WO2023001247A1 - 哒嗪酮类化合物 - Google Patents

哒嗪酮类化合物 Download PDF

Info

Publication number
WO2023001247A1
WO2023001247A1 PCT/CN2022/107127 CN2022107127W WO2023001247A1 WO 2023001247 A1 WO2023001247 A1 WO 2023001247A1 CN 2022107127 W CN2022107127 W CN 2022107127W WO 2023001247 A1 WO2023001247 A1 WO 2023001247A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
mmol
stirred
ethyl acetate
reaction solution
Prior art date
Application number
PCT/CN2022/107127
Other languages
English (en)
French (fr)
Inventor
付翔宇
丁照中
胡利红
曾旭
江文
黎健
陈曙辉
Original Assignee
南京明德新药研发有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 南京明德新药研发有限公司 filed Critical 南京明德新药研发有限公司
Priority to CN202280051608.XA priority Critical patent/CN117751108A/zh
Publication of WO2023001247A1 publication Critical patent/WO2023001247A1/zh

Links

Classifications

    • 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
    • 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
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D247/00—Heterocyclic compounds containing rings having two nitrogen atoms as the only ring hetero atoms, according to more than one of groups C07D229/00 - C07D245/00
    • C07D247/02—Heterocyclic compounds containing rings having two nitrogen atoms as the only ring hetero atoms, according to more than one of groups C07D229/00 - C07D245/00 having the nitrogen atoms in positions 1 and 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings

Definitions

  • the invention discloses a series of pyridazinone compounds and their application in the preparation of medicines for treating related diseases.
  • Adenosine diphosphate-ribosylation is a reversible post-transcriptional modification process of proteins, which is involved in the regulation of various biological processes in vivo, including transcriptional regulation, mRNA stability, cell division and protein degradation, etc. It plays an important role in the stability and apoptosis of cells.
  • the poly(ADP-ribose) polymerase family PARPs
  • ART adenosine diphosphate-ribose transferase
  • Humans have been found to express 17 PARP family proteins, namely PARP1-17. According to their structure and function, PARP family members can be divided into three different types: polyPARPs that can transfer multiple ADP-ribose, monoPARPs that can only transfer a single ADP-ribose and lack of activity.
  • PARP7 belongs to the monoPARPs family, and the identified substrates of PARP7 include Aryl hydrocarbon receptor (AhR) and TANK Binding Kinase 1 (TBK1); PARP7 inhibits the activity of these substrates through ADP ribosylation.
  • AhR Aryl hydrocarbon receptor
  • TBK1 TANK Binding Kinase 1
  • PARP7 inhibits the activity of these substrates through ADP ribosylation.
  • RBN-2397 developed by Ribon is a PARP7 small-molecule inhibitor currently in clinical phase I. Preclinical studies have shown that RBN-2397 can significantly inhibit the proliferation of various tumor cells, and at the same time, it has shown anti-inflammatory effects in mouse immune models. Clear efficacy.
  • small-molecule inhibitors targeting PARP7 could be an advanced cancer treatment option.
  • the present invention provides a compound of formula (IV) or a pharmaceutically acceptable salt thereof
  • Ring A is selected from a 4-10 membered heterocycloalkyl group and a C 4-10 cycloalkyl group, and the 4-10 membered heterocycloalkyl group and a C 4-10 cycloalkyl group are independently optionally replaced by 1, 2 or 3 R a replaces;
  • R a are independently selected from H, CN, OH, F, Cl, Br, -COOH, -CONH 2 , C 1-3 alkyl, C 1-3 alkylamino and C 1-3 alkoxy, the -COOH, -CONH 2 , C 1-3 alkyl, C 1-3 alkylamino and C 1-3 alkoxy are independently optionally substituted by 1, 2 or 3 R;
  • ring B is selected from 5-6 Metaheteroaryl;
  • L 5 is selected from single bond, -O-, -S- and -NR 1 -;
  • R 1 are independently selected from H, D, -C 1-3 alkyl-OH, -C 1-3 alkyl-NH 2 and C 1-3 alkyl, the -C 1-3 alkyl-OH , -C 1-3 alkyl-NH 2 and C 1-3 alkyl are optionally substituted by 1, 2 or 3 R b ;
  • R b are independently selected from H, F, Cl, Br, D and C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by 1, 2 or 3 R;
  • L 2 and L 4 are independently selected from single bond, -CH 2 -, -CH 2 -CH 2 - and -CH 2 -CH 2 -CH 2 -, said -CH 2 -, -CH 2 -CH 2 - and -CH 2 -CH 2 -CH 2 - are independently optionally substituted by 1 or 2 R c ;
  • R c are independently selected from H, F, Cl, Br, D, C 1-3 alkyl, -OC 1-3 alkyl and -C 1-3 alkyl-OC 1-3 alkyl, said C 1-3 alkyl groups are independently optionally substituted by 1, 2 or 3 R;
  • R 2a and R 2b are independently selected from H, F, Cl, Br, D, and C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by 1, 2 or 3 R;
  • R 4 is selected from H, D and C 1-3 alkyl, said C 1-3 alkyl is optionally substituted by 1, 2 or 3 R;
  • R 3 are independently selected from H, CN, OH, F, Cl, Br, -COOH, -CONH 2 , C 1-3 alkyl, C 1-3 alkylamino, C 1-3 alkoxy and C 3 -6 cycloalkyl, said -COOH, -CONH 2 , C 1-3 alkyl, C 1-3 alkylamino, C 1-3 alkoxy and C 3-6 cycloalkyl are independently optionally 1, 2 or 3 R substitutions;
  • Each R is independently selected from D, OH, CN, F, Cl and Br;
  • n is selected from 1, 2 and 3;
  • the 4-10 membered heterocycloalkyl groups each independently contain 1, 2 or 3 heteroatoms or heteroatom groups selected from N, O, S and NH.
  • the above compounds are selected from:
  • Ring A is selected from a 4-10 membered heterocycloalkyl group and a C 4-10 cycloalkyl group, and the 4-10 membered heterocycloalkyl group and a C 4-10 cycloalkyl group are independently optionally replaced by 1, 2 or 3 R a replaces;
  • R a are independently selected from H, CN, OH, F, Cl, Br, -COOH, -CONH 2 , C 1-3 alkyl, C 1-3 alkylamino and C 1-3 alkoxy, the -COOH, -CONH 2 , C 1-3 alkyl, C 1-3 alkylamino and C 1-3 alkoxy are independently optionally substituted by 1, 2 or 3 R;
  • ring B is selected from 5-6 Metaheteroaryl;
  • L 5 is selected from single bond, -O-, -S- and -NR 1 -;
  • R 1 are independently selected from H, D, -C 1-3 alkyl-OH, -C 1-3 alkyl-NH 2 and C 1-3 alkyl, the -C 1-3 alkyl-OH , -C 1-3 alkyl-NH 2 and C 1-3 alkyl are optionally substituted by 1, 2 or 3 R b ;
  • R b are independently selected from H, F, Cl, Br, D and C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by 1, 2 or 3 R;
  • L 2 and L 4 are each independently selected from a single bond, -CH 2 -, -CH 2 -CH 2 - and -CH 2 -CH 2 -CH 2 -, and the -CH 2 - is independently optionally replaced by 1 or 2 R c substitutions;
  • R c are independently selected from H, F, Cl, Br, D, C 1-3 alkyl, -OC 1-3 alkyl and -C 1-3 alkyl-OC 1-3 alkyl, said C 1-3 alkyl groups are independently optionally substituted by 1, 2 or 3 R;
  • R 2a and R 2b are independently selected from H, F, Cl, Br, D, and C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by 1, 2 or 3 R;
  • R 4 is selected from H, D and C 1-3 alkyl, said C 1-3 alkyl is optionally substituted by 1, 2 or 3 R;
  • R 3 are independently selected from H, CN, OH, F, Cl, Br, -COOH, -CONH 2 , C 1-3 alkyl, C 1-3 alkylamino and C 1-3 alkoxy, the -COOH, -CONH 2 , C 1-3 alkyl, C 1-3 alkylamino and C 1-3 alkoxy are independently optionally substituted by 1, 2 or 3 R; each R is independently selected from D, OH, CN, F, Cl and Br;
  • n is selected from 1, 2 and 3;
  • the 4-10 membered heterocycloalkyl groups each independently contain 1, 2 or 3 heteroatoms or heteroatom groups selected from N, O, S and NH.
  • the above compounds are selected from:
  • n, ring A, ring B, L 1 , L 2 , L 3 , L 4 , L 5 , R 2a , R 2b and R 3 are as defined in the present invention.
  • the above compounds are selected from:
  • n, ring A, ring B, L 1 , L 2 , L 3 , R 2a , R 2b , and R 3 are as defined in the present invention.
  • Carbon atoms with "*" are chiral carbon atoms and exist as (R) or (S) single enantiomer or enrichment of one enantiomer.
  • the above compounds are selected from:
  • n, ring A, ring B, L 1 , L 2 , L 3 , L 4 , L 5 , R a , R 2a , R 2b and R 3 are as defined in claim 1.
  • the above compounds are selected from:
  • X is -O-, -CH 2 -, -NH- or -N(CH 3 )-;
  • Y is N and Z is CH; or, Y is CH and Z is N;
  • Ring C is selected from 4-10 membered heterocycloalkyl, and the 4-10 membered heterocycloalkyl is optionally substituted by 1, 2 or 3 R a ;
  • p 1 or 2;
  • Ring A, Ring B, L 1 , L 2 , L 3 , R 2a , R 2b , Rc, R 3 are as defined in the present invention.
  • Carbon atoms with "*" are chiral carbon atoms and exist as (R) or (S) single enantiomer or enrichment of one enantiomer.
  • the above compounds are selected from:
  • Ring A is selected from a 4-10 membered heterocycloalkyl group and a C 4-10 cycloalkyl group, and the 4-10 membered heterocycloalkyl group and a C 4-10 cycloalkyl group are independently optionally replaced by 1, 2 or 3 R a replaces;
  • R a are independently selected from H, CN, OH, F, Cl, Br, -COOH, -CONH 2 , C 1-3 alkyl, C 1-3 alkylamino and C 1-3 alkoxy, the -COOH, -CONH 2 , C 1-3 alkyl, C 1-3 alkylamino and C 1-3 alkoxy are independently optionally substituted by 1, 2 or 3 R;
  • ring B is selected from 5-6 Metaheteroaryl;
  • L 5 is selected from single bond, -O-, -S- and -NR 1 -;
  • R 1 are independently selected from H, D, -C 1-3 alkyl-OH, -C 1-3 alkyl-NH 2 and C 1-3 alkyl, the -C 1-3 alkyl-OH , -C 1-3 alkyl-NH 2 and C 1-3 alkyl are optionally substituted by 1, 2 or 3 R b ;
  • R b are independently selected from H, F, Cl, Br, D and C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by 1, 2 or 3 R;
  • L 2 and L 4 are each independently selected from a single bond, -CH 2 -, -CH 2 -CH 2 - and -CH 2 -CH 2 -CH 2 -, and the -CH 2 - is independently optionally replaced by 1 or 2 R c substitutions;
  • R c are independently selected from H, F, Cl, Br, D and C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by 1, 2 or 3 R;
  • R 2a and R 2b are independently selected from H, F, Cl, Br, D, and C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by 1, 2 or 3 R;
  • R 4 is selected from H, D and C 1-3 alkyl, said C 1-3 alkyl is optionally substituted by 1, 2 or 3 R;
  • R 3 are independently selected from H, CN, OH, F, Cl, Br, -COOH, -CONH 2 , C 1-3 alkyl, C 1-3 alkylamino and C 1-3 alkoxy, the -COOH, -CONH 2 , C 1-3 alkyl, C 1-3 alkylamino and C 1-3 alkoxy are independently optionally substituted by 1, 2 or 3 R; each R is independently selected from D, OH, CN, F, Cl and Br;
  • the 4-10 membered heterocycloalkyl groups each independently contain 1, 2 or 3 heteroatoms or heteroatom groups selected from N, O, S and NH.
  • the above compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from
  • ring A, ring B, L 1 , L 2 , L 3 , L 4 , L 5 , R 2a , R 2b and R 3 are as defined in the present invention.
  • the above compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from
  • Ring A, Ring B, L 1 , L 2 , L 3 , R 2a , R 2b , R 3 are as defined in the present invention.
  • Carbon atoms with "*" are chiral carbon atoms and exist as (R) or (S) single enantiomer or enrichment of one enantiomer.
  • the above-mentioned ring A is selected from the group consisting of azetidinyl, piperidinyl, piperazinyl, 1,4-diazacyclohexyl, 3,8-diazabicyclo[3.2 .1] octanyl and 2,5-diazabicyclo[2.2.2]octyl described azetidinyl, piperidinyl, piperazinyl, 1,4-diazacyclohexane Base, 3,8-diazabicyclo[3.2.1]octyl and 2,5-diazabicyclo[2.2.2]octyl are independently optionally substituted by 1, 2 or 3 R a , other variables are as defined in the present invention.
  • the above ring A is selected from piperidinyl, piperazinyl, 1,4-diazacyclohexyl, 3,8-diazabicyclo[3.2.1]octyl and 2,5-diazabicyclo[2.2.2]octyl, other variables are as defined herein.
  • the above ring B is selected from pyrimidinyl, pyridyl, pyridazinyl, pyrazolyl, thienyl and thiazolyl, and other variables are as defined in the present invention.
  • the above-mentioned ring B is selected from pyrimidinyl, pyridyl, pyridazinyl, pyrazolyl and thiazolyl, and other variables are as defined in the present invention.
  • the above-mentioned L 5 is selected from -NH-, and other variables are as defined in the present invention.
  • the above-mentioned L 4 is selected from -CH(CH 3 )-, -CH(CH 2 OCH 3 )-, -CH(CH 3 )CH 2 CH 2 -, -CH(CH 3 )CH 2- , -CH( CH2CH2CH3 ) - , -CH( CH2CH2OCH3 ) - , and -CH ( CH2OH) - , other variables are as defined herein.
  • the aforementioned L 4 is selected from -CH(CH 3 )-, -CH(CH 2 OCH 3 )- and -CH(CH 2 OH)-, and other variables are as defined in the present invention.
  • the above compound or a pharmaceutically acceptable salt thereof, wherein, L 4 is selected from -CH(CH 3 )-, and other variables are as defined in the present invention.
  • R 2a and R 2b are independently selected from H and F, and other variables are as defined in the present invention.
  • the above compound or a pharmaceutically acceptable salt thereof, wherein, L is selected from -C( O), and other variables are as defined in the present invention.
  • the above-mentioned L 3 is selected from single bond, -CH 2 -, -O-, -NH- and -N(CH 3 )-, and other variables are as defined in the present invention.
  • the above-mentioned L 3 is selected from -O-, -NH- and -N(CH 3 )-, and other variables are as defined in the present invention.
  • the above compound or a pharmaceutically acceptable salt thereof, wherein L 3 is selected from -O- and -NH-, and other variables are as defined in the present invention.
  • the above-mentioned L 2 is selected from -CH 2 - and a single bond, and other variables are as defined in the present invention.
  • the above-mentioned structural units selected from Other variables are as defined herein.
  • the above-mentioned compound or a pharmaceutically acceptable salt thereof, wherein, the structural unit selected from Other variables are as defined herein.
  • the present invention provides a compound of the following formula or a pharmaceutically acceptable salt thereof:
  • the above compounds are selected from:
  • the present invention also provides the application of the above compounds or pharmaceutically acceptable salts thereof in the preparation of PARP7 inhibitors.
  • the invention provides a novel PARP7 inhibitor.
  • the molecule of the present invention has good in vitro inhibitory activity and selectivity to PARP7, and is expected to provide a new and more effective cancer treatment scheme.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms, which are suitable for use in contact with human and animal tissues within the scope of sound medical judgment , without undue toxicity, irritation, allergic reaction or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to a salt of a compound of the present invention, which is prepared from a compound having a specific substituent found in the present invention and a relatively non-toxic acid or base.
  • base addition salts can be obtained by contacting such compounds with a sufficient amount of base, either neat solution or in a suitable inert solvent.
  • acid addition salts can be obtained by contacting such compounds with a sufficient amount of the acid, either neat solution or in a suitable inert solvent.
  • Certain specific compounds of the present invention contain basic and acidic functional groups and can thus be converted into either base or acid addition salts.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing acid groups or bases by conventional chemical methods.
  • such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of both.
  • the terms "effective amount” or “therapeutically effective amount” refer to a non-toxic amount that achieves the desired effect. The determination of the effective amount varies from person to person, depending on the age and general condition of the recipient, and also depends on the specific active substance. The appropriate effective amount in each case can be determined by those skilled in the art according to routine experiments.
  • the compounds of the invention may exist in particular geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and their racemic and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which are subject to the present within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
  • enantiomer or “optical isomer” refer to stereoisomers that are mirror images of each other.
  • cis-trans isomers or “geometric isomers” arise from the inability to rotate freely due to the double bond or the single bond of the carbon atoms forming the ring.
  • diastereoisomer refers to stereoisomers whose molecules have two or more chiral centers and which are not mirror images of the molecules.
  • keys with wedge-shaped solid lines and dotted wedge keys Indicates the absolute configuration of a stereocenter, with a straight solid-line bond and straight dashed keys Indicates the relative configuration of the stereocenter, with a wavy line Indicates wedge-shaped solid-line bond or dotted wedge key or with tilde Indicates a straight solid line key or straight dotted key
  • tautomer or “tautomeric form” means that isomers with different functional groups are in dynamic equilibrium at room temperature and are rapidly interconvertible. If tautomerism is possible (eg, in solution), then chemical equilibrium of the tautomers can be achieved.
  • proton tautomers also called prototropic tautomers
  • prototropic tautomers include interconversions via migration of a proton, such as keto-enol isomerization and imine-ene Amine isomerization.
  • Valence isomers (valence tautomers) involve interconversions by recombination of some bonding electrons.
  • keto-enol tautomerization is the interconversion between two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
  • the terms “enriched in an isomer”, “enriched in an isomer”, “enriched in an enantiomer” or “enantiomerically enriched” refer to one of the isomers or enantiomers
  • the content of the enantiomer is less than 100%, and the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or Greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.
  • the terms “isomer excess” or “enantiomeric excess” refer to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the other isomer or enantiomer is 10%, then the isomer or enantiomeric excess (ee value) is 80% .
  • Optically active (R)- and (S)-isomers as well as D and L-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliary agents, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure desired enantiomer.
  • a diastereoisomeric salt is formed with an appropriate optically active acid or base, and then a diastereomeric salt is formed by a conventional method known in the art. Diastereomeric resolution is performed and the pure enantiomers are recovered. Furthermore, the separation of enantiomers and diastereomers is usually accomplished by the use of chromatography using chiral stationary phases, optionally in combination with chemical derivatization methods (e.g. amines to amino groups formate).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compounds.
  • compounds may be labeled with radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C).
  • radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C).
  • heavy hydrogen can be used to replace hydrogen to form deuterated drugs.
  • the bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon.
  • deuterated drugs can reduce toxic side effects and increase drug stability. , enhance the efficacy, prolong the biological half-life of drugs and other advantages. All changes in isotopic composition of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
  • substituted means that any one or more hydrogen atoms on a specified atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence of the specified atom is normal and the substituted compound is stable.
  • any variable eg, R
  • its definition is independent at each occurrence.
  • said group may optionally be substituted with up to two R, with independent options for each occurrence of R.
  • substituents and/or variations thereof are permissible only if such combinations result in stable compounds.
  • linking group When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond, and -C 0alkyl -A means that the structure is actually -A.
  • this substituent can be bonded through any atom, for example, pyridyl as a substituent can be connected to any atom on the pyridine ring.
  • the carbon atom is attached to the group being substituted.
  • a substituent can be bonded to any atom on a ring when the bond of a substituent can cross-link two or more atoms on the ring, e.g., structural unit It means that the substituent R can be substituted at any position on cyclohexyl or cyclohexadiene.
  • linking group listed does not indicate its linking direction
  • its linking direction is arbitrary, for example,
  • the connecting group L in the middle is -MW-, at this time -MW- can connect ring A and ring B in the same direction as the reading order from left to right to form It can also be formed by connecting loop A and loop B in the opposite direction to the reading order from left to right
  • any one or more sites of the group can be linked to other groups through chemical bonds.
  • connection method of the chemical bond is not positioned, and there is an H atom at the connectable site, when the chemical bond is connected, the number of H atoms at the site will decrease correspondingly with the number of chemical bonds connected to become the corresponding valence group.
  • the chemical bonds that the site connects with other groups can use straight solid line bonds Straight dotted key or tilde express.
  • the straight-shaped solid-line bond in -OCH3 indicates that it is connected to other groups through the oxygen atom in the group;
  • the straight dotted line bond indicates that the two ends of the nitrogen atom in the group are connected to other groups;
  • the wavy lines in indicate that the 1 and 2 carbon atoms in the phenyl group are connected to other groups;
  • C 1-3 alkyl is used to denote a straight or branched chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms.
  • the C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine) .
  • Examples of C 1-3 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
  • C 4-8 cycloalkyl means a saturated cyclic hydrocarbon group composed of 4 to 8 carbon atoms, which includes monocyclic and bicyclic systems, wherein bicyclic systems include spiro rings, fused rings and bridge ring.
  • the C 4-8 cycloalkyl group includes C 4-5 , C 4-6 , C 4-7 , C 5-6 , C 5-7 , C 5-8 , C 6- 7 , C 6-8 , C 7-8 , C 4 , C 5 , C 6 , C 7 , C 8 cycloalkyl, etc.; it may be monovalent, divalent or multivalent.
  • C 4-8 cycloalkyl examples include, but are not limited to, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, [2.2.2]bicyclooctane and the like.
  • bicyclic ring systems include spiro rings, fused rings and bridged rings, and also includes cases where one ring is aromatic.
  • a heteroatom may occupy the attachment position of the heterocycloalkyl to the rest of the molecule.
  • the 4-8 membered heterocycloalkyl group includes 4-6, 4-7, 4-8, 5-6, 5-7, 5-8, 6-7, 6-8 , 7-8, 4, 5, 6, 7, 8, 9, 10-membered heterocycloalkyl, etc.
  • Examples of 4-10 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl ( Including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2- piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), Dioxanyl, dithianyl, isoxazolidinyl, isothiazolid
  • the 5-6 membered heteroaryl can be attached to the rest of the molecule through a heteroatom or a carbon atom.
  • the 5-6 membered heteroaryl includes 5 and 6 membered heteroaryl.
  • Examples of the 5-6 membered heteroaryl groups include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrrolyl Azolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5- Oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1, 2,4-triazolyl, etc.
  • C 3-10 cycloalkyl means a saturated cyclic hydrocarbon group consisting of 4 to 10 carbon atoms, which includes monocyclic, bicyclic and tricyclic systems, wherein bicyclic and tricyclic systems include Spiral, parallel and bridged rings.
  • the C 3-10 cycloalkyl group includes C 4-8 , C 4-6 , C 4-5 , C 4-10 , C 4-6 , C 4-5 , C 5-8 or C 5-6 etc. ; which may be monovalent, divalent or polyvalent.
  • C 4-10 cycloalkyl groups include, but are not limited to, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, [2.2.2] bicyclooctane, [4.4.0] Bicyclodecane, etc.
  • C 1-3 alkoxy denotes those alkyl groups containing 1 to 3 carbon atoms attached to the rest of the molecule through an oxygen atom.
  • the C 1-3 alkoxy group includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy groups and the like.
  • Examples of C 1-3 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
  • C 1-3 alkylamino denotes those alkyl groups containing 1 to 3 carbon atoms attached to the rest of the molecule through an amino group.
  • the C 1-3 alkylamino group includes C 1-2 , C 3 and C 2 alkylamino groups and the like.
  • Examples of C 1-3 alkylamino include, but are not limited to, -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 3 )CH 2 CH 3 , -NHCH 2 CH 2 CH 3 , -NHCH 2 CH 2 CH 3 , -NHCH 2 (CH 3 ) 2 etc.
  • C 1-3 alkylthio denotes those alkyl groups containing 1 to 3 carbon atoms attached to the rest of the molecule through a sulfur atom.
  • the C 1-3 alkylthio group includes C 1-3 , C 1-2 and C 3 alkylthio groups and the like.
  • Examples of C 1-3 alkylthio include, but are not limited to, -SCH 3 , -SCH 2 CH 3 , -SCH 2 CH 2 CH 3 , -SCH 2 (CH 3 ) 2 and the like.
  • halogen or halogen by itself or as part of another substituent means a fluorine, chlorine, bromine or iodine atom.
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and the methods well known to those skilled in the art Equivalent alternatives, preferred embodiments include but are not limited to the examples of the present invention.
  • the structure of the compounds of the present invention can be confirmed by conventional methods known to those skilled in the art. If the present invention involves the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, in single crystal X-ray diffraction (SXRD), the cultured single crystal is collected with a Bruker D8 venture diffractometer to collect diffraction intensity data, the light source is CuK ⁇ radiation, and the scanning method is: After scanning and collecting relevant data, the absolute configuration can be confirmed by further analyzing the crystal structure by direct method (Shelxs97).
  • SXRD single crystal X-ray diffraction
  • the solvent used in the present invention is commercially available.
  • aq stands for water
  • HATU O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • EDC represents N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride
  • m-CPBA 3-chloroperoxybenzoic acid
  • eq represents equivalent, equivalent
  • CDI represents Carbonyldiimidazole
  • DCM stands for dichloromethane
  • PE stands for petroleum ether
  • DIAD stands for diisopropyl azodicarboxylate
  • DMF stands for N,N-dimethylformamide
  • DMSO stands for dimethylsulfoxide
  • EtOAc stands for ethyl acetate EtOH stands for ethanol
  • MeOH stands for methanol
  • CBz stands for benzyloxycarbonyl, which is an amine protecting group
  • Step A Add sodium hydrogen (11.34 g , 283.60 mmol, 60% purity, 1.2 equivalents), then p-methoxybenzyl chloride (44.41 g, 283.60 mmoles, 38.62 ml, 1.2 equivalents) was added, and the mixed system was stirred at 25 degrees Celsius for 6 hours. Under stirring, a saturated ammonium chloride aqueous solution was slowly added to the reaction solution until no gas was released, the above mixture was filtered, the filter cake was washed with water (3 ml ⁇ 2), and the filter cake was dried under reduced pressure to obtain compound 1-2.
  • Step B Potassium hydroxide (33.75 g, 601.56 mmol, 3 eq) was added to a solution of compound 1-2 (75 g, 200.52 mmol, 1 eq) in methanol (750 ml), and the mixed system was stirred at 25 degrees Celsius 6 hours. Concentrate the reaction solution to 100-150 ml, filter the above liquid, and collect the filter cake. The above filter cake was added into water (500 ml), stirred at 25 degrees Celsius for 30 minutes, filtered, and the filter cake was dried under reduced pressure to obtain compound 1-3.
  • Step C To compound 1-3 (55 g, 169.15 mmol, 1 eq) and compound 1-4 (97.49 g, 507.45 mmol, 64.56 ml, 3 eq) in N-methylpyrrolidone (500 ml) was added Cuprous iodide (16.11 g, 84.57 mmol, 0.5 equivalent), the mixed system was heated to 100 degrees Celsius and stirred for 3 hours.
  • Step D Add iodotrimethylsilane (29.71 g, 148.49 mmol, 20.21 mL, 1.5 equivalents), the mixed system was heated to 85 degrees Celsius and stirred for 12 hours. After cooling to room temperature, a saturated ammonium chloride (150 ml) aqueous solution was added to the reaction solution, and the above mixed solution was filtered with celite, and the filtrate was extracted with ethyl acetate (200 ml ⁇ 3), the organic phases were combined, and washed with saturated salt Washed with water (100 ml ⁇ 2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the obtained residue was analyzed by column chromatography ( 1000 grams Silica gel column, eluent gradient 0-100% ethyl acetate/petroleum ether 44 ml/min) was purified to obtain compound 1-6.
  • column chromatography 1000 grams Silica gel column, eluent gradient 0-100%
  • Step E To a solution of compound 1-6 (12 g, 39.97 mmol, 1 eq) in N,N-dimethylformamide (120 mL) was added oxalyl chloride (10.15 g, 79.94 mmol, 7.00 ml, 2 equivalents), the mixed system was stirred at 25 degrees Celsius for 8 hours.
  • reaction solution was quenched with water (200 ml), extracted with ethyl acetate (150 ml ⁇ 3), the organic phases were combined, washed with saturated brine (100 ml ⁇ 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain The residue was analyzed by column chromatography ( 120 grams Silica gel column, eluent gradient 0-100% ethyl acetate/petroleum ether 66 ml/min) was purified to obtain compound 1-7.
  • Step F Add compound 1-9 (4.39 g, 23.56 mmol, 1 equivalent) and potassium carbonate (6.51 g, 47.12 mmol, 2 equivalents), and the reaction solution was stirred at 80 degrees Celsius for 1 hour. After the reaction solution was cooled to room temperature, water (200 ml) was added, and a white solid was precipitated, filtered to collect the filter cake, and dried under reduced pressure to obtain compound 1-10.
  • Step G To a solution of 1-10 (7.8 g, 23.47 mmol, 1 eq) in anhydrous dioxane (80 mL) was added dioxane hydrochloride (4 moles per liter, 78.00 mL, 13.29 eq), The reaction solution was stirred at 25° C. for 1 hour. After filtering at room temperature and collecting the filter cake, the hydrochloride of compound 1-11 was obtained after drying under reduced pressure. MS (ESI) m/z: 233.1 [M+H + ].
  • Step I Compound 1-14 (900 mg, 3.70 mmol, 1 eq) was dissolved in dioxane hydrochloride (10 mL), stirred at 25°C for 15 minutes. The reaction liquid was concentrated to obtain the hydrochloride of compound 1-15. MS (ESI) m/z: 144.1 [M+H + ].
  • Step K To a solution of compound 1-16 (1 g, 2.35 mmol, 1 eq) in trifluoroacetic acid (10 mL) was added trifluoromethanesulfonic acid (1.76 g, 11.75 mmol, 1.04 mL, 5 eq), The reaction was stirred at 25°C for 1 hour.
  • Step L To a solution of compound 1-17 (460 mg, 1.51 mmol, 1 eq) in THF (10 mL) at 0 °C was added diisobutylaluminum hydride (1 mol per L, 4.52 mL, 3 eq) , the reaction solution was kept at 0°C and stirred for 30 minutes. Add saturated sodium sulfate aqueous solution (5 milliliters) to the reaction solution, then add ethyl acetate (100 milliliters), continue to stir at 25 degrees Celsius for 10 minutes, the above-mentioned mixture is filtered, and the filter cake is washed with ethyl acetate (30 milliliters).
  • Step M To a solution of compound 1-18 (230 mg, 873.81 micromol, 1 eq) in dichloromethane (5 mL) was added N,N-carbonyldiimidazole (170.03 mg, 1.05 mmol, 1.2 eq), above The mixture was stirred at 25° C. for 30 minutes, then a dihydrogen solution of 1-11 (352.14 mg, 1.31 mmol, 1.5 eq, hydrochloride) and triethylamine (265.26 mg, 2.62 mmol, 364.87 ⁇ l, 3 eq) was added. Chloromethane (5 mL) solution. The reaction was stirred at 25°C for 12 hours.
  • Step N Compound 1-19 (5.9 g, 11.32 mmol, 1 eq) was resolved by chiral resolution (column: DAICEL CHIRALCEL OJ (250 mm*30 mm, 10 microns); mobile phase: [0.1% ammoniacal methanol] ; methanol %: 25%-25%, 3 minutes), to obtain compound 1a.
  • Compound 1a was detected by SFC [column model: Chiralcel OJ-3 50 ⁇ 4.6mm I.D., 3 ⁇ m; mobile phase: phase A is supercritical carbon dioxide, phase B is methanol (0.05% diethylamine); gradient (B%): 5 %-40%] Obtained: the retention time of compound 1a is 1.162min, and the e.e. value is 100%.
  • Step A To a solution of compound 1-17 (420 mg, 1.38 mmol, 1 eq) in THF (10 mL) was added diisobutylaluminum hydride (1 mol per L, 4.13 mL, 3 eq) at 0 °C , the reaction solution was kept at 0°C and stirred for 30 minutes. Add saturated sodium sulfate aqueous solution (10 milliliters) to the reaction solution, then add ethyl acetate (100 milliliters), continue to stir at 25 degrees Celsius for 10 minutes, the above-mentioned mixture is filtered, and the filter cake is washed with ethyl acetate (100 milliliters).
  • Compound 1-18a was detected by SFC [column model: Chiralcel OJ-3 50 ⁇ 4.6mm I.D., 3 ⁇ m; mobile phase: phase A is supercritical carbon dioxide, phase B is isopropanol (0.05% diethylamine); gradient (B %): 5%-40%] Obtained: the retention time of compound 1-18a is 1.146min, and the e.e. value is 99.122%.
  • Step C Add triphenylphosphine (245.70 mg, 936.76 micromoles, 1.5 equivalents) to a solution of compound 2-1 (180 mg, 624.50 micromoles, 1 equivalent) in tetrahydrofuran (5 milliliters), and the mixed system is heated at 25 degrees Celsius Stir for 30 minutes. Water (0.5 ml) was added to the reaction mixture, and the mixture was stirred at 40° C. for 12 hours. Water (30 mL) was added to the reaction solution for dilution, extracted with ethyl acetate (30 mL), and the aqueous phase was concentrated to obtain compound 2-2. MS(ESI)m/z:263.1[M+H + ].
  • Step D Add N,N-carbonyldiimidazole (96.46 mg, 594.89 micromol , 1.3 equivalents) and diisopropylethylamine (295.71 mg, 2.29 mmol, 398.53 microliters, 5 equivalents), the mixed system was stirred at 25 degrees Celsius for 2 hours.
  • Compound 1-11 (212.52 mg, 915.22 micromoles, 2 equivalents) was added to the reaction solution, and the mixed system was stirred at 60° C. for 12 hours.
  • reaction solution was purified by high performance liquid chromatography (column: Unisil 3-100 C18 Ultra 150*50 mm*3 microns; mobile phase: [water (formic acid)-acetonitrile]; acetonitrile %: 39%-69%, 7 minutes) , to obtain compound 2.
  • Compound 2 was detected by SFC [column model: Chiralpak AD-3 50 ⁇ 4.6mm I.D., 3 ⁇ m; mobile phase: phase A is supercritical carbon dioxide, phase B is methanol (0.05% diethylamine); gradient (B%): 5 %-40%] Obtained: the retention time of compound 2 is 1.702min, and the e.e. value is 99.390%.
  • Step A Compound 1-18 (516 mg, 1.96 mmol, 1 equiv) was dissolved in toluene (6 mL), and 1.8-diazabicyclo[5.4.0]undec-7-ene (358.13 mg, 2.35 mmol, 354.58 ⁇ l, 1.2 eq) and diphenylphosphoryl azide (647.39 mg, 2.35 mmol, 509.76 ⁇ l, 1.2 eq). The reaction solution was stirred at 80°C for 2 hours.
  • Step B Compound 3-1 (280 mg, 971.45 micromol, 1 eq) was dissolved in THF (3 mL), and triphenylphosphine (382.20 mg, 1.46 mmol, 1.5 eq) was added. The reaction solution was stirred at 25° C. for 0.5 hour, and water (0.5 mL) was added to the reaction solution. The reaction solution was stirred at 25°C for 1 hour. After the reaction was complete, ethyl acetate (50 mL) was added for dilution, and washed with water (50 mL ⁇ 4). The combined aqueous phases were directly concentrated to obtain compound 3-2. MS (ESI) m/z: 263.0 [M+H + ].
  • Step B Compound 1-8 (500 mg, 2.74 mmol, 1 eq) was dissolved in N,N-dimethylformamide (5 ml), and compound 3-3 (430.64 mg, 2.74 mmol, 422.19 microliter, 1 equivalent) and potassium carbonate (757.16 mg, 5.48 mmol, 2 equivalents). The reaction solution was stirred at 90°C for 1 hour. After the reaction was complete, it was cooled to room temperature, the reaction solution was diluted with water (10 mL), and extracted with ethyl acetate (10 mL ⁇ 3). The combined organic phases were washed with saturated brine (10 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 3-4.
  • Step C Compound 3-4 (0.75 g, 2.47 mmol, 1 eq) was dissolved in methanol (10 mL) and water (10 mL), and lithium hydroxide monohydrate (311.32 mg, 7.42 mmol, 3 eq) was added , and the reaction solution was stirred at 25° C. for 1 hour. After the reaction was complete, hydrochloric acid (1 mole per liter) was added to the reaction solution to adjust the pH to 5, extracted with ethyl acetate (20 ml ⁇ 3), and the combined organic phases were washed with saturated brine (20 ml ⁇ 2). Dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain compound 3-5.
  • Step D Compound 3-5 (83.96 mg, 305.07 ⁇ mol, 1 eq) was dissolved in THF (1 mL), triethylamine (61.74 mg, 610.15 ⁇ mol, 84.93 ⁇ l, 2 eq) and O- (7-Azabenzotriazol-1-yl)N,N,N,N-tetramethyluronium hexafluorophosphate (174.00 mg, 457.61 micromoles, 1.5 equivalents), the reaction solution was stirred at 25 degrees Celsius After reacting for 30 minutes, compound 3-2 (80 mg, 305.07 ⁇ mol, 1 equivalent) was added. The reaction solution was stirred at 25°C for 1 hour.
  • reaction solution was diluted with water (50 mL), extracted with ethyl acetate (50 mL ⁇ 3), and the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated.
  • Step B Add compound 4-1 (100 mg, 471.06 micromoles, 1 eq) and compound 1-8 (85.98 mg, 471.06 micromoles, 1 eq) in N,N-dimethylformamide (5 ml) Potassium carbonate (130.21 mg, 942.12 micromoles, 2 equivalents) was added to the mixture, and the reaction solution was heated to 90°C and stirred for 2 hours.
  • the reaction solution was poured into water (50 ml), extracted with ethyl acetate (50 ml), the organic phases were combined, washed with saturated brine (50 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 4- 2.
  • Step C Compound 4-2 (160 mg, 446.48 micromoles, 1 equiv) was added to ethyl acetate hydrochloride (5 ml, 4 moles per liter), and the reaction mixture was stirred at 25°C for 15 minutes. The reaction liquid was concentrated to obtain the hydrochloride of compound 4-3. MS (ESI) m/z: 259.1 [M+H + ].
  • Step D To a solution of compound 1-18a (20 mg, 75.98 ⁇ mol, 1 eq) in N,N-dimethylformamide (1 mL) was added N,N-carbonyldiimidazole (24.64 mg, 151.96 ⁇ mol , 2 equivalents) and triethylamine (30.75 mg, 303.92 micromoles, 42.30 microliters, 4 equivalents), the mixture was stirred at 25 degrees Celsius for 2 hours, and compound 4-3 (33.59 mg, 113.97 micromoles, 1.5 equivalents , hydrochloride), the reaction solution was stirred at 25 degrees Celsius for 12 hours, then heated to 50 degrees Celsius and stirred for 24 hours.
  • reaction solution was poured into water (30 mL), extracted with ethyl acetate (30 mL ⁇ 2), the organic phases were combined, washed with saturated brine (30 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated.
  • the reaction solution was prepared by high performance liquid chromatography (column: Phenomenex luna C18 150*25mm*10 microns; mobile phase: [water (formic acid)-acetonitrile]: acetonitrile%: 41%-71%, 10 minutes) purification, Compound 4 was obtained.
  • Compound 4 was detected by SFC [column model: Chiralpak AD-3 50 ⁇ 4.6mm I.D., 3 ⁇ m; mobile phase: phase A is supercritical carbon dioxide, phase B is methanol (0.05% diethylamine); gradient (B%): 5 %-40%] Obtained: the retention time of compound 4 is 1.853min, and the e.e. value is 100%.
  • Step A Add potassium carbonate (130.21 mg, 942.12 micromol, 2 equiv) and compound 1-8 to a solution of compound 5-1 (100 mg, 471.06 micromol, 1 eq) in N-methylpyrrolidone (2 mL) (85.98 mg, 471.06 micromole, 1 eq), and the mixed system was stirred at 80°C for 2 hours. After the reaction solution was cooled to 25 degrees Celsius, water (10 ml) was added, and a yellow solid was precipitated. The filter cake was collected by filtration, and dried under reduced pressure to obtain compound 5-2. MS(ESI)m/z:303.0[M+H + -56].
  • Step B Add ethyl acetate hydrochloride (4 moles, 1 ml, 13.03 equivalents) to a solution of 5-2 (110 mg, 306.96 micromoles, 1 equivalent) in ethyl acetate (1 milliliter), and the mixed system was heated at 25 degrees Celsius Stirring was continued for 0.5 hours. The reaction solution was directly dried under reduced pressure to obtain the hydrochloride of compound 5-3. MS(ESI)m/z:259.2[M+H + ].
  • Step C Add N,N-carbonyldiimidazole (36.96 mg, 227.95 , 2 equivalents) and triethylamine (34.60 mg, 341.92 micromoles, 47.59 microliters, 3 equivalents), the mixed system was stirred at 25 degrees Celsius for 12 hours, and then compound 5-3 (44.15 mg, 170.96 micromoles, 1.5 equivalent), the mixed system was stirred at 50 degrees Celsius for 24 hours.
  • Compound 5 was detected by SFC [column model: Chiralpak AD-3 50 ⁇ 4.6mm I.D., 3 ⁇ m; mobile phase: phase A is supercritical carbon dioxide, phase B is methanol (0.05% diethylamine); gradient (B%): 40 %-40%] Obtained: the retention time of compound 5 is 0.651min and 1.124min, and the e.e. value is 1.394%.
  • Step A Compound 6-1 (1.68 g, 6.93 mmol, 1.41 mL, 1.2 eq) was dissolved in THF (10 mL), potassium hydroxide (323.92 mg, 5.77 mmol, 1 eq) and compound 1- 12 (1 g, 5.77 mmol, 1 equiv). The reaction mixture was stirred at 25 °C for 12 hours.
  • Step B Compound 6-2 (840 mg, 3.21 mmol, 1 eq) was dissolved in ethyl acetate (8 mL), and ethyl acetate hydrochloride (4 mol, 8 mL, 9.95 eq) was added. The reaction mixture was stirred at 25 °C for 1 hour. After the reaction was complete, the reaction solution was concentrated in vacuo to obtain the hydrochloride of compound 6-3. MS (ESI) m/z: 162.1 [M+H + ]
  • Step C Compound 6-3 (724 mg, 4.49 mmol, 1 equiv, hydrochloride) was dissolved in N,N-dimethylformamide (10 mL), and triethylamine (1.36 g, 13.48 mL mol, 1.88 ml, 3 eq) and compound 1-7 (1.43 g, 4.49 mmol, 1 eq). The reaction solution was stirred at 25° C. for 12 hours.
  • Step D Compound 6-4 (1.24 g, 2.80 mmol, 1 eq) was dissolved in trifluoroacetic acid (10 mL), and trifluoromethanesulfonic acid (1.70 g, 11.33 mmol, 1 mL, 4.05 eq) was added , the reaction mixture was stirred at 25 °C for 10 min. After the reaction was complete, the reaction solution was slowly added dropwise to a saturated sodium carbonate solution (200 ml), and solid sodium carbonate was added to adjust the pH to 9, followed by extraction with ethyl acetate (200 ml ⁇ 3).
  • Step E Compound 6-5 (0.5 g, 1.55 mmol, 1 eq) was dissolved in THF (6 mL), and diisobutylaluminum hydride (1 mol, 9.28 mL, 6 eq) was added at 0°C. The reaction mixture was stirred at 25 °C for 1 hour. After the reaction was complete, saturated ammonium chloride solution (5 mL) was added to quench, and ethyl acetate (5 mL ⁇ 4) was extracted. The combined organic phases were washed with saturated brine (5 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product.
  • Step F Compound 6-6 (92 mg, 327.16 ⁇ mol, 1 eq) was dissolved in THF (4 mL), and N,N-carbonyldiimidazole (106.10 mg, 654.32 ⁇ mol, 2 eq) and triethyl Amine (99.32 mg, 981.49 micromoles, 136.61 microliters, 3 equivalents), the reaction mixture was stirred at 25 degrees Celsius for 1 hour, and compound 1-11 (87.90 mg, 327.16 micromoles, 1 equivalents, hydrochloride salt) was added to the reaction solution . The reaction mixture was stirred at 50 °C for 17 hours.
  • reaction solution was cooled to 25° C., water (20 ml) was added to the reaction solution, and ethyl acetate (20 ml ⁇ 4) was extracted.
  • the combined organic phases were washed with saturated brine (20 ml ⁇ 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product through high performance liquid chromatography (column: Phenomenex Synergi C18 150*25 mm*10 microns; mobile Phase: [water (formic acid)-acetonitrile]; acetonitrile %: 42%-72%, 10 minutes) to give compound 6.
  • Compound 6 was detected by SFC [column model: OD 50 ⁇ 4.6mm I.D., 3 ⁇ m; mobile phase: phase A is supercritical carbon dioxide, phase B is methanol (0.05% diethylamine); gradient (B%): 5%-40 %] Obtained: the retention time of compound 6 was 1.189min, and the e.e. value was 100%.
  • Step A Compound 7-1 (0.5 g, 3.58 mmol, 1 eq) and compound 1-9 (667.36 mg, 3.58 mmol, 1 eq) were dissolved in N-methylpyrrolidone (10 mL), and carbonic acid was added Potassium (990.45 mg, 7.17 mmol, 2 equiv). The reaction mixture was stirred at 100°C for 2 hours. After the reaction was complete, the reaction liquid was cooled to 25°C, poured into water (30 ml), filtered, and the filter cake was spin-dried in vacuum to obtain compound 7-2.
  • 1 H NMR 400MHz, chloroform-d
  • Step B Compound 7-2 (400 mg, 1.38 mmol, 1 eq) was dissolved in ethyl acetate (2 mL), and ethyl acetate hydrochloride (4 mol/L, 2 mL, 5.79 eq) was added. The reaction mixture was stirred at 25 °C for 0.5 h. After the reaction was complete, the reaction solution was directly concentrated to obtain the hydrochloride of compound 7-3.
  • Step C Compound 1-18a (10 mg, 37.99 micromol, 1 equiv) was dissolved in THF (1 mL), and N,N-carbonyldiimidazole (7.39 mg, 45.59 micromol, 1 equiv) and triethyl Amine (11.53 mg, 113.79 ⁇ mol, 15.86 ⁇ L, 3 equiv). The reaction solution was stirred at 25°C for 3 hours. Further carbonyldiimidazole (6.16 mg, 37.99 ⁇ mol, 1 equiv) was added, and the reaction mixture was stirred at 25° C. for 2 hours.
  • Compound 7 was detected by SFC [column model: Chiralcel OJ-3 50 ⁇ 4.6mm I.D., 3 ⁇ m; mobile phase: phase A is supercritical carbon dioxide, phase B is methanol (0.05% diethylamine); gradient (B%): 5 %-40%] Obtained: the retention time of compound 7 was 1.689min, and the e.e. value was 99.104%.
  • Step A Compound 8-1 (1.17 g, 8.86 mmol, 1.1 eq) was dissolved in isopropanol (10 mL), compound 1-9 (1.5 g, 8.05 mmol, 1 eq) and N,N - Diisopropylethylamine (2.08 g, 16.11 mmol, 2.81 ml, 2 equiv). The reaction mixture was stirred at 120°C for 0.5 hours. After the reaction was complete, the reaction liquid was cooled to 25°C, water (50 ml) was added to the reaction liquid, stirred at 25°C for 0.5 hour, the reaction liquid was filtered, and the filter cake was spin-dried in vacuum to obtain compound 8-2.
  • Step B Compound 8-2 (0.5 g, 1.77 mmol, 1 eq) was dissolved in ethyl acetate (5 mL), and ethyl acetate hydrochloride (4 mol, 5 mL, 11.29 eq) was added. The reaction mixture was stirred at 25 °C for 0.5 h. After the reaction was complete, the reaction solution was filtered, and the filter cake was vacuum spin-dried to obtain the hydrochloride of compound 8-3. MS(ESI) m/z: 183.0[M+H + ].
  • Step C Compound 1-18a (20 mg, 75.98 micromol, 1 equiv) was dissolved in THF (1 mL), and N,N-carbonyldiimidazole (12.32 mg, 75.98 micromol, 1 equiv) and triethyl Amine (23.07 mg, 227.95 micromoles, 31.73 microliters, 3 equivalents), the reaction mixture was stirred at 25 degrees Celsius for 1 hour, compound 8-3 (16.61 mg, 75.98 micromoles, 1 equivalent, hydrochloride) was added to the reaction solution . The reaction mixture was stirred at 25 °C for 12 hours.
  • Compound 8 was detected by SFC [column model: Chiralpak AD-3 50 ⁇ 4.6mm I.D., 3 ⁇ m; mobile phase: phase A is supercritical carbon dioxide, phase B is methanol (0.05% diethylamine); gradient (B%): 5 %-40%] Obtained: the retention time of compound 8 is 2.069min, and the e.e. value is 100%.
  • Step A Compound 9-1 (100 mg, 701.54 micromol, 1 eq) and compound 1-9 (130.66 mg, 701.54 mmol, 1 eq) were dissolved in THF (5 mL), and N,N-di Isopropylethylamine (181.34 mg, 1.40 mmol, 244.39 ⁇ L, 2 equiv). The reaction mixture was stirred at 25°C for 1 hour. After the reaction was complete, water (50 mL) was added to the reaction solution, and extracted with ethyl acetate (50 mL ⁇ 2).
  • Step B Compound 9-2 (100 mg, 342.08 ⁇ mol, 1 eq) was dissolved in dichloromethane (5 mL), and diethylaminosulfur trifluoride (110.28 mg, 684.15 ⁇ mol, 90.39 ⁇ l, 2 equivalents). The reaction mixture was stirred at 25 °C for 13 hours. After the reaction was complete, water (30 mL) was added to the reaction solution, and extracted with ethyl acetate (30 mL ⁇ 2).
  • Step C Compound 9-3 (60 mg, 190.88 ⁇ mol, 1 eq) was dissolved in dioxane hydrochloride (4 mol, 5 mL). The reaction mixture was stirred at 25°C for 15 minutes. After the reaction was complete, the reaction solution was directly concentrated to obtain the hydrochloride of compound 9-4. MS(ESI) m/z: 215.0[M+H + ].
  • Step D Compound 1-18a (15 mg, 56.99 ⁇ mol, 1 equivalent) was dissolved in N,N-dimethylformamide (1 mL), and N,N-carbonyldiimidazole (18.48 mg, 113.97 ⁇ mol mol, 2 equiv) and triethylamine (28.83 mg, 284.98 micromole, 39.66 microliter, 5 equiv). The reaction solution was stirred at 25°C for 2 hours. Compound 9-4 (28.57 mg, 113.97 ⁇ mol, 2 equiv, hydrochloride) was added, and the reaction mixture was stirred at 25° C. for 24 hours.
  • Compound 9 was detected by SFC [column model: Chiralcel OJ-3 50 ⁇ 4.6mm I.D., 3 ⁇ m; mobile phase: phase A is supercritical carbon dioxide, phase B is methanol (0.05% diethylamine); gradient (B%): 5 %-40%] Obtained: the retention time of compound 9 is 1.613min, and the e.e. value is 100%.
  • Step A Compound 10-1 (100 mg, 430.99 micromol, 1 equiv) was dissolved in N-methylpyrrolidone (2 mL), and cesium carbonate (280.85 mg, 861.99 mmol, 2 equiv) was added to compound 1-9 (80.27 mg, 430.99 mmol, 1 equiv). The reaction mixture was stirred at 110°C for 1 hour. After the reaction was complete, the reaction solution was cooled to 25 degrees Celsius, and ethyl acetate (10 ml), water (10 ml ⁇ 3) and saturated brine (10 ml ⁇ 2) were added to the reaction solution to wash, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuo to obtain compound 10-2.
  • Step B Compound 10-2 (190 mg, 536.20 ⁇ mol, 1 eq) was dissolved in ethyl acetate (2 mL), and ethyl acetate hydrochloride (4 mol/L, 2 mL) was added. The reaction mixture was stirred at 25 °C for 0.5 h. After the reaction was complete, the reaction solution was directly concentrated to obtain the hydrochloride of compound 10-3. MS (ESI) m/z: 238.0 [M+H + ]
  • Step C Compound 1-18a (15 mg, 56.99 ⁇ mol, 1 eq) was dissolved in THF (2 mL), and N,N-carbonyldiimidazole (18.48 mg, 113.97 ⁇ mol, 2 eq) and triethyl Amine (23.07 mg, 227.95 micromol, 31.73 microliter, 4 equiv). The reaction solution was stirred at 50°C for 4 hours. Then add carbonyldiimidazole (13.86 mg, 85.48 micromoles, 1.5 equivalents), and the reaction mixture is stirred at 50 degrees Celsius for 12 hours.
  • Compound 10 was detected by SFC [column model: Chiralcel OD-3 50 ⁇ 4.6mm I.D., 3 ⁇ m; mobile phase: phase A is supercritical carbon dioxide, phase B is methanol (0.05% diethylamine); gradient (B%): 5 %-40%] Obtained: the retention time of compound 10 is 1.540min, and the e.e. value is 100%.
  • Step A Add potassium carbonate (1.08 g, 7.78 mmol, 2 eq) and compound 11-1 to a solution of compound 1-9 (0.5 g, 3.89 mmol, 1 eq) in N-methylpyrrolidone (10 mL) (724.38 mg, 3.89 mmol, 1 equivalent), and the mixed system was stirred at 100 degrees Celsius for 12 hours. After the reaction solution was cooled to room temperature, water (50 ml) was added, and a white solid was precipitated. The filter cake was collected by filtration and dried under reduced pressure to obtain compound 11-2. MS(ESI)m/z:223.2[M+H + -56].
  • Step B Add ethyl acetate hydrochloride (4 moles per liter, 10 ml, 11.13 equivalents) to a solution of 11-2 (1 gram, 3.59 mmol, 1 equivalent) in ethyl acetate (10 milliliters), and the mixed system is Stir for 0.5 h at 25°C. The reaction solution was directly dried under reduced pressure to obtain the hydrochloride of compound 11-3. MS(ESI)m/z:179.2[M+H + ].
  • Step C To a solution of compound 1-13 (12.94 g, 57.73 mmol, 11.45 mL, 1 eq) in THF (30 mL) was added lithium chloride (2.94 g, 69.28 mmol, 1.42 mL, 1.2 eq) and three Ethylamine (7.01 grams, 69.28 mmoles, 9.64 milliliters, 1.2 equivalents), the mixed system was stirred at 0 degrees Celsius for 0.5 hours, and then compound 1-12 (10 grams, 57.73 millimoles, 1 equivalents) in tetrahydrofuran (50 milliliters ) solution, the mixed system was stirred at 25 degrees Celsius for 6 hours.
  • reaction solution was added to water (300 ml), extracted with ethyl acetate (300 ml ⁇ 2), the organic phases were combined, washed with saturated brine (300 ml ⁇ 2), dried over anhydrous sodium sulfate, and concentrated to obtain compound 11-4 .
  • Step D To a solution of compound 11-4 (14 g, 57.54 mmol, 1 eq) in ethyl acetate (80 mL), add ethyl acetate hydrochloride (4 moles per liter, 80 mL, 5.56 eq), and the mixture The system was stirred at 25°C for 1 hour. The reaction solution was directly concentrated to obtain the hydrochloride of compound 11-5.
  • Step E Triethylamine (34.98 g, 345.68 mmol, 48.11 mL, 3 eq) and compound 11-5 (20.7 g, 115.23 mmol, 1 eq, hydrochloride salt), the mixed system was stirred at 25 degrees Celsius for 12 hours.
  • reaction solution was diluted with ethyl acetate (500 ml), washed with water (500 ml ⁇ 3), washed with saturated brine (500 ml ⁇ 2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the crude product was passed through high-efficiency liquid Purified by phase chromatography (column: Phenomenex luna C18 250*80 mm*10 microns; mobile phase: [water (formic acid)-acetonitrile]: acetonitrile %: 50%-80%, 20 minutes) to obtain compound 11-6.
  • Step F To a solution of compound 11-6 (10 g, 23.51 mmol, 1 eq) in trifluoroacetic acid (100 mL) was added trifluoromethanesulfonic acid (17.00 g, 113.28 mmol, 10 mL, 4.82 eq), The mixed system was stirred for 1 hour at 25°C.
  • Step G To compound 11-7 (5 g, 16.38 mmol, 1 eq) in THF (50 mL) was added diisobutylaluminum hydride (1 mole per liter, 49.14 mL, 3 eq. ), the mixed system was stirred at 10 degrees Celsius for 1 hour. Add saturated sodium potassium tartrate (50 ml) solution to the reaction solution, stir at 25 degrees Celsius for 1 hour, extract with ethyl acetate (100 ml ⁇ 3), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain compound 11 -8.
  • diisobutylaluminum hydride 1 mole per liter, 49.14 mL, 3 eq.
  • Compound 11-8 was detected by SFC [column model: Chiralcel OJ-3 50 ⁇ 4.6mm I.D., 3 ⁇ m; mobile phase: phase A is supercritical carbon dioxide, phase B is isopropanol (0.05% diethylamine); gradient (B %): 5%-40%] Obtained: the retention time of compound 11-8 is 1.146min, and the e.e. value is 95.652%.
  • Step H To a solution of compound 11-8 (3 g, 11.40 mmol, 1 eq) in toluene (30 mL) was added 1,8-diazacycloundec-7-ene (2.08 g, 13.68 mmol , 2.06 ml, 1.2 eq) and diphenylphosphoryl azide (3.76 g, 13.68 mmol, 2.96 ml, 1.2 eq), the mixture was stirred at 80°C for 1 hour.
  • Step I Add triphenylphosphine (2.73 g, 10.41 mmol, 1.5 eq) to a solution of compound 11-9 (2 g, 6.94 mmol, 1 eq) in tetrahydrofuran (20 ml), and the mixed system is heated at 40° C. Stir for 0.5 hours. Water (3 ml) was added to the reaction mixture, and the mixture was stirred at 40° C. for 1.5 hours.
  • Step H To a solution of compound 11-10 (50 mg, 190.67 micromol, 1 equiv) in N,N-dimethylformamide (1 mL) Add N,N-carbonyldiimidazole (37.10 mg, 228.81 micromoles, 1.2 equivalents) and triethylamine (77.18 mg, 762.69 micromoles, 106.16 microliters, 4 equivalents), and the mixed system is stirred at 25 degrees Celsius for 1 hour , and then compound 11-3 (40.94 mg, 190.67 micromole, 989.50 microliter, 1 equivalent, hydrochloride) was added, and the mixed system was stirred at 25 degrees Celsius for 1 hour.
  • N,N-carbonyldiimidazole 37.10 mg, 228.81 micromoles, 1.2 equivalents
  • triethylamine 77.18 mg, 762.69 micromoles, 106.16 microliters, 4 equivalents
  • Compound 11 was detected by SFC [column model: OD-3 50 ⁇ 4.6mm I.D., 3 ⁇ m; mobile phase: phase A is supercritical carbon dioxide, phase B is methanol (0.05% diethylamine); gradient (B%): 5% -40%] Obtained: the retention time of compound 11 was 1.641 min, and the e.e. value was 96.060%.
  • Step A Add potassium carbonate (260.41 mg, 1.88 mmol, 2 eq) and compound 1-8 to a solution of compound 12-1 (200 mg, 942.12 micromol, 1 eq) in N-methylpyrrolidone (2 mL) (171.97 mg, 942.12 micromole, 1 eq), and the mixed system was stirred at 80°C for 2 hours. After the reaction solution was cooled to room temperature, water (10 ml) was added, and a solid precipitated out. The filter cake was collected by filtration and dried under reduced pressure to obtain compound 12-2. MS(ESI)m/z:303.1[M+H + -56].
  • Step B Add ethyl acetate hydrochloride (4 moles per liter, 3 milliliters, 13.87 equivalents) to a solution of 12-2 (310 mg, 865.06 micromoles, 1 equivalent) in ethyl acetate (3 milliliters), and the mixed system was Stir for 1 hour at 25°C. The reaction solution was directly dried under reduced pressure to obtain the hydrochloride of compound 12-3. MS(ESI)m/z:259.0[M+H + -56].
  • Step C Add N-methylmorpholine (46.29 mg, 457.61 ) and compound 12-4 (73.79 mg, 366.08 micromole, 1.2 equivalents), the mixed system was stirred at 25 degrees Celsius for 12 hours. Dilute with water (20 mL), extract with dichloromethane (20 mL ⁇ 2), combine organic phases, wash with saturated brine (20 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain compound 12-5. MS(ESI)m/z:428.1[M+H + ].
  • Step D Add compound 12-3 (91.03 mg, 308.89 micromol, 1.2 equiv , hydrochloride) and triethylamine (31.26 mg, 308.89 micromoles, 42.99 microliters, 1.2 equivalents), the mixed system was stirred at 25 degrees Celsius for 12 hours.
  • Compound 12 was detected by SFC [column model: Chiralcel OD-3 50 ⁇ 4.6mm I.D., 3 ⁇ m; mobile phase: phase A is supercritical carbon dioxide, phase B is isopropanol (0.05% diethylamine); gradient (B%) : 5%-40%] Obtained: the retention time of compound 12 was 1.675min, and the e.e. value was 97.136%.
  • Step A Add potassium carbonate to a solution of compound 1-9 (1 g, 5.48 mmol, 1 eq) and compound 13-1 (1.02 g, 5.48 mmol, 1 eq) in N-methylpyrrolidone (20 mL) (1.51 g, 10.96 mmol, 2 eq), and the mixed system was stirred at 100° C. for 12 hours. After the reaction solution was cooled to room temperature, water (100 ml) was added, and the mixture was stirred at 25 degrees Celsius for 10 minutes, a white solid precipitated out, filtered and the filter cake was collected, and dried under reduced pressure to obtain compound 13-2. MS(ESI)m/z:277.1[M+H + -56].
  • Step B Add ethyl acetate hydrochloride (4 moles per liter, 10 milliliters, 8.31 equivalents) to a solution of 13-2 (1.6 grams, 4.81 mmoles, 1 equivalent) in ethyl acetate (10 milliliters), and the mixed system is Stir for 1 hour at 25°C. The reaction solution was directly dried under reduced pressure to obtain the hydrochloride of compound 13-3. MS(ESI)m/z:233.1[M+H + ].
  • Step C Add N,N-carbonyldiimidazole (37.10 mg, 228.81 , 1.2 equivalents) and triethylamine (77.18 mg, 762.69 micromoles, 106.16 microliters, 4 equivalents), the mixed system was stirred at 25 degrees Celsius for 1 hour, and then compound 13-3 (51.23 mg, 190.67 micromoles, 1 Equivalent, hydrochloride), the mixed system was stirred at 40 degrees Celsius for 3 hours.
  • Compound 13 was detected by SFC [column model: Chiralcel OJ-3 50 ⁇ 4.6mm I.D., 3 ⁇ m; mobile phase: phase A is supercritical carbon dioxide, phase B is methanol (0.05% diethylamine); gradient (B%): 5 %-40%] Obtained: the retention time of compound 13 is 1.475min, and the e.e. value is 96.192%.
  • Step A To a solution of compound 11-8 (2.15 g, 8.17 mmol, 1 eq) in dimethyl sulfoxide (20 mL) was added 2-iodobenzoic acid (4.57 g, 16.34 mmol, 2 eq), The reaction solution was stirred at 25° C. for 24 hours.
  • Step B Add methylamine hydrochloride (594.53 mg , 8.81 mmol, 10 equivalents), the reaction solution was stirred at 25 degrees Celsius for 12 hours, then sodium acetate borohydride (466.56 mg, 2.20 mmoles, 2.5 equivalents) was added, and the reaction solution was continued to stir at 25 degrees Celsius for 12 hours.
  • reaction solution was concentrated, and the crude product was prepared in reverse (column: 330g Flash Column Welch Ultimate XB_C18 20-40 ⁇ m; 120A, sample dissolution solvent: about 2.00 g of sample was dissolved in 10 ml of methanol, flow rate: 100 ml/min, mobile phase: Acetonitrile/water, gradient water %: 0-30% for 30 minutes; 30-100% for 25 minutes; instrument: TELEDYNE ISCO CombiFlashRf150) was purified to obtain compound 14-2.
  • Step C To a solution of compound 14-2 (80 mg, 289.58 ⁇ mol, 1 eq) in dichloromethane (2 mL) was added N-methylmorpholine (58.58 mg, 579.17 ) and compound 12-4 (87.55 mg, 434.38 micromole, 1.5 equiv), and the reaction solution was stirred at 25 degrees Celsius for 12 hours.
  • Step D To a solution of compound 14-3 (40 mg, 90.63 micromol, 1 eq) in N,N-dimethylformamide (1 mL) was added N,N-diisopropylethylamine (35.14 mg , 271.89 ⁇ mol, 47.36 ⁇ l, 3 equivalents) and compound 1-11 (48.70 mg, 181.26umol, 2 equivalents, hydrochloride), the reaction solution was stirred at 100 degrees Celsius for 12 hours.
  • N,N-diisopropylethylamine 35.14 mg , 271.89 ⁇ mol, 47.36 ⁇ l, 3 equivalents
  • compound 1-11 48.70 mg, 181.26umol, 2 equivalents, hydrochloride
  • reaction solution was poured into water (30 ml), extracted with ethyl acetate (30 ml ⁇ 2), the organic phases were combined, washed with saturated brine (30 ml ⁇ 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated.
  • Compound 14 was detected by SFC [column model: Chiralpak AD-3 50 ⁇ 4.6mm I.D., 3 ⁇ m; mobile phase: phase A is supercritical carbon dioxide, phase B is methanol (0.05% diethylamine); gradient (B%): 5 %-40%] Obtained: the retention time of compound 14 was 1.878min, and the e.e. value was 99.036%.
  • Step A To a solution of compound 1-8 (0.5 g, 2.74 mmol, 1 eq) and compound 15-1 (548.61 mg, 2.74 mmol, 1 eq) in N,N-dimethylformamide (8 mL) Potassium carbonate (757.16 mg, 5.48 mmol, 2 eq) was added to the mixture, and the reaction solution was heated to 80°C and stirred for 2 hours. The reaction solution was poured into water (50 ml), extracted with ethyl acetate (50 ml ⁇ 2), the organic phases were combined, washed with saturated brine (50 ml ⁇ 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain Compound 15-2. MS(ESI)m/z:247.1[M+H + -100].
  • Step B Add ethyl acetate hydrochloride (10 ml, 4 moles per liter) to a solution of compound 15-2 (1 g, 2.89 mmol, 1 eq) in methanol (10 ml), and stir the reaction solution at 25 degrees Celsius for 30 minutes . The reaction solution was concentrated to obtain the hydrochloride of compound 15-3.
  • Step C To a solution of compound 11-10 (60 mg, 228.81 ⁇ mol, 1 eq) in N,N-dimethylformamide (1.5 mL) was added carbonyldiimidazole (55.65 mg, 343.22 ⁇ mol, 1.5 eq) and N,N-diisopropylethylamine (147.86 mg, 1.14 mmol, 199.27 microliters, 5 equivalents), the mixture was stirred at 25 degrees Celsius for 1 hour, and then 15-3 (129.37 mg, 457.62 micromoles, 2 equivalents, hydrochloride), the reaction solution was heated to 60 degrees Celsius and stirred for 12 hours.
  • reaction solution was directly subjected to high performance liquid chromatography (column: Unisil 3-100 C18 Ultra 150*50 mm*3 micron; mobile phase: [water (formic acid)-acetonitrile]; acetonitrile%: 34%-64%, 7 minute) purification, and then purified by chiral column (column: DAICEL CHIRALPAK AD (250 mm * 30 mm, 10 microns); mobile phase: [0.1% ammonia isopropanol]; isopropanol %: 40%-40%, 4.9 min) to give compound 15. MS(ESI)m/z:535.2[M+H + ].
  • Compound 15 was detected by SFC [column model: Chiralpak AD-3 50 ⁇ 4.6mm I.D., 3 ⁇ m; mobile phase: phase A is supercritical carbon dioxide, phase B is ethanol (0.05% diethylamine); gradient (B%): 5 %-40%] Obtained: the retention time of compound 15 is 3.164min and 3.507min, and the e.e. value is 3.696%.
  • Step A Add compound 16-1 (500 mg, 2.20 mmol, 1 eq) and compound 1-9 (410.28 mg, 2.20 mmol, 1 eq) in 1,4-dioxane solution (5 ml) Add tris(dibenzylideneacetone)dipalladium (100.86 mg, 110.14 micromole, 0.05 equiv), 2-bicyclohexylphosphine-2,6-diisopropoxy-,1,1-biphenyl (51.40 mg, 110.14 micromoles, 0.05 equivalents) and cesium carbonate (1.44 grams, 4.41 mmoles, 2 equivalents), the reaction system was replaced with nitrogen, and then the reaction solution was heated to 80 degrees Celsius and stirred for 12 hours.
  • Step B Compound 16-2 (520 mg, 1.56 mmol, 1 eq) and ethyl acetate hydrochloride (20 mL, 4 mol per liter) were added to the reaction flask, and the reaction solution was stirred at 25°C for 15 minutes. The reaction solution was concentrated to obtain the hydrochloride of compound 16-3. MS(ESI)m/z:233.1[M+H + ].
  • Step C Add N,N-carbonyldiimidazole (55.65 mg, 343.22 , 1.5 equivalents) and triethylamine (115.76 mg, 1.14 mmol, 159.23 microliters, 5 equivalents), the mixture was stirred at 25 degrees Celsius for 1 hour, then 16-3 (129.37 mg, 457.62 micromoles, 2 equivalents, hydrochloride), the reaction solution was heated to 60 degrees Celsius and stirred for 12 hours.
  • N,N-carbonyldiimidazole 55.65 mg, 343.22 , 1.5 equivalents
  • triethylamine 115.76 mg, 1.14 mmol, 159.23 microliters, 5 equivalents
  • Compound 16 was detected by SFC [column model: Chiralcel OJ-3 50 ⁇ 4.6mm I.D., 3 ⁇ m; mobile phase: phase A is supercritical carbon dioxide, phase B is methanol (0.05% diethylamine); gradient (B%): 5 %-40%] Obtained: the retention time of compound 16 is 1.578min, and the e.e. value is 96.492%.
  • Step A Add compound 1-8 (1 g, 5.48 mmol, 1 eq) and compound 17-1 (1.10 g, 5.48 mmol, 1.08 ml, 1 eq) to N,N-dimethylformamide (15 mL) solution was added potassium carbonate (1.51 g, 10.96 mmol, 2 equivalents), and the reaction solution was heated to 80 degrees Celsius and stirred for 2 hours.
  • the reaction solution was poured into water (80 ml), extracted with ethyl acetate (80 ml ⁇ 2), the organic phases were combined, washed with saturated brine (80 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 17 -2.
  • Step B Compound 17-2 (1.9 g, 5.49 mmol, 1 eq) and ethyl acetate hydrochloride (20 mL, 4 mol per liter) were added to the reaction flask, and the reaction solution was stirred at 25°C for 15 minutes. The reaction solution was concentrated to obtain the hydrochloride of compound 17-3. MS(ESI)m/z:247.1[M+H + ].
  • Step C Add N,N-carbonyldiimidazole (44.52 mg, 274.57 , 1.2 equivalents) and triethylamine (115.76 mg, 1.14 mmol, 159.23 microliters, 5 equivalents), the mixture was stirred at 25 degrees Celsius for 1 hour, then 17-3 (97.02 mg, 343.21 micromoles, 1.5 equivalents, hydrochloride), the reaction solution was stirred at 25 degrees Celsius for 12 hours.
  • Compound 17 was detected by SFC [column model: Chiralcel OJ-3 50 ⁇ 4.6mm I.D., 3 ⁇ m; mobile phase: phase A is supercritical carbon dioxide, phase B is methanol (0.05% diethylamine); gradient (B%): 5 %-40%] Obtained: the retention time of compound 17 was 1.041min, and the e.e. value was 96.008%.
  • Step A To a solution of compound 1-9 (1.33 g, 7.17 mmol, 1 eq) and compound 18-1 (1 g, 7.17 mmol, 1 eq) in N-methylpyrrolidone (20 mL) was added potassium carbonate (1.49 g, 10.75 mmol, 1.5 equivalents), the reaction solution was heated to 80 degrees Celsius and stirred for 2 hours. The reaction solution was poured into water (100 ml), extracted with ethyl acetate (100 ml ⁇ 2), the organic phases were combined, washed with saturated brine (100 ml ⁇ 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain Compound 18-2. MS(ESI)m/z:234.1[M+H + -56].
  • Step B Compound 18-2 (1.9 g, 6.57 mmol, 1 eq) and methanol hydrochloride (20 ml, 4 mol per liter) were added to the reaction flask, and the reaction solution was stirred at 25°C for 30 minutes. The reaction solution was concentrated to obtain the hydrochloride of compound 18-3. MS (ESI) m/z: 190.2 [M+H + ].
  • Step C To a solution of compound 11-10 (100 mg, 381.34 micromol, 1 equiv) in N,N-dimethylformamide (2 mL) Added N,N-carbonyldiimidazole (80.38 mg, 495.75 micromoles, 1.3 equivalents) and triethylamine (192.94 mg, 1.91 mmoles, 265.39 microliters, 5 equivalents), the mixture was stirred at 25 degrees Celsius for 1 hour, and then 18-3 (86.06 mg, 381.34 micromole, 1 equivalent, hydrochloride) was added to the reaction solution, and the reaction solution was stirred at 25 degrees Celsius for 12 hours.
  • N,N-carbonyldiimidazole 80.38 mg, 495.75 micromoles, 1.3 equivalents
  • triethylamine (192.94 mg, 1.91 mmoles, 265.39 microliters, 5 equivalents
  • Compound 18 was detected by SFC [column model: Chiralcel OJ-3 50 ⁇ 4.6mm I.D., 3 ⁇ m; mobile phase: phase A is supercritical carbon dioxide, phase B is methanol (0.05% diethylamine); gradient (B%): 5 %-40%] Obtained: the retention time of compound 18 is 1.552min, and the e.e. value is 100%.
  • Step A Add compound 19-1 (3 g, 12.98 mmol, 1 eq) and compound 1-9 (2.90 g, 15.58 mmol, 1.2 eq) in 1,4-dioxane (30 ml) Add 2-bicyclohexylphosphine-2,6-diisopropoxy-1,1-biphenyl (605.79 mg, 1.30 mmol, 0.1 eq), sodium tert-butoxide (2.50 g, 25.96 mmol, 2 eq) , tris(dibenzylideneacetone) dipalladium (594.39 mg, 649.10 micromoles, 0.05 equivalents), nitrogen replacement three times and stirred at 100 degrees Celsius for 12 hours, after the reaction was completed, 10 milliliters of ethyl acetate was added, filtered, and the filtrate was concentrated under reduced pressure The obtained crude product was purified by silica gel thin-layer chromatography (petroleum ether/ethyl a
  • Step B Add glacial acetic acid (10 milliliters) and water (10 milliliters) to compound 19-2 (3 g, 8.92 mmol, 1 equivalent) in THF (10 milliliters) solution. Stir at 70°C for 12 hours. After the reaction was completed, adjust the pH of the reaction solution to 7 with saturated sodium carbonate solution, extract the reaction solution with ethyl acetate (30 ml ⁇ 3), wash with saturated brine (30 ml ⁇ 2), dry over anhydrous sodium sulfate, and filter , the crude product obtained by concentrating the filtrate under reduced pressure was purified by column chromatography (silica gel column, eluent gradient 0-30% petroleum ether/ethyl acetate, 100 ml/min) to obtain compound 19-3. MS(ESI) m/z: 253.2[M+H + ].
  • Step C Add potassium fluoride (355.06 mg, 6.11 mmol, 143.17 microliters, 2 equivalents), and the mixed system was stirred at 25 degrees Celsius for 4 hours. After the reaction was complete, acetonitrile (5 milliliters) was added to the reaction solution, filtered, and the filtrate was vacuum-dried to obtain a residue with column chromatography (silica gel column, eluent gradient 0 ⁇ 15% sherwood oil/ethyl acetate 100 milliliters/min ) was purified to obtain compound 19-5. MS(ESI)m/z:303.1[M+H + ].
  • Step D To a solution of compound 19-5 (885 mg, 2.93 mmol, 1 eq) in ethyl acetate (6 mL) was added ethyl acetate hydrochloride (4 moles per liter, 6 mL, 8.2 eq), and the mixed The solution was stirred at 25°C for 12 hours. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure to obtain the hydrochloride of compound 19-6. MS(ESI) m/z: 203.2[M+H + ].
  • Step E Triethylamine (192.94 mg, 1.91 mmol, 265.39 ⁇ l , 5 equivalents) and N,N-carbonyldiimidazole (80.38 mg, 495.75 micromoles, 1.3 equivalents), the mixed system was stirred at 25 degrees Celsius for 1 hour, compound 19-6 (109.22 mg, 457.61 micromoles, 1.2 equivalent , hydrochloride) was added to the reaction solution, and the mixed system was stirred at 25 degrees Celsius for 12 hours.
  • Step A To a solution of compound 20-1 (500 mg, 2.50 mmol, 1 eq) and compound 1-8 (455.70 mg, 2.50 mmol, 1 eq) in N,N-dimethylformamide (5 mL) Potassium carbonate (690.07 mg, 4.99 mmol, 2 eq) was added to the mixture, and the reaction solution was heated to 80°C and stirred for 1 hour. Water (15 ml) was added to the reaction solution, the reaction solution was stirred at 25°C for 15 minutes, the reaction solution was filtered, and the filter cake was concentrated under reduced pressure to obtain compound 20-2. MS(ESI)m/z:291.1[M+H + -56].
  • Step B Add compound 20-2 (460 mg, 1.33 mmol, 1 equivalent) and ethyl acetate (4 milliliters), ethyl acetate hydrochloride (4 milliliters, 4 moles per liter, 12.05 equivalents) to the reaction flask, the The reaction solution was stirred at 25°C for 12 hours. The reaction solution was concentrated to obtain the hydrochloride of compound 20-3. MS(ESI)m/z:247.1[M+H + ].
  • Step C Add N,N-carbonyldiimidazole (80.38 mg, 495.75 , 1.3 equivalents) and triethylamine (192.94 mg, 1.91 mmol, 265.39 microliters, 5 equivalents), the mixture was stirred at 25 degrees Celsius for 1 hour, then 20-3 (129.36 mg, 457.61 micromoles, 1.2 equivalents, hydrochloride), the reaction solution was stirred at 25 degrees Celsius for 1 hour. The reaction solution was poured into water (10 ml), extracted with ethyl acetate (10 ml ⁇ 3), the organic phases were combined, washed with saturated brine (10 ml ⁇ 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated.
  • Compound 20 was detected by SFC [column model: OD-3 50 ⁇ 4.6mm I.D., 3 ⁇ m; mobile phase: phase A is supercritical carbon dioxide, phase B is methanol (0.05% diethylamine); gradient (B%): 5% -40%] Obtained: the retention time of compound 20 is 1.318min, and the e.e. value is 100%.
  • Step A To a solution of compound 21-1 (500 mg, 2.50 mmol, 1 eq) and compound 1-8 (455.70 mg, 2.50 mmol, 1 eq) in N,N-dimethylformamide (5 mL) Potassium carbonate (690.07 mg, 4.99 mmol, 2 eq) was added to the mixture, and the reaction solution was heated to 80°C and stirred for 1 hour. Water (15 ml) was added to the reaction solution, the reaction solution was stirred at 25°C for 15 minutes, the reaction solution was filtered, and the filter cake was concentrated under reduced pressure to obtain compound 21-2. MS(ESI)m/z:291.1[M+H + -56].
  • Step B Add compound 21-2 (437 mg, 1.26 mmol, 1 equivalent) and ethyl acetate (4 milliliters), ethyl acetate hydrochloride (4 milliliters, 4 moles per liter, 12.68 equivalents) to the reaction flask, the The reaction solution was stirred at 25°C for 12 hours. The reaction solution was concentrated to obtain the hydrochloride of compound 21-3. MS(ESI)m/z:247.2[M+H + ].
  • Step C Add N,N-carbonyldiimidazole (80.38 mg, 495.75 , 1.3 equivalents) and triethylamine (192.94 mg, 1.91 mmol, 265.39 microliters, 5 equivalents), the mixture was stirred at 25 degrees Celsius for 1 hour, then 21-3 (129.36 mg, 457.61 micromoles, 1.2 equivalents, hydrochloride), the reaction solution was stirred at 25 degrees Celsius for 1 hour. The reaction solution was poured into water (10 ml), extracted with ethyl acetate (10 ml ⁇ 3), the organic phases were combined, washed with saturated brine (10 ml ⁇ 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated.
  • Compound 21 was detected by SFC [column model: Chiralpak IG-3 50 ⁇ 4.6mm I.D., 3 ⁇ m; mobile phase: phase A is supercritical carbon dioxide, phase B is methanol (0.05% diethylamine); gradient (B%): 20 %-20%] Obtained: the retention time of compound 21 is 2.511min, and the e.e. value is 100%.
  • Step A Add compound 22-1 (500 mg, 1.62 mmol, 1 eq) and compound 1-8 (354.19 mg, 1.94 mmol, 1.2 eq) in 1,4-dioxane (5 mL) Dichlorobis(triphenylphosphine)palladium(II) (113.50 mg, 161.70 micromoles, 0.1 equiv), cesium carbonate (2.11 g, 6.47 mmol, 4 equiv), water (1 ml) were added, and nitrogen was replaced three times Stir at 100 degrees Celsius for 12 hours, add 10 ml of ethyl acetate after the reaction, filter, and concentrate the filtrate under reduced pressure to obtain the crude product through silica gel column chromatography (silica gel column, eluent gradient 0 ⁇ 8% petroleum ether/ethyl acetate , 100 ml/min) to obtain compound 22-2.
  • Step B Add compound 22-2 (420 mg, 1.28 mmol, 1 equivalent) and ethanol (4 ml), palladium carbon (80 mg, purity: 10%) to the reaction flask, and replace the reaction liquid with hydrogen for three times Stir at 25°C for 1 hour under the protection of hydrogen (15 psi). The reaction solution was filtered and the filtrate was concentrated to obtain compound 22-3. MS (ESI) m/z: 276.1 [M+H+-56].
  • Step C add compound 22-3 (375 mg, 1.13 mmol, 1 equivalent) and ethyl acetate (2 milliliters), ethyl acetate hydrochloride (2 milliliters, 4 moles per liter) to the reaction flask, and the reaction solution is Stir at 25°C for 12 hours. The reaction solution was concentrated to obtain the hydrochloride of compound 22-4. MS(ESI)m/z:232.2[M+H + ].
  • Step D To a solution of compound 11-10 (100 mg, 381.34 ⁇ mol, 1 eq) in N,N-dimethylformamide (3 mL) was added N,N-carbonyldiimidazole (80.38 mg, 495.75 ⁇ mol , 1.3 equivalents) and triethylamine (192.94 mg, 1.91 mmol, 265.39 microliters, 5 equivalents), the mixture was stirred at 25 degrees Celsius for 1 hour, then 22-4 (122.49 mg, 457.61 micromoles, 1.2 equivalents, hydrochloride), the reaction solution was stirred at 25 degrees Celsius for 1 hour.
  • Compound 22 was detected by SFC [column model: Chiralpak IG-3 50 ⁇ 4.6mm I.D., 3 ⁇ m; mobile phase: phase A is supercritical carbon dioxide, phase B is methanol (0.05% diethylamine); gradient (B%): 5 %-40%] Obtained: the retention time of compound 22 is 2.322min, and the e.e. value is 96.406%.
  • Step A Add compound 23-1 (1 g, 5.32 mmol, 1 eq) and compound 1-9 (1.19 g, 6.38 mmol, 1.2 eq) in 1,4-dioxane (10 ml) Add (R)-(+)-2,2-bis(diphenylphosphino)-1,1-binaphthyl (331.13 mg, 531.79 micromol, 0.1 equiv), cesium carbonate (2.60 g, 7.98 mmol, 1.5 Equivalent), palladium acetate (119.39 milligrams, 531.79 micromole, 0.1 equivalent), nitrogen replacement three times and stirred at 100 degrees Celsius for 12 hours, added 10 milliliters of ethyl acetate after the reaction, filtered, and the thick product obtained by concentrating the filtrate under reduced pressure was subjected to high-efficiency Liquid chromatography (column: Phenomenex luna C18 250*70 mm*10 microns; mobile phase: [water (0.
  • Step B Add compound 23-2 (300 mg, 1.02 mmol, 1 equivalent) and ethyl acetate (3 milliliters), ethyl acetate hydrochloride (3 milliliters, 4 moles per liter, 11.74 equivalents) to the reaction flask, the The reaction solution was stirred at 25°C for 12 hours. The reaction solution was concentrated to obtain the hydrochloride of compound 23-3. MS(ESI)m/z:194.1[M+H + ].
  • Step C Add N,N-carbonyldiimidazole (80.38 mg, 495.75 , 1.3 equivalents) and triethylamine (192.94 mg, 1.91 mmol, 265.39 microliters, 5 equivalents), the mixture was stirred at 25 degrees Celsius for 0.5 hours to obtain a solution of compound 23-4 in N,N-dimethylformamide. for the next step.
  • Step D Add compound 23-3 (105.12 mg, 457.60 micromol, 1.2 equiv, hydrochloride) to compound 23-4 (135.87 mg, 381.33 micromol, 1 equiv) in N,N-dimethylformamide solution, the reaction solution was stirred at 25 degrees Celsius for 12 hours. The reaction solution was poured into water (10 ml), extracted with ethyl acetate (10 ml ⁇ 3), the organic phases were combined, washed with saturated brine (10 ml ⁇ 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated.
  • Compound 23 was detected by SFC [column model: Chiralcel OJ-3 50 ⁇ 4.6mm I.D., 3 ⁇ m; mobile phase: phase A is supercritical carbon dioxide, phase B is methanol (0.05% diethylamine); gradient (B%): 5 %-40%] Obtained: the retention time of compound 23 was 1.524min, and the e.e. value was 96.872%.
  • Step A To a solution of compound 1-13 (6.11 g, 27.26 mmol, 2.5 eq) in acetonitrile (45 mL) at 0 °C was added lithium chloride (1.16 g, 27.26 mmol, 2.5 eq) and N,N - Diisopropylethylamine (3.52g, 27.26mmol, 2.5eq), the mixture was stirred at 0°C for 0.5h. At 0°C, a solution of compound 24-1 (2.5 g, 10.90 mmol, 1.0 eq) in acetonitrile (30 ml) was slowly dropped into the system, and the mixed system was stirred at 0°C for 2.5 hours.
  • Step B To a solution of compound 24-2 (1.6 g, 5.34 mmol, 1 eq) in dichloromethane (10 mL) was added trifluoroacetic acid (12.19 g, 206.89 mmol, 7.91 mL, 20 eq. ) and water (2.21 g, 122.93 mmol, 2.21 ml, 23 equivalents), the mixed system was stirred at 25 degrees Celsius for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the trifluoroacetic acid salt of compound 24-3. MS(ESI)m/z:159.1[M+H + ].
  • Step D To a solution of compound 24-4 (0.3 g, 675.38 ⁇ mol, 1 equiv) in trifluoroacetic acid (3 mL) was added trifluoromethanesulfonic acid (510 mg, 3.4 mmol, 300 ⁇ L) at 0 °C , 5.03 equivalents), the mixed system was stirred at 0 degrees Celsius for 0.5 hours.
  • reaction solution was slowly added dropwise to a saturated aqueous solution of sodium bicarbonate (50 ml), stirred for 5 minutes, extracted with ethyl acetate (50 ml ⁇ 2), the combined organic phases were washed with saturated brine (50 ml ⁇ 2) , dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 24-5.
  • Step E To a solution of compound 24-5 (0.2 g, 622.56 ⁇ mol, 1 equiv) in dichloromethane (5 mL) was added 3,4-dihydropyran (78.55 mg, 933.85 ⁇ mol, 1.5 equivalents) and trifluoroacetic acid (7.10 mg, 62.26 micromoles, 0.1 equivalents), the mixture was stirred at 25 degrees Celsius for 2 hours.
  • Step F 0 degrees Celsius, under the protection of nitrogen, slowly drop diisobutyl lithium aluminum hydride (1 mol per liter, 1.78 ml, 3 equivalents), the mixed system was stirred at 0° C. under nitrogen for 0.5 hours. Slowly add saturated aqueous ammonium chloride (50ml) to the reaction solution, stir for 5 minutes, extract with ethyl acetate (50ml ⁇ 2), combine the organic phases, wash with saturated brine (50ml ⁇ 2), and anhydrous sulfuric acid Dry over sodium, filter, and concentrate the filtrate to afford compound 24-7.
  • Step G To a solution of compound 24-7 (210 mg, 577.98 ⁇ mol, 1 eq) in dichloromethane (5 mL) was added N-methylmorpholine (64.31 mg, 635.78 mmol, 69.90 ⁇ l, 1.1 eq ) and compound 12-4 (128.15 mg, 635.78 micromole, 1.1 equiv), and the reaction system was stirred at 25 degrees Celsius for 16 hours.
  • Step H Add compound 1-11 (160.15 mg, 596.10 micromol, 1.05 equiv , hydrochloride) and N,N-diisopropylethylamine (110.06 mg, 851.57 micromoles, 148.33 microliters, 1.5 equivalents), the reaction system was stirred at 25 degrees Celsius for 3 hours. Water (50 mL) was added to the reaction solution, stirred for 5 minutes, extracted with ethyl acetate (50 mL ⁇ 2), the organic phases were combined, washed with saturated brine (50 mL ⁇ 2), dried over anhydrous sodium sulfate, Filtration and concentration of the filtrate afforded compound 24-9. MS(ESI)m/z:622.3[M+H + ].
  • Step I Add trifluoroacetic acid (1.54 g, 13.51 mmol, 1 mL, 27.98 eq) to a solution of compound 24-9 (0.3 g, 482.68 ⁇ mol, 1 eq) in dichloromethane (5 mL), and the mixture The system was stirred for 1 hour at 25°C. The reaction solution was concentrated, and the residue was subjected to high performance liquid chromatography (column: Waters Xbridge C18 150*50 mm*10 microns; mobile phase: [water (ammonium bicarbonate)-acetonitrile]; acetonitrile%: 26%-56%, 10 minutes) to obtain compound 24. MS(ESI)m/z:538.1[M+H + ].
  • Compound 24 was detected by SFC [column model: Chiralcel OJ-3 50 ⁇ 4.6mm I.D., 3 ⁇ m; mobile phase: phase A is supercritical carbon dioxide, phase B is methanol (0.05% diethylamine); gradient (B%): 5 %-40%] Obtained: the retention time of compound 24 is 1.505min, and the e.e. value is 100%.
  • Step A Compound 1-9 (1.02 g, 5.48 mmol, 1 eq) was added to a solution of compound 25-1 (1 g, 5.48 mmol, 662.25 ⁇ l, 1 eq) in N-methylpyrrolidone (10 mL) ), the mixed system was stirred at 80 degrees Celsius for 1 hour. After cooling to room temperature, water (50 ml) was added to the reaction solution, and after stirring for 5 minutes, the above mixture was filtered, and the filter cake was dried under reduced pressure to obtain compound 25-2. MS(ESI)m/z:333.1[M+H + ].
  • Step B Compound 25-2 (1 g, 3.01 mmol, 1 eq) was added to a solution of ethyl acetate hydrochloride (4 moles per liter, 10 mL, 13.29 eq), and the mixture was stirred at 25°C for 1 hour. Filter and collect the filter cake to obtain the hydrochloride of compound 25-3. MS(ESI)m/z:233.2[M+H + ].
  • Step D Compound 25-3 (60.40 mg, 225.65 micromol, 1.2 equiv , hydrochloride) and triethylamine (57.08 mg, 564.13 micromoles, 78.52 microliters, 3 equivalents), and the mixed system was stirred at 25 degrees Celsius for 1 hour.
  • Compound 25 was detected by SFC [column model: OD-3 50 ⁇ 4.6mm I.D., 3 ⁇ m; mobile phase: phase A is supercritical carbon dioxide, phase B is methanol (0.05% diethylamine); gradient (B%): 5% -40%] Obtained: the retention time of compound 25 was 1.413 min, and the e.e. value was 100%.
  • Step A N, N-dimethylformamide ( 30 ml) solution was added N,N-diisopropylethylamine (2.08 g, 16.11 mmol, 2.81 ml, 1 equiv), and the mixed system was stirred at 40°C for 12 hours. Dilute with water (50 mL), extract with ethyl acetate (50 mL ⁇ 2), combine the organic phases, wash with saturated brine (30 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain compound 26-2.
  • Step B Add sodium tert-butoxide (6.06 g, 63.08 mmol, 3 eq) and Compound 26-3 (4.37 g, 21.03 mmol, 2.94 ml, 1 equiv), the mixed system was stirred at 100°C for 12 hours.
  • Step C Add ethyl acetate hydrochloride (4 moles per liter, 2 ml, 13.92 equivalents) to a solution of compound 26-4 (230 mg, 574.54 micromoles, 1 equivalent) in ethyl acetate (2 ml), and the mixed system Stir at 25 °C for 0.5 h. The reaction solution was directly dried under reduced pressure to obtain the hydrochloride of compound 26-5.
  • Step D To a solution of compound 11-10 (50 mg, 190.67 ⁇ mol, 1 eq) in N,N-dimethylformamide (3 mL) was added N,N-carbonyldiimidazole (37.10 mg, 228.81 ⁇ mol , 1.2 equivalents) and triethylamine (77.18 mg, 762.69 micromoles, 106.16 microliters, 4 equivalents), the mixed system was stirred at 25 degrees Celsius for 1 hour, and then compound 26-5 (64.19 mg, 190.67 micromoles, 1 Equivalent, hydrochloride), the mixed system was stirred at 25 degrees Celsius for 12 hours.
  • N,N-carbonyldiimidazole 37.10 mg, 228.81 ⁇ mol , 1.2 equivalents
  • triethylamine 77.18 mg, 762.69 micromoles, 106.16 microliters, 4 equivalents
  • Compound 26 was detected by SFC [column model: Chiralcel OD-3 50 ⁇ 4.6mm I.D., 3 ⁇ m; mobile phase: phase A is supercritical carbon dioxide, phase B is methanol (0.05% diethylamine); gradient (B%): 5 %-40%] Obtained: the retention time of compound 26 is 1.118min, and the e.e. value is 100%.
  • Step A Add palladium on carbon (0.1 g, 4.00 mmol, 10% purity) to a solution of compound 11-6 (1.7 g, 4.00 mmol, 1 eq) in ethanol (20 ml), and replace it with hydrogen three times. Under the protection of , the mixed system was stirred at 25 °C for 3 hours. The reaction solution was filtered, and the filtrate was collected and concentrated to obtain compound 27-1. MS(ESI)m/z:428.2[M+H + ].
  • Step B To a solution of compound 27-1 (1.68 g, 3.93 mmol, 1 eq) in tetrahydrofuran (20 mL), add diisobutylaluminum hydride (1 mole per liter, 11.79 mL, 3 eq), and the mixture The system was stirred at 0°C for 1 hour. Add saturated sodium potassium tartrate (60 ml) solution to the reaction solution, stir at 25° C.
  • Step C To a solution of compound 27-2 (0.9 g, 2.34 mmol, 1 eq) in DMSO (10 mL) was added 2-iodobenzoic acid (784.73 mg, 2.80 mmol, 1.2 eq), The mixed system was stirred at 60 degrees Celsius for 2 hours, water (50 ml) was added to the reaction solution for dilution, extracted with ethyl acetate (50 ml ⁇ 2), the organic phases were combined, washed with saturated brine (50 ml), and Dry over sodium sulfate, filter, and concentrate the filtrate to give compound 27-3.
  • Step D To a solution of compound 1-13 (467.84 mg, 2.09 mmol, 414.02 ⁇ L, 1 eq) in THF (10 mL) was added lithium chloride (106.16 mg, 2.50 mmol, 51.29 ⁇ L, 1.2 eq) and triethylamine (253.39 mg, 2.50 mmol, 348.54 microliters, 1.2 equivalents), the mixed system was stirred at 0 degrees Celsius for 0.5 hours, and then at 0 degrees Celsius, compound 27-3 (800 mg, 2.09 millimoles, 1 equivalent), the mixed system was reacted at 25 degrees Celsius for 1.5 hours.
  • lithium chloride 106.16 mg, 2.50 mmol, 51.29 ⁇ L, 1.2 eq
  • triethylamine 253.39 mg, 2.50 mmol, 348.54 microliters, 1.2 equivalents
  • Step E To a solution of compound 27-4 (675 mg, 1.49 mmol, 1 eq) in trifluoroacetic acid (10 mL) was added trifluoromethanesulfonic acid (1.70 g, 11.33 mmol, 1 mL, 7.61 eq), The mixed system was stirred for 1 hour at 25°C.
  • Step F To a solution of compound 27-5 (150 mg, 450.04 micromol, 1 equiv) in methanol (2 mL) was added lithium hydroxide monohydrate (37.77 mg, 900.08 micromol, 2 equiv) and water (2 mL) , and the mixed system was stirred at 25 degrees Celsius for 12 hours. Add hydrochloric acid (1 mole per liter) to the reaction solution to adjust the pH to 6, add water (30 ml) to dilute, extract with ethyl acetate (30 ml ⁇ 2), combine the organic phases, wash with saturated brine (30 ml ⁇ 2 ), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 27-6. MS(ESI)m/z:305.9[M+H + ].
  • Step G To a solution of compound 27-6 (50 mg, 163.80 ⁇ mol, 1 eq) in THF (2 mL) was added O-(7-azabenzotriazol-1-yl)-N,N, N, N-tetramethyluronium hexafluorophosphine salt (93.42 mg, 245.70 micromoles, 1.5 equivalents) and triethylamine (66.30 mg, 655.20 micromoles, 91.19 microliters, 5 equivalents), the mixed system was stirred at 25 degrees Celsius 1 hour. Compound 1-11 (44.01 mg, 163.80 micromole, 1 equiv, hydrochloride) was added to the reaction solution, and the mixed system was stirred at 25° C.
  • O-(7-azabenzotriazol-1-yl)-N,N, N, N-tetramethyluronium hexafluorophosphine salt 93.42 mg, 245.70 micromoles, 1.5 equivalents
  • Compound 27 was detected by SFC [column model: (S,S) Whelk-Ol OD-3 100 ⁇ 4.6mm I.D., 3.5 ⁇ m; mobile phase: phase A is supercritical carbon dioxide, phase B is isopropanol (0.05% diethyl alcohol Amine); Gradient (B%): 40%-40%] Obtained: the retention time of compound 27 was 2.457min, and the e.e. value was 96.016%.
  • Step A Compound 1-8 (168.79 mg, 927.74 micromol, 1 equiv) and potassium carbonate were added to a solution of compound 28-1 (200 mg, 927.74 micromol, 1 equiv) in N-methylpyrrolidone (2 mL) (255.61 mg, 1.85 mmol, 2 equivalents), and the mixed system was stirred at 100 degrees Celsius for 2 hours. After the reaction solution was cooled to 25 degrees Celsius, water (20 ml) was added, and the mixture was stirred at 25 degrees Celsius for 10 minutes, and a solid precipitated out, which was filtered to collect the filter cake, and dried under reduced pressure to obtain compound 28-2. MS(ESI)m/z:307.1[M+H + -56].
  • Step B Add ethyl acetate hydrochloride (4 moles per liter, 2 ml) to a solution of 28-2 (360 mg, 993.52 micromoles, 1 eq) in ethyl acetate (2 ml), and the mixed system is heated at 25 degrees Celsius Stir for 1 hour. The reaction solution was directly dried under reduced pressure to obtain the hydrochloride of compound 28-3. MS(ESI)m/z:263.1[M+H + ].
  • Step C Add N,N-carbonyldiimidazole (74.20 mg, 457.61 , 1.2 equivalents) and triethylamine (154.35 mg, 1.53 mmol, 212.31 microliters, 4 equivalents), the mixed system was stirred at 25 degrees Celsius for 1 hour, and then compound 28-3 (136.68 mg, 457.61 micromoles, 1.2 Equivalent, hydrochloride), the mixed system was stirred at 25 degrees Celsius for 11 hours.
  • Step D Compound 28-4 is resolved by chirality (column: Phenomenex-Cellulose-2 (250 mm * 25 mm, 10 microns); mobile phase: [acetonitrile/methanol (0.1% ammonia water)]; methanol %: 40% -40%, 4.5 minutes) to obtain compound 28A and compound 28B.
  • Step A To a solution of compound 29-1 (0.75 g, 3.47 mmol, 1 eq) in N-methylpyrrolidone (10 mL) was added compound 1-8 (632.98 mg, 3.47 mmol, 1 eq) and potassium carbonate (958.56 mg, 6.94 mmol, 2 equivalents), and the mixed system was stirred at 100 degrees Celsius for 2 hours. After the reaction solution was cooled to 25 degrees Celsius, water (50 ml) was added, and a solid precipitated out. The filter cake was collected by filtration and dried under reduced pressure to obtain compound 29-2. MS(ESI)m/z:307.1[M+H + -56].
  • Step B Add ethyl acetate hydrochloride (4 moles per liter, 2 ml) to a solution of 29-2 (540 mg, 1.49 mmol, 1 eq) in ethyl acetate (2 ml), and the mixed system is heated at 25 degrees Celsius Stir for 0.5 hours. The reaction solution was directly dried under reduced pressure to obtain the hydrochloride of compound 29-3. MS(ESI)m/z:263.2[M+H + ].
  • Step C Add N,N-carbonyldiimidazole (111.30 mg, 686.41 , 1.2 equivalents) and triethylamine (231.53 mg, 2.29 mmoles, 318.47 microliters, 4 equivalents), the mixed system was stirred at 25 degrees Celsius for 1 hour, and then compound 29-3 (170.85 mg, 572.01 micromoles, 1 Equivalent, hydrochloride), the mixed system was stirred at 25 degrees Celsius for 12 hours.
  • Step D Compound 29-4 is resolved by chirality (column: DAICEL CHIRALPAK AS (250 mm * 30 mm, 10 microns); mobile phase: [0.1% ammonia isopropanol]; isopropanol %: 30%-30 %, 5.3 minutes) to obtain compound 29A and compound 29B.
  • Step A To a solution of compound 30-1 (2 g, 14.43 mmol, 1 eq) and compound 1-9 (2.69 g, 14.43 mmol, 1 eq) in N,N-dimethylformamide (30 mL) Potassium carbonate (1.99 g, 14.43 mmol, 1 eq) was added to the mixture, and the mixture was stirred at 80°C for 12 hours. After the reaction solution was cooled to room temperature, water (100 ml) was added, and the mixture was stirred at 25 degrees Celsius for 10 minutes, and a solid precipitated out, which was filtered to collect the filter cake, and dried under reduced pressure to obtain compound 30-2. MS(ESI)m/z:233.1[M+H + -56].
  • Step B Add ethyl acetate hydrochloride (4 moles, 10 milliliters, 11.53 equivalents) to a solution of 30-2 (1 gram, 3.47 mmoles, 1 equivalent) in ethyl acetate (10 milliliters), and the mixed system is heated at 25 degrees Celsius Stirring was continued for 0.5 hours. The reaction solution was directly dried under reduced pressure to obtain the hydrochloride of compound 30-3. MS(ESI)m/z:189.2[M+H + ].
  • Step C To a solution of compound 11-8 (100 mg, 379.92 ⁇ mol, 1 eq) in THF (3 mL) was added N,N-carbonyldiimidazole (73.92 mg, 455.90 ⁇ mol, 1.2 eq) and triethylamine (153.77 mg, 1.52 mmol, 211.52 microliters, 4 equivalents), the mixed system was stirred at 40 degrees Celsius for 1 hour, and then compound 30-3 (85.36 mg, 379.92 micromoles, 1 equivalent, hydrochloride) was added, the The mixed system was stirred at 60°C for 24 hours.
  • N,N-carbonyldiimidazole 73.92 mg, 455.90 ⁇ mol, 1.2 eq
  • triethylamine 153.77 mg, 1.52 mmol, 211.52 microliters, 4 equivalents
  • Compound 30 was detected by SFC [column model: Chiralpak IC-3 50 ⁇ 4.6mm I.D, 3 ⁇ m; mobile phase: phase A is supercritical carbon dioxide, phase B is methanol + acetonitrile (0.05% diethylamine); gradient (B%) : 40%-40%] Obtained: the retention time of compound 30 is 1.965min, and the e.e value is 100%.
  • Step A To a solution of compound 1-7 (5 g, 15.69 mmol, 1 eq) in trifluoroacetic acid (30 mL) was added trifluoromethanesulfonic acid (5.10 g, 33.98 mmol, 3 mL, 2.17 eq), The mixed system was stirred at 25 degrees Celsius for 0.5 hours.
  • Step A To a solution of compound 31-2 (10 g, 48.72 mmol, 1 eq) in dimethyl sulfoxide (100 mL) was added 2-iodobenzoic acid (27.29 g, 97.44 mmol, 2 eq), The reaction was stirred at 25°C for 12 hours. Add ethyl acetate (200 ml) and water (200 ml) to the reaction solution and stir for 5 minutes, filter the above mixture, add ethyl acetate (100 ml) to the filtrate for extraction, and wash the organic phase with water (200 ml ⁇ 2) , dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 31-3.
  • 2-iodobenzoic acid 27.29 g, 97.44 mmol, 2 eq
  • Step B To a solution of compound 1-13 (9.49 g, 42.32 mmol, 8.40 mL, 1 eq) in THF (100 mL) was added triethylamine (5.14 g, 50.78 mmol, 7.07 mL, 1.2 eq) and chlorine Lithium chloride (2.15 grams, 50.78 mmoles, 1.04 milliliters, 1.2 equivalents), the mixture was stirred at 25 degrees Celsius for 30 minutes, and compound 31-3 (8.6 grams, 42.32 mmoles, 1 equivalents) in tetrahydrofuran ( 80 ml) solution, the reaction solution was stirred at 25 degrees Celsius for 12 hours.
  • Step C Compound 31-5 (4.6 g, 16.83 mmol, 1 eq) was dissolved in ethyl acetate hydrochloride (40 mL, 4 mol/L), and stirred at 25°C for 15 minutes. The reaction liquid was concentrated to obtain the hydrochloride of compound 31-6.
  • Step D To a solution of compound 31-6 (1 g, 4.77 mmol, 1 eq, hydrochloride salt) and compound 31-1 (946.87 mg, 4.77 mmol, 1 eq) in acetonitrile (20 mL) was added potassium acetate (1.17 g, 11.92 mmol, 2.5 eq), and the reaction was stirred at 25°C for 48 hours.
  • Step E At 0°C, a solution of compound 31-7 (6.67 g, 19.89 mmol, 1 eq) in tetrahydrofuran (50 ml) was replaced with nitrogen three times, and diisobutylaluminum hydride ( 1 mole, 79.58 ml, 4 equivalents), the mixed system was stirred at 0°C for 2 hours.
  • Step F To a solution of compound 31-8 (0.4 g, 1.36 mmol, 1 eq) in THF (10 mL) and N,N-dimethylformamide (5 mL) was added N,N-carbonyldiimidazole (265.42 mg, 1.64 mmol, 1.2 equivalents) and triethylamine (690.14 mg, 6.82 mmoles, 949.30 microliters, 5 equivalents), the mixed system was stirred at 25 degrees Celsius for 1 hour, and then compound 7-3 (369.41 mg, 1.64 mmol, 1.2 equivalents, hydrochloride), the mixed system was stirred at 70 degrees Celsius for 6 hours.
  • N,N-carbonyldiimidazole 265.42 mg, 1.64 mmol, 1.2 equivalents
  • triethylamine 690.14 mg, 6.82 mmoles, 949.30 microliters, 5 equivalents
  • Compound 31 was detected by SFC [column model: Chiralcel OJ-3 50 ⁇ 4.6mm I.D., 3 ⁇ m; mobile phase: phase A is supercritical carbon dioxide, phase B is methanol (0.05% diethylamine); gradient (B%): 5 %-40%] Obtained: the retention time of compound 31 is 1.800min, and the e.e. value is 100.000%.
  • Step A To a solution of compound 1-9 (500 mg, 2.68 mmol, 1 eq) and compound 32-1 (449.53 mg, 3.22 mmol, 1.2 eq) in N,N-dimethylformamide (5 ml) Potassium carbonate (742.06 mg, 5.37 mmol, 2 eq) was added to the mixture, and the reaction solution was heated to 80°C and stirred for 1 hour. Water (15 ml) was added to the reaction solution, the reaction solution was stirred at 25°C for 15 minutes, the reaction solution was filtered, and the filter cake was concentrated under reduced pressure to obtain compound 32-2. MS (ESI) m/z: 234.1 [M+H + -56].
  • Step B add compound 32-2 (400 mg, 1.38 mmol, 1 equivalent) and ethyl acetate (2 milliliters), ethyl acetate hydrochloride (2 milliliters, 4 moles per liter, 5.79 equivalents) to the reaction flask, the The reaction solution was stirred at 25°C for 12 hours. The reaction solution was concentrated to obtain the hydrochloride of compound 32-3. MS (ESI) m/z: 190.1 [M+H + ].
  • Step C To a solution of compound 11-8 (100 mg, 379.92 ⁇ mol, 1 eq) in THF (3 mL) was added N,N-carbonyldiimidazole (80.08 mg, 493.89 ⁇ mol, 1.3 eq) and triethylamine (192.22 mg, 1.90 mmol, 264.40 microliters, 5 equivalents), the mixture was stirred at 60 degrees Celsius for 1 hour, after the detection reaction was completed, compound 32-4 was directly used in the next step without post-treatment.
  • N,N-carbonyldiimidazole 80.08 mg, 493.89 ⁇ mol, 1.3 eq
  • triethylamine (192.22 mg, 1.90 mmol, 264.40 microliters, 5 equivalents
  • Step D Compound 32-3 (102.89 mg, 455.90 micromoles, 1.2 equiv, hydrochloride) was added to compound 32-4 (135.74 mg, 379.92 micromoles, 1 equiv, tetrahydrofuran solution), and the reaction solution was heated at 60 degrees Celsius Stir for 12 hours.
  • the reaction solution was poured into water (10 ml), extracted with ethyl acetate (10 ml ⁇ 3), the organic phases were combined, washed with saturated brine (10 ml ⁇ 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated.
  • Compound 32 was detected by SFC [column model: Chiralcel OJ-3 50*4.6mm I.D., 3 microns; mobile phase: phase A is supercritical carbon dioxide, phase B is methanol (0.05% DEA); gradient (B%): 5% -40%] Obtained: the retention time of compound 32 is 1.748min, and the e.e. value is 95.128%.
  • Step A To a solution of compound 1-8 (546.83 mg, 3.00 mmol, 1.2 eq) and compound 33-1 (500 mg, 2.50 mmol, 1 eq) in N,N-dimethylformamide (5 mL) Potassium carbonate (690.07 mg, 4.99 mmol, 2 eq) was added to the mixture, and the reaction solution was heated to 80°C and stirred for 1 hour. Water (15 ml) was added to the reaction solution, the reaction solution was stirred at 25°C for 15 minutes, the reaction solution was filtered, and the filter cake was concentrated under reduced pressure to obtain compound 33-2. MS (ESI) m/z: 291.1 [M+H + -56].
  • Step B Add compound 33-2 (786 mg, 2.27 mmol, 1 equivalent) and ethyl acetate (4 milliliters), ethyl acetate hydrochloride (4 milliliters, 4 moles per liter, 7.05 equivalents) to the reaction flask, the The reaction solution was stirred at 25°C for 12 hours. The reaction solution was concentrated to obtain the hydrochloride of compound 33-3. MS (ESI) m/z: 247.1 [M+H + ].
  • Step C To a solution of compound 11-8 (200 mg, 759.83 ⁇ mol, 1 eq) in THF (5 mL) was added N,N-carbonyldiimidazole (160.17 mg, 987.78 ⁇ mol, 1.3 eq) and triethylamine (384.44 mg, 3.80 mmol, 528.80 microliters, 5 equivalents), the mixture was stirred at 60° C. for 1 hour, and after the detection reaction was completed, compound 32-4 was directly used in the next step without post-treatment.
  • N,N-carbonyldiimidazole 160.17 mg, 987.78 ⁇ mol, 1.3 eq
  • triethylamine 384.44 mg, 3.80 mmol, 528.80 microliters, 5 equivalents
  • Step D Add compound 33-3 (257.76 mg, 911.80 micromole, 1.2 eq, hydrochloride salt) to compound 32-4 (271.48 mg, 759.84 micromole, 1 eq, tetrahydrofuran solution), and heat the reaction solution at 60°C Stir for 12 hours.
  • the reaction solution was poured into water (10 ml), extracted with ethyl acetate (10 ml ⁇ 3), the organic phases were combined, washed with saturated brine (10 ml ⁇ 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated.
  • Compound 33 was detected by SFC [column model: Chiralpak AD-3 50*4.6mm I.D., 3 microns; mobile phase: phase A is supercritical carbon dioxide, phase B is methanol (0.05% DEA); gradient (B%): 5% -40%] Obtained: the retention time of compound 33 is 1.892min, and the e.e. value is 97.612%;
  • Step A To a solution of compound 31-8 (2 g, 6.82 mmol, 1 eq) in THF (20 mL) and N,N-dimethylformamide (10 mL) was added N,N'-carbonyldiimidazole (1.33 grams, 8.18 mmol, 1.2 equivalents) and triethylamine (3.45 grams, 34.10 mmoles, 4.75 milliliters, 5 equivalents), the mixed system was stirred at 25 degrees Celsius for 1 hour, and then compound 8-3 (1.79 grams , 8.18 mmol, 1.2 equivalents, hydrochloride), the mixed system was stirred at 60 degrees Celsius for 3 hours.
  • Compound 34 was detected by SFC [column model: Chiralpak IG-3 50 ⁇ 4.6mm ID, 3 ⁇ m; mobile phase: A The phase is supercritical carbon dioxide, and the phase B is methanol+acetonitrile (0.05% diethylamine); gradient (B%): 40%-40%] Obtained: the retention time of compound 34 is 1.316min, and the ee value is 100.000%.
  • Step A To a solution of compound 31-8 (300 mg, 1.02 mmol, 1 eq) in dichloromethane (10 mL) was added triethylamine (155.28 mg, 1.53 mmol, 213.59 ⁇ l, 1.5 eq) and compound 12-4 (247.45mg, 1.23mmol, 1.2eq), the mixture was stirred at 25°C for 12 hours. The reaction solution was directly spin-dried to obtain compound 35-1. MS(ESI)m/z:459.1[M+H + ].
  • Step B To a solution of compound 35-2 (500.00 mg, 2.50 mmol, 1 eq) in N,N-dimethylformamide (10 mL) was added potassium carbonate (345.04 mg, 2.50 mmol, 1 eq) and Compound 7-1 (348.37 mg, 2.50 mmol, 1 equivalent), the mixed system was stirred at 80 degrees Celsius for 12 hours. The reaction solution was cooled to 25 degrees Celsius, and water (50 ml) was added, and a yellow solid precipitated out. After filtration, the filter cake was collected and dried under reduced pressure to obtain compound 35-3. MS(ESI)m/z:204.2[M+H + -100].
  • Step C Add ethyl acetate hydrochloride (4 moles, 5 milliliters, 12.38 equivalents) to a solution of compound 35-3 (490 mg, 1.62 mmol, 1 equivalent) in ethyl acetate (5 milliliters), and the reaction solution was obtained at 25 Stir for 12 hours at °C. The reaction solution was concentrated to obtain the hydrochloride of compound 35-4. MS(ESI)m/z:204.2[M+H + ].
  • Step D N, N-dimethylformamide ( 5 ml) solution was added triethylamine (88.31 mg, 872.70 micromoles, 121.47 microliters, 2 equivalents), and the mixture was stirred at 25 degrees Celsius for 12 hours.
  • the reaction solution was diluted with water (30 ml), extracted with ethyl acetate (30 ml ⁇ 2), the organic phases were combined, washed with saturated brine (30 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated.
  • Compound 35 was detected by SFC [column model: Chiralcel OJ-3 50 ⁇ 4.6mm I.D., 3 ⁇ m; mobile phase: phase A is supercritical carbon dioxide, phase B is ethanol (0.05% diethylamine); gradient (B%): 5 %-40%] Obtained: the retention time of compound 35 is 1.681min, and the e.e. value is 100.000%.
  • Step A To a solution of compound 36-2 (600.00 mg, 3.00 mmol, 1 eq) in N,N-dimethylformamide (10 mL) was added potassium carbonate (414.04 mg, 3.00 mmol, 1 eq) and Compound 7-1 (418.05 mg, 3.00 mmol, 1 equivalent), the mixed system was stirred at 80°C for 12 hours. The reaction liquid was cooled to 25 degrees Celsius, and water (80 ml) was added, and a solid precipitated out, filtered, and the filter cake was collected, and dried under reduced pressure to obtain compound 36-3. MS(ESI)m/z:204.2[M+H + -100].
  • Step B Add ethyl acetate hydrochloride (4 moles, 7 milliliters, 11.48 equivalents) to a solution of compound 36-3 (740 mg, 2.44 mmol, 1 equivalent) in ethyl acetate (7 milliliters), and the reaction solution was obtained at 25 Stir for 12 hours at °C. The reaction solution was concentrated to obtain the hydrochloride of compound 36-4. MS(ESI)m/z:204.3[M+H + ].
  • Step C N, N-dimethylformamide ( 5 ml) solution was added triethylamine (88.31 mg, 872.71 micromoles, 121.47 microliters, 2 equivalents), and the mixture was stirred at 25°C for 12 hours.
  • the reaction solution was diluted with water (30 ml), extracted with ethyl acetate (30 ml ⁇ 2), the organic phases were combined, washed with saturated brine (30 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated.
  • Compound 36 was detected by SFC [column model: Chiralcel OJ-3 50 ⁇ 4.6mm I.D., 3 ⁇ m; mobile phase: phase A is supercritical carbon dioxide, phase B is ethanol (0.05% diethylamine); gradient (B%): 5 %-40%] Obtained: the retention time of compound 36 is 1.744min, and the e.e. value is 100.000%.
  • Step A Lithium chloride (2.74 g, 64.59 mmol, 1.32 mL, 2.5 eq) was dissolved in acetonitrile (40 mL), and compound 37-2 (5.02 g, 25.84 mmol, 1 equivalent) and N,N-diisopropylethylamine (8.35 grams, 64.59 mmoles, 2.5 equivalents), after stirring for 0.5 hours, compound 37-1 (3 grams, 25.84 mmoles, 1 equivalents) in acetonitrile ( 40 ml) solution was added to the above solution, and the temperature was kept at 25 degrees Celsius to continue stirring for 2.5 hours.
  • Step B Compound 37-3 (1.7 g, 10.88 mmol, 1 eq) was dissolved in THF (20 mL) and water (20 mL), and lithium hydroxide monohydrate (593.75 mg, 14.15 mmol, 1.3 eq ), and the reaction solution was stirred at room temperature for 1 hour. After the reaction was completed, the pH of the reaction solution was adjusted to 5 with hydrochloric acid (2 mol per liter), and the aqueous phase was extracted with ethyl acetate (50 ml ⁇ 4). The organic phases were combined, washed with saturated brine (60 ml ⁇ 2), dried over anhydrous sodium sulfate, filtered and spin-dried to obtain compound 37-4.
  • Step C Add compound 7-3 (1.19 g, 5.28 mmol, 1 eq, hydrochloride) to a solution of compound 37-4 (750 mg, 5.28 mmol, 1 eq) in THF (30 mL), O- (7-Azabenzotriazole-1-YL)-N,N,N,N-tetramethyluronium hexafluorophosphine salt (2.21 g, 5.8 mmol, 1.1 equiv.) and N,N-diiso Propylethylamine (1.7 g, 13.19 mmol, 2.3 mL, 2.5 equiv), and the mixture was stirred at 25°C for 16 hours.
  • Step D To a solution of compound 37-5 (0.5 g, 1.58 mmol, 1 eq) in THF (10 mL) was added tetraethyl titanate (1.81 g, 7.92 mmol, 1.64 mL, 5 eq) and compound 37 -6 (958.36 mg, 7.92 mmol, 5 equivalents), the mixed system was stirred at 70 degrees Celsius for 48 hours under nitrogen protection.
  • Step E To a solution of compound 37-7 (0.5 g, 1.2 mmol, 1 eq) in dichloromethane (10 mL) was slowly added sodium cyanoborohydride (75.43 mg, 1.2 mmol, 1 eq. ) and acetic acid (36.04 mg, 600.18 micromoles, 34.33 microliters, 0.5 equivalents), the mixed system was stirred at 0 degrees Celsius for 1 hour.
  • Step F To a solution of compound 37-8 (30 mg, 71.68 ⁇ mol, 1 eq) in ethyl acetate (3 mL) was added hydrochloric acid in ethyl acetate (4 moles per liter, 1.5 mL, 83.71 eq), and the mixture The system was stirred at 25°C for 1 hour. After the reaction was completed, it was concentrated and spin-dried to obtain the hydrochloride of compound 37-9. MS(ESI)m/z:298.1[M+H + -16].
  • Step G To a solution of compound 31-1 (12.81 mg, 64.55 ⁇ mol, 1 eq) in acetonitrile (3 mL) was added compound 37-9 (25 mg, 64.55 ⁇ mol, 1 eq, 2 hydrochloride) and carbonic acid Sodium hydrogen (16.27 mg, 193.65 micromole, 7.53 microliter, 3 equivalents), the mixed system was stirred at 25 degrees Celsius for 16 hours.
  • Step A To a solution of compound 38-1 (0.25 g, 1.62 mmol, 1 eq) in N,N-dimethylformamide (20 mL) was added potassium carbonate (447.00 mg, 3.23 mmol, 2 eq) and Compound 1-9 (301.19 mg, 1.62 mmol, 1 eq), the mixed system was stirred at 100°C for 24 hours. The reaction liquid was cooled to 25 degrees Celsius, poured into water (100 ml), a white solid was precipitated, filtered, the filter cake was collected, and concentrated under reduced pressure to obtain compound 38-2. MS(ESI)m/z:249.2[M+H + -56].
  • Step B Add ethyl acetate hydrochloride (4 moles, 5 milliliters, 16.91 equivalents) to a solution of compound 38-2 (360 mg, 1.18 mmoles, 1 equivalent) in ethyl acetate (5 milliliters), and the reaction solution was obtained at 25 Stir for 2 hours at °C. The reaction solution was concentrated to obtain the hydrochloride of compound 38-3. MS(ESI)m/z:205.3[M+H + ].
  • Step C To a solution of compound 31-8 (80 mg, 272.81 ⁇ mol, 1 eq) in THF (2 mL) and N,N-dimethylformamide (2 mL) was added N,N-carbonyldiimidazole (53.08 mg, 327.37 micromoles, 1.2 equivalents) and triethylamine (138.03 mgs, 1.36 mmoles, 189.86 microliters, 5 equivalents), the mixed system was stirred at 25 degrees Celsius for 2 hours, and then compound 38-3 (78.81 mg , 327.37 micromoles, 1.2 equivalents, hydrochloride), the mixed system was stirred at 60 degrees Celsius for 12 hours.
  • N,N-carbonyldiimidazole 53.08 mg, 327.37 micromoles, 1.2 equivalents
  • triethylamine 138.03 mgs, 1.36 mmoles, 189.86 microliters, 5 equivalents
  • reaction solution was diluted with water (30 ml), extracted with ethyl acetate (30 ml ⁇ 2), the organic phases were combined, washed with saturated brine (30 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. Purified by liquid chromatography (column: Phenomenex luna C18 150*25 mm*10 microns; mobile phase: [water (formic acid)-acetonitrile]; acetonitrile %: 42%-72%, 10 minutes) to obtain compound 38. MS(ESI)m/z:524.3[M+H + ].
  • Compound 38 was detected by SFC [column model: Chiralcel OJ-3 50 ⁇ 4.6mm I.D., 3 ⁇ m; mobile phase: phase A is supercritical carbon dioxide, phase B is isopropanol (0.05% diethylamine); gradient (B%) : 5%-40%] Obtained: the retention time of compound 38 is 1.922min, and the e.e. value is 100.000%.
  • Step A Add potassium carbonate (1.04 g, 7.54 mmol, 1 eq) and Compound 35-2 (755.05 mg, 3.77 mmol, 1 eq), the mixed system was stirred at 80°C for 12 hours.
  • the reaction solution was cooled to 25 degrees Celsius, the reaction solution was diluted with water (30 ml), extracted with ethyl acetate (30 ml ⁇ 2), the organic phases were combined, washed with saturated brine (30 ml), dried over anhydrous sodium sulfate, and filtered.
  • Step B Add ethyl acetate hydrochloride (4 moles, 8 milliliters, 11.03 equivalents) to a solution of compound 39-1 (860 mg, 2.90 mmoles, 1 equivalent) in ethyl acetate (8 milliliters), and the reaction solution was obtained at 25 Stir for 4 hours at °C. The reaction solution was concentrated to obtain the hydrochloride of compound 39-2. MS(ESI)m/z:197.2[M+H + ].
  • Step C N, N-dimethylformamide ( 5 ml) solution was added triethylamine (88.31 mg, 872.70 micromoles, 121.47 microliters, 2 equivalents), and the mixture was stirred at 25 degrees Celsius for 12 hours.
  • the reaction solution was diluted with water (30 ml), extracted with ethyl acetate (30 ml ⁇ 2), the organic phases were combined, washed with saturated brine (30 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated.
  • Compound 39 was detected by SFC [column model: Chiralcel OJ-3 50 ⁇ 4.6mm I.D., 3 ⁇ m; mobile phase: phase A is supercritical carbon dioxide, phase B is ethanol (0.05% diethylamine); gradient (B%): 5 %-40%] Obtained: the retention time of compound 39 is 1.420min, and the e.e. value is 100.000%.
  • Step A Add 40-1 (1 gram, 4.29 mmol, 1 equivalent) of tetrahydrofuran (5 mL) solution, and the mixed system was stirred at 0°C for 2 hours. After detecting the completion of the reaction, slowly add methanol (10 ml) to the reaction solution with stirring at 0°C until no gas is released, add ethyl acetate (100 ml) to dilute, wash with 1 mole per liter of hydrochloric acid (30 ml), and then wash with saturated It was washed with brine (10 ml ⁇ 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude compound 40-2, which was directly used in the next reaction.
  • Step B Add Dess-Martin oxidant (1.32 g, 3.10 mmol, 1 eq) in portions to a solution of 40-2 (0.68 g, 3.10 mmol, 1 eq. ). The mixed system was stirred at 25°C for 12 hours. After detecting the completion of the reaction, the reaction solution was concentrated to dryness, and the residue was subjected to silica gel column chromatography (silica 1000 mesh silica gel, eluent gradient ethyl acetate/petroleum ether 10/1 to 2/1) to obtain compound 40-3 .
  • Step C Add compound 1-13 (846.15 mg, 3.77 mmol, 2 eq) and diisopropylethylamine (731.69 mg, 5.66 mmol, 3 eq) in acetonitrile (10 mL) at 0°C Lithium chloride (240.01 mg, 5.66 mmol, 3 equiv) was added, and the mixture was stirred at 0°C for half an hour. Then a solution of 40-3 (0.41 g, 1.89 mmol, 1 eq) in acetonitrile (3 mL) was added dropwise to the above reaction solution. The reaction mixture was stirred at 25 °C for 12 hours.
  • Step D Compound 40-4 (0.32 g, 1.11 mmol, 1 eq) was stirred in methanolic hydrogen chloride solution (4 mol/L, 5 mL, 20 mmol, 17.96 eq) at 0°C for 2 hours. Concentrate to obtain crude compound 40-5.
  • Step E Compound 40-5 (0.208 g, 1.11 mmol, 1 eq), compound 31-1 (0.15 g, 755.55 ⁇ mol, 0.68 eq) and sodium bicarbonate (373.29 mg, 4.44 mmol, 4 eq) in in acetonitrile (8 mL), stirred at 25°C for 12 hours.
  • Step F To compound 40-6 (0.155 g, 0.444 mmol, 1 equiv) in THF (8 mL) was slowly added dropwise diisobutylaluminum hydride (1 mol per liter, 1.77 mL, 4 equivalent) solution, the mixed system was stirred at 0°C for 3 hours.
  • Step G To a solution of compound 40-7 (36.00 mg, 117.16 micromol, 1 equiv) in THF (5 mL) was added N,N'-carbonyldiimidazole (28.5 mg, 175.74 micromol, 1.5 equiv) and triethyl Amine (59.28 mg, 0.586 mmol, 5 equiv), the mixture was stirred at 25°C for 12 hours.
  • Compound 7-3 52.88mg, 0.234mmol, 2eq, hydrochloride was added to the above reaction solution, and the mixed system was stirred at 25°C for 12 hours.
  • Compound 40 was detected by SFC [column model: Chiralcel OJ-3 50 ⁇ 4.6mm ID, 3 ⁇ m; mobile phase: phase A is supercritical carbon dioxide , Phase B is methanol (0.05% diethylamine); gradient (B%): 5%-40%] Obtained: the retention time of compound 40 is 1.741min, and the ee value is 92.500%.
  • Step A Add 41-1 (2.8 g, 12.89 mmol, 1 eq) in tetrahydrofuran (10 mL) solution, the mixed system was stirred at 0-10 degrees Celsius for 2 hours. Detect that the reaction is complete, slowly add methanol (30 milliliters) to the reaction solution under stirring at 0 degrees Celsius until no gas is released, add ethyl acetate (100 milliliters) to dilute, wash with 1 mole per liter of hydrochloric acid (50 milliliters), and then use The mixture was washed with saturated sodium carbonate (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude compound 41-2, which was directly used in the next reaction.
  • Step B To a solution of 41-2 (2.1 g, 10.33 mmol, 1 eq) in dichloromethane (20 mL) was added portionwise the Dess-Martin oxidant (4.47 g, 10.54 ). The mixed system was stirred at 25°C for 12 hours. After detecting the completion of the reaction, the reaction solution was concentrated to dryness, and the residue was subjected to silica gel column chromatography (silica 1000 mesh silica gel, eluent gradient ethyl acetate/petroleum ether 10/1 to 2/1) to obtain compound 41-3 .
  • Step C To a solution of compound 1-13 (3.41 g, 15.20 mmol, 2 eq) and lithium chloride (966.75 mg, 22.81 mmol, 3 eq) in acetonitrile (20 mL) at 0 °C was added N, N-Diisopropylethylamine (2.95 g, 22.81 mmol, 3 equivalents), the mixed system was stirred at 0°C for half an hour. Then a solution of 41-3 (1.53 g, 7.60 mmol, 1 eq) in acetonitrile (3 mL) was added dropwise to the above reaction solution. The reaction mixture was stirred at 25 °C for 12 hours.
  • Step D Compound 41-4 (700 mg, 2.58 mmol, 1 equivalent) in methanolic hydrogen chloride solution (4 moles per liter, 30 mL, 20 mmol, 46.52 equivalents) and stirred at 25°C for 2 hours. It was detected that the reaction was complete, and concentrated to obtain the crude compound 41-5.
  • Step E Compound 41-5 (0.44 g, 2.57 mmol, 1 eq), compound 31-1 (0.46 g, 755.55 ⁇ mol, 0.9 eq) and sodium bicarbonate (647.58 mg, 7.71 mmol, 3 eq) in in acetonitrile (10 mL), stirred at 25°C for 12 hours.
  • Step F To compound 41-6 (0.57 g, 1.71 mmol, 1 equiv) in THF (15 mL) was slowly added dropwise diisobutylaluminum hydride (1 mol per liter, 6.84 mL, 4 equivalent) solution, the mixed system was stirred at 0°C for 3 hours.
  • Step G To a solution of compound 41-7 (0.288 g, 0.985 mmol, 1 eq) in THF (10 mL) was added N,N-carbonyldiimidazole (239.66 mg, 1.48 mmol, 1.5 eq) and triethylamine (498.54 mg, 4.93 mmol, 5 equivalents), and the mixed system was stirred at 25° C. for 1 hour.
  • Compound 7-3 (0.445 g, 1.97 mmol, 2 eq, hydrochloride) was added to the above reaction solution, and the mixed system was stirred at 25 degrees Celsius for 12 hours.
  • Compound 41 was detected by SFC [column model: Chiralcel OJ-3 50 ⁇ 4.6mm I.D., 3 ⁇ m; mobile phase: phase A is supercritical carbon dioxide, phase B is methanol (0.05% diethylamine); gradient (B%): 5 %-40%] Obtained: the retention time of compound 41 is 1.682min, and the e.e. value is 100.000%.
  • Step A To a solution of compound 42-1 (10 g, 112.19 mmol, 1 eq) in THF (30 mL) and water (30 mL) was added potassium carbonate (31.01 g, 224.38 mmol, 2 eq) and dicarbonic acid Di-tert-butyl ester (25.71 g, 117.80 mmol, 27.06 ml, 1.05 equiv), and the mixture was stirred at 25°C for 12 hours. The reaction solution was extracted with ethyl acetate (100 mL ⁇ 2), the organic phases were combined, washed with saturated brine (30 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 42-2.
  • potassium carbonate 31.01 g, 224.38 mmol, 2 eq
  • dicarbonic acid Di-tert-butyl ester 25.71 g, 117.80 mmol, 27.06 ml, 1.05 equi
  • Step B To a solution of compound 42-2 (21.20 g, 112.02 mmol, 1 equiv) in dichloromethane (200 mL) at 0 °C was added Dess-Martin oxidant (46.56 g, 109.78 mmol, 33.99 mL, 0.98 equivalent), the mixture was stirred at 25 degrees Celsius for 2 hours. Add saturated sodium thiosulfate solution (100 ml) to the reaction solution to quench, stir for 10 minutes, extract with ethyl acetate (300 ml), wash the organic phase with saturated brine (100 ml), and dry over anhydrous sodium sulfate.
  • Dess-Martin oxidant 46.56 g, 109.78 mmol, 33.99 mL, 0.98 equivalent
  • Step C To a solution of compound 42-3 (19.45 g, 103.88 mmol, 1 eq) and lithium chloride (13.21 g, 311.64 mmol, 6.38 mL, 3 eq) in acetonitrile (100 mL) at 0 °C was added N,N-diisopropylethylamine (40.28 grams, 311.64 mmol, 54.28 milliliters, 3 equivalents), the mixture was stirred at 0 degrees Celsius for 30 minutes, and then compound 1-13 (46.58 grams, 207.76 millimoles, 41.22 milliliters, 2 equivalents) in acetonitrile (20 milliliters) solution, the mixture was naturally warmed to 25 degrees Celsius, and stirred for 12 hours.
  • N,N-diisopropylethylamine 40.28 grams, 311.64 mmol, 54.28 milliliters, 3 equivalents
  • Step D To compound 42-4 ((22.18 g, 86.19 mmol, 1 eq) in THF (200 mL) was added diisobutylaluminum hydride (1 mole per liter, 258.58 mL, 3 eq. ), the reaction solution was stirred at 0 degrees Celsius for 3 hours. In the reaction solution, an aqueous solution (60 milliliters) of saturated sodium potassium tartrate was added dropwise, and the temperature was maintained at 0 degrees Celsius during the dropwise addition, and then naturally warmed to 25 degrees Celsius and stirred for 12 hours.
  • diisobutylaluminum hydride 1 mole per liter, 258.58 mL, 3 eq.
  • Step F Sodium cyanide (0.63 g, 12.86 mmol, 1.79 eq) was added to a solution of compound 42-6 (2 g, 7.19 mmol, 1 eq) in dimethyl sulfoxide (20 ml), and the reaction solution Heated to 100 degrees Celsius for 5 hours. The reaction solution was cooled to 25° C., water (50 ml) was added, and stirred for 5 minutes.
  • Step G Compound 42-7 (350 mg, 1.56 mmol, 1 equiv) was added to methanol hydrochloride (4 moles per liter, 10 ml), and stirred at 25°C for 2 hours. The reaction solution was concentrated to obtain compound 42-8.
  • Step H Compound 42-8 (0.302 g, 1.56 mmol, 1 eq, hydrochloride salt), 1-7 (496.93 mg, 1.56 mmol, 1 eq) and sodium bicarbonate (524.00 mg, 6.24 mmol, 242.59 ⁇ l, 4 equivalents) was added to acetonitrile (10 ml), and the mixture was stirred at 25°C for 12 hours.
  • Step I Trifluoromethanesulfonic acid (0.6 mL) was added to a solution of compound 42-9 (0.173 g, 393.69 ⁇ mol, 1 eq) in trifluoroacetic acid (3 mL), and the reaction solution was stirred at 25°C for 2 hours. The reaction liquid was concentrated to obtain the crude product compound 42-10. MS(ESI)m/z:320.0[M+H + ].
  • Step J To a solution of compound 42-10 (125 mg, 391.51 micromol, 1 eq) in methanol (5 mL) and water (5 mL) was added lithium hydroxide (93.76 mg, 3.92 mmol, 10 eq), the The reaction solution was stirred at 25°C for 12 hours. The pH of the reaction solution was adjusted to 3 with hydrochloric acid, extracted with ethyl acetate (80 ml), washed with saturated brine (30 ml), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 42-11. MS(ESI)m/z:306.1[M+H + ].
  • Step K To a solution of compound 42-11 (0.12 g, 393.121 ⁇ mol, 1 eq) in N,N-dimethylformamide (3 mL) was added O-(7-azabenzotriazole-1 -yl) N,N,N,N-Tetramethyluronium hexafluorophosphate (298.95 mg, 786.23 micromoles, 2 equivalents) and N,N-diisopropylethylamine (254.04 mg, 1.97 mmoles, 342.37 microliters, 5 equivalents), then compound 7-3 (148.77 mg, 786.23 micromoles, 2 equivalents) was added, and the reaction solution was stirred at 25 degrees Celsius for 12 hours.
  • O-(7-azabenzotriazole-1 -yl) N,N,N,N-Tetramethyluronium hexafluorophosphate 298.95 mg, 786.23 micromoles, 2 equivalents
  • Step A To a solution of compound 11-8 (300 mg, 1.14 mmol, 1 eq) in dichloromethane (6 mL) was added N-methylmorpholine (172.93 mg, 1.71 ) and compound 12-4 (275.68 mg, 1.37 mmol, 1.2 equivalents), the mixed system was stirred at 25 degrees Celsius for 12 hours.
  • Step A To a solution of compound 43-2 (2 g, 9.33 mmol, 1 eq) in N,N-dimethylformamide (50 mL) was added potassium carbonate (1.93 g, 14.00 mmol, 1.5 eq) and Compound 7-1 (1.82 g, 13.07 mmol, 1.4 eq), the mixed system was stirred at 80°C for 12 hours. The reaction liquid was cooled to 25 degrees Celsius, and water (200 ml) was added, and a white solid was precipitated, filtered, and the filter cake was collected, and concentrated under reduced pressure to obtain compound 43-3. MS(ESI)m/z:218.2[M+H + -100].
  • Step B To a solution of compound 43-3 (2.4 g, 7.56 mmol, 1 eq) in ethyl acetate (25 mL) was added ethyl acetate hydrochloride (4 moles per liter, 25 mL, 13.22 eq), the reaction solution Stir for 1 hour at 25°C. The reaction solution was concentrated to obtain the hydrochloride of compound 43-4. MS(ESI)m/z:218.1[M+H + ].
  • Step C N, N-dimethylformamide ( 30 ml) solution was added triethylamine (602.43 mg, 5.95 mmol, 828.65 ⁇ l, 1.5 eq), and the mixture was stirred at 25°C for 12 hours.
  • reaction solution was diluted with water (100 ml), extracted with ethyl acetate (100 ml ⁇ 2), the organic phases were combined, washed with saturated brine (100 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and the obtained crude product was passed through a column Purification by chromatography (silica gel column, eluent gradient 0-100% petroleum ether/ethyl acetate, 80 ml/min) gave compound 43. MS(ESI)m/z:507.2[M+H + ].
  • Compound 43 was detected by SFC [column model: Chiralpak IC-3 50 ⁇ 4.6mm I.D., 3 ⁇ m; mobile phase: phase A is supercritical carbon dioxide, phase B is methanol + acetonitrile (0.05% diethylamine); gradient (B%) : 50%-50%] Obtained: the retention time of compound 43 is 0.893min, and the e.e. value is 95.318%.
  • Step A Add compound 44-1 (300 mg, 1.61 mmol, 1 eq) and compound 7-1 (269.72 mg, 1.93 mmol, 1.2 eq) in N,N-dimethylformamide (5 mL) Potassium carbonate (333.92 mg, 2.42 mmol, 1.5 equivalents) was added to the mixture, and the mixture was stirred at 90°C for 2 hours. The reaction liquid was cooled to 25 degrees Celsius, and water (50 ml) was added, and a white solid was precipitated, filtered, and the filter cake was collected, and concentrated under reduced pressure to obtain compound 44-2. MS(ESI)m/z:234.1[M+H + -56].
  • Step B To a solution of compound 44-2 (155 mg, 535.72 micromoles, 1 eq) in ethyl acetate (2 ml) was added ethyl acetate hydrochloride (4 moles per liter, 2 ml, 14.93 eq), the reaction solution Stir for 2 hours at 25°C. The reaction solution was concentrated to obtain the hydrochloride of compound 44-3. MS(ESI)m/z:190.1[M+H + ].
  • Step C N, N-dimethylformamide ( 5 mL) solution was added triethylamine (56.05 mg, 553.89 micromole, 77.09 microliter, 1.5 equiv), and the mixture was stirred at 25°C for 12 hours.
  • the reaction solution was diluted with water (50 ml), extracted with ethyl acetate (50 ml ⁇ 2), the organic phases were combined, washed with saturated brine (50 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated.
  • Compound 44 was detected by SFC [column model: Chiralpak IC-3 50 ⁇ 4.6mm I.D., 3 ⁇ m; mobile phase: phase A is supercritical carbon dioxide, phase B is methanol + acetonitrile (0.05% diethylamine); gradient (B%) : 40%-40%] Obtained: the retention time of compound 44 is 1.340min, and the e.e. value is 100.000%.
  • This assay is used to examine the potency of compounds to inhibit PARP7 enzymatic activity, where lower IC50 values indicate high potency of compounds as PARP7 inhibitors in the following assay settings.
  • PARP7 Chemiluminescent Detection Kit was purchased from BPS Bioscience.
  • PBST buffer preparation 1X PBS contains 0.05% Tween-20, that is, add 5 ⁇ L 100% Tween-20 to 10mL PBS
  • Compound solution preparation the compound to be tested was diluted 5 times with 100% DMSO to the 8th concentration, that is, diluted from 1000 ⁇ M to 12.8 nM. Then use 1 times the test buffer to dilute each compound to be tested into a 10% DMSO working solution, add 2.5 ⁇ L/well to a microwell plate, and set up a double-well experiment.
  • the reaction system is incubated at 25°C for 60 minutes;
  • the compound of the present invention has excellent in vitro inhibitory activity on PARP7.
  • RPMI-1640 medium penicillin/streptomycin antibiotics were purchased from Vicente, and fetal bovine serum was purchased from Biosera.
  • CellTiter-Glo Cell Viability Chemiluminescence Detection Reagent
  • NCI-H1373 cell line was purchased from Nanjing Kebai Biotechnology Co., Ltd. Nivo Multilabel Analyzer (PerkinElmer).
  • the H1373 cells were seeded in a white 96-well plate, 80 ⁇ L of cell suspension per well, which contained 3000 H1373 cells. Cell plates were cultured overnight in a carbon dioxide incubator.
  • the compound to be tested was diluted 5 times to the 9th concentration with a row gun, that is, diluted from 2mM to 5.12nM, and a double-well experiment was set up.
  • Compound concentrations transferred to cell plates ranged from 10 [mu]M to 0.0256 nM.
  • Cell plates were cultured in a carbon dioxide incubator for 6 days. Another cell plate was prepared, and the signal value was read as the maximum value on the day of drug addition to participate in data analysis.
  • Table 2 provides the inhibitory activity of the compounds of the present invention on the proliferation of H1373 cells.
  • the compound of the present invention has excellent anti-proliferation activity of H1373.
  • RPMI-1640 medium was purchased from Viva cell, fetal bovine serum was purchased from Biosera, RNA extraction, reverse transcription and qPCR reagents were purchased from Novozyme.
  • the CT26 cell line was purchased from the Cell Bank of the Chinese Academy of Sciences. Quantstuio 6 fluorescence quantitative PCR (Thermo fisher).
  • the CT26 cells were seeded in a 24-well plate, with 400 ⁇ L of cell suspension per well, which contained 200,000 CT26 cells. Cell plates were cultured overnight in a carbon dioxide incubator.
  • the compound to be tested was diluted 3 times to the 8th concentration, that is, diluted from 200 ⁇ M to 914.5 nM. Add 156 ⁇ L of medium to the middle plate, then transfer 4 ⁇ L of each well of the gradient dilution compound to the middle plate according to the corresponding position, transfer 100 ⁇ L of each well to the cell plate after mixing. Compound concentrations transferred to cell plates ranged from 10 [mu]M to 4.57 nM. Cell plates were cultured in a carbon dioxide incubator for 24 hours.
  • RNA extraction reagent remove the medium in the cell plate, add 500 ⁇ L of RNA extraction reagent per well to the cell plate, and extract RNA according to the instructions. 1 ⁇ g of RNA was used for reverse transcription to obtain cDNA, and the cDNA solution was diluted 1:4, and 2 ⁇ L per well was added to the qPCR reaction.
  • the original CT value data is converted into relative expression data, and the EC 50 value can be obtained by curve fitting with four parameters.
  • Table 3 provides the inducing activity of the compounds of the present invention on CT26 CXCL10 mRNA expression.
  • the compound of the present invention can induce the expression of CXCL10 mRNA in CT26 cells.
  • PARP1 Chemiluminescent Detection Kit was purchased from BPS Bioscience; EnVision Multilabel Analyzer (PerkinElmer).
  • PBST buffer preparation 1X PBS contains 0.05% Tween-20, that is, add 5 ⁇ L 100% Tween-20 to 10mL PBS
  • Compound solution preparation the compound to be tested was diluted 4 times with 100% DMSO to the 8th concentration, that is, diluted from 200 ⁇ M to 120 nM. Then use 1X test buffer to dilute each gradient of the compound to be tested into a working solution with 10% DMSO.
  • the compound of the present invention has high selectivity to PARP1.
  • RPMI-1640 medium, fetal bovine serum, and penicillin/streptomycin antibiotics were purchased from Vicente.
  • the MDA-MB-436 cell line was purchased from the Cell Bank of the Chinese Academy of Sciences. Envision Multilabel Analyzer (PerkinElmer).
  • the MDA-MB-436 cells were seeded in a white 96-well plate, 80 ⁇ L of cell suspension per well, which contained 3000 MDA-MB-436 cells. Cell plates were cultured overnight in a carbon dioxide incubator.
  • the compound to be tested was diluted 5 times to the 8th concentration with a row gun, that is, diluted from 2mM to 26nM, and a double-well experiment was set up.
  • Cell plates were cultured in a carbon dioxide incubator for 7 days. Another cell plate was prepared, and the signal value was read on the day of drug addition as the Max value to participate in data analysis.
  • Add 25 ⁇ L Promega CellTiter-Glo to each well of the cell plate and incubate at room temperature for 10 minutes to stabilize the luminescent signal. Reads were performed using a PerkinElmer Envision Multilabel Analyzer.
  • Table 6 provides the inhibitory activity of the compounds of the present invention on the proliferation of MDA-MB-436 cells.
  • the compound of the present invention has no obvious inhibitory effect on the antiproliferative activity of MDA-MB-436.
  • DMEM medium was purchased from Viva cell. Hela cells were purchased from Nanjing Kebai. Poly/Mono-ADP Ribose (E6F6A) Rabbit mAb was purchased from CST. Fluorescein(FITC)-conjugated Affinipure Goat Anti-Rabbit IgG(H+L) was purchased from Wuhan Sanying. Hydrogen peroxide was purchased from Aladdin. DAPI was purchased from Aladdin. PBS was purchased from Vicente. Methanol was purchased from Sinopharm. Acetone was purchased from Sinopharm. Tween-20 was purchased from Sinopharm. Skimmed milk powder was purchased from Yili. Envision Multilabel Analyzer (PerkinElmer).
  • the H1373 cells were seeded in a white 96-well plate, 80 ⁇ L of cell suspension per well, which contained 3000 H1373 cells. Cell plates were cultured overnight in a carbon dioxide incubator.
  • Hela cells were plated according to 60000 cells/well, 37 degrees, 5% CO 2 , overnight.
  • Washing solution Add Tween-20 to 1X PBS, the final concentration of Tween-20 is 0.05%.
  • Blocking solution Add skimmed milk powder to the washing solution, the final concentration of skimmed milk powder is 5%.
  • Cell fixative Mix methanol and acetone at a ratio of 7:3.
  • the compound to be tested was diluted 5-fold to the 8th concentration, that is, from 1 mM to 13 nM, and the DMSO concentration was 100%.
  • Negative control and positive control add 1% DMSO
  • Negative control well add 25 ⁇ L/well blocking solution
  • Blank control well add 25 ⁇ L/well blocking solution
  • FITC Excitation 480nm, Emission 530nm
  • DAPI Excitation 360nm, Emission 460nm.
  • the original data is normalized, and the normalized data is converted into an inhibition rate, and the value of IC 50 can be obtained by curve fitting with four parameters.
  • Table 6 provides the inhibitory activity of compounds of the invention.
  • the compound of the present invention has weak inhibitory effect on PARYlation in Hela cells and good selectivity.
  • the purpose of this experiment is to evaluate the pharmacokinetic behavior of the compound after a single intravenous injection and intragastric administration, and to investigate the bioavailability after intragastric administration.
  • the animals in the intravenous group were given the corresponding compound through a single injection of the tail vein, and the administration volume was 5 ml/kg; the animals in the oral group were given the corresponding compound through a single gavage, and the administration volume was 10 ml/kg.
  • the animals were weighed before administration, and the administration volume was calculated according to the body weight.
  • Sample collection time 0.083 hours, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours, 24 hours for the injection group, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 24 hours.
  • the compounds of the present invention have excellent pharmacokinetic properties.
  • the compound of the present invention has excellent AUC and bioavailability after oral administration in mice, and has good pharmacokinetic properties.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

一系列哒嗪酮类化合物及其药学上可接受的盐，及其在制备治疗相关疾病的药物中的应用，具体公开了式(IV)化合物及其药学上可接受的盐。

Description

哒嗪酮类化合物
本申请主张如下优先权：
CN202110827385.9，申请日2021年07月21日；
CN202110872908.1，申请日2021年07月30日；
CN202111509969.8，申请日2021年12月10日；
CN202210399423.X，申请日2022年04月15日；
CN202210730508.1，申请日2022年06月24日。
技术领域
本发明公开了一系列哒嗪酮类化合物，及其在制备治疗相关疾病的药物中的应用。
背景技术
腺苷二磷酸核糖基化(ADP-ribosylation)是蛋白质的一种可逆的转录后修饰过程，参与调节体内多种生物过程，包括转录调控、mRNA稳定性、细胞分裂和蛋白质降解等，在维持基因的稳定性和细胞凋亡等方面发挥着重要的作用。聚腺苷二磷酸核糖聚合酶家族(PARPs)，也被称作腺苷二磷酸核糖转移酶(ART)，是目前研究最多的腺苷二磷酸核糖基转移酶。目前发现人类表达17种PARP家族蛋白，即PARP1-17。依据其结构和功能的不同，PARP家族成员可分为三种不同的类型：能够转移多个ADP-核糖的polyPARPs，只能转移一个单ADP-核糖的monoPARPs和缺乏活性的。
PARP7属于monoPARPs家族，已经确认的PARP7的底物包含Aryl hydrocarbon receptor(AhR)及TANK Binding Kinase 1(TBK1)；PARP7通过ADP核糖基化来抑制这些底物活性。研究表明，PARP7在众多癌症中均高表达，许多癌症细胞的存活都要依赖PARP7来实现，抑制PARP7能够抑制癌细胞的生长。另一方面，PARP7与癌细胞的免疫逃逸有关，抑制PARP7可重新激活TBK1，恢复胞内核酸感应通路活性，从而诱导I型IFN的表达与合成。升高的I型IFN水平可阻止肿瘤细胞增殖并诱导更强的抗肿瘤免疫反应。
Ribon公司开发的RBN-2397是目前在临床I期的PARP7小分子抑制剂，临床前研究表明，RBN-2397对多种肿瘤细胞的增殖均有明显抑制，同时在小鼠免疫模型中展现出了明确的药效。
综上，靶向PARP7的小分子抑制剂能够成为一种进步的癌症治疗方案。
发明内容
本发明提供式(IV)化合物或其药学上可接受的盐
Figure PCTCN2022107127-appb-000001
其中，
环A选自4-10元杂环烷基和C 4-10环烷基，所述4-10元杂环烷基和C 4-10环烷基分别独立地任选被1、2或3个R a取代；
R a分别独立地选自H、CN、OH、F、Cl、Br、-COOH、-CONH 2、C 1-3烷基、C 1-3烷氨基和C 1-3烷氧基，所述-COOH、-CONH 2、C 1-3烷基、C 1-3烷氨基和C 1-3烷氧基分别独立地任选被1、2或3个R取代；环B选自5-6元杂芳基；
L 5选自单键、-O-、-S-和-NR 1-；
R 1分别独立地选自H、D、-C 1-3烷基-OH、-C 1-3烷基-NH 2和C 1-3烷基，所述-C 1-3烷基-OH、-C 1-3烷基-NH 2和C 1-3烷基任选被1、2或3个R b取代；
R b分别独立地选自H、F、Cl、Br、D和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R取代；
L 2和L 4分别独立地选自单键、-CH 2-、-CH 2-CH 2-和-CH 2-CH 2-CH 2-，所述-CH 2-、-CH 2-CH 2-和-CH 2-CH 2-CH 2-分别独立地任选被1或2个R c取代；
R c分别独立地选自H、F、Cl、Br、D、C 1-3烷基、-O-C 1-3烷基和-C 1-3烷基-O-C 1-3烷基，所述C 1-3烷基分别独立地任选被1、2或3个R取代；
R 2a和R 2b分别独立地选自H、F、Cl、Br、D和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R取代；
L 1选自单键、-CH 2-、-O-、-C(＝O)-、-C(＝O)-NR 4-和-NR 4-；
L 3选自单键、-CH 2-、-O-、-C(＝O)-、-C(＝O)-NR 4-和-NR 4-；
R 4选自H、D和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R取代；
R 3分别独立地选自H、CN、OH、F、Cl、Br、-COOH、-CONH 2、C 1-3烷基、C 1-3烷氨基、C 1-3烷氧基和C 3-6环烷基，所述-COOH、-CONH 2、C 1-3烷基、C 1-3烷氨基、C 1-3烷氧基和C 3-6环烷基分别独立地任选被1、2或3个R取代；
各R分别独立地选自D、OH、CN、F、Cl和Br；
n选自1、2和3；
所述4-10元杂环烷基分别独立包含1、2或3个选自N、O、S和NH的杂原子或杂原子团。
在本发明的一些方案中，上述化合物选自
Figure PCTCN2022107127-appb-000002
其中，
环A选自4-10元杂环烷基和C 4-10环烷基，所述4-10元杂环烷基和C 4-10环烷基分别独立地任选被1、2或3个R a取代；
R a分别独立地选自H、CN、OH、F、Cl、Br、-COOH、-CONH 2、C 1-3烷基、C 1-3烷氨基和C 1-3烷氧基，所述-COOH、-CONH 2、C 1-3烷基、C 1-3烷氨基和C 1-3烷氧基分别独立地任选被1、2或3个R取代；环B选自5-6元杂芳基；
L 5选自单键、-O-、-S-和-NR 1-；
R 1分别独立地选自H、D、-C 1-3烷基-OH、-C 1-3烷基-NH 2和C 1-3烷基，所述-C 1-3烷基-OH、-C 1-3烷基-NH 2和C 1-3烷基任选被1、2或3个R b取代；
R b分别独立地选自H、F、Cl、Br、D和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R取代；
L 2和L 4分别独立地选自单键、-CH 2-、-CH 2-CH 2-和-CH 2-CH 2-CH 2-，所述-CH 2-分别独立地任选被1或2个R c取代；
R c分别独立地选自H、F、Cl、Br、D、C 1-3烷基、-O-C 1-3烷基和-C 1-3烷基-O-C 1-3烷基，所述C 1-3烷基分别独立地任选被1、2或3个R取代；
R 2a和R 2b分别独立地选自H、F、Cl、Br、D和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R取代；
L 1选自单键、-O-、-C(＝O)-、-C(＝O)-NH-和-NR 4-；
L 3选自单键、-O-、-C(＝O)-、-C(＝O)-NH-和-NR 4-；
R 4选自H、D和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R取代；
R 3分别独立地选自H、CN、OH、F、Cl、Br、-COOH、-CONH 2、C 1-3烷基、C 1-3烷氨基和C 1-3烷氧基，所述-COOH、-CONH 2、C 1-3烷基、C 1-3烷氨基和C 1-3烷氧基分别独立地任选被1、2或3个R取代；各R分别独立地选自D、OH、CN、F、Cl和Br；
n选自1、2和3；
所述4-10元杂环烷基分别独立包含1、2或3个选自N、O、S和NH的杂原子或杂原子团。
在本发明的一些方案中，上述化合物选自
Figure PCTCN2022107127-appb-000003
其中，n、环A、环B、L 1、L 2、L 3、L 4、L 5、R 2a、R 2b和R 3如本发明所定义。
在本发明的一些方案中，上述化合物选自
Figure PCTCN2022107127-appb-000004
其中，n、环A、环B、L 1、L 2、L 3、R 2a、R 2b、R 3如本发明所定义。
带“*”碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在。
在本发明的一些方案中，上述化合物选自
Figure PCTCN2022107127-appb-000005
其中，n、环A、环B、L 1、L 2、L 3、L 4、L 5、R a、R 2a、R 2b和R 3如权利要求1所定义。
在本发明的一些方案中，上述化合物选自
Figure PCTCN2022107127-appb-000006
其中，
X为-O-，-CH 2-、-NH-或-N(CH 3)-；
Y为N，Z为CH；或者，Y为CH，Z为N；
环C选自4-10元杂环烷基，所述4-10元杂环烷基任选被1、2或3个R a取代；
p为1或2；
n、环A、环B、L 1、L 2、L 3、R 2a、R 2b、Rc、R 3如本发明所定义；
带“*”碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在。
在本发明的一些方案中，上述化合物选自
Figure PCTCN2022107127-appb-000007
其中，
环A选自4-10元杂环烷基和C 4-10环烷基，所述4-10元杂环烷基和C 4-10环烷基分别独立地任选被1、2或3个R a取代；
R a分别独立地选自H、CN、OH、F、Cl、Br、-COOH、-CONH 2、C 1-3烷基、C 1-3烷氨基和C 1-3烷氧基，所述-COOH、-CONH 2、C 1-3烷基、C 1-3烷氨基和C 1-3烷氧基分别独立地任选被1、2或3个R取代；环B选自5-6元杂芳基；
L 5选自单键、-O-、-S-和-NR 1-；
R 1分别独立地选自H、D、-C 1-3烷基-OH、-C 1-3烷基-NH 2和C 1-3烷基，所述-C 1-3烷基-OH、-C 1-3烷基-NH 2和C 1-3烷基任选被1、2或3个R b取代；
R b分别独立地选自H、F、Cl、Br、D和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R取代；
L 2和L 4分别独立地选自单键、-CH 2-、-CH 2-CH 2-和-CH 2-CH 2-CH 2-，所述-CH 2-分别独立地任选被1或2个R c取代；
R c分别独立地选自H、F、Cl、Br、D和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R取代；
R 2a和R 2b分别独立地选自H、F、Cl、Br、D和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R取代；
L 1选自单键、-O-、-C(＝O)-和-NR 4-；
L 3选自单键、-O-、-C(＝O)-和-NR 4-；
R 4选自H、D和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R取代；
R 3分别独立地选自H、CN、OH、F、Cl、Br、-COOH、-CONH 2、C 1-3烷基、C 1-3烷氨基和C 1-3烷氧基，所述-COOH、-CONH 2、C 1-3烷基、C 1-3烷氨基和C 1-3烷氧基分别独立地任选被1、2或3个R取代；各R分别独立地选自D、OH、CN、F、Cl和Br；
所述4-10元杂环烷基分别独立包含1、2或3个选自N、O、S和NH的杂原子或杂原子团。
在本发明的一些方案中，上述化合物或其药学上可接受的盐，其中，化合物选自
Figure PCTCN2022107127-appb-000008
其中，环A、环B、L 1、L 2、L 3、L 4、L 5、R 2a、R 2b和R 3如本发明所定义。
在本发明的一些方案中，上述化合物或其药学上可接受的盐，其中，化合物选自
Figure PCTCN2022107127-appb-000009
其中，环A、环B、L 1、L 2、L 3、R 2a、R 2b、R 3如本发明所定义；
带“*”碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在。
在本发明的一些方案中，上述环A选自氮杂环丁烷基、哌啶基、哌嗪基、1,4-二氮杂环己烷基、3,8-二氮杂双环[3.2.1]辛烷基和2,5-二氮杂双环[2.2.2]辛烷基所述氮杂环丁烷基、哌啶基、哌嗪基、1,4-二氮杂环己烷基、3,8-二氮杂双环[3.2.1]辛烷基和2,5-二氮杂双环[2.2.2]辛烷基分别独立地任选被1、2或3个R a取代，其他变量如本发明所定义。
在本发明的一些方案中，上述环A选自哌啶基、哌嗪基、1,4-二氮杂环己烷基、3,8-二氮杂双环[3.2.1]辛烷基和2,5-二氮杂双环[2.2.2]辛烷基，其他变量如本发明所定义。
在本发明的一些方案中，上述环B选自嘧啶基、吡啶基、哒嗪基、吡唑基、噻吩基和噻唑基，其他变量如本发明所定义。
在本发明的一些方案中，上述环B选自嘧啶基、吡啶基、哒嗪基、吡唑基和噻唑基，其他变量如本发明所定义。
在本发明的一些方案中，上述化合物或其药学上可接受的盐，其中，环B选自嘧啶基和噻唑基，其他变量如本发明所定义。
在本发明的一些方案中，上述L 5选自-NH-，其他变量如本发明所定义。
在本发明的一些方案中，上述L 4选自-CH(CH 3)-、-CH(CH 2OCH 3)-、-CH(CH 3)CH 2CH 2-、-CH(CH 3)CH 2-、-CH(CH 2CH 2CH 3)-、-CH(CH 2CH 2OCH 3)-和-CH(CH 2OH)-，其他变量如本发明所定义。
在本发明的一些方案中，上述L 4选自-CH(CH 3)-、-CH(CH 2OCH 3)-和-CH(CH 2OH)-，其他变量如本发明所定义。在本发明的一些方案中，上述化合物或其药学上可接受的盐，其中，L 4选自-CH(CH 3)-，其他变量如本发明所定义。
在本发明的一些方案中，上述R 2a和R 2b分别独立地选自H和F，其他变量如本发明所定义。
在本发明的一些方案中，上述L 1选-C(＝O)、-CH 2-、-C(＝O)-NH-和-C(＝O)-N(CH 3)-，其他变量如本发明所定义。
在本发明的一些方案中，上述L 1选-C(＝O)、-CH 2-和-C(＝O)-NH-，其他变量如本发明所定义。
在本发明的一些方案中，上述化合物或其药学上可接受的盐，其中，L 1选-C(＝O)，其他变量如本发明所定义。
在本发明的一些方案中，上述L 3选自单键、-CH 2-、-O-、-NH-和-N(CH 3)-，其他变量如本发明所定义。
在本发明的一些方案中，上述L 3选自-O-、-NH-和-N(CH 3)-，其他变量如本发明所定义。在本发明的一些方案中，上述化合物或其药学上可接受的盐，其中，L 3选自-O-和-NH-，其他变量如本发明所定义。
在本发明的一些方案中，上述L 2选自-CH 2-和单键，其他变量如本发明所定义。
在本发明的一些方案中，上述化合物或其药学上可接受的盐，其中，L 2选自-CH 2-，其他变量如本发明所定义。
在本发明的一些方案中，上述结构单元
Figure PCTCN2022107127-appb-000010
选自
Figure PCTCN2022107127-appb-000011
Figure PCTCN2022107127-appb-000012
Figure PCTCN2022107127-appb-000013
其他变量如本发明所定义。
在本发明的一些方案中，上述结构单元
Figure PCTCN2022107127-appb-000014
选自
Figure PCTCN2022107127-appb-000015
Figure PCTCN2022107127-appb-000016
Figure PCTCN2022107127-appb-000017
其他变量如本发明所定义。在本发明的一些方案中，上述化合物或其药学上可接受的盐，其中，结构单元
Figure PCTCN2022107127-appb-000018
选自
Figure PCTCN2022107127-appb-000019
其他变量如本发明所定义。
在本发明的一些方案中，上述结构单元
Figure PCTCN2022107127-appb-000020
选自
Figure PCTCN2022107127-appb-000021
Figure PCTCN2022107127-appb-000022
其他变量如本发明所定义。
在本发明的一些方案中，上述结构单元
Figure PCTCN2022107127-appb-000023
选自
Figure PCTCN2022107127-appb-000024
Figure PCTCN2022107127-appb-000025
Figure PCTCN2022107127-appb-000026
Figure PCTCN2022107127-appb-000027
其他变量如本发明所定义。
在本发明的一些方案中，上述化合物或其药学上可接受的盐，其中，结构单元
Figure PCTCN2022107127-appb-000028
选自
Figure PCTCN2022107127-appb-000029
Figure PCTCN2022107127-appb-000030
其他变量如本发明所定义。
本发明提供下式化合物或其药学上可接受的盐：
Figure PCTCN2022107127-appb-000031
Figure PCTCN2022107127-appb-000032
Figure PCTCN2022107127-appb-000033
Figure PCTCN2022107127-appb-000034
在本发明的一些方案中，上述化合物选自
Figure PCTCN2022107127-appb-000035
Figure PCTCN2022107127-appb-000036
Figure PCTCN2022107127-appb-000037
Figure PCTCN2022107127-appb-000038
Figure PCTCN2022107127-appb-000039
本发明还有一些方案是由上述各变量任意组合而来。
本发明还提供上述化合物或其药学上可接受的盐在制备PARP7抑制剂中的应用。
技术效果
本发明提供了一种新型的PARP7抑制剂。本发明分子对PARP7具有较好的体外抑制活性和选择性，有望提供一种新的、更有效的治疗癌症的方案。
定义和说明
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。
这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物接触的方式获得碱加成盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物接触的方式获得酸加成盐。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。
除非另有规定，术语“有效量”或“治疗有效量”是指无毒的但能达到预期效果的用量。有效量的确定因人而异，取决于受体的年龄和一般情况，也取决于具体的活性物质，个案中合适的有效量可以由本领域技术人员根据常规试验确定。
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。
除非另有说明，术语“对映异构体”或者“旋光异构体”是指互为镜像关系的立体异构体。
除非另有说明，术语“顺反异构体”或者“几何异构体”系由因双键或者成环碳原子单键不能自由旋转而引起。
除非另有说明，术语“非对映异构体”是指分子具有两个或多个手性中心，并且分子间为非镜像的关系的立体异构体。
除非另有说明，“(+)”表示右旋，“(-)”表示左旋，“(±)”表示外消旋。
除非另有说明，用楔形实线键
Figure PCTCN2022107127-appb-000040
和楔形虚线键
Figure PCTCN2022107127-appb-000041
表示一个立体中心的绝对构型，用直形实线键
Figure PCTCN2022107127-appb-000042
和直形虚线键
Figure PCTCN2022107127-appb-000043
表示立体中心的相对构型，用波浪线
Figure PCTCN2022107127-appb-000044
表示楔形实线键
Figure PCTCN2022107127-appb-000045
或楔形虚线键
Figure PCTCN2022107127-appb-000046
或用波浪线
Figure PCTCN2022107127-appb-000047
表示直形实线键
Figure PCTCN2022107127-appb-000048
或直形虚线键
Figure PCTCN2022107127-appb-000049
除非另有说明，术语“互变异构体”或“互变异构体形式”是指在室温下，不同官能团异构体处于动态平衡，并能很快的相互转化。若互变异构体是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(proton tautomer)(也称质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。价键异构体(valence tautomer)包括一些成键电子的重组来进行的相互转化。其中酮-烯醇互变异构化的具体实例是戊烷-2,4-二酮与4-羟基戊-3-烯-2-酮两个互变异构体之间的互变。
除非另有说明，术语“富含一种异构体”、“异构体富集”、“富含一种对映体”或者“对映体富集”指其中一种异构体或对映体的含量小于100％，并且，该异构体或对映体的含量大于等于60％，或者大于等于70％，或者大于等于80％，或者大于等于90％，或者大于等于95％，或者大于等于96％，或者大于等于97％，或者大于等于98％，或者大于等于99％，或者大于等于99.5％，或者大于等于99.6％，或者大于等于99.7％，或者大于等于99.8％，或者大于等于99.9％。
除非另有说明，术语“异构体过量”或“对映体过量”指两种异构体或两种对映体相对百分数之间的差值。例如，其中一种异构体或对映体的含量为90％，另一种异构体或对映体的含量为10％，则异构体或对映体过量(ee值)为80％。
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚( 3H)，碘-125( 125I)或C-14( 14C)。又例如，可用重氢取代氢形成氘代药物，氘与碳构成的键比普通氢与碳构成的键更坚固，相比于未氘化药物，氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。
术语“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中 所述事件或状况发生的情况以及所述事件或状况不发生的情况。
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，取代基可以包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧(即＝O)时，意味着两个氢原子被取代。
术语“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
当一个连接基团的数量为0时，比如-(CRR) 0-，表示该连接基团为单键，-C 0烷基-A表示该结构实际上是-A。
当一个取代基数量为0时，表示该取代基是不存在的，比如-A-(R) 0表示该结构实际上是-A。
当一个取代基为空缺时，表示该取代基是不存在的，比如A-X中X为空缺时表示该结构实际上是A。
当其中一个变量选自单键时，表示其连接的两个基团直接相连，比如A-L-Z中L代表单键时表示该结构实际上是A-Z。
当一个取代基为空缺时，表示该取代基是不存在的，比如A-X中X为空缺时表示该结构实际上是A。
当所列举的取代基中没有指明其通过哪一个原子连接到被取代的基团上时，这种取代基可以通过其任何原子相键合，例如，吡啶基作为取代基可以通过吡啶环上任意一个碳原子连接到被取代的基团上。
当一个取代基的键可以交叉连接到一个环上的两一个以上原子时，这种取代基可以与这个环上的任意原子相键合，例如，结构单元
Figure PCTCN2022107127-appb-000050
表示其取代基R可在环己基或者环己二烯上的任意一个位置发生取代。
当所列举的连接基团没有指明其连接方向，其连接方向是任意的，例如，
Figure PCTCN2022107127-appb-000051
中连接基团L为-M-W-，此时-M-W-既可以按与从左往右的读取顺序相同的方向连接环A和环B构成
Figure PCTCN2022107127-appb-000052
也可以按照与从左往右的读取顺序相反的方向连接环A和环B构成
Figure PCTCN2022107127-appb-000053
所述连接基团、取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
除非另有规定，当某一基团具有一个或多个可连接位点时，该基团的任意一个或多个位点可以通过 化学键与其他基团相连。当该化学键的连接方式是不定位的，且可连接位点存在H原子时，则连接化学键时，该位点的H原子的个数会随所连接化学键的个数而对应减少变成相应价数的基团。所述位点与其他基团连接的化学键可以用直形实线键
Figure PCTCN2022107127-appb-000054
直形虚线键
Figure PCTCN2022107127-appb-000055
或波浪线
Figure PCTCN2022107127-appb-000056
表示。例如-OCH 3中的直形实线键表示通过该基团中的氧原子与其他基团相连；
Figure PCTCN2022107127-appb-000057
中的直形虚线键表示通过该基团中的氮原子的两端与其他基团相连；
Figure PCTCN2022107127-appb-000058
中的波浪线表示通过该苯基基团中的1和2位碳原子与其他基团相连；
Figure PCTCN2022107127-appb-000059
表示该哌啶基上的任意可连接位点可以通过1个化学键与其他基团相连，至少包括
Figure PCTCN2022107127-appb-000060
这4种连接方式，即使-N-上画出了H原子，但是
Figure PCTCN2022107127-appb-000061
仍包括
Figure PCTCN2022107127-appb-000062
这种连接方式的基团，只是在连接1个化学键时，该位点的H会对应减少1个变成相应的一价哌啶基。
除非另有规定，术语“C 1-3烷基”用于表示直链或支链的由1至3个碳原子组成的饱和碳氢基团。所述C 1-3烷基包括C 1-2和C 2-3烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C 1-3烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)等。
除非另有规定，“C 4-8环烷基”表示由4至8个碳原子组成的饱和环状碳氢基团，其包括单环和双环体系，其中双环体系包括螺环、并环和桥环。所述C 4-8环烷基包括C 4-5、C 4-6、C 4-7、C 5-6、C 5-7、C 5-8、C 6- 7、C 6-8、C 7-8、C 4、C 5、C 6、C 7、C 8环烷基等；其可以是一价、二价或者多价。C 4-8环烷基的实例包括，但不限于，环丁基、环戊基、环己基、环庚基、降冰片烷基、[2.2.2]二环辛烷等。
除非另有规定，术语“4-10元杂环烷基”本身或者与其他术语联合分别表示由4至10个环原子组成的饱和环状基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子，其中氮原子任选地被季铵化，碳、氮和硫杂原子可任选被氧化(即C(＝O)、NO和S(O)p，p是1或2)。其包括单环和双环体系，其中双环体系包括螺环、并环和桥环，也包括其中一个环为芳香环的情形。此外，就该“4-8元杂环烷基”而言，杂原子可以占据杂环烷基与分子其余部分的连接位置。所述4-8元杂环烷基包括4-6元、4-7元、4-8元、5-6元、5-7元、5-8元、6-7元、6-8元、7-8元、4元、5元、6元、7元、8元、9元、10元杂环烷基等。4-10元杂环烷基的实例包括但不限于氮杂环丁基、氧杂环丁基、硫杂环丁基、吡咯烷基、吡唑烷基、咪唑烷基、四氢噻吩基(包括四氢噻吩-2-基和四氢噻吩-3-基等)、四氢呋喃基(包括四氢呋喃-2-基等)、四氢吡喃基、哌啶基(包括1-哌啶基、2-哌啶基和3-哌啶基等)、哌嗪基(包括1-哌嗪基和2-哌嗪基等)、吗啉基(包括3-吗啉基和4-吗啉基等)、二噁烷基、二噻烷基、异噁唑烷基、异噻唑烷基、1,2-噁嗪基、1,2-噻嗪基、六氢哒嗪基、高哌嗪基、高哌啶基或二氧杂环庚烷基等。
除非另有规定，本发明术语“5-6元杂芳环”和“5-6元杂芳基”可以互换使用，术语“5-6元杂芳基”表示由5至6个环原子组成的具有共轭π电子体系的单环基团，其1、2、3或4个环原子为独立选自O、 S和N的杂原子，其余为碳原子，其中氮原子任选地被季铵化，碳、氮和硫杂原子可任选被氧化(即C(＝O)、NO和S(O)p，p是1或2)。5-6元杂芳基可通过杂原子或碳原子连接到分子的其余部分。所述5-6元杂芳基包括5元和6元杂芳基。所述5-6元杂芳基的实例包括但不限于吡咯基(包括N-吡咯基、2-吡咯基和3-吡咯基等)、吡唑基(包括2-吡唑基和3-吡唑基等)、咪唑基(包括N-咪唑基、2-咪唑基、4-咪唑基和5-咪唑基等)、噁唑基(包括2-噁唑基、4-噁唑基和5-噁唑基等)、三唑基(1H-1,2,3-三唑基、2H-1,2,3-三唑基、1H-1,2,4-三唑基和4H-1,2,4-三唑基等)、四唑基、异噁唑基(3-异噁唑基、4-异噁唑基和5-异噁唑基等)、噻唑基(包括2-噻唑基、4-噻唑基和5-噻唑基等)、呋喃基(包括2-呋喃基和3-呋喃基等)、噻吩基(包括2-噻吩基和3-噻吩基等)、吡啶基(包括2-吡啶基、3-吡啶基和4-吡啶基等)、吡嗪基或嘧啶基(包括2-嘧啶基和4-嘧啶基等)。
除非另有规定，“C 3-10环烷基”表示由4至10个碳原子组成的饱和环状碳氢基团，其包括单环、双环和三环体系，其中双环和三环体系包括螺环、并环和桥环。所述C 3-10环烷基包括C 4-8、C 4-6、C 4-5、C 4-10、C 4-6、C 4-5、C 5-8或C 5-6等；其可以是一价、二价或者多价。C 4-10环烷基的实例包括，但不限于，环丁基、环戊基、环己基、环庚基、降冰片烷基、[2.2.2]二环辛烷、[4.4.0]二环癸烷等。
除非另有规定，术语“C 1-3烷氧基”表示通过一个氧原子连接到分子的其余部分的那些包含1至3个碳原子的烷基基团。所述C 1-3烷氧基包括C 1-2、C 2-3、C 3和C 2烷氧基等。C 1-3烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基(包括正丙氧基和异丙氧基)等。
除非另有规定，术语“C 1-3烷氨基”表示通过氨基连接到分子的其余部分的那些包含1至3个碳原子的烷基基团。所述C 1-3烷氨基包括C 1-2、C 3和C 2烷氨基等。C 1-3烷氨基的实例包括但不限于-NHCH 3、-N(CH 3) 2、-NHCH 2CH 3、-N(CH 3)CH 2CH 3、-NHCH 2CH 2CH 3、-NHCH 2(CH 3) 2等。
除非另有规定，术语“C 1-3烷硫基”表示通过硫原子连接到分子的其余部分的那些包含1至3个碳原子的烷基基团。所述C 1-3烷硫基包括C 1-3、C 1-2和C 3烷硫基等。C 1-3烷硫基的实例包括但不限于-SCH 3、-SCH 2CH 3、-SCH 2CH 2CH 3、-SCH 2(CH 3) 2等。
除非另有规定，术语“卤代素”或“卤素”本身或作为另一取代基的一部分表示氟、氯、溴或碘原子。
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。
本发明的化合物可以通过本领域技术人员所熟知的常规方法来确认结构，如果本发明涉及化合物的绝对构型，则该绝对构型可以通过本领域常规技术手段予以确证。例如单晶X射线衍射法(SXRD)，把培养出的单晶用Bruker D8 venture衍射仪收集衍射强度数据，光源为CuKα辐射，扫描方式：
Figure PCTCN2022107127-appb-000063
扫描，收集相关数据后，进一步采用直接法(Shelxs97)解析晶体结构，便可以确证绝对构型。
本发明所使用的溶剂可经市售获得。
本发明采用下述缩略词：aq代表水；HATU代表O-(7-氮杂苯并三唑-1-基)-N，N，N'，N'-四甲基脲六氟磷酸盐；EDC代表N-(3-二甲基氨基丙基)-N'-乙基碳二亚胺盐酸盐；m-CPBA代表3-氯过氧苯甲酸；eq代表当量、等量；CDI代表羰基二咪唑；DCM代表二氯甲烷；PE代表石油醚；DIAD代表偶氮二羧酸二异丙酯；DMF代表N，N-二甲基甲酰胺；DMSO代表二甲亚砜；EtOAc代表乙酸乙酯； EtOH代表乙醇；MeOH代表甲醇；CBz代表苄氧羰基，是一种胺保护基团；BOC代表叔丁氧羰基是一种胺保护基团；HOAc代表乙酸；NaCNBH 3代表氰基硼氢化钠；r.t.代表室温；O/N代表过夜；THF代表四氢呋喃；Boc 2O代表二-叔丁基二碳酸酯；TFA代表三氟乙酸；DIPEA代表二异丙基乙基胺；SOCl 2代表氯化亚砜；CS 2代表二硫化碳；TsOH代表对甲苯磺酸；NFSI代表N-氟-N-(苯磺酰基)苯磺酰胺；NCS代表1-氯吡咯烷-2,5-二酮；n-Bu 4NF代表氟化四丁基铵；iPrOH代表2-丙醇；mp代表熔点；LDA代表二异丙基胺基锂。
化合物依据本领域常规命名原则或者使用
Figure PCTCN2022107127-appb-000064
软件命名，市售化合物采用供应商目录名称。
具体实施方式
下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。
实施例1
Figure PCTCN2022107127-appb-000065
步骤A：在0～10摄氏度，向化合物1-1(60克，236.33毫摩尔，1当量)的N,N-二甲基甲酰胺(500毫升)溶液中分批缓慢加入钠氢(11.34克，283.60毫摩尔，60％纯度，1.2当量)，然后加入对甲氧基苄氯(44.41克，283.60毫摩尔，38.62毫升，1.2当量)，该混合体系在25摄氏度搅拌6小时。搅拌下，向反应液中缓慢加入饱和氯化铵水溶液至无气体放出，将上述混合液过滤，滤饼用水(3毫升×2)洗涤，滤饼减压干燥得到化合物1-2。 1H NMR(400MHz,DMSO-d 6)δppm 8.15(s,1H),7.27-7.25(m,2H),6.90-6.87(m,2H),5.18(s,2H),3.72(s,3H)。MS(ESI)m/z:374.8[M+H +]。
步骤B：向化合物1-2(75克，200.52毫摩尔，1当量)的甲醇(750毫升)溶液中加入氢氧化钾(33.75克，601.56毫摩尔，3当量)，该混合体系在25摄氏度搅拌6小时。将反应液浓缩至100～150毫升，将上述液体过滤，收集滤饼。将上述滤饼加入到水(500毫升)中，在25摄氏度搅拌30分钟，过滤，滤饼减压干燥得到化合物1-3。 1H NMR(400MHz,DMSO-d 6)δppm 8.15(s,1H),7.24(d,J＝8.8Hz,2H),6.89-6.86(m,2H),5.21(s,2H),4.05(s,3H),3.72(s,3H)。
步骤C：向化合物1-3(55克，169.15毫摩尔，1当量)和化合物1-4(97.49克，507.45毫摩尔，64.56毫升，3当量)的N-甲基吡咯烷酮(500毫升)中加入碘化亚铜(16.11克，84.57毫摩尔，0.5当量)，将该混合体系加热至100摄氏度搅拌3小时。冷却至室温后，向反应液中加入水(150毫升)，用二氯 甲烷(200毫升×3)萃取，合并有机相，用饱和食盐水(200毫升×3)洗涤，无水硫酸钠干燥，过滤，浓缩滤液，得到的残留物用柱层析(
Figure PCTCN2022107127-appb-000066
1000克
Figure PCTCN2022107127-appb-000067
硅胶柱，洗脱液梯度0～100％乙酸乙酯/石油醚66毫升/分钟)纯化得到化合物1-5。MS(ESI)m/z:315.3[M+H +]。
步骤D：向化合物1-5(31.11克，98.99毫摩尔，1当量)的N,N-二甲基甲酰胺(250毫升)溶液中加入三甲基碘硅烷(29.71克，148.49毫摩尔，20.21毫升，1.5当量)，将该混合体系加热至85摄氏度搅拌12小时。冷却至室温后，向反应液中加入饱和氯化铵(150毫升)水溶液，将上述混合液垫硅藻土过滤，滤液用乙酸乙酯(200毫升×3)萃取，合并有机相，用饱和食盐水(100毫升×2)洗涤，无水硫酸钠干燥，过滤，浓缩滤液，得到的残留物用柱层析(
Figure PCTCN2022107127-appb-000068
1000克
Figure PCTCN2022107127-appb-000069
硅胶柱，洗脱液梯度0～100％乙酸乙酯/石油醚44毫升/分钟)纯化得到化合物1-6。 1H NMR(400MHz,DMSO-d 6)δppm7.78(s,1H),7.24(d,J＝8.8Hz,2H),6.89(d,J＝8.8Hz,2H),5.09(s,2H),3.72(s,3H)。MS(ESI)m/z:323.0,325.0[M+Na +]。
步骤E：在0摄氏度，向化合物1-6(12克，39.97毫摩尔，1当量)的N,N-二甲基甲酰胺(120毫升)溶液中加入草酰氯(10.15克，79.94毫摩尔，7.00毫升，2当量)，该混合体系在25摄氏度搅拌8小时。将反应液用水(200毫升)淬灭，乙酸乙酯(150毫升×3)萃取，合并有机相，用饱和食盐水(100毫升×2)洗涤，无水硫酸钠干燥，过滤，浓缩滤液，得到的残留物用柱层析(
Figure PCTCN2022107127-appb-000070
120克
Figure PCTCN2022107127-appb-000071
硅胶柱，洗脱液梯度0～100％乙酸乙酯/石油醚66毫升/分钟)纯化得到化合物1-7。 1H NMR(400MHz,DMSO-d 6)δppm 7.78(s,1H),7.24(d,J＝8.4Hz,2H),6.89(d,J＝8.4Hz,2H),5.19(s,2H),3.72(s,3H)。
Figure PCTCN2022107127-appb-000072
步骤F：在氮气保护下，向化合物1-8(4.3克，23.56毫摩尔，1当量)的N-甲基吡咯烷酮(50毫升)溶液中加入化合物1-9(4.39克，23.56毫摩尔，1当量)和碳酸钾(6.51克，47.12毫摩尔，2当量)，反应液在80摄氏度下搅拌1个小时。待反应液冷却到室温后加入水(200毫升),有白色固体析出，过滤并收集滤饼，减压干燥后得到化合物1-10。MS(ESI)m/z:277.1[M+H +-56]。
步骤G：向1-10(7.8克，23.47毫摩尔，1当量)的无水二氧六环(80毫升)溶液中加入盐酸二氧六环(4摩尔每升，78.00毫升，13.29当量)，反应液在25摄氏度下搅拌1个小时。室温下过滤并收集滤饼，减压干燥后得到化合物1-11的盐酸盐。MS(ESI)m/z:233.1[M+H +]。
Figure PCTCN2022107127-appb-000073
步骤H：向化合物1-12(3克，17.32毫摩尔，1当量)和化合物1-13(3.88克，17.32毫摩尔，3.44毫升，1当量)的四氢呋喃(10毫升)溶液中加入叔丁醇钾(2.92克，25.98毫摩尔，1.5当量)，反应液在25摄氏度搅拌12小时。向反应液中加入水(100毫升)，用乙酸乙酯(100毫升×2)萃取，合并有机相，用饱和食盐水(100毫升×2)洗涤，无水硫酸钠干燥，过滤，浓缩滤液，粗品通过硅胶柱层析(石油醚/乙酸乙酯＝10/1)纯化，得到化合物1-14。MS(ESI)m/z:144.2[M+H +-100]。
步骤I：将化合物1-14(900毫克，3.70毫摩尔，1当量)溶解到盐酸二氧六环(10毫升)中，在25摄氏度搅拌15分钟。将反应液浓缩，得到化合物1-15的盐酸盐。MS(ESI)m/z:144.1[M+H +]。
步骤J：向化合物1-15(700毫克，3.90毫摩尔，1当量，盐酸盐)的N,N-二甲基甲酰胺(20毫升)溶液中加入三乙胺(1.18克，11.69毫摩尔，1.63毫升，3当量)和化合物1-7(1.24克，3.90毫摩尔，1当量)。该反应液在25摄氏度搅拌12小时。将水(60毫升)加入到反应液中，乙酸乙酯(60毫升×2)萃取，合并有机相，用饱和食盐水(60毫升×2)洗涤，无水硫酸钠干燥，过滤，浓缩滤液，粗品通过硅胶柱层析(石油醚/乙酸乙酯＝10/1到2/1)纯化，得到化合物1-16。MS(ESI)m/z:426.3[M+H +]。
步骤K：向化合物1-16(1克，2.35毫摩尔，1当量)的三氟乙酸(10毫升)溶液中加入三氟甲磺酸(1.76克，11.75毫摩尔，1.04毫升，5当量)，该反应液在25摄氏度搅拌1小时。将反应液倒入水(100毫升)中，用碳酸氢钠调节pH至7～8，乙酸乙酯(100毫升×2)萃取，有机相用无水硫酸钠干燥，过滤，浓缩滤液，粗品通过硅胶柱层析(石油醚/乙酸乙酯＝10/1到1/1)纯化，得到化合物1-17。MS(ESI)m/z:306.1[M+H +]。
步骤L：在0摄氏度，向化合物1-17(460毫克，1.51毫摩尔，1当量)的四氢呋喃(10毫升)溶液中加入二异丁基氢化铝(1摩尔每升，4.52毫升，3当量)，反应液保持0摄氏度搅拌30分钟。向反应液中加入饱和硫酸钠水溶液(5毫升)，然后加入乙酸乙酯(100毫升)，继续在25摄氏度搅拌10分钟，将上述混合液过滤，滤饼用乙酸乙酯(30毫升)洗涤，浓缩滤液，粗品通过硅胶柱层析(石油醚/乙酸 乙酯＝10/1到1/1)纯化，得到化合物1-18。MS(ESI)m/z:264.2[M+H +]。
步骤M：向化合物1-18(230毫克，873.81微摩尔，1当量)的二氯甲烷(5毫升)溶液中加入N,N-羰基二咪唑(170.03毫克，1.05毫摩尔，1.2当量)，上述混合液在25摄氏度搅拌30分钟，然后加入1-11(352.14毫克，1.31毫摩尔，1.5当量，盐酸盐)和三乙胺(265.26毫克，2.62毫摩尔，364.87微升，3当量)的二氯甲烷(5毫升)溶液。该反应液在25摄氏度搅拌12小时。将反应液倒入水(80毫升)中，乙酸乙酯(80毫升×2)萃取，合并有机相，用饱和食盐水(80毫升×2)洗涤，无水硫酸钠干燥，过滤，浓缩滤液，粗品通过高效液相色谱(柱子：Waters Xbridge 150*25毫米*5微米；流动相：[水(10毫摩尔每升碳酸氢铵)-乙腈]；碳酸氢铵％：40％-70％，8分钟)纯化得到化合物1-19。MS(ESI)m/z:522.3[M+H +]。 1H NMR(400MHz,氯仿-d)δppm 10.22(s,1H),8.51(s,2H),7.58(s,1H),5.84-5.75(m,2H),5.47-5.44(m,1H),4.67-4.62(m,2H),4.29-4.26-(m,1H),3.93-3.91(m,4H),3.58-3.56(m,4H),1.46(d,J＝6.4Hz,3H)。
步骤N：将化合物1-19(5.9克，11.32毫摩尔，1当量)通过手性拆分(柱子:DAICEL CHIRALCEL OJ(250毫米*30毫米，10微米)；流动相：[0.1％氨水甲醇]；甲醇％:25％-25％，3分钟)，得到化合物1a.MS(ESI)m/z:522.2[M+H +]。 1H NMR(400MHz,氯仿-d)δppm 10.91(s,1H),8.51(s,2H),7.59(s,1H),5.88-5.72(m,2H),5.54-5.39(m,1H),4.75-4.58(m,2H),4.35-4.24(m,1H),4.00–3.88(m,4H),3.70-3.52(m,4H),1.45(d,J＝6.8Hz,3H).
化合物1a经SFC检测【柱型号：Chiralcel OJ-3 50×4.6mm I.D.,3μm；流动相：A相为超临界二氧化碳，B相为甲醇(0.05％二乙胺)；梯度(B％)：5％-40％】得到：化合物1a的保留时间为1.162min，e.e.值为100％。
实施例2
Figure PCTCN2022107127-appb-000074
步骤A：在0摄氏度，向化合物1-17(420毫克，1.38毫摩尔，1当量)的四氢呋喃(10毫升)溶液中加入二异丁基氢化铝(1摩尔每升，4.13毫升，3当量)，反应液保持0摄氏度搅拌30分钟。向反应液中加入饱和硫酸钠水溶液(10毫升)，然后加入乙酸乙酯(100毫升)，继续在25摄氏度搅拌10分钟，将上述混合液过滤，滤饼用乙酸乙酯(100毫升)洗涤，浓缩滤液，粗品通过硅胶薄层色谱(石油醚/乙酸乙酯＝1/2)纯化，得到产品通过手性拆分(柱子:DAICEL CHIRALPAK AD(250毫米*30毫米，10微米)；流动相：[0.1％氨水异丙醇]；异丙醇％：20％-20％,5.3分钟)得到化合物1-18a。MS(ESI)m/z:264.1[M+H +]。
化合物1-18a经SFC检测【柱型号：Chiralcel OJ-3 50×4.6mm I.D.,3μm；流动相：A相为超临界二氧化碳，B相为异丙醇(0.05％二乙胺)；梯度(B％)：5％-40％】得到：化合物1-18a的保留时间为1.146min，e.e.值为99.122％。
Figure PCTCN2022107127-appb-000075
步骤B：向化合物1-18a(200毫克，759.83微摩尔，1当量)的甲苯(10毫升)溶液中加入1,8-二氮杂环十一碳-7-烯(173.51毫克，1.14毫摩尔，171.79微升，1.5当量)和叠氮磷酸二苯酯(313.66毫克，1.14毫摩尔，246.98微升，1.5当量)，该混合体系在80摄氏度搅拌2小时。浓缩反应液，粗品通过柱层析(二氧化硅，石油醚/乙酸乙酯＝10/1，1/1)纯化，得到化合物2-1。MS(ESI)m/z:289.1[M+H +].
步骤C：向化合物2-1(180毫克，624.50微摩尔，1当量)的四氢呋喃(5毫升)溶液中加入三苯基膦(245.70毫克，936.76微摩尔，1.5当量)，该混合体系在25摄氏度搅拌30分钟。再向反应液中加入水(0.5毫升)，该混合体系在40摄氏度搅拌12小时。向反应液中加入水(30毫升)稀释，用乙酸乙酯(30毫升)萃取，将水相浓缩，得到化合物2-2。MS(ESI)m/z:263.1[M+H +].
步骤D：向化合物2-2(120毫克，457.61微摩尔，1当量)的N,N-二甲基甲酰胺(5毫升)溶液中加入N,N-羰基二咪唑(96.46毫克，594.89微摩尔，1.3当量)和二异丙基乙胺(295.71毫克，2.29毫摩尔，398.53微升，5当量)，该混合体系在25摄氏度搅拌2小时。再向反应液中加入化合物1-11(212.52毫克，915.22微摩尔，2当量)，该混合体系在60摄氏度搅拌12小时。将反应液通过高效液相色谱(柱子:Unisil 3-100 C18 Ultra 150*50毫米*3微米；流动相:[水(甲酸)-乙腈]；乙腈％:39％-69％，7分钟)纯化，得到化合物2。MS(ESI)m/z:521.3[M+H +]. 1H NMR(400MHz,氯仿-d)δppm 11.05(br s,1H),8.51(s,2H),7.61(s,1H)5.59-5.80(m,2H),5.50-5.39(m,1H),4.85-4.82(m,1H),4.32-4.19(m,1H),4.02-3.82(m,6H),3.61-3.45(m,4H),1.42(d,J＝6.8Hz,3H).
化合物2经SFC检测【柱型号：Chiralpak AD-3 50×4.6mm I.D.,3μm；流动相：A相为超临界二氧化碳，B相为甲醇(0.05％二乙胺)；梯度(B％)：5％-40％】得到：化合物2的保留时间为1.702min，e.e.值为99.390％。
实施例3
Figure PCTCN2022107127-appb-000076
步骤A：将化合物1-18(516毫克，1.96毫摩尔，1当量)溶解在甲苯(6毫升)中，加入1.8-二氮杂二环[5.4.0]十一烷-7-烯(358.13毫克，2.35毫摩尔，354.58微升，1.2当量)和叠氮磷酸二苯酯(647.39毫克，2.35毫摩尔，509.76微升，1.2当量)。反应液在80摄氏度下搅拌2小时。反应液反应完全后冷却至室温，加水(50毫升)稀释，乙酸乙酯(50毫升×3)萃取，合并后的有机相用饱和的食盐水(50毫升×1)洗涤，无水硫酸钠干燥，过滤，浓缩滤液，得到的粗品经过柱层析(硅胶，石油醚/乙酸乙酯＝3/1到1/1)得到化合物3-1。
步骤B：将化合物3-1(280毫克，971.45微摩尔，1当量)溶解在四氢呋喃(3毫升)中，加入三苯基膦(382.20毫克，1.46毫摩尔，1.5当量)。反应液在25摄氏度下搅拌0.5小时，将水(0.5毫升)加入反应液中。反应液在25摄氏度下搅拌1小时。反应完全后加入乙酸乙酯(50毫升)稀释，用水(50毫升×4)洗涤。合并后的水相直接浓缩得到化合物3-2。MS(ESI)m/z:263.0[M+H +]。
Figure PCTCN2022107127-appb-000077
步骤B：将化合物1-8(500毫克，2.74毫摩尔，1当量)溶解在N,N-二甲基甲酰胺(5毫升)中，加入化合物3-3(430.64毫克，2.74毫摩尔，422.19微升，1当量)和碳酸钾(757.16毫克，5.48毫摩尔，2当量)。反应液在90摄氏度下搅拌1小时。反应完全后冷却至室温，反应液用水(10毫升)稀释，乙酸乙酯(10毫升×3)萃取。合并后的有机相用饱和的食盐水(10毫升×2)洗涤，无水硫酸钠干燥，过滤，滤液浓缩得到化合物3-4。
步骤C：将化合物3-4(0.75克，2.47毫摩尔，1当量)溶解在甲醇(10毫升)和水(10毫升)，加入一水合氢氧化锂(311.32毫克，7.42毫摩尔，3当量)，反应液在25摄氏度下搅拌1小时。反应完全后，往反应液中加入盐酸(1摩尔每升)调节pH到5，用乙酸乙酯(20毫升×3)萃取，合并后的有机相用饱和食盐水(20毫升×2)洗涤，无水硫酸钠干燥，过滤，滤液浓缩得到化合物3-5。MS(ESI)m/z:276.0[M+H +].
步骤D：将化合物3-5(83.96毫克，305.07微摩尔，1当量)溶解在四氢呋喃(1毫升)中，加入三乙胺(61.74毫克，610.15微摩尔，84.93微升，2当量)和O-(7-氮杂苯并三氮唑-1-基)N,N,N,N-四甲基脲六氟磷酸盐(174.00毫克，457.61微摩尔，1.5当量)，反应液在25摄氏度下搅拌反应30分钟，加入化合物3-2(80毫克，305.07微摩尔，1当量)。反应液在25摄氏度下搅拌1小时。反应完全后，反应液用水(50毫升)稀释，用乙酸乙酯(50毫升×3)萃取，合并后有机相用饱和食盐水(50毫升)洗涤，无水硫酸钠干燥，过滤，滤液浓缩。粗品经过薄层色谱分离(硅胶，石油醚/乙酸乙酯＝0/1)，得到化合物再经过高效液相色谱法(柱子：Phenomenex Synergi C18 150*25毫米*10微米；流动相:[水(甲酸)-乙腈]；乙腈％:36％-56％，9分钟)得到化合物3。MS(ESI)m/z:520.2[M+H +]. 1H NMR(400MHz,DMSO-d 6)δppm 8.67(s,2H),8.02(t,J＝5.2Hz,1H),7.80(s,1H),6.47-6.38(m,1H),5.62-5.57(m,2H),4.72-4.65(m,2H),4.54-4.46(m,1H),3.65(br s,2H),3.09–2.98(m,2H),2.46-2.42(m,1H),1.80-1.71(m,2H),1.55-1.42(m,2H),1.29(d,J＝5.6Hz,3H).
实施例4
Figure PCTCN2022107127-appb-000078
步骤B：向化合物4-1(100毫克，471.06微摩尔，1当量)和化合物1-8(85.98毫克，471.06微摩尔，1当量)的N,N-二甲基甲酰胺(5毫升)溶液中加入碳酸钾(130.21毫克，942.12微摩尔，2当量)，将反应液加热到90摄氏度搅拌2小时。将反应液倒入水(50毫升)中，乙酸乙酯(50毫升)萃取，合并有机相，用饱和食盐水(50毫升)洗涤，无水硫酸钠干燥，过滤，浓缩滤液，得到化合物4-2。MS(ESI)m/z:303.1[M+H +-56]。
步骤C：将化合物4-2(160毫克，446.48微摩尔，1当量)加入到盐酸乙酸乙酯(5毫升，4摩尔每升)中，反应液在25摄氏度搅拌15分钟。将反应液浓缩，得到化合物4-3的盐酸盐。MS(ESI)m/z:259.1[M+H +]。
步骤D：向化合物1-18a(20毫克，75.98微摩尔，1当量)的N,N-二甲基甲酰胺(1毫升)溶液中加入N,N-羰基二咪唑(24.64毫克，151.96微摩尔，2当量)和三乙胺(30.75毫克，303.92微摩尔，42.30微升，4当量)，该混合液在25摄氏度搅拌2小时后，加入化合物4-3(33.59毫克，113.97微摩尔，1.5当量，盐酸盐)，反应液在25摄氏度搅拌12小时，然后加热到50摄氏度搅拌24小时。将反应液倒入水(30毫升)中，乙酸乙酯(30毫升×2)萃取，合并有机相，用饱和食盐水(30毫升×2)洗涤，无水硫酸钠干燥，过滤，浓缩滤液，得到将反应液通过高效液相色谱制备(柱子：Phenomenex luna C18 150*25毫米*10微米；流动相：[水(甲酸)-乙腈]：乙腈％:41％-71％，10分钟)纯化，得到化合物4。MS(ESI)m/z:550.2[M+H +]。 1HNMR(400MHz,DMSO-d 6)δppm 12.52(s,1H),8.72(s,2H),7.81(s,1H),6.50-6.47(m,1H),5.65-5.90(m,2H),4.79(br s,2H),4.45-4.66(m,3H),3.73-3.88(m,2H),2.97-3.18(m,2H),1.87-1.98(m,2H),1.68-1.67(m,2H),1.31(d,J＝6.80Hz,3H).
化合物4经SFC检测【柱型号：Chiralpak AD-3 50×4.6mm I.D.,3μm；流动相：A相为超临界二氧化碳，B相为甲醇(0.05％二乙胺)；梯度(B％)：5％-40％】得到：化合物4的保留时间为1.853min，e.e.值为100％。
实施例5
Figure PCTCN2022107127-appb-000079
步骤A：向化合物5-1(100毫克，471.06微摩尔，1当量)的N-甲基吡咯烷酮(2毫升)溶液中加入碳酸钾(130.21毫克，942.12微摩尔，2当量)和化合物1-8(85.98毫克，471.06微摩尔，1当量)，该混合体系在80摄氏度下搅拌2小时。待反应液冷却到25摄氏度后加入水(10毫升),有黄色固体析出，过滤并收集滤饼，减压干燥后得到化合物5-2。MS(ESI)m/z:303.0[M+H +-56].
步骤B：向5-2(110毫克，306.96微摩尔，1当量)的乙酸乙酯(1毫升)溶液中加入盐酸乙酸乙酯(4摩尔，1毫升，13.03当量)，该混合体系在25摄氏度下搅拌0.5小时。将反应液直接减压干燥后得到化合物5-3的盐酸盐。MS(ESI)m/z:259.2[M+H +].
步骤C：向化合物1-18a(30毫克，113.97微摩尔，1当量)的N,N-二甲基甲酰胺(2毫升)溶液中加入N,N-羰基二咪唑(36.96毫克，227.95微摩尔，2当量)和三乙胺(34.60毫克，341.92微摩尔，47.59微升，3当量)，该混合体系在25摄氏度下搅拌12小时，然后加入化合物5-3(44.15毫克，170.96微摩尔，1.5当量)，该混合体系在50摄氏度下搅拌24小时。加水(10毫升)稀释，用乙酸乙酯(10毫升×2)萃取，合并有机相，用饱和食盐水(10毫升×2)洗涤，无水硫酸钠干燥，过滤，浓缩滤液，粗品通过高效液相色谱(柱子:Phenomenex Synergi C18 150*25毫米*10微米；流动相：[水(甲酸)-乙腈]；乙腈％：41％-71％，10分钟)纯化，得到化合物5。MS(ESI)m/z:548.2[M+H +].1H NMR(400MHz,DMSO-d 6)δppm 12.51(br s,1H),8.70-8.69(m,2H),7.82-7.81(m,1H),6.49-6.48(m,1H),5.81-5.76(m,2H),4.98-4.96(m,1H),4.56-4.52(m,3H),4.31-4.28(m,1H),3.67(br s,2H),3.56-3.50(m,2H),1.90-1.78(m,4H),1.32-1.28(m,3H).
化合物5经SFC检测【柱型号：Chiralpak AD-3 50×4.6mm I.D.,3μm；流动相：A相为超临界二氧化碳，B相为甲醇(0.05％二乙胺)；梯度(B％)：40％-40％】得到：化合物5的保留时间为0.651min和1.124min，e.e.值为1.394％。
实施例6
Figure PCTCN2022107127-appb-000080
步骤A：将化合物6-1(1.68克，6.93毫摩尔，1.41毫升，1.2当量)溶解在四氢呋喃(10毫升)中，加入氢氧化钾(323.92毫克，5.77毫摩尔，1当量)和化合物1-12(1克，5.77毫摩尔，1当量)。反应混合物在25摄氏度下搅拌12小时。反应完全后，往反应液加入水(50毫升)，乙酸乙酯(50毫升×3)萃取，合并后的有机相用饱和食盐水(50毫升)洗涤，无水硫酸钠干燥，过滤，滤液浓缩得到粗品经过柱层析(
Figure PCTCN2022107127-appb-000081
25g
Figure PCTCN2022107127-appb-000082
硅胶柱,洗脱剂梯度0～6％石油醚：乙酸乙酯80毫升/分钟)得到化合物6-2。MS(ESI)m/z：206.0[M+H +-56]. 1H NMR(400MHz,氯仿-d)δppm 6.08-5.90(m,1H)5.06-4.93(m,1H)4.42-4.50(m,1H)4.29-4.23(m,2H)1.37(s,9H)1.31-1.28(m,3H)1-25-1.23(m,3H)
步骤B：将化合物6-2(840毫克，3.21毫摩尔，1当量)溶解在乙酸乙酯(8毫升)中，加入盐酸乙酸乙酯(4摩尔，8毫升，9.95当量)。反应混合物在25摄氏度下搅拌1小时。反应完全后，将反应液真空浓缩得到化合物6-3的盐酸盐。MS(ESI)m/z：162.1[M+H +]
步骤C：将化合物6-3(724毫克，4.49毫摩尔，1当量，盐酸盐)溶解在N,N-二甲基甲酰胺(10毫升)中，加入三乙胺(1.36克，13.48毫摩尔，1.88毫升，3当量)和化合物1-7(1.43克，4.49毫摩尔，1当量)。反应液在25摄氏度下搅拌12小时。反应完全后，往反应液中加入乙酸乙酯(50毫升)，用水(50毫升×3)和饱和食盐水(50毫升×2)洗涤，无水硫酸钠干燥，过滤，滤液，浓缩得到粗品经过柱层析(
Figure PCTCN2022107127-appb-000083
25g
Figure PCTCN2022107127-appb-000084
硅胶柱，洗脱剂梯度0-6％乙酸乙酯：石油醚80毫升/分钟)得到化合物6-4。MS(ESI)m/z：444.2[M+H +]
步骤D：将化合物6-4(1.24克，2.80毫摩尔，1当量)溶解在三氟乙酸(10毫升)中，加入三氟甲磺酸(1.70克，11.33毫摩尔，1毫升，4.05当量)，反应混合物在25摄氏度下搅拌10分钟。反应完全后，将反应液缓慢滴加到饱和的碳酸钠溶液(200毫升)中，加入碳酸钠固体调节pH到9，然后用乙酸乙酯(200毫升×3)萃取。合并后的有机相用饱和食盐水(200毫升)洗涤，无水硫酸钠干燥，过滤，滤液浓缩得到粗 品经过柱层析(
Figure PCTCN2022107127-appb-000085
12g
Figure PCTCN2022107127-appb-000086
硅胶柱，洗脱剂梯度0-16％乙酸乙酯：石油醚(1％二氯甲烷)60毫升/分钟)得到化合物6-5。MS(ESI)m/z：324.0[M+H +]
步骤E：将化合物6-5(0.5克，1.55毫摩尔，1当量)溶解在四氢呋喃(6毫升)中，在0摄氏度下加入二异丁基氢化铝(1摩尔，9.28毫升，6当量)。反应混合物在25摄氏度下搅拌1小时。反应完全后加入饱和氯化铵溶液(5毫升)淬灭，乙酸乙酯(5毫升×4)萃取。合并后的有机相由饱和食盐水(5毫升)洗涤，无水硫酸钠干燥，过滤，滤液浓缩得到粗品经过板分离(石油醚/乙酸乙酯＝1/2)得到产物在经过手型拆分(柱子：DAICEL CHIRALCEL OJ(250毫米*30毫米,10微米)；流动相：[0.1％氨水异丙醇]；异丙醇％：15％-15％，5.6分钟)得到化合物6-6。MS(ESI)m/z：282.0[M+H +]
步骤F：将化合物6-6(92毫克，327.16微摩尔，1当量)溶解在四氢呋喃(4毫升)中，加入N,N-羰基二咪唑(106.10毫克，654.32微摩尔，2当量)和三乙胺(99.32毫克，981.49微摩尔，136.61微升，3当量)，反应混合物在25摄氏度下搅拌1小时，将化合物1-11(87.90毫克，327.16微摩尔，1当量，盐酸盐)加入反应液。反应混合物在50摄氏度下搅拌17小时。反应完全后，反应液冷却至25摄氏度，往反应液中加入水(20毫升)，乙酸乙酯(20毫升×4)萃取。合并后的有机相用饱和食盐水(20毫升×2)洗涤，无水硫酸钠干燥，过滤，滤液浓缩得到粗品经过高效液相色谱法(柱子：Phenomenex Synergi C18 150*25毫米*10微米；流动相：[水(甲酸)-乙腈]；乙腈％：42％-72％，10分钟)得到化合物6。MS(ESI)m/z：540.2[M+H +] 1H NMR(400MHz,DMSO-d 6)δppm 12.60(s,1H),8.73(s,2H),7.77(s,1H),6.66-6.58(m,1H),5.39(dd,J＝36.0Hz,1H),4.89-4.77(m,1H),4.69(d,J＝16.0Hz,2H),3.89-3.80(m,4H),3.52-3.44(m,4H),1.34(d,J＝8.0Hz,3H).
化合物6经SFC检测【柱型号：OD 50×4.6mm I.D.,3μm；流动相：A相为超临界二氧化碳，B相为甲醇(0.05％二乙胺)；梯度(B％)：5％-40％】得到：化合物6的保留时间为1.189min，e.e.值为100％。
实施例7
Figure PCTCN2022107127-appb-000087
步骤A：将化合物7-1(0.5克，3.58毫摩尔，1当量)和化合物1-9(667.36毫克，3.58毫摩尔，1当量)溶解在N-甲基吡咯烷酮(10毫升)中，加入碳酸钾(990.45毫克，7.17毫摩尔，2当量)。反应液混合物在100摄氏度下搅拌2小时。反应完全后，反应液冷却至25摄氏度，将反应液倒入水(30毫升) 中，过滤，滤饼真空旋干得到化合物7-2。 1H NMR(400MHz,氯仿-d)δppm 8.50-8.47(m,2H),3.90-3.51(m,8H),1.50(s,9H).
步骤B：将化合物7-2(400毫克，1.38毫摩尔，1当量)溶解在乙酸乙酯(2毫升)中，加入盐酸乙酸乙酯(4摩尔每升，2毫升，5.79当量)。反应混合物在25摄氏度下搅拌0.5小时。反应完全后，将反应液直接浓缩得到化合物7-3的盐酸盐。
步骤C：将化合物1-18a(10毫克，37.99微摩尔，1当量)溶解在四氢呋喃(1毫升)中，加入N,N-羰基二咪唑(7.39毫克，45.59微摩尔，1当量)和三乙胺(11.53毫克，113.79微摩尔，15.86微升，3当量)。反应液在25摄氏度下搅拌3小时。再加入羰基二咪唑(6.16毫克，37.99微摩尔，1当量)，反应混合物在25摄氏度下搅拌2小时。加入化合物7-3(17.15毫克75.98微摩尔，2当量，盐酸盐)，反应混合物在50摄氏度下搅拌24小时。反应完全后，反应液用水(5毫升)稀释，乙酸乙酯(5毫升×2)萃取。合并后的有机相用饱和食盐水(5毫升×2)洗涤，无水硫酸钠干燥，过滤，滤液浓缩得到粗品经过高效液相色谱(柱子；Phenomenex Synergi C18 150*25毫米*10微米；流动相[水(甲酸)-乙腈]；乙腈：％28％-58％，10分钟)得到化合物7。MS(ESI)m/z：479.2[M+H +]. 1H NMR(400MHz,DMSO-d 6)δppm 12.53-12.49(m,1H),8.79(s,2H),7.82(s,1H),6.52-6.49(m,1H),5.86–5.73(m,2H),4.57-4.54(m,3H),3.85-3.83(m,4H),3.47(br s,4H),1.35(d,J＝6.8Hz,3H)
化合物7经SFC检测【柱型号：Chiralcel OJ-3 50×4.6mm I.D.,3μm；流动相：A相为超临界二氧化碳，B相为甲醇(0.05％二乙胺)；梯度(B％)：5％-40％】得到：化合物7的保留时间为1.689min，e.e.值为99.104％。
实施例8
Figure PCTCN2022107127-appb-000088
步骤A：将化合物8-1(1.17克，8.86毫摩尔，1.1当量)溶解在异丙醇(10毫升)中，加入化合物1-9(1.5克，8.05毫摩尔，1当量)和N,N-二异丙基乙胺(2.08克，16.11毫摩尔，2.81毫升，2当量)。反应混合物在120摄氏度下搅拌0.5小时。反应完全后，反应液冷却至25摄氏度，往反应液加入水(50毫升)，在25摄氏度下搅拌0.5小时，将反应液过滤，滤饼真空旋干得到化合物8-2。MS(ESI)m/z： 183.0[M+H +-100]. 1H NMR(400MHz,氯仿-d)δppm 8.22(s,2H)3.80-3.73(m,4H)3.54-3.48(m,4H)1.51(s,9H).
步骤B：将化合物8-2(0.5克，1.77毫摩尔，1当量)溶解在乙酸乙酯(5毫升)中，加入盐酸乙酸乙酯(4摩尔，5毫升，11.29当量)。反应混合物在25摄氏度下搅拌0.5小时。反应完全后，将反应液过滤，滤饼真空旋干得到化合物8-3的盐酸盐。MS(ESI)m/z：183.0[M+H +].
步骤C：将化合物1-18a(20毫克，75.98微摩尔，1当量)溶解在四氢呋喃(1毫升)中，加入N,N-羰基二咪唑(12.32毫克，75.98微摩尔，1当量)和三乙胺(23.07毫克，227.95微摩尔，31.73微升，3当量)，反应混合物在25摄氏度下搅拌1小时，将化合物8-3(16.61毫克，75.98微摩尔，1当量，盐酸盐)加入反应液。反应混合物在25摄氏度下搅拌12小时。反应完全后，往反应液中加入水(10毫升)，乙酸乙酯(10毫升×3)萃取。合并后的有机相用饱和食盐水(10毫升×2)洗涤，无水硫酸钠干燥，过滤，滤液浓缩，粗品经过高效液相色谱(柱子：Phenomenex Synergi C18 150*25毫米*10微米；流动相：[水(甲酸)-乙腈]；乙腈％：34％-61％，9分钟)纯化得到化合物8。MS(ESI)m/z：472.1[M+H +]。 1H NMR(400MHz,DMSO-d 6)δppm 12.55(s,1H),8.47(s,2H),7.82(s,1H),6.56-6.49(m,1H),5.88-5.70(m,2H),4.60-4.50(m,3H),3.71-3.64(m,4H),3.49-3.41(m,4H),1.32(d,J＝8.0Hz,3H).
化合物8经SFC检测【柱型号：Chiralpak AD-3 50×4.6mm I.D.,3μm；流动相：A相为超临界二氧化碳，B相为甲醇(0.05％二乙胺)；梯度(B％)：5％-40％】得到：化合物8的保留时间为2.069min，e.e.值为100％。
实施例9
Figure PCTCN2022107127-appb-000089
步骤A：将化合物9-1(100毫克，701.54微摩尔，1当量)和化合物1-9(130.66毫克，701.54毫摩尔，1当量)溶解在四氢呋喃(5毫升)中，加入N,N-二异丙基乙胺(181.34毫克，1.40毫摩尔，244.39微升，2当量)。反应液混合物在25摄氏度下搅拌1小时。反应完全后，反应液中加入水(50毫升)，用乙酸乙酯(50毫升×2)萃取。合并后的有机相用饱和食盐水(50毫升)洗涤，无水硫酸钠干燥，过滤，滤液真空浓缩得到化合物9-2。MS(ESI)m/z：193.1[M+H +-100].
步骤B：将化合物9-2(100毫克，342.08微摩尔，1当量)溶解在二氯甲烷(5毫升)中，加入二乙氨基三氟化硫(110.28毫克，684.15微摩尔，90.39微升，2当量)。反应混合物在25摄氏度下搅拌13小 时。反应完全后，反应液中加入水(30毫升)，用乙酸乙酯(30毫升×2)萃取。合并后的有机相用饱和食盐水(30毫升)洗涤，无水硫酸钠干燥，过滤，滤液真空浓缩得到粗品经过薄层色谱纯化(硅胶，石油醚/乙酸乙酯＝4/1)得到化合物9-3。MS(ESI)m/z：259.0[M+H +-56].
步骤C:将化合物9-3(60毫克，190.88微摩尔，1当量)溶解在盐酸二氧六环(4摩尔，5毫升)中。反应混合物在25摄氏度下搅拌15分钟。反应完全后，将反应液直接浓缩得到化合物9-4的盐酸盐。MS(ESI)m/z：215.0[M+H +].
步骤D：将化合物1-18a(15毫克，56.99微摩尔，1当量)溶解在N,N-二甲基甲酰胺(1毫升)中，加入N,N-羰基二咪唑(18.48毫克，113.97微摩尔，2当量)和三乙胺(28.83毫克，284.98微摩尔，39.66微升，5当量)。反应液在25摄氏度下搅拌2小时。加入化合物9-4(28.57毫克，113.97微摩尔，2当量，盐酸盐)，反应混合物在25摄氏度下搅拌24小时。反应完全后，反应液中加入水(30毫升)，用乙酸乙酯(30毫升×2)萃取。合并后的有机相用饱和食盐水(30毫升×2)洗涤，无水硫酸钠干燥，过滤，滤液浓缩得到粗品经过高效液相色谱(柱子；Unisil 3-100 C18 Ultra 150*50毫米*3微米；流动相[水(甲酸)-乙腈]；乙腈％：28％-58％，10分钟)得到化合物9。MS(ESI)m/z：504.3[M+H +]. 1H NMR(400MHz,氯仿-d)δppm 9.99(brs,1H),8.45(s,2H),7.58(s,1H),6.59(t,J＝56.0Hz,1H)5.84-5.73(m,2H),5.55-5.40(m,1H),4.71-4.61(m,2H),4.35-4.22(m,1H),3.93-3.90(m,4H),3.61-3.57(m,4H),1.46(d,J＝6.8Hz,3H).
化合物9经SFC检测【柱型号：Chiralcel OJ-3 50×4.6mm I.D.,3μm；流动相：A相为超临界二氧化碳，B相为甲醇(0.05％二乙胺)；梯度(B％)：5％-40％】得到：化合物9的保留时间为1.613min，e.e.值为100％。
实施例10
Figure PCTCN2022107127-appb-000090
步骤A：将化合物10-1(100毫克，430.99微摩尔，1当量)溶解在N-甲基吡咯烷酮(2毫升)中，加入碳酸铯(280.85毫克，861.99毫摩尔，2当量)化合物1-9(80.27毫克，430.99毫摩尔，1当量)。反应液混合物在110摄氏度下搅拌1小时。反应完全后，反应液冷却至25摄氏度，反应液中加入乙酸 乙酯(10毫升)，水(10毫升×3)和饱和食盐水(10毫升×2)洗涤，无水硫酸钠干燥，过滤，滤液真空浓缩得到化合物10-2。MS(ESI)m/z：282.0[M+H +-56]
步骤B：将化合物10-2(190毫克，536.20微摩尔，1当量)溶解在乙酸乙酯(2毫升)中，加入盐酸乙酸乙酯(4摩尔每升，2毫升)。反应混合物在25摄氏度下搅拌0.5小时。反应完全后，将反应液直接浓缩得到化合物10-3的盐酸盐。MS(ESI)m/z：238.0[M+H +]
步骤C：将化合物1-18a(15毫克，56.99微摩尔，1当量)溶解在四氢呋喃(2毫升)中，加入N,N-羰基二咪唑(18.48毫克，113.97微摩尔，2当量)和三乙胺(23.07毫克，227.95微摩尔，31.73微升，4当量)。反应液在50摄氏度下搅拌4小时。再加入羰基二咪唑(13.86毫克，85.48微摩尔，1.5当量)，反应混合物在50摄氏度下搅拌12小时.再加入羰基二咪唑(13.86毫克，85.48微摩尔，1.5当量)，反应混合物在25摄氏度下搅拌3小时。然后加入化合物10-3(18.72毫克68.38微摩尔，1.2当量，盐酸盐)，反应混合物在50摄氏度下搅拌24小时。反应完全后，反应液冷却至25摄氏度，反应液用水(5毫升)稀释，乙酸乙酯(5毫升×3)萃取。合并后的有机相用饱和食盐水(5毫升×2)洗涤，无水硫酸钠干燥，过滤，滤液浓缩，得到粗品经过高效液相色谱(柱子；Phenomenex Synergi C18 150*25毫米*10微米；流动相[水(甲酸)-乙腈]；乙腈％：40％-70％，10分钟)纯化得到化合物10。MS(ESI)m/z：527.1[M+H +]. 1H NMR(400MHz,DMSO-d 6)δppm 12.55(brs,1H),7.82-7.75(m,2H),6.52-6.50(m,1H),5.86–5.74(m,2H),4.55-4.54(m,3H),3.52(s,8H),1.31(d,J＝6.8Hz,3H).
化合物10经SFC检测【柱型号：Chiralcel OD-3 50×4.6mm I.D.,3μm；流动相：A相为超临界二氧化碳，B相为甲醇(0.05％二乙胺)；梯度(B％)：5％-40％】得到：化合物10的保留时间为1.540min，e.e.值为100％。
实施例11
Figure PCTCN2022107127-appb-000091
步骤A：向化合物1-9(0.5克，3.89毫摩尔，1当量)的N-甲基吡咯烷酮(10毫升)溶液中加入碳酸钾(1.08克，7.78毫摩尔，2当量)和化合物11-1(724.38毫克，3.89毫摩尔，1当量)，该混合体系在100摄氏度下搅拌12小时。待反应液冷却到室温后加入水(50毫升),白色固体析出，过滤并收集滤饼，减压干燥后得到化合物11-2。MS(ESI)m/z:223.2[M+H +-56].
步骤B：向11-2(1克，3.59毫摩尔，1当量)的乙酸乙酯(10毫升)溶液中加入盐酸乙酸乙酯(4摩尔每升，10毫升，11.13当量)，该混合体系在25摄氏度下搅拌0.5小时。将反应液直接减压干燥后得到化合物11-3的盐酸盐。MS(ESI)m/z:179.2[M+H +].
Figure PCTCN2022107127-appb-000092
步骤C：向化合物1-13(12.94克，57.73毫摩尔，11.45毫升，1当量)的四氢呋喃(30毫升)溶液中加入氯化锂(2.94克，69.28毫摩尔，1.42毫升，1.2当量)和三乙胺(7.01克，69.28毫摩尔，9.64毫升，1.2当量)，该混合体系在0摄氏度下搅拌0.5小时，然后加入化合物1-12(10克，57.73毫摩尔，1当量)的四氢呋喃(50毫升)溶液，该混合体系在25摄氏度下搅拌6小时。将反应液加入水(300毫升)，用乙酸乙酯(300毫升×2)萃取，合并有机相，用饱和食盐水(300毫升×2)洗涤，无水硫酸钠干燥，浓缩得到化合物11-4。
步骤D：向化合物11-4(14克，57.54毫摩尔，1当量)的乙酸乙酯(80毫升)溶液中，加入盐酸乙酸乙酯(4摩尔每升，80毫升，5.56当量)，该混合体系在25摄氏度下搅拌1小时。直接浓缩反应液，得到化合物11-5的盐酸盐。
步骤E：向化合物1-7(36.72克，115.23毫摩尔，1当量)的N,N-二甲基甲酰胺(250毫升)溶液中加入三乙胺(34.98克，345.68毫摩尔，48.11毫升，3当量)和化合物11-5(20.7克，115.23毫摩尔，1当量，盐酸盐)，该混合体系在25摄氏度下搅拌12小时。将反应液加入乙酸乙酯(500毫升)稀释，用水(500毫升×3)洗涤，再用饱和食盐水(500毫升×2)洗涤，无水硫酸钠干燥，过滤，浓缩滤液，粗品通过高效液相色谱(柱子：Phenomenex luna C18 250*80毫米*10微米；流动相：[水(甲酸)-乙腈]：乙腈％：50％-80％，20分钟)纯化，得到化合物11-6。MS(ESI)m/z:426.2[M+H +].
步骤F：向化合物11-6(10克，23.51毫摩尔，1当量)的三氟乙酸(100毫升)溶液中加入三氟甲磺酸(17.00克，113.28毫摩尔，10毫升，4.82当量)，该混合体系在25摄氏度搅拌1小时。向反应液中加入饱和的碳酸钠水溶液调节pH至5，用乙酸乙酯(300毫升×5)萃取，合并有机相，用饱和食盐水(500毫升×2)洗涤，无水硫酸钠干燥，过滤，浓缩滤液，粗品通过柱层析(硅胶柱,洗脱液梯度0～50％石油醚/乙酸乙酯，100毫升/分钟)纯化，得到化合物11-7。MS(ESI)m/z:305.9[M+H +].
步骤G：在0摄氏度下，向化合物11-7(5克，16.38毫摩尔，1当量)的四氢呋喃(50毫升)溶液中加入二异丁基氢化铝(1摩尔每升，49.14毫升，3当量)，该混合体系在10摄氏度搅拌1小时。向反应液中加入饱和的酒石酸钾钠(50毫升)溶液，在25摄氏度下搅拌1小时，用乙酸乙酯(100毫升×3)萃取，无水硫酸钠干燥，过滤，浓缩滤液，得到化合物11-8。
化合物11-8经SFC检测【柱型号：Chiralcel OJ-3 50×4.6mm I.D.,3μm；流动相：A相为超临界二氧化碳，B相为异丙醇(0.05％二乙胺)；梯度(B％)：5％-40％】得到：化合物11-8的保留时间为1.146min， e.e.值为95.652％。
步骤H：向化合物11-8(3克，11.40毫摩尔，1当量)的甲苯(30毫升)溶液中加入1,8-二氮杂环十一碳-7-烯(2.08克，13.68毫摩尔，2.06毫升，1.2当量)和叠氮磷酸二苯酯(3.76克，13.68毫摩尔，2.96毫升，1.2当量)，该混合体系在80摄氏度搅拌1小时。向反应液中加入水(100毫升)稀释，用乙酸乙酯(100毫升×2)萃取，合并有机相，用饱和食盐水(200毫升)洗涤，无水硫酸钠干燥，过滤，浓缩滤液，粗品通过柱层析(二氧化硅，石油醚/乙酸乙酯＝3/1，1/1)纯化，得到化合物11-9。
步骤I：向化合物11-9(2克，6.94毫摩尔，1当量)的四氢呋喃(20毫升)溶液中加入三苯基膦(2.73克，10.41毫摩尔，1.5当量)，该混合体系在40摄氏度搅拌0.5小时。再向反应液中加入水(3毫升)，该混合体系在40摄氏度搅拌1.5小时。加入水(50毫升)稀释，用乙酸乙酯(50毫升×2)萃取，合并有机相，用饱和食盐水(50毫升)洗涤，无水硫酸钠干燥，过滤，浓缩滤液，粗品通过柱层析(二氧化硅，石油醚/乙酸乙酯＝1/1，乙酸乙酯/甲醇＝5/1)纯化，得到化合物11-10。MS(ESI)m/z:263.15[M+H +].步骤H：向化合物11-10(50毫克，190.67微摩尔，1当量)的N,N-二甲基甲酰胺(1毫升)溶液中加入N,N-羰基二咪唑(37.10毫克，228.81微摩尔，1.2当量)和三乙胺(77.18毫克，762.69微摩尔，106.16微升，4当量)，该混合体系在25摄氏度下搅拌1小时，然后加入化合物11-3(40.94毫克，190.67微摩尔，989.50微升，1当量，盐酸盐)，该混合体系在25摄氏度下搅拌1小时。加水(30毫升)稀释，用乙酸乙酯(30毫升×2)萃取，合并有机相，用饱和食盐水(30毫升×2)洗涤，无水硫酸钠干燥，过滤，浓缩滤液，粗品通过高效液相色谱(柱子:Phenomenex Synergi C18 150*25毫米*10微米；流动相:[水(甲酸)-乙腈]；乙腈％：23％-41％,9分钟)纯化，得到化合物11。MS(ESI)m/z:467.1[M+H +]. 1H NMR(400MHz,DMSO-d 6)δppm 12.50(s,1H),8.23(s,2H),7.82(s,1H),6.77-6.46(m,1H),6.44(br dd,J＝3.2Hz,1H),5.65-5.60(m,2H),4.49(br d,J＝5.6Hz,1H),3.67-3.50(m,6H),3.36(br s,4H),2.08(s,3H),1.29(d,J＝6.4Hz,3H).
化合物11经SFC检测【柱型号：OD-3 50×4.6mm I.D.,3μm；流动相：A相为超临界二氧化碳，B相为甲醇(0.05％二乙胺)；梯度(B％)：5％-40％】得到：化合物11的保留时间为1.641min，e.e.值为96.060％。
实施例12
Figure PCTCN2022107127-appb-000093
步骤A：向化合物12-1(200毫克，942.12微摩尔，1当量)的N-甲基吡咯烷酮(2毫升)溶液中加入碳酸钾(260.41毫克，1.88毫摩尔，2当量)和化合物1-8(171.97毫克，942.12微摩尔，1当量)，该混合体系在80摄氏度下搅拌2小时。待反应液冷却到室温后加入水(10毫升)，固体析出，过滤并收集滤饼，减压干燥后得到化合物12-2。MS(ESI)m/z:303.1[M+H +-56].
步骤B：向12-2(310毫克，865.06微摩尔，1当量)的乙酸乙酯(3毫升)溶液中加入盐酸乙酸乙酯(4摩尔每升，3毫升，13.87当量)，该混合体系在25摄氏度下搅拌1小时。将反应液直接减压干燥后得到化合物12-3的盐酸盐。MS(ESI)m/z:259.0[M+H +-56].
Figure PCTCN2022107127-appb-000094
步骤C：向化合物11-10(80毫克，305.07微摩尔，1当量)的二氯甲烷(2毫升)溶液中加入N-甲基吗啉(46.29毫克，457.61微摩尔，50.31微升，1.5当量)和化合物12-4(73.79毫克，366.08微摩尔，1.2当量)，该混合体系在25摄氏度下搅拌12小时。加水(20毫升)稀释，用二氯甲烷(20毫升×2)萃取，合并有机相，用饱和食盐水(20毫升)洗涤，无水硫酸钠干燥，过滤，浓缩滤液，得到化合物12-5。MS(ESI)m/z:428.1[M+H +].
步骤D：向化合物12-5(110毫克，257.41微摩尔，1当量)的N,N-二甲基甲酰胺(3毫升)溶液中加入化合物12-3(91.03毫克，308.89微摩尔，1.2当量，盐酸盐)和三乙胺(31.26毫克，308.89微摩尔，42.99微升，1.2当量)，该混合体系在25摄氏度下搅拌12小时。加乙酸乙酯(20毫升)稀释，用水(20毫升×2)洗涤，合并有机相，用饱和食盐水(20毫升×2)洗涤，无水硫酸钠干燥，过滤，浓缩滤液，粗品通过高效液相色谱(柱子:Phenomenex Synergi C18 150*25毫米*10微米；流动相:[水(甲酸)-乙腈]；乙腈％：37％-67％，10分钟)纯化，再经过手性拆分(柱子:DAICEL CHIRALCEL OD(250毫米*30毫米，10微米)；流动相：[0.1％氨水异丙醇]；异丙醇％：30％-30％，3.3分钟)得到化合物12。MS(ESI)m/z:547.3[M+H +]. 1H NMR(400MHz,DMSO-d 6)δppm 12.48(br s,1H),8.70(s,2H),7.82(s,1H),6.93–6.90(m,1H),6.45-6.44(m,1H),5.64-5.60(m,2H),4.51-4.35(m,1H),4.37(br d,J＝10.4Hz,4H),3.69-3.66(t,2H),3.10(br d,J＝12.4Hz,2H),1.77-1.75(m,2H),1.52-1.50(m,2H),1.25(d,J＝6.8Hz,3H).
化合物12经SFC检测【柱型号：Chiralcel OD-3 50×4.6mm I.D.,3μm；流动相：A相为超临界二氧化碳，B相为异丙醇(0.05％二乙胺)；梯度(B％)：5％-40％】得到：化合物12的保留时间为1.675min，e.e.值为97.136％。
实施例13
Figure PCTCN2022107127-appb-000095
步骤A：向化合物1-9(1克，5.48毫摩尔，1当量)和化合物13-1(1.02克，5.48毫摩尔，1当量)的N-甲基吡咯烷酮(20毫升)溶液中加入碳酸钾(1.51克，10.96毫摩尔，2当量)，该混合体系在100摄氏度下搅拌12小时。待反应液冷却到室温后加入水(100毫升),混合液在25摄氏度下搅拌10分钟，白色固体析出，过滤并收集滤饼，减压干燥后得到化合物13-2。MS(ESI)m/z:277.1[M+H +-56].
步骤B：向13-2(1.6克，4.81毫摩尔，1当量)的乙酸乙酯(10毫升)溶液中加入盐酸乙酸乙酯(4摩尔每升，10毫升，8.31当量)，该混合体系在25摄氏度下搅拌1小时。将反应液直接减压干燥后得到化合物 13-3的盐酸盐。MS(ESI)m/z:233.1[M+H +].
步骤C：向化合物11-10(50毫克，190.67微摩尔，1当量)的N,N-二甲基甲酰胺(3毫升)溶液中加入N,N-羰基二咪唑(37.10毫克，228.81微摩尔，1.2当量)和三乙胺(77.18毫克，762.69微摩尔，106.16微升，4当量)，该混合体系在25摄氏度下搅拌1小时，然后加入化合物13-3(51.23毫克，190.67微摩尔，1当量，盐酸盐)，该混合体系在40摄氏度下搅拌3小时。加水(30毫升)稀释，用乙酸乙酯(30毫升×2)萃取，合并有机相，用饱和食盐水(30毫升×2)洗涤，无水硫酸钠干燥，过滤，浓缩滤液，粗品通过高效液相色谱(柱子:Phenomenex Synergi C18 150*25毫米*10微米；流动相:[水(甲酸)-乙腈]；乙腈％:25％-55％,10分钟)纯化，得到化合物13。MS(ESI)m/z:521.1[M+H +]. 1H NMR(400MHz,DMSO-d 6)δppm 12.50(s,1H),7.83-7.81(m,2H),7.42(d,J＝9.6Hz,1H),6.82–6.80(m,1H),6.44–6.43(br dd,J＝3.6Hz,1H),5.65-5.60(m,2H),4.51-4.50(m,1H),3.72-3.66(m,4H),3.46–3.45(m,2H),3.45-3.40(m,4H),1.29(d,J＝6.4Hz,3H).
化合物13经SFC检测【柱型号：Chiralcel OJ-3 50×4.6mm I.D.,3μm；流动相：A相为超临界二氧化碳，B相为甲醇(0.05％二乙胺)；梯度(B％)：5％-40％】得到：化合物13的保留时间为1.475min，e.e.值为96.192％。
实施例14
Figure PCTCN2022107127-appb-000096
步骤A：向化合物11-8(2.15克，8.17毫摩尔，1当量)的二甲基亚砜(20毫升)溶液中加入2-碘酰基苯甲酸(4.57克，16.34毫摩尔，2当量)，反应液在25摄氏度下搅拌24个小时。将反应液倒入水(80毫升)中，用乙酸乙酯(80毫升×2)萃取，合并有机相，用饱和食盐水(80毫升×2)洗涤，无水硫酸钠干燥，过滤，浓缩滤液，粗品经过硅胶柱层析(石油醚/乙酸乙酯＝10/1到1/1)纯化，得到化合物14-1。MS(ESI)m/z:262.1[M+H +].
步骤B：向化合物14-1(230毫克，880.55微摩尔，1当量)的1,2-二氯乙烷(6毫升)和四氢呋喃(6毫升)的溶液中加入甲胺盐酸盐(594.53毫克，8.81毫摩尔，10当量)，反应液在25摄氏度下搅拌12小时，然后加入醋酸硼氢化钠(466.56毫克，2.20毫摩尔，2.5当量)，该反应液继续在25摄氏度搅拌12小时。将反应液浓缩，粗品通过反向制备(柱子：330g Flash Column Welch Ultimate XB_C18 20-40μm；120A，样品溶解溶剂：大约2.00克样品溶解到10毫升甲醇中，流速：100毫升/分钟，流动相：乙腈/水，梯度水％：0-30％30分钟；30-100％25分钟；仪器：TELEDYNE ISCO CombiFlashRf150)纯化得到化合物14-2。MS(ESI)m/z:277.1[M+H +]。
步骤C：向化合物14-2(80毫克，289.58微摩尔，1当量)的二氯甲烷(2毫升)溶液中加入N-甲基吗啡啉(58.58毫克，579.17微摩尔，63.68微升，2当量)和化合物12-4(87.55毫克，434.38微摩尔，1.5当量)，反应液在25摄氏度下搅拌12小时。将反应液倒入水(80毫升)中，用乙酸乙酯(80毫升×2)萃取，合并有机相，用饱和食盐水(80毫升×2)洗涤，无水硫酸钠干燥，过滤，浓缩滤液，粗品通过薄层色谱(石油醚/乙酸乙酯＝1/1)纯化得到化合物14-3。MS(ESI)m/z:442.1[M+H +].
步骤D：向化合物14-3(40毫克，90.63微摩尔，1当量)的N,N-二甲基甲酰胺(1毫升)溶液中加入N,N-二异丙基乙基胺(35.14毫克，271.89微摩尔，47.36微升，3当量)和化合物1-11(48.70毫克，181.26umol,2当量，盐酸盐)，反应液在100摄氏度下搅拌12小时。反应液倒入水(30毫升)中，用乙酸乙酯(30毫升×2)萃取，合并有机相，用饱和食盐水(30毫升×2)洗涤，无水硫酸钠干燥，过滤，浓缩滤液，粗品经过高效液相色谱(柱子：Phenomenex Synergi C18 150*25毫米*10微米；流动相：[水(甲酸)-乙腈]；乙腈％：40％-70％，10分钟)纯化，再经过手性分离(柱子：DAICEL CHIRALCEL OJ(250mm*30毫米，10微米)；流动相：[0.1％氨水甲醇]；甲醇％:15％-15％，4.5分钟)纯化，T＝1.882分钟，得到化合物14。MS(ESI)m/z:535.3[M+H +]. 1H NMR(400MHz,氯仿-d)δppm 10.82(s,1H),8.51(s,2H),7.62(s,1H),5.82-5.61(m,2H),5.52-5.41(m,1H),4.35-4.22(m,1H),3.96-3.90(m,4H),3.89-3.75(m,2H),3.28-3.40(m,4H),2.82(s,3H),1.45(d,J＝6.4Hz,3H).
化合物14经SFC检测【柱型号：Chiralpak AD-3 50×4.6mm I.D.,3μm；流动相：A相为超临界二氧化碳，B相为甲醇(0.05％二乙胺)；梯度(B％)：5％-40％】得到：化合物14的保留时间为1.878min，e.e.值为99.036％。
实施例15
Figure PCTCN2022107127-appb-000097
步骤A：向化合物1-8(0.5克，2.74毫摩尔，1当量)和化合物15-1(548.61毫克，2.74毫摩尔，1当量)的N,N-二甲基甲酰胺(8毫升)溶液中加入碳酸钾(757.16毫克，5.48毫摩尔，2当量)，将反应液加热到80摄氏度搅拌2小时。反应液倒入水(50毫升)中，用乙酸乙酯(50毫升×2)萃取，合并有机相，用饱和食盐水(50毫升×2)洗涤，无水硫酸钠干燥，过滤，浓缩滤液得到化合物15-2。MS(ESI)m/z:247.1[M+H +-100].
步骤B：向化合物15-2(1克，2.89毫摩尔，1当量)的甲醇(10毫升)溶液中加入盐酸乙酸乙酯(10毫升，4摩尔每升)，反应液在25摄氏度搅拌30分钟。将反应液浓缩得到化合物15-3的盐酸盐。MS(ESI)m/z:247.1[M+H +].
步骤C：向化合物11-10(60毫克，228.81微摩尔，1当量)的N,N-二甲基甲酰胺(1.5毫升)溶液中加入羰基二咪唑(55.65毫克，343.22微摩尔，1.5当量)和N,N-二异丙基乙基胺(147.86毫克，1.14毫摩尔，199.27微升，5当量)，该混合物在25摄氏度搅拌1小时，然后向反应液中加入15-3(129.37毫克，457.62 微摩尔，2当量，盐酸盐)，将反应液加热到60摄氏度搅拌12小时。冷却后，反应液直接经过高效液相色谱(柱子：Unisil 3-100 C18 Ultra 150*50毫米*3微米；流动相：[水(甲酸)-乙腈]；乙腈％：34％-64％，7分钟)纯化，然后经过手性柱纯化(柱子：DAICEL CHIRALPAK AD(250毫米*30毫米，10微米)；流动相：[0.1％氨水异丙醇]；异丙醇％：40％-40％，4.9分钟)得到化合物15。MS(ESI)m/z:535.2[M+H +]. 1H NMR(400MHz,CHLOROFORM-d)δppm 10.28(br s,1H),8.50(s,2H),7.59(s,1H),5.80-5.69(m,1H),5.68-5.59(m,1H),5.50-5.39(m,1H),4.72-4.56(m,3H),4.30-4.18(m,2H),4.02–3.78(m,3H),3.40-3.31(m,1H),3.28-3.14(m,2H),1.43(d,J＝6.4Hz,3H),1.17(d,J＝6.8Hz,3H).
化合物15经SFC检测【柱型号：Chiralpak AD-3 50×4.6mm I.D.,3μm；流动相：A相为超临界二氧化碳，B相为乙醇(0.05％二乙胺)；梯度(B％)：5％-40％】得到：化合物15的保留时间为3.164min和3.507min，e.e.值为3.696％。
实施例16
Figure PCTCN2022107127-appb-000098
步骤A：向化合物16-1(500毫克，2.20毫摩尔，1当量)和化合物1-9(410.28毫克，2.20毫摩尔，1当量)的1,4-二氧六环溶液(5毫升)中加入三(二亚苄基丙酮)二钯(100.86毫克，110.14微摩尔，0.05当量)，2-双环己基膦-2,6-二异丙氧基-,1,1-联苯(51.40毫克，110.14微摩尔，0.05当量)和碳酸铯(1.44克，4.41毫摩尔，2当量)，反应体系用氮气置换，然后将反应液加热至80摄氏度搅拌12小时。反应液倒入水(60毫升)中，用乙酸乙酯(60毫升×2)萃取，合并有机相，用饱和食盐水(60毫升×2)洗涤，无水硫酸钠干燥，过滤，浓缩滤液，粗品通过硅胶柱层析(石油醚/乙酸乙酯＝10/1到3/1)纯化，得到化合物16-2。MS(ESI)m/z:333.2[M+H +].
步骤B：向反应瓶中加入化合物16-2(520毫克，1.56毫摩尔，1当量)和盐酸乙酸乙酯(20毫升，4摩尔每升)，该反应液在25摄氏度搅拌15分钟。将反应液浓缩得到化合物16-3的盐酸盐。MS(ESI)m/z:233.1[M+H +].
步骤C：向化合物11-10(60毫克，228.81微摩尔，1当量)的N,N-二甲基甲酰胺(1毫升)溶液中加入N,N-羰基二咪唑(55.65毫克，343.22微摩尔，1.5当量)和三乙胺(115.76毫克，1.14毫摩尔，159.23微升，5当量)，该混合物在25摄氏度搅拌1小时，然后向反应液中加入16-3(129.37毫克，457.62微摩尔，2当量，盐酸盐)，将反应液加热到60摄氏度搅拌12小时。反应液倒入水(50毫升)中，用乙酸乙酯(50毫升×2)萃取，合并有机相，用饱和食盐水(50毫升)洗涤，无水硫酸钠干燥，过滤，浓缩滤液，得到的粗品通过高效液相色谱(柱子：YMC Triart C18 150*25毫米*5微米；流动相：[水(甲酸)-乙腈]；乙腈％：23％-53％，10分钟)纯化得到化合物16。MS(ESI)m/z:521.3[M+H +]. 1H NMR(400MHz,氯仿-d)δppm10.20(br s,1H),8.42(s,2H),7.59(s,1H),5.80-5.59(m,2H),5.49-5.39(m,1H),4.72-4.56(m,1H),4.18-4.33(m,1H),4.03–3.87(m,2H),3.68-3.58(m,4H),3.46-3.37(m,4H)，1.43(d,J＝6.8Hz,3H).
化合物16经SFC检测【柱型号：Chiralcel OJ-3 50×4.6mm I.D.,3μm；流动相：A相为超临界二氧化碳， B相为甲醇(0.05％二乙胺)；梯度(B％)：5％-40％】得到：化合物16的保留时间为1.578min，e.e.值为96.492％。
实施例17
Figure PCTCN2022107127-appb-000099
步骤A：向化合物1-8(1克，5.48毫摩尔，1当量)和化合物17-1(1.10克，5.48毫摩尔，1.08毫升，1当量)的N,N-二甲基甲酰胺(15毫升)溶液中加入碳酸钾(1.51克，10.96毫摩尔，2当量)，将反应液加热到80摄氏度搅拌2小时。反应液倒入水(80毫升)中，用乙酸乙酯(80毫升×2)萃取，合并有机相，用饱和食盐水(80毫升)洗涤，无水硫酸钠干燥，过滤，浓缩滤液得到化合物17-2。MS(ESI)m/z:291.1[M+H +-56].
步骤B：向反应瓶中加入化合物17-2(1.9克，5.49毫摩尔，1当量)和盐酸乙酸乙酯(20毫升，4摩尔每升)，该反应液在25摄氏度搅拌15分钟。将反应液浓缩得到化合物17-3的盐酸盐。MS(ESI)m/z:247.1[M+H +].
步骤C：向化合物11-10(60毫克，228.81微摩尔，1当量)的N,N-二甲基甲酰胺(2毫升)溶液中加入N,N-羰基二咪唑(44.52毫克，274.57微摩尔，1.2当量)和三乙胺(115.76毫克，1.14毫摩尔，159.23微升，5当量)，该混合物在25摄氏度搅拌1小时，然后向反应液中加入17-3(97.02毫克，343.21微摩尔，1.5当量，盐酸盐)，反应液在25摄氏度搅拌12小时。反应液倒入水(50毫升)中，用乙酸乙酯(50毫升×2)萃取，合并有机相，用饱和食盐水(50毫升)洗涤，无水硫酸钠干燥，过滤，浓缩滤液，得到的粗品通过高效液相色谱(柱子：Unisil 3-100 C18 Ultra 150*50毫米*3微米；流动相：[水(甲酸)-乙腈]；乙腈％：26％-56％，7分钟)纯化得到化合物17。MS(ESI)m/z:535.3[M+H +]. 1H NMR(400MHz,氯仿-d)δppm11.69(br s,1H),8.48(s,2H),7.60(s,1H),5.75-5.53(m,2H),5.48-5.38(m,1H),4.80(br s,1H),4.29-4.16(m,1H),3.99-3.92(m,2H),3.90-3.79(m,4H),3.60(t,J＝5.6Hz,2H),3.39(t,J＝6.0Hz,2H),2.02–1.93(m,2H),1.39(d,J＝6.4Hz,3H).
化合物17经SFC检测【柱型号：Chiralcel OJ-3 50×4.6mm I.D.,3μm；流动相：A相为超临界二氧化碳，B相为甲醇(0.05％二乙胺)；梯度(B％)：5％-40％】得到：化合物17的保留时间为1.041min，e.e.值为96.008％。
实施例18
Figure PCTCN2022107127-appb-000100
步骤A：向化合物1-9(1.33克，7.17毫摩尔，1当量)和化合物18-1(1克，7.17毫摩尔，1当量)的N-甲基吡咯烷酮(20毫升)溶液中加入碳酸钾(1.49克，10.75毫摩尔，1.5当量)，将反应液加热到80摄氏度搅拌2小时。反应液倒入水(100毫升)中，用乙酸乙酯(100毫升×2)萃取，合并有机相，用饱和食盐水(100毫升×2)洗涤，无水硫酸钠干燥，过滤，浓缩滤液得到化合物18-2。MS(ESI)m/z:234.1[M+H +-56].
步骤B：向反应瓶中加入化合物18-2(1.9克，6.57毫摩尔，1当量)和盐酸甲醇(20毫升，4摩尔每升)，该反应液在25摄氏度搅拌30分钟。将反应液浓缩得到化合物18-3的盐酸盐。MS(ESI)m/z:190.2[M+H +].步骤C：向化合物11-10(100毫克，381.34微摩尔，1当量)的N,N-二甲基甲酰胺(2毫升)溶液中加入N,N-羰基二咪唑(80.38毫克，495.75微摩尔，1.3当量)和三乙胺(192.94毫克，1.91毫摩尔，265.39微升，5当量)，该混合物在25摄氏度搅拌1小时，然后向反应液中加入18-3(86.06毫克，381.34微摩尔，1当量，盐酸盐)，反应液在25摄氏度搅拌12小时。反应液倒入水(40毫升)中，用乙酸乙酯(40毫升×2)萃取，合并有机相，用饱和食盐水(40毫升×2)洗涤，无水硫酸钠干燥，过滤，浓缩滤液，得到的粗品通过高效液相色谱(柱子：Unisil 3-100 C18 Ultra 150*50毫米*3微米；流动相：[水(甲酸)-乙腈]；乙腈％：19％-49％，7分钟)纯化得到化合物18。MS(ESI)m/z:478.2[M+H +]。 1H NMR(400MHz,DMSO-d 6)δppm 12.49(br s,1H),7.89(d,J＝10.0Hz,1H),7.82(s,1H),7.36(d,J＝9.6Hz,1H),6.82-6.79(m,1H),6.45–6.43(m,1H),5.71-5.55(m,2H),4.56-4.44(m,1H),3.78-3.70(m,4H),3.67-3.65(m,2H),3.49-3.41(m,4H),1.29(d,J＝6.4Hz,3H).
化合物18经SFC检测【柱型号：Chiralcel OJ-3 50×4.6mm I.D.,3μm；流动相：A相为超临界二氧化碳，B相为甲醇(0.05％二乙胺)；梯度(B％)：5％-40％】得到：化合物18的保留时间为1.552min，e.e.值为100％。
实施例19
Figure PCTCN2022107127-appb-000101
步骤A：向化合物19-1(3克，12.98毫摩尔，1当量)和化合物1-9(2.90克，15.58毫摩尔，1.2当量)的1，4-二氧六环(30毫升)溶液中加入2-双环己基膦-2，6-二异丙氧基-1,1-联苯(605.79毫克，1.30毫摩尔，0.1当量)，叔丁醇钠(2.50克，25.96毫摩尔，2当量)，三(二亚苄基丙酮)二钯(594.39毫克,649.10微摩尔,0.05当量)，氮气置换三次后在100摄氏度搅拌12小时，反应完后加入10毫升乙酸乙酯，过滤，滤液减压浓缩得到的粗产品经硅胶薄层色谱法(石油醚/乙酸乙酯＝1:1)纯化得到化合物19- 2。MS(ESI)m/z：337.2[M+H +].
步骤B：向化合物19-2(3克，8.92毫摩尔，1当量)的四氢呋喃(10毫升)溶液中加入冰醋酸(10毫升)和水(10毫升)，该混合体系在氮气置换三次后在70摄氏度搅拌12小时。反应完成后，用饱和的碳酸钠溶液调节反应液的PH为7，反应液用乙酸乙酯(30毫升×3)萃取，饱和食盐水洗涤(30毫升×2)，无水硫酸钠干燥，过滤，滤液减压浓缩得到的粗产品通过柱层析(硅胶柱,洗脱液梯度0～30％石油醚/乙酸乙酯，100毫升/分钟)纯化得到化合物19-3。MS(ESI)m/z：253.2[M+H +].
步骤C：向化合物19-3(771毫克，3.06毫摩尔，1当量)和化合物19-4(815.90毫克，3.06毫摩尔，1当量)的乙腈(10毫升)中加入氟化钾(355.06毫克，6.11毫摩尔，143.17微升，2当量)，将该混合体系在25摄氏度搅拌4小时。反应完全后，乙腈(5毫升)加入到反应液中，过滤，滤液真空干燥得到的残留物用柱层析(硅胶柱，洗脱液梯度0～15％石油醚/乙酸乙酯100毫升/分钟)纯化得到化合物19-5。MS(ESI)m/z:303.1[M+H +].
步骤D：向化合物19-5(885毫克，2.93毫摩尔，1当量)的乙酸乙酯(6毫升)溶液中加入盐酸乙酸乙酯(4摩尔每升，6毫升，8.2当量)，将该混合液在25摄氏度搅拌12小时。反应完成后，直接将反应液减压浓缩得到化合物19-6的盐酸盐。MS(ESI)m/z：203.2[M+H +].
步骤E：向化合物11-10(100毫克，381.34微摩尔，1当量)的N,N-二甲基甲酰胺(2毫升)溶液中加入三乙胺(192.94毫克，1.91毫摩尔，265.39微升，5当量)和N,N-羰基二咪唑(80.38毫克，495.75微摩尔，1.3当量)，该混合体系在25摄氏度搅拌1小时后，将化合物19-6(109.22毫克，457.61微摩尔，1.2当量，盐酸盐)加入到反应液中，该混合体系在25摄氏度搅拌12小时。反应完成后，向反应液中加水(10毫升)，乙酸乙酯(10毫升×3)萃取，合并有机相，用饱和食盐水(10毫升×2)洗涤，无水硫酸钠干燥，过滤，浓缩滤液，残留物用高效液相色谱(柱子：Phenomenex Synergi C18 150*25毫米*10微米；流动相：[水(0.225％甲酸)-乙腈]；乙腈％：22％-42％，10分钟)纯化，得到化合物19。MS(ESI)m/z:491.1[M+H +]. 1H NMR(400MHz,DMSO-d 6)δppm 12.57-12.45(m,1H),8.00-7.93(m,1H),7.82(s,1H),7.70-7.35(m,1H),6.86-6.72(m,1H),6.54-6.39(m,1H),6.21-6.06(m,1H),5.74-5.52(m,2H),4.56-4.43(m,1H),3.65(br t,J＝4.8Hz,2H),3.45(br d,J＝4.4Hz,1H),3.40-3.35(m,4H),3.11(br d,J＝4.8Hz,2H),2.85-2.78(m,1H),1.29(br d,J＝6.4Hz,3H).
实施例20
Figure PCTCN2022107127-appb-000102
步骤A：向化合物20-1(500毫克，2.50毫摩尔，1当量)和化合物1-8(455.70毫克，2.50毫摩尔，1当量)的N,N-二甲基甲酰胺(5毫升)溶液中加入碳酸钾(690.07毫克，4.99毫摩尔，2当量)，将反应液加热到80摄氏度搅拌1小时。水(15毫升)加入到反应液中，反应液25摄氏度搅拌15分钟，反应液过滤，滤饼减压浓缩得到化合物20-2。MS(ESI)m/z:291.1[M+H +-56].
步骤B：向反应瓶中加入化合物20-2(460毫克，1.33毫摩尔，1当量)和乙酸乙酯(4毫升)，盐酸乙 酸乙酯(4毫升，4摩尔每升，12.05当量)，该反应液在25摄氏度搅拌12小时。将反应液浓缩得到化合物20-3的盐酸盐。MS(ESI)m/z:247.1[M+H +].
步骤C：向化合物11-10(100毫克，381.34微摩尔，1当量)的N,N-二甲基甲酰胺(5毫升)溶液中加入N,N-羰基二咪唑(80.38毫克，495.75微摩尔，1.3当量)和三乙胺(192.94毫克，1.91毫摩尔，265.39微升，5当量)，该混合物在25摄氏度搅拌1小时，然后向反应液中加入20-3(129.36毫克，457.61微摩尔，1.2当量，盐酸盐)，将反应液25摄氏度搅拌1小时。反应液倒入水(10毫升)中，用乙酸乙酯(10毫升×3)萃取，合并有机相，用饱和食盐水(10毫升×2)洗涤，无水硫酸钠干燥，过滤，浓缩滤液，得到的粗品再经过手性分离(柱子：DAICEL CHIRALCEL OD(250毫米*30毫米，10微米)；流动相：[0.1％氨水甲醇]；甲醇％:20％-20％，4.1分钟)纯化，T＝1.318分钟，得到化合物20。MS(ESI)m/z:535.2[M+H +]. 1H NMR(400MHz,DMSO-d 6)δppm 12.49(s,1H),8.72(s,2H),7.81(s,1H),6.76(t,J＝5.6Hz,1H),6.42(br dd,J＝7.2,3.6Hz,1H),5.74-5.49(m,2H),4.80(td,J＝6.4,3.2Hz,1H),4.55-4.47(m,1H),4.45-4.38(m,1H),3.98(br d,J＝12.8Hz,1H),3.86(br d,J＝13.6Hz,1H),3.67(br t,J＝4.4Hz,2H),3.24-3.16(m,1H),3.07(dd,J＝13.6,4.0Hz,1H),2.92-2.82(m,1H),1.29(d,J＝6.4Hz,3H),1.10(d,J＝6.8Hz,3H).
化合物20经SFC检测【柱型号：OD-3 50×4.6mm I.D.,3μm；流动相：A相为超临界二氧化碳，B相为甲醇(0.05％二乙胺)；梯度(B％)：5％-40％】得到：化合物20的保留时间为1.318min，e.e.值为100％。
实施例21
Figure PCTCN2022107127-appb-000103
步骤A：向化合物21-1(500毫克，2.50毫摩尔，1当量)和化合物1-8(455.70毫克，2.50毫摩尔，1当量)的N,N-二甲基甲酰胺(5毫升)溶液中加入碳酸钾(690.07毫克，4.99毫摩尔，2当量)，将反应液加热到80摄氏度搅拌1小时。水(15毫升)加入到反应液中，反应液25摄氏度搅拌15分钟，反应液过滤，滤饼减压浓缩得到化合物21-2。MS(ESI)m/z:291.1[M+H +-56].
步骤B：向反应瓶中加入化合物21-2(437毫克，1.26毫摩尔，1当量)和乙酸乙酯(4毫升)，盐酸乙酸乙酯(4毫升，4摩尔每升，12.68当量)，该反应液在25摄氏度搅拌12小时。将反应液浓缩得到化合物21-3的盐酸盐。MS(ESI)m/z:247.2[M+H +].
步骤C：向化合物11-10(100毫克，381.34微摩尔，1当量)的N,N-二甲基甲酰胺(5毫升)溶液中加入N,N-羰基二咪唑(80.38毫克，495.75微摩尔，1.3当量)和三乙胺(192.94毫克，1.91毫摩尔，265.39微升，5当量)，该混合物在25摄氏度搅拌1小时，然后向反应液中加入21-3(129.36毫克，457.61微摩尔，1.2当量，盐酸盐)，将反应液25摄氏度搅拌1小时。反应液倒入水(10毫升)中，用乙酸乙酯(10毫升×3)萃取，合并有机相，用饱和食盐水(10毫升×2)洗涤，无水硫酸钠干燥，过滤，浓缩滤液，得到的粗品再经过手性分离(柱子：DAICEL CHIRAL Pak IG(250毫米*30毫米，10微米)；流动相：[0.1％氨水甲醇]；甲醇％：30％-30％，5.7分钟)纯化，T＝2.511分钟，得到化合物21。MS(ESI)m/z:535.1[M+H +]. 1H NMR(400MHz,DMSO-d 6)δppm 12.49(s,1H),8.72(s,2H),7.81(s,1H),6.76(t,J＝5.6Hz,1H),6.42(br  dd,J＝7.6,3.6Hz,1H),5.71-5.46(m,2H),4.80(td,J＝6.0,3.2Hz,1H),4.55-4.46(m,1H),4.44-4.38(m,1H),3.98(br d,J＝13.2Hz,1H),3.86(br d,J＝13.2Hz,1H),3.72-3.62(m,2H),3.26-3.15(m,1H),3.07(dd,J＝13.6,3.6Hz,1H),2.87(dt,J＝12.4,3.6Hz,1H),1.29(d,J＝6.4Hz,3H),1.10(d,J＝6.4Hz,3H).
化合物21经SFC检测【柱型号：Chiralpak IG-3 50×4.6mm I.D.,3μm；流动相：A相为超临界二氧化碳，B相为甲醇(0.05％二乙胺)；梯度(B％)：20％-20％】得到：化合物21的保留时间为2.511min，e.e.值为100％。
实施例22
Figure PCTCN2022107127-appb-000104
步骤A：向化合物22-1(500毫克，1.62毫摩尔，1当量)和化合物1-8(354.19毫克，1.94毫摩尔，1.2当量)的1，4-二氧六环(5毫升)溶液中加入二氯双(三苯基膦)钯(II)(113.50毫克，161.70微摩尔，0.1当量)，碳酸铯(2.11克，6.47毫摩尔，4当量)，水(1毫升)，氮气置换三次后在100摄氏度搅拌12小时，反应完后加入10毫升乙酸乙酯，过滤，滤液减压浓缩得到的粗产品经硅胶柱层析(硅胶柱,洗脱液梯度0～8％石油醚/乙酸乙酯，100毫升/分钟)纯化得到化合物22-2。MS(ESI)m/z:274.1[M+H +-56].
步骤B：向反应瓶中加入化合物22-2(420毫克，1.28毫摩尔，1当量)和乙醇(4毫升)，钯碳(80毫克，纯度：10％)，该反应液氢气置换三次后在氢气(15磅每平方英寸)保护下25摄氏度搅拌1小时。将反应液过滤浓缩滤液得到化合物22-3。MS(ESI)m/z:276.1[M+H+-56]。
步骤C：向反应瓶中加入化合物22-3(375毫克，1.13毫摩尔，1当量)和乙酸乙酯(2毫升)，盐酸乙酸乙酯(2毫升，4摩尔每升)，该反应液在25摄氏度搅拌12小时。将反应液浓缩得到化合物22-4的盐酸盐。MS(ESI)m/z:232.2[M+H +].
步骤D：向化合物11-10(100毫克，381.34微摩尔，1当量)的N,N-二甲基甲酰胺(3毫升)溶液中加入N,N-羰基二咪唑(80.38毫克，495.75微摩尔，1.3当量)和三乙胺(192.94毫克，1.91毫摩尔，265.39微升，5当量)，该混合物在25摄氏度搅拌1小时，然后向反应液中加入22-4(122.49毫克，457.61微摩尔，1.2当量，盐酸盐)，将反应液25摄氏度搅拌1小时。反应液倒入水(10毫升)中，用乙酸乙酯(10毫升×3)萃取，合并有机相，用饱和食盐水(10毫升×2)洗涤，无水硫酸钠干燥，过滤，浓缩滤液，残留物用高效液相色谱(柱子:Phenomenex Synergi C18 150*25毫米*10微米；流动相：[水(0.225％甲酸)-乙腈]；乙腈％：28％-58％，10分钟)纯化，得到化合物22。MS(ESI)m/z:520.1[M+H +]. 1H NMR(400MHz,DMSO- d 6)δppm 12.48(br s,1H),9.21(s,2H),7.82(s,1H),6.70(br s,1H),6.42(br d,J＝2.4Hz,1H),5.80-5.42(m,2H),4.50(br d,J＝5.6Hz,1H),4.03(br d,J＝12.8Hz,2H),3.65(br s,2H),3.16-3.08(m,1H),2.83(br t,J＝12.4Hz,2H),1.92(br d,J＝12.0Hz,2H),1.72-1.53(m,2H),1.29(br d,J＝6.4Hz,3H).
化合物22经SFC检测【柱型号：Chiralpak IG-3 50×4.6mm I.D.,3μm；流动相：A相为超临界二氧化碳，B相为甲醇(0.05％二乙胺)；梯度(B％)：5％-40％】得到：化合物22的保留时间为2.322min，e.e.值为96.406％。
实施例23
Figure PCTCN2022107127-appb-000105
步骤A：向化合物23-1(1克，5.32毫摩尔，1当量)和化合物1-9(1.19克，6.38毫摩尔，1.2当量)的1，4-二氧六环(10毫升)溶液中加入(R)-(+)-2,2-双(二苯膦基)-1,1-联萘(331.13毫克，531.79微摩尔，0.1当量)，碳酸铯(2.60克，7.98毫摩尔，1.5当量)，醋酸钯(119.39毫克，531.79微摩尔，0.1当量)，氮气置换三次后在100摄氏度搅拌12小时，反应完后加入10毫升乙酸乙酯，过滤，滤液减压浓缩得到的粗产品经高效液相色谱(柱子:Phenomenex luna C18 250*70毫米*10微米；流动相：[水(0.225％甲酸)-乙腈]；乙腈％：35％-65％，20分钟)纯化，得到化合物23-2。MS(ESI)m/z:294.1[M+H +].
步骤B：向反应瓶中加入化合物23-2(300毫克，1.02毫摩尔，1当量)和乙酸乙酯(3毫升)，盐酸乙酸乙酯(3毫升，4摩尔每升，11.74当量)，该反应液在25摄氏度搅拌12小时。将反应液浓缩得到化合物23-3的盐酸盐。MS(ESI)m/z:194.1[M+H +].
Figure PCTCN2022107127-appb-000106
步骤C：向化合物11-10(100毫克，381.34微摩尔，1当量)的N,N-二甲基甲酰胺(3毫升)溶液中加入N,N-羰基二咪唑(80.38毫克，495.75微摩尔，1.3当量)和三乙胺(192.94毫克，1.91毫摩尔，265.39微升，5当量)，该混合物在25摄氏度搅拌0.5小时，得到化合物23-4的N,N-二甲基甲酰胺溶液直接用于下一步。MS(ESI)m/z:357.1[M+H +].
步骤D：将化合物23-3(105.12毫克，457.60微摩尔，1.2当量，盐酸盐)加入到化合物23-4(135.87毫克，381.33微摩尔，1当量)的N,N-二甲基甲酰胺溶液中，将反应液25摄氏度搅拌12小时。反应液倒入水(10毫升)中，用乙酸乙酯(10毫升×3)萃取，合并有机相，用饱和食盐水(10毫升×2)洗涤，无水硫酸钠干燥，过滤，浓缩滤液，残留物用高效液相色谱(柱子:Phenomenex Synergi C18 150*25毫米*10微米；流动相：[水(0.225％甲酸)-乙腈]；乙腈％：31％-51％，10分钟)纯化，得到化合物23。MS(ESI)m/z:482.1[M+H +]. 1H NMR(400MHz,DMSO-d 6)δppm 12.50(br s,1H),7.81(s,1H),7.62(d,J＝4.4Hz,1H),6.85(br  t,J＝5.2Hz,1H),6.44(br d,J＝3.6Hz,1H),6.30(d,J＝4.4Hz,1H),5.70-5.51(m,2H),4.57-4.42(m,1H),3.65(br t,J＝4.4Hz,2H),3.48-3.43(m,4H),3.21(br t,J＝4.8Hz,4H),1.29(d,J＝6.4Hz,3H).
化合物23经SFC检测【柱型号：Chiralcel OJ-3 50×4.6mm I.D.,3μm；流动相：A相为超临界二氧化碳，B相为甲醇(0.05％二乙胺)；梯度(B％)：5％-40％】得到：化合物23的保留时间为1.524min，e.e.值为96.872％。
实施例24
Figure PCTCN2022107127-appb-000107
步骤A：在0摄氏度，向化合物1-13(6.11克，27.26毫摩尔，2.5当量)的乙腈(45毫升)溶液中加入氯化锂(1.16克，27.26毫摩尔，2.5当量)和N,N-二异丙基乙基胺(3.52克，27.26毫摩尔，2.5当量)，该混合体系在0摄氏度下搅拌0.5小时。在0摄氏度下，向体系中缓慢滴化合物24-1(2.5克，10.90毫摩尔，1.0当量)的乙腈(30毫升)溶液，该混合体系在0摄氏度下继续搅拌2.5个小时。将反应液浓缩干，残留物用柱层析(硅胶,石油醚/乙酸乙酯＝10/1，5/1)纯化，得到化合物24-2。MS(ESI)m/z:322.1[M+Na +]. 1H NMR(400MHz,氯仿-d)δppm 6.93-6.73(m,1H),6.04–5.75(m,1H),4.63-4.36(m,1H),4.24-4.06(m,3H),3.80(dd,J＝9.2Hz,1H),1.66-1.58(m,3H),1.57-1.41(m,12H),1.32-1.25(m,3H).
步骤B：25摄氏度下，向化合物24-2(1.6克，5.34毫摩尔，1当量)的二氯甲烷(10毫升)溶液中加入三氟乙酸(12.19克，206.89毫摩尔，7.91毫升，20当量)和水(2.21克，122.93毫摩尔，2.21毫升，23当量)，该混合体系在25摄氏度搅拌1小时。将反应液减压浓缩得到化合物24-3的三氟乙酸盐。MS(ESI)m/z:159.1[M+H +].
步骤C：25摄氏度下，向化合物24-3(2克，5.16毫摩尔，1当量，三氟乙酸盐)的N,N-二甲基甲酰胺(50毫升)溶液中，加入化合物1-7(1.65克，5.16毫摩尔，1当量)和三乙胺(2.61克，25.82毫摩 尔，3.59毫升，5.0当量)，该混合体系在25摄氏度下搅拌1个小时。向反应液中加入水(200毫升)，用乙酸乙酯(100毫升×2)萃取，合并有机相，用饱和食盐水(50毫升×4)洗涤，无水硫酸钠干燥，过滤，浓缩。得到的残留物用柱层析(硅胶,石油醚/乙酸乙酯＝2/1，1/1)纯化得到化合物24-4。MS(ESI)m/z:442.0[M+H +].
步骤D：0摄氏度下，向化合物24-4(0.3克，675.38微摩尔，1当量)的三氟乙酸(3毫升)溶液中加入三氟甲磺酸(510毫克，3.4毫摩尔，300微升，5.03当量)，该混合体系在0摄氏度下搅拌0.5小时。将反应液缓慢滴加到饱和碳酸氢钠(50毫升)水溶液中，搅拌5分钟后，用乙酸乙酯(50毫升×2)萃取，合并有机相，用饱和食盐水(50毫升×2)洗涤，无水硫酸钠干燥，过滤，浓缩滤液，得到化合物24-5。MS(ESI)m/z:322.2,[M+H +].
步骤E：在25摄氏度，向化合物24-5(0.2克，622.56微摩尔，1当量)的二氯甲烷(5毫升)溶液中加入3,4-二氢吡喃(78.55毫克，933.85微摩尔，1.5当量)和三氟乙酸(7.10毫克，62.26微摩尔，0.1当量)，该混合体系在25摄氏度搅拌2小时。向反应液中加入水(50毫升)，搅拌5分钟后，用乙酸乙酯(50毫升×2)萃取，合并有机相，用饱和食盐水(50毫升×2)洗涤，无水硫酸钠干燥，过滤，浓缩滤液，得到化合物24-6。MS(ESI)m/z:406.1[M+H +].
步骤F：0摄氏度，氮气保护下，向化合物24-6(240毫克，592.05微摩尔，1当量)的四氢呋喃(5毫升)溶液中缓慢滴加二异丁基氢化铝锂(1摩尔每升，1.78毫升，3当量)，该混合体系在0摄氏度，氮气下保护下搅拌0.5小时。向反应液中缓慢加入饱和氯化铵(50ml)水溶液，搅拌5分钟，用乙酸乙酯(50毫升×2)萃取，合并有机相，用饱和食盐水(50毫升×2)洗涤，无水硫酸钠干燥，过滤，浓缩滤液，得到化合物24-7。MS(ESI)m/z:364.0[M+H +].
步骤G：向化合物24-7(210毫克，577.98微摩尔，1当量)的二氯甲烷(5毫升)溶液中加入N-甲基吗啡啉(64.31毫克，635.78毫摩尔，69.90微升，1.1当量)和化合物12-4(128.15毫克，635.78微摩尔，1.1当量)，该反应体系在25摄氏度搅拌16小时。向反应液中加入水(50毫升)，搅拌5分钟后，用乙酸乙酯(50毫升×2)萃取，合并有机相，用饱和食盐水(50毫升×2)洗涤，无水硫酸钠干燥，过滤，浓缩滤液，得到化合物24-8。MS(ESI)m/z:529.2[M+H +].
步骤H：向化合物24-8(0.3克，567.71微摩尔，1当量)的N,N-二甲基甲酰胺(5毫升)溶液中加入化合物1-11(160.15毫克，596.10微摩尔，1.05当量，盐酸盐)和N,N-二异丙基乙基胺(110.06毫克，851.57微摩尔，148.33微升，1.5当量)，该反应体系在25摄氏度搅拌3个小时。向反应液中加入水(50毫升)，搅拌5分钟后，用乙酸乙酯(50毫升×2)萃取，合并有机相，用饱和食盐水(50毫升×2)洗涤，无水硫酸钠干燥，过滤，浓缩滤液，得到化合物24-9。MS(ESI)m/z:622.3[M+H +].
步骤I：向化合物24-9(0.3克，482.68微摩尔，1当量)的二氯甲烷(5毫升)溶液中加入三氟乙酸(1.54克，13.51毫摩尔，1毫升，27.98当量)，该混合体系在25摄氏度搅拌1小时。将反应液浓缩，残留物用高效液相色谱(柱子:Waters Xbridge C18 150*50毫米*10微米；流动相：[水(碳酸氢铵)-乙腈]；乙腈％：26％-56％，10分钟)纯化，得到化合物24。MS(ESI)m/z:538.1[M+H +]. 1H NMR(400MHz,DMSO-d 6)δppm 10.57–10.16(m,1H),8.52(s,2H),7.55(s,1H),6.43-6.12(m,1H),6.02–5.68(m,2H),4.69(d,J＝4.8Hz,2H),4.28(br s,1H),3.93(br t,J＝4.8Hz,5H),3.85-3.79(m,1H),3.61-3.55(m,4H),2.34-2.02(m,1H).
化合物24经SFC检测【柱型号：Chiralcel OJ-3 50×4.6mm I.D.,3μm；流动相：A相为超临界二氧化碳，B相为甲醇(0.05％二乙胺)；梯度(B％)：5％-40％】得到：化合物24的保留时间为1.505min，e.e.值为100％。
实施例25
Figure PCTCN2022107127-appb-000108
步骤A：向化合物25-1(1克，5.48毫摩尔，662.25微升，1当量)的N-甲基吡咯烷酮(10毫升)溶液中加入化合物1-9(1.02克，5.48毫摩尔，1当量)，该混合体系在80摄氏度搅拌1小时。冷却至室温，向反应液中加入水(50毫升)，搅拌5分钟后，将上述混合液过滤，滤饼减压干燥得到化合物25-2。MS(ESI)m/z:333.1[M+H +].
步骤B：将化合物25-2(1克，3.01毫摩尔，1当量)加入到盐酸乙酸乙酯(4摩尔每升，10毫升，13.29当量)溶液中，该混合体系在25摄氏度搅拌1小时。过滤，收集滤饼,得到化合物25-3的盐酸盐。MS(ESI)m/z:233.2[M+H +].
步骤D：向化合物23-4(67.00毫克，188.04微摩尔，1当量)的N,N-二甲基甲酰胺(5毫升)溶液中加入化合物25-3(60.40毫克，225.65微摩尔，1.2当量，盐酸盐)和三乙胺(57.08毫克，564.13微摩尔，78.52微升，3当量)，将该混合体系在25摄氏度搅拌1小时。反应液浓缩，得到的残留物用高效液相色谱(柱子:Waters Xbridge C18 150*50毫米*10微米；流动相:[水(碳酸氢铵)-乙腈]；％：27％-27％，10分钟)，和手性拆分(DAICEL CHIRALCEL OD(250毫米*30毫米，10微米)；流动相：[0.1％氨水甲醇]；甲醇％：20％-20％，2.6分钟)纯化得到化合物25。MS(ESI)m/z:521.2[M+H +]. 1H NMR(400MHz,DMSO-d 6)δppm 12.51(s,1H),8.71(d,J＝4.8Hz,1H),7.83(s,1H),7.05(d,J＝4.8Hz,1H),6.80(br s,1H),6.46(br s,1H),5.70-5.54(m,2H),4.51(br d,J＝5.6Hz,1H),3.76-3.71(m,4H),3.66(br d,J＝4.2Hz,2H),3.41-3.38(m,4H),1.30(br d,J＝6.4Hz,3H).
化合物25经SFC检测【柱型号：OD-3 50×4.6mm I.D.,3μm；流动相：A相为超临界二氧化碳，B相为甲醇(0.05％二乙胺)；梯度(B％)：5％-40％】得到：化合物25的保留时间为1.413min，e.e.值为100％。
实施例26
Figure PCTCN2022107127-appb-000109
步骤A：向化合物1-9(3克，16.11毫摩尔，1当量)和化合物26-1(2.36克，16.11毫摩尔，1当量，盐酸盐)的N,N-二甲基甲酰胺(30毫升)溶液中加入N,N-二异丙基乙胺(2.08克，16.11毫摩尔，2.81毫升，1当量)，该混合体系在40摄氏度下搅拌12小时。加水(50毫升)稀释，用乙酸乙酯(50毫升×2)萃取，合并有机相，用饱和食盐水(30毫升)洗涤，无水硫酸钠干燥，过滤，浓缩滤液，得到化合物26-2。MS(ESI)m/z:229.1[M+H +].
步骤B：在氮气保护下，向26-2(4.8克，21.03毫摩尔，1当量)的异丙醇(40毫升)溶液中加入叔丁醇钠(6.06克，63.08毫摩尔，3当量)和化合物26-3(4.37克，21.03毫摩尔，2.94毫升，1当量)，该混合体系在100摄氏度下搅拌12小时。将反应液冷却到25摄氏度，加水(100毫升)稀释，用乙酸乙酯(100毫升×2)萃取，合并有机相，用饱和食盐水(100毫升)洗涤，无水硫酸钠干燥，过滤，浓缩滤液，粗品通过柱层析(硅胶柱，洗脱液梯度0～30％石油醚/乙酸乙酯，80毫升/分钟)纯化，得到化合物26-4。MS(ESI)m/z:301.1[M+H +-100].
步骤C：向化合物26-4(230毫克，574.54微摩尔，1当量)的乙酸乙酯(2毫升)溶液中加入盐酸乙酸乙酯(4摩尔每升，2毫升，13.92当量)，该混合体系在25摄氏度下搅拌0.5小时。将反应液直接减压干燥后得到化合物26-5的盐酸盐。MS(ESI)m/z:301.3[M+H +].
步骤D：向化合物11-10(50毫克，190.67微摩尔，1当量)的N,N-二甲基甲酰胺(3毫升)溶液中加入N,N-羰基二咪唑(37.10毫克，228.81微摩尔，1.2当量)和三乙胺(77.18毫克，762.69微摩尔，106.16微升，4当量)，该混合体系在25摄氏度下搅拌1小时，然后加入化合物26-5(64.19毫克，190.67微摩尔，1当量，盐酸盐)，该混合体系在25摄氏度下搅拌12小时。加水(30毫升)稀释，用乙酸乙酯(30毫升×2)萃取，合并有机相，用饱和食盐水(30毫升×2)洗涤，无水硫酸钠干燥，过滤，浓缩滤液，粗品通过高效液相色谱(柱子：Phenomenex Synergi C18 150*25毫米*10微米；流动相：[水(甲酸)-乙腈]；乙腈％：45％-75％，2分钟)纯化，得到化合物26。MS(ESI)m/z:589.1[M+H +]. 1H NMR(400MHz,DMSO-d 6)δppm 12.50(s,1H),7.82(s,1H),7.46(s,1H),6.83–6.81(t,1H),6.45(br dd,J＝3.2Hz,1H),5.68-5.57(m,2H),4.52-4.48(m,1H),3.78-3.75(m,4H),3.67–3.66(m,2H),3.48-3.41(m,4H),1.29(d,J＝6.4Hz,3H).
化合物26经SFC检测【柱型号：Chiralcel OD-3 50×4.6mm I.D.,3μm；流动相：A相为超临界二氧化 碳，B相为甲醇(0.05％二乙胺)；梯度(B％)：5％-40％】得到：化合物26的保留时间为1.118min，e.e.值为100％。
实施例27
Figure PCTCN2022107127-appb-000110
步骤A：向化合物11-6(1.7克，4.00毫摩尔，1当量)的乙醇(20毫升)溶液中加入钯碳(0.1克，4.00毫摩尔，10％纯度)，用氢气置换三次，在氢气的保护下，该混合体系在25摄氏度下搅拌3小时。将反应液过滤，收集滤液并浓缩，得到化合物27-1。MS(ESI)m/z:428.2[M+H +].
步骤B：向化合物27-1(1.68克，3.93毫摩尔，1当量)的四氢呋喃(20毫升)溶液中，加入二异丁基氢化铝(1摩尔每升，11.79毫升，3当量)，该混合体系在0摄氏度下搅拌1小时。向反应液中加入饱和的酒石酸钾钠(60毫升)溶液，在25摄氏度下搅拌1小时，用乙酸乙酯(60毫升×2)萃取，合并有机相，用饱和食盐水(60毫升)洗涤，无水硫酸钠干燥，过滤，浓缩滤液，粗品通过柱层析(二氧化硅，石油醚/乙酸乙酯＝3/1，1/1)纯化，得到化合物27-2。
步骤C：向化合物27-2(0.9克，2.34毫摩尔，1当量)的二甲基亚砜(10毫升)溶液中加入2-碘酰基苯甲酸(784.73毫克，2.80毫摩尔，1.2当量)，该混合体系在60摄氏度下搅拌2小时，向反应液中加入水(50毫升)稀释，用乙酸乙酯(50毫升×2)萃取，合并有机相，用饱和食盐水(50毫升)洗涤，无水硫酸钠干燥，过滤，浓缩滤液，得到化合物27-3。MS(ESI)m/z:384.0[M+H +].
步骤D：向化合物1-13(467.84毫克，2.09毫摩尔，414.02微升，1当量)的四氢呋喃(10毫升)溶液中加入氯化锂(106.16毫克，2.50毫摩尔，51.29微升，1.2当量)和三乙胺(253.39毫克，2.50毫摩尔，348.54微升，1.2当量)，该混合体系在0摄氏度搅拌0.5小时，然后在0摄氏度下，向反应液中加入化合物27-3(800毫克，2.09毫摩尔，1当量)，该混合体系在25摄氏度下反应1.5小时。加水(50毫升)稀释，用乙酸乙酯(50毫升×2)萃取，合并有机相，用饱和食盐水(50毫升×2)洗涤，无水硫酸钠干燥，过滤，浓缩滤液，粗品通过柱层析(二氧化硅，石油醚/乙酸乙酯＝5/1，3/1)纯化，得到化 合物27-4。MS(ESI)m/z:454.1[M+H +].
步骤E：向化合物27-4(675毫克，1.49毫摩尔，1当量)的三氟乙酸(10毫升)溶液中加入三氟甲磺酸(1.70克，11.33毫摩尔，1毫升，7.61当量)，该混合体系在25摄氏度搅拌1小时。向反应液中加入水(50毫升)稀释，加入饱和的碳酸钠水溶液调节pH至4，用乙酸乙酯(50毫升×2)萃取，合并有机相，用饱和食盐水(50毫升×2)洗涤，无水硫酸钠干燥，过滤，浓缩滤液，粗品通过高效液相色谱：(柱子：Phenomenex luna C18150*40毫米*15微米；流动相：[水(甲酸)-乙腈]：乙腈％：28％-58％，10分钟)纯化，得到化合物27-5。MS(ESI)m/z:334.2[M+H +].
步骤F：向化合物27-5(150毫克，450.04微摩尔，1当量)的甲醇(2毫升)溶液中加入一水合氢氧化锂(37.77毫克，900.08微摩尔，2当量)和水(2毫升)，该混合体系在25摄氏度搅拌12小时。向反应液中加入盐酸(1摩尔每升)调节pH至6，加入水(30毫升)稀释，用乙酸乙酯(30毫升×2)萃取，合并有机相，用饱和食盐水(30毫升×2)洗涤，无水硫酸钠干燥，过滤，浓缩滤液，得到化合物27-6。MS(ESI)m/z:305.9[M+H +].
步骤G：向化合物27-6(50毫克，163.80微摩尔，1当量)的四氢呋喃(2毫升)溶液中加入O-(7-氮杂苯并三氮唑-1-基)-N,N,N,N-四甲基脲六氟膦盐(93.42毫克，245.70微摩尔，1.5当量)和三乙胺(66.30毫克，655.20微摩尔，91.19微升，5当量)，该混合体系在25摄氏度搅拌1小时。再向反应液中加入化合物1-11(44.01毫克，163.80微摩尔，1当量，盐酸盐)，该混合体系在25摄氏度搅拌2小时。加水(30毫升)稀释，用乙酸乙酯(30毫升×2)萃取，合并有机相，用饱和食盐水(30毫升)洗涤，无水硫酸钠干燥，过滤，浓缩滤液，粗品通过高效液相色谱(柱子：Phenomenex Synergi C18 Ultra 150*25毫米*10微米；流动相：[水(甲酸)-乙腈]；乙腈％：36％-66％，10分钟)纯化，再经过手性拆分(柱子：REGIS(S,S)WHELK-O1(250毫米*25毫米，10微米)；流动相：[0.1％氨水异丙醇]；异丙醇％：40％-40％，5.2分钟)纯化，得到化合物27。MS(ESI)m/z:520.2[M+H +].
化合物27经SFC检测【柱型号：(S,S)Whelk-Ol OD-3 100×4.6mm I.D.,3.5μm；流动相：A相为超临界二氧化碳，B相为异丙醇(0.05％二乙胺)；梯度(B％)：40％-40％】得到：化合物27的保留时间为2.457min，e.e.值为96.016％。
实施例28
Figure PCTCN2022107127-appb-000111
步骤A：向化合物28-1(200毫克，927.74微摩尔，1当量)的N-甲基吡咯烷酮(2毫升)溶液中加入化合物1-8(168.79毫克，927.74微摩尔，1当量)和碳酸钾(255.61毫克，1.85毫摩尔，2当量)，该混合体系在100摄氏度下搅拌2小时。待反应液冷却到25摄氏度后加入水(20毫升)，混合液在25摄氏度下搅拌10分钟，固体析出，过滤并收集滤饼，减压干燥后得到化合物28-2。MS(ESI)m/z:307.1[M+H +-56].
步骤B：向28-2(360毫克，993.52微摩尔，1当量)的乙酸乙酯(2毫升)溶液中加入盐酸乙酸乙酯(4摩尔每升，2毫升)，该混合体系在25摄氏度下搅拌1小时。将反应液直接减压干燥后得到化合物28-3的盐酸盐。MS(ESI)m/z:263.1[M+H +].
步骤C：向化合物11-10(100毫克，381.34微摩尔，1当量)的N,N-二甲基甲酰胺(3毫升)溶液中加入N,N-羰基二咪唑(74.20毫克，457.61微摩尔，1.2当量)和三乙胺(154.35毫克，1.53毫摩尔，212.31微升，4当量)，该混合体系在25摄氏度下搅拌1小时，然后加入化合物28-3(136.68毫克，457.61微摩尔，1.2当量，盐酸盐)，该混合体系在25摄氏度下搅拌11小时。加水(20毫升)稀释，用乙酸乙酯(20毫升×2)萃取，合并有机相，用饱和食盐水(20毫升×2)洗涤，无水硫酸钠干燥，过滤，浓缩滤液，粗品通过高效液相色谱(柱子：Phenomenex luna C18 150*25毫米*10微米；流动相：[水(甲酸)-乙腈]；乙腈％：28％-58％，2分钟)纯化，得到化合物28-4。MS(ESI)m/z:551.1[M+H +].
步骤D：化合物28-4通过手性拆分(柱子：Phenomenex-Cellulose-2(250毫米*25毫米，10微米)；流动相：[乙腈/甲醇(0.1％氨水)]；甲醇％：40％-40％，4.5分钟)纯化，得到化合物28A和化合物28B。28A:MS(ESI)m/z:551.4[M+H +].
1H NMR(400MHz,DMSO-d 6)δppm 12.49(br s,1H),8.71(s,2H),7.82(s,1H),6.70(t,J＝5.6Hz,1H),6.42(br dd,J＝7.2,3.2Hz,1H),5.77-5.50(m,2H),4.83(t,J＝5.6Hz,1H),4.71(br d,J＝2.0Hz,1H),4.54-4.32(m,2H),4.10-3.84(m,2H),3.66(br t,J＝4.8Hz,2H),3.56-3.44(m,2H),3.24-3.14(m,1H),3.04(dd,J＝4.0,13.6Hz,1H),2.96-2.84(m,1H),1.29(d,J＝6.4Hz,3H).
28B:MS(ESI)m/z:551.4[M+H +].
经SFC检测【柱型号：UniChiral OZ-5H 50×4.6mm I.D.,5μm；流动相：A相为超临界二氧化碳，B相为甲醇+乙腈(0.05％二乙胺)；梯度(B％)：40％-40％】得到：化合物28A的保留时间为0.533min，e.e.值为100％,化合物28B的保留时间为0.769min，e.e.值为99.756％。
实施例29
Figure PCTCN2022107127-appb-000112
步骤A：向化合物29-1(0.75克，3.47毫摩尔，1当量)的N-甲基吡咯烷酮(10毫升)溶液中加入化合物1-8(632.98毫克，3.47毫摩尔，1当量)和碳酸钾(958.56毫克，6.94毫摩尔，2当量)，该混合体系在100摄氏度下搅拌2小时。待反应液冷却到25摄氏度后加入水(50毫升)，固体析出，过滤并收集滤饼，减压干燥后得到化合物29-2。MS(ESI)m/z:307.1[M+H +-56].
步骤B：向29-2(540毫克，1.49毫摩尔，1当量)的乙酸乙酯(2毫升)溶液中加入盐酸乙酸乙酯(4摩尔每升，2毫升)，该混合体系在25摄氏度下搅拌0.5小时。将反应液直接减压干燥后得到化合物29-3的盐酸盐。MS(ESI)m/z:263.2[M+H +].
步骤C：向化合物11-10(150毫克，572.01微摩尔，1当量)的N,N-二甲基甲酰胺(5毫升)溶液中加入N,N-羰基二咪唑(111.30毫克，686.41微摩尔，1.2当量)和三乙胺(231.53毫克，2.29毫摩尔，318.47微升，4当量)，该混合体系在25摄氏度下搅拌1小时，然后加入化合物29-3(170.85毫克，572.01微摩尔，1当量，盐酸盐)，该混合体系在25摄氏度下搅拌12小时。加水(30毫升)稀释，用乙酸乙酯(30毫升×2)萃取，合并有机相，用饱和食盐水(30毫升)洗涤，无水硫酸钠干燥，过滤，浓缩滤液，粗品通过高效液相色谱(柱子：Phenomenex Synergi C18 150*25毫米*10微米；流动相：[水(甲酸)-乙腈]；乙腈％：25％-55％，10分钟)纯化，得到化合物29-4。MS(ESI)m/z:551.2[M+H +].
步骤D：化合物29-4通过手性拆分(柱子：DAICEL CHIRALPAK AS(250毫米*30毫米，10微米)；流动相：[0.1％氨水异丙醇]；异丙醇％：30％-30％，5.3分钟)纯化，得到化合物29A和化合物29B。29A:MS(ESI)m/z:551.3[M+H +]. 1H NMR(400MHz,DMSO-d 6)δppm 12.49(br s,1H),8.71(s,2H),7.81(s,1H),6.65(br t,J＝5.6Hz,1H),6.42(br dd,J＝7.2,3.2Hz,1H),5.78-5.51(m,2H),4.76(t,J＝5.2Hz,1H),4.64(br d,J＝12.8Hz,1H),4.56-4.43(m,1H),4.33(br d,J＝13.2Hz,1H),4.09(br s,1H),3.85(br d,J＝13.2Hz,1H),3.66(br s,2H),3.35(br s,3H),3.22-3.02(m,2H),1.29(d,J＝6.4Hz,3H).
29B:MS(ESI)m/z:551.3[M+H +]. 1H NMR(400MHz,DMSO-d 6)δppm 12.49(br s,1H),8.71(s,2H),7.82(s,1H),6.65(t,J＝5.6Hz,1H),6.42(br dd,J＝7.2,3.2Hz,1H),5.73-5.53(m,2H),4.75(t,J＝5.2Hz,1H),4.64(br d,J＝12.0Hz,1H),4.55-4.44(m,1H),4.40-4.28(m,1H),4.15-4.03(m,1H),3.91-3.80(m,1H),3.66(br s,2H),3.40-3.33(m,3H),3.22-3.02(m,2H),1.29(d,J＝6.4Hz,3H).
经SFC检测【柱型号：Chiralpak AS-3 50×4.6mm I.D.,3μm；流动相：A相为超临界二氧化碳，B相为 异丙醇(0.05％二乙胺)；梯度(B％)：5％-40％】得到：化合物29A的保留时间为1.617min，e.e.值为100％。化合物29B的保留时间为1.893min，e.e.值为98.914％。
实施例30
Figure PCTCN2022107127-appb-000113
步骤A：向化合物30-1(2克，14.43毫摩尔，1当量)和化合物1-9(2.69克，14.43毫摩尔，1当量)的N,N-二甲基甲酰胺(30毫升)溶液中加入碳酸钾(1.99克，14.43毫摩尔，1当量)，该混合体系在80摄氏度下搅拌12小时。待反应液冷却到室温后加入水(100毫升),混合液在25摄氏度下搅拌10分钟，固体析出，过滤并收集滤饼，减压干燥后得到化合物30-2。MS(ESI)m/z:233.1[M+H +-56].
步骤B：向30-2(1克，3.47毫摩尔，1当量)的乙酸乙酯(10毫升)溶液中加入盐酸乙酸乙酯(4摩尔，10毫升，11.53当量)，该混合体系在25摄氏度下搅拌0.5小时。将反应液直接减压干燥后得到化合物30-3的盐酸盐。MS(ESI)m/z:189.2[M+H +].
步骤C：向化合物11-8(100毫克，379.92微摩尔，1当量)的四氢呋喃(3毫升)溶液中加入N,N-羰基二咪唑(73.92毫克，455.90微摩尔，1.2当量)和三乙胺(153.77毫克，1.52毫摩尔，211.52微升，4当量)，该混合体系在40摄氏度下搅拌1小时，然后加入化合物30-3(85.36毫克，379.92微摩尔，1当量，盐酸盐)，该混合体系在60摄氏度下搅拌24小时。加水(30毫升)稀释，用乙酸乙酯(30毫升×2)萃取，合并有机相，用饱和食盐水(30毫升)洗涤，无水硫酸钠干燥，过滤，浓缩滤液，粗品通过高效液相色谱(柱子:Phenomenex Synergi C18 150*25毫米*10微米；流动相:[水(甲酸)-乙腈]；乙腈％:27％-57％,10分钟)纯化，得到化合物30。MS(ESI)m/z:478.1[M+H +]. 1H NMR(400MHz,DMSO-d 6)δppm 12.52(br s,1H),8.50(d,J＝2.4Hz,1H),7.92-7.85(m,1H),7.82(s,1H),6.93(d,J＝9.2Hz,1H),6.51(br dd,J＝3.6,7.2Hz,1H),5.90-5.69(m,2H),4.55(br d,J＝4.8Hz,3H),3.75-3.65(m,4H),3.47(br s,4H),1.31(d,J＝6.4Hz,3H).
化合物30经SFC检测【柱型号：Chiralpak IC-3 50×4.6mm I.D,3μm；流动相：A相为超临界二氧化碳，B相为甲醇+乙腈(0.05％二乙胺)；梯度(B％)：40％-40％】得到：化合物30的保留时间为1.965min，e.e值为100％。
实施例31
Figure PCTCN2022107127-appb-000114
步骤A：向化合物1-7(5克，15.69毫摩尔，1当量)的三氟乙酸(30毫升)溶液中加入三氟甲磺酸(5.10克，33.98毫摩尔，3毫升，2.17当量)，该混合体系在25摄氏度下搅拌0.5小时。加水(100毫升)稀释，加入碳酸钠调节pH至7，用乙酸乙酯(100毫升×2)萃取，合并有机相，用饱和食盐水(100毫升)洗涤，无水硫酸钠干燥，过滤，浓缩滤液，粗品通过柱层析(硅胶柱,洗脱液梯度0～100％石油醚/乙酸乙酯，80毫升/分钟)纯化，得到化合物31-1。
Figure PCTCN2022107127-appb-000115
步骤A：向化合物31-2(10克，48.72毫摩尔，1当量)的二甲基亚砜(100毫升)溶液中加入2-碘酰基苯甲酸(27.29克，97.44毫摩尔，2当量)，该反应液在25摄氏度搅拌12小时。向反应液中加入乙酸乙酯(200毫升)和水(200毫升)并搅拌5分钟，将上述混合液过滤，滤液加入乙酸乙酯(100毫升)萃取，有机相用水(200毫升×2)洗涤，无水硫酸钠干燥，过滤，浓缩得到化合物31-3。
步骤B：向化合物1-13(9.49克，42.32毫摩尔，8.40毫升，1当量)的四氢呋喃(100毫升)溶液中加入三乙胺(5.14克，50.78毫摩尔，7.07毫升，1.2当量)和氯化锂(2.15克，50.78毫摩尔，1.04毫升，1.2当量)，该混合液在25摄氏度搅拌30分钟，向反应液中加入化合物31-3(8.6克，42.32毫摩尔，1当量)的四氢呋喃(80毫升)溶液，该反应液在25摄氏度搅拌12小时。将反应液倒入水(200毫升)中，乙酸乙酯(200毫升×2)萃取，合并有机相，用水(200毫升×2)洗涤，无水硫酸钠干燥，过滤，滤液浓缩，粗品通过硅胶柱层析(石油醚/乙酸乙酯＝1/1，3/1)纯化，得到化合物31-5。MS(ESI)m/z:174.2[M+H +]。 1H NMR(400MHz,氯仿-d)δppm 6.91(dd,J＝15.6,4.8Hz,1H),5.97(dd,J＝15.6,1.6Hz,1H),5.03-4.98(m,1H),4.46(br s,1H),4.24-4.15(m,2H),3.50(br d,J＝4.03Hz,2H),3.35(s,3H),1.45(s,9H),1.29(t,J＝7.2Hz,3H).
步骤C：将化合物31-5(4.6克，16.83毫摩尔，1当量)溶解到盐酸乙酸乙酯(40毫升，4摩尔每升)中，在25摄氏度搅拌15分钟。将反应液浓缩，得到化合物31-6的盐酸盐。
步骤D：向化合物31-6(1克，4.77毫摩尔，1当量，盐酸盐)和化合物31-1(946.87毫克，4.77毫摩尔，1当量)的乙腈(20毫升)溶液中加入乙酸钾(1.17克，11.92毫摩尔，2.5当量)，该反应液在25摄氏度搅拌48小时。用盐酸(1摩尔每升)将反应液pH调节至4～5，将上述混合液倒入水(100毫升)中，乙酸乙酯(100毫升×2)萃取，合并有机相，用饱和食盐水(100毫升×2)洗涤，无水硫酸钠干燥，过滤，滤液浓缩，粗品通过高效液相色谱制备(柱子:Phenomenex luna C18 150*40毫米*15微米；流动相：[水(三氟乙酸)-乙腈]；乙腈％：18％-48％，10分钟))得到化合物31-7。MS(ESI)m/z:336.1[M+H +]。
步骤E：在0摄氏度下，将化合物31-7(6.67克，19.89毫摩尔，1当量)的四氢呋喃(50毫升)溶液用氮气置换三次，向该混合体系中滴加二异丁基氢化铝(1摩尔，79.58毫升，4当量)，该混合体系在0摄氏度搅拌2小时。向反应液中加入饱和的酒石酸钾钠(50毫升)溶液，在25摄氏度下搅拌12小时，用水(150毫升)稀释，乙酸乙酯(200毫升×2)萃取，合并有机相，用饱和食盐水(100毫升)洗涤，无水硫酸钠干燥，过滤，浓缩滤液，粗品通过柱层析(硅胶柱,洗脱液梯度0～100％，石油醚/乙酸乙酯，100毫升/分钟)纯化，再通过手性拆分(柱子:DAICEL CHIRALPAK AD(250毫米*30毫米,10微米)；流动相：[(0.1％氨水)异丙醇]；异丙醇％：30％-30％，4.1分钟)纯化，得到化合物31-8。MS(ESI)m/z:294.1[M+H +].
步骤F：向化合物31-8(0.4克，1.36毫摩尔，1当量)的四氢呋喃(10毫升)溶液和N,N-二甲基甲酰胺(5毫升)溶液中加入N,N-羰基二咪唑(265.42毫克，1.64毫摩尔，1.2当量)和三乙胺(690.14毫克，6.82毫摩尔，949.30微升，5当量)，该混合体系在25摄氏度下搅拌1小时，然后加入化合物7-3(369.41毫克，1.64毫摩尔，1.2当量，盐酸盐)，该混合体系在70摄氏度下搅拌6小时。加水(80毫升)稀释，用乙酸乙酯(80毫升×2)萃取，合并有机相，用饱和食盐水(80毫升)洗涤，无水硫酸钠干燥，过滤，浓缩滤液，粗品通过高效液相色谱(柱子:Phenomenex luna C18 250*25毫米，10微米；流动相：[水(甲酸)-乙腈]；乙腈％：26％-56％,10分钟)纯化，得到化合物31。MS(ESI)m/z:509.4[M+H +]. 1H NMR(400MHz,DMSO-d 6)δ＝12.56(s,1H),8.77(s,2H),7.83(s,1H),6.47(br dd,J＝4.0,7.6Hz,1H),5.99-5.64(m,2H),4.75-4.63(m,1H),4.56(d,J＝4.8Hz,2H),3.84(dd,J＝4.4,6.4Hz,4H),3.64-3.42(m,6H),3.29(s,3H).
化合物31经SFC检测【柱型号：Chiralcel OJ-3 50×4.6mm I.D.,3μm；流动相：A相为超临界二氧化碳，B相为甲醇(0.05％二乙胺)；梯度(B％)：5％-40％】得到：化合物31的保留时间为1.800min，e.e.值为100.000％。
实施例32
Figure PCTCN2022107127-appb-000116
步骤A：向化合物1-9(500毫克，2.68毫摩尔，1当量)和化合物32-1(449.53毫克，3.22毫摩尔， 1.2当量)的N,N-二甲基甲酰胺(5毫升)溶液中加入碳酸钾(742.06毫克，5.37毫摩尔，2当量)，将反应液加热到80摄氏度搅拌1小时。水(15毫升)加入到反应液中，反应液25摄氏度搅拌15分钟，反应液过滤，滤饼减压浓缩得到化合物32-2。MS(ESI)m/z:234.1[M+H +-56]。
步骤B：向反应瓶中加入化合物32-2(400毫克，1.38毫摩尔，1当量)和乙酸乙酯(2毫升)，盐酸乙酸乙酯(2毫升，4摩尔每升，5.79当量)，该反应液在25摄氏度搅拌12小时。将反应液浓缩得到化合物32-3的盐酸盐。MS(ESI)m/z:190.1[M+H +]。
Figure PCTCN2022107127-appb-000117
步骤C：向化合物11-8(100毫克，379.92微摩尔，1当量)的四氢呋喃(3毫升)溶液中加入N,N-羰基二咪唑(80.08毫克，493.89微摩尔，1.3当量)和三乙胺(192.22毫克，1.90毫摩尔，264.40微升，5当量)，该混合物在60摄氏度搅拌1小时，检测反应完成后，无需后处理，得到化合物32-4直接用于下一步。
步骤D：将化合物32-3(102.89毫克，455.90微摩尔，1.2当量，盐酸盐)加入到化合物32-4(135.74毫克，379.92微摩尔，1当量，四氢呋喃溶液)中，将反应液60摄氏度搅拌12小时。反应液倒入水(10毫升)中，用乙酸乙酯(10毫升×3)萃取，合并有机相，用饱和食盐水(10毫升×2)洗涤，无水硫酸钠干燥，过滤，浓缩滤液，残留物用高效液相色谱(柱子:Phenomenex Synergi C18 150*25毫米*10微米；流动相:[水(0.225％甲酸)-乙腈]；乙腈％:31％-61％，10分钟)纯化，得到化合物32。MS(ESI)m/z:479.2[M+H +]。
1H NMR(400MHz,DMSO-d 6)δ＝12.51(br s,1H),8.66(d,J＝4.8Hz,1H),7.82(s,1H),7.18(d,J＝4.8Hz,1H),6.51(br dd,J＝7.2,3.6Hz,1H),5.93-5.66(m,2H),4.56(br s,2H),3.81-3.71(m,4H),3.45(br d,J＝6.4Hz,4H),1.31(d,J＝6.4Hz,3H),1.05(t,J＝7.2Hz,1H).
化合物32经SFC检测【柱型号：Chiralcel OJ-3 50*4.6mm I.D.,3微米；流动相：A相为超临界二氧化碳，B相为甲醇(0.05％DEA)；梯度(B％)：5％-40％】得到：化合物32的保留时间为1.748min，e.e.值为95.128％。
实施例33
Figure PCTCN2022107127-appb-000118
步骤A：向化合物1-8(546.83毫克，3.00毫摩尔，1.2当量)和化合物33-1(500毫克，2.50毫摩尔，1当量)的N,N-二甲基甲酰胺(5毫升)溶液中加入碳酸钾(690.07毫克，4.99毫摩尔，2当量)，将反应液加热到80摄氏度搅拌1小时。水(15毫升)加入到反应液中，反应液25摄氏度搅拌15分钟，反应液过滤，滤饼减压浓缩得到化合物33-2。MS(ESI)m/z:291.1[M+H +-56]。
步骤B：向反应瓶中加入化合物33-2(786毫克，2.27毫摩尔，1当量)和乙酸乙酯(4毫升)，盐酸乙酸乙酯(4毫升，4摩尔每升，7.05当量)，该反应液在25摄氏度搅拌12小时。将反应液浓缩得到化合物33-3的盐酸盐。MS(ESI)m/z:247.1[M+H +]。
Figure PCTCN2022107127-appb-000119
步骤C：向化合物11-8(200毫克，759.83微摩尔，1当量)的四氢呋喃(5毫升)溶液中加入N,N-羰基二咪唑(160.17毫克，987.78微摩尔，1.3当量)和三乙胺(384.44毫克，3.80毫摩尔，528.80微升，5当量)，该混合物在60摄氏度搅拌1小时，检测反应完成后，无需后处理，得到化合物32-4直接用于下一步。
步骤D：将化合物33-3(257.76毫克，911.80微摩尔，1.2当量，盐酸盐)加入到化合物32-4(271.48毫克，759.84微摩尔，1当量，四氢呋喃溶液)中，将反应液60摄氏度搅拌12小时。反应液倒入水(10毫升)中，用乙酸乙酯(10毫升×3)萃取，合并有机相，用饱和食盐水(10毫升×2)洗涤，无水硫酸钠干燥，过滤，浓缩滤液，残留物用高效液相色谱(柱子:Phenomenex C18 75*30毫米*3微米；流动相:[水(0.225％甲酸)-乙腈]；B％:38％-68％，7分钟)纯化，得到化合物33。MS(ESI)m/z:536.2[M+H +].
1H NMR(400MHz,DMSO-d 6)δ＝12.52(s,1H),8.68(s,2H),7.81(s,1H),7.26(br d,J＝8.0Hz,1H),6.48(br d,J＝3.6Hz,1H),5.97-5.61(m,2H),4.54(br d,J＝13.2Hz,3H),4.45(br d,J＝4.8Hz,2H),3.72-3.55(m,1H),3.18(br t,J＝11.6Hz,2H),1.82(br dd,J＝3.6,13.0Hz,2H),1.30(br d,J＝6.4Hz,5H).
化合物33经SFC检测【柱型号：Chiralpak AD-3 50*4.6mm I.D.,3微米；流动相：A相为超临界二氧化碳，B相为甲醇(0.05％DEA)；梯度(B％)：5％-40％】得到：化合物33的保留时间为1.892min，e.e.值为97.612％；
实施例34
Figure PCTCN2022107127-appb-000120
步骤A：向化合物31-8(2克，6.82毫摩尔，1当量)的四氢呋喃(20毫升)和N,N-二甲基甲酰胺(10毫升)溶液中加入N,N’-羰基二咪唑(1.33克，8.18毫摩尔，1.2当量)和三乙胺(3.45克，34.10毫摩尔，4.75毫升，5当量)，该混合体系在25摄氏度下搅拌1小时，然后加入化合物8-3(1.79克，8.18毫摩尔，1.2当量，盐酸盐)，该混合体系在60摄氏度下搅拌3小时。加水(100毫升)稀释，用乙酸乙酯(100毫升×2)萃取，合并有机相，用饱和食盐水(100毫升)洗涤，无水硫酸钠干燥，过滤，浓缩滤液，粗品通过高效液相色谱(柱子:Phenomenex luna C18 250*70毫米，10微米；流动相：[水(甲酸)-乙腈]；乙腈％：30％-60％,20分钟)纯化，得到化合物34。MS(ESI)m/z:502.2[M+H +]. 1H NMR(400MHz, DMSO-d 6)δ＝12.56(s,1H),8.48(s,2H),7.83(s,1H),6.48(br dd,J＝4.0,7.6Hz,1H),5.91-5.68(m,2H),4.76-4.64(m,1H),4.56(d,J＝4.8Hz,2H),3.69(dd,J＝4.4,6.4Hz,4H),3.61-3.40(m,6H),3.28(s,3H).化合物34经SFC检测【柱型号：Chiralpak IG-3 50×4.6mm I.D.,3μm；流动相：A相为超临界二氧化碳，B相为甲醇+乙腈(0.05％二乙胺)；梯度(B％)：40％-40％】得到：化合物34的保留时间为1.316min，e.e.值为100.000％。
实施例35
Figure PCTCN2022107127-appb-000121
步骤A：向化合物31-8(300毫克，1.02毫摩尔，1当量)的二氯甲烷(10毫升)溶液中加入三乙胺(155.28毫克，1.53毫摩尔，213.59微升，1.5当量)和化合物12-4(247.45毫克，1.23毫摩尔，1.2当量)，该混合体系在25摄氏度搅拌12小时。将反应液直接旋干得到化合物35-1。MS(ESI)m/z:459.1[M+H +].
Figure PCTCN2022107127-appb-000122
步骤B：向化合物35-2(500.00毫克，2.50毫摩尔，1当量)的N,N-二甲基甲酰胺(10毫升)溶液中加入碳酸钾(345.04毫克，2.50毫摩尔，1当量)和化合物7-1(348.37毫克，2.50毫摩尔，1当量)，该混合体系在80摄氏度下搅拌12小时。将反应液冷却至25摄氏度，加入水(50毫升)，黄色固体析出，过滤，收集滤饼，经减压干燥得到化合物35-3。MS(ESI)m/z:204.2[M+H +-100].
步骤C：向化合物35-3(490毫克，1.62毫摩尔，1当量)的乙酸乙酯(5毫升)溶液中加入盐酸乙酸乙酯(4摩尔，5毫升，12.38当量)，该反应液在25摄氏度搅拌12小时。将反应液浓缩得到化合物35-4的盐酸盐。MS(ESI)m/z:204.2[M+H +].
步骤D：向化合物35-1(200毫克，436.35微摩尔，1当量)和化合物35-4(156.89毫克，654.53微摩尔，1.5当量，盐酸盐)的N,N-二甲基甲酰胺(5毫升)溶液中加入三乙胺(88.31毫克，872.70微摩尔，121.47微升，2当量)，该混合物在25摄氏度搅拌12小时。反应液用水(30毫升)稀释，乙酸乙酯(30毫升×2)萃取，合并有机相，用饱和食盐水(30毫升)洗涤，无水硫酸钠干燥，过滤，浓缩滤 液，得到的粗品通过高效液相色谱(柱子:Phenomenex luna C18 150*25毫米*10微米；流动相：[水(甲酸)-乙腈]；乙腈％：36％-66％，10分钟)纯化，得到化合物35。MS(ESI)m/z:523.4[M+H +].
1H NMR(400MHz,DMSO-d 6)δ＝12.55(s,1H),8.90-8.51(m,2H),7.82(s,1H),6.58-6.29(m,1H),6.00-5.63(m,2H),4.75-4.64(m,1H),4.63-4.43(m,4H),4.36-4.23(m,1H),3.93-3.77(m,1H),3.59-3.45(m,2H),3.29(s,4H),3.19-3.05(m,2H),1.01(d,J＝6.8Hz,3H).
化合物35经SFC检测【柱型号：Chiralcel OJ-3 50×4.6mm I.D.,3μm；流动相：A相为超临界二氧化碳，B相为乙醇(0.05％二乙胺)；梯度(B％)：5％-40％】得到：化合物35的保留时间为1.681min，e.e.值为100.000％。
实施例36
Figure PCTCN2022107127-appb-000123
步骤A：向化合物36-2(600.00毫克，3.00毫摩尔，1当量)的N,N-二甲基甲酰胺(10毫升)溶液中加入碳酸钾(414.04毫克，3.00毫摩尔，1当量)和化合物7-1(418.05毫克，3.00毫摩尔，1当量)，该混合体系在80摄氏度下搅拌12小时。将反应液冷却至25摄氏度，加入水(80毫升)，固体析出，过滤，收集滤饼，经减压干燥得到化合物36-3。MS(ESI)m/z:204.2[M+H +-100].
步骤B：向化合物36-3(740毫克，2.44毫摩尔，1当量)的乙酸乙酯(7毫升)溶液中加入盐酸乙酸乙酯(4摩尔，7毫升，11.48当量)，该反应液在25摄氏度搅拌12小时。将反应液浓缩得到化合物36-4的盐酸盐。MS(ESI)m/z:204.3[M+H +].
步骤C：向化合物35-1(200毫克，436.35微摩尔，1当量)和化合物36-4(156.89毫克，654.53微摩尔，1.5当量，盐酸盐)的N,N-二甲基甲酰胺(5毫升)溶液中加入三乙胺(88.31毫克，872.71微摩尔，121.47微升，2当量)，该混合物在25摄氏度搅拌12小时。反应液用水(30毫升)稀释，乙酸乙酯(30毫升×2)萃取，合并有机相，用饱和食盐水(30毫升)洗涤，无水硫酸钠干燥，过滤，浓缩滤液，得到的粗品通过高效液相色谱(柱子:Phenomenex luna C18 150*25毫米*10微米；流动相：[水(甲酸)-乙腈]；乙腈％：36％-66％，10分钟)纯化，得到化合物36。MS(ESI)m/z:523.4[M+H +].
1H NMR(400MHz,DMSO-d 6)δ＝12.55(s,1H),8.77(s,2H),7.91-7.68(m,1H),6.58-6.37(m,1H),6.17-5.68(m,2H),4.75-4.63(m,1H),4.62-4.42(m,4H),4.36-4.24(m,1H),3.96-3.80(m,1H),3.60-3.45(m,2H),3.29(s,4H),3.20-3.01(m,2H),1.02(d,J＝6.8Hz,3H).
化合物36经SFC检测【柱型号：Chiralcel OJ-3 50×4.6mm I.D.,3μm；流动相：A相为超临界二氧化碳，B相为乙醇(0.05％二乙胺)；梯度(B％)：5％-40％】得到：化合物36的保留时间为1.744min，e.e.值为100.000％。
实施例37
Figure PCTCN2022107127-appb-000124
步骤A：将氯化锂(2.74克，64.59毫摩尔，1.32毫升，2.5当量)溶解在乙腈(40毫升)中，25摄氏度下，向溶液中加入化合物37-2(5.02克，25.84毫摩尔，1当量)和N,N-二异丙基乙胺(8.35克，64.59毫摩尔，2.5当量)，搅拌0.5小时后，将化合物37-1(3克，25.84毫摩尔，1当量)的乙腈(40毫升)溶液加入到上述溶液中，保持温度在25摄氏度下继续搅拌2.5小时。反应完毕，向反应液中加入水(50毫升)，搅拌5分钟，加入乙酸乙酯(50毫升×2)萃取，有机相用饱和食盐水(50毫升×2)洗涤，用无水硫酸钠干燥，过滤后旋干。得到的残留物经硅胶柱纯化(石油醚：乙酸乙酯＝2:1至1:1)得到化合物37-3。MS(ESI)m/z:125.3[M+H +-32].
1H NMR(400MHz,氯仿-d)δ＝6.90-6.72(m,1H),6.19-5.99(m,1H),3.70(s,3H),2.62-2.45(m,4H),2.24(s,3H).
步骤B：将化合物37-3(1.7克，10.88毫摩尔，1当量)溶于四氢呋喃(20毫升)和水(20毫升)中，加入一水合氢氧化锂(593.75毫克，14.15毫摩尔，1.3当量)，反应液在室温下搅拌1个小时。反应完毕后，将反应液用盐酸(2摩尔每升)调pH至5，水相用乙酸乙酯(50毫升×4)萃取。合并有机相，用饱和食盐水(60毫升×2)洗涤，有机相用无水硫酸钠干燥，过滤旋干,得到化合物37-4。MS(ESI)m/z:141.0[M-H +].
步骤C：向化合物37-4(750毫克，5.28毫摩尔，1当量)的四氢呋喃(30毫升)溶液中加入化合物7-3(1.19克，5.28毫摩尔，1当量，盐酸盐)，O-(7-氮杂苯并三氮唑-1-YL)-N,N,N,N-四甲基脲六氟膦盐(2.21克,5.8毫摩尔,1.1当量)和N,N-二异丙基乙胺(1.7克，13.19毫摩尔，2.3毫升，2.5当量)，该混合体系在25摄氏度下搅拌16个小时。反应完毕后，向反应液里加入水(50毫升)，搅拌5分钟后过滤，滤液用乙酸乙酯(50毫升×2)萃取，合并有机相，用饱和食盐水(50毫升×2)洗涤，用无水硫酸钠干燥，过滤，旋干。得到的残留物经硅胶柱纯化(石油醚：乙酸乙酯＝1:1至0:1)得到化合物37-5。MS(ESI)m/z:314.2[M+H +].
步骤D：向化合物37-5(0.5克，1.58毫摩尔，1当量)的四氢呋喃(10毫升)溶液中加入钛酸四乙酯(1.81克，7.92毫摩尔，1.64毫升，5当量)和化合物37-6(958.36毫克，7.92毫摩尔，5当量)，该混合体系在70摄氏度，氮气保护下搅拌48个小时。反应完毕后，向反应液里加入水(50毫升)，搅拌5分钟后过滤，滤液用乙酸乙酯(50毫升×2)萃取，合并有机相，用饱和食盐水(50毫升×2)洗涤，用无水硫酸钠干燥，过滤，旋干。得到化合物37-7。MS(ESI)m/z:417.3[M+H +].
步骤E：0摄氏度下，向化合物37-7(0.5克，1.2毫摩尔，1当量)的二氯甲烷(10毫升)溶液中缓慢加氰基硼氢化钠(75.43毫克，1.2毫摩尔，1当量)和醋酸(36.04毫克，600.18微摩尔，34.33微升，0.5当量)，该混合体系在0摄氏度搅拌1个小时。反应完毕后，向反应液里加入水(50毫升)，搅拌5分钟，水相用乙酸乙酯(50毫升×2)萃取，合并有机相，用饱和食盐水(50毫升×2)洗涤，用无水硫酸钠干燥，过滤，旋干。得到化合物37-8。MS(ESI)m/z:419.2[M+H +].
步骤F：向化合物37-8(30毫克，71.68微摩尔，1当量)的乙酸乙酯(3毫升)溶液中加入盐酸乙酸乙酯溶液(4摩尔每升，1.5毫升，83.71当量)，该混合体系在25摄氏度下搅拌1小时。反应完毕后，浓缩旋干，得到化合物37-9的盐酸盐。MS(ESI)m/z:298.1[M+H +-16].
步骤G：向化合物31-1(12.81毫克，64.55微摩尔，1当量)的乙腈(3毫升)溶液中加入化合物37-9(25毫克，64.55微摩尔，1当量，2盐酸盐)和碳酸氢钠(16.27毫克，193.65微摩尔，7.53微升，3当量)，该混合体系在25摄氏度搅拌16小时。反应完毕，向反应液里加入水(50毫升)，搅拌5分钟，水相用乙酸乙酯(50毫升×2)萃取，合并有机相，用饱和食盐水(50毫升×2)洗涤，用无水硫酸钠干燥，过滤，旋干。得到残留物经高效液相色谱(柱子:Phenomenex luna C18 150*25毫米*10微米；流动相:[水(甲酸)-乙腈]；乙腈％:24％-54％，10分钟)纯化得到化合物37。
MS(ESI)m/z:477.2[M+H +].
1H NMR(400MHz,DMSO-d 6)δ＝12.50(br s,1H),8.79(s,2H),7.81(s,1H),6.39(br d,J＝3.2Hz,1H),5.74-5.62(m,1H),5.61-5.50(m,1H),4.46(br d,J＝6.0Hz,1H),3.85(br d,J＝4.4Hz,2H),3.83-3.77(m,2H),3.55(br s,4H),2.43(br s,2H),2.25(q,J＝6.8Hz,2H),1.28(d,J＝6.8Hz,3H).
实施例38
Figure PCTCN2022107127-appb-000125
步骤A：向化合物38-1(0.25克，1.62毫摩尔，1当量)的N,N-二甲基甲酰胺(20毫升)溶液中加入碳酸钾(447.00毫克，3.23毫摩尔，2当量)和化合物1-9(301.19毫克，1.62毫摩尔，1当量)，该混合体系在100摄氏度下搅拌24小时。将反应液冷却至25摄氏度，倒入水(100毫升)中，白色固体析出，过滤，收集滤饼，经减压浓缩得到化合物38-2。MS(ESI)m/z:249.2[M+H +-56].
步骤B：向化合物38-2(360毫克，1.18毫摩尔，1当量)的乙酸乙酯(5毫升)溶液中加入盐酸乙酸乙酯(4摩尔，5毫升，16.91当量)，该反应液在25摄氏度搅拌2小时。将反应液浓缩得到化合物38-3的盐酸盐。MS(ESI)m/z:205.3[M+H +].
步骤C：向化合物31-8(80毫克，272.81微摩尔，1当量)的四氢呋喃(2毫升)溶液和N,N-二甲基甲酰胺(2毫升)溶液中加入N,N-羰基二咪唑(53.08毫克，327.37微摩尔，1.2当量)和三乙胺(138.03毫克，1.36毫摩尔，189.86微升，5当量)，该混合体系在25摄氏度搅拌2小时，然后加入化合物38-3(78.81毫克，327.37微摩尔，1.2当量，盐酸盐)，该混合体系在60摄氏度搅拌12小时。反应液用水(30毫升)稀释，乙酸乙酯(30毫升×2)萃取，合并有机相，用饱和食盐水(30毫升)洗涤，无水硫酸钠干燥，过滤，浓缩滤液，得到的粗品通过高效液相色谱(柱子:Phenomenex luna C18 150*25毫米*10微米；流动相：[水(甲酸)-乙腈]；乙腈％：42％-72％，10分钟)纯化，得到化合物38。MS(ESI)m/z:524.3[M+H +].
1H NMR(400MHz,DMSO-d 6)δ＝12.68-12.47(m,1H),8.22-8.10(m,2H),7.83(s,1H),6.53-6.41(m,1H),5.96-5.68(m,2H),4.73-4.64(m,1H),4.55(d,J＝4.8Hz,2H),3.72-3.64(m,4H),3.62-3.40(m,6H),3.28(s,3H),1.80-1.71(m,1H),0.91-0.83(m,2H),0.66-0.59(m,2H).
化合物38经SFC检测【柱型号：Chiralcel OJ-3 50×4.6mm I.D.,3μm；流动相：A相为超临界二氧化碳，B相为异丙醇(0.05％二乙胺)；梯度(B％)：5％-40％】得到：化合物38的保留时间为1.922min，e.e.值为100.000％。
实施例39
Figure PCTCN2022107127-appb-000126
步骤A：向化合物8-1(0.5克，3.77毫摩尔，1当量)的N,N-二甲基甲酰胺(20毫升)溶液中加入碳酸钾(1.04克，7.54毫摩尔，1当量)和化合物35-2(755.05毫克，3.77毫摩尔，1当量)，该混合体系在80摄氏度下搅拌12小时。将反应液冷却至25摄氏度，反应液用水(30毫升)稀释，乙酸乙酯(30毫升×2)萃取，合并有机相，用饱和食盐水(30毫升)洗涤，无水硫酸钠干燥，过滤，浓缩滤液，粗品通过柱层析(硅胶柱,洗脱液梯度0～15％，石油醚/乙酸乙酯，100毫升/分钟)纯化,得到化合物39-1。MS(ESI)m/z:197.1[M+H +-100].
步骤B：向化合物39-1(860毫克，2.90毫摩尔，1当量)的乙酸乙酯(8毫升)溶液中加入盐酸乙酸乙酯(4摩尔，8毫升，11.03当量)，该反应液在25摄氏度搅拌4小时。将反应液浓缩得到化合物39-2的盐酸盐。MS(ESI)m/z:197.2[M+H +].
步骤C：向化合物35-1(200毫克，436.35微摩尔，1当量)和化合物39-2(152.30毫克，654.53微摩尔，1.5当量，盐酸盐)的N,N-二甲基甲酰胺(5毫升)溶液中加入三乙胺(88.31毫克，872.70微摩尔，121.47微升，2当量)，该混合物在25摄氏度搅拌12小时。反应液用水(30毫升)稀释，乙酸乙酯(30毫升×2)萃取，合并有机相，用饱和食盐水(30毫升)洗涤，无水硫酸钠干燥，过滤，浓缩滤液，得到的粗品通过高效液相色谱(柱子:Phenomenex luna C18 150*25毫米*10微米；流动相：[水(甲酸)-乙腈]；乙腈％：40％-70％，10分钟)纯化，得到化合物39。MS(ESI)m/z:516.4[M+H +].
1H NMR(400MHz,DMSO-d 6)δ＝12.54(br s,1H),8.45(s,2H),7.82(s,1H),6.54-6.38(m,1H),5.94-5.70(m,2H),4.74-4.64(m,1H),4.62-4.47(m,2H),4.46-4.31(m,2H),4.30-4.18(m,1H),3.85-3.80(m,1H),3.60-3.46(m,2H),3.28(s,3H),3.19-3.06(m,2H),2.99-2.92(m,1H),1.04(d,J＝6.4Hz,3H).
化合物39经SFC检测【柱型号：Chiralcel OJ-3 50×4.6mm I.D.,3μm；流动相：A相为超临界二氧化碳，B相为乙醇(0.05％二乙胺)；梯度(B％)：5％-40％】得到：化合物39的保留时间为1.420min，e.e.值为100.000％。
实施例40
Figure PCTCN2022107127-appb-000127
步骤A：在0摄氏度下，向硼烷四氢呋喃(1摩尔每升,12.86毫升,12.86毫摩尔，3当量)溶液中滴加40-1(1克,4.29毫摩尔，1当量)的四氢呋喃(5毫升)溶液，该混合体系在0摄氏度搅拌2小时。检测反应完毕，0摄氏度搅拌下向反应液中缓慢加入甲醇(10毫升)至无气体放出，加入乙酸乙酯(100毫升)稀释，用1摩尔每升的盐酸(30毫升)洗涤，随后用饱和食盐水(10毫升×2)洗涤，无水硫酸钠干燥，过滤，浓缩得化合物40-2粗品，直接用于下一步反应。 1H NMR(氯仿-d,400MHz):δppm 5.40-4.80(m,1H),3.88-3.73(m,1H),3.71-3.61(m,2H),3.58-3.49(m,1H),3.49-3.42(m,1H),3.38(s,3H),3.30-3.04(m,1H),1.97-1.86(m,1H),1.86-1.75(m,1H),1.50-1.42(m,9H).
步骤B：在0摄氏度下，40-2(0.68克,3.10毫摩尔，1当量)的二氯甲烷(20毫升)溶液中分批加入戴斯-马丁氧化剂(1.32克,3.10毫摩尔，1当量)。该混合体系在25摄氏度搅拌12小时。检测反应完毕，将反应液浓缩至干，残物用硅胶柱柱层析(二氧化硅1000目硅胶，洗脱液梯度乙酸乙酯/石油醚10/1至2/1)得化合物40-3。 1H NMR(氯仿-d,400MHz):δ(ppm)9.56(s,1H),5.66-5.32(m,1H),4.19(s,1H),3.55-3.38(m,2H),3.28(s,3H),2.20-1.95(m,2H),1.46(s,9H).
步骤C：在0摄氏度下，向化合物1-13(846.15毫克，3.77毫摩尔，2当量)和二异丙基乙胺(731.69毫克，5.66毫摩尔，3当量)的乙腈(10毫升)溶液中加入氯化锂(240.01毫克，5.66毫摩尔，3当量)，将该混合体系在0摄氏度搅拌半小时。随后将40-3(0.41克，1.89毫摩尔，1当量)的乙腈(3毫升)溶液滴加到上述反应液中。该反应混合物在25摄氏度下搅拌12小时。检测反应完毕，向反应液中加入1摩尔每升盐酸(50毫升)，用乙酸乙酯(80毫升×2)萃取，合并有机相，用饱和食盐水(30毫升)洗涤，无水硫酸钠干燥，过滤，浓缩滤液，得到的残留物用柱层析(二氧化硅1000目硅胶，洗脱液梯度乙酸乙酯/石油醚100/1至3/1)纯化得到化合物40-4。 1H NMR(氯仿-d,400MHz):δppm 6.95-6.77(m,1H),6.00-5.87(m,1H),5.33-4.97(m,1H),4.67-4.35(m,1H),4.28-4.15(m,2H),3.51-3.37(m,2H),3.32(s,3H),2.02-1.86(m,1H),1.83-1.67(m,1H),1.45(s,9H),1.29(s,3H).
步骤D：化合物40-4(0.32克，1.11毫摩尔，1当量)在氯化氢甲醇溶液(4摩尔每升，5毫升，20毫 摩尔，17.96当量)中0摄氏度下搅拌2小时。浓缩得化合物40-5粗品。
步骤E：化合物40-5(0.208克，1.11毫摩尔，1当量)，化合物31-1(0.15克，755.55微摩尔，0.68当量)和碳酸氢钠(373.29毫克，4.44毫摩尔，4当量)在乙腈(8毫升)中，25摄氏度搅拌12小时。检测反应完毕，向反应液中加入水(20毫升)，用乙酸乙酯(80毫升)萃取，用饱和食盐水(30毫升)洗涤，无水硫酸钠干燥，过滤，浓缩滤液，得到的残留物用薄层色谱层析(二氧化硅硅胶，洗脱剂：乙酸乙酯/石油醚＝2/1)纯化得到化合物40-6。MS(ESI)m/z:350.1[M+H +].
步骤F：0摄氏度下，向化合物40-6(0.155克，0.444毫摩尔，1当量)的四氢呋喃(8毫升)溶液中缓慢滴加二异丁基氢化铝(1摩尔每升，1.77毫升，4当量)溶液，该混合体系在0摄氏度下搅拌3小时。检测反应完毕，向反应液中加入饱和酒石酸钠钾水溶液(60毫升)淬灭，继续搅拌12小时，用乙酸乙酯(100毫升×2)萃取，合并有机相，用饱和食盐水(50毫升×2)洗涤，无水硫酸钠干燥，过滤，浓缩滤液，得到的残留物用柱层析(二氧化硅1000目硅胶，洗脱液梯度乙酸乙酯/石油醚100/1至2/1)纯化得到化合物40-7。MS(ESI)m/z:308.1[M+H +].
步骤G：向化合物40-7(36.00毫克，117.16微摩尔，1当量)的四氢呋喃(5毫升)溶液中加入N,N’-羰基二咪唑(28.5毫克，175.74微摩尔，1.5当量)和三乙胺(59.28毫克，0.586毫摩尔，5当量)，该混合体系在25摄氏度下搅拌12小时。将化合物7-3(52.88毫克，0.234毫摩尔，2当量，盐酸盐)加入到上述反应液中,混合体系在25摄氏度下搅拌12小时。检测反应完毕，向反应液中加入水(40毫升)淬灭，乙酸乙酯(40毫升×2)萃取，合并有机相，用饱和食盐水(40毫升×2)洗涤，无水硫酸钠干燥，过滤，浓缩滤液，得到的残留物用高效液相色谱(柱子：Phenomenex luna C18 150*25毫米*10微米；流动相：[水(甲酸)-乙腈]；乙腈％：32％-62％，10分钟)纯化得到化合物40。MS(ESI)m/z:523.2[M+H +]. 1H NMR(CD 3OD,400MHz):δ(ppm)8.88-8.55(m,2H),8.03-7.53(m,1H),6.03-5.71(m,2H),4.70-4.67(m,1H),4.61(br s,2H),3.95(br s,4H),3.58(br s,6H),3.35-3.45(m,3H),2.25-2.04(m,1H),1.80-2.01-1.80(m,1H).化合物40经SFC检测【柱型号：Chiralcel OJ-3 50×4.6mm I.D.,3μm；流动相：A相为超临界二氧化碳，B相为甲醇(0.05％二乙胺)；梯度(B％)：5％-40％】得到：化合物40的保留时间为1.741min，e.e.值为92.500％。
实施例41
Figure PCTCN2022107127-appb-000128
步骤A：在0摄氏度下，向硼烷四氢呋喃(1摩尔每升，38.66毫升，38.66毫摩尔，3当量)溶液中滴加41-1(2.8克，12.89毫摩尔，1当量)的四氢呋喃(10毫升)溶液，该混合体系在0-10摄氏度搅拌2小时。检测反应完毕，0摄氏度搅拌下向反应液中缓慢加入甲醇(30毫升)至无气体放出，加入乙酸乙酯(100毫升)稀释，用1摩尔每升的盐酸(50毫升)洗涤，随后分别用饱和碳酸钠(50毫升)和食盐水(50毫升)洗涤，无水硫酸钠干燥，过滤浓缩得化合物41-2粗品，直接用于下一步反应。 1H NMR(CD 3OD,400MHz):δ(ppm)3.58-3.51(m,1H),3.51-3.40(m,2H),1.66-1.49(m,2H),1.48-1.39(m,9H),1.39-1.28(m,2H),0.96(s,3H).
步骤B：在0摄氏度下，41-2(2.1克，10.33毫摩尔，1当量)的二氯甲烷(20毫升)溶液中分批加入戴斯-马丁氧化剂(4.47克，10.54毫摩尔，1.02当量)。该混合体系在25摄氏度搅拌12小时。检测反应完毕，将反应液浓缩至干，残物用硅胶柱柱层析(二氧化硅1000目硅胶，洗脱液梯度乙酸乙酯/石油醚10/1至2/1)得化合物41-3。 1H NMR(氯仿-d,400MHz):δ(ppm)9.67-9.46(m,1H),5.29(br s,1H),4.35-4.15(m,1H),1.58-1.53(m,2H),1.46-1.43(m,9H),1.43-1.32(m,2H),0.96(t,J＝7.2Hz,3H).
步骤C：在0摄氏度下，向化合物1-13(3.41克，15.20毫摩尔，2当量)和氯化锂(966.75毫克，22.81毫摩尔，3当量)的乙腈(20毫升)溶液中加入N,N-二异丙基乙胺(2.95克，22.81毫摩尔，3当量)，将该混合体系在0摄氏度搅拌半小时。随后将41-3(1.53克，7.60毫摩尔，1当量)的乙腈(3毫升)溶液滴加到上述反应液中。该反应混合物在25摄氏度下搅拌12小时。检测反应完毕，向反应液中加入1摩尔每升盐酸(50毫升)，用乙酸乙酯(80毫升×2)萃取，合并有机相，用饱和食盐水(50毫升×2)洗涤，无水硫酸钠干燥，过滤，浓缩滤液，得到的残留物用柱层析(二氧化硅1000目硅胶，洗脱液梯度乙酸乙酯/石油醚100/1至3/1)纯化得到化合物41-4。 1H NMR(CD 3OD,400MHz):δ(ppm)6.94-6.77(m,1H),5.98-5.83(m,1H),4.67-4.20(m,3H),1.63-1.48(m,2H),1.47(s,9H),1.44(s,2H),1.30(t,J＝7.2Hz,3H),0.96(s,3H).步骤D：化合物41-4(700毫克，2.58毫摩尔，1当量)在氯化氢甲醇溶液(4摩尔每升，30毫升，20 毫摩尔，46.52当量)中25摄氏度下搅拌2小时。检测反应完毕，浓缩得化合物41-5粗品。
步骤E：化合物41-5(0.44克，2.57毫摩尔，1当量)，化合物31-1(0.46克，755.55微摩尔，0.9当量)和碳酸氢钠(647.58毫克，7.71毫摩尔，3当量)在乙腈(10毫升)中，25摄氏度搅拌12小时。检测反应完毕，向反应液中加入1摩尔每升盐酸(50毫升)，用乙酸乙酯(80毫升×2)萃取，用饱和食盐水(30毫升×2)洗涤，无水硫酸钠干燥，过滤，浓缩滤液，得到的残留物用柱层析(二氧化硅1000目硅胶，洗脱液梯度乙酸乙酯/石油醚100/1至2/1)纯化得到化合物41-6。MS(ESI)m/z:334.1[M+H +].
步骤F：0摄氏度下，向化合物41-6(0.57克，1.71毫摩尔，1当量)的四氢呋喃(15毫升)溶液中缓慢滴加二异丁基氢化铝(1摩尔每升，6.84毫升，4当量)溶液，该混合体系在0摄氏度下搅拌3小时。检测反应完毕，向反应液中加入饱和酒石酸钠钾水溶液(60毫升)淬灭，继续搅拌12小时，用乙酸乙酯(100毫升×2)萃取，合并有机相，用饱和食盐水(100毫升×2)洗涤，无水硫酸钠干燥，过滤，浓缩滤液，得到的残留物用柱层析(二氧化硅1000目硅胶，洗脱液梯度乙酸乙酯/石油醚100/1至2/1)纯化得到化合物41-7。MS(ESI)m/z:292.1[M+H +].
步骤G：向化合物41-7(0.288克，0.985毫摩尔，1当量)的四氢呋喃(10毫升)溶液中加入N,N-羰基二咪唑(239.66毫克，1.48毫摩尔，1.5当量)和三乙胺(498.54毫克，4.93毫摩尔，5当量)，该混合体系在25摄氏度下搅拌1小时。将化合物7-3(0.445克，1.97毫摩尔，2当量，盐酸盐)加入到上述反应液中,混合体系在25摄氏度下搅拌12小时。检测反应完毕，向反应液中加入水(30毫升)淬灭，乙酸乙酯(40毫升×2)萃取，合并有机相，用饱和食盐水(20毫升×2)洗涤，无水硫酸钠干燥，过滤，浓缩滤液，得到的残留物用高效液相色谱(柱子:Phenomenex luna C18 150*25毫米*10微米；流动相[水(甲酸)-乙腈]；乙腈％：34％-64％，12分钟)，然后通过SFC分离(柱子:DAICEL CHIRALCEL OJ(250毫米*30毫米，10微米)；流动相：[0.1％氨水甲醇]；甲醇％：30％-30％，2.8分钟)纯化得到化合物41。MS(ESI)m/z:507.2[M+H +].
1H NMR(CD 3OD,400MHz):δppm 8.64(s,2H),7.91-7.80(m,1H),5.91-5.76(m,2H),4.62(br d,J＝4.8Hz,2H),4.44-4.28(m,1H),4.02-3.87(m,4H),3.58(br s,4H),1.84-1.62(m,2H),1.57-1.36(m,2H),1.00(t,J＝7.2Hz,3H).
化合物41经SFC检测【柱型号：Chiralcel OJ-3 50×4.6mm I.D.,3μm；流动相：A相为超临界二氧化碳，B相为甲醇(0.05％二乙胺)；梯度(B％)：5％-40％】得到：化合物41的保留时间为1.682min，e.e.值为100.000％。
实施例42
Figure PCTCN2022107127-appb-000129
步骤A：向化合物42-1(10克，112.19毫摩尔，1当量)的四氢呋喃(30毫升)和水(30毫升)溶液中加入碳酸钾(31.01克，224.38毫摩尔，2当量)和二碳酸二叔丁酯(25.71克，117.80毫摩尔，27.06毫升，1.05当量)，该混合体系在25摄氏度搅拌12小时。反应液用乙酸乙酯萃取(100毫升×2)，合并有机相，饱和食盐水(30毫升×2)洗涤，无水硫酸钠干燥，过滤，浓缩得到化合物42-2。 1H NMR(氯仿-d,400MHz):δ(ppm)4.72-4.28(m,1H),4.02-3.81(m,1H),3.64(dd,J＝7.6,2.8Hz,2H),3.05-2.57(m,1H),1.94-1.72(m,1H),1.46(s,9H),1.40-1.29(m,1H),1.20(d,J＝6.8Hz,3H).
步骤B：在0摄氏度，向化合物42-2(21.20克，112.02毫摩尔，1当量)的二氯甲烷(200毫升)溶液中加入戴斯-马丁氧化剂(46.56克，109.78毫摩尔，33.99毫升，0.98当量)，该混合液在25摄氏度搅拌2小时。向反应液中加入饱和硫代硫酸钠溶液(100毫升)淬灭，搅拌10分钟，用乙酸乙酯(300毫升)萃取，有机相用饱和食盐水洗涤(100毫升)，无水硫酸钠干燥，过滤，浓缩，残留物通过柱层析(二氧化硅1000目硅胶，洗脱液梯度乙酸乙酯/石油醚10/1至2/1)纯化得到化合物42-3。 1H NMR(氯仿-d,400MHz):δ(ppm)9.76(s,1H),5.00-4.59(m,1H),4.21-4.07(m,1H),2.69-2.50(m,2H),1.43(s,9H),1.23(d,J＝6.8Hz,3H).
步骤C：在0摄氏度，向化合物42-3(19.45克，103.88毫摩尔，1当量)和氯化锂(13.21克，311.64毫摩尔，6.38毫升，3当量)的乙腈(100毫升)溶液中加入N,N-二异丙基乙基胺(40.28克，311.64毫摩尔，54.28毫升，3当量)，该混合液在0摄氏度搅拌30分钟，然后在0摄氏度加入化合物1-13(46.58克，207.76毫摩尔，41.22毫升，2当量)的乙腈(20毫升)溶液，该混合液自然升温至25摄氏度，搅拌12小时。向反应液中加入盐酸(1摩尔每升，250毫升)，25摄氏度搅拌2分钟，乙酸乙酯(380毫升)萃取，有机相用饱和食盐水(100毫升)洗涤，无水硫酸钠干燥，过滤，滤液浓缩，残留物通过柱层析(二氧化硅1000目硅胶，洗脱液梯度乙酸乙酯/石油醚100/1至3/1)纯化得到化合物42-4。 1H NMR(氯仿-d,400MHz):δ(ppm)7.01-6.85(m,1H),5.94-5.82(m,1H),4.65-4.28(m,1H),4.21(d,J＝6.4Hz,2H),3.97-3.64(m,1H),2.61-2.18(m,2H),1.45(s,9H),1.30(s,3H),1.21-1.10(m,3H).
步骤D：在0摄氏度，向化合物42-4((22.18克，86.19毫摩尔，1当量)的四氢呋喃(200毫升)溶液中加入二异丁基氢化铝(1摩尔每升，258.58毫升，3当量)，反应液在0摄氏度搅拌3小时。向反应液中滴加饱和酒石酸钠钾的水溶液(60毫升)，滴加时保持温度0摄氏度，然后自然升温至25摄氏度搅拌12小时，该混合液用乙酸乙酯(200毫升)萃取，有机相用饱和食盐水洗涤(50毫升×2)，无水硫酸钠干燥，过滤，浓缩，残留物通过柱层析(二氧化硅1000目硅胶，洗脱液梯度乙酸乙酯/石油醚100/1至2/1)纯化得到化合物42-5。 1H NMR(氯仿-d,400MHz):δ(ppm)5.83-5.57(m,2H),4.54-4.22(m,1H),4.12(d,J＝4.4Hz,2H),3.85-3.56(m,1H),2.21(s,2H),1.46(s,9H),1.14(d,J＝6.8Hz,3H).
步骤E：在0摄氏度，向化合物42-5(5.63克，26.15毫摩尔，1当量)的二氯甲烷(40毫升)溶液中加入三苯基磷(9.7克，36.98毫摩尔，1.41当量)和四溴化碳(12.23克，36.87毫摩尔，1.41当量)，该混合液在0摄氏度反应2小时。将反应液浓缩，残留物通过柱层析(1000目硅胶，石油醚/乙酸乙酯＝1000/1，10/1)纯化，得到化合物42-6。 1H NMR(氯仿-d,400MHz):δ(ppm)5.87-5.69(m,2H),4.58-4.20(m,1H),4.03-3.93(m,2H),3.86-3.62(m,1H),2.39-2.13(m,2H),1.46(s,9H),1.14(d,J＝6.8Hz,3H).
步骤F：向化合物42-6(2克，7.19毫摩尔，1当量)的二甲基亚砜(20毫升)溶液中加入氰化钠(0.63克，12.86毫摩尔，1.79当量)，将反应液加热到100摄氏度反应5小时。将反应液冷却至25摄氏度，加入水(50毫升)，搅拌5分钟。用乙酸乙酯(80毫升×2)萃取，合并有机相，饱和食盐水(30毫升×2)洗涤，无水硫酸钠干燥，过滤，浓缩，得到的残留物通过柱层析(1000目硅胶，石油醚/乙酸乙酯＝100/1，5/1)纯化，得到化合物42-7。 1H NMR(氯仿-d,400MHz):δppm 4.12-3.85(m,2H),2.93(br s,2H),2.14-1.89(m,2H),1.80-1.61(m,1H),1.50(s,9H),1.12-1.32(m,3H).
步骤G：将化合物42-7(350毫克，1.56毫摩尔，1当量)加入到盐酸甲醇(4摩尔每升，10毫升)中，在25摄氏度搅拌2小时。将反应液浓缩得到化合物42-8。
步骤H：将化合物42-8(0.302克，1.56毫摩尔，1当量，盐酸盐)，1-7(496.93毫克，1.56毫摩尔，1当量)和碳酸氢钠(524.00毫克，6.24毫摩尔，242.59微升，4当量)加入到乙腈(10毫升)中，该混合液在25摄氏度搅拌12小时。向反应液中加入水(20毫升)，搅拌2分钟，水相用乙酸乙酯(80毫升)萃取，饱和食盐水(30毫升×2)洗涤，无水硫酸钠干燥，过滤，浓缩，得到的残留物通过薄层色谱(石油醚/乙酸乙酯＝3/1)纯化，得到化合物42-9。MS(ESI)m/z:440.1[M+H +].
步骤I：向化合物42-9(0.173克，393.69微摩尔，1当量)的三氟乙酸(3毫升)溶液中加入三氟甲磺酸(0.6 毫升)，反应液在25摄氏度搅拌2小时。将反应液浓缩，得到粗产品化合物42-10。MS(ESI)m/z:320.0[M+H +].
步骤J：向化合物42-10(125毫克，391.51微摩尔，1当量)的甲醇(5毫升)和水(5毫升)溶液中加入氢氧化锂(93.76毫克，3.92毫摩尔，10当量)，该反应液在25摄氏度搅拌12小时。用盐酸调节反应液pH至3，用乙酸乙酯(80毫升)萃取，饱和食盐水(30毫升)洗涤，无水硫酸钠干燥，过滤，浓缩，得到化合物42-11。MS(ESI)m/z:306.1[M+H +].
步骤K：向化合物42-11(0.12克，393.121微摩尔，1当量)的N,N-二甲基甲酰胺(3毫升)溶液中加入O-(7-氮杂苯并三氮唑-1-基)N,N,N,N-四甲基脲六氟磷酸盐(298.95毫克，786.23微摩尔，2当量)和N,N-二异丙基乙基胺(254.04毫克，1.97毫摩尔，342.37微升，5当量)，然后加入化合物7-3(148.77毫克，786.23微摩尔，2当量)，该反应液在25摄氏度搅拌12小时。向反应液中加入盐酸(20毫升，1摩尔每升)，搅拌5分钟，水相用乙酸乙酯(80毫升×2)萃取，合并有机相，饱和食盐水(20毫升×2)洗涤，无水硫酸钠干燥，过滤，浓缩，残留物通过高效液相色谱(柱子：Phenomenex luna C18 150*25毫米*10微米；流动相：[水(甲酸)-乙腈]；乙腈％:27％-57％，10分钟)纯化，得到化合物42。MS(ESI)m/z:477.2[M+H +]. 1H NMR(氯仿-d,400MHz):δ(ppm)8.59-8.52(m,2H),7.78-7.70(m,1H),5.58-5.51(m,2H),4.77-4.65(m,1H),3.98-3.79(m,4H),3.76-3.52(m,4H),2.63-2.41(m,2H),2.40-2.26(m,2H),1.39-1.37(m,3H).
实施例43
Figure PCTCN2022107127-appb-000130
步骤A：向化合物11-8(300毫克，1.14毫摩尔，1当量)的二氯甲烷(6毫升)溶液中加入N-甲基吗啡啉(172.93毫克，1.71毫摩尔，187.97微升，1.5当量)和化合物12-4(275.68毫克，1.37毫摩尔，1.2当量)，该混合体系在25摄氏度搅拌12小时。反应液用水(30毫升)稀释，乙酸乙酯(30毫升×2)萃取，合并有机相，用饱和食盐水(30毫升)洗涤，无水硫酸钠干燥，过滤，浓缩滤液，粗品通过柱层析(硅胶柱,石油醚/乙酸乙酯＝3/1，1/1，0/1)纯化，得到化合物43-1。MS(ESI)m/z:429.1[M+H +].
Figure PCTCN2022107127-appb-000131
步骤A：向化合物43-2(2克，9.33毫摩尔，1当量)的N,N-二甲基甲酰胺(50毫升)溶液中加入碳酸钾(1.93克，14.00毫摩尔，1.5当量)和化合物7-1(1.82克，13.07毫摩尔，1.4当量)，该混合体系在80摄氏度下搅拌12小时。将反应液冷却至25摄氏度，加入水(200毫升)，白色固体析出，过滤，收集滤饼，经减压浓缩得到化合物43-3。MS(ESI)m/z:218.2[M+H +-100].
步骤B：向化合物43-3(2.4克，7.56毫摩尔，1当量)的乙酸乙酯(25毫升)溶液中加入盐酸乙酸乙酯(4摩尔每升，25毫升，13.22当量)，该反应液在25摄氏度搅拌1小时。将反应液浓缩得到化合物43-4的盐酸盐。MS(ESI)m/z:218.1[M+H +].
步骤C：向化合物43-1(1.7克，3.97毫摩尔，1当量)和化合物43-4(1.31克，5.16毫摩尔，1.3当量，盐酸盐)的N,N-二甲基甲酰胺(30毫升)溶液中加入三乙胺(602.43毫克，5.95毫摩尔，828.65微升，1.5当量)，该混合物在25摄氏度搅拌12小时。反应液用水(100毫升)稀释，乙酸乙酯(100毫升×2)萃取，合并有机相，用饱和食盐水(100毫升)洗涤，无水硫酸钠干燥，过滤，浓缩滤液，得到的粗品通过柱层析(硅胶柱，洗脱液梯度0～100％石油醚/乙酸乙酯，80毫升/分钟)纯化，得到化合物43。MS(ESI)m/z:507.2[M+H +].
1H NMR(400MHz,DMSO-d 6)δ＝12.52(br s,1H),8.74(s,2H),7.82(s,1H),6.49(br d,J＝3.6Hz,1H),5.86-5.65(m,2H),4.82(br d,J＝12.8Hz,2H),4.52(br s,3H),4.14(br s,1H),3.01(br s,2H),2.68(s,3H),1.70-1.55(m,4H),1.31(br d,J＝6.4Hz,3H)
化合物43经SFC检测【柱型号：Chiralpak IC-3 50×4.6mm I.D.,3μm；流动相：A相为超临界二氧化碳，B相为甲醇+乙腈(0.05％二乙胺)；梯度(B％)：50％-50％】得到：化合物43的保留时间为0.893min，e.e.值为95.318％。
实施例44
Figure PCTCN2022107127-appb-000132
步骤A：向化合物44-1(300毫克，1.61毫摩尔，1当量)和化合物7-1(269.72毫克，1.93毫摩尔，1.2当量)的N,N-二甲基甲酰胺(5毫升)溶液中加入碳酸钾(333.92毫克，2.42毫摩尔，1.5当量)，该混合体系在90摄氏度下搅拌2小时。将反应液冷却至25摄氏度，加入水(50毫升)，白色固体析出，过滤，收集滤饼，经减压浓缩得到化合物44-2。MS(ESI)m/z:234.1[M+H +-56].
步骤B：向化合物44-2(155毫克，535.72微摩尔，1当量)的乙酸乙酯(2毫升)溶液中加入盐酸乙酸乙酯(4摩尔每升，2毫升，14.93当量)，该反应液在25摄氏度搅拌2小时。将反应液浓缩得到化合物44-3的盐酸盐。MS(ESI)m/z:190.1[M+H +].
1H NMR(400MHz,DMSO-d 6)δ＝9.86(br s,2H),8.79(s,2H),4.38(br s,2H),4.31-4.24(m,2H),4.16-4.06(m,1H),2.55(t,J＝5.2Hz,3H).
步骤C：向化合物43-1(158.16毫克，369.26微摩尔，1当量)和化合物44-3(100毫克，443.11微摩尔，1.2当量，盐酸盐)的N,N-二甲基甲酰胺(5毫升)溶液中加入三乙胺(56.05毫克，553.89微摩尔，77.09微升，1.5当量)，该混合物在25摄氏度搅拌12小时。反应液用水(50毫升)稀释，乙酸乙酯(50毫升×2)萃取，合并有机相，用饱和食盐水(50毫升)洗涤，无水硫酸钠干燥，过滤，浓缩滤液，得到的粗品通过高效液相色谱(柱子:Phenomenex luna C18 150*25毫米*10微米；流动相:[水(甲酸)-乙腈]；乙腈％:22％-52％,2分钟)，高效液相色谱(柱子:Waters Xbridge 150*25毫米*5微米；流动相:[水(碳酸氢铵)-乙腈]；乙腈％:25％-55％,8分钟)纯化，得到化合物44。MS(ESI)m/z:479.2[M+H +].
1H NMR(400MHz,DMSO-d 6)δ＝12.51(br s,1H),8.74(s,2H),7.82(s,1H),6.50(br d,J＝3.6Hz,1H),5.92-5.68(m,2H),4.98(br s,1H),4.53(d,J＝5.2Hz,2H),4.37-4.17(m,4H),2.93(s,3H),2.07(s,1H),1.30(d,J＝6.4Hz,3H)
化合物44经SFC检测【柱型号：Chiralpak IC-3 50×4.6mm I.D.,3μm；流动相：A相为超临界二氧化碳，B相为甲醇+乙腈(0.05％二乙胺)；梯度(B％)：40％-40％】得到：化合物44的保留时间为1.340min，e.e.值为100.000％。
实验例1：PARP7酶活性测试实验
实验目的：
此测定法用于检查化合物抑制PARP7酶活性的效力，其中较低的IC 50值表示作为PARP7抑制剂的化合物在以下测定设置中的高效力。
实验材料：
PARP7化学荧光检测试剂盒购自BPS Bioscience。
实验方法：
PBST缓冲液配制：1倍PBS中包含0.05％Tween-20，即10mL PBS中加入5μL 100％Tween-20
将试剂盒中的组蛋白溶液用1倍PBS进行5倍稀释，取25μL/孔稀释液到微孔板中，置于4℃过夜孵育；结束孵育后，弃去孔中液体，取100μL/孔PBST洗板3次，弃去孔中残留液体；取100μL/孔封闭液到微孔板中，置于25℃孵育90分钟；结束孵育后，弃去孔中液体，取100μL/孔PBST洗板3次，弃去孔中残留液体；
1倍测试缓冲液配制：将10倍PARP测试缓冲液用双蒸水进行10倍稀释；
化合物溶液配制：将待测化合物用100％DMSO进行5倍稀释至第8个浓度，即从1000μM稀释至12.8nM。再用1倍测试缓冲液将待测化合物各梯度稀释成DMSO为10％的工作液，取2.5μL/孔加到微孔板，设置双复孔实验。
取12.5μL/孔底物混合溶液(1.25μL 10倍PARP测试缓冲液；1.25μL 10倍PARP测试混合液；10μL双蒸水)到微孔板。
将PARP7酶稀释到6ng/μL，取10μL/孔加入到微孔板，此时化合物终浓度梯度为10μM至0.128nM，PARP7(60ng/孔)，反应体系置于25℃孵育60分钟；
结束孵育后，弃去孔中液体，取100μL/孔PBST洗板3次，弃去孔中残留液体；
将Streptavidin-HRP用封闭液进行50倍稀释，然后取25μL/孔到微孔板，置于25℃孵育30分钟；
结束孵育后，弃去孔中液体，取100μL/孔PBST洗板3次，弃去孔中残留液体；
按照1:1(v/v)混匀ELISA ECL底物A和ELISA ECL底物B，取50μL/孔到微孔板，读取化学发光值。
实验结果：见表1。
表1抑制PARP7酶活性
样品 PARP7 IC 50(nM)
化合物1 57.76
化合物2 10.98
化合物3 10.42
化合物4 24.94
化合物5 77.13
化合物6 53.76
化合物7 75.69
化合物8 36.38
化合物10 29.78
化合物11 7.97
化合物12 4.54
化合物13 9.15
化合物14 8.68
化合物15 9.18
化合物16 32.00
化合物17 5.81
化合物18 13.35
化合物19 9.37
化合物20 11.27
化合物21 5.35
化合物22 8.38
化合物23 21.12
化合物24 5.05
化合物25 11.68
化合物27 18.34
化合物28A 7.32
化合物28B 7.13
化合物29A 7.41
化合物29B 6.64
化合物30 4.91
化合物31 4.89
化合物32 6.06
化合物33 6.10
化合物34 7.18
化合物37 13.81
化合物43 8.65
结论：本发明化合物对PARP7具有优异的体外抑制活性。
实验例2：H1373细胞抗增殖实验
实验材料：
RPMI-1640培养基，盘尼西林/链霉素抗生素购自维森特，胎牛血清购自Biosera。CellTiter-Glo(细胞活率化学发光检测试剂)试剂购自Promega。NCI-H1373细胞系购自南京科佰生物科技有限公司。 Nivo多标记分析仪(PerkinElmer)。
实验方法：
将H1373细胞种于白色96孔板中，80μL细胞悬液每孔，其中包含3000个H1373细胞。细胞板置于二氧化碳培养箱中过夜培养。
将待测化合物用排枪进5倍稀释至第9个浓度，即从2mM稀释至5.12nM，设置双复孔实验。向中间板中加入78μL培养基，再按照对应位置，转移2μL每孔的梯度稀释化合物至中间板，混匀后转移20μL每孔到细胞板中。转移到细胞板中的化合物浓度范围是10μM至0.0256nM。细胞板置于二氧化碳培养箱中培养6天。另准备一块细胞板，在加药当天读取信号值作为最大值参与数据分析。向此细胞板每孔加入25μL细胞活率化学发光检测试剂，室温孵育10分钟使发光信号稳定。采用多标记分析仪读数。
给药6天后向细胞板中加入每孔25μL的细胞活率化学发光检测试剂，室温孵育10分钟使发光信号稳定。采用多标记分析仪读数。
数据分析：
原始数据换算成抑制率，IC 50的值即可通过四参数进行曲线拟合得出。表2提供了本发明的化合物对H1373细胞增殖的抑制活性。
实验结果：见表2：
表2本发明的化合物对H1373细胞增殖的抑制活性
样品 H1373抗增殖IC 50(纳摩尔每升)
化合物1 5.06
化合物2 12.52
化合物4 73.14
化合物6 10.35
化合物7 33.53
化合物8 66.16
化合物9 57.74
化合物10 14.50
化合物11 83.01
化合物12 105.1
化合物14 69.86
化合物20 23.05
化合物21 158.2
化合物24 16.23
化合物25 71.64
化合物28B 72.95
化合物31 11.81
化合物34 22.81
结论：本发明化合物具有优异的H1373抗增殖活性。
实验例3：CT26 CXCL10 mRNA激活实验
实验材料：
RPMI-1640培养基购自Viva cell，胎牛血清购自Biosera，RNA提取，反转录及qPCR试剂购自诺唯赞。CT26细胞系购自中国科学院细胞库。Quantstuio 6荧光定量PCR(Thermo fisher)。
实验方法：
将CT26细胞种于24孔板中，400μL细胞悬液每孔，其中包含200000个CT26细胞。细胞板置于二氧化碳培养箱中过夜培养。
将待测化合物用排枪进行3倍稀释至第8个浓度，即从200μM稀释至914.5nM。向中间板中加入156μL培养基，再按照对应位置，转移4μL每孔的梯度稀释化合物至中间板，混匀后转移100μL每孔到细胞板中。转移到细胞板中的化合物浓度范围是10μM至4.57nM。细胞板置于二氧化碳培养箱中培养24小时。
去掉细胞板中培养基，向细胞板中加入每孔500μL的RNA抽提试剂，并按照说明书操作提取RNA。使用1μg RNA进行反转录获得cDNA，cDNA溶液按照1：4进行稀释后每孔按照2μL加到qPCR反应中。
数据分析：
原始CT值数据换算成相对表达量数据，EC 50的值即可通过四参数进行曲线拟合得出。表3提供了本发明的化合物对CT26 CXCL10 mRNA表达的诱导活性。
实验结果：见表3：
表3本发明的化合物对CT26细胞中CXCL10的mRNA表达诱导活性
样品 CXCL10 EC 50(纳摩尔每升)
化合物2 299.9
化合物7 14.75
化合物8 22.33
化合物14 162.7
化合物22 329
化合物24 97.71
化合物25 389.1
化合物30 114.1
化合物31 28.97
化合物34 75.15
结论：本发明化合物能够诱导CT26细胞中CXCL10mRNA表达。
试验例4：PARP1酶活性测试实验
实验材料：
PARP1化学荧光检测试剂盒购自BPS Bioscience；EnVision多标记分析仪(PerkinElmer)。
实验方法：
1、试剂配制：
PBST缓冲液配制：1X PBS中包含0.05％Tween-20，即10mL PBS中加入5μL 100％Tween-20
1X测试缓冲液配制：将10X PARP测试缓冲液用双蒸水进行10倍稀释
2、化合物配制：
化合物溶液配制：将待测化合物用100％DMSO进行4倍稀释至第8个浓度，即从200μM稀释至120nM。再用1X测试缓冲液将待测化合物各梯度稀释成DMSO为10％的工作液。
3、实验操作：
将试剂盒中的组蛋白溶液用1X PBS进行5倍稀释，取25μL/孔稀释液到微孔板中，置于4℃过夜孵育；
结束孵育后，弃去孔中液体，取100μL/孔PBST洗板3次，弃去孔中残留液体；
取100μL/孔封闭液到微孔板中，置于25℃孵育90分钟；结束孵育后，弃去孔中液体，取100μL/孔PBST洗板3次，弃去孔中残留液体；
取12.5μL/孔底物混合溶液(1.25μL 10X PARP测试缓冲液；1.25μL 10X PARP测试混合液；2.5μl Activated DNA；7.5μL双蒸水)到微孔板。
取2.5μL/孔的化合物工作溶液到微孔板，设置双复孔实验。
将PARP1酶稀释到2ng/μL，取10μL/孔加入到微孔板，此时待测化合物终浓度梯度为2μM至0.12nM，PARP1(20ng/孔)，反应体系置于25℃孵育60分钟；
结束孵育后，弃去孔中液体，取100μL/孔PBST洗板3次，弃去孔中残留液体；
将Streptavidin-HRP用封闭液进行50倍稀释，然后取25μL/孔到微孔板，置于25℃孵育30分钟；
结束孵育后，弃去孔中液体，取100μL/孔PBST洗板3次，弃去孔中残留液体；
按照1:1(v/v)混匀ELISA ECL底物A和ELISA ECL底物B，取50μL/孔到微孔板，读取化学发光值。
数据分析
将原始数据换算成酶活，IC 50的值即可通过四参数进行曲线拟合得出。
实验结果：见表4：
表4本发明的化合物抑制PARP1酶活性
样品 PARP1 IC 50(纳摩尔每升)
化合物31 3635
化合物34 4308
化合物39 6079
化合物40 254.9
化合物41 221.3
结论：本发明化合物对PARP1具有高选择性。
实验例5：MDA-MB-436细胞抗增殖实验
实验材料：
RPMI-1640培养基，胎牛血清，盘尼西林/链霉素抗生素购自维森特。MDA-MB-436细胞系购自中国科学院细胞库。Envision多标记分析仪(PerkinElmer)。
实验方法：
将MDA-MB-436细胞种于白色96孔板中，80μL细胞悬液每孔，其中包含3000个MDA-MB-436细胞。细胞板置于二氧化碳培养箱中过夜培养。
将待测化合物用排枪进行5倍稀释至第8个浓度，即从2mM稀释至26nM，设置双复孔实验。向中间板中加入78μL培养基，再按照对应位置，转移2μL每孔的梯度稀释化合物至中间板，混匀后转移20μL每孔到细胞板中。细胞板置于二氧化碳培养箱中培养7天。另准备一块细胞板，在加药当天读取信号值作为Max值参与数据分析。向此细胞板每孔加入25μL Promega CellTiter-Glo，室温孵育10分钟使发光信号稳定。采用PerkinElmer Envision多标记分析仪读数。
向细胞板中加入每孔25μL的Promega CellTiter-Glo试剂，室温孵育10分钟使发光信号稳定。采用PerkinElmer Envision多标记分析仪读数。
数据分析：
原始数据换算成抑制率，IC 50的值即可通过四参数进行曲线拟合得出。表6提供了本发明的化合物对MDA-MB-436细胞增殖的抑制活性。
实验结果：见表5：
表5本发明的化合物对MDA-MB-436细胞增殖的抑制活性
样品 MDA-MB-436抗增殖IC 50(纳摩尔每升)
化合物2 2096
化合物31 2675
化合物34 2739
结论：本发明化合物对MDA-MB-436抗增殖活性无明显抑制作用。
实验例6：PARYlation细胞实验
实验材料：
DMEM培养基购自Viva cell。Hela细胞购自南京科佰。Poly/Mono-ADP Ribose(E6F6A)Rabbit mAb购自CST。Fluorescein(FITC)-conjugated Affinipure Goat Anti-Rabbit IgG(H+L)购自武汉三鹰。双氧水购自阿拉丁。DAPI购自阿拉丁。PBS购自维森特。甲醇购自国药。丙酮购自国药。Tween-20购自国药。脱脂奶粉购自伊利。Envision多标记分析仪(PerkinElmer)。
实验方法：
将H1373细胞种于白色96孔板中，80μL细胞悬液每孔，其中包含3000个H1373细胞。细胞板置于二氧化碳培养箱中过夜培养。
第一天：
Hela细胞按照60000细胞/孔铺板，37度，5％CO 2，过夜。
第二天：
试剂配制：
洗涤液：1X PBS中加入Tween-20，Tween-20的终浓度为0.05％。
封闭液：在洗涤液中加入脱脂奶粉，脱脂奶粉的终浓度为5％。
细胞固定液：甲醇和丙酮按照7:3比例混合。
待测化合物配制：
将待测化合物用排枪进行5倍稀释至第8个浓度，即从1mM稀释至13nM，DMSO浓度为100％。
取1μL化合物各浓度梯度到化合物中间板1中，加入99μL PBS混匀备用，此时化合物终浓度为10μM至0.13nM，DMSO浓度为1％。设置双复孔。
取1μL化合物各浓度梯度到化合物中间板2中，加入99μL含有50mM双氧水的PBS混匀备用，此时化合物终浓度为10μM至0.13nM，DMSO浓度为1％。设置双复孔。
实验步骤：
1.细胞去掉上清，从化合物中间板1中取每孔40μL化合物到细胞板，37度，孵育30分钟。其中需要包括：
化合物孔：加入相应化合物，DMSO 1％
阴性对照与阳性对照：加入1％DMSO
空白对照：无细胞孔，加入PBS
2.结束孵育后，从化合物中间板2中取每孔40μL化合物到细胞板，H2O2终浓度为0.5mM。
化合物孔：化合物+1mM H 2O 2
阳性对照与阴性对照：1％DMSO+1mM H 2O 2
空白对照：无细胞孔，加入PBS
3. 25度孵育10分钟。
4.结束孵育后，用冰上预冷的PBS洗涤1遍，每孔再加入提前预冷的100μL细胞固定液，在-20度放10分钟，之后甩掉细胞固定液。
5.空气中风干细胞板后，加入每孔200μL PBS洗涤，弃去PBS。
6.加入每孔100μL封闭液25度孵育30分钟，之后甩掉封闭液。
7.加入每孔25μL Poly/Mono-ADP Ribose(E6F6A)Rabbit mAb，Poly/Mono-ADP Ribose(E6F6A)Rabbit mAb以1:500稀释在封闭液中，25度孵育60分钟。
阴性对照孔：加入25μL/孔封闭液
空白对照孔：加入25μL/孔封闭液
8.结束孵育后，用每孔200μL洗涤液洗涤细胞板4次，每次3分钟，甩掉洗涤液。
9.加入每孔25μL封闭液包含1:200稀释Fluorescein(FITC)-conjugated Affinipure Goat Anti-Rabbit IgG(H+L)和0.5μg/mL DAPI，25度孵育60分钟。
10.结束孵育后，用每孔200μL洗涤液洗涤细胞板4次，每次3分钟。
11.移除液体后，在Envision上读数相应荧光值：FITC：Excitation 480nm，Emission 530nm；DAPI：Excitation 360nm，Emission 460nm。
数据分析：
将原始数据进行数据归一化处理，归一化后的数据换算成抑制率，IC 50的值即可通过四参数进行曲线拟合得出。表6提供了本发明的化合物的抑制活性。
实验结果：见表6：
表6本发明的化合物对Hela细胞PARYlation的抑制
样品 PARYlation IC 50(纳摩尔每升)
化合物2 8278
化合物31 2818
化合物34 >10000
结论：本发明化合物在Hela细胞中对PARYlation的抑制作用弱，选择性好。
实验例7：小鼠体内药代动力学研究
实验目的：
本实验目的是评价化合物单次静脉注射和灌胃给药后的药代动力学行为，考察灌胃给药后的生物利用度。
实验操作：
选取7至10周龄的CD-1雄性小鼠。小鼠在给药前禁食至少12小时，给药4小时后恢复供食，整个试验期间自由饮水。
实验当天静脉组动物通过尾静脉单次注射给予相应化合物，给药体积为5毫升每公斤；口服组动物通过单次灌胃给予相应化合物，给药体积为10毫升每公斤。在给药前称量动物体重，根据体重计算给药体积。样品采集时间：注射组为0.083小时、0.25小时、0.5小时、1小时、2小时、4小时、8小时、24小时，灌胃组为0.25小时、0.5小时、1小时、2小时、4小时、6小时、8小时、24小时。每个时间点通过隐静脉采集大约30μL全血用于制备血浆供高效液相色谱-串联质谱(LC-MS/MS)进行浓度测定。所有动物在采集完最后一个时间点的PK样品后进行CO 2麻醉安乐死。采用WinNonlin TM Version 6.3(Pharsight,Mountain View,CA)药动学软件的非房室模型处理血浆浓度，使用线性对数梯形法方法计算药动学参数。
实验结果：PK性质评价结果见表7。
实验结论：
本发明化合物具有优异的药代动力学性质。
表7体内PK性质评价结果
Figure PCTCN2022107127-appb-000133
实验结论：
本发明化合物在小鼠体内口服AUC、生物利用度优异，具有良好的药代动力学性质。

Claims (16)

  1. 式(IV)化合物或其药学上可接受的盐
    Figure PCTCN2022107127-appb-100001
    其中，
    环A选自4-10元杂环烷基和C 4-10环烷基，所述4-10元杂环烷基和C 4-10环烷基分别独立地任选被1、2或3个R a取代；
    R a分别独立地选自H、CN、OH、F、Cl、Br、-COOH、-CONH 2、C 1-3烷基、C 1-3烷氨基和C 1-3烷氧基，所述-COOH、-CONH 2、C 1-3烷基、C 1-3烷氨基和C 1-3烷氧基分别独立地任选被1、2或3个R取代；
    环B选自5-6元杂芳基；
    L 5选自单键、-O-、-S-和-NR 1-；
    R 1分别独立地选自H、D、-C 1-3烷基-OH、-C 1-3烷基-NH 2和C 1-3烷基，所述-C 1-3烷基-OH、-C 1-3烷基-NH 2和C 1-3烷基任选被1、2或3个R b取代；
    R b分别独立地选自H、F、Cl、Br、D和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R取代；
    L 2和L 4分别独立地选自单键、-CH 2-、-CH 2-CH 2-和-CH 2-CH 2-CH 2-，所述-CH 2-、-CH 2-CH 2-和-CH 2-CH 2-CH 2-分别独立地任选被1或2个R c取代；
    R c分别独立地选自H、F、Cl、Br、D、C 1-3烷基、-O-C 1-3烷基和-C 1-3烷基-O-C 1-3烷基，所述C 1-3烷基分别独立地任选被1、2或3个R取代；
    R 2a和R 2b分别独立地选自H、F、Cl、Br、D和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R取代；
    L 1选自单键、-CH 2-、-O-、-C(＝O)-、-C(＝O)-NR 4-和-NR 4-；
    L 3选自单键、-CH 2-、-O-、-C(＝O)-、-C(＝O)-NR 4-和-NR 4-；
    R 4选自H、D和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R取代；
    R 3分别独立地选自H、CN、OH、F、Cl、Br、-COOH、-CONH 2、C 1-3烷基、C 1-3烷氨基、C 1-3烷氧基和C 3-6环烷基，所述-COOH、-CONH 2、C 1-3烷基、C 1-3烷氨基、C 1-3烷氧基和C 3-6环烷基分别独立地任选被1、2或3个R取代；
    各R分别独立地选自D、OH、CN、F、Cl和Br；
    n选自1、2和3；
    所述4-10元杂环烷基分别独立包含1、2或3个选自N、O、S和NH的杂原子或杂原子团。
  2. 根据权利要求1所述的化合物或其药学上可接受的盐，其中，化合物选自
    Figure PCTCN2022107127-appb-100002
    其中，n、环A、环B、L 1、L 2、L 3、L 4、L 5、R a、R 2a、R 2b和R 3如权利要求1所定义。
  3. 根据权利要求1所述的化合物或其药学上可接受的盐，其中，化合物选自
    Figure PCTCN2022107127-appb-100003
    其中，
    X为-O-，-CH 2-、-NH-或-N(CH 3)-；
    Y为N，Z为CH；或者，Y为CH，Z为N；
    环C选自4-10元杂环烷基，所述4-10元杂环烷基任选被1、2或3个R a取代；
    p为1或2；
    n、环A、环B、L 1、L 2、L 3、R 2a、R 2b、Rc、R 3如权利要求1所定义；
    带“*”碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在。
  4. 根据权利要求1-3任意一项所述的化合物或其药学上可接受的盐，其中，环A选自氮杂环丁烷基、哌啶基、哌嗪基、1,4-二氮杂环己烷基、3,8-二氮杂双环[3.2.1]辛烷基和2,5-二氮杂双环[2.2.2]辛烷基所述氮杂环丁烷基、哌啶基、哌嗪基、1,4-二氮杂环己烷基、3,8-二氮杂双环[3.2.1]辛烷基和2,5-二氮杂双环[2.2.2]辛烷基分别独立地任选被1、2或3个R a取代。
  5. 根据权利要求1-3任意一项所述的化合物或其药学上可接受的盐，其中，环B选自嘧啶基、吡啶基、哒嗪基、吡唑基、噻吩基和噻唑基。
  6. 根据权利要求1或2所述的化合物或其药学上可接受的盐，其中，L 5选自-NH-。
  7. 根据权利要求1或2所述的化合物或其药学上可接受的盐，其中，L 4选自-CH(CH 3)-、-CH(CH 2OCH 3)-、-CH(CH 3)CH 2CH 2-、-CH(CH 3)CH 2-、-CH(CH 2CH 2CH 3)-、-CH(CH 2CH 2OCH 3)-和-CH(CH 2OH)-。
  8. 根据权利要求1-3任意一项所述的化合物或其药学上可接受的盐，其中，R 2a和R 2b分别独立地选自H和F。
  9. 根据权利要求1-3任意一项所述的化合物或其药学上可接受的盐，其中，L 1选-C(＝O)、-CH 2-、-C(＝O)-NH-和-C(＝O)-N(CH 3)-。
  10. 根据权利要求1-3任意一项所述的化合物或其药学上可接受的盐，其中，L 3选自单键、-CH 2-、-O-、-NH-和-N(CH 3)-。
  11. 根据权利要求1-3任意一项所述的化合物或其药学上可接受的盐，其中，L 2选自-CH 2-和单键。
  12. 根据权利要求1或2所述的化合物或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2022107127-appb-100004
    选自
    Figure PCTCN2022107127-appb-100005
    Figure PCTCN2022107127-appb-100006
  13. 根据权利要求1或3所述的化合物或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2022107127-appb-100007
    选自
    Figure PCTCN2022107127-appb-100008
    Figure PCTCN2022107127-appb-100009
  14. 下式化合物或其药学上可接受的盐：
    Figure PCTCN2022107127-appb-100010
    Figure PCTCN2022107127-appb-100011
    Figure PCTCN2022107127-appb-100012
    Figure PCTCN2022107127-appb-100013
  15. 根据权利要求14所述的化合物或其药学上可接受的盐，其中化合物选自
    Figure PCTCN2022107127-appb-100014
    Figure PCTCN2022107127-appb-100015
    Figure PCTCN2022107127-appb-100016
    Figure PCTCN2022107127-appb-100017
    Figure PCTCN2022107127-appb-100018
  16. 根据权利要求1-15任意一项所述的化合物或其药学上可接受的盐在制备PARP7抑制剂中的应用。
PCT/CN2022/107127 2021-07-21 2022-07-21 哒嗪酮类化合物 WO2023001247A1 (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202280051608.XA CN117751108A (zh) 2021-07-21 2022-07-21 哒嗪酮类化合物

Applications Claiming Priority (10)

Application Number Priority Date Filing Date Title
CN202110827385 2021-07-21
CN202110827385.9 2021-07-21
CN202110872908.1 2021-07-30
CN202110872908 2021-07-30
CN202111509969.8 2021-12-10
CN202111509969 2021-12-10
CN202210399423 2022-04-15
CN202210399423.X 2022-04-15
CN202210730508 2022-06-24
CN202210730508.1 2022-06-24

Publications (1)

Publication Number Publication Date
WO2023001247A1 true WO2023001247A1 (zh) 2023-01-26

Family

ID=84979745

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2022/107127 WO2023001247A1 (zh) 2021-07-21 2022-07-21 哒嗪酮类化合物

Country Status (2)

Country Link
CN (1) CN117751108A (zh)
WO (1) WO2023001247A1 (zh)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11678712B2 (en) 2013-04-19 2023-06-20 Adidas Ag Shoe

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101855221A (zh) * 2007-11-15 2010-10-06 P.安杰莱蒂分子生物学研究所 作为parp抑制剂的哒嗪酮衍生物
CN103570725A (zh) * 2012-08-01 2014-02-12 中国科学院上海药物研究所 哌嗪并三唑类化合物及其制备方法和用途
CN103833756A (zh) * 2012-11-26 2014-06-04 中国科学院上海药物研究所 一类哒嗪酮类化合物及其制备方法和用途
CN112424188A (zh) * 2018-04-30 2021-02-26 里邦医疗公司 作为parp7抑制剂的哒嗪酮
WO2021087025A1 (en) * 2019-10-30 2021-05-06 Ribon Therapeutics, Inc. Pyridazinones as parp7 inhibitors
WO2021087018A1 (en) * 2019-10-30 2021-05-06 Ribon Therapeutics, Inc. Pyridazinones as parp7 inhibitors

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101855221A (zh) * 2007-11-15 2010-10-06 P.安杰莱蒂分子生物学研究所 作为parp抑制剂的哒嗪酮衍生物
CN103570725A (zh) * 2012-08-01 2014-02-12 中国科学院上海药物研究所 哌嗪并三唑类化合物及其制备方法和用途
CN103833756A (zh) * 2012-11-26 2014-06-04 中国科学院上海药物研究所 一类哒嗪酮类化合物及其制备方法和用途
CN112424188A (zh) * 2018-04-30 2021-02-26 里邦医疗公司 作为parp7抑制剂的哒嗪酮
WO2021087025A1 (en) * 2019-10-30 2021-05-06 Ribon Therapeutics, Inc. Pyridazinones as parp7 inhibitors
WO2021087018A1 (en) * 2019-10-30 2021-05-06 Ribon Therapeutics, Inc. Pyridazinones as parp7 inhibitors

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11678712B2 (en) 2013-04-19 2023-06-20 Adidas Ag Shoe

Also Published As

Publication number Publication date
CN117751108A (zh) 2024-03-22

Similar Documents

Publication Publication Date Title
US20230279025A1 (en) Kras g12d inhibitors
CA2944475C (en) Bicyclic-fused heteroaryl or aryl compounds
CA3192601A1 (en) Compounds as glp-1r agonists
CA2953798C (en) Aminopyridazinone compounds as protein kinase inhibitors
EP3242873B1 (en) Cyclic ureas as inhibitors of rock
KR102376354B1 (ko) 6-(5-히드록시-1h-피라졸-1-일)니코틴아미드 유도체 및 ｐｈｄ의 저해제로서의 그의 용도
CN112028870B (zh) 一种具有苄氧基芳环结构的化合物，其制备方法和用途
US11981663B2 (en) Benzamides of pyrazolylamino-pyrimidinyl derivatives, and compositions and methods thereof
TWI739779B (zh) 布魯頓氏酪胺酸激酶抑制劑及其使用方法
TW201940485A (zh) 作為激酶抑制劑之胺基吡咯并三
US20230102927A1 (en) Glp-1r modulating compounds
US20220144838A1 (en) Compounds as Inhibitors of Macrophage Migration Inhibitory Factor
AU2021256157A1 (en) Tricyclic compounds as EGFR inhibitors
AU2020226422A1 (en) Heterocyclic compound, pharmaceutical composition comprising same, preparation method therefor, and use thereof
WO2023001247A1 (zh) 哒嗪酮类化合物
CN117098763A (zh) Tyk2抑制剂
CN115916755A (zh) 氮杂环丁烷环状脲
CN112876419A (zh) 烯丙胺衍生物及其制备方法和用途
US12030870B2 (en) Benzamides of pyrazolylamino-pyrimidinyl derivatives, and compositions and methods thereof
JP7514025B2 (ja) Ｊａｋ阻害剤化合物及びその使用
JP2024089673A (ja) ピラゾリル－アミノ－ピリミジニル誘導体のベンズアミド、およびその組成物ならびに方法
JP2024088646A (ja) ピラゾリル－アミノ－ピリミジニル誘導体のベンズアミド、およびその組成物ならびに方法
WO2022233442A1 (en) 2,8-dihydropyrazolo[3,4-b]indole derivatives for use in the treatment of cancer
AU2021444255A1 (en) 2,8-dihydropyrazolo[3,4-b]indole derivatives for use in the treatment of cancer
US20240226114A1 (en) Inhibitors and uses thereof

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22845410

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 202280051608.X

Country of ref document: CN

NENP Non-entry into the national phase

Ref country code: DE