个(例如0、1、2、3或4)选自H、卤素、＝O、OH、氰基、C 1-4烷基、卤素取代的C 1-4烷基、C 1-4烷氧基、C 3-6环烷基的取代基所取代，所述的杂环含有1至3个(例如1、2或3个)选自O、S、N的杂原子。 The present invention relates to some embodiments of general formula (I), (II), (II-a), R k1 and R k1 , R k2 and R k2 , R k1 and R k2 , R k3 and R k3 , R k4 Directly linked to Rk4, Rk5 and Rk5 , Rk6 and Rk6 to form a C3-6 carbocycle (eg C3, C4 , C5 or C6 ) or 4 to 7 membered (eg 4, 5, 6) or 7-membered) heterocycle, said carbocycle or heterocycle is optionally further 0 to 4 (eg 0, 1, 2, 3 or 4) 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 substituents, the heterocycle contains 1 to 3 (for example 1, 2 or 3) heteroatoms selected from O, S, N.
本发明涉及通式(I)、(II)、(II-a)、(II-b)或(II-c)的一些实施方案中，Q1、Q5各自独立的选自O、S、N(R q)、C(＝O)、C(＝O)N(R q)、N(R q)C(＝O)、C(＝O)O、OC(＝O)、S(＝O)、S(＝O) 2、S(＝O) 2N(R q)、N(R q)S(＝O) 2、N(R q)C(＝O)N(R q)、N(R q)C(＝O)N(R q)。 The present invention relates to some embodiments of general formula (I), (II), (II-a), (II-b) or (II-c), Q1, Q5 are independently selected from O, S, N ( Rq ), C(=O), C(=O)N( Rq ), N( Rq )C(=O), C(=O)O, OC(=O), S(=O) , S(=O) 2 , S(=O) 2 N(R q ), N(R q )S(=O) 2 , N(R q )C(=O)N(R q ), N( R q )C(=O)N(R q ).
本发明涉及通式(I)、(II)、(II-a)、(II-b)或(II-c)的一些实施方案中，Q1、Q5各自独立的选自O、S、N(R q)、C(＝O)、C(＝O)N(R q)、N(R q)C(＝O)、S(＝O) 2。 The present invention relates to some embodiments of general formula (I), (II), (II-a), (II-b) or (II-c), Q1, Q5 are independently selected from O, S, N ( R q ), C(=O), C(=O)N(R q ), N(R q )C(=O), S(=O) 2 .
本发明涉及通式(I)、(II)、(II-a)、(II-b)或(II-c)的一些实施方案中，Q2、Q3、Q4、Q6各自独立的选自键或者Q1。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.
本发明涉及通式(I)、(II)、(II-a)、(II-b)或(II-c)的一些实施方案中，环E选自C 3-6碳环或4至7元杂环，所述的杂环含有1至3个(例如1、2或3个)选自O、S、N的杂原子。 In some embodiments of the present invention relating to general formula (I), (II), (II-a), (II-b) or (II-c), 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.
本发明涉及通式(I)、(II)、(II-a)、(II-b)或(II-c)的一些实施方案中，环E选自C 3-6碳环或4至6元杂环，所述的杂环含有1至3个(例如1、2或3个)选自O、S、N的杂原子。 In some embodiments of the present invention relating to general formula (I), (II), (II-a), (II-b) or (II-c), 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.
本发明涉及通式(I)、(II)、(II-a)、(II-b)或(II-c)的一些实施方案中，环E选自苯基或5-6元杂芳基，所述的杂芳基含有1至3个(例如1、2或3个)选自O、S、N的杂原子。In some embodiments of the present invention relating to general formula (I), (II), (II-a), (II-b) or (II-c), 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.
本发明涉及通式(I)、(II)、(II-a)、(II-b)或(II-c)的一些实施方案中，环E选自苯环或 吡啶。In some embodiments of the present invention relating to general formula (I), (II), (II-a), (II-b) or (II-c), Ring E is selected from a benzene ring or a pyridine.
本发明涉及通式(I)、(II)、(II-a)、(II-b)或(II-c)的一些实施方案中，R q各自独立的选自H、C 1-6烷基或C 3-6环烷基，所述的烷基或环烷基任选进一步被0至4个(例如0、1、2、3或4)选自H、卤素、CF 3、OH、氰基、NH 2、C 1-6烷基或C 1-6烷氧基的取代基所取代。 In some embodiments of the present invention relating to general formula (I), (II), (II-a), (II-b) or (II-c), 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.
本发明涉及通式(I)、(II)、(II-a)的一些实施方案中，R q各自独立的选自H、C 1-4烷基，所述的烷基任选进一步被0至4个(例如0、1、2、3或4)选自H、卤素、CF 3、OH、氰基、NH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代。 The present invention relates to some embodiments of general formula (I), (II), (II-a), 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.
本发明涉及通式(I)、(II)、(II-a)、(II-b)或(II-c)的一些实施方案中，R q各自独立的选自H、甲基、乙基。 In some embodiments of the present invention relating to general formula (I), (II), (II-a), (II-b) or (II-c), each Rq is independently selected from H, methyl, ethyl .
本发明涉及通式(I)、(II)、(II-a)、(II-b)或(II-c)的一些实施方案中，R q与R k1或R k2直接连接，形成4至7元的杂环，所述的杂环任选进一步被0至4个(例如0、1、2、3或4)选自H、卤素、＝O、OH、氰基、C 1-6烷基、卤素取代的C 1-6烷基、C 1-6烷氧基、C 3-6环烷基的取代基所取代，所述的杂环含有1至3个(例如1、2或3个)选自O、S、N的杂原子。 In some embodiments of the present invention relating to general formula (I), (II), (II-a), (II-b) or (II-c), R q is directly linked to R k1 or R k2 to form 4 to 7-membered heterocycle optionally further selected by 0 to 4 (eg 0, 1, 2, 3 or 4) selected from H, halogen, =O, OH, cyano, C 1-6 alkane substituted by substituents of C 1-6 alkyl, halogen-substituted C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, and the heterocycle contains 1 to 3 (for example, 1, 2 or 3 ) heteroatoms selected from O, S, N.
本发明涉及通式(I)、(II)、(II-a)、(II-b)或(II-c)的一些实施方案中，R q与R k1、R q与R k2直接连接形成4至7元的杂环，所述的杂环任选进一步被0至4个(例如0、1、2、3或4)选自H、卤素、＝O、OH、氰基、C 1-4烷基、卤素取代的C 1-4烷基、C 1-4烷氧基、C 3-6环烷基的取代基所取代，所述的杂环含有1至3个(例如1、2或3个)选自O、S、N的杂原子。 The present invention relates to some embodiments of general formula (I), (II), (II-a), (II-b) or (II-c), R q and R k1 , R q and R k2 are directly linked to form 4- to 7-membered heterocycle, optionally further 0 to 4 (eg 0, 1, 2, 3 or 4) 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 substituent, the heterocycle contains 1 to 3 (for example, 1, 2 or 3) heteroatoms selected from O, S, N.
本发明涉及通式(I)、(II)、(II-a)、(II-b)或(II-c)的一些实施方案中，R q与R k1、R q与R k2直接连接形成4至7元的杂环，所述的杂环任选进一步被0至4个(例如0、1、2、3或4)选自H、卤素、＝O、OH、氰基、甲基、乙基、丙基、异丙基、甲氧基、乙氧基、环丙基的取代基所取代，所述的杂环含有1至3个(例如1、2或3个)选自O、S、N的杂原子。 The present invention relates to some embodiments of general formula (I), (II), (II-a), (II-b) or (II-c), R q and R k1 , R q and R k2 are directly linked to form A 4- to 7-membered heterocycle optionally further selected from 0 to 4 (eg 0, 1, 2, 3 or 4) from H, halogen, =O, OH, cyano, methyl, substituted by substituents of ethyl, propyl, isopropyl, methoxy, ethoxy, and cyclopropyl, and the heterocycle contains 1 to 3 (for example, 1, 2 or 3) selected from O, S and N heteroatoms.
本发明涉及通式(I)、(II)、(II-a)、(II-b)或(II-c)的一些实施方案中，L1选自
Figure PCTCN2022088446-appb-000125
In some embodiments of the present invention relating to general formula (I), (II), (II-a), (II-b) or (II-c), L1 is selected from
Figure PCTCN2022088446-appb-000125
Figure PCTCN2022088446-appb-000126
Figure PCTCN2022088446-appb-000126
Figure PCTCN2022088446-appb-000127
Figure PCTCN2022088446-appb-000128
右侧与环B连接。
Figure PCTCN2022088446-appb-000127
Figure PCTCN2022088446-appb-000128
The right side is connected to ring B.
本发明涉及通式(I)、(II)、(II-a)、(II-b)或(II-c)的一些实施方案中，L1选自
Figure PCTCN2022088446-appb-000129
Figure PCTCN2022088446-appb-000130
Figure PCTCN2022088446-appb-000131
右侧与环B连接。 In some embodiments of the present invention relating to general formula (I), (II), (II-a), (II-b) or (II-c), L1 is selected from
Figure PCTCN2022088446-appb-000129
Figure PCTCN2022088446-appb-000130
Figure PCTCN2022088446-appb-000131
The right side is connected to ring B.
本发明涉及通式(I)、(II)、(II-a)、(II-b)或(II-c)的一些实施方案中，L选自
Figure PCTCN2022088446-appb-000132
或者
Figure PCTCN2022088446-appb-000133
右侧与环B连接。 In some embodiments of the present invention relating to general formula (I), (II), (II-a), (II-b) or (II-c), L is selected from
Figure PCTCN2022088446-appb-000132
or
Figure PCTCN2022088446-appb-000133
The right side is connected to ring B.
本发明涉及通式(I)、(II)、(II-a)、(II-b)或(II-c)的一些实施方案中，L选自
Figure PCTCN2022088446-appb-000134
Figure PCTCN2022088446-appb-000135
右侧与环B连接。 In some embodiments of the present invention relating to general formula (I), (II), (II-a), (II-b) or (II-c), L is selected from
Figure PCTCN2022088446-appb-000134
Figure PCTCN2022088446-appb-000135
The right side is connected to ring B.
本发明涉及通式(I)、(II)、(II-a)、(II-b)或(II-c)的一些实施方案中，L选自
Figure PCTCN2022088446-appb-000136
Figure PCTCN2022088446-appb-000137
右侧与环B连接。 In some embodiments of the present invention relating to general formula (I), (II), (II-a), (II-b) or (II-c), L is selected from
Figure PCTCN2022088446-appb-000136
Figure PCTCN2022088446-appb-000137
The right side is connected to ring B.
本发明涉及通式(I)、(II)、(II-a)、(II-b)或(II-c)的一些实施方案中，L2选自
Figure PCTCN2022088446-appb-000138
Figure PCTCN2022088446-appb-000139
右侧与环B连接。 In some embodiments of the present invention relating to general formula (I), (II), (II-a), (II-b) or (II-c), L2 is selected from
Figure PCTCN2022088446-appb-000138
Figure PCTCN2022088446-appb-000139
The right side is connected to ring B.
本发明涉及通式(I)、(II)、(II-a)、(II-b)或(II-c)的一些实施方案中，L3选自
Figure PCTCN2022088446-appb-000140
右侧与环B连接。 In some embodiments of the present invention relating to general formula (I), (II), (II-a), (II-b) or (II-c), L3 is selected from
Figure PCTCN2022088446-appb-000140
The right side is connected to ring B.
本发明涉及通式(I)、(II)的一些实施方案中，q各自独立的选自0、1、2、3或4。In some embodiments of the present invention relating to general formulae (I) and (II), each q is independently selected from 0, 1, 2, 3 or 4.
本发明涉及通式(I)、(II)的一些实施方案中，a选自0、1、2、3或4。In some embodiments of the present invention relating to general formulae (I), (II), a is selected from 0, 1, 2, 3 or 4.
本发明涉及通式(I)、(II)的一些实施方案中，b选自0、1、2、3或4。In some embodiments of the present invention relating to general formulae (I), (II), b is selected from 0, 1, 2, 3 or 4.
本发明涉及通式(I)、(II)的一些实施方案中，x选自0、1、2、3或4。In some embodiments of the present invention relating to general formulae (I), (II), x is selected from 0, 1, 2, 3 or 4.
本发明涉及通式(I)、(II)、(II-a)、(II-b)或(II-c)的一些实施方案中，s1选自0、1、2、3或4。In some embodiments of the present invention relating to general formula (I), (II), (II-a), (II-b) or (II-c), s1 is selected from 0, 1, 2, 3 or 4.
本发明涉及通式(I)、(II)、(II-a)、(II-b)或(II-c)的一些实施方案中，s2选自0、1、2、3或4。In some embodiments of the present invention relating to general formula (I), (II), (II-a), (II-b) or (II-c), s2 is selected from 0, 1, 2, 3 or 4.
本发明涉及通式(I)、(II)、(II-a)、(II-b)或(II-c)的一些实施方案中，s3选自0、1、2、3或4。In some embodiments of the present invention relating to general formula (I), (II), (II-a), (II-b) or (II-c), s3 is selected from 0, 1, 2, 3 or 4.
本发明涉及一种药物组合物，包括任意上述化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，以及要学上可接受的载体。The present invention relates to 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 .
本发明涉及任意上述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶在用于制备治疗与PARP7活性或表达量相关疾病的药物中的应用，优选地，所述疾病选自肿瘤。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 In applications, preferably, the disease is selected from tumors.
除非有相反的陈述，在说明书和权利要求书中使用的术语具有下述含义。Unless stated to the contrary, terms used in the specification and claims have the following meanings.
本发明所述基团和化合物中所涉及的碳、氢、氧、硫、氮或F、Cl、Br、I均包括它们的同位素情况，及本发明所述基团和化合物中所涉及的碳、氢、氧、硫或氮任选进一步被一个或多个它们对应的同位素所替代，其中碳的同位素包括 12C、 13C和 14C，氢的同位素包括氕(H)、氘(D，又叫重氢)、氚(T，又叫超重氢)，氧的同位素包括 16O、 17O和 18O，硫的同位素包括 32S、 33S、 34S和 36S，氮的同位素包括 14N和 15N，氟的同位素包括 17F和 19F，氯的同位素包括 35Cl和 37Cl，溴的同位素包括 79Br和 81Br。 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.
“卤素”是指F、Cl、Br或I。"Halogen" means F, Cl, Br or I.
“卤素取代的”是指F、Cl、Br或I取代，包括但不限于1至10个选自F、Cl、Br或I的取代基所取代，1至6个选自F、Cl、Br或I的取代基所取代，为1至4个选自F、Cl、Br或I的取代基所取代。“卤素取代的”简称为“卤代”。"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".
“烷基”是指取代的或者未取代的直链或支链饱和脂肪族烃基，包括但不限于1至20 个碳原子的烷基、1至8个碳原子的烷基、1至6个碳原子的烷基、1至4个碳原子的烷基。非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、仲丁基、新丁基、叔丁基、正戊基、异戊基、新戊基、正己基及其各种支链异构体；本文中出现的烷基，其定义与本定义一致。烷基可以是一价、二价、三价或四价。"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.
“杂烷基”指取代的或者未取代的烷基中的1个或多个(包括但不限于2、3、4、5或6个)碳原子被杂原子(包括但不限于N、O或S)替换。非限制性实施例包括-X(CH 2)v-X(CH 2)v-X(CH 2)v-H(v为1至5的整数，X各自独立地选自键或杂原子，杂原子包括但不限于N、O或S，且至少有1个X选自杂原子，且杂原子中的N或S可被氧化成各种氧化态)。杂烷基可以是一价、二价、三价或四价。 "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.
“亚烷基”是指取代的或者未取代的直链和支链的二价饱和烃基，包括-(CH 2) v-(v为1至10的整数)，亚烷基实施例包括但不限于亚甲基、亚乙基、亚丙基和亚丁基等。 "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.
“亚杂烷基”是指取代的或者未取代的亚烷基中的1个或多个(包括但不限于2、3、4、5或6个)碳原子被杂原子(包括但不限于N、O或S)替换。非限制性实施例包括-X(CH 2)v-X(CH 2)v-X(CH 2)v-，v为1至5的整数，X各自独立地选自键、N、O或S，且至少有1个X选自N、O或S。 "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.
“环烷基”是指取代的或者未取代的饱和的碳环烃基，通常有3至10个碳原子，非限制性实施例包括环丙基、环丁基、环戊基、环己基或环庚基等。本文中出现的环烷基，其定义如上所述。环烷基可以是一价、二价、三价或四价。"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.
“杂环烷基”是指取代的或者未取代的饱和的含有杂原子的环烃基，包括但不限于3至10个原子、3至8个原子，包含1至3个选自N、O或S的杂原子，杂环烷基的环中选择性取代的N、S可被氧化成各种氧化态。杂环烷基可以连接在杂原子或者碳原子上，杂环烷基可以连接在芳香环上或者非芳香环上，杂环烷基可以连接有桥环或者螺环，非限制性实施例包括环氧乙基、氮杂环丙基、氧杂环丁基、氮杂环丁基、四氢呋喃基、四氢-2H-吡喃基、二氧戊环基、二氧六环基、吡咯烷基、哌啶基、咪唑烷基、噁唑烷基、噁嗪烷基、吗啉基、六氢嘧啶基、哌嗪基。杂环烷基可以是一价、二价、三价或四价"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
“烯基”是指取代的或者未取代的直链和支链的不饱和烃基，其具有至少1个，通常有1、2或3个碳碳双键，主链包括但不限于2至10个、2至6个或2至4个碳原子，烯基实施例包括但不限于乙烯基、烯丙基、1-丙烯基、2-丙烯基、1-丁烯基、2-丁烯基、3-丁烯基、1-戊烯基、2-戊烯基、3-戊烯基、4-戊烯基、1-甲基-1-丁烯基、2-甲基-1-丁烯基、2-甲基-3-丁烯基、1-己烯基、2-己烯基、3-己烯基、4-己烯基、5-己烯基、1-甲基-1- 戊烯基、2-甲基-1-戊烯基、1-庚烯基、2-庚烯基、3-庚烯基、4-庚烯基、1-辛烯基、3-辛烯基、1-壬烯基、3-壬烯基、1-癸烯基、4-癸烯基、1,3-丁二烯、1,3-戊二烯、1,4-戊二烯和1,4-己二烯等；本文中出现的烯基，其定义与本定义一致。烯基可以是一价、二价、三价或四价。"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, examples of 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, 4-heptenyl, 1-octenyl, 3-octene yl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene and 1,4-hexadiene, etc.; alkenyl groups appearing herein are defined in accordance with this definition. Alkenyl groups can be monovalent, divalent, trivalent or tetravalent.
“炔基”是指取代的或者未取代的直链和支链的一价不饱和烃基，其具有至少1个，通常有1、2或3个碳碳三键，包括但不限于在主链包括2至10个碳原子、2至6个碳原子、2至4个碳原子，炔基实施例包括但不限于乙炔基、炔丙基、1-丙炔基、2-丙炔基、1-丁炔基、2-丁炔基、3-丁炔基、1-戊炔基、2-戊炔基、3-戊炔基、4-戊炔基、1-甲基-1-丁炔基、2-甲基-1-丁炔基、2-甲基-3-丁炔基、1-己炔基、2-己炔基、3-己炔基、4-己炔基、5-己炔基、1-甲基-1-戊炔基、2-甲基-1-戊炔基、1-庚炔基、2-庚炔基、3-庚炔基、4-庚炔基、1-辛炔基、3-辛炔基、1-壬炔基、3-壬炔基、1-癸炔基、4-癸炔基等；炔基可以是一价、二价、三价或四价。"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 Hexynyl, 1-methyl-1-pentynyl, 2-methyl-1-pentynyl, 1-heptynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 1-octynyl, 3-octynyl, 1-nonynyl, 3-nonynyl, 1-decynyl, 4-decynyl, etc.; alkynyl can be monovalent, divalent, trivalent or Four price.
“烷氧基”是指取代的或者未取代的-O-烷基。非限制性实施例包括甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、仲丁氧基、叔丁氧基、正戊氧基、正己氧基、环丙氧基和环丁氧基。"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.
“碳环基”或“碳环”是指取代的或未取代的饱和或不饱和的芳香环或者非芳香环，芳香环或者非芳香环可以是3至8元的单环、4至12元双环或者10至15元三环体系，碳环基可以连接在芳香环上或者非芳香环上，芳香环或者非芳香环任选为单环、桥环或者螺环。非限制性实施例包括环丙烷、环丁烷、环戊烷、环己烷、环庚烷、1-环戊基-1-烯基、1-环戊基-2-烯基、1-环戊基-3-烯基、环己基、1-环己基-2-烯基、1-环己基-3-烯基、环己烯基、苯环、萘环、
Figure PCTCN2022088446-appb-000141
“碳环基”或“碳环”可以是一价、二价、三价或四价。 "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,
Figure PCTCN2022088446-appb-000141
A "carbocyclyl" or "carbocycle" can be monovalent, divalent, trivalent or tetravalent.
“杂环基”或“杂环”是指取代的或未取代的饱和或不饱和的芳香环或者非芳香环，芳香环或者非芳香环可以是3至8元的单环、4至12元双环或者10至15元三环体系，且包含1个或多个(包括但不限于2、3、4或5个)选自N、O或S的杂原子，杂环基的环中选择性取代的N、S可被氧化成各种氧化态。杂环基可以连接在杂原子或者碳原子上，杂环基可以连接在芳香环上或者非芳香环上，杂环基可以是单环、并环、桥环或者螺环，非限制性实施例包括环氧乙基、氮杂环丙基、氧杂环丁基、氮杂环丁基、1,3-二氧戊环基、1,4-二氧戊环基、1,3-二氧六环基、氮杂环庚基、吡啶基、呋喃基、噻吩基、吡 喃基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑基、哌啶基、吗啉基、硫代吗啉基、1,3-二噻基、二氢呋喃基、二氢吡喃基、二噻戊环基、四氢呋喃基、四氢吡咯基、四氢咪唑基、四氢噻唑基、四氢吡喃基、苯并咪唑基、苯并吡啶基、吡咯并吡啶基、苯并二氢呋喃基、吡咯基、吡唑基、噻唑基、噁唑基、吡嗪基、吲唑基、苯并噻吩基、苯并呋喃基、苯并吡咯基、苯并咪唑基、苯并噻唑基、苯并噁唑基、苯并吡啶基、苯并嘧啶基、苯并吡嗪基、哌嗪基、氮杂二环[3.2.1]辛烷基、氮杂二环[5.2.0]壬烷基、氧杂三环[5.3.1.1]十二烷基、氮杂金刚烷基、氧杂螺[3.3]庚烷基、
Figure PCTCN2022088446-appb-000142
Figure PCTCN2022088446-appb-000143
Figure PCTCN2022088446-appb-000144
“杂环基”或“杂环”可以是一价、二价、三价或四价。 "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, dihydrofuranyl, dihydropyranyl, dithiopenyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl , tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridyl, chromanyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazinyl, indazolyl , benzothienyl, benzofuranyl, benzopyrrolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzopyridyl, benzopyrimidinyl, benzopyrazinyl, piperazine base, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl, oxa spiro[3.3]heptyl,
Figure PCTCN2022088446-appb-000142
Figure PCTCN2022088446-appb-000143
Figure PCTCN2022088446-appb-000144
"Heterocyclyl" or "heterocycle" can be monovalent, divalent, trivalent or tetravalent.
“螺环”或“螺环基”是指取代的或未取代的单环之间共用一个原子(称螺原子)的多环基团，螺环体系中环原子的个数包括但不限于含有5至20个、6至14个、6至12个、6至10个，其中一个或多个环可以含有0个或多个(包括但不限于1、2、3或4)双键，且任选可以含有0至5个选自N、O或S(＝O) n的杂原子。非限制性实施例包括： "Spirocycle" or "spirocyclyl" refers to a polycyclic group in which substituted or unsubstituted monocyclic rings share one atom (called a spiro atom). The number of ring atoms in the spiro ring system includes but is not limited to containing 5 to 20, 6 to 14, 6 to 12, 6 to 10, wherein one or more rings may contain 0 or more (including but not limited to 1, 2, 3 or 4) double bonds, and any Select may contain 0 to 5 heteroatoms selected from N, O or S(=O) n . Non-limiting examples include:
Figure PCTCN2022088446-appb-000145
Figure PCTCN2022088446-appb-000146
“螺环”或“螺环基”可以是一价、二价、三价或四价。
Figure PCTCN2022088446-appb-000145
Figure PCTCN2022088446-appb-000146
A "spiro" or "spirocyclyl" can be monovalent, divalent, trivalent or tetravalent.
“并环”或“并环基”是指系统中的每个环与体系中的其他环共享毗邻的一对原子的多环基团，其中一个或多个环可以含有0个或多个(包括但不限于1、2、3或4)双键，且可以是取代的或未取代，并环体系中的各个环可以含0至5个杂原子或含有杂原子的基团(包括但不限于选自N、S(＝O) n或O，n为0、1或2)。并环体系中环原子的个数包括但不限于5至20个，5至14个，5至12个，5至10个。非限定性实例包括：
Figure PCTCN2022088446-appb-000147
Figure PCTCN2022088446-appb-000148
“并环”或“并环基”可以是一价、二价、三价或四价。 "Paracyclo" or "cyclocyclyl" refers to a polycyclic group in which each ring in a system shares an adjacent pair of atoms with other rings in the system, wherein one or more rings may contain zero or more ( including but not limited to 1, 2, 3 or 4) double bonds, and may be substituted or unsubstituted, and each ring in the ring system may contain 0 to 5 heteroatoms or heteroatom-containing groups (including but not limited to Limited to be selected from N, S(=O) n or O, where n is 0, 1 or 2). 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:
Figure PCTCN2022088446-appb-000147
Figure PCTCN2022088446-appb-000148
A "cyclo-cyclo" or "cyclo-cyclo group" can be monovalent, divalent, trivalent or tetravalent.
“桥环”或“桥环基”是指取代的或未取代的含有任意两个不直接连接的原子的多环基团，可以含有0个或多个双键，并环体系中的任意环可以含0至5个选自杂原子或含有杂原子的基团(包括但不限于N、S(＝O) n或O，其中n为0、1、2)。环原子个数包括但不限于5至20个、5至14个、5至12个或5至10个。非限定性实例包括
Figure PCTCN2022088446-appb-000149
Figure PCTCN2022088446-appb-000150
立方烷、金刚烷。“桥环”或“桥环基”可以是一价、二价、三价或四价。 "Bridged ring" or "bridged ring group" refers to a substituted or unsubstituted polycyclic group containing any two atoms that are not directly connected, may contain 0 or more double bonds, and any ring in the ring system May contain 0 to 5 groups selected from heteroatoms or heteroatom-containing groups (including but not limited to N, S(=O) n or O, where n is 0, 1, 2). 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
Figure PCTCN2022088446-appb-000149
Figure PCTCN2022088446-appb-000150
Cubicane, Adamantane. A "bridged ring" or "bridged ring group" can be monovalent, divalent, trivalent or tetravalent.
“碳螺环”、“螺环碳环基”、“螺碳环基”或者“碳螺环基”是指环体系仅有碳原子组成的“螺环”。本文中出现的“碳螺环”、“螺环碳环基”、“螺碳环基”或者“碳螺环基”，其定义与螺环一致。"Carbospiro", "spirocarbocyclyl", "spirocarbocyclyl" or "carbospirocyclyl" refers to a "spirocycle" in which the ring system consists of only carbon atoms. "Carbospiro", "spirocarbocyclyl", "spirocarbocyclyl" or "carbospirocyclyl" appearing herein have the same definition as spiro.
“碳并环”、“并环碳环基”、“并碳环基”或者“碳并环基”是指环体系仅有碳原子组成的“并环”。本文中出现的“碳并环”、“并环碳环基”、“并碳环基”或者“碳并环基”，其定义与并环一致。"Carbocyclyl", "carbocyclyl", "carbocyclyl" or "carbocyclyl" refers to a "carbocyclyl" in which the ring system consists of only carbon atoms. When used herein, "carbocyclyl", "carbocyclyl", "carbocyclyl" or "carbocyclyl" are defined in the same way as for cyclocarbocyclyl.
“碳桥环”、“桥环碳环基”、“桥碳环基”或者“碳桥环基”是指环体系仅有碳原子组成的“桥环”。本文中出现的“碳桥环”、“桥环碳环基”、“桥碳环基”或者“碳桥环基”，其定义与桥环一致。"Carbon-bridged ring", "bridged-ring carbocyclyl", "bridged carbocyclyl" or "carbo-bridged cyclyl" refers to a "bridged ring" in which the ring system consists only of carbon atoms. When used herein, "carbon-bridged ring", "bridged ring carbocyclyl", "bridged carbocyclyl" or "carbon-bridged cyclyl" is defined in accordance with the bridged ring.
“杂单环”、“单环杂环基”或“杂单环基”是指单环体系的“杂环基”或“杂环”，本文中出 现的杂环基、“单环杂环基”或“杂单环基”，其定义与杂环一致。"Heterocyclyl", "monocyclic heterocyclyl" or "heteromonocyclyl" refers to a "heterocyclyl" or "heterocycle" of a monocyclic ring system, heterocyclyl, "monocyclic heterocyclyl" appearing herein group" or "heteromonocyclyl" as defined in heterocycle.
“杂并环”、“杂并环基”、“并环杂环基”或“杂并环基”是指含有杂原子的“并环”。本文中出现的杂并环、“杂并环基”、“并环杂环基”或“杂并环基”，其定义与并环一致。"Heterocyclyl", "heterocyclyl", "heterocyclyl" or "heterocyclyl" refers to a "heterocyclyl" containing a heteroatom. Heterocyclyl, "heterocyclyl", "bicycloheterocyclyl" or "heterocyclyl" appearing herein have the same definitions as for bicyclyl.
“杂螺环”、“杂螺环基”、“螺环杂环基”或“杂螺环基”是指含有杂原子的“螺环”。本文中出现的杂螺环、“杂螺环基”、“螺环杂环基”或“杂螺环基”，其定义与螺环一致。"Heterospirocycle", "heterospirocyclyl", "spirocyclic heterocyclyl" or "heterospirocyclyl" refers to a "spirocycle" containing a heteroatom. As used herein, heterospirocycle, "heterospirocyclyl", "spirocyclic heterocyclyl" or "heterospirocyclyl" are defined in accordance with spirocycle.
“杂桥环”、“杂桥环基”、“桥环杂环基”或“杂桥环基”是指含有杂原子的“桥环”。本文中出现的杂桥环、“杂桥环基”、“桥环杂环基”或“杂桥环基”，其定义与桥环一致。"Heterobridged ring", "heterobridged cyclyl", "bridged heterocyclyl" or "heterobridged cyclyl" refers to a "bridged ring" containing a heteroatom. As used herein, a heterobridged ring, "heterobridged cyclyl", "bridged heterocyclyl" or "heterobridged cyclyl" is defined in accordance with the bridged ring.
“芳基”或“芳环”是指取代的或者未取代的具有单环或稠合环的芳香族烃基，芳香环中环原子个数包括但不限于6至18、6至12或6至10个碳原子。芳基环可以稠合于饱和或不饱和的碳环或杂环上，其中与母体结构连接在一起的环为芳基环，非限制性实施例包含苯环、萘环、
Figure PCTCN2022088446-appb-000151
“芳基”或“芳环”可以是一价、二价、三价或四价。当为二价、三价或四价时，连接位点位于芳基环上。 "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,
Figure PCTCN2022088446-appb-000151
"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.
“杂芳基”或“杂芳环”是指取代或未取代的芳香族烃基，且含有1至5个选杂原子或含有杂原子的基团(包括但不限于N、O或S(＝O)n，n为0、1、2)，杂芳香环中环原子个数包括但不限于5至15、5至10或5至6个。杂芳基的非限制性实施例包括但不限于吡啶基、呋喃基、噻吩基、吡啶基、吡喃基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑基、苯并吡唑、苯并咪唑、苯并吡啶、吡咯并吡啶等。所述杂芳基环可以稠合于饱和或不饱和的碳环或杂环上，其中与母体结构连接在一起的环为杂芳基环，非限制性实施例包含
Figure PCTCN2022088446-appb-000152
Figure PCTCN2022088446-appb-000153
本文中出现的杂芳基，其定义与本定义一致。杂芳基可以是一价、二价、三价或四价。当为二价、三价或四价时，连接位点位于杂芳基环上。 "Heteroaryl" or "heteroaromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group containing 1 to 5 selected heteroatoms or heteroatom-containing groups (including but not limited to N, O or S (= O)n, n is 0, 1, 2), and the number of ring atoms in the heteroaromatic ring includes but is not limited to 5 to 15, 5 to 10 or 5 to 6. Non-limiting examples of 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
Figure PCTCN2022088446-appb-000152
Figure PCTCN2022088446-appb-000153
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元环并5元杂芳环”是指5并5元的稠合杂芳环，2个并环中至少有1个环含有1个以上的杂原子(包括但不限于O、S或N)，整个基团具有芳香性，非限制实施例包括了吡咯并吡咯环、吡唑并吡咯环、吡唑并吡唑环、吡咯并呋喃环、吡唑并呋喃环、吡咯并噻吩环、吡唑并噻吩环。"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并6元杂芳环”是指5并6元的稠合杂芳环，2个并环中至少有1个环含有1个以上的杂原子(包括但不限于O、S或N)，整个基团具有芳香性，非限制实施例包括了苯并 5元杂芳环、6元杂芳环并5元杂芳环。"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.
“取代”或“取代的”是指被1个或多个(包括但不限于2、3、4或5个)取代基所取代，取代基包括但不限于H、F、Cl、Br、I、烷基、环烷基、烷氧基、卤代烷基、硫醇、羟基、硝基、巯基、氨基、氰基、异氰基、芳基、杂芳基、杂环基、桥环基、螺环基、并环基、羟基烷基、＝O、羰基、醛、羧酸、甲酸酯、-(CH 2) m-C(＝O)-R a、-O-(CH 2) m-C(＝O)-R a、-(CH 2) m-C(＝O)-NR bR c、-(CH 2) mS(＝O) nR a、-(CH 2) m-烯基-R a、OR d或-(CH 2) m-炔基-R a(其中m、n为0、1或2)、芳基硫基、硫代羰基、硅烷基或-NR bR c等基团，其中R b与R c独立选自包括H、羟基、氨基、羰基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基、磺酰基、三氟甲磺酰基，作为选择，R b与R c可形成五或六元环烷基或杂环基，R a与R d各自独立选自芳基、杂芳基、烷基、烷氧基、环烷基、杂环基、羰基、酯基、桥环基、螺环基或并环基。 "Substituted" or "substituted" means substituted by one or more (including but not limited to 2, 3, 4 or 5) substituents including but not limited to H, F, Cl, Br, I , alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxyl, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged ring, spiro Cyclic, cyclo, hydroxyalkyl, =O, carbonyl, aldehyde, carboxylic acid, formate, -(CH 2 ) m -C(=O)-R a , -O-(CH 2 ) m - C(=O)-R a , -(CH 2 ) m -C(=O)-NR b R c , -(CH 2 ) m S(=O) n R a , -(CH 2 ) m -ene -R a , OR d or -(CH 2 ) m -alkynyl-R a (where m, n are 0, 1 or 2), arylthio, thiocarbonyl, silyl or -NR b R c and other groups, wherein R b and R c are independently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethane Sulfonyl, alternatively, R b and R c can form a five- or six-membered cycloalkyl or heterocyclic group, and R a and R d are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkane group, heterocyclyl, carbonyl, ester, bridged, spiro or acyl.
“含有1至5个选自O、S、N的杂原子”是指含有1、2、3、4或5个选自O、S、N的杂原子。"Containing 1 to 5 heteroatoms selected from O, S, N" means containing 1, 2, 3, 4 or 5 heteroatoms selected from O, S, N.
“0至X个取代基所取代”是指被0、1、2、3….X个取代基所取代，X选自1至10之间的任意整数。如“0至4个取代基所取代”是指被0、1、2、3或4个取代基所取代。如“0至5个取代基所取代”是指被0、1、2、3、4或5个取代基所取代。如“杂桥环任选进一步被0至4个选自H或F的取代基所取代”是指杂桥环任选进一步被0、1、2、3或4个选自H或F的取代基所取代。"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. As in "substituted with 0 to 4 substituents" means substituted with 0, 1, 2, 3 or 4 substituents. As in "substituted with 0 to 5 substituents" means substituted with 0, 1, 2, 3, 4 or 5 substituents. Such as "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.
X-Y元的环(X选自小于Y大于等于3的整数，Y选自4至12之间的任意整数)包括了X+1、X+2、X+3、X+4….Y元的环。环包括了杂环、碳环、芳环、芳基、杂芳基、环烷基、杂单环、杂并环、杂螺环或杂桥环。如“4-7元杂单环”是指4元、5元、6元或7元的杂单环，“5-10元杂并环”是指5元、6元、7元、8元、9元或10元的杂并环。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. For example, "4-7 membered heteromonocycle" refers to a 4-membered, 5-membered, 6-membered or 7-membered heteromonocycle, and "5-10 membered heterocyclic ring" refers to 5-membered, 6-membered, 7-membered, 8-membered , 9- or 10-membered heterocyclic ring.
“任选”或“任选地”是指随后所描述的事件或环境可以但不必须发生，该说明包括该事件或环境发生或不发生的场合。如：“任选被F取代的烷基”指烷基可以但不必须被F取代，说明包括烷基被F取代的情形和烷基不被F取代的情形。"Optional" or "optionally" means that the subsequently described event or circumstance can, but need not, occur, and that the description includes instances where the event or circumstance does or does not occur. For example, "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.
“药学上可接受的盐”或者“其药学上可接受的盐”是指本发明化合物保持游离酸或者游离碱的生物有效性和特性，且所述的游离酸通过与无毒的无机碱或者有机碱，所述的游离碱通过与无毒的无机酸或者有机酸反应获得的盐。"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.
“药物组合物”是指一种或多种本发明所述化合物、或者其立体异构体、互变异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶和其它化学组分形成的 混合物，其中，“其它化学组分”是指药学上可接受的载体、赋形剂和/或一种或多种其它治疗剂。"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.
药物组合物以适合于待治疗(或预防)的疾病的方式给予。适当的剂量以及合适的给予持续时间和频率将由诸如患者的状况、患者的疾病的类型和严重程度、活性成分的特定形式以及给予方法的因素来确定。可以使用实验模型和/或临床试验来确定最佳剂量。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.
在一些实施方案中，本方法涉及给予约0.1μg至约500mg本发明的至少一种化合物/kg受试者体重。更普遍地使用从约10μg至约200mg剂量的本申请公开的化合物，取决于受试者的生理反应。例如，用于治疗和/或预防如本申请描述的疾病的本申请描述的化合物的剂量是约0.001至约1mg/kg受试者体重/天，例如约0.001mg、约0.002mg、约0.005mg、约0.010mg、0.015mg、约0.020mg、约0.025mg、约0.050mg、约0.075mg、约0.1mg、约0.15mg、约0.2mg、约0.25mg、约0.5mg、约0.75mg或约1mg/kg体重/天。在一些实施方案中，用于所描述的方法的本申请描述的化合物的剂量是约1至约1000mg/kg所治疗的受试者体重/天，约1mg、约2mg、约5mg、约10mg、约15mg、约20mg、约25mg、约50mg、约75mg、约100mg、约150mg、约200mg、约250mg、约500mg、约750mg或约1000mg/天。In some embodiments, the methods involve administering from about 0.1 μg 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 μg to about 200 mg of the compounds disclosed herein are used, depending on the physiological response of the subject. For example, 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. In some embodiments, 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.
“载体”是指不会对生物体产生明显刺激且不会消除所给予化合物的生物活性和特性的材料。"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.
“赋形剂”是指加入到药物组合物中以促进化合物给药的惰性物质。非限制性实施例包括碳酸钙、磷酸钙、糖、淀粉、纤维素衍生物(包括微晶纤维素)、明胶、植物油、聚乙二醇类、稀释剂、成粒剂、润滑剂、粘合剂和崩解剂。"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.
“前药”是指可经体内代谢转化为具有生物活性的本发明化合物。本发明的前药通过修饰本发明化合物中的氨基或者羧基来制备，该修饰可以通过常规的操作或者在体内被除去，而得到母体化合物。当本发明的前药被施予哺乳动物个体时，前药被割裂形成游离的氨基或者羧基。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. When the prodrugs of the present invention are administered to a mammalian subject, the prodrugs are cleaved to form free amino or carboxyl groups.
“共晶”是指活性药物成分(API)和共晶形成物(CCF)在氢键或其他非共价键的作用下结合而成的晶体，其中API和CCF的纯态在室温下均为固体，并且各组分间存在固定的化学计量比。共晶是一种多组分晶体，既包含两种中性固体之间形成的二元共晶，也包含中性固体与盐或溶剂化物形成的多元共晶。"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.
“动物”是指包括哺乳动物，例如人、陪伴动物、动物园动物和家畜，优选人、马或者犬。"Animal" is meant to include mammals such as humans, companion animals, zoo animals and domestic animals, preferably humans, horses or dogs.
“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体，包括顺反异构体、对映异构体和构象异构体。"Stereoisomers" refer to isomers resulting from different arrangements of atoms in a molecule in space, including cis-trans isomers, enantiomers and conformational isomers.
“互变异构体”是指分子中某一原子在两个位置迅速移动而产生的官能团异构体，如酮式-烯醇式异构和酰胺-亚胺醇式异构等。"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.
“任选”或“任选地”或“选择性的”或“选择性地”是指随后所述的事件或状况可以但未必发生，该描述包括其中发生该事件或状况的情况及其中未发生的情况。例如，“选择性地被烷基取代的杂环基”是指该烷基可以但未必存在，该描述包括其中杂环基被烷基取代的情况，及其中杂环基未被烷基取代的情况。"Optional" or "optionally" or "selective" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not occur what happened. For example, "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.
“IC 50”是对指定的生物过程(或该过程中的某个组分比如酶、受体、细胞等)抑制一半时所需的药物或者抑制剂的浓度。 " 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.).
具体实施方式Detailed ways
以下实施例详细说明本发明的技术方案，但本发明的保护范围包括但是不限于此。The following examples illustrate the technical solutions of the present invention in detail, but the protection scope of the present invention includes but is not limited thereto.
化合物的结构是通过核磁共振(NMR)或(和)质谱(MS)来确定的。NMR位移(δ)以10 -6(ppm)的单位给出。NMR的测定是用(Bruker Avance III 400和Bruker Avance 300)核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)，氘代氯仿(CDCl 3)，氘代甲醇(CD 3OD)，内标为四甲基硅烷(TMS)； The structures of the compounds were determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). NMR shifts ([delta]) are given in units of 10<" 6 > (ppm). NMR was measured using (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic instruments, and the solvents were deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD) ), the internal standard is tetramethylsilane (TMS);
MS的测定用(Agilent 6120B(ESI)和Agilent 6120B(APCI))；For MS determination (Agilent 6120B (ESI) and Agilent 6120B (APCI));
HPLC的测定使用Agilent 1260DAD高效液相色谱仪(Zorbax SB-C18 100×4.6mm,3.5μM)；The determination of HPLC used Agilent 1260DAD high performance liquid chromatograph (Zorbax SB-C18 100×4.6mm, 3.5μM);
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm-0.20mm，薄层层析分离纯化产品采用的规格是0.4mm-0.5mm；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;
柱层析一般使用烟台黄海硅胶200-300目硅胶为载体；Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier;
为了完成本发明的目的，根据本邻域技术人员已知的有机合成技术，从市售的化学品和/或化学文献中描述的化合物开始，包括上海阿拉丁生化科技股份有限公司，上海麦克林生化科技有限公司，Sigma-Aldrich，阿法埃莎(中国)化学有限公司，梯希爱(上海)化成工业发展有限公司，安耐吉化学，上海泰坦科技股份有限公司，科龙化工，百灵威科技有限公司等。For the purposes of the present invention, starting from commercially available chemicals and/or compounds described in the chemical literature, including Shanghai Aladdin Biochemical Technology Co., Ltd., Shanghai McLean, according to organic synthesis techniques known to those skilled in the art Biochemical Technology Co., Ltd., Sigma-Aldrich, Alfa Aesar (China) Chemical Co., Ltd., Tixiai (Shanghai) Chemical Industry Development Co., Ltd., Annagy Chemical, Shanghai Titan Technology Co., Ltd., Kelon Chemical, Bailingwei Technology Ltd. etc.
DMSO：二甲基亚砜；DMA：二甲基乙酰胺；Solutol：聚乙二醇-15-羟基硬脂酸酯； PEG400：聚乙二醇400；20％SBE-β-CD：磺丁基-β-环糊精；Saline：生理盐水；MC：甲基纤维素溶液；CO 2：二氧化碳；MeOH：甲醇；DEA：二乙胺；DIPEA：N,N-二异丙基乙胺：DMF：N,N-二甲基甲酰胺； DMSO: dimethyl sulfoxide; DMA: dimethylacetamide; Solutol: polyethylene glycol-15-hydroxystearate; PEG400: polyethylene glycol 400; 20% SBE-β-CD: sulfobutyl -β-cyclodextrin; Saline: physiological saline; MC: methylcellulose solution; CO2 : carbon dioxide; MeOH: methanol; DEA: diethylamine; DIPEA: N,N-diisopropylethylamine: DMF: N,N-dimethylformamide;
HATU：CAS 148893-10-1；HATU: CAS 148893-10-1;
PyBOP：CAS 128625-52-。PyBOP: CAS 128625-52-.
实施例1：5-(((S)-1-(3-氧代-3-((R)-3-(三氟甲基)-6a,7,9,10-四氢吡嗪并[1,2-d]吡啶并[3,2-b][1,4]噁嗪-8(6H)-基)丙氧基)丙-2-基)氨基)-4-(三氟甲基)哒嗪-3(2H)-酮(化合物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)
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)-one5-(((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
Figure PCTCN2022088446-appb-000154
Figure PCTCN2022088446-appb-000154
第一步：(3R)-3-(羟甲基)-4-(3-硝基-5-(三氟甲基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(1c)The first step: (3R)-3-(hydroxymethyl)-4-(3-nitro-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (1c)
tert-butyl(3R)-3-(hydroxymethyl)-4-(3-nitro-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylatetert-butyl(3R)-3-(hydroxymethyl)-4-(3-nitro-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate
Figure PCTCN2022088446-appb-000155
Figure PCTCN2022088446-appb-000155
室温下，将2-氯-3-硝基-5-(三氟甲基)吡啶(1a)(2.00g,8.83mmol)加入到DMF(20mL)，加入(3R)-3-(羟甲基)哌嗪-1-羧酸叔丁酯(1.91g,8.83mmol)和DIPEA(3.42g,26.49mmol)。混合物在室温下搅拌过夜。加水(20mL)淬灭反应，乙酸乙酯(20mL x 2)萃取，合 并有机相，有机相用饱和食盐水洗涤，无水硫酸钠干燥后过滤，滤液减压浓缩后得粗品。粗品经制备柱分离纯化(石油醚：乙酸乙酯(v/v)＝10:1)得(3R)-3-(羟甲基)-4-(3-硝基-5-(三氟甲基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(1c)(3.50g,97％)。2-Chloro-3-nitro-5-(trifluoromethyl)pyridine (1a) (2.00 g, 8.83 mmol) was added to DMF (20 mL) at room temperature, (3R)-3-(hydroxymethyl) was added ) piperazine-1-carboxylate tert-butyl ester (1.91 g, 8.83 mmol) and DIPEA (3.42 g, 26.49 mmol). The mixture was stirred at room temperature overnight. Water (20 mL) was added to quench the reaction, extracted with ethyl acetate (20 mL x 2), 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 crude product was separated and purified by preparative column (petroleum ether:ethyl acetate (v/v)=10:1) to obtain (3R)-3-(hydroxymethyl)-4-(3-nitro-5-(trifluoromethyl) yl)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (1c) (3.50 g, 97%).
LCMS m/z＝351.1[M-55] +。 LCMS m/z = 351.1 [M-55] + .
第二步：(R)-3-(三氟甲基)-6a,7,9,10-四氢吡嗪并[1,2-d]吡啶并[3,2-b][1,4]噁嗪-8(6H)-羧酸叔丁酯(1d)The second step: (R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2-b][1,4 ]oxazine-8(6H)-carboxylate tert-butyl ester (1d)
tert-butyl(R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2-b][1,4]oxazine-8(6H)-carboxylatetert-butyl(R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2-b][1,4]oxazine-8(6H)-carboxylate
Figure PCTCN2022088446-appb-000156
Figure PCTCN2022088446-appb-000156
将(3R)-3-(羟甲基)-4-(3-硝基-5-(三氟甲基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(1c)(1.0g,2.46mmol)加入到DMF(20ml)溶液中、加入NaH(0.34g,8.5mmol)。混合物40℃反应16小时。冷却，加水(10mL)淬灭反应，乙酸乙酯(10mL x 2)萃取，合并有机相，有机相用饱和食盐水洗涤，无水硫酸钠干燥后过滤，滤液减压浓缩后得粗品。粗品经制备柱分离纯化(石油醚：乙酸乙酯(v/v)＝10:1)得到(R)-3-(三氟甲基)-6a,7,9,10-四氢吡嗪并[1,2-d]吡啶并[3,2-b][1,4]噁嗪-8(6H)-羧酸叔丁酯(1d)(0.5g,56％)。(3R)-3-(hydroxymethyl)-4-(3-nitro-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (1c) (1.0 g , 2.46 mmol) was added to a solution of DMF (20 ml) and NaH (0.34 g, 8.5 mmol) was added. The mixture was reacted at 40°C for 16 hours. Cool, add water (10 mL) to quench the reaction, extract with ethyl acetate (10 mL x 2), combine the organic phases, wash the organic phases with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude product. The crude product was separated and purified by preparative column (petroleum ether:ethyl acetate (v/v)=10:1) to obtain (R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino [1,2-d]pyrido[3,2-b][1,4]oxazine-8(6H)-carboxylate tert-butyl ester (1d) (0.5 g, 56%).
LCMS m/z＝360.2[M+1] +。 LCMS m/z=360.2[M+1] + .
第三步：(R)-3-(三氟甲基)-6,6a,7,8,9,10-六氢吡嗪并[1,2-d]吡啶并[3,2-b][1,4]噁嗪(1e)的三氟乙酸盐The third step: (R)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydropyrazino[1,2-d]pyrido[3,2-b] Trifluoroacetate salt of [1,4]oxazine (1e)
(R)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]oxazinetrifluoroacetate(R)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]oxazinetrifluoroacetate
Figure PCTCN2022088446-appb-000157
Figure PCTCN2022088446-appb-000157
将(R)-3-(三氟甲基)-6a,7,9,10-四氢吡嗪并[1,2-d]吡啶并[3,2-b][1,4]噁嗪-8(6H)-羧酸叔丁酯(1d)(0.37g,1.03mmol)溶于DCM(4mL)，加入TFA(2mL)，混合物在室温下搅拌反应2h。直接将反应液减压浓缩，得(R)-3-(三氟甲基)-6,6a,7,8,9,10-六氢吡嗪并[1,2-d]吡啶并[3,2-b][1,4]噁嗪的三氟乙酸盐(1e)(380mg,100％)，直接用于下一步。(R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2-b][1,4]oxazine -8(6H)-Carboxylic acid tert-butyl ester (1d) (0.37 g, 1.03 mmol) was dissolved in DCM (4 mL), TFA (2 mL) was added, and the mixture was stirred at room temperature for 2 h. The reaction solution was directly concentrated under reduced pressure to obtain (R)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydropyrazino[1,2-d]pyrido[3 ,2-b][1,4]oxazine trifluoroacetate salt (1e) (380 mg, 100%) was used directly in the next step.
LCMS m/z＝260.2[M+1] +。 LCMS m/z=260.2[M+1] + .
第四步：(R)-1-(3-(三氟甲基)-6a,7,9,10-四氢吡嗪并[1,2-d]吡啶基[3,2-b][1,4]噁嗪-8(6 H)-基)丙-2-烯-1-酮(1f)The fourth step: (R)-1-(3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyridyl[3,2-b][ 1,4]oxazin-8(6H)-yl)prop-2-en-1-one (1f)
(R)-1-(3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2-b][1,4]oxazin-8(6H)-yl)prop-2-en-1-one(R)-1-(3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2-b][1,4]oxazin-8(6H)-yl )prop-2-en-1-one
Figure PCTCN2022088446-appb-000158
Figure PCTCN2022088446-appb-000158
将(R)-3-(三氟甲基)-6,6a,7,8,9,10-六氢吡嗪并[1,2-d]吡啶并[3,2-b][1,4]噁嗪(1e)的三氟乙酸盐(380mg,1.02mmol)溶于二氯甲烷(4mL)中，然后加入丙烯酸酐(0.15g,1.22mmol)和三乙胺(0.31mg,3.06mmol)，混合物在20℃反应24h后，直接减压浓缩反应液，得粗品，粗品经制备柱分离纯化(石油醚：乙酸乙酯(v/v)＝10:1)得(R)-1-(3-(三氟甲基)-6a,7,9,10-四氢吡嗪并[1,2-d]吡啶基[3,2-b][1,4]噁嗪-8(6H)-基)丙-2-烯-1-酮(1f)(0.3g,94％)。(R)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydropyrazino[1,2-d]pyrido[3,2-b][1, 4] The trifluoroacetate salt of oxazine (1e) (380 mg, 1.02 mmol) was dissolved in dichloromethane (4 mL), then acrylic anhydride (0.15 g, 1.22 mmol) and triethylamine (0.31 mg, 3.06 mmol) were added ), after the mixture was reacted at 20°C for 24 hours, the reaction solution was directly concentrated under reduced pressure to obtain a crude product, which was separated and purified by a preparative column (petroleum ether:ethyl acetate (v/v)=10:1) to obtain (R)-1- (3-(Trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyridinyl[3,2-b][1,4]oxazine-8(6H )-yl)prop-2-en-1-one (1f) (0.3 g, 94%).
LCMS m/z＝314.1[M+1] +。 LCMS m/z=314.1[M+1] + .
第五步：((S)-1-(3-氧代-3-((R)-3-(三氟甲基)-6a,7,9,10-四氢吡嗪并[1,2-d]吡啶并[3,2-b][1,4]噁嗪-8(6H)-基)丙氧基)丙-2-基)氨基甲酸酯叔丁酯(1g)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)
tert-butyl((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)carbamatetert-butyl((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)carbamate
Figure PCTCN2022088446-appb-000159
Figure PCTCN2022088446-appb-000159
将(R)-1-(3-(三氟甲基)-6a,7,9,10-四氢吡嗪并[1,2-d]吡啶基[3,2-b][1,4]噁嗪-8(6H)-基)丙-2-烯-1-酮(1f)(300mg,0.96mmol)溶于乙腈(1.8mL)中，然后加入N-Boc-L-丙氨醇(0.87g,5mmol)和碳酸铯(0.42mg,1.29mmol)，混合物在20℃反应48h。将反应液直接过滤，滤液减压浓缩得残留物，残留物经制备柱分离纯化(石油醚：乙酸乙酯(v/v)＝10:1)得((S)-1-(3-氧代-3-((R)-3-(三氟甲基)-6a,7,9,10-四氢吡嗪并[1,2-d]吡啶并[3,2-b][1,4]噁嗪-8(6H)-基)丙氧基)丙-2-基)氨基甲酸酯叔丁酯(1g)(0.34g,72％)。(R)-1-(3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyridinyl[3,2-b][1,4 ]oxazin-8(6H)-yl)prop-2-en-1-one (1f) (300 mg, 0.96 mmol) was dissolved in acetonitrile (1.8 mL), followed by the addition of N-Boc-L-alaninol ( 0.87g, 5mmol) and cesium carbonate (0.42mg, 1.29mmol), the mixture was reacted at 20°C for 48h. The reaction solution was directly filtered, and the filtrate was concentrated under reduced pressure to obtain a residue, which was separated and purified by a preparative column (petroleum ether:ethyl acetate (v/v)=10:1) to obtain ((S)-1-(3-oxygen) Substituted-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) (0.34 g, 72%).
LCMS m/z＝489.2[M+1] +。 LCMS m/z=489.2[M+1] + .
第六步：3-((S)-2-氨基丙氧基)-1-((R)-3-(三氟甲基)-6a,7,9,10-四氢吡嗪并[1,2-d]吡啶基[3,2-b][1,4]噁嗪-8(6H)-基)丙-1-酮(1h)的盐酸盐The sixth step: 3-((S)-2-aminopropoxy)-1-((R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1 ,2-d]pyridinyl[3,2-b][1,4]oxazin-8(6H)-yl)propan-1-one (1h) hydrochloride
3-((S)-2-aminopropoxy)-1-((R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2-b][1,4]oxazin-8(6H)-yl)propan-1-one hydrochloride3-((S)-2-aminopropoxy)-1-((R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2-b][ 1,4]oxazin-8(6H)-yl)propan-1-one hydrochloride
Figure PCTCN2022088446-appb-000160
Figure PCTCN2022088446-appb-000160
((S)-1-(3-氧代-3-((R)-3-(三氟甲基)-6a,7,9,10-四氢吡嗪并[1,2-d]吡啶并[3,2-b][1,4]噁嗪-8(6H)-基)丙氧基)丙-2-基)氨基甲酸酯叔丁酯(1g)(0.34g,0.7mmol)加入到HCl/二氧六环(4mL,4N)中，混合物在室温下搅拌反应2h。将反应液直接减压浓缩，得3-((S)-2-氨基丙氧基)-1-((R)-3-(三氟甲基)-6a,7,9,10-四氢吡嗪并[1,2-d]吡啶基[3,2-b][1,4]噁嗪-8(6H)-基)丙-1-酮(1h)的盐酸盐(230mg,77％)，直接用于下一步。((S)-1-(3-oxo-3-((R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyridine [3,2-b][1,4]oxazin-8(6H)-yl)propoxy)prop-2-yl)carbamate tert-butyl ester (1 g) (0.34 g, 0.7 mmol) It was added to HCl/dioxane (4 mL, 4 N), and the mixture was stirred at room temperature for 2 h. The reaction solution was directly concentrated under reduced pressure to obtain 3-((S)-2-aminopropoxy)-1-((R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydro Pyrazino[1,2-d]pyridinyl[3,2-b][1,4]oxazin-8(6H)-yl)propan-1-one (1h) hydrochloride salt (230 mg, 77 %), used directly in the next step.
LCMS m/z＝389.3[M+1] +。 LCMS m/z=389.3[M+1] + .
第七步：2-(4-甲氧基苄基)-5-(((S)-1-(3-氧代-3-((R)-3-(三氟甲基)-6a,7,9,10-四氢吡嗪并[1,2-d]吡啶并[3,2-b][1,4]噁嗪-8(6H)-基)丙氧基)丙-2-基)氨基)-4-(三氟甲基)哒嗪-3(2H)-酮(1j)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)
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)-one2-(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
Figure PCTCN2022088446-appb-000161
Figure PCTCN2022088446-appb-000161
将3-((S)-2-氨基丙氧基)-1-((R)-3-(三氟甲基)-6a,7,9,10-四氢吡嗪并[1,2-d]吡啶基[3,2-b][1,4]噁嗪-8(6H)-基)丙-1-酮(1h)的盐酸盐(0.18g,0.42mmol)溶于乙腈(3mL)中，加入5-氯-2-[(4-甲氧基苯基)甲基]-4-(三氟甲基)-2,3-二氢哒嗪-3-酮(0.13g,0.42mmol)和三乙胺(127.26mg,1.26mmol)，混合物在室温下搅拌反应24h。将反应液直接减压浓缩，得粗品，粗品经prep-TLC(展开剂：石油醚：乙酸乙酯＝1:2)得到2-(4-甲氧基苄基)-5-(((S)-1-(3-氧代-3-((R)-3-(三氟甲基)-6a,7,9,10-四氢吡嗪并[1,2-d]吡啶并[3,2-b][1,4]噁嗪-8(6H)-基)丙氧基)丙-2-基)氨基)-4-(三氟甲基)哒嗪-3(2H)-酮(1j)(130mg,46％)。3-((S)-2-aminopropoxy)-1-((R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2- d]Pyridinyl[3,2-b][1,4]oxazin-8(6H)-yl)propan-1-one (1h) hydrochloride (0.18 g, 0.42 mmol) was dissolved in acetonitrile (3 mL) ), add 5-chloro-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one (0.13 g, 0.42 g mmol) and triethylamine (127.26 mg, 1.26 mmol), the mixture was stirred at room temperature for 24 h. The reaction solution was directly concentrated under reduced pressure to obtain a crude product, which was subjected to prep-TLC (developing solvent: petroleum ether: ethyl acetate=1:2) to obtain 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) (130 mg, 46%).
LCMS m/z＝671.3[M+1] +。 LCMS m/z=671.3[M+1] + .
第八步：5-(((S)-1-(3-氧代-3-((R)-3-(三氟甲基)-6a,7,9,10-四氢吡嗪并[1,2-d]吡啶并[3,2-b][1,4]噁嗪-8(6H)-基)丙氧基)丙-2-基)氨基)-4-(三氟甲基)哒嗪-3(2H)-酮(化合物1)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)
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)-one5-(((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
Figure PCTCN2022088446-appb-000162
Figure PCTCN2022088446-appb-000162
将2-(4-甲氧基苄基)-5-(((S)-1-(3-氧代-3-((R)-3-(三氟甲基)-6a,7,9,10-四氢吡嗪并[1,2-d]吡啶并[3,2-b][1,4]噁嗪-8(6H)-基)丙氧基)丙-2-基)氨基)-4-(三氟甲基)哒嗪-3(2H)-酮(1j)(0.13g,0.19mmol)溶于三氟乙酸(5mL)中，加入三氟甲磺酸(0.14g,0.95mmol)。混合物在室温下搅拌反应1h。反应液经减压浓缩后，得粗品。粗品用甲醇溶解，滴加DIPE A调pH至8-9，减压浓缩后，残余物经Pre-HPLC纯化(仪器及制备柱：采用Waters 2767制备液相，制备柱型号是XBridge@Prep C 18，内径×长度＝19mm×250mm)。制备方法：粗品用DMF溶解，并用0.45μm滤膜过滤，制备成样品液。流动相体系：乙腈/水(含0.05％的氨水)。梯度洗脱方法：乙腈由10％梯度洗脱至55％(流速：12mL/min；洗脱时间17min)得到5-(((S)-1-(3-氧代-3-((R)-3-(三氟甲基)-6a,7,9,10-四氢吡嗪并[1,2-d]吡啶并[3,2-b][1,4]噁嗪-8(6H)-基)丙氧基)丙-2-基)氨基)-4-(三氟甲基)哒嗪-3(2H)-酮(化合物1)(10mg,9.37％)。 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) (0.13 g, 0.19 mmol) was dissolved in trifluoroacetic acid (5 mL), trifluoromethanesulfonic acid (0.14 g, 0.95 mmol). The mixture was stirred at room temperature for 1 h. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was dissolved in methanol, and DIPE A was added dropwise to adjust the pH to 8-9. After concentration under reduced pressure, the residue was purified by Pre-HPLC (instrument and preparative column: Waters 2767 was used to prepare the liquid phase, and the preparative column model was XBridge@Prep C 18 , inner diameter×length=19mm×250mm). Preparation method: the crude product is dissolved in DMF, and filtered with a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile/water (containing 0.05% ammonia water). Gradient elution method: acetonitrile gradient from 10% to 55% (flow rate: 12 mL/min; elution time 17 min) to obtain 5-(((S)-1-(3-oxo-3-((R) -3-(Trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2-b][1,4]oxazine-8(6H )-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 1) (10 mg, 9.37%).
LCMS m/z＝551.2[M+1] +。 LCMS m/z=551.2[M+1] + .
实施例2：5-(((S)-1-(3-氧代-3-((S)-3-(三氟甲基)-6a,7,9,10-四氢吡嗪并[1,2-d]吡啶并[3,2-b][1,4]噁嗪-8(6H)-基)丙氧基)丙-2-基)氨基)-4-(三氟甲基)哒嗪-3(2H)-酮(化合物2)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)
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)-one5-(((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
Figure PCTCN2022088446-appb-000163
Figure PCTCN2022088446-appb-000163
Figure PCTCN2022088446-appb-000164
Figure PCTCN2022088446-appb-000164
第一步：(3S)-3-(羟甲基)-4-(3-硝基-5-(三氟甲基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(2c)The first step: (3S)-3-(hydroxymethyl)-4-(3-nitro-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (2c)
tert-butyl(3S)-3-(hydroxymethyl)-4-(3-nitro-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylatetert-butyl(3S)-3-(hydroxymethyl)-4-(3-nitro-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate
Figure PCTCN2022088446-appb-000165
Figure PCTCN2022088446-appb-000165
室温下，将2-氯-3-硝基-5-(三氟甲基)吡啶(1a)(2.00g,8.83mmol)加入到DMF(20mL)，加入(3S)-3-(羟甲基)哌嗪-1-羧酸叔丁酯(1.91g,8.83mmol)和DIPEA(3.42g,26.49mmol)。混合物在室温下搅拌过夜。加水(20mL)淬灭反应，乙酸乙酯(20mL x 2)萃取，合并有机相，有机相用饱和食盐水洗涤，无水硫酸钠干燥后过滤，滤液减压浓缩后得粗品。粗品经制备柱分离纯化(石油醚：乙酸乙酯(v/v)＝10:1)得(3S)-3-(羟甲基)-4-(3-硝基-5-(三氟甲基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(2c)(3.00g,83％)。2-Chloro-3-nitro-5-(trifluoromethyl)pyridine (1a) (2.00 g, 8.83 mmol) was added to DMF (20 mL) at room temperature, (3S)-3-(hydroxymethyl) was added ) piperazine-1-carboxylate tert-butyl ester (1.91 g, 8.83 mmol) and DIPEA (3.42 g, 26.49 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 crude product was separated and purified by a preparative column (petroleum ether:ethyl acetate (v/v)=10:1) to obtain (3S)-3-(hydroxymethyl)-4-(3-nitro-5-(trifluoromethyl) yl)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (2c) (3.00 g, 83%).
LCMS m/z＝351.1[M-55] +。 LCMS m/z = 351.1 [M-55] + .
第二步：(S)-3-(三氟甲基)-6a,7,9,10-四氢吡嗪并[1,2-d]吡啶并[3,2-b][1,4]噁嗪-8(6H)-羧酸叔丁酯(2d)The second step: (S)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2-b][1,4 ]oxazine-8(6H)-carboxylate tert-butyl ester (2d)
tert-butyl(S)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2-b][1,4]oxazine-8(6H)-carboxylatetert-butyl(S)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2-b][1,4]oxazine-8(6H)-carboxylate
Figure PCTCN2022088446-appb-000166
Figure PCTCN2022088446-appb-000166
将(3S)-3-(羟甲基)-4-(3-硝基-5-(三氟甲基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(2c)(1.0g,2.46mmol)加入到DMF(20ml)溶液中、加入NaH(0.34g,8.5mmol)。混合物40℃反应1 6小时。冷却，加水(10mL)淬灭反应，乙酸乙酯(10mL x 2)萃取，合并有机相，有机相用饱和食盐水洗涤，无水硫酸钠干燥后过滤，滤液减压浓缩后得粗品。粗品经制备柱分离纯化(石油醚：乙酸乙酯(v/v)＝10:1)得到(S)-3-(三氟甲基)-6a,7,9,10-四氢吡嗪并[1,2-d]吡啶并[3,2-b][1,4]噁嗪-8(6H)-羧酸叔丁酯(2d)(0.54g,61％)。(3S)-3-(hydroxymethyl)-4-(3-nitro-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (2c) (1.0 g , 2.46 mmol) was added to a solution of DMF (20 ml) and NaH (0.34 g, 8.5 mmol) was added. The mixture was reacted at 40°C for 16 hours. Cool, add water (10 mL) to quench the reaction, extract with ethyl acetate (10 mL x 2), combine the organic phases, wash the organic phases with saturated brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the crude product. The crude product was separated and purified by a preparative column (petroleum ether:ethyl acetate (v/v)=10:1) to obtain (S)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino [1,2-d]pyrido[3,2-b][1,4]oxazine-8(6H)-carboxylate tert-butyl ester (2d) (0.54 g, 61%).
LCMS m/z＝360.2[M+1] +。 LCMS m/z=360.2[M+1] + .
第三步：(S)-3-(三氟甲基)-6,6a,7,8,9,10-六氢吡嗪并[1,2-d]吡啶并[3,2-b][1,4]噁嗪(2e)的三氟乙酸盐The third step: (S)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydropyrazino[1,2-d]pyrido[3,2-b] Trifluoroacetate salt of [1,4]oxazine (2e)
(S)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]oxazinetrifluoroacetate(S)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]oxazinetrifluoroacetate
Figure PCTCN2022088446-appb-000167
Figure PCTCN2022088446-appb-000167
将(S)-3-(三氟甲基)-6a,7,9,10-四氢吡嗪并[1,2-d]吡啶并[3,2-b][1,4]噁嗪-8(6H)-羧酸叔丁酯(2d)(0.56g,1.42mmol)溶于DCM(4mL)，加入TFA(2mL)，混合物在室温下搅拌反应2h。直接将反应液减压浓缩，得(S)-3-(三氟甲基)-6,6a,7,8,9,10-六氢吡嗪并[1,2-d]吡啶并[3,2-b][1,4]噁嗪的三氟乙酸盐(2e)(530mg,100％)，直接用于下一步。(S)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2-b][1,4]oxazine -8(6H)-Carboxylic acid tert-butyl ester (2d) (0.56 g, 1.42 mmol) was dissolved in DCM (4 mL), TFA (2 mL) was added, and the mixture was stirred at room temperature for 2 h. The reaction solution was directly concentrated under reduced pressure to obtain (S)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydropyrazino[1,2-d]pyrido[3 ,2-b][1,4]oxazine trifluoroacetate salt (2e) (530 mg, 100%) was used directly in the next step.
LCMS m/z＝260.1[M+1] +。 LCMS m/z=260.1[M+1] + .
第四步：(S)-1-(3-(三氟甲基)-6a,7,9,10-四氢吡嗪并[1,2-d]吡啶基[3,2-b][1,4]噁嗪-8(6H)-基)丙-2-烯-1-酮(2f)The fourth step: (S)-1-(3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyridyl[3,2-b][ 1,4]oxazin-8(6H)-yl)prop-2-en-1-one (2f)
(S)-1-(3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2-b][1,4]oxazin-8(6H)-yl)prop-2-en-1-one(S)-1-(3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2-b][1,4]oxazin-8(6H)-yl )prop-2-en-1-one
Figure PCTCN2022088446-appb-000168
Figure PCTCN2022088446-appb-000168
将(S)-3-(三氟甲基)-6,6a,7,8,9,10-六氢吡嗪并[1,2-d]吡啶并[3,2-b][1,4]噁嗪(2e)的三氟乙酸盐(530mg,1.42mmol)溶于二氯甲烷(4mL)中，然后加入丙烯酸酐(0.21g,1.69mmol)和三乙胺(430mg,4.26mmol)，混合物在20℃反应24h后，直接减压浓缩反应液，得粗品，粗品经制备柱分离纯化(石油醚：乙酸乙酯(v/v)＝10:1)得(S)-1-(3-(三氟甲基)-6a,7,9,10-四氢吡嗪并[1,2-d]吡啶基[3,2-b][1,4]噁嗪-8(6H)-基)丙-2-烯-1-酮(2f)(0.34g,76％)。(S)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydropyrazino[1,2-d]pyrido[3,2-b][1, 4] The trifluoroacetate salt of oxazine (2e) (530 mg, 1.42 mmol) was dissolved in dichloromethane (4 mL), followed by the addition of acrylic anhydride (0.21 g, 1.69 mmol) and triethylamine (430 mg, 4.26 mmol) , the mixture was reacted at 20°C for 24h, and the reaction solution was directly concentrated under reduced pressure to obtain a crude product, which was separated and purified by a preparative column (petroleum ether:ethyl acetate (v/v)=10:1) to obtain (S)-1-( 3-(Trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyridinyl[3,2-b][1,4]oxazine-8(6H) -yl)prop-2-en-1-one (2f) (0.34 g, 76%).
LCMS m/z＝314.1[M+1] +。 LCMS m/z=314.1[M+1] + .
第五步：((S)-1-(3-氧代-3-((S)-3-(三氟甲基)-6a,7,9,10-四氢吡嗪并[1,2-d]吡啶并[3,2-b][1,4]噁嗪-8(6H)-基)丙氧基)丙-2-基)氨基甲酸酯叔丁酯(2g)The fifth step: ((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)carbamate tert-butyl ester (2g)
tert-butyl((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)carbamatetert-butyl((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)carbamate
Figure PCTCN2022088446-appb-000169
Figure PCTCN2022088446-appb-000169
将(S)-1-(3-(三氟甲基)-6a,7,9,10-四氢吡嗪并[1,2-d]吡啶基[3,2-b][1,4]噁嗪-8(6H)-基)丙-2-烯-1-酮(2f)(278mg,0.89mmol)溶于乙腈(1.4mL)中，然后加入N-Boc-L-丙氨醇(0.78g,4.44mmol)和碳酸铯(376mg,1.16mmol)，混合物在20℃反应48h。将反应液直接过滤，滤液减压浓缩得残留物，残留物经制备柱分离纯化(石油醚：乙酸乙酯(v/v)＝10:1)得((S)-1-(3-氧代-3-((S)-3-(三氟甲基)-6a,7,9,10-四氢吡嗪并[1,2-d]吡啶并[3,2-b][1,4]噁嗪-8(6H)-基)丙氧基)丙-2-基)氨基甲酸酯叔丁酯(2g)(0.28g,64％)。(S)-1-(3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyridinyl[3,2-b][1,4 ]oxazin-8(6H)-yl)prop-2-en-1-one (2f) (278 mg, 0.89 mmol) was dissolved in acetonitrile (1.4 mL), followed by the addition of N-Boc-L-alaninol ( 0.78g, 4.44mmol) and cesium carbonate (376mg, 1.16mmol), the mixture was reacted at 20°C for 48h. The reaction solution was directly filtered, and the filtrate was concentrated under reduced pressure to obtain a residue, which was separated and purified by a preparative column (petroleum ether:ethyl acetate (v/v)=10:1) to obtain ((S)-1-(3-oxygen) Substituted-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)carbamate tert-butyl ester (2 g) (0.28 g, 64%).
LCMS m/z＝489.3[M+1] +。 LCMS m/z=489.3[M+1] + .
第六步：3-((S)-2-氨基丙氧基)-1-((S)-3-(三氟甲基)-6a,7,9,10-四氢吡嗪并[1,2-d]吡啶基[3,2-b][1,4]噁嗪-8(6H)-基)丙-1-酮(2h)的盐酸盐The sixth step: 3-((S)-2-aminopropoxy)-1-((S)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1 ,2-d]pyridyl[3,2-b][1,4]oxazin-8(6H)-yl)propan-1-one (2h) hydrochloride
3-((S)-2-aminopropoxy)-1-((S)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2-b][1,4]oxazin-8(6H)-yl)propan-1-one hydrochloride3-((S)-2-aminopropoxy)-1-((S)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2-b][ 1,4]oxazin-8(6H)-yl)propan-1-one hydrochloride
Figure PCTCN2022088446-appb-000170
Figure PCTCN2022088446-appb-000170
((S)-1-(3-氧代-3-((S)-3-(三氟甲基)-6a,7,9,10-四氢吡嗪并[1,2-d]吡啶并[3,2-b][1,4]噁嗪-8(6H)-基)丙氧基)丙-2-基)氨基甲酸酯叔丁酯(2g)(0.28g,0.57mmol)加入到HCl/二氧六环(4mL,4N)中，混合物在室温下搅拌反应2h。将反应液直接减压浓缩，得3-((S)-2-氨基丙氧基)-1-((S)-3-(三氟甲基)-6a,7,9,10-四氢吡嗪并[1,2-d]吡啶基[3,2-b][1,4]噁嗪-8(6H)-基)丙-1-酮(2h)的盐酸盐(180mg,74％)，直接用于下一步。((S)-1-(3-oxo-3-((S)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyridine Ipo[3,2-b][1,4]oxazin-8(6H)-yl)propoxy)propan-2-yl)carbamate tert-butyl ester (2g) (0.28g, 0.57mmol) It was added to HCl/dioxane (4 mL, 4 N), and the mixture was stirred at room temperature for 2 h. The reaction solution was directly concentrated under reduced pressure to obtain 3-((S)-2-aminopropoxy)-1-((S)-3-(trifluoromethyl)-6a,7,9,10-tetrahydro Pyrazino[1,2-d]pyridinyl[3,2-b][1,4]oxazin-8(6H)-yl)propan-1-one (2h) hydrochloride (180 mg, 74 %), used directly in the next step.
LCMS m/z＝389.1[M+1] +。 LCMS m/z=389.1[M+1] + .
第七步：2-(4-甲氧基苄基)-5-(((S)-1-(3-氧代-3-((S)-3-(三氟甲基)-6a,7,9,10-四氢吡嗪并[1,2-d]吡啶并[3,2-b][1,4]噁嗪-8(6H)-基)丙氧基)丙-2-基)氨基)-4-(三氟甲基)哒嗪-3(2H)-酮(2j)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)
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)-one2-(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
Figure PCTCN2022088446-appb-000171
Figure PCTCN2022088446-appb-000171
将3-((S)-2-氨基丙氧基)-1-((S)-3-(三氟甲基)-6a,7,9,10-四氢吡嗪并[1,2-d]吡啶基[3,2-b][1,4]噁嗪-8(6H)-基)丙-1-酮(2h)的盐酸盐(0.14g,0.36mmol)溶于乙腈(3mL)中，加入5-氯-2-[(4-甲氧基苯基)甲基]-4-(三氟甲基)-2,3-二氢哒嗪-3-酮(0.12g,0.36mmol)和三乙胺(109.08mg,1.08mmol)，混合物在室温下搅拌反应24h。将反应液直接减压浓缩，得粗品，粗品经prep-TLC(展开剂：石油醚：乙酸乙酯＝1:2)得到2-(4-甲氧基苄基)-5-(((S)-1-(3-氧代-3-((S)-3-(三氟甲基)-6a,7,9,10-四氢吡嗪并[1,2-d]吡啶并[3,2-b][1,4]噁嗪-8(6H)-基)丙氧基)丙-2-基)氨基)-4-(三氟甲基)哒嗪-3(2H)-酮(2j)(106mg,44％)。3-((S)-2-aminopropoxy)-1-((S)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2- d] The hydrochloride salt of pyridinyl[3,2-b][1,4]oxazin-8(6H)-yl)propan-1-one (2h) (0.14 g, 0.36 mmol) was dissolved in acetonitrile (3 mL) ), add 5-chloro-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one (0.12 g, 0.36 g mmol) and triethylamine (109.08 mg, 1.08 mmol), the mixture was stirred at room temperature for 24 h. The reaction solution was directly concentrated under reduced pressure to obtain a crude product, which was subjected to prep-TLC (developing solvent: petroleum ether: ethyl acetate=1:2) to obtain 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) (106 mg, 44%).
LCMS m/z＝671.3[M+1] +。 LCMS m/z=671.3[M+1] + .
第八步：5-(((S)-1-(3-氧代-3-((S)-3-(三氟甲基)-6a,7,9,10-四氢吡嗪并[1,2-d]吡啶并[3,2-b][1,4]噁嗪-8(6H)-基)丙氧基)丙-2-基)氨基)-4-(三氟甲基)哒嗪-3(2H)-酮(化合物2)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)
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)-one5-(((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
Figure PCTCN2022088446-appb-000172
Figure PCTCN2022088446-appb-000172
将2-(4-甲氧基苄基)-5-(((S)-1-(3-氧代-3-((S)-3-(三氟甲基)-6a,7,9,10-四氢吡嗪并[1,2-d]吡啶并[3,2-b][1,4]噁嗪-8(6H)-基)丙氧基)丙-2-基)氨基)-4-(三氟甲基)哒嗪-3(2H-酮(2j)(0.11g,0.16mmol)溶于三氟乙酸(5mL)中，加入三氟甲磺酸(0.12g,0.80mmol)。混合物在室温下搅拌反应1h。反应液经减压浓缩后，得粗品。粗品用甲醇溶解，滴加DIPEA调pH至8-9，减压浓缩后，残余物经Pre-HPLC纯化(仪器及制备柱：采用Waters 2767 制备液相，制备柱型号是XBridge@Prep C 18，内径×长度＝19mm×250mm)。制备方法：粗品用DMF溶解，并用0.45μm滤膜过滤，制备成样品液。流动相体系：乙腈/水(含0.05％的氨水)。梯度洗脱方法：乙腈由10％梯度洗脱至55％(流速：12mL/min；洗脱时间17min)得到5-(((S)-1-(3-氧代-3-((S)-3-(三氟甲基)-6a,7,9,10-四氢吡嗪并[1,2-d]吡啶并[3,2-b][1,4]噁嗪-8(6H)-基)丙氧基)丙-2-基)氨基)-4-(三氟甲基)哒嗪-3(2H)-酮(化合物2)(12mg,13％)。 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) (0.11 g, 0.16 mmol) was dissolved in trifluoroacetic acid (5 mL), trifluoromethanesulfonic acid (0.12 g, 0.80 mmol) was added ). The mixture was stirred and reacted at room temperature for 1 h. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was dissolved in methanol, and DIPEA was added dropwise to adjust the pH to 8-9. After concentration under reduced pressure, the residue was purified by Pre-HPLC (instrument And preparative column: use Waters 2767 to prepare the liquid phase, the preparative column model is XBridge@Prep C 18 , inner diameter×length=19mm×250mm).Preparation method: The crude product is dissolved in DMF, and filtered with a 0.45 μm filter membrane to prepare a sample liquid. Mobile phase system: acetonitrile/water (containing 0.05% ammonia water). Gradient elution method: acetonitrile gradient elution from 10% to 55% (flow rate: 12 mL/min; elution time 17 min) to obtain 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 ( Compound 2) (12 mg, 13%).
LCMS m/z＝551.2[M+1] +。 LCMS m/z=551.2[M+1] + .
实施例3：5-(((2S)-1-(3-氧代-3-(3-(三氟甲基)-6,7,7a,8,10,11-六氢-9H-吡嗪并[1,2-d]吡啶并[3,2-b][1,4]氧氮杂-9-基)丙氧基)丙-2-基)氨基)-4-(三氟甲基)哒嗪-3(2H)-酮(化合物3)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)
5-(((2S)-1-(3-oxo-3-(3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazepin-9-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one5-(((2S)-1-(3-oxo-3-(3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyrido[ 3,2-b][1,4]oxazepin-9-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one
Figure PCTCN2022088446-appb-000173
Figure PCTCN2022088446-appb-000173
第一步：3-(2-羟乙基)哌嗪-1-甲酸叔丁酯(3b)The first step: tert-butyl 3-(2-hydroxyethyl)piperazine-1-carboxylate (3b)
tert-butyl 3-(2-hydroxyethyl)piperazine-1-carboxylatetert-butyl 3-(2-hydroxyethyl)piperazine-1-carboxylate
Figure PCTCN2022088446-appb-000174
Figure PCTCN2022088446-appb-000174
冰浴下，将3-(2-甲氧基-2-氧乙基)哌嗪-1-甲酸叔丁酯(3a)(1.00g,3.87mmol)加入到T HF(10mL)，加入LiAlH 4(0.11g,2.90mmol)。混合物在冰浴下搅拌2h。依次加入水(0.11mL)、2N NaOH(0.11mL)和水(0.33mL)淬灭反应，加入乙酸乙酯(20mL)和无水MgSO 4(2g)，混合物搅拌1h,过滤，滤液减压浓缩后得3-(2-羟乙基)哌嗪-1-羧酸叔丁酯(3b)(1.00g,89％)，直接用于下一步。 Under ice bath, 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. Water (0.11 mL), 2N NaOH (0.11 mL) and water (0.33 mL) were added successively to quench the reaction, ethyl acetate (20 mL) and anhydrous MgSO 4 (2 g) were added, the mixture was stirred for 1 h, filtered, and the filtrate was concentrated under reduced pressure This gave tert-butyl 3-(2-hydroxyethyl)piperazine-1-carboxylate (3b) (1.00 g, 89%), which was used directly in the next step.
LCMS m/z＝231.2[M+1] +。 LCMS m/z=231.2[M+1] + .
第二步：(3-(2-羟乙基)-4-(3-硝基-5-(三氟甲基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(3c)The second step: (3-(2-hydroxyethyl)-4-(3-nitro-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (3c)
tert-butyl 3-(2-hydroxyethyl)-4-(3-nitro-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylatetert-butyl 3-(2-hydroxyethyl)-4-(3-nitro-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate
Figure PCTCN2022088446-appb-000175
Figure PCTCN2022088446-appb-000175
室温下，将2-氯-3-硝基-5-(三氟甲基)吡啶(0.98g,4.33mmol)加入到DMF(10mL)，加入3-(2-羟乙基)哌嗪-1-羧酸叔丁酯(3b)(1.00g,4.33mmol)和DIPEA(1.68g,12.99mmol)。混合物在室温下搅拌过夜。加水(20mL)淬灭反应，乙酸乙酯(20mL x 2)萃取，合并有机相，有机相用饱和食盐水洗涤，无水硫酸钠干燥后过滤，滤液减压浓缩后得粗品。粗品经制备柱分离纯化(石油醚：乙酸乙酯(v/v)＝10:1)得((3-(2-羟乙基)-4-(3-硝基-5-(三氟甲基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(3c)(0.64g,35％)。2-Chloro-3-nitro-5-(trifluoromethyl)pyridine (0.98 g, 4.33 mmol) was added to DMF (10 mL) at room temperature, 3-(2-hydroxyethyl)piperazine-1 was added - tert-butyl carboxylate (3b) (1.00 g, 4.33 mmol) and DIPEA (1.68 g, 12.99 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 crude product was separated and purified by a preparative column (petroleum ether:ethyl acetate (v/v)=10:1) to obtain ((3-(2-hydroxyethyl)-4-(3-nitro-5-(trifluoromethyl)) yl)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (3c) (0.64 g, 35%).
LCMS m/z＝365.1[M-55] +。 LCMS m/z = 365.1 [M-55] + .
第三步：3-(三氟甲基)-6,7,7a,8,10,11-六氢-9H-吡嗪并[1,2-d]吡啶并[3,2-b][1,4]氧氮杂-9-甲酸叔丁酯(3d)The third step: 3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyrido[3,2-b][ 1,4] tert-Butyl oxazepine-9-carboxylate (3d)
tert-butyl 3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazepine-9-carboxylatetert-butyl 3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazepine-9- carboxylate
Figure PCTCN2022088446-appb-000176
Figure PCTCN2022088446-appb-000176
将((3-(2-羟乙基)-4-(3-硝基-5-(三氟甲基)吡啶-2-基)哌嗪-1-甲酸叔丁酯(3c)(0.63g,1.55mmol)加入到DMF(10ml)溶液中、加入NaH(0.19g,4.65mmol)。混合物40℃反应16小时。冷却，加水(10mL)淬灭反应，乙酸乙酯(10mL x 2)萃取，合并有机相，有机相用饱和食盐水洗涤，无水硫酸钠干燥后过滤，滤液减压浓缩后得粗品。粗品经制备柱分离纯化(石油醚：乙酸乙酯(v/v)＝10:1)得到3-(三氟甲基)-6,7,7a,8,10,11-六氢-9H-吡嗪 并[1,2-d]吡啶并[3,2-b][1,4]氧氮杂-9-甲酸叔丁酯(3d)(0.5g,86％)。((3-(2-hydroxyethyl)-4-(3-nitro-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (3c) (0.63 g) , 1.55 mmol) was added to DMF (10 ml) solution, NaH (0.19 g, 4.65 mmol) was added. The mixture was reacted at 40 ° C for 16 hours. Cooled, water (10 mL) was added to quench the reaction, and ethyl acetate (10 mL x 2) was extracted. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by a preparative column (petroleum ether: ethyl acetate (v/v) = 10:1 ) to give 3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyrido[3,2-b][1, 4] tert-butyl oxazepine-9-carboxylate (3d) (0.5 g, 86%).
LCMS m/z＝374.2[M+1] +。 LCMS m/z=374.2[M+1] + .
第四步：3-(三氟甲基)-7,7a,8,9,10,11-六氢-6H-吡嗪并[1,2-d]吡啶并[3,2-b][1,4]氧氮杂(3e)的三氟乙酸盐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
3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-6H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazepine trifluoroacetate3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-6H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazepine trifluoroacetate
Figure PCTCN2022088446-appb-000177
Figure PCTCN2022088446-appb-000177
将(3-(三氟甲基)-6,7,7a,8,10,11-六氢-9H-吡嗪并[1,2-d]吡啶并[3,2-b][1,4]氧氮杂-9-甲酸叔丁酯(3d)(0.45g,1.21mmol)溶于DCM(4mL)，加入TFA(2mL)，混合物在室温下搅拌反应2h。直接将反应液减压浓缩，得3-(三氟甲基)-7,7a,8,9,10,11-六氢-6H-吡嗪并[1,2-d]吡啶并[3,2-b][1,4]氧氮杂(3e)的三氟乙酸盐(470mg,100％)，直接用于下一步。(3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyrido[3,2-b][1, 4] Tert-butyl oxazepine-9-carboxylate (3d) (0.45 g, 1.21 mmol) was dissolved in DCM (4 mL), TFA (2 mL) was added, and the mixture was stirred at room temperature for 2 h. The reaction solution was directly concentrated under reduced pressure , to give 3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-6H-pyrazino[1,2-d]pyrido[3,2-b][1, 4] The trifluoroacetate salt of oxazepine (3e) (470 mg, 100%) was used directly in the next step.
LCMS m/z＝274.1[M+1] +。 LCMS m/z=274.1[M+1] + .
第五步：1-(3-(三氟甲基)-6,7,7a,8,10,11-六氢-9H-吡嗪并[1,2-d]吡啶并[3,2-b][1,4]氧氮杂-9-基)丙-2-烯-1-酮(3f)The fifth step: 1-(3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyrido[3,2- b][1,4]oxazepin-9-yl)prop-2-en-1-one (3f)
1-(3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazepin-9-yl)prop-2-en-1-one1-(3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazepin-9- yl)prop-2-en-1-one
Figure PCTCN2022088446-appb-000178
Figure PCTCN2022088446-appb-000178
将3-(三氟甲基)-7,7a,8,9,10,11-六氢-6H-吡嗪并[1,2-d]吡啶并[3,2-b][1,4]氧氮杂(3e)的三氟乙酸盐(460mg,1.19mmol)溶于二氯甲烷(4mL)中，然后加入丙烯酸酐(0.15g,1.19mmol)和三乙胺(601mg,5.95mmol)，混合物在20℃反应24h后，直接减压浓缩反应液，得粗品，粗品经制备柱分离纯化(石油醚：乙酸乙酯(v/v)＝10:1)得1-(3-(三氟甲基)-6,7,7a,8,10,11-六氢-9H-吡嗪并[1,2-d]吡啶并[3,2-b][1,4]氧氮杂-9-基)丙-2-烯-1-酮(3f)(0.36g,92％)。3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydro-6H-pyrazino[1,2-d]pyrido[3,2-b][1,4 ] The trifluoroacetate salt of oxazepine (3e) (460 mg, 1.19 mmol) was dissolved in dichloromethane (4 mL), followed by the addition of acrylic anhydride (0.15 g, 1.19 mmol) and triethylamine (601 mg, 5.95 mmol) , after the mixture was reacted at 20°C for 24h, the reaction solution was directly concentrated under reduced pressure to obtain a crude product, which was separated and purified by a preparative column (petroleum ether:ethyl acetate (v/v)=10:1) to obtain 1-(3-(trimethylbenzene) Fluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazepine- 9-yl)prop-2-en-1-one (3f) (0.36 g, 92%).
LCMS m/z＝328.1[M+1] +。 LCMS m/z=328.1[M+1] + .
第六步：(2S)-1-(3-氧代-3-(3-(三氟甲基)-6,7,7a,8,10,11-六氢-9H-吡嗪并[1,2-d]吡啶并 [3,2-b][1,4]氧氮杂-9-基)丙氧基)丙-2-基)氨基甲酸叔丁酯(3g)The sixth step: (2S)-1-(3-oxo-3-(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)carbamic acid tert-butyl ester (3g)
tert-butyl((2S)-1-(3-oxo-3-(3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazepin-9-yl)propoxy)propan-2-yl)carbamatetert-butyl((2S)-1-(3-oxo-3-(3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyrido[ 3,2-b][1,4]oxazepin-9-yl)propoxy)propan-2-yl)carbamate
Figure PCTCN2022088446-appb-000179
Figure PCTCN2022088446-appb-000179
将1-(3-(三氟甲基)-6,7,7a,8,10,11-六氢-9H-吡嗪并[1,2-d]吡啶并[3,2-b][1,4]氧氮杂-9-基)丙-2-烯-1-酮(3f)(350mg,1.07mmol)溶于乙腈(1.8mL)中，然后加入N-Boc-L-丙氨醇(0.94g,5.35mmol)和碳酸铯(452mg,1.39mmol)，混合物在20℃反应48h。将反应液直接过滤，滤液减压浓缩得残留物，残留物经制备柱分离纯化(石油醚：乙酸乙酯(v/v)＝10:1)得((2S)-1-(3-氧代-3-(3-(三氟甲基)-6,7,7a,8,10,11-六氢-9H-吡嗪并[1,2-d]吡啶并[3,2-b][1,4]氧氮杂-9-基)丙氧基)丙-2-基)氨基甲酸叔丁酯(3g)(0.33g,61％)。1-(3-(Trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyrido[3,2-b][ 1,4]oxazepin-9-yl)prop-2-en-1-one (3f) (350 mg, 1.07 mmol) was dissolved in acetonitrile (1.8 mL) followed by the addition of N-Boc-L-alaninol (0.94 g, 5.35 mmol) and cesium carbonate (452 mg, 1.39 mmol), the mixture was reacted at 20° C. for 48 h. The reaction solution was directly filtered, and the filtrate was concentrated under reduced pressure to obtain a residue, which was separated and purified by a preparative column (petroleum ether:ethyl acetate (v/v)=10:1) to obtain ((2S)-1-(3-oxygen) Substituted-3-(3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyrido[3,2-b] tert-Butyl [1,4]oxazepin-9-yl)propoxy)prop-2-yl)carbamate (3 g) (0.33 g, 61%).
LCMS m/z＝503.2[M+1] +。 LCMS m/z=503.2[M+1] + .
第七步：3-((S)-2-氨基丙氧基)-1-(3-(三氟甲基)-6,7,7a,8,10,11-六氢-9H-吡嗪并[1,2-d]吡啶[3,2-b][1,4]氧氮杂-9-基)丙-1-酮(3h)的盐酸盐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)
3-((S)-2-aminopropoxy)-1-(3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazepin-9-yl)propan-1-one hydrochloride3-((S)-2-aminopropoxy)-1-(3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyrido[3,2 -b][1,4]oxazepin-9-yl)propan-1-one hydrochloride
Figure PCTCN2022088446-appb-000180
Figure PCTCN2022088446-appb-000180
将((2S)-1-(3-氧代-3-(3-(三氟甲基)-6,7,7a,8,10,11-六氢-9H-吡嗪并[1,2-d]吡啶并[3,2-b][1,4]氧氮杂-9-基)丙氧基)丙-2-基)氨基甲酸叔丁酯(3g)(0.3g,0.6mmol)加入到HCl/二氧六环(4mL,4N)中，混合物在室温下搅拌反应2h。将反应液直接减压浓缩，得3-((S)-2-氨基丙氧基)-1-(3-(三氟甲基)-6,7,7a,8,10,11-六氢-9H-吡嗪并[1,2-d]吡啶[3,2-b][1,4]氧氮杂-9-基)丙-1-酮(3h)的盐酸盐(260mg,98％)，直接用于下一步。((2S)-1-(3-oxo-3-(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)carbamate tert-butyl ester (3g) (0.3g, 0.6mmol) It was added to HCl/dioxane (4 mL, 4 N), and the mixture was stirred at room temperature for 2 h. The reaction solution was directly concentrated under reduced pressure to obtain 3-((S)-2-aminopropoxy)-1-(3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro -9H-pyrazino[1,2-d]pyridin[3,2-b][1,4]oxazepin-9-yl)propan-1-one (3h) hydrochloride (260 mg, 98 %), used directly in the next step.
LCMS m/z＝403.1[M+1] +。 LCMS m/z=403.1[M+1] + .
第八步：2-(4-甲氧基苄基)-5-(((2S)-1-(3-氧代-3-(3-(三氟甲基)-6,7,7a,8,10,11-六氢-9H吡嗪并[1,2-d]吡啶并[3,2-b][1,4]氧氮杂-9-基)丙氧基)丙-2-基)氨基)-4-(三氟甲基)哒嗪-3(2 H)-酮(3I)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)
2-(4-methoxybenzyl)-5-(((2S)-1-(3-oxo-3-(3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazepin-9-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one2-(4-methoxybenzyl)-5-(((2S)-1-(3-oxo-3-(3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[ 1,2-d]pyrido[3,2-b][1,4]oxazepin-9-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one
Figure PCTCN2022088446-appb-000181
Figure PCTCN2022088446-appb-000181
将3-((S)-2-氨基丙氧基)-1-(3-(三氟甲基)-6,7,7a,8,10,11-六氢-9H-吡嗪并[1,2-d]吡啶[3,2-b][1,4]氧氮杂-9-基)丙-1-酮(3h)的盐酸盐(0.16g,0.36mmol)溶于乙腈(3mL)中，加入5-氯-2-[(4-甲氧基苯基)甲基]-4-(三氟甲基)-2,3-二氢哒嗪-3-酮(0.11g,0.36mmol)和三乙胺(109.08mg,1.08mmol)，混合物在室温下搅拌反应24h。将反应液直接减压浓缩，得粗品，粗品经prep-TLC(展开剂：石油醚：乙酸乙酯＝1:2)得到2-(4-甲氧基苄基)-5-(((2S)-1-(3-氧代-3-(3-(三氟甲基)-6,7,7a,8,10,11-六氢-9H吡嗪并[1,2-d]吡啶并[3,2-b][1,4]氧氮杂-9-基)丙氧基)丙-2-基)氨基)-4-(三氟甲基)哒嗪-3(2H)-酮(3I)(100mg,41％)。3-((S)-2-aminopropoxy)-1-(3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1 ,2-d]pyridin[3,2-b][1,4]oxazepin-9-yl)propan-1-one (3h) hydrochloride (0.16 g, 0.36 mmol) was dissolved in acetonitrile (3 mL) ), add 5-chloro-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one (0.11 g, 0.36 g mmol) and triethylamine (109.08 mg, 1.08 mmol), the mixture was stirred at room temperature for 24 h. The reaction solution was directly concentrated under reduced pressure to obtain a crude product, which was subjected to prep-TLC (developing solvent: petroleum ether: ethyl acetate=1:2) to obtain 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) (100 mg, 41%).
LCMS m/z＝685.2[M+1] +。 LCMS m/z=685.2[M+1] + .
第九步：5-(((2S)-1-(3-氧代-3-(3-(三氟甲基)-6,7,7a,8,10,11-六氢-9H-吡嗪并[1,2-d]吡啶并[3,2-b][1,4]氧氮杂-9-基)丙氧基)丙-2-基)氨基)-4-(三氟甲基)哒嗪-3(2H)-酮(化合物3)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)
5-(((2S)-1-(3-oxo-3-(3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazepin-9-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one5-(((2S)-1-(3-oxo-3-(3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyrido[ 3,2-b][1,4]oxazepin-9-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one
Figure PCTCN2022088446-appb-000182
Figure PCTCN2022088446-appb-000182
将2-(4-甲氧基苄基)-5-(((2S)-1-(3-氧代-3-(3-(三氟甲基)-6,7,7a,8,10,11-六氢-9H-吡嗪并[1,2-d]吡啶并[3,2-b][1,4]氧氮杂-9-基)丙氧基)丙-2-基)氨基)-4-(三氟甲基)哒嗪-3(2H)-酮(3I)(0.1g,0.15mmol)溶于三氟乙酸(5mL)中，加入三氟甲磺酸(0.14g,0.95mmol)。混合物在室温下搅拌反应1h。反应液经减压浓缩后，得粗品。粗品用甲醇溶解，滴加DIPEA调pH至8-9，减压浓缩后，残余物经Pre-HPLC纯化(仪器及制备柱：采用Waters2767制备液相，制备柱型号是XBridge@Prep C 18，内径×长度＝19mm×250mm)。制备方 法：粗品用DMF溶解，并用0.45μm滤膜过滤，制备成样品液。流动相体系：乙腈/水(含0.05％的氨水)。梯度洗脱方法：乙腈由10％梯度洗脱至55％(流速：12mL/min；洗脱时间17min)得到5-(((2S)-1-(3-氧代-3-(3-(三氟甲基)-6,7,7a,8,10,11-六氢-9H-吡嗪并[1,2-d]吡啶并[3,2-b][1,4]氧氮杂-9-基)丙氧基)丙-2-基)氨基)-4-(三氟甲基)哒嗪-3(2H)-酮(化合物3)(10mg,11.8％)。 2-(4-Methoxybenzyl)-5-(((2S)-1-(3-oxo-3-(3-(trifluoromethyl)-6,7,7a,8,10 ,11-Hexahydro-9H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazepin-9-yl)propoxy)propan-2-yl) Amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (3I) (0.1 g, 0.15 mmol) was dissolved in trifluoroacetic acid (5 mL), trifluoromethanesulfonic acid (0.14 g, 0.95 mmol). The mixture was stirred at room temperature for 1 h. The reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was dissolved in methanol, and DIPEA was added dropwise to adjust the pH to 8-9. After concentration under reduced pressure, the residue was purified by Pre-HPLC (instrument and preparative column: Waters2767 was used to prepare the liquid phase, the preparative column model was XBridge@Prep C 18 , inner diameter ×Length=19mm×250mm). Preparation method: the crude product is dissolved in DMF, and filtered with a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile/water (containing 0.05% ammonia water). Gradient elution method: acetonitrile gradient from 10% to 55% (flow rate: 12 mL/min; elution time 17 min) to obtain 5-(((2S)-1-(3-oxo-3-(3-( trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazepine -9-yl)propoxy)prop-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (compound 3) (10 mg, 11.8%).
LCMS m/z＝565.0[M+1] +。 LCMS m/z=565.0[M+1] + .
1H NMR(400MHz,DMSO-d 6)δ12.43(s,1H),8.17-8.12(m,1H),7.93-7.88(m,1H),7.34(s,1H),6.29-6.20(m,1H),4.35-4.19(m,2H),4.18-4.08(m,1H),4.06-3.96(m,1H),3.91-3.76(m,2H),3.75-3.31(m,8H),2.59-2.51(m,2H),2.18-2.00(m,1H),1.95-1.83(m 1H)，1.19-1.10(m，3H)。 1 H NMR (400MHz, DMSO-d 6 )δ12.43(s,1H), 8.17-8.12(m,1H), 7.93-7.88(m,1H), 7.34(s,1H), 6.29-6.20(m ,1H),4.35-4.19(m,2H),4.18-4.08(m,1H),4.06-3.96(m,1H),3.91-3.76(m,2H),3.75-3.31(m,8H),2.59 -2.51 (m, 2H), 2.18-2.00 (m, 1H), 1.95-1.83 (m, 1H), 1.19-1.10 (m, 3H).
实施例4：(R)-8-(3-((S)-2-((6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基)丙氧基)丙酰基)-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪[1,2-a]吡啶[3,2-e]吡嗪-6(6aH)-酮(化合物4)Example 4: (R)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino )propoxy)propionyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazine[1,2-a]pyridine[3,2-e]pyrazine -6(6aH)-one (compound 4)
(R)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one(R)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl) -7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one
Figure PCTCN2022088446-appb-000183
Figure PCTCN2022088446-appb-000183
第一步：1-叔丁基3-甲基(3R)-4-(3-硝基-5-(三氟甲基)吡啶-2-基)哌嗪-1,3-二羧酸酯(4c)The first step: 1-tert-butyl 3-methyl(3R)-4-(3-nitro-5-(trifluoromethyl)pyridin-2-yl)piperazine-1,3-dicarboxylate (4c)
1-Tert-butyl-3-methyl-(3R)-4-(3-nitro-5-(trifluoromethyl)pyridin-2-yl)piperazine-1,3-dicarboxylate1-Tert-butyl-3-methyl-(3R)-4-(3-nitro-5-(trifluoromethyl)pyridin-2-yl)piperazine-1,3-dicarboxylate
Figure PCTCN2022088446-appb-000184
Figure PCTCN2022088446-appb-000184
室温下，将2-氯-3-硝基-5-(三氟甲基)吡啶(4a)(2.00g,8.83mmol)加入到DMF(20mL)，再加入(3R)-哌嗪-1-甲酸叔丁酯-3-甲酸甲酯(4b)(2.16g,8.83mmol)和DIPEA(3.42g,26.49mmol)。混合物在室温下搅拌过夜。加水(40mL)淬灭反应，乙酸乙酯(40mL x 2)萃取，合并有机相，有机相用饱和食盐水洗涤，无水硫酸钠干燥后过滤，滤液减压浓缩后得粗品。粗品经制备柱分离纯化(石油醚：乙酸乙酯(v/v)＝10:1)得1-叔丁基3-甲基(3R)-4-(3-硝基-5-(三氟甲基)吡啶-2-基)哌嗪-1,3-二羧酸酯(4c)(2.70g,70％)。At room temperature, 2-chloro-3-nitro-5-(trifluoromethyl)pyridine (4a) (2.00 g, 8.83 mmol) was added to DMF (20 mL) followed by (3R)-piperazine-1- tert-Butyl formate-3-methyl carboxylate (4b) (2.16 g, 8.83 mmol) and DIPEA (3.42 g, 26.49 mmol). The mixture was stirred at room temperature overnight. Water (40 mL) was added to quench the reaction, ethyl acetate (40 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 crude product was separated and purified by a preparative column (petroleum ether:ethyl acetate (v/v)=10:1) to obtain 1-tert-butyl 3-methyl(3R)-4-(3-nitro-5-(trifluoro) Methyl)pyridin-2-yl)piperazine-1,3-dicarboxylate (4c) (2.70 g, 70%).
LCMS m/z＝379.1[M-55] +。 LCMS m/z = 379.1 [M-55] + .
第二步：叔丁基-(R)-6-氧代-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-8-羧酸酯(4d)The second step: 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 (4d)
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-carboxylateTert-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
Figure PCTCN2022088446-appb-000185
Figure PCTCN2022088446-appb-000185
室温下，将1-叔丁基3-甲基(3R)-4-(3-硝基-5-(三氟甲基)吡啶-2-基)哌嗪-1,3-二羧酸酯(4c)(1.0g,2.30mmol)溶于无水甲醇(20mL)，然后再加入10％钯碳(200mg)。氢气置换三次后，室温反应16小时。干燥过滤，滤液减压浓缩后得粗品。粗品经柱层析分离纯化(石油醚：乙酸乙酯(v/v)＝4:1)得到叔丁基-(R)-6-氧代-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-8-羧酸酯(4d)(380mg,44％)。1-tert-Butyl 3-methyl(3R)-4-(3-nitro-5-(trifluoromethyl)pyridin-2-yl)piperazine-1,3-dicarboxylate at room temperature (4c) (1.0 g, 2.30 mmol) was dissolved in anhydrous methanol (20 mL), and then 10% palladium on carbon (200 mg) was added. After hydrogen replacement three times, the reaction was carried out at room temperature for 16 hours. After drying and filtration, the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate (v/v)=4:1) to obtain 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 (4d) (380 mg, 44%) .
LCMS m/z＝317.1[M-55] +。 LCMS m/z = 317.1 [M-55] + .
第三步：(R)-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪[1,2-a]吡啶[3,2-e]吡嗪-6(6aH)-酮(4e)的盐酸盐The third step: (R)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazine[1,2-a]pyridine[3,2-e]pyrazine- 6(6aH)-keto (4e) hydrochloride
(R)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one hydrochloride(R)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one hydrochloride
Figure PCTCN2022088446-appb-000186
Figure PCTCN2022088446-appb-000186
室温下，将叔丁基-(R)-6-氧代-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-8-羧酸酯(4d)(100mg,0.27mmol)溶于1,4-二氧六环(5mL)溶液中，再加入氯化氢-1,4-二氧六环溶液(4.0M，10mL,40mmol)，室温反应4小时。反应结束后，减压浓缩除去溶剂后得(R)-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪[1,2-a]吡啶[3,2-e]吡嗪-6(6aH)-酮(4e)的盐酸盐(83.0mg,100％)。At room temperature, 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 (4d) (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. After the reaction, the solvent was removed by concentration under reduced pressure to obtain (R)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazine[1,2-a]pyridine[3, 2-e] Pyrazin-6(6aH)-one (4e) hydrochloride salt (83.0 mg, 100%).
LCMS m/z＝273.1[M+1] +。 LCMS m/z=273.1[M+1] + .
第四步：5-{[(2S)-1-羟基丙烷-2-基]氨基}-2-[(4-甲氧基苯基)甲基]-4-(三氟甲基)-2,3-二氢哒嗪-3-酮(4g)The fourth step: 5-{[(2S)-1-hydroxypropan-2-yl]amino}-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-2 ,3-Dihydropyridazin-3-one (4g)
5-{[(2S)-1-hydroxypropan-2-yl]amino}-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one5-{[(2S)-1-hydroxypropan-2-yl]amino}-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one
Figure PCTCN2022088446-appb-000187
Figure PCTCN2022088446-appb-000187
室温下，将5-氯-2-[(4-甲氧基苯基)甲基]-4-(三氟甲基)-2,3-二氢哒嗪-3-酮(4f)(15.0g,47.07mmol)和(2S)-2-氨基丙烷-1-醇(5.40g,71.9mmol)溶于无水乙腈中(100mL)，然后再加入DIPEA(30.0g,233mmol)。室温下搅拌反应4小时。反应结束后，减压浓缩除去反应溶剂。加入水(50mL)，乙酸乙酯萃取(50mL x 3)，合并有机相，干燥过滤，滤液减压浓缩后得5-{[(2S)-1-羟基丙烷-2-基]氨基}-2-[(4-甲氧基苯基)甲基]-4-(三氟甲基)-2,3-二氢哒嗪-3-酮(4g)(16.5g,98％)。5-Chloro-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one (4f) (15.0 g, 47.07 mmol) and (2S)-2-aminopropan-1-ol (5.40 g, 71.9 mmol) were dissolved in dry acetonitrile (100 mL), followed by the addition of DIPEA (30.0 g, 233 mmol). The reaction was stirred at room temperature for 4 hours. After the reaction was completed, the reaction solvent was removed by concentration under reduced pressure. Water (50 mL) was added, extracted with ethyl acetate (50 mL x 3), the organic phases were combined, dried and filtered, and the filtrate was concentrated under reduced pressure to obtain 5-{[(2S)-1-hydroxypropan-2-yl]amino}-2 -[(4-Methoxyphenyl)methyl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one (4 g) (16.5 g, 98%).
LCMS m/z＝358.2[M+1] +。 LCMS m/z=358.2[M+1] + .
第五步：甲基-3-[(2S)-2-[(1-[(4-甲氧基苯基)甲基]-6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基]丙氧基]丙酸酯(4h)The fifth step: methyl-3-[(2S)-2-[(1-[(4-methoxyphenyl)methyl]-6-oxo-5-(trifluoromethyl)-1, 6-Dihydropyridazin-4-yl)amino]propoxy]propionate (4h)
Methyl-3-[(2S)-2-[(1-[(4-methoxyphenyl)methyl]-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino]propoxy]propanoateMethyl-3-[(2S)-2-[(1-[(4-methoxyphenyl)methyl]-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino]propoxy]propanoate
Figure PCTCN2022088446-appb-000188
Figure PCTCN2022088446-appb-000188
室温下，将5-{[(2S)-1-羟基丙烷-2-基]氨基}-2-[(4-甲氧基苯基)甲基]-4-(三氟甲基)-2,3-二氢哒嗪-3-酮(4g)(13.5g,37.82mmol)和丙-2-烯酸甲酯(33g,378.2mmol)溶于乙腈溶液(90mL)，然后加入碳酸铯(13.6g,41.60mmol)，室温搅拌反应48小时。反应结束后，减压浓缩除去溶剂后，残留物用硅胶柱色谱分离提纯(石油醚:乙酸乙酯(V/V)＝7:3)得到甲基-3-[(2S)-2-[(1-[(4-甲氧基苯基)甲基]-6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基]丙氧基]丙酸酯(4h)(6.0g,36％)。At room temperature, 5-{[(2S)-1-hydroxypropan-2-yl]amino}-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-2 , 3-dihydropyridazin-3-one (4 g) (13.5 g, 37.82 mmol) and methyl prop-2-enoate (33 g, 378.2 mmol) were dissolved in acetonitrile solution (90 mL), followed by the addition of cesium carbonate (13.6 g, 41.60 mmol), and the reaction was stirred at room temperature for 48 hours. After the reaction was completed, the solvent was removed by concentration under reduced pressure, and the residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V/V)=7:3) to obtain methyl-3-[(2S)-2-[ (1-[(4-Methoxyphenyl)methyl]-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino]propoxy] Propionate (4h) (6.0 g, 36%).
LCMS m/z＝444.2[M+1] +。 LCMS m/z=444.2[M+1] + .
第六步：甲基-3-[(2S)-2-[(6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基]丙氧基]丙酸酯(4i)The sixth step: methyl-3-[(2S)-2-[(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino]propoxy ]Propionate (4i)
Methyl-3-[(2S)-2-[(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino]propoxy]propanoateMethyl-3-[(2S)-2-[(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino]propoxy]propanoate
Figure PCTCN2022088446-appb-000189
Figure PCTCN2022088446-appb-000189
室温下，将甲基-3-[(2S)-2-[(1-[(4-甲氧基苯基)甲基]-6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基]丙氧基]丙酸酯(4h)(6.0g,13.5mmol)溶于三氟乙酸(30mL)，向其中加入三氟甲磺酸(5mL)，然后室温搅拌反应2小时。反应结束后，减压浓缩除去反应溶剂得甲基-3-[(2S)-2-[(6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基]丙氧基]丙酸酯(4i)粗品，无需纯化，直接用于下一步反应。At room temperature, methyl-3-[(2S)-2-[(1-[(4-methoxyphenyl)methyl]-6-oxo-5-(trifluoromethyl)-1, 6-Dihydropyridazin-4-yl)amino]propoxy]propionate (4h) (6.0 g, 13.5 mmol) was dissolved in trifluoroacetic acid (30 mL), to which was added trifluoromethanesulfonic acid (5 mL) , and then the reaction was stirred at room temperature for 2 hours. After the reaction, the reaction solvent was removed by concentration under reduced pressure to obtain methyl-3-[(2S)-2-[(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4- The crude product of (4i) amino]propoxy]propionate (4i) was used in the next reaction without purification.
LCMS m/z＝324.1[M+1] +。 LCMS m/z=324.1[M+1] + .
第七步：3-[(2S)-2-[(6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基]丙氧基]丙酸(4j)Step 7: 3-[(2S)-2-[(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino]propoxy]propionic acid (4j)
3-[(2S)-2-[(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino]propoxy]propanoic acid3-[(2S)-2-[(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino]propoxy]propanoic acid
Figure PCTCN2022088446-appb-000190
Figure PCTCN2022088446-appb-000190
室温下，将甲基-3-[(2S)-2-[(6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基]丙氧基]丙 酸酯(4i)粗品溶于甲醇(30mL)和水(30mL)的混合溶液中，用氢氧化锂一水合物调pH＝7～8，然后加入氢氧化锂一水合物(1.14g,27mmol)，室温搅拌反应16小时。反应结束后，在冰水浴下，用2M的盐酸水溶液调pH＝5左右，过滤，滤液减压浓缩得残留物，残留物用硅胶柱色谱分离提纯(二氯甲烷：甲醇(V/V)＝15：1)得3-[(2S)-2-[(6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基]丙氧基]丙酸(4j)(2.5g,60％)。At room temperature, methyl-3-[(2S)-2-[(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino]propoxy ] The crude propionate (4i) was dissolved in a mixed solution of methanol (30 mL) and water (30 mL), adjusted to pH=7-8 with lithium hydroxide monohydrate, and then added with lithium hydroxide monohydrate (1.14 g, 27 mmol) and the reaction was stirred at room temperature for 16 hours. After the reaction, under an ice-water bath, adjust pH=5 with 2M aqueous hydrochloric acid solution, filter, and concentrate the filtrate under reduced pressure to obtain a residue, which is separated and purified by silica gel column chromatography (dichloromethane: methanol (V/V)= 15:1) to obtain 3-[(2S)-2-[(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino]propoxy]propane Acid (4j) (2.5 g, 60%).
LCMS m/z＝310.1[M+1] +。 LCMS m/z=310.1[M+1] + .
第八步：(R)-8-(3-((S)-2-((6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基)丙氧基)丙酰基)-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪[1,2-a]吡啶[3,2-e]吡嗪-6(6aH)-酮(化合物4)The eighth step: (R)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino )propoxy)propionyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazine[1,2-a]pyridine[3,2-e]pyrazine -6(6aH)-one (compound 4)
(R)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one(R)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl) -7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one
Figure PCTCN2022088446-appb-000191
Figure PCTCN2022088446-appb-000191
室温下，将3-[(2S)-2-[(6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基]丙氧基]丙酸(4j)(50mg,0.16mmol)和(R)-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪[1,2-a]吡啶[3,2-e]吡嗪-6(6aH)-酮(4e)的盐酸盐(49mg,0.16mmol)溶于DMF(5mL)中，加入DIPEA(83mg,0.64mmol)和HATU(46mg,0.12mmol)后，室温反应3小时。反应结束后，反应液经Pre-HPLC纯化(仪器及制备柱：采用WATERS 2767制备液相，制备柱型号是Xselect C18，5μm，内径×长度＝19mm×150mm)。制备方法：反应液用0.45μm滤膜过滤，制备成样品液。流动相体系：乙腈/水(含0.05％氨水)。梯度洗脱方法：乙腈由5％梯度洗脱至50％(洗脱时间15min)。冻干后得到(R)-8-(3-((S)-2-((6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基)丙氧基)丙酰基)-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪[1,2-a]吡啶[3,2-e]吡嗪-6(6aH)-酮(化合物4)(10mg,11％)。3-[(2S)-2-[(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino]propoxy]propionic acid at room temperature (4j) (50 mg, 0.16 mmol) and (R)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazine[1,2-a]pyridine[3,2 -e] The hydrochloride salt of pyrazin-6(6aH)-one (4e) (49 mg, 0.16 mmol) was dissolved in DMF (5 mL), and after the addition of DIPEA (83 mg, 0.64 mmol) and HATU (46 mg, 0.12 mmol) , and react at room temperature for 3 hours. After the reaction, the reaction solution was purified by Pre-HPLC (instrument and preparative column: WATERS 2767 was used to prepare the liquid phase, the preparative column model was Xselect C18, 5 μm, inner diameter×length=19mm×150mm). Preparation method: The reaction solution was filtered with a 0.45 μm 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). Lyophilized to give (R)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino )propoxy)propionyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazine[1,2-a]pyridine[3,2-e]pyrazine -6(6aH)-one (compound 4) (10 mg, 11%).
LCMS m/z＝564.2[M+1] +。 LCMS m/z=564.2[M+1] + .
1H NMR(400MHz,DMSO-d 6)δ12.42(s,1H),10.93(s,1H),8.12(s,1H),7.90(s,1H),7.16(d,1H),6.31-6.20(m,1H),4.85-4.44(m,2H),4.27-3.96(m,3H),3.74-3.63(m,2H),3.49(d,2H),3.27-3.06(m,1H),2.82-2.59(m,4H),1.16(d,3H)。 1 H NMR (400MHz, DMSO-d 6 )δ12.42(s,1H), 10.93(s,1H), 8.12(s,1H), 7.90(s,1H), 7.16(d,1H), 6.31- 6.20(m, 1H), 4.85-4.44(m, 2H), 4.27-3.96(m, 3H), 3.74-3.63(m, 2H), 3.49(d, 2H), 3.27-3.06(m, 1H), 2.82-2.59 (m, 4H), 1.16 (d, 3H).
实施例5：5-甲基-8-(3-((S)-1-(6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)吡咯烷-2-基)甲氧基)丙酰基)-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪[1,2-a]吡啶[3,2-e]吡嗪-6(6aH)-酮(化合物5)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)
5-Methyl-8-(3-(((S)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one5-Methyl-8-(3-(((S)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)propanoyl)-3 -(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one
Figure PCTCN2022088446-appb-000192
Figure PCTCN2022088446-appb-000192
第一步：[(2S)-吡咯烷-2-基]甲醇的盐酸盐(5b)First step: [(2S)-pyrrolidin-2-yl]methanol hydrochloride (5b)
[(2S)-pyrrolidin-2-yl]methanol hydrochloride[(2S)-pyrrolidin-2-yl]methanol hydrochloride
Figure PCTCN2022088446-appb-000193
Figure PCTCN2022088446-appb-000193
向(2S)-2-(羟甲基)吡咯烷-1-羧酸叔丁酯(5a)(14.50g,72.05mmol)的1,4-二氧六环(60mL)溶液中加入氯化氢的1,4-二氧六环溶液(60mL，4N)，室温反应16h，减压浓缩除去溶剂后得[(2S)-吡咯烷-2-基]甲醇的盐酸盐(5b)(9.91g,100％)。To a solution of (2S)-2-(hydroxymethyl)pyrrolidine-1-carboxylate tert-butyl ester (5a) (14.50 g, 72.05 mmol) in 1,4-dioxane (60 mL) was added hydrogen chloride in 1 ,4-dioxane solution (60mL, 4N), reacted at room temperature for 16h, concentrated under reduced pressure to remove the solvent to obtain [(2S)-pyrrolidin-2-yl]methanol hydrochloride (5b) (9.91g, 100 %).
LCMS m/z＝101.7[M+1] +。 LCMS m/z=101.7[M+1] + .
第二步：5-[(2S)-2-(羟甲基)吡咯烷-1-基]-2-[(4-甲氧基苯基)甲基]-4-(三氟甲基)-2,3-二氢哒嗪-3-酮(5c)Step 2: 5-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl) -2,3-Dihydropyridazin-3-one (5c)
5-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one5-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one
Figure PCTCN2022088446-appb-000194
Figure PCTCN2022088446-appb-000194
将5-氯-2-[(4-甲氧基苯基)甲基]-4-(三氟甲基)-2,3-二氢哒嗪-3-酮(17.66g,55.42mmol)，[(2S)-吡咯烷-2-基]甲醇的盐酸盐(5b)(9.91g,72.05mmol)，DIPEA(28.65g,221.68mmol)依次加入到乙腈(150mL)中，室温反应2h，反应结束后，加入乙酸乙酯(500mL)稀释反应液，然后用饱和食盐水(200mL x 3)洗涤反应液，无水硫酸钠干燥，抽滤，滤液减压浓缩得5-[(2S)-2-(羟甲基)吡咯烷-1-基]-2-[(4-甲氧基苯基)甲基]-4-(三氟甲基)-2,3-二氢哒嗪-3-酮(5c)(20.77g,98％)。5-Chloro-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one (17.66 g, 55.42 mmol), [(2S)-pyrrolidin-2-yl]methanol hydrochloride (5b) (9.91 g, 72.05 mmol), DIPEA (28.65 g, 221.68 mmol) were sequentially added to acetonitrile (150 mL), and reacted at room temperature for 2 h. After the end, ethyl acetate (500mL) was added to dilute the reaction solution, then the reaction solution was washed with saturated brine (200mL×3), dried over anhydrous sodium sulfate, suction filtered, and the filtrate was concentrated under reduced pressure to obtain 5-[(2S)-2 -(Hydroxymethyl)pyrrolidin-1-yl]-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-2,3-dihydropyridazine-3- Ketone (5c) (20.77 g, 98%).
LCMS m/z＝384.2[M+1] +。 LCMS m/z=384.2[M+1] + .
第三步：3-{[(2S)-1-(1-[(4-甲氧基苯基)甲基]-6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)吡咯烷-2-基]甲氧基}丙酸甲酯(5d)The third step: 3-{[(2S)-1-(1-[(4-methoxyphenyl)methyl]-6-oxo-5-(trifluoromethyl)-1,6-di Hydropyridazin-4-yl)pyrrolidin-2-yl]methoxy}propionic acid methyl ester (5d)
Methyl 3-{[(2S)-1-(1-[(4-methoxyphenyl)methyl]-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl]methoxy}propanoateMethyl 3-{[(2S)-1-(1-[(4-methoxyphenyl)methyl]-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl]methoxy }propanoate
Figure PCTCN2022088446-appb-000195
Figure PCTCN2022088446-appb-000195
室温下，向5-[(2S)-2-(羟甲基)吡咯烷-1-基]-2-[(4-甲氧基苯基)甲基]-4-(三氟甲基)-2,3-二氢哒嗪-3-酮(5c)(16.40g,42.78mmol)和丙烯酸甲酯(36.83g,427.80mmol)的乙腈(100mL)溶液中加入碳酸铯(15.33g,47.06mmol)。室温反应48h后，过滤，滤液减压浓缩得残留物，残留物用硅胶柱色谱分离提纯(石油醚：乙酸乙酯(V/V)＝1:1)得3-{[(2S)-1-(1-[(4-甲氧基苯基)甲基]-6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)吡咯烷-2-基]甲氧基}丙酸甲酯(5d)(12.65g,63％)。At room temperature, to 5-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl) -2,3-dihydropyridazin-3-one (5c) (16.40 g, 42.78 mmol) and methyl acrylate (36.83 g, 427.80 mmol) in acetonitrile (100 mL) was added cesium carbonate (15.33 g, 47.06 mmol) ). After 48 hours of reaction at room temperature, the filtrate was filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V/V)=1:1) to obtain 3-{[(2S)-1 -(1-[(4-Methoxyphenyl)methyl]-6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidine-2- Methyl]methoxy}propionate (5d) (12.65 g, 63%).
LCMS m/z＝470.2[M+1] +。 LCMS m/z=470.2[M+1] + .
第四步：3-{[(2S)-1-(6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)吡咯烷-2-基]甲氧基}丙酸甲酯(5e)The fourth step: 3-{[(2S)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl]methane Methyl oxy}propionate (5e)
Methyl 3-{[(2S)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl]methoxy}propanoateMethyl 3-{[(2S)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl]methoxy}propanoate
Figure PCTCN2022088446-appb-000196
Figure PCTCN2022088446-appb-000196
室温下，将3-{[(2S)-1-(1-[(4-甲氧基苯基)甲基]-6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)吡咯烷-2-基]甲氧基}丙酸甲酯(5d)(12.65g,26.95mmol)溶于三氟乙酸(100mL)中，然后加入三氟甲磺酸(5mL)，室温反应2h。减压浓缩除去反应溶剂得3-{[(2S)-1-(6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)吡咯烷-2-基]甲氧基}丙酸甲酯(5e)粗品，无需纯化，直接用于下一步反应。At room temperature, 3-{[(2S)-1-(1-[(4-methoxyphenyl)methyl]-6-oxo-5-(trifluoromethyl)-1,6-di Hydropyridazin-4-yl)pyrrolidin-2-yl]methoxy}propionic acid methyl ester (5d) (12.65 g, 26.95 mmol) was dissolved in trifluoroacetic acid (100 mL) followed by trifluoromethanesulfonic acid (5 mL), and reacted at room temperature for 2 h. Concentrate under reduced pressure to remove the reaction solvent to obtain 3-{[(2S)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidine-2- The crude methyl] methoxy}propionate (5e) was used in the next reaction without purification.
LCMS m/z＝350.0[M+1] +。 LCMS m/z=350.0[M+1] + .
第五步：3-{[(2S)-1-(6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)吡咯烷-2-基]甲氧基}丙酸(5f)The fifth step: 3-{[(2S)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl]methane Oxy}propionic acid (5f)
3-{[(2S)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl]methoxy}propanoic acid3-{[(2S)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl]methoxy}propanoic acid
Figure PCTCN2022088446-appb-000197
Figure PCTCN2022088446-appb-000197
将3-{[(2S)-1-(6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)吡咯烷-2-基]甲氧基}丙酸甲酯(5e)溶于甲醇(60mL)和水(60mL)的混合溶液中，用氢氧化锂一水合物调pH＝7～8，然后加入氢氧化锂一水合物(1.70g,40.41mmol)，室温反应16h。反应结束后，用2M的盐酸水溶液调pH＝5左右，过滤，滤液减压浓缩得残留物，残留物用硅胶柱色谱分离提纯(甲醇：二氯甲烷(V/V)＝1:15)得3-{[(2S)-1-(6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)吡咯烷-2-基]甲氧基}丙酸(5f)(4.1g,45.39％)。3-{[(2S)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl]methoxy} 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. After the reaction, adjust pH=5 with 2M aqueous hydrochloric acid solution, filter, and concentrate the filtrate under reduced pressure to obtain a residue, which is separated and purified by silica gel column chromatography (methanol:dichloromethane (V/V)=1:15) to obtain 3-{[(2S)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl]methoxy}propane Acid (5f) (4.1 g, 45.39%).
LCMS m/z＝336.2[M+1] +。 LCMS m/z=336.2[M+1] + .
第六步：叔丁基-5-甲基-6-氧代-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-8-羧酸酯(5g)The sixth step: 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)
Tert-butyl-(R)-5-methyl-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8-carboxylateTert-butyl-(R)-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
Figure PCTCN2022088446-appb-000198
Figure PCTCN2022088446-appb-000198
室温下，将叔丁基-(R)-6-氧代-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-8-羧酸酯(4d)(200mg,0.54mmol)溶于无水四氢呋喃(10mL)中，降温至0℃，缓慢加入氢化钠(60％,93mg,2.32mmol)。在0℃下搅拌10分钟后，加入碘甲烷(232mg,1.62mmol)，然后室温搅拌反应16小时。反应结束后，在冰水浴下，缓慢加入饱和氯化铵溶液淬灭反应，加入10mL水，乙酸乙酯萃取(15mL x 3)。合并有机相，有机相用饱和食盐水洗涤，无水硫酸钠干燥后过滤，滤液减压浓缩后得粗品。粗品经制备柱分离纯化(石油醚：乙酸乙酯(v/v)＝7:3)得叔丁基-5-甲基-6-氧代-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-8-羧酸酯(5g)(155mg,74％)。At room temperature, 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 (4d) (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. After the reaction, under an ice-water bath, saturated ammonium chloride solution was slowly added to quench the reaction, 10 mL of water was added, and ethyl acetate was extracted (15 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by a preparative column (petroleum ether:ethyl acetate (v/v)=7:3) to obtain 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, 74%) .
LCMS m/z＝331.1[M-55] +。 LCMS m/z=331.1 [M-55] + .
第七步：5-甲基-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪[1,2-a]吡啶[3,2-e]吡嗪-6(6aH)-酮(5h)的盐酸盐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
5-Methyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one hydrochloride5-Methyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one hydrochloride
Figure PCTCN2022088446-appb-000199
Figure PCTCN2022088446-appb-000199
室温下，将叔丁基-5-甲基-6-氧代-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-8-羧酸酯(5g)(155mg,0.40mmol)溶于1,4-二氧六环(5mL)溶液中，再加入氯化氢-1,4-二氧六环溶液(4.0M，10mL,40mmol)，室温反应4小时。反应结束后，减压浓缩除去溶剂后得5-甲基-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪[1,2-a]吡啶[3,2-e]吡嗪-6(6aH)-酮(5h)的盐酸盐(130mg,100％)。At room temperature, 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. After the reaction, the solvent was removed by concentration under reduced pressure to obtain 5-methyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazine[1,2-a]pyridine[3 ,2-e]pyrazin-6(6aH)-one (5h) hydrochloride salt (130 mg, 100%).
LCMS m/z＝287.1[M+1] +。 LCMS m/z=287.1[M+1] + .
第八步：5-甲基-8-(3-((S)-1-(6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)吡咯烷-2-基)甲氧基)丙酰基)-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪[1,2-a]吡啶[3,2-e]吡嗪-6(6aH)-酮(化合物5)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)
5-Methyl-8-(3-(((S)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one5-Methyl-8-(3-(((S)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)propanoyl)-3 -(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one
Figure PCTCN2022088446-appb-000200
Figure PCTCN2022088446-appb-000200
室温下，将3-{[(2S)-1-(6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)吡咯烷-2-基]甲氧基}丙酸(5f)(63mg,0.19mmol)和5-甲基-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪[1,2-a]吡啶[3,2-e]吡嗪-6(6aH)-酮(5h)的盐酸盐(62mg,0.19mmol)溶于DMF(5mL)中，向其中分别加入DIPEA(120mg,0.95mmol)和HATU(54mg,0.14mmol)然后室温搅拌反应3小时。反应结束后，反应液经Pre-HPLC纯化(仪器及制备柱：采用WATERS 2767制备液相，制备柱型号是Xselect C18，5μm，内径×长度＝19mm×150mm)。制备方法：反应液用0.45μm滤膜过滤，制备成样品液。流动相体系：乙腈/水(含0.05％氨水)。梯度洗脱方法：乙腈由5％梯度洗脱至50％(洗脱时间15min)。冻干后得到5-甲基-8-(3-((S)-1-(6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)吡咯烷-2-基)甲氧基)丙酰基)-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪[1,2-a]吡啶[3,2-e]吡嗪-6(6aH)-酮(化合物5)(25mg,22％)。At room temperature, 3-{[(2S)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl]methane Oxy}propionic acid (5f) (63 mg, 0.19 mmol) and 5-methyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazine[1,2-a ]pyridin[3,2-e]pyrazin-6(6aH)-one (5h) hydrochloride (62 mg, 0.19 mmol) was dissolved in DMF (5 mL), to which was added DIPEA (120 mg, 0.95 mmol) separately and HATU (54 mg, 0.14 mmol) and then stirred at room temperature for 3 hours. After the reaction, the reaction solution was purified by Pre-HPLC (instrument and preparative column: WATERS 2767 was used to prepare the liquid phase, the preparative column model was Xselect C18, 5 μm, inner diameter×length=19mm×150mm). Preparation method: The reaction solution was filtered with a 0.45 μm 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). Lyophilized to give 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) (25 mg, 22%).
LCMS m/z＝604.2[M+1] +。 LCMS m/z=604.2[M+1] + .
实施例6：5-甲基-8-(3-((S)-2-((6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基)丙氧基)丙酰基)-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪[1,2-a]吡啶[3,2-e]吡嗪-6(6aH)-酮(化合物6)Example 6: 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-pyrazine[1,2-a]pyridine[3,2-e]pyridine Azin-6(6aH)-one (Compound 6)
5-Methyl-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one5-Methyl-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl) -7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one
Figure PCTCN2022088446-appb-000201
Figure PCTCN2022088446-appb-000201
室温下，将3-[(2S)-2-[(6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基]丙氧基]丙酸(4j)(50mg,0.16mmol)和5-甲基-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪[1,2-a]吡啶[3,2-e]吡嗪-6(6aH)-酮(5h)的盐酸盐(50mg,0.16mmol)溶于DMF(5mL)中，向其中分别加入DIPEA(83mg,0.64mmol)和HATU(46mg,0.12mmol)然后室温搅拌反应3小时。反应结束 后，反应液经Pre-HPLC纯化(仪器及制备柱：采用WATERS 2767制备液相，制备柱型号是Xselect C18，5μm，内径×长度＝19mm×150mm)。制备方法：反应液用0.45μm滤膜过滤，制备成样品液。流动相体系：乙腈/水(含0.05％氨水)。梯度洗脱方法：乙腈由5％梯度洗脱至50％(洗脱时间15min)。冻干后得到5-甲基-8-(3-((S)-2-((6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基)丙氧基)丙酰基)-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪[1,2-a]吡啶[3,2-e]吡嗪-6(6aH)-酮(化合物6)(15mg,17％)。3-[(2S)-2-[(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino]propoxy]propionic acid at room temperature (4j) (50 mg, 0.16 mmol) and 5-methyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazine[1,2-a]pyridine[3, The hydrochloride salt of 2-e]pyrazin-6(6aH)-one (5h) (50 mg, 0.16 mmol) was dissolved in DMF (5 mL), to which was added DIPEA (83 mg, 0.64 mmol) and HATU (46 mg, 0.64 mmol, respectively). 0.12 mmol) and then the reaction was stirred at room temperature for 3 hours. After the reaction, the reaction solution was purified by Pre-HPLC (instrument and preparative column: WATERS 2767 was used to prepare the liquid phase, the preparative column model was Xselect C18, 5 μm, inner diameter×length=19mm×150mm). Preparation method: The reaction solution was filtered with a 0.45 μm 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). Lyophilized to give 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-pyrazine[1,2-a]pyridine[3,2-e]pyridine Azin-6(6aH)-one (Compound 6) (15 mg, 17%).
LCMS m/z＝578.2[M+1] +。 LCMS m/z=578.2[M+1] + .
实施例7：5-(((S)-1-(3-氧代-3-((R)-3-(三氟甲基)-6,7,7a,8,10,11-六氢-9H-吡嗪并[1,2-d]吡啶并[3,2-b][1,4]氧氮杂-9-基)丙氧基)丙-2-基)氨基)-4-(三氟甲基)哒嗪-3(2H)-酮(化合物7-1)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)
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)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one5-(((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)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one
5-(((S)-1-(3-氧代-3-((S)-3-(三氟甲基)-6,7,7a,8,10,11-六氢-9H-吡嗪并[1,2-d]吡啶并[3,2-b][1,4]氧氮杂-9-基)丙氧基)丙-2-基)氨基)-4-(三氟甲基)哒嗪-3(2H)-酮(化合物7-2)5-(((S)-1-(3-oxo-3-((S)-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 7-2)
5-(((S)-1-(3-oxo-3-((S)-3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazepin-9-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one5-(((S)-1-(3-oxo-3-((S)-3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2- d]pyrido[3,2-b][1,4]oxazepin-9-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one
Figure PCTCN2022088446-appb-000202
Figure PCTCN2022088446-appb-000202
化合物3经SFC on AD column纯化(仪器及制备柱：采用Waters 150mgm，制备柱型号是DAICEL CHIRALPAK AD(250mm×30mm,10μm))。制备方法：化合物3用乙醇溶解，并用0.45μm滤膜过滤，制备成样品液。流动相体系：A for CO 2 and B for EtOH(0.1％NH 3·H 2O)。梯度洗脱方法：30％phase B(流速：120mL/min；洗脱时间2.5min)，冻干后得到化合物7-1和化合物7-2。 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 μm)). Preparation method: Compound 3 was dissolved in ethanol, and filtered through a 0.45 μm 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.
分析方法(仪器及制备柱：高效液相色谱仪-正相色谱，制备柱型号是：CHIRALPAKAD-H(4.6×250mm，5um))流动相体系：正己烷-异丙醇(80:20)，1.0ml/min。Analysis method (instrument and preparative column: high performance liquid chromatography-normal phase chromatography, preparative column model: CHIRALPAKAD-H (4.6×250mm, 5um)) mobile phase system: n-hexane-isopropanol (80:20), 1.0ml/min.
保留时间T＝16.489min为实施例7-A(实施例7-A为化合物7-1和化合物7-2结构之一)。Retention time T=16.489min is Example 7-A (Example 7-A is one of the structures of compound 7-1 and compound 7-2).
LCMS m/z＝565.3[M+1] +。 LCMS m/z=565.3[M+1] + .
1H NMR(400MHz,CD 3OD)δ8.09-8.05(m,1H),7.94-7.90(m,1H),7.28-7.25(m,1H),4.38-4.25(m,2H),4.18-4.02(m,2H),3.97-3.45(m,10H),2.74-2.57(m,2H),2.22-2.08(m,1H),2.03-1.90(m,1H),1.27-1.18(m,3H)。 1 H NMR (400MHz, CD 3 OD) δ 8.09-8.05(m, 1H), 7.94-7.90(m, 1H), 7.28-7.25(m, 1H), 4.38-4.25(m, 2H), 4.18- 4.02(m, 2H), 3.97-3.45(m, 10H), 2.74-2.57(m, 2H), 2.22-2.08(m, 1H), 2.03-1.90(m, 1H), 1.27-1.18(m, 3H ).
保留时间T＝19.522min为实施例7-B(实施例7-B为化合物7-1和化合物7-2结构之一)。Retention time T=19.522 min is Example 7-B (Example 7-B is one of the structures of compound 7-1 and compound 7-2).
LCMS m/z＝565.3[M+1] +。 LCMS m/z=565.3[M+1] + .
1H NMR(400MHz,CD 3OD)δ8.10-8.06(m,1H),7.93(s,1H),7.28-7.24(m,1H),4.39-4.25(m,2H),4.20-4.01(m,2H),3.98-3.45(m,10H),2.74-2.58(m,2H),2.22-2.08(m,1H),2.03-1.90(m,1H),1.24(d,3H)。 1 H NMR (400MHz, CD 3 OD) δ 8.10-8.06 (m, 1H), 7.93 (s, 1H), 7.28-7.24 (m, 1H), 4.39-4.25 (m, 2H), 4.20-4.01 ( m, 2H), 3.98-3.45 (m, 10H), 2.74-2.58 (m, 2H), 2.22-2.08 (m, 1H), 2.03-1.90 (m, 1H), 1.24 (d, 3H).
实施例8：5-((S)-2-((3-氧代-3-((S)-3-(三氟甲基)-6a,7,9,10-四氢吡嗪[1,2-d]吡啶[3,2-b][1,4]恶嗪-8(6H)-基)丙氧基)甲基)吡咯烷-1-基)-4-(三氟甲基)吡嗪-3(2H)-酮(化合物8)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)
5-((S)-2-((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)methyl)pyrrolidin-1-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one5-((S)-2-((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)methyl)pyrrolidin-1-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one
Figure PCTCN2022088446-appb-000203
Figure PCTCN2022088446-appb-000203
化合物8以(S)-3-(三氟甲基)-6a,7,9,10-四氢吡嗪并[1,2-d]吡啶并[3,2-b][1,4]噁嗪-8(6H)-羧酸叔丁酯(2d)和3-{[(2S)-1-(6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)吡咯烷-2-基]甲氧基}丙酸(5f)为原料，参考实施例4的合成方法，得到5-((S)-2-((3-氧代-3-((S)-3-(三氟甲基)-6a,7,9,10-四氢吡嗪[1,2-d]吡啶[3,2-b][1,4]恶嗪-8(6H)-基)丙氧基)甲基)吡咯烷-1-基)-4-(三氟甲基)吡嗪-3(2H)-酮(化合物8)。Compound 8 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 (2d) and 3-{[(2S)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine -4-yl)pyrrolidin-2-yl]methoxy}propionic acid (5f) as raw material, referring to the synthetic method of Example 4, 5-((S)-2-((3-oxo-3 -((S)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazine[1,2-d]pyridine[3,2-b][1,4]oxazine- 8(6H)-yl)propoxy)methyl)pyrrolidin-1-yl)-4-(trifluoromethyl)pyrazin-3(2H)-one (compound 8).
LCMS m/z＝577.3[M+1] +。 LCMS m/z=577.3[M+1] + .
1H NMR(400MHz,DMSO-d 6)δ12.34(s,1H),8.08-8.06(m,1H),8.00(s,1H),7.28(d,1H),4.58-4.37(m,4H),4.06-3.92(m,2H),3.71-3.58(m,2H),3.56-3.36(m,4H),3.25-3.17(m,1H),3.16-2.38(m,5H),2.14-2.02(m,1H),1.95-1.81(m,1H),1.71-1.56(m,2H)。 1 H NMR (400MHz, DMSO-d 6 ) δ 12.34(s, 1H), 8.08-8.06(m, 1H), 8.00(s, 1H), 7.28(d, 1H), 4.58-4.37(m, 4H) ),4.06-3.92(m,2H),3.71-3.58(m,2H),3.56-3.36(m,4H),3.25-3.17(m,1H),3.16-2.38(m,5H),2.14-2.02 (m, 1H), 1.95-1.81 (m, 1H), 1.71-1.56 (m, 2H).
实施例9：(R)-8-(3-(((S)-1-(6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)吡咯烷-2-基)甲氧基)丙酰基)-3-(三氟甲基)-7,8,9,10-四氢-5H-哒嗪[1,2-a]哒嗪[3,2-e]哒嗪-6(6aH)-酮(化合物9)Example 9: (R)-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-pyridazine[1,2-a]pyridazine[3, 2-e]pyridazin-6(6aH)-one (Compound 9)
(R)-8-(3-(((S)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one(R)-8-(3-(((S)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)propanoyl)-3 -(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one
Figure PCTCN2022088446-appb-000204
Figure PCTCN2022088446-appb-000204
化合物9以(R)-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪[1,2-a]吡啶[3,2-e]吡嗪-6(6aH)-酮盐酸盐(4e)和3-{[(2S)-1-(6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)吡咯烷-2-基]甲氧基}丙酸(5f)为原料，参考实施例4的合成方法，得到(R)-8-(3-(((S)-1-(6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)吡咯烷-2-基)甲氧基)丙酰基)-3-(三氟甲基)-7,8,9,10-四氢-5H-哒嗪[1,2-a]哒嗪[3,2-e]哒嗪-6(6aH)-酮(化合物9)。Compound 9 was identified as (R)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazine[1,2-a]pyridine[3,2-e]pyrazine-6 (6aH)-keto hydrochloride (4e) and 3-{[(2S)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl) Using pyrrolidin-2-yl]methoxy}propionic acid (5f) as raw material, referring to the synthetic method of Example 4, (R)-8-(3-(((S)-1-(6-oxo) was obtained -5-(Trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)propionyl)-3-(trifluoromethyl)-7,8 ,9,10-Tetrahydro-5H-pyridazin[1,2-a]pyridazin[3,2-e]pyridazin-6(6aH)-one (compound 9).
LCMS m/z＝590.3[M+1] +。 LCMS m/z=590.3[M+1] + .
1H NMR(400MHz,DMSO-d 6)δ12.41-12.28(m,1H),11.01-10.86(m,1H),8.13(s,1H),8.01(s,1H),7.16(d,1H),4.86-4.42(m,3H),4.27-3.91(m,2H),3.73-3.58(m,2H),3.56-3.46(m,2H),3.45-3.37(m,1H),3.26-3.02(m,2H),2.83-2.54(m,4H),2.14-2.01(m,1H),1.94-1.82(m,1H),1.72-1.55(m,2H)。 1 H NMR (400MHz, DMSO-d 6 )δ12.41-12.28(m,1H), 11.01-10.86(m,1H), 8.13(s,1H), 8.01(s,1H), 7.16(d,1H) ),4.86-4.42(m,3H),4.27-3.91(m,2H),3.73-3.58(m,2H),3.56-3.46(m,2H),3.45-3.37(m,1H),3.26-3.02 (m, 2H), 2.83-2.54 (m, 4H), 2.14-2.01 (m, 1H), 1.94-1.82 (m, 1H), 1.72-1.55 (m, 2H).
实施例10：(S)-8-(3-((S)-2-((6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基)丙氧基)丙酰基)-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-6(6aH)-酮(化合物10)Example 10: (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)
(S)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one(S)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl) -7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one
Figure PCTCN2022088446-appb-000205
Figure PCTCN2022088446-appb-000205
Figure PCTCN2022088446-appb-000206
Figure PCTCN2022088446-appb-000206
第一步：(S)-4-(3-硝基-5-(三氟甲基)吡啶-2-基)哌嗪-1-甲酸叔丁酯-3-甲酸甲酯(10c)The first step: (S)-4-(3-nitro-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester-3-carboxylic acid methyl ester (10c)
1-(tert-butyl)3-methyl(S)-4-(3-nitro-5-(trifluoromethyl)pyridin-2-yl)piperazine-1,3-dicarboxylate1-(tert-butyl)3-methyl(S)-4-(3-nitro-5-(trifluoromethyl)pyridin-2-yl)piperazine-1,3-dicarboxylate
Figure PCTCN2022088446-appb-000207
Figure PCTCN2022088446-appb-000207
室温下，将2-氯-3-硝基-5-(三氟甲基)吡啶(1a)(2.00g,8.83mmol)加入到DMF(20mL)，加入(3S)-哌嗪-1-甲酸叔丁酯-3-甲酸甲酯(10b)(2.16g,8.83mmol)和DIPEA(3.42g,26.49mmol)。混合物在室温下搅拌过夜。加水(40mL)淬灭反应，乙酸乙酯(40mL x 2)萃取，合并有机相，有机相用饱和食盐水洗涤，无水硫酸钠干燥后过滤，滤液减压浓缩后得粗品。粗品经制备柱分离纯化(石油醚：乙酸乙酯(v/v)＝10:1)得(S)-4-(3-硝基-5-(三氟甲基)吡啶-2-基)哌嗪-1-甲酸叔丁酯-3-甲酸甲酯(10c)(3.50g,91％)。2-Chloro-3-nitro-5-(trifluoromethyl)pyridine (1a) (2.00 g, 8.83 mmol) was added to DMF (20 mL) at room temperature, (3S)-piperazine-1-carboxylic acid was added Methyl tert-butyl ester-3-carboxylate (10b) (2.16 g, 8.83 mmol) and DIPEA (3.42 g, 26.49 mmol). The mixture was stirred at room temperature overnight. Water (40 mL) was added to quench the reaction, ethyl acetate (40 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 crude product was separated and purified by a preparative column (petroleum ether:ethyl acetate (v/v)=10:1) to obtain (S)-4-(3-nitro-5-(trifluoromethyl)pyridin-2-yl) Methyl piperazine-1-carboxylate-3-carboxylate (10c) (3.50 g, 91%).
LCMS m/z＝379.1[M-55] +。 LCMS m/z = 379.1 [M-55] + .
第二步：(S)-6-氧代-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-8-甲酸叔丁酯(10d)The second step: (S)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyridine Iso[3,2-e]pyrazine-8-carboxylate tert-butyl ester (10d)
tert-butyl(S)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8-carboxylatetert-butyl(S)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine -8-carboxylate
Figure PCTCN2022088446-appb-000208
Figure PCTCN2022088446-appb-000208
将(S)-4-(3-硝基-5-(三氟甲基)吡啶-2-基)哌嗪-1-甲酸叔丁酯-3-甲酸甲酯(10c)(3.5g,8.06mmol)加入到MeOH(50ml)溶液中、加入Pd/C(0.35g)。混合物室温氢气氛围下反应16小时。过滤、滤液减压浓缩得粗品。粗品经制备柱分离纯化(石油醚：乙酸乙酯(v/ v)＝10:1)得到(S)-6-氧代-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪将-8-甲酸叔丁酯(10d)(1.3g,43％)。(S)-methyl 4-(3-nitro-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate-3-carboxylate (10c) (3.5g, 8.06 g) mmol) was added to a solution of MeOH (50 ml) and Pd/C (0.35 g) was added. The mixture was reacted under a hydrogen atmosphere at room temperature for 16 hours. The filtrate was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by a preparative column (petroleum ether:ethyl acetate (v/v)=10:1) to obtain (S)-6-oxo-3-(trifluoromethyl)-5,6,6a,7, 9,10-Hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8-carboxylate tert-butyl ester (10d) (1.3 g, 43%).
LCMS m/z＝317.1[M-55] +。 LCMS m/z = 317.1 [M-55] + .
第三步：((S)-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-6(6aH)-酮(10e)的盐酸盐The third step: ((S)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e] Pyrazin-6(6aH)-one (10e) hydrochloride
(S)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one hydrochloric acid(S)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one hydrochloric acid
Figure PCTCN2022088446-appb-000209
Figure PCTCN2022088446-appb-000209
将(S)-6-氧代-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-8-甲酸叔丁酯(10d)(240mg,0.64mmol)溶于HCl/二氧六环(5mL,4M,20mmol)中，混合物在室温下搅拌反应2h。减压浓缩除去溶剂，得粗品((S)-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪并[1,2-a]吡啶并[3,2-E]吡嗪-6(6aH)-酮(10e)的盐酸盐(180mg,90％)，直接用于下一步。(S)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3 ,2-e]pyrazine-8-carboxylic acid tert-butyl ester (10d) (240 mg, 0.64 mmol) was dissolved in HCl/dioxane (5 mL, 4 M, 20 mmol), and the mixture was stirred at room temperature for 2 h. Concentrate under reduced pressure to remove the solvent to obtain the crude product ((S)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3, 2-E] The hydrochloride salt of pyrazin-6(6aH)-one (10e) (180 mg, 90%) was used directly in the next step.
LCMS m/z＝273.1[M+1] +。 LCMS m/z=273.1[M+1] + .
第四步：(S)-8-(3-((S)-2-((6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基)丙氧基)丙酰基)-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-6(6aH)-酮(化合物10)The fourth step: (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)
(S)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one(S)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl) -7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one
Figure PCTCN2022088446-appb-000210
Figure PCTCN2022088446-appb-000210
将(((S)-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪并[1,2-a]吡啶并[3,2-E]吡嗪-6(6aH)-酮(10e)的盐酸盐(49mg,0.16mmol)溶于DMF(2mL)中，加入3-[(2S)-2-[(6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基]丙氧基]丙酸(4j)(50mg,0.16mmol)，HATU(46mg,0.12mmol)和DIPEA(103mg,0.8mmol)，混合物在20℃反应2h，加水(10mL)淬灭反应，乙酸乙酯(10mL x 2)萃取，合并有机相，有机相用饱和食盐水洗涤，无水硫酸钠干燥后 过滤，滤液减压浓缩后得粗品。粗品经Pre-HPLC纯化(仪器及制备柱：采用Waters 2767制备液相，制备柱型号是XBridge@Prep C 18，内径×长度＝19mm×250mm)。制备方法：粗品用DMF溶解，并用0.45μm滤膜过滤，制备成样品液。流动相体系：乙腈/水(含0.05％的氨水)。梯度洗脱方法：乙腈由10％梯度洗脱至55％(流速：12mL/min；洗脱时间17min)得到(S)-8-(3-((S)-2-((6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基)丙氧基)丙酰基)-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-6(6aH)-酮(化合物10)(10mg,11％)。 (((S)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-E]pyrazine The hydrochloride salt of -6(6aH)-one (10e) (49 mg, 0.16 mmol) was dissolved in DMF (2 mL) and 3-[(2S)-2-[(6-oxo-5-(trifluoro) was added Methyl)-1,6-dihydropyridazin-4-yl)amino]propoxy]propionic acid (4j) (50 mg, 0.16 mmol), HATU (46 mg, 0.12 mmol) and DIPEA (103 mg, 0.8 mmol) , the mixture was reacted at 20 °C for 2 h, water (10 mL) was added to quench the reaction, extracted with ethyl acetate (10 mL x 2), the organic phases were combined, the organic phases were washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure The crude product is obtained afterward. The crude product is purified by Pre-HPLC (instrument and preparative column: adopt Waters 2767 to prepare the liquid phase, the preparative column model is XBridge@Prep C 18 , inner diameter×length=19mm×250mm).Preparation method: the crude product is dissolved in DMF, And filter with a 0.45 μm 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%).
LCMS m/z＝564.3[M+1] +。 LCMS m/z=564.3[M+1] + .
1H NMR(400MHz,DMSO-d 6)δ12.43(s,1H),10.92(s,1H),8.12(s,1H),7.93-7.86(m,1H),7.16(d,1H),6.31-6.21(m,1H),4.87-4.41(m,2H),4.29-3.93(m,3H),3.76-3.60(m,2H),3.49(d,2H),3.26-3.04(m，1H),2.84-2.57(m,4H),1.16(d,3H)。 1 H NMR (400MHz, DMSO-d 6 )δ12.43(s,1H), 10.92(s,1H), 8.12(s,1H), 7.93-7.86(m,1H), 7.16(d,1H), 6.31-6.21(m, 1H), 4.87-4.41(m, 2H), 4.29-3.93(m, 3H), 3.76-3.60(m, 2H), 3.49(d, 2H), 3.26-3.04(m, 1H) ), 2.84-2.57 (m, 4H), 1.16 (d, 3H).
实施例11：(S)-5-甲基-8-(3-((S)-2-((6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基)丙氧基)丙酰基)-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-6(6aH)-酮(化合物11)Example 11: (S)-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]pyrido[3 ,2-e]pyrazin-6(6aH)-one (Compound 11)
(S)-5-methyl-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one(S)-5-methyl-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3 -(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one
Figure PCTCN2022088446-appb-000211
Figure PCTCN2022088446-appb-000211
第一步：(S)-5-甲基-6-氧代-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-8-甲酸叔丁酯(11a)The first step: (S)-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 tert-butyl ester (11a)
tert-butyl(S)-5-methyl-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8-carboxylatetert-butyl(S)-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
Figure PCTCN2022088446-appb-000212
Figure PCTCN2022088446-appb-000212
室温下，将(S)-6-氧代-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-8-甲酸叔丁酯(10d)(1.00g,2.69mmol)加入到DMF(10mL)，加入K 2CO 3(1.10g,8.07mmol)和CH 3I(1.91g,13.45mmol)。混合物在室温下搅拌过夜。加水(40mL)淬灭反应，乙酸乙酯(40mL x 2)萃取，合并有机相，有机相用饱和食盐水洗涤，无水硫酸钠干燥后过滤，滤液减压浓缩后得粗品。粗品经制备柱分离纯化(石油醚：乙酸乙酯(v/v)＝10:1)得(S)-5-甲基-6-氧代-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-8-甲酸叔丁酯(11a)(0.33g,32％)。 (S)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyridine at room temperature Hemo[3,2-e]pyrazine-8-carboxylate tert-butyl ester (10d) (1.00 g, 2.69 mmol) was added to DMF (10 mL), K2CO3 (1.10 g , 8.07 mmol) and CH3I were added (1.91 g, 13.45 mmol). The mixture was stirred at room temperature overnight. Water (40 mL) was added to quench the reaction, extracted with ethyl acetate (40 mL x 2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by a preparative column (petroleum ether:ethyl acetate (v/v)=10:1) to obtain (S)-5-methyl-6-oxo-3-(trifluoromethyl)-5,6 ,6a,7,9,10-Hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8-carboxylic acid tert-butyl ester (11a) (0.33 g, 32 %).
LCMS m/z＝331.1[M-55] +。 LCMS m/z=331.1 [M-55] + .
第二步：(S)-5-甲基-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-6(6aH)-酮(11b)的盐酸盐The second step: (S)-5-methyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3, 2-e]pyrazin-6(6aH)-one (11b) hydrochloride
(S)-5-methyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one hydrochloric acid(S)-5-methyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one hydrochloric acid
Figure PCTCN2022088446-appb-000213
Figure PCTCN2022088446-appb-000213
将(S)-5-甲基-6-氧代-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-8-甲酸叔丁酯(11a)(120mg,0.31mmol)溶于HCl/二氧六环(5mL,4M,20mmol)中，混合物在室温下搅拌反应2h。减压浓缩除去溶剂，得粗品(S)-5-甲基-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-6-(6aH)-酮(11b)的盐酸盐(100mg,99％)，直接用于下一步。(S)-5-methyl-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a ]pyrido[3,2-e]pyrazine-8-carboxylic acid tert-butyl ester (11a) (120 mg, 0.31 mmol) was dissolved in HCl/dioxane (5 mL, 4 M, 20 mmol) and the mixture was stirred at room temperature The reaction was carried out for 2h. Concentrate under reduced pressure to remove the solvent to obtain crude (S)-5-methyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyridine The hydrochloride salt of [3,2-e]pyrazin-6-(6aH)-one (11b) (100 mg, 99%) was used directly in the next step.
LCMS m/z＝287.2[M+1] +。 LCMS m/z=287.2[M+1] + .
第三步：(S)-5-甲基-8-(3-((S)-2-((6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基)丙氧基)丙酰基)-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-6(6aH)-酮(化合物11)The third step: (S)-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]pyrido[3 ,2-e]pyrazin-6(6aH)-one (Compound 11)
(S)-5-methyl-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one(S)-5-methyl-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3 -(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one
Figure PCTCN2022088446-appb-000214
Figure PCTCN2022088446-appb-000214
将(S)-5-甲基-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-6(6aH)-酮(11b)的盐酸盐(48mg,0.15mmol)溶于DMF(2mL)中，然后加入3-[(2S)-2-[(6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基]丙氧基]丙酸(4j)(46mg,0.15mmol)，HATU(57mg,0.15mmol)和DIPEA(58mg,0.45mmol)，混合物在20℃反应2h，加水(10mL)淬灭反应，乙酸乙酯(10mL x 2)萃取，合并有机相，有机相用饱和食盐水洗涤，无水硫酸钠干燥后过滤，滤液减压浓缩后得粗品。粗品经Pre-HPLC纯化(仪器及制备柱：采用Waters 2767制备液相，制备柱型号是XBridge@Prep C 18，内径×长度＝19mm×250mm)。制备方法：粗品用DMF溶解，并用0.45μm滤膜过滤，制备成样品液。流动相体系：乙腈/水(含0.05％的氨水)。梯度洗脱方法：乙腈由10％梯度洗脱至55％(流速：12mL/min；洗脱时间17min)得到((S)-5-甲基-8-(3-((S)-2-((6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基)丙氧基)丙酰基)-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-6-(6aH)-酮(化合物11)(10mg,11％)。 (S)-5-methyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e ]pyrazin-6(6aH)-one (11b) hydrochloride (48 mg, 0.15 mmol) was dissolved in DMF (2 mL), followed by the addition of 3-[(2S)-2-[(6-oxo-5 -(Trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino]propoxy]propionic acid (4j) (46 mg, 0.15 mmol), HATU (57 mg, 0.15 mmol) and DIPEA (58 mg) , 0.45 mmol), the mixture was reacted at 20 °C for 2 h, water (10 mL) was added to quench the reaction, extracted with ethyl acetate (10 mL x 2), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate and filtered, The filtrate was concentrated under reduced pressure to obtain crude product. The crude product was purified by Pre-HPLC (instrument and preparative column: Waters 2767 preparative liquid phase was used, the preparative column model was XBridge@Prep C 18 , inner diameter×length=19mm×250mm). Preparation method: the crude product is dissolved in DMF, and filtered with a 0.45 μm 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%) .
LCMS m/z＝578.3[M+1] +。 LCMS m/z=578.3[M+1] + .
实施例12：(S)-8-(3-(((S)-1-(6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)吡咯烷-2-基)甲氧基)丙酰基)-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-6(6aH)-酮(化合物12)的三氟乙酸盐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
(S)-8-(3-(((S)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one trifluoroacetate(S)-8-(3-(((S)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)propanoyl)-3 -(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one trifluoroacetate
Figure PCTCN2022088446-appb-000215
Figure PCTCN2022088446-appb-000215
Figure PCTCN2022088446-appb-000216
Figure PCTCN2022088446-appb-000216
将(((S)-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-6-(6aH)-酮(10e)的盐酸盐(49mg,0.16mmol)溶于DMF(2mL)中，然后加入(3-{[(2S)-1-(6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)吡咯烷-2-基]甲氧基}丙酸(5f)(54mg,0.16mmol)，HATU(61mg,0.16mmol)和DIPEA(103mg,0.8mmol)，混合物在20℃反应2h，加水(10mL)淬灭反应，乙酸乙酯(10mL x 2)萃取，合并有机相，有机相用饱和食盐水洗涤，无水硫酸钠干燥后过滤，滤液减压浓缩后得粗品。粗品经Pre-HPLC纯化(仪器及制备柱：采用Waters 2767制备液相，制备柱型号是Sunfire@Prep C 18，5μm，内径×长度＝19mm×250mm)。制备方法：粗品用DMF溶解，并用0.45μm滤膜过滤，制备成样品液。流动相体系：乙腈/水(含1％的三氟乙酸)。梯度洗脱方法：乙腈由5％梯度洗脱至50％(流速：15mL/min；洗脱时间15min)，冻干得到(S)-8-(3-(((S)-1-(6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)吡咯烷-2-基)甲氧基)丙酰基)-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-6(6aH)-酮(化合物12)的三氟乙酸盐(10mg,9％)。 (((S)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine The hydrochloride salt of -6-(6aH)-one (10e) (49 mg, 0.16 mmol) was dissolved in DMF (2 mL), followed by the addition of (3-{[(2S)-1-(6-oxo-5- (Trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl]methoxy}propionic acid (5f) (54 mg, 0.16 mmol), HATU (61 mg, 0.16 mmol) and DIPEA (103 mg, 0.8 mmol), the mixture was reacted at 20 °C for 2 h, water (10 mL) was added to quench the reaction, extracted with ethyl acetate (10 mL x 2), the organic phases were combined, the organic phases were washed with saturated brine, anhydrous sodium sulfate Filter after drying, and the filtrate is concentrated under reduced pressure to obtain a crude product. The crude product is purified by Pre-HPLC (instrument and preparative column: use Waters 2767 to prepare the liquid phase, and the preparative column model is Sunfire@Prep C 18 , 5 μm, inner diameter×length=19mm×250mm ). Preparation method: the crude product was dissolved in DMF, and filtered with a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile/water (containing 1% trifluoroacetic acid). Gradient elution method: acetonitrile was washed with a 5% gradient Removed to 50% (flow rate: 15mL/min; elution time 15min), lyophilized to obtain (S)-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-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one (compound 12) as trifluoroacetate salt (10 mg, 9%).
LCMS m/z＝590.3[M+1] +。 LCMS m/z=590.3[M+1] + .
1H NMR(400MHz,CD 3OD)δ8.16-8.07(m,2H),7.19(s,1H),5.10-4.50(m,3H),4.46-4.00(m,2H),3.87-3.58(m,4H),3.52-3.40(m,1H),3.39-3.34(m,1H),3.29-3.15(m,1H),2.91-2.60(m,4H),2.28-2.15(m,1H),2.02-1.90(m,1H),1.79-1.60(m,2H)。 1 H NMR (400MHz, CD 3 OD) δ 8.16-8.07(m, 2H), 7.19(s, 1H), 5.10-4.50(m, 3H), 4.46-4.00(m, 2H), 3.87-3.58( m, 4H), 3.52-3.40(m, 1H), 3.39-3.34(m, 1H), 3.29-3.15(m, 1H), 2.91-2.60(m, 4H), 2.28-2.15(m, 1H), 2.02-1.90 (m, 1H), 1.79-1.60 (m, 2H).
实施例13：(S)-5-甲基-8-(3-(((S)-1-(6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)吡咯烷-2-基)甲氧基)丙酰基)-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-6(6aH)-酮(化合物13)的三氟乙酸盐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
(S)-5-methyl-8-(3-(((S)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one trifluoroacetate(S)-5-methyl-8-(3-(((S)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy) propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one trifluoroacetate
Figure PCTCN2022088446-appb-000217
Figure PCTCN2022088446-appb-000217
Figure PCTCN2022088446-appb-000218
Figure PCTCN2022088446-appb-000218
将(S)-5-甲基-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-6-(6aH)-酮(11b)的盐酸盐(48mg,0.15mmol)溶于DMF(2mL)中，然后加入3-{[(2S)-1-(6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)吡咯烷-2-基]甲氧基}丙酸(5f)(50mg,0.15mmol),HATU(57mg,0.15mmol)和DIPEA(58mg,0.45mmol)，混合物在20℃反应2h，加水(10mL)淬灭反应，乙酸乙酯(10mL x 2)萃取，合并有机相，有机相用饱和食盐水洗涤，无水硫酸钠干燥后过滤，滤液减压浓缩后得粗品。粗品经Pre-HPLC纯化(仪器及制备柱：采用Waters 2767制备液相，制备柱型号是Sunfire@Prep C 18，5μm，内径×长度＝19mm×250mm)。制备方法：粗品用DMF溶解，并用0.45μm滤膜过滤，制备成样品液。流动相体系：乙腈/水(含1％的三氟乙酸)。梯度洗脱方法：乙腈由5％梯度洗脱至50％(流速：15mL/min；洗脱时间15min)，冻干得到(S)-5-甲基-8-(3-(((S)-1-(6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)吡咯烷-2-基)甲氧基)丙酰基)-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-6-(6aH)-酮(化合物13)的三氟乙酸盐(10mg,9％)。 (S)-5-methyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e ]pyrazin-6-(6aH)-one (11b) hydrochloride (48 mg, 0.15 mmol) was dissolved in DMF (2 mL), followed by the addition of 3-{[(2S)-1-(6-oxo- 5-(Trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl]methoxy}propionic acid (5f) (50 mg, 0.15 mmol), HATU (57 mg, 0.15 mmol) and DIPEA (58 mg, 0.45 mmol), the mixture was reacted at 20 °C for 2 h, water (10 mL) was added to quench the reaction, extracted with ethyl acetate (10 mL x 2), the organic phases were combined, the organic phase was washed with saturated brine, and anhydrous After drying over sodium sulfate, it was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by Pre-HPLC (instrument and preparative column: Waters 2767 preparative liquid phase was used, the preparative column model was Sunfire@Prep C 18 , 5 μm, inner diameter×length=19 mm×250 mm). Preparation method: the crude product is dissolved in DMF, and filtered with a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile/water (containing 1% trifluoroacetic acid). Gradient elution method: acetonitrile gradient from 5% to 50% (flow rate: 15 mL/min; elution time 15 min), lyophilized to obtain (S)-5-methyl-8-(3-((((S)) -1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)propionyl)-3-(tris Fluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6-(6aH)-one (Compound 13 ) in trifluoroacetate (10 mg, 9%).
LCMS m/z＝604.4[M+1] +。 LCMS m/z=604.4[M+1] + .
实施例14：5-((S)-2-((3-氧代-3-((R)-3-(三氟甲基)-6a,7,9,10-四氢吡嗪并[1,2-d]吡啶并[3,2-b][1,4]噁嗪-8(6H)-基)丙氧基)甲基)吡咯烷-1-基)-4-(三氟甲基)哒嗪-3(2H)-酮(化合物14)的三氟乙酸盐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
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-(trifluoromethyl)pyridazin-3(2H)-one trifluoroacetate5-((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-(trifluoromethyl)pyridazin-3(2H)-one trifluoroacetate
Figure PCTCN2022088446-appb-000219
Figure PCTCN2022088446-appb-000219
化合物14以(S)-3-(三氟甲基)-6a,7,9,10-四氢吡嗪并[1,2-d]吡啶并[3,2-b][1,4]噁嗪-8(6H)-甲酸叔丁酯(1d)和3-{[(2S)-1-(6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)吡咯烷-2-基]甲氧基}丙酸(5f)为起始原料参考实施例10的合成方法，得到5-((S)-2-((3-氧代-3-((R)-3-(三氟甲基)-6a,7,9,10-四氢吡嗪并[1,2-d]吡啶并[3,2-b][1,4]噁嗪-8(6H)-基)丙氧基)甲基)吡 咯烷-1-基)-4-(三氟甲基)哒嗪-3(2H)-酮(化合物14)的三氟乙酸盐。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. 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.
LCMS m/z＝577.4[M+1] +。 LCMS m/z=577.4[M+1] + .
1H NMR(400MHz,CD 3OD)δ8.11(d,1H),8.00(s,1H),7.18(s,1H),4.65-4.50(m,3H),4.43-4.33(m,1H),4.10-3.97(m,2H),3.82-3.59(m,4H),3.55-3.32(m,3H),3.29-2.51(m,5H),2.29-2.14(m,1H),2.01-1.91(m,1H),1.79-1.59(m,2H)。 1 H NMR (400MHz, CD 3 OD) δ 8.11 (d, 1H), 8.00 (s, 1H), 7.18 (s, 1H), 4.65-4.50 (m, 3H), 4.43-4.33 (m, 1H) ,4.10-3.97(m,2H),3.82-3.59(m,4H),3.55-3.32(m,3H),3.29-2.51(m,5H),2.29-2.14(m,1H),2.01-1.91( m, 1H), 1.79-1.59 (m, 2H).
实施例15：(5-((2S)-2-((3-氧代-3-(3-(三氟甲基)-6,7,7a,8,10,11六氢-9H-吡嗪并[1,2-d]吡啶并[3,2-b][1,4]氧氮杂-9-基)丙氧基)甲基)吡咯烷-1-基)-4-(三氟甲基)哒嗪-3(2H)-酮(化合物15)的三氟乙酸盐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
5-((2S)-2-((3-oxo-3-(3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazepin-9-yl)propoxy)methyl)pyrrolidin-1-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one trifluoroacetate5-((2S)-2-((3-oxo-3-(3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyrido[ 3,2-b][1,4]oxazepin-9-yl)propoxy)methyl)pyrrolidin-1-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one trifluoroacetate
Figure PCTCN2022088446-appb-000220
Figure PCTCN2022088446-appb-000220
化合物15以3-(三氟甲基)-6,7,7a,8,10,11-六氢-9H-吡嗪并[1,2-d]吡啶并[3,2-b][1,4]氧氮杂-9-甲酸叔丁酯(3d)和3-{[(2S)-1-(6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)吡咯烷-2-基]甲氧基}丙酸(5f)为起始原料参考实施例10的合成方法，得到(5-((2S)-2-((3-氧代-3-(3-(三氟甲基)-6,7,7a,8,10,11-六氢-9H-吡嗪并[1,2-d]吡啶并[3,2-b][1,4]氧氮杂-9-基)丙氧基)甲基)吡咯烷-1-基)-4-(三氟甲基)哒嗪-3(2H)-酮(化合物15)的三氟乙酸盐。Compound 15 was identified as 3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyrido[3,2-b][1 ,4] tert-butyl oxazepine-9-carboxylate (3d) and 3-{[(2S)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine -4-yl)pyrrolidin-2-yl]methoxy}propionic acid (5f) was used as the starting material, referring to the synthetic method of Example 10 to obtain (5-((2S)-2-((3-oxo) -3-(3-(Trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyrido[3,2-b][ Tris of 1,4]oxazepin-9-yl)propoxy)methyl)pyrrolidin-1-yl)-4-(trifluoromethyl)pyridazin-3(2H)-one (compound 15) Fluoroacetate.
LCMS m/z＝591.3[M+1] +。 LCMS m/z=591.3[M+1] + .
1H NMR(400MHz,CD 3OD)δ8.14-8.05(m,2H),7.43-7.30(m,1H),4.64-4.51(m,1H),4.44-4.27(m,2H),4.22-4.08(m,1H),3.96-3.75(m,5H),3.74-3.52(m,5H),3.46-3.34(m,2H),2.68-2.49(m,2H),2.28-2.09(m,2H),2.07-1.91(m,2H),1.79-1.58(m,2H)。 1 H NMR (400MHz, CD 3 OD) δ 8.14-8.05 (m, 2H), 7.43-7.30 (m, 1H), 4.64-4.51 (m, 1H), 4.44-4.27 (m, 2H), 4.22- 4.08(m,1H),3.96-3.75(m,5H),3.74-3.52(m,5H),3.46-3.34(m,2H),2.68-2.49(m,2H),2.28-2.09(m,2H ), 2.07-1.91 (m, 2H), 1.79-1.58 (m, 2H).
实施例16：9-(3-((S)-2-((6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基)丙氧基)丙酰基)-3-(三氟甲基)-7,7a,8,9,10,11-六氢吡嗪并[1,2-d]吡啶并[3,2-b][1,4]二氮杂-6(5H)-酮(化合物16)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)
9-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepin-6(5H)-one9-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl)-7,7a ,8,9,10,11-hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepin-6(5H)-one
Figure PCTCN2022088446-appb-000221
Figure PCTCN2022088446-appb-000221
第一步：3-(2-甲氧基-2-氧乙基)-4-(3-硝基-5-(三氟甲基)吡啶-2-基)哌嗪-1-羧酸叔丁酯(16c)The first step: 3-(2-methoxy-2-oxoethyl)-4-(3-nitro-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylic acid tertiary Butyl ester (16c)
Tert-butyl 3-(2-methoxy-2-oxoethyl)-4-(3-nitro-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylateTert-butyl 3-(2-methoxy-2-oxoethyl)-4-(3-nitro-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate
Figure PCTCN2022088446-appb-000222
Figure PCTCN2022088446-appb-000222
室温下，将2-氯-3-硝基-5-(三氟甲基)吡啶(16a)(1.50g,6.62mmol)加入到DMF(20mL)，加入3-(2-甲氧基-2-氧乙基)哌嗪-1-羧酸叔丁酯(3a)(2.16g,8.83mmol)和DIPEA(3.42g,26.49mmol)。混合物在室温下搅拌过夜。加水(40mL)淬灭反应，乙酸乙酯(40mL x 2)萃取，合并有机相，有机相用饱和食盐水洗涤(40mL x 3)，无水硫酸钠干燥后过滤，滤液减压浓缩后得粗品。粗品经制备柱分离纯化(石油醚：乙酸乙酯(v/v)＝8:1)得3-(2-甲氧基-2-氧乙基)-4-(3-硝基-5-(三氟甲基)吡啶-2-基)哌嗪-1-羧酸叔丁酯(16c)(2.4g,81％)。2-Chloro-3-nitro-5-(trifluoromethyl)pyridine (16a) (1.50 g, 6.62 mmol) was added to DMF (20 mL) at room temperature, 3-(2-methoxy-2 -Oxoethyl)piperazine-1-carboxylate tert-butyl ester (3a) (2.16 g, 8.83 mmol) and DIPEA (3.42 g, 26.49 mmol). The mixture was stirred at room temperature overnight. 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 crude product was separated and purified by a preparative column (petroleum ether:ethyl acetate (v/v)=8:1) to obtain 3-(2-methoxy-2-oxoethyl)-4-(3-nitro-5- (Trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate tert-butyl ester (16c) (2.4 g, 81%).
LCMS m/z＝393.1[M-55] +。 LCMS m/z = 393.1 [M-55] + .
第二步：4-(3-氨基-5-(三氟甲基)吡啶-2-基)-3-(2-甲氧基-2-氧乙基)哌嗪-1-羧酸叔丁酯(16d)The second step: 4-(3-amino-5-(trifluoromethyl)pyridin-2-yl)-3-(2-methoxy-2-oxyethyl)piperazine-1-carboxylic acid tert-butyl Esters (16d)
Tert-butyl 4-(3-amino-5-(trifluoromethyl)pyridin-2-yl)-3-(2-methoxy-2-oxoethyl)piperazine-1-carboxylatteTert-butyl 4-(3-amino-5-(trifluoromethyl)pyridin-2-yl)-3-(2-methoxy-2-oxoethyl)piperazine-1-carboxylatte
Figure PCTCN2022088446-appb-000223
Figure PCTCN2022088446-appb-000223
将3-(2-甲氧基-2-氧乙基)-4-(3-硝基-5-(三氟甲基)吡啶-2-基)哌嗪-1-羧酸叔丁酯(16c)(3.2g,7.14mmol)加入到MeOH(50ml)溶液中、加入Pd/C(0.35g)。混合物室温氢气氛围下反应16小时。过滤、滤液减压浓缩得粗品。粗品经制备柱分离纯化(石油醚：乙酸乙酯(v/v)＝5:1)得到4-(3-氨基-5-(三氟甲基)吡啶-2-基)-3-(2-甲氧基-2-氧乙基)哌嗪-1-羧酸叔丁酯(16d)(2.2g,75％)。3-(2-Methoxy-2-oxoethyl)-4-(3-nitro-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate tert-butyl ester ( 16c) (3.2 g, 7.14 mmol) was added to a solution of MeOH (50 ml) and Pd/C (0.35 g) was added. The mixture was reacted under a hydrogen atmosphere at room temperature for 16 hours. The filtrate was filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by preparative column (petroleum ether:ethyl acetate (v/v)=5:1) to obtain 4-(3-amino-5-(trifluoromethyl)pyridin-2-yl)-3-(2 -Methoxy-2-oxoethyl)piperazine-1-carboxylate tert-butyl ester (16d) (2.2 g, 75%).
LCMS m/z＝419.2[M+1] +。 LCMS m/z=419.2[M+1] + .
第三步：叔丁基-6-氧代-3-(三氟甲基)-6,7,7a,8,10,11六氢吡嗪并[1,2-d]吡啶并[3,2-b][1,4]二氮杂-9-(5H)-羧酸酯(16e)The third step: tert-butyl-6-oxo-3-(trifluoromethyl)-6,7,7a,8,10,11hexahydropyrazino[1,2-d]pyrido[3, 2-b][1,4]diaza-9-(5H)-carboxylate (16e)
Tert-butyl 6-oxo-3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepine-9(5H)-carboxylateTert-butyl 6-oxo-3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepine-9( 5H)-carboxylate
Figure PCTCN2022088446-appb-000224
Figure PCTCN2022088446-appb-000224
室温下，4-(3-氨基-5-(三氟甲基)吡啶-2-基)-3-(2-甲氧基-2-氧乙基)哌嗪-1-羧酸叔丁酯(16d)(2.20g,5.26mmol)加入到DMF(20mL)，加入碳酸钾(2.20g,15.94mmol)。混合物在室温下搅拌过夜。加水(40mL)淬灭反应，乙酸乙酯(40mL x 3)萃取，合并有机相，有机相用饱和食盐水洗涤(40mL x 3)，无水硫酸钠干燥后过滤，滤液减压浓缩后得粗品。粗品经制备柱分离纯化(石油醚：乙酸乙酯(v/v)＝4:1)得3-(三氟甲基)-7,7a,8,9,10,11-六氢吡嗪并[1,2-d]吡啶并[3,2-B][1,4]二氮杂-6(5H)-酮(16e)(1.3g,65％)。4-(3-Amino-5-(trifluoromethyl)pyridin-2-yl)-3-(2-methoxy-2-oxoethyl)piperazine-1-carboxylate tert-butyl ester at room temperature (16d) (2.20 g, 5.26 mmol) was added to DMF (20 mL) and potassium carbonate (2.20 g, 15.94 mmol) was added. The mixture was stirred at room temperature overnight. 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 . The crude product was separated and purified by preparative column (petroleum ether:ethyl acetate (v/v)=4:1) to obtain 3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydropyrazino [1,2-d]pyrido[3,2-B][1,4]diaza-6(5H)-one (16e) (1.3 g, 65%).
LCMS m/z＝331.1[M-55] +。 LCMS m/z=331.1 [M-55] + .
第四步：3-(三氟甲基)-7,7a,8,9,10,11-六氢吡嗪并[1,2-d]吡啶并[3,2-B][1,4]二氮杂-6(5H)-酮(16f)的盐酸盐The fourth step: 3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydropyrazino[1,2-d]pyrido[3,2-B][1,4 ] Diaza-6(5H)-one (16f) hydrochloride
3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepin-6(5H)-one hydrochloric acid3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepin-6(5H)-one hydrochloric acid
Figure PCTCN2022088446-appb-000225
Figure PCTCN2022088446-appb-000225
将(3-(三氟甲基)-7,7a,8,9,10,11-六氢吡嗪并[1,2-d]吡啶并[3,2-B][1,4]二氮杂-6(5H)-酮(16e)(170mg,0.44mmol)溶于HCl/二氧六环(5mL,4M,20mmol)中，混合物在室温下搅拌反应2h。减压浓缩除去溶剂，得粗品3-(三氟甲基)-7,7a,8,9,10,11-六氢吡嗪并[1,2-d]吡啶并[3,2-B][1,4]二氮杂-6(5H)-酮(16f)的盐酸盐(130mg,92％)，直接用于下一步。(3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydropyrazino[1,2-d]pyrido[3,2-B][1,4]di Aza-6(5H)-one (16e) (170 mg, 0.44 mmol) was dissolved in HCl/dioxane (5 mL, 4 M, 20 mmol), and the mixture was stirred at room temperature for 2 h. The solvent was removed by concentration under reduced pressure to obtain Crude 3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydropyrazino[1,2-d]pyrido[3,2-B][1,4]diazepine The hydrochloride salt of hetero-6(5H)-one (16f) (130 mg, 92%) was used directly in the next step.
LCMS m/z＝287.2[M+1] +。 LCMS m/z=287.2[M+1] + .
第五步:9-(3-((S)-2-((6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基)丙氧基)丙酰基)-3-(三氟甲基)-7,7a,8,9,10,11-六氢吡嗪并[1,2-d]吡啶并[3,2-b][1,4]二氮杂-6(5H)-酮(化合物16)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)
9-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepin-6(5H)-one9-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl)-7,7a ,8,9,10,11-hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepin-6(5H)-one
Figure PCTCN2022088446-appb-000226
Figure PCTCN2022088446-appb-000226
将3-(三氟甲基)-7,7a,8,9,10,11-六氢吡嗪并[1,2-d]吡啶并[3,2-B][1,4]二氮杂-6(5H)-酮(16f)的盐酸盐(55mg,0.17mmol)溶于DMF(2mL)中，加入3-[(2S)-2-[(6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基]丙氧基]丙酸(4j)(50mg,0.16mmol)，HATU(45.6mg,0.12mmol)和DIPEA(103.2mg,0.8mmol)，混合物在20℃反应2h。粗品经Pre-HPLC纯化(仪器及制备柱：采用Waters 2767制备液相，制备柱型号是Sunfire@Prep C 18，5μm，内径×长度＝19mm×250mm)。制备方法：反应液用0.45μm滤膜过滤，制备成样品液。流动相体系：乙腈/水(含0.1％氨水)。梯度洗脱方法：乙腈由5％梯度洗脱至50％(流速：15mL/min；洗脱时间15min)，冻干后得到9-(3-((S)-2-((6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基)丙氧基)丙酰基)-3-(三氟甲基)-7,7a,8,9,10,11-六氢吡嗪并[1,2-d]吡啶并[3,2-b][1,4]二氮杂-6(5H)-酮(化合物16)(10mg,11％)。 3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydropyrazino[1,2-d]pyrido[3,2-B][1,4]diazepine The hydrochloride salt of hetero-6(5H)-one (16f) (55 mg, 0.17 mmol) was dissolved in DMF (2 mL) and 3-[(2S)-2-[(6-oxo-5-(tris) was added. Fluoromethyl)-1,6-dihydropyridazin-4-yl)amino]propoxy]propionic acid (4j) (50 mg, 0.16 mmol), HATU (45.6 mg, 0.12 mmol) and DIPEA (103.2 mg, 0.8 mmol), the mixture was reacted at 20 °C for 2 h. The crude product was purified by Pre-HPLC (instrument and preparative column: Waters 2767 preparative liquid phase was used, the preparative column model was Sunfire@Prep C 18 , 5 μm, inner diameter×length=19 mm×250 mm). Preparation method: The reaction solution was filtered with a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile/water (containing 0.1% ammonia). Gradient elution method: acetonitrile gradient from 5% to 50% (flow rate: 15 mL/min; elution time 15 min), 9-(3-((S)-2-((6-oxo) after lyophilization -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) (10 mg, 11%) .
LCMS m/z＝578.3[M+1] +。 LCMS m/z=578.3[M+1] + .
1H NMR(400MHz,DMSO-d 6)δ12.43(s,1H),9.85(s,1H),8.40(s,1H),7.91(s,1H),7.49(d,1H),6.30-6.18(m,1H),4.41-4.30(m,1H),4.18-4.08(m,1H),3.97-3.83(m 2H),3.77-3.58(m,3H),3.49(d,2H),3.28-3.15(m,1H),3.12-2.90(m,2H),2.82-2.54(m,3H),2.46-2.34(m,1H),1.16(d,3H)。 1 H NMR (400MHz, DMSO-d 6 )δ12.43(s,1H), 9.85(s,1H), 8.40(s,1H), 7.91(s,1H), 7.49(d,1H), 6.30- 6.18(m, 1H), 4.41-4.30(m, 1H), 4.18-4.08(m, 1H), 3.97-3.83(m 2H), 3.77-3.58(m, 3H), 3.49(d, 2H), 3.28 -3.15 (m, 1H), 3.12-2.90 (m, 2H), 2.82-2.54 (m, 3H), 2.46-2.34 (m, 1H), 1.16 (d, 3H).
实施例17：9-(3-(((S)-1-(6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)吡咯烷-2-基)甲氧基)丙酰基)-3-(三氟甲基)-7,7a,8,9,10,11-六氢吡嗪并[1,2-d]吡啶并[3,2-b][1,4]二氮杂-6(5H)-酮(化合物17)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)
9-(3-(((S)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)propanoyl)-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepin-6(5H)-one9-(3-(((S)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)propanoyl)-3-(trifluoromethyl) -7,7a,8,9,10,11-hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepin-6(5H)-one
Figure PCTCN2022088446-appb-000227
Figure PCTCN2022088446-appb-000227
将(((S)-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-6-(6aH)-酮(16f)的盐酸盐(55mg,0.17mmol)溶于DMF(3mL)中，然后加入(S)-3-((1-(6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)吡咯烷-2-基)甲氧基)丙酸(5f)(55mg,0.17mmol)，HATU(61mg,0.16mmol)和DIPEA(105mg,0.8mmol)，混合物在20℃反应2h。反应液经Pre-HPLC纯化(仪器及制备柱：采用Waters 2767制备液相，制备柱型号是Sunfire@Prep C 1 8，5μm，内径×长度＝19mm×250mm)。制备方法：反应液用0.45μm滤膜过滤，制备成样品液。流动相体系：乙腈/水(含0.1％氨水)。梯度洗脱方法：乙腈由5％梯度洗脱至50％(流速：15mL/min；洗脱时间15min)，冻干后得到9-(3-(((S)-1-(6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)吡咯烷-2-基)甲氧基)丙酰基)-3-(三氟甲基)-7,7a,8,9,10,11-六氢吡嗪并[1,2-d]吡啶并[3,2-b][1,4]二氮杂-6(5H)-酮(化合物17)(12mg,12％)。 (((S)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine The hydrochloride salt of -6-(6aH)-one (16f) (55 mg, 0.17 mmol) was dissolved in DMF (3 mL), followed by the addition of (S)-3-((1-(6-oxo-5-( Trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)propionic acid (5f) (55 mg, 0.17 mmol), HATU (61 mg, 0.16 mmol) and DIPEA (105 mg, 0.8 mmol), the mixture was reacted at 20°C for 2 h. The reaction solution was purified by Pre-HPLC (instrument and preparative column: Waters 2767 was used to prepare the liquid phase, the preparative column model was Sunfire@Prep C 1 8 , 5 μm, inner diameter × Length=19mm×250mm). Preparation method: The reaction solution was filtered with a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile/water (containing 0.1% ammonia water). Gradient elution method: acetonitrile was eluted by a 5% gradient to 50% (flow rate: 15 mL/min; elution time 15 min), 9-(3-(((S)-1-(6-oxo-5-(trifluoromethyl)-1) was obtained after lyophilization, 6-Dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)propionyl)-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydropyridine Azino[1,2-d]pyrido[3,2-b][1,4]diaza-6(5H)-one (Compound 17) (12 mg, 12%).
LCMS m/z＝604.3[M+1] +。 LCMS m/z=604.3[M+1] + .
1H NMR(400MHz,DMSO-d 6)δ12.32(s,1H),9.85(s,1H),8.43-8.39(m,1H),8.00(s,1H),7.49(d,1H),4.59-4.46(m,1H),4.41-4.26(m,1H),3.95-3.84(m,2H),3.76-3.59(m,3H),3.57-3.45(m,2H),3.44-3.35(m,1H),3.25-2.55(m,7H),2.47-2.34 (m,1H),2.14-2.02(m,1H),1.96-1.84(m,1H),1.72-1.57(m,2H)。 1 H NMR (400MHz, DMSO-d 6 )δ12.32(s,1H), 9.85(s,1H), 8.43-8.39(m,1H), 8.00(s,1H), 7.49(d,1H), 4.59-4.46(m, 1H), 4.41-4.26(m, 1H), 3.95-3.84(m, 2H), 3.76-3.59(m, 3H), 3.57-3.45(m, 2H), 3.44-3.35(m , 1H), 3.25-2.55 (m, 7H), 2.47-2.34 (m, 1H), 2.14-2.02 (m, 1H), 1.96-1.84 (m, 1H), 1.72-1.57 (m, 2H).
实施例18：5-甲基-9-(3-((S)-2-((6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基)丙氧基)丙酰基)-3-(三氟甲基)-7,7a,8,9,10,11-六氢吡嗪并[1,2-d]吡啶并[3,2-b][1,4]二氮杂-6(5H)-酮(化合物18)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)
5-methyl-9-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepin-6(5H)-one5-methyl-9-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl) -7,7a,8,9,10,11-hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepin-6(5H)-one
Figure PCTCN2022088446-appb-000228
Figure PCTCN2022088446-appb-000228
第一步：叔丁基5-甲基-6-氧代-3-(三氟甲基)-6,7,7a,8,10,11-六氢吡嗪并[1,2-d]吡啶并[3,2-B][1,4]二氮杂9(5H)-羧酸叔丁酯(18a)The first step: tert-butyl 5-methyl-6-oxo-3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydropyrazino[1,2-d] Pyrido[3,2-B][1,4]diaza 9(5H)-carboxylate tert-butyl ester (18a)
Tert-butyl 5-methyl-6-oxo-3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepine-9(5H)-carboxylateTert-butyl 5-methyl-6-oxo-3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4] diazepine-9(5H)-carboxylate
Figure PCTCN2022088446-appb-000229
Figure PCTCN2022088446-appb-000229
室温下，叔丁基-6-氧代-3-(三氟甲基)-6,7,7a,8,10,11-六氢吡嗪并[1,2-d]吡啶并[3,2-B][1,4]二氮杂-9-(5H)-羧酸酯(16e)(300mg,0.78mmol)加入到DMF(5mL)，加入K 2CO 3(321mg,2.33mmol)和CH 3I(133gm,0.93mmol)。混合物在室温下搅拌过夜。加水(15mL)淬灭反应，乙酸乙酯(20mL x 3)萃取，合并有机相，有机相用饱和食盐水洗涤，无水硫酸钠干燥后过滤，滤液减压浓缩后得粗品。粗品经制备柱分离纯化(石油醚：乙酸乙 酯(v/v)＝5:1)得叔丁基5-甲基-6-氧代-3-(三氟甲基)-6,7,7a,8,10,11-六氢吡嗪并[1,2-d]吡啶并[3,2-b][1,4]二氮杂9(5H)-羧酸叔丁酯(18a)(150mg,50％)。 At room temperature, 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. Water (15 mL) was added to quench the reaction, extracted with ethyl acetate (20 mL x 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by a preparative column (petroleum ether:ethyl acetate (v/v)=5:1) to obtain tert-butyl 5-methyl-6-oxo-3-(trifluoromethyl)-6,7, 7a,8,10,11-Hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepine 9(5H)-carboxylate tert-butyl ester (18a) (150 mg, 50%).
LCMS m/z＝345.2[M-55] +。 LCMS m/z=345.2[M-55] + .
第二步：5-甲基-3-(三氟甲基)-7,7a,8,9,10,11-六氢吡嗪并[1,2-d]吡啶并[3,2-B][1,4]二氮杂-6(5H)-酮(18b)的盐酸盐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
5-methyl-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepin-6(5H)-one5-methyl-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepin-6(5H)- one
Figure PCTCN2022088446-appb-000230
Figure PCTCN2022088446-appb-000230
将叔丁基5-甲基-6-氧代-3-(三氟甲基)-6,7,7a,8,10,11-六氢吡嗪并[1,2-d]吡啶并[3,2-B][1,4]二氮杂9(5H)-羧酸叔丁酯(18a)(150mg,0.38mmol)溶于HCl/二氧六环(4mL,4M,16mmol)中，混合物在室温下搅拌反应2h。减压浓缩除去溶剂，得粗品5-甲基-3-(三氟甲基)-7,7a,8,9,10,11-六氢吡嗪并[1,2-d]吡啶并[3,2-B][1,4]二氮杂-6(5H)-酮的盐酸盐(18b)(110mg,87％)，直接用于下一步。tert-Butyl 5-methyl-6-oxo-3-(trifluoromethyl)-6,7,7a,8,10,11-hexahydropyrazino[1,2-d]pyrido[ 3,2-B][1,4]diazepine 9(5H)-carboxylate tert-butyl ester (18a) (150 mg, 0.38 mmol) was dissolved in HCl/dioxane (4 mL, 4 M, 16 mmol), The mixture was stirred at room temperature for 2 h. Concentrate under reduced pressure to remove the solvent to obtain crude 5-methyl-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydropyrazino[1,2-d]pyrido[3 ,2-B][1,4]diaza-6(5H)-one hydrochloride salt (18b) (110 mg, 87%) was used directly in the next step.
LCMS m/z＝301.2[M+1] +。 LCMS m/z=301.2[M+1] + .
第三步：5-甲基-9-(3-((S)-2-((6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基)丙氧基)丙酰基)-3-(三氟甲基)-7,7a,8,9,10,11-六氢吡嗪并[1,2-d]吡啶并[3,2-b][1,4]二氮杂-6(5H)-酮(化合物18)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)
5-methyl-9-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepin-6(5H)-one5-methyl-9-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl) -7,7a,8,9,10,11-hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepin-6(5H)-one
Figure PCTCN2022088446-appb-000231
Figure PCTCN2022088446-appb-000231
将5-甲基-3-(三氟甲基)-7,7a,8,9,10,11-六氢吡嗪并[1,2-d]吡啶并[3,2-b][1,4]二氮杂-6(5H)-酮(18b)的盐酸盐(55mg,0.15mmol)溶于DMF(3mL)中，然后加入3-[(2S)-2-[(6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基]丙氧基]丙酸(4j)(50mg,0.16mmol)，HATU(45.6mg,0.12mmol)和DIPEA(103.2mg,0.8mmol)，混合物在20℃反应2h。反应 液经Pre-HPLC纯化(仪器及制备柱：采用Waters 2767制备液相，制备柱型号是Sunfire@Prep C 18，5μm，内径×长度＝19mm×250mm)。制备方法：反应液用0.45μm滤膜过滤，制备成样品液。流动相体系：乙腈/水(含0.1％氨水)。梯度洗脱方法：乙腈由5％梯度洗脱至50％(流速：15mL/min；洗脱时间15min)，冻干后得到5-甲基-9-(3-((S)-2-((6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基)丙氧基)丙酰基)-3-(三氟甲基)-7,7a,8,9,10,11-六氢吡嗪并[1,2-d]吡啶并[3,2-b][1,4]二氮杂-6(5H)-酮(化合物18)(12mg,14％)。 5-Methyl-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydropyrazino[1,2-d]pyrido[3,2-b][1 ,4] The hydrochloride salt of diazepin-6(5H)-one (18b) (55 mg, 0.15 mmol) was dissolved in DMF (3 mL), followed by the addition of 3-[(2S)-2-[(6-oxo Sub-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino]propoxy]propionic acid (4j) (50 mg, 0.16 mmol), HATU (45.6 mg, 0.12 mmol) and DIPEA (103.2 mg, 0.8 mmol), the mixture was reacted at 20 °C for 2 h. The reaction solution was purified by Pre-HPLC (instrument and preparative column: Waters 2767 preparative liquid phase was used, the preparative column model was Sunfire@Prep C 18 , 5 μm, inner diameter×length=19mm×250mm). Preparation method: The reaction solution was filtered with a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile/water (containing 0.1% ammonia). Gradient elution method: acetonitrile gradient from 5% to 50% (flow rate: 15mL/min; elution time 15min), 5-methyl-9-(3-((S)-2-() after lyophilization (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) ( 12 mg, 14%).
LCMS m/z＝592.3[M+1] +。 LCMS m/z=592.3[M+1] + .
1H NMR(400MHz,DMSO-d 6)δ12.42(s,1H),8.49(s,1H),8.01(d,1H),7.91(s,1H),6.30-6.19(m,1H),4.46-4.29(m,1H),4.21-4.07(m,1H),4.00-3.85(m,1H),3.84-3.44(m,6H),3.24(s,3H),3.11-2.84(m,2H),2.80-2.54(m,4H),2.43-2.32(m,1H),1.16(d,3H)。 1 H NMR (400MHz, DMSO-d 6 )δ12.42(s,1H), 8.49(s,1H), 8.01(d,1H), 7.91(s,1H), 6.30-6.19(m,1H), 4.46-4.29(m, 1H), 4.21-4.07(m, 1H), 4.00-3.85(m, 1H), 3.84-3.44(m, 6H), 3.24(s, 3H), 3.11-2.84(m, 2H) ), 2.80-2.54 (m, 4H), 2.43-2.32 (m, 1H), 1.16 (d, 3H).
实施例19：5-甲基-9-(3-(((S)-1-(6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)吡咯烷-2-基)甲氧基)丙酰基)-3-(三氟甲基)-7,7a,8,9,10,11-六氢吡嗪并[1,2-d]吡啶并[3,2-b][1,4]二氮杂-6(5H)-酮(化合物19)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)
5-methyl-9-(3-(((S)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)propanoyl)-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepin-6(5H)-one5-methyl-9-(3-(((S)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)propanoyl)-3 -(trifluoromethyl)-7,7a,8,9,10,11-hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]diazepin-6(5H)-one
Figure PCTCN2022088446-appb-000232
Figure PCTCN2022088446-appb-000232
将5-甲基-3-(三氟甲基)-7,7a,8,9,10,11-六氢吡嗪并[1,2-d]吡啶并[3,2-B][1,4]二氮杂-6(5H)-酮(18b)的盐酸盐(55mg,0.15mmol)溶于DMF(3mL)中，然后加入(S)-3-((1-(6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)吡咯烷-2-基)甲氧基)丙酸(5f)(55mg,0.17mmol)，HATU(61mg,0.16mmol)和DIPEA(105mg,0.8mmol)，混合物在20℃反应2h。反应液经Pre-HPLC纯化(仪器及制备柱：采用Waters 2767制备液相，制备柱型号是Sunfire@Prep C 18，5μm，内径×长度＝19mm×250mm)。制备方法：反应液用0.45μm滤膜过滤，制备成样品液。流动相体系：乙腈/水(含0.1％氨水)。梯度洗脱方法：乙腈由5％梯度洗 脱至50％(流速：15mL/min；洗脱时间15min)，冻干得到(5-甲基-9-(3-(((S)-1-(6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)吡咯烷-2-基)甲氧基)丙酰基)-3-(三氟甲基)-7,7a,8,9,10,11-六氢吡嗪并[1,2-d]吡啶并[3,2-b][1,4]二氮杂-6(5H)-酮(化合物19)(14mg,15％)。 5-Methyl-3-(trifluoromethyl)-7,7a,8,9,10,11-hexahydropyrazino[1,2-d]pyrido[3,2-B][1 ,4] The hydrochloride salt of diazepin-6(5H)-one (18b) (55 mg, 0.15 mmol) was dissolved in DMF (3 mL), followed by the addition of (S)-3-((1-(6-oxo) Sub-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)propionic acid (5f) (55 mg, 0.17 mmol), HATU (61 mg) , 0.16 mmol) and DIPEA (105 mg, 0.8 mmol), the mixture was reacted at 20 °C for 2 h. The reaction solution was purified by Pre-HPLC (instrument and preparative column: Waters 2767 preparative liquid phase was used, the preparative column model was Sunfire@Prep C 18 , 5 μm, inner diameter×length=19mm×250mm). Preparation method: The reaction solution was filtered with a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile/water (containing 0.1% ammonia). Gradient elution method: acetonitrile gradient from 5% to 50% (flow rate: 15 mL/min; elution time 15 min), lyophilized to obtain (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) (14 mg, 15%).
LCMS m/z＝618.3[M+1] +。 LCMS m/z=618.3[M+1] + .
1H NMR(400MHz,DMSO-d 6)δ12.32(s,1H),8.52-8.47(m,1H),8.03-7.99(m,2H),4.57-4.48(m,1H),4.43-4.29(m,1H),3.95-3.85(m,1H),3.83-3.74(m,1H),3.68-3.47(m,5H),3.44-3.38(m,1H),3.26-2.69(m,8H),2.65-2.53(m,2H),2.46-2.35(m,1H),2.13-2.03(m,1H),1.94-1.85(m,1H),1.72-1.59(m,2H)。 1 H NMR (400MHz, DMSO-d 6 )δ12.32(s,1H), 8.52-8.47(m,1H), 8.03-7.99(m,2H), 4.57-4.48(m,1H), 4.43-4.29 (m,1H),3.95-3.85(m,1H),3.83-3.74(m,1H),3.68-3.47(m,5H),3.44-3.38(m,1H),3.26-2.69(m,8H) , 2.65-2.53(m, 2H), 2.46-2.35(m, 1H), 2.13-2.03(m, 1H), 1.94-1.85(m, 1H), 1.72-1.59(m, 2H).
实施例20：9-(3-((S)-2-((6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基)丙氧基)丙酰基)-7,7a,9,10,11-六氢-6H-吡嗪并[1,2-d]吡啶并[3,2-b][1,4]氧氮杂-3-甲腈(化合物20)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)
9-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-7,7a,8,9,10,11-hexahydro-6H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazepine-3-carbonitrile9-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-7,7a,8,9,10 ,11-hexahydro-6H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazepine-3-carbonitrile
Figure PCTCN2022088446-appb-000233
Figure PCTCN2022088446-appb-000233
第一步：(4-(5-氰基-3-硝基吡啶-2-基)-3-(2-羟乙基)哌嗪-1-甲酸叔丁酯(20b)The first step: (4-(5-cyano-3-nitropyridin-2-yl)-3-(2-hydroxyethyl)piperazine-1-carboxylic acid tert-butyl ester (20b)
Tert-butyl 4-(5-cyano-3-nitropyridin-2-yl)-3-(2-hydroxyethyl)piperazine-1-carboxylateTert-butyl 4-(5-cyano-3-nitropyridin-2-yl)-3-(2-hydroxyethyl)piperazine-1-carboxylate
Figure PCTCN2022088446-appb-000234
Figure PCTCN2022088446-appb-000234
室温下，将6-氯-5-硝基吡啶-3-甲腈(20a)(1g,5.45mmol)溶于DMF(10mL)中，加入3-(2-羟乙基)哌嗪-1-甲酸叔丁酯(3b)(1.26g,5.45mmol)和DIPEA(2.11g,16.35mmol)。混合物在室温下搅拌过夜。加水(20mL)淬灭反应，乙酸乙酯(20mL x 2)萃取，合并有机相，有机相用饱和食盐水洗涤，无水硫酸钠干燥后过滤，滤液减压浓缩后得粗品。粗品经制备柱分离纯化(石油醚：乙酸乙酯(v/v)＝10:1)得(4-(5-氰基-3-硝基吡啶-2-基)-3-(2-羟乙基)哌嗪-1-甲酸叔丁酯(20b)(1g,48％)。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 crude product was separated and purified by preparative column (petroleum ether:ethyl acetate (v/v)=10:1) to obtain (4-(5-cyano-3-nitropyridin-2-yl)-3-(2-hydroxyl) Ethyl)piperazine-1-carboxylate tert-butyl ester (20b) (1 g, 48%).
LCMS m/z＝322.2[M-55] +。 LCMS m/z=322.2[M-55] + .
第二步：3-氰基-6,7,7a,8,10,11-六氢-9H-吡嗪并[1,2-d]吡啶并[3,2-b][1,4]氧氮杂-9-甲酸叔丁酯(20c)Step 2: 3-cyano-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyrido[3,2-b][1,4] tert-Butyl oxazepine-9-carboxylate (20c)
Tert-butyl 3-cyano-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazepine-9-carboxylateTert-butyl 3-cyano-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazepine-9-carboxylate
Figure PCTCN2022088446-appb-000235
Figure PCTCN2022088446-appb-000235
将(4-(5-氰基-3-硝基吡啶-2-基)-3-(2-羟乙基)哌嗪-1-甲酸叔丁酯(20b)(0.5g,1.32mmol)溶于DMF(10ml)中、加入K 2CO 3(540mg,3.97mmol)。混合物100℃反应16小时。冷却至室温，加水(10mL)淬灭反应，乙酸乙酯(10mL x 2)萃取，合并有机相，有机相用饱和食盐水洗涤，无水硫酸钠干燥后过滤，滤液减压浓缩后得粗品。粗品经制备柱分离纯化(石油醚：乙酸乙酯(v/v)＝10:1)得到3-氰基-6,7,7a,8,10,11-六氢-9H-吡嗪并[1,2-d]吡啶并[3,2-b][1,4]氧氮杂-9-甲酸叔丁酯(20c)(0.23g,53％)。 (4-(5-Cyano-3-nitropyridin-2-yl)-3-(2-hydroxyethyl)piperazine-1-carboxylic acid tert-butyl ester (20b) (0.5 g, 1.32 mmol) was dissolved in In DMF (10 ml), K 2 CO 3 (540 mg, 3.97 mmol) was added. The mixture was reacted at 100° C. for 16 hours. Cooled to room temperature, water (10 mL) was added to quench the reaction, extracted with ethyl acetate (10 mL×2), and the organic phase, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by a preparative column (petroleum ether: ethyl acetate (v/v)=10:1) to obtain 3-cyano-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazepine- tert-Butyl 9-carboxylate (20c) (0.23 g, 53%).
LCMS m/z＝275.1[M-55] +。 LCMS m/z = 275.1 [M-55] + .
第三步：3-氰基-7,7a,8,9,10,11-六氢-6H-吡嗪并[1,2-d]吡啶并[3,2-b][1,4]氧氮杂(20d)的盐酸盐The third step: 3-cyano-7,7a,8,9,10,11-hexahydro-6H-pyrazino[1,2-d]pyrido[3,2-b][1,4] oxazepine (20d) hydrochloride
3-cyano-7,7a,8,9,10,11-hexahydro-6H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazepinehydrochloric acid3-cyano-7,7a,8,9,10,11-hexahydro-6H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazepinehydrochloric acid
Figure PCTCN2022088446-appb-000236
Figure PCTCN2022088446-appb-000236
将3-氰基-6,7,7a,8,10,11-六氢-9H-吡嗪并[1,2-d]吡啶并[3,2-b][1,4]氧氮杂-9-甲酸叔丁酯(20c)(120mg,0.36mmol)溶于HCl/二氧六环(5mL,4M,20mmol)中，混合物在室温下搅拌反应2h。减压浓缩除去溶剂，得3-氰基-7,7a,8,9,10,11-六氢-6H-吡嗪并[1,2-d]吡啶并[3,2-b][1,4]氧氮杂(20d)的盐酸盐(96mg,100％)，直接用于下一步。3-cyano-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazepine tert-Butyl-9-carboxylate (20c) (120 mg, 0.36 mmol) was dissolved in HCl/dioxane (5 mL, 4 M, 20 mmol), and the mixture was stirred at room temperature for 2 h. Concentrate under reduced pressure to remove the solvent to obtain 3-cyano-7,7a,8,9,10,11-hexahydro-6H-pyrazino[1,2-d]pyrido[3,2-b][1 ,4] The hydrochloride salt of oxazepine (20d) (96 mg, 100%) was used directly in the next step.
LCMS m/z＝231.2[M+1] +。 LCMS m/z=231.2[M+1] + .
第四步：9-(3-((S)-2-((6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基)丙氧基)丙酰基)-7,7a,9,10,11-六氢-6H-吡嗪并[1,2-d]吡啶并[3,2-b][1,4]氧氮杂-3-甲腈(化合物20)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)
9-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-7,7a,8,9,10,11-hexahydro-6H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazepine-3-carbonitrile9-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-7,7a,8,9,10 ,11-hexahydro-6H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazepine-3-carbonitrile
Figure PCTCN2022088446-appb-000237
Figure PCTCN2022088446-appb-000237
将(3-氰基-7,7a,8,9,10,11-六氢-6H-吡嗪并[1,2-d]吡啶并[3,2-b][1,4]氧氮杂(20d)的盐酸盐(48mg,0.18mmol)溶于DMF(2mL)中，加入3-[(2S)-2-[(6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基]丙氧基]丙酸(4j)(46mg,0.18mmol)，HATU(51mg,0.14mmol)和DIPEA(70mg,0.54mmol)，混合物在20℃反应2h，加水(10mL)淬灭反应，乙酸乙酯(10mL x 2)萃取，合并有机相，有机相用饱和食盐水洗涤，无水硫酸钠干燥后过滤，滤液减压浓缩后得粗品。粗品经Pre-HPLC纯化(仪器及制备柱：采用Waters 2767制备液相，制备柱型号是XBridge@Prep C 18，内径×长度＝19mm×250mm)。制备方法：粗品用DMF溶解，并用0.45μm滤膜过滤，制备成样品液。流动相体系：乙腈/水(含0.05％的氨水)。梯度洗脱方法：乙腈由10％梯度洗脱至55％(流速：12mL/min；洗脱时间17min)得到9-(3-((S)-2-((6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基)丙氧基)丙酰基)-7,7a,9,10,11-六氢-6H-吡嗪并[1,2-d]吡啶并[3,2-b][1,4]氧氮杂-3-甲腈(化合物20)(10mg,12％)。 (3-cyano-7,7a,8,9,10,11-hexahydro-6H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxonitrogen Hetero(20d) hydrochloride (48 mg, 0.18 mmol) was dissolved in DMF (2 mL), 3-[(2S)-2-[(6-oxo-5-(trifluoromethyl)-1 was added, 6-Dihydropyridazin-4-yl)amino]propoxy]propionic acid (4j) (46mg, 0.18mmol), HATU (51mg, 0.14mmol) and DIPEA (70mg, 0.54mmol), the mixture was reacted at 20°C 2h, add water (10mL) to quench the reaction, extract with ethyl acetate (10mL x 2), combine the organic phases, wash the organic phases with saturated brine, filter after drying over anhydrous sodium sulfate, and concentrate the filtrate under reduced pressure to obtain the crude product. Pre-HPLC purification (instrument and preparative column: use Waters 2767 to prepare the liquid phase, the preparative column model is XBridge@Prep C 18 , inner diameter×length=19mm×250mm).Preparation method: The crude product is dissolved in DMF and filtered with a 0.45 μm filter membrane. , prepared into 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; elution time 17min) to obtain 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-carbonitrile (Compound 20 ) (10 mg, 12%).
LCMS m/z＝522.2[M+1] +。 LCMS m/z=522.2[M+1] + .
1H NMR(400MHz,CD 3OD)δ8.14-8.11(m,1H),7.95-7.90(m,1H),7.30-7.27(m,1H),4.39-4.08(m,4H),4.01-3.44(m,10H),2.70-2.59(m,2H),2.22-2.07(m,1H),2.04-1.91(m,1H),1.28-1.18(m,3H)。 1 H NMR (400 MHz, CD 3 OD) δ 8.14-8.11 (m, 1H), 7.95-7.90 (m, 1H), 7.30-7.27 (m, 1H), 4.39-4.08 (m, 4H), 4.01- 3.44 (m, 10H), 2.70-2.59 (m, 2H), 2.22-2.07 (m, 1H), 2.04-1.91 (m, 1H), 1.28-1.18 (m, 3H).
实施例21：9-(3-(((S)-1-(6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)吡咯烷-2-基)甲氧基)丙酰基)-7,7a,8,9,10,11-六氢-6H-吡嗪并[1,2-d]吡啶并[3,2-b][1,4]氧氮杂-3-甲腈(化合物21)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)
9-(3-(((S)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)propanoyl)-7,7a,8,9,10,11-hexahydro-6H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazepine-3-carbonitrile9-(3-(((S)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)propanoyl)-7,7a,8 ,9,10,11-hexahydro-6H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxazepine-3-carbonitrile
Figure PCTCN2022088446-appb-000238
Figure PCTCN2022088446-appb-000238
Figure PCTCN2022088446-appb-000239
Figure PCTCN2022088446-appb-000239
将(3-氰基-7,7a,8,9,10,11-六氢-6H-吡嗪并[1,2-d]吡啶并[3,2-b][1,4]氧氮杂(20d)的盐酸盐(48mg,0.18mmol)溶于DMF(2mL)中，然后加入3-{[(2S)-1-(6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)吡咯烷-2-基]甲氧基}丙酸(5f)(60mg,0.18mmol)，HATU(68mg,0.18mmol)和DIPEA(70mg,0.54mmol)，混合物在20℃反应2h，加水(10mL)淬灭反应，乙酸乙酯(10mL x 2)萃取，合并有机相，有机相用饱和食盐水洗涤，无水硫酸钠干燥后过滤，滤液减压浓缩后得粗品。粗品经Pre-HPLC纯化(仪器及制备柱：采用Waters 2767制备液相，制备柱型号是XBridge@Prep C 18，内径×长度＝19mm×250mm)。制备方法：粗品用DMF溶解，并用0.45μm滤膜过滤，制备成样品液。流动相体系：乙腈/水(含0.05％的氨水)。梯度洗脱方法：乙腈由10％梯度洗脱至55％(流速：12mL/min；洗脱时间17min)得到9-(3-(((S)-1-(6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)吡咯烷-2-基)甲氧基)丙酰基)-7,7a,8,9,10,11-六氢-6H-吡嗪并[1,2-d]吡啶并[3,2-b][1,4]氧氮杂-3-甲腈(化合物21)(10mg,10％)。 (3-cyano-7,7a,8,9,10,11-hexahydro-6H-pyrazino[1,2-d]pyrido[3,2-b][1,4]oxonitrogen The hydrochloride salt of hetero(20d) (48 mg, 0.18 mmol) was dissolved in DMF (2 mL), followed by the addition of 3-{[(2S)-1-(6-oxo-5-(trifluoromethyl)-1 ,6-dihydropyridazin-4-yl)pyrrolidin-2-yl]methoxy}propionic acid (5f) (60 mg, 0.18 mmol), HATU (68 mg, 0.18 mmol) and DIPEA (70 mg, 0.54 mmol) , the mixture was reacted at 20 °C for 2 h, water (10 mL) was added to quench the reaction, extracted with ethyl acetate (10 mL x 2), the organic phases were combined, the organic phases were washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure The crude product is obtained afterward. The crude product is purified by Pre-HPLC (instrument and preparative column: adopt Waters 2767 to prepare the liquid phase, the preparative column model is XBridge@Prep C 18 , inner diameter×length=19mm×250mm).Preparation method: the crude product is dissolved in DMF, And filter with a 0.45 μm 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 removal time 17min) to obtain 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) (10 mg, 10%).
LCMS m/z＝548.2[M+1] +。 LCMS m/z=548.2[M+1] + .
1H NMR(400MHz,CD 3OD)δ8.15-8.12(m,1H),8.11-8.09(m,1H),7.30(d,1H),4.61-4.50(m,1H),4.41-4.32(m,1H),4.31-4.23(m,1H),4.22-4.13(m,1H),4.02-3.47(m,10H),3.46-3.32(m,2H),2.65-2.49(m,2H),2.26-2.08(m,2H),2.04-1.89(m,2H),1.79-1.59(m,2H)。 1 H NMR (400MHz, CD 3 OD) δ 8.15-8.12 (m, 1H), 8.11-8.09 (m, 1H), 7.30 (d, 1H), 4.61-4.50 (m, 1H), 4.41-4.32 ( m,1H),4.31-4.23(m,1H),4.22-4.13(m,1H),4.02-3.47(m,10H),3.46-3.32(m,2H),2.65-2.49(m,2H), 2.26-2.08 (m, 2H), 2.04-1.89 (m, 2H), 1.79-1.59 (m, 2H).
实施例22：(R)-5-甲基-8-(3-((S)-2-((6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基)丙氧基)丙酰基)-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪并[1,2-a]吡啶[3,2-e]吡嗪-6(6aH)-酮(化合物22)Example 22: (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)
(R)-5-Methyl-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one(R)-5-Methyl-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3 -(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one
Figure PCTCN2022088446-appb-000240
Figure PCTCN2022088446-appb-000240
Figure PCTCN2022088446-appb-000241
Figure PCTCN2022088446-appb-000241
第一步：叔丁基-(R)-5-甲基-6-氧代-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡嗪并[1,2-a]吡啶[3,2-e]吡嗪-8-羧酸酯(22a)The first step: tert-butyl-(R)-5-methyl-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazine Ipo[1,2-a]pyridine[3,2-e]pyrazine-8-carboxylate (22a)
Tert-butyl-(R)-5-methyl-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8-carboxylateTert-butyl-(R)-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
Figure PCTCN2022088446-appb-000242
Figure PCTCN2022088446-appb-000242
室温下，将叔丁基-(R)-6-氧代-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡嗪并[1,2-a]吡啶[3,2-e]吡嗪-8-羧酸酯(4d)(16.0g,43.0mmol)溶于DMF(150mL)中，然后加入碳酸钾(17.82g,128.9mmol)、碘甲烷(18.43g,128.9mmol)，室温反应16小时。反应结束后，加入300mL水，乙酸乙酯萃取(300mL x 3)。合并有机相，有机相用饱和食盐水洗涤，无水硫酸钠干燥后过滤，滤液减压浓缩后得粗品。粗品经制备柱分离纯化(石油醚：乙酸乙酯(v/v)＝7:3)得叔丁基-(R)-5-甲基-6-氧代-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡嗪并[1,2-a]吡啶[3,2-e]吡嗪-8-羧酸酯(22a)(12.5g,75％)。At room temperature, 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 (4d) (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 organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by preparative column (petroleum ether:ethyl acetate (v/v)=7:3) to obtain tert-butyl-(R)-5-methyl-6-oxo-3-(trifluoromethyl) -5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyridine[3,2-e]pyrazine-8-carboxylate (22a) (12.5 g , 75%).
LCMS m/z＝331.1[M-55] +。 LCMS m/z=331.1 [M-55] + .
第二步：(R)-5-甲基-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪并[1,2-a]吡啶[3,2-e]吡嗪-6(6aH)-酮(22b)的盐酸盐The second step: (R)-5-methyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyridine[3,2 -e] The hydrochloride salt of pyrazin-6(6aH)-one (22b)
(R)-5-Methyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one hydrochloride(R)-5-Methyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one hydrochloride
Figure PCTCN2022088446-appb-000243
Figure PCTCN2022088446-appb-000243
室温下，将叔丁基-(R)-5-甲基-6-氧代-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡嗪并[1,2-a]吡啶[3,2-e]吡嗪-8-羧酸酯(22a)(12.5g,32.4mmol)溶于1,4-二氧六环(50mL)中，再加入氯化氢-1,4-二氧六环溶液(4.0M,150mL,600mmol)，室温反应16小时。反应结束后，减压浓缩除去溶剂后得(R)-5-甲基-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪并[1, 2-a]吡啶[3,2-e]吡嗪-6(6aH)-酮(22b)的盐酸盐(10.3g,87％)。At room temperature, tert-butyl-(R)-5-methyl-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazine Iso[1,2-a]pyridine[3,2-e]pyrazine-8-carboxylate (22a) (12.5 g, 32.4 mmol) was dissolved in 1,4-dioxane (50 mL), followed by Hydrogen chloride-1,4-dioxane solution (4.0 M, 150 mL, 600 mmol) was added, and the reaction was carried out at room temperature for 16 hours. After the reaction, the solvent was removed by concentration under reduced pressure to obtain (R)-5-methyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2- a] Pyridin[3,2-e]pyrazin-6(6aH)-one (22b) hydrochloride salt (10.3 g, 87%).
LCMS m/z＝287.1[M+1] +。 LCMS m/z=287.1[M+1] + .
第三步：(R)-5-甲基-8-(3-((S)-2-((6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基)丙氧基)丙酰基)-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪并[1,2-a]吡啶[3,2-e]吡嗪-6(6aH)-酮(化合物22)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)
(R)-5-Methyl-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one(R)-5-Methyl-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3 -(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one
Figure PCTCN2022088446-appb-000244
Figure PCTCN2022088446-appb-000244
室温下，将3-[(2S)-2-[(6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基]丙氧基]丙酸(4j)(8.5g,27.56mmol)和(R)-5-甲基-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪并[1,2-a]吡啶[3,2-e]吡嗪-6(6aH)-酮(22b)的盐酸盐(10.0g,27.84mmol)溶于DMF(100mL)中，向其中分别加入DIPEA(18.0g,139.2mmol)和HATU(10.6g,27.84mmol)。室温反应3小时，反应结束后，加入200mL水，乙酸乙酯萃取(250mL x 3)。合并有机相，有机相用饱和食盐水洗涤，无水硫酸钠干燥后过滤，滤液减压浓缩后得粗品。粗品经制备柱分离纯化(二氯甲烷：甲醇(v/v)＝95:5)得(R)-5-甲基-8-(3-((S)-2-((6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基)丙氧基)丙酰基)-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪并[1,2-a]吡啶[3,2-e]吡嗪-6(6aH)-酮(化合物22)(14.0g,87％)。3-[(2S)-2-[(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino]propoxy]propionic acid at room temperature (4j) (8.5 g, 27.56 mmol) and (R)-5-methyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2- a] The hydrochloride salt of pyrid[3,2-e]pyrazin-6(6aH)-one (22b) (10.0 g, 27.84 mmol) was dissolved in DMF (100 mL), to which was added DIPEA (18.0 g, 139.2 mmol) and HATU (10.6 g, 27.84 mmol). The reaction was carried out at room temperature for 3 hours. After the reaction was completed, 200 mL of water was added, followed by extraction with ethyl acetate (250 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by a preparative column (dichloromethane:methanol (v/v)=95:5) to obtain (R)-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]pyridin[3,2-e]pyrazin-6(6aH)-one (Compound 22) (14.0 g, 87%).
LCMS m/z＝578.2[M+1] +。 LCMS m/z=578.2[M+1] + .
实施例23：5-甲基-8-(3-((S)-2-((6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基)丙氧基)丙酰基)-3-(三氟甲基)-7,8,9,10-四氢-5H-二吡嗪[1,2-a:2',3'-e]吡嗪-6(6aH)-酮(化合物23)Example 23: 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)
5-methyl-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-dipyrazino[1,2-a:2',3'-e]pyrazin-6(6aH)-one5-methyl-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl) -7,8,9,10-tetrahydro-5H-dipyrazino[1,2-a:2',3'-e]pyrazin-6(6aH)-one
Figure PCTCN2022088446-appb-000245
Figure PCTCN2022088446-appb-000245
Figure PCTCN2022088446-appb-000246
Figure PCTCN2022088446-appb-000246
第一步：1-叔丁基3-甲基(3R)-4-(5-(三氟甲基)吡嗪-2-基)哌嗪-1,3-二羧酸酯(23b)The first step: 1-tert-butyl 3-methyl (3R)-4-(5-(trifluoromethyl)pyrazin-2-yl)piperazine-1,3-dicarboxylate (23b)
1-tert-butyl 3-methyl(3R)-4-(5-(trifluoromethyl)pyrazin-2-yl)piperazine-1,3-dicarboxylate1-tert-butyl 3-methyl(3R)-4-(5-(trifluoromethyl)pyrazin-2-yl)piperazine-1,3-dicarboxylate
Figure PCTCN2022088446-appb-000247
Figure PCTCN2022088446-appb-000247
将2-氯-5-(三氟甲基)吡嗪(23a)(1.00g,5.48mmol)，1-(叔丁基)3-甲基(R)-哌嗪-1,3-二羧酸酯(2.01g,8.22mmol)，DIPEA(2.12g,16.44mmol)依次加入到二甲亚砜(15mL)中，100℃反应16h，反应结束后，冷却至室温，将反应液倒入到水(150mL)中，乙酸乙酯(30mL x 3)萃取，合并有机相，有机相用饱和食盐水(30mL x3)反洗，无水硫酸钠干燥，抽滤，滤液减压浓缩得残留物。残留物用硅胶柱色谱分离提纯(石油醚：乙酸乙酯(V/V)＝2:1)得到1-叔丁基3-甲基(3R)-4-(5-(三氟甲基)吡嗪-2-基)哌嗪-1,3-二羧酸酯(23b)(900mg,42％)。2-Chloro-5-(trifluoromethyl)pyrazine (23a) (1.00 g, 5.48 mmol), 1-(tert-butyl)3-methyl(R)-piperazine-1,3-dicarboxylate Acetate (2.01g, 8.22mmol), DIPEA (2.12g, 16.44mmol) were added to dimethyl sulfoxide (15mL) in turn, reacted at 100°C for 16h, after the reaction was completed, cooled to room temperature, and the reaction solution was poured into water (150 mL), extract with ethyl acetate (30 mL×3), combine the organic phases, backwash the organic phase with saturated brine (30 mL×3), dry over anhydrous sodium sulfate, filter with suction, and concentrate the filtrate under reduced pressure to obtain a residue. The residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V/V)=2:1) to obtain 1-tert-butyl 3-methyl(3R)-4-(5-(trifluoromethyl)) Pyrazin-2-yl)piperazine-1,3-dicarboxylate (23b) (900 mg, 42%).
LCMS m/z＝335.0[M-55] +。 LCMS m/z = 335.0 [M-55] + .
第二步：1-叔丁基3-甲基(3R)-4-(3-氯-5-(三氟甲基)吡嗪-2-基)哌嗪-1,3-二羧酸酯(23c)The second step: 1-tert-butyl 3-methyl(3R)-4-(3-chloro-5-(trifluoromethyl)pyrazin-2-yl)piperazine-1,3-dicarboxylate (23c)
1-tert-butyl 3-methyl(3R)-4-(3-chloro-5-(trifluoromethyl)pyrazin-2-yl)piperazine-1,3-dicarboxylate1-tert-butyl 3-methyl(3R)-4-(3-chloro-5-(trifluoromethyl)pyrazin-2-yl)piperazine-1,3-dicarboxylate
Figure PCTCN2022088446-appb-000248
Figure PCTCN2022088446-appb-000248
向1-叔丁基3-甲基(3R)-4-(5-(三氟甲基)吡嗪-2-基)哌嗪-1,3-二羧酸酯(23b)(500mg,1.28mmol)的DMF(5mL)溶液中加入N-氯代丁二酰亚胺(188mg,1.41mmol)，室温反应16h，反应结束后，将反应液倒入到水(50mL)中，乙酸乙酯(20mL x 3)萃取，合并有机相，有机相用饱和食盐水(20mL x 3)反洗，无水硫酸钠干燥，抽滤，滤液减压浓缩得残留物。残留物用硅胶柱色谱分离提纯(石油醚：乙酸乙酯(V/V)＝3:1)得1-叔丁基3-甲基(3R)-4-(3-氯-5-(三氟甲基)吡嗪-2-基)哌嗪-1,3-二羧酸酯(23c)(396mg,73％)。To 1-tert-butyl 3-methyl(3R)-4-(5-(trifluoromethyl)pyrazin-2-yl)piperazine-1,3-dicarboxylate (23b) (500 mg, 1.28 mmol) in DMF (5 mL) was added N-chlorosuccinimide (188 mg, 1.41 mmol), and the reaction was carried out at room temperature for 16 h. After the reaction was completed, the 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 residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V/V)=3:1) to obtain 1-tert-butyl-3-methyl(3R)-4-(3-chloro-5-(tris) Fluoromethyl)pyrazin-2-yl)piperazine-1,3-dicarboxylate (23c) (396 mg, 73%).
LCMS m/z＝369.0[M-55] +。 LCMS m/z = 369.0 [M-55] + .
第三步：叔丁基5-甲基-6-氧代-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-二吡嗪[1,2-a:2',3'-e]吡嗪-8-羧酸酯(23d)The third step: tert-butyl 5-methyl-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-dipyrazine[1,2 -a:2',3'-e]pyrazine-8-carboxylate (23d)
Tert-butyl 5-methyl-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-dipyrazino[1,2-a:2',3'-e]pyrazine-8-carboxylateTert-butyl 5-methyl-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-dipyrazino[1,2-a:2',3'-e]pyrazine -8-carboxylate
Figure PCTCN2022088446-appb-000249
Figure PCTCN2022088446-appb-000249
向1-叔丁基3-甲基(3R)-4-(3-氯-5-(三氟甲基)吡嗪-2-基)哌嗪-1,3-二羧酸酯(23c)(348mg,0.82mmol)的乙醇(7mL)溶液中，依次加入甲胺盐酸盐(277mg4.1mmol)，DIPEA(1.06g,8.2mmol)。100℃闷罐反应16h，反应结束后，冷却至室温后，将反应液减压浓缩得残留物，残留物用硅胶柱色谱分离提纯(石油醚：乙酸乙酯(V/V)＝5:1)得叔丁基5-甲基-6-氧代-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-二吡嗪[1,2-a:2',3'-e]吡嗪-8-羧酸酯(23d)(265mg,83％)。To 1-tert-butyl 3-methyl(3R)-4-(3-chloro-5-(trifluoromethyl)pyrazin-2-yl)piperazine-1,3-dicarboxylate (23c) (348 mg, 0.82 mmol) in ethanol (7 mL), methylamine hydrochloride (277 mg, 4.1 mmol), followed by DIPEA (1.06 g, 8.2 mmol) was added. The reaction was carried out in a stuffy tank at 100 °C for 16 hours. After the reaction was completed, the reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain a residue. The residue was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate (V/V) = 5:1 ) to get tert-butyl 5-methyl-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-dipyrazine[1,2-a : 2',3'-e]pyrazine-8-carboxylate (23d) (265 mg, 83%).
LCMS m/z＝332.1[M-55] +。 LCMS m/z=332.1 [M-55] + .
第四步：5-甲基-3-(三氟甲基)-7,8,9,10-四氢-5H-二吡嗪[1,2-a:2',3'-e]吡嗪-6(6aH)-酮(2 3e)的盐酸盐The fourth step: 5-methyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-dipyrazine[1,2-a:2',3'-e]pyridine The hydrochloride salt of oxazin-6(6aH)-one (2 3e)
5-methyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-dipyrazino[1,2-a:2',3'-e]pyrazin-6(6aH)-one hydrochloride5-methyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-dipyrazino[1,2-a:2',3'-e]pyrazin-6(6aH)-one hydrochloride
Figure PCTCN2022088446-appb-000250
Figure PCTCN2022088446-appb-000250
将叔丁基5-甲基-6-氧代-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-二吡嗪[1,2-a:2',3'-e]吡嗪-8-羧酸酯(23d)(150mg,0.39mmol)加入到氯化氢的1,4-二氧六环溶液(5mL，4N)中，室温反应1h，反应结束后，减压浓缩得5-甲基-3-(三氟甲基)-7,8,9,10-四氢-5H-二吡嗪[1,2-a:2',3'-e]吡嗪-6(6aH)-酮(23e)的盐酸盐(130mg)粗品，直接用于下一步。tert-Butyl 5-methyl-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-dipyrazine[1,2-a: 2',3'-e]pyrazine-8-carboxylate (23d) (150mg, 0.39mmol) was added to a solution of hydrogen chloride in 1,4-dioxane (5mL, 4N), and reacted at room temperature for 1h, the reaction After completion, concentrated under reduced pressure to obtain 5-methyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-dipyrazine[1,2-a:2',3'- e] The crude hydrochloride salt of pyrazin-6(6aH)-one (23e) (130 mg) was used directly in the next step.
第五步：5-甲基-8-(3-((S)-2-((6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基)丙氧基)丙酰基)-3-(三氟甲基)-7,8,9,10-四氢-5H-二吡嗪[1,2-a:2',3'-e]吡嗪-6(6aH)-酮(化合物23)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)
5-methyl-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-dipyrazino[1,2-a:2',3'-e]pyrazin-6(6aH)-one5-methyl-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl) -7,8,9,10-tetrahydro-5H-dipyrazino[1,2-a:2',3'-e]pyrazin-6(6aH)-one
Figure PCTCN2022088446-appb-000251
Figure PCTCN2022088446-appb-000251
将5-甲基-3-(三氟甲基)-7,8,9,10-四氢-5H-二吡嗪[1,2-a:2',3'-e]吡嗪-6(6aH)-酮(22e)的盐酸盐(60mg,粗品)，3-[(2S)-2-[(6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基]丙氧基]丙酸(4j)(65mg,0.21mmol)，HATU(80mg,0.21mmol)和DIPEA(140mg,1.05mmol)依次加入到DMF(2mL)，室温反应1h。反应结束后，反应液经Pre-HPLC纯化(仪器及制备柱：采用Waters 2767制备液相，制备柱型号是Sunfire@Prep C 18，5μm，内径×长度＝19mm×250mm)。制备方法：反应液用0.45μm滤膜过滤，制备成样品液。流动相体系：乙腈/水(含0.1％氨水)。梯度洗脱方法：乙腈由5％梯度洗脱至50％(流速：15mL/min；洗脱时间15min)，冻干后得到5-甲基-8-(3-((S)-2-((6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基)丙氧基)丙酰基)-3-(三氟甲基)-7,8,9,10-四氢-5H-二吡嗪[1,2-a:2',3'-e]吡嗪-6(6aH)-酮(化合物23)(30mg,25％)。 5-Methyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-dipyrazine[1,2-a:2',3'-e]pyrazine-6 (6aH)-keto (22e) hydrochloride (60 mg, crude), 3-[(2S)-2-[(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridin Azin-4-yl)amino]propoxy]propionic acid (4j) (65mg, 0.21mmol), HATU (80mg, 0.21mmol) and DIPEA (140mg, 1.05mmol) were successively added to DMF (2mL), and the reaction was carried out at room temperature for 1h . After the reaction, the reaction solution was purified by Pre-HPLC (instrument and preparative column: Waters 2767 was used to prepare the liquid phase, the preparative column model was Sunfire@Prep C 18 , 5 μm, inner diameter×length=19mm×250mm). Preparation method: The reaction solution was filtered with a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile/water (containing 0.1% ammonia). Gradient elution method: acetonitrile gradient from 5% to 50% (flow rate: 15 mL/min; elution time 15 min), 5-methyl-8-(3-((S)-2-() after lyophilization (6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionyl)-3-(trifluoromethyl)-7,8 ,9,10-Tetrahydro-5H-dipyrazin[1,2-a:2',3'-e]pyrazin-6(6aH)-one (Compound 23) (30 mg, 25%).
LCMS m/z＝579.1[M+1] +。 LCMS m/z=579.1[M+1] + .
1H NMR(400MHz,DMSO-d 6)δ12.42(s,1H),8.18(s,1H),7.90(s,1H),6.30-6.20(m,1H),4.91-4.53(m,1H),4.53-3.98(m,4H),3.75-3.62(m,2H),3.49(d,2H),3.43-3.04(m,4H),2.91-2.81(m,1H),2.77-2.56(m,3H),1.16(d,3H)。 1 H NMR (400MHz, DMSO-d 6 )δ12.42(s,1H), 8.18(s,1H), 7.90(s,1H), 6.30-6.20(m,1H), 4.91-4.53(m,1H) ), 4.53-3.98(m, 4H), 3.75-3.62(m, 2H), 3.49(d, 2H), 3.43-3.04(m, 4H), 2.91-2.81(m, 1H), 2.77-2.56(m , 3H), 1.16(d, 3H).
实施例24：5-甲基-8-(3-(((S)-1-(6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)吡咯烷-2-基)甲氧基)丙酰基)-3-(三氟甲基)-7,8,9,10-四氢-5H-二吡嗪[1,2-a:2',3'-e]吡嗪-6(6aH)-酮(化合物24)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)
5-methyl-8-(3-(((S)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-dipyrazino[1,2-a:2',3'-e]pyrazin-6(6aH)-one5-methyl-8-(3-(((S)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)pyrrolidin-2-yl)methoxy)propanoyl)-3 -(trifluoromethyl)-7,8,9,10-tetrahydro-5H-dipyrazino[1,2-a:2',3'-e]pyrazin-6(6aH)-one
Figure PCTCN2022088446-appb-000252
Figure PCTCN2022088446-appb-000252
化合物24以5-甲基-3-(三氟甲基)-7,8,9,10-四氢-5H-二吡嗪[1,2-a:2',3'-e]吡嗪-6(6aH)-酮(22e)的盐酸盐和3-{[(2S)-1-(6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)吡咯烷-2-基]甲氧基}丙酸(5f)为原料，参考实施例22的合成方法，得到5-甲基-8-(3-(((S)-1-(6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)吡咯烷-2-基)甲氧基)丙酰基)-3-(三氟甲基)-7,8,9,10-四氢-5H-二吡嗪[1,2-a:2',3'-e]吡嗪-6(6aH)-酮(化合物24)。Compound 24 was identified as 5-methyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-dipyrazine[1,2-a:2',3'-e]pyrazine -6(6aH)-one (22e) hydrochloride and 3-{[(2S)-1-(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4 -yl)pyrrolidin-2-yl]methoxy}propionic acid (5f) as raw material, referring to the synthetic method of Example 22, 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-dipyrazin[1,2-a:2',3'-e]pyrazin-6(6aH)-one (compound 24).
LCMS m/z＝605.2[M+1] +。 LCMS m/z=605.2[M+1] + .
1H NMR(400MHz,DMSO-d 6)δ12.32(s,1H),8.19(s,1H),8.01(s,1H),4.93-3.96(m,5H),3.73-3.59(m,2H),3.57-3.46(m,2H),3.46-3.03(m,6H),2.91-2.80(m,1H),2.77-2.53(m,3H),2.15-2.00(m,1H),1.97-1.79(m,1H),1.72-1.55(s,2H)。 1 H NMR (400MHz, DMSO-d 6 )δ12.32(s,1H), 8.19(s,1H), 8.01(s,1H), 4.93-3.96(m,5H), 3.73-3.59(m,2H) ),3.57-3.46(m,2H),3.46-3.03(m,6H),2.91-2.80(m,1H),2.77-2.53(m,3H),2.15-2.00(m,1H),1.97-1.79 (m, 1H), 1.72-1.55 (s, 2H).
实施例25：5-(((S)-1-(3-氧代-3-((R)-3-(三氟甲基)-6a,7,9,10-四氢二吡嗪[2,3-b:1',2'-d][1,4]恶嗪-8(6H)-基)丙氧基)丙-2-基)氨基)-4-(三氟甲基)哒嗪-3(2H)-酮(化合物25)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)
5-(((S)-1-(3-oxo-3-((R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydrodipyrazino[2,3-b:1',2'-d][1,4]oxazin-8(6H)-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one5-(((S)-1-(3-oxo-3-((R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydrodipyrazino[2,3-b:1',2'- d][1,4]oxazin-8(6H)-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one
Figure PCTCN2022088446-appb-000253
Figure PCTCN2022088446-appb-000253
第一步：(R)-3-(羟甲基)-4-(5-(三氟甲基)吡嗪-2-基)哌嗪-1-羧酸叔丁酯(25b)The first step: (R)-3-(hydroxymethyl)-4-(5-(trifluoromethyl)pyrazin-2-yl)piperazine-1-carboxylate tert-butyl ester (25b)
tert-butyl(R)-3-(hydroxymethyl)-4-(5-(trifluoromethyl)pyrazin-2-yl)piperazine-1-carboxylatetert-butyl(R)-3-(hydroxymethyl)-4-(5-(trifluoromethyl)pyrazin-2-yl)piperazine-1-carboxylate
Figure PCTCN2022088446-appb-000254
Figure PCTCN2022088446-appb-000254
将2-氯-5-(三氟甲基)吡嗪(25a)(1.00g,5.48mmol)，(R)-3-(羟甲基)哌嗪-1-羧酸叔丁酯(1.42g,6.58mmol)，DIPEA(1.42g,10.96mmol)依次加入到二甲亚砜(10mL)中，100℃反应16h，反应结束后，冷却至室温，将反应液倒入到水(150mL)中，乙酸乙酯(30mL x 3)萃取，合并有机相，有机相用饱和食盐水(30mL x 3)反洗，无水硫酸钠干燥，抽滤，滤液减压浓缩后得残留物。残留物用硅胶柱色谱分离提纯(石油醚：乙酸乙酯(V/V)＝2:1)得到(R)-3-(羟甲基)-4-(5-(三氟甲基)吡嗪-2-基)哌嗪-1-羧酸叔丁酯(25b)(1.77g,89％)。2-Chloro-5-(trifluoromethyl)pyrazine (25a) (1.00g, 5.48mmol), (R)-3-(hydroxymethyl)piperazine-1-carboxylate tert-butyl ester (1.42g) , 6.58 mmol), DIPEA (1.42 g, 10.96 mmol) were successively added to dimethyl sulfoxide (10 mL), reacted at 100 ° C for 16 h, after the reaction was completed, cooled to room temperature, the reaction solution was poured into water (150 mL), Extracted with ethyl acetate (30mL×3), combined the organic phases, the organic phase was backwashed with saturated brine (30mL×3), dried over anhydrous sodium sulfate, filtered with suction, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V/V)=2:1) to obtain (R)-3-(hydroxymethyl)-4-(5-(trifluoromethyl)pyridine) Azin-2-yl)piperazine-1-carboxylate tert-butyl ester (25b) (1.77 g, 89%).
LCMS m/z＝363.2[M+1] +。 LCMS m/z=363.2[M+1] + .
第二步：(R)-4-(3-氯-5-(三氟甲基)吡嗪-2-基)-3-(羟甲基)哌嗪-1-羧酸叔丁酯(25c)The second step: (R)-4-(3-chloro-5-(trifluoromethyl)pyrazin-2-yl)-3-(hydroxymethyl)piperazine-1-carboxylate tert-butyl ester (25c )
tert-butyl(R)-4-(3-chloro-5-(trifluoromethyl)pyrazin-2-yl)-3-(hydroxymethyl)piperazine-1-carboxylatetert-butyl(R)-4-(3-chloro-5-(trifluoromethyl)pyrazin-2-yl)-3-(hydroxymethyl)piperazine-1-carboxylate
Figure PCTCN2022088446-appb-000255
Figure PCTCN2022088446-appb-000255
向(R)-3-(羟甲基)-4-(5-(三氟甲基)吡嗪-2-基)哌嗪-1-羧酸叔丁酯(25b)(200mg,0.55mmol)的DMF(2mL)溶液中加入N-氯代丁二酰亚胺(81mg,0.61mmol)，室温反应16h，反应结束后，将反应液倒入到水(20mL)中，乙酸乙酯(20mL x 3)萃取，合并有机相，有机相用饱和食盐水(20mL x 3)反洗，无水硫酸钠干燥，抽滤，滤液减压浓缩后得残留物。残留物用硅胶柱色谱分离提纯(石油醚：乙酸乙酯(V/V)＝3:1)得(R)-4-(3-氯-5-(三氟甲基)吡嗪-2-基)-3-(羟甲基)哌嗪-1-羧酸叔丁酯(25c)(110mg,50％)。To (R)-tert-butyl 3-(hydroxymethyl)-4-(5-(trifluoromethyl)pyrazin-2-yl)piperazine-1-carboxylate (25b) (200 mg, 0.55 mmol) N-chlorosuccinimide (81 mg, 0.61 mmol) was added to the DMF (2 mL) solution of the solution, and the reaction was carried out at room temperature for 16 h. After the reaction was completed, the 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. The residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V/V)=3:1) to obtain (R)-4-(3-chloro-5-(trifluoromethyl)pyrazine-2- (25c) (110 mg, 50%).
LCMS m/z＝341.1[M-55] +。 LCMS m/z = 341.1 [M-55] + .
第三步：(R)-3-(三氟甲基)-6a,7,9,10-四氢二吡嗪[2,3-b:1',2'-d][1,4]恶嗪-8(6H)-羧酸叔丁酯(25d)The third step: (R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydrodipyrazine[2,3-b:1',2'-d][1,4] tert-Butyl oxazine-8(6H)-carboxylate (25d)
Tert-butyl(R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydrodipyrazino[2,3-b:1',2'-d][1,4]oxazine-8(6H)-carboxylateTert-butyl(R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydrodipyrazino[2,3-b:1',2'-d][1,4]oxazine-8(6H)-carboxylate
Figure PCTCN2022088446-appb-000256
Figure PCTCN2022088446-appb-000256
向(R)-4-(3-氯-5-(三氟甲基)吡嗪-2-基)-3-(羟甲基)哌嗪-1-羧酸叔丁酯(25c)(110mg,0.28mmol)的DMF(2mL)溶液中加入碳酸钾(116mg,0.84mmol)，100℃反应16h，反应结束后，冷却至室温，将反应液倒入到水(20mL)中，乙酸乙酯(20mL x 3)萃取，合并有机相，有机相用饱和食盐水(20mL x 3)反洗，无水硫酸钠干燥，抽滤，滤液减压浓缩得残留物。残留物用硅胶柱色谱分离提纯(石油醚：乙酸乙酯(V/V)＝3:1)得(R)-3-(三氟甲基)-6a,7,9,10-四氢二吡嗪[2,3-b:1',2'-d][1,4]恶嗪-8(6H)-羧酸叔丁酯(25d)(61mg,60％)。To (R)-tert-butyl 4-(3-chloro-5-(trifluoromethyl)pyrazin-2-yl)-3-(hydroxymethyl)piperazine-1-carboxylate (25c) (110 mg , 0.28 mmol) in DMF (2 mL) solution was added potassium carbonate (116 mg, 0.84 mmol), reacted at 100 ° C for 16 h, after the reaction was completed, cooled to room temperature, the reaction solution was poured into water (20 mL), 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 residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V/V)=3:1) to obtain (R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydrodicarbonate Pyrazine[2,3-b:1',2'-d][1,4]oxazine-8(6H)-carboxylate tert-butyl ester (25d) (61 mg, 60%).
LCMS m/z＝361.2[M+1] +。 LCMS m/z=361.2[M+1] + .
第四步：(R)-3-(三氟甲基)-6,6a,7,8,9,10-六氢二吡嗪[2,3-b:1',2'-d][1,4]恶嗪(25e)的盐酸盐The fourth step: (R)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydrodipyrazine[2,3-b:1',2'-d][ 1,4]oxazine (25e) hydrochloride
(R)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydrodipyrazino[2,3-b:1',2'-d][1,4]oxazine hydrochloride(R)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydrodipyrazino[2,3-b:1',2'-d][1,4]oxazine hydrochloride
Figure PCTCN2022088446-appb-000257
Figure PCTCN2022088446-appb-000257
将(R)-3-(三氟甲基)-6a,7,9,10-四氢二吡嗪[2,3-b:1',2'-d][1,4]恶嗪-8(6H)-羧酸叔丁酯(25d)(61mg,0.17mmol)加入到氯化氢的1,4-二氧六环溶液(5mL，4N)中，室温反应1h，反应结束后，减压浓缩得(R)-3-(三氟甲基)-6,6a,7,8,9,10-六氢二吡嗪[2,3-b:1',2'-d][1,4]恶嗪(25e)的盐酸盐(53mg)粗品，直接用于下一步反应。(R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydrodipyrazine[2,3-b:1',2'-d][1,4]oxazine- 8(6H)-Carboxylic acid tert-butyl ester (25d) (61 mg, 0.17 mmol) was added to a solution of hydrogen chloride in 1,4-dioxane (5 mL, 4N), and reacted at room temperature for 1 h. After the reaction was completed, concentrated under reduced pressure (R)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydrodipyrazine[2,3-b:1',2'-d][1,4 ] oxazine (25e) hydrochloride (53 mg) crude product, used directly in the next reaction.
LCMS m/z＝261.1[M+1] +。 LCMS m/z=261.1[M+1] + .
第五步：5-(((S)-1-(3-氧代-3-((R)-3-(三氟甲基)-6a,7,9,10-四氢二吡嗪[2,3-b:1',2'-d][1,4]恶嗪-8(6H)-基)丙氧基)丙-2-基)氨基)-4-(三氟甲基)哒嗪-3(2H)-酮(化合物25)The fifth step: 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)
5-(((S)-1-(3-oxo-3-((R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydrodipyrazino[2,3-b:1',2'-d][1,4]oxazin-8(6H)-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one5-(((S)-1-(3-oxo-3-((R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydrodipyrazino[2,3-b:1',2'- d][1,4]oxazin-8(6H)-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one
Figure PCTCN2022088446-appb-000258
Figure PCTCN2022088446-appb-000258
将(R)-3-(三氟甲基)-6,6a,7,8,9,10-六氢二吡嗪[2,3-b:1',2'-d][1,4]恶嗪(25e)的盐酸盐(53mg,粗品)，3-[(2S)-2-[(6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基]丙氧基]丙酸(4j)(56mg,0.18mmol)，HATU(68mg,0.18mmol)和DIPEA(116mg,0.90mmol)依次加入到DMF(2mL)，室温反应1h。反应结束后，反应液经Pre-HPLC纯化(仪器及制备柱：采用Waters 2767制备液相，制备柱型号是Sunfire@Prep C 18，5μm，内径×长度＝19mm×250mm)。制备方法：反应液用0.45μm滤膜过滤，制备成样品液。流动相体系：乙腈/水(含0.1％氨水)。梯度洗脱方法：乙腈由5％梯度洗脱至50％(流速：15mL/min；洗脱时间15min)，冻干后得到5-(((S)-1-(3-氧代-3-((R)-3-(三氟甲基)-6a,7,9,10-四氢二吡嗪[2,3-b:1',2'-d][1,4]恶嗪-8(6H)-基)丙氧基)丙-2-基)氨基)-4-(三氟甲基)哒嗪-3(2H)-酮(化合物2 5)(30mg,30％)。 (R)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydrodipyrazine[2,3-b:1',2'-d][1,4 ]oxazine (25e) hydrochloride (53 mg, crude), 3-[(2S)-2-[(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine- 4-yl)amino]propoxy]propionic acid (4j) (56mg, 0.18mmol), HATU (68mg, 0.18mmol) and DIPEA (116mg, 0.90mmol) were successively added to DMF (2mL) and reacted at room temperature for 1h. After the reaction, the reaction solution was purified by Pre-HPLC (instrument and preparative column: Waters 2767 was used to prepare the liquid phase, the preparative column model was Sunfire@Prep C 18 , 5 μm, inner diameter×length=19mm×250mm). Preparation method: The reaction solution was filtered with a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile/water (containing 0.1% ammonia). Gradient elution method: Gradient elution of acetonitrile from 5% to 50% (flow rate: 15 mL/min; elution time 15 min), 5-(((S)-1-(3-oxo-3- ((R)-3-(trifluoromethyl)-6a,7,9,10-tetrahydrodipyrazine[2,3-b:1',2'-d][1,4]oxazine- 8(6H)-yl)propoxy)prop-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (compound 25) (30 mg, 30%).
LCMS m/z＝552.2[M+1] +。 LCMS m/z=552.2[M+1] + .
1H NMR(400MHz,DMSO-d 6)δ12.43(s,1H),8.16(s,1H),7.90(s,1H),6.32-6.18(m,1H),4.66-4.54(m,1H),4.53-4.33(m,2H),4.24-3.98(m,3H),3.75-3.61(m,3H),3.49(d,2H),3.24-2.73(m,3H),2.66-2.58(m,2H),1.15(d,3H)。 1 H NMR (400MHz, DMSO-d 6 )δ12.43(s,1H), 8.16(s,1H), 7.90(s,1H), 6.32-6.18(m,1H), 4.66-4.54(m,1H) ), 4.53-4.33(m, 2H), 4.24-3.98(m, 3H), 3.75-3.61(m, 3H), 3.49(d, 2H), 3.24-2.73(m, 3H), 2.66-2.58(m , 2H), 1.15(d, 3H).
实施例26：5-(((S)-1-(3-氧代-3-((S)-3-(三氟甲基)-6a,7,9,10-四氢二吡嗪[2,3-b:1',2'-d][1,4]恶嗪-8(6H)-基)丙氧基)丙-2-基)氨基)-4-(三氟甲基)哒嗪-3(2H)-酮(化合物26)Example 26: 5-(((S)-1-(3-oxo-3-((S)-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 26)
5-(((S)-1-(3-oxo-3-((S)-3-(trifluoromethyl)-6a,7,9,10-tetrahydrodipyrazino[2,3-b:1',2'-d][1,4]oxazin-8(6H)-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one5-(((S)-1-(3-oxo-3-((S)-3-(trifluoromethyl)-6a,7,9,10-tetrahydrodipyrazino[2,3-b:1',2'- d][1,4]oxazin-8(6H)-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one
Figure PCTCN2022088446-appb-000259
Figure PCTCN2022088446-appb-000259
化合物26以2-氯-5-(三氟甲基)吡嗪(25a)和(S)-3-(羟甲基)哌嗪-1-羧酸叔丁酯为原料，参考实施例25的合成方法，得到5-(((S)-1-(3-氧代-3-((S)-3-(三氟甲基)-6a,7,9,10-四氢二吡嗪[2,3-b:1',2'-d][1,4]恶嗪-8(6H)-基)丙氧基)丙-2-基)氨基)-4-(三氟甲基)哒嗪-3(2H)-酮(化合物26)。Compound 26 uses 2-chloro-5-(trifluoromethyl)pyrazine (25a) and (S)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester as raw materials. Synthetic method to give 5-(((S)-1-(3-oxo-3-((S)-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 26).
LCMS m/z＝552.2[M+1] +。 LCMS m/z=552.2[M+1] + .
1H NMR(400MHz,DMSO-d 6)δ12.43(s,1H),8.16(s,1H),7.90(s,1H),6.29-6.21(m,1H),4.67-4.32(m,3H),4.26-3.98(m,3H),3.77-3.61(m,3H),3.49(d,2H),3.22-2.68(m,3H),2.66-2.57(m,2H),1.15(d,3H)。 1 H NMR (400MHz, DMSO-d 6 )δ12.43(s,1H), 8.16(s,1H), 7.90(s,1H), 6.29-6.21(m,1H), 4.67-4.32(m,3H) ), 4.26-3.98(m, 3H), 3.77-3.61(m, 3H), 3.49(d, 2H), 3.22-2.68(m, 3H), 2.66-2.57(m, 2H), 1.15(d, 3H) ).
实施例27：(R)-5-乙基-8-(3-((S)-2-((6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基)丙氧基)丙酰基)-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪[1,2-a]吡啶[3,2-e]吡嗪-6(6aH)-酮(化合物27)Example 27: (R)-5-Ethyl-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine- 4-yl)amino)propoxy)propionyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazine[1,2-a]pyridine[3,2 -e]pyrazin-6(6aH)-one (compound 27)
(R)-5-ethyl-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one(R)-5-ethyl-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3 -(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one
Figure PCTCN2022088446-appb-000260
Figure PCTCN2022088446-appb-000260
第一步：(R)-5-甲基-6-氧代-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-8-羧酸叔丁酯(27b)The first step: (R)-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 tert-butyl ester (27b)
Tert-butyl(R)-5-ethyl-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8-carboxylateTert-butyl(R)-5-ethyl-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2 -e]pyrazine-8-carboxylate
Figure PCTCN2022088446-appb-000261
Figure PCTCN2022088446-appb-000261
室温下，将(R)-6-氧代-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-8-羧酸叔丁酯(4d)(100mg,0.27mmol)，碳酸钾(112mg,0.81mmol)加入到DMF(2mL)，然后加入碘乙烷(84mg,0.54mmol)。室温反应16h，反应结束后，将反应液倒入到水(20mL)中，乙酸乙酯(20mL x 3)萃取，合并有机相，有机相用饱和食盐水(20mL x 3)反洗，无水硫酸钠干燥，抽滤，滤液减压浓缩得残留物。残留物用硅胶柱色谱分离提纯(石油醚：乙酸乙酯(V/V)＝3:1)得到(R)-5-甲基-6-氧代-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-8-羧酸叔丁酯(27b)(120mg,100％)。(R)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyridine at room temperature Hemo[3,2-e]pyrazine-8-carboxylate tert-butyl ester (4d) (100 mg, 0.27 mmol), potassium carbonate (112 mg, 0.81 mmol) was added to DMF (2 mL) followed by iodoethane (84 mg) , 0.54 mmol). The reaction was carried out at room temperature for 16 h. After the reaction was completed, the reaction solution was poured into water (20 mL), extracted with ethyl acetate (20 mL x 3), the organic phases were combined, and the organic phase was backwashed with saturated brine (20 mL x 3), anhydrous Dry over sodium sulfate, filter with suction, and concentrate the filtrate under reduced pressure to obtain a residue. The residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V/V)=3:1) to obtain (R)-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 tert-butyl ester (27b) (120 mg , 100%).
LCMS m/z＝345.1[M-55] +。 LCMS m/z = 345.1 [M-55] + .
第二步：(R)-5-乙基-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪[1,2-a]吡啶[3,2-e]吡嗪-6(6aH)-酮(27c)的盐酸盐The second step: (R)-5-ethyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazine[1,2-a]pyridine[3,2- e] The hydrochloride salt of pyrazin-6(6aH)-one (27c)
(R)-5-ethyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one hydrochloride(R)-5-ethyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one hydrochloride
Figure PCTCN2022088446-appb-000262
Figure PCTCN2022088446-appb-000262
将(R)-5-甲基-6-氧代-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-8-羧酸叔丁酯(27b)(120mg,0.30mmol)加入到氯化氢的1,4-二氧六环溶液(5mL，4N)中，室温反应1h，反应结束后，减压浓缩除去溶剂得(R)-5-乙基-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪[1,2-a]吡啶[3,2-e]吡嗪-6(6aH)-酮(27c)的盐酸盐(100mg)粗品，直接用于下一步。(R)-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 tert-butyl ester (27b) (120 mg, 0.30 mmol) was added to a solution of hydrogen chloride in 1,4-dioxane (5 mL, 4N) at room temperature The reaction was carried out for 1 h. After the reaction was completed, the solvent was removed by concentration under reduced pressure to obtain (R)-5-ethyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazine[1,2 Crude hydrochloride (100 mg) of -a]pyridin[3,2-e]pyrazin-6(6aH)-one (27c) was used directly in the next step.
LCMS m/z＝301.1[M+1] +。 LCMS m/z=301.1[M+1] + .
第三步：(R)-5-乙基-8-(3-((S)-2-((6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基)丙氧基)丙酰基)-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪[1,2-a]吡啶[3,2-e]吡嗪-6(6aH)-酮(化合物27)The third step: (R)-5-ethyl-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine- 4-yl)amino)propoxy)propionyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazine[1,2-a]pyridine[3,2 -e]pyrazin-6(6aH)-one (compound 27)
(R)-5-ethyl-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one(R)-5-ethyl-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3 -(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one
Figure PCTCN2022088446-appb-000263
Figure PCTCN2022088446-appb-000263
将(R)-5-乙基-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪[1,2-a]吡啶[3,2-e]吡嗪-6(6aH)-酮(27c)的盐酸盐(91mg,粗品)，3-[(2S)-2-[(6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基]丙氧基]丙酸(4j)(84mg,0.27mmol)，HATU(100mg,0.27mmol)和DIPEA(170mg,1.35mmol)依次加入到DMF(2mL)，室温反应1h。反应结束后，反应液经Pre-HPLC纯化(仪器及制备柱：采用Waters 2767制备液相，制备柱型号是Sunfire@Prep C 18，5μm，内径×长度＝19mm×250mm)。制备方法：反应液用0.45μm滤膜过滤，制备成样品液。流动相体系：乙腈/水(含0.1％氨水)。梯度洗脱方法：乙腈由5％梯度洗脱至50％(流速：15mL/min；洗脱时间15min)，冻干后得到(R)-5-乙基-8-(3-((S)-2-((6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基)丙氧基)丙酰基)-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪[1,2-a]吡啶[3,2-e]吡嗪-6(6aH)-酮(化合物27)(40mg,25％)。 (R)-5-ethyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazine[1,2-a]pyridine[3,2-e]pyridine Azin-6(6aH)-one (27c) hydrochloride (91 mg, crude), 3-[(2S)-2-[(6-oxo-5-(trifluoromethyl)-1,6- Dihydropyridazin-4-yl)amino]propoxy]propionic acid (4j) (84 mg, 0.27 mmol), HATU (100 mg, 0.27 mmol) and DIPEA (170 mg, 1.35 mmol) were sequentially added to DMF (2 mL), The reaction was carried out at room temperature for 1 h. After the reaction, the reaction solution was purified by Pre-HPLC (instrument and preparative column: Waters 2767 was used to prepare the liquid phase, the preparative column model was Sunfire@Prep C 18 , 5 μm, inner diameter×length=19mm×250mm). Preparation method: The reaction solution was filtered with a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile/water (containing 0.1% ammonia). Gradient elution method: acetonitrile gradient from 5% to 50% (flow rate: 15 mL/min; elution time 15 min), after lyophilization, (R)-5-ethyl-8-(3-((S) -2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionyl)-3-(trifluoromethyl) -7,8,9,10-Tetrahydro-5H-pyrazin[1,2-a]pyridin[3,2-e]pyrazin-6(6aH)-one (Compound 27) (40 mg, 25%) .
LCMS m/z＝592.2[M+1] +。 LCMS m/z=592.2[M+1] + .
1H NMR(400MHz,CD 3OD)δ8.14(d,1H),7.92(d,1H),7.43(s,1H),5.15-4.58(m,2H),4.55-3.93(m,5H),3.86-3.72(m,2H),3.64-3.57(m,1H),3.54-3.46(m,1H),3.28-2.62(m,5H),1.29-1.19(m,6H)。 1 H NMR (400MHz, CD 3 OD) δ 8.14(d,1H), 7.92(d,1H), 7.43(s,1H), 5.15-4.58(m,2H), 4.55-3.93(m,5H) , 3.86-3.72(m, 2H), 3.64-3.57(m, 1H), 3.54-3.46(m, 1H), 3.28-2.62(m, 5H), 1.29-1.19(m, 6H).
实施例28：(R)-5-环丙基甲基-8-(3-((S)-2-((6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基)丙氧基)丙酰基)-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪[1,2-a]吡啶[3,2-e]吡嗪-6(6aH)-酮(化合物28)Example 28: (R)-5-Cyclopropylmethyl-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydro Pyridazin-4-yl)amino)propoxy)propionyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazine[1,2-a]pyridine[ 3,2-e]pyrazin-6(6aH)-one (Compound 28)
(R)-5-(cyclopropylmethyl)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one(R)-5-(cyclopropylmethyl)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl) -3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one
Figure PCTCN2022088446-appb-000264
Figure PCTCN2022088446-appb-000264
第一步：(R)-5-环丙基甲基-6-氧代-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-8-羧酸叔丁酯(28b)The first step: (R)-5-cyclopropylmethyl-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino [1,2-a]pyrido[3,2-e]pyrazine-8-carboxylate tert-butyl ester (28b)
tert-butyl(R)-5-(cyclopropylmethyl)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8-carboxylatetert-butyl(R)-5-(cyclopropylmethyl)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3 ,2-e]pyrazine-8-carboxylate
Figure PCTCN2022088446-appb-000265
Figure PCTCN2022088446-appb-000265
室温下，将(R)-6-氧代-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-8-羧酸叔丁酯(4d)(100mg,0.27mmol)，碳酸钾(112mg,0.81mmol)加入到DMF(2mL)，然后加入(碘甲基)环丙烷(74mg,0.41mmol)。室温反应16h，反应结束后，将反应液倒入到水(20mL)中，乙酸乙酯(20mL x 3)萃取，合并有机相，有机相用饱和食盐水(20mL x 3)反洗，无水硫酸钠干燥，抽滤，滤液减压浓缩得残留物。残留物用硅胶柱色谱分离提纯(石油醚：乙酸乙酯(V/V)＝3:1)得到(R)-5-环丙基 甲基-6-氧代-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-8-羧酸叔丁酯(28b)(120mg,100％)。(R)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyridine at room temperature Hemo[3,2-e]pyrazine-8-carboxylate tert-butyl ester (4d) (100 mg, 0.27 mmol), potassium carbonate (112 mg, 0.81 mmol) was added to DMF (2 mL) followed by (iodomethyl) Cyclopropane (74 mg, 0.41 mmol). The reaction was carried out at room temperature for 16 h. After the reaction was completed, the reaction solution was poured into water (20 mL), extracted with ethyl acetate (20 mL x 3), the organic phases were combined, and the organic phase was backwashed with saturated brine (20 mL x 3), anhydrous Dry over sodium sulfate, filter with suction, and concentrate the filtrate under reduced pressure to obtain a residue. The residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V/V)=3:1) to obtain (R)-5-cyclopropylmethyl-6-oxo-3-(trifluoromethyl) )-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8-carboxylate tert-butyl ester (28b ) (120 mg, 100%).
LCMS m/z＝427.2[M+1] +。 LCMS m/z=427.2[M+1] + .
第二步：(R)-5-环丙基甲基-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪[1,2-a]吡啶[3,2-e]吡嗪-6(6aH)-酮(28c)的盐酸盐The second step: (R)-5-cyclopropylmethyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazine[1,2-a]pyridine[3 ,2-e]pyrazin-6(6aH)-one (28c) hydrochloride
(R)-5-(cyclopropylmethyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one hydrochloride(R)-5-(cyclopropylmethyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH) -one hydrochloride
Figure PCTCN2022088446-appb-000266
Figure PCTCN2022088446-appb-000266
将(R)-5-环丙基甲基-6-氧代-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-8-羧酸叔丁酯(28b)(120mg,0.28mmol)加入到氯化氢的1,4-二氧六环溶液(5mL，4N)中，室温反应1h，反应结束后，减压浓缩除去溶剂后得(R)-5-环丙基甲基-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪[1,2-a]吡啶[3,2-e]吡嗪-6(6aH)-酮(28c)的盐酸盐(100mg,粗品)，直接用于下一步。(R)-5-Cyclopropylmethyl-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1, 2-a]pyrido[3,2-e]pyrazine-8-carboxylate tert-butyl ester (28b) (120 mg, 0.28 mmol) was added to a solution of hydrogen chloride in 1,4-dioxane (5 mL, 4N) , react at room temperature for 1 h, after the reaction, concentrate under reduced pressure to remove the solvent to obtain (R)-5-cyclopropylmethyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H - The hydrochloride salt of pyrazin[1,2-a]pyridin[3,2-e]pyrazin-6(6aH)-one (28c) (100 mg, crude) was used directly in the next step.
LCMS m/z＝327.1[M+1] +。 LCMS m/z=327.1[M+1] + .
第三步：(R)-5-环丙基甲基-8-(3-((S)-2-((6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基)丙氧基)丙酰基)-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪[1,2-a]吡啶[3,2-e]吡嗪-6(6aH)-酮(化合物28)The third step: (R)-5-cyclopropylmethyl-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydro) Pyridazin-4-yl)amino)propoxy)propionyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazine[1,2-a]pyridine[ 3,2-e]pyrazin-6(6aH)-one (Compound 28)
(R)-5-(cyclopropylmethyl)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one(R)-5-(cyclopropylmethyl)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl) -3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one
Figure PCTCN2022088446-appb-000267
Figure PCTCN2022088446-appb-000267
将(R)-5-环丙基甲基-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪[1,2-a]吡啶[3,2-e]吡嗪-6(6aH)-酮(28c)的盐酸盐(98mg,粗品)，3-[(2S)-2-[(6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基]丙氧基]丙酸(4j)(84mg,0.27mmol)，HATU(100mg,0.27mmol)和DIPEA(17 0mg,1.35mmol)依次加入到DMF(2mL)，室温反应1h。反应结束后，反应液经Pre-HPLC纯化(仪器及制备柱：采用Waters 2767制备液相，制备柱型号是Sunfire@Prep C 18，5μm，内径×长度＝19mm×250mm)。制备方法：反应液用0.45μm滤膜过滤，制备成样品液。流动相体系：乙腈/水(含0.1％氨水)。梯度洗脱方法：乙腈由5％梯度洗脱至50％(流速：15mL/min；洗脱时间15min)，冻干后得到(R)-5-环丙基甲基-8-(3-((S)-2-((6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基)丙氧基)丙酰基)-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪[1,2-a]吡啶[3,2-e]吡嗪-6(6aH)-酮(化合物28)(40mg,24％)。 (R)-5-Cyclopropylmethyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazine[1,2-a]pyridine[3,2- e] Hydrochloride salt of pyrazin-6(6aH)-one (28c) (98 mg, crude), 3-[(2S)-2-[(6-oxo-5-(trifluoromethyl)-1 ,6-dihydropyridazin-4-yl)amino]propoxy]propionic acid (4j) (84mg, 0.27mmol), HATU (100mg, 0.27mmol) and DIPEA (170mg, 1.35mmol) were added to DMF sequentially (2 mL), and reacted at room temperature for 1 h. After the reaction, the reaction solution was purified by Pre-HPLC (instrument and preparative column: Waters 2767 was used to prepare the liquid phase, the preparative column model was Sunfire@Prep C 18 , 5 μm, inner diameter×length=19mm×250mm). Preparation method: The reaction solution was filtered with a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile/water (containing 0.1% ammonia). Gradient elution method: Gradient elution from 5% acetonitrile to 50% (flow rate: 15 mL/min; elution time 15 min), after lyophilization, (R)-5-cyclopropylmethyl-8-(3-( (S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionyl)-3-(trifluoromethyl) Methyl)-7,8,9,10-tetrahydro-5H-pyrazin[1,2-a]pyridin[3,2-e]pyrazin-6(6aH)-one (Compound 28) (40 mg, twenty four%).
LCMS m/z＝618.2[M+1] +。 LCMS m/z=618.2[M+1] + .
1H NMR(400MHz,DMSO-d 6)δ12.42(s,1H),8.21(s,1H),7.90(s,1H),7.63(s,1H),6.30-6.17(m,1H),4.90-4.42(m,2H),4.36-3.86(m,5H),3.75-3.63m,2H),3.49(d,2H),3.25-3.09(m,1H),2.87-2.58(m,4H),1.15(d,3H),1.11-0.99(m,1H),0.53-0.26(m,4H)。 1 H NMR (400MHz, DMSO-d 6 )δ12.42(s,1H), 8.21(s,1H), 7.90(s,1H), 7.63(s,1H), 6.30-6.17(m,1H), 4.90-4.42(m, 2H), 4.36-3.86(m, 5H), 3.75-3.63m, 2H), 3.49(d, 2H), 3.25-3.09(m, 1H), 2.87-2.58(m, 4H) , 1.15 (d, 3H), 1.11-0.99 (m, 1H), 0.53-0.26 (m, 4H).
实施例29：5-(((2S)-1-(3-氧-3-(3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡嗪并[1,2-a][1,8]萘啶-8-基)丙氧基)丙-2-基)氨基)-4-(三氟甲基)哒嗪-3(2H)-酮(化合物29)Example 29: 5-(((2S)-1-(3-oxo-3-(3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazine [1,2-a][1,8]Naphthyridin-8-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 29)
5-(((2S)-1-(3-oxo-3-(3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a][1,8]naphthyridin-8-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one5-(((2S)-1-(3-oxo-3-(3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a][1 ,8]naphthyridin-8-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one
Figure PCTCN2022088446-appb-000268
Figure PCTCN2022088446-appb-000268
第一步：4-(叔丁基)2-(羟甲基)哌嗪-1,4-二羧酸1-苄基酯(29b)The first step: 1-benzyl 4-(tert-butyl)2-(hydroxymethyl)piperazine-1,4-dicarboxylate (29b)
benzyl 4-(tert-butyl)2-(hydroxymethyl)piperazine-1,4-dicarboxylatebenzyl 4-(tert-butyl)2-(hydroxymethyl)piperazine-1,4-dicarboxylate
Figure PCTCN2022088446-appb-000269
Figure PCTCN2022088446-appb-000269
室温下，将1-苄基4-(叔丁基)2-甲基-哌嗪-1,2,4-三羧酸酯(29a)(5.3g,14.01mmol)溶于THF(30mL)中，加入EtOH(30mL)、NaBH 4(0.79g,21.02mmol)和LiCl(0.89g,21.02mmol)，混合物在室温搅拌过夜，将反应液倒入到水(50mL)中，乙酸乙酯(50mL x 3)萃取，合并有机相，有机相用饱和食盐水(30mL x 3)反洗，无水硫酸钠干燥，抽滤，滤液减压浓缩得残留物。残留物用硅胶柱色谱分离提纯(30％EA in PE)得到：(4-(叔丁基)2-(羟甲基)哌嗪-1,4-二羧酸1-苄基酯(29b)(3g,61％)。 1-Benzyl 4-(tert-butyl) 2-methyl-piperazine-1,2,4-tricarboxylate (29a) (5.3 g, 14.01 mmol) was dissolved in THF (30 mL) at room temperature , EtOH (30 mL), NaBH 4 (0.79 g, 21.02 mmol) and LiCl (0.89 g, 21.02 mmol) were added, the mixture was stirred at room temperature overnight, the reaction solution was poured into water (50 mL), ethyl acetate (50 mL x 3) Extraction, the organic phases were combined, the organic phase was backwashed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered with suction, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (30% EA in PE) to give: (4-(tert-butyl)2-(hydroxymethyl)piperazine-1,4-dicarboxylate 1-benzyl ester (29b) (3g, 61%).
LCMS m/z＝251.1[M-99] +。 LCMS m/z = 251.1 [M-99] + .
第二步：1-苄基4-(叔丁基)2-甲酰基哌嗪-1,4-二羧酸酯(29c)The second step: 1-benzyl 4-(tert-butyl) 2-formylpiperazine-1,4-dicarboxylate (29c)
1-benzyl 4-(tert-butyl)2-formylpiperazine-1,4-dicarboxylate1-benzyl 4-(tert-butyl)2-formylpiperazine-1,4-dicarboxylate
Figure PCTCN2022088446-appb-000270
Figure PCTCN2022088446-appb-000270
室温下，将(4-(叔丁基)2-(羟甲基)哌嗪-1,4-二羧酸1-苄基酯(29b)(3.9g,11.13mmol)溶解DCM(60mL)中，加入Dess-Martin氧化剂(4.96g,11.69mmol)，冰浴下反应4小时。反应完全后，加水淬灭反应，乙酸乙酯(50mL x 3)萃取，合并有机相，有机相用饱和食盐水(30mL x 3)反洗，无水硫酸钠干燥，抽滤，滤液减压浓缩得残留物。残留物用硅胶柱色谱分离提纯(20％EA in PE)得到：1-苄基4-(叔丁基)2-甲酰基哌嗪-1,4-二羧酸酯(29c)(3g,77％)。(4-(tert-Butyl)2-(hydroxymethyl)piperazine-1,4-dicarboxylic acid 1-benzyl ester (29b) (3.9 g, 11.13 mmol) was dissolved in DCM (60 mL) at room temperature , add Dess-Martin oxidant (4.96g, 11.69mmol), react under ice bath for 4 hours.After the reaction is complete, add water to quench the reaction, extract with ethyl acetate (50mL x 3), combine the organic phases, and use saturated brine for the organic phase (30mL×3) backwashed, dried over anhydrous sodium sulfate, suction filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. The residue was separated and purified by silica gel column chromatography (20% EA in PE) to obtain: 1-benzyl 4-(tertiary Butyl) 2-formylpiperazine-1,4-dicarboxylate (29c) (3 g, 77%).
LCMS m/z＝293.1[M-55] +。 LCMS m/z=293.1 [M-55] + .
第三步：1-苄基4-(叔丁基)2-乙烯基哌嗪-1,4-二羧酸酯(29d)The third step: 1-benzyl 4-(tert-butyl) 2-vinylpiperazine-1,4-dicarboxylate (29d)
1-benzyl 4-(tert-butyl)2-vinylpiperazine-1,4-dicarboxylate1-benzyl 4-(tert-butyl)2-vinylpiperazine-1,4-dicarboxylate
Figure PCTCN2022088446-appb-000271
Figure PCTCN2022088446-appb-000271
室温下，将甲基三苯基溴化膦(4.61g,12.91mmol)溶解于THF(60mL)中，氮气置换3次，将混合物冷却到-78℃，滴加n-BuLi(6.88mL,10.33mmol,1.5M)，滴加完毕，在此温度下搅拌1h,加入1-苄基4-(叔丁基)2-甲酰基哌嗪-1,4-二羧酸酯(29c)(3g,8.61mmol)，-78℃下反应2h。加水淬灭反应，乙酸乙酯(50mL x 3)萃取，合并有机相，有机相用饱和食盐水(30mL x 3)反洗，无水硫酸钠干燥，抽滤，滤液减压浓缩得残留物。残留物用硅胶柱色谱分离提纯(15％EA in PE)得到：1-苄基4-(叔丁基)2-乙烯基哌嗪-1,4-二羧酸酯(29d)(1.8g,60％)。At room temperature, methyltriphenylphosphine bromide (4.61 g, 12.91 mmol) was dissolved in THF (60 mL), nitrogen was replaced 3 times, the mixture was cooled to -78 °C, n-BuLi (6.88 mL, 10.33 mmol) was added dropwise mmol, 1.5M), the dropwise addition was completed, stirred at this temperature for 1 h, added 1-benzyl 4-(tert-butyl) 2-formylpiperazine-1,4-dicarboxylate (29c) (3g, 8.61 mmol), reacted at -78°C for 2h. Water was added to quench the reaction, extracted with ethyl acetate (50 mL×3), the organic phases were combined, the organic phase was backwashed with saturated brine (30 mL×3), dried over anhydrous sodium sulfate, filtered with suction, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (15% EA in PE) to give: 1-benzyl 4-(tert-butyl) 2-vinylpiperazine-1,4-dicarboxylate (29d) (1.8 g, 60%).
LCMS m/z＝247.2[M-99] +。 LCMS m/z=247.2[M-99] + .
第四步：1-苄基4-(叔丁基)-2-(2-(2-羟基-5-(三氟甲基)吡啶-3-基)乙烯基)哌嗪-1,4-二羧酸酯(化合物29e)The fourth step: 1-benzyl 4-(tert-butyl)-2-(2-(2-hydroxy-5-(trifluoromethyl)pyridin-3-yl)vinyl)piperazine-1,4- Dicarboxylate (Compound 29e)
1-benzyl 4-(tert-butyl)-2-(2-(2-hydroxy-5-(trifluoromethyl)pyridin-3-yl)vinyl)piperazine-1,4-dicarboxylate1-benzyl 4-(tert-butyl)-2-(2-(2-hydroxy-5-(trifluoromethyl)pyridin-3-yl)vinyl)piperazine-1,4-dicarboxylate
Figure PCTCN2022088446-appb-000272
Figure PCTCN2022088446-appb-000272
室温下，将1-苄基4-(叔丁基)2-乙烯基哌嗪-1,4-二羧酸酯(29d)(200mg,0.58mmol)溶解于DMF(6mL)中，加入3-溴-2-氟-5-(三氟甲基)吡啶(210mg,0.87mmol)，K 2CO 3(240mg,1.74mmol)，Xphos(110mg,0.23mmol)和Pd(OAc) 2(26mg,0.12mmol)。氮气置换3次，在100℃下搅拌过夜，加水淬灭反应，乙酸乙酯(10mL x 3)萃取，合并有机相，有机相用饱和食盐水(10mL x 3)反洗，无水硫酸钠干燥，抽滤，滤液减压浓缩得残留物。残留物用硅胶柱色谱分离提纯(30％EA in PE)得到：1-苄基4-(叔丁基)-2-(2-(2-羟基-5-(三氟甲基)吡啶-3-基)乙烯基)哌嗪-1,4-二羧酸酯(化合物29e)(38mg,13％)，平行投9锅，一共得到340mg。 1-Benzyl 4-(tert-butyl) 2-vinylpiperazine-1,4-dicarboxylate (29d) (200 mg, 0.58 mmol) was dissolved in DMF (6 mL) at room temperature, 3- Bromo-2-fluoro-5-(trifluoromethyl)pyridine (210 mg, 0.87 mmol), K 2 CO 3 (240 mg, 1.74 mmol), Xphos (110 mg, 0.23 mmol) and Pd(OAc) 2 (26 mg, 0.12 mmol). Replaced with nitrogen three times, stirred at 100 °C overnight, added water to quench the reaction, extracted with ethyl acetate (10 mL x 3), combined the organic phases, backwashed the organic phases with saturated brine (10 mL x 3), and dried over anhydrous sodium sulfate. , filtered with suction, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (30% EA in PE) to give: 1-benzyl 4-(tert-butyl)-2-(2-(2-hydroxy-5-(trifluoromethyl)pyridine-3) -yl)vinyl)piperazine-1,4-dicarboxylate (compound 29e) (38 mg, 13%), 9 pots were thrown in parallel to give a total of 340 mg.
LCMS m/z＝452.0[M-55] +。 LCMS m/z = 452.0 [M-55] + .
第五步：3-(2-(2-羟基-5-(三氟甲基)吡啶-3-基)乙基)哌嗪-1-羧酸叔丁酯(化合物29f)The fifth step: tert-butyl 3-(2-(2-hydroxy-5-(trifluoromethyl)pyridin-3-yl)ethyl)piperazine-1-carboxylate (compound 29f)
Tert-butyl 3-(2-(2-hydroxy-5-(trifluoromethyl)pyridin-3-yl)ethyl)piperazine-1-carboxylateTert-butyl 3-(2-(2-hydroxy-5-(trifluoromethyl)pyridin-3-yl)ethyl)piperazine-1-carboxylate
Figure PCTCN2022088446-appb-000273
Figure PCTCN2022088446-appb-000273
室温下，将1-苄基4-(叔丁基)-2-(2-(2-羟基-5-(三氟甲基)吡啶-3-基)乙烯基)哌嗪-1,4-二羧酸酯(化合物29e)(150mg,0.3mmol)溶于MeOH(5mL)中，加入Pd/C(15mg)，室温搅拌反应过夜，过滤，浓缩得到3-(2-(2-羟基-5-(三氟甲基)吡啶-3-基)乙基)哌嗪-1-羧酸叔丁酯(化合物29f)(100mg,粗品)未进一步纯化，直接投下一步。平行投两锅一共得到200mg。At room temperature, 1-benzyl 4-(tert-butyl)-2-(2-(2-hydroxy-5-(trifluoromethyl)pyridin-3-yl)vinyl)piperazine-1,4- Dicarboxylate (compound 29e) (150 mg, 0.3 mmol) was dissolved in MeOH (5 mL), Pd/C (15 mg) was added, the reaction was stirred at room temperature overnight, filtered and concentrated to give 3-(2-(2-hydroxy-5 -(Trifluoromethyl)pyridin-3-yl)ethyl)piperazine-1-carboxylate tert-butyl ester (compound 29f) (100 mg, crude) was not further purified and was directly taken to the next step. Throw two pots in parallel to get a total of 200mg.
LCMS m/z＝376.2[M+1] +。 LCMS m/z=376.2[M+1] + .
第六步：3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡嗪并[1,2-a][1,8]萘啶-8-羧酸叔丁酯(化合物29g)The sixth step: 3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a][1,8]naphthyridine-8- tert-Butyl carboxylate (compound 29g)
Tert-butyl 3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a][1,8]naphthyridine-8-carboxylateTert-butyl 3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a][1,8]naphthyridine-8-carboxylate
Figure PCTCN2022088446-appb-000274
Figure PCTCN2022088446-appb-000274
室温下，将3-(2-(2-羟基-5-(三氟甲基)吡啶-3-基)乙基)哌嗪-1-羧酸叔丁酯(化合物29f)(110mg,0.29mmol)溶解于DMSO(5mL)中，加入PyBOP(150mg,0.29mmol)和DIPEA(37mg,0.29mmol)。60℃下搅拌过夜，加水淬灭反应，乙酸乙酯(10mL x 3)萃取，合并有机相，有机相用饱和食盐水(10mL x 3)反洗，无水硫酸钠干燥，抽滤，滤液减压浓缩得残留物。残留物用硅胶柱色谱分离提纯(10％EA in PE)得到：3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡嗪并[1,2-a][1,8]萘啶-8-羧酸叔丁酯(化合物29g)(80mg,77％)。At room temperature, tert-butyl 3-(2-(2-hydroxy-5-(trifluoromethyl)pyridin-3-yl)ethyl)piperazine-1-carboxylate (compound 29f) (110 mg, 0.29 mmol) ) was dissolved in DMSO (5 mL), PyBOP (150 mg, 0.29 mmol) and DIPEA (37 mg, 0.29 mmol) were added. Stir overnight at 60°C, add water to quench the reaction, extract with ethyl acetate (10 mL x 3), combine the organic phases, backwash the organic phases with saturated brine (10 mL x 3), dry over anhydrous sodium sulfate, filter with suction, and reduce the filtrate to Concentrate under pressure to obtain a residue. The residue was purified by silica gel column chromatography (10% EA in PE) to give: 3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2 -a][1,8]Naphthyridine-8-carboxylate tert-butyl ester (compound 29g) (80 mg, 77%).
LCMS m/z＝358.2[M+1] +。 LCMS m/z=358.2[M+1] + .
第七步：3-(三氟甲基)-6,6a,7,8,9,10-六氢-5H-吡嗪并[1,2-a][1,8]萘啶(化合物29h)的 盐酸盐The seventh step: 3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1,8]naphthyridine (compound 29h ) of hydrochloride
3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1,8]naphthyridine hydrochloride3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1,8]naphthyridine hydrochloride
Figure PCTCN2022088446-appb-000275
Figure PCTCN2022088446-appb-000275
室温下，将3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡嗪并[1,2-a][1,8]萘啶-8-羧酸叔丁酯(化合物29g)(80mg,0.22mmol)溶于氯化氢/1,4-二氧六环溶液(4.0M，2mL,8mmol)，室温反应至反应完全。减压浓缩除去溶剂后得3-(三氟甲基)-6,6a,7,8,9,10-六氢-5H-吡嗪并[1,2-a][1,8]萘啶(化合物29h)的盐酸盐(65.0mg,粗品)，未进一步纯化，直接用于一步。At room temperature, 3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a][1,8]naphthyridine-8- Carboxylic acid tert-butyl ester (compound 29g) (80mg, 0.22mmol) was dissolved in hydrogen chloride/1,4-dioxane solution (4.0M, 2mL, 8mmol), and reacted at room temperature until the reaction was complete. Concentrate under reduced pressure to remove the solvent to obtain 3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1,8]naphthyridine The hydrochloride salt of (compound 29h) (65.0 mg, crude) was used in one step without further purification.
LCMS m/z＝258.2[M+1] +。 LCMS m/z=258.2[M+1] + .
第八步：5-(((2S)-1-(3-氧-3-(3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡嗪并[1,2-a][1,8]萘啶-8-基)丙氧基)丙-2-基)氨基)-4-(三氟甲基)哒嗪-3(2H)-酮(化合物29)The eighth step: 5-(((2S)-1-(3-oxo-3-(3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazine [1,2-a][1,8]Naphthyridin-8-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 29)
5-(((2S)-1-(3-oxo-3-(3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a][1,8]naphthyridin-8-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one5-(((2S)-1-(3-oxo-3-(3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a][1 ,8]naphthyridin-8-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one
Figure PCTCN2022088446-appb-000276
Figure PCTCN2022088446-appb-000276
室温下，将3-(三氟甲基)-6,6a,7,8,9,10-六氢-5H-吡嗪并[1,2-a][1,8]萘啶(化合物29h)的盐酸盐(65mg,粗品)和3-[(2S)-2-[(6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基]丙氧基]丙酸(4j)(68mg,0.22mmol)溶于DMF(2mL)中，向其中分别加入DIPEA(85mg,0.66mmol)和HATU(84mg,0.22mmol)然后室温搅拌反应3小时。反应结束后，反应液经Pre-HPLC纯化(仪器及制备柱：采用WATERS 2767制备液相，制备柱型号是Xselect C18,5μm，内径×长度＝19mm×150mm)。制备方法：反应液用0.45μm滤膜过滤，制备成样品液。流动相体系：乙腈/水(含0.05％氨水)。梯度洗脱方法：乙腈由5％梯度洗脱至50％(洗脱时间15min)。冻干后得到5-(((2S)-1-(3-氧-3-(3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡嗪并[1,2-a][1,8]萘啶-8-基)丙氧基)丙-2-基)氨基)-4-(三氟甲基)哒 嗪-3(2H)-酮(化合物29)(80mg,收率为66％)At room temperature, 3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1,8]naphthyridine (compound 29h ) hydrochloride (65 mg, crude) and 3-[(2S)-2-[(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino ]Propoxy]propionic acid (4j) (68 mg, 0.22 mmol) was dissolved in DMF (2 mL), DIPEA (85 mg, 0.66 mmol) and HATU (84 mg, 0.22 mmol) were added thereto and the reaction was stirred at room temperature for 3 hours. After the reaction, the reaction solution was purified by Pre-HPLC (instrument and preparative column: WATERS 2767 was used to prepare the liquid phase, the preparative column model was Xselect C18, 5 μm, inner diameter×length=19mm×150mm). Preparation method: The reaction solution was filtered with a 0.45 μm 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). 5-(((2S)-1-(3-oxo-3-(3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazine) after lyophilization [1,2-a][1,8]Naphthyridin-8-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 29) (80 mg, 66% yield)
LCMS m/z＝549.2[M+1] +。 LCMS m/z=549.2[M+1] + .
实施例30：5-(((S)-1-(3-氧代-3-((S)-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡嗪并[1,2-a][1,8]萘啶-8-基)丙氧基)丙-2-基)氨基)-4-(三氟甲基)哒嗪-3(2H)-酮(化合物30a)Example 30: 5-(((S)-1-(3-oxo-3-((S)-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro -8H-pyrazino[1,2-a][1,8]naphthyridin-8-yl)propoxy)prop-2-yl)amino)-4-(trifluoromethyl)pyridazine-3 (2H)-ketone (compound 30a)
5-(((S)-1-(3-oxo-3-((S)-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a][1,8]naphthyridin-8-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one5-(((S)-1-(3-oxo-3-((S)-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2- a][1,8]naphthyridin-8-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one
5-(((S)-1-(3-氧代-3-((R)-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡嗪并[1,2-a][1,8]萘啶-8-基)丙氧基)丙-2-基)氨基)-4-(三氟甲基)哒嗪-3(2H)-酮(化合物30b)5-(((S)-1-(3-oxo-3-((R)-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyridine Azino[1,2-a][1,8]naphthyridin-8-yl)propoxy)prop-2-yl)amino)-4-(trifluoromethyl)pyridazine-3(2H)- Ketone (Compound 30b)
5-(((S)-1-(3-oxo-3-((R)-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a][1,8]naphthyridin-8-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one5-(((S)-1-(3-oxo-3-((R)-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2- a][1,8]naphthyridin-8-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one
Figure PCTCN2022088446-appb-000277
Figure PCTCN2022088446-appb-000277
化合物29(70mg,0.13mmol)经SFC on AD column纯化(仪器及制备柱：采用Waters 150mgm，制备柱型号是Chiralpak Column)。制备方法：化合物29用乙腈溶解，制备成样品液。流动相体系：A for CO 2 and B for MeOH(0.1％NH 3·H 2O)。梯度洗脱方法：30％phase B(流速：110mL/min；洗脱时间3.3min)，冻干后得到化合物P1(20mg)和化合物P2(33.6mg)。 Compound 29 (70 mg, 0.13 mmol) was purified by SFC on AD column (instrument and preparative column: Waters 150 mgm, preparative column model is Chiralpak Column). Preparation method: Compound 29 was dissolved in acetonitrile to prepare a sample solution. Mobile phase system: A for CO 2 and B for MeOH (0.1% NH 3 ·H 2 O). Gradient elution method: 30% phase B (flow rate: 110 mL/min; elution time 3.3 min), after lyophilization, compound P1 (20 mg) and compound P2 (33.6 mg) were obtained.
分析方法(仪器及制备柱：SHIMADZULC-30AD sf，制备柱型号是：Chiralpak AD-3 50×4.6mm I.D.流动相体系：A for CO 2 and B for MeOH(0.05％DEA)，3.0ml/min。 Analytical method (instrument and preparative column: SHIMADZULC-30AD sf, preparative column model: Chiralpak AD-3 50×4.6 mm ID mobile phase system: A for CO 2 and B for MeOH (0.05% DEA), 3.0 ml/min.
保留时间T＝2.03min为化合物P1(化合物P1为化合物30a和化合物30b结构之一)。Retention time T=2.03min is compound P1 (compound P1 is one of the structures of compound 30a and compound 30b).
LCMS m/z＝549.2[M+1] +。 LCMS m/z=549.2[M+1] + .
1H NMR(400MHz,CDCl 3)δ10.46-10.25(m,1H),8.25(s,1H),7.65(s,1H),7.43-7.32(m,1H),5.88-5.70(m,1H),5.03-4.83(m,1H),4.72-4.55(m,1H),3.99-3.78(m,4H),3.71-3.61(m,1H),3.54-3.45(m,1H),3.44-2.77(m,5H),2.73-2.42(m,3H),2.19-2.04(m,1H),1.81-1.71(m,1H),1.30(d,3H)。 1 H NMR (400MHz, CDCl 3 )δ10.46-10.25(m,1H), 8.25(s,1H), 7.65(s,1H), 7.43-7.32(m,1H), 5.88-5.70(m,1H) ), 5.03-4.83(m, 1H), 4.72-4.55(m, 1H), 3.99-3.78(m, 4H), 3.71-3.61(m, 1H), 3.54-3.45(m, 1H), 3.44-2.77 (m, 5H), 2.73-2.42 (m, 3H), 2.19-2.04 (m, 1H), 1.81-1.71 (m, 1H), 1.30 (d, 3H).
保留时间T＝2.245min为化合物P2(化合物P2为化合物30a和化合物30b结构之一)。Retention time T=2.245min is compound P2 (compound P2 is one of the structures of compound 30a and compound 30b).
LCMS m/z＝549.2[M+1] +。 LCMS m/z=549.2[M+1] + .
1H NMR(400MHz,CDCl 3)δ10.34(s,1H),8.25(s,1H),7.66(s,1H),7.44-7.3 2(m,1H),5.90-5.70(m,1H),5.03-4.83(m,1H),4.73-4.54(m,1H),3.99-3.76(m,4H),3.71-3.57(m,1H),3.56-3.45(m,1H),3.44-2.77(m,5H),2.73-2.45(m,3H),2.23-2.04(m,1H),1.81-1.68(m,1H),1.30(d,3H)。 1 H NMR (400MHz, CDCl 3 ) δ 10.34(s, 1H), 8.25(s, 1H), 7.66(s, 1H), 7.44-7.3 2(m, 1H), 5.90-5.70(m, 1H) ,5.03-4.83(m,1H),4.73-4.54(m,1H),3.99-3.76(m,4H),3.71-3.57(m,1H),3.56-3.45(m,1H),3.44-2.77( m, 5H), 2.73-2.45 (m, 3H), 2.23-2.04 (m, 1H), 1.81-1.68 (m, 1H), 1.30 (d, 3H).
实施例31：5-((S)-1-(3-((R)-5-甲基-6-硫基-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡嗪[1,2-a]吡啶[3,2-e]吡嗪-8-基)-3-氧丙氧基-2-基)氨基)-4-(三氟甲基)吡嗪-3(2H)-酮(化合物31)Example 31: 5-((S)-1-(3-((R)-5-methyl-6-sulfanyl-3-(trifluoromethyl)-5,6,6a,7,9, 10-Hexahydro-8H-pyrazine[1,2-a]pyridin[3,2-e]pyrazin-8-yl)-3-oxopropoxy-2-yl)amino)-4-(tris Fluoromethyl)pyrazin-3(2H)-one (Compound 31)
5-(((S)-1-(3-((R)-5-methyl-6-thioxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-8-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one5-(((S)-1-(3-((R)-5-methyl-6-thioxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[ 1,2-a]pyrido[3,2-e]pyrazin-8-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one
Figure PCTCN2022088446-appb-000278
Figure PCTCN2022088446-appb-000278
第一步：(R)-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪[1,2-a]吡啶基[3,2-e]吡嗪-6(6aH)-酮盐酸盐(31a)The first step: (R)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazine[1,2-a]pyridyl[3,2-e]pyrazine -6(6aH)-keto hydrochloride (31a)
(R)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one(R)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one
Figure PCTCN2022088446-appb-000279
Figure PCTCN2022088446-appb-000279
室温下，将叔丁基(R)-6-氧代-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-8-羧酸酯(4d)(2g,5.38mmol)溶于1,4-二氧六环(30mL)溶液中，再加入氯化氢/1,4-二氧六环溶液(4.0M，30mL,40mmol)，室温反应4小时。反应结束后，减压浓缩除去溶剂得(R)-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪[1,2-a]吡啶基[3,2- e]吡嗪-6(6aH)-酮(31a)的盐酸盐(1.46g,粗品)，直接用于下一步。At room temperature, 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 (4d) (2g, 5.38mmol) was dissolved in 1,4-dioxane (30mL) solution, and then hydrogen chloride/1, 4-dioxane solution (4.0 M, 30 mL, 40 mmol) was reacted at room temperature for 4 hours. After the reaction, the solvent was removed by concentration under reduced pressure to obtain (R)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazine[1,2-a]pyridinyl[3, The hydrochloride salt of 2-e]pyrazin-6(6aH)-one (31a) (1.46 g, crude) was used directly in the next step.
LCMS m/z＝273.1[M+1] +。 LCMS m/z=273.1[M+1] + .
第二步：2-(三甲基硅基)乙基(R)-6-氧代-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡嗪[1,2-a]吡啶[3,2-e]吡嗪-8-羧酸酯(31b)The second step: 2-(trimethylsilyl)ethyl(R)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H- Pyrazine[1,2-a]pyridine[3,2-e]pyrazine-8-carboxylate (31b)
2-(trimethylsilyl)ethyl(R)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8-carboxylate2-(trimethylsilyl)ethyl(R)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2- e]pyrazine-8-carboxylate
Figure PCTCN2022088446-appb-000280
Figure PCTCN2022088446-appb-000280
室温下，将(R)-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪[1,2-a]吡啶基[3,2-e]吡嗪-6(6aH)-酮(31a)盐酸盐(1.46g,粗品)，N-[2-(三甲基硅基)乙氧羰氧基]琥珀酰亚胺(1.4g,5.38mmol)，三乙胺(1.76g,16.13mmol)溶于四氢呋喃(50mL)中，室温反应一小时。加水(50mL)淬灭反应，乙酸乙酯(50mL x 2)萃取，合并有机相，有机相用饱和食盐水洗涤，无水硫酸钠干燥后过滤，滤液减压浓缩后得粗品。粗品经制备柱分离纯化(石油醚：乙酸乙酯(v/v)＝8:1)得2-(三甲基硅基)乙基(R)-6-氧代-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡嗪[1,2-a]吡啶[3,2-e]吡嗪-8-羧酸酯(31b)(1.9g,85％)。At room temperature, (R)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazine[1,2-a]pyridyl[3,2-e]pyrazine -6(6aH)-keto(31a) hydrochloride (1.46 g, crude), N-[2-(trimethylsilyl)ethoxycarbonyloxy]succinimide (1.4 g, 5.38 mmol), Triethylamine (1.76 g, 16.13 mmol) was dissolved in tetrahydrofuran (50 mL) and reacted at room temperature for one hour. Water (50 mL) was added to quench the reaction, extracted with ethyl acetate (50 mL x 2), 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 crude product was separated and purified by a preparative column (petroleum ether:ethyl acetate (v/v)=8:1) to obtain 2-(trimethylsilyl)ethyl(R)-6-oxo-3-(trifluoromethyl) (31b)(1.9 g, 85%).
LCMS m/z＝415.1[M-1] -。 LCMS m/z=415.1 [M-1] − .
第三步：2-(三甲基硅基)乙基(R)-6-硫基-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡嗪[1,2-a]吡啶[3,2-e]吡嗪-8-羧酸酯(化合物31c)The third step: 2-(trimethylsilyl)ethyl(R)-6-sulfanyl-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H- Pyrazine[1,2-a]pyridine[3,2-e]pyrazine-8-carboxylate (Compound 31c)
2-(trimethylsilyl)ethyl(R)-6-thioxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8-carboxylate2-(trimethylsilyl)ethyl(R)-6-thioxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2- e]pyrazine-8-carboxylate
Figure PCTCN2022088446-appb-000281
Figure PCTCN2022088446-appb-000281
室温下，将2-(三甲基硅基)乙基(R)-6-氧代-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡嗪[1,2-a]吡啶[3,2-e]吡嗪-8-羧酸酯(31b)(3.4g,8.17mmol)和劳森试剂(6.8g,16.83mmol)溶于四氢呋喃(100mL)中，60℃搅拌反应3小时。反应结束后，减压浓缩后得粗品。粗品经制备柱分离纯化(石油醚：乙酸乙酯(v/v)＝8:1)得2-(三甲基硅基)乙基(R) -6-硫基-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡嗪[1,2-a]吡啶[3,2-e]吡嗪-8-羧酸酯(化合物31c)(1.95g,55％)。At room temperature, 2-(trimethylsilyl)ethyl(R)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H- Pyrazine[1,2-a]pyridine[3,2-e]pyrazine-8-carboxylate (31b) (3.4 g, 8.17 mmol) and Lawson's reagent (6.8 g, 16.83 mmol) were dissolved in tetrahydrofuran ( 100 mL), the reaction was stirred at 60°C for 3 hours. After the reaction was completed, the crude product was obtained after concentration under reduced pressure. The crude product was separated and purified by a preparative column (petroleum ether:ethyl acetate (v/v)=8:1) to obtain 2-(trimethylsilyl)ethyl(R)-6-sulfanyl-3-(trifluoromethyl) (Compound 31c)( 1.95g, 55%).
LCMS m/z＝431.1[M-1] -。 LCMS m/z=431.1 [M-1] − .
第四步：2-(三甲基硅基)乙基(R)-5-甲基-6-硫基-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡嗪[1,2-a]吡啶[3,2-e]吡嗪-8-羧酸酯(31d)The fourth step: 2-(trimethylsilyl)ethyl(R)-5-methyl-6-sulfanyl-3-(trifluoromethyl)-5,6,6a,7,9,10- Hexahydro-8H-pyrazine[1,2-a]pyridine[3,2-e]pyrazine-8-carboxylate (31d)
2-(trimethylsilyl)ethyl(R)-5-methyl-6-thioxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8-carboxylate2-(trimethylsilyl)ethyl(R)-5-methyl-6-thioxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[ 3,2-e]pyrazine-8-carboxylate
Figure PCTCN2022088446-appb-000282
Figure PCTCN2022088446-appb-000282
室温下，将2-(三甲基硅基)乙基(R)-6-硫基-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡嗪[1,2-a]吡啶[3,2-e]吡嗪-8-羧酸酯(化合物31c)(300mg,0.69mmol)，碘甲烷(200mg,1.39mmol)溶于DMF(5mL)中，加入碳酸钾(288mg,2.08mmol)。室温搅拌反应2小时。反应结束后，加入饱和食盐水(20mL)，加入乙酸乙酯萃取(20mLx2)。合并有机相，有机相用饱和食盐水洗涤(20mL x 3)，无水硫酸钠干燥，减压浓缩后得粗品。粗品经制备柱分离纯化(石油醚：乙酸乙酯(v/v)＝8:1)得到2-(三甲基硅基)乙基(R)-5-甲基-6-硫基-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡嗪[1,2-a]吡啶[3,2-e]吡嗪-8-羧酸酯(31d)(261mg,85％)。At room temperature, 2-(trimethylsilyl)ethyl(R)-6-sulfanyl-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H- Pyrazine[1,2-a]pyridine[3,2-e]pyrazine-8-carboxylate (Compound 31c) (300 mg, 0.69 mmol), iodomethane (200 mg, 1.39 mmol) was dissolved in DMF (5 mL) To this, potassium carbonate (288 mg, 2.08 mmol) was added. The reaction was stirred at room temperature for 2 hours. After the reaction, saturated brine (20 mL) was added, and ethyl acetate was added for extraction (20 mL×2). The organic phases were combined, washed with saturated brine (20 mL×3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by preparative column (petroleum ether:ethyl acetate (v/v)=8:1) to obtain 2-(trimethylsilyl)ethyl(R)-5-methyl-6-sulfanyl-3 -(Trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazine[1,2-a]pyridine[3,2-e]pyrazine-8-carboxylate (31d) (261 mg, 85%).
LCMS m/z＝447.1[M+1] +。 LCMS m/z=447.1[M+1] + .
第五步：(R)-5-甲基-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪[1,2-a]吡啶[3,2-e]吡嗪-6(6aH)-硫酮(31e)The fifth step: (R)-5-methyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazine[1,2-a]pyridine[3,2- e]pyrazine-6(6aH)-thione (31e)
(R)-5-methyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-6(6aH)-thione(R)-5-methyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-6(6aH)-thione
Figure PCTCN2022088446-appb-000283
Figure PCTCN2022088446-appb-000283
室温下，将2-(三甲基硅基)乙基(R)-5-甲基-6-硫基-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡嗪[1,2-a]吡啶[3,2-e]吡嗪-8-羧酸酯(31d)(261mg,0.59mmol)溶于四氢呋喃(3 mL)溶液中，再加入四丁基氟化铵-四氢呋喃溶液(1.0M，3mL,3.00mmol)，室温反应4小时。反应结束后，减压浓缩除去溶剂得粗品，粗品经制备柱分离纯化(石油醚：乙酸乙酯(v/v)＝1:8)得(R)-5-甲基-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪[1,2-a]吡啶[3,2-e]吡嗪-6(6aH)-硫酮(31e)(87mg,49％)。At room temperature, 2-(trimethylsilyl)ethyl(R)-5-methyl-6-sulfanyl-3-(trifluoromethyl)-5,6,6a,7,9,10- Hexahydro-8H-pyrazine[1,2-a]pyridine[3,2-e]pyrazine-8-carboxylate (31d) (261 mg, 0.59 mmol) was dissolved in tetrahydrofuran (3 mL), and then Tetrabutylammonium fluoride-tetrahydrofuran solution (1.0 M, 3 mL, 3.00 mmol) was added, and the reaction was carried out at room temperature for 4 hours. After the reaction, the solvent was concentrated under reduced pressure to remove the crude product. The crude product was separated and purified by a preparative column (petroleum ether:ethyl acetate (v/v)=1:8) to obtain (R)-5-methyl-3-(trifluoro) methyl)-7,8,9,10-tetrahydro-5H-pyrazine[1,2-a]pyridine[3,2-e]pyrazine-6(6aH)-thione (31e) (87mg, 49%).
LCMS m/z＝303.1[M+1] +。 LCMS m/z=303.1[M+1] + .
第六步：5-((S)-1-(3-((R)-5-甲基-6-硫基-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡嗪[1,2-a]吡啶[3,2-e]吡嗪-8-基)-3-氧丙氧基-2-基)氨基)-4-(三氟甲基)吡嗪-3(2H)-酮(化合物31)The sixth step: 5-((S)-1-(3-((R)-5-methyl-6-sulfanyl-3-(trifluoromethyl)-5,6,6a,7,9, 10-Hexahydro-8H-pyrazine[1,2-a]pyridin[3,2-e]pyrazin-8-yl)-3-oxopropoxy-2-yl)amino)-4-(tris Fluoromethyl)pyrazin-3(2H)-one (Compound 31)
5-(((S)-1-(3-((R)-5-methyl-6-thioxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-8-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one5-(((S)-1-(3-((R)-5-methyl-6-thioxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[ 1,2-a]pyrido[3,2-e]pyrazin-8-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one
Figure PCTCN2022088446-appb-000284
Figure PCTCN2022088446-appb-000284
室温下，将3-[(2S)-2-[(6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基]丙氧基]丙酸(4j)(81mg,0.26mmol)和(R)-5-甲基-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪[1,2-a]吡啶[3,2-e]吡嗪-6(6aH)-硫酮(31e)(80mg,0.26mmol)溶于DMF(3mL)中，向其中分别加入DIPEA(102mg,0.79mmol)和HATU(101mg,0.26mmol)然后室温搅拌反应3小时。反应结束后，反应液经Pre-HPLC纯化(仪器及制备柱：采用WATERS 2767制备液相，制备柱型号是Xselect C18，5μm，内径×长度＝19mm×150mm)。制备方法：反应液用0.45μm滤膜过滤，制备成样品液。流动相体系：乙腈/水(含0.05％氨水)。梯度洗脱方法：乙腈由5％梯度洗脱至50％(洗脱时间15min)。冻干后得到5-((S)-1-(3-((R)-5-甲基-6-硫基-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡嗪[1,2-a]吡啶[3,2-e]吡嗪-8-基)-3-氧丙氧基-2-基)氨基)-4-(三氟甲基)吡嗪-3(2H)-酮(化合物31)(20mg,12％)。3-[(2S)-2-[(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino]propoxy]propionic acid at room temperature (4j) (81 mg, 0.26 mmol) and (R)-5-methyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazine[1,2-a] Pyridin[3,2-e]pyrazine-6(6aH)-thione (31e) (80 mg, 0.26 mmol) was dissolved in DMF (3 mL), to which was added DIPEA (102 mg, 0.79 mmol) and HATU (101 mg, respectively) , 0.26 mmol) and then the reaction was stirred at room temperature for 3 hours. After the reaction, the reaction solution was purified by Pre-HPLC (instrument and preparative column: WATERS 2767 was used to prepare the liquid phase, the preparative column model was Xselect C18, 5 μm, inner diameter×length=19mm×150mm). Preparation method: The reaction solution was filtered with a 0.45 μm 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). After lyophilization, 5-((S)-1-(3-((R)-5-methyl-6-sulfanyl-3-(trifluoromethyl)-5,6,6a,7,9, 10-Hexahydro-8H-pyrazine[1,2-a]pyridin[3,2-e]pyrazin-8-yl)-3-oxopropoxy-2-yl)amino)-4-(tris Fluoromethyl)pyrazin-3(2H)-one (Compound 31) (20 mg, 12%).
LCMS m/z＝594.3[M+1] +。 LCMS m/z=594.3[M+1] + .
1H NMR(400MHz,DMSO-d 6)δ12.43(s,1H),8.21(s,1H),7.90(s,1H),7.52-7.48(m,1H),6.31-6.19(m,1H),4.70-4.58(m,2H),4.50-4.34(m,1H),4.21-4.09(m,1H),4.04-3.87(m,1H),3.73-3.60(m,2H),3.57-3.45(m,2H),3.43-3.05(m,1H),2.93-2.56(m,4H),2.51(s,3H),1.15(d,3H)。 1 H NMR (400MHz, DMSO-d 6 )δ12.43(s,1H), 8.21(s,1H), 7.90(s,1H), 7.52-7.48(m,1H), 6.31-6.19(m,1H) ), 4.70-4.58(m, 2H), 4.50-4.34(m, 1H), 4.21-4.09(m, 1H), 4.04-3.87(m, 1H), 3.73-3.60(m, 2H), 3.57-3.45 (m, 2H), 3.43-3.05 (m, 1H), 2.93-2.56 (m, 4H), 2.51 (s, 3H), 1.15 (d, 3H).
实施例32：5-((S)-1-(3-((R)-3-氯-5-甲基-6-硫基-5,6,6a,7,9,10-六氢-8H-吡嗪[1,2-a]吡 啶[3,2-e]吡嗪-8-基)-3-氧丙氧基)丙烷-2-基)氨基)-4-(三氟甲基)吡嗪-3(2H)-酮(化合物32)Example 32: 5-((S)-1-(3-((R)-3-chloro-5-methyl-6-sulfanyl-5,6,6a,7,9,10-hexahydro- 8H-pyrazin[1,2-a]pyridin[3,2-e]pyrazin-8-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl) ) pyrazin-3(2H)-one (compound 32)
5-(((S)-1-(3-((R)-3-chloro-5-methyl-6-thioxo-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-8-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one5-(((S)-1-(3-((R)-3-chloro-5-methyl-6-thioxo-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1, 2-a]pyrido[3,2-e]pyrazin-8-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one
Figure PCTCN2022088446-appb-000285
Figure PCTCN2022088446-appb-000285
化合物32以2,5-二氯-3-硝基吡啶和(3R)-哌嗪-1-甲酸叔丁酯-3-甲酸甲酯(4b)为起始原料，参考实施例31的合成方法，得到5-((S)-1-(3-((R)-3-氯-5-甲基-6-硫基-5,6,6a,7,9,10-六氢-8H-吡嗪[1,2-a]吡啶[3,2-e]吡嗪-8-基)-3-氧丙氧基)丙烷-2-基)氨基)-4-(三氟甲基)吡嗪-3(2H)-酮(化合物32)Compound 32 uses 2,5-dichloro-3-nitropyridine and (3R)-piperazine-1-carboxylic acid tert-butyl ester-3-carboxylic acid methyl ester (4b) as starting materials, referring to the synthetic method of Example 31 , to give 5-((S)-1-(3-((R)-3-chloro-5-methyl-6-sulfanyl-5,6,6a,7,9,10-hexahydro-8H- Pyrazin[1,2-a]pyridin[3,2-e]pyrazin-8-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridine Azin-3(2H)-one (Compound 32)
LCMS m/z＝560.1[M+1] +。 LCMS m/z=560.1[M+1] + .
1H NMR(400MHz,DMSO-d 6)δ12.43(s,1H),7.96-7.85(m,2H),7.40(d,1H),6.34-6.16(m,1H),4.65-4.42(m,2H),4.39-4.24(m,1H),4.20-4.07(m,1H),4.00-3.83(m,1H),3.76-3.60(m,2H),3.54-3.44(m，2H),3.35-3.04(m,1H),2.86-2.55(m,4H),2.49(s,3H),1.15(d,3H)。 1 H NMR (400MHz, DMSO-d 6 ) δ 12.43(s, 1H), 7.96-7.85(m, 2H), 7.40(d, 1H), 6.34-6.16(m, 1H), 4.65-4.42(m ,2H),4.39-4.24(m,1H),4.20-4.07(m,1H),4.00-3.83(m,1H),3.76-3.60(m,2H),3.54-3.44(m,2H),3.35 -3.04(m, 1H), 2.86-2.55(m, 4H), 2.49(s, 3H), 1.15(d, 3H).
实施例33：(R)-5-异丁基-8-(3-((S)-2-((6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基)丙氧基)丙酰基)-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪并[1,2-a]吡啶并[3,2-E]吡嗪-6-(6aH)-酮(化合物33)Example 33: (R)-5-isobutyl-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]pyrido[ 3,2-E]pyrazin-6-(6aH)-one (Compound 33)
(R)-5-isobutyl-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one(R)-5-isobutyl-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3 -(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one
Figure PCTCN2022088446-appb-000286
Figure PCTCN2022088446-appb-000286
第一步：叔丁基(R)-5-异丁基-6-氧代-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-8-羧酸酯(33a)The first step: tert-butyl (R)-5-isobutyl-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazine Do[1,2-a]pyrido[3,2-e]pyrazine-8-carboxylate (33a)
tert-butyl-(R)-5-isobutyl-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8-carboxylatetert-butyl-(R)-5-isobutyl-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3, 2-e]pyrazine-8-carboxylate
Figure PCTCN2022088446-appb-000287
Figure PCTCN2022088446-appb-000287
室温下，将叔丁基(R)-6-氧代-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-8-羧酸酯(4d)(110mg,0.30mmol)，碘代异丁烷(83mg,0.45mmol)溶于DMF(5mL)中，加入碳酸钾(210mg,0.91mmol)。反应液在室温搅拌反应16小时。反应结束后，加入饱和食盐水(20mL)，加入乙酸乙酯萃取(20mLx2)。合并有机相，有机相用饱和食盐水洗涤(20mL x 3)，无水硫酸钠干燥，减压浓缩后得粗品。粗品经制备柱分离纯化(石油醚：乙酸乙酯(v/v)＝8:2)得叔丁基(R)-5-异丁基-6-氧代-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-8-羧酸酯(33a)(100mg,78％)。At room temperature, 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 (4d) (110 mg, 0.30 mmol), iodoisobutane (83 mg, 0.45 mmol) was dissolved in DMF (5 mL), carbonic acid was added Potassium (210 mg, 0.91 mmol). The reaction solution was stirred at room temperature for 16 hours. After the reaction, saturated brine (20 mL) was added, and ethyl acetate was added for extraction (20 mL×2). The organic phases were combined, washed with saturated brine (20 mL×3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by preparative column (petroleum ether:ethyl acetate (v/v)=8:2) to obtain tert-butyl(R)-5-isobutyl-6-oxo-3-(trifluoromethyl) -5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8-carboxylate (33a) (100 mg , 78%).
LCMS m/z＝373.1[M-55] +。 LCMS m/z = 373.1 [M-55] + .
第二步：(R)-5-异丁基-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-6(6aH)-酮盐酸盐(33b)The second step: (R)-5-isobutyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3 ,2-e]pyrazin-6(6aH)-one hydrochloride (33b)
(R)-5-isobutyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one hydrochloride(R)-5-isobutyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one hydrochloride
Figure PCTCN2022088446-appb-000288
Figure PCTCN2022088446-appb-000288
室温下，将(R)-5-异丁基-6-氧代-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-8-羧酸酯(33a)(100mg,0.23mmol)溶于1,4-二氧六环(3mL)溶液中，再加入氯化氢/1,4-二氧六环溶液(4.0M，3mL,40mmol)，室温反应4小时。反应结束后，减压浓缩后得(R)-5-异丁基-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-6(6aH)-酮盐酸盐(33b)(80mg,96％)粗品。At room temperature, (R)-5-isobutyl-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1 ,2-a]pyrido[3,2-e]pyrazine-8-carboxylate (33a) (100 mg, 0.23 mmol) was dissolved in 1,4-dioxane (3 mL), followed by hydrogen chloride /1,4-dioxane solution (4.0 M, 3 mL, 40 mmol), react at room temperature for 4 hours. After the reaction, concentrated under reduced pressure to obtain (R)-5-isobutyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a ]pyrido[3,2-e]pyrazin-6(6aH)-one hydrochloride (33b) (80 mg, 96%) crude.
LCMS m/z＝329.2[M+1] +。 LCMS m/z=329.2[M+1] + .
第三步：(R)-5-异丁基-8-(3-((S)-2-((6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基)丙氧基)丙酰基)-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪并[1,2-a]吡啶并[3,2-E]吡嗪-6-(6aH)-酮(化合物33)The third step: (R)-5-isobutyl-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]pyrido[ 3,2-E]pyrazin-6-(6aH)-one (Compound 33)
(R)-5-isobutyl-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one(R)-5-isobutyl-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3 -(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one
Figure PCTCN2022088446-appb-000289
Figure PCTCN2022088446-appb-000289
室温下，将3-[(2S)-2-[(6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基]丙氧基]丙酸(4j)(66mg,0.22mmol)和(R)-5-异丁基-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-6(6aH)-酮盐酸盐(33b)(80mg,0.22mmol)溶于DMF(3mL)中，向其中分别加入DIPEA(142mg,1.10mmol)和HATU(84mg,0.22mmol)然后室温搅拌反应3小时。反应结束后，反应液经Pre-HPLC纯化(仪器及制备柱：采用WATERS 2767制备液相，制备柱型号是Xselect C18，5μm，内径×长度＝19mm×150mm)。制备方法：反应液用0.45μm滤膜过滤，制备成样品液。流动相体系：乙腈/水(含0.05％氨水)。梯度洗脱方法：乙腈由5％梯度洗脱至50％(洗脱时间15min)。冻干后得到(R)-5-异丁基-8-(3-((S)-2-((6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基)丙氧基)丙酰基)-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪并[1,2-a]吡啶并[3,2-E]吡嗪-6-(6aH)-酮(化合物33)(20mg,12％)。3-[(2S)-2-[(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino]propoxy]propionic acid at room temperature (4j) (66 mg, 0.22 mmol) and (R)-5-isobutyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2- a] Pyrido[3,2-e]pyrazin-6(6aH)-one hydrochloride (33b) (80 mg, 0.22 mmol) was dissolved in DMF (3 mL), to which was added DIPEA (142 mg, 1.10 mmol, respectively) ) and HATU (84 mg, 0.22 mmol) were then stirred at room temperature for 3 hours. After the reaction, the reaction solution was purified by Pre-HPLC (instrument and preparative column: WATERS 2767 was used to prepare the liquid phase, the preparative column model was Xselect C18, 5 μm, inner diameter×length=19mm×150mm). Preparation method: The reaction solution was filtered with a 0.45 μm 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). Lyophilized to give (R)-5-isobutyl-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]pyrido[ 3,2-E]pyrazin-6-(6aH)-one (compound 33) (20 mg, 12%).
LCMS m/z＝620.3[M+1] +。 LCMS m/z=620.3[M+1] + .
1H NMR(400MHz,DMSO-d 6)δ12.42(s,1H),8.19(s,1H),7.90(s,1H),7.55(s,1H),6.30-6.19(m,1H),4.89-4.45(m,2H),4.31-3.98(m,3H),3.95-3.78(m,2H),3.75-3.62(m,2H),3.49(d,2H),3.28-3.09(m,1H),2.87-2.59(m,4H),1.97-1.85(m,1H),1.15(d,3H),0.98-0.77(m,6H)。 1 H NMR (400MHz, DMSO-d 6 )δ12.42(s,1H), 8.19(s,1H), 7.90(s,1H), 7.55(s,1H), 6.30-6.19(m,1H), 4.89-4.45(m, 2H), 4.31-3.98(m, 3H), 3.95-3.78(m, 2H), 3.75-3.62(m, 2H), 3.49(d, 2H), 3.28-3.09(m, 1H ), 2.87-2.59(m, 4H), 1.97-1.85(m, 1H), 1.15(d, 3H), 0.98-0.77(m, 6H).
实施例34：(R)-5-异丙基-8-(3-((S)-2-((6-氧-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基)丙氧基)丙酰基)-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-6(6aH)-酮(化合物34)Example 34: (R)-5-Isopropyl-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]pyrido[3 ,2-e]pyrazin-6(6aH)-one (Compound 34)
(R)-5-isopropyl-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one(R)-5-isopropyl-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3 -(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one
Figure PCTCN2022088446-appb-000290
Figure PCTCN2022088446-appb-000290
化合物34以叔丁基-(R)-6-氧代-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-8-羧酸酯(4d)和3-[(2S)-2-[(6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基]丙氧基]丙酸(4j)为原料，参考实施例33的合成方法，得到(R)-5-异丙基-8-(3-((S)-2-((6-氧-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基)丙氧基)丙酰基)-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-6(6aH)-酮(化合物34)。Compound 34 was identified as 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 (4d) and 3-[(2S)-2-[(6-oxo-5-(trifluoromethyl)-1, Using 6-dihydropyridazin-4-yl)amino]propoxy]propionic acid (4j) as raw material, referring to the synthetic method of Example 33, (R)-5-isopropyl-8-(3-( (S)-2-((6-Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionyl)-3-(trifluoromethyl) yl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one (Compound 34).
LCMS m/z＝606.2[M+1] +。 LCMS m/z=606.2[M+1] + .
1H NMR(400MHz,DMSO-d 6)δ12.42(s,1H),8.22(s,1H),7.90(s,1H),7.66-7.55(m,1H),6.32-6.18(m,1H),4.86-4.47(m,2H),4.39-4.30(m,1H),4.29-3.85(m,3H),3.77-3.60(m,2H),3.49(d,2H),3.25-3.09(m,1H),2.86-2.54(m,4H),1.63-1.24(m,6H),1.15(d,3H)。 1 H NMR (400MHz, DMSO-d 6 )δ12.42(s,1H), 8.22(s,1H), 7.90(s,1H), 7.66-7.55(m,1H), 6.32-6.18(m,1H) ), 4.86-4.47(m, 2H), 4.39-4.30(m, 1H), 4.29-3.85(m, 3H), 3.77-3.60(m, 2H), 3.49(d, 2H), 3.25-3.09(m , 1H), 2.86-2.54 (m, 4H), 1.63-1.24 (m, 6H), 1.15 (d, 3H).
实施例35：(6aR)-5-(氧杂环丁烷-2-基甲基)-8-(3-((S)-2-((6-氧-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基)丙氧基)丙酰基)-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-6(6aH)-酮(化合物35)Example 35: (6aR)-5-(oxetan-2-ylmethyl)-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 35)
(6aR)-5-(oxetan-2-ylmethyl)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one(6aR)-5-(oxetan-2-ylmethyl)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino) propoxy)propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one
Figure PCTCN2022088446-appb-000291
Figure PCTCN2022088446-appb-000291
Figure PCTCN2022088446-appb-000292
Figure PCTCN2022088446-appb-000292
第一步：(R)-6-氧代-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-8-羧酸苄酯(35a)The first step: (R)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyridine Benzyl [3,2-e]pyrazine-8-carboxylate (35a)
benzyl(R)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8-carboxylatebenzyl(R)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8 -carboxylate
Figure PCTCN2022088446-appb-000293
Figure PCTCN2022088446-appb-000293
室温下，将(R)-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-6(6aH)-酮(10e)(4g,11.59mmol)溶于THF(40mL)中，加入K 2CO 3(4.81g,34.77mmol)和H 2O(10mL)，混合物搅拌5min，冰浴下缓慢加入氯甲酸苄酯(1.21g,15.20mmol)，反应完全后，将反应液倒入到水(150mL)中，乙酸乙酯(50mL x 3)萃取，合并有机相，有机相用饱和食盐水(30mL x 3)反洗，无水硫酸钠干燥，抽滤，滤液减压浓缩得残留物。残留物用硅胶柱色谱分离提纯(石油醚：乙酸乙酯(V/V)＝5:1)得到：(R)-6-氧代-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-8-羧酸苄酯(35a)(4g,85％)。 At room temperature, (R)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyridine Zin-6(6aH)-one (10e) (4 g, 11.59 mmol) was dissolved in THF (40 mL), K 2 CO 3 (4.81 g, 34.77 mmol) and H 2 O (10 mL) were added, the mixture was stirred for 5 min, iced Benzyl chloroformate (1.21 g, 15.20 mmol) was slowly added under the bath, after the reaction was complete, the reaction solution was poured into water (150 mL), extracted with ethyl acetate (50 mL x 3), the organic phases were combined, and the organic phase was saturated with Backwashed with brine (30 mL x 3), dried over anhydrous sodium sulfate, suction filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V/V)=5:1) to obtain: (R)-6-oxo-3-(trifluoromethyl)-5,6,6a ,7,9,10-Hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8-carboxylate benzyl ester (35a) (4 g, 85%).
LCMS m/z＝407.1[M+1] +。 LCMS m/z=407.1[M+1] + .
第二步：(6aR)-5-(氧杂环丁烷-2-基甲基)-6-氧-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-8-羧酸苄酯(35b)The second step: (6aR)-5-(oxetan-2-ylmethyl)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexa Hydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8-carboxylate benzyl ester (35b)
Benzyl(6aR)-5-(oxetan-2-ylmethyl)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8-carboxylateBenzyl(6aR)-5-(oxetan-2-ylmethyl)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido [3,2-e]pyrazine-8-carboxylate
Figure PCTCN2022088446-appb-000294
Figure PCTCN2022088446-appb-000294
室温下，将(35a)(0.25g,0.62mmol)和2-碘甲基氧杂环丁烷(0.25g,1.24mmol)溶解DMF(2mL)中，加入碳酸钾(0.26g,1.86mmol)，室温反应36小时。反应完全后，加入乙酸乙酯(20mL x 2)，加入水洗(5mL x 3)，无水硫酸钠干燥，抽滤，滤液减压浓缩得残留物。残留物。残留物用硅胶柱色谱分离提纯(石油醚：乙酸乙酯(V/V)＝5:1)得到：(6aR)-5-(氧杂环丁烷-2-基甲基)-6-氧-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-8-羧酸苄酯(35b)(0.3g,100％)。At room temperature, (35a) (0.25g, 0.62mmol) and 2-iodomethyloxetane (0.25g, 1.24mmol) were dissolved in DMF (2mL), potassium carbonate (0.26g, 1.86mmol) was added, The reaction was carried out at room temperature for 36 hours. After the reaction was completed, ethyl acetate (20 mL×2) was added, washed with water (5 mL×3), dried over anhydrous sodium sulfate, filtered with suction, and the filtrate was concentrated under reduced pressure to obtain a residue. the remains. The residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V/V)=5:1) to obtain: (6aR)-5-(oxetan-2-ylmethyl)-6-oxo -3-(Trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8 - Benzyl carboxylate (35b) (0.3 g, 100%).
LCMS m/z＝477.3[M+1] +。 LCMS m/z=477.3[M+1] + .
第三步：(6aR)-5-(氧杂环丁烷-2-基甲基)-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-6(6aH)-酮(35c)The third step: (6aR)-5-(oxetan-2-ylmethyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[ 1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one (35c)
(6aR)-5-(oxetan-2-ylmethyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one(6aR)-5-(oxetan-2-ylmethyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin- 6(6aH)-one
Figure PCTCN2022088446-appb-000295
Figure PCTCN2022088446-appb-000295
室温条件下，将(6aR)-5-(氧杂环丁烷-2-基甲基)-6-氧-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-8-羧酸苄酯(35b)(0.30g,0.62mmol)溶解于甲醇(8mL)中，氮气置换3次，加入钯碳(45mg)，氢气置换3次，室温下反应4小时。反应完全后，用硅藻土过滤，合并滤液，减压浓缩后得到粗品(6aR)-5-(氧杂环丁烷-2-基甲基)-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-6(6aH)-酮(35c)(210mg,粗品),未进一步纯化，直接用于下一步。At room temperature, (6aR)-5-(oxetan-2-ylmethyl)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10- Hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8-carboxylate benzyl ester (35b) (0.30 g, 0.62 mmol) was dissolved in methanol (8 mL) , nitrogen was replaced 3 times, palladium carbon (45 mg) was added, hydrogen was replaced 3 times, and the reaction was carried out at room temperature for 4 hours. After the reaction is complete, filter through celite, combine the filtrates, and concentrate under reduced pressure to obtain crude product (6aR)-5-(oxetan-2-ylmethyl)-3-(trifluoromethyl)-7, 8,9,10-Tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one (35c) (210 mg, crude), not further Purified and used directly in the next step.
LCMS m/z＝343.1[M+1] +。 LCMS m/z=343.1[M+1] + .
第四步：(6a R)-5-(氧杂环丁烷-2-基甲基)-8-(3-((S)-2-((6-氧-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基)丙氧基)丙酰基)-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-6(6aH)-酮(化合物35)The fourth step: (6a R)-5-(oxetan-2-ylmethyl)-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 35)
(6aR)-5-(oxetan-2-ylmethyl)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one(6aR)-5-(oxetan-2-ylmethyl)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino) propoxy)propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one
Figure PCTCN2022088446-appb-000296
Figure PCTCN2022088446-appb-000296
室温下，将(6aR)-5-(氧杂环丁烷-2-基甲基)-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-6(6aH)-酮(35c)(210mg,0.61mmol)和3-[(2S)-2-[(6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基]丙氧基]丙酸(4j)(188mg,0.61mmol)溶于DMF(5mL)中，向其中分别加入DIPEA(240mg,1.83mmol)和HATU(230mg,0.61mmol)然后室温搅拌反应3小时。反应结束后，反应液经Pre-HPLC纯化(仪器及制备柱：采用WATERS 2767制备液相，制备柱型号是Xselect C18,5μm，内径×长度＝19mm×150mm)。制备方法：反应液用0.45μm滤膜过滤，制备成样品液。流动相体系：乙腈/水(含0.05％氨水)。梯度洗脱方法：乙腈由5％梯度洗脱至50％(洗脱时间15min)。冻干后得到(6aR)-5-(氧杂环丁烷-2-基甲基)-8-(3-((S)-2-((6-氧-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基)丙氧基)丙酰基)-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-6(6aH)-酮(化合物35)(20mg,5％)At room temperature, (6aR)-5-(oxetan-2-ylmethyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[ 1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one (35c) (210 mg, 0.61 mmol) and 3-[(2S)-2-[(6-oxo- 5-(Trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino]propoxy]propanoic acid (4j) (188 mg, 0.61 mmol) was dissolved in DMF (5 mL) and divided into DIPEA (240 mg, 1.83 mmol) and HATU (230 mg, 0.61 mmol) were added and the reaction was stirred at room temperature for 3 hours. After the reaction, the reaction solution was purified by Pre-HPLC (instrument and preparative column: WATERS 2767 was used to prepare the liquid phase, the preparative column model was Xselect C18, 5 μm, inner diameter×length=19mm×150mm). Preparation method: The reaction solution was filtered with a 0.45 μm 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). Lyophilized to give (6aR)-5-(oxetan-2-ylmethyl)-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 35) (20 mg, 5%)
LCMS m/z＝634.3[M+1] +。 LCMS m/z=634.3[M+1] + .
1H NMR(400MHz,DMSO-d6)δ12.42(s,1H),8.20(s,1H),7.90(s,1H),7.82(d,1H),6.32-6.19(m,1H),4.97-3.96(m,10H),3.76-3.60(m,2H),3.49(d,2H),3.28-2.59(m,7H),1.15(d,3H)。 1 H NMR(400MHz,DMSO-d6)δ12.42(s,1H),8.20(s,1H),7.90(s,1H),7.82(d,1H),6.32-6.19(m,1H),4.97 -3.96(m, 10H), 3.76-3.60(m, 2H), 3.49(d, 2H), 3.28-2.59(m, 7H), 1.15(d, 3H).
实施例36：(R)-5-(甲基-d3)-8-(3-((S)-2-((6-氧-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基)丙氧基)丙酰基)-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-6(6aH)-酮(化合物36)Example 36: (R)-5-(methyl-d3)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydro) Pyridazin-4-yl)amino)propoxy)propionyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyridine Ipo[3,2-e]pyrazin-6(6aH)-one (Compound 36)
(R)-5-(methyl-d3)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one(R)-5-(methyl-d3)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy) propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one
Figure PCTCN2022088446-appb-000297
Figure PCTCN2022088446-appb-000297
化合物34以叔丁基-(R)-6-氧代-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-8-羧酸酯(4d)和3-[(2S)-2-[(6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基]丙氧基]丙酸(4j)为原料，参考实施例33的合成方法，得到(R)-5-(甲基-d 3)-8-(3-((S)-2-((6-氧-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基)丙氧基)丙酰基)-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-6(6aH)-酮(化合物36)。 Compound 34 was identified as 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 (4d) and 3-[(2S)-2-[(6-oxo-5-(trifluoromethyl)-1, Using 6-dihydropyridazin-4-yl)amino]propoxy]propionic acid (4j) as raw material, referring to the synthetic method of Example 33, (R)-5-(methyl-d 3 )-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 36).
LCMS m/z＝581.3[M+1] +。 LCMS m/z=581.3[M+1] + .
1H NMR(400MHz,DMSO-d6)δ12.41(s,1H),8.19(s,1H),7.94-7.85(m,1H),7.53-7.40(m,1H),6.31-6.19(m,1H),4.90-4.46(m,2H),4.31-3.99(m,3H),3.77-3.62(m,2H),3.49(d,2H),3.28-3.04(m,1H),2.86-2.58(m,4H),1.15(d,3H)。1H NMR (400MHz, DMSO-d6) δ12.41(s,1H), 8.19(s,1H), 7.94-7.85(m,1H), 7.53-7.40(m,1H), 6.31-6.19(m,1H) ), 4.90-4.46(m, 2H), 4.31-3.99(m, 3H), 3.77-3.62(m, 2H), 3.49(d, 2H), 3.28-3.04(m, 1H), 2.86-2.58(m , 4H), 1.15(d, 3H).
实施例37：(R)-5-((1-甲基环丙基)甲基)-8-(3-((S)-2-((6-氧-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基))丙氧基)丙酰基)-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-6(6aH)-酮(化合物37)Example 37: (R)-5-((1-methylcyclopropyl)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 37)
(R)-5-((1-methylcyclopropyl)methyl)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one(R)-5-((1-methylcyclopropyl)methyl)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino )propoxy)propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one
Figure PCTCN2022088446-appb-000298
Figure PCTCN2022088446-appb-000298
第一步：(R)-5-((1-甲基环丙基)甲基)-6-氧代-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-8-羧酸叔丁酯(37a)The first step: (R)-5-((1-methylcyclopropyl)methyl)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10- Hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8-carboxylate tert-butyl ester (37a)
Tert-butyl(R)-5-((1-methylcyclopropyl)methyl)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8-carboxylateTert-butyl(R)-5-((1-methylcyclopropyl)methyl)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2- a]pyrido[3,2-e]pyrazine-8-carboxylate
Figure PCTCN2022088446-appb-000299
Figure PCTCN2022088446-appb-000299
室温下，将(R)-6-氧代-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-8-羧酸叔丁酯(4d)(150mg,0.40mmol)加入到超干四氢呋喃(15mL)中，再加入1-甲基环丙烷甲醇(38mg,0.44mmol)和三苯基膦(115mg,0.44mmol)，氮气置换三次，缓慢加入偶氮二羧酸二乙酯(77mg,0.44mmol)。混合物在室温下搅拌过夜。加水(30mL)淬灭反应，乙酸乙酯(30mL x 2)萃取，合并有机相，有机相用饱和食盐水洗涤，无水硫酸钠干燥后过滤，滤液减压浓缩后得粗品。粗品经制备柱分离纯化(石油醚：乙酸乙酯(v/v)＝8:1)得(R)-5-((1-甲基环丙基)甲基)-6-氧代-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-8-羧酸叔丁酯(37a)(70mg,40％)。(R)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyridine at room temperature Iso[3,2-e]pyrazine-8-carboxylate tert-butyl ester (4d) (150 mg, 0.40 mmol) was added to ultra-dry tetrahydrofuran (15 mL) followed by 1-methylcyclopropanemethanol (38 mg, 0.44 mmol) and triphenylphosphine (115 mg, 0.44 mmol), nitrogen purged three times, and diethyl azodicarboxylate (77 mg, 0.44 mmol) was added slowly. The mixture was stirred at room temperature overnight. The reaction was quenched by adding water (30 mL), extracted with ethyl acetate (30 mL x 2), 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 crude product was separated and purified by preparative column (petroleum ether:ethyl acetate (v/v)=8:1) to obtain (R)-5-((1-methylcyclopropyl)methyl)-6-oxo-3 -(Trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8-carboxy tert-Butyl acid (37a) (70 mg, 40%).
LCMS m/z＝385.1[M-55] +。 LCMS m/z = 385.1 [M-55] + .
第二步：(R)-5-((1-甲基环丙基)甲基)-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-6(6aH)-酮(37b)盐酸盐The second step: (R)-5-((1-methylcyclopropyl)methyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[ 1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one (37b) hydrochloride
(R)-5-((1-methylcyclopropyl)methyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one hydrochloride(R)-5-((1-methylcyclopropyl)methyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin -6(6aH)-one hydrochloride
Figure PCTCN2022088446-appb-000300
Figure PCTCN2022088446-appb-000300
室温下，将(R)-5-((1-甲基环丙基)甲基)-6-氧代-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-8-羧酸叔丁酯(37a)(70mg,0.16mmol)溶于1,4-二氧六环(3mL)溶液中，再加入氯化氢/1,4-二氧六环溶液(4.0M，3mL,40mmol)，室温反应4小时。反应结束后，减压浓缩除去溶剂后得(R)-5-((1-甲基环丙基)甲基)-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-6(6aH)-酮(37b)盐酸盐(60mg,粗品)。At room temperature, (R)-5-((1-methylcyclopropyl)methyl)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10- Hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8-carboxylate tert-butyl ester (37a) (70 mg, 0.16 mmol) in 1,4-di To the oxane (3 mL) solution, hydrogen chloride/1,4-dioxane solution (4.0 M, 3 mL, 40 mmol) was added, and the reaction was carried out at room temperature for 4 hours. After the reaction, the solvent was removed by concentration under reduced pressure to obtain (R)-5-((1-methylcyclopropyl)methyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro -5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one (37b) hydrochloride (60 mg, crude).
LCMS m/z＝341.1[M+1] +。 LCMS m/z=341.1[M+1] + .
第三步：(R)-5-((1-甲基环丙基)甲基)-8-(3-((S)-2-((6-氧-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基))丙氧基)丙酰基)-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-6(6aH)-酮(化合物37)The third step: (R)-5-((1-methylcyclopropyl)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 37)
(R)-5-((1-methylcyclopropyl)methyl)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one(R)-5-((1-methylcyclopropyl)methyl)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino )propoxy)propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one
Figure PCTCN2022088446-appb-000301
Figure PCTCN2022088446-appb-000301
室温下，将3-[(2S)-2-[(6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基]丙氧基]丙酸(4j)(49mg,0.16mmol)和(R)-5-((1-甲基环丙基)甲基)-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-6(6aH)-酮(37b)盐酸盐(60mg,粗品)溶于DMF(3mL)中，向其中分别加入DIPEA(103mg,0.80mmol)和HATU(61mg,0.16mmol)然后室温搅拌反应3小时。反应结束后，反应液经Pre-HPLC纯化(仪器及制备柱：采用WATERS 2767制备液相，制备柱型号是Xselect C18，5μm，内径×长度＝19mm×150mm)。制备方法：反应液用0.45μm滤膜过滤，制备成样品液。流动相体系：乙腈/水(含0.05％氨水)。梯度洗脱方法：乙腈由5％梯度洗脱至50％(洗脱时间15min)。冻干后得到(R)-5-((1-甲基环丙基)甲基)-8-(3-((S)-2-((6-氧-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基))丙氧基)丙酰基)-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-6(6aH)-酮(化合物37)(20mg,15％)。3-[(2S)-2-[(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino]propoxy]propionic acid at room temperature (4j) (49 mg, 0.16 mmol) and (R)-5-((1-methylcyclopropyl)methyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro- 5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one (37b) hydrochloride (60 mg, crude) was dissolved in DMF (3 mL) and added to DIPEA (103 mg, 0.80 mmol) and HATU (61 mg, 0.16 mmol) were respectively added thereto, and the reaction was stirred at room temperature for 3 hours. After the reaction, the reaction solution was purified by Pre-HPLC (instrument and preparative column: WATERS 2767 was used to prepare the liquid phase, the preparative column model was Xselect C18, 5 μm, inner diameter×length=19mm×150mm). Preparation method: The reaction solution was filtered with a 0.45 μm 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). Lyophilized to give (R)-5-((1-methylcyclopropyl)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 37) (20 mg, 15%).
LCMS m/z＝632.2[M+1] +。 LCMS m/z=632.2[M+1] + .
1H NMR(400MHz,DMSO-d 6)δ12.42(s,1H),8.21(s,1H),7.90(s,1H),7.69(s,1H),6.31-6.19(m,1H),4.90-4.40(m,2H),4.34-3.94(m,5H),3.76-3.62(m,2H),3.49(d,2H),3.27-3.10(m,1H),2.86-2.59(m,4H),1.15(d,3H),0.91(s,3H),0.55-0.45(m,2H),0.33-0.24(m,2H)。 1 H NMR (400MHz, DMSO-d 6 )δ12.42(s,1H), 8.21(s,1H), 7.90(s,1H), 7.69(s,1H), 6.31-6.19(m,1H), 4.90-4.40(m, 2H), 4.34-3.94(m, 5H), 3.76-3.62(m, 2H), 3.49(d, 2H), 3.27-3.10(m, 1H), 2.86-2.59(m, 4H) ), 1.15(d, 3H), 0.91(s, 3H), 0.55-0.45(m, 2H), 0.33-0.24(m, 2H).
实施例38：1-(((R)-6-氧-8-(3-((S)-2-((6-氧-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基)丙氧基)丙酰基)-3-(三氟甲基)-6,6a,7,8,9,10-六氢-5H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-5-基)甲基)环丙烷-1-腈(化合物38)Example 38: 1-(((R)-6-oxo-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridine) Azin-4-yl)amino)propoxy)propionyl)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2- a] Pyrido[3,2-e]pyrazin-5-yl)methyl)cyclopropane-1-carbonitrile (Compound 38)
1-(((R)-6-oxo-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a]pyrido[3,2- e]pyrazin-5-yl)methyl)cyclopropane-1-carbonitrile1-(((R)-6-oxo-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy) propanoyl)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-5-yl)methyl)cyclopropane -1-carbonitrile
Figure PCTCN2022088446-appb-000302
Figure PCTCN2022088446-appb-000302
第一步：1-(碘甲基)环丙烷-1-腈(38b)The first step: 1-(iodomethyl)cyclopropane-1-carbonitrile (38b)
1-(iodomethyl)cyclopropane-1-carbonitrile1-(iodomethyl)cyclopropane-1-carbonitrile
Figure PCTCN2022088446-appb-000303
Figure PCTCN2022088446-appb-000303
室温下，将1-(羟基甲基)环丙烷甲腈(38a)(1.00g,10.30mmol)、三苯基膦(3.24g,12.36mmol)和咪唑(0.84g,12.36mmol)加入到二氯甲烷(30mL)中，氮气置换三次，缓慢加入碘(2.61g,10.30mmol)。混合物在室温下搅拌过夜。加水(30mL)淬灭反应，二氯甲烷(30mL x 2)萃取，合并有机相，无水硫酸钠干燥后过滤，滤液减压浓缩后得粗品。粗品经制备柱分离纯化(石油醚：乙酸乙酯(v/v)＝12:1)得1-(碘甲基)环丙烷-1-腈(38b)(1.50g,75％)。1-(Hydroxymethyl)cyclopropanecarbonitrile (38a) (1.00 g, 10.30 mmol), triphenylphosphine (3.24 g, 12.36 mmol) and imidazole (0.84 g, 12.36 mmol) were added to dichloro at room temperature In methane (30 mL), nitrogen was replaced three times, and iodine (2.61 g, 10.30 mmol) was slowly added. The mixture was stirred at room temperature overnight. Water (30 mL) was added to quench the reaction, extracted with dichloromethane (30 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by preparative column (petroleum ether:ethyl acetate (v/v)=12:1) to obtain 1-(iodomethyl)cyclopropane-1-carbonitrile (38b) (1.50 g, 75%).
第二步：(R)-5-((1-氰基环丙基)甲基)-6-氧代-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-8-羧酸叔丁酯(38c)The second step: (R)-5-((1-cyanocyclopropyl)methyl)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10- Hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8-carboxylate tert-butyl ester (38c)
Tert-butyl(R)-5-((1-cyanocyclopropyl)methyl)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8-carboxylateTert-butyl(R)-5-((1-cyanocyclopropyl)methyl)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2- a]pyrido[3,2-e]pyrazine-8-carboxylate
Figure PCTCN2022088446-appb-000304
Figure PCTCN2022088446-appb-000304
室温下，将(R)-6-氧代-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-8-羧酸叔丁酯(4d)(110mg,0.30mmol)加入到DMF(5mL)中,再加入1-(碘甲基)环丙烷-1-腈(38b)(93mg,0.45mmol)和碳酸钾(210mg,0.91mmol)，混合物在室温下搅拌过夜。加饱和食盐水(30mL)淬灭反应，乙酸乙酯(30mL x 2)萃取，合并有机相，有机相用饱和食盐水洗涤(30mL x 3)，无水硫酸钠干燥后过滤，滤液减压浓缩后得粗品。粗品经制备柱分离纯化(石油醚：乙酸乙酯(v/v)＝8:1)得(R)-5-((1-氰基环丙基)甲基)-6-氧代-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-8-羧酸叔丁酯(38c)(100mg,74％)。(R)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyridine at room temperature Hemo[3,2-e]pyrazine-8-carboxylate tert-butyl ester (4d) (110 mg, 0.30 mmol) was added to DMF (5 mL) followed by 1-(iodomethyl)cyclopropane-1-carbonitrile (38b) (93 mg, 0.45 mmol) and potassium carbonate (210 mg, 0.91 mmol), the mixture was stirred at room temperature overnight. The reaction was quenched by adding saturated brine (30 mL), extracted with ethyl acetate (30 mL x 2), the organic phases were combined, the organic phases were washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure Crude products later. The crude product was separated and purified by preparative column (petroleum ether:ethyl acetate (v/v)=8:1) to obtain (R)-5-((1-cyanocyclopropyl)methyl)-6-oxo-3 -(Trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8-carboxy tert-Butyl acid (38c) (100 mg, 74%).
LCMS m/z＝396.1[M-55] +。 LCMS m/z = 396.1 [M-55] + .
第三步：(R)-1-((6-氧-3-(三氟甲基)-6,6a,7,8,9,10-六氢-5H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-5-基)甲基)环丙烷-1-甲腈(38d)盐酸盐The third step: (R)-1-((6-oxo-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2- a] Pyrido[3,2-e]pyrazin-5-yl)methyl)cyclopropane-1-carbonitrile (38d) hydrochloride
(R)-1-((6-oxo-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-5-yl)methyl)cyclopropane-1-carbonitrile hydrochloride(R)-1-((6-oxo-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a]pyrido[3,2-e] pyrazin-5-yl)methyl)cyclopropane-1-carbonitrile hydrochloride
Figure PCTCN2022088446-appb-000305
Figure PCTCN2022088446-appb-000305
室温下，将(R)-5-((1-氰基环丙基)甲基)-6-氧代-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-8-羧酸叔丁酯(38c)(100mg,0.22mmol)溶于1,4-二氧六环(3mL)溶液中，再加入氯化氢/1,4-二氧六环溶液(4.0M，3mL,40mmol)，室温反应4小时。反应结束后，减压浓缩除去溶剂后得(R)-1-((6-氧-3-(三氟甲基)-6,6a,7,8,9,10-六氢-5H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-5-基)甲基)环丙烷-1-甲腈(38d)盐酸盐(85mg,粗品)。At room temperature, (R)-5-((1-cyanocyclopropyl)methyl)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10- Hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8-carboxylate tert-butyl ester (38c) (100 mg, 0.22 mmol) in 1,4-di To the oxane (3 mL) solution, hydrogen chloride/1,4-dioxane solution (4.0 M, 3 mL, 40 mmol) was added, and the reaction was carried out at room temperature for 4 hours. After the reaction, the solvent was removed by concentration under reduced pressure to obtain (R)-1-((6-oxo-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyridine) Azino[1,2-a]pyrido[3,2-e]pyrazin-5-yl)methyl)cyclopropane-1-carbonitrile (38d) hydrochloride (85 mg, crude).
LCMS m/z＝352.1[M+1] +。 LCMS m/z=352.1[M+1] + .
第四步：1-(((R)-6-氧-8-(3-((S)-2-((6-氧-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基)丙氧基)丙酰基)-3-(三氟甲基)-6,6a,7,8,9,10-六氢-5H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-5-基)甲基)环丙烷-1-腈(化合物38)The fourth step: 1-(((R)-6-oxo-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridine Azin-4-yl)amino)propoxy)propionyl)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2- a] Pyrido[3,2-e]pyrazin-5-yl)methyl)cyclopropane-1-carbonitrile (Compound 38)
1-(((R)-6-oxo-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-5-yl)methyl)cyclopropane-1-carbonitrile1-(((R)-6-oxo-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy) propanoyl)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-5-yl)methyl)cyclopropane -1-carbonitrile
Figure PCTCN2022088446-appb-000306
Figure PCTCN2022088446-appb-000306
室温下，将3-[(2S)-2-[(6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基]丙氧基]丙酸(4j)(68mg,0.22mmol)和(R)-1-((6-氧-3-(三氟甲基)-6,6a,7,8,9,10-六氢-5H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-5-基)甲基)环丙烷-1-甲腈(38d)盐酸盐(85mg,粗品)溶于DMF(3mL)中，向其中分别加入DIPEA(142mg,1.10mmol)和HATU(84mg,0.22mmol)然后室温搅拌反应3小时。反应结束后，反应液经Pre-HPLC纯化(仪器及制备柱：采用WATERS 2767制备液相，制备柱型号是Xselect C18，5μm，内径×长度＝19mm×150mm)。制备方法：反应液用0.45μm滤膜过滤，制备成样品液。流动相体系：乙腈/水(含0.05％氨水)。梯度洗脱方法：乙腈由5％梯度洗脱至50％(洗脱时间15min)。冻干后得到1-(((R)-6-氧-8-(3-((S)-2-((6-氧-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基)丙氧基)丙酰基)-3-(三氟甲基)-6,6a,7,8,9,10-六氢-5H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-5-基)甲基)环丙烷-1-腈(化合物38)(20mg,14％)。3-[(2S)-2-[(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino]propoxy]propionic acid at room temperature (4j) (68 mg, 0.22 mmol) and (R)-1-((6-oxo-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazine) [1,2-a]pyrido[3,2-e]pyrazin-5-yl)methyl)cyclopropane-1-carbonitrile (38d) hydrochloride (85 mg, crude) was dissolved in DMF (3 mL) ), DIPEA (142 mg, 1.10 mmol) and HATU (84 mg, 0.22 mmol) were added thereto, respectively, and the reaction was stirred at room temperature for 3 hours. After the reaction, the reaction solution was purified by Pre-HPLC (instrument and preparative column: WATERS 2767 was used to prepare the liquid phase, the preparative column model was Xselect C18, 5 μm, inner diameter×length=19mm×150mm). Preparation method: The reaction solution was filtered with a 0.45 μm 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). After lyophilization, 1-(((R)-6-oxo-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridine) was obtained Azin-4-yl)amino)propoxy)propionyl)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2- a] Pyrido[3,2-e]pyrazin-5-yl)methyl)cyclopropane-1-carbonitrile (Compound 38) (20 mg, 14%).
LCMS m/z＝643.1[M+1]+。LCMS m/z=643.1[M+1]+.
1H NMR(400MHz,DMSO-d 6)δ12.42(s,1H),8.25(s,1H),7.90(s,2H),6.34-6.17(m,1H),4.91-4.42(m,2H),4.37-3.98(m,5H),3.77-3.62(m,2H),3.49(d,2H),3.27-3.10(m,1H),2.90-2.59(m,4H),1.32-1.12(m,7H)。 1 H NMR (400MHz, DMSO-d 6 )δ12.42(s,1H), 8.25(s,1H), 7.90(s,2H), 6.34-6.17(m,1H), 4.91-4.42(m,2H) ), 4.37-3.98(m, 5H), 3.77-3.62(m, 2H), 3.49(d, 2H), 3.27-3.10(m, 1H), 2.90-2.59(m, 4H), 1.32-1.12(m , 7H).
实施例39：5-(((S)-1-(3-((R)-5-(环丙基甲基)-3-氟-6-硫代-5,6,6a,7,9,10-六氢-8H-吡嗪[1,2-a]吡啶并[3,2-e]吡嗪-8-基)-3-氧代丙氧基)丙-2-基)氨基)-4-(三氟甲基)哒嗪-3(2H)-酮(化合物39)Example 39: 5-(((S)-1-(3-((R)-5-(cyclopropylmethyl)-3-fluoro-6-thio-5,6,6a,7,9 ,10-hexahydro-8H-pyrazine[1,2-a]pyrido[3,2-e]pyrazin-8-yl)-3-oxopropoxy)propan-2-yl)amino) -4-(Trifluoromethyl)pyridazin-3(2H)-one (Compound 39)
5-(((S)-1-(3-((R)-5-(cyclopropylmethyl)-3-fluoro-6-thioxo-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-8-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one5-(((S)-1-(3-((R)-5-(cyclopropylmethyl)-3-fluoro-6-thioxo-5,6,6a,7,9,10-hexahydro-8H-pyrazino[ 1,2-a]pyrido[3,2-e]pyrazin-8-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one
Figure PCTCN2022088446-appb-000307
Figure PCTCN2022088446-appb-000307
Figure PCTCN2022088446-appb-000308
Figure PCTCN2022088446-appb-000308
第一步：1-叔丁基3-甲基(3R)-4-(5-氟-3-硝基吡啶-2-基)哌嗪-1,3-二羧酸酯(39c)The first step: 1-tert-butyl 3-methyl (3R)-4-(5-fluoro-3-nitropyridin-2-yl)piperazine-1,3-dicarboxylate (39c)
1-tert-butyl 3-methyl(3R)-4-(5-fluoro-3-nitropyridin-2-yl)piperazine-1,3-dicarboxylate1-tert-butyl 3-methyl(3R)-4-(5-fluoro-3-nitropyridin-2-yl)piperazine-1,3-dicarboxylate
Figure PCTCN2022088446-appb-000309
Figure PCTCN2022088446-appb-000309
将2-氯-5-氟-3-硝基吡啶(39a)(2.00g,11.33mmol)，1-(叔丁基)3-甲基(R)-哌嗪-1,3-二羧酸酯(39b)(3.32g,13.60mmol)，DIPEA(5.00g,38.76mmol)依次加入到二甲亚砜(15mL)中，100℃反应16h，反应结束后，冷却至室温，将反应液倒入到水(150mL)中，乙酸乙酯(30mL x 3)萃取，合并有机相，有机相用饱和食盐水(30mL x 3)反洗，无水硫酸钠干燥，抽滤，滤液减压浓缩得残留物。残留物用硅胶柱色谱分离提纯(石油醚：乙酸乙酯(V/V)＝4:1)得到：1-叔丁基3-甲基(3R)-4-(5-氟-3-硝基吡啶-2-基)哌嗪-1,3-二羧酸酯(39c)(2.13g,49％)。2-Chloro-5-fluoro-3-nitropyridine (39a) (2.00 g, 11.33 mmol), 1-(tert-butyl)3-methyl(R)-piperazine-1,3-dicarboxylic acid Ester (39b) (3.32 g, 13.60 mmol), DIPEA (5.00 g, 38.76 mmol) were successively added to dimethyl sulfoxide (15 mL), and reacted at 100° C. for 16 h. After the reaction was completed, it was cooled to room temperature, and the reaction solution was poured into into water (150 mL), extracted with ethyl acetate (30 mL x 3), the organic phases were combined, the organic phase was backwashed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered with suction, and the filtrate was concentrated under reduced pressure to obtain a residue thing. The residue was separated and purified by silica gel column chromatography (petroleum ether:ethyl acetate (V/V)=4:1) to obtain: 1-tert-butyl-3-methyl(3R)-4-(5-fluoro-3-nitro) pyridin-2-yl)piperazine-1,3-dicarboxylate (39c) (2.13 g, 49%).
LCMS m/z＝329.1[M-55] +。 LCMS m/z = 329.1 [M-55] + .
第二步：(R)-3-氟-6-氧代-5,6,6a,7,9,10-六氢-8H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-8-羧酸叔丁酯(39d)Step 2: (R)-3-Fluoro-6-oxo-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2 -e]pyrazine-8-carboxylate tert-butyl ester (39d)
tert-butyl(R)-3-fluoro-6-oxo-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8-carboxylatetert-butyl(R)-3-fluoro-6-oxo-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8 -carboxylate
Figure PCTCN2022088446-appb-000310
Figure PCTCN2022088446-appb-000310
室温下，1-叔丁基3-甲基(3R)-4-(5-氟-3-硝基吡啶-2-基)哌嗪-1,3-二羧酸酯(39c)(2.13g,5.54mmol)溶于无水乙醇(30mL)，然后再加入锌粉(3.62g,55.4mmol)和氯化铵(2.96g,55.4mmol)。混合物在60℃搅拌反应16小时。反应液过滤，乙酸乙酯(40mL)洗涤滤饼，合并有机相，有机相用饱和食盐水洗涤，无水硫酸钠干燥后过滤，滤液减压浓缩后得粗品。粗品经柱层析分离纯化(石油醚：乙酸乙酯(v/v)＝4:1)得到(R)-3-氟-6-氧代-5,6,6a,7,9,10-六氢-8H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-8-羧酸叔丁酯(39d)(1.30g,73％)。1-tert-Butyl 3-methyl(3R)-4-(5-fluoro-3-nitropyridin-2-yl)piperazine-1,3-dicarboxylate (39c) (2.13g) at room temperature , 5.54 mmol) was dissolved in absolute ethanol (30 mL), and then zinc powder (3.62 g, 55.4 mmol) and ammonium chloride (2.96 g, 55.4 mmol) were added. The mixture was stirred at 60°C for 16 hours. The reaction solution was filtered, the filter cake was washed with ethyl acetate (40 mL), the organic phases were combined, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate (v/v)=4:1) to obtain (R)-3-fluoro-6-oxo-5,6,6a,7,9,10- Hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8-carboxylate tert-butyl ester (39d) (1.30 g, 73%).
LCMS m/z＝321.2[M-1] -。 LCMS m/z=321.2[M-1] - .
第三步：(R)-3-氟-7,8,9,10-四氢-5H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-6(6aH)-酮盐酸盐(39e)The third step: (R)-3-fluoro-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-6(6aH )-keto hydrochloride (39e)
(R)-3-fluoro-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one(R)-3-fluoro-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one
Figure PCTCN2022088446-appb-000311
Figure PCTCN2022088446-appb-000311
室温下，将(R)-3-氟-6-氧代-5,6,6a,7,9,10-六氢-8H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-8-羧酸叔丁酯(39d)(1.30g,4.03mmol)溶于1,4-二氧六环(5mL)溶液中，再加入氯化氢/1,4-二氧六环溶液(4.0M，10mL,40mmol)，室温反应4小时。反应结束后，减压浓缩除去溶剂后得(R)-3-氟-7,8,9,10-四氢-5H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-6(6aH)-酮(39e)盐酸盐(1.00g,粗品)。(R)-3-Fluoro-6-oxo-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2 -e] Pyrazine-8-carboxylate tert-butyl ester (39d) (1.30 g, 4.03 mmol) was dissolved in 1,4-dioxane (5 mL) solution, and then hydrogen chloride/1,4-dioxane was added The ring solution (4.0 M, 10 mL, 40 mmol) was reacted at room temperature for 4 hours. After the reaction was completed, the solvent was removed by concentration under reduced pressure to obtain (R)-3-fluoro-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e ]pyrazin-6(6aH)-one (39e) hydrochloride (1.00 g, crude).
LCMS m/z＝223.1[M+1] +。 LCMS m/z=223.1[M+1] + .
第四步：2-(三甲基甲硅烷基)乙基(R)-3-氟-6-氧代-5,6,6a,7,9,10-六氢-8H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-8-羧酸酯(39f)The fourth step: 2-(trimethylsilyl)ethyl(R)-3-fluoro-6-oxo-5,6,6a,7,9,10-hexahydro-8H-pyrazino[ 1,2-a]pyrido[3,2-e]pyrazine-8-carboxylate (39f)
2-(trimethylsilyl)ethyl(R)-3-fluoro-6-oxo-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8-carboxylate2-(trimethylsilyl)ethyl(R)-3-fluoro-6-oxo-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e] pyrazine-8-carboxylate
Figure PCTCN2022088446-appb-000312
Figure PCTCN2022088446-appb-000312
室温下，将(R)-3-氟-7,8,9,10-四氢-5H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-6(6aH)-酮盐酸盐(39e)(0.30g,1.35mmol)和三乙胺(0.41g,4.05mmol)溶于四氢呋喃(10mL)中，缓慢加入N-[2-(三甲基硅基)乙氧羰氧基]琥珀酰亚胺(0.35g,1.35mmol)。反应液在室温搅拌反应2小时。反应结束后，减压浓缩后得粗品。粗品经制备柱分离纯化(石油醚：乙酸乙酯(v/v)＝3:1)得2-(三甲基甲硅烷基)乙基(R)-3-氟-6-氧代-5,6,6a,7,9,10-六氢-8H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-8-羧酸酯(39f)(0.35g,71％)。At room temperature, (R)-3-fluoro-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-6(6aH )-keto hydrochloride (39e) (0.30 g, 1.35 mmol) and triethylamine (0.41 g, 4.05 mmol) were dissolved in tetrahydrofuran (10 mL), N-[2-(trimethylsilyl)ethyl was added slowly Oxycarbonyloxy]succinimide (0.35 g, 1.35 mmol). The reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, the crude product was obtained after concentration under reduced pressure. The crude product was separated and purified by preparative column (petroleum ether:ethyl acetate (v/v)=3:1) to obtain 2-(trimethylsilyl)ethyl(R)-3-fluoro-6-oxo-5 ,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8-carboxylate (39f) (0.35g, 71%).
LCMS m/z＝365.2[M-1] - LCMS m/z=365.2[M-1] -
第五步：2-(三甲基甲硅烷基)乙基(R)-3-氟-6-硫代-5,6,6a,7,9,10-六氢-8H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-8-羧酸酯(39g)The fifth step: 2-(trimethylsilyl)ethyl(R)-3-fluoro-6-thio-5,6,6a,7,9,10-hexahydro-8H-pyrazino[ 1,2-a]pyrido[3,2-e]pyrazine-8-carboxylate (39g)
2-(trimethylsilyl)ethyl(R)-3-fluoro-6-thioxo-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8-carboxylate2-(trimethylsilyl)ethyl(R)-3-fluoro-6-thioxo-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e] pyrazine-8-carboxylate
Figure PCTCN2022088446-appb-000313
Figure PCTCN2022088446-appb-000313
室温下，将叔2-(三甲基甲硅烷基)乙基(R)-3-氟-6-氧代-5,6,6a,7,9,10-六氢-8H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-8-羧酸酯(39f)(0.35g,0.96mmol)溶于四氢呋喃(5mL)中，再加入劳森试剂(0.78g,1.92mmol)，混合液在60℃下反应16小时。反应结束后，减压浓缩后得粗品。粗品经制备柱分离纯化(石油醚：乙酸乙酯(v/v)＝3:1)得2-(三甲基甲硅烷基)乙基(R)-3-氟-6-硫代-5,6,6a,7,9,10-六氢-8H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-8-羧酸酯(39g)(0.20g,54％)。At room temperature, tert-2-(trimethylsilyl)ethyl(R)-3-fluoro-6-oxo-5,6,6a,7,9,10-hexahydro-8H-pyrazino [1,2-a]pyrido[3,2-e]pyrazine-8-carboxylate (39f) (0.35 g, 0.96 mmol) was dissolved in tetrahydrofuran (5 mL), followed by the addition of Lawson's reagent (0.78 g) , 1.92 mmol), the mixture was reacted at 60 ° C for 16 hours. After the reaction was completed, the crude product was obtained after concentration under reduced pressure. The crude product was separated and purified by a preparative column (petroleum ether:ethyl acetate (v/v)=3:1) to obtain 2-(trimethylsilyl)ethyl(R)-3-fluoro-6-thio-5 ,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8-carboxylate (39g) (0.20g, 54%).
第六步：2-(三甲基甲硅烷基)乙基(R)-5-(环丙基甲基)-3-氟-6-硫代-5,6,6a,7,9,10-六氢-8H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-8-羧酸酯(39h)Step 6: 2-(Trimethylsilyl)ethyl(R)-5-(cyclopropylmethyl)-3-fluoro-6-thio-5,6,6a,7,9,10 - Hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8-carboxylate (39h)
2-(trimethylsilyl)ethyl(R)-5-(cyclopropylmethyl)-3-fluoro-6-thioxo-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8-carboxylate2-(trimethylsilyl)ethyl(R)-5-(cyclopropylmethyl)-3-fluoro-6-thioxo-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[ 3,2-e]pyrazine-8-carboxylate
Figure PCTCN2022088446-appb-000314
Figure PCTCN2022088446-appb-000314
室温下，将2-(三甲基甲硅烷基)乙基(R)-3-氟-6-硫代-5,6,6a,7,9,10-六氢-8H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-8-羧酸酯(39g)(110mg,0.26mmol)，(碘甲基)环丙烷(71mg,0.39mmol)溶于DMF(5mL)中，加入碳酸钾(110mg,0.78mmol)。反应液在室温搅拌反应16小时。反应结束后，加入饱和食盐水(20mL)，加入乙酸乙酯萃取(20mLx2)。合并有机相，有机相用饱和食盐水洗涤(20mL x 3)，无水硫酸钠干燥，减压浓缩后得粗品。粗品经制备柱分离纯化(石油醚：乙酸乙酯(v/v)＝6:1)得2-(三甲基甲硅烷基)乙基(R)-5-(环丙基甲基)-3-氟-6-硫代-5,6,6a,7,9,10-六氢-8H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-8-羧酸酯(39h)(70mg,62％)。2-(Trimethylsilyl)ethyl(R)-3-fluoro-6-thio-5,6,6a,7,9,10-hexahydro-8H-pyrazino[ 1,2-a]pyrido[3,2-e]pyrazine-8-carboxylate (39g) (110mg, 0.26mmol), (iodomethyl)cyclopropane (71mg, 0.39mmol) in DMF ( 5 mL), potassium carbonate (110 mg, 0.78 mmol) was added. The reaction solution was stirred at room temperature for 16 hours. After the reaction, saturated brine (20 mL) was added, and ethyl acetate was added for extraction (20 mL×2). The organic phases were combined, washed with saturated brine (20 mL×3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by a preparative column (petroleum ether:ethyl acetate (v/v)=6:1) to obtain 2-(trimethylsilyl)ethyl(R)-5-(cyclopropylmethyl)- 3-Fluoro-6-thio-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8- Carboxylic acid ester (39h) (70 mg, 62%).
LCMS m/z＝437.2[M+1] +。 LCMS m/z=437.2[M+1] + .
第七步：(R)-5-(环丙基甲基)-3-氟-7,8,9,10-四氢-5H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-6(6aH)-硫酮(39i)The seventh step: (R)-5-(cyclopropylmethyl)-3-fluoro-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3, 2-e]pyrazine-6(6aH)-thione (39i)
(R)-5-(cyclopropylmethyl)-3-fluoro-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-6(6aH)-thione(R)-5-(cyclopropylmethyl)-3-fluoro-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-6(6aH)-thione
Figure PCTCN2022088446-appb-000315
Figure PCTCN2022088446-appb-000315
室温下，将2-(三甲基甲硅烷基)乙基(R)-5-(环丙基甲基)-3-氟-6-硫代-5,6,6a,7,9,10-六氢-8H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-8-羧酸酯(39h)(70mg,0.16mmol)溶于四氢呋喃(3mL)中，再加入四丁基氟化铵的四氢呋喃溶液(1.0M，1.5mL,1.5mmol)，室温反应2小时。反应结束后，反应结束后，加入饱和食盐水(20mL)，加入乙酸乙酯萃取(20mLx2)。合并有机相，有机相用饱和食盐水洗涤(20mL x 3)，无水硫酸钠干燥，减压浓缩后得粗品。粗品经制备柱分离纯化(石油醚：乙酸乙酯(v/v)＝2:1)得(R)-5-(环丙基甲基)-3-氟-7,8,9,10-四氢-5H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-6(6aH)-硫酮(39i)(25mg,47％)。At room temperature, 2-(trimethylsilyl)ethyl(R)-5-(cyclopropylmethyl)-3-fluoro-6-thio-5,6,6a,7,9,10 - Hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-8-carboxylate (39h) (70 mg, 0.16 mmol) was dissolved in tetrahydrofuran (3 mL), Then, a solution of tetrabutylammonium fluoride in tetrahydrofuran (1.0 M, 1.5 mL, 1.5 mmol) was added, and the reaction was carried out at room temperature for 2 hours. After the reaction was completed, saturated brine (20 mL) was added, and ethyl acetate was added for extraction (20 mL×2). The organic phases were combined, washed with saturated brine (20 mL×3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by preparative column (petroleum ether:ethyl acetate (v/v)=2:1) to obtain (R)-5-(cyclopropylmethyl)-3-fluoro-7,8,9,10- Tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-6(6aH)-thione (39i) (25 mg, 47%).
LCMS m/z＝293.1[M+1] +。 LCMS m/z=293.1[M+1] + .
第八步：5-(((S)-1-(3-((R)-5-(环丙基甲基)-3-氟-6-硫代-5,6,6a,7,9,10-六氢-8H-吡嗪[1,2-a]吡啶并[3,2-e]吡嗪-8-基)-3-氧代丙氧基)丙-2-基)氨基)-4-(三氟甲基)哒嗪-3(2H)-酮(化合物39)The eighth step: 5-(((S)-1-(3-((R)-5-(cyclopropylmethyl)-3-fluoro-6-thio-5,6,6a,7,9 ,10-hexahydro-8H-pyrazine[1,2-a]pyrido[3,2-e]pyrazin-8-yl)-3-oxopropoxy)propan-2-yl)amino) -4-(Trifluoromethyl)pyridazin-3(2H)-one (Compound 39)
5-(((S)-1-(3-((R)-5-(cyclopropylmethyl)-3-fluoro-6-thioxo-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-8-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one5-(((S)-1-(3-((R)-5-(cyclopropylmethyl)-3-fluoro-6-thioxo-5,6,6a,7,9,10-hexahydro-8H-pyrazino[ 1,2-a]pyrido[3,2-e]pyrazin-8-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one
Figure PCTCN2022088446-appb-000316
Figure PCTCN2022088446-appb-000316
室温下，将3-[(2S)-2-[(6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基]丙氧基]丙酸(4j)(27mg,0.09mmol)和(R)-5-(环丙基甲基)-3-氟-7,8,9,10-四氢-5H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-6(6aH)-硫酮(39i)(25mg,0.09mmol)溶于DMF(3mL)中，向其中分别加入DIPEA(58mg,0.45mmol)和HATU(34mg,0.09mmol)然后室温搅拌反应3小时。反应结束后，反应液经Pre-HPLC纯化(仪器及制备柱：采用WATERS 2767制备液相，制备柱型号是Xselect C18，5μm，内径×长度＝19mm×150mm)。制备方法：反应液用0.45μm滤膜过滤，制备成样品液。流动相体系：乙腈/水(含0.05％醋酸铵)。梯度洗脱方法：乙腈由5％梯度洗脱至50％(洗脱时间15min)。冻干后得到5-(((S)-1-(3-((R)-5-(环丙基甲基)-3-氟-6-硫代-5,6,6a,7,9,10-六氢-8H-吡嗪[1,2-a]吡啶并[3,2-e]吡嗪-8-基)-3-氧代丙氧基)丙-2-基)氨基)-4-(三氟甲基)哒嗪-3(2H)-酮(化合物39)(10mg,18％)。3-[(2S)-2-[(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino]propoxy]propionic acid at room temperature (4j) (27 mg, 0.09 mmol) and (R)-5-(cyclopropylmethyl)-3-fluoro-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a ]pyrido[3,2-e]pyrazine-6(6aH)-thione (39i) (25 mg, 0.09 mmol) was dissolved in DMF (3 mL), to which was added DIPEA (58 mg, 0.45 mmol) and HATU, respectively (34 mg, 0.09 mmol) and the reaction was stirred at room temperature for 3 hours. After the reaction, the reaction solution was purified by Pre-HPLC (instrument and preparative column: WATERS 2767 was used to prepare the liquid phase, the preparative column model was Xselect C18, 5 μm, inner diameter×length=19mm×150mm). Preparation method: The reaction solution was filtered with a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile/water (containing 0.05% ammonium acetate). Gradient elution method: Gradient elution of acetonitrile from 5% to 50% (elution time 15 min). Lyophilized to give 5-(((S)-1-(3-((R)-5-(cyclopropylmethyl)-3-fluoro-6-thio-5,6,6a,7,9 ,10-hexahydro-8H-pyrazine[1,2-a]pyrido[3,2-e]pyrazin-8-yl)-3-oxopropoxy)propan-2-yl)amino) -4-(Trifluoromethyl)pyridazin-3(2H)-one (Compound 39) (10 mg, 18%).
LCMS m/z＝584.2[M+1] +。 LCMS m/z=584.2[M+1] + .
1H NMR(400MHz,DMSO-d 6)δ12.42(s,1H),7.95-7.86(m,2H),7.33(dd,1H),6.33-6.18(m,1H),4.64-4.34(m,2H),4.25-3.82(m,3H),3.75-3.59(m,2H),3.56-3.44(m,2H),3.17-2.53(m,7H),1.25-1.05(m,4H),0.63-0.49(m,2H),0.39-0.25(m,2H)。 1 H NMR (400MHz, DMSO-d 6 ) δ 12.42 (s, 1H), 7.95-7.86 (m, 2H), 7.33 (dd, 1H), 6.33-6.18 (m, 1H), 4.64-4.34 (m ,2H),4.25-3.82(m,3H),3.75-3.59(m,2H),3.56-3.44(m,2H),3.17-2.53(m,7H),1.25-1.05(m,4H),0.63 -0.49(m, 2H), 0.39-0.25(m, 2H).
实施例40：(R)-8-(3-((S)-2-((6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基)丙氧基)丙酰基)-5-丙基-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-6(6aH)-酮(化合物40)Example 40: (R)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino )propoxy)propionyl)-5-propyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3 ,2-e]pyrazin-6(6aH)-one (Compound 40)
(R)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-5-propyl-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one(R)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-5-propyl-3 -(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one
Figure PCTCN2022088446-appb-000317
Figure PCTCN2022088446-appb-000317
化合物40以叔丁基-(R)-6-氧代-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-8-羧酸酯(4d)、碘丙烷和3-[(2S)-2-[(6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基]丙氧基]丙酸(4j)为原料，参考实施例29的合成方法，得到(R)-8-(3-((S)-2-((6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基)丙氧基)丙酰基)-5-丙基-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-6(6aH)-酮(化合物40)。Compound 40 was identified as 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 (4d), iodopropane and 3-[(2S)-2-[(6-oxo-5-(trifluoromethyl) -1,6-Dihydropyridazin-4-yl)amino]propoxy]propionic acid (4j) was used as the raw material, referring to the synthetic method of Example 29, to obtain (R)-8-(3-((S) -2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionyl)-5-propyl-3-( Trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one (Compound 40 ).
LCMS m/z＝606.2[M+1] +。 LCMS m/z=606.2[M+1] + .
1H NMR(400MHz,DMSO-d 6)δ12.42(s,1H),8.19(s,1H),7.90(s,1H),7.52(s,1H),6.32-6.15(m,1H),4.93-4.39(m,2H),4.31-3.83(m,5H),3.74-3.58(m,2H),3.49(d,2H),3.27-3.04(m,1H),2.88-2.55(m,4H),1.62-1.43(m,2H),1.15(d,3H),0.88(t,3H)。 1 H NMR (400MHz, DMSO-d 6 )δ12.42(s,1H), 8.19(s,1H), 7.90(s,1H), 7.52(s,1H), 6.32-6.15(m,1H), 4.93-4.39(m, 2H), 4.31-3.83(m, 5H), 3.74-3.58(m, 2H), 3.49(d, 2H), 3.27-3.04(m, 1H), 2.88-2.55(m, 4H) ), 1.62-1.43(m, 2H), 1.15(d, 3H), 0.88(t, 3H).
实施例41：(R)-5-辛基-8-(3-((S)-2-((6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基)丙氧基)丙酰基)-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪并[1,2-a]吡啶并[3,2-E]吡嗪-6-(6aH)-酮(化合物41)Example 41: (R)-5-Octyl-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]pyrido[3 ,2-E]pyrazin-6-(6aH)-one (Compound 41)
(R)-5-octyl-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one(R)-5-octyl-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3 -(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one
Figure PCTCN2022088446-appb-000318
Figure PCTCN2022088446-appb-000318
化合物41以叔丁基-(R)-6-氧代-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-8-羧酸酯(4d)和3-[(2S)-2-[(6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基]丙氧基]丙酸(4j)为原料，参考实施例29的合成方法，得到(R)-5-辛基-8-(3-((S)-2-((6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基)丙氧基)丙酰基)-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-6-(6aH)-酮(化合物41)。Compound 41 was identified as 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 (4d) and 3-[(2S)-2-[(6-oxo-5-(trifluoromethyl)-1, Using 6-dihydropyridazin-4-yl)amino]propoxy]propionic acid (4j) as raw material, referring to the synthetic method of Example 29, (R)-5-octyl-8-(3-(( S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionyl)-3-(trifluoromethyl) yl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6-(6aH)-one (Compound 41).
LCMS m/z＝676.3[M+1] +。 LCMS m/z=676.3[M+1] + .
1H NMR(400MHz,DMSO-d 6)δ12.42(s,1H),8.19(s,1H),7.90(s,1H),7.49 (s,1H),6.30-6.18(m,1H),4.92-4.40(m,2H),4.34-3.86(m,5H),3.76-3.61(m,2H),3.49(d,2H),3.26-3.05(m,1H),2.85-2.55(m,4H),1.58-1.42(m,2H),1.35-1.12(m,13H),0.89-0.79(m,3H)。 1 H NMR (400MHz, DMSO-d 6 )δ12.42(s,1H),8.19(s,1H),7.90(s,1H),7.49(s,1H),6.30-6.18(m,1H), 4.92-4.40(m, 2H), 4.34-3.86(m, 5H), 3.76-3.61(m, 2H), 3.49(d, 2H), 3.26-3.05(m, 1H), 2.85-2.55(m, 4H ), 1.58-1.42(m, 2H), 1.35-1.12(m, 13H), 0.89-0.79(m, 3H).
实施例42：(S)-5-(甲基-D3)-8-(3-((S)-2-((6-氧-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基)丙氧基)丙酰基)-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-6(6aH)-酮(化合物42)Example 42: (S)-5-(Methyl-D3)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydro) Pyridazin-4-yl)amino)propoxy)propionyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyridine Ipo[3,2-e]pyrazin-6(6aH)-one (Compound 42)
(S)-5-(methyl-D 3)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one (S)-5-(methyl-D 3 )-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy )propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one
Figure PCTCN2022088446-appb-000319
Figure PCTCN2022088446-appb-000319
化合物42以叔丁基-(S)-6-氧代-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-8-羧酸酯(10d)氘代碘甲烷和3-[(2S)-2-[(6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基]丙氧基]丙酸(4j)为原料，参考实施例11的合成方法，得到(S)-5-(甲基-D 3)-8-(3-((S)-2-((6-氧-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基)丙氧基)丙酰基)-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-6(6aH)-酮(化合物42)。 Compound 42 was identified as tert-butyl-(S)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2- a]pyrido[3,2-e]pyrazine-8-carboxylate (10d) deuterated iodomethane and 3-[(2S)-2-[(6-oxo-5-(trifluoromethyl) )-1,6-dihydropyridazin-4-yl)amino]propoxy]propionic acid (4j) as raw material, referring to the synthetic method of Example 11 to obtain (S)-5-(methyl-D 3 )-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]pyrazine-6(6aH) - Ketone (compound 42).
LCMS m/z＝581.3[M+1] +。 LCMS m/z=581.3[M+1] + .
1H NMR(400MHz,CD 3OD)δ8.14(s,1H),7.91(d,1H),7.40(s,1H),5.15-4.57(m,2H),4.56-3.92(m,3H),3.88-3.68(m,2H),3.65-3.46(m,2H),3.27-3.18(m,1H),2.93-2.60(m,4H),1.25(d,3H)。 1 H NMR (400MHz, CD 3 OD) δ 8.14(s, 1H), 7.91(d, 1H), 7.40(s, 1H), 5.15-4.57(m, 2H), 4.56-3.92(m, 3H) , 3.88-3.68(m, 2H), 3.65-3.46(m, 2H), 3.27-3.18(m, 1H), 2.93-2.60(m, 4H), 1.25(d, 3H).
实施例43：5-(((S)-1-(3-((S)-5-甲基-6-硫基-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡嗪[1,2-a]吡啶并[3,2-e]吡嗪-8-基)-3-氧代丙氧基)丙-2-基)氨基)-4-(三氟甲基)哒嗪-3(2H)-酮(化合物43)Example 43: 5-(((S)-1-(3-((S)-5-methyl-6-sulfanyl-3-(trifluoromethyl)-5,6,6a,7,9 ,10-hexahydro-8H-pyrazine[1,2-a]pyrido[3,2-e]pyrazin-8-yl)-3-oxopropoxy)propan-2-yl)amino) -4-(Trifluoromethyl)pyridazin-3(2H)-one (Compound 43)
5-(((S)-1-(3-((S)-5-methyl-6-thioxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-8-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one5-(((S)-1-(3-((S)-5-methyl-6-thioxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[ 1,2-a]pyrido[3,2-e]pyrazin-8-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one
Figure PCTCN2022088446-appb-000320
Figure PCTCN2022088446-appb-000320
化合物43以叔丁基-(S)-6-氧代-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-8-羧酸酯(10d)和3-[(2S)-2-[(6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基]丙氧基]丙酸(4j)为原料，参考实施例31的合成方法，得到5-(((S)-1-(3-((S)-5-甲基-6-硫氧基-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡嗪[1,2-a]吡啶并[3,2-e]吡嗪-8-基)-3-氧代丙氧基)丙-2-基)氨基)-4-(三氟甲基)哒嗪-3(2H)-酮(化合物43)。Compound 43 was identified as tert-butyl-(S)-6-oxo-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2- a]pyrido[3,2-e]pyrazine-8-carboxylate (10d) and 3-[(2S)-2-[(6-oxo-5-(trifluoromethyl)-1, Using 6-dihydropyridazin-4-yl)amino]propoxy]propionic acid (4j) as raw material, referring to the synthetic method of Example 31, 5-((((S)-1-(3-(((S) )-5-methyl-6-thiooxy-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazine[1,2-a]pyrido [3,2-e]pyrazin-8-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one ( compound 43).
LCMS m/z＝594.2[M+1] +。 LCMS m/z=594.2[M+1] + .
1H NMR(400MHz,CDCl 3)δ10.14-9.87(m,1H),8.15(s,1H),7.65(s,1H),7.59-7.51(m,1H),5.83-5.70(m,1H),5.09-4.53(m,2H),4.41-4.23(m,1H),4.15-3.74(m,4H),3.71-3.59(m,1H),3.56-3.43(m,1H),3.39-3.14(m,1H),2.95-2.72(m,2H),2.71-2.48(m,5H),1.30(d,3H)。 1 H NMR (400MHz, CDCl 3 ) δ 10.14-9.87(m,1H), 8.15(s,1H), 7.65(s,1H), 7.59-7.51(m,1H), 5.83-5.70(m,1H) ), 5.09-4.53(m, 2H), 4.41-4.23(m, 1H), 4.15-3.74(m, 4H), 3.71-3.59(m, 1H), 3.56-3.43(m, 1H), 3.39-3.14 (m, 1H), 2.95-2.72 (m, 2H), 2.71-2.48 (m, 5H), 1.30 (d, 3H).
实施例44：(R)-5-环戊基甲基-8-(3-((S)-2-((6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基)丙氧基)丙酰基)-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪并[1,2-a]吡啶并[3,2-E]吡嗪-6-(6aH)-酮(化合物44)Example 44: (R)-5-Cyclopentylmethyl-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydro Pyridazin-4-yl)amino)propoxy)propionyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyridine Ipo[3,2-E]pyrazin-6-(6aH)-one (Compound 44)
(R)-5-(cyclopentylmethyl)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one(R)-5-(cyclopentylmethyl)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl) -3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one
Figure PCTCN2022088446-appb-000321
Figure PCTCN2022088446-appb-000321
化合物44以叔丁基-(R)-6-氧代-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-8-羧酸酯(4d)、碘甲基环戊烷和3-[(2S)-2-[(6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基]丙氧基]丙酸(4j)为原料，参考实施例33的合成方法，得到(R)-5-环戊基甲基-8-(3-((S)-2-((6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基)丙氧基)丙酰基)-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-6-(6aH)-酮(化合物44)。Compound 44 was identified as 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 (4d), iodomethylcyclopentane and 3-[(2S)-2-[(6-oxo-5-(tri Using fluoromethyl)-1,6-dihydropyridazin-4-yl)amino]propoxy]propionic acid (4j) as raw material, referring to the synthetic method of Example 33, (R)-5-cyclopentyl was obtained 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]pyrazine-6- (6aH)-ketone (compound 44).
LCMS m/z＝646.3[M+1] +。 LCMS m/z=646.3[M+1] + .
1H NMR(400MHz,DMSO-d 6)δ12.42(s,1H),8.20(s,1H),7.90(s,1H),7.58(s,1H),6.36-6.15(m,1H),4.99-4.41(m,2H),4.33-3.84(m,5H),3.78-3.60(m,2H),3.49(d,2H),3.27-3.07(m,1H),2.88-2.55(m,4H),2.22-2.07(m,1H),1.71-1.39(m,6H),1.31-1.18(m,2H)，1.15(d,3H)。 1 H NMR (400MHz, DMSO-d 6 )δ12.42(s,1H), 8.20(s,1H), 7.90(s,1H), 7.58(s,1H), 6.36-6.15(m,1H), 4.99-4.41(m, 2H), 4.33-3.84(m, 5H), 3.78-3.60(m, 2H), 3.49(d, 2H), 3.27-3.07(m, 1H), 2.88-2.55(m, 4H) ), 2.22-2.07 (m, 1H), 1.71-1.39 (m, 6H), 1.31-1.18 (m, 2H), 1.15 (d, 3H).
实施例45：(R)-5-异戊基-8-(3-((S)-2-((6-氧-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基))丙氧基)丙酰基)-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-6(6aH)-酮(化合物45)Example 45: (R)-5-Isoamyl-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]pyrido[ 3,2-e]pyrazin-6(6aH)-one (Compound 45)
(R)-5-isopentyl-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one(R)-5-isopentyl-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3 -(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one
Figure PCTCN2022088446-appb-000322
Figure PCTCN2022088446-appb-000322
化合物45以叔丁基-(R)-6-氧代-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-8-羧酸酯(4d)、异戊基碘和3-[(2S)-2-[(6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基]丙氧基]丙酸(4j)为原料，参考实施例33的合成方法，得到(R)-5-异戊基-8-(3-((S)-2-((6-氧-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基))丙氧基)丙酰基)-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-6(6aH)-酮(化合物45)。Compound 45 was identified as 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 (4d), isoamyl iodide and 3-[(2S)-2-[(6-oxo-5-(trifluoromethyl) base)-1,6-dihydropyridazin-4-yl)amino]propoxy]propionic acid (4j) as raw material, referring to the synthetic method of Example 33, to obtain (R)-5-isoamyl-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 45).
LCMS m/z＝634.3[M+1] +。 LCMS m/z=634.3[M+1] + .
1H NMR(400MHz,DMSO-d 6)δ12.42(s,1H),8.20(s,1H),7.90(s,1H),7.44(s,1H),6.30-6.18(m,1H),4.91-4.40(m,2H),4.36-3.90(m,5H),3.76-3.58(m,2H),3.49(d,2H),3.27-3.04(m,1H),2.87-2.56(m,4H),1.68-1.52(m,1H),1.44-1.33(m,2H),1.15(d,3H),0.97-0.84(m,6H)。 1 H NMR (400MHz, DMSO-d 6 )δ12.42(s,1H), 8.20(s,1H), 7.90(s,1H), 7.44(s,1H), 6.30-6.18(m,1H), 4.91-4.40(m, 2H), 4.36-3.90(m, 5H), 3.76-3.58(m, 2H), 3.49(d, 2H), 3.27-3.04(m, 1H), 2.87-2.56(m, 4H) ), 1.68-1.52 (m, 1H), 1.44-1.33 (m, 2H), 1.15 (d, 3H), 0.97-0.84 (m, 6H).
实施例46：(R)-5-(2-乙基丁基)-8-(3-((S)-2-((6-氧-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基))丙氧基)丙酰基)-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-6(6aH)-酮(化合物46)Example 46: (R)-5-(2-ethylbutyl)-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 46)
(R)-5-(2-ethylbutyl)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one(R)-5-(2-ethylbutyl)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy) propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one
Figure PCTCN2022088446-appb-000323
Figure PCTCN2022088446-appb-000323
化合物46以叔丁基-(R)-6-氧代-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-8-羧酸酯(4d)、2-乙基-1-丁醇和3-[(2S)-2-[(6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基]丙氧基]丙酸(4j)为原料，参考实施例37的合成方法，得到(R)-5-(2-乙基丁基)-8-(3-((S)-2-((6-氧-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基))丙氧基)丙酰基)-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-6(6aH)-酮(化合物46)。Compound 46 was identified as 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 (4d), 2-ethyl-1-butanol and 3-[(2S)-2-[(6-oxo-5- (Trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino]propoxy]propionic acid (4j) was used as the raw material, referring to the synthetic method of Example 37 to obtain (R)-5-( 2-ethylbutyl)-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 46).
LCMS m/z＝648.3[M+1] +。 LCMS m/z=648.3[M+1] + .
1H NMR(400MHz,DMSO-d 6)δ12.42(s,1H),8.21(s,1H),7.90(s,1H),7.46(s,1H),6.33-6.17(m,1H),4.94-4.39(m,2H),4.37-3.93(m,4H),3.90-3.79(m,1H),3.78-3.61(m,2H),3.49(d,2H),3.25-3.08(m,1H),2.88-2.55(m,4H),1.62-1.48(m,1H),1.36-1.18(m,4H),1.15(d,3H),0.92-0.76(m,6H)。 1 H NMR (400MHz, DMSO-d 6 )δ12.42(s,1H), 8.21(s,1H), 7.90(s,1H), 7.46(s,1H), 6.33-6.17(m,1H), 4.94-4.39(m, 2H), 4.37-3.93(m, 4H), 3.90-3.79(m, 1H), 3.78-3.61(m, 2H), 3.49(d, 2H), 3.25-3.08(m, 1H) ), 2.88-2.55(m, 4H), 1.62-1.48(m, 1H), 1.36-1.18(m, 4H), 1.15(d, 3H), 0.92-0.76(m, 6H).
实施例47：(R)-5-(2-甲基丁基)-8-(3-((S)-2-((6-氧-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基))丙氧基)丙酰基)-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-6(6aH)-酮(化合物47)Example 47: (R)-5-(2-methylbutyl)-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 47)
(R)-5-(2-methylbutyl)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one(R)-5-(2-methylbutyl)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy) propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one
Figure PCTCN2022088446-appb-000324
Figure PCTCN2022088446-appb-000324
化合物47以叔丁基-(R)-6-氧代-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-8-羧酸酯(4d)、2-甲基丁醇和3-[(2S)-2-[(6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基]丙氧基]丙酸(4j)为原料，参考实施例37的合成方法，得到(R)-5-(2-甲基丁基)-8-(3-((S)-2-((6-氧-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基))丙氧基)丙酰基)-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-6(6aH)-酮(化合物47)。Compound 47 was identified as 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 (4d), 2-methylbutanol and 3-[(2S)-2-[(6-oxo-5-(trifluoro Methyl)-1,6-dihydropyridazin-4-yl)amino]propoxy]propionic acid (4j) was used as raw material, and the synthetic method of Example 37 was used to obtain (R)-5-(2-methyl) ylbutyl)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino))propoxy yl)propionyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine- 6(6aH)-one (compound 47).
LCMS m/z＝634.3[M+1] +。 LCMS m/z=634.3[M+1] + .
1H NMR(400MHz,DMSO-d 6)δ12.42(s,1H),8.20(s,1H),7.90(s,1H),7.51(s,1H),6.31-6.19(m,1H),4.90-4.42(m,2H),4.34-3.78(m,5H),3.76-3.60(m,2H),3.49(d,2H),3.25-3.06(m,1H),2.90-2.58(m,4H),1.80-1.60(m,1H),1.46-1.28(m,1H),1.22-1.05(m,4H),0.91-0.73(m,6H)。 1 H NMR (400MHz, DMSO-d 6 )δ12.42(s,1H), 8.20(s,1H), 7.90(s,1H), 7.51(s,1H), 6.31-6.19(m,1H), 4.90-4.42(m, 2H), 4.34-3.78(m, 5H), 3.76-3.60(m, 2H), 3.49(d, 2H), 3.25-3.06(m, 1H), 2.90-2.58(m, 4H ), 1.80-1.60(m, 1H), 1.46-1.28(m, 1H), 1.22-1.05(m, 4H), 0.91-0.73(m, 6H).
实施例48：(R)-5-丁基-8-(3-((S)-2-((6-氧-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基))丙氧基)丙酰基)-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-6(6aH)-酮(化合物48)Example 48: (R)-5-Butyl-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]pyrido[3 ,2-e]pyrazin-6(6aH)-one (Compound 48)
(R)-5-butyl-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one(R)-5-butyl-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3 -(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one
Figure PCTCN2022088446-appb-000325
Figure PCTCN2022088446-appb-000325
化合物48以叔丁基-(R)-6-氧代-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-8-羧酸酯(4d)、1-碘丁烷和3-[(2S)-2-[(6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基]丙氧基]丙酸(4j)为原料，参考实施例33的合成方法，得到(R)-5-丁基-8-(3-((S)-2-((6-氧-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基))丙氧基)丙酰基)-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-6(6aH)-酮(化合物48)。Compound 48 was identified as 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 (4d), 1-iodobutane and 3-[(2S)-2-[(6-oxo-5-(trifluoro Using methyl)-1,6-dihydropyridazin-4-yl)amino]propoxy]propionic acid (4j) as raw material, referring to the synthetic method of Example 33, (R)-5-butyl-8 was obtained -(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 48).
LCMS m/z＝620.3[M+1] +。 LCMS m/z=620.3[M+1] + .
1H NMR(400MHz,DMSO-d 6)δ12.42(s,1H),8.19(s,1H),7.90(s,1H),7.51(s,1H),6.37-6.18(m,1H),4.94-4.40(m,2H),4.31-3.91(m,5H),3.81-3.60(m,2H),3.49(d,2H),3.24-3.05(m,1H),2.87-2.60(m,4H),1.58-1.42(m,2H),1.38-1.25(m,2H),1.15(d,3H),0.99-0.84(m,3H)。 1 H NMR (400MHz, DMSO-d 6 )δ12.42(s,1H), 8.19(s,1H), 7.90(s,1H), 7.51(s,1H), 6.37-6.18(m,1H), 4.94-4.40(m, 2H), 4.31-3.91(m, 5H), 3.81-3.60(m, 2H), 3.49(d, 2H), 3.24-3.05(m, 1H), 2.87-2.60(m, 4H ), 1.58-1.42(m, 2H), 1.38-1.25(m, 2H), 1.15(d, 3H), 0.99-0.84(m, 3H).
实施例49：(R)-5-((S)-2-甲基丁基)-8-(3-((S)-2-((6-氧-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基))丙氧基)丙酰基)-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-6(6aH)-酮(化合物49)Example 49: (R)-5-((S)-2-methylbutyl)-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 49)
(R)-5-((S)-2-methylbutyl)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one(R)-5-((S)-2-methylbutyl)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl) amino)propoxy)propanoyl)-3-(trifluoromethyl)-7,8,9,10-tetrahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazin-6(6aH)-one
Figure PCTCN2022088446-appb-000326
Figure PCTCN2022088446-appb-000326
化合物49以叔丁基-(R)-6-氧代-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-8-羧酸酯(4d)、S-(-)-2-甲基-1-丁醇和3-[(2S)-2-[(6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基]丙氧基]丙酸(4j)为原料，参考实施例37的合成方法，得到(R)-5-((S)-2-甲基丁基)-8-(3-((S)-2-((6-氧-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基))丙氧基)丙酰基)-3-(三氟甲基)-7,8,9,10-四氢-5H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-6(6aH)-酮(化合物49)。Compound 49 was identified as 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 (4d), S-(-)-2-methyl-1-butanol and 3-[(2S)-2-[(6 -Oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino]propoxy]propionic acid (4j) as raw material, with reference to the synthetic method of Example 37, to obtain ( R)-5-((S)-2-methylbutyl)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-di) Hydropyridazin-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 49).
LCMS m/z＝634.3[M+1] +。 LCMS m/z=634.3[M+1] + .
1H NMR(400MHz,DMSO-d 6)δ12.42(s,1H),8.20(s,1H),7.90(s,1H),7.50(s,1H),6.32-6.16(m,1H),4.95-4.37(m,2H),4.37-3.76(m,5H),3.74-3.59(m,2H),3.49(d,2H),3.28-3.06(m,1H),2.89-2.56(m,4H),1.76-1.60(m,1H),1.47-1.32(m,1H),1.26-1.08(m,4H),0.97-0.75(m,6H)。 1 H NMR (400MHz, DMSO-d 6 )δ12.42(s,1H), 8.20(s,1H), 7.90(s,1H), 7.50(s,1H), 6.32-6.16(m,1H), 4.95-4.37(m, 2H), 4.37-3.76(m, 5H), 3.74-3.59(m, 2H), 3.49(d, 2H), 3.28-3.06(m, 1H), 2.89-2.56(m, 4H ), 1.76-1.60(m, 1H), 1.47-1.32(m, 1H), 1.26-1.08(m, 4H), 0.97-0.75(m, 6H).
实施例50：(R)-5-(环丙基甲基)-8-(3-((S)-2-((6-氧-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基)丙氧基)丙酰基)-6-硫代-6,6a,7,8,9,10-六氢-5H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-3-腈(化合物50)Example 50: (R)-5-(Cyclopropylmethyl)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-di) Hydropyridazin-4-yl)amino)propoxy)propionyl)-6-thio-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a] Pyrido[3,2-e]pyrazine-3-carbonitrile (Compound 50)
(R)-5-(cyclopropylmethyl)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl)-6-thioxo-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-3-carbonitrile(R)-5-(cyclopropylmethyl)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propanoyl) -6-thioxo-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a]pyrido[3,2-e]pyrazine-3-carbonitrile
Figure PCTCN2022088446-appb-000327
Figure PCTCN2022088446-appb-000327
化合物50以6-氯-5-硝基烟腈和3-[(2S)-2-[(6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基]丙氧基]丙酸(4j)、(碘甲基)环丙烷和叔丁基-(R)-6-氧代-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-8-羧酸酯(4d)为原料，参考实施例39的合成方法，得到(R)-5-(环丙基甲基)-8-(3-((S)-2-((6-氧-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基)丙氧基)丙酰基)-6-硫代-6,6a,7,8,9,10-六氢-5H-吡嗪并[1,2-a]吡啶并[3,2-e]吡嗪-3-腈(化合物 50)。Compound 50 was synthesized with 6-chloro-5-nitronicotinonitrile and 3-[(2S)-2-[(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4- (4j), (iodomethyl)cyclopropane, and 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 (4d) was used as raw material, and the synthesis of reference example 39 method to give (R)-5-(cyclopropylmethyl)-8-(3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydro) Pyridazin-4-yl)amino)propoxy)propionyl)-6-thio-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a]pyridine Hepo[3,2-e]pyrazine-3-carbonitrile (Compound 50).
LCMS m/z＝591.2[M+1] +。 LCMS m/z=591.2[M+1] + .
1H NMR(400MHz,DMSO-d 6)δ12.43(s,1H),8.29(d,1H),7.90(s,1H),7.59(d,1H),6.33-6.19(m,1H),4.77-4.31(m,3H),4.24-3.88(m,2H),3.77-3.62(m,2H),3.55-3.45(m,2H),3.44-3.01(m,3H),2.94-2.56(m,4H),1.22-1.04(m,4H),0.61-0.50(m,2H),0.37-0.27(m,2H)。 1 H NMR (400MHz, DMSO-d 6 )δ12.43(s,1H), 8.29(d,1H), 7.90(s,1H), 7.59(d,1H), 6.33-6.19(m,1H), 4.77-4.31(m, 3H), 4.24-3.88(m, 2H), 3.77-3.62(m, 2H), 3.55-3.45(m, 2H), 3.44-3.01(m, 3H), 2.94-2.56(m , 4H), 1.22-1.04 (m, 4H), 0.61-0.50 (m, 2H), 0.37-0.27 (m, 2H).
实施例51：5-(((S)-1-(3-氧代-3-((R)-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡啶[1,6-a:2,3-b']二吡嗪-8-基)丙氧基)丙烷-2-基)氨基)-4-(三氟甲基)吡嗪-3(2H)-酮(化合物51)Example 51: 5-(((S)-1-(3-oxo-3-((R)-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro -8H-Pyridin[1,6-a:2,3-b']dipyrazin-8-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyrazine- 3(2H)-ketone (Compound 51)
5-(((S)-1-(3-oxo-3-((R)-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrido[1,6-a:2,3-b']dipyrazin-8-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one5-(((S)-1-(3-oxo-3-((R)-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrido[1,6- a:2,3-b']dipyrazin-8-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one
Figure PCTCN2022088446-appb-000328
Figure PCTCN2022088446-appb-000328
第一步：5-(三氟甲基)吡嗪-2-醇(51b)The first step: 5-(trifluoromethyl)pyrazin-2-ol (51b)
5-(trifluoromethyl)pyrazin-2-ol5-(trifluoromethyl)pyrazin-2-ol
Figure PCTCN2022088446-appb-000329
Figure PCTCN2022088446-appb-000329
将2-氯-5-(三氟甲基)吡嗪(2.00g,10.96mmol)(51a)溶于四氢呋喃(10mL)中，加入氢氧化钠(0.88g,21.92mmol)的水(4mL)溶液，升温至70℃反应3h。反应结束后，冰水浴下用盐酸溶液(2M)调pH至6～7。然后用乙酸乙酯(20mL x 3)萃取，合并有机相，饱和食盐水(20mL x 2)反洗，无水硫酸钠干燥，抽滤，滤液减压浓缩得5-(三 氟甲基)吡嗪-2-醇(51b)(1.60g,89％)。2-Chloro-5-(trifluoromethyl)pyrazine (2.00 g, 10.96 mmol) (51a) was dissolved in tetrahydrofuran (10 mL), and a solution of sodium hydroxide (0.88 g, 21.92 mmol) in water (4 mL) was added , and the temperature was raised to 70 °C for 3 h. After the reaction, the pH was adjusted to 6-7 with hydrochloric acid solution (2M) under ice-water bath. Then it was extracted with ethyl acetate (20mL×3), the organic phases were combined, backwashed with saturated brine (20mL×2), dried over anhydrous sodium sulfate, filtered with suction, and the filtrate was concentrated under reduced pressure to obtain 5-(trifluoromethyl)pyridine Azin-2-ol (51b) (1.60 g, 89%).
LCMS m/z＝165.0[M+1] +。 LCMS m/z=165.0[M+1] + .
第二步：3-溴-5-(三氟甲基)吡嗪-2-醇(51c)Step 2: 3-Bromo-5-(trifluoromethyl)pyrazin-2-ol (51c)
3-bromo-5-(trifluoromethyl)pyrazin-2-ol3-bromo-5-(trifluoromethyl)pyrazin-2-ol
Figure PCTCN2022088446-appb-000330
Figure PCTCN2022088446-appb-000330
冰水浴下，向5-(三氟甲基)吡嗪-2-醇(51b)(1.40g,8.53mmol)的DMF(15mL)溶液中缓慢滴加溴素(7.80g,48.81mmol)。滴完后，保持该温度反应3h。反应结束后，将反应液缓慢加入到冰水(100mL)中，乙酸乙酯(30mL x 3)萃取，合并有机相，有机相用饱和食盐水(20mL x 2)反洗，无水硫酸钠干燥，抽滤，滤液减压浓缩得残留物，残留物经制备柱分离纯化(甲醇：二氯甲烷(v/v)＝1:25)得3-溴-5-(三氟甲基)吡嗪-2-醇(51c)(1.40g,68％)。Bromine (7.80 g, 48.81 mmol) was slowly added dropwise to a solution of 5-(trifluoromethyl)pyrazin-2-ol (51b) (1.40 g, 8.53 mmol) in DMF (15 mL) under an ice-water bath. After dropping, the temperature was maintained for 3h. After the reaction, the reaction solution was slowly added to ice water (100mL), extracted with ethyl acetate (30mL×3), the organic phases were combined, the organic phase was backwashed with saturated brine (20mL×2), and dried over anhydrous sodium sulfate. , suction filtration, and the filtrate was concentrated under reduced pressure to obtain a residue, which was separated and purified by a preparative column (methanol:dichloromethane (v/v)=1:25) to obtain 3-bromo-5-(trifluoromethyl)pyrazine -2-ol (51c) (1.40 g, 68%).
LCMS m/z＝240.9[M-1] - LCMS m/z=240.9[M-1] -
第三步：1-苄基4-(叔丁基)(R)-2-(2-(3-羟基-6-(三氟甲基)吡嗪-2-基)乙烯基)哌嗪-1,4-二羧酸酯(51d)The third step: 1-benzyl 4-(tert-butyl)(R)-2-(2-(3-hydroxy-6-(trifluoromethyl)pyrazin-2-yl)vinyl)piperazine- 1,4-Dicarboxylate (51d)
1-benzyl 4-(tert-butyl)(R)-2-(2-(3-hydroxy-6-(trifluoromethyl)pyrazin-2-yl)vinyl)piperazine-1,4-dicarboxylate1-benzyl 4-(tert-butyl)(R)-2-(2-(3-hydroxy-6-(trifluoromethyl)pyrazin-2-yl)vinyl)piperazine-1,4-dicarboxylate
Figure PCTCN2022088446-appb-000331
Figure PCTCN2022088446-appb-000331
室温下，将1-苄基4-(叔丁基)(R)-2-乙烯基哌嗪-1,4-二羧酸酯(200mg,0.58mmol，以(S)-3-(羟甲基)哌嗪-1-羧酸叔丁酯为原料参照WO2007146066制备得到)溶于DMF(12mL)中，加入3-溴-5-(三氟甲基)吡嗪-2-醇(51c)(211mg,0.87mmol)，碳酸钾(240mg,1.74mmol)，2-二环己基膦-2',4',6'-三异丙基联苯(111mg,0.23mmol)和醋酸钯(26mg,0.12mmol)。氮气置换3次，100℃下反应16h。反应结束后，加水(40mL)和乙酸乙酯(40mL)，垫硅藻土过滤，滤液分层，水相用乙酸乙酯(40mL x 2)萃取，合并有机相，有机相用饱和食盐水(20mL x 2)反洗，无水硫酸钠干燥，抽滤， 滤液减压浓缩得残留物。残留物用硅胶柱色谱分离提纯(四氢呋喃：二氯甲烷(v/v)＝15:85)得1-苄基4-(叔丁基)(R)-2-(2-(3-羟基-6-(三氟甲基)吡嗪-2-基)乙烯基)哌嗪-1,4-二羧酸酯(51d)(100mg,34％)。At room temperature, 1-benzyl 4-(tert-butyl)(R)-2-vinylpiperazine-1,4-dicarboxylate (200 mg, 0.58 mmol, was added to (S)-3-(hydroxymethyl) yl)piperazine-1-carboxylate tert-butyl ester as raw material, prepared with reference to WO2007146066), dissolved in DMF (12 mL), added 3-bromo-5-(trifluoromethyl)pyrazin-2-ol (51c) ( 211 mg, 0.87 mmol), potassium carbonate (240 mg, 1.74 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (111 mg, 0.23 mmol) and palladium acetate (26 mg, 0.12 mmol). The nitrogen was replaced three times, and the reaction was carried out at 100 °C for 16 h. After the reaction, water (40 mL) and ethyl acetate (40 mL) were added, and the filtrate was filtered through celite. 20mL×2) backwashed, dried over anhydrous sodium sulfate, suction filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was separated and purified by silica gel column chromatography (tetrahydrofuran:dichloromethane (v/v)=15:85) to obtain 1-benzyl 4-(tert-butyl)(R)-2-(2-(3-hydroxy- 6-(Trifluoromethyl)pyrazin-2-yl)vinyl)piperazine-1,4-dicarboxylate (51d) (100 mg, 34%).
LCMS m/z＝453.0[M-55] +。 LCMS m/z = 453.0 [M-55] + .
第四步：(R)-3-(2-(3-羟基-6-(三氟甲基)吡嗪-2-基)乙基)哌嗪-1-羧酸叔丁酯(51e)The fourth step: (R)-tert-butyl 3-(2-(3-hydroxy-6-(trifluoromethyl)pyrazin-2-yl)ethyl)piperazine-1-carboxylate (51e)
tert-butyl(R)-3-(2-(3-hydroxy-6-(trifluoromethyl)pyrazin-2-yl)ethyl)piperazine-1-carboxylatetert-butyl(R)-3-(2-(3-hydroxy-6-(trifluoromethyl)pyrazin-2-yl)ethyl)piperazine-1-carboxylate
Figure PCTCN2022088446-appb-000332
Figure PCTCN2022088446-appb-000332
室温下，将1-苄基4-(叔丁基)(R)-2-(2-(3-羟基-6-(三氟甲基)吡嗪-2-基)乙烯基)哌嗪-1,4-二羧酸酯(51d)(150mg,0.29mmol)溶于MeOH(10mL)中，加入氨水(质量分数为25％-28％，0.1mL)，钯碳(20mg,10％)，氢气置换后，氢气氛围下室温反应16h，反应结束后，垫硅藻土过滤，滤液减压浓缩得(R)-3-(2-(3-羟基-6-(三氟甲基)吡嗪-2-基)乙基)哌嗪-1-羧酸叔丁酯(51e)(110mg)粗品，直接用于下一步。At room temperature, 1-benzyl 4-(tert-butyl)(R)-2-(2-(3-hydroxy-6-(trifluoromethyl)pyrazin-2-yl)vinyl)piperazine- 1,4-Dicarboxylate (51d) (150mg, 0.29mmol) was dissolved in MeOH (10mL), ammonia water (25%-28% by mass, 0.1mL), palladium on carbon (20mg, 10%) were added, After hydrogen replacement, the reaction was carried out at room temperature for 16 h under a hydrogen atmosphere. After the reaction was completed, the filtrate was filtered through a pad of celite, and the filtrate was concentrated under reduced pressure to obtain (R)-3-(2-(3-hydroxy-6-(trifluoromethyl)pyrazine) -2-yl)ethyl)piperazine-1-carboxylate tert-butyl ester (51e) (110 mg) crude was used directly in the next step.
LCMS m/z＝377.2[M+1] +。 LCMS m/z=377.2[M+1] + .
第五步：叔丁基(R)-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡啶[1,6-a:2,3-b']二吡嗪-8-羧酸酯(51f)The fifth step: tert-butyl (R)-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyridine[1,6-a:2,3-b '] Dipyrazine-8-carboxylate (51f)
tert-butyl(R)-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrido[1,6-a:2,3-b']dipyrazine-8-carboxylatetert-butyl(R)-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrido[1,6-a:2,3-b']dipyrazine-8-carboxylate
Figure PCTCN2022088446-appb-000333
Figure PCTCN2022088446-appb-000333
室温下，将(R)-3-(2-(3-羟基-6-(三氟甲基)吡嗪-2-基)乙基)哌嗪-1-羧酸叔丁酯(51e)(110mg,粗品)溶于二甲基亚砜(5mL)中，加入DIPEA(112mg,0.87mmol)和1H-苯并三唑-1-基氧三吡咯烷基六氟磷酸盐(151mg,0.29mmol)。升温至60℃下反应1h。反应结束后，将反应液倒入到水(50mL)中，乙酸乙酯(20mL x 3)萃取，合并有机相，有机相用饱和食盐水(20mL x 3)反洗，无水硫酸钠干燥，抽滤，滤液减压浓缩得残留物。残留物用硅胶柱色谱分离提纯(乙酸乙酯：石油醚(v/v)＝15:85)得 到叔丁基(R)-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡啶[1,6-a:2,3-b']二吡嗪-8-羧酸酯(51f)(52mg,50％，2步收率)。(R)-tert-butyl 3-(2-(3-hydroxy-6-(trifluoromethyl)pyrazin-2-yl)ethyl)piperazine-1-carboxylate (51e)( 110 mg, crude) was dissolved in dimethyl sulfoxide (5 mL), DIPEA (112 mg, 0.87 mmol) and 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate (151 mg, 0.29 mmol) were added . The temperature was raised to 60 °C for 1 h. After the reaction, the reaction solution was poured into water (50mL), extracted with ethyl acetate (20mL×3), the organic phases were combined, the organic phase was backwashed with saturated brine (20mL×3), dried over anhydrous sodium sulfate, After suction filtration, the filtrate was concentrated under reduced pressure to obtain a residue. The residue was separated and purified by silica gel column chromatography (ethyl acetate:petroleum ether (v/v)=15:85) to obtain tert-butyl(R)-3-(trifluoromethyl)-5,6,6a,7, 9,10-Hexahydro-8H-pyridine[1,6-a:2,3-b']dipyrazine-8-carboxylate (51f) (52 mg, 50%, 2 steps yield).
LCMS m/z＝303.1[M-55] +。 LCMS m/z=303.1 [M-55] + .
第六步：(R)-3-(三氟甲基)-6,6a,7,8,9,10-六氢-5H-吡啶[1,6-a:2,3-b']二吡嗪(51g)的盐酸盐The sixth step: (R)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyridine[1,6-a:2,3-b'] two Pyrazine (51g) hydrochloride
(R)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrido[1,6-a:2,3-b']dipyrazine(R)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrido[1,6-a:2,3-b']dipyrazine
Figure PCTCN2022088446-appb-000334
Figure PCTCN2022088446-appb-000334
室温下，将叔丁基(R)-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡啶[1,6-a:2,3-b']二吡嗪-8-羧酸酯(51f)(87mg,0.24mmol)溶于氯化氢/1,4-二氧六环溶液(10mL,4M)中，室温反应1h。反应结束后，减压浓缩得(R)-3-(三氟甲基)-6,6a,7,8,9,10-六氢-5H-吡啶[1,6-a:2,3-b']二吡嗪(51g)的盐酸盐(71mg)粗品，直接用于下一步反应。At room temperature, tert-butyl(R)-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyridine[1,6-a:2,3-b '] Dipyrazine-8-carboxylate (51f) (87 mg, 0.24 mmol) was dissolved in hydrogen chloride/1,4-dioxane solution (10 mL, 4 M), and reacted at room temperature for 1 h. After the reaction, concentrated under reduced pressure to obtain (R)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyridine[1,6-a:2,3- The crude hydrochloride salt (71 mg) of b']dipyrazine (51 g) was directly used in the next reaction.
LCMS m/z＝259.2[M+1] +。 LCMS m/z=259.2[M+1] + .
第七步：5-(((S)-1-(3-氧代-3-((R)-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡啶[1,6-a:2,3-b']二吡嗪-8-基)丙氧基)丙烷-2-基)氨基)-4-(三氟甲基)吡嗪-3(2H)-酮(化合物51)The seventh step: 5-(((S)-1-(3-oxo-3-((R)-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro -8H-Pyridin[1,6-a:2,3-b']dipyrazin-8-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyrazine- 3(2H)-ketone (Compound 51)
5-(((S)-1-(3-oxo-3-((R)-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrido[1,6-a:2,3-b']dipyrazin-8-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one5-(((S)-1-(3-oxo-3-((R)-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrido[1,6- a:2,3-b']dipyrazin-8-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one
Figure PCTCN2022088446-appb-000335
Figure PCTCN2022088446-appb-000335
室温下，将(R)-3-(三氟甲基)-6,6a,7,8,9,10-六氢-5H-吡啶[1,6-a:2,3-b']二吡嗪(51g)的盐酸盐(71mg,粗品)和3-[(2S)-2-[(6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基]丙氧基]丙酸(4j)(75mg,0.24mmol)溶于DMF(2mL)中，向其中分别加入DIPEA(93mg,0.72mmol)和HATU(91mg,0.24mmol)，然后室温搅拌反应1h。反应结束后，反应液经Pre-HPLC纯化(仪器及制备柱：采用WATERS 2767制备液相，制备柱型号是Xselect C18,5μm，内径×长度＝19mm×150mm)。制备方法：反应液用0.45μm滤膜过滤，制备成样品液。流动相体系：乙腈/水(含0.05％氨水)。梯度洗脱方法：乙腈由5％梯度洗脱至50％(洗脱时间15min)。冻干后得到5-(((S)-1-(3-氧代-3-((R)-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡啶[1,6-a:2,3-b']二吡嗪-8-基)丙氧基)丙烷-2-基)氨基)-4-(三氟甲基)吡 嗪-3(2H)-酮(化合物51)(55mg,42％，2步收率)。At room temperature, (R)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyridine[1,6-a:2,3-b']di Pyrazine (51g) hydrochloride (71mg, crude) and 3-[(2S)-2-[(6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazine-4 -yl)amino]propoxy]propionic acid (4j) (75 mg, 0.24 mmol) was dissolved in DMF (2 mL), to which were added DIPEA (93 mg, 0.72 mmol) and HATU (91 mg, 0.24 mmol), respectively, then room temperature The reaction was stirred for 1 h. After the reaction, the reaction solution was purified by Pre-HPLC (instrument and preparative column: WATERS 2767 was used to prepare the liquid phase, the preparative column model was Xselect C18, 5 μm, inner diameter×length=19mm×150mm). Preparation method: The reaction solution was filtered with a 0.45 μm 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). 5-(((S)-1-(3-oxo-3-((R)-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro) after lyophilization -8H-Pyridin[1,6-a:2,3-b']dipyrazin-8-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyrazine- 3(2H)-one (compound 51) (55 mg, 42%, 2 steps yield).
LCMS m/z＝550.1[M+1] +。 LCMS m/z=550.1[M+1] + .
1H NMR(400MHz,CDCl 3)δ10.46-10.19(m,1H),8.26-8.17(m,1H),7.65(s,1H),5.90-5.73(m,1H),4.82-4.56(m,2H),4.00-3.79(m,4H),3.69-3.63(m,1H),3.53-3.36(m,2H),3.32-2.48(m,7H),2.29-2.15(m,1H),1.93-1.77(m,1H),1.30(d,3H)。 1 H NMR (400MHz, CDCl 3 ) δ 10.46-10.19 (m, 1H), 8.26-8.17 (m, 1H), 7.65 (s, 1H), 5.90-5.73 (m, 1H), 4.82-4.56 (m ,2H),4.00-3.79(m,4H),3.69-3.63(m,1H),3.53-3.36(m,2H),3.32-2.48(m,7H),2.29-2.15(m,1H),1.93 -1.77(m, 1H), 1.30(d, 3H).
实施例52：5-(((S)-1-(3-氧代-3-((S)-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡啶[1,6-a:2,3-b']二吡嗪-8-基)丙氧基)丙烷-2-基)氨基)-4-(三氟甲基)吡嗪-3(2H)-酮(化合物52)Example 52: 5-(((S)-1-(3-oxo-3-((S)-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro -8H-Pyridin[1,6-a:2,3-b']dipyrazin-8-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyrazine- 3(2H)-ketone (Compound 52)
5-(((S)-1-(3-oxo-3-((S)-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrido[1,6-a:2,3-b']dipyrazin-8-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one5-(((S)-1-(3-oxo-3-((S)-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrido[1,6- a:2,3-b']dipyrazin-8-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one
Figure PCTCN2022088446-appb-000336
Figure PCTCN2022088446-appb-000336
化合物52以2-氯-5-(三氟甲基)吡嗪和(R)-3-(羟甲基)哌嗪-1-羧酸叔丁酯为原料，参考实施例51的合成方法，得到5-(((S)-1-(3-氧代-3-((S)-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡啶[1,6-a:2,3-b']二吡嗪-8-基)丙氧基)丙烷-2-基)氨基)-4-(三氟甲基)吡嗪-3(2H)-酮(化合物52)Compound 52 uses 2-chloro-5-(trifluoromethyl)pyrazine and (R)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester as raw materials, referring to the synthetic method of Example 51, 5-(((S)-1-(3-oxo-3-((S)-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H- Pyridin[1,6-a:2,3-b']dipyrazin-8-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyrazine-3(2H )-keto (Compound 52)
LCMS m/z＝550.3[M+1] +。 LCMS m/z=550.3[M+1] + .
1H NMR(400MHz,CDCl 3)δ10.68-10.45(m,1H),8.25-8.16(m,1H),7.65(s,1H),5.88-5.72(m,1H),4.85-4.53(m,2H),4.01-3.77(m,4H),3.70-3.62(m,1H),3.56-3.35(m,2H),3.32-2.49(m,7H),2.29-2.14(m,1H),1.94-1.76(m,1H),1.31(d,3H)。 1 H NMR (400MHz, CDCl 3 ) δ 10.68-10.45(m, 1H), 8.25-8.16(m, 1H), 7.65(s, 1H), 5.88-5.72(m, 1H), 4.85-4.53(m ,2H),4.01-3.77(m,4H),3.70-3.62(m,1H),3.56-3.35(m,2H),3.32-2.49(m,7H),2.29-2.14(m,1H),1.94 -1.76(m, 1H), 1.31(d, 3H).
实施例53：5-(((S)-1-(3-((S)-5,5-二氧化-3-(三氟甲基)-6a,7,9,10-四氢吡嗪[1,2-d]吡啶并[3,2-b][1,4]噻嗪-8(6H)-基)-3-氧代丙氧基)丙-2-基)氨基)-4-(三氟甲基)哒嗪-3(2H)-酮(化合物53)Example 53: 5-(((S)-1-(3-((S)-5,5-dioxy-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazine [1,2-d]pyrido[3,2-b][1,4]thiazin-8(6H)-yl)-3-oxopropoxy)propan-2-yl)amino)-4 -(Trifluoromethyl)pyridazin-3(2H)-one (Compound 53)
5-(((S)-1-(3-((S)-5,5-dioxido-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2-b][1,4]thiazin-8(6H)-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one5-(((S)-1-(3-((S)-5,5-dioxido-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3, 2-b][1,4]thiazin-8(6H)-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one
Figure PCTCN2022088446-appb-000337
Figure PCTCN2022088446-appb-000337
Figure PCTCN2022088446-appb-000338
Figure PCTCN2022088446-appb-000338
第一步：(S)-4-(3-溴-5-(三氟甲基)吡啶-2-基)-3-(羟甲基)哌嗪-1-羧酸叔丁酯(化合物53b)The first step: (S)-4-(3-bromo-5-(trifluoromethyl)pyridin-2-yl)-3-(hydroxymethyl)piperazine-1-carboxylate tert-butyl ester (compound 53b )
Tert-butyl(S)-4-(3-bromo-5-(trifluoromethyl)pyridin-2-yl)-3-(hydroxymethyl)piperazine-1-carboxylateTert-butyl(S)-4-(3-bromo-5-(trifluoromethyl)pyridin-2-yl)-3-(hydroxymethyl)piperazine-1-carboxylate
Figure PCTCN2022088446-appb-000339
Figure PCTCN2022088446-appb-000339
室温下，将(S)-1-BOC-3-羟甲基哌嗪(4.48g,20.73mmol)、N,N-二异丙基乙胺(5.36g,41.46mmol)加入到3-溴-2-氯-5-三氟甲基吡啶(53a)(5.40g,20.73mmol的N,N-二甲基甲酰胺(30mL)溶液中，氮气置换后，升温至100℃反应16小时。反应完毕后，冷却至室温，向反应液中加乙酸乙酯(50mL)稀释反应液，清水洗涤反应液(20mL x 3)。有机相经减压浓缩，得粗品。粗品经柱层析分离纯化(石油醚：乙酸乙酯(v/v)＝5：3)得(S)-4-(3-溴-5-(三氟甲基)吡啶-2-基)-3-(羟甲基)哌嗪-1-羧酸叔丁酯(53b)(3.80g,42％)。To 3-bromo- In 2-chloro-5-trifluoromethylpyridine (53a) (5.40g, 20.73mmol of N,N-dimethylformamide (30mL) solution, after nitrogen replacement, it was heated to 100°C and reacted for 16 hours. The reaction was completed After, be cooled to room temperature, in the reaction solution, add ethyl acetate (50mL) to dilute the reaction solution, wash the reaction solution with clear water (20mL × 3). The organic phase is concentrated under reduced pressure to obtain the crude product. The crude product is separated and purified by column chromatography (petroleum Ether: ethyl acetate (v/v)=5:3) to give (S)-4-(3-bromo-5-(trifluoromethyl)pyridin-2-yl)-3-(hydroxymethyl)piperidine Tert-butyl oxazine-1-carboxylate (53b) (3.80 g, 42%).
LCMS m/z＝384.1[M-55] +。 LCMS m/z = 384.1 [M-55] + .
第二步：(S)-3-((乙酰硫基)甲基)-4-(3-溴-5-(三氟甲基)吡啶-2-基)哌嗪-1-羧酸叔丁酯(化合物53c)The second step: (S)-3-((acetylthio)methyl)-4-(3-bromo-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylic acid tert-butyl Esters (Compound 53c)
Tert-butyl(S)-3-((acetylthio)methyl)-4-(3-bromo-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylateTert-butyl(S)-3-((acetylthio)methyl)-4-(3-bromo-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate
Figure PCTCN2022088446-appb-000340
Figure PCTCN2022088446-appb-000340
冰水浴下，将硫代乙酸(0.79g,10.36mmol)加入到(S)-4-(3-溴-5-(三氟甲基)吡啶-2-基)-3-(羟甲基)哌嗪-1-羧酸叔丁酯(53b)(3.80g,8.63mmol)、三苯基膦(2.72g,10.36mmol)、DEAD(1.80g,10.36mmol)的无水四氢呋喃(30mL)溶液中。保持冰水浴反应2小时后，升温至室温反应16小时。直接向反应液中加硅胶拌样，经柱层析分离纯化(石油醚：乙酸乙酯(v/v)＝10：1)得到(S)-3-((乙酰硫基)甲基)-4-(3-溴-5-(三氟甲基)吡啶-2-基)哌嗪-1-羧酸叔丁酯(53c)(0.20g,5％)。Under ice-water bath, thioacetic acid (0.79 g, 10.36 mmol) was added to (S)-4-(3-bromo-5-(trifluoromethyl)pyridin-2-yl)-3-(hydroxymethyl) A solution of piperazine-1-carboxylate tert-butyl ester (53b) (3.80 g, 8.63 mmol), triphenylphosphine (2.72 g, 10.36 mmol), DEAD (1.80 g, 10.36 mmol) in dry tetrahydrofuran (30 mL) . After keeping the reaction in an ice-water bath for 2 hours, the temperature was raised to room temperature and the reaction was performed for 16 hours. Silica gel was directly added to the reaction solution, and the sample was separated and purified by column chromatography (petroleum ether:ethyl acetate (v/v)=10:1) to obtain (S)-3-((acetylthio)methyl)- 4-(3-Bromo-5-(trifluoromethyl)pyridin-2-yl)piperazine-1-carboxylate tert-butyl ester (53c) (0.20 g, 5%).
LCMS m/z＝442.0[M-55] +。 LCMS m/z = 442.0 [M-55] + .
第三步：(S)-(1-(3-溴-5-(三氟甲基)吡啶-2-基)-4-(叔丁氧基羰基)哌嗪-2-基)甲硫醇(化合物53d)的钠盐The third step: (S)-(1-(3-bromo-5-(trifluoromethyl)pyridin-2-yl)-4-(tert-butoxycarbonyl)piperazin-2-yl)methanethiol (Compound 53d) sodium salt
sodium(S)-(1-(3-bromo-5-(trifluoromethyl)pyridin-2-yl)-4-(tert-butoxycarbonyl)piperazin-2-yl)methanethiolatesodium(S)-(1-(3-bromo-5-(trifluoromethyl)pyridin-2-yl)-4-(tert-butoxycarbonyl)piperazin-2-yl)methanethiolate
Figure PCTCN2022088446-appb-000341
Figure PCTCN2022088446-appb-000341
冰水浴下，将0.5M的乙醇钠溶液(15mg,0.64mmol，1.28mL)加入到(S)-3-((乙酰硫基)甲基)-4-(3-溴-5-(三氟甲基)吡啶-2-基)哌嗪-1-羧酸叔丁酯(53c)(0.32g,0.64mmol)的无水四氢呋喃(2mL)溶液中，然后保持室温反应0.5小时。反应完毕后，直接浓缩干反应液得到(S)-(1-(3-溴-5-(三氟甲基)吡啶-2-基)-4-(叔丁氧基羰基)哌嗪-2-基)甲硫醇(53d)的钠盐(300mg)无需纯化直接做下一步。Under ice-water bath, 0.5M sodium ethoxide solution (15 mg, 0.64 mmol, 1.28 mL) was added to (S)-3-((acetylthio)methyl)-4-(3-bromo-5-(trifluoro) Methyl)pyridin-2-yl)piperazine-1-carboxylate tert-butyl ester (53c) (0.32 g, 0.64 mmol) in anhydrous tetrahydrofuran (2 mL) and then kept at room temperature for 0.5 h. After the completion of the reaction, the dry reaction solution was directly concentrated to obtain (S)-(1-(3-bromo-5-(trifluoromethyl)pyridin-2-yl)-4-(tert-butoxycarbonyl)piperazine-2 -yl)methanethiol (53d) sodium salt (300 mg) was carried to the next step without purification.
LCMS m/z＝431.9[M-23] +。 LCMS m/z=431.9[M-23] + .
第四步：(S)-3-(三氟甲基)-6a,7,9,10-四氢吡嗪并[1,2-d]吡啶并[3,2-b][1,4]噻嗪-8(6H)-羧酸叔丁酯(化合物53e)The fourth step: (S)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2-b][1,4 ] Thiazine-8(6H)-carboxylate tert-butyl ester (Compound 53e)
Tert-butyl(S)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2-b][1,4]thiazine-8(6H)-carboxylateTert-butyl(S)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2-b][1,4]thiazine-8(6H)-carboxylate
Figure PCTCN2022088446-appb-000342
Figure PCTCN2022088446-appb-000342
氮气保护下，室温下，将三(二亚苄基茚丙酮)二钯(29mg,0.032mmol)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(36mg,0.063mmol)、N,N-二异丙基乙胺(163mg,1.26mmol)加入到(S)-(1-(3-溴-5-(三氟甲基)吡啶-2-基)-4-(叔丁氧基羰基)哌嗪-2-基)甲硫醇(53d)的钠盐(300mg)的干燥二氧六环(2mL)溶液中。置换氮气3次后，升温到70℃反应2小时。反应完全后，加水(2mL)淬灭反应，加乙酸乙酯(5mLx3)萃取，有机层经无水硫酸钠干燥，抽滤，减压浓缩滤液得粗品。粗品经制备板分离纯化(PE：EA(v/v)＝5：1)得到(S)-3-(三氟甲基)-6a,7,9,10-四氢吡嗪并[1,2-d]吡啶并[3,2-b][1,4]噻嗪-8(6H)-羧酸叔丁酯(53e)(100mg,41％，2步收率)。Under nitrogen protection, at room temperature, tris(dibenzylideneindenacetone)dipalladium (29mg, 0.032mmol), 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (36mg, 0.063 mmol), N,N-diisopropylethylamine (163 mg, 1.26 mmol) was added to (S)-(1-(3-bromo-5-(trifluoromethyl)pyridin-2-yl)-4- (tert-Butoxycarbonyl)piperazin-2-yl)methanethiol (53d) as a solution of the sodium salt (300 mg) in dry dioxane (2 mL). After replacing the nitrogen gas three times, the temperature was raised to 70° C. to react for 2 hours. After the reaction was completed, water (2 mL) was added to quench the reaction, ethyl acetate (5 mL×3) was added for extraction, the organic layer was dried over anhydrous sodium sulfate, filtered with suction, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by preparative plate (PE:EA(v/v)=5:1) to obtain (S)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1, 2-d]pyrido[3,2-b][1,4]thiazine-8(6H)-carboxylate tert-butyl ester (53e) (100 mg, 41%, 2 steps yield).
LCMS m/z＝376.1[M+1] +。 LCMS m/z=376.1[M+1] + .
第五步：(S)-3-(三氟甲基)-6a,7,9,10-四氢吡嗪并[1,2-d]吡啶并[3,2-b][1,4]噻嗪-8(6H)-羧酸叔丁酯5,5-二氧化物(化合物53f)The fifth step: (S)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2-b][1,4 ] Thiazine-8(6H)-carboxylate tert-butyl ester 5,5-dioxide (Compound 53f)
Tert-butyl(S)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2-b][1,4]thiazine-8(6H)-carboxylate 5,5-dioxideTert-butyl(S)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2-b][1,4]thiazine-8(6H)-carboxylate 5,5-dioxide
Figure PCTCN2022088446-appb-000343
Figure PCTCN2022088446-appb-000343
室温下，将间氯过氧苯甲酸(219mg,1.08mmol)分批次加入到(S)-3-(三氟甲基)-6a,7,9,10-四氢吡嗪并[1,2-d]吡啶并[3,2-b][1,4]噻嗪-8(6H)-羧酸叔丁酯(53e)(100mg,0.27mmol)的二氯甲烷(2mL)溶液中，保持室温反应5小时。反应完毕后，加水(2mL)淬灭反应，二氯甲烷萃取(10mLx2)，有机相经无水硫酸钠干燥，抽滤，减压浓缩滤液得粗品。 粗品经制备板分离纯化(石油醚：乙酸乙酯(v/v)＝5：2)得到目标产物(S)-3-(三氟甲基)-6a,7,9,10-四氢吡嗪并[1,2-d]吡啶并[3,2-b][1,4]噻嗪-8(6H)-羧酸叔丁酯5,5-二氧化物(53f)(60mg,55％)。At room temperature, m-chloroperoxybenzoic acid (219 mg, 1.08 mmol) was added portionwise to (S)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1, 2-d]pyrido[3,2-b][1,4]thiazine-8(6H)-carboxylate tert-butyl ester (53e) (100 mg, 0.27 mmol) in dichloromethane (2 mL), The reaction was kept at room temperature for 5 hours. After the reaction was completed, water (2 mL) was added to quench the reaction, dichloromethane was extracted (10 mL×2), the organic phase was dried over anhydrous sodium sulfate, filtered with suction, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by preparative plate (petroleum ether:ethyl acetate (v/v)=5:2) to obtain the target product (S)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyridine Azino[1,2-d]pyrido[3,2-b][1,4]thiazine-8(6H)-carboxylate tert-butyl ester 5,5-dioxide (53f) (60 mg, 55 %).
LCMS m/z＝352.1[M-55] +。 LCMS m/z = 352.1 [M-55] + .
第六步：(S)-3-(三氟甲基)-6,6a,7,8,9,10-六氢吡嗪并[1,2-d]吡啶并[3,2-b][1,4]噻嗪5,5-二氧化物(化合物53g)的盐酸盐The sixth step: (S)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydropyrazino[1,2-d]pyrido[3,2-b] Hydrochloride salt of [1,4]thiazine 5,5-dioxide (compound 53g)
(S)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]thiazine5,5-dioxide(S)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydropyrazino[1,2-d]pyrido[3,2-b][1,4]thiazine5,5-dioxide
Figure PCTCN2022088446-appb-000344
Figure PCTCN2022088446-appb-000344
室温下，将(S)-3-(三氟甲基)-6a,7,9,10-四氢吡嗪并[1,2-d]吡啶并[3,2-b][1,4]噻嗪-8(6H)-羧酸叔丁酯5,5-二氧化物(53f)(50mg,0.12mmol)溶于4N盐酸二氧六环溶液(4mL)中，保持室温搅拌反应2小时。反应完毕后，减压浓缩得到(S)-3-(三氟甲基)-6,6a,7,8,9,10-六氢吡嗪并[1,2-d]吡啶并[3,2-b][1,4]噻嗪5,5-二氧化物(53g)的盐酸盐(40mg)，无需纯化，直接做下一步反应。At room temperature, (S)-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2-b][1,4 ] Thiazine-8(6H)-carboxylate tert-butyl ester 5,5-dioxide (53f) (50mg, 0.12mmol) was dissolved in 4N hydrochloric acid dioxane solution (4mL), and the reaction was stirred at room temperature for 2 hours . After the reaction was completed, concentrated under reduced pressure to obtain (S)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydropyrazino[1,2-d]pyrido[3, The hydrochloride salt (40 mg) of 2-b][1,4]thiazine 5,5-dioxide (53 g) was directly used in the next reaction without purification.
LCMS m/z＝308.1[M+1] +。 LCMS m/z=308.1[M+1] + .
第七步：5-(((S)-1-(3-((S)-5,5-二氧化-3-(三氟甲基)-6a,7,9,10-四氢吡嗪[1,2-d]吡啶并[3,2-b][1,4]噻嗪-8(6H)-基)-3-氧代丙氧基)丙-2-基)氨基)-4-(三氟甲基)哒嗪-3(2H)-酮(化合物53)The seventh step: 5-(((S)-1-(3-((S)-5,5-dioxy-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazine [1,2-d]pyrido[3,2-b][1,4]thiazin-8(6H)-yl)-3-oxopropoxy)propan-2-yl)amino)-4 -(Trifluoromethyl)pyridazin-3(2H)-one (Compound 53)
5-(((S)-1-(3-((S)-5,5-dioxido-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2-b][1,4]thiazin-8(6H)-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one5-(((S)-1-(3-((S)-5,5-dioxido-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3, 2-b][1,4]thiazin-8(6H)-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one
Figure PCTCN2022088446-appb-000345
Figure PCTCN2022088446-appb-000345
室温下，将HATU(49mg,0.13mmol)加入到(S)-3-(三氟甲基)-6,6a,7,8,9,10-六氢吡嗪并[1,2-d]吡啶并[3,2-b][1,4]噻嗪5,5-二氧化物(53g)的盐酸盐(40mg)、3-[(2S)-2-[(6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基]丙氧基]丙酸(4j)(40mg,0.13mmol)、N,N-二异 丙基乙胺(17mg,0.13mmol)的N,N-二甲基甲酰胺(2mL)溶液中，然后保持室温搅拌反应1小时。反应完毕后，反应液经Pre-HPLC纯化(仪器及制备柱：采用WATERS 2767制备液相，制备柱型号是Xselect C18，5μm，内径×长度＝19mm×150mm)。制备方法：反应液用0.45μm滤膜过滤，制备成样品液。流动相体系：乙腈/水(含0.05％氨水)。梯度洗脱方法：乙腈由5％梯度洗脱至50％(洗脱时间15min)。冻干后得到5-(((S)-1-(3-((S)-5,5-二氧化-3-(三氟甲基)-6a,7,9,10-四氢吡嗪[1,2-d]吡啶并[3,2-b][1,4]噻嗪-8(6H)-基)-3-氧代丙氧基)丙-2-基)氨基)-4-(三氟甲基)哒嗪-3(2H)-酮(化合物53)(25mg,34％，2步收率)。HATU (49 mg, 0.13 mmol) was added to (S)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydropyrazino[1,2-d] at room temperature Pyrido[3,2-b][1,4]thiazine 5,5-dioxide (53g) hydrochloride (40mg), 3-[(2S)-2-[(6-oxo- 5-(Trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino]propoxy]propionic acid (4j) (40 mg, 0.13 mmol), N,N-diisopropylethylamine (17 mg, 0.13 mmol) in N,N-dimethylformamide (2 mL), then the reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was purified by Pre-HPLC (instrument and preparative column: WATERS 2767 was used to prepare the liquid phase, the preparative column model was Xselect C18, 5 μm, inner diameter×length=19mm×150mm). Preparation method: The reaction solution was filtered with a 0.45 μm 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). After lyophilization, 5-(((S)-1-(3-((S)-5,5-dioxy-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazine was obtained [1,2-d]pyrido[3,2-b][1,4]thiazin-8(6H)-yl)-3-oxopropoxy)propan-2-yl)amino)-4 -(Trifluoromethyl)pyridazin-3(2H)-one (Compound 53) (25 mg, 34%, 2 steps yield).
LCMS m/z＝599.2[M+1] +。 LCMS m/z=599.2[M+1] + .
1H NMR(400MHz,DMSO-d 6)δ11.91(s,1H),8.75(d,1H),8.23(d,1H),7.91(s,1H),6.34-6.19(m,1H),4.88-4.66(m,1H),4.61-4.30(m,1H),4.26-3.85(m,4H),3.76-3.61(m,3H),3.50(d,2H),3.29-3.06(m,2H),2.93-2.81(m,1H),2.74-2.56(m,2H),1.17(d,3H)。 1 H NMR (400MHz, DMSO-d 6 )δ11.91(s,1H), 8.75(d,1H), 8.23(d,1H), 7.91(s,1H), 6.34-6.19(m,1H), 4.88-4.66(m, 1H), 4.61-4.30(m, 1H), 4.26-3.85(m, 4H), 3.76-3.61(m, 3H), 3.50(d, 2H), 3.29-3.06(m, 2H) ), 2.93-2.81 (m, 1H), 2.74-2.56 (m, 2H), 1.17 (d, 3H).
实施例54：5-(((S)-1-(3-((R)-5,5-二氧化-3-(三氟甲基)-6a,7,9,10-四氢吡嗪[1,2-d]吡啶并[3,2-b][1,4]噻嗪-8(6H)-基)-3-氧代丙氧基)丙-2-基)氨基)-4-(三氟甲基)哒嗪-3(2H)-酮(化合物54)Example 54: 5-(((S)-1-(3-((R)-5,5-dioxy-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazine [1,2-d]pyrido[3,2-b][1,4]thiazin-8(6H)-yl)-3-oxopropoxy)propan-2-yl)amino)-4 -(Trifluoromethyl)pyridazin-3(2H)-one (Compound 54)
5-(((S)-1-(3-((R)-5,5-dioxido-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3,2-b][1,4]thiazin-8(6H)-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one5-(((S)-1-(3-((R)-5,5-dioxido-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazino[1,2-d]pyrido[3, 2-b][1,4]thiazin-8(6H)-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one
Figure PCTCN2022088446-appb-000346
Figure PCTCN2022088446-appb-000346
化合物54以3-溴-2-氯-5-三氟甲基吡啶、(R)-1-Boc-3-羟甲基哌嗪和3-[(2S)-2-[(6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基]丙氧基]丙酸(4j)为原料，参考实施例53的合成方法，得到5-(((S)-1-(3-((R)-5,5-二氧化-3-(三氟甲基)-6a,7,9,10-四氢吡嗪[1,2-d]吡啶并[3,2-b][1,4]噻嗪-8(6H)-基)-3-氧代丙氧基)丙-2-基)氨基)-4-(三氟甲基)哒嗪-3(2H)-酮(化合物54)。Compound 54 was prepared with 3-bromo-2-chloro-5-trifluoromethylpyridine, (R)-1-Boc-3-hydroxymethylpiperazine and 3-[(2S)-2-[(6-oxo -5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl)amino]propoxy]propionic acid (4j) was used as the raw material, referring to the synthetic method of Example 53, to obtain 5-(( (S)-1-(3-((R)-5,5-dioxy-3-(trifluoromethyl)-6a,7,9,10-tetrahydropyrazine[1,2-d]pyridine [3,2-b][1,4]thiazin-8(6H)-yl)-3-oxopropoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridin Azin-3(2H)-one (Compound 54).
LCMS m/z＝599.1[M+1] +。 LCMS m/z=599.1[M+1] + .
1H NMR(400MHz,DMSO-d 6)δ12.44(s,1H),8.74(s,1H),8.23(s,1H),7.91(s,1H),6.32-6.20(m,1H),4.85-4.67(m,1H),4.59-4.31(m,1H),4.21-3.89(m,4H),3.75-3.63(m,3H),3.49(d,2H),3.29-3.05(m,2H),2.93-2.81(m,1H),2.71-2.57(m,2H),1.16(d,3H) 1 H NMR (400MHz, DMSO-d 6 )δ12.44(s,1H), 8.74(s,1H), 8.23(s,1H), 7.91(s,1H), 6.32-6.20(m,1H), 4.85-4.67(m,1H),4.59-4.31(m,1H),4.21-3.89(m,4H),3.75-3.63(m,3H),3.49(d,2H),3.29-3.05(m,2H) ), 2.93-2.81(m, 1H), 2.71-2.57(m, 2H), 1.16(d, 3H)
实施例55：5-(((2S)-1-(2-羟基-3-氧代-3-((R)-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡啶并[1,6-a:2,3-b']二吡嗪-8-基)丙氧基)丙-2-基)氨基)-4-(三氟甲基)哒嗪-3(2H)-酮(化合物55)Example 55: 5-(((2S)-1-(2-hydroxy-3-oxo-3-((R)-3-(trifluoromethyl)-5,6,6a,7,9, 10-Hexahydro-8H-pyrido[1,6-a:2,3-b']dipyrazin-8-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl) yl)pyridazin-3(2H)-one (Compound 55)
5-(((2S)-1-(2-hydroxy-3-oxo-3-((R)-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrido[1,6-a:2,3-b']dipyrazin-8-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one5-(((2S)-1-(2-hydroxy-3-oxo-3-((R)-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrido[ 1,6-a:2,3-b']dipyrazin-8-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one
Figure PCTCN2022088446-appb-000347
Figure PCTCN2022088446-appb-000347
化合物55以(R)-3-(三氟甲基)-6,6a,7,8,9,10-六氢-5H-吡啶[1,6-a:2,3-b']二吡嗪(51g)的盐酸盐和2-羟基-3-((S)-2-((6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基)丙氧基)丙酸(55a)(中间体合成参照WO2021087018制备得到)为原料，参考实施例51的合成方法，得到5-(((2S)-1-(2-羟基-3-氧代-3-((R)-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡啶并[1,6-a:2,3-b']二吡嗪-8-基)丙氧基)丙-2-基)氨基)-4-(三氟甲基)哒嗪-3(2H)-酮(化合物55)。Compound 55 was identified as (R)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyridine[1,6-a:2,3-b']dipyridine The hydrochloride salt of oxazine (51 g) and 2-hydroxy-3-((S)-2-((6-oxo-5-(trifluoromethyl)-1,6-dihydropyridazin-4-yl) ) amino) propoxy) propionic acid (55a) (the intermediate synthesis was prepared by referring to WO2021087018) as the raw material, referring to the synthetic method of Example 51 to obtain 5-(((2S)-1-(2-hydroxy-3- Oxo-3-((R)-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrido[1,6-a:2,3-b '] Dipyrazin-8-yl)propoxy)prop-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (Compound 55).
LCMS m/z＝566.2[M+1] +。 LCMS m/z=566.2[M+1] + .
1H NMR(400MHz,CDCl 3)δ10.47-10.33(m,1H),8.23(s,1H),7.65(s,1H),5.82-5.58(m,1H),4.89-4.50(m,3H),4.00-3.41(m,8H),3.28-2.58(m,5H),2.32-2.13(m,1H),1.95-1.78(m,1H),1.31(d,3H)。 1 H NMR (400MHz, CDCl 3 )δ10.47-10.33(m,1H), 8.23(s,1H), 7.65(s,1H), 5.82-5.58(m,1H), 4.89-4.50(m,3H) ), 4.00-3.41(m, 8H), 3.28-2.58(m, 5H), 2.32-2.13(m, 1H), 1.95-1.78(m, 1H), 1.31(d, 3H).
实施例56：5-(((2S)-1-(2-羟基-3-氧代-3-((R)-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡嗪[1,2-a][1,8]萘啶-8-基)丙氧基)丙-2-基)氨基)-4-(三氟甲基)哒嗪-3(2H)-酮(化合物56)的三氟乙酸盐Example 56: 5-(((2S)-1-(2-hydroxy-3-oxo-3-((R)-3-(trifluoromethyl)-5,6,6a,7,9, 10-Hexahydro-8H-pyrazine[1,2-a][1,8]naphthyridin-8-yl)propoxy)prop-2-yl)amino)-4-(trifluoromethyl)pyridin Trifluoroacetate salt of oxazin-3(2H)-one (compound 56)
5-(((2S)-1-(2-hydroxy-3-oxo-3-((R)-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a][1,8]naphthyridin-8-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one trifluoroacetate5-(((2S)-1-(2-hydroxy-3-oxo-3-((R)-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[ 1,2-a][1,8]naphthyridin-8-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one trifluoroacetate
Figure PCTCN2022088446-appb-000348
Figure PCTCN2022088446-appb-000348
Figure PCTCN2022088446-appb-000349
Figure PCTCN2022088446-appb-000349
第一步：1-苄基4-(叔丁基)(R)-2-(2-(2-羟基-5-(三氟甲基)吡啶-3-基)乙烯基)哌嗪-1,4-二羧酸酯(化合物56b)The first step: 1-benzyl 4-(tert-butyl)(R)-2-(2-(2-hydroxy-5-(trifluoromethyl)pyridin-3-yl)vinyl)piperazine-1 ,4-Dicarboxylate (Compound 56b)
Benzyl 4-(tert-butyl)(R)-2-(2-(2-hydroxy-5-(trifluoromethyl)pyridin-3-yl)vinyl)piperazine-1,4-dicarboxylateBenzyl 4-(tert-butyl)(R)-2-(2-(2-hydroxy-5-(trifluoromethyl)pyridin-3-yl)vinyl)piperazine-1,4-dicarboxylate
Figure PCTCN2022088446-appb-000350
Figure PCTCN2022088446-appb-000350
室温下，将4-(叔丁基)(R)-2-乙烯基哌嗪-1,4-二羧酸1-苄基酯(56a)(参考专利WO2015013835合成得到)(2.5g,7.22mmol)溶解于DMF(20mL)中，加入3-溴-2-羟基-5-(三氟甲基)吡啶(2.62g,10.83mmol),DIPEA(2.80g,21.66mmol),Xphos(1.38g,2.89mmol)和Pd(OAc) 2(320mg,1.44mmol)。氮气置换3次，在115℃下搅拌过夜，加水淬灭反应，乙酸乙酯(50mL x 3)萃取，合并有机相，有机相用饱和食盐水(50mL x 3)反洗，无水硫酸钠干燥，抽滤，滤液减压浓缩得残留物。残留物用硅胶柱色谱分离提纯(DCM in THF＝5-10％)得到：1-苄基4-(叔丁基)(R)-2-(2-(2-羟基-5-(三氟甲基)吡啶-3-基)乙烯基)哌嗪-1,4-二羧酸酯(化合物56b)(530mg,14％)。 At room temperature, 4-(tert-butyl)(R)-2-vinylpiperazine-1,4-dicarboxylic acid 1-benzyl ester (56a) (synthesized with reference to patent WO2015013835) (2.5 g, 7.22 mmol) ) was dissolved in DMF (20 mL), 3-bromo-2-hydroxy-5-(trifluoromethyl)pyridine (2.62 g, 10.83 mmol), DIPEA (2.80 g, 21.66 mmol), Xphos (1.38 g, 2.89 mmol) were added mmol) and Pd(OAc) 2 (320 mg, 1.44 mmol). Replaced with nitrogen three times, stirred overnight at 115 °C, added water to quench the reaction, extracted with ethyl acetate (50 mL x 3), combined the organic phases, backwashed the organic phases with saturated brine (50 mL x 3), and dried over anhydrous sodium sulfate. , filtered with suction, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (DCM in THF=5-10%) to give: 1-benzyl 4-(tert-butyl)(R)-2-(2-(2-hydroxy-5-(trifluoro) Methyl)pyridin-3-yl)vinyl)piperazine-1,4-dicarboxylate (compound 56b) (530 mg, 14%).
LCMS m/z＝452.2[M-55] +。 LCMS m/z=452.2[M-55] + .
第二步：(R)-3-(2-(2-羟基-5-(三氟甲基)吡啶-3-基)乙基)哌嗪-1-羧酸叔丁酯(化合物56c)The second step: (R)-tert-butyl 3-(2-(2-hydroxy-5-(trifluoromethyl)pyridin-3-yl)ethyl)piperazine-1-carboxylate (compound 56c)
Tert-butyl(R)-3-(2-(2-hydroxy-5-(trifluoromethyl)pyridin-3-yl)ethyl)piperazine-1-carboxylateTert-butyl(R)-3-(2-(2-hydroxy-5-(trifluoromethyl)pyridin-3-yl)ethyl)piperazine-1-carboxylate
Figure PCTCN2022088446-appb-000351
Figure PCTCN2022088446-appb-000351
室温下，将1-苄基4-(叔丁基)(R)-2-(2-(2-羟基-5-(三氟甲基)吡啶-3-基)乙烯基)哌嗪-1,4-二羧酸酯(化合物56b)(1g,1.97mmol)溶于MeOH(5mL)中，加入Pd/C(100mg),室温搅拌反应过夜，过滤，滤液减压浓缩除去溶剂得到(R)-3-(2-(2-羟基-5-(三氟甲基)吡啶-3-基)乙基)哌嗪-1-羧酸叔丁酯(化合物56c)(700mg)，未进一步纯化，直接投下一步。At room temperature, 1-benzyl 4-(tert-butyl)(R)-2-(2-(2-hydroxy-5-(trifluoromethyl)pyridin-3-yl)vinyl)piperazine-1 ,4-dicarboxylate (compound 56b) (1 g, 1.97 mmol) was dissolved in MeOH (5 mL), Pd/C (100 mg) was added, the reaction was stirred at room temperature overnight, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent to obtain (R) - tert-butyl 3-(2-(2-hydroxy-5-(trifluoromethyl)pyridin-3-yl)ethyl)piperazine-1-carboxylate (Compound 56c) (700 mg) without further purification, Cast directly to the next step.
LCMS m/z＝376.2[M+1] +。 LCMS m/z=376.2[M+1] + .
第三步：(R)-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡嗪并[1,2-a][1,8]萘啶-8-羧酸叔丁酯(化合物56d)The third step: (R)-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a][1,8]naphthalene tert-Butyl pyridine-8-carboxylate (Compound 56d)
Tert-butyl(R)-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a][1,8]naphthyridine-8-carboxylateTert-butyl(R)-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a][1,8]naphthyridine-8-carboxylate
Figure PCTCN2022088446-appb-000352
Figure PCTCN2022088446-appb-000352
室温下，将(R)-3-(2-(2-羟基-5-(三氟甲基)吡啶-3-基)乙基)哌嗪-1-羧酸叔丁酯(化合物56c)(700mg,1.86mmol)溶解于DMSO(15mL)中，加入PyBOP(970mg,1.86mmol)和DIPEA(720mg,5.58mmol)。在60℃下搅拌过夜，加水淬灭反应，乙酸乙酯(10mL x 3)萃取，合并有机相，有机相用饱和食盐水(10mL x 3)反洗，无水硫酸钠干燥，抽滤，滤液减压浓缩得残留物。残留物用硅胶柱色谱分离提纯(10％EA in PE)得到(R)-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡嗪并[1,2-a][1,8]萘啶-8-羧酸叔丁酯(化合物56d)(270mg,38％,2步反应)。(R)-tert-butyl 3-(2-(2-hydroxy-5-(trifluoromethyl)pyridin-3-yl)ethyl)piperazine-1-carboxylate (compound 56c)( 700 mg, 1.86 mmol) was dissolved in DMSO (15 mL), PyBOP (970 mg, 1.86 mmol) and DIPEA (720 mg, 5.58 mmol) were added. Stir overnight at 60 °C, add water to quench the reaction, extract with ethyl acetate (10 mL x 3), combine the organic phases, backwash the organic phases with saturated brine (10 mL x 3), dry over anhydrous sodium sulfate, filter with suction, and the filtrate Concentration under reduced pressure gave a residue. The residue was purified by silica gel column chromatography (10% EA in PE) to give (R)-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[ 1,2-a][1,8]Naphthyridine-8-carboxylate tert-butyl ester (Compound 56d) (270 mg, 38%, 2 steps).
LCMS m/z＝358.2[M+1] +。 LCMS m/z=358.2[M+1] + .
第四步：(R)-3-(三氟甲基)-6,6a,7,8,9,10-六氢-5H-吡嗪并[1,2-a][1,8]萘啶(化合物56e)的盐酸盐The fourth step: (R)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1,8]naphthalene pyridine (compound 56e) hydrochloride
(R)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1,8]naphthyridine(R)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1,8]naphthyridine
Figure PCTCN2022088446-appb-000353
Figure PCTCN2022088446-appb-000353
室温下，将(R)-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡嗪并[1,2-a][1,8]萘啶-8-羧酸叔丁酯(化合物56d)(39mg，0.11mmol)溶于氯化氢-1,4-二氧六环溶液(4.0M，2mL,8mmol)，室温反应至反应完全。减压浓缩除去溶剂后得(R)-3-(三氟甲基)-6,6a,7,8,9,10-六氢-5H-吡嗪并[1,2-a][1,8]萘啶(化合物55e)的盐酸盐(36mg)，未进一步纯化，直接投下一步。(R)-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a][1,8]naphthalene at room temperature The tert-butyl pyridine-8-carboxylate (compound 56d) (39 mg, 0.11 mmol) was dissolved in a hydrogen chloride-1,4-dioxane solution (4.0 M, 2 mL, 8 mmol) and reacted at room temperature until the reaction was complete. After concentration under reduced pressure to remove the solvent, (R)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1, 8] The hydrochloride salt of naphthyridine (compound 55e) (36 mg), which was used in the next step without further purification.
LCMS m/z＝258.2[M+1]+LCMS m/z=258.2[M+1]+
第五步：5-(((2S)-1-(2-羟基-3-氧-3-((R)-(3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡嗪并[1,2-a][1,8]萘啶-8-基)丙氧基)丙-2-基)氨基)-4-(三氟甲基)哒嗪-3(2H)-酮(化合物56)的三氟乙酸盐The fifth step: 5-(((2S)-1-(2-hydroxy-3-oxo-3-((R)-(3-(trifluoromethyl)-5,6,6a,7,9, 10-Hexahydro-8H-pyrazino[1,2-a][1,8]naphthyridin-8-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl) Trifluoroacetate salt of pyridazin-3(2H)-one (compound 56)
5-(((2S)-1-(2-hydroxy-3-oxo-3-((R)-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a][1,8]naphthyridin-8-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one trifluoroacetate5-(((2S)-1-(2-hydroxy-3-oxo-3-((R)-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[ 1,2-a][1,8]naphthyridin-8-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one trifluoroacetate
Figure PCTCN2022088446-appb-000354
Figure PCTCN2022088446-appb-000354
室温下，将(R)-3-(三氟甲基)-6,6a,7,8,9,10-六氢-5H-吡嗪并[1,2-a][1,8]萘啶(化合物56e)的盐酸盐(36mg,0.11mmol)和2-羟基-3-[(2S)-2-[(6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基]丙氧基]丙酸(36mg,0.11mmol)溶于DMF(2mL)中，向其中分别加入DIPEA(43mg,0.33mmol)和HATU(42mg,0.11mmol)然后室温搅拌反应3小时。反应结束后，反应液经Pre-HPLC纯化(仪器及制备柱：采用SHIMADZULC-20AP制备液相，制备柱型号是Phenomenex C18。制备方法：反应液用0.45μm滤膜过滤，制备成样品液。流动相体系：乙腈/水(含0.01％三氟乙酸)。梯度洗脱方法：乙腈由10％-40％梯度洗脱(洗脱时间10min)。冻干后得到5-(((2S)-1-(2-羟基-3-氧代-3-((R)-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡嗪[1,2-a][1,8]萘啶-8-基)丙氧基)丙-2-基)氨基)-4-(三氟甲基)哒嗪-3(2H)-酮(化合物56)的三氟乙酸盐(10mg,14％,2步反应)。(R)-3-(trifluoromethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1,8]naphthalene at room temperature pyridine (compound 56e) hydrochloride (36 mg, 0.11 mmol) and 2-hydroxy-3-[(2S)-2-[(6-oxo-5-(trifluoromethyl)-1,6-di Hydropyridazin-4-yl)amino]propoxy]propionic acid (36 mg, 0.11 mmol) was dissolved in DMF (2 mL), to which were added DIPEA (43 mg, 0.33 mmol) and HATU (42 mg, 0.11 mmol) respectively and then The reaction was stirred at room temperature for 3 hours. After the reaction finishes, the reaction solution is purified by Pre-HPLC (instrument and preparation column: adopt SHIMADZULC-20AP to prepare the liquid phase, and the preparation column model is Phenomenex C18. Preparation method: the reaction solution is filtered with a 0.45 μm filter membrane to prepare a sample solution. Flow Phase system: acetonitrile/water (containing 0.01% trifluoroacetic acid). Gradient elution method: acetonitrile was eluted by gradient from 10% to 40% (elution time 10 min). After lyophilization, 5-(((2S)-1 was obtained -(2-Hydroxy-3-oxo-3-((R)-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazine[1,2 of -a][1,8]naphthyridin-8-yl)propoxy)prop-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one (compound 56) Trifluoroacetate salt (10 mg, 14%, 2 steps).
LCMS m/z＝565.3[M+1] +。 LCMS m/z=565.3[M+1] + .
1H NMR(400MHz,CDCl 3)δ10.94(s,1H),8.26(s,1H),7.76(s,1H),7.50-7.35(m,1H),5.87-5.61(m,1H),5.10-4.83(m,1H),4.76-4.50(m,2H),3.96-2.59(m,13H),2.30-2.01(m,1H),1.88-1.63(m,1H),1.31(d,3H)。 1 H NMR (400MHz, CDCl 3 )δ10.94(s,1H), 8.26(s,1H), 7.76(s,1H), 7.50-7.35(m,1H), 5.87-5.61(m,1H), 5.10-4.83(m, 1H), 4.76-4.50(m, 2H), 3.96-2.59(m, 13H), 2.30-2.01(m, 1H), 1.88-1.63(m, 1H), 1.31(d, 3H) ).
实施例56-1：5-(((S)-1-((S)-2-羟基-3-氧代-3-((R)-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡嗪[1,2-a][1,8]萘啶-8-基)丙氧基)丙-2-基)氨基)-4-(三氟甲基)哒嗪-3(2H)-酮(化合物56-1)Example 56-1: 5-(((S)-1-((S)-2-hydroxy-3-oxo-3-((R)-3-(trifluoromethyl)-5,6, 6a,7,9,10-Hexahydro-8H-pyrazine[1,2-a][1,8]naphthyridin-8-yl)propoxy)propan-2-yl)amino)-4-( Trifluoromethyl)pyridazin-3(2H)-one (Compound 56-1)
5-(((S)-1-((S)-2-hydroxy-3-oxo-3-((R)-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a][1,8]naphthyridin-8-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one5-(((S)-1-((S)-2-hydroxy-3-oxo-3-((R)-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro- 8H-pyrazino[1,2-a][1,8]naphthyridin-8-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one
5-(((S)-1-((R)-2-羟基-3-氧代-3-((R)-3-(三氟甲基)-5,6,6a,7,9,10-六氢-8H-吡嗪[1,2-a][1,8]萘啶-8-基)丙氧基)丙-2-基)氨基)-4-(三氟甲基)哒嗪-3(2H)-酮(化合物56-2)5-(((S)-1-((R)-2-Hydroxy-3-oxo-3-((R)-3-(trifluoromethyl)-5,6,6a,7,9, 10-Hexahydro-8H-pyrazine[1,2-a][1,8]naphthyridin-8-yl)propoxy)prop-2-yl)amino)-4-(trifluoromethyl)pyridin Azin-3(2H)-one (Compound 56-2)
5-(((S)-1-((R)-2-hydroxy-3-oxo-3-((R)-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro-8H-pyrazino[1,2-a][1,8]naphthyridin-8-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one5-(((S)-1-((R)-2-hydroxy-3-oxo-3-((R)-3-(trifluoromethyl)-5,6,6a,7,9,10-hexahydro- 8H-pyrazino[1,2-a][1,8]naphthyridin-8-yl)propoxy)propan-2-yl)amino)-4-(trifluoromethyl)pyridazin-3(2H)-one
Figure PCTCN2022088446-appb-000355
Figure PCTCN2022088446-appb-000355
化合物56经SFC on AD column纯化(仪器及制备柱：采用Waters 150 SFC，制备柱型号是Chiralcel Column(250mm*30mm,10μm))。制备方法：化合物56用乙腈溶解，并用0.45μm滤膜过滤，制备成样品液。流动相体系：A for CO 2 and B for MeOH(0.1％NH 3·H 2O)。梯度洗脱方法：25％phase B(流速：100mL/min；洗脱时间2.5min)，冻干后得到化合物56-1和化合物56-2。 Compound 56 was purified by SFC on AD column (instrument and preparative column: Waters 150 SFC was used, and the preparative column model was Chiralcel Column (250mm*30mm, 10μm)). Preparation method: Compound 56 was dissolved in acetonitrile, and filtered through a 0.45 μm filter to prepare a sample solution. Mobile phase system: A for CO 2 and B for MeOH (0.1% NH 3 ·H 2 O). Gradient elution method: 25% phase B (flow rate: 100 mL/min; elution time 2.5 min), after lyophilization, compound 56-1 and compound 56-2 were obtained.
分析方法(仪器及制备柱：高效液相色谱仪–正相色谱，制备柱型号是：SHIMADZULC-30AD sf(50×4.6mm，3um))流动相体系：A for CO 2 and B for MeOH(0.05％DEA)。 Analysis method (instrument and preparative column: high performance liquid chromatography - normal phase chromatography, preparative column model: SHIMADZULC-30AD sf (50×4.6mm, 3um)) mobile phase system: A for CO 2 and B for MeOH (0.05 %DEA).
保留时间T＝1.341min(P1)为实施例56-A(实施例56-A为化合物56-1和化合物56-2结构之一)。Retention time T=1.341 min (P1) is Example 56-A (Example 56-A is one of the structures of compound 56-1 and compound 56-2).
LCMS m/z＝565.3[M+1] +。 LCMS m/z=565.3[M+1] + .
1H NMR(400MHz,CDCl 3)δ10.05(s,1H),8.24(s,1H),7.65(s,1H),7.35(s,1H),5.81-5.66(m,1H),5.03-4.90(m,1H),4.72-4.50(m,2H),3.98-2.54(m,13H),2.17-2.03(m,1H),1.84-1.69(m,1H),1.31(d,3H). 1 H NMR (400MHz, CDCl 3 ) δ 10.05(s, 1H), 8.24(s, 1H), 7.65(s, 1H), 7.35(s, 1H), 5.81-5.66(m, 1H), 5.03- 4.90(m, 1H), 4.72-4.50(m, 2H), 3.98-2.54(m, 13H), 2.17-2.03(m, 1H), 1.84-1.69(m, 1H), 1.31(d, 3H).
保留时间T＝1.531min(P2)为实施例56-B(实施例56-B为化合物56-1和化合物56-2结构之一)。Retention time T=1.531 min (P2) is Example 56-B (Example 56-B is one of the structures of compound 56-1 and compound 56-2).
LCMS m/z＝565.3[M+1] + LCMS m/z=565.3[M+1] +
1H NMR(400MHz,CDCl 3)δ9.81(s,1H),8.24(s,1H),7.64(s,1H),7.34(s,1H),5.81-5.59(m,1H),5.03-4.86(m,1H),4.77-4.48(m,2H),3.96-2.63(m,13H),2.15-1.99(m,1H),1.82-1.67(m,1H),1.31(d,3H)。 1 H NMR (400MHz, CDCl 3 ) δ 9.81(s, 1H), 8.24(s, 1H), 7.64(s, 1H), 7.34(s, 1H), 5.81-5.59(m, 1H), 5.03- 4.86(m,1H), 4.77-4.48(m,2H), 3.96-2.63(m,13H), 2.15-1.99(m,1H), 1.82-1.67(m,1H), 1.31(d,3H).
实施例57：化合物57-A与化合物57-B的合成Example 57: Synthesis of Compound 57-A and Compound 57-B
Figure PCTCN2022088446-appb-000356
Figure PCTCN2022088446-appb-000356
第一步：化合物57a的制备Step 1: Preparation of compound 57a
Figure PCTCN2022088446-appb-000357
Figure PCTCN2022088446-appb-000357
3-(三氟甲基)-6,7,7a,8,10,11-六氢-9H-吡嗪并[1,2-d]吡啶并[3,2-b][1,4]氧氮杂环庚-9-甲酸叔丁酯(3d)经SFC on AD column纯化(仪器及制备柱：采用Waters 150 AP，制备柱型号是Chiralpak Column)。制备方法：化合物3d用乙腈溶解，并用0.45μm滤膜过滤，制备成样品液。流动相体系：A for CO 2 and B for MeOH(0.1％NH 3·H 2O)。梯度洗脱方法：10％phase B(流速：70mL/min；洗脱时间6min)，冻干后得到化合物3d-Peak-1和化合物3d-Peak-2。 3-(Trifluoromethyl)-6,7,7a,8,10,11-hexahydro-9H-pyrazino[1,2-d]pyrido[3,2-b][1,4] The tert-butyl oxazepine-9-carboxylate (3d) was purified by SFC on AD column (instrument and preparative column: Waters 150 AP was used, and the preparative column model was Chiralpak Column). Preparation method: Compound 3d was dissolved in acetonitrile, and filtered through a 0.45 μm filter to prepare a sample solution. Mobile phase system: A for CO 2 and B for MeOH (0.1% NH 3 ·H 2 O). Gradient elution method: 10% phase B (flow rate: 70 mL/min; elution time 6 min), after lyophilization, compound 3d-Peak-1 and compound 3d-Peak-2 were obtained.
分析方法(仪器及制备柱：SHIMADZU LC-30AD sfc，制备柱型号是：Chiralpak AD-3 50×4.6mm I.D.,3μm)流动相体系：A for CO 2 and B for MeOH(0.05％DEA)。 Analysis method (instrument and preparative column: SHIMADZU LC-30AD sfc, preparative column type: Chiralpak AD-3 50×4.6 mm ID, 3 μm) mobile phase system: A for CO 2 and B for MeOH (0.05% DEA).
化合物3d-Peak-1保留时间为T＝0.587min，为化合物57a。The retention time of compound 3d-Peak-1 is T=0.587min, which is compound 57a.
LCMS m/z＝374.2[M+1] +。 LCMS m/z=374.2[M+1] + .
化合物3d-Peak-2保留时间为T＝0.677min。The retention time of compound 3d-Peak-2 was T=0.677 min.
第二步：化合物57b的制备The second step: preparation of compound 57b
Figure PCTCN2022088446-appb-000358
Figure PCTCN2022088446-appb-000358
将化合物57a(0.29g,0.77mmol)溶于HCl/dioxane(10mL,4M)中，混合物在室温搅拌反应2h。直接将反应液减压浓缩，得化合物57b的盐酸盐(270mg),直接用于下一步。Compound 57a (0.29 g, 0.77 mmol) was dissolved in HCl/dioxane (10 mL, 4 M), and the mixture was stirred at room temperature for 2 h. The reaction solution was directly concentrated under reduced pressure to obtain the hydrochloride of compound 57b (270 mg), which was directly used in the next step.
LCMS m/z＝274.1[M+1] +。 LCMS m/z=274.1[M+1] + .
第三步：化合物57-A的制备The third step: preparation of compound 57-A
Figure PCTCN2022088446-appb-000359
Figure PCTCN2022088446-appb-000359
室温下，将HATU(300mg，0.78mmol)加入化合物57b的盐酸盐(270mg,0.78mmol)、2-羟基-3-((S)-2-((6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基)丙氧基)丙酸(55a)(250mg,0.78mmol)、DIPEA(300mg，0.78mmol)的N，N-二甲基甲酰胺(5mL)溶液中，然后保持室温搅拌反应1小时。反应完毕后，反应液经Pre-HPLC纯化(仪器及制备柱：采用SHIMADZU LC-20AP制备液相，制备柱型号是Phenomenex C18)。制备方法：反应液用0.45μm滤膜过滤，制备成样品液。流动相体系：A是10mM NH 4HCO 3 in H 2O；B是乙腈。梯度洗脱方法：乙腈由25％到50％(洗脱时间10min)。冻干后得到化合物57-A(化合物57为化合物57-1和化合物57-2结构之一)。 At room temperature, HATU (300 mg, 0.78 mmol) was added to the hydrochloride salt of compound 57b (270 mg, 0.78 mmol), 2-hydroxy-3-((S)-2-((6-oxo-5-(trifluoro) Methyl)-1,6-dihydropyridazin-4-yl)amino)propoxy)propionic acid (55a) (250 mg, 0.78 mmol), DIPEA (300 mg, 0.78 mmol) in N,N-dimethyl formamide (5 mL), then the reaction was stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was purified by Pre-HPLC (instrument and preparative column: the liquid phase was prepared by SHIMADZU LC-20AP, and the type of preparative column was Phenomenex C18). Preparation method: The reaction solution was filtered with a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: A is 10 mM NH4HCO3 in H2O ; B is acetonitrile. Gradient elution method: acetonitrile from 25% to 50% (elution time 10 min). After lyophilization, compound 57-A was obtained (compound 57 is one of the structures of compound 57-1 and compound 57-2).
LCMS m/z＝581.3[M+1] +。 LCMS m/z=581.3[M+1] + .
1H NMR(400MHz,DMSO-d 6)δ12.44(s,1H),8.15(s,1H),7.94-7.87(m,1H),7.38–7.32(m,1H),6.33-6.20(m,1H),5.31-5.18(m,1H),4.49-4.38(m,1H),4.35-4.20(m,2H),4.19-3.58(m,8H),3.58-3.35(m,4H),2.17-2.01(m,1H),1.99-1.85(m,1H),1.19-1.09(m,3H)。 1 H NMR (400MHz, DMSO-d 6 )δ12.44(s,1H),8.15(s,1H),7.94-7.87(m,1H),7.38-7.32(m,1H),6.33-6.20(m ,1H),5.31-5.18(m,1H),4.49-4.38(m,1H),4.35-4.20(m,2H),4.19-3.58(m,8H),3.58-3.35(m,4H),2.17 -2.01(m, 1H), 1.99-1.85(m, 1H), 1.19-1.09(m, 3H).
化合物57-B的制备Preparation of compound 57-B
Figure PCTCN2022088446-appb-000360
Figure PCTCN2022088446-appb-000360
化合物57-B可以通过化合物3d-Peak-2为起始物料，参考化合物57-A的合成方法得到，化合物57-B为化合物57-1和化合物57-2结构之一。Compound 57-B can be obtained by using compound 3d-Peak-2 as the starting material and referring to the synthesis method of compound 57-A. Compound 57-B is one of the structures of compound 57-1 and compound 57-2.
生物测试例Biological test case
1.NCI-H1373细胞增殖抑制1. NCI-H1373 cell proliferation inhibition
NCI-H1373细胞购置于ATCC，培养条件：RPMI-1640+10％FBS+1％双抗，培养于37℃，5％CO 2孵箱中。第一天收集指数生长期的NCI-H1373细胞铺板透明底白色96孔培养板，铺板密度为500个/孔，于37℃，5％CO 2孵箱中培养过夜，铺板同时铺T 0孔。第二天加药前，吸取培养基，每孔加入90μL新鲜培养基和10μL不同浓度化合物，使每孔DMSO终浓度均为0.1％，于37℃，5％CO 2孵箱中培养72小时后，更换培养基并新配化合物，继续培养72小时。第二天加药同时使用CellTiter-Glo试剂盒检测T 0板，记为RLU 0。培养结束后，每孔加入50μL检测液(Cell Viability Assay，Promega，G7573)，混匀2分钟，室温孵育10分钟，酶标仪检测化学发光读数。结果按照式(1)处理，计算出化合物各个浓度的细胞存活率，并使用origin9.2软件，计算增殖率为50％时化合物的浓度GI 50值。RLU compound为药物处理组的读数，RLU control为溶剂对照组的平均值。 NCI-H1373 cells were purchased from ATCC, culture conditions: RPMI-1640+10% FBS+1% double antibody, cultured at 37°C, 5% CO 2 incubator. On the first day, the NCI-H1373 cells in the exponential growth phase were collected and plated in a white 96-well culture plate with a transparent bottom at a plating density of 500 cells/well. The cells were cultured overnight at 37°C in a 5% CO 2 incubator, and T 0 wells were plated at the same time. On the second day before dosing, aspirate the medium, add 90 μL of fresh medium and 10 μL of compounds of different concentrations to each well, so that the final concentration of DMSO in each well is 0.1%. , the medium was replaced and the compound was newly formulated, and the culture was continued for 72 hours. On the second day, the drug was added and the T 0 plate was detected by the CellTiter-Glo kit, which was recorded as RLU 0 . After the incubation, 50 μL of detection solution (Cell Viability Assay, Promega, G7573) was added to each well, mixed for 2 minutes, incubated at room temperature for 10 minutes, and the chemiluminescence reading was detected by a microplate reader. The results were processed according to formula (1), and the cell viability of each concentration of the compound was calculated, and the GI 50 value of the compound concentration when the proliferation rate was 50% was calculated using origin9.2 software. RLU compound is the reading of the drug treated group and RLU control is the mean value of the solvent control group.
Growth％＝(RLU compound-RLU 0)/(RLU control-RLU 0)×100％  式(1) Growth%=(RLU compound -RLU 0 )/(RLU control -RLU 0 )×100% Formula (1)
表1化合物对NCI-H1373细胞的细胞增殖抑制Table 1 Inhibition of cell proliferation of NCI-H1373 cells by compounds
序号serial number 化合物编号Compound number GI 50(nM) GI50 (nM)
11 化合物1Compound 1 ＜50nM<50nM
22 化合物2Compound 2 ＜50nM<50nM
33 化合物3Compound 3 ＜50nM<50nM
44 化合物5Compound 5 ＜50nM<50nM
55 化合物6Compound 6 ＜50nM<50nM
66 实施例7-AExample 7-A ＜50nM<50nM
77 化合物10Compound 10 <100nM<100nM
88 化合物11Compound 11 <100nM<100nM
99 化合物13的三氟乙酸盐Trifluoroacetate salt of compound 13 ＜50nM<50nM
1010 化合物23Compound 23 ＜50nM<50nM
1111 化合物25Compound 25 ＜50nM<50nM
1212 化合物27Compound 27 ＜20nM<20nM
1313 化合物28Compound 28 ＜50nM<50nM
1414 化合物29Compound 29 ＜50nM<50nM
1515 化合物31Compound 31 ＜50nM<50nM
1616 化合物32Compound 32 ＜50nM<50nM
1717 化合物33Compound 33 ＜50nM<50nM
1818 化合物34Compound 34 ＜50nM<50nM
1919 化合物37Compound 37 ＜50nM<50nM
2020 化合物43Compound 43 ＜50nM<50nM
21twenty one 化合物44Compound 44 ＜50nM<50nM
22twenty two 化合物48Compound 48 ＜50nM<50nM
23twenty three 化合物50Compound 50 ＜50nM<50nM
24twenty four 化合物51Compound 51 ＜50nM<50nM
2525 化合物56的三氟乙酸盐Trifluoroacetate salt of compound 56 ＜50nM<50nM
2626 化合物57-ACompound 57-A ＜50nM<50nM
结论：本发明的化合物对NCI-H1373细胞具有细胞增殖抑制活性。对NCI-H1373细胞细胞增殖抑制活性GI 50＜100nM，例如，化合物28、31、43、51、56的三氟乙酸盐、57-A对NCI-H1373细胞细胞增殖抑制活性GI 50值分别为5.1nM、6nM、8nM、6nM、11nM、13nM。 Conclusion: The compounds of the present invention have cell proliferation inhibitory activity on NCI-H1373 cells. For NCI-H1373 cell proliferation inhibitory activity GI 50 <100nM, for example, compounds 28, 31, 43, 51, 56 trifluoroacetate, 57-A on NCI-H1373 cell proliferation inhibitory activity GI 50 values are respectively 5.1nM, 6nM, 8nM, 6nM, 11nM, 13nM.
2.PARP7酶活性测试实验2. PARP7 enzyme activity test experiment
PARP7化学荧光检测试剂盒购自BPS Bioscience。将试剂盒中的组蛋白溶液用1X PBS稀释5倍，取25μL组蛋白稀释液至微孔板中，于4℃孵育过夜。孵育结束后，P BST(0.05％Tween-20)洗板3次，取100μL封闭液至微孔板中，于25℃孵育90分钟；孵育结束后，PBST洗板3次。取测试缓冲液稀释的不同浓度的化合物2.5μL和12.5μL底物混合溶液(1.25μL10X PARP测试缓冲液；1.25μL10X PARP测试混合液；10μL双蒸水)至微孔板。将PARP7酶稀释到6ng/μL，取10μL至微孔板，反应体系于25℃孵育60分钟；PARP7 chemiluminescence detection kit was purchased from BPS Bioscience. Dilute the histone solution in the kit 5 times with 1X PBS, take 25 μL of histone dilution into the microplate, and incubate at 4°C overnight. After the incubation, the plate was washed three times with PBST (0.05% Tween-20), 100 μL of blocking solution was taken into the microplate, and incubated at 25°C for 90 minutes; after the incubation, the plate was washed three times with PBST. Take 2.5 μL of compounds with different concentrations diluted in test buffer and 12.5 μL of substrate mixed solution (1.25 μL of 10X PARP test buffer; 1.25 μL of 10X PARP test mixed solution; 10 μL of double distilled water) to the microplate. Dilute the PARP7 enzyme to 6ng/μL, take 10μL to the microplate, and incubate the reaction system at 25°C for 60 minutes;
孵育结束后，PBST洗板3次。将Streptavidin-HRP用封闭液稀释50倍，然后取25μL至微孔板，于25℃孵育30分钟。孵育结束后，PBST洗板3次，按照1:1(v/v)混匀ELISA ECL底物A和底物B，取50μL至微孔板，读取化学发光值。After the incubation, the plate was washed 3 times with PBST. Streptavidin-HRP was diluted 50-fold with blocking solution, and then 25 μL was transferred to a microplate and incubated at 25°C for 30 minutes. After the incubation, wash the plate three times with PBST, mix ELISA ECL substrate A and substrate B according to 1:1 (v/v), take 50 μL to the microplate, and read the chemiluminescence value.
根据式1计算抑制率，其中RLU sample为化合物孔读值，RLU max为溶剂对照孔读值，RLU min为不含PARP7酶对照孔读值，使用GraphPad Prism软件通过四参数(log(inhibitor)vs.response--Variable slope)进行曲线拟合并计算IC 50值。 Calculate the inhibition rate according to formula 1, where RLU sample is the reading value of the compound well, RLU max is the reading value of the solvent control well, and RLU min is the reading value of the control well without PARP7 enzyme. The four parameters (log(inhibitor) vs. .response--Variable slope) to perform curve fitting and calculate IC50 values.
Inhibition％＝(1-(RLU sample-RLU min)/(RLU max-RLU min))×100％(式1) Inhibition%=(1-(RLU sample -RLU min )/(RLU max -RLU min ))×100% (Formula 1)
表2.化合物对PARP7酶的抑制活性Table 2. Inhibitory activity of compounds on PARP7 enzyme
序号serial number 化合物compound PARP7 IC 50(nM) PARP7 IC50 (nM)
11 化合物1Compound 1 <100nM<100nM
22 化合物2Compound 2 <100nM<100nM
33 化合物5Compound 5 <100nM<100nM
44 化合物6Compound 6 <100nM<100nM
55 化合物13的三氟乙酸盐Trifluoroacetate salt of compound 13 <100nM<100nM
66 化合物33Compound 33 <100nM<100nM
77 化合物51Compound 51 <100nM<100nM
结论：本发明化合物对PARP7酶具有抑制作用，例如化合物33、51对PARP7酶的IC 50值分别为0.88nM、0.78nM。 Conclusion: The compounds of the present invention have inhibitory effect on PARP7 enzyme. For example, the IC 50 values of compounds 33 and 51 on PARP7 enzyme are 0.88nM and 0.78nM, respectively.
3.NCI-H1373细胞中MARylation测试实验3. MARylation test in NCI-H1373 cells
NCI-H1373细胞购置于ATCC，培养条件：RPMI-1640+10％FBS+1％双抗，培养于37℃，5％CO 2孵箱中。第一天收集指数生长期的NCI-H1373细胞铺板透明底白色6孔培养板，铺板密度为2×10 5个/孔，于37℃、5％CO 2孵箱中培养过夜。第二天加药前，吸弃培养基，每孔加入1mL新鲜培养基和1mL不同浓度化合物，使每孔DMSO终浓度均为0.1％，于37℃，5％CO 2孵箱中培养48小时。培养结束后，收集细胞。每管加入35μL细胞裂解液，冰上裂解15分钟，期间涡旋振荡；4℃、13000rpm条件下离心10分钟，取上清低温保存。采用BCA检测试剂盒(碧云天，P0009)进行蛋白定量，计算样品蛋白浓度。将每管样品蛋白浓度用0.1×sample buffer稀释为0.8mg/mL，取4μL稀释液和1μL 5×mix，混匀；95℃条件下放置5min进行蛋白变性。按照WES(ProteinSimple)说明书进行加样，其中Poly/Mono-ADP Ribose(E6F6A)Rabbit mAb稀释比为1:100，β-Actin(8H10D10)Mouse mAb稀释比为1:400，上机检测。结果按照式(2)处理，计算出化合物各个浓度的MARylation％，并使用GraphPad Prism 8软件拟合IC 50值。Corr.Area compound为药物处理组的峰面积，Corr.Area control为溶剂对照组的峰面积。 NCI-H1373 cells were purchased from ATCC, culture conditions: RPMI-1640+10% FBS+1% double antibody, cultured at 37°C, 5% CO 2 incubator. On the first day, NCI-H1373 cells in exponential growth phase were collected and plated in a white 6-well culture plate with a transparent bottom at a plating density of 2×10 5 cells/well, and cultured overnight in a 37°C, 5% CO 2 incubator. On the second day before dosing, the medium was aspirated, and 1 mL of fresh medium and 1 mL of compounds of different concentrations were added to each well, so that the final concentration of DMSO in each well was 0.1%, and cultured in a 37°C, 5% CO2 incubator for 48 hours . After the incubation period, the cells were collected. Add 35 μL of cell lysis solution to each tube, lyse on ice for 15 minutes, and vortex during the period; centrifuge at 4 °C and 13000 rpm for 10 minutes, and take the supernatant for cryopreservation. The BCA detection kit (Biyuntian, P0009) was used for protein quantification, and the sample protein concentration was calculated. Dilute the protein concentration of each tube with 0.1× sample buffer to 0.8 mg/mL, take 4 μL of the diluent and 1 μL of 5× mix, and mix well; place at 95°C for 5 min to denature the protein. The sample was added according to the instructions of WES (ProteinSimple), in which the dilution ratio of Poly/Mono-ADP Ribose (E6F6A) Rabbit mAb was 1:100, and the dilution ratio of β-Actin (8H10D10) Mouse mAb was 1:400, and the on-board detection was performed. The results were processed according to formula (2), the MARylation % of each concentration of the compound was calculated, and the IC 50 value was fitted using GraphPad Prism 8 software. Corr.Area compound is the peak area of the drug treatment group, and Corr.Area control is the peak area of the solvent control group.
MARylation％＝Average(Corr.Area compound/Corr.Area control)×100  式(2) MARylation%=Average (Corr.Area compound /Corr.Area control )×100 Equation (2)
表3.化合物在NCI-H1373细胞中MARylation的抑制活性Table 3. MARylation inhibitory activity of compounds in NCI-H1373 cells
序号serial number 化合物compound PARP7 IC 50(nM) PARP7 IC50 (nM)
11 化合物51Compound 51 <30nM<30nM
22 化合物57-ACompound 57-A <30nM<30nM
结论：本发明化合物在NCI-H1373细胞中对MARylation具有抑制作用。Conclusion: The compounds of the present invention have inhibitory effect on MARylation in NCI-H1373 cells.
4.小鼠药代动力学测试4. Mouse Pharmacokinetic Testing
1.1试验动物：雄性BALB/c小鼠，18～20g，9只/化合物。购于成都达硕实验动物有限公司。1.1 Test animals: male BALB/c mice, 18-20 g, 9 mice/compound. Purchased from Chengdu Dashuo Laboratory Animal Co., Ltd.
1.2试验设计：试验当天，36只BALB/c小鼠按体重随机分组。给药前1天禁食不禁水12～14h，给药后4h给食。1.2 Experimental design: On the day of the experiment, 36 BALB/c mice were randomly divided into groups according to body weight. Fasting for 12 to 14 hours before administration and 4 hours after administration.
给药信息Dosing Information
Figure PCTCN2022088446-appb-000361
Figure PCTCN2022088446-appb-000361
静脉给药溶媒：5％DMA+5％Solutol+90％Saline；Intravenous vehicle: 5%DMA+5%Solutol+90%Saline;
灌胃给药溶媒：5％DMSO+5％Solutol+30％PEG400+60％(20％SBE-β-CD)Oral administration vehicle: 5%DMSO+5%Solutol+30%PEG400+60%(20%SBE-β-CD)
于给药前及给药后异氟烷麻醉经眼眶取血0.06ml，置于EDTAK2离心管中，5000rpm，4℃离心10min，收集血浆。静脉和灌胃采血时间点为0,5,15,30min,1,2,4,6,8,24h。分析检测前，所有样品存于-80℃。Before and after administration of isoflurane anesthesia, 0.06 ml of blood was collected from the orbit, placed in an EDTAK2 centrifuge tube, centrifuged at 5000 rpm and 4°C for 10 min, and plasma was collected. The time points of intravenous and intragastric blood collection were 0, 5, 15, 30 min, 1, 2, 4, 6, 8, and 24 h. All samples were stored at -80°C prior to analysis.
表4.化合物在小鼠血浆中的药代动力学参数Table 4. Pharmacokinetic parameters of compounds in mouse plasma
Figure PCTCN2022088446-appb-000362
Figure PCTCN2022088446-appb-000362
-：不适用。-:Not applicable.
结论：本发明的化合物在小鼠上具有较高的暴露量。Conclusion: The compounds of the present invention have higher exposure in mice.
5.比格犬药代动力学测试5. Pharmacokinetic Testing in Beagle Dogs
实验目的：通过单剂量静脉和灌胃给予受试物于比格犬，测定比格犬血浆中受试物的浓度，评价受试物在比格犬体内药代特征。Experimental purpose: The test substance was administered to beagle dogs by single dose intravenously and by gavage, the concentration of the test substance in the plasma of the beagle dog was determined, and the pharmacokinetic characteristics of the test substance in the beagle dog were evaluated.
试验动物：雄性比格犬，8～11kg左右，3只/化合物，购于北京玛斯生物技术有限公司。Test animals: male beagle, about 8-11 kg, 3 animals/compound, purchased from Beijing Mars Biotechnology Co., Ltd.
试验方法：试验当天，12只比格犬按体重随机分组。给药前1天禁食不禁水12～14h，给药后4h给食。Test method: On the test day, 12 beagle dogs were randomly divided into groups according to their body weight. Fasting for 12 to 14 hours before administration and 4 hours after administration.
给药信息Dosing Information
Figure PCTCN2022088446-appb-000363
Figure PCTCN2022088446-appb-000363
静脉给药溶媒：5％DMA+5％Solutol+90％Saline；灌胃给药溶媒：0.5％MCVehicle for intravenous administration: 5% DMA+5% Solutol+90% Saline; vehicle for intragastric administration: 0.5% MC
取样：于给药前及给药后通过四肢静脉取血1ml，置于EDTAK2离心管中。5000rpm，4℃离心10min，收集血浆。Sampling: 1ml of blood was collected from extremity veins before and after administration, and placed in an EDTAK2 centrifuge tube. The plasma was collected by centrifugation at 5000 rpm and 4°C for 10 min.
采血时间点：0,5,15,30min,1,2,4,6,8,10,12,24h。分析检测前，所有样品存于-80℃。用LC-MS/MS对样品进行定量分析。Blood collection time points: 0,5,15,30min,1,2,4,6,8,10,12,24h. All samples were stored at -80°C prior to analysis. The samples were quantitatively analyzed by LC-MS/MS.
表5测试化合物在比格犬血浆中的药代动力学参数Table 5 Pharmacokinetic parameters of test compounds in beagle dog plasma
Figure PCTCN2022088446-appb-000364
Figure PCTCN2022088446-appb-000364
-：不适用。-:Not applicable.
结论：化合物33、51在比格犬上具有较好的PK性能。Conclusion: Compounds 33 and 51 have good PK properties in beagle dogs.
6.CYP450酶抑制测试6. CYP450 enzyme inhibition test
本试验采用混合人肝微粒体分别与不同浓度的受试化合物(0.05～50μM)和相应的探药共同孵育后，测定CYP酶活性的变化，计算IC 50值，评价受试化合物对每种CYP酶的抑制潜能。 In this test, mixed human liver microsomes were incubated with different concentrations of test compounds (0.05-50 μM) and the corresponding detection drugs, and the changes of CYP enzyme activities were measured, and IC 50 values were calculated to evaluate the effect of test compounds on each CYP. Enzyme inhibitory potential.
试验结果显示，化合物51对CYP1A2、CYP2C9、CYP2C19、CYP2D6和CYP3A4酶基本无抑制作用，IC 50值均大于50μM。 The test results showed that compound 51 had no inhibitory effect on CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 enzymes, and the IC 50 values were all greater than 50 μM.
7.hERG钾离子通道作用测试7.hERG potassium channel function test
实验平台：电生理手动膜片钳系统Experimental Platform: Electrophysiological Manual Patch Clamp System
细胞系：稳定表达hERG钾离子通道的中国仓鼠卵巢(CHO)细胞系Cell line: Chinese hamster ovary (CHO) cell line stably expressing hERG potassium channel
实验方法：稳定表达hERG钾通道的CHO(Chinese Hamster Ovary)细胞，在室温下用全细胞膜片钳技术记录hERG钾通道电流。玻璃微电极由玻璃电极毛胚(BF150-86-10，Sutter)经拉制仪拉制而成，灌注电极内液后的尖端电阻为2-5MΩ左右，将玻璃微电极插入放大器探头即可连接至膜片钳放大器。钳制电压和数据记录由pClamp 10软件通过电脑控制和记录，采样频率为10kHz，滤波频率为2kHz。在得到全细胞记录后，细胞钳制在-80mV，诱发hERG钾电流(I hERG)的步阶电压从-80mV给予一个2s的去极化电压到+20mV，再复极化到-50mV，持续1s后回到-80mV。每10s给予此电压刺激，确定hERG钾电流稳定后(至少1分钟)开始给药过程。化合物每个测试浓度至少给予1分钟，每个浓度至少测试2个细胞(n≥2)。 Experimental methods: CHO (Chinese Hamster Ovary) cells stably expressing hERG potassium channels were used to record hERG potassium channel currents by whole-cell patch-clamp technique at room temperature. The glass microelectrode is drawn from the glass electrode blank (BF150-86-10, Sutter) by a drawing machine. The tip resistance after filling the electrode liquid is about 2-5MΩ. Insert the glass microelectrode into the amplifier probe to connect to the patch clamp amplifier. Clamp voltages and data recording were controlled and recorded by a computer using pClamp 10 software with a sampling frequency of 10 kHz and a filtering frequency of 2 kHz. After obtaining whole-cell recordings, the cells were clamped at -80mV and the step voltage evoked hERG potassium current (I hERG ) was given a 2s depolarization voltage from -80mV to +20mV, and then repolarized to -50mV for 1s then back to -80mV. This voltage stimulation was given every 10 s, and the dosing process was started after it was determined that the hERG potassium current had stabilized (at least 1 min). Compounds were administered for at least 1 minute at each concentration tested and at least 2 cells were tested at each concentration (n > 2).
数据处理：数据分析处理采用pClamp 10，GraphPad Prism 5和Excel软件。不同化合物浓度对hERG钾电流(-50mV时诱发的hERG尾电流峰值)的抑制程度用以下公式计算：Data processing: Data analysis and processing used pClamp 10, GraphPad Prism 5 and Excel software. The degree of inhibition of hERG potassium current (peak hERG tail current evoked at -50mV) by different compound concentrations was calculated by the following formula:
Inhibition％＝[1–(I/Io)]×100％Inhibition%=[1–(I/Io)]×100%
其中，Inhibition％代表化合物对hERG钾电流的抑制百分率，I和Io分别表示在加药后和加药前hERG钾电流的幅度。Among them, Inhibition% represents the inhibition percentage of the compound on hERG potassium current, and I and Io represent the amplitude of hERG potassium current after drug addition and before drug addition, respectively.
化合物IC 50使用GraphPad Prism 5软件通过以下方程拟合计算得出： Compound IC50s were calculated using GraphPad Prism 5 software by fitting the following equation:
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))Y=Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))
其中，X为供试品检测浓度的Log值，Y为对应浓度下抑制百分率，Bottom和Top分别为最小和最大抑制百分率。Among them, X is the Log value of the test concentration, Y is the inhibition percentage at the corresponding concentration, Bottom and Top are the minimum and maximum inhibition percentages, respectively.
表6：化合物对hERG钾通道电流抑制作用的IC 50值 Table 6: IC50 values of compounds for inhibition of hERG potassium channel currents
化合物compound IC 50(μM) IC50 (μM)
化合物51Compound 51 >20μM>20μM
8、肝微粒体稳定性8. Liver microsome stability
本试验采用犬和人肝微粒体作为体外模型来评价化合物的代谢稳定性。在37℃条件下，1μM的化合物分别与上述种属肝微粒体辅以NADPH再生体系孵育不同时间(5,1 0,20,30,60min)，采用LC-MS/MS方法检测所产生的样品中所测试化合物的浓度。This assay uses canine and human liver microsomes as in vitro models to evaluate the metabolic stability of compounds. At 37 °C, 1 μM of the compound was incubated with the above species liver microsomes supplemented with NADPH regeneration system for different time (5, 10, 20, 30, 60 min), and the generated samples were detected by LC-MS/MS method. the concentration of the tested compound.
结论：本发明化合物具有良好的肝微粒体稳定性。Conclusion: The compounds of the present invention have good liver microsome stability.

Claims (13)

  1. 一种化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，化合物选自通式(I)所示的化合物，其中A compound or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, the compound is selected from the compound represented by the general formula (I), wherein
    Figure PCTCN2022088446-appb-100001
    Figure PCTCN2022088446-appb-100001
    Y选自O、S、S(＝O)、S(＝O) 2、S(＝O) 2N(R y)、N(R y)、C 1-4亚烷基、-OC 1-3亚烷基-、-C 1-3亚烷基O-、-C 1-3亚烷基S-、-C 1-3亚烷基S(＝O)-、-C 1-3亚烷基S(＝O) 2-、-N(R y)C 1-3亚烷基-或-C 1-3亚烷基N(R y)-，所述的亚烷基任选进一步被0至4个选自H、卤素、＝O、＝S、OH、氰基、C 1-6烷基、卤素取代的C 1-6烷基、C 1-6烷氧基或C 3-6环烷基的取代基所取代； Y is selected from O, S, S(=O), S(=O) 2 , S(=O) 2 N(R y ), N(R y ), C 1-4 alkylene, -OC 1- 3 alkylene-, -C 1-3 alkylene O-, -C 1-3 alkylene S-, -C 1-3 alkylene S(=O)-, -C 1-3 alkylene Base S(=O) 2 -, -N(R y )C 1-3 alkylene- or -C 1-3 alkylene N(R y )-, the alkylene group is optionally further modified by O to 4 selected from H, halogen, =O, =S, OH, cyano, C1-6 alkyl, halogen substituted C1-6 alkyl, C1-6 alkoxy or C3-6 ring Substituted by alkyl substituents;
    R y各自独立的选自H、C 1-6烷基或C 3-6环烷基，所述的烷基或环烷基任选进一步被0至4个选自H、氘、卤素、CF 3、OH、氰基、NH 2、C 1-6烷基、C 1-6烷氧基、3至8元杂环基或C 3-6环烷基的取代基所取代，所述的杂环基含有1至3个选自O、S或N的杂原子； 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 0 to 4 selected from H, deuterium, halogen, CF 3 , OH, cyano, NH 2 , C 1-6 alkyl, C 1-6 alkoxy, 3- to 8-membered heterocyclic group or C 3-6 cycloalkyl substituent, the heterocyclic The cyclic group contains 1 to 3 heteroatoms selected from O, S or N;
    环A选自C 6-10芳基、5-10元杂芳基或5-10元杂环基,所述的杂芳基或者杂环基含有1至5个选自O、S、N的杂原子； 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;
    环X选自C 6-10芳基、5-10元杂芳基、C 3-10碳环或5-10元杂环基，所述的杂芳基或者杂环基含有1至5个选自O、S或N的杂原子； 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 or N;
    R x、R a各自独立的选自H、卤素、氰基、OH、＝O、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6烷硫基、-SO 2-C 1-6烷基、-C(＝O)C 1-6烷基、-(CH 2) q-C 3-10碳环或-(CH 2) q-3至12元杂环，所述的-CH 2-、烷基、烯基、炔基、烷氧基、烷硫基、碳环或杂环任选进一步被0至4个选自H、卤素、OH、氰基、＝O、NH 2、NH(C 1-6烷基)、N(C 1-6烷基) 2、C 1-6烷基、卤素取代的C 1-6烷基、C 1-6烷氧基、C 3-6环烷基或3至10元杂环的取代基所取代，所述的杂环含有1至3个选自O、S或N的杂原子； R x and Ra are independently selected from H, halogen, cyano, OH, =O, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy , C 1-6 alkylthio, -SO 2 -C 1-6 alkyl, -C(=O)C 1-6 alkyl, -(CH 2 ) q -C 3-10 carbocyclic or -(CH 2 ) q -3- to 12-membered heterocycle, the -CH 2 -, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, carbocycle or heterocycle are optionally further selected from 0 to 4 From H, halogen, OH, cyano, =O, NH 2 , NH(C 1-6 alkyl), N(C 1-6 alkyl) 2 , 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 heterocyclic ring contains 1 to 3 selected from O, S or N heteroatom;
    环B选自4至11元含氮杂环或C 4-10碳环； Ring B is selected from 4- to 11-membered nitrogen-containing heterocycles or C 4-10 carbocycles;
    R b各自独立的选自H、卤素、氰基、OH、＝O、C 1-6烷基、C 1-6烷氧基或-(CH 2) q-C 3-6环烷基，所述的-CH 2-、烷基、烷氧基或环烷基任选进一步被0至4个选自H、卤素、OH、氰基、NH 2、C 1-6烷基、卤素取代的C 1-6烷基、C 1-6烷氧基或C 3-6环烷基的取代基所 取代； Each R b is independently selected from H, halogen, cyano, OH, =O, C 1-6 alkyl, C 1-6 alkoxy or -(CH 2 ) q -C 3-6 cycloalkyl, so Said -CH 2 -, alkyl, alkoxy or cycloalkyl is optionally further substituted by 0 to 4 C selected from H, halogen, OH, cyano, NH 2 , C 1-6 alkyl, halogen 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl substituent;
    W选自键、C 1-3亚烷基或者Q2，所示亚烷基任选进一步被0至4个选自H、卤素、CF 3、OH、氰基、NH 2、C 1-6烷基或C 1-6烷氧基的取代基所取代； W is selected from a bond, a C 1-3 alkylene group or Q2, and the indicated alkylene group is optionally further selected from 0 to 4 groups selected from H, halogen, CF 3 , OH, cyano, NH 2 , C 1-6 alkane substituted by substituents of C 1-6 alkoxy groups;
    L选自L1、L2或L3；L is selected from L1, L2 or L3;
    L1选自-Q1-Ak1-Q2-Ak2-Q3-，右侧与环B连接；L1 is selected from -Q1-Ak1-Q2-Ak2-Q3-, and the right side is connected to ring B;
    L2选自
    Figure PCTCN2022088446-appb-100002
    右侧与环B连接；     L2 is selected from
    Figure PCTCN2022088446-appb-100002
    The right side is connected with ring B;
    L3选自
    Figure PCTCN2022088446-appb-100003
    右侧与环B连接；     L3 is selected from
    Figure PCTCN2022088446-appb-100003
    The right side is connected with ring B;
    L4选自-Ak3-Q4-Ak4-K1-Q5-K2-Ak5-Q6-或-Ak3-Q4-Ak4-K1-Q5-，右侧与环B连接；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各自独立的选自C 1-4亚烷基、C 2-4亚烯基或C 2-4亚炔基，所述Ak1任选进一步被0至4个R k1取代，所述Ak2任选进一步被0至4个R k2取代； Ak1 and Ak2 are each independently selected from C 1-4 alkylene group, C 2-4 alkenylene group or C 2-4 alkynylene group, 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各自独立的选自键、C 1-4亚烷基、C 2-4亚烯基或C 2-4亚炔基，所述Ak3任选进一步被0至4个R k3取代，所述Ak4任选进一步被0至4个R k4取代，所述Ak5任选进一步被0至4个R k5取代； Ak3, Ak4, Ak5 are each independently selected from bond, C 1-4 alkylene group, C 2-4 alkenylene group or C 2-4 alkynylene group, said Ak3 is optionally further substituted by 0 to 4 R k3 , the Ak4 is optionally further substituted by 0 to 4 R k4 , and the Ak5 is optionally further substituted by 0 to 4 R k5 ;
    K1或K2选自C 1-2亚烷基、C 3-10碳环或3至12元杂环，所述的亚烷基任选进一步被0至4个R k6取代，所述的碳环或杂环任选进一步被0至4个选自H、卤素、OH、氰基、NH 2、C 1-6烷基、C 2-6烯基、C 2-6炔基、卤素取代的C 1-6烷基、C 1-6烷氧基、-C 1-6烷基-OC 1-6烷基、-O-C 1-6烷基-OC 1-6烷基、-O-C 3-8碳环、C 3-8碳环、4至10元杂环的取代基所取代，所述的杂环含有1至3个选自O、S或N的杂原子； K1 or K2 is selected from C 1-2 alkylene, C 3-10 carbocycle or 3- to 12-membered heterocycle, said alkylene is optionally further substituted by 0 to 4 R k6 , said carbocycle or heterocycle optionally further substituted with 0 to 4 C selected from H, halogen, OH, cyano, NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen 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 carbon substituted by substituents of ring, C 3-8 carbocyclic ring, 4- to 10-membered heterocyclic ring containing 1 to 3 heteroatoms selected from O, S or N;
    R k1、R k2、R k3、R k4、R k5、R k6、R L1、R L2各自独立的选自H、卤素、氰基、OH、＝O、NH 2、NHC 1-6烷基、N(C 1-6烷基) 2、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、-OC 3-6碳环、C 3-6碳环或4至7元杂环，所述的烷基、烯基、炔基、烷氧基、碳环或杂环任选进一步被0至4个选自H、卤素、OH、氰基、NH 2、C 1-6烷基、C 2-6烯基、C 2-6炔基、卤素取代的C 1-6烷基、C 1-6烷氧基、-O-C 3-8碳环、C 3-8碳环或4至10元杂环的取代基所取代，所述的杂环含有1至3个选自O、S或N的杂原子； R k1 , R k2 , R k3 , R k4 , R k5 , R k6 , R L1 , R L2 are each independently selected from H, halogen, cyano, OH, =O, NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, -OC 3-6 carbocycle, C 3 -6 -carbocycle or 4- to 7-membered heterocycle, said alkyl, alkenyl, alkynyl, alkoxy, carbocycle or heterocycle is optionally further substituted by 0 to 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, -OC 3-8 carbon substituted by substituents of ring, C 3-8 carbocyclic ring or 4- to 10-membered heterocyclic ring containing 1 to 3 heteroatoms selected from O, S or N;
    作为选择，R k1与R k1、R k2与R k2、R k1与R k2、R k3与R k3、R k4与R k4、R k5与R k5、R k 6与R k6直接连接形成C 3-6碳环或者4至7元的杂环，所述的碳环或杂环任选进一步被0至4个选自H、卤素、＝O、OH、氰基、C 1-6烷基、卤素取代的C 1-6烷基、C 1-6烷氧基或 C 3-6环烷基的取代基所取代，所述的杂环含有1至3个选自O、S或N的杂原子； Alternatively, Rk1 and Rk1 , Rk2 and Rk2 , Rk1 and Rk2 , Rk3 and Rk3 , Rk4 and Rk4, Rk5 and Rk5 , Rk6 and Rk6 are directly linked to form C3 -6 -carbocycle or 4- to 7-membered heterocycle, the carbocycle or heterocycle is optionally further substituted by 0 to 4 selected from H, halogen, =O, OH, cyano, C 1-6 alkyl, substituted by halogen-substituted C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl substituents, and the heterocycle contains 1 to 3 heterocycles selected from O, S or N atom;
    Q1、Q5各自独立的选自O、S、N(R q)、C(＝O)、C(＝O)N(R q)、N(R q)C(＝O)、C(＝O)O、OC(＝O)、S(＝O)、S(＝O) 2、S(＝O) 2N(R q)、N(R q)S(＝O) 2、N(R q)C(＝O)N(R q)或N(R q)C(＝O)N(R q)； Q1 and Q5 are independently selected from O, S, N(R q ), C(=O), C(=O) N(R q ), N(R q ), C(=O), C(=O )O, OC(=O), S(=O), S(=O) 2 , S(=O) 2 N(R q ), N(R q )S(=O) 2 , N(R q ) )C(=O)N( Rq ) or N( Rq )C(=O)N( Rq );
    Q2、Q3、Q4、Q6各自独立的选自键或者Q1；Q2, Q3, Q4, Q6 are each independently selected from the key or Q1;
    环E选自C 3-6碳环或4至7元杂环，所述的杂环含有1至3个选自O、S或N的杂原子； Ring E is selected from C 3-6 carbocycles or 4 to 7 membered heterocycles containing 1 to 3 heteroatoms selected from O, S or N;
    R q各自独立的选自H、C 1-6烷基或C 3-6环烷基，所述的烷基或环烷基任选进一步被0至4个选自H、卤素、CF 3、OH、氰基、NH 2、C 1-6烷基或C 1-6烷氧基的取代基所取代； 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 selected from 0 to 4 groups selected from H, halogen, CF 3 , substituted by the substituents of OH, cyano, NH 2 , C 1-6 alkyl or C 1-6 alkoxy;
    作为选择，R q与R k1或R k2直接连接，形成4至7元的杂环，所述的杂环任选进一步被0至4个选自H、卤素、＝O、OH、氰基、C 1-6烷基、卤素取代的C 1-6烷基、C 1-6烷氧基或C 3-6环烷基的取代基所取代，所述的杂环含有1至3个选自O、S或N的杂原子； Alternatively, R q is directly linked to R k1 or R k2 to form a 4- to 7-membered heterocycle optionally further substituted by 0 to 4 selected from H, halogen, =O, OH, cyano, C 1-6 alkyl, halogen-substituted C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl substituent, the heterocyclic ring contains 1 to 3 groups selected from Heteroatoms of O, S or N;
    q各自独立的选自0、1、2、3或4；q is independently selected from 0, 1, 2, 3 or 4;
    a选自0、1、2、3或4；a is selected from 0, 1, 2, 3 or 4;
    b选自0、1、2、3或4；b is selected from 0, 1, 2, 3 or 4;
    x选自0、1、2、3或4；x is selected from 0, 1, 2, 3 or 4;
    s1选自0、1、2、3或4；s1 is selected from 0, 1, 2, 3 or 4;
    s2选自0、1、2、3或4；s2 is selected from 0, 1, 2, 3 or 4;
    s3选自0、1、2、3或4。s3 is selected from 0, 1, 2, 3 or 4.
  2. 根据权利要求1所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，化合物选自通式(II)所示的化合物，The compound according to claim 1 or its stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, the compound is selected from the compound represented by the general formula (II),
    Figure PCTCN2022088446-appb-100004
    Figure PCTCN2022088446-appb-100004
    W 1选自N或C(R a4)； W 1 is selected from N or C(R a4 );
    环X选自苯基、5-6元杂芳基或5-6元杂环基，所述的杂芳基或杂环基含有1至5个选自O、S或N的杂原子；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 or N;
    R a1、R a2、R a4各自独立的选自H、卤素、氰基、OH、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 1-6烷氧基、C 1-6烷硫基、-SO 2-C 1-6烷基、-C(＝O)C 1-6烷基、-(CH 2) q-C 3-10碳环或-(CH 2) q-3 至12元杂环，所述的-CH 2-、烷基、烯基、炔基、烷氧基、烷硫基、碳环或杂环任选进一步被0至4个选自H、卤素、OH、氰基、＝O、C 1-6烷基、卤素取代的C 1-6烷基、C 1-6烷氧基、C 3-6环烷基或3至10元杂环的取代基所取代，所述的杂环含有1至3个选自O、S或N的杂原子； R a1 , R a2 and R a4 are each independently selected from H, halogen, cyano, OH, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy , C 1-6 alkylthio, -SO 2 -C 1-6 alkyl, -C(=O)C 1-6 alkyl, -(CH 2 ) q -C 3-10 carbocyclic or -(CH 2 ) q -3 to 12-membered heterocycle, said -CH2- , alkyl, alkenyl, alkynyl, alkoxy, alkylthio, carbocycle or heterocycle are optionally further selected from 0 to 4 From H, halogen, OH, cyano, =O, C 1-6 alkyl, halogen-substituted C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl or 3 to 10 membered substituted by a substituent of a heterocyclic ring containing 1 to 3 heteroatoms selected from O, S or N;
    R a3选自H、C 1-6烷基、-(CH 2) q-C 3-10碳环或-(CH 2) q-3至12元杂环，所述的-CH 2-、烷基、碳环或杂环任选进一步被0至4个选自H、卤素、OH、氰基、C 1-6烷基、卤素取代的C 1-6烷基、C 1-6烷氧基、C 3-6环烷基或3至10元杂环的取代基所取代，所述的杂环含有1至3个选自O、S或N的杂原子； 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 is optionally further 0 to 4 selected from H, halogen, OH, cyano, C 1-6 alkyl, halogen substituted C 1-6 alkyl, C 1-6 alkoxy , C 3-6 cycloalkyl or 3- to 10-membered heterocycle substituents, the heterocycle contains 1 to 3 heteroatoms selected from O, S or N;
    其余基团的定义与权1相同。The definitions of the remaining groups are the same as in weight 1.
  3. 根据权利要求2所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，The compound of claim 2, or a stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof,
    Y选自O、N(R y)、C 1-3亚烷基、-OC 1-2亚烷基-、-C 1-2亚烷基O-、-C 1-2亚烷基S-、-C 1-2亚烷基S(＝O) 2-、-N(R y)C 1-2亚烷基-或-C 1-2亚烷基N(R y)-，所述的亚烷基任选进一步被0至4个选自H、卤素、＝O、＝S、OH、氰基、C 1-4烷基、卤素取代的C 1-4烷基、C 1-4烷氧基或C 3-6环烷基的取代基所取代； Y is selected from O, N(R y ), C 1-3 alkylene, -OC 1-2 alkylene-, -C 1-2 alkylene O-, -C 1-2 alkylene S- , -C 1-2 alkylene S(=O) 2 -, -N(R y )C 1-2 alkylene- or -C 1-2 alkylene N(R y )-, the The alkylene group is optionally further substituted by 0 to 4 selected from H, halogen, =O, =S, OH, cyano, C1-4alkyl , C1-4alkyl substituted with halogen, C1-4alkane substituted by oxy or C 3-6 cycloalkyl substituent;
    R y各自独立的选自H、C 1-4烷基或C 3-6环烷基，所述的烷基或环烷基任选进一步被0至4个选自H、氘、卤素、CF 3、OH、氰基、NH 2、C 1-4烷基、C 1-4烷氧基、3至8元杂环基或C 3-6环烷基的取代基所取代，所述的杂环基含有1至3个选自O、S或N的杂原子； 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 0 to 4 selected from H, deuterium, halogen, CF 3 , OH, cyano, NH 2 , C 1-4 alkyl, C 1-4 alkoxy, 3- to 8-membered heterocyclic group or C 3-6 cycloalkyl substituent, the heterocyclic The cyclic group contains 1 to 3 heteroatoms selected from O, S or N;
    R x、R a1、R a2、R a4各自独立的选自H、卤素、氰基、OH、C 1-4烷基、C 2-4烯基、C 2- 4炔基、C 1-4烷氧基、C 1-4烷硫基、-SO 2-C 1-4烷基、-C(＝O)C 1-4烷基、-(CH 2) q-C 3-6碳环或-(CH 2) q-3至6元杂环，所述的-CH 2-、烷基、烯基、炔基、烷氧基、烷硫基、碳环或杂环任选进一步被0至4个选自H、卤素、OH、氰基、＝O、C 1-4烷基、卤素取代的C 1-4烷基、C 1-4烷氧基、C 3-6环烷基或3至6元杂环的取代基所取代，所述的杂环含有1至3个选自O、S或N的杂原子； R x , R a1 , R a2 , and R a4 are each independently selected from H, halogen, cyano, OH, C 1-4 alkyl , C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 Alkoxy, C 1-4 alkylthio, -SO 2 -C 1-4 alkyl, -C(=O)C 1-4 alkyl, -(CH 2 ) q -C 3-6 carbocyclic or -(CH 2 ) q -3- to 6-membered heterocycle, said -CH 2 -, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, carbocycle or heterocycle is optionally further substituted by 0 to 6 4 selected from H, halogen, OH, cyano, =O, C 1-4 alkyl, halogen substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl or 3 to 6-membered heterocyclic ring containing 1 to 3 heteroatoms selected from O, S or N;
    R a3选自H或C 1-4烷基，所述的烷基任选进一步被0至4个选自H、卤素、OH、氰基、C 1-4烷基、卤素取代的C 1-4烷基、C 1-4烷氧基或C 3-6环烷基的取代基所取代； R a3 is selected from H or C 1-4 alkyl, said alkyl is optionally further C 1- substituted by 0 to 4 selected from H, halogen, OH, cyano, C 1-4 alkyl, halogen 4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl substituent;
    环B选自4至7元单环含氮杂环、5-11元螺环含氮杂环、5-11元并环含氮杂环、5-11元桥环含氮杂环或C 4-7单环碳环； 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;
    R b各自独立的选自H、卤素、氰基、OH、＝O、C 1-4烷基、C 1-4烷氧基或-(CH 2) q-C 3-6 环烷基，所述的-CH 2-、烷基、烷氧基或环烷基任选进一步被0至4个选自H、卤素、OH、氰基、NH 2、C 1-4烷基、卤素取代的C 1-4烷基、C 1-4烷氧基或C 3-6环烷基的取代基所取代； R b is each independently selected from H, halogen, cyano, OH, =O, C 1-4 alkyl, C 1-4 alkoxy or -(CH 2 ) q -C 3-6 cycloalkyl, where Said -CH 2 -, alkyl, alkoxy or cycloalkyl is optionally further substituted by 0 to 4 C selected from H, halogen, OH, cyano, NH 2 , C 1-4 alkyl, halogen 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl substituent;
    Ak1、Ak2各自独立的选自C 1-3亚烷基、C 2-3亚烯基或C 2-3亚炔基，所述Ak1任选进一步被0至4个R k1取代，所述Ak2任选进一步被0至4个R k2取代； Ak1 and Ak2 are each independently selected from C 1-3 alkylene group, C 2-3 alkenylene group or C 2-3 alkynylene group, 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各自独立的选自键、C 1-3亚烷基、C 2-3亚烯基或C 2-3亚炔基，所述Ak3任选进一步被0至4个R k3取代，所述Ak4任选进一步被0至4个R k4取代，所述Ak5任选进一步被0至4个R k5取代； Ak3, Ak4, Ak5 are each independently selected from bond, C 1-3 alkylene group, C 2-3 alkenylene group or C 2-3 alkynylene group, and said Ak3 is optionally further substituted by 0 to 4 R k3 , the Ak4 is optionally further substituted by 0 to 4 R k4 , and the Ak5 is optionally further substituted by 0 to 4 R k5 ;
    K1或K2选自C 1-2亚烷基、C 3-6碳环或3至7元杂环，所述的亚烷基任选进一步被0至4个R k6取代，所述的碳环或杂环任选进一步被0至4个选自H、卤素、OH、氰基、NH 2、C 1-4烷基、C 2-4烯基、C 2-4炔基、卤素取代的C 1-4烷基、C 1-4烷氧基、-C 1-4烷基-OC 1-4烷基、-O-C 1-4烷基-OC 1-4烷基、-O-C 3-6碳环、C 3-6碳环或4至7元杂环的取代基所取代，所述的杂环含有1至3个选自O、S或N的杂原子； K1 or K2 is selected from C 1-2 alkylene, C 3-6 carbocycle or 3- to 7-membered heterocycle, said alkylene is optionally further substituted by 0 to 4 R k6 , said carbocycle or heterocycle optionally further substituted by 0 to 4 C selected from H, halogen, OH, cyano, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen 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 carbon substituted by substituents of ring, C 3-6 carbocyclic ring or 4- to 7-membered heterocyclic ring containing 1 to 3 heteroatoms selected from O, S or N;
    R k1、R k2、R k3、R k4、R k5、R k6、R L1、R L2各自独立的选自H、卤素、氰基、OH、＝O、NH 2、NHC 1-4烷基、N(C 1-4烷基) 2、C 1-4烷基、C 1-4烷氧基、C 3-6碳环或4至7元杂环，所述的烷基、烷氧基、碳环或杂环任选进一步被0至4个选自H、卤素、OH、氰基、NH 2、C 1-4烷基、卤素取代的C 1-4烷基、C 1-4烷氧基、C 3-6碳环或4至6元杂环的取代基所取代，所述的杂环含有1至3个选自O、S或N的杂原子； R k1 , R k2 , R k3 , R k4 , R k5 , R k6 , R L1 , R L2 are each independently selected from H, halogen, cyano, OH, =O, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 alkoxy, C 3-6 carbocycle or 4- to 7-membered heterocycle, the alkyl, alkoxy, The carbocycle or heterocycle is optionally further substituted by 0 to 4 selected from H, halogen, OH, cyano, NH2 , C1-4alkyl , halogen-substituted C1-4alkyl , C1-4alkoxy substituted by substituents of C 3-6 carbocyclic ring or 4- to 6-membered heterocyclic ring containing 1 to 3 heteroatoms selected from O, S or N;
    作为选择，R k1与R k1、R k2与R k2、R k1与R k2、R k3与R k3、R k4与R k4、R k5与R k5、R k 6与R k6直接连接形成C 3-6碳环(例如C 3、C 4、C 5或C 6)或者4至7元(例如4、5、6或7元)的杂环，所述的碳环或杂环任选进一步被0至4个选自H、卤素、＝O、OH、氰基、C 1-4烷基、卤素取代的C 1-4烷基、C 1-4烷氧基或C 3-6环烷基的取代基所取代，所述的杂环含有1至3个选自O、S或N的杂原子； Alternatively, Rk1 and Rk1 , Rk2 and Rk2 , Rk1 and Rk2 , Rk3 and Rk3 , Rk4 and Rk4, Rk5 and Rk5 , Rk6 and Rk6 are directly linked to form C3 -6 carbocycle (eg C3, C4 , C5 or C6 ) or 4 to 7 membered (eg 4, 5, 6 or 7 membered) heterocycle optionally further 0 to 4 selected from H, halogen, =O, OH, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl substituted by the substituent, the heterocycle contains 1 to 3 heteroatoms selected from O, S or N;
    Q1、Q5各自独立的选自O、S、N(R q)、C(＝O)、C(＝O)N(R q)、N(R q)C(＝O)或S(＝O) 2； Q1 and Q5 are independently selected from O, S, N( Rq ), C(=O), C(=O)N( Rq ), N( Rq )C(=O) or S(=O ) 2 ;
    Q2、Q3、Q4、Q6各自独立的选自键或者Q1；Q2, Q3, Q4, Q6 are each independently selected from the key or Q1;
    环E选自C 3-6碳环或4至6元杂环，所述的杂环含有1至3个选自O、S或N的杂原子； Ring E is selected from C 3-6 carbocycles or 4 to 6 membered heterocycles containing 1 to 3 heteroatoms selected from O, S or N;
    R q各自独立的选自H或C 1-4烷基，所述的烷基任选进一步被0至4个选自H、卤素、CF 3、OH、氰基、NH 2、C 1-4烷基或C 1-4烷氧基的取代基所取代； R q are each independently selected from H or C 1-4 alkyl, and said alkyl is optionally further selected from 0 to 4 groups selected from H, halogen, CF 3 , OH, cyano, NH 2 , C 1-4 Substituted by alkyl or C 1-4 alkoxy substituent;
    作为选择，R q与R k1、R q与R k2直接连接形成4至7元的杂环，所述的杂环任选进一步被0至4个选自H、卤素、＝O、OH、氰基、C 1-4烷基、卤素取代的C 1-4烷基、C 1-4烷氧基或C 3-6环烷基的取代基所取代，所述的杂环含有1至3个选自O、S或N的杂原子。 Alternatively, R q and R k1 , and R q and R k2 are directly linked to form a 4- to 7-membered heterocycle optionally further substituted by 0 to 4 selected from H, halogen, =O, OH, cyano substituted by substituents of C 1-4 alkyl group, C 1-4 alkyl group, halogen-substituted C 1-4 alkyl group, C 1-4 alkoxy group or C 3-6 cycloalkyl group, and the heterocyclic ring contains 1 to 3 A heteroatom selected from O, S or N.
  4. 根据权利要求3所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中，The compound of claim 3, or a stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein,
    W 1选自N或CH； W 1 is selected from N or CH;
    环X选自苯基、吡啶基、嘧啶基、吡嗪基、哒嗪基、噻吩基、噻唑基、呋喃基、噁唑基、吡咯基、吡唑基或咪唑基；Ring X is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, thiazolyl, furyl, oxazolyl, pyrrolyl, pyrazolyl or imidazolyl;
    R x、R a1、R a2各自独立的选自H、F、Cl、Br、I、氰基、OH、甲基、乙基、丙基、异丙基、丁基、叔丁基、乙烯基、乙炔基、甲氧基、乙氧基、-SCH 3、-SCH 2CH 3、-SO 2CH 3、-SO 2CH 2CH 3、-C(＝O)CH 3、-C(＝O)CH 2CH 3、环丙基、环丁基、环戊基或环己基，所述的甲基、乙基、丙基、异丙基、丁基、叔丁基、乙烯基、乙炔基、甲氧基、乙氧基、-SCH 3、-SCH 2CH 3、-SO 2CH 3、-SO 2CH 2CH 3、-C(＝O)CH 3、-C(＝O)CH 2CH 3、环丙基、环丁基、环戊基、环己基任选进一步被0至4个选自H、卤素、OH、氰基、C 1-4烷基、卤素取代的C 1-4烷基、C 1-4烷氧基或C 3-6环烷基的取代基所取代； R x , R a1 , R a2 are each independently selected from H, F, Cl, Br, I, cyano, OH, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, vinyl , ethynyl, methoxy, ethoxy, -SCH 3 , -SCH 2 CH 3 , -SO 2 CH 3 , -SO 2 CH 2 CH 3 , -C(=O)CH 3 , -C(=O ) CH 2 CH 3 , cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, the methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, vinyl, ethynyl, Methoxy, ethoxy, -SCH 3 , -SCH 2 CH 3 , -SO 2 CH 3 , -SO 2 CH 2 CH 3 , -C(=O)CH 3 , -C(=O)CH 2 CH 3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl optionally further substituted by 0 to 4 C 1-4 alkanes selected from H, halogen, OH, cyano, C 1-4 alkyl, halogen substituted with substituents of C 1-4 alkoxy or C 3-6 cycloalkyl;
    R a3选自H、甲基、乙基、丙基或异丙基，所述的甲基、乙基、丙基或异丙基任选进一步被0至4个选自H、卤素、OH、氰基、C 1-4烷基、卤素取代的C 1-4烷基、C 1-4烷氧基或C 3-6环烷基的取代基所取代； R a3 is selected from H, methyl, ethyl, propyl or isopropyl, and said methyl, ethyl, propyl or isopropyl is optionally further 0 to 4 selected from H, halogen, OH, substituted by substituents of cyano, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl;
    Y选自O、N(R y)、-N(R y)C(＝O)-、-C(＝O)N(R y)-、-CH 2-、-CH 2CH 2-、-CH 2CH 2CH 2-、-OCH 2-、-OCH 2CH 2-、-CH 2O-、-CH 2CH 2O-、-CH 2S-、-CH 2CH 2S-、-CH 2S(＝O) 2-、-CH 2CH 2S(＝O) 2-、-N(R y)CH 2-、-N(R y)CH 2CH 2-、-CH 2N(R y)-、-CH 2CH 2N(R y)-、-N(R y)C(＝O)CH 2-或-CH 2C(＝O)N(R y)-，所述CH 2任选进一步被0至2个选自H、＝O、＝S、OH、氰基、C 1-4烷基、卤素取代的C 1-4烷基、C 1-4烷氧基或C 3-6环烷基的取代基所取代； Y is selected from O, N( Ry ), -N( Ry )C(=O)-, -C(=O)N( Ry )-, -CH2- , -CH2CH2- , - CH 2 CH 2 CH 2 -, -OCH 2 -, -OCH 2 CH 2 -, -CH 2 O-, -CH 2 CH 2 O-, -CH 2 S-, -CH 2 CH 2 S-, -CH 2 S(=O) 2 -, -CH 2 CH 2 S(=O) 2 -, -N(R y )CH 2 -, -N(R y )CH 2 CH 2 -, -CH 2 N(R y )-, -CH 2 CH 2 N(R y )-, -N(R y )C(=O)CH 2 - or -CH 2 C(=O)N(R y )-, the CH 2 optionally further substituted with 0 to 2 C1-4 alkyl groups selected from H, =O, = S , OH, cyano, C1-4alkyl , halogen, C1-4alkoxy or C3 -6 cycloalkyl substituents;
    R y各自独立的选自H、甲基、乙基、丙基、异丙基、丁基、叔丁基、仲丁基、异丁基、环丙基、环丁基、环戊基或环己基，所述的甲基、乙基、丙基、异丙基、丁基、叔丁基、仲丁基、异丁基、环丙基、环丁基、环戊基、环己基任选进一步被0至4个选自H、氘、卤素、CF 3、OH、氰基、NH 2、C 1-4烷基、C 1-4烷氧基、3至8元杂环基或C 3-6环烷基的取代基所取代，所述的杂环基含有1至3个选自O、S或N的杂原子； R y are each independently selected from H, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclopentyl Hexyl, the methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl are optionally further by 0 to 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 are substituted, and the heterocyclic group contains 1 to 3 heteroatoms selected from O, S or N;
    环B选自环丁基、环戊基、环己基、氮杂环丁基、吡咯烷基、哌啶基、哌嗪基、Ring B is selected from cyclobutyl, cyclopentyl, cyclohexyl, azetidine, pyrrolidinyl, piperidinyl, piperazinyl,
    Figure PCTCN2022088446-appb-100005
    Figure PCTCN2022088446-appb-100005
    R b各自独立的选自H、F、Cl、Br、I、氰基、OH、＝O、甲基、乙基、丙基或异丙基，所述的甲基、乙基、丙基或异丙基任选进一步被0至4个选自H、卤素、OH、氰基、NH 2、C 1-4烷基、卤素取代的C 1-4烷基、C 1-4烷氧基或C 3-6环烷基的取代基所取代； R b is each independently selected from H, F, Cl, Br, I, cyano, OH, =O, methyl, ethyl, propyl or isopropyl, said methyl, ethyl, propyl or Isopropyl is optionally further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, NH 2 , C 1-4 alkyl, halogen substituted C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl substituents are substituted;
    Ak1、Ak2各自独立的选自亚甲基、亚乙基、亚丙基、亚乙烯基、亚丙烯基、亚乙炔基或亚丙炔基，所述Ak1任选进一步被0至4个R k1取代，所述Ak2任选进一步被0至4个R k2取代； Ak1, Ak2 are each independently selected from methylene, ethylene, propylene, vinylene, propenylene, ethynylene or propynylene, and said Ak1 is optionally further replaced by 0 to 4 R k1 substituted, the Ak2 is optionally further substituted by 0 to 4 R k2 ;
    Ak3、Ak4、Ak5各自独立的选自键、亚甲基、亚乙基、亚丙基、亚乙烯基、亚丙烯基、亚乙炔基或亚丙炔基，所述Ak3任选进一步被0至4个R k3取代，所述Ak4任选进一步被0至4个R k4取代，所述Ak5任选进一步被0至4个R k5取代； Ak3, Ak4, Ak5 are each independently selected from bond, methylene group, ethylene group, propylene group, vinylidene group, propenylene group, ethynylene group or propynylene group, and said Ak3 is optionally further selected from 0 to 4 R k3 substitutions, the Ak4 is optionally further substituted with 0 to 4 R k4 , and the Ak5 is optionally further substituted with 0 to 4 R k5 ;
    K1或K2选自亚甲基、亚乙基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氮杂环戊基、氮杂环己基、哌嗪、吗啉、氧杂环丁基、氧杂环戊基、氧杂环己基、苯环、吡啶、吡嗪、嘧啶或哒嗪，所述的亚甲基、亚乙基任选进一步被0至4个R k6取代，所述的环丙基、环丁基、环戊基、环己基、氮杂环丁基、氮杂环戊基、氮杂环己基、哌嗪、吗啉、氧杂环丁基、氧杂环戊基、氧杂环己基、苯环、吡啶、吡嗪、嘧啶、哒嗪任选进一步被0至4个选自H、卤素、OH、氰基、NH 2、C 1-4烷基、C 2-4烯基、C 2-4炔基、卤素取代的C 1-4烷基、C 1-4烷氧基、-C 1-4烷基-OC 1-4烷基、-O-C 1-4烷基-OC 1-4烷基、-O-C 3-6碳环、C 3-6碳环或4至7元杂环的取代基所取代，所述的杂环含有1至3个选自O、S或N的杂原子； 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 or pyridazine, the methylene group and ethylene group are optionally further replaced by 0 to 4 R k6 is substituted, the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidine, azetidine, azetidine, piperazine, morpholine, oxetanyl, oxolane, oxanyl, benzene ring, pyridine, pyrazine, pyrimidine, pyridazine are optionally further selected from 0 to 4 groups selected from H, halogen, OH, cyano, NH 2 , C 1-4 alkane base, 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 alkyl, - OC 1-4 alkyl-OC 1-4 alkyl, -OC 3-6 carbocycle, C 3-6 carbocycle or 4- to 7-membered heterocycle substituents, the heterocycle contains 1 to 3 a heteroatom selected from O, S or N;
    R k1、R k2、R k3、R k4、R k5、R k6、R L1、R L2各自独立的选自H、F、Cl、Br、I、氰基、OH、＝O、NH 2、NH(CH 3)、N(CH 3) 2、甲基、乙基、丙基、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氮杂环戊基、氮杂环己基、氧杂环丁基、氧杂 环戊基、氧杂环己基、吡啶或苯基，所述甲基、乙基、丙基、甲氧基、乙氧基、环丙基、环丁基、环戊基、环己基、氮杂环丁基、氮杂环戊基、氮杂环己基、氧杂环丁基、氧杂环戊基、氧杂环己基、吡啶或苯基任选进一步被0至4个选自H、卤素、OH、氰基、NH 2、C 1-4烷基、卤素取代的C 1-4烷基、C 1-4烷氧基、C 3-6碳环或4至6元杂环的取代基所取代，所述的杂环含有1至3个选自O、S或N的杂原子； R k1 , R k2 , R k3 , R k4 , R k5 , R k6 , R L1 , R L2 are each independently selected from H, F, Cl, Br, I, cyano, OH, =O, NH 2 , NH (CH 3 ), N(CH 3 ) 2 , methyl, ethyl, propyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidine, Azacyclopentyl, azacyclohexyl, oxetanyl, oxolane, oxanyl, pyridine or phenyl, the methyl, ethyl, propyl, methoxy, ethoxy cyclopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidine, azacyclopentyl, azacyclohexyl, oxetanyl, oxolane, oxetyl , pyridine or phenyl optionally further substituted by 0 to 4 groups selected from H, halogen, OH, cyano, NH 2 , C 1-4 alkyl, halogen substituted C 1-4 alkyl, C 1-4 alkoxy substituted by substituents of C 3-6 carbocyclic ring or 4- to 6-membered heterocyclic ring containing 1 to 3 heteroatoms selected from O, S or N;
    作为选择，R k1与R k1、R k2与R k2、R k1与R k2、R k3与R k3、R k4与R k4、R k5与R k5、R k 6与R k6直接连接形成C 3-6碳环(例如C 3、C 4、C 5或C 6)或者4至7元(例如4、5、6或7元)的杂环，所述的碳环或杂环任选进一步被0至4个选自H、卤素、＝O、OH、氰基、C 1-4烷基、卤素取代的C 1-4烷基、C 1-4烷氧基或C 3-6环烷基的取代基所取代，所述的杂环含有1至3个选自O、S或N的杂原子； Alternatively, Rk1 and Rk1 , Rk2 and Rk2 , Rk1 and Rk2 , Rk3 and Rk3 , Rk4 and Rk4, Rk5 and Rk5 , Rk6 and Rk6 are directly linked to form C3 -6 carbocycle (eg C3, C4 , C5 or C6 ) or 4 to 7 membered (eg 4, 5, 6 or 7 membered) heterocycle optionally further 0 to 4 selected from H, halogen, =O, OH, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl substituted by the substituent, the heterocycle contains 1 to 3 heteroatoms selected from O, S or N;
    Q1、Q5各自独立的选自O、S、N(R q)、C(＝O)、C(＝O)N(R q)、N(R q)C(＝O)或S(＝O) 2； Q1 and Q5 are independently selected from O, S, N( Rq ), C(=O), C(=O)N( Rq ), N( Rq )C(=O) or S(=O ) 2 ;
    Q2、Q3、Q4、Q6各自独立的选自键或者Q1；Q2, Q3, Q4, Q6 are each independently selected from the key or Q1;
    环E选自苯基或5-6元杂芳基，所述的杂芳基含有1至3个选自O、S或N的杂原子；Ring E is selected from phenyl or 5-6 membered heteroaryl, and the heteroaryl contains 1 to 3 heteroatoms selected from O, S or N;
    R q各自独立的选自H、甲基或乙基； R q are each independently selected from H, methyl or ethyl;
    作为选择，R q与R k1、R q与R k2直接连接形成4至7元的杂环，所述的杂环任选进一步被0至4个选自H、卤素、＝O、OH、氰基、C 1-4烷基、卤素取代的C 1-4烷基、C 1-4烷氧基或C 3-6环烷基的取代基所取代，所述的杂环含有1至3个选自O、S或N的杂原子。 Alternatively, R q and R k1 , and R q and R k2 are directly linked to form a 4- to 7-membered heterocycle optionally further substituted by 0 to 4 selected from H, halogen, =O, OH, cyano substituted by substituents of C 1-4 alkyl group, C 1-4 alkyl group, halogen-substituted C 1-4 alkyl group, C 1-4 alkoxy group or C 3-6 cycloalkyl group, and the heterocyclic ring contains 1 to 3 A heteroatom selected from O, S or N.
  5. 根据权利要求4所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中The compound of claim 4, or a stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein
    Figure PCTCN2022088446-appb-100006
    选自
    Figure PCTCN2022088446-appb-100007
    Figure PCTCN2022088446-appb-100008
    左侧与L连接；
    Figure PCTCN2022088446-appb-100006
    selected from
    Figure PCTCN2022088446-appb-100007
    Figure PCTCN2022088446-appb-100008
    The left side is connected with L;
    L1选自-N(R q)-Ak1-O-Ak2-C(＝O)-、-O-Ak1-O-Ak2-C(＝O)-、-O-Ak1-N(R q)-Ak2-C(＝O)-、-N(R q)-Ak1-N(R q)-Ak2-C(＝O)-、-N(R q)-Ak1-O-Ak2-N(R q)C(＝O)-、-O-Ak1-O-Ak2-N(R q)C(＝O)-、-N(R q)-Ak1-Ak2-C(＝O)-、-N(R q)-Ak1-Ak2-N(R q)C(＝O)-、-O-Ak1-N(R q)-Ak2-N(R q)C(＝O)-、-S-Ak1-O-Ak2-C(＝O)-、-O-Ak1-S-Ak2-C(＝O)-、-N(R q)-Ak1-O-Ak2-S(＝O) 2-、- O-Ak1-O-Ak2-S(＝O) 2-、-N(R q)-Ak1-O-Ak2-或-O-Ak1-O-Ak2-，右侧与环B连接； L1 is selected from -N( Rq )-Ak1-O-Ak2-C(=O)-, -O-Ak1-O-Ak2-C(=O)-, -O-Ak1-N( Rq )- Ak2-C(=O)-, -N( Rq )-Ak1-N( Rq )-Ak2-C(=O)-, -N( Rq )-Ak1-O-Ak2-N( Rq )C(=O)-,-O-Ak1-O-Ak2-N( Rq )C(=O)-,-N( Rq )-Ak1-Ak2-C(=O)-,-N( R q )-Ak1-Ak2-N(R q )C(=O)-, -O-Ak1-N(R q )-Ak2-N(R q )C(=O)-, -S-Ak1- O-Ak2-C(=O)-, -O-Ak1-S-Ak2-C(=O)-, -N(R q )-Ak1-O-Ak2-S(=O) 2 -, -O -Ak1-O-Ak2-S(=O) 2 -, -N(R q )-Ak1-O-Ak2- or -O-Ak1-O-Ak2-, the right side is connected to ring B;
    或者L1选自-N(R q)-Ak1-O-Ak2-C(＝O)N(R q)-、-O-Ak1-N(R q)-Ak2-C(＝O)N(R q)-或-O-Ak1-O-C(＝O)N(R q)-，右侧与环B连接； Or L1 is selected from -N( Rq )-Ak1-O-Ak2-C(=O)N( Rq )-, -O-Ak1-N( Rq )-Ak2-C(=O)N(R q )- or -O-Ak1-OC(=O)N(R q )-, the right side is connected to ring B;
    L4选自-Ak3-O-K1-C(＝O)-、-Ak3-N(R q)-K1-C(＝O)-或-Ak3-N(R q)-K1-C(＝O)-，右侧与环B连接； L4 is selected from -Ak3-O-K1-C(=O)-, -Ak3-N( Rq )-K1-C(=O)- or -Ak3-N( Rq )-K1-C(=O )-, the right side is connected with ring B;
    环E选自苯环或吡啶；Ring E is selected from benzene ring or pyridine;
    Y选自-NHC(＝O)-、-C(＝O)NH-、-CH 2-、-CH 2CH 2-、-CH 2CH 2CH 2-、-OCH 2-、-OCH 2CH 2-、-CH 2O-、-CH 2CH 2O-、-NHCH 2-、-NHCH 2CH 2-、-CH 2NH-、-CH 2CH 2NH-、-NHC(＝O)CH 2-或-CH 2C(＝O)NH-； Y is selected from -NHC(=O) - , -C (=O) NH- , -CH2- , -CH2CH2- , -CH2CH2CH2- , -OCH2- , -OCH2CH 2- , -CH2O- , -CH2CH2O- , -NHCH2- , -NHCH2CH2- , -CH2NH- , -CH2CH2NH- , -NHC ( =O) CH 2 -or- CH2C (=O)NH-;
    或者Y选自O、-N(CH 3)C(＝O)-、-C(＝O)N(CH 3)-、-CH 2C(＝O)NH-或-CH 2C(＝O)N(CH 3)-； or Y is selected from O, -N( CH3 )C(=O)-, -C(=O)N( CH3 )-, -CH2C (=O)NH- or -CH2C (=O )N( CH3 )-;
    或者Y选自-N(CH 2CH 3)C(＝O)-、-N(CH(CH 3) 2)C(＝O)-、-N(CH 2CH(CH 3) 2)C(＝O)-、-N(环丙基)C(＝O)-、-N(CH 2-环丙基)C(＝O)-、-C(＝O)N(CH 2CH 3)-、-C(＝O)N(CH(CH 3) 2)-、-C(＝O)N(CH 2CH(CH 3) 2)-、-C(＝O)N(环丙基)-或-C(＝O)N(CH 2-环丙基)-； Or Y is selected from -N( CH2CH3 )C(=O)-, -N(CH( CH3 ) 2 )C(=O)-, -N(CH2CH( CH3 ) 2 ) C( =O)-, -N(cyclopropyl)C(=O)-, -N( CH2 -cyclopropyl)C(=O)-, -C(=O)N( CH2CH3 ) - , -C(=O)N(CH(CH 3 ) 2 )-, -C(=O)N(CH 2 CH(CH 3 ) 2 )-, -C(=O)N(cyclopropyl)- or -C(=O)N( CH2 -cyclopropyl)-;
    或者Y各自独立的选自-C(＝O)N(CD 3)-、-C(＝O)N(CH 2-氧杂环丁基)-、-C(＝O)N(CH 2-氧杂环戊基)-、-C(＝O)N(CH 2-氮杂环丁基)-、-C(＝O)N(CH 2-吡咯烷基)-、-C(＝O)N(CH 2-环戊基)-、-C(＝O)N(CH 2CH 2CH 3)-、-C(＝O)N(CH 2CH(CH 2CH 3) 2)-、-C(＝O)N(CH 2CH 2CH 2CH 3)-、-C(＝O)N(CH 2CH 2CH(CH 3) 2)-、-C(＝O)N(CH 2CH(CH 3)CH 2CH 3)-、-C(＝O)N(正辛基)-、-C(＝S)N(CH 3)-、-C(＝S)N(CH 2CH 3)-、-C(＝S)N(CH 2-环丙基)-、
    Figure PCTCN2022088446-appb-100009
    Figure PCTCN2022088446-appb-100010
    Or each Y is independently selected from -C(=O)N(CD 3 )-, -C(=O)N(CH 2 -oxetanyl)-, -C(=O)N(CH 2 - oxolane)-, -C(=O)N(CH 2 -azetidinyl)-, -C(=O)N(CH 2 -pyrrolidinyl)-, -C(=O) N(CH 2 -cyclopentyl)-, -C(=O)N(CH 2 CH 2 CH 3 )-, -C(=O)N(CH 2 CH(CH 2 CH 3 ) 2 )-,- C(=O)N(CH 2 CH 2 CH 2 CH 3 )-, -C(=O)N(CH 2 CH 2 CH(CH 3 ) 2 )-, -C(=O)N(CH 2 CH (CH 3 )CH 2 CH 3 )-, -C(=O)N(n-octyl)-, -C(=S)N(CH 3 )-, -C(=S)N(CH 2 CH 3 )-, -C(=S)N(CH 2 -cyclopropyl)-,
    Figure PCTCN2022088446-appb-100009
    Figure PCTCN2022088446-appb-100010
    或者Y选自-CH 2S(＝O) 2-； or Y is selected from -CH 2 S(=O) 2 -;
    R a2选自H； R a2 is selected from H;
    W 1选自N。 W 1 is selected from N.
  6. 根据权利要求5所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，The compound of claim 5, or a stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof,
    L1选自
    Figure PCTCN2022088446-appb-100011
    L1 is selected from
    Figure PCTCN2022088446-appb-100011
    Figure PCTCN2022088446-appb-100012
    Figure PCTCN2022088446-appb-100012
    Figure PCTCN2022088446-appb-100013
    Figure PCTCN2022088446-appb-100014
    右侧与环B连接；
    Figure PCTCN2022088446-appb-100013
    Figure PCTCN2022088446-appb-100014
    The right side is connected with ring B;
    或者L1选自
    Figure PCTCN2022088446-appb-100015
    Figure PCTCN2022088446-appb-100016
    Figure PCTCN2022088446-appb-100017
    右侧与环B连接；     or L1 is selected from
    Figure PCTCN2022088446-appb-100015
    Figure PCTCN2022088446-appb-100016
    Figure PCTCN2022088446-appb-100017
    The right side is connected with ring B;
    L2选自
    Figure PCTCN2022088446-appb-100018
    Figure PCTCN2022088446-appb-100019
    Figure PCTCN2022088446-appb-100020
    右侧与环B连接；     L2 is selected from
    Figure PCTCN2022088446-appb-100018
    Figure PCTCN2022088446-appb-100019
    Figure PCTCN2022088446-appb-100020
    The right side is connected with ring B;
    L3选自
    Figure PCTCN2022088446-appb-100021
    右侧与环B连接；     L3 is selected from
    Figure PCTCN2022088446-appb-100021
    The right side is connected with ring B;
    R x各自独立的选自H、F、Cl、Br、I、氰基、OH、甲基、乙基、丙基、异丙基、丁基、叔丁基、乙炔基、甲氧基、乙氧基、-SCH 3、-SCH 2CH 3、环丙基、环丁基、环戊基或环己基，所述的甲基、乙基、丙基、异丙基、乙炔基、甲氧基、乙氧基、-SCH 3、-SCH 2CH 3、环丙基、环丁基、环戊基或环己基任选进一步被0至4个选自H、F、OH、氰基、甲基、乙基、甲氧基或乙氧基的取代基所取代； R x is each independently selected from H, F, Cl, Br, I, cyano, OH, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, ethynyl, methoxy, ethynyl Oxy group, -SCH 3 , -SCH 2 CH 3 , cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, said methyl, ethyl, propyl, isopropyl, ethynyl, methoxy , ethoxy, -SCH 3 , -SCH 2 CH 3 , cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl optionally further substituted by 0 to 4 selected from H, F, OH, cyano, methyl , ethyl, methoxy or ethoxy substituents;
    R a1选自H、F、Cl、Br、I、氰基、CF 3、CHF 2、CH 2F、甲基、乙基、丙基、异丙基、乙炔基、甲氧基、乙氧基、-SCH 3、-SCH 2CH 3、环丙基、环丁基、环戊基或环己基； 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选自H或甲基； R a3 is selected from H or methyl;
    R b各自独立的选自H、F、Cl、Br、I、氰基、OH、＝O、甲基、乙基、丙基或异丙基。 R b is each independently selected from H, F, Cl, Br, I, cyano, OH, =O, methyl, ethyl, propyl or isopropyl.
  7. 根据权利要求6所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，化合物选自通式(II-a)、(II-b)或(II-c)所示的化合物，The compound according to claim 6 or its stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, the compound is selected from the group consisting of general formula (II-a), (II) -b) or a compound represented by (II-c),
    Figure PCTCN2022088446-appb-100022
    Figure PCTCN2022088446-appb-100022
    Y选自-NHC(＝O)-、-C(＝O)NH-、-CH 2CH 2CH 2-、-OCH 2-、-CH 2CH 2-、-CH 2O-、-CH 2CH 2O-或-OCH 2CH 2-； Y is selected from -NHC(=O) - , -C (=O) NH- , -CH2CH2CH2- , -OCH2- , -CH2CH2- , -CH2O- , -CH2 CH 2 O- or -OCH 2 CH 2 -;
    或者Y选自O、-N(CH 3)C(＝O)-、-C(＝O)N(CH 3)-、-CH 2C(＝O)NH-或-CH 2C(＝O)N(CH 3)-； or Y is selected from O, -N( CH3 )C(=O)-, -C(=O)N( CH3 )-, -CH2C (=O)NH- or -CH2C (=O )N( CH3 )-;
    或者Y选自-N(CH 2CH 3)C(＝O)-、-N(CH(CH 3) 2)C(＝O)-、-N(CH 2CH(CH 3) 2)C(＝O)-、-N(环丙基)C(＝O)-、-N(CH 2-环丙基)C(＝O)-、-C(＝O)N(CH 2CH 3)-、-C(＝O)N(CH(CH 3) 2)-、-C(＝O)N(CH 2CH(CH 3) 2)-、-C(＝O)N(环丙基)-或-C(＝O)N(CH 2-环丙基)-； Or Y is selected from -N( CH2CH3 )C(=O)-, -N(CH( CH3 ) 2 )C(=O)-, -N(CH2CH( CH3 ) 2 ) C( =O)-, -N(cyclopropyl)C(=O)-, -N( CH2 -cyclopropyl)C(=O)-, -C(=O)N( CH2CH3 ) - , -C(=O)N(CH(CH 3 ) 2 )-, -C(=O)N(CH 2 CH(CH 3 ) 2 )-, -C(=O)N(cyclopropyl)- or -C(=O)N( CH2 -cyclopropyl)-;
    或者Y各自独立的选自-C(＝O)N(CD 3)-、-C(＝O)N(CH 2-氧杂环丁基)-、-C(＝O)N(CH 2-氧杂环戊基)-、-C(＝O)N(CH 2-氮杂环丁基)-、-C(＝O)N(CH 2-吡咯烷基)-、-C(＝O)N(CH 2-环戊基)-、-C(＝O)N(CH 2CH 2CH 3)-、-C(＝O)N(CH 2CH(CH 2CH 3) 2)-、-C(＝O)N(CH 2CH 2CH 2CH 3)-、-C(＝O)N(CH 2CH 2CH(CH 3) 2)-、-C(＝O)N(CH 2CH(CH 3)CH 2CH 3)-、-C(＝O)N(正辛基)-、-C(＝S)N(CH 3)-、-C(＝S)N(CH 2CH 3)-、-C(＝S)N(CH 2-环丙基)-、
    Figure PCTCN2022088446-appb-100023
    Figure PCTCN2022088446-appb-100024
    Or each Y is independently selected from -C(=O)N(CD 3 )-, -C(=O)N(CH 2 -oxetanyl)-, -C(=O)N(CH 2 - oxolane)-, -C(=O)N(CH 2 -azetidinyl)-, -C(=O)N(CH 2 -pyrrolidinyl)-, -C(=O) N(CH 2 -cyclopentyl)-, -C(=O)N(CH 2 CH 2 CH 3 )-, -C(=O)N(CH 2 CH(CH 2 CH 3 ) 2 )-,- C(=O)N(CH 2 CH 2 CH 2 CH 3 )-, -C(=O)N(CH 2 CH 2 CH(CH 3 ) 2 )-, -C(=O)N(CH 2 CH (CH 3 )CH 2 CH 3 )-, -C(=O)N(n-octyl)-, -C(=S)N(CH 3 )-, -C(=S)N(CH 2 CH 3 )-, -C(=S)N(CH 2 -cyclopropyl)-,
    Figure PCTCN2022088446-appb-100023
    Figure PCTCN2022088446-appb-100024
    或者Y选自-CH 2S(＝O) 2-； or Y is selected from -CH 2 S(=O) 2 -;
    X 1、X 2、X 3、X 4各自独立的选自N或CR x，X 1、X 2、X 3、X 4至多含有2个N； X 1 , X 2 , X 3 , and X 4 are each independently selected from N or CR x , and X 1 , X 2 , X 3 , and X 4 contain at most 2 N;
    R x各自独立的选自H、F、Cl、氰基、甲基、乙基、异丙基、三氟甲基、甲氧基、乙氧基、-SO 2CH 3、-SO 2CH 2CH 3、-C(＝O)CH 3、-C(＝O)CH 2CH 3或环丙基； R x is each independently selected from H, F, Cl, cyano, methyl, ethyl, isopropyl, trifluoromethyl, methoxy, ethoxy, -SO 2 CH 3 , -SO 2 CH 2 CH3 , -C(=O) CH3 , -C( = O) CH2CH3 or cyclopropyl;
    其余基团定义与权6相同。The rest of the group definitions are the same as in 6.
  8. 根据权利要求7所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，The compound of claim 7, or a stereoisomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof,
    L选自
    Figure PCTCN2022088446-appb-100025
    或者
    Figure PCTCN2022088446-appb-100026
    右侧与环B连接；     L is selected from
    Figure PCTCN2022088446-appb-100025
    or
    Figure PCTCN2022088446-appb-100026
    The right side is connected with ring B;
    或者L选自
    Figure PCTCN2022088446-appb-100027
    Figure PCTCN2022088446-appb-100028
    右侧与环B连接；     or L is selected from
    Figure PCTCN2022088446-appb-100027
    Figure PCTCN2022088446-appb-100028
    The right side is connected with ring B;
    或者L选自
    Figure PCTCN2022088446-appb-100029
    Figure PCTCN2022088446-appb-100030
    右侧与环B连接；     or L is selected from
    Figure PCTCN2022088446-appb-100029
    Figure PCTCN2022088446-appb-100030
    The right side is connected with ring B;
    X 1选自N，X 2选自CH，X 3选自CH、CF、CCl、CCN或CCF 3，X 4选自CH或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.
  9. 根据权利要求1所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，其中该化合物选自如下结构之一：The compound of claim 1 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:
    Figure PCTCN2022088446-appb-100031
    Figure PCTCN2022088446-appb-100031
    Figure PCTCN2022088446-appb-100032
    Figure PCTCN2022088446-appb-100032
    Figure PCTCN2022088446-appb-100033
    Figure PCTCN2022088446-appb-100033
    Figure PCTCN2022088446-appb-100034
    Figure PCTCN2022088446-appb-100034
    Figure PCTCN2022088446-appb-100035
    Figure PCTCN2022088446-appb-100035
    Figure PCTCN2022088446-appb-100036
    Figure PCTCN2022088446-appb-100036
    Figure PCTCN2022088446-appb-100037
    Figure PCTCN2022088446-appb-100037
    Figure PCTCN2022088446-appb-100038
    Figure PCTCN2022088446-appb-100038
    Figure PCTCN2022088446-appb-100039
    Figure PCTCN2022088446-appb-100039
    Figure PCTCN2022088446-appb-100040
    Figure PCTCN2022088446-appb-100040
    Figure PCTCN2022088446-appb-100041
    Figure PCTCN2022088446-appb-100041
    Figure PCTCN2022088446-appb-100042
    Figure PCTCN2022088446-appb-100042
    Figure PCTCN2022088446-appb-100043
    Figure PCTCN2022088446-appb-100043
    Figure PCTCN2022088446-appb-100044
    Figure PCTCN2022088446-appb-100044
    Figure PCTCN2022088446-appb-100045
    Figure PCTCN2022088446-appb-100045
    Figure PCTCN2022088446-appb-100046
    Figure PCTCN2022088446-appb-100046
    Figure PCTCN2022088446-appb-100047
    Figure PCTCN2022088446-appb-100047
    Figure PCTCN2022088446-appb-100048
    Figure PCTCN2022088446-appb-100048
  10. 一种药物组合物，包括治疗有效量的权利要求1-9任意一项所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶，以及药学上可接受的载体，任选地包含一种多或多种其它化学治疗剂。A pharmaceutical composition comprising a therapeutically effective amount of the compound of any one of claims 1-9 or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co- The crystals, along with a pharmaceutically acceptable carrier, optionally contain one or more other chemotherapeutic agents.
  11. 根据权利要求10所述的药物组合物，其中所述的治疗有效量是指，药物组合物以适合于待治疗(或预防)的疾病的剂量给予，例如给予约0.1μg至约50mg的至少一种化合物/kg受试者体重，优选约10μg至约200mg/kg体重/天。The pharmaceutical composition according to claim 10, wherein the therapeutically effective amount means that the pharmaceutical composition is administered in a dose suitable for the disease to be treated (or prevented), for example, about 0.1 μg to about 50 mg of at least one compound/kg body weight of the subject, preferably from about 10 μg to about 200 mg/kg body weight/day.
  12. 根据权利要求1-9任意一项所述的化合物或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶在用于制备治疗与PARP7活性或表达量相关疾病的药物中的应用。A compound according to any one of claims 1-9, or a stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, for use in the preparation of a therapeutic with PARP7 activity or Application of expression-related diseases in medicine.
  13. 根据权利要求12所述的应用，其特征在于，所述的疾病选自肿瘤。The use according to claim 12, wherein the disease is selected from tumors.
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Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996023789A1 (en) * 1995-02-03 1996-08-08 Sankyo Company, Limited Hexahydropyrazinoquinoline derivatives
WO2001090077A1 (en) * 2000-05-19 2001-11-29 Guilford Pharmaceuticals, Inc. Sulfonamide and carbamide derivatives of 6(5h)phenanthridinones and their uses
US20050171101A1 (en) * 2002-03-26 2005-08-04 Fujisawa Pharmaceutical Co. Ltd. Phenanthridinones as parp inhibitors
CN1948298A (en) * 2006-11-09 2007-04-18 东南大学 Dopamine D3 acceptor portion agonist and its application
CN1976931A (en) * 2004-04-09 2007-06-06 千禧药品公司 Beta-carbolines useful for treating inflammatory disease
CN101501006A (en) * 2006-05-31 2009-08-05 P.安杰莱蒂分子生物学研究所 Pyridinone and pyridazinone derivatives as inhibitors of poly(ADP-ribose)polymerase (PARP)
CN102341394A (en) * 2009-01-23 2012-02-01 武田药品工业株式会社 Poly(ADP-ribose) polymerase (PARP) inhibitors
CN104884435A (en) * 2012-12-06 2015-09-02 协和发酵麒麟株式会社 Pyridone compound
CN112424188A (en) * 2018-04-30 2021-02-26 里邦医疗公司 Pyridazinones as PARP7 inhibitors

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996023789A1 (en) * 1995-02-03 1996-08-08 Sankyo Company, Limited Hexahydropyrazinoquinoline derivatives
WO2001090077A1 (en) * 2000-05-19 2001-11-29 Guilford Pharmaceuticals, Inc. Sulfonamide and carbamide derivatives of 6(5h)phenanthridinones and their uses
US20050171101A1 (en) * 2002-03-26 2005-08-04 Fujisawa Pharmaceutical Co. Ltd. Phenanthridinones as parp inhibitors
CN1976931A (en) * 2004-04-09 2007-06-06 千禧药品公司 Beta-carbolines useful for treating inflammatory disease
CN101501006A (en) * 2006-05-31 2009-08-05 P.安杰莱蒂分子生物学研究所 Pyridinone and pyridazinone derivatives as inhibitors of poly(ADP-ribose)polymerase (PARP)
CN1948298A (en) * 2006-11-09 2007-04-18 东南大学 Dopamine D3 acceptor portion agonist and its application
CN102341394A (en) * 2009-01-23 2012-02-01 武田药品工业株式会社 Poly(ADP-ribose) polymerase (PARP) inhibitors
CN104884435A (en) * 2012-12-06 2015-09-02 协和发酵麒麟株式会社 Pyridone compound
CN112424188A (en) * 2018-04-30 2021-02-26 里邦医疗公司 Pyridazinones as PARP7 inhibitors

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