WO2023202687A1 - Pyrazinone derivative and use thereof in medicine - Google Patents

Pyrazinone derivative and use thereof in medicine Download PDF

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Publication number
WO2023202687A1
WO2023202687A1 PCT/CN2023/089655 CN2023089655W WO2023202687A1 WO 2023202687 A1 WO2023202687 A1 WO 2023202687A1 CN 2023089655 W CN2023089655 W CN 2023089655W WO 2023202687 A1 WO2023202687 A1 WO 2023202687A1
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Prior art keywords
alkyl
ring
compound
halogen
substituted
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PCT/CN2023/089655
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French (fr)
Chinese (zh)
Inventor
张晨
赵明亮
李路
余彦
唐平明
邓华
杨定菊
刘含波
李瑶
严庞科
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四川海思科制药有限公司
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Publication of WO2023202687A1 publication Critical patent/WO2023202687A1/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
    • A61K31/4985—Pyrazines or piperazines 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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to a compound described in general formula (I) or its stereoisomers, deuterated products, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals, as well as intermediates and preparation methods thereof , and its application in the preparation of drugs for the treatment of diseases related to PARP7 activity or expression.
  • PARP stands for poly-ADP-ribose polymerase, which is poly-ADP ribose polymerase. It participates in a series of cellular processes including DNA repair, genome stability, etc. This protein family consists of 17 members, divided into polyPARPs and monoPARPs. The MonoPARP protein family plays a role in multiple stress responses associated with the development of cancer, inflammatory diseases, and neurodegenerative diseases. Its member PARP7 has been shown to be overactive in tumors and plays a key role in cancer cell survival.
  • PARP7 allows cancer cells to "hide” from the immune system. Inhibiting PARP7 can effectively inhibit the growth of cancer cells and restore interferon signaling, effectively releasing the "brakes” that cancer uses to evade the immune system and suppress innate and adaptive immune mechanisms.
  • PARP7 inhibitors have demonstrated durable tumor growth inhibition, potent antiproliferative activity, and restoration of interferon signaling. PARP7 inhibitors are expected to become targets for the development of new anticancer drugs.
  • the purpose of the present invention is to provide a class of heterocyclic compounds or pharmaceutically acceptable salts thereof, which can be used as PARP7 inhibitors.
  • the compounds of the present invention can effectively inhibit PARP7 and can be used to treat tumors and other diseases.
  • the present invention provides a compound described in general formula (A) or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein
  • W is selected from bonds
  • compounds of Formula (A) are selected from compounds of Formula (I),
  • compounds of Formula (I) are selected from compounds of Formula (II),
  • Ring B is selected from Is a single bond or a double bond
  • Z is selected from N, C, or CH;
  • R y is each independently selected from H, C 1-6 alkyl or C 3-6 cycloalkyl, and the alkyl or cycloalkyl is optionally substituted by 1 to 4 selected from deuterium, Substituted with 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, so The above-mentioned heterocyclic group contains 1 to 3 heteroatoms selected from O, S, and N;
  • each R y is independently selected from H, C 1-4 alkyl or C 3-6 cycloalkyl, and the alkyl or cycloalkyl is optionally substituted by 1 to 4 selected from deuterium, Substituted with 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, so The above-mentioned heterocyclic group contains 1 to 3 heteroatoms selected from O, S, and N;
  • each R y 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 substituted by 1 to 4 members selected from deuterium, halogen, CF 3 , OH, cyano, NH 2 , C 1-4 alkyl, C 1-4 alkoxy, 3 to 8 membered heterocyclyl or Substituted with a substituent of C 3-6 cycloalkyl, the heterocyclic group contains 1 to 3 heteroatom
  • Ring A is selected from a C 6-10 aromatic ring, a 5-10 membered heteroaromatic ring or a 5-10 membered heterocyclic ring, and the heteroaromatic ring or heterocyclic ring contains 1 to 5 atoms selected from O, Heteroatoms of S and N; in some embodiments, ring The aromatic ring or heterocyclic ring contains 1 to 5 heteroatoms selected from O, S, and N;
  • Ring Or the heterocyclic ring contains 1 to 5 heteroatoms selected from O, S, and N;
  • Ring of heteroatoms are in some embodiments, Ring of heteroatoms
  • Ring Cyclic heteroaromatic ring or 8-10 membered cyclic heterocyclic ring, the heterocycloalkyl group, heteroaromatic ring or heterocyclic ring contains 1 to 5 heteroatoms selected from O, S, and N;
  • Ring 5 heteroatoms selected from O, S, and N;
  • Ring is asymmetric
  • R a is selected from R a1 , R a2 ;
  • Rx is 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 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, the methyl, ethyl, propyl, iso Propyl, vinyl, ethynyl, methoxy, ethoxy, -SCH 3 , -SCH 2 CH 3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl , phenyl, pyridyl, thiazolyl, thienyl, oxazolyl, furyl, pyrrol
  • Rx is each independently selected from H, F, Cl, Br, cyano, isopropyl, CD3 , CF3 , CHF2 , CH2F , cyclopropyl, cyclobutyl;
  • R a1 is selected from H, F, Cl, Br, I, cyano, CF 3 , CHF 2 , CH 2 F, methyl, ethyl, propyl, isopropyl, ethynyl, methyl Oxy, ethoxy, -SCH 3 , -SCH 2 CH 3 , cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;
  • R a1 is selected from F, Cl, Br, CF 3 , CHF 2 , CH 2 F, methyl, cyano, cyclopropyl, isopropyl;
  • R a2 is selected from H
  • L is selected from -Q1-Ak1-Q2-Ak2-, connected to ring B on the right side;
  • L is selected from -N(R q )-Ak1-O-Ak2-, -O-Ak1-O-Ak2-, -O-Ak1-N(R q )-Ak2-, -N( R q )-Ak1-N(R q )-Ak2-, the left side is directly connected to the pyridazinone ring;
  • L is selected from The left side is directly connected to the pyridazinone ring;
  • L is selected from The left side is directly connected to the pyridazinone ring;
  • L is selected from
  • Ak1 and Ak2 are each independently selected from C 1-4 alkylene, C 2-4 alkenylene, C 2-4 alkynylene, and the Ak1 is optionally replaced by 0 to 4 R k1 Substituted, the Ak2 is optionally substituted by 0 to 4 R k2 ;
  • Ak1 and Ak2 are each independently selected from C 1-3 alkylene, C 2-3 alkenylene, C 2-3 alkynylene, and the Ak1 is optionally replaced by 0 to 4 R k1 Substituted, the Ak2 is optionally substituted by 0 to 4 R k2 ;
  • Ak1 and Ak2 are each independently selected from methylene, ethylene, propylene, vinylene, propenylene, ethynylene, and propynylene, and Ak1 is optionally replaced by 0 to 4 R k1 substituted, and the Ak2 is optionally substituted by 0 to 4 R k2 ;
  • the alkyl, alkenyl, alkynyl, alkoxy, carbocyclic or heterocyclic groups are optionally substituted by 1 to 4 selected from halogen, OH, cyano, NH 2 , C 1-6 alkyl, C 2-6 alkene Base, C 2-6 alkynyl group, halogen-substituted C 1-6 alkyl group, C 1-6 alkoxy group, -OC 3-8 carbocyclic ring, C 3-8 carbocyclic ring, 4 to
  • R q is each independently selected from H, C 1-6 alkyl or C 3-6 cycloalkyl, and the alkyl or cycloalkyl is optionally substituted by 1 to 4 selected from halogen, Substituted with substituents of CF 3 , OH, cyano, NH 2 , C 1-6 alkyl or C 1-6 alkoxy;
  • R q is each independently selected from H, C 1-4 alkyl, and the alkyl is optionally substituted by 1 to 4 selected from halogen, CF 3 , OH, cyano, NH 2 , C Substituted with 1-4 alkyl or C 1-4 alkoxy substituents;
  • each R q is independently selected from H, methyl, and ethyl
  • substituents such as C 1-4 alkyl, halogen-substituted C 1-4 alkyl, C 1-4 alkoxy, and C 3-6 cycloalkyl
  • the heterocyclic ring contains 1 to 3 Heteroatom selected from O, S, N;
  • substituents such as C 1-4 alkyl, halogen-substituted C 1-4 alkyl, C 1-4 alkoxy, and C 3-6 cycloalkyl
  • the heterocyclic ring contains 1 to 3 Heteroatom selected from O, S, N;
  • 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;
  • b is selected from 0, 1, 2, 3;
  • x is selected from 1, 2;
  • Ring B is selected from Is a single bond or a double bond
  • Z is selected from N, C or CH
  • R y are each independently selected from H, C 1-6 alkyl or C 3-6 cycloalkyl, and the alkyl or cycloalkyl is optionally substituted by 1 to 4 selected from deuterium, halogen, CF 3 , OH , cyano group, NH 2 , C 1-6 alkyl group, C 1-6 alkoxy group, 3 to 8 membered heterocyclic group or C 3-6 cycloalkyl substituent, the heterocyclic group contains 1 to 3 heteroatoms selected from O, S, and N;
  • Ring A is selected from a C 6-10 aromatic ring, a 5-10 membered heteroaromatic ring or a 5-10 membered heterocyclic ring.
  • the heteroaromatic ring or heterocyclic ring contains 1 to 5 heteroatoms selected from O, S, and N. ;
  • Ring _ S, N heteroatoms
  • L is selected from -Q1-Ak1-Q2-Ak2-, and is connected to ring B on the right side;
  • Ak1 and Ak2 are each independently selected from C 1-4 alkylene, C 2-4 alkenylene, C 2-4 alkynylene, the Ak1 is optionally substituted by 0 to 4 R k1 , and the Ak2 is optionally The selection is replaced by 0 to 4 R k2 ;
  • R q is each independently selected from H, C 1-6 alkyl or C 3-6 cycloalkyl, and the alkyl or cycloalkyl is optionally substituted by 1 to 4 selected from halogen, CF 3 , OH, cyanide Substituted with substituents of base, NH 2 , C 1-6 alkyl or C 1-6 alkoxy;
  • 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;
  • the compound of general formula (A) is selected from the compounds represented by general formula (I)
  • R y are each independently selected from H, C 1-4 alkyl or C 3-6 cycloalkyl, and the alkyl or cycloalkyl is optionally substituted by 1 to 4 selected from deuterium, halogen, CF 3 , OH , cyano group, NH 2 , C 1-4 alkyl group, C 1-4 alkoxy group, 3 to 8 membered heterocyclic group or C 3-6 cycloalkyl substituent, the heterocyclic group contains 1 to 3 heteroatoms selected from O, S, and N;
  • Ak1 and Ak2 are each independently selected from C 1-3 alkylene, C 2-3 alkenylene, and C 2-3 alkynylene.
  • the Ak1 is optionally substituted by 0 to 4 R k1
  • the Ak2 is optionally The selection is replaced by 0 to 4 R k2 ;
  • R q is each independently selected from H, C 1-4 alkyl, and the alkyl is optionally substituted by 1 to 4 selected from halogen, CF 3 , OH, cyano, NH 2 , C 1-4 alkyl or Substituted with C 1-4 alkoxy substituents;
  • R y is each independently selected from H, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentyl, Hexyl, the methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl are optionally 1 to 4 selected from 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 with a substituent of a base, the heterocyclic group contains 1 to 3 heteroatoms selected from
  • Ak1 and Ak2 are each independently selected from methylene, ethylene, propylene, vinylene, propenylene, ethynylene, and propynylene, and the Ak1 is optionally substituted by 0 to 4 R k1 , the Ak2 is optionally replaced by 0 to 4 R k2 ;
  • R q is each independently selected from H, methyl, and ethyl
  • L is selected from -N(R q )-Ak1-O-Ak2-, -O-Ak1-O-Ak2-, -O-Ak1-N(R q )-Ak2-, -N(R q )-Ak1- N(R q )-Ak2-, the left side is directly connected to the pyridazinone ring;
  • L is selected from The left side is directly connected to the pyridazinone ring;
  • R x is independently selected from H, F, Cl, Br, I, cyano, OH, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, vinyl, ethynyl, methoxy base, ethoxy, -SCH 3 , -SCH 2 CH 3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl base, bicyclo[1.1.1]pentyl, phenyl, pyridyl, thiazolyl, thienyl, oxazolyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, the methyl, ethyl, propyl base, isopropyl, vinyl, ethynyl, methoxy, ethoxy, -SCH 3 , -SCH 2 CH 3 , cyclopropyl, cyclobutyl, cyclopen
  • 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;
  • L is selected from The left side is directly connected to the pyridazinone ring;
  • R a1 is selected from F, Cl, Br, CF 3 , CHF 2 , CH 2 F, methyl, cyano, cyclopropyl, isopropyl;
  • R x is each independently selected from H, F, Cl, Br, cyano, isopropyl, CD 3 , CF 3 , CHF 2 , CH 2 F, cyclopropyl, cyclobutyl;
  • b is selected from 0, 1, 2, 3;
  • x is selected from 1, 2;
  • Ring -10-membered heterocyclic ring the heterocycloalkyl group, heteroaromatic ring or heterocyclic ring contains 1 to 5 heteroatoms selected from O, S, and N;
  • Ring _ Single-membered monocyclic heterocycloalkyl, 5- to 10-membered pentacyclic heterocycloalkyl, 5- to 11-membered spirocyclic heterocycloalkyl, 5- to 11-membered bridged heterocycloalkyl, phenyl, 5-6-membered heteroaryl Ring, 8-10 membered heteroaromatic ring, the heterocycloalkyl group, heteroaromatic ring or heterocyclic ring contains 1 to 5 heteroatoms selected from O, S, N;
  • the present invention relates to the compound shown below or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein the compound is selected from the structure shown in Table E-1 one.
  • the present invention relates to a pharmaceutical composition, including any of the above compounds or their stereoisomers, deuterated products, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals, and a pharmaceutically acceptable carrier. .
  • the present invention relates to a pharmaceutical composition, comprising a therapeutically effective dose of the above-mentioned compound of the present invention or its stereoisomer, deuterium Substitutes, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals, and pharmaceutically acceptable carriers.
  • the pharmaceutical composition of the present invention may be in the form of a unit preparation (the amount of the main drug in a unit preparation is also referred to as "preparation strength").
  • Effective amount or “therapeutically effective amount” as used herein refers to administration of a sufficient amount of a compound disclosed herein that will alleviate to some extent the disease or disorder being treated (eg, PARP7-related diseases such as prostate cancer) one or more symptoms. In some embodiments, the result is reduction and/or alleviation of signs, symptoms, or causes of disease, or any other desired change in a biological system.
  • an "effective amount” for therapeutic use is the amount of a composition containing a compound disclosed herein that is required to provide a clinically significant reduction in disease symptoms.
  • therapeutically effective amounts include, but are not limited to, 1-1500 mg, 1-1200 mg, 1-1000 mg, 1-900 mg, 1-800 mg, 1-700 mg, 1-600 mg, 2-600 mg, 3-600 mg, 4-600 mg, 5 -600mg, 6-600mg, 10-600mg, 20-600mg, 25-600mg, 30-600mg, 40-600mg, 50-600mg, 60-600mg, 70-600mg, 75-600mg, 80-600mg, 90-600mg , 100-600mg, 200-600mg, 1-500mg, 2-500mg, 3-500mg, 4-500mg, 5-500mg, 6-500mg, 10-500mg, 20-500mg, 25-500mg, 30-500mg, 40 -500mg, 50-500mg, 60-500mg, 70-500mg, 75-500mg, 80-500mg, 90-500mg, 100-500mg, 125-500mg, 150-
  • the pharmaceutical composition includes, but is not limited to, 1-1000 mg, 20-800 mg, 40-800 mg, 40-400 mg, 25-200 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40mg, 45mg, 50mg, 55mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 110mg, 120mg, 125mg, 130mg, 140mg, 150mg, 160mg, 170mg, 180mg, 190mg, 200mg, 210mg, 220mg, 230 mg, 240 mg, 250 mg, 300 mg, 320 mg, 400 mg, 480 mg, 500 mg, 600 mg, 640 mg, 840 mg of the compound of the present invention or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic.
  • a method for treating diseases in mammals comprising administering to a subject a therapeutically effective amount of a compound of the present invention or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable
  • the salt or co-crystal, the therapeutically effective amount is preferably 1-1500 mg, and the disease preferably inhibits or degrades AR or AR splicing mutant-related diseases (such as prostate cancer).
  • a method for treating diseases in mammals includes: adding a pharmaceutical compound of the present invention or its stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal to A daily dose of 1-1000 mg/day is administered to the subject, and the daily dose may be a single dose or divided dose.
  • the daily dose includes but is not limited to 10-1500 mg/day, 10-1000 mg/day, 10 -800mg/day, 25-800mg/day, 50-800mg/day, 100-800mg/day, 200-800mg/day, 25-400mg/day, 50-400mg/day, 100-400mg/day, 200-400mg /day, in some embodiments, daily dosages include, but are not limited to, 10 mg/day, 20 mg/day, 25 mg/day, 50 mg/day, 80 mg/day, 100 mg/day, 125 mg/day, 150 mg/day, 160 mg/day , 200mg/day, 300mg/day, 320mg/day, 400mg/day, 480mg/day, 600mg/day, 640mg/day, 800mg/day, 1000mg/day.
  • the present invention relates to a kit which may comprise a composition in single dose or multiple dose form, the kit comprising the Compounds of the invention or their stereoisomers, deuterated products, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals, compounds of the invention or their stereoisomers, deuterated products, solvates, prodrugs
  • the amounts of metabolites, pharmaceutically acceptable salts or co-crystals are the same as those in the above pharmaceutical compositions.
  • the present invention relates to any of the above compounds or their stereoisomers, deuterated products, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals used in the preparation of drugs for the treatment of diseases related to PARP7 activity or expression levels.
  • the disease is selected from tumors.
  • the present invention relates to the application of the above pharmaceutical composition in the preparation of drugs for treating diseases related to PARP7 activity or expression.
  • the diseases are selected from tumors.
  • the compound of the present invention can be prepared by the following scheme:
  • PG, PG1 or PG2 are each independently selected from amino protecting groups, preferably Boc (tert-butyloxycarbonyl), Cbz (benzyloxycarbonyl), PMB (p-methoxybenzyl);
  • R is selected from C 1-4 alkyl, preferably methyl or ethyl
  • X is selected from leaving groups, preferably halogen, OMs, OTs or OTf,
  • the compound of general formula (M-4) can obtain the compound of general formula (M-5) through deamination protecting group reaction;
  • the compound of general formula (M-5) reacts under alkaline conditions (such as triethylamine, DIPEA) to obtain the compound of general formula (M-6);
  • alkaline conditions such as triethylamine, DIPEA
  • the compound of general formula (M-6) can obtain the compound of general formula (M-7) through deamination protecting group reaction;
  • the compound of general formula (M-8) is reacted under reducing agent (such as NaBH 4 , LiAlH 4 ) to obtain the compound of general formula (M-9);
  • reducing agent such as NaBH 4 , LiAlH 4
  • the compound of general formula (M-9) and the compound of general formula (A-2) obtain the compound of general formula (M-10) through nucleophilic substitution reaction;
  • the compound of the general formula (N-1) is obtained through a reduction reaction of the intermediate (M-6) compound under the condition of a reducing agent (such as NaBH 4 , LiAlH 4 );
  • the compound of general formula (M-9) can be used to obtain the compound of general formula (M-13) through Scheme 1.
  • the carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds described in the present invention all include their isotope conditions, and the carbon involved in the groups and compounds described in the present invention , hydrogen, oxygen, sulfur or nitrogen are optionally replaced by one or more of their corresponding isotopes, where the isotopes of carbon include 12 C, 13 C and 14 C, and the isotopes of hydrogen include protium (H), deuterium (D), and (called deuterium), tritium (T, also called superheavy hydrogen), oxygen isotopes include 16 O, 17 O and 18 O, sulfur isotopes include 32 S, 33 S, 34 S and 36 S, and nitrogen isotopes 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.
  • the isotopes of carbon include 12 C, 13 C and 14 C
  • Halogen refers to F, Cl, Br or I.
  • Halo-substituted means substituted by 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 a substituent of I, substituted by 1 to 4 substituents selected from F, Cl, Br or I. "Halo-substituted” is simply referred to as "halogenated.”
  • Alkyl refers to a substituted or unsubstituted linear or branched 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 group of carbon atoms, alkyl group of 1 to 4 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neo-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and its various branched chain isomers; the alkyl group appearing in this article has the same definition as this definition.
  • Alkyl groups may be monovalent, divalent, trivalent or tetravalent.
  • Heteroalkyl refers to a substituted or unsubstituted alkyl group in which 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( CH2 )vX( CH2 )vX( CH2 )vH (v is an integer from 1 to 5, each , O or S, and at least 1 X is selected from heteroatoms, and N or S in the heteroatoms can be oxidized to various oxidation states).
  • Heteroalkyl groups may 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 are not Limited to methylene, ethylene, propylene, butylene, etc.
  • Heteroalkylene refers to a substituted or unsubstituted alkylene group in which 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) substitution.
  • Non-limiting examples include -X( CH2 )vX( CH2 )vX( CH2 )v-, v is an integer from 1 to 5, 1 X is selected from N, O or S.
  • Cycloalkyl refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon group, usually having 3 to 10 carbon atoms. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloalkyl. Gengji et al. Cycloalkyl groups appearing herein are as defined above. The cycloalkyl group may be monovalent, divalent, trivalent or tetravalent.
  • Heterocycloalkyl refers to a substituted or unsubstituted saturated cyclic hydrocarbon group containing heteroatoms, including but not limited to 3 to 10 atoms, 3 to 8 atoms, including 1 to 3 selected from N, O or
  • the heteroatoms of S and the selectively substituted N and S in the heterocycloalkyl ring can be oxidized to various oxidation states.
  • the heterocycloalkyl group can be connected to a heteroatom or a carbon atom, the heterocycloalkyl group can be connected to an aromatic ring or a non-aromatic ring, the heterocycloalkyl group can be connected to a bridged ring or a spiro ring, non-limiting examples include rings Oxyethyl, azetidinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, dioxolanyl, dioxanyl, pyrrolidinyl, Piperidinyl, imidazolidinyl, oxazolidinyl, oxazinyl, morpholinyl, hexahydropyrimidinyl, piperazinyl. Heterocycloalkyl groups can be monovalent, divalent, trivalent or tetravalent
  • alkenyl refers to substituted or unsubstituted straight-chain and branched unsaturated hydrocarbon groups, which have 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 , 2 to 6 or 2 to 4 carbon atoms
  • alkenyl 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 straight-chain and branched unsaturated hydrocarbon groups, which have at least 1, usually 1, 2 or 3 carbon-carbon triple bonds, including but not limited to 2 in the main chain. to 10 carbon atoms, 2 to 6 carbon atoms, 2 to 4 carbon atoms, alkynyl examples include but are not limited to ethynyl, propargyl, 1-propynyl, 2-propynyl, 1-butyl Alkynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-1-butynyl, 2-Methyl-1-butynyl, 2-methyl-3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl base, 1-methyl
  • Alkoxy refers to substituted or unsubstituted -O-alkyl. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy, cyclopropyloxy Oxygen and cyclobutoxy.
  • Carbocyclyl or “carbocyclic ring” refers to a substituted or unsubstituted saturated or unsaturated aromatic ring or non-aromatic ring.
  • the aromatic ring or non-aromatic ring can be a 3- to 8-membered monocyclic ring or a 4- to 12-membered ring.
  • Bicyclic or 10 to 15-membered tricyclic system the carbocyclic group can be connected to an aromatic ring or a non-aromatic ring, and the aromatic ring or non-aromatic ring can be optionally a single ring, a bridged ring or a spiro ring.
  • Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclohexane Pentyl-3- Alkenyl, cyclohexyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexenyl, benzene ring, naphthalene ring, "Carbocyclyl” or “carbocycle” may be monovalent, divalent, trivalent or tetravalent.
  • Heterocyclyl or “heterocycle” refers to a substituted or unsubstituted saturated or unsaturated aromatic ring or non-aromatic ring.
  • the aromatic ring or non-aromatic ring can be a 3- to 8-membered monocyclic ring or a 4- to 12-membered ring.
  • Sexually substituted N and S can be oxidized into various oxidation states.
  • the heterocyclyl group can be connected to a heteroatom or a carbon atom.
  • the heterocyclyl group can be connected to an aromatic ring or a non-aromatic ring.
  • the heterocyclyl group can be connected to a bridged ring or a spiro ring.
  • Non-limiting examples include epoxyethyl. , aziridyl, oxetanyl, azetidinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxanyl, nitrogen Heterocycloheptyl, pyridyl, furyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorphyl Phyllinyl, 1,3-dithiyl, dihydrofuryl, dihydropyranyl, dithiopentanyl, tetrahydrofuranyl
  • Spirocyclic 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: .
  • Spiro or “spiryl” may be monovalent, divalent, trivalent or tetravalent.
  • the number of ring atoms in the parallel ring system includes but is not limited to 5 to 20, 5 to 14, 5 to 12, and 5 to 10. Non-limiting examples include:
  • And ring or “and ring group” can be monovalent, divalent, trivalent or tetravalent.
  • the "bridging ring” or “bridging ring base” may be monovalent, divalent, trivalent or tetravalent.
  • Carbospirocycle refers to a “spirocycle” in which the ring system consists only of carbon atoms.
  • Carbospirocycle refers to a “spirocycle” in which the ring system consists only of carbon atoms.
  • Carbospirocycle refers to a “spirocycle” in which the ring system consists only of carbon atoms.
  • Carbospirocycle “spirocarbocyclyl”, “spirocarbocyclyl” or “carbospirocyclyl” appearing in this article have the same definition as spirocycle.
  • Carbocyclic ring refers to a “carbocyclic ring” in which the ring system only consists of carbon atoms.
  • the definition of “carbocyclic ring”, “carbocyclic ring group”, “carbocyclic ring group” or “carbocyclic ring group” appearing in this article is consistent with that of carbocyclic ring.
  • Carbon bridged ring refers to a “bridged ring” in which the ring system consists only of carbon atoms.
  • the definitions of “carbon bridged ring”, “bridged carbocyclic ring group”, “bridged carbocyclic ring group” or “carbon bridged ring group” appearing in this article are consistent with those of the bridged ring.
  • Heteromonocycle refers to the “heterocyclyl” or “heterocycle” of a monocyclic system.
  • Heterocyclic ring refers to a “heterocyclic ring” containing heteroatoms.
  • heterocyclic ring refers to a “heterocyclic ring” containing heteroatoms.
  • the definitions of heterocyclic ring, “heterocyclic ring group”, “heterocyclic heterocyclyl group” or “heterocyclic ring group” appearing in this article are consistent with those of the heterocyclic ring group.
  • Heterospirocycle refers to a “spirocycle” containing heteroatoms. Heterospirocycle, “heterospirocyclyl”, “spirocycloheterocyclyl” or “heterospirocyclyl” appearing in this article have the same definition as spirocycle.
  • Heterobridged ring refers to a “bridged ring” containing heteroatoms.
  • the definition of hetero-bridged ring, “hetero-bridged cyclyl”, “bridged-ring heterocyclyl” or “hetero-bridged cyclyl” appearing in this article is consistent with that of bridged ring.
  • Aryl or "aromatic ring” refers to a substituted or unsubstituted aromatic hydrocarbon group with a single or fused ring, and the ring atoms in the aromatic ring The number 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, in which the ring connected to the parent structure is an aryl ring.
  • Non-limiting examples include benzene ring, naphthalene ring, "Aryl” or “aryl ring” may be monovalent, divalent, trivalent or tetravalent. When divalent, trivalent or tetravalent, the attachment site 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 have the same definition as this definition. Heteroaryl groups may be monovalent, divalent, trivalent or tetravalent. When divalent, trivalent or tetravalent, the attachment site is on the heteroaryl ring.
  • 5-membered 5-membered heteroaromatic ring refers to a 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 entire group is aromatic, non-limiting examples include pyrrolopyrrole ring, pyrazolopyrrole ring, pyrazolopyrazole ring, pyrrolofuran ring, pyrazolofuran ring, pyrrolothiophene ring, Pyrazolothiophene ring.
  • 5-6-membered heteroaromatic ring refers to a 5-6-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 entire group is aromatic, and non-limiting examples include benzo 5-membered heteroaryl, 6-membered heteroaromatic ring and 5-membered heteroaromatic ring.
  • Constant 1 to 5 heteroatoms selected from O, S, and N means containing 1, 2, 3, 4, or 5 heteroatoms selected from O, S, and N.
  • Substituted by 0 to X substituents means substituted by 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.
  • the heterobridged ring is optionally substituted by 0 to 4 substituents selected from H or F means that the heterobridged ring is optionally substituted by 0, 1, 2, 3 or 4 substituents selected from H or F. replace.
  • Rings include heterocycles, carbocycles, aromatic rings, aryl groups, heteroaryl groups, cycloalkyl groups, heteromonocycles, heterocycles, heterospirocycles or heterobridged rings.
  • “4-7 membered heteromonocyclic ring” refers to 4-, 5-, 6-, or 7-membered heteromonocyclic rings
  • “5-10-membered heterocyclic ring” refers to 5-, 6-, 7-, or 8-membered heterocyclic rings. , 9- or 10-membered heterocyclic rings.
  • Alkyl optionally substituted by F means that the alkyl group can but does not have to be substituted by F, including 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 “pharmaceutically acceptable salt thereof” means that the compound of the present invention retains the biological effectiveness and properties of the free acid or free base, and the free acid is combined with a non-toxic inorganic base or Organic base, the salt of the free base obtained by reacting with a non-toxic inorganic acid or organic acid.
  • “Pharmaceutical composition” refers to one or more compounds of the present invention, or their stereoisomers, tautomers, deuterates, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or A mixture of cocrystals and other chemical components, where "other chemical components” refers to pharmaceutically acceptable carriers, excipients and/or one or more other therapeutic agents.
  • Carrier refers to a material that does not cause significant irritation to an organism and does not eliminate the biological activity and properties of the compound to which it is administered.
  • Preparation specification refers to the weight of the main drug contained in each tube, tablet or other unit preparation.
  • Prodrug refers to a compound of the present invention that can be converted into a biologically active compound through metabolism in the body.
  • the prodrugs of the present invention are prepared by modifying the amino group or carboxyl group in the compound of the present invention. The modification can be removed by conventional operations or in vivo to obtain the parent compound.
  • the prodrug of the present invention is administered to a mammalian subject, the prodrug is cleaved to form a free amino or carboxyl group.
  • Co-crystal refers to a crystal formed by combining an active pharmaceutical ingredient (API) and a co-crystal form (CCF) under the action of hydrogen bonds or other non-covalent bonds.
  • API active pharmaceutical ingredient
  • CCF co-crystal form
  • the pure states of API and CCF are both Solids, and there are fixed stoichiometric ratios between the components.
  • a eutectic is a multicomponent crystal that includes both a binary eutectic formed between two neutral solids and a multicomponent eutectic formed between a neutral solid and a salt or solvate.
  • Animal is meant to include mammals, such as humans, companion animals, zoo animals and livestock, preferably humans, horses or dogs.
  • Stepoisomers refer to isomers produced by different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers and conformational isomers.
  • Tautomers refer to functional group isomers produced by rapid movement of an atom in a molecule between two positions, such as keto-enol isomerism and amide-iminol isomerism.
  • IC 50 is the concentration of a drug or inhibitor required to inhibit half of a specified biological process (or a component in the process such as an enzyme, receptor, cell, etc.).
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). NMR shift( ⁇ ) Given in units of 10 -6 (ppm). NMR was measured using (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic instruments, and the measurement solvents were deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), and deuterated methanol (CD 3 OD ), deuterated acetic acid (CD 3 COOD), the internal standard is tetramethylsilane (TMS);
  • DMSO-d 6 deuterated dimethyl sulfoxide
  • CDCl 3 deuterated chloroform
  • CD 3 OD deuterated methanol
  • CD 3 COOD deuterated acetic acid
  • TMS tetramethylsilane
  • HPLC HPLC was measured using Agilent 1260DAD high-pressure liquid chromatograph (Zorbax SB-C18 100 ⁇ 4.6mm, 3.5 ⁇ M);
  • Thin layer chromatography silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates.
  • the specifications of silica gel plates used in thin layer chromatography (TLC) are 0.15mm-0.20mm.
  • the specifications used for thin layer chromatography separation and purification products are 0.4mm. -0.5mm;
  • the compounds used in the reactions described herein are prepared according to organic synthesis techniques known to those skilled in the art, starting from commercially available chemicals and/or compounds described in the chemical literature.
  • “Chemicals” were obtained from standard commercial sources, including Shanghai Aladdin Biochemical Technology Co., Ltd., Shanghai McLean Biochemical Technology Co., Ltd., Sigma-Aldrich, Alfa Aesar (China) Chemical Co., Ltd., TiXia ( Shanghai) Chemical Industry Development Co., Ltd., Anaiji Chemical, Shanghai Titan Technology Co., Ltd., Kelon Chemical, Bailingwei Technology Co., Ltd., etc.
  • the temperature is room temperature unless otherwise specified.
  • THF Tetrahydrofuran
  • DMF N,N-dimethylformamide
  • DIPEA N,N-diisopropylethylamine
  • HATU CAS 148893-10-1
  • Triethylamine (53.93g, 532.72mmol) was added to (2S)-2-aminopropan-1-ol (1a”) (10.00g, 133.18mmol) and phthalic anhydride (19.73g, 133.18mmol).
  • Dissolve 1b (14.70g, 87.03mmol,) and imidazole (23.70g, 348.12mmol) in DMF (50mL), slowly add tert-butyldiphenylsilyl chloride (29.90g, 108.79mmol) dropwise, and react at room temperature overnight.
  • Dissolve 1e (1.62g, 3.01mmol) in dichloromethane (20mL), add trifluoroacetic acid (20mL), and react at room temperature for 2h. Concentrate under reduced pressure. Dissolve in dichloromethane (20mL x 2) and concentrate under reduced pressure to obtain the crude product of 1f trifluoroacetate.
  • Extract with ethyl acetate 50mL x 3
  • Dissolve 1j (45 mg, 0.07 mmol) in trifluoroacetic acid (2 mL), add trifluoromethanesulfonic acid (0.2 mL), and react at room temperature for 1 h.
  • Preparation method Dissolve the crude product in DMF and filter it with a 0.45 ⁇ m filter membrane to prepare a sample solution.
  • Compound 1 was purified by SFC on ID column (instrument and preparation column: Waters 150SFC was used, and the preparation column model was: Chiralcel OJ-Column (250*30mm, ID 30mm, 10um particle size).
  • Preparation method Dissolve compound 3 with methanol, and use Filter through a 0.45 ⁇ m filter membrane to prepare a sample solution.
  • Mobile phase system A for CO 2 and B for MeOH (0.1% NH3 ⁇ H2O).
  • Gradient elution method 30% B iso-gradient elution (flow rate: 100mL/min; Elution time: 1.6 min), and compound 2-1 and compound 2-2 were obtained after lyophilization.
  • Trifluoroacetic acid (4 mL) was added to a solution of 3d (1.25 g, 2.38 mmol) in DCM (4 mL), and the reaction was stirred at room temperature for 2 h. Concentrate under reduced pressure to obtain crude trifluoroacetate salt (1.2g) of 3e.
  • Compound 3 was purified by SFC on ID column (instrument and preparation column: Waters 150SFC was used, and the preparation column model was: Chiralcel Column (250*30mm, ID 30mm, 10um particle size).
  • Preparation method Compound 3 was dissolved in methanol, and used with 0.45 ⁇ m Filter through the membrane 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 20% B iso-gradient elution (flow rate: 110mL/min ; elution time 2.5 min), and compound 4-1 and compound 4-2 were obtained after lyophilization.
  • Compound 5 was purified by SFC on OJ column (instrument and preparation column: Waters 150SFC was used, and the preparation column model was: Chiralcel OJ Column (250*30mm, ID 30mm, 10um particle size).
  • Preparation method Compound 5 was dissolved in methanol and mixed with 0.45 Filter through a ⁇ m filter membrane and 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% B iso-gradient elution (flow rate: 100mL/ min; elution time 2 min), compound 6-1 and compound 6-2 were obtained after lyophilization.
  • Preparation method Filter the reaction solution with a 0.45 ⁇ m filter membrane to prepare a sample solution.
  • Mobile phase system acetonitrile/water (containing 0.05% ammonia).
  • Gradient elution method acetonitrile gradient elution from 5% to 50% (elution time 15 minutes). After lyophilization, compound 7-A (6 mg, 5%) and compound 7-B (8 mg, 7%) were obtained.
  • Analytical method (instrument: Shimadzu high performance liquid chromatography (instrument model: LC-20AT) – reversed-phase chromatography; brand and model of preparative column: Yuexu (Xtimate C18 4.6*50mm, 3 ⁇ m); mobile phase system: mobile phase A is 0.05% TFA solution, mobile phase B is acetonitrile; flow rate: 1.0 mL/min.
  • Compound 7-B (58mg) was purified by SFC on ID column (instrument and preparation column: Waters 150SFC was used, and the preparation column model was: Chiralcel OJ-Column (250*30mm, ID 30mm, 10um particle size).
  • Preparation method Compound 7- Dissolve B in methanol and filter it with a 0.45 ⁇ m filter membrane 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% B isotropic gradient Elution (flow rate: 100 mL/min; elution time 4.5 min), and compound 8-A (26 mg) and compound 8-B (20 mg) were obtained after lyophilization.
  • Triethylamine (1.52g, 15.04mmol) was added to a solution of 9b (1.40g, crude product) in ethanol (15mL), and the reaction was carried out at 90°C for 16h. After cooling to room temperature, it was concentrated under reduced pressure to obtain 9f (1.20 g, crude product).
  • Potassium carbonate (2.10g, 15.24mmol) was added to the solution of 9d hydrochloride (1.00g, crude product) and 2,5-dichloropyrimidine (0.68g, 4.57mmol) in dimethyl sulfoxide (10mL). React at 90°C for 2 hours. Cool to room temperature, add water (20ml) to quench the reaction, extract with ethyl acetate (30mlx3), and combine the organic phases.
  • Trifluoromethanesulfonic acid 105 mg, 0.70 mmol was added to a solution of compound 9n (100 mg, 0.16 mmol) in trifluoroacetic acid (2 mL), and the reaction was carried out at room temperature for 1 h. Concentrate under reduced pressure, and add ethyl acetate (20 mL) to dilute the crude product. The pH of the mixture was adjusted to 8-9 with saturated sodium carbonate solution. Extract with ethyl acetate (20mL ) to obtain compound 9 (45 mg, 55%).
  • Compound 9 is one of the structures of compound 9-1 and compound 9-2.
  • Example 10 Preparation of compound 10p and its stereoisomers (compound 10-a, compound 10-b, compound 10-c, compound 10-d)
  • Dissolve 10b (33.00g, 94.18mmol) in dichloromethane (600mL), add Dess-Martin oxidant (41.94g, 98.89mmol) at 0°C, and react at 0°C for 2 hours.
  • Dess-Martin oxidant 41.94g, 98.89mmol
  • Slowly add saturated sodium bicarbonate aqueous solution 200 mL to quench the reaction, let stand and separate layers to obtain an organic phase.
  • Concentrate under reduced pressure, and the crude product is slurried with a mixed solution of water (500 mL) and ethyl acetate (500 mL) and filtered.
  • Trifluoroacetic acid (10 ml) was added to a solution of 10f (1.50 g, 4.80 mmol) in dichloromethane (20 mL), and the reaction was carried out at room temperature for 3 h. Concentrate under reduced pressure to obtain 10g of trifluoroacetate (1.50g, crude product).
  • trifluoromethanesulfonic acid 594 mg, 3.95 mmol was added to the 10 h (740 mg, 1.13 mmol) trifluoroacetic acid (10 mL) solution, and the reaction was carried out at 0° C. for 1 hour.
  • Concentrate under reduced pressure add ethyl acetate (20mL) and water (10mL) to dissolve the crude product, add saturated sodium carbonate solution to adjust the pH to 8-9, and extract with ethyl acetate (20mL x 3).
  • Step 13 Preparation of compound 10-a, compound 10-b, compound 10-c, and compound 10-d
  • Compound 10p was purified by SFC on AD column (instrument and preparation column: Waters 150SFC was used, and the preparation column model was: Chiralpak AD Column (250*30mm, ID 30mm, 10um particle size).
  • Preparation method Compound 10p was dissolved in methanol and mixed with 0.45 Filter through a ⁇ m filter membrane and prepare a sample solution.
  • Mobile phase system A for CO 2 and B for etoh.
  • Gradient elution method 35%
  • B iso-gradient elution (flow rate: 100ml/min; elution time 4.5min; column temperature : 25°C; column pressure: 100bar, absorption wavelength: 220nm) to obtain compound 10-P1, compound 10-P2 and compound 10-P3, of which compound 10-P3 is a mixture of two configurations.
  • Compound 10-P3 was purified by SFC on OJ column (instrument and preparation column: Waters 150SFC was used, and the preparation column model was: Chiralcel OJ-Column (250*30mm, ID 30mm, 10um particle size)).
  • Preparation method Compound 10-P3 was dissolved in methanol and filtered with a 0.45 ⁇ m filter membrane to prepare a sample solution.
  • Mobile phase system A for CO 2 and B for EtOH (0.1% NH 3 ⁇ H 2 O).
  • Potassium carbonate (2.19g, 15.84mmol) was added to a solution of 9g hydrochloride (1.04g, crude product) and 2-chloro, 5-cyclopropylpyrimidine (730mg, 4.75mmol) in dimethyl sulfoxide (10ml). Medium, react at 90°C for 16 hours. Cool to room temperature, add water (20 mL) to quench the reaction, extract with ethyl acetate (30 mLx3), and combine the organic phases.
  • Compound 11c-1 is compound 11c.
  • Compound 11 is one of the structures of compound 11-1 and compound 11-2.
  • Diethyl malonate (9.19g, 57.35mmol) was dissolved in anhydrous tetrahydrofuran solution (100mL). After nitrogen replacement, sodium hydride (2.29g, 57.35mmol, 60%Wt) was added in batches at 0°C. React at 0°C for 20 minutes, slowly add 12d (5.60g, 11.47mmol) anhydrous tetrahydrofuran (50mL) solution dropwise, and react at room temperature for 16h.
  • Dissolve 12f (5.10g, 10.35mmol) in methanol solution (100mL), add ammonia water (0.3mL, content: 25%-28%) and palladium carbon (510mg, 10%) to it respectively, and replace it with hydrogen three times. React at room temperature for 16 hours. Filter through diatomaceous earth, and the filtrate is concentrated under reduced pressure to obtain 12g) (3.71g, crude product).
  • Extract with ethyl acetate 50mL x 3
  • combine the organic phases dry the organic phases over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain
  • Trifluoromethanesulfonic acid (340 mg, 2.27 mmol) was added to a solution of compound 12n (220 mg, 0.32 mmol) in trifluoroacetic acid (2 mL), and the reaction was carried out at room temperature for 1 h. Concentrate under reduced pressure, add water (4 mL) to quench the reaction, and adjust the pH to 7-9 with ammonia water. After concentration under reduced pressure, it is purified by Pre-HPLC (instrument and preparation column: SHIMADZU LC-20AP is used to prepare the liquid phase.
  • Preparation method Dissolve the crude product in acetonitrile and water, filter with a 0.45 ⁇ m filter membrane, and prepare a sample solution.
  • Mobile phase system acetonitrile/water (containing 10Mm ammonium carbonate).
  • Gradient elution method acetonitrile gradient elution from 32% to 62% (elution time 15 minutes). Compound 12 was obtained after lyophilization.
  • Compound 12 was purified by SFC on AD column (instrument and preparation column: Waters 150SFC was used, and the preparation column model was Chiralpak IG Column (250*30mm, ID 30mm, 10um particle size).
  • Preparation method Compound 12 was dissolved in acetonitrile, and 0.45 ⁇ m Filter through the membrane to prepare a sample solution.
  • Mobile phase system A for CO 2 and B for EtOH+ACN (0.1% NH 3 ⁇ H 2 O).
  • Gradient elution method 50% phase B (flow rate: 100mL/min; Elution time: 2.8 min) to obtain compound 12-Peak-1 and compound 12-Peak-2.
  • Compound 14 was obtained using 14a as the starting material by referring to the synthetic method of compound 9.
  • Compound 14 is one of the structures of compound 14-1 and compound 14-2.
  • Compound 15 was obtained using 15b as the substrate by referring to the synthetic method of compound 9.
  • Compound 15 is one of the structures of compound 15-1 and compound 15-2.
  • 16a (438 mg, crude product) was dissolved in 4N dioxane hydrochloride (10 mL) and reacted at room temperature for 2 h. Concentrate under reduced pressure to obtain 16b hydrochloride (339 mg, crude product).
  • the trifluoroacetate of compound 16 was obtained by using the hydrochloride of 16b as the substrate and referring to the synthesis method of compound 9.
  • Compound 16 is one of the structures of compound 16-1 and compound 16-2.
  • Compound 17 was obtained using 17a as a substrate by referring to the synthetic method of compound 9.
  • Compound 17 is one of the structures of compound 17-1 and compound 17-2.
  • Compound 18 was obtained using 18a as the substrate by referring to the synthetic method of compound 9.
  • Compound 18 is a combination of compound 18-1 and One of the structures of Object 18-2
  • Compound 19 was obtained using 19a as a substrate by referring to the synthetic method of compound 9.
  • Compound 19 is one of the structures of compound 19-1 and compound 19-2.
  • Compound 20 was obtained using 20c as a substrate by referring to the synthetic method of compound 9.
  • Compound 20 is one of the structures of compound 20-1 and compound 20-2.
  • Compound 21 was obtained using 21a as the substrate by referring to the synthetic method of compound 9.
  • Compound 21 is one of the structures of compound 21-1 and compound 21-2.
  • N-bromosuccinimide (2.81g, 15.82mmol) was added in batches to a solution of 22a (2.15g, 13.18mmol) in acetonitrile (20mL), and the reaction was carried out at room temperature for 16h. Concentrate under reduced pressure to obtain 22b (3.10 g, crude product).
  • Compound 22 was obtained using 22d as the substrate by referring to the synthetic method of compound 16.
  • Compound 22 is one of the structures of compound 22-1 and compound 22-2.
  • Compound 23 was obtained using 23c as a substrate by referring to the synthetic method of compound 16.
  • Compound 23 is one of the structures of compound 23-1 and compound 23-2.
  • Compound 24 was obtained by using 9 g of hydrochloride and 3-chloro-6-trifluoromethylpyridazine as substrates by referring to the synthetic method of compound 9.
  • Compound 24 is one of the structures of compound 24-1 and compound 24-2.
  • Compound 25 was obtained using 2-chloro-5-fluoropyrimidine as a substrate by referring to the synthetic method of compound 9.
  • Compound 25 is one of the structures of compound 25-1 and compound 25-2.
  • Compound 26 was obtained using 2,6-dichlorobenzothiazole as a substrate and referring to the synthetic method of compound 9.
  • Compound 26 is one of the structures of compound 26-1 and compound 26-2.
  • N,N-dimethylformamide dimethyl acetal (1086 mg, 9.11 mmol) was added to a solution of 27b (2.72 g, 7.01 mmol) in toluene (20 mL), and the reaction was carried out at 120°C overnight. Cool to room temperature and concentrate under reduced pressure to obtain 27c (3.20 g, crude product).
  • Compound 27 was obtained using 27d as the substrate by referring to the synthetic method of compound 9.
  • Compound 27 is one of the structures of compound 27-1 and compound 27-2.
  • N-Chlorosuccinimide (1.31g, 9.80mmol) was added to a solution of 28b (3.15g, 8.17mmol) in DMF (30mL), and the reaction was carried out at room temperature for 16h.
  • Add saturated aqueous sodium bicarbonate solution (100mL) to quench the reaction, and extract with ethyl acetate (20mL x 2).
  • the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered.
  • Compound 28 was obtained using 28c as a substrate by referring to the synthetic method of compound 9.
  • Compound 28 is one of the structures of compound 28-1 and compound 28-2.
  • methylene chloride containing 9% methanol
  • petroleum ether containing 16% ethyl acetate
  • 29c-1 is 29c
  • Compound 29 was obtained using 29c as a substrate by referring to the synthetic method of compound 16.
  • Compound 29 is one of the structures of compound 29-1 and compound 29-2.
  • Ethyl isothiocyanatoformate 14.47g, 110.36mmol was added to the solution of 30a (15.00g, 91.97mmol) in 1,4-dioxane (150mL), and the reaction was carried out at 35°C for 72h.
  • Compound 30 was obtained using 30e as the substrate by referring to the synthetic method of compound 16.
  • Compound 30 is one of the structures of compound 30-1 and compound 30-2.
  • 31c-1 is 31c
  • Compound 31 was obtained using 31c as the substrate by referring to the synthetic method of compound 16.
  • Compound 31 is a combination of compound 31-1 and One of the structures of Object 31-2
  • Compound 32e-1 is compound 32e
  • Triethylamine (154 mg, 1.52 mmol) was added to a solution of intermediate 1 (145 mg, 0.46 mmol) and 32 g (160 mg, crude product) in acetonitrile (4 mL), and the reaction was carried out at room temperature for 16 h.
  • Compound 33 was obtained using 33a as a substrate by referring to the synthetic method of compound 32.
  • Compound 33 is a combination of compound 33-1 and compound 33-1.
  • Compound 34e-1 is compound 34e
  • Triethylamine (73 mg, 0.72 mmol) was added to a solution of intermediate 1 (86 mg, 0.27 mmol) and 34 g (110 mg, crude product) in acetonitrile (10 mL), and the reaction was carried out at room temperature for 16 h.
  • 35G-1 is 35G.
  • Compound 35 was obtained using 35G as the substrate by referring to the synthetic method of compound 16.
  • Compound 35 is one of the structures of compound 35-1 and compound 35-2.
  • Compound 36 was obtained using 36A as a substrate by referring to the synthetic method of compound 32.
  • Compound 36 is one of the structures of compound 36-1 and compound 36-2.
  • Compound 37 was obtained by using compound 34e-2 as the starting material and referring to the synthesis method of compound 34.
  • the retention time T 39.932 min is compound 37, and compound 37 is one of the structures of compound 34-1 and compound 34-2.
  • Compound 38 was obtained using compound 32e-2 as the substrate and referring to the synthesis method of compound 32.
  • the retention time T 42.395 min is compound 38, and compound 38 is one of the structures of compound 32-1 and compound 32-2.
  • 39b (diastereomer 1) H on C2 ( ⁇ 2.71–2.53) on ring A and H 1 on C4 ( ⁇ 1.72-1.60) have obvious 1 H- 1 H NOESY signals (deuterated solvent is CD 3 COOD, 1 H- 1 H COSY (see Figure 1, 1 H- 1 H NOESY (see Figure 2)), prove that the configuration of 39b is as follows:
  • NCI-H1373 cells were purchased from ATCC, culture conditions: RPMI-1640+10% FBS+1% double antibody, cultured at 37°C, 5% CO2 incubator. On the first day, NCI-H1373 cells in the exponential growth phase were collected and plated into a transparent-bottomed white 96-well culture plate at a plating density of 500 cells/well. They were cultured overnight in a 37°C, 5% CO 2 incubator, and T 0 wells were plated at the same time.
  • the compounds of the present invention such as the example compounds, have good cell proliferation inhibitory activity on NCI-H1373 cells.
  • the inhibitory activity of some compounds on NCI-H1373 cell proliferation is shown in Table 1.
  • Test animals Male Balb/c mice, about 22g, 6 to 8 weeks old, 6 mice/compound. Purchased from Chengdu Dashuo Experimental Animal Co., Ltd.
  • mice were randomly divided into groups according to body weight. 1 day before administration, fast and drink for 12 to 14 hours. Give food 4 hours after taking the medicine.
  • Intravenous administration vehicle 5% DMA+5% Solutol+90% Saline; gastric administration vehicle: 0.5% MC
  • the compounds of the present invention have good pharmacokinetic properties. Specifically, compound 8-B, compound 9, compound 31 and compound 34 have high exposure in mice and good bioavailability. Spend.
  • mice male beagle dogs, about 8 to 11 kg, 6/compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.
  • Test method On the day of the test, the beagle dogs were randomly divided into groups according to their weight. No food and water for 12 to 14 hours one day before administration, and food 4 hours after administration.
  • Intravenous administration vehicle 5% DMA+5% Solutol+90% Saline; gastric administration vehicle: 0.5% MC
  • Sampling Take 1ml of blood from the veins of the limbs before and after administration, and place it in an EDTAK2 centrifuge tube. Centrifuge at 5000 rpm and 4°C for 10 min to collect plasma.
  • the compounds of the present invention have good pharmacokinetic properties. Specifically, compound 34 has good PK performance in beagle dogs.
  • the purpose of this study is to apply an in vitro test system to evaluate the effect of test substances on the activity of five isoenzymes of human liver microsomal cytochrome P450 (CYP) (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4).
  • CYP human liver microsomal cytochrome P450
  • the specific probe substrates of CYP450 isoenzymes were incubated with human liver microsomes and test substances of different concentrations, and reduced nicotinamide adenine dinucleotide phosphate (NADPH) was added to start the reaction.
  • NADPH nicotinamide adenine dinucleotide phosphate
  • the compounds of the present invention have poor inhibitory activity on CYP enzymes. Specifically, the IC50 values of compound 8-B against CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 are all greater than 50 ⁇ M.
  • Cell line Chinese hamster ovary (CHO) cell line stably expressing hERG potassium channel
  • CHO (Chinese Hamster Ovary) cells stably expressing hERG potassium channels were used to record hERG potassium channel currents at room temperature using whole-cell patch clamp technology.
  • the glass microelectrode is drawn from a glass electrode blank (BF150-86-10, Sutter) by a drawing instrument.
  • the tip resistance after infusion of the electrode liquid is about 2-5M ⁇ .
  • the glass microelectrode can be connected by inserting it into the amplifier probe. to the patch clamp amplifier. Clamping voltage and data recording were controlled and recorded via computer by pClamp 10 software, with a sampling frequency of 10kHz and a filtering frequency of 2kHz.
  • the cells were clamped at -80mV, and the step voltage of induced hERG potassium current (I hERG) was given a 2s depolarization voltage from -80mV to +20mV, and then repolarization to -50mV for 1s. then returns to -80mV.
  • This voltage stimulation was given every 10 s, and the administration process was started after confirming that the hERG potassium current was stable (at least 1 minute).
  • Compounds were administered for at least 1 min at each concentration tested, and at least 2 cells were tested at each concentration (n ⁇ 2).
  • Inhibition% represents the inhibition percentage of the hERG potassium current by the compound
  • I and Io represent the amplitude of the hERG potassium current after and before the addition of the drug, respectively.
  • X is the Log value of the detected concentration of the test product
  • Y is the inhibition percentage at the corresponding concentration
  • Bottom and Top are the minimum and maximum inhibition percentages respectively.
  • the compounds of the present invention have poor inhibitory activity on hERG. Specifically, the IC 50 of compounds 31 and 34 on the inhibitory effect of hERG potassium channel current is greater than 20 ⁇ M.
  • PARP7 chemical fluorescence detection kit was purchased from BPS Bioscience. Dilute the histone solution in the kit 5 times with 1X PBS, add 25 ⁇ L of the histone dilution solution to the microplate, and incubate at 4°C overnight. After the incubation, wash the plate three times with PBST (0.05% Tween-20), add 100 ⁇ L of blocking solution to the microwell plate, and incubate at 25°C for 90 minutes; after the incubation, wash the plate three times with PBST.
  • PBST 0.05% Tween-20
  • the compounds of the present invention such as the example compounds, have inhibitory effects on PARP7 enzyme.
  • NCI-H1373 cells were purchased from ATCC, culture conditions: RPMI-1640+10% FBS+1% double antibody, cultured at 37°C, 5% CO2 incubator.
  • NCI-H1373 cells in the exponential growth phase were collected and plated into a transparent-bottomed white 6-well culture plate at a plating density of 2 ⁇ 10 5 cells/well, and cultured overnight in a 37°C, 5% CO 2 incubator.
  • aspirate the culture medium add 1 mL of fresh culture medium and 1 mL of compounds of different concentrations to each well so that the final DMSO concentration in each well is 0.1%, and incubate in a 37°C, 5% CO2 incubator for 48 hours. .
  • cells are collected. Add 35 ⁇ L of cell lysis solution to each tube, lyse on ice for 15 minutes, vortex during the period; centrifuge at 4°C, 13,000 rpm for 10 minutes, and take the supernatant and store it at low temperature.
  • BCA detection kit (Beyotime, P0009) was used for protein quantification and the sample protein concentration was calculated. Dilute the protein concentration of each tube of sample to 0.8 mg/mL with 0.1 ⁇ sample buffer, take 4 ⁇ L of diluent and 1 ⁇ L of 5 ⁇ mix, mix well, and place at 95°C for 5 minutes for protein denaturation.
  • the compounds of the present invention have inhibitory effects on MARylation in NCI-H1373 cells. Specifically, the inhibitory activity of compound 8-B on MARylation in NCI-H1373 cells is better than that of the control RBN-2397.
  • This experiment uses human liver microsomes as an in vitro model to evaluate the metabolic stability of the test substance.
  • LC-MS/ The MS method detects the concentration of the test substance in the sample, calculates T 1/2 based on the ln value of the remaining rate of the drug in the incubation system and the incubation time, and further calculates the hepatic intrinsic clearance rate of liver microsomes CL int(Liver) .
  • the compounds of the present invention such as the example compounds, have good metabolic stability in human liver microsomes.

Abstract

The present invention relates to a compound as represented by general formula (A) or a stereoisomer, a deuterated substance, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or a cocrystal thereof, an intermediate thereof, a preparation method therefor, and the use thereof in the preparation of a drug for treating diseases related to PARP7 activity or expression quantity.

Description

一种吡嗪酮衍生物及其在医药上的应用A kind of pyrazinone 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 described in general formula (I) or its stereoisomers, deuterated products, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals, as well as intermediates and preparation methods thereof , and its application in the preparation of drugs for the treatment of diseases related to PARP7 activity or expression.
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。PARP stands for poly-ADP-ribose polymerase, which is poly-ADP ribose polymerase. It participates in a series of cellular processes including DNA repair, genome stability, etc. This protein family consists of 17 members, divided into polyPARPs and monoPARPs. The MonoPARP protein family plays a role in multiple stress responses associated with the development of cancer, inflammatory diseases, and neurodegenerative diseases. 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。Studies have found that many cancer cells rely on PARP7 for intrinsic cell survival, and PARP7 allows cancer cells to "hide" from the immune system. Inhibiting PARP7 can effectively inhibit the growth of cancer cells and restore interferon signaling, effectively releasing the "brakes" that cancer uses to evade the immune system and suppress innate and adaptive immune mechanisms. In several cancer models, PARP7 inhibitors have demonstrated durable tumor growth inhibition, potent antiproliferative activity, and restoration of interferon signaling. PARP7 inhibitors are expected to become targets for the development of new anticancer drugs.
发明内容Contents 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 purpose of the present invention is to provide a class of heterocyclic compounds or pharmaceutically acceptable salts thereof, which can be used as PARP7 inhibitors. The compounds of 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(A)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 described in general formula (A) or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein
在一些实施方案中，W选自键、C(＝O)；In some embodiments, W is selected from bond, C(=O);
在一些实施方案中，W选自键；In some embodiments, W is selected from bonds;
在一些实施方案中，W选自C(＝O)；In some embodiments, W is selected from C(=O);
在一些实施方案中，通式(A)化合物选自通式(I)化合物, In some embodiments, compounds of Formula (A) are selected from compounds of Formula (I),
在一些实施方案中，通式(I)化合物选自通式(II)化合物, In some embodiments, compounds of Formula (I) are selected from compounds of Formula (II),
在一些实施方案中，选自 In some embodiments, Selected from
在一些实施方案中，选自 In some embodiments, Selected from
在一些实施方案中，选自 In some embodiments, Selected from
在一些实施方案中，环B选自 为单键或者双键；In some embodiments, Ring B is selected from Is a single bond or a double bond;
在一些实施方案中，选自 In some embodiments, Selected from
在一些实施方案中，选自 In some embodiments, Selected from
在一些实施方案中，Z选自N、C或CH；In some embodiments, Z is selected from N, C, or CH;
在一些实施方案中，Y选自键、-O-、-S-、-S(＝O)-、-S(＝O)2-、-S(＝O)2N(Ry)-、-N(Ry)-、C1-4亚烷基、-OC1-3亚烷基-、-C1-3亚烷基O-、-C1-2亚烷基O-C1-2亚烷基、-C1-3亚烷基S-、-C1-3亚烷 基S(＝O)-、-C1-3亚烷基S(＝O)2-、-N(Ry)C1-3亚烷基-、-C1-3亚烷基N(Ry)-、-C1-2亚烷基N(Ry)-C1-2亚烷基，所述的亚烷基任选被1至4个选自卤素、＝O、＝S、OH、氰基、C1-6烷基、卤素取代的C1-6烷基、C1-6烷氧基、C3-6环烷基的取代基所取代；In some embodiments, Y is selected from the group consisting of bonds, -O-, -S-, -S(=O)-, -S(=O) 2- , -S(=O) 2N ( Ry )-, -N(R y )-, C 1-4 alkylene, -OC 1-3 alkylene-, -C 1-3 alkylene O-, -C 1-2 alkylene OC 1-2 Alkyl, -C 1-3 alkylene S-, -C 1-3 alkylene Group S(=O)-, -C 1-3 alkylene S(=O) 2 -, -N(R y )C 1-3 alkylene-, -C 1-3 alkylene N(R y )-, -C 1-2 alkylene N(R y )-C 1-2 alkylene, the alkylene group is optionally 1 to 4 selected from halogen, =O, =S, OH , cyano group, C 1-6 alkyl, halogen-substituted C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl substituents;
在一些实施方案中，Y选自键、-O-、-N(Ry)-、C1-3亚烷基、-OC1-2亚烷基-、-C1-2亚烷基O-、-C1-2亚烷基O-C1-2亚烷基、-C1-2亚烷基S-、-C1-2亚烷基S(＝O)2-、-N(Ry)C1-2亚烷基-、-C1-2亚烷基N(Ry)-、-C1-2亚烷基N(Ry)-C1-2亚烷基，所述的亚烷基任选被1至4个选自卤素、＝O、＝S、OH、氰基、C1-4烷基、卤素取代的C1-4烷基、C1-4烷氧基、C3-6环烷基的取代基所取代；In some embodiments, Y is selected from bond, -O-, -N(R y )-, C 1-3 alkylene, -OC 1-2 alkylene-, -C 1-2 alkylene O -, -C 1-2 alkylene OC 1-2 alkylene, -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 )-, -C 1-2 alkylene N(R y )-C 1-2 alkylene, the The alkylene group is optionally substituted by 1 to 4 C 1-4 alkyl groups selected from halogen, =O, =S, OH, cyano, C 1-4 alkyl, halogen, C 1-4 alkoxy , Substituted with C 3-6 cycloalkyl substituent;
在一些实施方案中，Y选自键、-O-、-N(Ry)-、-N(Ry)C(＝O)-、-C(＝O)N(Ry)-、-CH2-、-CH2CH2-、-CH2CH2CH2-、-OCH2-、-OCH2CH2-、-CH2O-、-CH2CH2O-、-CH2OCH2-、-CH2S-、-CH2CH2S-、-CH2S(＝O)2-、-CH2CH2S(＝O)2-、-N(Ry)CH2-、-N(Ry)CH2CH2-、-CH2N(Ry)-、-CH2CH2N(Ry)-、-N(Ry)C(＝O)CH2-、-CH2C(＝O)N(Ry)-，所述CH2任选被0至2个选自H、＝O、＝S、OH、氰基、C1-4烷基、卤素取代的C1-4烷基、C1-4烷氧基、C3-6环烷基的取代基所取代；In some embodiments, Y is selected from the group consisting of bonds, -O-, -N(R y )-, -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 OCH 2 -, -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 is optionally substituted by 0 to 2 selected from H, =O, =S, OH, cyano, C 1-4 alkyl, halogen Substituted with substituents of C 1-4 alkyl, C 1-4 alkoxy and C 3-6 cycloalkyl;
在一些实施方案中，Y选自键、-O-、-NHC(＝O)-、-C(＝O)NH-、-CH2-、-CH2CH2-、-CH2CH2CH2-、-OCH2-、-OCH2CH2-、-CH2O-、-CH2CH2O-、-NHCH2-、-NHCH2CH2-、-CH2NH-、-CH2CH2NH-、-NHC(＝O)CH2-、-CH2C(＝O)NH-、-N(CH3)C(＝O)-、-C(＝O)N(CH3)-、-CH2C(＝O)NH-、-CH2C(＝O)N(CH3)-、-N(CH2CH3)C(＝O)-、-N(CH(CH3)2)C(＝O)-、-N(CH2CH(CH3)2)C(＝O)-、-N(环丙基)C(＝O)-、-N(CH2-环丙基)C(＝O)-、-C(＝O)N(CH2CH3)-、-C(＝O)N(CH(CH3)2)-、-C(＝O)N(CH2CH(CH3)2)-、-C(＝O)N(环丙基)-、-C(＝O)N(CH2-环丙基)-、-C(＝O)N(CD3)-、-C(＝O)N(CH2-氧杂环丁基)-、-C(＝O)N(CH2-氧杂环戊基)-、-C(＝O)N(CH2-氮杂环丁基)-、-C(＝O)N(CH2-吡咯烷基)-、-C(＝O)N(CH2-环戊基)-、-C(＝O)N(CH2CH2CH3)-、-C(＝O)N(CH2CH(CH2CH3)2)-、-C(＝O)N(CH2CH2CH2CH3)-、-C(＝O)N(CH2CH2CH(CH3)2)-、-C(＝O)N(CH2CH(CH3)CH2CH3)-、-C(＝O)N(正辛基)-、-C(＝S)N(CH3)-、-C(＝S)N(CH2CH3)-、-C(＝S)N(CH2-环丙基)-、-CH2S(＝O)2-；In some embodiments, Y is selected from the group consisting of bonds, -O-, -NHC(=O)-, -C(=O)NH-, -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-, -NHCH 2 -, -NHCH 2 CH 2 -, -CH 2 NH-, -CH 2 CH 2 NH-, -NHC(=O)CH 2 -, -CH 2 C(=O)NH-, -N(CH 3 )C(=O)-, -C(=O)N(CH 3 ) -, -CH 2 C(=O)NH-, -CH 2 C(=O)N(CH 3 )-, -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 -ring Propyl)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)-, -C(=O)N( CD 3 )-, -C(=O)N(CH 2 -oxetanyl)-, -C(=O)N(CH 2 -oxetanyl)-, -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 -ring propyl)-, -CH 2 S(＝O) 2 -;
在一些实施方案中，Ry各自独立的选自H、C1-6烷基或C3-6环烷基，所述的烷基或环烷基任选被1至4个选自氘、卤素、CF3、OH、氰基、NH2、C1-6烷基、C1-6烷氧基、3至8元杂环基或C3-6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 is each independently selected from H, C 1-6 alkyl or C 3-6 cycloalkyl, and the alkyl or cycloalkyl is optionally substituted by 1 to 4 selected from deuterium, Substituted with 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, so The above-mentioned heterocyclic group contains 1 to 3 heteroatoms selected from O, S, and N;
在一些实施方案中，Ry各自独立的选自H、C1-4烷基或C3-6环烷基，所述的烷基或环烷基任选被1至4个选自氘、卤素、CF3、OH、氰基、NH2、C1-4烷基、C1-4烷氧基、3至8元杂环基或C3-6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 y is independently selected from H, C 1-4 alkyl or C 3-6 cycloalkyl, and the alkyl or cycloalkyl is optionally substituted by 1 to 4 selected from deuterium, Substituted with 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, so The above-mentioned heterocyclic group contains 1 to 3 heteroatoms selected from O, S, and N;
在一些实施方案中，Ry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、环己基任选被1至4个选自氘、卤素、CF3、OH、氰基、NH2、C1-4烷基、C1-4烷氧基、3至8元杂环基或C3-6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 y 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 substituted by 1 to 4 members selected from deuterium, halogen, CF 3 , OH, cyano, NH 2 , C 1-4 alkyl, C 1-4 alkoxy, 3 to 8 membered heterocyclyl or Substituted with a substituent of C 3-6 cycloalkyl, the heterocyclic group contains 1 to 3 heteroatoms selected from O, S, and N;
在一些实施方案中，Rb各自独立的选自H、卤素、氰基、OH、＝O、C1-6烷基、C1-6烷氧基、-(CH2)q-C3-6环烷基，所述的-CH2-、烷基、烷氧基或环烷基任选被1至4个选自卤素、OH、氰基、 NH2、C1-6烷基、卤素取代的C1-6烷基、C1-6烷氧基或C3-6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, the -CH 2 -, alkyl, alkoxy or cycloalkyl is optionally substituted by 1 to 4 selected from halogen, OH, cyano, Substituted by NH 2 , C 1-6 alkyl, halogen-substituted C 1-6 alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl substituents;
在一些实施方案中，Rb各自独立的选自H、卤素、氰基、OH、＝O、C1-4烷基、C1-4烷氧基、-(CH2)q-C3-6环烷基，所述的-CH2-、烷基、烷氧基或环烷基任选被1至4个选自卤素、OH、氰基、NH2、C1-4烷基、卤素取代的C1-4烷基、C1-4烷氧基或C3-6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, the -CH 2 -, alkyl, alkoxy or cycloalkyl is optionally substituted by 1 to 4 selected from halogen, OH, cyano, NH 2 , C 1-4 alkyl, halogen Substituted by substituted C 1-4 alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl substituents;
在一些实施方案中，Rb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、丙基或异丙基任选被1至4个选自卤素、OH、氰基、NH2、C1-4烷基、卤素取代的C1-4烷基、C1-4烷氧基或C3-6环烷基的取代基所取代；In some embodiments, R b is each independently selected from H, F, Cl, Br, I, cyano, OH, =O, methyl, ethyl, propyl or isopropyl, and the methyl, Ethyl, propyl or isopropyl is optionally substituted by 1 to 4 C 1-4 alkyl, C 1-4 alkyl selected from halogen, OH, cyano, NH 2 , C 1-4 alkyl, halogen Substituted with oxygen or C 3-6 cycloalkyl substituents;
在一些实施方案中，Rb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，环A选自C6-10芳环、5-10元杂芳环或5-10元杂环，所述的杂芳环或者杂环含有1至5个选自O、S、N的杂原子；在一些实施方案中，环X选自C6-10芳环、5-10元杂芳环、C3-10碳环或5-10元杂环，所述的杂芳环或者杂环含有1至5个选自O、S、N的杂原子；In some embodiments, Ring A is selected from a C 6-10 aromatic ring, a 5-10 membered heteroaromatic ring or a 5-10 membered heterocyclic ring, and the heteroaromatic ring or heterocyclic ring contains 1 to 5 atoms selected from O, Heteroatoms of S and N; in some embodiments, ring The aromatic ring or heterocyclic ring contains 1 to 5 heteroatoms selected from O, S, and N;
在一些实施方案中，环X选自5-6元杂芳环、5-6元杂环、8-10元并环杂芳环或8-10元并环杂环，所述的杂芳环或杂环含有1至5个选自O、S、N的杂原子；In some embodiments, Ring Or the heterocyclic ring contains 1 to 5 heteroatoms selected from O, S, and N;
在一些实施方案中，环X选自5-6元杂芳环或5-6元杂环，所述的杂芳环或杂环含有1至5个选自O、S、N的杂原子；In some embodiments, ring
在一些实施方案中，环X选自8-10元并环杂芳环或8-10元并环杂环，所述的杂芳环或杂环含有1至5个选自O、S、N的杂原子；In some embodiments, Ring of heteroatoms;
在一些实施方案中，环X选自C3-10环烷基、4至10元杂环烷基、苯基、5-6元杂芳环、5-6元杂环、8-10元并环杂芳环或8-10元并环杂环，所述的杂环烷基、杂芳环或杂环含有1至5个选自O、S、N的杂原子；In some embodiments , Ring Cyclic heteroaromatic ring or 8-10 membered cyclic heterocyclic ring, the heterocycloalkyl group, heteroaromatic ring or heterocyclic ring contains 1 to 5 heteroatoms selected from O, S, and N;
在一些实施方案中，环X选自C3-6单环环烷基、C5-10并环环烷基、C5-11螺环环烷基、C5-11桥环环烷基、4至7元单环杂环烷基、5至10元并环杂环烷基、5至11元螺环杂环烷基、5至11元桥环杂环烷基、苯基、5-6元杂芳环、8-10元并环杂芳环，所述的杂环烷基、杂芳环或杂环含有1至5个选自O、S、N的杂原子；In some embodiments , Ring 4 to 7-membered monocyclic heterocycloalkyl, 5 to 10-membered pendant ring heterocycloalkyl, 5 to 11-membered spirocyclic heterocycloalkyl, 5 to 11-membered bridged ring heterocycloalkyl, phenyl, 5-6 1-membered heteroaromatic ring, 8-10 membered heteroaromatic ring, the heterocycloalkyl group, heteroaromatic ring or heterocyclic ring contains 1 to 5 heteroatoms selected from O, S, N;
在一些实施方案中，环X选自苯基、5-6元杂芳环、5元环并5元杂芳环、5元环并6元杂芳环，所述的杂芳环含有1至5个选自O、S、N的杂原子；In some embodiments, Ring 5 heteroatoms selected from O, S, and N;
在一些实施方案中，环X选自吡啶环、嘧啶环、吡嗪环、哒嗪环、噻吩环、噻唑环、呋喃环、噁唑环、吡咯环、吡唑环或咪唑环；In some embodiments, Ring
在一些实施方案中，环X选自三嗪环、苯并噻唑环、吡啶并噻唑环、嘧啶并噻唑环、哒嗪并噻唑环、吡嗪并噻唑环、苯并噁唑环、吡啶并噁唑环、嘧啶并噁唑环、哒嗪并噁唑环、吡嗪并噁唑环、吡啶并吡咯环、吡啶并吡唑环、嘧啶并噻吩环、嘧啶并吡唑环、嘧啶并吡咯环、嘧啶并咪唑环、嘧啶并三氮唑环、嘧啶并呋喃环、嘧啶并吡咯环、喹啉环、异喹啉环、嘧啶并吡啶环、三氮唑环、三氮唑并吡啶环()、三氮唑并噻唑环(如)、三氮唑并噁唑环、三氮唑并咪唑环、三氮唑并吡唑环、 In some embodiments, Ring Azole ring, pyrimidooxazole ring, pyridazinooxazole ring, pyrazinooxazole ring, pyridopyrrole ring, pyridopyrazole ring, pyrimidothiophene ring, pyrimidopyrazole ring, pyrimidopyrrole ring, Pyrimidoimidazole ring, pyrimidotriazole ring, pyrimidinofuran ring, pyrimidopyrrole ring, Quinoline ring, isoquinoline ring, pyrimidopyridine ring, triazole ring, triazolopyridine ring (), triazolothiazole ring (such as), triazoloxazole ring, triazolo Imidazole ring, triazolopyrazole ring,
在一些实施方案中，环X选自环丙基、环丁基、环戊基、环己基、环丁基螺环丁基、环丁基螺环戊基、环丁基螺环己基、环戊基螺环戊基、环戊基螺环己基、环己基螺环己基、环丁基螺氮杂环丁基、环丁基螺氮杂环戊基、环丁基螺氮杂环己基、环戊基螺氮杂环戊基、环戊基螺氮杂环己基、环己基氮杂螺环己基、氮杂环丁基螺氮杂环己基、氮杂环戊基螺氮杂环戊基、氮杂环戊基螺氮杂环己基、氮杂环己基氮杂螺环己基、环丁基并环丁基、环丁基并环戊基、环丁基并环己基、环戊基并环戊基、环戊基并环己基、环己基并环己基、环丁基并氮杂环丁基、环丁基并氮杂环戊基、环丁基并氮杂环己基、环戊基并氮杂环戊基、环戊基并氮杂环己基、环己基氮杂并环己基、氮杂环丁基并氮杂环己基、氮杂环戊基并氮杂环戊基、氮杂环戊基并氮杂环己基、氮杂环己基氮杂并环己基、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、三嗪环、苯并噻唑环、吡啶并噻唑环、嘧啶并噻唑环、哒嗪并噻唑环、吡嗪并噻唑环、苯并噁唑环、吡啶并噁唑环、嘧啶并噁唑环、哒嗪并噁唑环、吡嗪并噁唑环、吡啶并吡咯环、吡啶并吡唑环、嘧啶并噻吩环、嘧啶并吡唑环、嘧啶并吡咯环、嘧啶并咪唑环、嘧啶并三氮唑环、嘧啶并呋喃环、嘧啶并吡咯环、喹啉环、异喹啉环、嘧啶并吡啶环、三氮唑环、三氮唑并吡啶环、三氮唑并噻唑环、三氮唑并噁唑环、三氮唑并咪唑环、三氮唑并吡唑环、、吡啶环、嘧啶环、吡嗪环、哒嗪环、噻吩环、噻唑环、呋喃环、噁唑环、吡咯环、吡唑环或咪唑环；In some embodiments, Ring Spirocyclopentyl, cyclopentylspirocyclohexyl, cyclohexylspirocyclohexyl, cyclobutylspiroazetidinyl, cyclobutylspiroazetidinyl, cyclobutylspiroazetihexyl, cyclopentyl Azetidinylspiroazepinyl, cyclopentylspiroazepinyl, cyclohexylspiroazepinyl, azetidinylspiroazepinyl, azetidinylspiroazepinyl, azetidine Cyclopentylspiroazacyclohexyl, azepanylazaspirocyclohexyl, cyclobutylcyclobutyl, cyclobutylcyclopentyl, cyclobutylcyclohexyl, cyclopentylcyclopentyl, Cyclopentacyclohexyl, cyclohexylcyclohexyl, cyclobutylazetidinyl, cyclobutylazetidine, cyclobutylazepine, cyclopentylazetidine base, cyclopenta-azacyclohexyl, cyclohexyl-aza-cyclohexyl, azeti-a-a-zepine- Cyclohexyl, azetyl azacyclohexyl, azetidinyl, azetyl, azetyl, oxetanyl, oxetanyl, oxetanyl, triazine ring , benzothiazole ring, pyridinothiazole ring, pyrimidothiazole ring, pyridazinothiazole ring, pyrazinothiazole ring, benzoxazole ring, pyridinoxazole ring, pyrimidoxazole ring, pyridazinoxazole ring Azole ring, pyrazinooxazole ring, pyridopyrrole ring, pyridopyrazole ring, pyrimidothiophene ring, pyrimidopyrazole ring, pyrimidopyrrole ring, pyrimidoimidazole ring, pyrimidotriazole ring, pyrimidine Furan ring, pyrimidopyrrole ring, Quinoline ring, isoquinoline ring, pyrimidopyridine ring, triazole ring, triazolopyridine ring, triazolothiazole ring, triazoloxazole ring, triazoloimidazole ring, trinitrogen Azolopyrazole ring,, Pyridine ring, pyrimidine ring, pyrazine ring, pyridazine ring, thiophene ring, thiazole ring, furan ring, oxazole ring, pyrrole ring, pyrazole ring or imidazole ring;
在一些实施方案中，选自 In some embodiments, Selected from
在一些实施方案中，Rx、Ra各自独立的选自H、卤素、氰基、OH、＝O、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、-SO2-C1-6烷基、-C(＝O)C1-6烷基、-(CH2)q-C3-10碳环或-(CH2)q-3至12元杂环，所述的-CH2-、烷基、烯基、炔基、烷氧基、烷硫基、碳环或杂环任选被1至4个选自卤素、OH、氰基、＝O、NH2、NH(C1-6烷基)、N(C1-6烷基)2、C1-6烷基、卤素取代的C1-6烷基、C1-6烷氧基、C3-6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、N的杂原子；In some embodiments, 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 group, C 1-6 alkylthio group, -SO 2 -C 1-6 alkyl group, -C(=O)C 1-6 alkyl group, -(CH 2 ) q -C 3-10 Carbocyclic ring or -(CH 2 ) q -3 to 12-membered heterocyclic ring, the -CH 2 -, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, carbocyclic or heterocyclic ring is optionally 1 to 4 selected from halogen, OH, cyano, =O, NH 2 , NH (C 1-6 alkyl), N (C 1-6 alkyl) 2 , C 1-6 alkyl, halogen substituted Substituted with 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 , N heteroatoms;
在一些实施方案中，Ra选自Ra1、Ra2；In some embodiments, R a is selected from R a1 , R a2 ;
在一些实施方案中，Ra1、Ra2各自独立的选自H、卤素、氰基、OH、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、-SO2-C1-6烷基、-C(＝O)C1-6烷基、-(CH2)q-C3-10碳环或-(CH2)q-3至12元杂环，所述的-CH2-、烷基、烯基、炔基、烷氧基、烷硫基、碳环或杂环任选被1至4个选自卤素、OH、氰基、＝O、C1-6烷基、卤素取代的C1-6烷基、C1-6烷氧基、C3-6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、N的杂原子；In some embodiments, R a1 and R a2 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 group, C 1-6 alkylthio group, -SO 2 -C 1-6 alkyl group, -C(=O)C 1-6 alkyl group, -(CH 2 ) q -C 3-10 carbocyclic ring or -(CH 2 ) q -3 to 12-membered heterocyclic ring, the -CH 2 -, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, carbocyclic or heterocyclic ring is optionally replaced by 1 to 4 Each is selected from 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 Substituted with a substituent of a one-membered heterocyclic ring, the heterocyclic ring contains 1 to 3 heteroatoms selected from O, S, and N;
在一些实施方案中，Rx、Ra1、Ra2各自独立的选自H、卤素、氰基、OH、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C1-4烷硫基、-SO2-C1-4烷基、-C(＝O)C1-4烷基、-(CH2)q-C3-6碳环或-(CH2)q-3至6元杂环，所述的-CH2-、烷基、烯基、炔基、烷氧基、烷硫基、碳环或杂环任选被1至4个选自卤素、OH、氰基、＝O、C1-4烷基、卤素取代的C1-4烷基、C1-4烷氧基、C3-6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、N的杂原子；In some embodiments, R x , R a1 , and R a2 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 group, C 1-4 alkylthio group, -SO 2 -C 1-4 alkyl group, -C(=O)C 1-4 alkyl group, -(CH 2 ) q -C 3-6 Carbocyclic ring or -(CH 2 ) q -3 to 6-membered heterocyclic ring, the -CH 2 -, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, carbocyclic or heterocyclic ring is optionally 1 to 4 selected from halogen, OH, cyano, =O, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl or 3 Substituted with a substituent of a 6-membered heterocyclic ring, the heterocyclic ring contains 1 to 3 heteroatoms selected from O, S, and N;
在一些实施方案中，Rx、Ra1、Ra2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、-SCH3、-SCH2CH3、-SO2CH3、-S O2CH2CH3、-C(＝O)CH3、-C(＝O)CH2CH3、环丙基、环丁基、环戊基、环己基、双环[1.1.1]戊基、苯基、吡啶基、噻唑基、噻吩基、噁唑基、呋喃基、吡咯基、吡唑基、咪唑基，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、-SCH3、-SCH2CH3、-SO2CH3、-SO2CH2CH3、-C(＝O)CH3、-C(＝O)CH2CH3、环丙基、环丁基、环戊基、环己基、双环[1.1.1]戊基、苯基、吡啶基、噻唑基、噻吩基、噁唑基、呋喃基、吡咯基、吡唑基、咪唑基任选被1至4个选自卤素、OH、氰基、C1-4烷基、卤素取代的C1-4烷基、C1-4烷氧基、C3-6环烷基的取代基所取代；In some embodiments, R x , R a1 , and 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 , -S O 2 CH 2 CH 3 , -C(=O)CH 3 , -C(=O)CH 2 CH 3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl, phenyl, pyridyl, thiazolyl, thienyl, oxazole base, furyl, pyrrolyl, pyrazolyl, imidazolyl, the methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, vinyl, ethynyl, methoxy, ethoxy Base, -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 group, Cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl, phenyl, pyridyl, thiazolyl, thienyl, oxazolyl, furyl, pyrrolyl, pyrazolyl, imidazolyl optional Substituted by 1 to 4 substituents selected from halogen, OH, cyano, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl replace;
在一些实施方案中，Rx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、-SCH3、-SCH2CH3、环丙基、环丁基、环戊基、环己基，所述的甲基、乙基、丙基、异丙基、乙烯基、乙炔基、甲氧基、乙氧基、-SCH3、-SCH2CH3、环丙基、环丁基、环戊基、环己基、双环[1.1.1]戊基、苯基、吡啶基、噻唑基、噻吩基、噁唑基、呋喃基、吡咯基、吡唑基、咪唑基任选被1至4个选自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, Rx is 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 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, the methyl, ethyl, propyl, iso Propyl, vinyl, ethynyl, methoxy, ethoxy, -SCH 3 , -SCH 2 CH 3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl , phenyl, pyridyl, thiazolyl, thienyl, oxazolyl, furyl, pyrrolyl, pyrazolyl, imidazolyl optionally 1 to 4 selected from F, OH, cyano, methyl, ethyl , substituted by methoxy or ethoxy substituents;
在一些实施方案中，Rx各自独立的选自H、F、Cl、Br、氰基、异丙基、CD3、CF3、CHF2、CH2F、环丙基、环丁基；In some embodiments, Rx is each independently selected from H, F, Cl, Br, cyano, isopropyl, CD3 , CF3 , CHF2 , CH2F , cyclopropyl, cyclobutyl;
在一些实施方案中，Ra1选自H、F、Cl、Br、I、氰基、CF3、CHF2、CH2F、甲基、乙基、丙基、异丙基、乙炔基、甲氧基、乙氧基、-SCH3、-SCH2CH3、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, CF 3 , CHF 2 , CH 2 F, 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，Ra1选自F、Cl、Br、CF3、CHF2、CH2F、甲基、氰基、环丙基、异丙基；In some embodiments, R a1 is selected from F, Cl, Br, CF 3 , CHF 2 , CH 2 F, methyl, cyano, cyclopropyl, isopropyl;
在一些实施方案中，Ra2选自H；In some embodiments, R a2 is selected from H;
在一些实施方案中，L选自-Q1-Ak1-Q2-Ak2-，右侧与环B连接；In some embodiments, L is selected from -Q1-Ak1-Q2-Ak2-, connected to ring B on the right side;
在一些实施方案中，L选自-N(Rq)-Ak1-O-Ak2-、-O-Ak1-O-Ak2-、-O-Ak1-N(Rq)-Ak2-、-N(Rq)-Ak1-N(Rq)-Ak2-，左侧与哒嗪酮环直接连接；In some embodiments, L is selected from -N(R q )-Ak1-O-Ak2-, -O-Ak1-O-Ak2-, -O-Ak1-N(R q )-Ak2-, -N( R q )-Ak1-N(R q )-Ak2-, the left side is directly connected to the pyridazinone ring;
在一些实施方案中，L选自 左侧与哒嗪酮环直接连接；In some embodiments, L is selected from The left side is directly connected to the pyridazinone ring;
在一些实施方案中，L选自 左侧与哒嗪酮环直接连接；In some embodiments, L is selected from The left side is directly connected to the pyridazinone ring;
在一些实施方案中，L选自 In some embodiments, L is selected from
在一些实施方案中，Ak1、Ak2各自独立的选自C1-4亚烷基、C2-4亚烯基、C2-4亚炔基，所述Ak1任选被0至4个Rk1取代，所述Ak2任选被0至4个Rk2取代；In some embodiments, Ak1 and Ak2 are each independently selected from C 1-4 alkylene, C 2-4 alkenylene, C 2-4 alkynylene, and the Ak1 is optionally replaced by 0 to 4 R k1 Substituted, the Ak2 is optionally substituted by 0 to 4 R k2 ;
在一些实施方案中，Ak1、Ak2各自独立的选自C1-3亚烷基、C2-3亚烯基、C2-3亚炔基，所述Ak1任选被0至4个Rk1取代，所述Ak2任选被0至4个Rk2取代；In some embodiments, Ak1 and Ak2 are each independently selected from C 1-3 alkylene, C 2-3 alkenylene, C 2-3 alkynylene, and the Ak1 is optionally replaced by 0 to 4 R k1 Substituted, the Ak2 is optionally substituted by 0 to 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任选被0至4个Rk1取代，所述Ak2任选被0至4个Rk2取代；In some embodiments, Ak1 and Ak2 are each independently selected from methylene, ethylene, propylene, vinylene, propenylene, ethynylene, and propynylene, and Ak1 is optionally replaced by 0 to 4 R k1 substituted, and the Ak2 is optionally substituted by 0 to 4 R k2 ;
在一些实施方案中，Rk1、Rk2各自独立的选自卤素、氰基、OH、＝O、NH2、NHC1-6烷基、N(C1-6烷基)2、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、-OC3-6碳环、C3-6碳环或4至7元杂环，所述的烷基、烯基、炔基、烷氧基、碳环或杂环任选被1至4个选自卤素、OH、氰基、NH2、C1-6烷基、C2-6烯基、C2-6炔基、卤素取代的C1-6烷基、C1-6烷氧基、-O-C3-8碳环、C3-8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、N的杂原子；In some embodiments, R k1 and R k2 are each independently selected from 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 carbocyclic ring, C 3-6 carbocyclic ring or 4 to 7 membered heterocyclic ring, the above The alkyl, alkenyl, alkynyl, alkoxy, carbocyclic or heterocyclic groups are optionally substituted by 1 to 4 selected from halogen, OH, cyano, NH 2 , C 1-6 alkyl, C 2-6 alkene Base, C 2-6 alkynyl group, halogen-substituted C 1-6 alkyl group, C 1-6 alkoxy group, -OC 3-8 carbocyclic ring, C 3-8 carbocyclic ring, 4 to 10 membered heterocyclic ring substitution Substituted with a base, the heterocyclic ring contains 1 to 3 heteroatoms selected from O, S, and N;
在一些实施方案中，Rk1、Rk2各自独立的选自卤素、氰基、OH、＝O、NH2、NHC1-4烷基、N(C1-4烷基)2、C1-4烷基、C1-4烷氧基、C3-6碳环或4至7元杂环，所述的烷基、烷氧基、碳环或杂环任选被1至4个选自卤素、OH、氰基、NH2、C1-4烷基、卤素取代的C1-4烷基、C1-4烷氧基、C3-6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个选自O、S、N的杂原子；In some embodiments, R k1 and R k2 are each independently selected from 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 carbocyclic ring or 4 to 7 membered heterocyclic ring, the alkyl group, alkoxyl group, carbocyclic ring or heterocyclic ring is optionally selected from 1 to 4 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 substitution Substituted with a base, the heterocyclic ring contains 1 to 3 heteroatoms selected from O, S, and N;
在一些实施方案中，Rk1、Rk2各自独立的选自F、Cl、Br、I、氰基、OH、＝O、NH2、NH(CH3)、N(CH3)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、苯基任选被1至4个选自卤素、OH、氰基、NH2、C1-4烷基、卤素取代的C1-4烷基、C1-4烷氧基、C3-6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个选自O、S、N的杂原子；In some embodiments, R k1 and R k2 are each independently selected from 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, azepanyl, azepanyl, oxacyclo Butyl, oxanyl, oxanyl, pyridine, phenyl, the methyl, ethyl, propyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl, azetidinyl, azetanyl, azetanyl, oxetanyl, oxetanyl, oxetanyl, pyridine and phenyl are optionally selected from 1 to 4 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 substitution Substituted with a base, the heterocyclic ring contains 1 to 3 heteroatoms selected from O, S, and N;
在一些实施方案中，Rk1与Rk1、Rk2与Rk2、Rk1与Rk2直接连接形成C3-6碳环或者4至7元 的杂环，所述的碳环或杂环任选被1至4个选自卤素、＝O、OH、氰基、C1-6烷基、卤素取代的C1-6烷基、C1-6烷氧基、C3-6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、N的杂原子；In some embodiments, R k1 and R k1 , R k2 and R k2 , R k1 and R k2 are directly connected to form a C 3-6 carbocyclic ring or a 4 to 7 membered Heterocycle, the carbocyclic or heterocyclic ring is optionally substituted by 1 to 4 C 1-6 alkyl, C 1 selected from halogen, =O, OH, cyano, C 1-6 alkyl, halogen Substituted with -6 alkoxy and C 3-6 cycloalkyl substituents, the heterocyclic ring contains 1 to 3 heteroatoms selected from O, S, and N;
在一些实施方案中，Rk1与Rk1、Rk2与Rk2、Rk1与Rk2直接连接形成C3-6碳环或者4至7元的杂环，所述的碳环或杂环任选被1至4个选自卤素、＝O、OH、氰基、C1-4烷基、卤素取代的C1-4烷基、C1-4烷氧基、C3-6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、N的杂原子；In some embodiments, R k1 and R k1 , R k2 and R k2 , R k1 and R k2 are directly connected to form a C 3-6 carbocyclic ring or a 4 to 7-membered heterocyclic ring, and the carbocyclic ring or heterocyclic ring is either Selected from 1 to 4 selected from halogen, =O, OH, cyano, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl Substituted with substituents, the heterocyclic ring contains 1 to 3 heteroatoms selected from O, S, and N;
在一些实施方案中，Q1、Q2各自独立的选自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)2N(Rq)、N(Rq)S(＝O)2、N(Rq)C(＝O)N(Rq)、N(Rq)C(＝O)N(Rq)；In some embodiments, Q1 and Q2 are each 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(R q ), N(R q )C(=O)N(R q );
在一些实施方案中，Q1、Q2各自独立的选自O、S、N(Rq)、C(＝O)、C(＝O)N(Rq)、N(Rq)C(＝O)、S(＝O)2；In some embodiments, Q1 and Q2 are each independently selected from O, S, N(R q ), C(=O), C(=O)N(R q ), N(R q )C(=O ), S(=O) 2 ;
在一些实施方案中，Rq各自独立的选自H、C1-6烷基或C3-6环烷基，所述的烷基或环烷基任选被1至4个选自卤素、CF3、OH、氰基、NH2、C1-6烷基或C1-6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, and the alkyl or cycloalkyl is optionally substituted by 1 to 4 selected from halogen, Substituted with substituents of CF 3 , OH, cyano, NH 2 , C 1-6 alkyl or C 1-6 alkoxy;
在一些实施方案中，Rq各自独立的选自H、C1-4烷基，所述的烷基任选被1至4个选自卤素、CF3、OH、氰基、NH2、C1-4烷基或C1-4烷氧基的取代基所取代；In some embodiments, R q is each independently selected from H, C 1-4 alkyl, and the alkyl is optionally substituted by 1 to 4 selected from halogen, CF 3 , OH, cyano, NH 2 , C Substituted with 1-4 alkyl or C 1-4 alkoxy substituents;
在一些实施方案中，Rq各自独立的选自H、甲基、乙基；In some embodiments, each R q is independently selected from H, methyl, and ethyl;
在一些实施方案中，Rq与Rk1或Rk2直接连接形成4至7元的杂环，所述的杂环任选被1至4个选自卤素、＝O、OH、氰基、C1-6烷基、卤素取代的C1-6烷基、C1-6烷氧基、C3-6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、N的杂原子；In some embodiments, R q is directly connected to R k1 or R k2 to form a 4- to 7-membered heterocycle, which is optionally substituted by 1 to 4 members selected from the group consisting of halogen, =O, OH, cyano, C Substituted with 1-6 alkyl, halogen-substituted C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl substituents, the heterocyclic ring contains 1 to 3 selected from O , S, N heteroatoms;
在一些实施方案中，Rq与Rk1、Rq与Rk2直接连接形成4至7元的杂环，所述的杂环任选被1至4个选自卤素、＝O、OH、氰基、C1-4烷基、卤素取代的C1-4烷基、C1-4烷氧基、C3-6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、N的杂原子；In some embodiments, R q and R k1 , R q and R k2 are directly connected to form a 4- to 7-membered heterocycle, and the heterocycle is optionally substituted by 1 to 4 members selected from halogen, =O, OH, and cyanide. Substituted with substituents such as C 1-4 alkyl, halogen-substituted C 1-4 alkyl, C 1-4 alkoxy, and C 3-6 cycloalkyl, the heterocyclic ring contains 1 to 3 Heteroatom selected from O, S, N;
在一些实施方案中，Rq与Rk1、Rq与Rk2直接连接形成4至7元的杂环，所述的杂环任选被1至4个选自卤素、＝O、OH、氰基、C1-4烷基、卤素取代的C1-4烷基、C1-4烷氧基、C3-6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、N的杂原子；In some embodiments, R q and R k1 , R q and R k2 are directly connected to form a 4- to 7-membered heterocycle, and the heterocycle is optionally substituted by 1 to 4 members selected from halogen, =O, OH, and cyanide. Substituted with substituents such as C 1-4 alkyl, halogen-substituted C 1-4 alkyl, C 1-4 alkoxy, and C 3-6 cycloalkyl, the heterocyclic ring contains 1 to 3 Heteroatom selected from O, S, N;
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，b选自0、1、2、3；In some embodiments, b is selected from 0, 1, 2, 3;
在一些实施方案中，x选自1、2；In some embodiments, x is selected from 1, 2;
任选地，通式(A)所示的化合物中有1至10个H被D替换。Optionally, 1 to 10 H's in the compound represented by general formula (A) are replaced by D.
作为本发明的第一种实施方案，下述通式(A)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 following general formula (A) or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,
W选自键、C(＝O)；W is selected from bond, C(=O);
环B选自 为单键或者双键；Ring B is selected from Is a single bond or a double bond;
Z选自N、C或CH；Z is selected from N, C or CH;
Y选自键、-O-、-S-、-S(＝O)-、-S(＝O)2-、-S(＝O)2N(Ry)-、-N(Ry)-、C1-4亚烷基、-OC1-3亚烷基-、-C1-3亚烷基O-、-C1-2亚烷基O-C1-2亚烷基、-C1-3亚烷基S-、-C1-3亚烷基S(＝O)-、-C1-3亚烷基S(＝O)2-、-N(Ry)C1-3亚烷基-、-C1-3亚烷基N(Ry)-、-C1-2亚烷基N(Ry)-C1-2亚烷基，所述的亚烷基任选被1至4个选自卤素、＝O、＝S、OH、氰基、C1-6烷基、卤素取代的C1-6烷基、C1-6烷氧基、C3-6环烷基的取代基所取代；Y is selected from the group consisting of bonds, -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 1-2 alkylene OC 1-2 alkylene, -C 1 -3 Alkylene S-, -C 1-3 Alkylene S(=O)-, -C 1-3 Alkylene S(=O) 2 -, -N(R y )C 1-3 Alkyl-, -C 1-3 alkylene N(R y )-, -C 1-2 alkylene N(R y )-C 1-2 alkylene, the alkylene group is optionally 1 to 4 selected from 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 substituent of the base;
Ry各自独立的选自H、C1-6烷基或C3-6环烷基，所述的烷基或环烷基任选被1至4个选自氘、卤素、CF3、OH、氰基、NH2、C1-6烷基、C1-6烷氧基、3至8元杂环基或C3-6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 the alkyl or cycloalkyl is optionally substituted by 1 to 4 selected from deuterium, halogen, CF 3 , OH , cyano group, NH 2 , C 1-6 alkyl group, C 1-6 alkoxy group, 3 to 8 membered heterocyclic group or C 3-6 cycloalkyl substituent, the heterocyclic group contains 1 to 3 heteroatoms selected from O, S, and N;
Rb各自独立的选自H、卤素、氰基、OH、＝O、C1-6烷基、C1-6烷氧基、-(CH2)q-C3-6环烷基，所述的-CH2-、烷基、烷氧基或环烷基任选被1至4个选自卤素、OH、氰基、NH2、C1-6烷基、卤素取代的C1-6烷基、C1-6烷氧基或C3-6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 The -CH 2 -, alkyl, alkoxy or cycloalkyl group is optionally substituted by 1 to 4 C 1-6 selected from halogen, OH, cyano, NH 2 , C 1-6 alkyl, and halogen. Substituted by alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl substituents;
环A选自C6-10芳环、5-10元杂芳环或5-10元杂环，所述的杂芳环或者杂环含有1至5个选自O、S、N的杂原子；Ring A is selected from a C 6-10 aromatic ring, a 5-10 membered heteroaromatic ring or a 5-10 membered heterocyclic ring. The heteroaromatic ring or heterocyclic ring contains 1 to 5 heteroatoms selected from O, S, and N. ;
环X选自C6-10芳环、5-10元杂芳环、C3-10碳环或5-10元杂环，所述的杂芳环或者杂环含有1至5个选自O、S、N的杂原子； Ring _ , S, N heteroatoms;
Rx、Ra各自独立的选自H、卤素、氰基、OH、＝O、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、-SO2-C1-6烷基、-C(＝O)C1-6烷基、-(CH2)q-C3-10碳环或-(CH2)q-3至12元杂环，所述的-CH2-、烷基、烯基、炔基、烷氧基、烷硫基、碳环或杂环任选被1至4个选自卤素、OH、氰基、＝O、NH2、NH(C1-6烷基)、N(C1-6烷基)2、C1-6烷基、卤素取代的C1-6烷基、C1-6烷氧基、C3-6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、N的杂原子；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 group, -SO 2 -C 1-6 alkyl group, -C(=O)C 1-6 alkyl group, -(CH 2 ) q -C 3-10 carbocyclic ring or -(CH 2 ) q -3 to 12 membered heterocyclic ring, the -CH 2 -, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, carbocyclic or heterocyclic ring is optionally selected from 1 to 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 alkyl , C 1-6 alkoxy group, C 3-6 cycloalkyl group or a 3 to 10 membered heterocyclic substituent, the heterocyclic ring contains 1 to 3 heteroatoms selected from O, S, N;
L选自-Q1-Ak1-Q2-Ak2-，右侧与环B连接；L is selected from -Q1-Ak1-Q2-Ak2-, and is connected to ring B on the right side;
Ak1、Ak2各自独立的选自C1-4亚烷基、C2-4亚烯基、C2-4亚炔基，所述Ak1任选被0至4个Rk1取代，所述Ak2任选被0至4个Rk2取代；Ak1 and Ak2 are each independently selected from C 1-4 alkylene, C 2-4 alkenylene, C 2-4 alkynylene, the Ak1 is optionally substituted by 0 to 4 R k1 , and the Ak2 is optionally The selection is replaced by 0 to 4 R k2 ;
Rk1、Rk2各自独立的选自卤素、氰基、OH、＝O、NH2、NHC1-6烷基、N(C1-6烷基)2、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、-OC3-6碳环、C3-6碳环或4至7元杂环，所述的烷基、烯基、炔基、烷氧基、碳环或杂环任选被1至4个选自卤素、OH、氰基、NH2、C1-6烷基、C2-6烯基、C2-6炔基、卤素取代的C1-6烷基、C1-6烷氧基、-O-C3-8碳环、C3-8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、N的杂原子；R k1 and R k2 are each independently selected from 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 carbocyclic ring, C 3-6 carbocyclic ring or 4 to 7 membered heterocyclic ring, the alkyl group and alkenyl group , alkynyl, alkoxy, carbocyclic or heterocyclic is optionally 1 to 4 selected from 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 carbocyclic, C 3-8 carbocyclic, 4 to 10 membered heterocyclic substituents, the The heterocycle contains 1 to 3 heteroatoms selected from O, S, and N;
作为选择，Rk1与Rk1、Rk2与Rk2、Rk1与Rk2直接连接形成C3-6碳环或者4至7元的杂环，所述的碳环或杂环任选被1至4个选自卤素、＝O、OH、氰基、C1-6烷基、卤素取代的C1-6烷基、C1-6烷氧基、C3-6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、N的杂原子；Alternatively, R k1 and R k1 , R k2 and R k2 , R k1 and R k2 are directly connected to form a C 3-6 carbocyclic ring or a 4 to 7-membered heterocyclic ring, and the said carbocyclic ring or heterocyclic ring is optionally replaced by 1 To 4 substituents selected from halogen, =O, OH, cyano, C 1-6 alkyl, halogen-substituted C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl Substituted, the heterocyclic ring contains 1 to 3 heteroatoms selected from O, S, and N;
Q1、Q2各自独立的选自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)2N(Rq)、N(Rq)S(＝O)2、N(Rq)C(＝O)N(Rq)、N(Rq)C(＝O)N(Rq)；Q1 and Q2 are each 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(R q ), N(R q )C(=O)N(R q );
Rq各自独立的选自H、C1-6烷基或C3-6环烷基，所述的烷基或环烷基任选被1至4个选自卤素、CF3、OH、氰基、NH2、C1-6烷基或C1-6烷氧基的取代基所取代；R q is each independently selected from H, C 1-6 alkyl or C 3-6 cycloalkyl, and the alkyl or cycloalkyl is optionally substituted by 1 to 4 selected from halogen, CF 3 , OH, cyanide Substituted with substituents of base, NH 2 , C 1-6 alkyl or C 1-6 alkoxy;
作为选择，Rq与Rk1或Rk2直接连接形成4至7元的杂环，所述的杂环任选被1至4个选自卤素、＝O、OH、氰基、C1-6烷基、卤素取代的C1-6烷基、C1-6烷氧基、C3-6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、N的杂原子；Alternatively, R q is directly connected to R k1 or R k2 to form a 4 to 7-membered heterocycle, which is optionally substituted by 1 to 4 members selected from halogen, =O, OH, cyano, C 1-6 Substituted with alkyl, halogen-substituted C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl substituents, the heterocyclic ring contains 1 to 3 selected from O, S, N heteroatoms;
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;
任选地，通式(A)所示的化合物中有1至10个H被D替换。Optionally, 1 to 10 H's in the compound represented by general formula (A) are replaced by D.
作为本发明的第二种实施方案，上述通式(A)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 a second embodiment of the present invention, the compound represented by the above general formula (A) or its stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,
通式(A)化合物选自通式(I)所示的化合物
The compound of general formula (A) is selected from the compounds represented by general formula (I)
各个基团定义与第一种实施方案相同。The definitions of each group are the same as in the first embodiment.
作为本发明的第三种实施方案，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 third embodiment of the present invention, the compound represented by the following general formula (II) or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,
环X选自5-6元杂芳环或5-6元杂环，所述的杂芳环或杂环含有1至5个选自O、S、N的杂原子；Ring
或者环X选自8-10元并环杂芳环或8-10元并环杂环，所述的杂芳环或杂环含有1至5个选自O、S、N的杂原子；Alternatively, ring
Ra1、Ra2各自独立的选自H、卤素、氰基、OH、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、-SO2-C1-6烷基、-C(＝O)C1-6烷基、-(CH2)q-C3-10碳环或-(CH2)q-3至12元杂环，所述的-CH2-、烷基、烯基、炔基、烷氧基、烷硫基、碳环或杂环任选被1至4个选自卤素、OH、氰基、＝O、C1-6烷基、卤素取代的C1-6烷基、C1-6烷氧基、C3-6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、N的杂原子；R a1 and R a2 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 group, -SO 2 -C 1-6 alkyl group, -C(=O)C 1-6 alkyl group, -(CH 2 ) q -C 3-10 carbocyclic ring or -(CH 2 ) q -3 to 12-membered heterocyclic ring, the -CH 2 -, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, carbocyclic or heterocyclic ring is optionally substituted by 1 to 4 selected from 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 heterocyclic substituents Substituted, the heterocyclic ring contains 1 to 3 heteroatoms selected from O, S, and N;
其余基团定义与本发明第二种实施方案相同。The definitions of the remaining groups are the same as in the second embodiment of the invention.
作为本发明的第四种实施方案，上述通式(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 above general formula (II) or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,
Y选自键、-O-、-N(Ry)-、C1-3亚烷基、-OC1-2亚烷基-、-C1-2亚烷基O-、-C1-2亚烷基O-C1-2亚烷基、-C1-2亚烷基S-、-C1-2亚烷基S(＝O)2-、-N(Ry)C1-2亚烷基-、-C1-2亚烷基N(Ry)-、-C1-2亚烷基N(Ry)-C1-2亚烷基，所述的亚烷基任选被1至4个选自卤素、＝O、＝S、OH、氰基、C1-4烷基、卤素取代的C1-4烷基、C1-4烷氧基、C3-6环烷基的取代基所取代；Y is selected from bond, -O-, -N(R y )-, C 1-3 alkylene, -OC 1-2 alkylene-, -C 1-2 alkylene O-, -C 1- 2 alkylene OC 1-2 alkylene, -C 1-2 alkylene S-, -C 1-2 alkylene S(=O) 2 -, -N(R y )C 1-2 ylene Alkyl-, -C 1-2 alkylene N(R y )-, -C 1-2 alkylene N(R y )-C 1-2 alkylene, the alkylene group is optionally 1 to 4 selected from halogen, =O, =S, OH, cyano, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl Substituted by the substituent of the base;
Ry各自独立的选自H、C1-4烷基或C3-6环烷基，所述的烷基或环烷基任选被1至4个选自氘、卤素、CF3、OH、氰基、NH2、C1-4烷基、C1-4烷氧基、3至8元杂环基或C3-6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 the alkyl or cycloalkyl is optionally substituted by 1 to 4 selected from deuterium, halogen, CF 3 , OH , cyano group, NH 2 , C 1-4 alkyl group, C 1-4 alkoxy group, 3 to 8 membered heterocyclic group or C 3-6 cycloalkyl substituent, the heterocyclic group contains 1 to 3 heteroatoms selected from O, S, and N;
Rx、Ra1、Ra2各自独立的选自H、卤素、氰基、OH、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C1-4烷硫基、-SO2-C1-4烷基、-C(＝O)C1-4烷基、-(CH2)q-C3-6碳环或-(CH2)q-3至6元杂环，所述的-CH2-、烷基、烯基、炔基、烷氧基、烷硫基、碳环或杂环任选被1至4个选自卤素、OH、氰基、＝O、C1-4烷基、卤素取代的C1-4烷基、C1-4烷氧基、C3-6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、N的杂原子；R x , R a1 , and R a2 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 group, -SO 2 -C 1-4 alkyl group, -C(=O)C 1-4 alkyl group, -(CH 2 ) q -C 3-6 carbocyclic ring or -(CH 2 ) q -3 to 6 membered heterocyclic ring, the -CH 2 -, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, carbocyclic or heterocyclic ring is optionally selected from 1 to 4 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 Substituted with substituents, the heterocyclic ring contains 1 to 3 heteroatoms selected from O, S, and N;
Rb各自独立的选自H、卤素、氰基、OH、＝O、C1-4烷基、C1-4烷氧基、-(CH2)q-C3-6环烷基，所述的-CH2-、烷基、烷氧基或环烷基任选被1至4个选自卤素、OH、氰基、NH2、C1-4烷基、卤素取代的C1-4烷基、C1-4烷氧基或C3-6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 The -CH 2 -, alkyl, alkoxy or cycloalkyl group is optionally substituted by 1 to 4 C 1-4 selected from halogen, OH, cyano, NH 2 , C 1-4 alkyl, and halogen. Substituted by alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl substituents;
Ak1、Ak2各自独立的选自C1-3亚烷基、C2-3亚烯基、C2-3亚炔基，所述Ak1任选被0至4个Rk1取代，所述Ak2任选被0至4个Rk2取代；Ak1 and Ak2 are each independently selected from C 1-3 alkylene, C 2-3 alkenylene, and C 2-3 alkynylene. The Ak1 is optionally substituted by 0 to 4 R k1 , and the Ak2 is optionally The selection is replaced by 0 to 4 R k2 ;
Rk1、Rk2各自独立的选自卤素、氰基、OH、＝O、NH2、NHC1-4烷基、N(C1-4烷基)2、C1-4烷基、C1-4烷氧基、C3-6碳环或4至7元杂环，所述的烷基、烷氧基、碳环或杂环任选被1至4个选自卤素、OH、氰基、NH2、C1-4烷基、卤素取代的C1-4烷基、C1-4烷氧基、C3-6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个选自O、S、N的杂原子；R k1 and R k2 are each independently selected from halogen, cyano, OH, =O, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1 -4 alkoxy group, C 3-6 carbocyclic ring or 4 to 7 membered heterocyclic ring, the alkyl group, alkoxy group, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 selected from halogen, OH, cyano group , NH 2 , C 1-4 alkyl, halogen-substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 carbocyclic, 4 to 6-membered heterocyclic substituents, the The heterocycle contains 1 to 3 heteroatoms selected from O, S, and N;
作为选择，Rk1与Rk1、Rk2与Rk2、Rk1与Rk2直接连接形成C3-6碳环或者4至7元的杂环，所述的碳环或杂环任选被1至4个选自卤素、＝O、OH、氰基、C1-4烷基、卤素取代的C1-4烷基、C1-4烷氧基、C3-6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、N的杂原子；Alternatively, R k1 and R k1 , R k2 and R k2 , R k1 and R k2 are directly connected to form a C 3-6 carbocyclic ring or a 4 to 7-membered heterocyclic ring, and the said carbocyclic ring or heterocyclic ring is optionally replaced by 1 to 4 substituents selected from halogen, =O, OH, cyano, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl Substituted, the heterocyclic ring contains 1 to 3 heteroatoms selected from O, S, and N;
Q1、Q2各自独立的选自O、S、N(Rq)、C(＝O)、C(＝O)N(Rq)、N(Rq)C(＝O)、S(＝O)2；Q1 and Q2 are each independently selected from O, S, N(R q ), C(=O), C(=O)N(R q ), N(R q )C(=O), S(=O ) 2 ;
Rq各自独立的选自H、C1-4烷基，所述的烷基任选被1至4个选自卤素、CF3、OH、氰基、NH2、C1-4烷基或C1-4烷氧基的取代基所取代；R q is each independently selected from H, C 1-4 alkyl, and the alkyl is optionally substituted by 1 to 4 selected from halogen, CF 3 , OH, cyano, NH 2 , C 1-4 alkyl or Substituted with C 1-4 alkoxy substituents;
作为选择，Rq与Rk1、Rq与Rk2直接连接形成4至7元的杂环，所述的杂环任选被1至4个选自卤素、＝O、OH、氰基、C1-4烷基、卤素取代的C1-4烷基、C1-4烷氧基、C3-6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、N的杂原子；Alternatively, R q and R k1 , R q and R k2 are directly connected to form a 4 to 7-membered heterocycle, and the heterocycle is optionally substituted by 1 to 4 members selected from halogen, =O, OH, cyano, C Substituted with 1-4 alkyl, halogen-substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl substituents, the heterocyclic ring contains 1 to 3 selected from O , S, N heteroatoms;
其余基团定义与本发明第二种或者第三种实施方案相同。The definitions of the remaining groups are the same as in the second or third embodiment of the present invention.
作为本发明的第五种实施方案，上述通式(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 above general formula (II) or its stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,
环X选自吡啶环、嘧啶环、吡嗪环、哒嗪环、噻吩环、噻唑环、呋喃环、噁唑环、吡咯环、吡唑环或咪唑环；Ring
或者环X选自三嗪环、苯并噻唑环、吡啶并噻唑环、嘧啶并噻唑环、哒嗪并噻唑环、吡嗪并噻唑环、苯并噁唑环、吡啶并噁唑环、嘧啶并噁唑环、哒嗪并噁唑环、吡嗪并噁唑环、吡啶并吡咯环、吡啶并吡唑环、嘧啶并噻吩环、嘧啶并吡唑环、嘧啶并吡咯环、嘧啶并咪唑环、嘧啶并三 氮唑环、嘧啶并呋喃环、嘧啶并吡咯环、喹啉环、异喹啉环、嘧啶并吡啶环、三氮唑环、三氮唑并吡啶环、三氮唑并噻唑环、三氮唑并噁唑环、三氮唑并咪唑环、三氮唑并吡唑环、 Alternatively, Ring Oxazole ring, pyridazinooxazole ring, pyrazinooxazole ring, pyridopyrrole ring, pyridopyrazole ring, pyrimidothiophene ring, pyrimidopyrazole ring, pyrimidopyrrole ring, pyrimidoimidazole ring, pyrimidinotri Azole ring, pyrimidofuran ring, pyrimidopyrrole ring, Quinoline ring, isoquinoline ring, pyrimidopyridine ring, triazole ring, triazolopyridine ring, triazolothiazole ring, triazoloxazole ring, triazoloimidazole ring, trinitrogen Azolopyrazole ring,
Rx、Ra1、Ra2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、-SCH3、-SCH2CH3、-SO2CH3、-S O2CH2CH3、-C(＝O)CH3、-C(＝O)CH2CH3、环丙基、环丁基、环戊基、环己基、双环[1.1.1]戊基、苯基、吡啶基、噻唑基、噻吩基、噁唑基、呋喃基、吡咯基、吡唑基、咪唑基，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、-SCH3、-SCH2CH3、-SO2CH3、-SO2CH2CH3、-C(＝O)CH3、-C(＝O)CH2CH3、环丙基、环丁基、环戊基、环己基、双环[1.1.1]戊基、苯基、吡啶基、噻唑基、噻吩基、噁唑基、呋喃基、吡咯基、吡唑基、咪唑基任选被1至4个选自卤素、OH、氰基、C1-4烷基、卤素取代的C1-4烷基、C1-4烷氧基、C3-6环烷基的取代基所取代；R x , R a1 , and 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 , -S O 2 CH 2 CH 3 , -C(＝O)CH 3 , -C(＝O )CH 2 CH 3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl, phenyl, pyridyl, thiazolyl, thienyl, oxazolyl, furyl, pyrrole base, pyrazolyl, imidazolyl, 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 base, cyclohexyl, bicyclo[1.1.1]pentyl, phenyl, pyridyl, thiazolyl, thienyl, oxazolyl, furyl, pyrrolyl, pyrazolyl, imidazolyl optionally selected from 1 to 4 Substituted from halogen, OH, cyano, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl substituents;
Rb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、丙基或异丙基任选被1至4个选自卤素、OH、氰基、NH2、C1-4烷基、卤素取代的C1-4烷基、C1-4烷氧基或C3-6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, the methyl, ethyl, propyl or Isopropyl is optionally substituted by 1 to 4 C 1-4 alkyl groups selected from halogen, OH, cyano, NH 2 , C 1-4 alkyl, halogen, C 1-4 alkoxy or C 3- Substituted by 6 cycloalkyl substituents;
Y选自键、-O-、-N(Ry)-、-N(Ry)C(＝O)-、-C(＝O)N(Ry)-、-CH2-、-CH2CH2-、-CH2CH2CH2-、-OCH2-、-OCH2CH2-、-CH2O-、-CH2CH2O-、-CH2OCH2-、-CH2S-、-CH2CH2S-、-CH2S(＝O)2-、-CH2CH2S(＝O)2-、-N(Ry)CH2-、-N(Ry)CH2CH2-、-CH2N(Ry)-、-CH2CH2N(Ry)-、-N(Ry)C(＝O)CH2-、-CH2C(＝O)N(Ry)-，所述CH2任选被0至2个选自H、＝O、＝S、OH、氰基、C1-4烷基、卤素取代的C1-4烷基、C1-4烷氧基、C3-6环烷基的取代基所取代；Y is selected from the group consisting of bonds, -O-, -N(R y )-, -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 OCH 2 -, -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 is optionally substituted by 0 to 2 C 1-4 alkyl selected from H, =O, =S, OH, cyano, C 1-4 alkyl, and halogen Substituted with substituents of base, C 1-4 alkoxy group, and C 3-6 cycloalkyl group;
Ry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、环己基任选被1至4个选自氘、卤素、CF3、OH、氰基、NH2、C1-4烷基、C1-4烷氧基、3至8元杂环基或C3-6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 is each independently selected from H, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentyl, Hexyl, the methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl are optionally 1 to 4 selected from 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 with a substituent of a base, the heterocyclic group contains 1 to 3 heteroatoms selected from O, S, and N;
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任选被0至4个Rk1取代，所述Ak2任选被0至4个Rk2取代；Ak1 and Ak2 are each independently selected from methylene, ethylene, propylene, vinylene, propenylene, ethynylene, and propynylene, and the Ak1 is optionally substituted by 0 to 4 R k1 , the Ak2 is optionally replaced by 0 to 4 R k2 ;
Rk1、Rk2各自独立的选自F、Cl、Br、I、氰基、OH、＝O、NH2、NH(CH3)、N(CH3)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、苯基任选被1至4个选自卤素、OH、氰基、NH2、C1-4烷基、卤素取代的C1-4烷基、C1-4烷氧基、C3-6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个选自O、S、N的杂原子；R k1 and R k2 are each independently selected from 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, azetanyl, azetanyl, oxetanyl, oxetanyl Pentyl, oxanyl, pyridine, phenyl, the methyl, ethyl, propyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetyl Butyl, azetanyl, azepanyl, oxetanyl, oxetanyl, oxetanyl, pyridine, phenyl are optionally selected from 1 to 4 halogen, OH, cyano , NH 2 , C 1-4 alkyl, halogen-substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 carbocyclic, 4 to 6-membered heterocyclic substituents, the The heterocycle contains 1 to 3 heteroatoms selected from O, S, and N;
作为选择，Rk1与Rk1、Rk2与Rk2、Rk1与Rk2直接连接形成C3-6碳环或者4至7元的杂环，所述的碳环或杂环任选被1至4个选自卤素、＝O、OH、氰基、C1-4烷基、卤素取代的C1-4烷基、 C1-4烷氧基、C3-6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、N的杂原子；Alternatively, R k1 and R k1 , R k2 and R k2 , R k1 and R k2 are directly connected to form a C 3-6 carbocyclic ring or a 4 to 7-membered heterocyclic ring, and the said carbocyclic ring or heterocyclic ring is optionally replaced by 1 to 4 selected from halogen, =O, OH, cyano, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, Substituted with substituents of C 1-4 alkoxy and C 3-6 cycloalkyl, the heterocyclic ring contains 1 to 3 heteroatoms selected from O, S, and N;
Q1、Q2各自独立的选自O、S、N(Rq)、C(＝O)、C(＝O)N(Rq)、N(Rq)C(＝O)、S(＝O)2；Q1 and Q2 are each independently selected from O, S, N(R q ), C(=O), C(=O)N(R q ), N(R q )C(=O), S(=O ) 2 ;
Rq各自独立的选自H、甲基、乙基；R q is each independently selected from H, methyl, and ethyl;
作为选择，Rq与Rk1、Rq与Rk2直接连接形成4至7元的杂环，所述的杂环任选被1至4个选自卤素、＝O、OH、氰基、C1-4烷基、卤素取代的C1-4烷基、C1-4烷氧基、C3-6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、N的杂原子；Alternatively, R q and R k1 , R q and R k2 are directly connected to form a 4 to 7-membered heterocycle, and the heterocycle is optionally substituted by 1 to 4 members selected from halogen, =O, OH, cyano, C Substituted with 1-4 alkyl, halogen-substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl substituents, the heterocyclic ring contains 1 to 3 selected from O , S, N heteroatoms;
其余基团定义与本发明第三或四种实施方案中任意一种相同。The definitions of the remaining groups are the same as in any one of the 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 product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,
L选自-N(Rq)-Ak1-O-Ak2-、-O-Ak1-O-Ak2-、-O-Ak1-N(Rq)-Ak2-、-N(Rq)-Ak1-N(Rq)-Ak2-，左侧与哒嗪酮环直接连接；L is selected from -N(R q )-Ak1-O-Ak2-, -O-Ak1-O-Ak2-, -O-Ak1-N(R q )-Ak2-, -N(R q )-Ak1- N(R q )-Ak2-, the left side is directly connected to the pyridazinone ring;
Y选自键、-O-、-NHC(＝O)-、-C(＝O)NH-、-CH2-、-CH2CH2-、-CH2CH2CH2-、-OCH2-、-OCH2CH2-、-CH2O-、-CH2CH2O-、-NHCH2-、-NHCH2CH2-、-CH2NH-、-CH2CH2NH-、-NHC(＝O)CH2-、-CH2C(＝O)NH-、-N(CH3)C(＝O)-、-C(＝O)N(CH3)-、-CH2C(＝O)NH-、-CH2C(＝O)N(CH3)-、-N(CH2CH3)C(＝O)-、-N(CH(CH3)2)C(＝O)-、-N(CH2CH(CH3)2)C(＝O)-、-N(环丙基)C(＝O)-、-N(CH2-环丙基)C(＝O)-、-C(＝O)N(CH2CH3)-、-C(＝O)N(CH(CH3)2)-、-C(＝O)N(CH2CH(CH3)2)-、-C(＝O)N(环丙基)-、-C(＝O)N(CH2-环丙基)-、-C(＝O)N(CD3)-、-C(＝O)N(CH2-氧杂环丁基)-、-C(＝O)N(CH2-氧杂环戊基)-、-C(＝O)N(CH2-氮杂环丁基)-、-C(＝O)N(CH2-吡咯烷基)-、-C(＝O)N(CH2-环戊基)-、-C(＝O)N(CH2CH2CH3)-、-C(＝O)N(CH2CH(CH2CH3)2)-、-C(＝O)N(CH2CH2CH2CH3)-、-C(＝O)N(CH2CH2CH(CH3)2)-、-C(＝O)N(CH2CH(CH3)CH2CH3)-、-C(＝O)N(正辛基)-、-C(＝S)N(CH3)-、-C(＝S)N(CH2CH3)-、-C(＝S)N(CH2-环丙基)-、-CH2S(＝O)2-；Y is selected from the group consisting of bonds, -O-, -NHC(=O)-, -C(=O)NH-, -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-, -NHCH 2 -, -NHCH 2 CH 2 -, -CH 2 NH-, -CH 2 CH 2 NH-, - NHC(=O)CH 2 -, -CH 2 C(=O)NH-, -N(CH 3 )C(=O)-, -C(=O)N(CH 3 )-, -CH 2 C (＝O)NH-, -CH 2 C(＝O)N(CH 3 )-, -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)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)-, -C(=O)N(CD 3 )-, - C(=O)N(CH 2 -oxetanyl)-, -C(=O)N(CH 2 -oxetanyl)-, -C(=O)N(CH 2 -aza cyclobutyl)-, -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-octane base)-, -C(=S)N(CH 3 )-, -C(=S)N(CH 2 CH 3 )-, -C(=S)N(CH 2 -cyclopropyl)-, -CH 2 S(＝O) 2 -;
其余基团定义与本发明第三、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 one of the third, fourth or fifth embodiments of the present invention.
作为本发明的第七种实施方案，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 a seventh embodiment of the present invention, the compound represented by the aforementioned general formula (II) or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,
L选自 左侧与哒嗪酮环直接连接；L is selected from The left side is directly connected to the pyridazinone ring;
Rx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、-SCH3、-SCH2CH3、环丙基、环丁基、环戊基、环己 基、双环[1.1.1]戊基、苯基、吡啶基、噻唑基、噻吩基、噁唑基、呋喃基、吡咯基、吡唑基、咪唑基，所述的甲基、乙基、丙基、异丙基、乙烯基、乙炔基、甲氧基、乙氧基、-SCH3、-SCH2CH3、环丙基、环丁基、环戊基、环己基、双环[1.1.1]戊基、苯基、吡啶基、噻唑基、噻吩基、噁唑基、呋喃基、吡咯基、吡唑基、咪唑基任选被1至4个选自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 independently selected from H, F, Cl, Br, I, cyano, OH, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, vinyl, ethynyl, methoxy base, ethoxy, -SCH 3 , -SCH 2 CH 3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl base, bicyclo[1.1.1]pentyl, phenyl, pyridyl, thiazolyl, thienyl, oxazolyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, the methyl, ethyl, propyl base, isopropyl, vinyl, ethynyl, methoxy, ethoxy, -SCH 3 , -SCH 2 CH 3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1 ] Pentyl, phenyl, pyridyl, thiazolyl, thienyl, oxazolyl, furyl, pyrrolyl, pyrazolyl, imidazolyl optionally 1 to 4 selected from F, OH, cyano, methyl , substituted by ethyl, methoxy or ethoxy substituents;
Ra1选自H、F、Cl、Br、I、氰基、CF3、CHF2、CH2F、甲基、乙基、丙基、异丙基、乙炔基、甲氧基、乙氧基、-SCH3、-SCH2CH3、环丙基、环丁基、环戊基或环己基；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;
选自 Selected from
Rb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三、四、五或六种实施方案中任意一种相同。The remaining group definitions are the same as in any one of the 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)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 an eighth embodiment of the present invention, the compound represented by the above general formula (II) or its stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,
L选自左侧与哒嗪酮环直接连接；L is selected from The left side is directly connected to the pyridazinone ring;
Ra1选自F、Cl、Br、CF3、CHF2、CH2F、甲基、氰基、环丙基、异丙基；R a1 is selected from F, Cl, Br, CF 3 , CHF 2 , CH 2 F, methyl, cyano, cyclopropyl, isopropyl;
Rx各自独立的选自H、F、Cl、Br、氰基、异丙基、CD3、CF3、CHF2、CH2F、环丙基、环丁基；R x is each independently selected from H, F, Cl, Br, cyano, isopropyl, CD 3 , CF 3 , CHF 2 , CH 2 F, cyclopropyl, cyclobutyl;
b选自0、1、2、3；b is selected from 0, 1, 2, 3;
x选自1、2；x is selected from 1, 2;
其余基团定义与本发明第第三、四、五、六或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 one of the third, fourth, fifth, sixth or seventh embodiments of the present invention.
作为本发明的第九种实施方案，上述通式(A)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 ninth embodiment of the present invention, the compound represented by the above general formula (A) or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,
W选自C(＝O)； W is selected from C(=O);
环X选自C3-10环烷基、4至10元杂环烷基、苯基、5-6元杂芳环、5-6元杂环、8-10元并环杂芳环或8-10元并环杂环，所述的杂环烷基、杂芳环或杂环含有1至5个选自O、S、N的杂原子； Ring -10-membered heterocyclic ring, the heterocycloalkyl group, heteroaromatic ring or heterocyclic ring contains 1 to 5 heteroatoms selected from O, S, and N;
优先地，环X选自C3-6单环环烷基、C5-10并环环烷基、C5-11螺环环烷基、C5-11桥环环烷基、4至7元单环杂环烷基、5至10元并环杂环烷基、5至11元螺环杂环烷基、5至11元桥环杂环烷基、苯基、5-6元杂芳环、8-10元并环杂芳环，所述的杂环烷基、杂芳环或杂环含有1至5个选自O、S、N的杂原子； Preferably , Ring _ Single-membered monocyclic heterocycloalkyl, 5- to 10-membered pentacyclic heterocycloalkyl, 5- to 11-membered spirocyclic heterocycloalkyl, 5- to 11-membered bridged heterocycloalkyl, phenyl, 5-6-membered heteroaryl Ring, 8-10 membered heteroaromatic ring, the heterocycloalkyl group, heteroaromatic ring or heterocyclic ring contains 1 to 5 heteroatoms selected from O, S, N;
优先地，环X选自环丙基、环丁基、环戊基、环己基、环丁基螺环丁基、环丁基螺环戊基、环丁基螺环己基、环戊基螺环戊基、环戊基螺环己基、环己基螺环己基、环丁基螺氮杂环丁基、环丁基螺氮杂环戊基、环丁基螺氮杂环己基、环戊基螺氮杂环戊基、环戊基螺氮杂环己基、环己基氮杂螺环己基、氮杂环丁基螺氮杂环己基、氮杂环戊基螺氮杂环戊基、氮杂环戊基螺氮杂环己基、氮杂环己基氮杂螺环己基、环丁基并环丁基、环丁基并环戊基、环丁基并环己基、环戊基并环戊基、环戊基并环己基、环己基并环己基、环丁基并氮杂环丁基、环丁基并氮杂环戊基、环丁基并氮杂环己基、环戊基并氮杂环戊基、环戊基并氮杂环己基、环己基氮杂并环己基、氮杂环丁基并氮杂环己基、氮杂环戊基并氮杂环戊基、氮杂环戊基并氮杂环己基、氮杂环己基氮杂并环己基、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，或者环X如权利要求5所述；Preferably, Ring Pentyl, cyclopentylspirocyclohexyl, cyclohexylspirocyclohexyl, cyclobutylspiroazetidinyl, cyclobutylspiroazetidine, cyclobutylspiroazetidine, cyclopentylspiroazetidine Cyclopentyl, cyclopentylspiroazepinyl, cyclohexylazespirohexyl, azetidinylspiroazepinyl, azetidinylspiroazepinyl, azepentyl Spiroazacyclohexyl, azacyclylaspirocyclohexyl, cyclobutylcyclobutyl, cyclobutylcyclopentyl, cyclobutylcyclohexyl, cyclopentylcyclopentyl, cyclopentyl and cyclohexyl, cyclohexyl and cyclohexyl, cyclobutyl azetidinyl, cyclobutyl azeticyclopentyl, cyclobutyl azeticyclohexyl, cyclopentyl azetidinyl, cyclo Pentyl azepanyl, cyclohexyl azepanyl, azetidinyl azepanyl, azetanyl azepanyl, azetanyl azepanyl, AzepanylAzacyclohexyl, azetidinyl, azetanyl, azetanyl, oxetanyl, oxetanyl, oxetanyl, or Ring X as claimed 5 mentioned;
其余基团定义与本发明第第二、三、四、五、六、七或八种实施方案中任意一种相同。The definitions of the remaining groups are the same as in any one of the second, third, fourth, fifth, sixth, seventh or eighth embodiments of the present invention.
作为本发明的第十种实施方案，上述通式(A)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 a tenth embodiment of the present invention, the compound represented by the above general formula (A) or its stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,
选自 Selected from
其余基团定义与本发明第第九种实施方案中任意一种相同。The definitions of the remaining groups are the same as in any one of the ninth embodiment 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，其中该化合物选自表E-1所示结构之一。The present invention relates to the compound shown below or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein the compound is selected from the structure shown in Table E-1 one.
表E-1






































Table E-1






































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, including any of the above compounds or their stereoisomers, deuterated products, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals, and a pharmaceutically acceptable carrier. .
本发明涉及一种药物组合物，包括治疗有效量的本发明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，以及药学上可接受的载体。The present invention relates to a pharmaceutical composition, comprising a therapeutically effective dose of the above-mentioned compound of the present invention or its stereoisomer, deuterium Substitutes, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals, and pharmaceutically acceptable carriers.
在一些实施方案中，本发明的药物组合物可以为单位制剂形式(单位制剂中主药的量也被称为“制剂规格”)。In some embodiments, the pharmaceutical composition of the present invention may be in the form of a unit preparation (the amount of the main drug in a unit preparation is also referred to as "preparation strength").
本申请中所述“有效量”或“治疗有效量”是指给予足够量的本申请公开的化合物，其将在某种程度上缓解所治疗的疾病或病症(例如PARP7相关疾病如前列腺癌)的一种或多种症状。在一些实施方案中，结果是减少和/或缓和疾病的体征、症状或原因，或生物系统的任何其它希望改变。例如，针对治疗用途的“有效量”是提供临床上显著的疾病症状降低所需的包含本申请公开的化合物的组合物的量。治疗有效量的实例包括但不限于1-1500mg、1-1200mg、1-1000mg、1-900mg、1-800mg、1-700mg、1-600mg、2-600mg、3-600mg、4-600mg、5-600mg、6-600mg、10-600mg、20-600mg、25-600mg、30-600mg、40-600mg、50-600mg、60-600mg、70-600mg、75-600mg、80-600mg、90-600mg、100-600mg、200-600mg、1-500mg、2-500mg、3-500mg、4-500mg、5-500mg、6-500mg、10-500mg、20-500mg、25-500mg、30-500mg、40-500mg、50-500mg、60-500mg、70-500mg、75-500mg、80-500mg、90-500mg、100-500mg、125-500mg、150-500mg、200-500mg、250-500mg、300-500mg、400-500mg、5-400mg、10-400mg、20-400mg、25-400mg、30-400mg、40-400mg、50-400mg、60-400mg、70-400mg、75-400mg、80-400mg、90-400mg、100-400mg、125-400mg、150-400mg、200-400mg、250-400mg、300-400mg、1-300mg、2-300mg、5-300mg、10-300mg、20-300mg、25-300mg、30-300mg、40-300mg、50-300mg、60-300mg、70-300mg、75-300mg、80-300mg、90-300mg、100-300mg、125-300mg、150-300mg、200-300mg、250-300mg、1-200mg、2-200mg、5-200mg、10-200mg、20-200mg、25-200mg、30-200mg、40-200mg、50-200mg、60-200mg、70-200mg、75-200mg、80-200mg、90-200mg、100-200mg、125-200mg、150-200mg、80-1000mg、80-800mg。"Effective amount" or "therapeutically effective amount" as used herein refers to administration of a sufficient amount of a compound disclosed herein that will alleviate to some extent the disease or disorder being treated (eg, PARP7-related diseases such as prostate cancer) one or more symptoms. In some embodiments, the result is reduction and/or alleviation of signs, symptoms, or causes of disease, or any other desired change in a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition containing a compound disclosed herein that is required to provide a clinically significant reduction in disease symptoms. Examples of therapeutically effective amounts include, but are not limited to, 1-1500 mg, 1-1200 mg, 1-1000 mg, 1-900 mg, 1-800 mg, 1-700 mg, 1-600 mg, 2-600 mg, 3-600 mg, 4-600 mg, 5 -600mg, 6-600mg, 10-600mg, 20-600mg, 25-600mg, 30-600mg, 40-600mg, 50-600mg, 60-600mg, 70-600mg, 75-600mg, 80-600mg, 90-600mg , 100-600mg, 200-600mg, 1-500mg, 2-500mg, 3-500mg, 4-500mg, 5-500mg, 6-500mg, 10-500mg, 20-500mg, 25-500mg, 30-500mg, 40 -500mg, 50-500mg, 60-500mg, 70-500mg, 75-500mg, 80-500mg, 90-500mg, 100-500mg, 125-500mg, 150-500mg, 200-500mg, 250-500mg, 300-500mg , 400-500mg, 5-400mg, 10-400mg, 20-400mg, 25-400mg, 30-400mg, 40-400mg, 50-400mg, 60-400mg, 70-400mg, 75-400mg, 80-400mg, 90 -400mg, 100-400mg, 125-400mg, 150-400mg, 200-400mg, 250-400mg, 300-400mg, 1-300mg, 2-300mg, 5-300mg, 10-300mg, 20-300mg, 25-300mg , 30-300mg, 40-300mg, 50-300mg, 60-300mg, 70-300mg, 75-300mg, 80-300mg, 90-300mg, 100-300mg, 125-300mg, 150-300mg, 200-300mg, 250 -300mg, 1-200mg, 2-200mg, 5-200mg, 10-200mg, 20-200mg, 25-200mg, 30-200mg, 40-200mg, 50-200mg, 60-200mg, 70-200mg, 75-200mg , 80-200mg, 90-200mg, 100-200mg, 125-200mg, 150-200mg, 80-1000mg, 80-800mg.
在一些实施方案中，该药物组合物包括但不限于1-1000mg、20-800mg、40-800mg、40-400mg、25-200mg、1mg、5mg、10mg、15mg、20mg、25mg、30mg、35mg、40mg、45mg、50mg、55mg、65mg、70mg、75mg、80mg、85mg、90mg、95mg、100mg、110mg、120mg、125mg、130mg、140mg、150mg、160mg、170mg、180mg、190mg、200mg、210mg、220mg、230mg、240mg、250mg、300mg、320mg、400mg、480mg、500mg、600mg、640mg、840mg的本发明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。In some embodiments, the pharmaceutical composition includes, but is not limited to, 1-1000 mg, 20-800 mg, 40-800 mg, 40-400 mg, 25-200 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40mg, 45mg, 50mg, 55mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 110mg, 120mg, 125mg, 130mg, 140mg, 150mg, 160mg, 170mg, 180mg, 190mg, 200mg, 210mg, 220mg, 230 mg, 240 mg, 250 mg, 300 mg, 320 mg, 400 mg, 480 mg, 500 mg, 600 mg, 640 mg, 840 mg of the compound of the present invention or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or eutectic.
一种用于治疗哺乳动物的疾病的方法，所述方法包括给予受试者治疗有效量的本发明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，治疗有效量优选1-1500mg，所述的疾病优选抑制或降解AR或AR剪切突变体相关疾病(如前列腺癌)。A method for treating diseases in mammals, the method comprising administering to a subject a therapeutically effective amount of a compound of the present invention or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable The salt or co-crystal, the therapeutically effective amount is preferably 1-1500 mg, and the disease preferably inhibits or degrades AR or AR splicing mutant-related diseases (such as prostate cancer).
一种用于治疗哺乳动物的疾病的方法所述方法包括，将药物本发明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1-1000mg/天的日剂量给予受试者，所述日剂量可以为单剂量或分剂量，在一些实施方案中，日剂量包括但不限于10-1500mg/天、10-1000mg/天、10-800mg/天、25-800mg/天、50-800mg/天、100-800mg/天、200-800mg/天、25-400mg/天、50-400mg/天、100-400mg/天、200-400mg/天，在一些实施方案中，日剂量包括但不限于10mg/天、20mg/天、25mg/天、50mg/天、80mg/天、100mg/天、125mg/天、150mg/天、160mg/天、200mg/天、300mg/天、320mg/天、400mg/天、480mg/天、600mg/天、640mg/天、800mg/天、1000mg/天。A method for treating diseases in mammals. The method includes: adding a pharmaceutical compound of the present invention or its stereoisomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal to A daily dose of 1-1000 mg/day is administered to the subject, and the daily dose may be a single dose or divided dose. In some embodiments, the daily dose includes but is not limited to 10-1500 mg/day, 10-1000 mg/day, 10 -800mg/day, 25-800mg/day, 50-800mg/day, 100-800mg/day, 200-800mg/day, 25-400mg/day, 50-400mg/day, 100-400mg/day, 200-400mg /day, in some embodiments, daily dosages include, but are not limited to, 10 mg/day, 20 mg/day, 25 mg/day, 50 mg/day, 80 mg/day, 100 mg/day, 125 mg/day, 150 mg/day, 160 mg/day , 200mg/day, 300mg/day, 320mg/day, 400mg/day, 480mg/day, 600mg/day, 640mg/day, 800mg/day, 1000mg/day.
本发明涉及一种试剂盒，该试剂盒可以包括单剂量或多剂量形式的组合物，该试剂盒包含本 发明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，本发明化合物的或者其立体异构体、氘代物、溶剂化物、前药、代谢产物、药学上可接受的盐或共晶的量与上述药物组合物中其量相同。The present invention relates to a kit which may comprise a composition in single dose or multiple dose form, the kit comprising the Compounds of the invention or their stereoisomers, deuterated products, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals, compounds of the invention or their stereoisomers, deuterated products, solvates, prodrugs The amounts of metabolites, pharmaceutically acceptable salts or co-crystals are the same as those in the above pharmaceutical compositions.
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 compounds or their stereoisomers, deuterated products, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals used in the preparation of drugs for the treatment of diseases related to PARP7 activity or expression levels. For application in the invention, preferably, the disease is selected from tumors.
本发明涉及上述的药物组合物在用于制备治疗与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 the application of the above pharmaceutical composition in the preparation of drugs for treating diseases related to PARP7 activity or expression. Preferably, the diseases are selected from tumors.
本发明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的量在每种情况下以游离碱的形式换算。The amounts of the compounds of the invention or of their stereoisomers, deuterates, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals are in each case converted to the free base form.
合成方法resolve resolution
为了完成本发明的目的，本发明化合物可以由以下方案制备而得：In order to achieve the purpose of the present invention, the compound of the present invention can be prepared by the following scheme:
方案一：通式(II)化合物选自通式(M-13)化合物时合成方法
Scheme 1: Synthetic method when the compound of general formula (II) is selected from the compounds of general formula (M-13)
PG、PG1或PG2各自独立的选自氨基保护基,优选Boc(叔丁基氧基羰基)、Cbz(苄基氧基羰基)、PMB(对甲氧基苄基)；PG, PG1 or PG2 are each independently selected from amino protecting groups, preferably Boc (tert-butyloxycarbonyl), Cbz (benzyloxycarbonyl), PMB (p-methoxybenzyl);
R选自C1-4烷基，优选甲基或乙基；R is selected from C 1-4 alkyl, preferably methyl or ethyl;
X选自离去基团，优选卤素、OMs、OTs或OTf，X is selected from leaving groups, preferably halogen, OMs, OTs or OTf,
其余基团定义与前述通式化合物(II)一致；The definitions of the remaining groups are consistent with the aforementioned general formula compound (II);
通式(M-1)化合物与氨基保护试剂反应得到通式(M-2)化合物； The compound of general formula (M-1) reacts with an amino protecting reagent to obtain the compound of general formula (M-2);
通式(M-2)化合物与X2通过亲核取代反应得到通式(M-3)化合物；The compound of general formula (M-2) and X 2 obtain the compound of general formula (M-3) through nucleophilic substitution reaction;
通式(M-3)化合物与在碱性试剂(如NaH)下通过亲核取代反应得到通式(M-4)化合物；Compounds of general formula (M-3) and Compounds of general formula (M-4) are obtained through nucleophilic substitution reaction in the presence of alkaline reagents (such as NaH);
通式(M-4)化合物通过脱氨基保护基反应得到通式(M-5)化合物；The compound of general formula (M-4) can obtain the compound of general formula (M-5) through deamination protecting group reaction;
通式(M-5)化合物在碱性条件下(如三乙胺、DIPEA)反应得到通式(M-6)化合物；The compound of general formula (M-5) reacts under alkaline conditions (such as triethylamine, DIPEA) to obtain the compound of general formula (M-6);
通式(M-6)化合物通过脱氨基保护基反应得到通式(M-7)化合物；The compound of general formula (M-6) can obtain the compound of general formula (M-7) through deamination protecting group reaction;
通式(M-7)化合物与通式(A-1)在碱性条件下(如碳酸钾、碳酸铯)通过亲核取代反应得到通式(M-8)化合物；Compounds of general formula (M-7) and general formula (A-1) are reacted with nucleophilic substitution under alkaline conditions (such as potassium carbonate, cesium carbonate) to obtain compounds of general formula (M-8);
或者通式(M-7)化合物与通式(A-1)在金属催化剂存在下通过偶联反应得到通式(M-8)化合物；Or the compound of general formula (M-7) and the general formula (A-1) can obtain the compound of general formula (M-8) through a coupling reaction in the presence of a metal catalyst;
通式(M-8)化合物在还原剂(如NaBH4、LiAlH4)条件下通过反应得到通式(M-9)化合物；The compound of general formula (M-8) is reacted under reducing agent (such as NaBH 4 , LiAlH 4 ) to obtain the compound of general formula (M-9);
通式(M-9)化合物与通式(A-2)化合物通过亲核取代反应得到通式(M-10)化合物；The compound of general formula (M-9) and the compound of general formula (A-2) obtain the compound of general formula (M-10) through nucleophilic substitution reaction;
通式(M-10)化合物脱氨基保护基反应得到通式(M-11)化合物；The compound of general formula (M-10) undergoes a deamination protecting group reaction to obtain a compound of general formula (M-11);
通式(M-11)化合物与通式(A-3)化合物在碱性条件下(如三乙胺、DIPEA)通过亲核取代反应得到通式(M-12)化合物；Compounds of general formula (M-11) and compounds of general formula (A-3) are obtained through nucleophilic substitution reaction under alkaline conditions (such as triethylamine, DIPEA) to obtain compounds of general formula (M-12);
通式(M-12)化合物脱氨基保护基反应得到通式(M-13)化合物。The compound of general formula (M-12) is reacted with the deamination protecting group to obtain the compound of general formula (M-13).
方案二：中间体M-9的合成方法
Scheme 2: Synthesis method of intermediate M-9
中间体(M-6)化合物在还原剂(如NaBH4、LiAlH4)条件下通过还原反应得到通式(N-1)化合物；The compound of the general formula (N-1) is obtained through a reduction reaction of the intermediate (M-6) compound under the condition of a reducing agent (such as NaBH 4 , LiAlH 4 );
通式(N-1)化合物通过脱氨基保护反应得到通式(N-2)化合物；Compounds of general formula (N-1) are obtained through deamination protection reaction to obtain compounds of general formula (N-2);
通式(N-2)化合物与通式(A-1)化合物在碱性条件下(如碳酸钾、碳酸铯)通过亲核取代反应得到通式(M-9)化合物；Compounds of general formula (N-2) and compounds of general formula (A-1) are obtained through nucleophilic substitution reaction under alkaline conditions (such as potassium carbonate, cesium carbonate) to obtain compounds of general formula (M-9);
或者通式(N-2)化合物与通式(A-1)化合物在金属催化剂存在下通过偶联反应得到通式(M-9)化合物；Or the compound of general formula (N-2) and the compound of general formula (A-1) can obtain the compound of general formula (M-9) through a coupling reaction in the presence of a metal catalyst;
通式(M-9)化合物通过方案一得到通式(M-13)化合物。The compound of general formula (M-9) can be used to obtain the compound of general formula (M-13) through Scheme 1.
方案三：通式I-B和通式I-C的合成

Scheme 3: Synthesis of general formula IB and general formula IC

具体合成条件参考化合物11的合成。For specific synthesis conditions, refer to the synthesis of compound 11.
1c”与M-14B反应，参考化合物11的合成，可以得到通式I-C所示的化合物。
By reacting 1c” with M-14B and referring to the synthesis of compound 11, the compound represented by the general formula IC can be obtained.
各个基团的定义与前面任意方案相同。The definition of each group is the same as in any previous scheme.
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, the 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 described in the present invention all include their isotope conditions, and the carbon involved in the groups and compounds described in the present invention , hydrogen, oxygen, sulfur or nitrogen are optionally replaced by one or more of their corresponding isotopes, where the isotopes of carbon include 12 C, 13 C and 14 C, and the isotopes of hydrogen include protium (H), deuterium (D), and (called deuterium), tritium (T, also called superheavy hydrogen), oxygen isotopes include 16 O, 17 O and 18 O, sulfur isotopes include 32 S, 33 S, 34 S and 36 S, and nitrogen isotopes 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" refers to 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”。"Halo-substituted" means substituted by 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 a substituent of I, substituted by 1 to 4 substituents selected from F, Cl, Br or I. "Halo-substituted" is simply referred to as "halogenated."
“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 linear or branched 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 group of carbon atoms, alkyl group of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neo-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and its various branched chain isomers; the alkyl group appearing in this article has the same definition as this definition. Alkyl groups may 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(CH2)v-X(CH2)v-X(CH2)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 group in which 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( CH2 )vX( CH2 )vX( CH2 )vH (v is an integer from 1 to 5, each , O or S, and at least 1 X is selected from heteroatoms, and N or S in the heteroatoms can be oxidized to various oxidation states). Heteroalkyl groups may 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-(CH2)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 are not Limited to methylene, ethylene, propylene, 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(CH2)v-X(CH2)v-X(CH2)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 group in which 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) substitution. Non-limiting examples include -X( CH2 )vX( CH2 )vX( CH2 )v-, v is an integer from 1 to 5, 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" refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon group, usually having 3 to 10 carbon atoms. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloalkyl. Gengji et al. Cycloalkyl groups appearing herein are as defined above. The cycloalkyl group may 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 cyclic hydrocarbon group containing heteroatoms, including but not limited to 3 to 10 atoms, 3 to 8 atoms, including 1 to 3 selected from N, O or The heteroatoms of S and the selectively substituted N and S in the heterocycloalkyl ring can be oxidized to various oxidation states. The heterocycloalkyl group can be connected to a heteroatom or a carbon atom, the heterocycloalkyl group can be connected to an aromatic ring or a non-aromatic ring, the heterocycloalkyl group can be connected to a bridged ring or a spiro ring, non-limiting examples include rings Oxyethyl, azetidinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, dioxolanyl, dioxanyl, pyrrolidinyl, Piperidinyl, imidazolidinyl, oxazolidinyl, oxazinyl, morpholinyl, hexahydropyrimidinyl, piperazinyl. Heterocycloalkyl groups 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 straight-chain and branched unsaturated hydrocarbon groups, which have 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 , 2 to 6 or 2 to 4 carbon atoms, examples of alkenyl 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-octenyl base, 1-nonenyl, 3-nonenyl, 1-decene, 4-decene, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene and 1,4-hexadiene, etc.; the alkenyl group appearing in this article has the same definition as this definition. Alkenyl groups may 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 straight-chain and branched unsaturated hydrocarbon groups, which have at least 1, usually 1, 2 or 3 carbon-carbon triple bonds, including but not limited to 2 in the main chain. to 10 carbon atoms, 2 to 6 carbon atoms, 2 to 4 carbon atoms, alkynyl examples include but are not limited to ethynyl, propargyl, 1-propynyl, 2-propynyl, 1-butyl Alkynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-1-butynyl, 2-Methyl-1-butynyl, 2-methyl-3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl base, 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.; the alkynyl group can be monovalent, divalent, trivalent or tetravalent .
“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 substituted or unsubstituted -O-alkyl. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, n-hexyloxy, cyclopropyloxy Oxygen 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、 “碳环基”或“碳环”可以是一价、二价、三价或四价。"Carbocyclyl" or "carbocyclic ring" refers to a substituted or unsubstituted saturated or unsaturated aromatic ring or non-aromatic ring. The aromatic ring or non-aromatic ring can be a 3- to 8-membered monocyclic ring or a 4- to 12-membered ring. Bicyclic or 10 to 15-membered tricyclic system, the carbocyclic group can be connected to an aromatic ring or a non-aromatic ring, and the aromatic ring or non-aromatic ring can be optionally a single ring, a bridged ring or a spiro ring. Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclohexane Pentyl-3- Alkenyl, cyclohexyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexenyl, benzene ring, naphthalene ring, "Carbocyclyl" or "carbocycle" may 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)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、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、 “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 ring or non-aromatic ring. The aromatic ring or non-aromatic ring can be a 3- to 8-membered monocyclic ring or a 4- to 12-membered ring. Bicyclic or 10 to 15-membered tricyclic system, and containing 1 or more (including but not limited to 2, 3, 4 or 5) heteroatoms selected from N, O or S, selected from the ring of the heterocyclyl group Sexually substituted N and S can be oxidized into various oxidation states. The heterocyclyl group can be connected to a heteroatom or a carbon atom. The heterocyclyl group can be connected to an aromatic ring or a non-aromatic ring. The heterocyclyl group can be connected to a bridged ring or a spiro ring. Non-limiting examples include epoxyethyl. , aziridyl, oxetanyl, azetidinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxanyl, nitrogen Heterocycloheptyl, pyridyl, furyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorphyl Phyllinyl, 1,3-dithiyl, dihydrofuryl, dihydropyranyl, dithiopentanyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyran base, benzimidazolyl, benzopyridyl, pyrrolopyridyl, benzodihydrofuranyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazinyl, indazolyl, benzothienyl , benzofuranyl, benzopyrrolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzopyridinyl, benzopyrimidinyl, benzopyrazinyl, piperazinyl, azabis Cycl[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl, oxaspiro[3.3]heptyl alkyl, "Heterocyclyl" or "heterocycle" may 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：。“螺环”或“螺环基”可以是一价、二价、三价或四价。"Spirocyclic" 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 spirocyclic system includes but is not limited to 5 to 20, 6 to 14, 6 to 12, 6 to 10, one or more rings may contain 0 or more (including but not limited to 1, 2, 3 or 4) double bonds, and any may contain 0 to 5 heteroatoms selected from N, O or S(=O) n . Non-limiting examples include: . "Spiro" or "spiryl" may 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： "Ring ring" or "ring ring group" refers to a polycyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, in which one or more rings may contain 0 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 selected from N, S (=O) n or O, n is 0, 1 or 2). The number of ring atoms in the parallel ring system includes but is not limited to 5 to 20, 5 to 14, 5 to 12, and 5 to 10. Non-limiting examples include:
“并环”或“并环基”可以是一价、二价、三价或四价。"And ring" or "and ring 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 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. It may contain 0 or more double bonds and any ring in the ring system. It may contain 0 to 5 selected from heteroatoms or groups containing heteroatoms (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 Cubane, adamantane. The "bridging ring" or "bridging ring base" may 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。"Carbospirocycle", "spirocarbocyclyl", "spirocarbocyclyl" or "carbospirocyclyl" refers to a "spirocycle" in which the ring system consists only of carbon atoms. "Carbospirocycle", "spirocarbocyclyl", "spirocarbocyclyl" or "carbospirocyclyl" appearing in this article have the same definition as spirocycle.
“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。"Carbocyclic ring", "carbocyclic ring radical", "carbocyclic ring radical" or "carbocyclic ring radical" refers to a "carbocyclic ring" in which the ring system only consists of carbon atoms. The definition of "carbocyclic ring", "carbocyclic ring group", "carbocyclic ring group" or "carbocyclic ring group" appearing in this article is consistent with that of carbocyclic ring.
“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 carbocyclyl", "bridged carbocyclyl" or "carbon bridged ring" refers to a "bridged ring" in which the ring system consists only of carbon atoms. The definitions of "carbon bridged ring", "bridged carbocyclic ring group", "bridged carbocyclic ring group" or "carbon bridged ring group" appearing in this article are consistent with those of 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。"Heteromonocycle", "monocyclic heterocyclyl" or "heteromonocyclyl" refers to the "heterocyclyl" or "heterocycle" of a monocyclic system. The heterocyclyl, "monocyclic heterocycle" appearing in this article "Basic" or "heteromonocyclyl", its definition is consistent with heterocyclic.
“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。"Heterocyclic ring", "heterocyclic ring group", "heterocyclic heterocyclyl group" or "heterocyclic ring radical" refers to a "heterocyclic ring" containing heteroatoms. The definitions of heterocyclic ring, "heterocyclic ring group", "heterocyclic heterocyclyl group" or "heterocyclic ring group" appearing in this article are consistent with those of the heterocyclic ring group.
“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", "spirocycloheterocyclyl" or "heterospirocyclyl" refers to a "spirocycle" containing heteroatoms. Heterospirocycle, "heterospirocyclyl", "spirocycloheterocyclyl" or "heterospirocyclyl" appearing in this article have the same definition as 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 heteroatoms. The definition of hetero-bridged ring, "hetero-bridged cyclyl", "bridged-ring heterocyclyl" or "hetero-bridged cyclyl" appearing in this article is consistent with that of 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、“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 or fused ring, and the ring atoms in the aromatic ring The number 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, in which the ring connected to the parent structure is an aryl ring. Non-limiting examples include benzene ring, naphthalene ring, "Aryl" or "aryl ring" may be monovalent, divalent, trivalent or tetravalent. When divalent, trivalent or tetravalent, the attachment site 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 "Heteroaryl" or "heteroaryl ring" refers to a substituted or unsubstituted aromatic hydrocarbon group, and contains 1 to 5 optional heteroatoms or heteroatom-containing groups (including but not limited to N, O or S (= O)n, n is 0, 1, 2), 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
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 groups appearing herein have the same definition as this definition. Heteroaryl groups may be monovalent, divalent, trivalent or tetravalent. When divalent, trivalent or tetravalent, the attachment site 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 5-membered heteroaromatic ring" refers to a 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 entire 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元杂芳基、6元杂芳环并5元杂芳环。"5-6-membered heteroaromatic ring" refers to a 5-6-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 entire group is aromatic, and non-limiting examples include benzo 5-membered heteroaryl, 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、-(CH2)m-C(＝O)-Ra、-O-(CH2)m-C(＝O)-Ra、-(CH2)m-C(＝O)-NRbRc、-(CH2)mS(＝O)nRa、-(CH2)m-烯基-Ra、ORd或-(CH2)m-炔基-Ra(其中m、n为0、1或2)、芳基硫基、硫代羰基、硅烷基或-NRbRc等基团，其中Rb与Rc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，Rb与Rc可形成五或六元环烷基或杂环基，Ra与Rd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, isocyanyl, aryl, heteroaryl, heterocyclyl, bridged cyclic group, spiro Cyclic group, cyclic group, hydroxyalkyl group, =O, carbonyl group, 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 Base -R a , OR d or -(CH 2 ) m -alkynyl-R a (where m, n is 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 including H, hydroxyl, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethyl Sulfonyl group, as an option, R b and R c can form a five- or six-membered cycloalkyl or heterocyclyl group, and R a and R d are each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl group, heterocyclic group, carbonyl group, ester group, bridged cyclic group, spirocyclic group or paracyclic group.
“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, and N" means containing 1, 2, 3, 4, or 5 heteroatoms selected from O, S, and 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“杂桥环任选被0至4个选自H或F的取代基所取代”是指杂桥环任选被0、1、2、3或4个选自H或F的取代基所取代。"Substituted by 0 to X substituents" means substituted by 0, 1, 2, 3...X substituents, and X is selected from any integer between 1 and 10. For example, "substituted with 0 to 4 substituents" means substituted with 0, 1, 2, 3 or 4 substituents. For example, "substituted with 0 to 5 substituents" means substituted with 0, 1, 2, 3, 4 or 5 substituents. For example, "the heterobridged ring is optionally substituted by 0 to 4 substituents selected from H or F" means that the heterobridged ring is optionally substituted by 0, 1, 2, 3 or 4 substituents selected from H or F. replace.
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、 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 Rings of X+1, X+2, X+3, X+4….Y elements. Rings include heterocycles, carbocycles, aromatic rings, aryl groups, heteroaryl groups, cycloalkyl groups, heteromonocycles, heterocycles, heterospirocycles or heterobridged rings. For example, "4-7 membered heteromonocyclic ring" refers to 4-, 5-, 6-, or 7-membered heteromonocyclic rings, and "5-10-membered heterocyclic ring" refers to 5-, 6-, 7-, or 8-membered heterocyclic rings. , 9- or 10-membered heterocyclic rings.
“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 may but need not occur, and that 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 can but does not have to be substituted by F, including 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 "pharmaceutically acceptable salt thereof" means that the compound of the present invention retains the biological effectiveness and properties of the free acid or free base, and the free acid is combined with a non-toxic inorganic base or Organic base, the salt of the free base obtained by reacting with a non-toxic inorganic acid or organic acid.
“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 compounds of the present invention, or their stereoisomers, tautomers, deuterates, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or A mixture of cocrystals and other chemical components, where "other chemical components" refers to pharmaceutically acceptable carriers, excipients and/or one or more other therapeutic agents.
“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 does not cause significant irritation to an organism and does not eliminate the biological activity and properties of the compound to which it is administered.
“制剂规格”是指每一支、片或其他每一个单位制剂中含有主药的重量。“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。"Preparation specification" refers to the weight of the main drug contained in each tube, tablet or other unit preparation. "Prodrug" refers to a compound of the present invention that can be converted into a biologically active compound through metabolism in the body. The prodrugs of the present invention are prepared by modifying the amino group or carboxyl group in the compound of the present invention. The modification can be removed by conventional operations or in vivo to obtain the parent compound. When the prodrug of the present invention is administered to a mammalian subject, the prodrug is cleaved to form a free amino or carboxyl group.
“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 combining an active pharmaceutical ingredient (API) and a co-crystal form (CCF) under the action of hydrogen bonds or other non-covalent bonds. The pure states of API and CCF are both Solids, and there are fixed stoichiometric ratios between the components. A eutectic is a multicomponent crystal that includes both a binary eutectic formed between two neutral solids and a multicomponent eutectic formed between a neutral solid and a salt or solvate.
“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 livestock, 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 produced by different spatial arrangements of atoms in a molecule, 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。"Tautomers" refer to functional group isomers produced by rapid movement of an atom in a molecule between two positions, such as keto-enol isomerism and amide-iminol isomerism.
“IC50”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。“IC 50 ” is the concentration of a drug or inhibitor required to inhibit half of a specified biological process (or a component in the process such as an enzyme, receptor, cell, etc.).
附图说明：Picture description:
附图1：39b的1H-1H COSY(400MHz.CD3COOD)；Figure 1: 1H-1H COSY of 39b (400MHz.CD 3 COOD);
附图2：39b的1H-1H NOESY(400MHz.CD3COOD)。Figure 2: 1H-1H NOESY of 39b (400MHz.CD 3 COOD).
具体实施方式Detailed ways
以下结合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 technical solution of the present invention will be described in detail below with reference to the examples, 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-d6)，氘代氯仿(CDCl3)，氘代甲醇(CD3OD)，氘代乙酸(CD3COOD)，内标为四甲基硅烷(TMS)；The structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). NMR shift(δ) Given in units of 10 -6 (ppm). NMR was measured using (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic instruments, and the measurement solvents were deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), and deuterated methanol (CD 3 OD ), deuterated acetic acid (CD 3 COOD), the internal standard is tetramethylsilane (TMS);
MS的测定用(Agilent 6120B(ESI)和Agilent 6120B(APCI))；For MS measurement (Agilent 6120B (ESI) and Agilent 6120B (APCI));
HPLC的测定使用Agilent 1260DAD高压液相色谱仪(Zorbax SB-C18 100×4.6mm,3.5μM)；HPLC was measured using Agilent 1260DAD high-pressure 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；Thin layer chromatography silica gel plates use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates. The specifications of silica gel plates used in thin layer chromatography (TLC) are 0.15mm-0.20mm. The specifications used for thin layer chromatography separation and purification products are 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，制备本文所述反应中使用的化合物“商业上可用的化学品”是从标准的商业来源获得的，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, the compounds used in the reactions described herein are prepared according to organic synthesis techniques known to those skilled in the art, starting from commercially available chemicals and/or compounds described in the chemical literature. "Chemicals" were obtained from standard commercial sources, including Shanghai Aladdin Biochemical Technology Co., Ltd., Shanghai McLean Biochemical Technology Co., Ltd., Sigma-Aldrich, Alfa Aesar (China) Chemical Co., Ltd., TiXia ( Shanghai) Chemical Industry Development Co., Ltd., Anaiji Chemical, Shanghai Titan Technology Co., Ltd., Kelon Chemical, Bailingwei Technology Co., Ltd., etc.
合成实验中，无特殊说明，温度为室温。In the synthesis experiment, the temperature is room temperature unless otherwise specified.
THF：四氢呋喃；DMF：N,N-二甲基甲酰胺；DIPEA：N,N-二异丙基乙胺；HATU：CAS 148893-10-1THF: Tetrahydrofuran; DMF: N,N-dimethylformamide; DIPEA: N,N-diisopropylethylamine; HATU: CAS 148893-10-1
5-氯-2-[(4-甲氧基苄基)甲基]-4-(三氟甲基)-2,3-二氢哒嗪-3-酮为中间体1： 5-Chloro-2-[(4-methoxybenzyl)methyl]-4-(trifluoromethyl)-2,3-dihydropyridazin-3-one is intermediate 1:
实施例1：化合物1的制备
Example 1: Preparation of Compound 1
第一步：1b’的制备Step 1: Preparation of 1b’
冰水浴下，将1a’(5.00g,19.36mmol)加入到四氢呋喃(40mL)，氮气置换后，加入氢化铝锂(0.74g,19.43mmol)，冰水浴搅拌2h。加入十水硫酸钠至体系不再产生气体,室温搅拌10min。垫硅藻土过滤，滤饼用四氢呋喃(40mL x 3)淋洗，滤液减压浓缩后得1b’(4.00g，90％)。Under an ice-water bath, 1a' (5.00g, 19.36mmol) was added to tetrahydrofuran (40 mL). After nitrogen replacement, lithium aluminum hydride (0.74g, 19.43mmol) was added, and the mixture was stirred for 2 hours in an ice-water bath. Add sodium sulfate decahydrate until the system no longer produces gas, and stir at room temperature for 10 minutes. Filter through diatomaceous earth, rinse the filter cake with tetrahydrofuran (40mL x 3), and concentrate the filtrate under reduced pressure to obtain 1b’ (4.00g, 90%).
LCMS m/z＝231.1[M+1]+。LCMS m/z=231.1[M+1] + .
第二步：1b”的制备Step 2: Preparation of 1b”
将三乙胺(53.93g,532.72mmol)加入到(2S)-2-氨基丙烷-1-醇(1a”)(10.00g,133.18mmol)，邻苯二甲酸酐(19.73g,133.18mmol)的甲苯(500mL)溶液中，145℃回流分水反应7h。冷却到室温，加入硅胶，减压浓缩后柱层析分离纯化(二氯甲烷：甲醇(v/v)＝100:3)得到1b”(20.00g,73％)。Triethylamine (53.93g, 532.72mmol) was added to (2S)-2-aminopropan-1-ol (1a”) (10.00g, 133.18mmol) and phthalic anhydride (19.73g, 133.18mmol). In toluene (500 mL) solution, perform a reflux and water separation reaction at 145°C for 7 hours. Cool to room temperature, add silica gel, concentrate under reduced pressure and then separate and purify by column chromatography (dichloromethane: methanol (v/v) = 100:3) to obtain 1b" (20.00g, 73%).
LCMS m/z＝206.1[M+1]+ LCMS m/z＝206.1[M+1] +
第三步：1c”的制备Step 3: Preparation of 1c”
向1b”(2g,11.41mmol)的二氯甲烷(40mL)溶液中加入1,8-二氮杂二环[5.4.0]十一碳-7-烯(1.48g,9.74mmol)，三氯乙腈(3.52g,24.35mmol)，室温反应2h。加入硅胶，减压浓缩后经柱层析分离纯化(石油醚：四氢呋喃(v/v)＝5:1)得到1c”(1.74g)粗品。To a solution of 1b” (2g, 11.41mmol) in dichloromethane (40mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (1.48g, 9.74mmol), trichloro Acetonitrile (3.52g, 24.35mmol), react at room temperature for 2 hours. Add silica gel, concentrate under reduced pressure, and then separate and purify by column chromatography (petroleum ether: tetrahydrofuran (v/v) = 5:1) to obtain 1c" (1.74g) crude product.
1H NMR(400MHz,DMSO-d6)δ9.41(s,1H),7.89-7.79(m,4H),4.74-4.62(m,2H),4.53-4.42(m,1H),1.45(d,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ9.41(s,1H),7.89-7.79(m,4H),4.74-4.62(m,2H),4.53-4.42(m,1H),1.45(d ,3H).
第四步：1b的制备Step 4: Preparation of 1b
将L-丝氨酸(10.50g,99.88mmol)和溴化钾(40.41g,339.59mmol)溶于水(80mL)中，氮气置换，缓慢滴加氢溴酸(33.67g,199.76mmol,48％)，降温至-15℃，缓慢滴加亚硝酸钠(8.68g,125.82mmol)的水(25mL)溶液，室温反应6h。氮气鼓吹0.5h，乙酸乙酯(100mL x6)萃取，合并有机相，有机相用饱和食盐水(100mL)洗涤1次，无水硫酸钠干燥，抽滤，滤液经减压浓缩得1b(14.76g) 粗品。Dissolve L-serine (10.50g, 99.88mmol) and potassium bromide (40.41g, 339.59mmol) in water (80mL), replace with nitrogen, and slowly add hydrobromic acid (33.67g, 199.76mmol, 48%). Cool the temperature to -15°C, slowly add sodium nitrite (8.68g, 125.82mmol) in water (25mL) dropwise, and react at room temperature for 6 hours. Blow nitrogen for 0.5h, extract with ethyl acetate (100mL ) Crude.
LCMS m/z＝166.9[M-1]-。LCMS m/z=166.9[M-1] - .
第五步：1c的制备Step 5: Preparation of 1c
将1b(14.70g,87.03mmol,)，咪唑(23.70g,348.12mmol)溶于DMF(50mL)中，缓慢滴加叔丁基二苯基氯硅烷(29.90g,108.79mmol)，室温反应过夜。倒入到水(500mL)中，乙酸乙酯(200mL x 2)萃取，合并有机相，有机相用饱和食盐水(100mL x 2)洗涤，无水硫酸钠干燥，抽滤，滤液经减压浓缩得粗品，粗品经柱层析分离纯化(石油醚：四氢呋喃(v/v)＝9:1，1‰冰醋酸)得1c(20.90g,51％,2步收率)。Dissolve 1b (14.70g, 87.03mmol,) and imidazole (23.70g, 348.12mmol) in DMF (50mL), slowly add tert-butyldiphenylsilyl chloride (29.90g, 108.79mmol) dropwise, and react at room temperature overnight. Pour into water (500mL), extract with ethyl acetate (200mL x 2), combine the organic phases, wash the organic phase with saturated brine (100mL x 2), dry over anhydrous sodium sulfate, filter with suction, and concentrate the filtrate under reduced pressure A crude product was obtained, which was separated and purified by column chromatography (petroleum ether: tetrahydrofuran (v/v) = 9:1, 1‰ glacial acetic acid) to obtain 1c (20.90g, 51%, 2-step yield).
LCMS m/z＝405.0[M-1]-。LCMS m/z=405.0[M-1] - .
第六步：1d的制备Step 6: Preparation of 1d
将1c(2.52g,6.19mmol)溶于草酰氯(25mL)中，加入0.1mL DMF，50℃反应2h。减压浓缩，用二氯甲烷(20mL)溶解后减压浓缩。冰水浴下，将残留物的二氯甲烷(10mL)溶液缓慢滴加到1b’(1.43g,6.20mmol)和DIPEA(2.40g,18.60mmol)的二氯甲烷(20mL)溶液中，室温反应1h。加入硅胶，减压浓缩后柱层析分离纯化(石油醚：四氢呋喃(v/v)＝4:1)得1d(3.39g,88％)。Dissolve 1c (2.52g, 6.19mmol) in oxalyl chloride (25mL), add 0.1mL DMF, and react at 50°C for 2h. Concentrate under reduced pressure, dissolve in dichloromethane (20 mL) and concentrate under reduced pressure. Under an ice-water bath, slowly add the residue solution in dichloromethane (10 mL) dropwise to the solution of 1b' (1.43g, 6.20mmol) and DIPEA (2.40g, 18.60mmol) in dichloromethane (20mL), and react at room temperature for 1 hour. . Silica gel was added, concentrated under reduced pressure, and then separated and purified by column chromatography (petroleum ether: tetrahydrofuran (v/v) = 4:1) to obtain 1d (3.39 g, 88%).
LCMS m/z＝541.2[M-77]+。LCMS m/z=541.2[M-77] + .
第七步：1e的制备Step 7: Preparation of 1e
将1d(2.39g,3.85mmol)溶于四氢呋喃(10mL)中，氮气置换后，0℃分批加入钠氢(231mg,5.78mmol,60％)，0℃反应1h。加入饱和氯化铵溶液(30mL)淬灭反应，乙酸乙酯(30mL x 3)萃取，合并有机相，饱和食盐水(20mL)洗涤1次，无水硫酸钠干燥，抽滤，滤液经减压浓缩得粗品，粗品经柱层析分离纯化(石油醚：四氢呋喃(v/v)＝4:1)得1e(1.22g,59％)。Dissolve 1d (2.39g, 3.85mmol) in tetrahydrofuran (10mL), and after nitrogen replacement, add sodium hydrogen (231mg, 5.78mmol, 60%) in batches at 0°C, and react at 0°C for 1 hour. Add saturated ammonium chloride solution (30mL) to quench the reaction, extract with ethyl acetate (30mL Concentrate to obtain a crude product, which is separated and purified by column chromatography (petroleum ether: tetrahydrofuran (v/v) = 4:1) to obtain 1e (1.22g, 59%).
LCMS m/z＝461.3[M-77]+。LCMS m/z=461.3[M-77] + .
第八步：1f的三氟乙酸盐的制备Step 8: Preparation of trifluoroacetate salt of 1f
将1e(1.62g,3.01mmol)溶于二氯甲烷(20mL)中，加入三氟乙酸(20mL)，室温反应2h。减压浓缩用二氯甲烷(20mL x 2)溶解后减压浓缩得1f的三氟乙酸盐的粗品。Dissolve 1e (1.62g, 3.01mmol) in dichloromethane (20mL), add trifluoroacetic acid (20mL), and react at room temperature for 2h. Concentrate under reduced pressure. Dissolve in dichloromethane (20mL x 2) and concentrate under reduced pressure to obtain the crude product of 1f trifluoroacetate.
LCMS m/z＝439.3[M+1]+。LCMS m/z=439.3[M+1] + .
第九步：1g的制备Step 9: Preparation of 1g
将1f的三氟乙酸盐粗品，2-氯-5-(三氟甲基)嘧啶(690mg,3.78mmol)，碳酸钾(1.56g,11.25mmol)依次加入到N-甲基吡咯烷酮(2mL)中，90℃反应2h。倒入到水(30mL)中，乙酸乙酯(20mL x 3)萃取，合并有机相，饱和食盐水(20mL x 5)洗涤，无水硫酸钠干燥，抽滤，滤液减压浓缩得粗品，粗品经柱层析分离纯化(100％四氢呋喃)得1g(546mg,52％,2步收率)。Add the crude trifluoroacetate of 1f, 2-chloro-5-(trifluoromethyl)pyrimidine (690mg, 3.78mmol), and potassium carbonate (1.56g, 11.25mmol) to N-methylpyrrolidone (2mL) in sequence Medium, react at 90°C for 2 hours. Pour into water (30mL), extract with ethyl acetate (20mL Separate and purify by column chromatography (100% tetrahydrofuran) to obtain 1 g (546 mg, 52%, 2-step yield).
LCMS m/z＝347.0[M+1]+。LCMS m/z=347.0[M+1] + .
第十步：化合物1h的制备Step 10: Preparation of Compound 1h
将1g(50mg,0.14mmol)，1c”(98mg,0.28mmol)溶于甲苯(10mL)中，氮气置换后0℃加入三溴化硼乙醚络合物(0.5mL)，23℃反应16h。0℃缓慢滴加饱和碳酸氢钠溶液(10mL)淬灭反应。乙酸乙酯(50mL x3)萃取，合并有机相，有机相用饱和食盐水(20mL)洗涤1次，无水硫酸钠干燥，抽滤，滤液减压浓缩得残留物，残留物柱层析分离纯化(石油醚：四氢呋喃(v/v)＝3:2)得1h(16mg,21％)。Dissolve 1g (50mg, 0.14mmol) and 1c″ (98mg, 0.28mmol) in toluene (10mL). After nitrogen replacement, add boron tribromide diethyl ether complex (0.5mL) at 0°C and react at 23°C for 16h. 0 ℃, slowly drop saturated sodium bicarbonate solution (10mL) to quench the reaction. Extract with ethyl acetate (50mL x 3), combine the organic phases, wash the organic phase once with saturated brine (20mL), dry over anhydrous sodium sulfate, and filter , the filtrate was concentrated under reduced pressure to obtain a residue, which was separated and purified by column chromatography (petroleum ether: tetrahydrofuran (v/v) = 3:2) to obtain 1h (16 mg, 21%).
LCMS m/z＝534.3[M+1]+。 LCMS m/z=534.3[M+1] + .
第十一步：1i的制备Step 11: Preparation of 1i
将1h(80mg,0.15mmol)溶于乙醇(2mL)中，加入水合肼(47mg,0.75mmol,80％)。室温反应2h。减压浓缩，粗品经制备板(二氯甲烷：甲醇(v/v)＝10:1)纯化得1i(27mg,45％)。Dissolve 1h (80 mg, 0.15 mmol) in ethanol (2 mL), and add hydrazine hydrate (47 mg, 0.75 mmol, 80%). React at room temperature for 2 hours. Concentrate under reduced pressure, and the crude product was purified by preparation plate (dichloromethane: methanol (v/v) = 10:1) to obtain 1i (27 mg, 45%).
LCMS m/z＝404.2[M+1]+。LCMS m/z=404.2[M+1] + .
第十二步：1j的制备Step 12: Preparation of 1j
将1i(27mg,0.7mmol)溶于乙腈(2mL)中，加入三乙胺(14mg,0.13mmol)，室温反应16h。减压浓缩，粗品经Prep-TLC(石油醚：乙酸乙酯(v/v)＝1:2)纯化得1j(45mg,98％)。Dissolve 1i (27 mg, 0.7 mmol) in acetonitrile (2 mL), add triethylamine (14 mg, 0.13 mmol), and react at room temperature for 16 h. Concentrate under reduced pressure, and the crude product was purified by Prep-TLC (petroleum ether: ethyl acetate (v/v) = 1:2) to obtain 1j (45 mg, 98%).
LCMS m/z＝686.2[M+1]+。LCMS m/z=686.2[M+1] + .
第十三步：化合物1的制备Step 13: Preparation of Compound 1
将1j(45mg,0.07mmol)溶于三氟乙酸(2mL)中，加入三氟甲磺酸(0.2mL)，室温反应1h。减压浓缩，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 C18，内径x长度＝19mm x250mm)。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)得到化合物1(15mg,40％)。Dissolve 1j (45 mg, 0.07 mmol) in trifluoroacetic acid (2 mL), add trifluoromethanesulfonic acid (0.2 mL), and react at room temperature for 1 h. Concentrate under reduced pressure, dissolve the crude product in methanol, add DIPEA dropwise to adjust the pH to 8-9, after concentration under reduced pressure, the residue is purified by Pre-HPLC (instrument and preparation column: Waters 2767 is used to prepare the liquid phase, and the preparation column model is XBridge@ Prep C 18 , inner diameter x length = 19mm x 250mm). Preparation method: Dissolve the crude product in DMF and filter it with a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile/water (containing 0.05% ammonia). Gradient elution method: acetonitrile gradient elution from 10% to 55% (flow rate: 12 mL/min; elution time 17 min) to obtain compound 1 (15 mg, 40%).
LCMS m/z＝566.1[M+1]+。LCMS m/z=566.1[M+1] + .
1H NMR(400MHz,DMSO-d6)δ12.42(s,1H),8.74(s,2H),7.91(s,1H),6.31-6.20(m,1H),4.44-4.36(m,1H),4.35-4.26(m,2H),4.20-4.09(m,1H),4.08-4.01(m,2H),3.89-3.80(m,1H),3.77-3.67(m,4H),3.63-3.56(m,1H),3.55-3.46(m,3H),1.83-1.70(m,1H),1.68-1.60(m,1H),1.16(d,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ12.42(s,1H),8.74(s,2H),7.91(s,1H),6.31-6.20(m,1H),4.44-4.36(m,1H ),4.35-4.26(m,2H),4.20-4.09(m,1H),4.08-4.01(m,2H),3.89-3.80(m,1H),3.77-3.67(m,4H),3.63-3.56 (m,1H),3.55-3.46(m,3H),1.83-1.70(m,1H),1.68-1.60(m,1H),1.16(d,3H).
实施例2：化合物2-1和化合物2-2的制备
Example 2: Preparation of Compound 2-1 and Compound 2-2
化合物1经SFC on I.D column纯化(仪器及制备柱：采用Waters 150SFC，制备柱型号是：Chiralcel OJ-Column(250*30mm,I.D 30mm,10um particle size)。制备方法：化合物3用甲醇溶解，并用0.45μm滤膜过滤，制备成样品液。流动相体系：A for CO2 and B for MeOH(0.1％NH3·H2O)。梯度洗脱方法：30％B等梯度洗脱(流速：100mL/min；洗脱时间1.6min)，冻干后得到化合物2-1和化合物2-2。Compound 1 was purified by SFC on ID column (instrument and preparation column: Waters 150SFC was used, and the preparation column model was: Chiralcel OJ-Column (250*30mm, ID 30mm, 10um particle size). Preparation method: Dissolve compound 3 with methanol, and use Filter through a 0.45μm filter membrane to prepare a sample solution. Mobile phase system: A for CO 2 and B for MeOH (0.1% NH3·H2O). Gradient elution method: 30% B iso-gradient elution (flow rate: 100mL/min; Elution time: 1.6 min), and compound 2-1 and compound 2-2 were obtained 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：Chiralcel OJ-3 50×4.6mm I.D.,3μm；流动相体系：A for CO2 and B for MeOH(0.05％DEA)，3.0ml/min。Analytical method (instrument and preparation column: high performance liquid chromatography - normal phase chromatography, preparation column model: Chiralcel OJ-3 50×4.6mm I.D., 3μm; mobile phase system: A for CO2 and B for MeOH (0.05% DEA ), 3.0ml/min.
保留时间T＝1.325min为化合物2-A(化合物2-A为化合物2-1和化合物2-2结构之一)。The retention time T=1.325min is compound 2-A (compound 2-A is one of the structures of compound 2-1 and compound 2-2).
LCMS m/z＝566.2[M+1]+ LCMS m/z＝566.2[M+1] +
1H NMR(400MHz,CD3OD)δ8.59(s,2H),7.96(s,1H),4.53-4.44(m,1H),4.35-4.27(m,2H),4.20-4.06(m,3H),4.01-3.93(m,1H),3.89-3.78(m,4H),3.72-3.61(m,3H),3.56-3.50(m,1H), 1.97-1.84(m,1H),1.75-1.66(m,1H),1.27(d,3H). 1 H NMR (400MHz, CD 3 OD) δ8.59(s,2H),7.96(s,1H),4.53-4.44(m,1H),4.35-4.27(m,2H),4.20-4.06(m, 3H),4.01-3.93(m,1H),3.89-3.78(m,4H),3.72-3.61(m,3H),3.56-3.50(m,1H), 1.97-1.84(m,1H),1.75-1.66(m,1H),1.27(d,3H).
保留时间T＝1.666min为化合物2-B(化合物2-B为化合物2-1和化合物2-2结构之一)。The retention time T=1.666min is compound 2-B (compound 2-B is one of the structures of compound 2-1 and compound 2-2).
LCMS m/z＝566.2[M+1]+ LCMS m/z＝566.2[M+1] +
1H NMR(400MHz,CD3OD)δ8.60(s,2H),7.95(s,1H),4.56-4.47(m,1H),4.36-4.27(m,2H),4.21-4.07(m,3H),3.99-3.93(m,1H),3.90-3.76(m,4H),3.72-3.58(m,3H),3.54-3.49(m,1H),1.95-1.83(m,1H),1.74-1.65(m,1H),1.27(d,3H). 1 H NMR (400MHz, CD 3 OD) δ8.60(s,2H),7.95(s,1H),4.56-4.47(m,1H),4.36-4.27(m,2H),4.21-4.07(m, 3H),3.99-3.93(m,1H),3.90-3.76(m,4H),3.72-3.58(m,3H),3.54-3.49(m,1H),1.95-1.83(m,1H),1.74- 1.65(m,1H),1.27(d,3H).
实施例3：化合物3的制备
Example 3: Preparation of Compound 3
第一步：3c的制备Step 1: Preparation of 3c
冰水浴下，将草酰氯(8.29g，65.31mmol)缓慢滴加到1c(3.80g，9.33mmol)的DCM(30mL)、DMF(0.05mL)溶液中，50℃反应2h。减压浓缩得酰氯粗品。Under an ice-water bath, oxalyl chloride (8.29g, 65.31mmol) was slowly added dropwise to the solution of 1c (3.80g, 9.33mmol) in DCM (30mL) and DMF (0.05mL), and the reaction was carried out at 50°C for 2h. Concentrate under reduced pressure to obtain crude acid chloride.
冰水浴下，将已制得酰氯的二氯甲烷溶液(10mL)缓慢滴加到3-(羟甲基)哌嗪-1-羧酸叔丁酯(1.93g，8.92mmol)、DIPEA(4.61g，35.68mmol)的DCM(20mL)溶液中，室温反应1h。加入硅胶，减压浓缩后经柱层析分离纯化(石油醚：四氢呋喃(V:V)＝5:1，210nm波长检测)得到3c(3.60g，64％)。Under an ice-water bath, the dichloromethane solution (10 mL) of the prepared acid chloride was slowly added dropwise to 3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester (1.93g, 8.92mmol) and DIPEA (4.61g , 35.68 mmol) in DCM (20 mL) solution, react at room temperature for 1 h. Silica gel was added, concentrated under reduced pressure, and then separated and purified by column chromatography (petroleum ether: tetrahydrofuran (V:V) = 5:1, 210 nm wavelength detection) to obtain 3c (3.60 g, 64%).
LCMS m/z＝527.0[M-77]+ LCMS m/z＝527.0[M-77] +
第二步：化合物3d的制备Step 2: Preparation of Compound 3d
冰水浴下，将钠氢(0.36g，9.03mmol，含量：60％)分批加入到3c(3.60g，5.94mmol)的THF(30mL)溶液中，冰水浴反应1h，室温反应1h。加饱和氯化铵溶液(2ml)淬灭反应。二氯甲烷萃取(30mLx3)。有机相经无水硫酸钠干燥、抽滤，滤液减压浓缩后得粗品，粗品经柱层析分离纯化(石油醚：四氢呋喃(V:V)＝5:1，210nm波长检测)得3d(1.50g，48％)。Under an ice-water bath, add sodium hydrogen (0.36g, 9.03mmol, content: 60%) in batches to a solution of 3c (3.60g, 5.94mmol) in THF (30mL), react in an ice-water bath for 1 hour, and react at room temperature for 1 hour. The reaction was quenched by adding saturated ammonium chloride solution (2 ml). Dichloromethane extraction (30mLx3). The organic phase was dried over anhydrous sodium sulfate and suction filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (petroleum ether: tetrahydrofuran (V:V) = 5:1, 210nm wavelength detection) to obtain 3d (1.50 g, 48%).
LCMS m/z＝447.2[M-77]+ LCMS m/z＝447.2[M-77] +
第三步：3e的三氟乙酸盐制备Step 3: Preparation of trifluoroacetate salt of 3e
将三氟乙酸(4mL)加入到3d(1.25g，2.38mmol)的DCM(4mL)溶液中，室温搅拌反应2h。减压浓缩得到3e的三氟乙酸盐(1.2g)粗品。Trifluoroacetic acid (4 mL) was added to a solution of 3d (1.25 g, 2.38 mmol) in DCM (4 mL), and the reaction was stirred at room temperature for 2 h. Concentrate under reduced pressure to obtain crude trifluoroacetate salt (1.2g) of 3e.
LCMS m/z＝425.3[M+1]+ LCMS m/z＝425.3[M+1] +
第四步：3f的制备Step 4: Preparation of 3f
将碳酸钾(1.23g，8.92mmol)加入到3e的三氟乙酸盐(1.2g)、2-氯-5-(三氟甲基)嘧啶(0.45g，2.45mmol)的DMSO(4mL)溶液中，95℃反应3h。冷却到室温，加乙酸乙酯50mL稀释反应液，饱 和氯化钠水溶液洗涤(20mLx3)，有机相经无水硫酸钠干燥、抽滤，滤液减压浓缩后得粗品，粗品经柱层析分离纯化(石油醚：四氢呋喃(v:v)＝5:2)得到3f(600mg，76％，2步收率)。Potassium carbonate (1.23g, 8.92mmol) was added to a solution of 3e trifluoroacetate (1.2g), 2-chloro-5-(trifluoromethyl)pyrimidine (0.45g, 2.45mmol) in DMSO (4mL) Medium, react at 95°C for 3 hours. Cool to room temperature, add 50 mL of ethyl acetate to dilute the reaction solution, saturate Wash with sodium chloride aqueous solution (20mLx3), dry the organic phase over anhydrous sodium sulfate, and suction filtrate. The filtrate is concentrated under reduced pressure to obtain a crude product. The crude product is separated and purified by column chromatography (petroleum ether: tetrahydrofuran (v:v) = 5: 2) Obtain 3f (600 mg, 76%, 2-step yield).
LCMS m/z＝333.1[M+1]+ LCMS m/z＝333.1[M+1] +
第五步：3g的制备Step 5: Preparation of 3g
将3f(400mg，1.20mmol)，1c”(839mg，2.4mmol)溶于甲苯(80mL)中，氮气置换后，0℃加入三氟化硼乙醚(4mL)，23℃反应16h。0℃缓慢滴加饱和碳酸氢钠溶液(20mL)淬灭反应，乙酸乙酯萃取(50mLx3)，合并有机相，有机相经减压浓缩后得粗品，粗品经柱层析分离纯化(石油醚：四氢呋喃(v:v)＝3:2)得3g(110mg，18％)。Dissolve 3f (400 mg, 1.20 mmol) and 1c” (839 mg, 2.4 mmol) in toluene (80 mL). After nitrogen replacement, add boron trifluoride ether (4 mL) at 0°C and react for 16 hours at 23°C. Drop slowly at 0°C. Add saturated sodium bicarbonate solution (20 mL) to quench the reaction, extract with ethyl acetate (50 mL v)=3:2) to get 3g (110mg, 18%).
LCMS m/z＝520.1[M+1]+ LCMS m/z＝520.1[M+1] +
第六步：3h的制备Step 6: Preparation for 3h
将水合肼(0.15mL)加入到3g(164mg，0.32mmol)的乙醇(4mL)溶液中，室温反应16h。减压浓缩后经Prep-TLC分离纯化(二氯甲烷：甲醇(v:v)＝10:1)得3h(75mg，61％)。Hydrazine hydrate (0.15 mL) was added to a solution of 3 g (164 mg, 0.32 mmol) in ethanol (4 mL), and the reaction was carried out at room temperature for 16 h. After concentration under reduced pressure, it was separated and purified by Prep-TLC (dichloromethane: methanol (v:v) = 10:1) to obtain 3h (75 mg, 61%).
LCMS m/z＝390.2[M+1]+ LCMS m/z＝390.2[M+1] +
第七步：3j的制备Step Seven: Preparation of 3j
将中间体1(73mg，0.23mmol)加入到3h(75mg，0.19mmol)、三乙胺(58mg，0.57mmol)的乙腈(2mL)溶液中，室温反应16h。减压浓缩后经柱层析分离纯化(石油醚：乙酸乙酯(v:v)＝1:2)得到3j(40mg，31％)。Intermediate 1 (73 mg, 0.23 mmol) was added to a solution of 3 h (75 mg, 0.19 mmol) and triethylamine (58 mg, 0.57 mmol) in acetonitrile (2 mL), and the reaction was carried out at room temperature for 16 h. After concentration under reduced pressure, the product was separated and purified by column chromatography (petroleum ether: ethyl acetate (v:v) = 1:2) to obtain 3j (40 mg, 31%).
LCMS m/z＝672.1[M+1]+ LCMS m/z＝672.1[M+1] +
第八步：化合物3的制备Step 8: Preparation of Compound 3
将三氟甲磺酸(32mg，0.21mmol)加入到3j(40mg，0.06mmol)的TFA(2mL)溶液中，室温反应1h。减压浓缩，加水(4mL)淬灭反应，氨水调节PH＝8。水溶液经C18柱分离纯化(流动相体系：乙腈/水(含0.1％的氨水)；梯度洗脱方法：乙腈由5％梯度洗脱至40％)得到化合物3(12mg，37％)。Trifluoromethanesulfonic acid (32 mg, 0.21 mmol) was added to a solution of 3j (40 mg, 0.06 mmol) in TFA (2 mL), and the reaction was carried out at room temperature for 1 h. Concentrate under reduced pressure, add water (4 mL) to quench the reaction, and adjust pH=8 with ammonia. The aqueous solution was separated and purified through C 18 column (mobile phase system: acetonitrile/water (containing 0.1% ammonia); gradient elution method: acetonitrile gradient elution from 5% to 40%) to obtain compound 3 (12 mg, 37%).
LCMS m/z＝552.2[M+1]+ LCMS m/z＝552.2[M+1] +
1H NMR(400MHz,DMSO-d6)δ12.41(s,1H),8.73(s,2H),7.91(s,1H),6.32-6.20(m,1H),4.72-4.63(m,2H),4.45-4.35(m,1H),4.23(d,1H),4.15(s,1H),3.95-3.81(m,3H),3.79-3.70(m,1H),3.58-3.46(m,3H),3.04-2.88(m,2H),2.85-2.74(m,1H),1.14(d,3H). 1 H NMR (400MHz, DMSO-d6) δ12.41(s,1H),8.73(s,2H),7.91(s,1H),6.32-6.20(m,1H),4.72-4.63(m,2H) ,4.45-4.35(m,1H),4.23(d,1H),4.15(s,1H),3.95-3.81(m,3H),3.79-3.70(m,1H),3.58-3.46(m,3H) ,3.04-2.88(m,2H),2.85-2.74(m,1H),1.14(d,3H).
实施例4：
Example 4:
化合物3经SFC on I.D column纯化(仪器及制备柱：采用Waters 150SFC，制备柱型号是：Chiralcel Column(250*30mm,I.D 30mm,10um particle size)。制备方法：化合物3用甲醇溶解，并用0.45μm滤膜过滤，制备成样品液。流动相体系：A for CO2 and B for MeOH(0.1％NH3.H2O)。梯度洗脱方法：20％B等梯度洗脱(流速：110mL/min；洗脱时间2.5min)，冻干后得到化合物4-1和化合物4-2。Compound 3 was purified by SFC on ID column (instrument and preparation column: Waters 150SFC was used, and the preparation column model was: Chiralcel Column (250*30mm, ID 30mm, 10um particle size). Preparation method: Compound 3 was dissolved in methanol, and used with 0.45 μm Filter through the membrane 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: 20% B iso-gradient elution (flow rate: 110mL/min ; elution time 2.5 min), and compound 4-1 and compound 4-2 were obtained 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：Chiralcel OD-3 50×4.6mm I.D.,3μm；流动相体系：A for CO2 and B for MeOH(0.05％DEA)，3.0ml/min。 Analytical method (instrument and preparation column: high performance liquid chromatography – normal phase chromatography, preparation column model: Chiralcel OD-3 50×4.6mm ID, 3μm; mobile phase system: A for CO2 and B for MeOH (0.05% DEA ), 3.0ml/min.
保留时间T＝1.435min为化合物4-A(化合物4-A为化合物4-1和化合物4-2结构之一)。The retention time T=1.435min is compound 4-A (compound 4-A is one of the structures of compound 4-1 and compound 4-2).
LCMS m/z＝552.1[M+1]+ LCMS m/z＝552.1[M+1] +
1H NMR(400MHz,CD3OD)δ8.59(s,2H),7.94(s,1H),4.91-4.84(m,1H),4.80-4.76(m,1H),4.58-4.51(m,1H),4.30-4.25(m,1H),4.20-4.10(m,1H),4.05-3.95(m,3H),3.88-3.82(m,1H),3.68-3.62(m,1H),3.60-3.50(m,2H),3.17-3.07(m,1H),3.05-2.96(m,1H),2.92-2.81(m,1H),1.24(d,3H). 1 H NMR (400MHz, CD 3 OD) δ8.59(s,2H),7.94(s,1H),4.91-4.84(m,1H),4.80-4.76(m,1H),4.58-4.51(m, 1H),4.30-4.25(m,1H),4.20-4.10(m,1H),4.05-3.95(m,3H),3.88-3.82(m,1H),3.68-3.62(m,1H),3.60- 3.50(m,2H),3.17-3.07(m,1H),3.05-2.96(m,1H),2.92-2.81(m,1H),1.24(d,3H).
保留时间T＝1.720min为化合物4-B(化合物4-B为化合物4-1和化合物4-2结构之一)。The retention time T=1.720min is compound 4-B (compound 4-B is one of the structures of compound 4-1 and compound 4-2).
LCMS m/z＝552.1[M+1]+ LCMS m/z＝552.1[M+1] +
1H NMR(400MHz,CD3OD)δ8.61(s,2H),7.95(s,1H),4.88-4.84(m,1H),4.82-4.79(m,1H),4.60-4.54(m,1H),4.31-4.27(m,1H),4.21-4.15(m,1H),4.07-3.95(m,3H),3.87-3.81(m,1H),3.65-3.54(m,3H),3.12-2.99(m,2H),2.92-2.84(m,1H),1.27(d,3H).1H NMR (400MHz, CD 3 OD) δ8.61(s,2H),7.95(s,1H),4.88-4.84(m,1H),4.82-4.79(m,1H),4.60-4.54(m,1H ),4.31-4.27(m,1H),4.21-4.15(m,1H),4.07-3.95(m,3H),3.87-3.81(m,1H),3.65-3.54(m,3H),3.12-2.99 (m,2H),2.92-2.84(m,1H),1.27(d,3H).
实施例5：化合物5的制备
Example 5: Preparation of Compound 5
第一步：5b的制备Step 1: Preparation of 5b
将D-丝氨酸(10.00g,95.13mmol)和溴化钾(40.41g,339.59mmol)溶于水(80mL)中，氮气置换，缓慢滴加氢溴酸(33.47g,190.26mmol,48％)，-15℃缓慢滴加亚硝酸钠(7.88g,114.16mmol)的水(25mL)溶液，室温反应6h。氮气鼓吹0.5h，乙酸乙酯(100mL x6)萃取，合并有机相，有机相用饱和食盐水(100mL)洗涤1次，无水硫酸钠干燥，抽滤，滤液经减压浓缩得5b(13.00g)粗品。Dissolve D-serine (10.00g, 95.13mmol) and potassium bromide (40.41g, 339.59mmol) in water (80mL), replace with nitrogen, and slowly add hydrobromic acid (33.47g, 190.26mmol, 48%). A solution of sodium nitrite (7.88g, 114.16mmol) in water (25mL) was slowly added dropwise at -15°C, and the reaction was carried out at room temperature for 6 hours. Blow nitrogen for 0.5h, extract with ethyl acetate (100mL )Crude.
LCMS m/z＝166.9[M-1]-。LCMS m/z=166.9[M-1] - .
第二步：5c的制备Step 2: Preparation of 5c
将5b(13.00g)，咪唑(20.95g,307.76mmol)溶于DMF(50mL)中，缓慢滴加叔丁基二苯基氯硅烷(25.38g,92.33mmol)，室温反应过夜。将反应液倒入到水(500mL)中，乙酸乙酯(200mL x 2)萃取，合并有机相，有机相用饱和食盐水(100mL x 2)洗涤，无水硫酸钠干燥，抽滤，滤液经减压浓缩得粗品，粗品经柱层析分离纯化(石油醚：四氢呋喃(v/v)＝9:1，1‰冰醋酸)得5c(12.00g,31％,2步收率)。Dissolve 5b (13.00g) and imidazole (20.95g, 307.76mmol) in DMF (50mL), slowly add tert-butyldiphenylsilyl chloride (25.38g, 92.33mmol) dropwise, and react at room temperature overnight. Pour the reaction solution into water (500mL), extract with ethyl acetate (200mL Concentrate under reduced pressure to obtain a crude product, which was separated and purified by column chromatography (petroleum ether: tetrahydrofuran (v/v) = 9:1, 1‰ glacial acetic acid) to obtain 5c (12.00g, 31%, 2-step yield).
LCMS m/z＝405.1[M-1]-。LCMS m/z=405.1[M-1] - .
第三步：5d的制备Step 3: Preparation of 5d
将草酰氯(8.29g，65.31mmol)加入到5c(3.80g,9.33mmol)、0.1mL DMF的二氯甲烷溶液 (20mL)中，50℃反应2h。减压浓缩，用二氯甲烷(20mL)溶解后减压浓缩得到残留物。冰水浴下，将残留物的二氯甲烷(10mL)溶液缓慢滴加到1b’(2.15g,9.33mmol)和DIPEA(2.40g,18.60mmol)的二氯甲烷(20mL)溶液中，室温反应1h。加入硅胶，减压浓缩后柱层析分离纯化(石油醚：四氢呋喃(v/v)＝4:1)得5d(1.80g,31％)。Oxalyl chloride (8.29g, 65.31mmol) was added to a solution of 5c (3.80g, 9.33mmol), 0.1mL DMF in dichloromethane. (20mL), react at 50°C for 2h. Concentrate under reduced pressure, dissolve in dichloromethane (20 mL) and concentrate under reduced pressure to obtain a residue. Under an ice-water bath, slowly add the residue solution in dichloromethane (10 mL) dropwise to the solution of 1b' (2.15g, 9.33mmol) and DIPEA (2.40g, 18.60mmol) in dichloromethane (20mL), and react at room temperature for 1 hour. . Silica gel was added, concentrated under reduced pressure, and then separated and purified by column chromatography (petroleum ether: tetrahydrofuran (v/v) = 4:1) to obtain 5d (1.80 g, 31%).
第四步：5e的制备Step 4: Preparation of 5e
将5d(1.80g,2.90mmol)溶于四氢呋喃(15mL)中，氮气置换后，0℃分批加入钠氢(231mg,5.78mmol,60％)，0℃反应1h。加入饱和氯化铵溶液(30mL)淬灭反应，乙酸乙酯(30mL x 3)萃取，合并有机相，饱和食盐水(20mL)洗涤1次，无水硫酸钠干燥，抽滤，滤液经减压浓缩得粗品，粗品经柱层析分离纯化(石油醚：四氢呋喃(v/v)＝4:1)得5e(900mg,58％)。Dissolve 5d (1.80g, 2.90mmol) in tetrahydrofuran (15mL). After nitrogen replacement, add sodium hydrogen (231mg, 5.78mmol, 60%) in batches at 0°C and react at 0°C for 1 hour. Add saturated ammonium chloride solution (30mL) to quench the reaction, extract with ethyl acetate (30mL Concentrate to obtain a crude product, which is separated and purified by column chromatography (petroleum ether: tetrahydrofuran (v/v) = 4:1) to obtain 5e (900 mg, 58%).
第五步：5f的三氟乙酸盐的制备Step 5: Preparation of trifluoroacetate salt of 5f
室将5e(900mg,3.01mmol)溶于二氯甲烷(4mL)中，加入三氟乙酸(4mL)，室温反应2h。减压浓缩用二氯甲烷(20mL x 2)溶解后减压浓缩得化合物5f的三氟乙酸盐粗品。Dissolve 5e (900 mg, 3.01 mmol) in dichloromethane (4 mL), add trifluoroacetic acid (4 mL), and react at room temperature for 2 h. Concentrate under reduced pressure. Dissolve in dichloromethane (20mL x 2) and concentrate under reduced pressure to obtain the crude trifluoroacetate salt of compound 5f.
LCMS m/z＝439.2[M+1]+。LCMS m/z=439.2[M+1] + .
第六步：5g的制备Step 6: Preparation of 5g
将5f的三氟乙酸盐粗品，2-氯-5-(三氟甲基)嘧啶(309mg,1.69mmol)，碳酸钾(851g,6.16mmol)依次加入到二甲基亚砜(4mL)中，95℃反应1h。倒入到水(30mL)中，乙酸乙酯(20mL x 3)萃取，合并有机相，饱和食盐水(20mL x 5)洗涤，无水硫酸钠干燥，抽滤，滤液减压浓缩得粗品，粗品经柱层析分离纯化(100％四氢呋喃)得5g(400mg,69％,2步收率)。The crude trifluoroacetate of 5f, 2-chloro-5-(trifluoromethyl)pyrimidine (309 mg, 1.69 mmol), and potassium carbonate (851 g, 6.16 mmol) were added to dimethyl sulfoxide (4 mL) in sequence. , react at 95°C for 1 hour. Pour into water (30mL), extract with ethyl acetate (20mL Separate and purify by column chromatography (100% tetrahydrofuran) to obtain 5g (400mg, 69%, 2-step yield).
LCMS m/z＝347.1[M+1]+。LCMS m/z=347.1[M+1] + .
第七步：5h的制备Step 7: Preparation for 5h
将5g(400mg,1.16mmol)，1c”(811mg,2.32mmol)溶于甲苯(80mL)中，氮气置换后，降温至0℃，加入三溴化硼乙醚络合物(4mL)，23℃反应16h。降温至0℃，缓慢滴加饱和碳酸氢钠溶液(80mL)淬灭反应。乙酸乙酯(50mL x3)萃取，合并有机相，有机相减压浓缩得残留物，残留物经柱层析分离纯化(石油醚：四氢呋喃(v/v)＝3:2)得5h(150mg,24％)。Dissolve 5g (400mg, 1.16mmol), 1c” (811mg, 2.32mmol) in toluene (80mL), replace with nitrogen, cool to 0°C, add boron tribromide etherate complex (4mL), and react at 23°C 16h. Cool to 0°C, slowly add saturated sodium bicarbonate solution (80mL) dropwise to quench the reaction. Extract with ethyl acetate (50mL x3), combine the organic phases, and concentrate the organic phases under reduced pressure to obtain a residue. The residue is subjected to column chromatography. After separation and purification (petroleum ether: tetrahydrofuran (v/v) = 3:2), 5h (150 mg, 24%) was obtained.
LCMS m/z＝534.3[M+1]+。LCMS m/z=534.3[M+1] + .
第八步：5j的制备Step 8: Preparation of 5j
将5h(150mg,0.28mmol)溶于乙醇(2mL)中，加入水合肼(172mg,0.15mL,80％)。室温反应16h。减压浓缩后经Prep-TLC(二氯甲烷：甲醇(v/v)＝10:1)纯化得5j(70mg,62％)。Dissolve 5h (150 mg, 0.28 mmol) in ethanol (2 mL), and add hydrazine hydrate (172 mg, 0.15 mL, 80%). React at room temperature for 16 hours. After concentration under reduced pressure, the product was purified by Prep-TLC (dichloromethane: methanol (v/v) = 10:1) to obtain 5j (70 mg, 62%).
LCMS m/z＝404.2[M+1]+。LCMS m/z=404.2[M+1] + .
第九步：5k的制备Step 9: Preparation for 5k
将5-氯-2-[(4-甲氧基苯基)甲基]-4-(三氟甲基)-2,3-二氢吡嗪-3-酮(60mg,0.19mmol)，5j(70mg,0.17mmol)溶于乙腈(2mL)中，加入三乙胺(34.4mg,0.34mmol)，室温反应16h。减压浓缩后经Prep-TLC(石油醚：乙酸乙酯(v/v)＝1:2)纯化得5k(40mg,34％)。5-Chloro-2-[(4-methoxyphenyl)methyl]-4-(trifluoromethyl)-2,3-dihydropyrazin-3-one (60 mg, 0.19 mmol), 5j (70 mg, 0.17 mmol) was dissolved in acetonitrile (2 mL), triethylamine (34.4 mg, 0.34 mmol) was added, and the reaction was carried out at room temperature for 16 h. After concentration under reduced pressure, the product was purified by Prep-TLC (petroleum ether: ethyl acetate (v/v) = 1:2) to obtain 5k (40 mg, 34%).
LCMS m/z＝686.2[M+1]+。LCMS m/z=686.2[M+1] + .
第十步：化合物5的制备Step 10: Preparation of Compound 5
将5k(40mg,0.06mmol)溶于三氟乙酸(2mL)中，加入三氟甲磺酸(0.2mL)。室温反应1h。减压浓缩后甲醇溶解，滴加DIPEA调PH至8-9，减压浓缩后，残余物经C18纯化(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0.1％的氨水)。 梯度洗脱方法：乙腈由10％梯度洗脱至55％(流速：60mL/min；洗脱时间20min)得到化合物5(17mg,52％)。Dissolve 5k (40 mg, 0.06 mmol) in trifluoroacetic acid (2 mL), and add trifluoromethanesulfonic acid (0.2 mL). React at room temperature for 1 hour. After concentration under reduced pressure, methanol was dissolved, and DIPEA was added dropwise to adjust the pH to 8-9. After concentration under reduced pressure, the residue was purified by C 18 (preparation method: the crude product was dissolved in DMF, and filtered with a 0.45 μm filter to prepare a sample solution. Flow. Phase system: acetonitrile/water (containing 0.1% ammonia). Gradient elution method: acetonitrile gradient elution from 10% to 55% (flow rate: 60 mL/min; elution time 20 min) to obtain compound 5 (17 mg, 52%).
LCMS m/z＝566.2[M+1]+。LCMS m/z=566.2[M+1] + .
1H NMR(400MHz,DMSO-d6)δ12.42(s,1H),8.74(s,2H),7.91(s,1H),6.31-6.19(m,1H),4.45-4.37(m,1H),4.36-4.26(m,2H),4.21-4.10(m,1H),4.09-3.98(m,2H),3.88-3.80(m,1H),3.78-3.66(m,4H),3.63-3.46(m,4H),1.83-1.70(m,1H),1.68-1.59(m,1H),1.16(d,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ12.42(s,1H),8.74(s,2H),7.91(s,1H),6.31-6.19(m,1H),4.45-4.37(m,1H ),4.36-4.26(m,2H),4.21-4.10(m,1H),4.09-3.98(m,2H),3.88-3.80(m,1H),3.78-3.66(m,4H),3.63-3.46 (m,4H),1.83-1.70(m,1H),1.68-1.59(m,1H),1.16(d,3H).
实施例6：
Example 6:
化合物5经SFC on OJ column纯化(仪器及制备柱：采用Waters 150SFC，制备柱型号是：Chiralcel OJ Column(250*30mm,I.D 30mm,10um particle size)。制备方法：化合物5用甲醇溶解，并用0.45μm滤膜过滤，制备成样品液。流动相体系：A for CO2 and B for MeOH(0.1％NH3.H2O)。梯度洗脱方法：25％B等梯度洗脱(流速：100mL/min；洗脱时间2min)，冻干后得到化合物6-1和化合物6-2。Compound 5 was purified by SFC on OJ column (instrument and preparation column: Waters 150SFC was used, and the preparation column model was: Chiralcel OJ Column (250*30mm, ID 30mm, 10um particle size). Preparation method: Compound 5 was dissolved in methanol and mixed with 0.45 Filter through a μm filter membrane and 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% B iso-gradient elution (flow rate: 100mL/ min; elution time 2 min), compound 6-1 and compound 6-2 were obtained 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：Chiralcel OJ-3 50×4.6mm I.D.,3μm；流动相体系：A for CO2 and B for MeOH(0.05％二乙胺),3mL/min。Analytical method (instrument and preparation column: high performance liquid chromatography – normal phase chromatography, preparation column model: Chiralcel OJ-3 50×4.6mm ID, 3μm; mobile phase system: A for CO 2 and B for MeOH (0.05% Diethylamine), 3mL/min.
保留时间T＝1.326min为化合物6-A(化合物6-A为化合物6-1和化合物6-2结构之一)。The retention time T=1.326min is compound 6-A (compound 6-A is one of the structures of compound 6-1 and compound 6-2).
LCMS m/z＝566.2[M+1]+ LCMS m/z＝566.2[M+1] +
1H NMR(400MHz,CD3OD)δ8.60(s,2H),7.96(s,1H),4.51-4.45(m,1H),4.36-4.28(m,2H),4.21-4.07(m,3H),4.01-3.94(m,1H),3.90-3.78(m,4H),3.73-3.62(m,3H),3.57-3.51(m,1H),1.96-1.84(m,1H),1.75-1.67(m,1H),1.27(d,3H). 1 H NMR (400MHz, CD 3 OD) δ8.60(s,2H),7.96(s,1H),4.51-4.45(m,1H),4.36-4.28(m,2H),4.21-4.07(m, 3H),4.01-3.94(m,1H),3.90-3.78(m,4H),3.73-3.62(m,3H),3.57-3.51(m,1H),1.96-1.84(m,1H),1.75- 1.67(m,1H),1.27(d,3H).
保留时间T＝1.665min为化合物6-B(化合物6-B为化合物6-1和化合物6-2结构之一)。The retention time T=1.665min is compound 6-B (compound 6-B is one of the structures of compound 6-1 and compound 6-2).
LCMS m/z＝566.2[M+1]+ LCMS m/z＝566.2[M+1] +
1H NMR(400MHz,CD3OD)δ8.60(s,2H),7.95(s,1H),4.54-4.46(m,1H),4.35-4.28(m,2H),4.18-4.08(m,3H),3.99-3.92(m,1H),3.89-3.76(m,4H),3.72-3.59(m,3H),3.55-3.49(m,1H),1.96-1.84(m,1H),1.74-1.66(m,1H),1.27(d,3H). 1 H NMR (400MHz, CD 3 OD) δ8.60 (s, 2H), 7.95 (s, 1H), 4.54-4.46 (m, 1H), 4.35-4.28 (m, 2H), 4.18-4.08 (m, 3H),3.99-3.92(m,1H),3.89-3.76(m,4H),3.72-3.59(m,3H),3.55-3.49(m,1H),1.96-1.84(m,1H),1.74- 1.66(m,1H),1.27(d,3H).
实施例7：
Example 7:
第一步：7a的制备Step One: Preparation of 7a
将1b'(4.00g,17.37mmol)溶于四氢呋喃(50mL)和水(25mL)中，加入碳酸氢钠(13.02g,154.94mmol)，0℃加入氯甲酸苄酯(3.56g,20.84mmol)，室温反应16h，加入20mL水，乙酸乙酯萃取(20mL x 2)。合并有机相，有机相用饱和食盐水洗涤(30mL x 2)后，经无水硫酸钠干燥、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：四氢呋喃(v/v)＝77:23)得7a(5.00g,79％)。Dissolve 1b' (4.00g, 17.37mmol) in tetrahydrofuran (50mL) and water (25mL), add sodium bicarbonate (13.02g, 154.94mmol), and add benzyl chloroformate (3.56g, 20.84mmol) at 0°C. React at room temperature for 16 hours, add 20mL water, and extract with ethyl acetate (20mL x 2). The organic phases were combined, washed with saturated brine (30mL x 2), 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 column chromatography (petroleum ether: tetrahydrofuran (v/v) = 77:23) to obtain 7a (5.00 g, 79%).
LCMS m/z＝309.1[M-55]+ LCMS m/z＝309.1[M-55] +
第二步：7b的制备Step 2: Preparation of 7b
将三苯基膦(7.20g,27.44mmol)和咪唑(1.87g,27.44mmol)溶于无水干燥的二氯甲烷(30mL)溶液中，0℃缓慢加入碘单质(6.96g,27.44mmol)，室温反应10分钟，0℃缓慢加入7a(5.00g，13.72mmol)，室温反应16h。加入硅胶，减压浓缩后经柱层析分离纯化(石油醚：四氢呋喃(v/v)＝85:15)得7b(5.00g，77％)Dissolve triphenylphosphine (7.20g, 27.44mmol) and imidazole (1.87g, 27.44mmol) in anhydrous dry dichloromethane (30mL) solution, and slowly add iodine element (6.96g, 27.44mmol) at 0°C. React at room temperature for 10 minutes, slowly add 7a (5.00g, 13.72mmol) at 0°C, and react at room temperature for 16 hours. Add silica gel, concentrate under reduced pressure and then separate and purify by column chromatography (petroleum ether: tetrahydrofuran (v/v) = 85:15) to obtain 7b (5.00g, 77%)
LCMS m/z＝375.0[M-99]+ LCMS m/z＝375.0[M-99] +
第三步：7c的制备Step 3: Preparation of 7c
将丙二酸二乙酯(8.44g，52.70mmol)溶于无水四氢呋喃溶液(60mL)，氮气置换体系后，0℃分批加入氢化钠(2.11g，52.70mmol,60％w/t)，0℃搅拌20分钟后，缓慢加入7b(5.00g，10.54mmol)，室温反应16h。0℃加入饱和氯化铵水溶液猝灭反应，饱和食盐水(40mL)洗涤，乙酸乙酯(40mL x 3)萃取，合并有机相，有机相用无水硫酸钠干燥后过滤，滤液减压浓缩后经柱层析分离纯化(石油醚：四氢呋喃(v/v)＝85:15)得到7c(5.50g,粗品)。Dissolve diethyl malonate (8.44g, 52.70mmol) in anhydrous tetrahydrofuran solution (60mL). After replacing the system with nitrogen, add sodium hydride (2.11g, 52.70mmol, 60% w/t) in batches at 0°C. After stirring at 0°C for 20 minutes, 7b (5.00g, 10.54mmol) was slowly added and the reaction was carried out at room temperature for 16h. Add saturated ammonium chloride aqueous solution at 0°C to quench the reaction, wash with saturated brine (40mL), extract with ethyl acetate (40mL x 3), combine the organic phases, dry the organic phases with anhydrous sodium sulfate and filter, and concentrate the filtrate under reduced pressure. Separation and purification by column chromatography (petroleum ether: tetrahydrofuran (v/v) = 85:15) gave 7c (5.50 g, crude product).
LCMS m/z＝407.3[M-99]+ LCMS m/z＝407.3[M-99] +
第四步：7d的制备Step 4: Preparation of 7d
将7c(2.50g)溶于甲醇溶液中(30mL)，加入氨水(0.7mL)和钯碳(600mg)，氢气置换三次后，室温反应16h。垫硅藻土过滤，滤液减压浓缩得7d(1.84g,粗品)。Dissolve 7c (2.50g) in methanol solution (30mL), add ammonia water (0.7mL) and palladium carbon (600mg), replace with hydrogen three times, and react at room temperature for 16h. Filter through diatomaceous earth, and the filtrate is concentrated under reduced pressure to obtain 7d (1.84g, crude product).
LCMS m/z＝373.2[M+1]+ LCMS m/z＝373.2[M+1] +
第五步：化合物7e的制备Step 5: Preparation of compound 7e
将7d(1.84g，粗品)和乙醇(30mL)加入到玻璃封管中，加入三乙胺(2.50g，24.7mmol)，90℃密封反应16h。减压浓缩得7e(1.61g，粗品)。Add 7d (1.84g, crude product) and ethanol (30mL) into a glass sealed tube, add triethylamine (2.50g, 24.7mmol), and seal for 16 hours at 90°C. Concentrate under reduced pressure to obtain 7e (1.61g, crude product).
LCMS m/z＝327.2[M+1]+ LCMS m/z＝327.2[M+1] +
第六步：7f的的盐酸盐制备Step 6: Preparation of 7f hydrochloride
7e(1.61g,粗品)溶于氯化氢-1,4-二氧六环溶液(4.0M,20mL,80mmol)，室温反应2h。减压浓缩得7f的盐酸盐(1.48g)粗品。7e (1.61g, crude product) was dissolved in hydrogen chloride-1,4-dioxane solution (4.0M, 20mL, 80mmol), and reacted at room temperature for 2h. Concentrate under reduced pressure to obtain the crude product of 7f hydrochloride (1.48g).
LCMS m/z＝227.2[M+1]+ LCMS m/z＝227.2[M+1] +
第七步：7g的制备Step 7: Preparation of 7g
将7f的盐酸盐(1.48g，粗品)和2-氯-5-三氟甲基嘧啶(0.99g,5.42mmol)溶于N-甲基吡咯烷酮(25mL)中，加入碳酸钾(2.04g,14.74mmol)，90℃反应16h。向反应液中加入饱和食盐水(30mL)，用乙酸乙酯萃取(30mL x 2)。合并有机相，有机相经饱和食盐水洗涤(30mL x 2)后，用无水硫酸钠干燥、过滤，滤液减压浓缩后经制备柱分离纯化(石油醚：乙酸乙酯(v/v)＝11:9)得7g(1.65g)。Dissolve the hydrochloride of 7f (1.48g, crude product) and 2-chloro-5-trifluoromethylpyrimidine (0.99g, 5.42mmol) in N-methylpyrrolidone (25mL), and add potassium carbonate (2.04g, 14.74mmol), reacted at 90℃ for 16h. Saturated brine (30 mL) was added to the reaction solution, and extracted with ethyl acetate (30 mL x 2). Combine the organic phases, wash the organic phase with saturated brine (30mL 11:9) to get 7g (1.65g).
LCMS m/z＝373.2[M+1]+ LCMS m/z＝373.2[M+1] +
第八步：7h的制备Step 8: 7h preparation
将7g(1.20g,3.22mmol)溶于四氢呋喃(50mL)和无水乙醇(50mL)的混合溶液中，加入硼氢化钠(122mg,3.22mmol)，室温搅拌1h，0℃下分批加入氯化钙(208mg,1.61mmol)，0℃反应2h。缓慢滴加饱和氯化铵水溶液淬灭反应，加入饱和食盐水洗涤(30mL)，乙酸乙酯萃取(30mL x 2)，合并有机相，有机相经水硫酸钠干燥、过滤，滤液减压浓缩后经柱层析分离纯化(石油醚：乙酸乙酯(v/v)＝4:1)得7h(800mg,75％)Dissolve 7g (1.20g, 3.22mmol) in a mixed solution of tetrahydrofuran (50mL) and absolute ethanol (50mL), add sodium borohydride (122mg, 3.22mmol), stir at room temperature for 1 hour, and add chlorine in batches at 0°C. Calcium (208 mg, 1.61 mmol), react at 0°C for 2 hours. Slowly add saturated aqueous ammonium chloride solution to quench the reaction, add saturated brine for washing (30mL), extract with ethyl acetate (30mL x 2), combine the organic phases, dry the organic phases over sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Separate and purify by column chromatography (petroleum ether: ethyl acetate (v/v) = 4:1) to obtain 7h (800mg, 75%)
LCMS m/z＝331.1[M+1]+ LCMS m/z＝331.1[M+1] +
第九步：7i的制备Step 9: Preparation of 7i
将7h(900mg,2.72mmol)，1c”(1.90g,5.44mmol)溶于甲苯(180mL)中。氮气置换后，0℃加入三氟化硼乙醚溶液(9mL)。23℃反应16h。0℃加饱和碳酸氢钠调节PH直至没有气泡，且固体完全溶解。乙酸乙酯萃取(50mL x 3)，合并有机相，有机相经无水硫酸钠干燥、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：四氢呋喃(v:v)＝5:1)得到7i(250mg,18％)。Dissolve 7h (900mg, 2.72mmol), 1c” (1.90g, 5.44mmol) in toluene (180mL). After nitrogen replacement, add boron trifluoride ether solution (9mL) at 0°C. React at 23°C for 16h. 0°C Add saturated sodium bicarbonate to adjust the pH until there are no bubbles and the solid is completely dissolved. Extract with ethyl acetate (50mL x 3), combine the organic phases, dry and filter over anhydrous sodium sulfate, and concentrate the filtrate under reduced pressure to obtain crude product. Separation and purification by column chromatography (petroleum ether: tetrahydrofuran (v:v) = 5:1) gave 7i (250 mg, 18%).
LCMS m/z＝518.2[M+1]+ LCMS m/z＝518.2[M+1] +
第十步：7j的制备Step 10: Preparation of 7j
将水合肼(1mL，含量：80％)加入到7i(250mg,0.48mmol)的乙醇(4mL)溶液中，室温反应16h。减压浓缩后经Prep-TLC分离纯化(二氯甲烷：甲醇(v:v)＝10:1)得7j(150mg,80％)。Hydrazine hydrate (1 mL, content: 80%) was added to a solution of 7i (250 mg, 0.48 mmol) in ethanol (4 mL), and the reaction was carried out at room temperature for 16 h. After concentration under reduced pressure, it was separated and purified by Prep-TLC (dichloromethane: methanol (v:v) = 10:1) to obtain 7j (150 mg, 80%).
LCMS m/z＝388.2[M+1]+ LCMS m/z＝388.2[M+1] +
第十一步：7k的制备Step 11: Preparation of 7k
将7j(150mg,0.39mmol)，中间体1(137mg,0.43mmol)溶于乙腈(5mL)中，加入三乙胺(79mg,0.78mmol)，室温反应16h。减压浓缩后经柱层析分离纯化(石油醚：乙酸乙酯(v/v)＝1:2)得7k(150mg,58％)。Dissolve 7j (150 mg, 0.39 mmol) and intermediate 1 (137 mg, 0.43 mmol) in acetonitrile (5 mL), add triethylamine (79 mg, 0.78 mmol), and react at room temperature for 16 h. After concentration under reduced pressure, the product was separated and purified by column chromatography (petroleum ether: ethyl acetate (v/v) = 1:2) to obtain 7k (150 mg, 58%).
LCMS m/z＝670.3[M+1]+。LCMS m/z=670.3[M+1] + .
第十二步：化合物7-1和化合物7-2的制备Step 12: Preparation of compound 7-1 and compound 7-2
将三氟甲磺酸(116mg,0.77mmol)加入到7k(150mg,0.22mmol)的三氟乙酸(2mL)溶液中， 室温反应1h。减压浓缩，加水(4mL)淬灭反应，氨水调节PH至7-9。水溶液经C18柱纯化得到45mg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50％(洗脱时间15min)。冻干后得到化合物7-A(6mg,5％)与化合物7-B(8mg,7％)。Trifluoromethanesulfonic acid (116 mg, 0.77 mmol) was added to a solution of 7k (150 mg, 0.22 mmol) in trifluoroacetic acid (2 mL). React at room temperature for 1 hour. Concentrate under reduced pressure, add water (4 mL) to quench the reaction, and adjust the pH to 7-9 with ammonia. The aqueous solution was purified by C 18 column to obtain 45 mg of crude product, which was purified by Pre-HPLC (instrument and preparation column: WATERS 2767 was used to prepare the liquid phase, and the preparation column model was Xselect C18, 5 μm, inner diameter * length = 19 mm * 150 mm). Preparation method: Filter the reaction solution with a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile/water (containing 0.05% ammonia). Gradient elution method: acetonitrile gradient elution from 5% to 50% (elution time 15 minutes). After lyophilization, compound 7-A (6 mg, 5%) and compound 7-B (8 mg, 7%) were obtained.
分析方法(仪器：岛津高效液相色谱仪(仪器型号：LC-20AT)–反相色谱；制备柱的品牌及型号：月旭(Xtimate C18 4.6*50mm，3μm)；流动相体系：流动相A为0.05％TFA溶液，流动相B为乙腈；流速：1.0mL/min。Analytical method (instrument: Shimadzu high performance liquid chromatography (instrument model: LC-20AT) – reversed-phase chromatography; brand and model of preparative column: Yuexu (Xtimate C18 4.6*50mm, 3μm); mobile phase system: mobile phase A is 0.05% TFA solution, mobile phase B is acetonitrile; flow rate: 1.0 mL/min.
保留时间T＝4.224为化合物7-A(化合物7-A为化合物7-1与化合物7-2结构之一)。The retention time T=4.224 is compound 7-A (compound 7-A is one of the structures of compound 7-1 and compound 7-2).
LCMS m/z＝550.2[M+1]+ LCMS m/z＝550.2[M+1] +
1H NMR(400MHz,DMSO-d6)δ12.41(s,1H),8.72(s,2H),7.93(d,1H),6.35-6.20(m,1H),4.70-4.53(m,2H),4.52-4.42(m,1H),4.26-4.12(m,1H),3.77-3.55(m,2H),3.54-3.40(m,3H),2.99-2.88(m,1H),2.86-2.76(m,1H),2.73-2.62(m,1H),2.49-2.45(m,1H),2.04-1.61(m,4H),1.16(d,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ12.41(s,1H),8.72(s,2H),7.93(d,1H),6.35-6.20(m,1H),4.70-4.53(m,2H) ),4.52-4.42(m,1H),4.26-4.12(m,1H),3.77-3.55(m,2H),3.54-3.40(m,3H),2.99-2.88(m,1H),2.86-2.76 (m,1H),2.73-2.62(m,1H),2.49-2.45(m,1H),2.04-1.61(m,4H),1.16(d,3H).
保留时间T＝4.284为化合物7-B(化合物7-B为化合物7-1与化合物7-2结构之一)。The retention time T=4.284 is compound 7-B (compound 7-B is one of the structures of compound 7-1 and compound 7-2).
LCMS m/z＝550.2[M+1]+ LCMS m/z＝550.2[M+1] +
1H NMR(400MHz,DMSO-d6)δ12.34(s,1H),8.73(s,2H),7.89(d,1H),6.32-6.15(m,1H),4.72-4.58(m,2H),4.52-4.39(m,1H),4.25-4.09(m,1H),3.76-3.57(m,2H),3.53-3.37(m,3H),3.09-2.95(m,1H),2.86-2.74(m,1H),2.71-2.58(m,1H),2.47-2.37(m,1H),2.08-1.95(m,1H),1.88-1.77(m,1H),1.63-1.42(m,2H),1.15(d,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ12.34(s,1H),8.73(s,2H),7.89(d,1H),6.32-6.15(m,1H),4.72-4.58(m,2H ),4.52-4.39(m,1H),4.25-4.09(m,1H),3.76-3.57(m,2H),3.53-3.37(m,3H),3.09-2.95(m,1H),2.86-2.74 (m,1H),2.71-2.58(m,1H),2.47-2.37(m,1H),2.08-1.95(m,1H),1.88-1.77(m,1H),1.63-1.42(m,2H) ,1.15(d,3H).
实施例8：
Example 8:
化合物7-B(58mg)经SFC on I.D column纯化(仪器及制备柱：采用Waters 150SFC，制备柱型号是：Chiralcel OJ-Column(250*30mm,I.D 30mm,10um particle size。制备方法：化合物7-B用甲醇溶解，并用0.45μm滤膜过滤，制备成样品液。流动相体系：A for CO2 and B for MeOH(0.1％NH3.H2O)。梯度洗脱方法：30％B等梯度洗脱(流速：100mL/min；洗脱时间4.5min)，冻干后得到化合物8-A(26mg)和化合物8-B(20mg)。Compound 7-B (58mg) was purified by SFC on ID column (instrument and preparation column: Waters 150SFC was used, and the preparation column model was: Chiralcel OJ-Column (250*30mm, ID 30mm, 10um particle size). Preparation method: Compound 7- Dissolve B in methanol and filter it with a 0.45μm filter membrane 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% B isotropic gradient Elution (flow rate: 100 mL/min; elution time 4.5 min), and compound 8-A (26 mg) and compound 8-B (20 mg) were obtained after lyophilization.
分析方法(仪器：岛津LC-30AD sf；制备柱型号是：Chiralcel OJ-3 50×4.6mm I.D.，3μm；流动相体系：A for CO2 and B for MeOH(0.05％DEA)，3.0ml/min。保留时间T＝1.387min为化合物8-A(化合物8-A为化合物8-1，化合物8-2，化合物8-3，化合物8-4结构之一)。保留时间T＝2.009 min为化合物8-B(化合物8-B为化合物8-1，化合物8-2，化合物8-3，化合物8-4结构之一)。Analytical method (instrument: Shimadzu LC-30AD sf; preparative column model: Chiralcel OJ-3 50×4.6mm ID, 3μm; mobile phase system: A for CO2 and B for MeOH (0.05% DEA), 3.0ml/min .Retention time T=1.387min for compound 8-A (compound 8-A is one of the structures of compound 8-1, compound 8-2, compound 8-3, and compound 8-4). Retention time T=2.009 min is compound 8-B (compound 8-B is one of the structures of compound 8-1, compound 8-2, compound 8-3, and compound 8-4).
化合物8-A：Compound 8-A:
LCMS m/z＝550.6[M+1]+ LCMS m/z＝550.6[M+1] +
1H NMR(400MHz,DMSO-d6)δ12.40(s,1H),8.73(s,2H),7.90(s,1H),6.33-6.15(m,1H),4.72-4.56(m,2H),4.49-4.38(m,1H),4.24-4.09(m,1H),3.73-3.60(m,2H),3.55-3.45(m,1H),3.43-3.34(m,2H),3.09-2.96(m,1H),2.85-2.75(m,1H),2.70-2.57(m,1H),2.46-2.37(m,1H),2.08-1.95(m,1H),1.88-1.78(m,1H),1.64-1.39(m,2H),1.15(d,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ12.40(s,1H),8.73(s,2H),7.90(s,1H),6.33-6.15(m,1H),4.72-4.56(m,2H ),4.49-4.38(m,1H),4.24-4.09(m,1H),3.73-3.60(m,2H),3.55-3.45(m,1H),3.43-3.34(m,2H),3.09-2.96 (m,1H),2.85-2.75(m,1H),2.70-2.57(m,1H),2.46-2.37(m,1H),2.08-1.95(m,1H),1.88-1.78(m,1H) ,1.64-1.39(m,2H),1.15(d,3H).
化合物8-B：Compound 8-B:
LCMS m/z＝550.6[M+1]+ LCMS m/z＝550.6[M+1] +
1H NMR(400MHz,DMSO-d6)δ12.40(s,1H),8.73(s,2H),7.88(s,1H),6.31-6.17(m,1H),4.71-4.57(m,2H),4.52-4.42(m,1H),4.23-4.09(m,1H),3.75-3.67(m,1H),3.65-3.57(m,1H),3.51-3.40(m,2H),3.40-3.32(m,1H),3.09-2.94(m,1H),2.85-2.73(m,1H),2.72-2.59(m,1H),2.47-2.34(m1H),2.06-1.93(m,1H),1.90-1.77(m,1H),1.60-1.42(m,2H),1.15(d,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ12.40(s,1H),8.73(s,2H),7.88(s,1H),6.31-6.17(m,1H),4.71-4.57(m,2H ),4.52-4.42(m,1H),4.23-4.09(m,1H),3.75-3.67(m,1H),3.65-3.57(m,1H),3.51-3.40(m,2H),3.40-3.32 (m,1H),3.09-2.94(m,1H),2.85-2.73(m,1H),2.72-2.59(m,1H),2.47-2.34(m1H),2.06-1.93(m,1H),1.90 -1.77(m,1H),1.60-1.42(m,2H),1.15(d,3H).
实施例9：化合物9的制备
Example 9: Preparation of Compound 9
第一步：9b的制备Step 1: Preparation of 9b
将9a(18.28g,79.37mmol)溶于四氢呋喃(200mL)和水(100mL)的混合溶液中，加入碳酸氢钠 (59.48g,708mmol)，0℃缓慢滴加氯甲酸苄酯(16.25g,95.24mmol)的四氢呋喃溶液，室温反应16h。加入100mL水，乙酸乙酯萃取(80mL x 2)。合并有机相，有机相用饱和食盐水洗涤(80mL x 2)后，经无水硫酸钠干燥、过滤，滤液减压浓缩经柱层析分离纯化(石油醚：四氢呋喃(v/v)＝81:19)得9b(15.48g,54％)。Dissolve 9a (18.28g, 79.37mmol) in a mixed solution of tetrahydrofuran (200mL) and water (100mL), and add sodium bicarbonate (59.48g, 708mmol), a tetrahydrofuran solution of benzyl chloroformate (16.25g, 95.24mmol) was slowly added dropwise at 0°C, and the reaction was carried out at room temperature for 16h. Add 100 mL of water and extract with ethyl acetate (80 mL x 2). Combine the organic phases, wash them with saturated brine (80mL 19) Obtain 9b (15.48g, 54%).
LCMS m/z＝309.2[M-55]+ LCMS m/z＝309.2[M-55] +
第二步：9c的制备Step 2: Preparation of 9c
将三苯基膦(22.28g,84.96mmol)和咪唑(5.78g,84.96mmol)溶于无水二氯甲烷(120mL)中，0℃缓慢加入碘单质(21.56g,84.96mmol)，室温反应10分钟。0℃缓慢滴加9b(15.48g，42.48mmol)的二氯甲烷溶液，室温反应16h。0℃缓慢滴加饱和硫代硫酸钠水溶液，加入饱和食盐水100mL水，乙酸乙酯萃取(80mL x 2)。合并有机相，经无水硫酸钠干燥、过滤，滤液减压浓缩经柱层析分离纯化(石油醚：四氢呋喃(v/v)＝9:1)得9c(18.00g,89％)。Dissolve triphenylphosphine (22.28g, 84.96mmol) and imidazole (5.78g, 84.96mmol) in anhydrous dichloromethane (120mL), slowly add iodine element (21.56g, 84.96mmol) at 0°C, and react at room temperature for 10 minute. The methylene chloride solution of 9b (15.48g, 42.48mmol) was slowly added dropwise at 0°C, and the reaction was carried out at room temperature for 16 hours. Slowly add saturated sodium thiosulfate aqueous solution dropwise at 0°C, add 100mL of saturated brine, and extract with ethyl acetate (80mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (petroleum ether: tetrahydrofuran (v/v) = 9:1) to obtain 9c (18.00 g, 89%).
LCMS m/z＝375.1[M-99]+ LCMS m/z＝375.1[M-99] +
第三步：9d的制备Step 3: Preparation of 9d
将丙二酸二乙酯(30.39g，189.75mmol)溶于无水四氢呋喃(120mL)，氮气置换后，0℃分批加入氢化钠(7.59g，189.75mmol,60％)，0℃搅拌20分钟，缓慢滴加9c(18.00g，37.95mmol)的四氢呋喃溶液，室温反应16h。0℃加入饱和氯化铵水溶液猝灭反应，饱和食盐水(80mL)洗涤，乙酸乙酯(80mL x 3)萃取，合并有机相，有机相用无水硫酸钠干燥后过滤，滤液减压浓缩经柱层析分离纯化(石油醚：四氢呋喃(v/v)＝85:15)得9d(17.50g,91％)。Dissolve diethyl malonate (30.39g, 189.75mmol) in anhydrous tetrahydrofuran (120mL). After nitrogen replacement, add sodium hydride (7.59g, 189.75mmol, 60%) in batches at 0°C and stir for 20 minutes at 0°C. , slowly add the tetrahydrofuran solution of 9c (18.00g, 37.95mmol) dropwise, and react at room temperature for 16h. Add saturated ammonium chloride aqueous solution at 0°C to quench the reaction, wash with saturated brine (80mL), extract with ethyl acetate (80mL x 3), combine the organic phases, dry the organic phases with anhydrous sodium sulfate and filter, and concentrate the filtrate under reduced pressure. Separation and purification by column chromatography (petroleum ether: tetrahydrofuran (v/v) = 85:15) gave 9d (17.50 g, 91%).
LCMS m/z＝407.4[M-99]+ LCMS m/z＝407.4[M-99] +
第四步：9e的制备Step 4: Preparation of 9e
将钯碳(400mg，10％)加入到9d(2.00g,3.95mmol)的甲醇(20mL)、氨水(0.05mL，含量：25％-28％)溶液中，氢气氛围室温反应16h。过滤、滤液减压浓缩得9e(1.40g，粗品)。Palladium on carbon (400 mg, 10%) was added to the solution of 9d (2.00 g, 3.95 mmol) in methanol (20 mL) and ammonia (0.05 mL, content: 25%-28%), and the reaction was carried out at room temperature in a hydrogen atmosphere for 16 hours. Filter and concentrate the filtrate under reduced pressure to obtain 9e (1.40g, crude product).
LCMS m/z＝373.4[M+1]+ LCMS m/z＝373.4[M+1] +
第五步：9f的制备Step 5: Preparation of 9f
将三乙胺(1.52g,15.04mmol)加入到9b(1.40g，粗品)的乙醇(15mL)溶液中，90℃反应16h。冷却至室温后，减压浓缩得9f(1.20g，粗品)。Triethylamine (1.52g, 15.04mmol) was added to a solution of 9b (1.40g, crude product) in ethanol (15mL), and the reaction was carried out at 90°C for 16h. After cooling to room temperature, it was concentrated under reduced pressure to obtain 9f (1.20 g, crude product).
LCMS m/z＝327.1[M+1]+ LCMS m/z＝327.1[M+1] +
第六步：9g盐酸盐的制备Step 6: Preparation of 9g hydrochloride
将9f(1.20g，粗品)溶于4N盐酸二氧六环(10mL)中，室温反应2h。减压浓缩除得9g的盐酸盐(1.00g，粗品)。Dissolve 9f (1.20g, crude product) in 4N dioxane hydrochloride (10mL) and react at room temperature for 2h. Concentrate under reduced pressure to obtain 9g of hydrochloride (1.00g, crude product).
LCMS m/z＝227.2[M+1]+ LCMS m/z＝227.2[M+1] +
第七步：9h的制备Step 7: Preparation for 9h
将碳酸钾(2.10g,15.24mmol)加入到9d的盐酸盐(1.00g，粗品)、2,5-二氯嘧啶(0.68g,4.57mmol)的二甲基亚砜(10mL)溶液中，90℃反应2h。冷却至室温，加水(20ml)淬灭反应，乙酸乙酯(30mlx3)萃取，合并有机相。有机相经无水硫酸钠干燥、过滤、滤液减压浓缩后经柱层析分离纯化(石油醚：四氢呋喃(v:v)＝5:1)得9h(1.25g,四步收率：93％)Potassium carbonate (2.10g, 15.24mmol) was added to the solution of 9d hydrochloride (1.00g, crude product) and 2,5-dichloropyrimidine (0.68g, 4.57mmol) in dimethyl sulfoxide (10mL). React at 90°C for 2 hours. Cool to room temperature, add water (20ml) to quench the reaction, extract with ethyl acetate (30mlx3), and combine the organic phases. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and then separated and purified by column chromatography (petroleum ether: tetrahydrofuran (v:v) = 5:1) to obtain 9h (1.25g, four-step yield: 93% )
LCMS m/z＝339.1[M+1]+ LCMS m/z＝339.1[M+1] +
第八步：9j的制备
Step 8: Preparation of 9j
冰盐浴下，依次将氯化钙(1.44g,13mmol)、硼氢化钠(0.98g,26mmol)加入到化合物9h(1.10g,3.25mmol)的四氢呋喃(12mL)、甲醇(3mL)混合溶液中，冰盐浴反应0.5h。加入乙酸乙酯(30mL)、饱和碳酸钠溶液(10mL)淬灭反应，搅拌1h后过滤，滤液经减压浓缩后得粗品，粗品经柱层析分离纯化(二氯甲烷(含9％甲醇)：石油醚(含16％乙酸乙酯)(v:v)＝5:1)得到化合物9j-1(180mg,19％)和化合物9j-2。Under an ice-salt bath, calcium chloride (1.44g, 13mmol) and sodium borohydride (0.98g, 26mmol) were sequentially added to the mixed solution of compound 9h (1.10g, 3.25mmol) in tetrahydrofuran (12mL) and methanol (3mL). , ice-salt bath reaction for 0.5h. Add ethyl acetate (30 mL) and saturated sodium carbonate solution (10 mL) to quench the reaction, stir for 1 hour and then filter. The filtrate is concentrated under reduced pressure to obtain a crude product. The crude product is separated and purified by column chromatography (dichloromethane (containing 9% methanol) : Petroleum ether (containing 16% ethyl acetate) (v:v) = 5:1) to obtain compound 9j-1 (180 mg, 19%) and compound 9j-2.
化合物9j-1为化合物9jCompound 9j-1 is compound 9j
LCMS m/z＝297.1[M+1]+。LCMS m/z=297.1[M+1] + .
1H NMR(400MHz,DMSO-d6)δ8.45(s,2H),4.59-4.41(m,4H),3.73-3.52(m,2H),3.45-3.34(m,1H),2.97-2.85(m,1H),2.76-2.57(m,2H),2.35-2.23(m,1H),2.10-2.00(m,1H),1.93-1.84(m,1H),1.65-1.42(m,2H). 1 H NMR (400MHz, DMSO-d 6 ) δ8.45 (s, 2H), 4.59-4.41 (m, 4H), 3.73-3.52 (m, 2H), 3.45-3.34 (m, 1H), 2.97-2.85 (m,1H),2.76-2.57(m,2H),2.35-2.23(m,1H),2.10-2.00(m,1H),1.93-1.84(m,1H),1.65-1.42(m,2H) .
化合物9j-2Compound 9j-2
LCMS m/z＝297.1[M+1]+。LCMS m/z=297.1[M+1] + .
1H NMR(400MHz,DMSO-d6)δ8.44(s,2H),4.69-4.63(m,1H),4.56-4.42(m,3H),3.69-3.53(m,2H),3.47-3.38(m,1H),2.93-2.83(m,1H),2.82-2.73(m,1H),2.69-2.59(m,1H),2.40-2.30(m,1H),1.93-1.81(m,2H),1.80-1.62(m,2H). 1 H NMR (400MHz, DMSO-d 6 ) δ8.44(s,2H),4.69-4.63(m,1H),4.56-4.42(m,3H),3.69-3.53(m,2H),3.47-3.38 (m,1H),2.93-2.83(m,1H),2.82-2.73(m,1H),2.69-2.59(m,1H),2.40-2.30(m,1H),1.93-1.81(m,2H) ,1.80-1.62(m,2H).
第九步：9k的制备Step 9: Preparation of 9k
0℃下，将9j(120mg,0.40mmol)、1c”(280mg,0.80mmol)溶于甲苯(10mL)中。氮气置换后，0℃下缓慢加入三氟化硼乙醚(1mL)，23℃反应16h。0℃下用饱和碳酸钠溶液调PH至7-8。乙酸乙酯萃取(100mLx3)，合并有机相，有机相经减压浓缩后得粗品，粗品经柱层析分离纯化(石油醚：四氢呋喃(v:v)＝10:3)得9k(70mg,36％)。Dissolve 9j (120mg, 0.40mmol) and 1c” (280mg, 0.80mmol) in toluene (10mL) at 0°C. After nitrogen replacement, slowly add boron trifluoride ether (1mL) at 0°C and react at 23°C. 16h. Adjust the pH to 7-8 with saturated sodium carbonate solution at 0°C. Extract with ethyl acetate (100mLx3), combine the organic phases, and concentrate the organic phases under reduced pressure to obtain a crude product. The crude product is separated and purified by column chromatography (petroleum ether: Tetrahydrofuran (v:v)=10:3) gave 9k (70 mg, 36%).
LCMS m/z＝484.2[M+1]+ LCMS m/z＝484.2[M+1] +
第十步：化合物9m的制备Step 10: Preparation of Compound 9m
将水合肼(0.1mL，含量：80％)加入到化合物9k(135mg,0.28mmol)的乙醇(4mL)溶液中，室温反应16h。减压浓缩后用乙酸乙酯打浆，过滤，滤饼用乙酸乙酯洗涤(10mLx3)，滤液减压浓缩得化合物9m(100mg，粗品)。Hydrazine hydrate (0.1 mL, content: 80%) was added to a solution of compound 9k (135 mg, 0.28 mmol) in ethanol (4 mL), and the reaction was carried out at room temperature for 16 h. After concentration under reduced pressure, the mixture was pulped with ethyl acetate, filtered, and the filter cake was washed with ethyl acetate (10 mLx3). The filtrate was concentrated under reduced pressure to obtain compound 9m (100 mg, crude product).
LCMS m/z＝354.2[M+1]+ LCMS m/z＝354.2[M+1] +
第十一步：化合物9n的制备Step 11: Preparation of Compound 9n
将中间体1(116mg,0.36mmol)加入到化合物9m(100mg，粗品)、三乙胺(113mg,1.12mmol)的乙腈(5mL)溶液中，室温反应6h。加入硅胶，减压浓缩后经柱层析分离纯化(二氯甲烷：四氢呋喃(v:v)＝5:1)得化合物9n(100mg,两步收率56％)。Intermediate 1 (116 mg, 0.36 mmol) was added to a solution of compound 9m (100 mg, crude product) and triethylamine (113 mg, 1.12 mmol) in acetonitrile (5 mL), and the reaction was carried out at room temperature for 6 h. Silica gel was added, concentrated under reduced pressure, and then separated and purified by column chromatography (dichloromethane: tetrahydrofuran (v:v) = 5:1) to obtain compound 9n (100 mg, two-step yield 56%).
LCMS m/z＝636.3[M+1]+ LCMS m/z＝636.3[M+1] +
第十二步：化合物9的制备Step 12: Preparation of Compound 9
将三氟甲磺酸(105mg,0.70mmol)加入到化合物9n(100mg,0.16mmol)的三氟乙酸(2mL)溶液中，室温反应1h。减压浓缩，加乙酸乙酯(20mL)稀释粗品。混合物用饱和碳酸钠溶液调PH至8-9。 乙酸乙酯萃取(20mL x 3)，合并有机相，有机相经无水硫酸钠干燥、过滤、滤液减压浓缩后经柱层析分离纯化(石油醚:四氢呋喃(v:v)＝5:2)得化合物9(45mg,55％)。Trifluoromethanesulfonic acid (105 mg, 0.70 mmol) was added to a solution of compound 9n (100 mg, 0.16 mmol) in trifluoroacetic acid (2 mL), and the reaction was carried out at room temperature for 1 h. Concentrate under reduced pressure, and add ethyl acetate (20 mL) to dilute the crude product. The pH of the mixture was adjusted to 8-9 with saturated sodium carbonate solution. Extract with ethyl acetate (20mL ) to obtain compound 9 (45 mg, 55%).
化合物9为化合物9-1和化合物9-2结构之一。
Compound 9 is one of the structures of compound 9-1 and compound 9-2.
LCMS m/z＝516.2[M+1]+ LCMS m/z＝516.2[M+1] +
1H NMR(400MHz,DMSO-d6)δ12.40(s,1H),8.45(s,2H),7.88(s,1H),6.30-6.17(m,1H),4.57-4.40(m,3H),4.22-4.11(m,1H),3.74-3.68(m,1H),3.64-3.58(m,1H),3.49-3.40(m,2H),3.37-3.31(m,1H),2.95-2.86(m,1H),2.73-2.57(m,2H),2.46-2.37(m,1H),2.05-1.95m,1H),1.86-1.77(m,1H),1.58-1.41(m,2H),1.15(d,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ12.40(s,1H),8.45(s,2H),7.88(s,1H),6.30-6.17(m,1H),4.57-4.40(m,3H ),4.22-4.11(m,1H),3.74-3.68(m,1H),3.64-3.58(m,1H),3.49-3.40(m,2H),3.37-3.31(m,1H),2.95-2.86 (m,1H),2.73-2.57(m,2H),2.46-2.37(m,1H),2.05-1.95m,1H),1.86-1.77(m,1H),1.58-1.41(m,2H), 1.15(d,3H).
实施例10：化合物10p及其立体异构体(化合物10-a、化合物10-b、化合物10-c、化合物10-d)的制备
Example 10: Preparation of compound 10p and its stereoisomers (compound 10-a, compound 10-b, compound 10-c, compound 10-d)
第一步：10b的制备Step One: Preparation of 10b
0℃下，将氯甲酸苄酯(17.35g,101.73mmol)的二氯甲烷(50ml)溶液缓慢滴加到10a (20.00g,92.48mmol)的二氯甲烷(300mL)与饱和碳酸氢钠溶液(300mL)混合溶液中，室温反应16h。二氯甲烷萃取(300mL x 2)，向有机相加入硅胶，减压浓缩后柱层析分离纯化(石油醚：四氢呋喃酯(v:v:＝20：3)得10b(32.00g,99％)。At 0°C, a solution of benzyl chloroformate (17.35g, 101.73mmol) in dichloromethane (50ml) was slowly added dropwise to 10a. (20.00g, 92.48mmol) in a mixed solution of dichloromethane (300mL) and saturated sodium bicarbonate solution (300mL), react at room temperature for 16h. Extract with dichloromethane (300mL .
LCMS m/z＝251.0[M-99]+ LCMS m/z＝251.0[M-99] +
第二步：10c的制备Step 2: Preparation of 10c
将10b(33.00g,94.18mmol)溶于二氯甲烷(600mL)中，0℃加入戴斯-马丁氧化剂(41.94g,98.89mmol)，0℃反应2h。缓慢加入饱和碳酸氢钠水溶液(200mL)猝灭反应，静置分层，得有机相。减压浓缩，粗品经水(500mL)、乙酸乙酯(500mL)混合溶液打浆，过滤。滤液经乙酸乙酯萃取(500mL x 2)，合并有机相，有机相经饱和食盐水洗涤，无水硫酸钠干燥、过滤。滤液减压浓缩得粗品。粗品经柱层析分离纯化(石油醚：四氢呋喃(v:v)＝5:1)得10c(24.00g,73％)。Dissolve 10b (33.00g, 94.18mmol) in dichloromethane (600mL), add Dess-Martin oxidant (41.94g, 98.89mmol) at 0°C, and react at 0°C for 2 hours. Slowly add saturated sodium bicarbonate aqueous solution (200 mL) to quench the reaction, let stand and separate layers to obtain an organic phase. Concentrate under reduced pressure, and the crude product is slurried with a mixed solution of water (500 mL) and ethyl acetate (500 mL) and filtered. The filtrate was extracted with ethyl acetate (500mL 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 separated and purified by column chromatography (petroleum ether: tetrahydrofuran (v:v) = 5:1) to obtain 10c (24.00g, 73%).
LCMS m/z＝293.2[M-55]+ LCMS m/z＝293.2[M-55] +
第三步：10d的制备Step 3: Preparation of 10d
将丙二酸二乙酯(5.75g,35.88mmol)加入到10c(10.00g,28.70mmol)、苯甲酸(1.05g,8.61mmol)、六氢吡啶(0.73g,8.61mmol)的甲苯(100mL)溶液中，135℃分水反应8h。冷却到室温，加入硅胶，减压浓缩后柱层析分离纯化(石油醚：四氢呋喃(v:v)＝10：1)得10d(5.20g,33％)。Diethyl malonate (5.75g, 35.88mmol) was added to 10c (10.00g, 28.70mmol), benzoic acid (1.05g, 8.61mmol), hexahydropyridine (0.73g, 8.61mmol) and toluene (100mL) In the solution, react with water at 135°C for 8 hours. Cool to room temperature, add silica gel, concentrate under reduced pressure and then separate and purify by column chromatography (petroleum ether: tetrahydrofuran (v:v) = 10:1) to obtain 10d (5.20g, 33%).
LCMS m/z＝435.1[M-55]+ LCMS m/z＝435.1[M-55] +
第四步：10e的制备Step 4: Preparation of 10e
将钯碳(0.50g,10％)加入到化合物10d(5.20g,10.60mmol)的甲醇(50mL)、氨水(0.05mL，含量：25％-28％)溶液中，氢气氛围室温反应16h。垫硅藻土过滤，滤液减压浓缩得化合物10e(3.50g,粗品)。Palladium on carbon (0.50g, 10%) was added to a solution of compound 10d (5.20g, 10.60mmol) in methanol (50mL) and ammonia (0.05mL, content: 25%-28%), and the reaction was carried out at room temperature in a hydrogen atmosphere for 16h. The mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain compound 10e (3.50 g, crude product).
LCMS m/z＝359.3[M+1]+ LCMS m/z＝359.3[M+1] +
第五步：10f的制备Step 5: Preparation of 10f
将三乙胺(3.20g,29.28mmol)加入到10e(3.50g,9.76mmol)的乙醇(30mL)溶液的封管中，90℃反应2h。冷却至室温，加入硅胶，减压浓缩后经柱层析分离纯化(石油醚：四氢呋喃(v:v)＝5:1)得10f(1.50g,49％)。Triethylamine (3.20g, 29.28mmol) was added to a sealed tube of a solution of 10e (3.50g, 9.76mmol) in ethanol (30mL), and the reaction was carried out at 90°C for 2 hours. Cool to room temperature, add silica gel, concentrate under reduced pressure and then separate and purify by column chromatography (petroleum ether: tetrahydrofuran (v:v) = 5:1) to obtain 10f (1.50g, 49%).
LCMS m/z＝257.3[M-55]+ LCMS m/z＝257.3[M-55] +
第六步：10g的制备Step 6: Preparation of 10g
将三氟乙酸(10ml)加入到10f(1.50g,4.80mmol)的二氯甲烷(20mL)溶液中，室温反应3h。减压浓缩得10g的三氟乙酸盐(1.50g，粗品)。Trifluoroacetic acid (10 ml) was added to a solution of 10f (1.50 g, 4.80 mmol) in dichloromethane (20 mL), and the reaction was carried out at room temperature for 3 h. Concentrate under reduced pressure to obtain 10g of trifluoroacetate (1.50g, crude product).
LCMS m/z＝213.1[M+1]+ LCMS m/z＝213.1[M+1] +
第七步：10n的制备Step 7: Preparation of 10n
将碳酸钾(2.54g,18.4mmol)加入到10g的三氟乙酸盐(1.50g，粗品)、2-氯-5-(三氟甲基)嘧啶(0.92g,5.06mmol)的二甲基亚砜(10mL)溶液中，95℃反应3h。冷却至室温后加水(20mL)淬灭反应，乙酸乙酯(50mL x 3)萃取，合并有机相。有机相经无水硫酸钠干燥、过滤、滤液减压浓缩得粗品，粗品经柱层析(石油醚：乙酸乙酯(v:v)＝4:1)纯化得10n(1.20g,两步收率：69％)。Potassium carbonate (2.54g, 18.4mmol) was added to 10g of trifluoroacetate (1.50g, crude product), 2-chloro-5-(trifluoromethyl)pyrimidine (0.92g, 5.06mmol) dimethyl In sulfoxide (10 mL) solution, react at 95°C for 3 hours. After cooling to room temperature, water (20 mL) was added to quench the reaction, extracted with ethyl acetate (50 mL x 3), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate (v:v) = 4:1) to obtain 10n (1.20g, collected in two steps). rate: 69%).
LCMS m/z＝359.1[M+1]+ LCMS m/z＝359.1[M+1] +
第八步：10j的制备Step 8: Preparation of 10j
冰盐浴下，依次将氯化钙(1.36g,12.25mmol)、硼氢化钠(0.93g,24.59mmol)加入到10n (1.10g,3.07mmol)的四氢呋喃(12mL)、乙醇(3mL)混合溶液中，冰盐浴反应0.5h。加饱和碳酸钠溶液(10mL)、乙酸乙酯(100mL)淬灭反应，搅拌0.5h。过滤，滤液减压浓缩经柱层析分离纯化(二氯甲烷：甲醇(v:v)＝10:1)得10j(930mg,96％)。Under ice-salt bath, add calcium chloride (1.36g, 12.25mmol) and sodium borohydride (0.93g, 24.59mmol) in sequence to 10n (1.10g, 3.07mmol) in a mixed solution of tetrahydrofuran (12mL) and ethanol (3mL), react in an ice-salt bath for 0.5h. Add saturated sodium carbonate solution (10 mL) and ethyl acetate (100 mL) to quench the reaction, and stir for 0.5 h. Filter, and the filtrate is concentrated under reduced pressure and separated and purified by column chromatography (dichloromethane: methanol (v:v) = 10:1) to obtain 10j (930 mg, 96%).
LCMS m/z＝317.1[M+1]+ LCMS m/z＝317.1[M+1] +
第九步：10k的制备Step 9: Preparation of 10k
0℃下，将10j(1.00g,3.16mmol)，1c”(2.21g,6.32mmol)溶于甲苯(50mL)中，氮气置换后，缓慢滴加三氟化硼乙醚(3mL)，23℃反应16h。0℃加饱和碳酸钠溶液调PH至8-9。乙酸乙酯萃取(100mL x 3)，合并有机相，减压浓缩后经柱层析分离纯化(石油醚：四氢呋喃(v:v)＝10:3)得10k(0.80g,50％)。Dissolve 10j (1.00g, 3.16mmol) and 1c″ (2.21g, 6.32mmol) in toluene (50mL) at 0°C. After nitrogen replacement, slowly add boron trifluoride ether (3mL) dropwise and react at 23°C. 16h. Add saturated sodium carbonate solution at 0℃ to adjust the pH to 8-9. Extract with ethyl acetate (100mL x 3), combine the organic phases, concentrate under reduced pressure and then separate and purify by column chromatography (petroleum ether: tetrahydrofuran (v:v) =10:3) to get 10k (0.80g, 50%).
LCMS m/z＝504.2[M+1]+ LCMS m/z＝504.2[M+1] +
第十步：10m的制备Step 10: Preparation of 10m
将水合肼(0.5ml，80％)加入到10k(800mg,1.59mmol)的乙醇(10mL)溶液中，室温反应16h。过滤，滤液经减压浓缩后得粗品。粗品经乙酸乙酯(50mL)打浆，再次过滤，滤液经减压浓缩后得10m(600mg)的粗品。Hydrazine hydrate (0.5 ml, 80%) was added to a solution of 10k (800 mg, 1.59 mmol) in ethanol (10 mL), and the reaction was carried out at room temperature for 16 h. Filter, and the filtrate is concentrated under reduced pressure to obtain crude product. The crude product was slurried with ethyl acetate (50 mL) and filtered again. The filtrate was concentrated under reduced pressure to obtain 10 m (600 mg) of the crude product.
LCMS m/z＝374.2[M+1]+ LCMS m/z＝374.2[M+1] +
第十一步：10h的制备Step 11: Preparation for 10h
将中间体1(667mg,2.09mmol)加入到10m(600mg，粗品)、三乙胺(0.65g,6.44mmol)的乙腈(20mL)溶液中，室温反应16h。加入硅胶，减压浓缩后经柱层析分离纯化(二氯甲烷：乙酸乙酯(v:v)＝2:1)得10h(740mg,两步收率：71％)。Intermediate 1 (667 mg, 2.09 mmol) was added to a solution of 10 m (600 mg, crude product) and triethylamine (0.65 g, 6.44 mmol) in acetonitrile (20 mL), and the reaction was carried out at room temperature for 16 h. Silica gel was added, concentrated under reduced pressure, and then separated and purified by column chromatography (dichloromethane: ethyl acetate (v:v) = 2:1) to obtain 10h (740 mg, two-step yield: 71%).
LCMS m/z＝656.8[M+1]+ LCMS m/z＝656.8[M+1] +
第十二步：10p的制备Step 12: Preparation of 10p
0℃下，将三氟甲磺酸(594mg,3.95mmol)加入到10h(740mg,1.13mmol)的三氟乙酸(10mL)溶液中，0℃反应1h。减压浓缩，加乙酸乙酯(20mL)、水(10mL)溶解粗品，加入饱和碳酸钠溶液调PH至8-9，乙酸乙酯萃取(20mL x 3)。合并有机相，有机相经减压浓缩后经柱层析分离纯化(二氯甲烷：乙酸乙酯(v:v)＝5:4)得10p(440mg,73％)。At 0°C, trifluoromethanesulfonic acid (594 mg, 3.95 mmol) was added to the 10 h (740 mg, 1.13 mmol) trifluoroacetic acid (10 mL) solution, and the reaction was carried out at 0° C. for 1 hour. Concentrate under reduced pressure, add ethyl acetate (20mL) and water (10mL) to dissolve the crude product, add saturated sodium carbonate solution to adjust the pH to 8-9, and extract with ethyl acetate (20mL x 3). The organic phases were combined, concentrated under reduced pressure, and then separated and purified by column chromatography (dichloromethane: ethyl acetate (v:v) = 5:4) to obtain 10p (440 mg, 73%).
LCMS m/z＝536.1[M+1]+ LCMS m/z＝536.1[M+1] +
第十三步：化合物10-a、化合物10-b、化合物10-c、化合物10-d的制备Step 13: Preparation of compound 10-a, compound 10-b, compound 10-c, and compound 10-d
化合物10p经SFC on AD column纯化(仪器及制备柱：采用Waters 150SFC，制备柱型号是：Chiralpak AD Column(250*30mm,I.D 30mm,10um particle size)。制备方法：化合物10p用甲醇溶解，并用0.45μm滤膜过滤，制备成样品液。流动相体系：A for CO2 and B for etoh。梯度洗脱方法：35％B等梯度洗脱(流速：100ml/min；洗脱时间4.5min；柱温：25℃；柱压：100bar，吸收波长：220nm)得化合物10-P1、化合物10-P2和化合物10-P3，其中化合物10-P3为两个构型混合物。Compound 10p was purified by SFC on AD column (instrument and preparation column: Waters 150SFC was used, and the preparation column model was: Chiralpak AD Column (250*30mm, ID 30mm, 10um particle size). Preparation method: Compound 10p was dissolved in methanol and mixed with 0.45 Filter through a μm filter membrane and prepare a sample solution. Mobile phase system: A for CO 2 and B for etoh. Gradient elution method: 35% B iso-gradient elution (flow rate: 100ml/min; elution time 4.5min; column temperature : 25°C; column pressure: 100bar, absorption wavelength: 220nm) to obtain compound 10-P1, compound 10-P2 and compound 10-P3, of which compound 10-P3 is a mixture of two configurations.
分析方法(仪器：岛津LC-30AD sf；制备柱型号是：Chiralpak AD-3 50×4.6mm I.D.,3μm；流动相体系：A for CO2 and B for etoh(0.05％DEA)。保留时间T＝1.635min为化合物10-P1(化合物10-P1为化合物10-a，化合物10-b，化合物10-c，化合物10-d结构之一)；保留时间T＝1.886min为化合物10-P2(化合物10-P2为化合物10-a，化合物10-b，化合物10-c，化合物10-d结构之一)；保留时间T＝2.288min为化合物10-P3(化合物10-P3为化合物10-a，化合物10-b，化合物10-c，化合物10-d中两个结构的混合物)。 Analytical method (instrument: Shimadzu LC-30AD sf; preparative column model: Chiralpak AD-3 50×4.6mm ID, 3μm; mobile phase system: A for CO 2 and B for etoh (0.05% DEA). Retention time T =1.635min is compound 10-P1 (compound 10-P1 is one of the structures of compound 10-a, compound 10-b, compound 10-c, compound 10-d); retention time T = 1.886min is compound 10-P2 ( Compound 10-P2 is one of the structures of compound 10-a, compound 10-b, compound 10-c, and compound 10-d); the retention time T=2.288min is compound 10-P3 (compound 10-P3 is compound 10-a , compound 10-b, compound 10-c, a mixture of two structures in compound 10-d).
化合物10-P1Compound 10-P1
LCMS m/z＝536.1[M+1]+ LCMS m/z＝536.1[M+1] +
1H NMR(400MHz,DMSO-d6)δ12.37(s,1H),8.73(d,2H),7.87(s,1H),6.27-6.13(m,1H),4.84-4.69(m,2H),4.20-4.07(m,1H),3.95-3.87(m,1H),3.68-3.62(m,1H),3.54-3.38(m,4H),2.94-2.84(m,1H),2.82-2.71(m,2H),2.70-2.62(m,1H),2.05-1.95(m,1H),1.86-1.75(m,1H),1.13(d,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ12.37(s,1H),8.73(d,2H),7.87(s,1H),6.27-6.13(m,1H),4.84-4.69(m,2H ),4.20-4.07(m,1H),3.95-3.87(m,1H),3.68-3.62(m,1H),3.54-3.38(m,4H),2.94-2.84(m,1H),2.82-2.71 (m,2H),2.70-2.62(m,1H),2.05-1.95(m,1H),1.86-1.75(m,1H),1.13(d,3H).
化合物10-P2Compound 10-P2
LCMS m/z＝536.1[M+1]+ LCMS m/z＝536.1[M+1] +
1H NMR(400MHz,DMSO-d6)δ12.42(s,1H),8.73(d,2H),7.93(s,1H),6.34-6.16(m,1H),4.94-4.82(m,1H),4.81-4.72(m,1H),4.28-4.15(m,1H),3.92-3.82(m,1H),3.69-3.56(m,2H),3.54-3.42(m,3H),2.91-2.71(m,2H),2.69-2.56(m,2H),2.28-2.16(m,1H),1.55-1.44(m,1H),1.16(d,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ12.42(s,1H),8.73(d,2H),7.93(s,1H),6.34-6.16(m,1H),4.94-4.82(m,1H ),4.81-4.72(m,1H),4.28-4.15(m,1H),3.92-3.82(m,1H),3.69-3.56(m,2H),3.54-3.42(m,3H),2.91-2.71 (m,2H),2.69-2.56(m,2H),2.28-2.16(m,1H),1.55-1.44(m,1H),1.16(d,3H).
化合物10-P3经SFC on OJ column纯化(仪器及制备柱：采用Waters 150SFC，制备柱型号是：Chiralcel OJ-Column(250*30mm,I.D 30mm,10um particle size))。制备方法：化合物10-P3用甲醇溶解，并用0.45μm滤膜过滤，制备成样品液。流动相体系：A for CO2 and B for EtOH(0.1％NH3·H2O)。梯度洗脱方法：30％B等梯度洗脱(流速：120ml/min；洗脱时间2.0min；柱温：25℃；柱压：100bar，吸收波长：220nm)得到化合物10-P3-1、化合物10-P3-2。Compound 10-P3 was purified by SFC on OJ column (instrument and preparation column: Waters 150SFC was used, and the preparation column model was: Chiralcel OJ-Column (250*30mm, ID 30mm, 10um particle size)). Preparation method: Compound 10-P3 was dissolved in methanol and filtered with a 0.45 μm filter membrane 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% B isotropic elution (flow rate: 120ml/min; elution time 2.0min; column temperature: 25°C; column pressure: 100bar, absorption wavelength: 220nm) to obtain compound 10-P3-1 and compound 10-P3-2.
分析方法(仪器：岛津LC-30AD SFC；制备柱型号是：Chiralcel OJ-3 50×4.6mm I.D.,3μm；流动相体系：A for CO2,B for 0.05％DEA in EtOH。保留时间T＝1.124min为化合物10-P3-1(化合物10-P3-P1为化合物10-a，化合物10-b，化合物10-c，化合物10-d结构之一)；保留时间T＝1.886min为化合物10-P3-2(化合物10-P3-P2为化合物10-a，化合物10-b，化合物10-c，化合物10-d结构之一)。Analytical method (instrument: Shimadzu LC-30AD SFC; preparative column model: Chiralcel OJ-3 50×4.6mm ID, 3μm; mobile phase system: A for CO 2 , B for 0.05% DEA in EtOH. Retention time T＝ 1.124min is compound 10-P3-1 (compound 10-P3-P1 is one of the structures of compound 10-a, compound 10-b, compound 10-c, and compound 10-d); the retention time T=1.886min is compound 10 -P3-2 (Compound 10-P3-P2 is one of the structures of compound 10-a, compound 10-b, compound 10-c, and compound 10-d).
化合物10-P3-1Compound 10-P3-1
LCMS m/z＝536.1[M+1]+ LCMS m/z＝536.1[M+1] +
1H NMR(400MHz,DMSO-d6)δ12.38(s,1H),8.73(s,2H),7.89(s,1H),6.25-6.10(m,1H),4.88-4.67(m,2H),4.25-4.10(m,1H),3.95-3.84(m,1H),3.64-3.53(m,2H),3.52-3.37(m,3H),2.94-2.83(m,1H),2.82-2.70(m,2H),2.69-2.61(m,1H),2.08-1.98(m,1H),1.86-1.75(m,1H),1.12(d,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ12.38(s,1H),8.73(s,2H),7.89(s,1H),6.25-6.10(m,1H),4.88-4.67(m,2H ),4.25-4.10(m,1H),3.95-3.84(m,1H),3.64-3.53(m,2H),3.52-3.37(m,3H),2.94-2.83(m,1H),2.82-2.70 (m,2H),2.69-2.61(m,1H),2.08-1.98(m,1H),1.86-1.75(m,1H),1.12(d,3H).
化合物10-P3-2Compound 10-P3-2
LCMS m/z＝536.1[M+1]+ LCMS m/z＝536.1[M+1] +
1H NMR(400MHz,DMSO-d6)δ12.42(s,1H),8.74(s,2H),7.92(s,1H),6.41-6.28(m,1H),4.90-4.73(m,2H),4.29-4.11(m,1H),3.95-3.82(m,1H),3.73-3.62(m,1H),3.57-3.41(m,4H),2.88-2.72(m,2H),2.69-2.52(m,2H),2.28-2.17(m,1H),1.53-1.41(m,1H),1.15(d,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ12.42(s,1H),8.74(s,2H),7.92(s,1H),6.41-6.28(m,1H),4.90-4.73(m,2H ),4.29-4.11(m,1H),3.95-3.82(m,1H),3.73-3.62(m,1H),3.57-3.41(m,4H),2.88-2.72(m,2H),2.69-2.52 (m,2H),2.28-2.17(m,1H),1.53-1.41(m,1H),1.15(d,3H).
实施例11：化合物11的制备
Example 11: Preparation of Compound 11
第一步：11b的制备Step One: Preparation of 11b
将碳酸钾(2.19g,15.84mmol)加入到9g的盐酸盐(1.04g,粗品)、2-氯,5-环丙基嘧啶(730mg,4.75mmol)的二甲基亚砜(10ml)溶液中，90℃反应16h。冷却至室温，加水(20mL)淬灭反应，乙酸乙酯(30mLx3)萃取，合并有机相。有机相经无水硫酸钠干燥、过滤、滤液减压浓缩经柱层分离纯化(石油醚：四氢呋喃(v:v)＝5:1)得化合物11b(1.00g,73％)Potassium carbonate (2.19g, 15.84mmol) was added to a solution of 9g hydrochloride (1.04g, crude product) and 2-chloro, 5-cyclopropylpyrimidine (730mg, 4.75mmol) in dimethyl sulfoxide (10ml). Medium, react at 90°C for 16 hours. Cool to room temperature, add water (20 mL) to quench the reaction, extract with ethyl acetate (30 mLx3), and combine the organic phases. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (petroleum ether: tetrahydrofuran (v:v) = 5:1) to obtain compound 11b (1.00g, 73%).
LCMS m/z＝345.3[M+1]+ LCMS m/z＝345.3[M+1] +
第二步：化合物11c的制备
Step 2: Preparation of Compound 11c
将氯化钙(1.03g,9.28mmol)加入到化合物11b(800mg,2.32mmol)的四氢呋喃(10ml)、甲醇(2ml)混合溶液中，-60℃下分批加入硼氢化钠(352mg,9.28mmol)，-5℃反应0.5h，-5℃下加入乙酸乙酯(30mL)、饱和氯化铵溶液(10mL)淬灭反应。搅拌1h后，过滤，滤液经减压浓缩后得粗品。粗品经柱层析分离纯化(二氯甲烷(含9％甲醇)：石油醚(含16％乙酸乙酯)(v:v)＝5:1)得化合物11c-1(200mg,29％)和化合物11c-2。Calcium chloride (1.03g, 9.28mmol) was added to a mixed solution of compound 11b (800mg, 2.32mmol) in tetrahydrofuran (10ml) and methanol (2ml), and sodium borohydride (352mg, 9.28mmol) was added in batches at -60°C. ), react at -5°C for 0.5h, add ethyl acetate (30 mL) and saturated ammonium chloride solution (10 mL) at -5°C to quench the reaction. After stirring for 1 hour, filter and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was separated and purified by column chromatography (dichloromethane (containing 9% methanol): petroleum ether (containing 16% ethyl acetate) (v:v) = 5:1) to obtain compound 11c-1 (200 mg, 29%) and Compound 11c-2.
化合物11c-1为化合物11c。Compound 11c-1 is compound 11c.
LCMS m/z＝303.4[M+1]+ LCMS m/z＝303.4[M+1] +
1H NMR(400MHz,CD3OD)δ8.15(s,2H),4.70-4.52(m,3H),3.87-3.72(m,2H),3.53-3.40(m,1H),3.01-2.89(m,1H),2.80-2.64(m,2H),2.49-2.38(m,1H),2.19-2.08(m,1H),2.02-1.92(m,1H),1.82-1.66(m,2H),1.66-1.54(m,1H),0.97-0.88(m,2H),0.66-0.59(m,2H). 1 H NMR (400MHz, CD 3 OD) δ8.15(s,2H),4.70-4.52(m,3H),3.87-3.72(m,2H),3.53-3.40(m,1H),3.01-2.89( m,1H),2.80-2.64(m,2H),2.49-2.38(m,1H),2.19-2.08(m,1H),2.02-1.92(m,1H),1.82-1.66(m,2H), 1.66-1.54(m,1H),0.97-0.88(m,2H),0.66-0.59(m,2H).
化合物11c-2Compound 11c-2
LCMS m/z＝303.4[M+1]+ LCMS m/z＝303.4[M+1] +
1H NMR(400MHz,CD3OD)δ8.16(s,2H),4.65-4.52(m,3H),3.86-3.74(m,2H),3.56-3.44(m,1H),2.99-2.88(m,1H),2.85-2.70(m,2H),2.56-2.46(m,1H),2.06-1.94(m,2H),1.91-1.72(m,3H),0.97-0.89(m,2H),0.66-0.59(m,2H). 1 H NMR (400MHz, CD 3 OD) δ8.16(s,2H),4.65-4.52(m,3H),3.86-3.74(m,2H),3.56-3.44(m,1H),2.99-2.88( m,1H),2.85-2.70(m,2H),2.56-2.46(m,1H),2.06-1.94(m,2H),1.91-1.72(m,3H),0.97-0.89(m,2H), 0.66-0.59(m,2H).
第三步：化合物11d的制备Step 3: Preparation of Compound 11d
0℃下，将化合物11c(235mg,0.78mmol)、化合物1c”(545mg,1.56mmol)溶于甲苯(10mL)中。氮气置换后，向体系中缓慢滴加三氟化硼乙醚(1mL)，23℃反应16h。0℃用饱和碳酸钠溶液调PH至7-8。乙酸乙酯萃取(100mLx3)，合并有机相，有机相经减压浓缩后得粗品，粗品经柱层析分离纯化(石油醚：四氢呋喃(v:v)＝10:3)得化合物11d(190mg,50％)。Compound 11c (235 mg, 0.78 mmol) and compound 1c” (545 mg, 1.56 mmol) were dissolved in toluene (10 mL) at 0°C. After nitrogen replacement, boron trifluoride ether (1 mL) was slowly added dropwise to the system. React for 16 hours at 23°C. Adjust the pH to 7-8 with saturated sodium carbonate solution at 0°C. Extract with ethyl acetate (100mLx3), combine the organic phases, and concentrate the organic phases under reduced pressure to obtain a crude product. The crude product is separated and purified by column chromatography (petroleum) Ether: tetrahydrofuran (v:v) = 10:3) to obtain compound 11d (190 mg, 50%).
LCMS m/z＝490.2[M+1]+ LCMS m/z＝490.2[M+1] +
第四步：化合物11e的制备Step 4: Preparation of compound 11e
将水合肼(0.1mL，含量：80％)加入到化合物11d(217mg,0.44mmol)的乙醇(4mL)溶液中，室温反应16h。减压浓缩，粗品经乙腈打浆，过滤，滤液减压浓缩后得化合物11e(150mg，粗品)。Hydrazine hydrate (0.1 mL, content: 80%) was added to a solution of compound 11d (217 mg, 0.44 mmol) in ethanol (4 mL), and the reaction was carried out at room temperature for 16 h. The mixture was concentrated under reduced pressure, and the crude product was slurried with acetonitrile and filtered. The filtrate was concentrated under reduced pressure to obtain compound 11e (150 mg, crude product).
LCMS m/z＝360.6[M+1]+ LCMS m/z＝360.6[M+1] +
第五步：化合物11f的制备Step 5: Preparation of Compound 11f
将中间体1(174mg,0.55mmol)加入到化合物11e(150mg，粗品)、三乙胺(170mg,1.68mmol)的乙腈(5mL)溶液中，室温反应16h。加入硅胶，减压浓缩后柱层析分离纯化(二氯甲烷：四氢呋喃(v:v)＝5:1)得化合物11f(150mg,两步收率53％)。Intermediate 1 (174 mg, 0.55 mmol) was added to a solution of compound 11e (150 mg, crude product) and triethylamine (170 mg, 1.68 mmol) in acetonitrile (5 mL), and the reaction was carried out at room temperature for 16 h. Silica gel was added, concentrated under reduced pressure, and then separated and purified by column chromatography (dichloromethane: tetrahydrofuran (v:v) = 5:1) to obtain compound 11f (150 mg, two-step yield 53%).
LCMS m/z＝642.4[M+1]+ LCMS m/z＝642.4[M+1] +
第六步：化合物11的制备Step 6: Preparation of Compound 11
0℃下，将三氟甲磺酸(116mg,0.77mmol)加入到化合物11f(140mg,0.22mmol)的三氟乙酸(4mL)溶液中0℃反应1h。减压浓缩，粗品经乙酸乙酯(20ml)稀释后，用饱和碳酸钠溶液调pH至8-9。乙酸乙酯萃取(20mLx3),合并有机相，有机相经无水硫酸钠干燥、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:四氢呋喃(v:v)＝5:2)得化合物11(72mg,63％)。Trifluoromethanesulfonic acid (116 mg, 0.77 mmol) was added to a solution of compound 11f (140 mg, 0.22 mmol) in trifluoroacetic acid (4 mL) at 0° C. and the reaction was carried out at 0° C. for 1 hour. Concentrate under reduced pressure. After the crude product was diluted with ethyl acetate (20 ml), the pH was adjusted to 8-9 with saturated sodium carbonate solution. Extract with ethyl acetate (20mLx3), combine the organic phases, dry the organic phases 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 column chromatography (petroleum ether:tetrahydrofuran (v:v)=5:2) to obtain compound 11 (72 mg, 63%).
化合物11为化合物11-1和化合物11-2结构之一。
Compound 11 is one of the structures of compound 11-1 and compound 11-2.
LCMS m/z＝522.5[M+1]+ LCMS m/z＝522.5[M+1] +
1H NMR(400MHz,DMSO-d6)δ12.40(s,1H),8.19(s,2H),7.88(s,1H),6.30-6.17(m,1H),4.60-4.49(m,2H),4.49-4.41(m,1H),4.22-4.10(m,1H),3.74-3.66(m,1H),3.65-3.58(m,1H),3.50-3.40(m,2H),3.34-3.25(m,1H),2.87-2.74(m,1H),2.65-2.53(m,2H),2.46-2.36(m,1H),2.04-1.95(m,1H),1.87-1.72(m,2H),1.59-1.41(m,2H),1.15(d,3H),0.92-0.84(m,2H),0.68-0.59(m,2H). 1 H NMR (400MHz, DMSO-d 6 ) δ12.40(s,1H),8.19(s,2H),7.88(s,1H),6.30-6.17(m,1H),4.60-4.49(m,2H ),4.49-4.41(m,1H),4.22-4.10(m,1H),3.74-3.66(m,1H),3.65-3.58(m,1H),3.50-3.40(m,2H),3.34-3.25 (m,1H),2.87-2.74(m,1H),2.65-2.53(m,2H),2.46-2.36(m,1H),2.04-1.95(m,1H),1.87-1.72(m,2H) ,1.59-1.41(m,2H),1.15(d,3H),0.92-0.84(m,2H),0.68-0.59(m,2H).
实施例12：化合物12及其立体异构体制备
Example 12: Preparation of compound 12 and its stereoisomers
第一步：12b的制备Step One: Preparation of 12b
将2-(二甲氧基磷酰基)乙酸甲酯(26.19g,143.79mmol)溶解于四氢呋喃(50mL)中,氮气置换，冷却至-78℃滴加双(三甲基硅烷基)氨基钾(143.79mL,143.79mmol,1M)，-78℃反应1h后,滴加12a(参考专利WO2015013835合成得到)(16.7g,47.93mmol)的四氢呋喃(50mL)溶液，-78℃反应2h。滴加饱和氯化铵溶液淬灭反应，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)洗涤，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：四氢呋喃(v/v)＝9:1)得12b(14g,72％)。Dissolve 2-(dimethoxyphosphoryl)methyl acetate (26.19g, 143.79mmol) in tetrahydrofuran (50mL), replace with nitrogen, cool to -78°C, and dropwise add potassium bis(trimethylsilyl)amide ( 143.79mL, 143.79mmol, 1M), reacted at -78℃ for 1h, then added dropwise a solution of 12a (synthesized with reference to patent WO2015013835) (16.7g, 47.93mmol) in tetrahydrofuran (50mL), and reacted at -78℃ for 2h. Add saturated ammonium chloride solution dropwise to quench the reaction, extract with ethyl acetate (50mL Concentrate to a residue. The residue was separated and purified by silica gel column chromatography (petroleum ether: tetrahydrofuran (v/v) = 9:1) to obtain 12b (14 g, 72%).
LCMS m/z＝349.1[M-55]+ LCMS m/z＝349.1[M-55] +
第二步：12c的制备Step 2: Preparation of 12c
将12b(12.5g,30.91mmol)溶于四氢呋喃(150mL)中,0℃下分批加入硼氢化锂(6.73g,309.1mmol)，室温反应18h。缓慢滴加稀盐酸(1M)调pH至8-9,加入乙酸乙酯(150mL x 3)萃取，合并有机相，有机相用饱和食盐水(150mL x 3)洗涤，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：四氢呋喃(v/v)＝4:1)得12c(7g,60％)。Dissolve 12b (12.5g, 30.91mmol) in tetrahydrofuran (150mL), add lithium borohydride (6.73g, 309.1mmol) in batches at 0°C, and react at room temperature for 18h. Slowly add dilute hydrochloric acid (1M) dropwise to adjust the pH to 8-9, add ethyl acetate (150mL x 3) for extraction, combine the organic phases, wash the organic phase with saturated brine (150mL x 3), dry over anhydrous sodium sulfate, and pump Filter, and the filtrate is concentrated under reduced pressure to obtain a residue. The residue was separated and purified by silica gel column chromatography (petroleum ether: tetrahydrofuran (v/v) = 4:1) to obtain 12c (7 g, 60%).
LCMS m/z＝279.2[M-99]+ LCMS m/z＝279.2[M-99] +
第三步：12d的制备Step 3: Preparation of 12d
将三苯基膦(9.45g,36.96mmol)和咪唑(2.52g,36.96mmol)溶于无水二氯甲烷(210mL)中，氮气保护0℃缓慢加入碘单质(9.38g,36.96mmol)，室温反应10分钟后，0℃缓慢滴加12c(7.00g，18.48mmol)，室温反应16h。加入硅胶，减压浓缩后柱层析分离纯化(石油醚：四氢呋喃(v/v)＝12:1)得12d(7.00g，77％)Dissolve triphenylphosphine (9.45g, 36.96mmol) and imidazole (2.52g, 36.96mmol) in anhydrous dichloromethane (210mL), slowly add iodine element (9.38g, 36.96mmol) under nitrogen protection at 0°C, at room temperature. After reacting for 10 minutes, 12c (7.00g, 18.48mmol) was slowly added dropwise at 0°C, and the reaction was carried out at room temperature for 16 hours. Add silica gel, concentrate under reduced pressure and then separate and purify by column chromatography (petroleum ether: tetrahydrofuran (v/v) = 12:1) to obtain 12d (7.00g, 77%)
LCMS m/z＝389.0[M-99]+ LCMS m/z＝389.0[M-99] +
第四步：12e的制备Step 4: Preparation of 12e
将丙二酸二乙酯(9.19g，57.35mmol)溶于无水四氢呋喃溶液(100mL)，氮气置换后，0℃分批加入氢化钠(2.29g，57.35mmol,60％Wt)。0℃反应20分钟，缓慢滴加12d(5.60g，11.47mmol)的无水四氢呋喃(50mL)溶液，室温反应16h。0℃下，缓慢滴加饱和氯化铵水溶液猝灭反应，饱和食盐水(50mL)洗涤，乙酸乙酯(50mL x 3)萃取，合并有机相，有机相用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：四氢呋喃(v/v)＝8:1)得12e(4.50g,75％)。Diethyl malonate (9.19g, 57.35mmol) was dissolved in anhydrous tetrahydrofuran solution (100mL). After nitrogen replacement, sodium hydride (2.29g, 57.35mmol, 60%Wt) was added in batches at 0°C. React at 0°C for 20 minutes, slowly add 12d (5.60g, 11.47mmol) anhydrous tetrahydrofuran (50mL) solution dropwise, and react at room temperature for 16h. At 0°C, slowly add saturated aqueous ammonium chloride solution dropwise to quench the reaction, wash with saturated brine (50mL), extract with ethyl acetate (50mL x 3), combine the organic phases, dry the organic phases with anhydrous sodium sulfate and filter, and the filtrate After concentration under reduced pressure, the crude product was obtained. The crude product was separated and purified by column chromatography (petroleum ether: tetrahydrofuran (v/v) = 8:1) to obtain 12e (4.50 g, 75%).
LCMS m/z＝421.3[M-99]+ LCMS m/z＝421.3[M-99] +
第五步：12f的制备Step 5: Preparation of 12f
将12e(4.50g，8.64mmol)溶于乙醇(50mL)中,加入水(8.64mL)和氢氧化钠(0.35g，8.64mmol)， 室温反应16h。减压浓缩，在0℃下，加入稀盐酸(2N)调PH＝5-6，乙酸乙酯(50mL x 3)萃取，合并有机相，有机相用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(甲醇：二氯甲烷(v/v)＝5:95)得12f(4.20g,98％)。Dissolve 12e (4.50g, 8.64mmol) in ethanol (50mL), add water (8.64mL) and sodium hydroxide (0.35g, 8.64mmol), React at room temperature for 16 hours. Concentrate under reduced pressure. At 0°C, add dilute hydrochloric acid (2N) to adjust pH=5-6, extract with ethyl acetate (50mL After concentration, the crude product is obtained. The crude product was separated and purified by column chromatography (methanol: dichloromethane (v/v) = 5:95) to obtain 12f (4.20 g, 98%).
LCMS m/z＝393.2[M-99]+ LCMS m/z＝393.2[M-99] +
第六步：12g的制备Step 6: Preparation of 12g
将12f(5.10g,10.35mmol)溶于甲醇溶液中(100mL)，向其中分别加入氨水(0.3mL，含量：25％-28％)和钯碳(510mg，10％)，氢气置换三次后，室温反应16h。垫硅藻土过滤，滤液减压浓缩得12g)(3.71g,粗品)。Dissolve 12f (5.10g, 10.35mmol) in methanol solution (100mL), add ammonia water (0.3mL, content: 25%-28%) and palladium carbon (510mg, 10%) to it respectively, and replace it with hydrogen three times. React at room temperature for 16 hours. Filter through diatomaceous earth, and the filtrate is concentrated under reduced pressure to obtain 12g) (3.71g, crude product).
LCMS m/z＝359.2[M+1]+ LCMS m/z＝359.2[M+1] +
第七步：12h的制备Step 7: Preparation for 12h
将12g(3.71g,粗品)溶于DMF(30mL)中，加入DIPEA(4.01g,31.05mmol)和HATU(3.94g,10.35mmol),室温反应过夜。加入水(50mL)，乙酸乙酯(50mL x 3)萃取，合并有机相，有机相用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(四氢呋喃：石油醚(v/v)＝1:10)得12h(3.52g,粗品)。Dissolve 12g (3.71g, crude product) in DMF (30mL), add DIPEA (4.01g, 31.05mmol) and HATU (3.94g, 10.35mmol), and react at room temperature overnight. Add water (50mL), extract with ethyl acetate (50mL x 3), combine the organic phases, dry the organic phase with anhydrous sodium sulfate and filter, and concentrate the filtrate under reduced pressure to obtain the crude product. The crude product was separated and purified by column chromatography (tetrahydrofuran: petroleum ether (v/v) = 1:10) to obtain 12h (3.52g, crude product).
LCMS m/z＝341.2[M+1]+ LCMS m/z＝341.2[M+1] +
第八步：12i的盐酸盐的制备Step 8: Preparation of 12i hydrochloride
将12h(3.52g,粗品)溶于氯化氢-1,4-二氧六环溶液(4.0M,20mL,80mmol)中，室温反应2h。减压浓缩得12i的盐酸盐(2.86g，粗品)。Dissolve 12h (3.52g, crude product) in hydrogen chloride-1,4-dioxane solution (4.0M, 20mL, 80mmol) and react at room temperature for 2h. Concentrate under reduced pressure to obtain 12i hydrochloride (2.86g, crude product).
LCMS m/z＝241.2[M+1]+ LCMS m/z＝241.2[M+1] +
第九步：12j的制备Step 9: Preparation of 12j
将12i的盐酸盐(2.86g，粗品)和2-氯-5-三氟甲基嘧啶(1.89g,10.33mmol)溶于二甲基亚砜(50mL)中，加入碳酸钾(4.28g,30.99mmol)，90℃反应16h。冷却至室温，加入饱和食盐水(50mL)，乙酸乙酯萃取(50mL x 2)。合并有机相，有机相经饱和食盐水洗涤(50mL x 2)，无水硫酸钠干燥、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12j(2g,64％)。Dissolve the hydrochloride of 12i (2.86g, crude product) and 2-chloro-5-trifluoromethylpyrimidine (1.89g, 10.33mmol) in dimethyl sulfoxide (50mL), and add potassium carbonate (4.28g, 30.99mmol), reacted at 90℃ for 16h. Cool to room temperature, add saturated brine (50mL), and extract with ethyl acetate (50mL x 2). The organic phases were combined, washed with saturated brine (50mL x 2), 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) = 5:1) to obtain 12j (2g, 64%).
LCMS m/z＝387.7[M+1]+ LCMS m/z＝387.7[M+1] +
第十步：12k的制备Step 10: Preparation of 12k
将12j(0.90g,2.33mmol)溶于四氢呋喃(39mL)和无水乙醇(39mL)的混合溶液中，加入硼氢化钠(88.14mg,2.33mmol)，室温反应1h。0℃下分批加入氯化钙(150.28mg,1.17mmol)，0℃反应2h。缓慢滴加饱和氯化铵水溶液淬灭反应，加入饱和食盐水洗涤(30mL)，乙酸乙酯萃取(30mL x2)，合并有机相，有机相经无水硫酸钠干燥、过滤，滤液减压浓缩经柱层析分离纯化(石油醚：乙酸乙酯(v/v)＝5:3)得12k(750mg,93％)。Dissolve 12j (0.90g, 2.33mmol) in a mixed solution of tetrahydrofuran (39mL) and absolute ethanol (39mL), add sodium borohydride (88.14mg, 2.33mmol), and react at room temperature for 1 hour. Calcium chloride (150.28 mg, 1.17 mmol) was added in batches at 0°C, and the reaction was carried out at 0°C for 2 hours. Slowly add saturated aqueous ammonium chloride solution to quench the reaction, add saturated brine for washing (30 mL), extract with ethyl acetate (30 mL x 2), combine the organic phases, dry the organic phases over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Separate and purify by column chromatography (petroleum ether: ethyl acetate (v/v) = 5:3) to obtain 12k (750 mg, 93%).
LCMS m/z＝345.4[M+1]+ LCMS m/z＝345.4[M+1] +
第十一步：12l的制备Step 11: Preparation of 12l
将12k(700mg,2.03mmol)、1c”(1.38g,3.95mmol)溶于甲苯(70mL)中,氮气置换后，降温至0℃，加入三氟化硼乙醚溶液(7mL)，23℃反应16h。0℃加饱和碳酸氢钠调PH直至没有气泡，且固体完全溶解。乙酸乙酯萃取(50mL x 3)，合并有机相，有机相经无水硫酸钠干燥、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：四氢呋喃(v:v)＝5:1)得12l(380mg,35％)。 Dissolve 12k (700mg, 2.03mmol) and 1c” (1.38g, 3.95mmol) in toluene (70mL). After nitrogen replacement, cool to 0℃, add boron trifluoride ether solution (7mL), and react at 23℃ for 16h. . Add saturated sodium bicarbonate to adjust the pH at 0°C until there are no bubbles and the solid is completely dissolved. Extract with ethyl acetate (50mL x 3), combine the organic phases, dry the organic phases over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain The crude product was separated and purified by column chromatography (petroleum ether: tetrahydrofuran (v:v) = 5:1) to obtain 12l (380 mg, 35%).
LCMS m/z＝532.2[M+1]+ LCMS m/z＝532.2[M+1] +
第十二步：12m的制备Step 12: Preparation of 12m
水合肼(0.22mL，含量：80％)加入到12l(380mg,0.71mmol)的乙醇(15mL)溶液中，室温反应16h。减压浓缩得粗品，粗品经制备板分离纯化(二氯甲烷：甲醇(v:v)＝10:1)得12m(190mg,66％)。Hydrazine hydrate (0.22 mL, content: 80%) was added to a solution of 12 liters (380 mg, 0.71 mmol) of ethanol (15 mL), and the reaction was carried out at room temperature for 16 hours. Concentrate under reduced pressure to obtain a crude product, which was separated and purified through a preparation plate (dichloromethane: methanol (v:v) = 10:1) to obtain 12m (190 mg, 66%).
LCMS m/z＝402.2[M+1]+ LCMS m/z＝402.2[M+1] +
第十三步：12n的制备Step 13: Preparation of 12n
将12m(190mg,0.47mmol)，中间体1(150mg,0.47mmol)溶于乙腈(6mL)中，加入三乙胺(190mg,1.88mmol)，室温反应16h。减压浓缩后经柱层析分离纯化(石油醚：乙酸乙酯(v/v)＝1:2)得12n(220mg,68％)。Dissolve 12m (190 mg, 0.47 mmol) and intermediate 1 (150 mg, 0.47 mmol) in acetonitrile (6 mL), add triethylamine (190 mg, 1.88 mmol), and react at room temperature for 16 h. After concentration under reduced pressure, the product was separated and purified by column chromatography (petroleum ether: ethyl acetate (v/v) = 1:2) to obtain 12n (220 mg, 68%).
LCMS m/z＝684.2[M+1]+。LCMS m/z=684.2[M+1] + .
第十四步：化合物12及其立体异构体的制备Step 14: Preparation of compound 12 and its stereoisomers
将三氟甲磺酸(340mg,2.27mmol)加入到化合物12n(220mg,0.32mmol)的三氟乙酸(2mL)溶液中，室温反应1h。减压浓缩，加水(4mL)淬灭反应，氨水调PH至7-9。减压浓缩后经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 C18，5μm，内径*长度＝19mm*150mm)。制备方法：粗品经乙腈和水溶解，0.45μm滤膜过滤，制备成样品液。流动相体系：乙腈/水(含10Mm碳酸铵)。梯度洗脱方法：乙腈由32％梯度洗脱62％(洗脱时间15min)。冻干后得化合物12。Trifluoromethanesulfonic acid (340 mg, 2.27 mmol) was added to a solution of compound 12n (220 mg, 0.32 mmol) in trifluoroacetic acid (2 mL), and the reaction was carried out at room temperature for 1 h. Concentrate under reduced pressure, add water (4 mL) to quench the reaction, and adjust the pH to 7-9 with ammonia water. After concentration under reduced pressure, it is purified by Pre-HPLC (instrument and preparation column: SHIMADZU LC-20AP is used to prepare the liquid phase. The preparation column model is Phenomenex C18, 5 μm, inner diameter * length = 19mm * 150mm). Preparation method: Dissolve the crude product in acetonitrile and water, filter with a 0.45 μm filter membrane, and prepare a sample solution. Mobile phase system: acetonitrile/water (containing 10Mm ammonium carbonate). Gradient elution method: acetonitrile gradient elution from 32% to 62% (elution time 15 minutes). Compound 12 was obtained after lyophilization.
化合物12经SFC on AD column纯化(仪器及制备柱：采用Waters 150SFC，制备柱型号是Chiralpak IG Column(250*30mm,I.D 30mm,10um particle size)。制备方法：化合物12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 CO2 and B for EtOH+ACN(0.1％NH3·H2O)。梯度洗脱方法：50％phase B(流速：100mL/min；洗脱时间2.8min)得化合物12-Peak-1和化合物12-Peak-2。Compound 12 was purified by SFC on AD column (instrument and preparation column: Waters 150SFC was used, and the preparation column model was Chiralpak IG Column (250*30mm, ID 30mm, 10um particle size). Preparation method: Compound 12 was dissolved in acetonitrile, and 0.45 μm Filter through the membrane to prepare a sample solution. Mobile phase system: A for CO 2 and B for EtOH+ACN (0.1% NH 3 ·H 2 O). Gradient elution method: 50% phase B (flow rate: 100mL/min; Elution time: 2.8 min) to obtain compound 12-Peak-1 and compound 12-Peak-2.
分析方法(仪器及制备柱：SHIMADZU LC-30AD sf，制备柱型号是：Chiralpak AD-3 50×4.6mm I.D.,3μm)流动相体系：A for CO2 and B for MeOH(0.05％DEA)。保留时间T＝0.971为化合物12-Peak-1(81mg)(化合物12-Peak-1为化合物12-P1,化合物12-P2，化合物12-P3与化合物12-P4结构之一)；保留时间T＝1.845为化合物12-Peak-2(77mg)(化合物12-Peak-1为化合物12-P1,化合物12-P2，化合物12-P3与化合物12-P4结构之一)。
Analysis method (instrument and preparation column: SHIMADZU LC-30AD sf, preparation column model: Chiralpak AD-3 50×4.6mm ID, 3μm) Mobile phase system: A for CO 2 and B for MeOH (0.05% DEA). The retention time T=0.971 is compound 12-Peak-1 (81 mg) (compound 12-Peak-1 is one of the structures of compound 12-P1, compound 12-P2, compound 12-P3 and compound 12-P4); retention time T =1.845 is compound 12-Peak-2 (77 mg) (compound 12-Peak-1 is one of the structures of compound 12-P1, compound 12-P2, compound 12-P3 and compound 12-P4).
化合物12-Peak-1Compound 12-Peak-1
LCMS m/z＝564.7[M+1]+ LCMS m/z＝564.7[M+1] +
1H NMR(400MHz,DMSO-d6)δ12.41(s,1H),8.72(s,2H),7.90(s,1H),6.31-6.18(m,1H),4.25-3.98(m,4H),3.95-3.86(m,1H),3.72-3.56(m,4H),3.56-3.49(m,1H),3.45-3.37(m,1H),3.28-3.23(m,1H),2.85-2.75(m,1H),1.77-1.65(m,2H),1.65-1.47(m,2H),1.45-1.32(m,1H),1.18-1.03(m,4H). 1 H NMR (400MHz, DMSO-d 6 ) δ12.41(s,1H),8.72(s,2H),7.90(s,1H),6.31-6.18(m,1H),4.25-3.98(m,4H ),3.95-3.86(m,1H),3.72-3.56(m,4H),3.56-3.49(m,1H),3.45-3.37(m,1H),3.28-3.23(m,1H),2.85-2.75 (m,1H),1.77-1.65(m,2H),1.65-1.47(m,2H),1.45-1.32(m,1H),1.18-1.03(m,4H).
化合物12-Peak-2Compound 12-Peak-2
LCMS m/z＝564.6[M+1]+ LCMS m/z＝564.6[M+1] +
1H NMR(400MHz,DMSO-d6)δ12.41(s,1H),8.71(s,2H),7.91(s,1H),6.28-6.18(m,1H),4.23-4.05(m,3H),4.04-3.97(m,1H),3.96-3.87(m,1H),3.72-3.55(m,4H),3.49-3.45(m,2H),3.33-3.29(m,1H),2.87-2.77(m,1H),1.81-1.66(m,2H),1.66-1.51(m,2H),1.45-1.32(m,1H),1.19-1.05(m,4H). 1 H NMR (400MHz, DMSO-d 6 ) δ12.41(s,1H),8.71(s,2H),7.91(s,1H),6.28-6.18(m,1H),4.23-4.05(m,3H ),4.04-3.97(m,1H),3.96-3.87(m,1H),3.72-3.55(m,4H),3.49-3.45(m,2H),3.33-3.29(m,1H),2.87-2.77 (m,1H),1.81-1.66(m,2H),1.66-1.51(m,2H),1.45-1.32(m,1H),1.19-1.05(m,4H).
实施例13：化合物13的制备
Example 13: Preparation of Compound 13
化合物13以12c为起始物料，参考化合物1的合成方法得到。Compound 13 was obtained using 12c as the starting material and referring to the synthesis method of compound 1.
LCMS m/z＝580.3[M+1]+。LCMS m/z=580.3[M+1] + .
1H NMR(400MHz,DMSO-d6)δ12.44(s,1H),8.72(s,2H),7.94-7.88(m,1H),6.30-6.19(m,1H),4.80-4.70(m,1H),4.68-4.46(m,3H),4.24-4.07(m,2H),3.91-3.82(m,1H),3.74-3.57(m,3H),3.56-3.46(m,2H),3.43-3.35(m,1H),3.15-3.02(m,1H),2.89-2.77(m,1H),1.88-1.63(m,2H),1.55-1.43(m,1H),1.28-1.19(m,1H),1.16(d,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ12.44(s,1H),8.72(s,2H),7.94-7.88(m,1H),6.30-6.19(m,1H),4.80-4.70(m ,1H),4.68-4.46(m,3H),4.24-4.07(m,2H),3.91-3.82(m,1H),3.74-3.57(m,3H),3.56-3.46(m,2H),3.43 -3.35(m,1H),3.15-3.02(m,1H),2.89-2.77(m,1H),1.88-1.63(m,2H),1.55-1.43(m,1H),1.28-1.19(m, 1H),1.16(d,3H).
实施例14：化合物14的制备

Example 14: Preparation of Compound 14

化合物14以14a为起始物料，参考化合物9的合成方法得到，化合物14为化合物14-1和化合物14-2结构之一。Compound 14 was obtained using 14a as the starting material by referring to the synthetic method of compound 9. Compound 14 is one of the structures of compound 14-1 and compound 14-2.
LCMS m/z＝550.2[M+1]+ LCMS m/z＝550.2[M+1] +
1H NMR(400MHz,DMSO-d6)δ12.40(s,1H),9.24(s,1H),7.88(s,1H),7.73-7.63(m,2H),7.63-7.57(m,1H),6.30-6.18(m,1H),4.81-4.68(m,2H),4.56-4.46(m,1H),4.23–4.08(m,1H),3.76-3.67(m,1H),3.66-3.58(m,1H),3.50-3.42(m,2H),3.42-3.33(m,1H),3.02-2.90(m,1H),2.77-2.62(m,2H),2.47-2.38(m,1H),2.12-1.99(m,1H),1.91-1.77(m,1H),1.61-1.45(m,2H),1.15(d,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ12.40(s,1H),9.24(s,1H),7.88(s,1H),7.73-7.63(m,2H),7.63-7.57(m,1H ),6.30-6.18(m,1H),4.81-4.68(m,2H),4.56-4.46(m,1H),4.23–4.08(m,1H),3.76-3.67(m,1H),3.66-3.58 (m,1H),3.50-3.42(m,2H),3.42-3.33(m,1H),3.02-2.90(m,1H),2.77-2.62(m,2H),2.47-2.38(m,1H) ,2.12-1.99(m,1H),1.91-1.77(m,1H),1.61-1.45(m,2H),1.15(d,3H).
实施例15：化合物15的制备
Example 15: Preparation of Compound 15
第一步：15b的制备Step One: Preparation of 15b
将15a(3.00g,15.48mmol)、2-氟苯硼酸(2.17g,15.48mmol)、碳酸铯(10.09g,30.96mmol)、1,4-二氧六环(40mL)和水(4mL)依次加入到单口瓶中，氮气置换后，加入四(三苯基膦)钯(1.79g,1.55mmol)，90℃反应16h。减压浓缩，加入水(50mL)淬灭反应，乙酸乙酯(40mL x 2)萃取，合并有机相，用饱和食盐水(30mL)洗涤后，经无水硫酸钠干燥，抽滤，滤液经减压浓缩得粗品，粗 品经柱层析分离纯化(石油醚：二氯甲烷(v/v)＝7:3)得15b(2.60g,80％)Add 15a (3.00g, 15.48mmol), 2-fluorophenylboronic acid (2.17g, 15.48mmol), cesium carbonate (10.09g, 30.96mmol), 1,4-dioxane (40mL) and water (4mL) in sequence Add it to a one-neck bottle, and after nitrogen replacement, add tetrakis(triphenylphosphine)palladium (1.79g, 1.55mmol) and react at 90°C for 16 hours. Concentrate under reduced pressure, add water (50mL) to quench the reaction, extract with ethyl acetate (40mL x 2), combine the organic phases, wash with saturated brine (30mL), dry over anhydrous sodium sulfate, suction filter, and reduce the filtrate to Concentrated under pressure to obtain crude product, crude The product was separated and purified by column chromatography (petroleum ether: dichloromethane (v/v) = 7:3) to obtain 15b (2.60g, 80%)
LCMS m/z＝209.0[M+1]+ LCMS m/z＝209.0[M+1] +
化合物15以15b为底物，参考化合物9的合成方法得到，化合物15为化合物15-1和化合物15-2结构之一Compound 15 was obtained using 15b as the substrate by referring to the synthetic method of compound 9. Compound 15 is one of the structures of compound 15-1 and compound 15-2.
LCMS m/z＝576.3[M+1]+ LCMS m/z＝576.3[M+1] +
1H NMR(400MHz,DMSO-d6)δ12.41(s,1H),8.61(d,2H),7.89(s,1H),7.60-7.55(m,1H),7.45-7.38(m,1H),7.36-7.28(m,2H),6.30-6.19(m,1H),4.72-4.61(m,2H),4.53-4.45(m,1H),4.23-4.10(m,1H),3.75-3.68(m,1H),3.66-3.59(m,1H),3.49-3.41(m,2H),3.41-3.32(m,1H),2.99-2.89(m,1H),2.76-2.60m,2H),2.47-2.38(m,1H),2.07-1.97(m,1H),1.89-1.78(m,1H),1.60-1.44(m,2H),1.15(d,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ12.41(s,1H),8.61(d,2H),7.89(s,1H),7.60-7.55(m,1H),7.45-7.38(m,1H ),7.36-7.28(m,2H),6.30-6.19(m,1H),4.72-4.61(m,2H),4.53-4.45(m,1H),4.23-4.10(m,1H),3.75-3.68 (m,1H),3.66-3.59(m,1H),3.49-3.41(m,2H),3.41-3.32(m,1H),2.99-2.89(m,1H),2.76-2.60m,2H), 2.47-2.38(m,1H),2.07-1.97(m,1H),1.89-1.78(m,1H),1.60-1.44(m,2H),1.15(d,3H).
实施例16：化合物16的三氟乙酸盐的制备
Example 16: Preparation of trifluoroacetate salt of compound 16
第一步：16a的制备Step One: Preparation of 16a
0℃下，依次将硼氢化钠(58mg,1.53mmol)、氯化钙(85mg,0.77mmol)加入到9f(500mg,1.53mmol)的四氢呋喃(5mL)、乙醇(5mL)混合溶液中，0℃反应1h。加入乙酸乙酯(30mL)、饱和氯化铵溶液(10mL)淬灭反应。分液，有机相经减压浓缩后得16a(438mg，粗品)。At 0°C, sodium borohydride (58mg, 1.53mmol) and calcium chloride (85mg, 0.77mmol) were added to the mixed solution of 9f (500mg, 1.53mmol) in tetrahydrofuran (5mL) and ethanol (5mL), 0°C Reaction 1h. Ethyl acetate (30 mL) and saturated ammonium chloride solution (10 mL) were added to quench the reaction. The liquids were separated, and the organic phase was concentrated under reduced pressure to obtain 16a (438 mg, crude product).
LCMS m/z＝285.4[M+1]+。LCMS m/z=285.4[M+1] + .
第二步：16b盐酸盐的制备Step 2: Preparation of 16b hydrochloride
将16a(438mg，粗品)溶于4N盐酸二氧六环(10mL)中，室温反应2h。减压浓缩得16b的盐酸盐(339mg，粗品)。16a (438 mg, crude product) was dissolved in 4N dioxane hydrochloride (10 mL) and reacted at room temperature for 2 h. Concentrate under reduced pressure to obtain 16b hydrochloride (339 mg, crude product).
LCMS m/z＝185.2[M+1]+ LCMS m/z＝185.2[M+1] +
化合物16的三氟乙酸盐以16b的盐酸盐为底物，参考化合物9的合成方法得到，化合物16为化合物16-1和化合物16-2结构之一。 The trifluoroacetate of compound 16 was obtained by using the hydrochloride of 16b as the substrate and referring to the synthesis method of compound 9. Compound 16 is one of the structures of compound 16-1 and compound 16-2.
LCMS m/z＝538.2[M+1]+ LCMS m/z＝538.2[M+1] +
1H NMR(400MHz,CD3OD)δ8.81(s,1H),7.91(s,1H),7.26-7.18(m,2H),4.80-4.70(m,2H),4.64-4.56(m,1H),4.23-4.11(m,1H),4.02-3.92(m,1H),3.64-3.53(m,2H),3.52-3.36(m,2H),3.15-3.03(m,1H),2.93-2.83(m,1H),2.82-2.74(m,1H),2.55-2.45(m,1H),2.17-2.07(m,1H),1.95-1.85(m,1H),1.75-1.52(m,2H),1.25(d,3H). 1 H NMR (400MHz, CD 3 OD) δ8.81(s,1H),7.91(s,1H),7.26-7.18(m,2H),4.80-4.70(m,2H),4.64-4.56(m, 1H),4.23-4.11(m,1H),4.02-3.92(m,1H),3.64-3.53(m,2H),3.52-3.36(m,2H),3.15-3.03(m,1H),2.93- 2.83(m,1H),2.82-2.74(m,1H),2.55-2.45(m,1H),2.17-2.07(m,1H),1.95-1.85(m,1H),1.75-1.52(m,2H ),1.25(d,3H).
实施例17：化合物17的制备
Example 17: Preparation of Compound 17
化合物17以17a为底物，参考化合物9的合成方法得到，化合物17为化合物17-1和化合物17-2结构之一。Compound 17 was obtained using 17a as a substrate by referring to the synthetic method of compound 9. Compound 17 is one of the structures of compound 17-1 and compound 17-2.
LCMS m/z＝522.3[M+1]+ LCMS m/z＝522.3[M+1] +
1H NMR(400MHz,DMSO-d6)δ12.39(s,1H),8.19(s,1H),7.88(s,1H),6.27-6.20(m,1H),4.62-4.53(m,2H),4.50-4.42(m,1H),4.21-4.10(m,1H),3.74-3.66(m,1H),3.64-3.58(m,1H),3.49-3.40(m,2H),3.36-3.33(m,1H),2.82-2.72(m,5H),2.62-2.53(m,2H),2.45-2.37(m,1H),2.04-1.95(m,3H),1.86-1.78(m,1H),1.58-1.40(m,2H),1.15(d,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ12.39(s,1H),8.19(s,1H),7.88(s,1H),6.27-6.20(m,1H),4.62-4.53(m,2H ),4.50-4.42(m,1H),4.21-4.10(m,1H),3.74-3.66(m,1H),3.64-3.58(m,1H),3.49-3.40(m,2H),3.36-3.33 (m,1H),2.82-2.72(m,5H),2.62-2.53(m,2H),2.45-2.37(m,1H),2.04-1.95(m,3H),1.86-1.78(m,1H) ,1.58-1.40(m,2H),1.15(d,3H).
实施例18：化合物18的制备
Example 18: Preparation of Compound 18
化合物18以18a为底物，参考化合物9的合成方法得到，化合物18为化合物18-1和化合 物18-2结构之一Compound 18 was obtained using 18a as the substrate by referring to the synthetic method of compound 9. Compound 18 is a combination of compound 18-1 and One of the structures of Object 18-2
LCMS m/z＝536.7[M+1]+ LCMS m/z＝536.7[M+1] +
1H NMR(400MHz,DMSO-d6)δ12.36(s,1H),9.14(s,1H),7.92(s,1H),7.88(s,1H),6.32-6.16(m,1H),4.70-4.57(m,2H),4.54-4.43(m,1H),4.22-4.11(m,1H),4.07(s,3H),3.76-3.67(m,1H),3.66-3.58(m,1H),3.53-3.41(m,3H),2.91-2.80(m,1H),2.70-2.58(m,2H),2.47-2.37(m,1H),2.09-1.97(m,1H),1.88-1.79(m,1H),1.62-1.42(m,2H),1.15(d,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ12.36(s,1H),9.14(s,1H),7.92(s,1H),7.88(s,1H),6.32-6.16(m,1H), 4.70-4.57(m,2H),4.54-4.43(m,1H),4.22-4.11(m,1H),4.07(s,3H),3.76-3.67(m,1H),3.66-3.58(m,1H ),3.53-3.41(m,3H),2.91-2.80(m,1H),2.70-2.58(m,2H),2.47-2.37(m,1H),2.09-1.97(m,1H),1.88-1.79 (m,1H),1.62-1.42(m,2H),1.15(d,3H).
实施例19：化合物19的制备
Example 19: Preparation of Compound 19
化合物19以19a为底物，参考化合物9的合成方法得到，化合物19为化合物19-1和化合物19-2结构之一。Compound 19 was obtained using 19a as a substrate by referring to the synthetic method of compound 9. Compound 19 is one of the structures of compound 19-1 and compound 19-2.
LCMS m/z＝538.1[M+1]+ LCMS m/z＝538.1[M+1] +
1H NMR(400MHz,DMSO-d6)δ12.40(s,1H),9.09(s,1H),8.28(d,1H),7.88(s,1H),7.28(d,1H),6.32-6.16(m,1H),4.75-4.58(m,2H),4.55-4.43(m,1H),4.25-4.08(m,1H),3.76-3.68(m,1H),3.66-3.58(m,1H),3.50-3.41(m,2H),3.40-3.33(m,1H),2.96-2.82(m,1H),2.73-2.58(m,2H),2.48-2.37(m,1H),2.11-1.97(m,1H),1.90-1.76(m,1H),1.60-1.43(m,2H),1.15(d,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ12.40(s,1H),9.09(s,1H),8.28(d,1H),7.88(s,1H),7.28(d,1H),6.32- 6.16(m,1H),4.75-4.58(m,2H),4.55-4.43(m,1H),4.25-4.08(m,1H),3.76-3.68(m,1H),3.66-3.58(m,1H ),3.50-3.41(m,2H),3.40-3.33(m,1H),2.96-2.82(m,1H),2.73-2.58(m,2H),2.48-2.37(m,1H),2.11-1.97 (m,1H),1.90-1.76(m,1H),1.60-1.43(m,2H),1.15(d,3H).
实施例20：化合物20的制备

Example 20: Preparation of Compound 20

第一步：20b的制备Step One: Preparation of 20b
将20a(3.00g,17.75mmol)、溶于乙腈(150mL)中，依次加入亚硝酸钠(2.45g,35.50mmol)和氢溴酸水溶液(6mL，含量：48％)，室温反应16h。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)＝75:25)得20b(3.00g,73％)Dissolve 20a (3.00g, 17.75mmol) in acetonitrile (150mL), add sodium nitrite (2.45g, 35.50mmol) and hydrobromic acid aqueous solution (6mL, content: 48%) in sequence, and react at room temperature for 16h. Concentrate under reduced pressure to obtain a crude product, which is separated and purified by column chromatography (petroleum ether: ethyl acetate (v/v) = 75:25) to obtain 20b (3.00g, 73%)
LCMS m/z＝232.0[M+1]+ LCMS m/z＝232.0[M+1] +
第二步：20c的制备Step 2: Preparation of 20c
将20b(2.67g,11.49mmol)溶于1,4-二氧六环(30mL)中，依次加入9g(2.60g,粗品)，碳酸钾(3.18g,22.98mmol)，三(二亚苄基丙酮)钯(526.08mg,0.57mmol)，4,5-双二苯基膦-9,9-二甲基氧杂蒽(664.83mg,1.15mmol)，氮气置换3次，100℃反应16h。冷却至室温，加水(50mL)，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(60mL x 2)，无水硫酸钠干燥、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)＝25:75)得20c(850mg,20％)Dissolve 20b (2.67g, 11.49mmol) in 1,4-dioxane (30mL), and add 9g (2.60g, crude product), potassium carbonate (3.18g, 22.98mmol), tris(dibenzylidene) in sequence Acetone) palladium (526.08 mg, 0.57 mmol), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (664.83 mg, 1.15 mmol), nitrogen replacement 3 times, reaction at 100°C for 16 hours. Cool to room temperature, add water (50mL), and extract with ethyl acetate (50mL x 2). Combine the organic phases, wash the organic phase with saturated brine (60mL v)=25:75) get 20c (850mg, 20%)
LCMS m/z＝378.1[M+1]+ LCMS m/z＝378.1[M+1] +
化合物20以20c为底物，参考化合物9的合成方法得到，化合物20为化合物20-1和化合物20-2结构之一。Compound 20 was obtained using 20c as a substrate by referring to the synthetic method of compound 9. Compound 20 is one of the structures of compound 20-1 and compound 20-2.
LCMS m/z＝555.2[M+1]+ LCMS m/z＝555.2[M+1] +
1H NMR(400MHz,DMSO-d6)δ12.41(s,1H),8.70(d,1H),7.88(s,1H),7.67(d,1H),7.04(dd,1H),6.33-6.15(m,1H),4.58-4.46(m,1H),4.23-4.03(m,3H),3.75-3.66(m,1H),3.65-3.57(m,1H),3.51-3.40(m,3H),2.92-2.80(m,1H),2.75-2.60(m,2H),2.45-2.36(m,1H),2.08-1.95(m,1H),1.89-1.76(m,1H),1.59-1.39(m,2H),1.15(d,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ12.41(s,1H),8.70(d,1H),7.88(s,1H),7.67(d,1H),7.04(dd,1H),6.33- 6.15(m,1H),4.58-4.46(m,1H),4.23-4.03(m,3H),3.75-3.66(m,1H),3.65-3.57(m,1H),3.51-3.40(m,3H ),2.92-2.80(m,1H),2.75-2.60(m,2H),2.45-2.36(m,1H),2.08-1.95(m,1H),1.89-1.76(m,1H),1.59-1.39 (m,2H),1.15(d,3H).
实施例21：化合物21的制备

Example 21: Preparation of Compound 21

化合物21以21a为底物，参考化合物9的合成方法得到，化合物21为化合物21-1和化合物21-2结构之一Compound 21 was obtained using 21a as the substrate by referring to the synthetic method of compound 9. Compound 21 is one of the structures of compound 21-1 and compound 21-2.
LCMS m/z＝507.2[M+1]+ LCMS m/z＝507.2[M+1] +
1H NMR(400MHz,DMSO-d6)δ12.40(s,1H),8.79(s,2H),7.87(s,1H),6.32-6.17(m,1H),4.70-4.57(m,2H),4.52-4.40(m,1H),4.22-4.08(m,1H),3.76-3.68(m,1H),3.64-3.57(m,1H),3.48-3.42(m,3H),3.09-2.98(m,1H),2.87-2.76(m,1H),2.70-2.60(m,1H),2.45-2.38(m,1H),2.05-1.95(m,1H),1.87-1.77(m,1H),1.60-1.41(m,2H),1.14(d,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ12.40(s,1H),8.79(s,2H),7.87(s,1H),6.32-6.17(m,1H),4.70-4.57(m,2H ),4.52-4.40(m,1H),4.22-4.08(m,1H),3.76-3.68(m,1H),3.64-3.57(m,1H),3.48-3.42(m,3H),3.09-2.98 (m,1H),2.87-2.76(m,1H),2.70-2.60(m,1H),2.45-2.38(m,1H),2.05-1.95(m,1H),1.87-1.77(m,1H) ,1.60-1.41(m,2H),1.14(d,3H).
实施例22：化合物22的制备
Example 22: Preparation of Compound 22
第一步：22-b的制备Step One: Preparation of 22-b
将N-溴代丁二酰亚胺(2.81g,15.82mmol)分批加入到22a(2.15g,13.18mmol)的乙腈(20mL)溶液中，室温反应16h。减压浓缩得22b(3.10g，粗品)。N-bromosuccinimide (2.81g, 15.82mmol) was added in batches to a solution of 22a (2.15g, 13.18mmol) in acetonitrile (20mL), and the reaction was carried out at room temperature for 16h. Concentrate under reduced pressure to obtain 22b (3.10 g, crude product).
LCMS m/z＝241.9[M+1]+ LCMS m/z＝241.9[M+1] +
第二步：22c的制备Step 2: Preparation of 22c
将硫氰酸钾(1.49g,15.37mmol)加入到22b(3.10g，粗品)的醋酸(30mL)溶液中,140℃反应3h。减压浓缩得粗品，粗品用水(20mL)打浆，过滤，滤饼烘干后得22c(1.90g,两步收率：65％)。Potassium thiocyanate (1.49g, 15.37mmol) was added to the acetic acid (30mL) solution of 22b (3.10g, crude product), and the reaction was carried out at 140°C for 3 hours. Concentrate under reduced pressure to obtain a crude product, which is beaten with water (20 mL), filtered, and the filter cake is dried to obtain 22c (1.90 g, two-step yield: 65%).
LCMS m/z＝221.1[M+1]+ LCMS m/z＝221.1[M+1] +
第三步：22d的制备 Step 3: Preparation of 22d
将22c(1.80g,8.18mmol)溶于乙腈(20mL)溶液中，依次加入亚硝酸叔丁酯(1.69g,16.36mmol)，溴化铜(3.65g,16.36mmol)，氮气氛围60℃反应3h。冷却至室温，加入100mL饱和氯化钠溶液，乙酸乙酯萃取(100mL x 3)。合并有机相，有机相用饱和食盐水洗涤(80mL x 2)，无水硫酸钠干燥、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)＝83:17)得到22d(1.00g，43％)。Dissolve 22c (1.80g, 8.18mmol) in acetonitrile (20mL) solution, add tert-butyl nitrite (1.69g, 16.36mmol) and copper bromide (3.65g, 16.36mmol) in sequence, and react at 60°C for 3 hours in a nitrogen atmosphere. . Cool to room temperature, add 100mL saturated sodium chloride solution, and extract with ethyl acetate (100mL x 3). Combine the organic phases, wash the organic phase with saturated brine (80mL v) = 83:17) to obtain 22d (1.00 g, 43%).
1H NMR(400MHz,DMSO-d6)δ9.68(s,1H). 1 H NMR (400MHz, DMSO-d6) δ9.68 (s, 1H).
化合物22以22d为底物，参考化合物16的合成方法得到，化合物22为化合物22-1和化合物22-2的结构之一Compound 22 was obtained using 22d as the substrate by referring to the synthetic method of compound 16. Compound 22 is one of the structures of compound 22-1 and compound 22-2.
LCMS m/z＝607.2[M+1]+ LCMS m/z＝607.2[M+1] +
1H NMR(400MHz,DMSO-d6)δ12.41(s,1H),8.92(s,1H),7.88(s,1H),6.34-6.18(m,1H),4.58-4.46(m,1H),4.30-4.00(m,3H),3.79-3.68(m,1H),3.64-3.55(m,1H),3.54-3.41(m,3H),3.37-3.26(m,1H),3.20-3.07(m,1H),2.86-2.73(m,1H),2.48-2.39(m,1H),2.12-2.02(m,1H),1.89-1.77(m,1H),1.59-1.42(m,2H),1.15(d,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ12.41(s,1H),8.92(s,1H),7.88(s,1H),6.34-6.18(m,1H),4.58-4.46(m,1H ),4.30-4.00(m,3H),3.79-3.68(m,1H),3.64-3.55(m,1H),3.54-3.41(m,3H),3.37-3.26(m,1H),3.20-3.07 (m,1H),2.86-2.73(m,1H),2.48-2.39(m,1H),2.12-2.02(m,1H),1.89-1.77(m,1H),1.59-1.42(m,2H) ,1.15(d,3H).
实施例23：化合物23的制备
Example 23: Preparation of Compound 23
第一步：23b的制备Step One: Preparation of 23b
将双三苯基膦二氯化钯(1.56g,2.23mmol)加入到23a(7.80g,44.57mmol)、2-氟苯硼酸(6.24g,44.57mmol)、碳酸钾(13.55g,98.05mmol)的二氧六环(150mL)、水(10mL)的混合溶液中氮气氛围95℃反应16h。冷却至室温，向反应液中加饱和氯化钠溶液(200mL),乙酸乙酯萃取(200mLx3)。合并有机相，有机相减压浓缩得残留物，残留物经柱层析分离纯化(二氯甲烷：四氢呋喃(v/v)＝83:17)得到23b(6.40g,76％)。Bistriphenylphosphine palladium dichloride (1.56g, 2.23mmol) was added to 23a (7.80g, 44.57mmol), 2-fluorophenylboronic acid (6.24g, 44.57mmol), and potassium carbonate (13.55g, 98.05mmol) A mixed solution of dioxane (150 mL) and water (10 mL) was reacted in a nitrogen atmosphere at 95°C for 16 hours. Cool to room temperature, add saturated sodium chloride solution (200mL) to the reaction solution, and extract with ethyl acetate (200mLx3). The organic phases were combined and concentrated under reduced pressure to obtain a residue. The residue was separated and purified by column chromatography (dichloromethane: tetrahydrofuran (v/v) = 83:17) to obtain 23b (6.40 g, 76%).
LCMS m/z＝191.1[M+1]+，LCMS m/z＝191.1[M+1] + ,
第二步：23c的制备Step 2: Preparation of 23c
将亚硝酸叔丁酯(3.69g,35.76mmol)滴加到23b(3.40g,17.88mmol)、氯化铜(2.68g,26.82mmol)的乙腈(50mL)溶液中，60℃反应1h。冷却至室温，加入饱和氯化钠溶液(50mL)，乙酸乙酯萃取(80mLx3)。合并有机相，有机相减压浓缩得残留物，残留物经柱层析分离纯化(石油醚：乙酸乙酯(v/v)＝83:17)得23c(1.40g,37％)。 Tert-butyl nitrite (3.69g, 35.76mmol) was added dropwise to a solution of 23b (3.40g, 17.88mmol) and copper chloride (2.68g, 26.82mmol) in acetonitrile (50mL), and the reaction was carried out at 60°C for 1 hour. Cool to room temperature, add saturated sodium chloride solution (50 mL), and extract with ethyl acetate (80 mLx3). The organic phases were combined and concentrated under reduced pressure to obtain a residue. The residue was separated and purified by column chromatography (petroleum ether: ethyl acetate (v/v) = 83:17) to obtain 23c (1.40 g, 37%).
LCMS m/z＝210.1[M+1]+ LCMS m/z＝210.1[M+1] +
化合物23以23c为底物，参考化合物16的合成方法得到，化合物23为化合物23-1和化合物23-2的结构之一。Compound 23 was obtained using 23c as a substrate by referring to the synthetic method of compound 16. Compound 23 is one of the structures of compound 23-1 and compound 23-2.
LCMS m/z＝577.3[M+1]+ LCMS m/z＝577.3[M+1] +
1H NMR(400MHz,DMSO-d6)δ12.36(s,1H),8.71(d,1H),7.95-7.85(m,2H),7.58-7.48(m,1H),7.42-7.33(m,2H),6.32-6.18(m,1H),4.77-4.60(m,2H),4.57-4.46(m,1H),4.24-4.10(m,1H),3.78-3.69(m,1H),3.65-3.58(m,1H),3.50-3.38(m,3H),3.15-3.02(m,1H),2.92-2.82(m,1H),2.79-2.68(m,1H),2.48-2.41(m,1H),2.12-1.98(m,1H),1.89-1.81(m,1H),1.60-1.46(m,2H),1.15(d,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ12.36(s,1H),8.71(d,1H),7.95-7.85(m,2H),7.58-7.48(m,1H),7.42-7.33(m ,2H),6.32-6.18(m,1H),4.77-4.60(m,2H),4.57-4.46(m,1H),4.24-4.10(m,1H),3.78-3.69(m,1H),3.65 -3.58(m,1H),3.50-3.38(m,3H),3.15-3.02(m,1H),2.92-2.82(m,1H),2.79-2.68(m,1H),2.48-2.41(m, 1H),2.12-1.98(m,1H),1.89-1.81(m,1H),1.60-1.46(m,2H),1.15(d,3H).
实施例24：化合物24的制备
Example 24: Preparation of Compound 24
化合物24以9g的盐酸盐、3-氯-6-三氟甲基哒嗪为底物，参考化合物9的合成方法得到，化合物24为化合物24-1和化合物24-2结构之一。Compound 24 was obtained by using 9 g of hydrochloride and 3-chloro-6-trifluoromethylpyridazine as substrates by referring to the synthetic method of compound 9. Compound 24 is one of the structures of compound 24-1 and compound 24-2.
LCMS m/z＝550.8[M+1]+。LCMS m/z=550.8[M+1] + .
1H NMR(400MHz,DMSO-d6)δ12.41(s,1H),7.89(s,1H),7.84(d,1H),7.45(d,1H),6.31-6.18(m,1H),4.54-4.37(m,3H),4.23-4.12(m,1H),3.79-3.68(m,1H),3.64-3.57(m,1H),3.50-3.39(m,3H),3.12-3.00(m,1H),2.87-2.71(m,2H),2.48-2.40(m,1H),2.06-1.96(m,1H),1.90-1.78(m,1H),1.62-1.42(m,2H),1.15(d,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ12.41(s,1H),7.89(s,1H),7.84(d,1H),7.45(d,1H),6.31-6.18(m,1H), 4.54-4.37(m,3H),4.23-4.12(m,1H),3.79-3.68(m,1H),3.64-3.57(m,1H),3.50-3.39(m,3H),3.12-3.00(m ,1H),2.87-2.71(m,2H),2.48-2.40(m,1H),2.06-1.96(m,1H),1.90-1.78(m,1H),1.62-1.42(m,2H),1.15 (d,3H).
实施例25：化合物25的制备

Example 25: Preparation of Compound 25

化合物25以2-氯-5-氟嘧啶为底物，参考化合物9的合成方法得到，化合物25为化合物25-1和化合物25-2结构之一。Compound 25 was obtained using 2-chloro-5-fluoropyrimidine as a substrate by referring to the synthetic method of compound 9. Compound 25 is one of the structures of compound 25-1 and compound 25-2.
LCMS m/z＝500.7[M+1]+。LCMS m/z=500.7[M+1] + .
1H NMR(400MHz,DMSO-d6)δ12.41(s,1H),8.47(s,2H),7.88(s,1H),6.32-6.18(m,1H),4.58-4.40(m,3H),4.23-4.09(m,1H),3.76-3.67(m,1H),3.64-3.57(m,1H),3.51-3.37(m,3H),2.92-2.83(m,1H),2.70-2.57(m,2H),2.46-2.38(m,1H),2.05-1.95(m,1H),1.87-1.76(m,1H),1.59-1.41(m,2H),1.15(d,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ12.41(s,1H),8.47(s,2H),7.88(s,1H),6.32-6.18(m,1H),4.58-4.40(m,3H ),4.23-4.09(m,1H),3.76-3.67(m,1H),3.64-3.57(m,1H),3.51-3.37(m,3H),2.92-2.83(m,1H),2.70-2.57 (m,2H),2.46-2.38(m,1H),2.05-1.95(m,1H),1.87-1.76(m,1H),1.59-1.41(m,2H),1.15(d,3H).
实施例26：化合物26的制备
Example 26: Preparation of Compound 26
化合物26以2,6-二氯苯并噻唑为底物，参考化合物9的合成方法得到，化合物26为化合物26-1和化合物26-2结构之一。Compound 26 was obtained using 2,6-dichlorobenzothiazole as a substrate and referring to the synthetic method of compound 9. Compound 26 is one of the structures of compound 26-1 and compound 26-2.
LCMS m/z＝571.1[M+1]+ LCMS m/z＝571.1[M+1] +
1H NMR(400MHz,DMSO-d6)δ12.32(s,1H),7.93(d,1H),7.89(s,1H),7.45(d,1H),7.31(dd,1H),6.34-6.18(m,1H),4.57-4.46(m,1H),4.23-4.11(m,1H),4.07-3.93(m,2H),3.75-3.68(m,1H), 3.65-3.58(m,1H),3.48-3.43(m,3H),3.18-3.09(m,1H),3.00-2.91(m,1H),2.79-2.69(m,1H),2.48-2.39(m,1H),2.10-1.99(m,1H),1.88-1.79(m,1H),1.60-1.41(m,2H),1.15(d,3H). 1 H NMR(400MHz,DMSO-d6)δ12.32(s,1H),7.93(d,1H),7.89(s,1H),7.45(d,1H),7.31(dd,1H),6.34-6.18 (m,1H),4.57-4.46(m,1H),4.23-4.11(m,1H),4.07-3.93(m,2H),3.75-3.68(m,1H), 3.65-3.58(m,1H),3.48-3.43(m,3H),3.18-3.09(m,1H),3.00-2.91(m,1H),2.79-2.69(m,1H),2.48-2.39(m ,1H),2.10-1.99(m,1H),1.88-1.79(m,1H),1.60-1.41(m,2H),1.15(d,3H).
实施例27：化合物27的制备
Example 27: Preparation of Compound 27
第一步：27b的制备Step One: Preparation of 27b
将碳酸钾(5.08g,36.76mmol)加入到9g的盐酸盐(2.08g，粗品)和27a(2.18g,11.04mmol)的二甲基亚砜(15mL)溶液中，室温反应过夜。冷却至室温，加入水(80mL)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(50mL x 2)，无水硫酸钠干燥、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)＝68:32)得27b(2.72g,64％)Potassium carbonate (5.08g, 36.76mmol) was added to a solution of 9g hydrochloride (2.08g, crude product) and 27a (2.18g, 11.04mmol) in dimethyl sulfoxide (15mL), and the reaction was carried out at room temperature overnight. Cool to room temperature, add water (80mL) to quench the reaction, and extract with ethyl acetate (20mL x 2). Combine the organic phases, wash the organic phase with saturated brine (50mL v)=68:32) gets 27b (2.72g, 64%)
LCMS m/z＝388.1[M+1]+ LCMS m/z＝388.1[M+1] +
第二步：27c的制备Step 2: Preparation of 27c
将N,N-二甲基甲酰胺二甲基缩醛(1086mg,9.11mmol)加入到27b(2.72g,7.01mmol)的甲苯(20mL)溶液中，120℃反应过夜。冷却至室温，减压浓缩得27c(3.20g,粗品)。N,N-dimethylformamide dimethyl acetal (1086 mg, 9.11 mmol) was added to a solution of 27b (2.72 g, 7.01 mmol) in toluene (20 mL), and the reaction was carried out at 120°C overnight. Cool to room temperature and concentrate under reduced pressure to obtain 27c (3.20 g, crude product).
LCMS m/z＝443.1[M+1]+ LCMS m/z＝443.1[M+1] +
第三步：27d的制备Step 3: Preparation of 27d
冰水浴下，将羟胺磺酸(1084mg,9.59mmol)，吡啶(1083mg,13.7mmol)加入到27c(3.03g,粗品)的甲醇(30mL)溶液中，室温反应18h。加入饱和碳酸钠水溶液调节pH值到8-9，减压浓缩，加入水(100mL)，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(50mL x 2)，无水硫酸钠干燥、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：四氢呋喃(v/v)＝64:36)得27d(2.30g,两步收率79％)Under an ice-water bath, add hydroxylamine sulfonic acid (1084 mg, 9.59 mmol) and pyridine (1083 mg, 13.7 mmol) to a solution of 27c (3.03 g, crude product) in methanol (30 mL), and react at room temperature for 18 h. Add saturated sodium carbonate aqueous solution to adjust the pH value to 8-9, concentrate under reduced pressure, add water (100mL), and extract with ethyl acetate (50mL x 2). Combine the organic phases, wash the organic phase with saturated brine (50mL =64:36) to get 27d (2.30g, two-step yield 79%)
LCMS m/z＝413.5[M+1]+ LCMS m/z＝413.5[M+1] +
化合物27以27d为底物，参考化合物9的合成方法得到，化合物27为化合物27-1和化合物27-2结构之一。Compound 27 was obtained using 27d as the substrate by referring to the synthetic method of compound 9. Compound 27 is one of the structures of compound 27-1 and compound 27-2.
化合物27：Compound 27:
LCMS m/z＝590.3[M+1]+ LCMS m/z＝590.3[M+1] +
1H NMR(400MHz,DMSO-d6)δ12.37(s,1H),8.65(s,1H),8.38(s,1H),7.88(s,1H),6.30-6.18(m,1H),5.13(t,2H),4.57-4.40(m,1H),4.25-4.06(m,1H),3.77-3.66(m,1H),3.65-3.59(m,1H),3.58-3.50(m,1H),3.49-3.40(m,2H),3.29-3.24(m,1H),3.15-3.04(m,1H),2.92-2.80(m,1H),2.47-2.38(m,1H),2.04-1.91(m,1H),1.90-1.75(m,1H),1.60-1.44(m,2H),1.15(d,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ12.37(s,1H),8.65(s,1H),8.38(s,1H),7.88(s,1H),6.30-6.18(m,1H), 5.13(t,2H),4.57-4.40(m,1H),4.25-4.06(m,1H),3.77-3.66(m,1H),3.65-3.59(m,1H),3.58-3.50(m,1H ),3.49-3.40(m,2H),3.29-3.24(m,1H),3.15-3.04(m,1H),2.92-2.80(m,1H),2.47-2.38(m,1H),2.04-1.91 (m,1H),1.90-1.75(m,1H),1.60-1.44(m,2H),1.15(d,3H).
实施例28：化合物28的制备
Example 28: Preparation of Compound 28
第一步：28b的制备Step 1: Preparation of 28b
将DIPEA(2.31g,17.85mmol)加入到9g的盐酸盐(1.62g，粗品)和28a(1.00g,5.97mmol)的正丁醇(20mL)溶液中，120℃微波反应2h。减压浓缩得粗品，粗品经柱层析分离纯化(二氯甲烷：乙酸乙酯(v/v)＝62:38)得28b(1.58g,68％)DIPEA (2.31g, 17.85mmol) was added to a solution of 9g hydrochloride (1.62g, crude product) and 28a (1.00g, 5.97mmol) in n-butanol (20mL), and the reaction was carried out under microwave at 120°C for 2h. Concentrate under reduced pressure to obtain a crude product, which is separated and purified by column chromatography (dichloromethane: ethyl acetate (v/v) = 62:38) to obtain 28b (1.58g, 68%)
LCMS m/z＝386.2[M+1]+ LCMS m/z＝386.2[M+1] +
第二步：28c的制备Step 2: Preparation of 28c
将N-氯代丁二酰亚胺(1.31g,9.80mmol)加入到28b(3.15g,8.17mmol)的DMF(30mL)溶液中，室温反应16h。加入饱和碳酸氢钠水溶液(100mL)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(50mL)洗涤，无水硫酸钠干燥、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)＝58:42)得到28c(1.76g,51％)。N-Chlorosuccinimide (1.31g, 9.80mmol) was added to a solution of 28b (3.15g, 8.17mmol) in DMF (30mL), and the reaction was carried out at room temperature for 16h. Add saturated aqueous sodium bicarbonate solution (100mL) to quench the reaction, and extract with ethyl acetate (20mL x 2). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified by column chromatography (petroleum ether: ethyl acetate (v/v) =58:42) to obtain 28c (1.76g, 51%).
LCMS m/z＝420.2[M+1]+ LCMS m/z＝420.2[M+1] +
化合物28以28c为底物，参考化合物9的合成方法得到，化合物28为化合物28-1和化合物28-2结构之一。Compound 28 was obtained using 28c as a substrate by referring to the synthetic method of compound 9. Compound 28 is one of the structures of compound 28-1 and compound 28-2.
化合物28：Compound 28:
LCMS m/z＝569.2[M+1]+ LCMS m/z＝569.2[M+1] +
1H NMR(400MHz,DMSO-d6)δ12.41(s,1H),8.43(s,1H),7.89(s,1H),7.55(s,1H),6.35-6.17(m,1H),5.23-4.97(m,2H),4.57-4.43(m,1H),4.20(s,3H),4.19-4.10(m,1H),3.7-3.56(m,2H),3.51-3.36(m,3H),3.08-2.91(m,1H),2.81-2.63(m,2H),2.47-2.37(m,1H),2.07-1.93(m,1H),1.89-1.77(m,1H),1.60-1.44(m,2H),1.15(d,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ12.41(s,1H),8.43(s,1H),7.89(s,1H),7.55(s,1H),6.35-6.17(m,1H), 5.23-4.97(m,2H),4.57-4.43(m,1H),4.20(s,3H),4.19-4.10(m,1H),3.7-3.56(m,2H),3.51-3.36(m,3H ),3.08-2.91(m,1H),2.81-2.63(m,2H),2.47-2.37(m,1H),2.07-1.93(m,1H),1.89-1.77(m,1H),1.60-1.44 (m,2H),1.15(d,3H).
实施例29：化合物29的制备
Example 29: Preparation of Compound 29
第一步：29b的制备Step 1: Preparation of 29b
将亚硝酸钠(1.64g,23.72mmol)加入到29a(2g,11.86mmol)的乙腈(100mL)溶液中，缓慢滴入氢溴酸水溶液(4mL，含量：48％)，室温反应16h。加入硅胶，减压浓缩后经柱层析分离纯化(石油醚：四氢呋喃(v:v)＝4:1)，得29b(1.92g,70％)。Sodium nitrite (1.64g, 23.72mmol) was added to the solution of 29a (2g, 11.86mmol) in acetonitrile (100mL), and aqueous hydrobromic acid solution (4mL, content: 48%) was slowly dropped into the solution, and the reaction was carried out at room temperature for 16h. Silica gel was added, concentrated under reduced pressure and then separated and purified by column chromatography (petroleum ether: tetrahydrofuran (v:v) = 4:1) to obtain 29b (1.92g, 70%).
LCMS m/z＝232.0[M+1]+ LCMS m/z＝232.0[M+1] +
第二步：29c的制备
Step 2: Preparation of 29c
将29b(0.82g,3.53mmol)加入到16b的盐酸盐(0.65g，粗品)、DIPEA(1.37g,10.56mmol)、4-二甲氨基吡啶(43mg,0.35mmol)的乙醇(20mL)溶液中，120℃微波反应3h。加入硅胶，减压浓缩后经柱层析分离纯化(二氯甲烷(含9％甲醇)：石油醚(含16％乙酸乙酯)(v/v)＝20:80)得29c-1(0.165g,14％)和29c-2。29b (0.82g, 3.53mmol) was added to a solution of 16b hydrochloride (0.65g, crude product), DIPEA (1.37g, 10.56mmol), and 4-dimethylaminopyridine (43mg, 0.35mmol) in ethanol (20mL). Medium, microwave reaction at 120°C for 3 hours. Add silica gel, concentrate under reduced pressure, and then separate and purify by column chromatography (methylene chloride (containing 9% methanol): petroleum ether (containing 16% ethyl acetate) (v/v) = 20:80) to obtain 29c-1 (0.165 g, 14%) and 29c-2.
29c-1为29c29c-1 is 29c
LCMS m/z＝336.2[M+1]+。LCMS m/z=336.2[M+1] + .
1H NMR(400MHz,DMSO-d6)δ9.05-8.98(m,1H),7.62-7.56(m,1H),7.53-7.49(m,1H),4.59-4.46(m,2H),4.17-4.05(m,2H),3.73-3.64(m,1H),3.63-3.53(m,1H),3.52-3.41(m,1H),2.94-2.81(m,1H),2.78-2.60(m,2H),2.35-2.23(m,1H),2.14-2.00(m,1H),1.95-1.83(m,1H),1.66-1.42(m,2H). 1 H NMR (400MHz, DMSO-d 6 ) δ9.05-8.98(m,1H),7.62-7.56(m,1H),7.53-7.49(m,1H),4.59-4.46(m,2H),4.17 -4.05(m,2H),3.73-3.64(m,1H),3.63-3.53(m,1H),3.52-3.41(m,1H),2.94-2.81(m,1H),2.78-2.60(m, 2H),2.35-2.23(m,1H),2.14-2.00(m,1H),1.95-1.83(m,1H),1.66-1.42(m,2H).
29c-229c-2
LCMS m/z＝336.2[M+1]+。LCMS m/z=336.2[M+1] + .
1H NMR(400MHz,DMSO-d6)δ9.05-8.98(m,1H),7.62-7.55(m,1H),7.54-7.47(m,1H),4.67(t, 1H),4.58-4.46(m,1H),4.14-4.03(m,2H),3.70-3.43(m,3H),2.92-2.75(m,2H),2.74-2.63(m,1H),2.41-2.30(m,1H),1.94-1.81(m,2H),1.80-1.63(m,2H). 1 H NMR (400MHz, DMSO-d 6 ) δ9.05-8.98(m,1H),7.62-7.55(m,1H),7.54-7.47(m,1H),4.67(t, 1H),4.58-4.46(m,1H),4.14-4.03(m,2H),3.70-3.43(m,3H),2.92-2.75(m,2H),2.74-2.63(m,1H),2.41- 2.30(m,1H),1.94-1.81(m,2H),1.80-1.63(m,2H).
化合物29以29c为底物，参考化合物16的合成方法得到，化合物29为化合物29-1和化合物29-2结构之一。Compound 29 was obtained using 29c as a substrate by referring to the synthetic method of compound 16. Compound 29 is one of the structures of compound 29-1 and compound 29-2.
化合物29：Compound 29:
LCMS m/z＝555.2[M+1]+ LCMS m/z＝555.2[M+1] +
1H NMR(400MHz,DMSO-d6)δ12.41(s,1H),9.06-8.98(m,1H),7.88(s,1H),7.62-7.56(m,1H),7.54-7.49(m,1H),6.29-6.20(m,1H),4.57-4.47(m,1H),4.22-4.03(m,3H),3.74-3.66(m,1H),3.65-3.58(m,1H),3.49-3.36(m,3H),2.92-2.81(m,1H),2.73-2.61(m,2H),2.45-2.38(m,1H),2.07-1.95(m,1H),1.88-1.77(m,1H),1.60-1.41(m,2H),1.15(d,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ12.41(s,1H),9.06-8.98(m,1H),7.88(s,1H),7.62-7.56(m,1H),7.54-7.49(m ,1H),6.29-6.20(m,1H),4.57-4.47(m,1H),4.22-4.03(m,3H),3.74-3.66(m,1H),3.65-3.58(m,1H),3.49 -3.36(m,3H),2.92-2.81(m,1H),2.73-2.61(m,2H),2.45-2.38(m,1H),2.07-1.95(m,1H),1.88-1.77(m, 1H),1.60-1.41(m,2H),1.15(d,3H).
实施例30：化合物30的制备
Example 30: Preparation of Compound 30
第一步：30b的制备Step 1: Preparation of 30b
将异硫氰酰甲酸乙酯(14.47g,110.36mmol)加入到30a(15.00g,91.97mmol)的1,4-二氧六环(150mL)溶液中，35℃反应72h。加入硅胶，减压浓缩后经柱层析分离纯化(石油醚：四氢呋喃(v:v)＝80:20)得30b(7.00g,26％)。Ethyl isothiocyanatoformate (14.47g, 110.36mmol) was added to the solution of 30a (15.00g, 91.97mmol) in 1,4-dioxane (150mL), and the reaction was carried out at 35°C for 72h. Silica gel was added, concentrated under reduced pressure and then separated and purified by column chromatography (petroleum ether: tetrahydrofuran (v:v) = 80:20) to obtain 30b (7.00g, 26%).
LCMS m/z＝295.1[M+1]+ LCMS m/z＝295.1[M+1] +
第二步：30c的制备Step 2: Preparation of 30c
依次将盐酸羟胺(6.61g,95.16mmol)、三乙胺(7.22g,71.35mmol)加入到30b(7.00g,23.79mmol)的甲醇(100mL)和乙醇(100mL)混合溶液中，室温反应2h，80℃反应4h。加入硅胶，减压浓缩 后经柱层析分离纯化(石油醚：四氢呋喃(v:v)＝67:33)得30c(3.88g,80％)。Hydroxylamine hydrochloride (6.61g, 95.16mmol) and triethylamine (7.22g, 71.35mmol) were added to the mixed solution of 30b (7.00g, 23.79mmol) in methanol (100mL) and ethanol (100mL) in sequence, and the reaction was carried out at room temperature for 2 hours. React at 80°C for 4 hours. Add silica gel and concentrate under reduced pressure After separation and purification by column chromatography (petroleum ether: tetrahydrofuran (v:v) = 67:33), 30c (3.88g, 80%) was obtained.
LCMS m/z＝204.1[M+1]+ LCMS m/z＝204.1[M+1] +
第三步：30d的制备Step 3: Preparation of 30d
将亚硝酸钠(2.65g,38.40mmol)加入到30c(3.90g,19.20mmol)的乙腈(100mL)溶液中，缓慢滴入浓盐酸水溶液(10mL)，室温反应16h。加入硅胶，减压浓缩后经柱层析分离纯化(石油醚：四氢呋喃(v:v)＝80:20)得30d(1.16g,27％)。Sodium nitrite (2.65g, 38.40mmol) was added to the solution of 30c (3.90g, 19.20mmol) in acetonitrile (100mL), concentrated hydrochloric acid aqueous solution (10mL) was slowly added dropwise, and the reaction was carried out at room temperature for 16h. Silica gel was added, concentrated under reduced pressure and then separated and purified by column chromatography (petroleum ether: tetrahydrofuran (v:v) = 80:20) to obtain 30d (1.16g, 27%).
LCMS m/z＝223.1[M+1]+ LCMS m/z＝223.1[M+1] +
第四步：30e的制备
Step 4: Preparation of 30e
将30d(0.79g,3.53mmol)加入到16b的盐酸盐(0.65g，粗品)、DIPEA(1.82g,14.12mmol)、4-二甲氨基吡啶(43mg,0.35mmol)的乙醇(20mL)溶液中，120℃微波反应3h。加入硅胶，减压浓缩后经柱层析分离纯化(二氯甲烷(含9％甲醇)：石油醚(含16％乙酸乙酯)(v/v)＝20:80)得30e-1(0.36g,27％)和30e-2。30d (0.79g, 3.53mmol) was added to a solution of 16b hydrochloride (0.65g, crude product), DIPEA (1.82g, 14.12mmol), and 4-dimethylaminopyridine (43mg, 0.35mmol) in ethanol (20mL). Medium, microwave reaction at 120°C for 3 hours. Add silica gel, concentrate under reduced pressure and then separate and purify by column chromatography (methylene chloride (containing 9% methanol): petroleum ether (containing 16% ethyl acetate) (v/v) = 20:80) to obtain 30e-1 (0.36 g, 27%) and 30e-2.
30e-1为30e30e-1 is 30e
LCMS m/z＝371.4[M+1]+。LCMS m/z=371.4[M+1] + .
1H NMR(400MHz,DMSO-d6)δ9.64(s,1H),8.14(s,1H),4.62-4.49(m,2H),4.23-4.12(m,2H),3.73-3.64(m,1H),3.63-3.55(m,1H),3.54-3.43(m,1H),3.08-2.95(m,1H),2.90-2.80(m,1H),2.76-2.64(m,1H),2.37-2.23(m,1H),2.15-2.03(m,1H),1.96-1.85(m,1H),1.67-1.44(m,2H). 1 H NMR (400MHz, DMSO-d 6 ) δ9.64(s,1H),8.14(s,1H),4.62-4.49(m,2H),4.23-4.12(m,2H),3.73-3.64(m ,1H),3.63-3.55(m,1H),3.54-3.43(m,1H),3.08-2.95(m,1H),2.90-2.80(m,1H),2.76-2.64(m,1H),2.37 -2.23(m,1H),2.15-2.03(m,1H),1.96-1.85(m,1H),1.67-1.44(m,2H).
30e-230e-2
LCMS m/z＝371.4[M+1]+。LCMS m/z=371.4[M+1] + .
1H NMR(400MHz,DMSO-d6)δ9.64(s,1H),8.14(s,1H),4.78-4.46(m,2H),4.25-4.06(m,2H),3.74-3.48(m,3H),3.04-2.86(m,2H),2.76-2.65(m,1H),2.40-2.32(m,1H),1.96-1.82(m,2H),1.81-1.67(m,2H). 1 H NMR (400MHz, DMSO-d 6 ) δ9.64(s,1H),8.14(s,1H),4.78-4.46(m,2H),4.25-4.06(m,2H),3.74-3.48(m ,3H),3.04-2.86(m,2H),2.76-2.65(m,1H),2.40-2.32(m,1H),1.96-1.82(m,2H),1.81-1.67(m,2H).
化合物30以30e为底物，参考化合物16的合成方法得到，化合物30为化合物30-1和化合物30-2结构之一Compound 30 was obtained using 30e as the substrate by referring to the synthetic method of compound 16. Compound 30 is one of the structures of compound 30-1 and compound 30-2.
化合物30：Compound 30:
LCMS m/z＝590.8[M+1]+ LCMS m/z＝590.8[M+1] +
1H NMR(400MHz,DMSO-d6)δ12.38(s,1H),9.64(s,1H),8.14(s,1H),7.88(s,1H),6.30-6.18(m,1H),4.60-4.48(m,1H),4.25-4.09(m,3H),3.76-3.67(m,1H),3.65-3.56(m,1H),3.49-3.36(m,3H),3.07-2.93(m,1H),2.87-2.76(m,1H),2.73-2.62(m,1H),2.47-2.38(m,1H),2.10-1.97(m,1H),1.89-1.77(m,1H),1.61-1.42(m,2H),1.15(d,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ12.38(s,1H),9.64(s,1H),8.14(s,1H),7.88(s,1H),6.30-6.18(m,1H), 4.60-4.48(m,1H),4.25-4.09(m,3H),3.76-3.67(m,1H),3.65-3.56(m,1H),3.49-3.36(m,3H),3.07-2.93(m ,1H),2.87-2.76(m,1H),2.73-2.62(m,1H),2.47-2.38(m,1H),2.10-1.97(m,1H),1.89-1.77(m,1H),1.61 -1.42(m,2H),1.15(d,3H).
实施例31：化合物31的制备
Example 31: Preparation of Compound 31
第一步：31b的制备Step One: Preparation of 31b
将钯碳(400mg,10％)、碳酸钾(1.60g,11.56mmol)加入到31a(2.00g,8.89mmol)的四氢呋喃(50mL)溶液中，氢气置换后，保持高压釜(2.5MPa氢气压力)30℃反应24h。垫硅藻土过滤，向滤液中加入硅胶，减压浓缩后经柱层析分离纯化(石油醚：四氢呋喃(v:v)＝80:20)，得31b(0.80g,47％)。Palladium on carbon (400 mg, 10%) and potassium carbonate (1.60 g, 11.56 mmol) were added to the solution of 31a (2.00 g, 8.89 mmol) in tetrahydrofuran (50 mL). After hydrogen replacement, the autoclave (2.5 MPa hydrogen pressure) was maintained. React at 30°C for 24 hours. Filter through diatomaceous earth, add silica gel to the filtrate, concentrate under reduced pressure and then separate and purify by column chromatography (petroleum ether: tetrahydrofuran (v:v) = 80:20) to obtain 31b (0.80g, 47%).
LCMS m/z＝191.1[M+1]+ LCMS m/z＝191.1[M+1] +
第二步：31c的制备
Step 2: Preparation of 31c
将31a(0.67g,3.53mmol)加入到16b的盐酸盐(0.65g，粗品)、DIPEA(1.82g,14.12mmol)、4-二甲氨基吡啶(43mg,0.35mmol)的乙醇(20mL)溶液中，120℃微波反应3h。加入硅胶，减压浓缩后经柱层析分离纯化粗品经柱层析分离纯化(二氯甲烷(含9％甲醇)：石油醚(含16％乙酸乙酯)(v/v)＝20:80)得到31c-1(0.42g,35％)和31c-2。31a (0.67g, 3.53mmol) was added to a solution of 16b hydrochloride (0.65g, crude product), DIPEA (1.82g, 14.12mmol), and 4-dimethylaminopyridine (43mg, 0.35mmol) in ethanol (20mL). Medium, microwave reaction at 120°C for 3 hours. Add silica gel, concentrate under reduced pressure, and then separate and purify by column chromatography. The crude product is separated and purified by column chromatography (dichloromethane (containing 9% methanol): petroleum ether (containing 16% ethyl acetate) (v/v) = 20:80 ) to obtain 31c-1 (0.42g, 35%) and 31c-2.
31c-1为31c31c-1 is 31c
LCMS m/z＝339.2[M+1]+。LCMS m/z=339.2[M+1] + .
1H NMR(400MHz,DMSO-d6)δ8.58(s,1H),4.64-4.45(m,4H),3.72-3.64(m,1H),3.63-3.54(m,1H),3.47-3.36(m,1H),2.99-2.80(m,3H),2.77-2.51(m,4H),2.35-2.24(m,1H),2.14-2.02(m,1H),1.95-1.84(m,1H),1.67-1.43(m,2H). 1 H NMR (400MHz, DMSO-d 6 ) δ8.58(s,1H),4.64-4.45(m,4H),3.72-3.64(m,1H),3.63-3.54(m,1H),3.47-3.36 (m,1H),2.99-2.80(m,3H),2.77-2.51(m,4H),2.35-2.24(m,1H),2.14-2.02(m,1H),1.95-1.84(m,1H) ,1.67-1.43(m,2H).
31c-231c-2
LCMS m/z＝339.2[M+1]+。LCMS m/z=339.2[M+1] + .
1H NMR(400MHz,DMSO-d6)δ8.58(s,1H),4.70-4.65(m,1H),4.64-4.43(m,3H),3.72-3.53(m,2H),3.50-3.37(m,1H),2.94-2.75(m,4H),2.71-2.52(m,3H),2.42-2.31(m,1H),1.94-1.82(m,2H),1.81-1.65(m,2H). 1 H NMR (400MHz, DMSO-d 6 ) δ8.58(s,1H),4.70-4.65(m,1H),4.64-4.43(m,3H),3.72-3.53(m,2H),3.50-3.37 (m,1H),2.94-2.75(m,4H),2.71-2.52(m,3H),2.42-2.31(m,1H),1.94-1.82(m,2H),1.81-1.65(m,2H) .
化合物31以31c为底物，参考化合物16的合成方法得到，化合物31为化合物31-1和化合 物31-2结构之一Compound 31 was obtained using 31c as the substrate by referring to the synthetic method of compound 16. Compound 31 is a combination of compound 31-1 and One of the structures of Object 31-2
化合物31：Compound 31:
LCMS m/z＝558.6[M+1]+ LCMS m/z＝558.6[M+1] +
1H NMR(400MHz,DMSO-d6)δ12.40(s,1H),8.59(s,1H),7.88(s,1H),6.35-6.10(m,1H),4.66-4.52(m,2H),4.51-4.40(m,1H),4.24-4.08(m,1H),3.76-3.57(m,2H),3.50-3.40(m,2H),3.40-3.31(m,1H),3.00-2.80(m,3H),2.75-2.52(m,4H),2.47-2.36(m,1H),2.10-1.94(m,1H),1.88-1.78(m,1H),1.63-1.41(m,2H),1.15(d,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ12.40(s,1H),8.59(s,1H),7.88(s,1H),6.35-6.10(m,1H),4.66-4.52(m,2H ),4.51-4.40(m,1H),4.24-4.08(m,1H),3.76-3.57(m,2H),3.50-3.40(m,2H),3.40-3.31(m,1H),3.00-2.80 (m,3H),2.75-2.52(m,4H),2.47-2.36(m,1H),2.10-1.94(m,1H),1.88-1.78(m,1H),1.63-1.41(m,2H) ,1.15(d,3H).
实施例32：化合物32的制备
Example 32: Preparation of Compound 32
第一步：32b的制备Step 1: Preparation of 32b
将异硫氰酰甲酸乙酯(2.67g，20.36mmol)加入到32a(3.00g，18.51mmol)的二氧六环(30mL)溶液中，氮气氛围100℃反应16h。冷却至室温，减压浓缩后得粗品。粗品用混合溶剂(石油醚：四氢呋喃(v/v)＝5:1)打浆，过滤，滤饼即是32b(5.00g，92％)。Ethyl isothiocyanatoformate (2.67g, 20.36mmol) was added to a solution of 32a (3.00g, 18.51mmol) in dioxane (30mL), and the reaction was carried out at 100°C for 16h in a nitrogen atmosphere. Cool to room temperature and concentrate under reduced pressure to obtain crude product. The crude product was beaten with a mixed solvent (petroleum ether: tetrahydrofuran (v/v) = 5:1) and filtered. The filter cake was 32b (5.00g, 92%).
LCMS m/z＝294.2[M+1]+ LCMS m/z＝294.2[M+1] +
第二步：32c的制备Step 2: Preparation of 32c
将32b(4.70g，16.03mmol)加入到盐酸羟胺(4.46g，64.12mmol)，三乙胺(4.87g，48.09mmol)的乙醇(40mL)溶液中，氮气氛围100℃反应3h。减压浓缩得残留物。残留物加入乙酸乙酯(50mL)和石油醚(50mL)搅拌1h，过滤，滤液再次浓缩得粗品。粗品用混合溶剂(石油醚：乙酸乙酯(v/v)＝5:1)打浆，过滤，滤饼即是32c(2.40g，74％)。32b (4.70g, 16.03mmol) was added to a solution of hydroxylamine hydrochloride (4.46g, 64.12mmol) and triethylamine (4.87g, 48.09mmol) in ethanol (40mL), and the reaction was carried out at 100°C for 3 hours in a nitrogen atmosphere. Concentrate under reduced pressure to obtain a residue. Ethyl acetate (50 mL) and petroleum ether (50 mL) were added to the residue, stirred for 1 h, filtered, and the filtrate was concentrated again to obtain crude product. The crude product was beaten with a mixed solvent (petroleum ether: ethyl acetate (v/v) = 5:1) and filtered. The filter cake was 32c (2.40g, 74%).
LCMS m/z＝203.2[M+1]+ LCMS m/z＝203.2[M+1] +
第三步：32d的制备Step 3: Preparation of 32d
冰水浴下，将浓盐酸(1mL)加入到32c(1.10g，5.44mmol)，亚硝酸钠(940mg，13.60mmol)的乙腈(10mL)溶液中，缓慢升至室温反应2h。加入乙酸乙酯(100mL)稀释反应液，加饱和碳酸 钠溶液调节pH值至8-9。乙酸乙酯萃取(100mL x 2)，合并有机相。有机相经无水硫酸钠干燥、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：四氢呋喃(v/v)＝83:17)得32d(1.00g，83％)。Under an ice-water bath, add concentrated hydrochloric acid (1 mL) to a solution of 32c (1.10 g, 5.44 mmol) and sodium nitrite (940 mg, 13.60 mmol) in acetonitrile (10 mL), and slowly rise to room temperature for 2 h. Add ethyl acetate (100mL) to dilute the reaction solution, and add saturated carbonic acid The sodium solution adjusts the pH to 8-9. Extract with ethyl acetate (100mL x 2), and combine the organic phases. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (petroleum ether: tetrahydrofuran (v/v) = 83:17) to obtain 32d (1.00g, 83%). .
LCMS m/z＝222.1[M+1]+ LCMS m/z＝222.1[M+1] +
第四步：32e的制备
Step 4: Preparation of 32e
将32d(510mg，2.30mmol)加入到16b的三氟乙酸盐(755mg，2.53mmol)、碳酸钾(1.59g，11.50mmol)的二甲基亚砜(7mL)溶液中，100℃反应16h。冷却至室温，加水(20mL)淬灭反应，乙酸乙酯(30mL x 3)萃取，合并有机相。有机相经无水硫酸钠干燥、过滤，滤液减压浓缩后得粗品，粗品经柱层析分离纯化(二氯甲烷(含9％甲醇)：石油醚(含16％乙酸乙酯)(v/v)＝75:25)得32e-1(450mg，53％)及其非对映异构体32e-2。32d (510 mg, 2.30 mmol) was added to a solution of 16b trifluoroacetate (755 mg, 2.53 mmol) and potassium carbonate (1.59 g, 11.50 mmol) in dimethyl sulfoxide (7 mL), and the reaction was carried out at 100°C for 16 h. Cool to room temperature, add water (20mL) to quench the reaction, extract with ethyl acetate (30mL x 3), and combine the organic phases. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (methylene chloride (containing 9% methanol): petroleum ether (containing 16% ethyl acetate) (v/ v)=75:25) gave 32e-1 (450 mg, 53%) and its diastereomer 32e-2.
化合物32e-1为化合物32eCompound 32e-1 is compound 32e
LCMS m/z＝370.2[M+1]+ LCMS m/z＝370.2[M+1] +
1H NMR(400MHz,CD3OD)δ8.72-8.66(m,1H),7.80-7.72(m,1H),7.24-7.17(m,1H),4.73-4.60(m,1H),4.33-4.20(m,2H),3.88-3.74(m,2H),3.65-3.54(m,1H),3.11-2.99(m,1H),2.90-2.76(m,2H),2.51-2.41(m,1H),2.23-2.14(m,1H),2.04-1.94(m,1H),1.81-1.55(m,2H). 1 H NMR (400MHz, CD 3 OD) δ8.72-8.66(m,1H),7.80-7.72(m,1H),7.24-7.17(m,1H),4.73-4.60(m,1H),4.33- 4.20(m,2H),3.88-3.74(m,2H),3.65-3.54(m,1H),3.11-2.99(m,1H),2.90-2.76(m,2H),2.51-2.41(m,1H ),2.23-2.14(m,1H),2.04-1.94(m,1H),1.81-1.55(m,2H).
化合物32e-2Compound 32e-2
LCMS m/z＝370.2[M+1]+ LCMS m/z＝370.2[M+1] +
1H NMR(400MHz,CD3OD)δ8.70(d,1H),7.76(s,1H),7.21(dd,1H),4.73-4.64(m,1H),4.31-4.16(m,2H),3.91-3.77(m,2H),3.71-3.59(m,1H),3.12-2.92(m,2H),2.91-2.80(m,1H),2.60-2.46(m,1H),2.13-1.97(m,2H),1.94-1.80(m,2H). 1 H NMR (400MHz, CD 3 OD) δ8.70(d,1H),7.76(s,1H),7.21(dd,1H),4.73-4.64(m,1H),4.31-4.16(m,2H) ,3.91-3.77(m,2H),3.71-3.59(m,1H),3.12-2.92(m,2H),2.91-2.80(m,1H),2.60-2.46(m,1H),2.13-1.97( m,2H),1.94-1.80(m,2H).
第五步：32f的制备Step 5: Preparation of 32f
冰水浴下，将三氟化硼乙醚(4.5mL)加入到32e(450mg，1.22mmol)和1c”(853mg，2.44mmol)的甲苯(45mL)溶液中，氮气氛围35℃反应16h。冰水浴下，用饱和碳酸钠溶液调pH值至7-8，乙酸乙酯萃取(30mL x 3)，合并有机相。有机相用饱和食盐水洗涤(60mL)，无水硫酸钠干燥、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：四氢呋喃(v/v)＝67:33)得32f(40mg，6％)。Under an ice-water bath, add boron trifluoride ether (4.5 mL) to a solution of 32e (450 mg, 1.22 mmol) and 1c″ (853 mg, 2.44 mmol) in toluene (45 mL), and react at 35°C for 16 hours in a nitrogen atmosphere. Under an ice-water bath , adjust the pH value to 7-8 with saturated sodium carbonate solution, extract with ethyl acetate (30mL After concentration, a crude product was obtained, which was separated and purified by column chromatography (petroleum ether: tetrahydrofuran (v/v) = 67:33) to obtain 32f (40 mg, 6%).
LCMS m/z＝557.2[M+1]+ LCMS m/z＝557.2[M+1] +
第六步：32g的制备Step 6: Preparation of 32g
将水合肼(0.5mL，含量：80％)加入到32f(220mg，0.40mmol)的乙醇(5mL)溶液中，室温反应16h。过滤，滤饼用乙腈洗涤(10mL x 3)。滤液经减压浓缩后，再次用乙腈(10mL)打浆，过滤，滤液减压浓缩后得32g(160mg，粗品)。Hydrazine hydrate (0.5 mL, content: 80%) was added to a solution of 32f (220 mg, 0.40 mmol) in ethanol (5 mL), and the reaction was carried out at room temperature for 16 h. Filter and wash the filter cake with acetonitrile (10mL x 3). After the filtrate was concentrated under reduced pressure, it was slurried again with acetonitrile (10 mL) and filtered. The filtrate was concentrated under reduced pressure to obtain 32 g (160 mg, crude product).
LCMS m/z＝427.3[M+1]+ LCMS m/z＝427.3[M+1] +
第七步：32h的制备 Step 7: Preparation for 32h
向中间体1(145mg，0.46mmol)和32g(160mg，粗品)的乙腈(4mL)溶液中加入三乙胺(154mg，1.52mmol)，室温反应16h。加入硅胶，减压浓缩后经柱层析分离纯化(石油醚(含16％乙酸乙酯)：二氯甲烷(含9％甲醇)(v/v)＝75:25)得32h(160mg，两步收率：57％)。Triethylamine (154 mg, 1.52 mmol) was added to a solution of intermediate 1 (145 mg, 0.46 mmol) and 32 g (160 mg, crude product) in acetonitrile (4 mL), and the reaction was carried out at room temperature for 16 h. Add silica gel, concentrate under reduced pressure and then separate and purify by column chromatography (petroleum ether (containing 16% ethyl acetate): dichloromethane (containing 9% methanol) (v/v) = 75:25) to obtain 32h (160 mg, two Step recovery rate: 57%).
LCMS m/z＝709.3[M+1]+ LCMS m/z＝709.3[M+1] +
第八步：化合物32的制备Step 8: Preparation of compound 32
冰水浴下，将三氟甲磺酸(121mg，0.81mmol)加入到32h(160mg，0.23mmol)的三氟乙酸(2mL)溶液中，冰水浴反应2h。反应液减压浓缩后，残留物用乙酸乙酯(10mL)溶解，饱和碳酸钠溶液调pH至8-9，乙酸乙酯萃取(10mL x 3)，合并有机相。有机相经无水硫酸钠干燥、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(含16％乙酸乙酯)：二氯甲烷(含9％甲醇)(v/v)＝75:25)得化合物32(100mg，75％)。Under an ice-water bath, add trifluoromethanesulfonic acid (121 mg, 0.81 mmol) to the 32h (160 mg, 0.23 mmol) trifluoroacetic acid (2 mL) solution, and react in an ice-water bath for 2 hours. After the reaction solution was concentrated under reduced pressure, the residue was dissolved in ethyl acetate (10 mL), the pH was adjusted to 8-9 with saturated sodium carbonate solution, extracted with ethyl acetate (10 mL x 3), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain crude product. The crude product was separated and purified by column chromatography (petroleum ether (containing 16% ethyl acetate): dichloromethane (containing 9% methanol) (v/v) = 75:25) to obtain compound 32 (100 mg, 75%).
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：AD-H(4.6*2.50mm,5um))流动相体系：正己烷：异丙醇(80:20),柱温：35℃，流速：1.0mL/min。Analysis method (instrument and preparation column: high performance liquid chromatography – normal phase chromatography, preparation column model: AD-H (4.6*2.50mm, 5um)) Mobile phase system: n-hexane: isopropyl alcohol (80:20) , Column temperature: 35°C, flow rate: 1.0mL/min.
保留时间T＝27.431min为化合物32，化合物32为化合物32-1和化合物32-2的结构之一
The retention time T=27.431min is compound 32, which is one of the structures of compound 32-1 and compound 32-2.
LCMS m/z＝589.7[M+1]+ LCMS m/z＝589.7[M+1] +
1H NMR(400MHz,DMSO-d6)δ12.41(s,1H),8.91(d,1H),7.98(s,1H),7.89(s,1H),7.26(dd,1H),6.32-6.16(m,1H),4.61-4.46(m,1H),4.25-4.06(m,3H),3.77-3.67(m,1H),3.66-3.58(m,1H),3.51-3.35(m,3H),3.00-2.85(m,1H),2.80-2.61(m,2H),2.47-2.36(m,1H),2.10-1.96(m,1H),1.90-1.78(m,1H),1.62-1.41(m,2H),1.15(d,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ12.41(s,1H),8.91(d,1H),7.98(s,1H),7.89(s,1H),7.26(dd,1H),6.32- 6.16(m,1H),4.61-4.46(m,1H),4.25-4.06(m,3H),3.77-3.67(m,1H),3.66-3.58(m,1H),3.51-3.35(m,3H ),3.00-2.85(m,1H),2.80-2.61(m,2H),2.47-2.36(m,1H),2.10-1.96(m,1H),1.90-1.78(m,1H),1.62-1.41 (m,2H),1.15(d,3H).
实施例33：化合物33的制备
Example 33: Preparation of Compound 33
化合物33以33a为底物，参考化合物32的合成方法得到，化合物33为化合物33-1和化合 物33-2结构之一。Compound 33 was obtained using 33a as a substrate by referring to the synthetic method of compound 32. Compound 33 is a combination of compound 33-1 and compound 33-1. One of the structures of Object 33-2.
LCMS m/z＝590.2[M+1]+ LCMS m/z＝590.2[M+1] +
1H NMR(400MHz,DMSO-d6)δ12.39(s,1H),9.37(d,1H),7.88(s,1H),7.56(d,1H),6.31-6.14(m,1H),4.62-4.47(m,1H),4.26-4.06(m,3H),3.78-3.66(m,1H),3.65-3.56(m,1H),3.51-3.34(m,3H),3.06-2.92(m,1H),2.88-2.75(m,1H),2.73-2.60(m,1H),2.47-2.38(m,1H),2.10-1.99(m,1H),1.89-1.77(m,1H),1.60-1.43(m,2H),1.15(d,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ12.39(s,1H),9.37(d,1H),7.88(s,1H),7.56(d,1H),6.31-6.14(m,1H), 4.62-4.47(m,1H),4.26-4.06(m,3H),3.78-3.66(m,1H),3.65-3.56(m,1H),3.51-3.34(m,3H),3.06-2.92(m ,1H),2.88-2.75(m,1H),2.73-2.60(m,1H),2.47-2.38(m,1H),2.10-1.99(m,1H),1.89-1.77(m,1H),1.60 -1.43(m,2H),1.15(d,3H).
实施例34：化合物34的制备
Example 34: Preparation of Compound 34
第一步：34b的制备Step 1: Preparation of 34b
将异硫氰酰甲酸乙酯(4.86g,37.02mmol)加入到34a(5.00g,30.85mmol)的1,4-二氧六环(50mL)溶液中，100℃反应16h。减压浓缩得粗品，粗品用混合溶剂(石油醚：乙酸乙酯(v:v)＝5:1)打浆，过滤，滤饼干燥后得34b(7g,77％)。Ethyl isothiocyanatoformate (4.86g, 37.02mmol) was added to the solution of 34a (5.00g, 30.85mmol) in 1,4-dioxane (50mL), and the reaction was carried out at 100°C for 16h. Concentrate under reduced pressure to obtain a crude product. The crude product is slurried with a mixed solvent (petroleum ether: ethyl acetate (v:v) = 5:1), filtered, and the filter cake is dried to obtain 34b (7g, 77%).
LCMS m/z＝294.1[M+1]+ LCMS m/z＝294.1[M+1] +
第二步：34c的制备Step 2: Preparation of 34c
依次将盐酸羟胺(4.74g,68.20mmol)、三乙胺(5.18g,51.15mmol)加入到34b(5.00g,17.05mmol)的乙醇(50mL)溶液中，室温搅拌1h，80℃反应16h。加入硅胶，减压浓缩后经柱层析分离纯化(石油醚：四氢呋喃(v:v)＝67:33)，得34c(3.20g,93％)。Hydroxylamine hydrochloride (4.74g, 68.20mmol) and triethylamine (5.18g, 51.15mmol) were added to the solution of 34b (5.00g, 17.05mmol) in ethanol (50mL) in sequence, stirred at room temperature for 1h, and reacted at 80°C for 16h. Silica gel was added, concentrated under reduced pressure, and then separated and purified by column chromatography (petroleum ether: tetrahydrofuran (v:v) = 67:33) to obtain 34c (3.20 g, 93%).
LCMS m/z＝203.1[M+1]+ LCMS m/z＝203.1[M+1] +
第三步：34d的制备Step 3: Preparation of 34d
将亚硝酸钠(2.18g,31.66mmol)加入到34c(3.20g,15.83mmol)的乙腈(50mL)溶液中，缓慢滴入浓盐酸(5mL)，室温反应16h。加入硅胶，减压浓缩后经柱层析分离纯化(石油醚：四氢呋喃(v:v)＝80:20)，得34d(2.60g,74％)。Sodium nitrite (2.18g, 31.66mmol) was added to the solution of 34c (3.20g, 15.83mmol) in acetonitrile (50mL), concentrated hydrochloric acid (5mL) was slowly added dropwise, and the reaction was carried out at room temperature for 16h. Silica gel was added, concentrated under reduced pressure, and then separated and purified by column chromatography (petroleum ether: tetrahydrofuran (v:v) = 80:20) to obtain 34d (2.60 g, 74%).
LCMS m/z＝222.0[M+1]+ LCMS m/z＝222.0[M+1] +
第四步：34e的制备
Step 4: Preparation of 34e
将34d(0.45g,2.03mmol)加入到16b的盐酸盐(0.45g，粗品)、DIPEA(1.05g,8.12mmol)、4-二甲氨基吡啶(25mg,0.20mmol)的乙醇(8mL)溶液中，120℃微波反应3h。加入硅胶，减压浓缩经柱层析分离纯化(二氯甲烷(含9％甲醇)：石油醚(含16％乙酸乙酯)(v/v)＝20:80)得化合物34e-1(80mg,11％)和化合物34e-2。34d (0.45g, 2.03mmol) was added to a solution of 16b hydrochloride (0.45g, crude product), DIPEA (1.05g, 8.12mmol), and 4-dimethylaminopyridine (25mg, 0.20mmol) in ethanol (8mL). Medium, microwave reaction at 120°C for 3 hours. Add silica gel, concentrate under reduced pressure and purify through column chromatography (dichloromethane (containing 9% methanol): petroleum ether (containing 16% ethyl acetate) (v/v) = 20:80) to obtain compound 34e-1 (80 mg ,11%) and compound 34e-2.
化合物34e-1为化合物34eCompound 34e-1 is compound 34e
LCMS m/z＝370.2[M+1]+ LCMS m/z＝370.2[M+1] +
1H NMR(400MHz,DMSO-d6)δ9.40-9.27(m,1H),7.83-7.75(m,1H),7.70-7.60(m,1H),4.63-4.46(m,2H),4.22-4.08(m,2H),3.74-3.64(m,1H),3.63-3.54(m,1H),3.53-3.43(m,1H),3.02-2.86(m,1H),2.85-2.61(m,2H),2.37-2.23(m,1H),2.14–2.03(m,1H),1.96-1.83(m,1H),1.68–1.43(m,2H). 1 H NMR (400MHz, DMSO-d 6 ) δ9.40-9.27(m,1H),7.83-7.75(m,1H),7.70-7.60(m,1H),4.63-4.46(m,2H),4.22 -4.08(m,2H),3.74-3.64(m,1H),3.63-3.54(m,1H),3.53-3.43(m,1H),3.02-2.86(m,1H),2.85-2.61(m, 2H),2.37-2.23(m,1H),2.14–2.03(m,1H),1.96-1.83(m,1H),1.68–1.43(m,2H).
化合物34e-2Compound 34e-2
LCMS m/z＝370.2[M+1]+ LCMS m/z＝370.2[M+1] +
1H NMR(400MHz,DMSO-d6)δ9.39-9.25(m,1H),7.84-7.72(m,1H),7.70-7.59(m,1H),4.76-4.62(m,1H),4.60-4.46(m,1H),4.18–4.04(m,2H),3.71–3.47(m,3H),3.01-2.79(m,2H),2.78-2.64(m,1H),2.44-2.31(m,1H),1.96-1.83(m,2H),1.82–1.65(m,2H). 1 H NMR (400MHz, DMSO-d 6 ) δ9.39-9.25(m,1H),7.84-7.72(m,1H),7.70-7.59(m,1H),4.76-4.62(m,1H),4.60 -4.46(m,1H),4.18–4.04(m,2H),3.71–3.47(m,3H),3.01-2.79(m,2H),2.78-2.64(m,1H),2.44-2.31(m, 1H),1.96-1.83(m,2H),1.82–1.65(m,2H).
第五步：34f的制备Step 5: Preparation of 34f
将34e(0.19g,0.51mmol)和1c”(0.36g,1.02mmol)溶于甲苯(9.5mL)中，氮气置换后，0℃下缓慢加入三氟化硼乙醚(0.57mL)。35℃反应16h。0℃用饱和碳酸钠溶液调pH值至7-8，乙酸乙酯萃取(20mL x 3)，合并有机相。有机相用饱和食盐水洗涤(20mL)，无水硫酸钠干燥、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：四氢呋喃(v/v)＝70:30)得34f(100mg,35％)Dissolve 34e (0.19g, 0.51mmol) and 1c″ (0.36g, 1.02mmol) in toluene (9.5mL). After nitrogen replacement, boron trifluoride ether (0.57mL) is slowly added at 0°C. React at 35°C. 16h. Adjust the pH value to 7-8 with saturated sodium carbonate solution at 0°C, extract with ethyl acetate (20mL x 3), and combine the organic phases. Wash the organic phase with saturated brine (20mL), dry over anhydrous sodium sulfate, and filter. The filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified by column chromatography (petroleum ether: tetrahydrofuran (v/v) = 70:30) to obtain 34f (100 mg, 35%).
LCMS m/z＝557.2[M+1]+ LCMS m/z＝557.2[M+1] +
第六步：34g的制备Step 6: Preparation of 34g
将水合肼(0.5mL，含量：80％)加入到34f(100mg,0.18mmol)的乙醇(5mL)溶液中，室温反应16h。过滤，滤饼用乙酸乙酯洗涤(10mL x 3)，滤液减压浓缩得残留物。残留物用乙酸乙酯(10mL)打浆，过滤，滤饼用乙酸乙酯洗涤(10mL x 3)，滤液减压浓缩得34g(110mg，粗品)。Hydrazine hydrate (0.5 mL, content: 80%) was added to a solution of 34f (100 mg, 0.18 mmol) in ethanol (5 mL), and the reaction was carried out at room temperature for 16 h. Filter, wash the filter cake with ethyl acetate (10mL x 3), and concentrate the filtrate under reduced pressure to obtain a residue. The residue was slurried with ethyl acetate (10mL), filtered, the filter cake was washed with ethyl acetate (10mL x 3), and the filtrate was concentrated under reduced pressure to obtain 34g (110mg, crude product).
LCMS m/z＝427.4[M+1]+ LCMS m/z＝427.4[M+1] +
第七步：34h的制备Step 7: Preparation for 34h
向中间体1(86mg,0.27mmol)和34g(110mg，粗品)的乙腈(10mL)溶液中加入三乙胺(73mg,0.72mmol)，室温反应16h。加入硅胶，减压浓缩后柱层析分离纯化(石油醚：乙酸乙酯(v/v)＝50:50)得34h(85mg，两步收率67％)。Triethylamine (73 mg, 0.72 mmol) was added to a solution of intermediate 1 (86 mg, 0.27 mmol) and 34 g (110 mg, crude product) in acetonitrile (10 mL), and the reaction was carried out at room temperature for 16 h. Silica gel was added, concentrated under reduced pressure and then separated and purified by column chromatography (petroleum ether: ethyl acetate (v/v) = 50:50) to obtain 34h (85 mg, two-step yield 67%).
LCMS m/z＝709.3[M+1]+ LCMS m/z＝709.3[M+1] +
第八步：化合物34的制备Step 8: Preparation of compound 34
在冰水浴下，将三氟甲磺酸(0.2mL)加入到34h(85mg,0.12mmol)的三氟乙酸(2mL)溶液中，室温反应1h。减压浓缩后加乙酸乙酯(20mL)稀释粗品，用饱和碳酸钠溶液调pH至8-9，乙酸乙 酯萃取(20mL x 3)，合并有机相。有机相经无水硫酸钠干燥、过滤，滤液减压浓缩后得粗品，粗品经硅胶柱层析纯化(二氯甲烷(含9％甲醇)：石油醚(含16％乙酸乙酯)(v/v)＝20:80)得到化合物34(10mg,14％)。Under an ice-water bath, trifluoromethanesulfonic acid (0.2 mL) was added to the 34h (85 mg, 0.12 mmol) trifluoroacetic acid (2 mL) solution, and the reaction was carried out at room temperature for 1 h. After concentration under reduced pressure, add ethyl acetate (20 mL) to dilute the crude product, adjust the pH to 8-9 with saturated sodium carbonate solution, add ethyl acetate Ester extraction (20mL x 3), combined organic phases. The organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (dichloromethane (containing 9% methanol): petroleum ether (containing 16% ethyl acetate) (v/ v) = 20:80) to obtain compound 34 (10 mg, 14%).
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：AD-H(4.6*2.50mm,5um))流动相体系：正己烷：异丙醇(80:20),柱温：35℃，流速：1.0mL/min。Analysis method (instrument and preparation column: high performance liquid chromatography – normal phase chromatography, preparation column model: AD-H (4.6*2.50mm, 5um)) Mobile phase system: n-hexane: isopropyl alcohol (80:20) , Column temperature: 35°C, flow rate: 1.0mL/min.
保留时间T＝26.649min为化合物34，化合物34为化合物34-1和化合物34-2结构之一。
The retention time T=26.649min is compound 34, and compound 34 is one of the structures of compound 34-1 and compound 34-2.
LCMS m/z＝589.2[M+1]+ LCMS m/z＝589.2[M+1] +
1H NMR(400MHz,DMSO-d6)δ12.39(s,1H),9.32(s,1H),7.88(s,1H),7.81-7.76(m,1H),7.65(d,1H),6.32-6.13(m,1H),4.59–4.45(m,1H),4.23-4.03(m,3H),3.76-3.66(m,1H),3.65-3.57(m,1H),3.50–3.34(m,3H),2.98–2.87(m,1H),2.80–2.60(m,2H),2.47-2.38(m,1H),2.08–1.97(m,1H),1.89-1.76(m,1H),1.61-1.42(m,2H),1.15(d,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ12.39(s,1H),9.32(s,1H),7.88(s,1H),7.81-7.76(m,1H),7.65(d,1H), 6.32-6.13(m,1H),4.59–4.45(m,1H),4.23-4.03(m,3H),3.76-3.66(m,1H),3.65-3.57(m,1H),3.50–3.34(m ,3H),2.98–2.87(m,1H),2.80–2.60(m,2H),2.47-2.38(m,1H),2.08–1.97(m,1H),1.89-1.76(m,1H),1.61 -1.42(m,2H),1.15(d,3H).
实施例35：化合物35的制备
Example 35: Preparation of Compound 35
第一步：35B的制备Step One: Preparation of 35B
0℃下，将苄醇(9.31g,86.07mmol)，碳酸钾(16.98g,122.90mmol)加入到35A(15.00g，81.93mmol)的N,N-二甲基甲酰胺(150mL)溶液中，室温反应16h，反应完毕后，将反应液加入到水(400mL)中，正己烷(100mL x 2)萃取，合并有机相。有机相经饱和食盐水(100mL)洗涤，无水硫酸钠 干燥，过滤，滤液减压浓缩得到粗品，粗品经柱层析分离纯化(石油醚：乙酸乙酯(v/v)＝99:1)得35B(14.30g，收率：64％)At 0°C, add benzyl alcohol (9.31g, 86.07mmol) and potassium carbonate (16.98g, 122.90mmol) to the solution of 35A (15.00g, 81.93mmol) in N,N-dimethylformamide (150mL). React at room temperature for 16 hours. After the reaction is completed, add the reaction solution to water (400 mL), extract with n-hexane (100 mL x 2), and combine the organic phases. The organic phase was washed with saturated brine (100 mL) and anhydrous sodium sulfate. Dry, filter, and concentrate the filtrate under reduced pressure to obtain a crude product, which is separated and purified by column chromatography (petroleum ether: ethyl acetate (v/v) = 99:1) to obtain 35B (14.30g, yield: 64%)
1H NMR(400MHz,DMSO-d6)δ8.47-8.42(m,1H),8.23(dd,1H),7.57-7.46(m,2H),7.45-7.30(m,3H),5.53(s,2H). 1 H NMR (400MHz, DMSO-d 6 ) δ8.47-8.42(m,1H),8.23(dd,1H),7.57-7.46(m,2H),7.45-7.30(m,3H),5.53(s ,2H).
第二步：35C的制备Step 2: Preparation of 35C
-78℃下，将正丁基锂(10.02mL,25.04mmol,2.5M in hexane)滴加到35B(7.00g,25.81mmol)的四氢呋喃(70mL)溶液中，-78℃反应30min后，加入N,N-二甲基甲酰胺(2.26g,30.97mmol)，继续反应1h。反应结束后，加入饱和氯化铵水溶液(50mL)淬灭反应，乙酸乙酯(50mL x 2)萃取，合并有机相。有机相经饱和食盐水(80mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗品，粗品经柱层析分离纯化(石油醚：乙酸乙酯(v/v)＝95:5)得35C(6.02g，收率:78％)。At -78°C, add n-butyllithium (10.02mL, 25.04mmol, 2.5M in hexane) dropwise into a solution of 35B (7.00g, 25.81mmol) in tetrahydrofuran (70mL). After reacting at -78°C for 30 minutes, add N , N-dimethylformamide (2.26g, 30.97mmol), continue the reaction for 1h. After the reaction, add saturated aqueous ammonium chloride solution (50 mL) to quench the reaction, extract with ethyl acetate (50 mL x 2), and combine the organic phases. The organic phase was washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified by column chromatography (petroleum ether: ethyl acetate (v/v) = 95:5) Obtain 35C (6.02g, yield: 78%).
1H NMR(400MHz,DMSO-d6)δ10.32(d,1H),8.56(s,1H),7.55-7.46(m,2H),7.45-7.33(m,3H),5.57(s,2H). 1 H NMR (400MHz, DMSO-d 6 ) δ10.32(d,1H),8.56(s,1H),7.55-7.46(m,2H),7.45-7.33(m,3H),5.57(s,2H) ).
第三步：35D的制备Step 3: Preparation of 35D
室温下，将水合肼(33mL,含量:80％)加入到35C(11.20g,37.43mmol)的乙醇(30mL)与1,4-二氧六环(150mL)的混合溶液中，95℃反应16h。反应完毕后，减压浓缩，再加入水(100mL)。乙酸乙酯(100mL x 2)萃取，合并有机相，有机相经饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得粗品，经柱层析分离纯化(石油醚：乙酸乙酯(v/v)＝91:9)得35D(7.38g，收率：67％)。At room temperature, add hydrazine hydrate (33mL, content: 80%) to a mixed solution of ethanol (30mL) and 1,4-dioxane (150mL) at 35C (11.20g, 37.43mmol), and react at 95°C for 16h. . After the reaction was completed, the mixture was concentrated under reduced pressure, and water (100 mL) was added. Extract with ethyl acetate (100mL Ethyl acetate (v/v)=91:9) to obtain 35D (7.38g, yield: 67%).
LCMS m/z＝294.1[M+H]+ LCMS m/z＝294.1[M+H] +
第四步：35E的制备Step 4: Preparation of 35E
0℃下，将氢化钠(764mg,19.1mmol,含量:60％)分批加入到35D(4.00g，13.64mmol)的四氢呋喃(40mL)溶液中。0℃反应30min后，加入碘甲烷(2.42g,17.05mmol)，室温反应1h。反应完毕后加入饱和氯化铵水溶液(10mL)淬灭反应，减压浓缩后，加入水(100mL)。二氯甲烷(100mL x 2)萃取，合并有机相，有机相经饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得粗品，经柱层析分离纯化(石油醚：乙酸乙酯(v/v)＝88:12)得35E(2.59g，收率：62％)。At 0°C, sodium hydride (764 mg, 19.1 mmol, content: 60%) was added in portions to a solution of 35D (4.00 g, 13.64 mmol) in tetrahydrofuran (40 mL). After reacting at 0°C for 30 minutes, add methyl iodide (2.42g, 17.05mmol) and react at room temperature for 1 hour. After the reaction was completed, saturated aqueous ammonium chloride solution (10 mL) was added to quench the reaction, and after concentration under reduced pressure, water (100 mL) was added. Extract with dichloromethane (100mL Ethyl acetate (v/v) = 88:12) to obtain 35E (2.59g, yield: 62%).
LCMS m/z＝308.1[M+H]+ LCMS m/z＝308.1[M+H] +
1H NMR(400MHz,DMSO-d6)δ8.60(s,1H),8.08-8.02(m,1H),7.57-7.47(m,2H),7.456-7.31(m,3H),5.61(s,2H),4.24(s,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ8.60(s,1H),8.08-8.02(m,1H),7.57-7.47(m,2H),7.456-7.31(m,3H),5.61(s ,2H),4.24(s,3H).
第五步：35F的制备Step 5: Preparation of 35F
将钯碳(519mg,含量:10％)加入到化合物35E(2.59g，8.43mmol)的甲醇(40mL)溶液中，氢气氛围下室温反应16h。反应完毕后，垫硅藻土过滤，用二氯甲烷:甲醇(v/v)＝10:1(100mL)淋洗，滤液减压浓缩得35F(1.88g，粗品)。Palladium on carbon (519 mg, content: 10%) was added to a solution of compound 35E (2.59 g, 8.43 mmol) in methanol (40 mL), and the reaction was carried out at room temperature under a hydrogen atmosphere for 16 h. After the reaction is completed, filter through diatomaceous earth, rinse with dichloromethane: methanol (v/v) = 10:1 (100 mL), and concentrate the filtrate under reduced pressure to obtain 35F (1.88 g, crude product).
LCMS m/z＝218.1[M+H]+ LCMS m/z＝218.1[M+H] +
第六步：35G的制备
Step 6: Preparation of 35G
将化合物16b的盐酸盐(1.31g,粗品)，1H-苯并三唑-1-基氧三吡咯烷基六氟磷酸盐(4.03g,7.74mmol)，1,8-二氮杂二环[5.4.0]十一碳-7-烯(3.93g,25.80mmol)依次加入到化合物35F(1.40g,粗品)的N,N-二甲基甲酰胺(15mL)中，室温反应16h。反应完毕后，加入水(100mL)，乙酸乙酯(30mL x 3)萃取，合并有机相，有机相经饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗品，经柱层析分离纯化(二氯甲烷：二氯甲烷(含9％甲醇)(v:v)＝71/29)得35G-1(643mg,两步收率:15％)和35G-2。The hydrochloride of compound 16b (1.31g, crude product), 1H-benzotriazol-1-yloxytripyrrolidinyl hexafluorophosphate (4.03g, 7.74mmol), 1,8-diazabicyclo [5.4.0] Undec-7-ene (3.93g, 25.80mmol) was sequentially added to compound 35F (1.40g, crude product) in N,N-dimethylformamide (15mL), and the reaction was carried out at room temperature for 16h. After the reaction is completed, add water (100mL), extract with ethyl acetate (30mL After separation and purification by column chromatography (dichloromethane: dichloromethane (containing 9% methanol) (v:v) = 71/29), 35G-1 (643 mg, two-step yield: 15%) and 35G-2 were obtained.
35G-1为35G。35G-1 is 35G.
LCMS m/z＝384.2[M+H]+ LCMS m/z＝384.2[M+H] +
1H NMR(400MHz,DMSO-d6)δ8.43(s,1H),7.93-7.88(m,1H),5.53-5.15(m,2H),4.64-4.42(m,2H),4.22(s,3H),3.74-3.65(m,1H),3.64-3.55(m,1H),3.54-3.44(m,1H),3.24-3.11(m,1H),2.97-2.86(m,1H),2.80-2.69(m,1H),2.38-2.26(m,1H),2.11-2.02(m,1H),1.97-1.87(m,1H),1.67-1.47(m,2H). 1 H NMR (400MHz, DMSO-d 6 ) δ8.43(s,1H),7.93-7.88(m,1H),5.53-5.15(m,2H),4.64-4.42(m,2H),4.22(s ,3H),3.74-3.65(m,1H),3.64-3.55(m,1H),3.54-3.44(m,1H),3.24-3.11(m,1H),2.97-2.86(m,1H),2.80 -2.69(m,1H),2.38-2.26(m,1H),2.11-2.02(m,1H),1.97-1.87(m,1H),1.67-1.47(m,2H).
35G-235G-2
LCMS m/z＝384.5[M+H]+ LCMS m/z＝384.5[M+H] +
1H NMR(400MHz,DMSO-d6)δ8.44(s,1H),7.98-7.85(m,1H),5.51-5.16(m,2H),5.06-4.41(m,2H),4.22(s,3H),3.73-3.64(m,1H),3.63-3.57(m,1H),3.56-3.45(m,1H),3.22-3.07(m,1H),3.03-2.89(m,1H),2.82-2.69(m,1H),2.44-2.32(m,1H),1.96-1.83(m,2H),1.82-1.66(m,2H). 1 H NMR (400MHz, DMSO-d 6 ) δ8.44(s,1H),7.98-7.85(m,1H),5.51-5.16(m,2H),5.06-4.41(m,2H),4.22(s ,3H),3.73-3.64(m,1H),3.63-3.57(m,1H),3.56-3.45(m,1H),3.22-3.07(m,1H),3.03-2.89(m,1H),2.82 -2.69(m,1H),2.44-2.32(m,1H),1.96-1.83(m,2H),1.82-1.66(m,2H).
化合物35以35G为底物，参考化合物16的合成方法得到，化合物35为化合物35-1和化合物35-2结构之一Compound 35 was obtained using 35G as the substrate by referring to the synthetic method of compound 16. Compound 35 is one of the structures of compound 35-1 and compound 35-2.
LCMS m/z＝603.7[M+1]+ LCMS m/z＝603.7[M+1] +
1H NMR(400MHz,DMSO-d6)δ12.41(s,1H),8.44(s,1H),7.94-7.85(m,2H),6.39-6.12(m,1H),5.50-5.14(m,2H),4.56-4.45(m,1H),4.26-4.09(m,4H),3.75-3.58(m,2H),3.52-3.37(m,3H),3.24-3.09(m,1H),2.96-2.82(m,1H),2.79-2.69(m,1H),2.48-2.39(m,1H),2.05-1.94(m,1H),1.90-1.78(m,1H),1.61-1.44(m,2H),1.15(d,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ12.41(s,1H),8.44(s,1H),7.94-7.85(m,2H),6.39-6.12(m,1H),5.50-5.14(m ,2H),4.56-4.45(m,1H),4.26-4.09(m,4H),3.75-3.58(m,2H),3.52-3.37(m,3H),3.24-3.09(m,1H),2.96 -2.82(m,1H),2.79-2.69(m,1H),2.48-2.39(m,1H),2.05-1.94(m,1H),1.90-1.78(m,1H),1.61-1.44(m, 2H),1.15(d,3H).
实施例36：化合物36的制备
Example 36: Preparation of Compound 36
化合物36以36A为底物，参考化合物32的合成方法得到，化合物36为化合物36-1和化合物36-2结构之一。Compound 36 was obtained using 36A as a substrate by referring to the synthetic method of compound 32. Compound 36 is one of the structures of compound 36-1 and compound 36-2.
LCMS m/z＝590.6[M+1]+ LCMS m/z＝590.6[M+1] +
1H NMR(400MHz,DMSO-d6)δ12.40(s,1H),9.55(s,1H),9.09(s,1H),7.88(s,1H),6.39-6.14(m,1H),4.63-4.45(m,1H),4.25-4.06(m,3H),3.79-3.67(m,1H),3.65-3.55(m,1H),3.50-3.37(m,3H),3.06-2.94(m,1H),2.88-2.76(m,1H),2.74-2.60(m,1H),2.47-2.37(m,1H),2.11-1.97(m,1H),1.90-1.74(m,1H),1.60-1.42(m,2H),1.15(d,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ12.40(s,1H),9.55(s,1H),9.09(s,1H),7.88(s,1H),6.39-6.14(m,1H), 4.63-4.45(m,1H),4.25-4.06(m,3H),3.79-3.67(m,1H),3.65-3.55(m,1H),3.50-3.37(m,3H),3.06-2.94(m ,1H),2.88-2.76(m,1H),2.74-2.60(m,1H),2.47-2.37(m,1H),2.11-1.97(m,1H),1.90-1.74(m,1H),1.60 -1.42(m,2H),1.15(d,3H).
实施例37：化合物37的制备
Example 37: Preparation of Compound 37
化合物37以化合物34e-2为起始物料，参考化合物34的合成方法得到。Compound 37 was obtained by using compound 34e-2 as the starting material and referring to the synthesis method of compound 34.
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：AD-H(4.6*2.50mm,5um))流动相体系：正己烷：异丙醇(80:20),柱温：35℃，流速：1.0mL/min。Analysis method (instrument and preparation column: high performance liquid chromatography – normal phase chromatography, preparation column model: AD-H (4.6*2.50mm, 5um)) Mobile phase system: n-hexane: isopropyl alcohol (80:20) , Column temperature: 35°C, flow rate: 1.0mL/min.
保留时间T＝39.932min为化合物37，化合物37为化合物34-1和化合物34-2结构之一。The retention time T = 39.932 min is compound 37, and compound 37 is one of the structures of compound 34-1 and compound 34-2.
LCMS m/z＝589.2[M+1]+ LCMS m/z＝589.2[M+1] +
1H NMR(400MHz,CD3OD)δ9.00(s,1H),7.98(s,1H),7.75(dd,1H),7.58(d,1H),4.70–4.62(m,1H),4.30-4.12(m,3H),3.93-3.81(m,1H),3.76-3.69(m,1H),3.68-3.58(m,2H),3.54-3.44(m,1H),3.04-2.80(m,3H),2.67-2.56(m,1H),2.09-1.78(m,4H),1.28(d,3H). 1 H NMR (400MHz, CD 3 OD) δ9.00(s,1H),7.98(s,1H),7.75(dd,1H),7.58(d,1H),4.70–4.62(m,1H),4.30 -4.12(m,3H),3.93-3.81(m,1H),3.76-3.69(m,1H),3.68-3.58(m,2H),3.54-3.44(m,1H),3.04-2.80(m, 3H),2.67-2.56(m,1H),2.09-1.78(m,4H),1.28(d,3H).
实施例38：化合物38的制备
Example 38: Preparation of Compound 38
化合物38以化合物32e-2为底物，参考化合物32的合成方法得到。Compound 38 was obtained using compound 32e-2 as the substrate and referring to the synthesis method of compound 32.
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：AD-H(4.6*2.50mm,5um))流动相体系：正己烷：异丙醇(80:20),柱温：35℃，流速：1.0mL/min。Analysis method (instrument and preparation column: high performance liquid chromatography – normal phase chromatography, preparation column model: AD-H (4.6*2.50mm, 5um)) Mobile phase system: n-hexane: isopropyl alcohol (80:20) , Column temperature: 35°C, flow rate: 1.0mL/min.
保留时间T＝42.395min为化合物38，化合物38为化合物32-1和化合物32-2结构之一。The retention time T = 42.395 min is compound 38, and compound 38 is one of the structures of compound 32-1 and compound 32-2.
LCMS m/z＝589.3[M+1]+ LCMS m/z＝589.3[M+1] +
1H NMR(400MHz,CD3OD)δ8.70(d,1H),7.97(s,1H),7.77(s,1H),7.22(dd,1H),4.72-4.62(m,1H),4.30-4.13(m,3H),3.93-3.83(m,1H),3.77-3.69(m,1H),3.68-3.59(m,2H),3.54–3.45(m,1H),3.04-2.80(m,3H),2.67–2.56(m,1H),2.10-1.79(m,4H),1.28(d,3H). 1 H NMR (400MHz, CD 3 OD) δ8.70(d,1H),7.97(s,1H),7.77(s,1H),7.22(dd,1H),4.72-4.62(m,1H),4.30 -4.13(m,3H),3.93-3.83(m,1H),3.77-3.69(m,1H),3.68-3.59(m,2H),3.54–3.45(m,1H),3.04-2.80(m, 3H),2.67–2.56(m,1H),2.10-1.79(m,4H),1.28(d,3H).
实施例39：化合物8-4的合成方法：
Example 39: Synthesis method of compound 8-4:
第一步：39a的合成Step 1: Synthesis of 39a
将9g的盐酸盐(4.61g，粗品)和2-氯-5-三氟甲基嘧啶(3.66g,20.05mmol)溶于二甲亚砜(50mL)中，加入碳酸钾(6.39g,46.23mmol)，90℃反应16小时。冷却至室温，向反应液中加入饱和食盐水(40mL)，乙酸乙酯萃取(60mL x 2)。合并有机相，有机相经饱和食盐水洗涤(50mL x 3)后，无水硫酸钠干燥、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39a(5.00g)。Dissolve 9g of hydrochloride (4.61g, crude product) and 2-chloro-5-trifluoromethylpyrimidine (3.66g, 20.05mmol) in dimethyl sulfoxide (50mL), and add potassium carbonate (6.39g, 46.23 mmol), react at 90°C for 16 hours. Cool to room temperature, add saturated brine (40mL) to the reaction solution, and extract with ethyl acetate (60mL x 2). The organic phases were combined, washed with saturated brine (50mL x 3), 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)=7:3) to obtain 39a (5.00g).
LCMS m/z＝373.2[M+1]+ LCMS m/z＝373.2[M+1] +
第二步：39b的合成
Step 2: Synthesis of 39b
将39a(6.5g,17.46mmol)溶于四氢呋喃(250mL)和无水乙醇(250mL)的混合溶液中，加入硼氢化钠(660mg,17.46mmol)和氯化钙(970mg,8.74mmol)，保持0℃反应1小时。缓 慢滴加饱和氯化铵水溶液(6mL)和乙酸乙酯(6mL)淬灭反应，过滤，滤液减压浓缩后得粗品。粗品经柱层析分离纯化(0～25％(MeOH：DCM＝1:10)in(EA：PE＝1:5))得39b(2.18g,38％)。Dissolve 39a (6.5g, 17.46mmol) in a mixed solution of tetrahydrofuran (250mL) and absolute ethanol (250mL), add sodium borohydride (660mg, 17.46mmol) and calcium chloride (970mg, 8.74mmol), keep 0 ℃ reaction for 1 hour. slow Slowly add saturated aqueous ammonium chloride solution (6 mL) and ethyl acetate (6 mL) to quench the reaction, filter, and concentrate the filtrate under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (0-25% (MeOH:DCM=1:10) in (EA:PE=1:5)) to obtain 39b (2.18g, 38%).
39b(非对应异构体1)环A上C2上的H(δ2.71–2.53)与C4上的H1(δ1.72-1.60)有明显的1H-1H NOESY信号(氘代溶剂为CD3COOD，1H-1H COSY参见附图1，1H-1H NOESY参见附图2)，证明39b构型如下式所示：
39b (diastereomer 1) H on C2 (δ2.71–2.53) on ring A and H 1 on C4 (δ1.72-1.60) have obvious 1 H- 1 H NOESY signals (deuterated solvent is CD 3 COOD, 1 H- 1 H COSY (see Figure 1, 1 H- 1 H NOESY (see Figure 2)), prove that the configuration of 39b is as follows:
LCMS m/z＝331.1[M+1]+ LCMS m/z＝331.1[M+1] +
1H NMR(400MHz,CD3COOD)δ8.66(d,2H),4.88-4.73(m,2H),4.70-4.60(m,1H),4.08-3.94(m,1H),3.89-3.79(m,1H),3.66-3.54(m,1H),3.29-3.13(m,1H),3.00-2.83(m,2H),2.71–2.53(m,1H),2.27-2.14(m,1H),2.03-1.92(m,1H),1.85-1.72(m,1H),1.72-1.60(m,1H). 1 H NMR (400MHz, CD 3 COOD) δ8.66(d,2H),4.88-4.73(m,2H),4.70-4.60(m,1H),4.08-3.94(m,1H),3.89-3.79( m,1H),3.66-3.54(m,1H),3.29-3.13(m,1H),3.00-2.83(m,2H),2.71–2.53(m,1H),2.27-2.14(m,1H), 2.03-1.92(m,1H),1.85-1.72(m,1H),1.72-1.60(m,1H).
第三步：39c的合成Step 3: Synthesis of 39c
将39b(2.0g,6.05mmol)和1c”(4.10g,11.74mmol)溶于甲苯(100mL)中。氮气置换后，0℃下滴加三氟化硼乙醚溶液(6mL)，升温至25℃反应16h。降温至0℃，将反应液缓慢滴加到0℃的饱和碳酸氢钠溶液中。乙酸乙酯萃取(50mL x 3)，合并有机相。有机相经无水硫酸钠干燥、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：四氢呋喃(v:v)＝3:1)得39c(1.3g,41％)。Dissolve 39b (2.0g, 6.05mmol) and 1c” (4.10g, 11.74mmol) in toluene (100mL). After nitrogen replacement, boron trifluoride ether solution (6mL) was added dropwise at 0°C, and the temperature was raised to 25°C. React for 16 hours. Cool to 0°C and slowly drop the reaction solution into the saturated sodium bicarbonate solution at 0°C. Extract with ethyl acetate (50mL x 3) and combine the organic phases. The organic phase is dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified by column chromatography (petroleum ether: tetrahydrofuran (v:v) = 3:1) to obtain 39c (1.3g, 41%).
LCMS m/z＝518.1[M+1]+ LCMS m/z＝518.1[M+1] +
第四步：39d的合成Step 4: Synthesis of 39d
将水合肼(3mL，含量：80％)加入到39c(2.0g,3.86mmol)的乙醇(100mL)溶液中，保持室温反应16小时。过滤，滤饼用乙醇洗涤。滤液减压浓缩后，加入乙酸乙酯(100mL)，过滤，滤饼经乙酸乙酯洗涤。滤液经浓缩后得39d(1.5g,粗品)。Hydrazine hydrate (3 mL, content: 80%) was added to a solution of 39c (2.0 g, 3.86 mmol) in ethanol (100 mL), and the reaction was maintained at room temperature for 16 hours. Filter and wash the filter cake with ethanol. After the filtrate was concentrated under reduced pressure, ethyl acetate (100 mL) was added, filtered, and the filter cake was washed with ethyl acetate. The filtrate was concentrated to obtain 39d (1.5g, crude product).
LCMS m/z＝388.1[M+1]+ LCMS m/z＝388.1[M+1] +
第五步：39e的合成Step 5: Synthesis of 39e
将39d(1.5g,粗品)，中间体1(1.6g,5.03mmol)溶于乙腈(20mL)中，加入三乙胺(1.57g,15.48mmol)，室温反应16小时。，将反应液直接减压浓缩后得粗品，粗品经柱层析分离纯化(石油醚：四氢呋喃(v/v)＝1:1)得39e(2.138g,83％，2步收率)。Dissolve 39d (1.5g, crude product) and intermediate 1 (1.6g, 5.03mmol) in acetonitrile (20mL), add triethylamine (1.57g, 15.48mmol), and react at room temperature for 16 hours. , the reaction solution was directly concentrated under reduced pressure to obtain a crude product, which was separated and purified by column chromatography (petroleum ether: tetrahydrofuran (v/v) = 1:1) to obtain 39e (2.138g, 83%, 2-step yield).
LCMS m/z＝670.8[M+1]+。LCMS m/z=670.8[M+1] + .
第六步：化合物8-4的合成Step 6: Synthesis of compound 8-4
将39e(2.138g,3.19mmol)溶于三氟乙酸(20mL)溶液中，0℃下，加入三氟甲磺酸(20mL)，保持室温反应2小时。减压浓缩干反应液，加入乙酸乙酯(50mL)。0℃下，缓慢加入饱和碳酸氢钠水溶液将体系PH值调至弱碱性。分离有机相，水相用乙酸乙酯萃取(50mL x 2)，合并有机相。有机相经无水硫酸钠干燥，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)＝1:9)得化合物8-4(1.1g，63％)。Dissolve 39e (2.138g, 3.19mmol) in trifluoroacetic acid (20mL) solution, add trifluoromethanesulfonic acid (20mL) at 0°C, and keep the reaction at room temperature for 2 hours. The reaction solution was concentrated to dryness under reduced pressure, and ethyl acetate (50 mL) was added. At 0°C, slowly add saturated aqueous sodium bicarbonate solution to adjust the pH value of the system to weak alkalinity. Separate the organic phase, extract the aqueous phase with ethyl acetate (50mL x 2), and combine the organic phases. The organic phase was 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 column chromatography (petroleum ether: ethyl acetate (v/v) = 1:9) to obtain compound 8-4 (1.1 g, 63%).
LCMS m/z＝550.6[M+1]+。LCMS m/z=550.6[M+1] + .
1H NMR(400MHz,DMSO-d6)δ12.40(s,1H),8.73(s,2H),7.88(s,1H),6.31-6.17(m,1H), 4.71-4.57(m,2H),4.52-4.42(m,1H),4.23-4.09(m,1H),3.75-3.67(m,1H),3.65-3.57(m,1H),3.51-3.40(m,2H),3.40-3.32(m,1H),3.09-2.94(m,1H),2.85-2.73(m,1H),2.72-2.59(m,1H),2.47-2.34(m1H),2.06-1.93(m,1H),1.90-1.77(m,1H),1.60-1.42(m,2H),1.15(d,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ12.40(s,1H),8.73(s,2H),7.88(s,1H),6.31-6.17(m,1H), 4.71-4.57(m,2H),4.52-4.42(m,1H),4.23-4.09(m,1H),3.75-3.67(m,1H),3.65-3.57(m,1H),3.51-3.40(m ,2H),3.40-3.32(m,1H),3.09-2.94(m,1H),2.85-2.73(m,1H),2.72-2.59(m,1H),2.47-2.34(m1H),2.06-1.93 (m,1H),1.90-1.77(m,1H),1.60-1.42(m,2H),1.15(d,3H).
手性HPLC：分析方法(仪器：岛津LC-30AD sf；制备柱型号是：Chiralcel OJ-3 50×4.6mm I.D.，3μm；流动相体系：A for CO2 and B for MeOH(0.05％DEA)，3.0ml/min，保留时间T＝2.009min。Chiral HPLC: Analytical method (instrument: Shimadzu LC-30AD sf; preparative column model: Chiralcel OJ-3 50×4.6mm I.D., 3μm; mobile phase system: A for CO2 and B for MeOH (0.05% DEA), 3.0ml/min, retention time T=2.009min.
通过1H NMR和手性HPLC确认，实施例8得到的化合物8-B即为化合物8-4。It was confirmed by 1 H NMR and chiral HPLC that compound 8-B obtained in Example 8 was compound 8-4.
生物测试例Biological test examples
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％CO2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％CO2孵箱中培养过夜，铺板同时铺T0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％CO2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T0板，记为RLU0。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GI50值。RLUcompound为药物处理组的读数，RLUcontrol为溶剂对照组的平均值。
Growth％＝(RLUcompound-RLU0)/(RLUcontrol-RLU0)×100％    式(1)NCI-H1373 cells were purchased from ATCC, culture conditions: RPMI-1640+10% FBS+1% double antibody, cultured at 37°C, 5% CO2 incubator. On the first day, NCI-H1373 cells in the exponential growth phase were collected and plated into a transparent-bottomed white 96-well culture plate at a plating density of 500 cells/well. They were cultured overnight in a 37°C, 5% CO 2 incubator, and T 0 wells were plated at the same time. Before adding medicine on the next day, absorb the culture medium, add 90 μL of fresh culture medium and 10 μL of compounds of different concentrations to each well, so that the final DMSO concentration in each well is 0.1%, and incubate in a 37°C, 5% CO2 incubator for 72 hours. , replace the culture medium and prepare new compounds, and continue culturing for 72 hours. The next day, the drug was added and the CellTiter-Glo kit was used to detect the T 0 plate, which was recorded as RLU 0 . After the culture, add 50 μL of detection solution (Cell Viability Assay, Promega, G7573) to each well, mix for 2 minutes, incubate at room temperature for 10 minutes, and detect the chemiluminescence reading with a microplate reader. The results were processed according to formula (1), the cell survival rate of each concentration of the compound was calculated, and origin9.2 software was used to calculate the GI 50 value of the concentration of the compound when the proliferation rate was 50%. RLU compound is the reading of the drug treatment group, and RLU control is the average value of the solvent control group.
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
结论：本发明的化合物，例如实施例化合物对NCI-H1373细胞具有良好的细胞增殖抑制活性，部分化合物对NCI-H1373细胞增殖抑制活性见表1。Conclusion: The compounds of the present invention, such as the example compounds, have good cell proliferation inhibitory activity on NCI-H1373 cells. The inhibitory activity of some compounds on NCI-H1373 cell proliferation is shown in Table 1.
2.小鼠药代动力学测试2. Mouse pharmacokinetic test
2.1试验动物：雄性Balb/c小鼠，22g左右，6～8周龄，6只/化合物。购于成都达硕实验动物有限公司。2.1 Test animals: Male Balb/c mice, about 22g, 6 to 8 weeks old, 6 mice/compound. Purchased from Chengdu Dashuo Experimental Animal Co., Ltd.
2.2试验设计：试验当天，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。2.2 Experimental design: On the day of the experiment, Balb/c mice were randomly divided into groups according to body weight. 1 day before administration, fast and drink for 12 to 14 hours. Give food 4 hours after taking the medicine.
表2.给药信息
Table 2. Dosing information
静脉给药溶媒：5％DMA+5％Solutol+90％Saline；灌胃给药溶媒：0.5％MCIntravenous administration vehicle: 5% DMA+5% Solutol+90% Saline; gastric administration vehicle: 0.5% MC
于给药前及给药后异氟烷麻醉经眼眶取血0.03ml，置于EDTAK2离心管中，5000rpm，4℃离心10min，收集血浆。静脉组和灌胃组采血时间点：0,2,5,15,30min,1,2,4,7h；分析检测前，所有样品存于-80℃。Before and after administration, 0.03 ml of blood was taken from the orbit under isoflurane anesthesia, placed in an EDTAK2 centrifuge tube, centrifuged at 5000 rpm and 4°C for 10 min to collect plasma. Blood collection time points for the intravenous group and intragastric group were: 0, 2, 5, 15, 30min, 1, 2, 4, and 7h; before analysis and detection, all samples were stored at -80°C.
表3.测试化合物在小鼠血浆中的药代动力学参数

-：不适用。Table 3. Pharmacokinetic parameters of test compounds in mouse plasma

-:not applicable.
结论：本发明化合物，例如实施例化合物具有良好的药代动力学性质，具体的如化合物8-B，化合物9，化合物31和化合物34在小鼠上具有较高的暴露量，良好的生物利用度。Conclusion: The compounds of the present invention, such as the example compounds, have good pharmacokinetic properties. Specifically, compound 8-B, compound 9, compound 31 and compound 34 have high exposure in mice and good bioavailability. Spend.
3.比格犬药代动力学测试3. Pharmacokinetic test 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。Purpose of the experiment: To administer the test substance to beagle dogs through a single dose intravenously and intragastrically, to measure the concentration of the test substance in the plasma of beagle dogs, and to evaluate the pharmacokinetic characteristics of the test substance in the beagle dogs.
试验动物：雄性比格犬，8～11kg左右，6只/化合物，购于成都达硕实验动物有限公司。Experimental animals: male beagle dogs, about 8 to 11 kg, 6/compound, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.
试验方法：试验当天，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 day of the test, the beagle dogs were randomly divided into groups according to their weight. No food and water for 12 to 14 hours one day before administration, and food 4 hours after administration.
表4.给药信息
Table 4. Dosing information
静脉给药溶媒：5％DMA+5％Solutol+90％Saline；灌胃给药溶媒：0.5％MCIntravenous administration vehicle: 5% DMA+5% Solutol+90% Saline; gastric administration vehicle: 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: Take 1ml of blood from the veins of the limbs before and after administration, and place it in an EDTAK2 centrifuge tube. Centrifuge at 5000 rpm and 4°C for 10 min to collect plasma.
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. Before analysis and detection, all samples were stored at -80°C. Samples were quantitatively analyzed using 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

-：不适用。Table 5. Pharmacokinetic parameters of test compounds in beagle dog plasma

-:not applicable.
结论：本发明化合物，例如实施例化合物具有良好的药代动力学性质，具体的如化合物34在比格犬上具有较好的PK性能。Conclusion: The compounds of the present invention, such as the example compounds, have good pharmacokinetic properties. Specifically, compound 34 has good PK performance in beagle dogs.
4.CYP450酶抑制测试4.CYP450 enzyme inhibition test
本项研究的目的是应用体外测试体系评价受试物对人肝微粒体细胞色素P450(CYP)的5种同工酶(CYP1A2、CYP2C9、CYP2C19、CYP2D6和CYP3A4)活性的影响。CYP450同工酶的特异性探针底物分别与人肝微粒体以及不同浓度的受试物共同孵育，加入还原型烟酰胺腺嘌呤二核苷酸磷酸(NADPH)启动反应，在反应结束后，通过处理样品并采用液相色谱-串联质谱联用(LC-MS/MS)法定量检测特异性底物产生的代谢产物，测定CYP酶活性的变化，计算IC50值，评价受试物对各CYP酶亚型的抑制潜能。The purpose of this study is to apply an in vitro test system to evaluate the effect of test substances on the activity of five isoenzymes of human liver microsomal cytochrome P450 (CYP) (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4). The specific probe substrates of CYP450 isoenzymes were incubated with human liver microsomes and test substances of different concentrations, and reduced nicotinamide adenine dinucleotide phosphate (NADPH) was added to start the reaction. After the reaction, By processing the sample and using liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to quantitatively detect the metabolites produced by the specific substrate, determine the changes in CYP enzyme activity, calculate the IC50 value, and evaluate the effect of the test substance on each CYP Inhibitory potential of enzyme isoforms.
结论:本发明化合物，例如实施例化合物对CYP酶抑制活性差,具体的如化合物8-B对CYP1A2、CYP2C9、CYP2C19、CYP2D6和CYP3A4的IC50值均大于50μM。Conclusion: The compounds of the present invention, such as the example compounds, have poor inhibitory activity on CYP enzymes. Specifically, the IC50 values of compound 8-B against CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4 are all greater than 50 μM.
5.hERG钾离子通道作用测试5. hERG potassium ion channel function test
实验平台：电生理手动膜片钳系统Experimental platform: electrophysiology 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 method: CHO (Chinese Hamster Ovary) cells stably expressing hERG potassium channels were used to record hERG potassium channel currents at room temperature using whole-cell patch clamp technology. The glass microelectrode is drawn from a glass electrode blank (BF150-86-10, Sutter) by a drawing instrument. The tip resistance after infusion of the electrode liquid is about 2-5MΩ. The glass microelectrode can be connected by inserting it into the amplifier probe. to the patch clamp amplifier. Clamping voltage and data recording were controlled and recorded via computer by pClamp 10 software, with a sampling frequency of 10kHz and a filtering frequency of 2kHz. After obtaining the whole-cell recording, the cells were clamped at -80mV, and the step voltage of induced hERG potassium current (I hERG) was given a 2s depolarization voltage from -80mV to +20mV, and then repolarization to -50mV for 1s. then returns to -80mV. This voltage stimulation was given every 10 s, and the administration process was started after confirming that the hERG potassium current was stable (at least 1 minute). Compounds were administered for at least 1 min 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：
Inhibition％＝[1–(I/Io)]×100％Data processing: pClamp 10, GraphPad Prism 5 and Excel software were used for data analysis and processing. The degree of inhibition of hERG potassium current (peak hERG tail current induced at -50mV) at different compound concentrations was calculated using the following formula:
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 hERG potassium current by the compound, and I and Io represent the amplitude of the hERG potassium current after and before the addition of the drug, respectively.
化合物IC50使用GraphPad Prism 5软件通过以下方程拟合计算得出：
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope)) Compound IC 50 was calculated by fitting the following equation using GraphPad Prism 5 software:
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 detected concentration of the test product, 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IC50值
Table 6: IC 50 value of compounds on inhibition of hERG potassium channel current
结论:本发明化合物，例如实施例化合物对hERG抑制活性差，具体的如化合物31和34对hERG钾通道电流抑制作用的IC50大于20μM。Conclusion: The compounds of the present invention, such as the compounds in the examples, have poor inhibitory activity on hERG. Specifically, the IC 50 of compounds 31 and 34 on the inhibitory effect of hERG potassium channel current is greater than 20 μM.
7.PARP7酶活性测试实验7. 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，PBST(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 chemical fluorescence detection kit was purchased from BPS Bioscience. Dilute the histone solution in the kit 5 times with 1X PBS, add 25 μL of the histone dilution solution to the microplate, and incubate at 4°C overnight. After the incubation, wash the plate three times with PBST (0.05% Tween-20), add 100 μL of blocking solution to the microwell plate, and incubate at 25°C for 90 minutes; after the incubation, wash the plate three times with PBST. Take 2.5 μL of compounds of 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 mix; 10 μL of double-distilled water) to the microplate. Dilute the PARP7 enzyme to 6ng/μL, take 10μL into the microwell plate, 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, wash the plate three times with PBST. Dilute Streptavidin-HRP 50 times with blocking solution, then transfer 25 μL to the microplate and incubate at 25°C for 30 minutes. After the incubation, wash the plate three times with PBST, mix ELISA ECL substrate A and substrate B at a ratio of 1:1 (v/v), take 50 μL into the microplate, and read the chemiluminescence value.
根据式2计算抑制率，其中RLUsample为化合物孔读值，RLUmax为溶剂对照孔读值，RLUmin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IC50值。
Inhibition％＝(1-(RLUsample-RLUmin)/(RLUmax-RLUmin))×100％(式2)Calculate the inhibition rate according to formula 2, where RLU sample is the reading value of the compound well, RLU max is the reading value of the solvent control well, RLU min is the reading value of the control well without PARP7 enzyme, and GraphPad Prism software is used to pass four parameters (log(inhibitor) vs .response--Variable slope) to perform curve fitting and calculate IC 50 values.
Inhibition%=(1-(RLU sample -RLU min )/(RLU max -RLU min ))×100% (Formula 2)
结论：本发明化合物，例如实施例化合物对PARP7酶具有抑制作用。Conclusion: The compounds of the present invention, such as the example compounds, have inhibitory effects on PARP7 enzyme.
8.NCI-H1373细胞中MARylation测试实验8. MARylation test experiment 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％CO2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2×105个/孔，于37℃、5％CO2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％CO2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(3)处理，计算出化合物各个浓度的MARylation％，并使用GraphPad Prism 8软件拟合IC50值。Corr.Areacompound为药物处理组的峰面积，Corr.Areacontrol为溶剂对照组的峰面积。
MARylation％＝Average(Corr.Areacompound/Corr.Areacontrol)×100   式(3)NCI-H1373 cells were purchased from ATCC, culture conditions: RPMI-1640+10% FBS+1% double antibody, cultured at 37°C, 5% CO2 incubator. On the first day, NCI-H1373 cells in the exponential growth phase were collected and plated into a transparent-bottomed white 6-well culture plate at a plating density of 2 × 10 5 cells/well, and cultured overnight in a 37°C, 5% CO 2 incubator. Before adding the medicine on the next day, aspirate the culture medium, add 1 mL of fresh culture medium and 1 mL of compounds of different concentrations to each well so that the final DMSO concentration in each well is 0.1%, and incubate in a 37°C, 5% CO2 incubator for 48 hours. . After the culture is completed, cells are collected. Add 35 μL of cell lysis solution to each tube, lyse on ice for 15 minutes, vortex during the period; centrifuge at 4°C, 13,000 rpm for 10 minutes, and take the supernatant and store it at low temperature. BCA detection kit (Beyotime, P0009) was used for protein quantification and the sample protein concentration was calculated. Dilute the protein concentration of each tube of sample to 0.8 mg/mL with 0.1× sample buffer, take 4 μL of diluent and 1 μL of 5× mix, mix well, and place at 95°C for 5 minutes for protein denaturation. Add samples according to the WES (ProteinSimple) instructions, in which the dilution ratio of Poly/Mono-ADP Ribose (E6F6A) Rabbit mAb is 1:100, and the dilution ratio of β-Actin (8H10D10) Mouse mAb is 1:400, and the detection is carried out on the machine. The results were processed according to formula (3), 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 Formula (3)
表7.化合物在NCI-H1373细胞中MARylation的抑制活性
Table 7. Inhibitory activity of compounds on MARylation in NCI-H1373 cells
结论：本发明化合物，例如实施例化合物在NCI-H1373细胞中对MARylation具有抑制作用，具体的如化合物8-B在NCI-H1373细胞中MARylation的抑制活性优于对照RBN-2397。Conclusion: The compounds of the present invention, such as the example compounds, have inhibitory effects on MARylation in NCI-H1373 cells. Specifically, the inhibitory activity of compound 8-B on MARylation in NCI-H1373 cells is better than that of the control RBN-2397.
9.肝微粒体稳定性测试9. Liver Microsome Stability Test
本实验采用人肝微粒体作为体外模型来评价受试物的代谢稳定性。This experiment uses human liver microsomes as an in vitro model to evaluate the metabolic stability of the test substance.
在37℃条件下，1μM的受试物与微粒体蛋白、辅酶NADPH共同孵育，反应至一定时间(5,10,20,30,60min)加入冰冷含内标的乙腈终止反应，采用LC-MS/MS方法检测样品中受试物浓度，以孵育体系中药物剩余率的ln值和孵育时间求得T1/2，并进一步计算肝微粒体肝固有清除率CLint(Liver)。At 37°C, 1 μM of the test substance was incubated with microsomal protein and coenzyme NADPH. After the reaction reached a certain time (5, 10, 20, 30, 60 min), ice-cold acetonitrile containing an internal standard was added to terminate the reaction. LC-MS/ The MS method detects the concentration of the test substance in the sample, calculates T 1/2 based on the ln value of the remaining rate of the drug in the incubation system and the incubation time, and further calculates the hepatic intrinsic clearance rate of liver microsomes CL int(Liver) .
表8.人肝微粒体稳定性结果
Table 8. Human liver microsome stability results
结论：本发明化合物，例如实施例化合物在人肝微粒体代谢稳定性良好。 Conclusion: The compounds of the present invention, such as the example compounds, have good metabolic stability in human liver microsomes.

Claims (15)

  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(A)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 compounds represented by the general formula (A), wherein
    W选自键、C(＝O)；W is selected from bond, C(=O);
    环B选自为单键或者双键；Ring B is selected from Is a single bond or a double bond;
    Z选自N、C或CH；Z is selected from N, C or CH;
    Y选自键、-O-、-S-、-S(＝O)-、-S(＝O)2-、-S(＝O)2N(Ry)-、-N(Ry)-、C1-4亚烷基、-OC1-3亚烷基-、-C1-3亚烷基O-、-C1-2亚烷基O-C1-2亚烷基、-C1-3亚烷基S-、-C1-3亚烷基S(＝O)-、-C1-3亚烷基S(＝O)2-、-N(Ry)C1-3亚烷基-、-C1-3亚烷基N(Ry)-、-C1-2亚烷基N(Ry)-C1-2亚烷基，所述的亚烷基任选被1至4个选自卤素、＝O、＝S、OH、氰基、C1-6烷基、卤素取代的C1-6烷基、C1-6烷氧基、C3-6环烷基的取代基所取代；Y is selected from the group consisting of bonds, -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 1-2 alkylene OC 1-2 alkylene, -C 1 -3 Alkylene S-, -C 1-3 Alkylene S(=O)-, -C 1-3 Alkylene S(=O) 2 -, -N(R y )C 1-3 Alkyl-, -C 1-3 alkylene N(R y )-, -C 1-2 alkylene N(R y )-C 1-2 alkylene, the alkylene group is optionally 1 to 4 selected from 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 substituent of the base;
    Ry各自独立的选自H、C1-6烷基或C3-6环烷基，所述的烷基或环烷基任选被1至4个选自氘、卤素、CF3、OH、氰基、NH2、C1-6烷基、C1-6烷氧基、3至8元杂环基或C3-6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 the alkyl or cycloalkyl is optionally substituted by 1 to 4 selected from deuterium, halogen, CF 3 , OH , cyano group, NH 2 , C 1-6 alkyl group, C 1-6 alkoxy group, 3 to 8 membered heterocyclic group or C 3-6 cycloalkyl substituent, the heterocyclic group contains 1 to 3 heteroatoms selected from O, S, and N;
    Rb各自独立的选自H、卤素、氰基、OH、＝O、C1-6烷基、C1-6烷氧基、-(CH2)q-C3-6环烷基，所述的-CH2-、烷基、烷氧基或环烷基任选被1至4个选自卤素、OH、氰基、NH2、C1-6烷基、卤素取代的C1-6烷基、C1-6烷氧基或C3-6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 The -CH 2 -, alkyl, alkoxy or cycloalkyl group is optionally substituted by 1 to 4 C 1-6 selected from halogen, OH, cyano, NH 2 , C 1-6 alkyl, and halogen. Substituted by alkyl, C 1-6 alkoxy or C 3-6 cycloalkyl substituents;
    环A选自C6-10芳环、5-10元杂芳环或5-10元杂环，所述的杂芳环或者杂环含有1至5个选自O、S、N的杂原子；Ring A is selected from a C 6-10 aromatic ring, a 5-10 membered heteroaromatic ring or a 5-10 membered heterocyclic ring. The heteroaromatic ring or heterocyclic ring contains 1 to 5 heteroatoms selected from O, S, and N. ;
    环X选自C6-10芳环、5-10元杂芳环、C3-10碳环或5-10元杂环，所述的杂芳环或者杂环含有1至5个选自O、S、N的杂原子； Ring _ , S, N heteroatoms;
    Rx、Ra各自独立的选自H、卤素、氰基、OH、＝O、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、-SO2-C1-6烷基、-C(＝O)C1-6烷基、-(CH2)q-C3-10碳环或-(CH2)q-3至12元杂环，所述的-CH2-、烷基、烯基、炔基、烷氧基、烷硫基、碳环或杂环任选被1至4个选自卤素、OH、氰基、＝O、NH2、NH(C1-6烷基)、N(C1-6烷基)2、C1-6烷基、卤素取代的C1-6烷基、C1-6烷氧基、C3-6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、N的杂原子；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 group, -SO 2 -C 1-6 alkyl group, -C(=O)C 1-6 alkyl group, -(CH 2 ) q -C 3-10 carbocyclic ring or -(CH 2 ) q -3 to 12 membered heterocyclic ring, the -CH 2 -, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, carbocyclic or heterocyclic ring is optionally selected from 1 to 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 alkyl , C 1-6 alkoxy group, C 3-6 cycloalkyl group or a 3 to 10 membered heterocyclic substituent, the heterocyclic ring contains 1 to 3 heteroatoms selected from O, S, N;
    L选自-Q1-Ak1-Q2-Ak2-，右侧与环B连接；L is selected from -Q1-Ak1-Q2-Ak2-, and is connected to ring B on the right side;
    Ak1、Ak2各自独立的选自C1-4亚烷基、C2-4亚烯基、C2-4亚炔基，所述Ak1任选被0至4个Rk1取代，所述Ak2任选被0至4个Rk2取代；Ak1 and Ak2 are each independently selected from C 1-4 alkylene, C 2-4 alkenylene, C 2-4 alkynylene, the Ak1 is optionally substituted by 0 to 4 R k1 , and the Ak2 is optionally The selection is replaced by 0 to 4 R k2 ;
    Rk1、Rk2各自独立的选自卤素、氰基、OH、＝O、NH2、NHC1-6烷基、N(C1-6烷基)2、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、-OC3-6碳环、C3-6碳环或4至7元杂环，所述的烷基、烯 基、炔基、烷氧基、碳环或杂环任选被1至4个选自卤素、OH、氰基、NH2、C1-6烷基、C2-6烯基、C2-6炔基、卤素取代的C1-6烷基、C1-6烷氧基、-O-C3-8碳环、C3-8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、N的杂原子；R k1 and R k2 are each independently selected from 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 carbocyclic ring, C 3-6 carbocyclic ring or 4 to 7-membered heterocyclic ring, the alkyl, alkenyl The base, alkynyl, alkoxy, carbocyclic or heterocyclic ring is optionally 1 to 4 selected from 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 carbocyclic ring, C 3-8 carbocyclic ring, 4 to 10 membered heterocyclic substituents, so The above-mentioned heterocyclic ring contains 1 to 3 heteroatoms selected from O, S, and N;
    作为选择，Rk1与Rk1、Rk2与Rk2、Rk1与Rk2直接连接形成C3-6碳环或者4至7元的杂环，所述的碳环或杂环任选被1至4个选自卤素、＝O、OH、氰基、C1-6烷基、卤素取代的C1-6烷基、C1-6烷氧基、C3-6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、N的杂原子；Alternatively, R k1 and R k1 , R k2 and R k2 , R k1 and R k2 are directly connected to form a C 3-6 carbocyclic ring or a 4 to 7-membered heterocyclic ring, and the said carbocyclic ring or heterocyclic ring is optionally replaced by 1 To 4 substituents selected from halogen, =O, OH, cyano, C 1-6 alkyl, halogen-substituted C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl Substituted, the heterocyclic ring contains 1 to 3 heteroatoms selected from O, S, and N;
    Q1、Q2各自独立的选自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)2N(Rq)、N(Rq)S(＝O)2、N(Rq)C(＝O)N(Rq)、N(Rq)C(＝O)N(Rq)；Q1 and Q2 are each 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(R q ), N(R q )C(=O)N(R q );
    Rq各自独立的选自H、C1-6烷基或C3-6环烷基，所述的烷基或环烷基任选被1至4个选自卤素、CF3、OH、氰基、NH2、C1-6烷基或C1-6烷氧基的取代基所取代；R q is each independently selected from H, C 1-6 alkyl or C 3-6 cycloalkyl, and the alkyl or cycloalkyl is optionally substituted by 1 to 4 selected from halogen, CF 3 , OH, cyanide Substituted with substituents of base, NH 2 , C 1-6 alkyl or C 1-6 alkoxy;
    作为选择，Rq与Rk1或Rk2直接连接形成4至7元的杂环，所述的杂环任选被1至4个选自卤素、＝O、OH、氰基、C1-6烷基、卤素取代的C1-6烷基、C1-6烷氧基、C3-6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、N的杂原子；Alternatively, R q is directly connected to R k1 or R k2 to form a 4 to 7-membered heterocycle, which is optionally substituted by 1 to 4 members selected from halogen, =O, OH, cyano, C 1-6 Substituted with alkyl, halogen-substituted C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl substituents, the heterocyclic ring contains 1 to 3 selected from O, S, N heteroatoms;
    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;
    任选地，通式(A)所示的化合物中有1至10个H被D替换。Optionally, 1 to 10 H's in the compound represented by general formula (A) are replaced by D.
  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，通式(A)化合物选自通式(I)所示的化合物，其中
    The compound according to claim 1 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, the compound of general formula (A) is selected from the group consisting of general formula (I) The compound shown, where
  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，化合物选自通式(II)所示的化合物，
    The compound according to claim 2 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, the compound is selected from the compounds represented by general formula (II),
    环X选自5-6元杂芳环或5-6元杂环，所述的杂芳环或杂环含有1至5个选自O、S、N的杂原子；Ring
    或者环X选自8-10元并环杂芳环或8-10元并环杂环，所述的杂芳环或杂环含有1至5个选自O、S、N的杂原子；Alternatively, ring
    Ra1、Ra2各自独立的选自H、卤素、氰基、OH、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、-SO2-C1-6烷基、-C(＝O)C1-6烷基、-(CH2)q-C3-10碳环或-(CH2)q-3至12元杂环，所述的-CH2-、烷基、烯基、炔基、烷氧基、烷硫基、碳环或杂环任选被1至4个选自卤素、OH、氰 基、＝O、C1-6烷基、卤素取代的C1-6烷基、C1-6烷氧基、C3-6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、N的杂原子；R a1 and R a2 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 group, -SO 2 -C 1-6 alkyl group, -C(=O)C 1-6 alkyl group, -(CH 2 ) q -C 3-10 carbocyclic ring or -(CH 2 ) q -3 to 12-membered heterocyclic ring, the -CH 2 -, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, carbocyclic or heterocyclic ring is optionally substituted by 1 to 4 selected from halogen, OH , cyanide Substituted with a substituent of base, =O, C 1-6 alkyl, halogen-substituted C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl or 3 to 10 membered heterocycle, The heterocyclic ring contains 1 to 3 heteroatoms selected from O, S, and N;
    其余基团的定义与权2相同。The definitions of the remaining groups are the same as in weight 2.
  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，The compound according to claim 3 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,
    Y选自键、-O-、-N(Ry)-、C1-3亚烷基、-OC1-2亚烷基-、-C1-2亚烷基O-、-C1-2亚烷基O-C1-2亚烷基、-C1-2亚烷基S-、-C1-2亚烷基S(＝O)2-、-N(Ry)C1-2亚烷基-、-C1-2亚烷基N(Ry)-、-C1-2亚烷基N(Ry)-C1-2亚烷基，所述的亚烷基任选被1至4个选自卤素、＝O、＝S、OH、氰基、C1-4烷基、卤素取代的C1-4烷基、C1-4烷氧基、C3-6环烷基的取代基所取代；Y is selected from bond, -O-, -N(R y )-, C 1-3 alkylene, -OC 1-2 alkylene-, -C 1-2 alkylene O-, -C 1- 2 alkylene OC 1-2 alkylene, -C 1-2 alkylene S-, -C 1-2 alkylene S(=O) 2 -, -N(R y )C 1-2 ylene Alkyl-, -C 1-2 alkylene N(R y )-, -C 1-2 alkylene N(R y )-C 1-2 alkylene, the alkylene group is optionally 1 to 4 selected from halogen, =O, =S, OH, cyano, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl Substituted by the substituent of the base;
    Ry各自独立的选自H、C1-4烷基或C3-6环烷基，所述的烷基或环烷基任选被1至4个选自氘、卤素、CF3、OH、氰基、NH2、C1-4烷基、C1-4烷氧基、3至8元杂环基或C3-6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 the alkyl or cycloalkyl is optionally substituted by 1 to 4 selected from deuterium, halogen, CF 3 , OH , cyano group, NH 2 , C 1-4 alkyl group, C 1-4 alkoxy group, 3 to 8 membered heterocyclic group or C 3-6 cycloalkyl substituent, the heterocyclic group contains 1 to 3 heteroatoms selected from O, S, and N;
    Rx、Ra1、Ra2各自独立的选自H、卤素、氰基、OH、C1-4烷基、C2-4烯基、C2-4炔基、C1-4烷氧基、C1-4烷硫基、-SO2-C1-4烷基、-C(＝O)C1-4烷基、-(CH2)q-C3-6碳环或-(CH2)q-3至6元杂环，所述的-CH2-、烷基、烯基、炔基、烷氧基、烷硫基、碳环或杂环任选被1至4个选自卤素、OH、氰基、＝O、C1-4烷基、卤素取代的C1-4烷基、C1-4烷氧基、C3-6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、N的杂原子；R x , R a1 , and R a2 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 group, -SO 2 -C 1-4 alkyl group, -C(=O)C 1-4 alkyl group, -(CH 2 ) q -C 3-6 carbocyclic ring or -(CH 2 ) q -3 to 6 membered heterocyclic ring, the -CH 2 -, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, carbocyclic or heterocyclic ring is optionally selected from 1 to 4 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 Substituted with substituents, the heterocyclic ring contains 1 to 3 heteroatoms selected from O, S, and N;
    Rb各自独立的选自H、卤素、氰基、OH、＝O、C1-4烷基、C1-4烷氧基、-(CH2)q-C3-6环烷基，所述的-CH2-、烷基、烷氧基或环烷基任选被1至4个选自卤素、OH、氰基、NH2、C1-4烷基、卤素取代的C1-4烷基、C1-4烷氧基或C3-6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 The -CH 2 -, alkyl, alkoxy or cycloalkyl group is optionally substituted by 1 to 4 C 1-4 selected from halogen, OH, cyano, NH 2 , C 1-4 alkyl, and halogen. Substituted by alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl substituents;
    Ak1、Ak2各自独立的选自C1-3亚烷基、C2-3亚烯基、C2-3亚炔基，所述Ak1任选被0至4个Rk1取代，所述Ak2任选被0至4个Rk2取代；Ak1 and Ak2 are each independently selected from C 1-3 alkylene, C 2-3 alkenylene, and C 2-3 alkynylene. The Ak1 is optionally substituted by 0 to 4 R k1 , and the Ak2 is optionally The selection is replaced by 0 to 4 R k2 ;
    Rk1、Rk2各自独立的选自卤素、氰基、OH、＝O、NH2、NHC1-4烷基、N(C1-4烷基)2、C1-4烷基、C1-4烷氧基、C3-6碳环或4至7元杂环，所述的烷基、烷氧基、碳环或杂环任选被1至4个选自卤素、OH、氰基、NH2、C1-4烷基、卤素取代的C1-4烷基、C1-4烷氧基、C3-6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个选自O、S、N的杂原子；R k1 and R k2 are each independently selected from halogen, cyano, OH, =O, NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1 -4 alkoxy group, C 3-6 carbocyclic ring or 4 to 7 membered heterocyclic ring, the alkyl group, alkoxy group, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 selected from halogen, OH, cyano group , NH 2 , C 1-4 alkyl, halogen-substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 carbocyclic, 4 to 6-membered heterocyclic substituents, the The heterocycle contains 1 to 3 heteroatoms selected from O, S, and N;
    作为选择，Rk1与Rk1、Rk2与Rk2、Rk1与Rk2直接连接形成C3-6碳环或者4至7元的杂环，所述的碳环或杂环任选被1至4个选自卤素、＝O、OH、氰基、C1-4烷基、卤素取代的C1-4烷基、C1-4烷氧基、C3-6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、N的杂原子；Alternatively, R k1 and R k1 , R k2 and R k2 , R k1 and R k2 are directly connected to form a C 3-6 carbocyclic ring or a 4 to 7-membered heterocyclic ring, and the said carbocyclic ring or heterocyclic ring is optionally replaced by 1 to 4 substituents selected from halogen, =O, OH, cyano, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl Substituted, the heterocyclic ring contains 1 to 3 heteroatoms selected from O, S, and N;
    Q1、Q2各自独立的选自O、S、N(Rq)、C(＝O)、C(＝O)N(Rq)、N(Rq)C(＝O)、S(＝O)2；Q1 and Q2 are each independently selected from O, S, N(R q ), C(=O), C(=O)N(R q ), N(R q )C(=O), S(=O ) 2 ;
    Rq各自独立的选自H、C1-4烷基，所述的烷基任选被1至4个选自卤素、CF3、OH、氰基、NH2、C1-4烷基或C1-4烷氧基的取代基所取代；R q is each independently selected from H, C 1-4 alkyl, and the alkyl is optionally substituted by 1 to 4 selected from halogen, CF 3 , OH, cyano, NH 2 , C 1-4 alkyl or Substituted with C 1-4 alkoxy substituents;
    作为选择，Rq与Rk1、Rq与Rk2直接连接形成4至7元的杂环，所述的杂环任选被1至4个选自卤素、＝O、OH、氰基、C1-4烷基、卤素取代的C1-4烷基、C1-4烷氧基、C3-6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、N的杂原子。Alternatively, R q and R k1 , R q and R k2 are directly connected to form a 4 to 7-membered heterocycle, and the heterocycle is optionally substituted by 1 to 4 members selected from halogen, =O, OH, cyano, C Substituted with 1-4 alkyl, halogen-substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl substituents, the heterocyclic ring contains 1 to 3 selected from O , S, N heteroatoms.
  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 according to claim 4 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein,
    环X选自吡啶环、嘧啶环、吡嗪环、哒嗪环、噻吩环、噻唑环、呋喃环、噁唑环、吡咯环、吡唑环或咪唑环；Ring
    或者环X选自三嗪环、苯并噻唑环、吡啶并噻唑环、嘧啶并噻唑环、哒嗪并噻唑环、吡嗪并噻唑环、苯并噁唑环、吡啶并噁唑环、嘧啶并噁唑环、哒嗪并噁唑环、吡嗪并噁唑环、吡啶并吡咯环、吡啶并吡唑环、嘧啶并噻吩环、嘧啶并吡唑环、嘧啶并吡咯环、嘧啶并咪唑环、嘧啶并三氮唑环、嘧啶并呋喃环、嘧啶并吡咯环、喹啉环、异喹啉环、嘧啶并吡啶环、三氮唑环、三氮唑并吡啶环、三氮唑并噻唑环、三氮唑并噁唑环、三氮唑并咪唑环、三氮唑并吡唑环、 Alternatively, Ring Oxazole ring, pyridazinooxazole ring, pyrazinooxazole ring, pyridopyrrole ring, pyridopyrazole ring, pyrimidothiophene ring, pyrimidopyrazole ring, pyrimidopyrrole ring, pyrimidoimidazole ring, Pyrimidotriazole ring, pyrimidofuran ring, pyrimidopyrrole ring, Quinoline ring, isoquinoline ring, pyrimidopyridine ring, triazole ring, triazolopyridine ring, triazolothiazole ring, triazoloxazole ring, triazoloimidazole ring, trinitrogen Azolopyrazole ring,
    Rx、Ra1、Ra2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、-SCH3、-SCH2CH3、-SO2CH3、-SO2CH2CH3、-C(＝O)CH3、-C(＝O)CH2CH3、环丙基、环丁基、环戊基、环己基、双环[1.1.1]戊基、苯基、吡啶基、噻唑基、噻吩基、噁唑基、呋喃基、吡咯基、吡唑基、咪唑基，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、-SCH3、-SCH2CH3、-SO2CH3、-SO2CH2CH3、-C(＝O)CH3、-C(＝O)CH2CH3、环丙基、环丁基、环戊基、环己基、双环[1.1.1]戊基、苯基、吡啶基、噻唑基、噻吩基、噁唑基、呋喃基、吡咯基、吡唑基、咪唑基任选被1至4个选自卤素、OH、氰基、C1-4烷基、卤素取代的C1-4烷基、C1-4烷氧基、C3-6环烷基的取代基所取代；R x , R a1 , and 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, bicyclo[1.1.1]pentyl, phenyl, pyridyl, thiazolyl, thienyl, oxazolyl, furyl, pyrrole base, pyrazolyl, imidazolyl, 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 base, cyclohexyl, bicyclo[1.1.1]pentyl, phenyl, pyridyl, thiazolyl, thienyl, oxazolyl, furyl, pyrrolyl, pyrazolyl, imidazolyl optionally selected from 1 to 4 Substituted from halogen, OH, cyano, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl substituents;
    Rb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、丙基或异丙基任选被1至4个选自卤素、OH、氰基、NH2、C1-4烷基、卤素取代的C1-4烷基、C1-4烷氧基或C3-6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, the methyl, ethyl, propyl or Isopropyl is optionally substituted by 1 to 4 C 1-4 alkyl groups selected from halogen, OH, cyano, NH 2 , C 1-4 alkyl, halogen, C 1-4 alkoxy or C 3- Substituted by 6 cycloalkyl substituents;
    Y选自键、-O-、-N(Ry)-、-N(Ry)C(＝O)-、-C(＝O)N(Ry)-、-CH2-、-CH2CH2-、-CH2CH2CH2-、-OCH2-、-OCH2CH2-、-CH2O-、-CH2CH2O-、-CH2OCH2-、-CH2S-、-CH2CH2S-、-CH2S(＝O)2-、-CH2CH2S(＝O)2-、-N(Ry)CH2-、-N(Ry)CH2CH2-、-CH2N(Ry)-、-CH2CH2N(Ry)-、-N(Ry)C(＝O)CH2-、-CH2C(＝O)N(Ry)-，所述CH2任选被0至2个选自H、＝O、＝S、OH、氰基、C1-4烷基、卤素取代的C1-4烷基、C1-4烷氧基、C3-6环烷基的取代基所取代；Y is selected from the group consisting of bonds, -O-, -N(R y )-, -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 OCH 2 -, -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 is optionally substituted by 0 to 2 C 1-4 alkyl selected from H, =O, =S, OH, cyano, C 1-4 alkyl, and halogen Substituted with substituents of base, C 1-4 alkoxy group, and C 3-6 cycloalkyl group;
    Ry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、环己基任选被1至4个选自氘、卤素、CF3、OH、氰基、NH2、C1-4烷基、C1-4烷氧基、3至8元杂环基或C3-6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 is each independently selected from H, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentyl, Hexyl, the methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, sec-butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl are optionally 1 to 4 selected from 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 with a substituent of a base, the heterocyclic group contains 1 to 3 heteroatoms selected from O, S, and N;
    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任选被0至4个Rk1取代，所述Ak2任选被0至4个Rk2取代；Ak1 and Ak2 are each independently selected from methylene, ethylene, propylene, vinylene, propenylene, ethynylene, and propynylene, and the Ak1 is optionally substituted by 0 to 4 R k1 , the Ak2 is optionally replaced by 0 to 4 R k2 ;
    Rk1、Rk2各自独立的选自F、Cl、Br、I、氰基、OH、＝O、NH2、NH(CH3)、N(CH3)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、苯基任选被1至4个选自卤素、OH、氰基、NH2、C1-4烷基、卤素取代的C1-4烷基、C1-4烷氧基、C3-6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个选自O、S、N的杂原子；R k1 and R k2 are each independently selected from 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, azetanyl, azetanyl, oxetanyl, oxetanyl Pentyl, oxanyl, pyridine, phenyl, the methyl, ethyl, propyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetyl Butyl, azepanyl, azepanyl, oxygen Heterocyclylbutyl, oxanyl, oxanyl, pyridine, and phenyl are optionally substituted by 1 to 4 C selected from halogen, OH, cyano, NH 2 , C 1-4 alkyl, and halogen. Substituted with 1-4 alkyl, C 1-4 alkoxy, C 3-6 carbocyclic ring, and 4 to 6-membered heterocyclic substituents. The heterocyclic ring contains 1 to 3 selected from O, S, N of heteroatoms;
    作为选择，Rk1与Rk1、Rk2与Rk2、Rk1与Rk2直接连接形成C3-6碳环或者4至7元的杂环，所述的碳环或杂环任选被1至4个选自卤素、＝O、OH、氰基、C1-4烷基、卤素取代的C1-4烷基、C1-4烷氧基、C3-6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、N的杂原子；Alternatively, R k1 and R k1 , R k2 and R k2 , R k1 and R k2 are directly connected to form a C 3-6 carbocyclic ring or a 4 to 7-membered heterocyclic ring, and the said carbocyclic ring or heterocyclic ring is optionally replaced by 1 to 4 substituents selected from halogen, =O, OH, cyano, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl Substituted, the heterocyclic ring contains 1 to 3 heteroatoms selected from O, S, and N;
    Q1、Q2各自独立的选自O、S、N(Rq)、C(＝O)、C(＝O)N(Rq)、N(Rq)C(＝O)、S(＝O)2；Q1 and Q2 are each independently selected from O, S, N(R q ), C(=O), C(=O)N(R q ), N(R q )C(=O), S(=O ) 2 ;
    Rq各自独立的选自H、甲基、乙基；R q is each independently selected from H, methyl, and ethyl;
    作为选择，Rq与Rk1、Rq与Rk2直接连接形成4至7元的杂环，所述的杂环任选被1至4个选自卤素、＝O、OH、氰基、C1-4烷基、卤素取代的C1-4烷基、C1-4烷氧基、C3-6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、N的杂原子。Alternatively, R q and R k1 , R q and R k2 are directly connected to form a 4 to 7-membered heterocycle, and the heterocycle is optionally substituted by 1 to 4 members selected from halogen, =O, OH, cyano, C Substituted with 1-4 alkyl, halogen-substituted C 1-4 alkyl, C 1-4 alkoxy, C 3-6 cycloalkyl substituents, the heterocyclic ring contains 1 to 3 selected from O , S, N heteroatoms.
  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，其中The compound according to claim 5 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein
    L选自-N(Rq)-Ak1-O-Ak2-、-O-Ak1-O-Ak2-、-O-Ak1-N(Rq)-Ak2-、-N(Rq)-Ak1-N(Rq)-Ak2-，左侧与哒嗪酮环直接连接；L is selected from -N(R q )-Ak1-O-Ak2-, -O-Ak1-O-Ak2-, -O-Ak1-N(R q )-Ak2-, -N(R q )-Ak1- N(R q )-Ak2-, the left side is directly connected to the pyridazinone ring;
    Y选自键、-O-、-NHC(＝O)-、-C(＝O)NH-、-CH2-、-CH2CH2-、-CH2CH2CH2-、-OCH2-、-OCH2CH2-、-CH2O-、-CH2CH2O-、-NHCH2-、-NHCH2CH2-、-CH2NH-、-CH2CH2NH-、-NHC(＝O)CH2-、-CH2C(＝O)NH-、-N(CH3)C(＝O)-、-C(＝O)N(CH3)-、-CH2C(＝O)NH-、-CH2C(＝O)N(CH3)-、-N(CH2CH3)C(＝O)-、-N(CH(CH3)2)C(＝O)-、-N(CH2CH(CH3)2)C(＝O)-、-N(环丙基)C(＝O)-、-N(CH2-环丙基)C(＝O)-、-C(＝O)N(CH2CH3)-、-C(＝O)N(CH(CH3)2)-、-C(＝O)N(CH2CH(CH3)2)-、-C(＝O)N(环丙基)-、-C(＝O)N(CH2-环丙基)-、-C(＝O)N(CD3)-、-C(＝O)N(CH2-氧杂环丁基)-、-C(＝O)N(CH2-氧杂环戊基)-、-C(＝O)N(CH2-氮杂环丁基)-、-C(＝O)N(CH2-吡咯烷基)-、-C(＝O)N(CH2-环戊基)-、-C(＝O)N(CH2CH2CH3)-、-C(＝O)N(CH2CH(CH2CH3)2)-、-C(＝O)N(CH2CH2CH2CH3)-、-C(＝O)N(CH2CH2CH(CH3)2)-、-C(＝O)N(CH2CH(CH3)CH2CH3)-、-C(＝O)N(正辛基)-、-C(＝S)N(CH3)-、-C(＝S)N(CH2CH3)-、-C(＝S)N(CH2-环丙基)-、-CH2S(＝O)2-；Y is selected from the group consisting of bonds, -O-, -NHC(=O)-, -C(=O)NH-, -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-, -NHCH 2 -, -NHCH 2 CH 2 -, -CH 2 NH-, -CH 2 CH 2 NH-, - NHC(=O)CH 2 -, -CH 2 C(=O)NH-, -N(CH 3 )C(=O)-, -C(=O)N(CH 3 )-, -CH 2 C (＝O)NH-, -CH 2 C(＝O)N(CH 3 )-, -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)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)-, -C(=O)N(CD 3 )-, - C(=O)N(CH 2 -oxetanyl)-, -C(=O)N(CH 2 -oxetanyl)-, -C(=O)N(CH 2 -aza cyclobutyl)-, -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-octane base)-, -C(=S)N(CH 3 )-, -C(=S)N(CH 2 CH 3 )-, -C(=S)N(CH 2 -cyclopropyl)-, -CH 2 S(＝O) 2 -;
    Ra2选自H。R a2 is selected from H.
  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，The compound according to claim 6 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,
    L选自 左侧与哒嗪酮环直接连接；L is selected from The left side is directly connected to the pyridazinone ring;
    Rx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、-SCH3、-SCH2CH3、环丙基、环丁基、环戊基、环己基、双环[1.1.1]戊基、苯基、吡啶基、噻唑基、噻吩基、噁唑基、呋喃基、吡咯基、吡唑基、咪唑基，所述的甲基、乙基、丙基、异丙基、乙烯基、乙炔基、甲氧基、乙氧基、-SCH3、-SCH2CH3、环丙基、环丁基、环戊基、环己基、双环[1.1.1]戊基、苯基、吡啶基、噻唑基、噻吩基、噁唑基、呋喃基、吡咯基、吡唑基、咪唑基任选被1至4个选自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 independently selected from H, F, Cl, Br, I, cyano, OH, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, vinyl, ethynyl, methoxy base, ethoxy, -SCH 3 , -SCH 2 CH 3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl, phenyl, pyridyl, thiazolyl, thiophene base, oxazolyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, the methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, methoxy, ethoxy, - SCH 3 , -SCH 2 CH 3 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1.1.1]pentyl, phenyl, pyridyl, thiazolyl, thienyl, oxazolyl, furan The base, pyrrolyl, pyrazolyl, and imidazolyl are optionally substituted by 1 to 4 substituents selected from F, OH, cyano, methyl, ethyl, methoxy or ethoxy;
    Ra1选自H、F、Cl、Br、I、氰基、CF3、CHF2、CH2F、甲基、乙基、丙基、异丙基、乙炔基、甲氧基、乙氧基、-SCH3、-SCH2CH3、环丙基、环丁基、环戊基或环己基；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;
    选自 Selected from
    Rb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。Each R b is independently selected from H, F, Cl, Br, I, cyano, OH, =O, methyl, ethyl, propyl or isopropyl.
  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 according to claim 7 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,
    L选自 左侧与哒嗪酮环直接连接；L is selected from The left side is directly connected to the pyridazinone ring;
    Ra1选自F、Cl、Br、CF3、CHF2、CH2F、甲基、氰基、环丙基、异丙基；R a1 is selected from F, Cl, Br, CF 3 , CHF 2 , CH 2 F, methyl, cyano, cyclopropyl, isopropyl;
    Rx各自独立的选自H、F、Cl、Br、氰基、异丙基、CD3、CF3、CHF2、CH2F、环丙基、环丁基；R x is each independently selected from H, F, Cl, Br, cyano, isopropyl, CD 3 , CF 3 , CHF 2 , CH 2 F, cyclopropyl, cyclobutyl;
    b选自0、1、2、3； b is selected from 0, 1, 2, 3;
    x选自1、2。x is selected from 1 and 2.
  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，The compound according to claim 1 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,
    W选自C(＝O)；W is selected from C(=O);
    环X选自C3-10环烷基、4至10元杂环烷基、苯基、5-6元杂芳环、5-6元杂环、8-10元并环杂芳环或8-10元并环杂环，所述的杂环烷基、杂芳环或杂环含有1至5个选自O、S、N的杂原子； Ring -10-membered heterocyclic ring, the heterocycloalkyl group, heteroaromatic ring or heterocyclic ring contains 1 to 5 heteroatoms selected from O, S, and N;
    优先地，环X选自C3-6单环环烷基、C5-10并环环烷基、C5-11螺环环烷基、C5-11桥环环烷基、4至7元单环杂环烷基、5至10元并环杂环烷基、5至11元螺环杂环烷基、5至11元桥环杂环烷基、苯基、5-6元杂芳环、8-10元并环杂芳环，所述的杂环烷基、杂芳环或杂环含有1至5个选自O、S、N的杂原子； Preferably , Ring _ Single-membered monocyclic heterocycloalkyl, 5- to 10-membered pentacyclic heterocycloalkyl, 5- to 11-membered spirocyclic heterocycloalkyl, 5- to 11-membered bridged heterocycloalkyl, phenyl, 5-6-membered heteroaryl Ring, 8-10 membered heteroaromatic ring, the heterocycloalkyl group, heteroaromatic ring or heterocyclic ring contains 1 to 5 heteroatoms selected from O, S, N;
    优先地，环X选自环丙基、环丁基、环戊基、环己基、环丁基螺环丁基、环丁基螺环戊基、环丁基螺环己基、环戊基螺环戊基、环戊基螺环己基、环己基螺环己基、环丁基螺氮杂环丁基、环丁基螺氮杂环戊基、环丁基螺氮杂环己基、环戊基螺氮杂环戊基、环戊基螺氮杂环己基、环己基氮杂螺环己基、氮杂环丁基螺氮杂环己基、氮杂环戊基螺氮杂环戊基、氮杂环戊基螺氮杂环己基、氮杂环己基氮杂螺环己基、环丁基并环丁基、环丁基并环戊基、环丁基并环己基、环戊基并环戊基、环戊基并环己基、环己基并环己基、环丁基并氮杂环丁基、环丁基并氮杂环戊基、环丁基并氮杂环己基、环戊基并氮杂环戊基、环戊基并氮杂环己基、环己基氮杂并环己基、氮杂环丁基并氮杂环己基、氮杂环戊基并氮杂环戊基、氮杂环戊基并氮杂环己基、氮杂环己基氮杂并环己基、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，或者环X如权利要求5所述；Preferably, Ring Pentyl, cyclopentylspirocyclohexyl, cyclohexylspirocyclohexyl, cyclobutylspiroazetidinyl, cyclobutylspiroazetidine, cyclobutylspiroazetidine, cyclopentylspiroazetidine Cyclopentyl, cyclopentylspiroazepinyl, cyclohexylazespirohexyl, azetidinylspiroazepinyl, azetidinylspiroazepinyl, azepentyl Spiroazacyclohexyl, azacyclylaspirocyclohexyl, cyclobutylcyclobutyl, cyclobutylcyclopentyl, cyclobutylcyclohexyl, cyclopentylcyclopentyl, cyclopentyl and cyclohexyl, cyclohexyl and cyclohexyl, cyclobutyl azetidinyl, cyclobutyl azeticyclopentyl, cyclobutyl azeticyclohexyl, cyclopentyl azetidinyl, cyclo Pentyl azepanyl, cyclohexyl azepanyl, azetidinyl azepanyl, azetanyl azepanyl, azetanyl azepanyl, AzepanylAzacyclohexyl, azetidinyl, azetanyl, azetanyl, oxetanyl, oxetanyl, oxetanyl, or Ring X as claimed 5 mentioned;
    其余基团的定义与权利要求2至8中任一项相同。The definitions of the remaining groups are the same as in any one of claims 2 to 8.
  10. 根据权利要求9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 according to claim 9 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal,
    选自 Selected from
  11. 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，其中该化合物选自表E-1所示结构之一。The compound according to claim 1 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, wherein the compound is selected from the structure shown in Table E-1 one.
  12. 一种药物组合物，包括权利要求1-11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，以及要学上可接受的载体，优选地，药物组合物中包含1-1500mg权利要求1-11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。A pharmaceutical composition, comprising the compound of any one of claims 1-11 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal, and A pharmaceutically acceptable carrier. Preferably, the pharmaceutical composition contains 1-1500 mg of the compound of any one of claims 1-11 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutical acceptable salts or eutectics.
  13. 根据权利要求1-11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。 The compound according to any one of claims 1-11 or its stereoisomer, deuterated product, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal is used in the preparation of treatments with PARP7 activity or Application in drugs for expression-related diseases.
  14. 根据权利要求13所述的应用，其特征在于，所述的疾病选自肿瘤。The application according to claim 13, characterized in that the disease is selected from tumors.
  15. 一种用于治疗哺乳动物的疾病的方法，所述方法包括给予受试者治疗有效量的权利要求1-11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，治疗有效量优选1-1500mg，所述的疾病优选PARP7活性或表达量相关疾病。 A method for treating diseases in mammals, the method comprising administering to a subject a therapeutically effective amount of the compound of any one of claims 1-11 or its stereoisomer, deuterated product, solvate, or pro Drug, metabolite, pharmaceutically acceptable salt or co-crystal, the therapeutically effective dose is preferably 1-1500 mg, and the disease is preferably a disease related to PARP7 activity or expression level.
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CN103570725A (en) * 2012-08-01 2014-02-12 中国科学院上海药物研究所 Piperazidinoltriazole compound as well as preparation method and application thereof
CN112424188A (en) * 2018-04-30 2021-02-26 里邦医疗公司 Pyridazinones as PARP7 inhibitors
CN113292536A (en) * 2020-02-21 2021-08-24 四川海思科制药有限公司 Compound capable of degrading Bcr-Abl or PARP and preparation method and pharmaceutical application thereof

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103570725A (en) * 2012-08-01 2014-02-12 中国科学院上海药物研究所 Piperazidinoltriazole compound as well as preparation method and application thereof
CN112424188A (en) * 2018-04-30 2021-02-26 里邦医疗公司 Pyridazinones as PARP7 inhibitors
CN113292536A (en) * 2020-02-21 2021-08-24 四川海思科制药有限公司 Compound capable of degrading Bcr-Abl or PARP and preparation method and pharmaceutical application thereof

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