WO2023208244A1 - Macrocyclic compound and use thereof - Google Patents

Macrocyclic compound and use thereof Download PDF

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Publication number
WO2023208244A1
WO2023208244A1 PCT/CN2023/092077 CN2023092077W WO2023208244A1 WO 2023208244 A1 WO2023208244 A1 WO 2023208244A1 CN 2023092077 W CN2023092077 W CN 2023092077W WO 2023208244 A1 WO2023208244 A1 WO 2023208244A1
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Prior art keywords
alkyl
compound
ring
pharmaceutically acceptable
stereoisomer
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PCT/CN2023/092077
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French (fr)
Chinese (zh)
Inventor
王建非
杨广文
孙继奎
张杨
陈曙辉
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南京明德新药研发有限公司
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Publication of WO2023208244A1 publication Critical patent/WO2023208244A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings

Definitions

  • the present invention relates to new macrocyclic compounds and their applications, specifically to the compounds represented by formula (I), their stereoisomers and their pharmaceutically acceptable salts.
  • JAK is a type of non-receptor tyrosine kinase, with four subtypes: JAK1, JAK2, JAK3, and TYK2.
  • the JAK-STAT signaling pathway mediated by them is related to cell proliferation, differentiation, apoptosis, and immune regulation.
  • the biological effects of more than 50 cytokines and growth factors are mediated through JAK kinases and their JAK-STAT pathway.
  • TYK2 is a member of the JAK family protein. It is a non-receptor tyrosine kinase that mediates immune signaling and is involved in the pathological processes of a variety of immune-related diseases.
  • JAK family proteins mediate the signaling of multiple cytokines
  • comprehensive inhibition of JAK family proteins will lead to various side effects.
  • the first-generation JAK inhibitors target multiple JAK family proteins, dose-related safety issues occurred in clinical trials, including infection, lymphopenia, thromboembolism, etc.
  • TYK2 inhibitors play a therapeutic role in the treatment of autoimmune diseases and chronic inflammatory diseases by selectively inhibiting the activation of TYK2 and blocking the signaling of inflammatory cytokines such as IL-23, IL-12, and type I IFN. At the same time, it effectively reduces toxic and side effects.
  • BMS-986165 defeated the oral standard drug Apremilast in a Phase III psoriasis clinical trial and had a good safety and tolerability. This reflects that highly selective TYK2 inhibitors have huge clinical application potential in the treatment of psoriasis and other targets, and have significant clinical application value.
  • the present invention provides compounds represented by formula (I), their stereoisomers or pharmaceutically acceptable salts thereof,
  • L 1 is selected from single bond and NH
  • L 3 is selected from -O-, -NH-, -C 1-3 alkyl-O-, -C 1-3 alkyl-NH- and -C 1-3 alkyl-OC 1-3 alkyl-,
  • the -C 1-3 alkyl-O-, -C 1-3 alkyl-NH- and -C 1-3 alkyl-OC 1-3 alkyl- are optionally substituted by 1, 2 or 3 R c replace;
  • R 1 is selected from -NH-C 1-3 alkyl, R 2 is selected from H;
  • R 1 and R 2 and the atoms to which they are connected together constitute a 5-6 membered heterocyclic alkenyl group
  • R 3 is selected from H, F, Cl, Br, I, OH, CN, NH 2 , C 1-4 alkyl, C 1-3 alkoxy and 6-membered heteroaryl, the C 1-4 alkyl , C 1-3 alkoxy group and 6-membered heteroaryl group are optionally substituted by 1, 2 or 3 R a ;
  • Ring A does not exist
  • Ring A is selected from C 3-5 cycloalkyl, 5-6 membered heterocycloalkyl and 5-6 membered heteroaryl, said C 3-5 cycloalkyl, 5-6 membered heterocycloalkyl and The 5-6 membered heteroaryl group is optionally substituted by 1, 2 or 3 R b ;
  • Ring B is selected from phenyl, 5-6-membered heteroaryl, 5-6-membered heterocycloalkyl, pyridopyrrolyl, benzoxazolyl, benzopyrrolyl, benzimidazolyl, benzopyrazolyl and
  • Ring C is selected from C 5-6 cycloalkyl, C 5-6 cycloalkenyl, 5-6 membered heterocycloalkyl and 5-6 membered heterocycloalkenyl;
  • Each R a is independently selected from F, Cl, Br, I, CH 3 and OCH 3 ;
  • Each R b is independently selected from F, Cl, Br, I, OH, C 1-3 alkyl and C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are optional Choose to be replaced by 1, 2 or 3 halogens;
  • 2 R b and the carbon atoms to which they are connected together constitute a C 3-5 cycloalkyl group
  • Each R c is independently selected from C 1-3 alkyl and phenyl;
  • ring A does not exist, ring B is selected from pyridopyrrolyl;
  • the above-mentioned compound, its stereoisomer or its pharmaceutically acceptable salt is selected from the structure represented by formula (II):
  • L 1 is selected from single bond and NH
  • L 3 is selected from -O-, -NH-, -C 1-3 alkyl-O-, -C 1-3 alkyl-NH- and -C 1-3 alkyl-OC 1-3 alkyl-,
  • the -C 1-3 alkyl-O-, -C 1-3 alkyl-NH- and -C 1-3 alkyl-OC 1-3 alkyl- are optionally substituted by 1, 2 or 3 R c replace;
  • R 1 is selected from -NH-C 1-3 alkyl, R 2 is selected from H;
  • R 1 and R 2 and the atoms to which they are connected together constitute a 5-6 membered heterocyclic alkenyl group
  • R 3 is selected from H, F, Cl, Br, I, OH, CN, NH 2 , C 1-4 alkyl, C 1-3 alkoxy and 5-6 membered heteroaryl, the C 1-4 Alkyl, C 1-3 alkoxy and 5-6 membered heteroaryl are optionally substituted by 1, 2 or 3 R a ;
  • Ring A does not exist
  • Ring A is selected from C 3-5 cycloalkyl, 5-6 membered heterocycloalkyl and 5-6 membered heteroaryl, said C 3-5 cycloalkyl, 5-6 membered heterocycloalkyl and The 5-6 membered heteroaryl group is optionally substituted by 1, 2 or 3 R b ;
  • Ring B is selected from phenyl, 5-6-membered heteroaryl, 5-6-membered heterocycloalkyl, pyridopyrrolyl, benzoxazolyl, benzopyrrolyl, benzimidazolyl, benzopyrazolyl and
  • Ring C is selected from 5-6 membered heterocycloalkyl and 5-6 membered heterocycloalkenyl;
  • Each R a is independently selected from F, Cl, Br, I, CH 3 and OCH 3 ;
  • Each R b is independently selected from F, Cl, Br, I, OH, C 1-3 alkyl and C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are optional Choose to be replaced by 1, 2 or 3 halogens;
  • 2 R b and the carbon atoms to which they are connected together constitute a C 3-5 cycloalkyl group
  • Each R c is independently selected from C 1-3 alkyl and phenyl;
  • ring A does not exist, ring B is selected from pyridopyrrolyl;
  • the above compounds, their stereoisomers or their pharmaceutically acceptable salts are selected from:
  • L 3 , R 3 and Ring A are as defined in the present invention.
  • the present invention provides compounds represented by formula (I) or pharmaceutically acceptable salts thereof,
  • L 1 is selected from single bond and NH
  • L 3 is selected from -O-, -NH-, -C 1-3 alkyl-O-, -C 1-3 alkyl-NH- and -C 1-3 alkyl-OC 1-3 alkyl-,
  • the -C 1-3 alkyl-O-, -C 1-3 alkyl-NH- and -C 1-3 alkyl-OC 1-3 alkyl- are optionally substituted by 1, 2 or 3 R c replace;
  • R 1 is selected from -NH-C 1-3 alkyl, R 2 is selected from H;
  • R 1 and R 2 and the atoms to which they are connected together constitute a 5-6 membered heterocyclic alkenyl group
  • R 3 is selected from H, F, Cl, Br, I, OH, CN, NH 2 , C 1-4 alkyl, C 1-3 alkoxy and 5-6 membered heteroaryl, the C 1-4 Alkyl, C 1-3 alkoxy and 5-6 membered heteroaryl are optionally substituted by 1, 2 or 3 R a ;
  • Ring A does not exist
  • Ring A is selected from C 3-5 cycloalkyl, 5-6 membered heterocycloalkyl and 5-6 membered heteroaryl, said C 3-5 cycloalkyl, 5-6 membered heterocycloalkyl and The 5-6 membered heteroaryl group is optionally substituted by 1, 2 or 3 R b ;
  • Ring B is selected from phenyl, 5-6-membered heteroaryl, 5-6-membered heterocycloalkyl, pyridopyrrolyl, benzoxazolyl, benzopyrrolyl, benzimidazolyl, benzopyrazolyl and
  • Ring C is selected from 5-6 membered heterocycloalkyl and 5-6 membered heterocycloalkenyl;
  • Each R a is independently selected from F, Cl, Br, I, CH 3 and OCH 3 ;
  • Each R b is independently selected from F, Cl, Br, I, OH, C 1-3 alkyl and C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are optional Choose to be replaced by 1, 2 or 3 halogens;
  • 2 R b and the carbon atoms to which they are connected together constitute a C 3-5 cycloalkyl group
  • Each R c is independently selected from C 1-3 alkyl and phenyl;
  • ring A does not exist, ring B is selected from pyridopyrrolyl;
  • the present invention provides compounds represented by formula (I) or pharmaceutically acceptable salts thereof,
  • L 1 is selected from single bond and NH
  • L 3 is selected from -O-, -NH-, -C 1-3 alkyl-O-, -C 1-3 alkyl-NH- and C 1-3 alkyl-OC 1-3 alkyl, said -C 1-3 alkyl-O-, -C 1-3 alkyl-NH- and -C 1-3 alkyl-OC 1-3 alkyl- are optionally substituted by 1, 2 or 3 R c ;
  • R 1 is selected from -NH-C 1-3 alkyl, R 2 is selected from H;
  • R 1 and R 2 and the atoms to which they are connected together constitute a 5-6 membered heterocyclic alkenyl group
  • R 3 is selected from H, F, Cl, Br, I, OH, CN, NH 2 , C 1-3 alkyl, C 1-3 alkoxy and 5-6 membered heteroaryl, the C 1-3 Alkyl, C 1-3 alkoxy and 5-6 membered heteroaryl are optionally substituted by 1, 2 or 3 R a ;
  • Ring A does not exist
  • Ring A is selected from C 3-5 cycloalkyl, 5-6 membered heterocycloalkyl and 5-6 membered heteroaryl, said C 3-5 cycloalkyl, 5-6 membered heterocycloalkyl and The 5-6 membered heteroaryl group is optionally substituted by 1, 2 or 3 R b ;
  • Ring B is selected from phenyl, 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl, pyridopyrrolyl and
  • Ring C is selected from 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkenyl and 5-6 membered heteroaryl;
  • Each R a is independently selected from F, Cl, Br, I, CH 3 and OCH 3 ;
  • Each R b is independently selected from F, Cl, Br, I, C 1-3 alkyl and C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are optionally 1, 2 or 3 halogen substitutions;
  • 2 R b and the carbon atoms to which they are connected together constitute a C 3-5 cycloalkyl group
  • Each R c is independently selected from C 1-3 alkyl and phenyl;
  • ring A does not exist, ring B is selected from pyridopyrrolyl;
  • the present invention provides compounds represented by formula (I) or pharmaceutically acceptable salts thereof,
  • L 1 is selected from single bond and NH
  • L 3 is selected from -O-, -NH-, -C 1-3 alkyl-O-, -C 1-3 alkyl-NH- and C 1-3 alkyl-OC 1-3 alkyl;
  • R 1 is selected from -NH-C 1-3 alkyl, R 2 is selected from H;
  • R 1 and R 2 and the atoms to which they are connected together constitute a 5-6 membered heterocyclic alkenyl group
  • R 3 is selected from H, F, Cl, Br, I, OH, CN, NH 2 , C 1-3 alkyl, C 1-3 alkoxy and 5-6 membered heteroaryl, the C 1-3 Alkyl, C 1-3 alkoxy and 5-6 membered heteroaryl are optionally substituted by 1, 2 or 3 R a ;
  • Ring A does not exist
  • Ring A is selected from C 3-5 cycloalkyl, 5-6 membered heterocycloalkyl and 5-6 membered heteroaryl, said C 3-5 cycloalkyl, 5-6 membered heterocycloalkyl and The 5-6 membered heteroaryl group is optionally substituted by 1, 2 or 3 R b ;
  • Ring B is selected from phenyl, 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl, pyridopyrrolyl and
  • Ring C is selected from 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkenyl and 5-6 membered heteroaryl;
  • Each R a is independently selected from F, Cl, Br, I, CH 3 and OCH 3 ;
  • Each R b is independently selected from F, Cl, Br, I, C 1-3 alkyl and C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are selected from 1 , 2 or 3 halogen substitutions;
  • 2 R b and the carbon atoms to which they are connected together constitute a C 3-5 cycloalkyl group
  • ring A does not exist, ring B is selected from pyridopyrrolyl;
  • the present invention provides compounds represented by formula (I) or pharmaceutically acceptable salts thereof,
  • L 1 is selected from single bond and NH
  • L 3 is selected from -O-, -NH-, -C 1-3 alkyl-O-, -C 1-3 alkyl-NH- and C 1-3 alkyl-OC 1-3 alkyl;
  • R 1 is selected from -NH-C 1-3 alkyl, R 2 is selected from H;
  • R 1 and R 2 and the atoms to which they are connected together constitute a 5-6 membered heterocyclic alkenyl group
  • R 3 is selected from H, F, Cl, Br, I, OH, CN, NH 2 , C 1-3 alkyl, C 1-3 alkoxy and 5-6 membered heteroaryl, the C 1-3 Alkyl, C 1-3 alkoxy and 5-6 membered heteroaryl are optionally substituted by 1, 2 or 3 R a ;
  • Ring A does not exist
  • Ring A is selected from C 3-5 cycloalkyl, 5-6 membered heterocycloalkyl and 5-6 membered heteroaryl, said C 3-5 cycloalkyl, 5-6 membered heterocycloalkyl and The 5-6 membered heteroaryl group is optionally substituted by 1, 2 or 3 R b ;
  • Ring B is selected from phenyl, 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl, pyridopyrrolyl and
  • Ring C is selected from 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkenyl and 5-6 membered heteroaryl;
  • Each R a is independently selected from F, Cl, Br, I, CH 3 and OCH 3 ;
  • Each R b is independently selected from F, Cl, Br, I, C 1-3 alkyl and C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are selected from 1 , 2 or 3 halogen substitutions;
  • 2 R b and the carbon atoms to which they are connected together constitute a C 3-5 cycloalkyl group
  • ring A does not exist, ring B is selected from pyridopyrrolyl;
  • the present invention provides compounds represented by formula (I) or pharmaceutically acceptable salts thereof,
  • L 1 is selected from single bond and NH
  • L 3 is selected from -O-, -NH-, -C 1-3 alkyl-O-, -C 1-3 alkyl-NH- and C 1-3 alkyl-OC 1-3 alkyl;
  • R 1 is selected from -NH-C 1-3 alkyl, R 2 is selected from H;
  • R 1 and R 2 and the atoms to which they are connected together constitute a 5-6 membered heterocyclic alkenyl group
  • R 3 is selected from H, F, Cl, Br, I, OH, CN, NH 2 , C 1-3 alkyl, C 1-3 alkoxy and 5-6 membered heteroaryl, the C 1-3 Alkyl, C 1-3 alkoxy and 5-6 membered heteroaryl are optionally substituted by 1, 2 or 3 R a ;
  • Ring A does not exist
  • Ring A is selected from C 3-5 cycloalkyl, 5-6 membered heterocycloalkyl and 5-6 membered heteroaryl, said C 3-5 cycloalkyl, 5-6 membered heterocycloalkyl and The 5-6 membered heteroaryl group is optionally substituted by 1, 2 or 3 R b ;
  • Ring B is selected from phenyl, 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl, pyridopyrrolyl and
  • Ring C is selected from 5-6 membered heterocycloalkyl and 5-6 heteroaryl;
  • Each R a is independently selected from F, Cl, Br, I, CH 3 and OCH 3 ;
  • Each R b is independently selected from F, Cl, Br, I, C 1-3 alkyl and C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are selected from 1 , 2 or 3 halogen substitutions;
  • each of the above R b is independently selected from F, Cl, Br, I, OH, CH 3 , CF 3 and OCH 3 , and other variables are as defined in the present invention.
  • each of the above R b is independently selected from F, Cl, Br, I, CH 3 , CF 3 and OCH 3 , and other variables are as defined in the present invention.
  • the above-mentioned L 3 is selected from -O-, -NH-, -CH 2 -O-, -CH 2 CH 2 -O-, -CH(CH 3 )-O-, -CH 2 -NH-, -CH 2 CH 2 -NH-, -CH 2 -O-CH 2 -, -CH 2 -O-CH 2 CH 2 -, -CH 2 -O-CH 2 C(CH 3 ) 2 - ,-CH 2 -O-CH 2 CH(CH 3 )-, Other variables are as defined in the present invention.
  • the above-mentioned L 3 is selected from -O-, -NH-, -CH 2 -O-, -CH 2 CH 2 -O-, -CH(CH 3 )-O-, -CH 2 -NH-, -CH 2 CH 2 -NH-, -CH 2 -O-CH 2 -, -CH 2 -O-CH 2 CH 2 -, -CH 2 -O-CH 2 C(CH 3 ) 2 - ,
  • Other variables are as defined in the present invention.
  • R 1 is selected from -NH-CH 3
  • R 2 is selected from H
  • other variables are as defined in the present invention.
  • R 3 is selected from H, F, Cl, Br, I, OH, CN, NH 2 , CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH 2 CH 2 CH 3 , C(CH 3 ) 3 , OCH 3 , OCH 2 CH 3 , pyridyl and pyrimidinyl, said CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH 2 CH 2 CH 3 , C(CH 3 ) 3 , OCH 3 , OCH 2 CH 3 , pyridyl and pyrimidinyl are optionally substituted by 1, 2 or 3 R a , and other variables are as defined in the present invention.
  • R 3 is selected from H, F, Cl, Br, I, OH, CN, NH 2 , CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , OCH 3 , OCH 2 CH 3 , pyridyl and pyrimidinyl, the CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , OCH 3 , OCH 2 CH 3 , pyridyl and pyrimidinyl are optionally replaced by 1, 2 or 3 R a Instead, other variables are as defined herein.
  • R 3 is selected from H, F, Cl, Br, I, OH, CN, NH 2 , CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , OCH 3 , OCH 2 CH 3 , C(CH 3 ) 3 ,
  • Other variables are as defined in the present invention.
  • R 3 is selected from H, F, Cl, Br, I, OH, CN, NH 2 , CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , OCH 3 , OCH 2 CH 3 , Other variables are as defined in the present invention.
  • the above-mentioned ring A is selected from cyclopropyl, cyclobutyl, cyclopentyl, pyrrolidinyl, tetrahydrofuryl, pyrrolyl, imidazolyl, pyrazolyl and triazolyl, and the ring Propyl, cyclobutyl, cyclopentyl, pyrrolidinyl, tetrahydrofuryl, pyrrolyl, imidazolyl, pyrazolyl and triazolyl are optionally substituted by 1, 2 or 3 R b , and other variables are as in the present invention defined.
  • the above-mentioned Ring A is selected from cyclopentyl, pyrrolidyl, pyrrolyl, imidazolyl, pyrazolyl and triazolyl, and the cyclopentyl, pyrrolyl, imidazolyl, Pyrazolyl and triazolyl are optionally substituted by 1, 2 or 3 R b , and other variables are as defined in the present invention.
  • the above-mentioned ring A is selected from Other variables are as defined in the present invention.
  • the above-mentioned ring A is selected from Other variables are as defined in the present invention.
  • the above-mentioned ring A is selected from Other variables are as defined in the present invention.
  • the above-mentioned ring A is selected from Other variables are as defined in the present invention.
  • the above-mentioned ring A is selected from Other variables are as defined in the present invention.
  • the above-mentioned ring A is selected from Other variables are as defined in the present invention.
  • the above-mentioned ring C is selected from dihydroxazolyl, cyclopentadienyl, Other variables are as defined in the present invention.
  • the above-mentioned ring C is selected from oxazolyl, dihydroxazolyl, oxazolonyl, pyrrolyl, imidazolyl, imidazolone, pyrazolyl, cyclopentadienyl, Other variables are as defined in the present invention.
  • the above-mentioned ring C is selected from oxazolyl, dihydroxazolyl, pyrrolyl, imidazolyl, cyclopentadienyl, Other variables are as defined in the present invention.
  • the above-mentioned ring C is selected from oxazolyl, Other variables are as defined in the present invention.
  • the above-mentioned ring B is selected from Other variables are as defined in the present invention.
  • the above-mentioned ring B is selected from Other variables are as defined in the present invention.
  • the above-mentioned ring B is selected from Other variables are as defined in the present invention.
  • the above-mentioned ring B is selected from Other variables are as defined in the present invention.
  • the present invention provides compounds represented by the following formula, their stereoisomers or pharmaceutically acceptable salts thereof,
  • the above compounds, their stereoisomers or their pharmaceutically acceptable salts are selected from:
  • the present invention also provides the use of the above compounds, their stereoisomers or their pharmaceutically acceptable salts in the preparation of drugs related to the treatment of TYK2 inhibitors.
  • the invention also provides the following synthesis method:
  • the compound of the present invention has a strong inhibitory effect on TYK2; the compound of the present invention has excellent pharmacokinetic properties.
  • the term "pharmaceutically acceptable” refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue. , without undue toxicity, irritation, allergic reactions, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • salts refers to salts of compounds of the present invention prepared from compounds having specific substituents found in the present invention and relatively non-toxic acids or bases.
  • base addition salts can be obtained by contacting such compounds with a sufficient amount of base in pure solution or in a suitable inert solvent.
  • acid addition salts may be obtained by contacting such compounds with a sufficient amount of acid in pure solution or in a suitable inert solvent.
  • Certain specific compounds of the present invention contain both basic and acidic functional groups and thus can be converted into either base or acid addition salts.
  • the pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid groups or bases.
  • 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 the two.
  • the term “isomer” is intended to include geometric isomers, cis-trans isomers, stereoisomers, enantiomers, optical isomers, diastereomers and tautomers isomer.
  • the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereoisomers isomer, the (D)-isomer, the (L)-isomer, as well as their racemic mixtures and other mixtures, such as enantiomeric or diastereomerically enriched mixtures, all of which belong to the present invention. 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.
  • enantiomers or “optical isomers” refer to stereoisomers that are mirror images of each other.
  • cis-trans isomers or “geometric isomers” refers to the inability of the double bonds or single bonds of the carbon atoms in the ring to rotate freely.
  • diastereomer refers to stereoisomers whose molecules have two or more chiral centers and are in a non-mirror image relationship between the molecules.
  • wedge-shaped solid line keys and wedge-shaped dotted keys Represents the absolute configuration of a three-dimensional center
  • using straight solid line keys and straight dotted keys Represent the relative configuration of the three-dimensional center with a wavy line
  • wedge-shaped solid line key or wedge-shaped dotted key or use tilde Represents a straight solid line key or straight dotted key
  • the following formula (A) indicates that the compound exists as a single isomer of formula (A-1) or formula (A-2) or as two isomers of formula (A-1) and formula (A-2) exists in the form of a mixture;
  • the following formula (B) indicates that the compound exists in the form of a single isomer of formula (B-1) or formula (B-2) or in the form of both formula (B-1) and formula (B-2) Exists as a mixture of isomers.
  • the following formula (C) indicates that the compound exists in the form of a single isomer of formula (C-1) or formula (C-2) or in the form of two isomers of formula (C-1) and formula (C-2). Exists in mixture form.
  • tautomer or “tautomeric form” means that at room temperature, isomers with different functional groups are in dynamic equilibrium and can quickly convert into each other. If tautomers are possible (eg in solution), a chemical equilibrium of tautomers can be achieved.
  • proton tautomers also called proton transfer tautomers
  • proton migration tautomers include interconversions by proton migration, such as keto-enol isomerization and imine-enol isomerization. Amine isomerization.
  • Valence tautomers include interconversions through the reorganization of some bonding electrons.
  • keto-enol tautomerization is the tautomerization between pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
  • the terms “enriched in an isomer,” “enantiomerically enriched,” “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%.
  • isomeric excess or “enantiomeric excess” refers 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 content of 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 the 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 auxiliaries, in which the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure desired enantiomer.
  • a diastereomeric salt is formed with a suitable optically active acid or base, and then the salt is formed by conventional methods 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 combined with chemical derivatization methods (e.g., generation of amino groups from amines). formate).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound.
  • compounds can be labeled with radioactive isotopes, such as tritium ( 3 H), iodine-125 ( 125 I), or C-14 ( 14 C).
  • deuterated drugs can be replaced by heavy hydrogen to form deuterated drugs. The bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs can reduce side effects and increase drug stability. , enhance efficacy, extend drug biological half-life and other advantages. All variations in the 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 specific atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence state of the specific atom is normal and the substituted compound is stable.
  • any variable e.g., R
  • its definition in each instance is independent.
  • said group may optionally be substituted by up to two R's, with independent options for R in each case.
  • substituents and/or variants thereof are permitted 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.
  • the substituent can be bonded to any atom on the ring, e.g., structural unit It means that the substituent R can be substituted at any position on the cyclohexyl or cyclohexadiene.
  • the substituent does not specify which atom it is connected to the substituted group through, the substituent can be bonded through any atom thereof.
  • a pyridyl group as a substituent can be bonded through any one of the pyridine rings. The carbon atom is attached to the substituted group.
  • the direction of connection is arbitrary, for example, The middle linking group L is -MW-.
  • -MW- can be connected to ring A and ring B in the same direction as the reading order from left to right. You can also connect ring A and ring B in the opposite direction to the reading order from left to right.
  • any one or more sites of the group can be connected to other groups through chemical bonds.
  • connection mode of the chemical bond is non-positioned and there are H atoms at the connectable site, when the chemical bond is connected, the number of H atoms at the site will be reduced correspondingly with the number of connected chemical bonds and become the corresponding valence. group.
  • the chemical bond connecting the site to other groups can be a straight solid line bond straight dashed key or wavy lines express.
  • the straight solid line bond in -OCH 3 means that it is connected to other groups through the oxygen atom in the group;
  • the straight dotted bond in means that it is connected to other groups through both ends of the nitrogen atoms in the group;
  • the wavy lines in indicate that the phenyl group is connected to other groups through the 1 and 2 carbon atoms in the phenyl group;
  • the number of atoms in a ring is usually defined as the number of ring members.
  • a "5- to 7-membered ring” refers to a “ring” with 5 to 7 atoms arranged around it.
  • halogen or halogen by itself or as part of another substituent means a fluorine, chlorine, bromine or iodine atom.
  • C 1-3 alkyl is used to mean 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 groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n - propyl and isopropyl), and the like.
  • C 1-4 alkyl is used to mean a straight or branched chain saturated hydrocarbon group consisting of 1 to 4 carbon atoms.
  • the C 1-4 alkyl group includes C 1-2 , C 1-3 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 1-4 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl , s-butyl and t-butyl), etc.
  • C 1-3 alkoxy means those alkyl groups containing 1 to 3 carbon atoms that are attached to the remainder 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, etc.; it can be monovalent, divalent or multivalent.
  • Examples of C 1-3 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
  • C 3-5 cycloalkyl means a saturated cyclic hydrocarbon group composed of 3 to 5 carbon atoms, which is a single ring system, and the C 3-5 cycloalkyl group includes C 3 -4 and C 4-5 cycloalkyl, etc.; it can be monovalent, divalent or polyvalent.
  • Examples of C 3-5 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and the like.
  • 5-6 membered heteroaromatic ring and “5-6 membered heteroaryl” may be used interchangeably in the present invention
  • the term “5-6 membered heteroaryl” means 5 to 6 ring atoms. It consists of a monocyclic group with a conjugated ⁇ electron system, in which 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms.
  • the nitrogen atoms are optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) p , p is 1 or 2).
  • a 5-6 membered heteroaryl group can be attached to the rest of the molecule through a heteroatom or a carbon atom.
  • the 5-6 membered heteroaryl group includes 5-membered and 6-membered heteroaryl groups. It can be monovalent, bivalent or polyvalent.
  • Examples of the 5-6 membered heteroaryl include but are not limited to pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrrolyl).
  • azolyl group, etc. imidazolyl group (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl) 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.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl , 4-thiazolyl and 5-thiazolyl, etc.), furyl (including 2-furyl and 3-furyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyrid
  • the term "5-6 membered heterocycloalkyl" by itself or in combination with other terms means a saturated cyclic group consisting of 5 to 6 ring atoms, with 1, 2, 3 or 4 ring atoms. are heteroatoms independently selected from O, S and N, and the remainder are carbon atoms, in which the nitrogen atoms are optionally quaternized, and the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O) p , p is 1 or 2). It includes single-ring and double-ring systems, of which double-ring Ring systems include spiro rings, parallel rings and bridged rings.
  • a heteroatom may occupy the attachment position of the heterocycloalkyl to the rest of the molecule.
  • the 5-6 membered heterocycloalkyl group includes 5-membered and 6-membered heterocycloalkyl groups. It can be monovalent, bivalent or polyvalent.
  • 5-6 membered heterocycloalkyl examples include but are not limited to pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, etc.) , tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidyl (including 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, etc.), piperazinyl (including 1 -piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazole Alkyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydr
  • the term "5-6 membered heterocycloalkenyl" by itself or in combination with other terms means a partially unsaturated cyclic group consisting of 5 to 6 ring atoms containing at least one carbon-carbon double bond. , 1, 2, 3 or 4 of its ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, in which the nitrogen atoms are optionally quaternized, and the nitrogen and sulfur heteroatoms can be optionally quaternized. Oxidation (i.e. NO and S(O) p , p is 1 or 2). It includes single-ring and bicyclic systems. The bicyclic system includes spiro ring, paracyclic ring and bridged ring.
  • any ring in this system is non-aromatic. It can be monovalent, bivalent or polyvalent.
  • a heteroatom may occupy the attachment position of the heterocycloalkenyl group to the rest of the molecule.
  • the 5-6 membered heterocyclic alkenyl group includes 5-membered and 6-membered heterocyclic alkenyl groups. Examples of 5-6 membered heterocyclenyl groups include, but are not limited to
  • the structure of the compound of the present invention can be confirmed by conventional methods well 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.
  • single crystal X-ray diffraction uses a Bruker D8 venture diffractometer to collect diffraction intensity data on the cultured single crystal.
  • the light source is CuK ⁇ radiation.
  • the scanning method is: After scanning and collecting relevant data, the direct method (Shelxs97) is further used to analyze the crystal structure, and the absolute configuration can be confirmed.
  • 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, embodiments formed by combining them with other chemical synthesis methods, and methods well known to those skilled in the art. Equivalent alternatives and preferred embodiments include, but are not limited to, embodiments of the present invention.
  • the solvent used in the present invention is commercially available.
  • Step 7 Synthesis of Compounds 006A, 006B, 006C and 006D
  • LCMS m/z 425.2[M+H] + .
  • Step 3 Synthesis of Compounds 007A, 007B, 007C and 007D
  • Adenosine Tri-Phosphate is a common energy carrier in various life activities in nature and is the smallest unit of energy storage and transfer.
  • CellTiter-Glo TM live cell detection kit uses luciferase as the detection substance, and luciferase requires the participation of ATP during the luminescence process.
  • the cell line is Ba/F3-FL-TYK2-E957D, which can stably express the exogenously introduced human TYK2-E957D gene.
  • the TYK2-E957D gene sequence contains JH1 and JH2 domains.
  • the cell lines were cultured in an incubator with culture conditions of 37°C and 5% CO2 . Passage regularly and use cells in the logarithmic growth phase for plating.
  • Inhibition Rate (Inh%) 100-(RLU Drug -RLU Min )/(RLU Max -RLU Min )*100%. Calculate the inhibition rates corresponding to different concentrations of compounds in EXCEL, then use GraphPad Prism software to analyze the data, and use nonlinear S-curve regression to fit the data to obtain a dose-effect curve, from which the IC 50 value is calculated. The data are shown in Table 1.
  • the compound of the present invention has strong inhibitory activity on the proliferation of Ba/F3 cells transfected with human TYK2-E957D gene, and the compound of the present invention is a highly active TYK2 inhibitor.
  • the LC/MS/MS method was used to determine the drug concentration of the compound in the plasma at different times after a single intravenous injection (IV) and oral administration (PO) of the compound. Study the pharmacokinetic behavior of the compound of the present invention in mice and evaluate its pharmacokinetic characteristics.
  • the pharmacokinetic profile of the compounds in rodents after intravenous and oral administration was tested using standard protocols.
  • the test animals were fasted for 10-14 hours before administration and fed 4 hours after administration.
  • the compounds were formulated into clear solutions with corresponding solvents for administration in IV (intravenous injection) and PO (gastric administration) groups.
  • the solvent is 10% DMSO+10% solutol+80% (10% HP- ⁇ -CD aqueous solution).
  • Sample quantitatively analyze the plasma drug concentration using LC-MS/MS analysis method, and calculate pharmacokinetic parameters, such as peak concentration, peak time, clearance rate, half-life, area under the drug-time curve, bioavailability,
  • the compounds of the present invention exhibit excellent pharmacokinetic properties in mice.

Abstract

Disclosed are a novel macrocyclic compound and use thereof, and particularly, disclosed are a compound represented by formula (I) and a pharmaceutically acceptable salt thereof.

Description

大环类化合物及其应用Macrocyclic compounds and their applications
本申请主张如下优先权：This application claims the following priority rights:
CN202210476383.4，申请日：2022年04月29日；CN202210476383.4, application date: April 29, 2022;
CN202210613430.5，申请日：2022年05月31日；CN202210613430.5, application date: May 31, 2022;
CN202210689548.6，申请日：2022年06月16日；CN202210689548.6, application date: June 16, 2022;
CN202210864278.8，申请日：2022年07月20日；CN202210864278.8, application date: July 20, 2022;
CN202211216969.3，申请日：2022年09月30日；CN202211216969.3, application date: September 30, 2022;
CN202211530422.0，申请日：2022年11月30日；CN202211530422.0, application date: November 30, 2022;
CN2023101668391，申请日：2023年02月24日。CN2023101668391, application date: February 24, 2023.
技术领域Technical field
本发明涉及新的大环类化合物及其应用，具体涉及式(I)所示化合物、其立体异构体及其药学上可接受的盐。The present invention relates to new macrocyclic compounds and their applications, specifically to the compounds represented by formula (I), their stereoisomers and their pharmaceutically acceptable salts.
背景技术Background technique
JAK是一类非受体酪氨酸激酶，共有JAK1、JAK2、JAK3、TYK2四种亚型，它们介导的JAK-STAT信号通路与细胞的增殖、分化、凋亡以及免疫调节有关。有超过50种细胞因子和生长因子的生物学效应是通过JAK激酶及其JAK-STAT途径介导发生。TYK2是JAK家族蛋白成员之一，是一种介导免疫信号的非受体酪氨酸激酶，参与多种免疫相关疾病的病理过程。JAK is a type of non-receptor tyrosine kinase, with four subtypes: JAK1, JAK2, JAK3, and TYK2. The JAK-STAT signaling pathway mediated by them is related to cell proliferation, differentiation, apoptosis, and immune regulation. The biological effects of more than 50 cytokines and growth factors are mediated through JAK kinases and their JAK-STAT pathway. TYK2 is a member of the JAK family protein. It is a non-receptor tyrosine kinase that mediates immune signaling and is involved in the pathological processes of a variety of immune-related diseases.
由于JAK家族蛋白介导多种细胞因子的信号传导，全面抑制JAK家族蛋白则会导致多种副作用。第一代JAK抑制剂由于靶向多个JAK家族蛋白，在临床试验中出现剂量相关的安全性问题，其中包括感染、淋巴细胞减少、血栓栓塞等。而TYK2抑制剂通过选择性地抑制TYK2的激活，阻断IL-23、IL-12、I型IFN等炎性细胞因子的信号传导，在发挥对自身免疫性疾病和慢性炎症性疾病的治疗作用的同时，有效降低毒副作用。Since JAK family proteins mediate the signaling of multiple cytokines, comprehensive inhibition of JAK family proteins will lead to various side effects. Because the first-generation JAK inhibitors target multiple JAK family proteins, dose-related safety issues occurred in clinical trials, including infection, lymphopenia, thromboembolism, etc. TYK2 inhibitors play a therapeutic role in the treatment of autoimmune diseases and chronic inflammatory diseases by selectively inhibiting the activation of TYK2 and blocking the signaling of inflammatory cytokines such as IL-23, IL-12, and type I IFN. At the same time, it effectively reduces toxic and side effects.
目前全球尚未有TYK2抑制剂获批上市，进展最快的同类在研化合物为BMS-986165，其开展了多项临床研究，涉及多种疾病。BMS-986165在银屑病临床三期实验中击败口服标准药物阿普斯特(Apremilast)，而且安全耐受性较好。这体现了高选择性TYK2抑制剂在治疗银屑病等靶点方面具有巨大的临床应用潜力，具有重大的临床应用价值。At present, no TYK2 inhibitor has been approved for marketing in the world. The fastest-growing similar compound under development is BMS-986165, which has carried out multiple clinical studies and involves a variety of diseases. BMS-986165 defeated the oral standard drug Apremilast in a Phase III psoriasis clinical trial and had a good safety and tolerability. This reflects that highly selective TYK2 inhibitors have huge clinical application potential in the treatment of psoriasis and other targets, and have significant clinical application value.
发明内容Contents of the invention
本发明提供了式(I)所示化合物、其立体异构体或其药学上可接受的盐，
The present invention provides compounds represented by formula (I), their stereoisomers or pharmaceutically acceptable salts thereof,
其中， in,
L1选自单键和NH；L 1 is selected from single bond and NH;
L2选自-NH-C(＝O)-；L 2 is selected from -NH-C(=O)-;
L3选自-O-、-NH-、-C1-3烷基-O-、-C1-3烷基-NH-和-C1-3烷基-O-C1-3烷基-，所述-C1-3烷基-O-、-C1-3烷基-NH-和-C1-3烷基-O-C1-3烷基-任选被1、2或3个Rc取代；L 3 is selected from -O-, -NH-, -C 1-3 alkyl-O-, -C 1-3 alkyl-NH- and -C 1-3 alkyl-OC 1-3 alkyl-, The -C 1-3 alkyl-O-, -C 1-3 alkyl-NH- and -C 1-3 alkyl-OC 1-3 alkyl- are optionally substituted by 1, 2 or 3 R c replace;
R1选自-NH-C1-3烷基，R2选自H；R 1 is selected from -NH-C 1-3 alkyl, R 2 is selected from H;
或者，R1和R2与它们相连的原子共同构成5-6元杂环烯基；Alternatively, R 1 and R 2 and the atoms to which they are connected together constitute a 5-6 membered heterocyclic alkenyl group;
R3选自H、F、Cl、Br、I、OH、CN、NH2、C1-4烷基、C1-3烷氧基和6元杂芳基，所述C1-4烷基、C1-3烷氧基和6元杂芳基任选被1、2或3个Ra取代；R 3 is selected from H, F, Cl, Br, I, OH, CN, NH 2 , C 1-4 alkyl, C 1-3 alkoxy and 6-membered heteroaryl, the C 1-4 alkyl , C 1-3 alkoxy group and 6-membered heteroaryl group are optionally substituted by 1, 2 or 3 R a ;
环A不存在；Ring A does not exist;
或者，环A选自C3-5环烷基、5-6元杂环烷基和5-6元杂芳基，所述C3-5环烷基、5-6元杂环烷基和5-6元杂芳基任选被1、2或3个Rb取代；Alternatively, Ring A is selected from C 3-5 cycloalkyl, 5-6 membered heterocycloalkyl and 5-6 membered heteroaryl, said C 3-5 cycloalkyl, 5-6 membered heterocycloalkyl and The 5-6 membered heteroaryl group is optionally substituted by 1, 2 or 3 R b ;
环B选自苯基、5-6元杂芳基、5-6元杂环烷基、吡啶并吡咯基、苯并噁唑基、苯并吡咯基、苯并咪唑基、苯并吡唑基和 Ring B is selected from phenyl, 5-6-membered heteroaryl, 5-6-membered heterocycloalkyl, pyridopyrrolyl, benzoxazolyl, benzopyrrolyl, benzimidazolyl, benzopyrazolyl and
环C选自C5-6环烷基、C5-6环烷烯基、5-6元杂环烷基和5-6元杂环烯基；Ring C is selected from C 5-6 cycloalkyl, C 5-6 cycloalkenyl, 5-6 membered heterocycloalkyl and 5-6 membered heterocycloalkenyl;
结构单元选自 Structural units Selected from
各Ra分别独立地选自F、Cl、Br、I、CH3和OCH3；Each R a is independently selected from F, Cl, Br, I, CH 3 and OCH 3 ;
各Rb分别独立地选自F、Cl、Br、I、OH、C1-3烷基和C1-3烷氧基，所述C1-3烷基和C1-3烷氧基任选被1、2或3个卤素取代；Each R b is independently selected from F, Cl, Br, I, OH, C 1-3 alkyl and C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are optional Choose to be replaced by 1, 2 or 3 halogens;
或者，2个Rb与它们相连的碳原子共同构成C3-5环烷基；Alternatively, 2 R b and the carbon atoms to which they are connected together constitute a C 3-5 cycloalkyl group;
各Rc分别独立地选自C1-3烷基和苯基；Each R c is independently selected from C 1-3 alkyl and phenyl;
条件是：1)环A不存在时，环B选自吡啶并吡咯基；The conditions are: 1) When ring A does not exist, ring B is selected from pyridopyrrolyl;
或者，2)结构单元选自时，环A不为环丙基或环丁基；Or, 2) structural unit Selected from When, ring A is not cyclopropyl or cyclobutyl;
所述5-6元杂芳基、6元杂芳基、55-6元杂环烷基和5-6元杂环烯基的“杂”分别独立地表示1、2或3个选自N、O、S、C(＝O)和NH的原子或原子团。The "hetero" of the 5-6-membered heteroaryl, 6-membered heteroaryl, 55-6-membered heterocycloalkyl and 5-6-membered heterocycloalkenyl independently represents 1, 2 or 3 selected from N , O, S, C (=O) and NH atoms or atomic groups.
在本发明的一些方案中，上述化合物、其立体异构体或其药学上可接受的盐，其选自式(II)所示结构：
In some aspects of the present invention, the above-mentioned compound, its stereoisomer or its pharmaceutically acceptable salt is selected from the structure represented by formula (II):
其中，in,
L1选自单键和NH；L 1 is selected from single bond and NH;
L3选自-O-、-NH-、-C1-3烷基-O-、-C1-3烷基-NH-和-C1-3烷基-O-C1-3烷基-，所述-C1-3烷基-O-、-C1-3烷基-NH-和-C1-3烷基-O-C1-3烷基-任选被1、2或3个Rc取代；L 3 is selected from -O-, -NH-, -C 1-3 alkyl-O-, -C 1-3 alkyl-NH- and -C 1-3 alkyl-OC 1-3 alkyl-, The -C 1-3 alkyl-O-, -C 1-3 alkyl-NH- and -C 1-3 alkyl-OC 1-3 alkyl- are optionally substituted by 1, 2 or 3 R c replace;
R1选自-NH-C1-3烷基，R2选自H；R 1 is selected from -NH-C 1-3 alkyl, R 2 is selected from H;
或者，R1和R2与它们相连的原子共同构成5-6元杂环烯基；Alternatively, R 1 and R 2 and the atoms to which they are connected together constitute a 5-6 membered heterocyclic alkenyl group;
R3选自H、F、Cl、Br、I、OH、CN、NH2、C1-4烷基、C1-3烷氧基和5-6元杂芳基，所述C1-4烷基、C1-3烷氧基和5-6元杂芳基任选被1、2或3个Ra取代；R 3 is selected from H, F, Cl, Br, I, OH, CN, NH 2 , C 1-4 alkyl, C 1-3 alkoxy and 5-6 membered heteroaryl, the C 1-4 Alkyl, C 1-3 alkoxy and 5-6 membered heteroaryl are optionally substituted by 1, 2 or 3 R a ;
环A不存在；Ring A does not exist;
或者，环A选自C3-5环烷基、5-6元杂环烷基和5-6元杂芳基，所述C3-5环烷基、5-6元杂环烷基和5-6元杂芳基任选被1、2或3个Rb取代；Alternatively, Ring A is selected from C 3-5 cycloalkyl, 5-6 membered heterocycloalkyl and 5-6 membered heteroaryl, said C 3-5 cycloalkyl, 5-6 membered heterocycloalkyl and The 5-6 membered heteroaryl group is optionally substituted by 1, 2 or 3 R b ;
环B选自苯基、5-6元杂芳基、5-6元杂环烷基、吡啶并吡咯基、苯并噁唑基、苯并吡咯基、苯并咪唑基、苯并吡唑基和 Ring B is selected from phenyl, 5-6-membered heteroaryl, 5-6-membered heterocycloalkyl, pyridopyrrolyl, benzoxazolyl, benzopyrrolyl, benzimidazolyl, benzopyrazolyl and
环C选自5-6元杂环烷基和5-6元杂环烯基；Ring C is selected from 5-6 membered heterocycloalkyl and 5-6 membered heterocycloalkenyl;
结构单元选自 Structural units Selected from
各Ra分别独立地选自F、Cl、Br、I、CH3和OCH3；Each R a is independently selected from F, Cl, Br, I, CH 3 and OCH 3 ;
各Rb分别独立地选自F、Cl、Br、I、OH、C1-3烷基和C1-3烷氧基，所述C1-3烷基和C1-3烷氧基任选被1、2或3个卤素取代；Each R b is independently selected from F, Cl, Br, I, OH, C 1-3 alkyl and C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are optional Choose to be replaced by 1, 2 or 3 halogens;
或者，2个Rb与它们相连的碳原子共同构成C3-5环烷基；Alternatively, 2 R b and the carbon atoms to which they are connected together constitute a C 3-5 cycloalkyl group;
各Rc分别独立地选自C1-3烷基和苯基；Each R c is independently selected from C 1-3 alkyl and phenyl;
条件是：1)环A不存在时，环B选自吡啶并吡咯基；The conditions are: 1) When ring A does not exist, ring B is selected from pyridopyrrolyl;
2)结构单元选自时，环A不为环丙基或环丁基； 2) Structural unit Selected from When, ring A is not cyclopropyl or cyclobutyl;
所述5-6元杂芳基、5-6元杂环烷基和5-6元杂环烯基的“杂”分别独立地表示1、2或3个选自N、O、S、C(＝O)和NH的原子或原子团。The "hetero" of the 5-6-membered heteroaryl, 5-6-membered heterocycloalkyl and 5-6-membered heterocycloalkenyl independently represents 1, 2 or 3 selected from N, O, S, C (=O) and NH atoms or groups of atoms.
在本发明的一些方案中，上述化合物、其立体异构体或其药学上可接受的盐，其选自：
In some aspects of the present invention, the above compounds, their stereoisomers or their pharmaceutically acceptable salts are selected from:
L3、R3和环A如本发明所定义。L 3 , R 3 and Ring A are as defined in the present invention.
本发明提供了式(I)所示化合物或其药学上可接受的盐，
The present invention provides compounds represented by formula (I) or pharmaceutically acceptable salts thereof,
其中，in,
L1选自单键和NH；L 1 is selected from single bond and NH;
L2选自-NH-C(＝O)-；L 2 is selected from -NH-C(=O)-;
L3选自-O-、-NH-、-C1-3烷基-O-、-C1-3烷基-NH-和-C1-3烷基-O-C1-3烷基-，所述-C1-3烷基-O-、-C1-3烷基-NH-和-C1-3烷基-O-C1-3烷基-任选被1、2或3个Rc取代；L 3 is selected from -O-, -NH-, -C 1-3 alkyl-O-, -C 1-3 alkyl-NH- and -C 1-3 alkyl-OC 1-3 alkyl-, The -C 1-3 alkyl-O-, -C 1-3 alkyl-NH- and -C 1-3 alkyl-OC 1-3 alkyl- are optionally substituted by 1, 2 or 3 R c replace;
R1选自-NH-C1-3烷基，R2选自H；R 1 is selected from -NH-C 1-3 alkyl, R 2 is selected from H;
或者，R1和R2与它们相连的原子共同构成5-6元杂环烯基；Alternatively, R 1 and R 2 and the atoms to which they are connected together constitute a 5-6 membered heterocyclic alkenyl group;
R3选自H、F、Cl、Br、I、OH、CN、NH2、C1-4烷基、C1-3烷氧基和5-6元杂芳基，所述C1-4烷基、C1-3烷氧基和5-6元杂芳基任选被1、2或3个Ra取代；R 3 is selected from H, F, Cl, Br, I, OH, CN, NH 2 , C 1-4 alkyl, C 1-3 alkoxy and 5-6 membered heteroaryl, the C 1-4 Alkyl, C 1-3 alkoxy and 5-6 membered heteroaryl are optionally substituted by 1, 2 or 3 R a ;
环A不存在；Ring A does not exist;
或者，环A选自C3-5环烷基、5-6元杂环烷基和5-6元杂芳基，所述C3-5环烷基、5-6元杂环烷基和5-6元杂芳基任选被1、2或3个Rb取代；Alternatively, Ring A is selected from C 3-5 cycloalkyl, 5-6 membered heterocycloalkyl and 5-6 membered heteroaryl, said C 3-5 cycloalkyl, 5-6 membered heterocycloalkyl and The 5-6 membered heteroaryl group is optionally substituted by 1, 2 or 3 R b ;
环B选自苯基、5-6元杂芳基、5-6元杂环烷基、吡啶并吡咯基、苯并噁唑基、苯并吡咯基、苯并咪唑基、苯并吡唑基和 Ring B is selected from phenyl, 5-6-membered heteroaryl, 5-6-membered heterocycloalkyl, pyridopyrrolyl, benzoxazolyl, benzopyrrolyl, benzimidazolyl, benzopyrazolyl and
环C选自5-6元杂环烷基和5-6元杂环烯基； Ring C is selected from 5-6 membered heterocycloalkyl and 5-6 membered heterocycloalkenyl;
结构单元选自 Structural units Selected from
各Ra分别独立地选自F、Cl、Br、I、CH3和OCH3；Each R a is independently selected from F, Cl, Br, I, CH 3 and OCH 3 ;
各Rb分别独立地选自F、Cl、Br、I、OH、C1-3烷基和C1-3烷氧基，所述C1-3烷基和C1-3烷氧基任选被1、2或3个卤素取代；Each R b is independently selected from F, Cl, Br, I, OH, C 1-3 alkyl and C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are optional Choose to be replaced by 1, 2 or 3 halogens;
或者，2个Rb与它们相连的碳原子共同构成C3-5环烷基；Alternatively, 2 R b and the carbon atoms to which they are connected together constitute a C 3-5 cycloalkyl group;
各Rc分别独立地选自C1-3烷基和苯基；Each R c is independently selected from C 1-3 alkyl and phenyl;
条件是：1)环A不存在时，环B选自吡啶并吡咯基；The conditions are: 1) When ring A does not exist, ring B is selected from pyridopyrrolyl;
2)结构单元选自时，环A不为环丙基或环丁基；2) Structural unit Selected from When, ring A is not cyclopropyl or cyclobutyl;
所述5-6元杂芳基、5-6元杂环烷基和5-6元杂环烯基的“杂”分别独立地表示1、2或3个选自N、O、S、C(＝O)和NH的原子或原子团。The "hetero" of the 5-6-membered heteroaryl, 5-6-membered heterocycloalkyl and 5-6-membered heterocycloalkenyl independently represents 1, 2 or 3 selected from N, O, S, C (=O) and NH atoms or groups of atoms.
本发明提供了式(I)所示化合物或其药学上可接受的盐，
The present invention provides compounds represented by formula (I) or pharmaceutically acceptable salts thereof,
其中，in,
L1选自单键和NH；L 1 is selected from single bond and NH;
L2选自-NH-C(＝O)-；L 2 is selected from -NH-C(=O)-;
L3选自-O-、-NH-、-C1-3烷基-O-、-C1-3烷基-NH-和C1-3烷基-O-C1-3烷基，所述-C1-3烷基-O-、-C1-3烷基-NH-和-C1-3烷基-O-C1-3烷基-任选被1、2或3个Rc取代；L 3 is selected from -O-, -NH-, -C 1-3 alkyl-O-, -C 1-3 alkyl-NH- and C 1-3 alkyl-OC 1-3 alkyl, said -C 1-3 alkyl-O-, -C 1-3 alkyl-NH- and -C 1-3 alkyl-OC 1-3 alkyl- are optionally substituted by 1, 2 or 3 R c ;
R1选自-NH-C1-3烷基，R2选自H；R 1 is selected from -NH-C 1-3 alkyl, R 2 is selected from H;
或者，R1和R2与它们相连的原子共同构成5-6元杂环烯基；Alternatively, R 1 and R 2 and the atoms to which they are connected together constitute a 5-6 membered heterocyclic alkenyl group;
R3选自H、F、Cl、Br、I、OH、CN、NH2、C1-3烷基、C1-3烷氧基和5-6元杂芳基，所述C1-3烷基、C1-3烷氧基和5-6元杂芳基任选被1、2或3个Ra取代；R 3 is selected from H, F, Cl, Br, I, OH, CN, NH 2 , C 1-3 alkyl, C 1-3 alkoxy and 5-6 membered heteroaryl, the C 1-3 Alkyl, C 1-3 alkoxy and 5-6 membered heteroaryl are optionally substituted by 1, 2 or 3 R a ;
环A不存在；Ring A does not exist;
或者，环A选自C3-5环烷基、5-6元杂环烷基和5-6元杂芳基，所述C3-5环烷基、5-6元杂环烷基和5-6元杂芳基任选被1、2或3个Rb取代； Alternatively, Ring A is selected from C 3-5 cycloalkyl, 5-6 membered heterocycloalkyl and 5-6 membered heteroaryl, said C 3-5 cycloalkyl, 5-6 membered heterocycloalkyl and The 5-6 membered heteroaryl group is optionally substituted by 1, 2 or 3 R b ;
环B选自苯基、5-6元杂芳基、5-6元杂环烷基、吡啶并吡咯基和 Ring B is selected from phenyl, 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl, pyridopyrrolyl and
环C选自5-6元杂环烷基、5-6元杂环烯基和5-6元杂芳基；Ring C is selected from 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkenyl and 5-6 membered heteroaryl;
结构单元选自 Structural units Selected from
各Ra分别独立地选自F、Cl、Br、I、CH3和OCH3；Each R a is independently selected from F, Cl, Br, I, CH 3 and OCH 3 ;
各Rb分别独立地选自F、Cl、Br、I、C1-3烷基和C1-3烷氧基，所述C1-3烷基和C1-3烷氧基任选被1、2或3个卤素取代；Each R b is independently selected from F, Cl, Br, I, C 1-3 alkyl and C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are optionally 1, 2 or 3 halogen substitutions;
或者，2个Rb与它们相连的碳原子共同构成C3-5环烷基；Alternatively, 2 R b and the carbon atoms to which they are connected together constitute a C 3-5 cycloalkyl group;
各Rc分别独立地选自C1-3烷基和苯基；Each R c is independently selected from C 1-3 alkyl and phenyl;
条件是：1)环A不存在时，环B选自吡啶并吡咯基；The conditions are: 1) When ring A does not exist, ring B is selected from pyridopyrrolyl;
2)结构单元选自时，环A不为环丙基或环丁基；2) Structural unit Selected from When, ring A is not cyclopropyl or cyclobutyl;
所述5-6元杂芳基、5-6元杂环烷基、5-6元杂环烯基和5-6元杂环烯基的“杂”分别独立地选自1、2或3个N、O、S、C(＝O)和NH的原子或原子团。The "hetero" of the 5-6-membered heteroaryl, 5-6-membered heterocycloalkyl, 5-6-membered heterocycloalkenyl and 5-6-membered heterocycloalkenyl are independently selected from 1, 2 or 3 Atoms or atomic groups of N, O, S, C (=O) and NH.
本发明提供了式(I)所示化合物或其药学上可接受的盐，
The present invention provides compounds represented by formula (I) or pharmaceutically acceptable salts thereof,
其中，in,
L1选自单键和NH；L 1 is selected from single bond and NH;
L2选自-NH-C(＝O)-；L 2 is selected from -NH-C(=O)-;
L3选自-O-、-NH-、-C1-3烷基-O-、-C1-3烷基-NH-和C1-3烷基-O-C1-3烷基；L 3 is selected from -O-, -NH-, -C 1-3 alkyl-O-, -C 1-3 alkyl-NH- and C 1-3 alkyl-OC 1-3 alkyl;
R1选自-NH-C1-3烷基，R2选自H；R 1 is selected from -NH-C 1-3 alkyl, R 2 is selected from H;
或者，R1和R2与它们相连的原子共同构成5-6元杂环烯基；Alternatively, R 1 and R 2 and the atoms to which they are connected together constitute a 5-6 membered heterocyclic alkenyl group;
R3选自H、F、Cl、Br、I、OH、CN、NH2、C1-3烷基、C1-3烷氧基和5-6元杂芳基，所述C1-3烷基、C1-3烷氧基和5-6元杂芳基任选被1、2或3个Ra取代；R 3 is selected from H, F, Cl, Br, I, OH, CN, NH 2 , C 1-3 alkyl, C 1-3 alkoxy and 5-6 membered heteroaryl, the C 1-3 Alkyl, C 1-3 alkoxy and 5-6 membered heteroaryl are optionally substituted by 1, 2 or 3 R a ;
环A不存在； Ring A does not exist;
或者，环A选自C3-5环烷基、5-6元杂环烷基和5-6元杂芳基，所述C3-5环烷基、5-6元杂环烷基和5-6元杂芳基任选被1、2或3个Rb取代；Alternatively, Ring A is selected from C 3-5 cycloalkyl, 5-6 membered heterocycloalkyl and 5-6 membered heteroaryl, said C 3-5 cycloalkyl, 5-6 membered heterocycloalkyl and The 5-6 membered heteroaryl group is optionally substituted by 1, 2 or 3 R b ;
环B选自苯基、5-6元杂芳基、5-6元杂环烷基、吡啶并吡咯基和 Ring B is selected from phenyl, 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl, pyridopyrrolyl and
环C选自5-6元杂环烷基、5-6元杂环烯基和5-6元杂芳基；Ring C is selected from 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkenyl and 5-6 membered heteroaryl;
结构单元选自 Structural units Selected from
各Ra分别独立地选自F、Cl、Br、I、CH3和OCH3；Each R a is independently selected from F, Cl, Br, I, CH 3 and OCH 3 ;
各Rb分别独立地选自F、Cl、Br、I、C1-3烷基和C1-3烷氧基，所述C1-3烷基和C1-3烷氧基人选被1、2或3个卤素取代；Each R b is independently selected from F, Cl, Br, I, C 1-3 alkyl and C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are selected from 1 , 2 or 3 halogen substitutions;
或者，2个Rb与它们相连的碳原子共同构成C3-5环烷基；Alternatively, 2 R b and the carbon atoms to which they are connected together constitute a C 3-5 cycloalkyl group;
条件是：1)环A不存在时，环B选自吡啶并吡咯基；The conditions are: 1) When ring A does not exist, ring B is selected from pyridopyrrolyl;
2)结构单元选自时，环A不为环丙基或环丁基；2) Structural unit Selected from When, ring A is not cyclopropyl or cyclobutyl;
所述5-6元杂芳基、5-6元杂环烷基、5-6元杂环烯基和5-6元杂环烯基分别独立地选自1、2或3个N、O、S、C(＝O)和NH的原子或原子团。The 5-6-membered heteroaryl, 5-6-membered heterocycloalkyl, 5-6-membered heterocycloalkenyl and 5-6-membered heterocycloalkenyl are independently selected from 1, 2 or 3 N, O , S, C (=O) and NH atoms or atomic groups.
本发明提供了式(I)所示化合物或其药学上可接受的盐，
The present invention provides compounds represented by formula (I) or pharmaceutically acceptable salts thereof,
其中，in,
L1选自单键和NH；L 1 is selected from single bond and NH;
L2选自-NH-C(＝O)-；L 2 is selected from -NH-C(=O)-;
L3选自-O-、-NH-、-C1-3烷基-O-、-C1-3烷基-NH-和C1-3烷基-O-C1-3烷基；L 3 is selected from -O-, -NH-, -C 1-3 alkyl-O-, -C 1-3 alkyl-NH- and C 1-3 alkyl-OC 1-3 alkyl;
R1选自-NH-C1-3烷基，R2选自H；R 1 is selected from -NH-C 1-3 alkyl, R 2 is selected from H;
或者，R1和R2与它们相连的原子共同构成5-6元杂环烯基；Alternatively, R 1 and R 2 and the atoms to which they are connected together constitute a 5-6 membered heterocyclic alkenyl group;
R3选自H、F、Cl、Br、I、OH、CN、NH2、C1-3烷基、C1-3烷氧基和5-6元杂芳基，所述C1-3烷基、C1-3烷氧基和5-6元杂芳基任选被1、2或3个Ra取代； R 3 is selected from H, F, Cl, Br, I, OH, CN, NH 2 , C 1-3 alkyl, C 1-3 alkoxy and 5-6 membered heteroaryl, the C 1-3 Alkyl, C 1-3 alkoxy and 5-6 membered heteroaryl are optionally substituted by 1, 2 or 3 R a ;
环A不存在；Ring A does not exist;
或者，环A选自C3-5环烷基、5-6元杂环烷基和5-6元杂芳基，所述C3-5环烷基、5-6元杂环烷基和5-6元杂芳基任选被1、2或3个Rb取代；Alternatively, Ring A is selected from C 3-5 cycloalkyl, 5-6 membered heterocycloalkyl and 5-6 membered heteroaryl, said C 3-5 cycloalkyl, 5-6 membered heterocycloalkyl and The 5-6 membered heteroaryl group is optionally substituted by 1, 2 or 3 R b ;
环B选自苯基、5-6元杂芳基、5-6元杂环烷基、吡啶并吡咯基和 Ring B is selected from phenyl, 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl, pyridopyrrolyl and
环C选自5-6元杂环烷基、5-6元杂环烯基和5-6元杂芳基；Ring C is selected from 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkenyl and 5-6 membered heteroaryl;
结构单元选自 Structural units Selected from
各Ra分别独立地选自F、Cl、Br、I、CH3和OCH3；Each R a is independently selected from F, Cl, Br, I, CH 3 and OCH 3 ;
各Rb分别独立地选自F、Cl、Br、I、C1-3烷基和C1-3烷氧基，所述C1-3烷基和C1-3烷氧基人选被1、2或3个卤素取代；Each R b is independently selected from F, Cl, Br, I, C 1-3 alkyl and C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are selected from 1 , 2 or 3 halogen substitutions;
或者，2个Rb与它们相连的碳原子共同构成C3-5环烷基；Alternatively, 2 R b and the carbon atoms to which they are connected together constitute a C 3-5 cycloalkyl group;
条件是：环A不存在时，环B选自吡啶并吡咯基；The conditions are: when ring A does not exist, ring B is selected from pyridopyrrolyl;
所述5-6元杂芳基、5-6元杂环烷基、5-6元杂环烯基和5-6元杂环烯基分别独立地选自1、2或3个N、O、S、C(＝O)和NH的原子或原子团。The 5-6-membered heteroaryl, 5-6-membered heterocycloalkyl, 5-6-membered heterocycloalkenyl and 5-6-membered heterocycloalkenyl are independently selected from 1, 2 or 3 N, O , S, C (=O) and NH atoms or atomic groups.
本发明提供了式(I)所示化合物或其药学上可接受的盐，
The present invention provides compounds represented by formula (I) or pharmaceutically acceptable salts thereof,
其中，in,
L1选自单键和NH；L 1 is selected from single bond and NH;
L2选自-NH-C(＝O)-；L 2 is selected from -NH-C(=O)-;
L3选自-O-、-NH-、-C1-3烷基-O-、-C1-3烷基-NH-和C1-3烷基-O-C1-3烷基；L 3 is selected from -O-, -NH-, -C 1-3 alkyl-O-, -C 1-3 alkyl-NH- and C 1-3 alkyl-OC 1-3 alkyl;
R1选自-NH-C1-3烷基，R2选自H；R 1 is selected from -NH-C 1-3 alkyl, R 2 is selected from H;
或者，R1和R2与它们相连的原子共同构成5-6元杂环烯基；Alternatively, R 1 and R 2 and the atoms to which they are connected together constitute a 5-6 membered heterocyclic alkenyl group;
R3选自H、F、Cl、Br、I、OH、CN、NH2、C1-3烷基、C1-3烷氧基和5-6元杂芳基，所述C1-3烷基、C1-3烷氧基和5-6元杂芳基任选被1、2或3个Ra取代；R 3 is selected from H, F, Cl, Br, I, OH, CN, NH 2 , C 1-3 alkyl, C 1-3 alkoxy and 5-6 membered heteroaryl, the C 1-3 Alkyl, C 1-3 alkoxy and 5-6 membered heteroaryl are optionally substituted by 1, 2 or 3 R a ;
环A不存在；Ring A does not exist;
或者，环A选自C3-5环烷基、5-6元杂环烷基和5-6元杂芳基，所述C3-5环烷基、5-6元杂环烷基和5-6元杂芳基任选被1、2或3个Rb取代； Alternatively, Ring A is selected from C 3-5 cycloalkyl, 5-6 membered heterocycloalkyl and 5-6 membered heteroaryl, said C 3-5 cycloalkyl, 5-6 membered heterocycloalkyl and The 5-6 membered heteroaryl group is optionally substituted by 1, 2 or 3 R b ;
环B选自苯基、5-6元杂芳基、5-6元杂环烷基、吡啶并吡咯基和 Ring B is selected from phenyl, 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl, pyridopyrrolyl and
环C选自5-6元杂环烷基和5-6杂芳基；Ring C is selected from 5-6 membered heterocycloalkyl and 5-6 heteroaryl;
结构单元选自 Structural units Selected from
各Ra分别独立地选自F、Cl、Br、I、CH3和OCH3；Each R a is independently selected from F, Cl, Br, I, CH 3 and OCH 3 ;
各Rb分别独立地选自F、Cl、Br、I、C1-3烷基和C1-3烷氧基，所述C1-3烷基和C1-3烷氧基人选被1、2或3个卤素取代；Each R b is independently selected from F, Cl, Br, I, C 1-3 alkyl and C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are selected from 1 , 2 or 3 halogen substitutions;
所述5-6元杂芳基、5-6元杂环烷基和5-6元杂环烯基包含1、2或3个分别独立地选自N、O、S、C(＝O)和NH的原子或原子团。The 5-6-membered heteroaryl group, 5-6-membered heterocycloalkyl group and 5-6-membered heterocycloalkenyl group contain 1, 2 or 3 members independently selected from N, O, S, C (=O) and NH atoms or groups of atoms.
在本发明的一些方案中，上述各Rb分别独立地选自F、Cl、Br、I、OH、CH3、CF3和OCH3，其他变量如本发明所定义。In some aspects of the present invention, each of the above R b is independently selected from F, Cl, Br, I, OH, CH 3 , CF 3 and OCH 3 , and other variables are as defined in the present invention.
在本发明的一些方案中，上述各Rb分别独立地选自F、Cl、Br、I、CH3、CF3和OCH3，其他变量如本发明所定义。In some solutions of the present invention, each of the above R b is independently selected from F, Cl, Br, I, CH 3 , CF 3 and OCH 3 , and other variables are as defined in the present invention.
在本发明的一些方案中，上述L3选自-O-、-NH-、-CH2-O-、-CH2CH2-O-、-CH(CH3)-O-、-CH2-NH-、-CH2CH2-NH-、-CH2-O-CH2-、-CH2-O-CH2CH2-、-CH2-O-CH2C(CH3)2-、-CH2-O-CH2CH(CH3)-、其他变量如本发明所定义。In some aspects of the invention, the above-mentioned L 3 is selected from -O-, -NH-, -CH 2 -O-, -CH 2 CH 2 -O-, -CH(CH 3 )-O-, -CH 2 -NH-, -CH 2 CH 2 -NH-, -CH 2 -O-CH 2 -, -CH 2 -O-CH 2 CH 2 -, -CH 2 -O-CH 2 C(CH 3 ) 2 - ,-CH 2 -O-CH 2 CH(CH 3 )-, Other variables are as defined in the present invention.
在本发明的一些方案中，上述L3选自-O-、-NH-、-CH2-O-、-CH2CH2-O-、-CH(CH3)-O-、-CH2-NH-、-CH2CH2-NH-、-CH2-O-CH2-、-CH2-O-CH2CH2-、-CH2-O-CH2C(CH3)2-、其他变量如本发明所定义。In some aspects of the invention, the above-mentioned L 3 is selected from -O-, -NH-, -CH 2 -O-, -CH 2 CH 2 -O-, -CH(CH 3 )-O-, -CH 2 -NH-, -CH 2 CH 2 -NH-, -CH 2 -O-CH 2 -, -CH 2 -O-CH 2 CH 2 -, -CH 2 -O-CH 2 C(CH 3 ) 2 - , Other variables are as defined in the present invention.
在本发明的一些方案中，上述R1选自-NH-CH3，R2选自H，其他变量如本发明所定义。In some aspects of the present invention, the above-mentioned R 1 is selected from -NH-CH 3 , R 2 is selected from H, and other variables are as defined in the present invention.
在本发明的一些方案中，上述R1和R2与它们相连的原子一起使结构单元为其他变量如本发明所定义。 In some aspects of the invention, the above-mentioned R 1 and R 2 together with the atoms to which they are connected form a structural unit for Other variables are as defined in the present invention.
在本发明的一些方案中，上述R1和R2与它们相连的原子共同构成其他变量如本发明所定义。In some aspects of the present invention, the above-mentioned R 1 and R 2 together with the atoms to which they are connected constitute Other variables are as defined in the present invention.
在本发明的一些方案中，上述R3选自H、F、Cl、Br、I、OH、CN、NH2、CH3、CH2CH3、CH(CH3)2、CH2CH2CH2CH3、C(CH3)3、OCH3、OCH2CH3、吡啶基和嘧啶基，所述CH3、CH2CH3、CH(CH3)2、CH2CH2CH2CH3、C(CH3)3、OCH3、OCH2CH3、吡啶基和嘧啶基任选被1、2或3个Ra取代，其他变量如本发明所定义。In some aspects of the invention, the above R 3 is selected from H, F, Cl, Br, I, OH, CN, NH 2 , CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH 2 CH 2 CH 3 , C(CH 3 ) 3 , OCH 3 , OCH 2 CH 3 , pyridyl and pyrimidinyl, said CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH 2 CH 2 CH 3 , C(CH 3 ) 3 , OCH 3 , OCH 2 CH 3 , pyridyl and pyrimidinyl are optionally substituted by 1, 2 or 3 R a , and other variables are as defined in the present invention.
在本发明的一些方案中，上述R3选自H、F、Cl、Br、I、OH、CN、NH2、CH3、CH2CH3、CH(CH3)2、OCH3、OCH2CH3、吡啶基和嘧啶基，所述CH3、CH2CH3、CH(CH3)2、OCH3、OCH2CH3、吡啶基和嘧啶基任选被1、2或3个Ra取代，其他变量如本发明所定义。In some aspects of the invention, the above R 3 is selected from H, F, Cl, Br, I, OH, CN, NH 2 , CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , OCH 3 , OCH 2 CH 3 , pyridyl and pyrimidinyl, the CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , OCH 3 , OCH 2 CH 3 , pyridyl and pyrimidinyl are optionally replaced by 1, 2 or 3 R a Instead, other variables are as defined herein.
在本发明的一些方案中，上述R3选自H、F、Cl、Br、I、OH、CN、NH2、CH3、CH2CH3、CH(CH3)2、OCH3、OCH2CH3、C(CH3)3、其他变量如本发明所定义。In some aspects of the invention, the above R 3 is selected from H, F, Cl, Br, I, OH, CN, NH 2 , CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , OCH 3 , OCH 2 CH 3 , C(CH 3 ) 3 , Other variables are as defined in the present invention.
在本发明的一些方案中，上述R3选自H、F、Cl、Br、I、OH、CN、NH2、CH3、CH2CH3、CH(CH3)2、OCH3、OCH2CH3、其他变量如本发明所定义。In some aspects of the invention, the above R 3 is selected from H, F, Cl, Br, I, OH, CN, NH 2 , CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , OCH 3 , OCH 2 CH 3 , Other variables are as defined in the present invention.
在本发明的一些方案中，上述环A选自环丙基、环丁基、环戊基、吡咯烷基、四氢呋喃基、吡咯基、咪唑基、吡唑基和三氮唑基，所述环丙基、环丁基、环戊基、吡咯烷基、四氢呋喃基、吡咯基、咪唑基、吡唑基和三氮唑基任选被1、2或3个Rb取代，其他变量如本发明所定义。In some aspects of the invention, the above-mentioned ring A is selected from cyclopropyl, cyclobutyl, cyclopentyl, pyrrolidinyl, tetrahydrofuryl, pyrrolyl, imidazolyl, pyrazolyl and triazolyl, and the ring Propyl, cyclobutyl, cyclopentyl, pyrrolidinyl, tetrahydrofuryl, pyrrolyl, imidazolyl, pyrazolyl and triazolyl are optionally substituted by 1, 2 or 3 R b , and other variables are as in the present invention defined.
在本发明的一些方案中，上述环A选自环戊烷基、吡咯烷基、吡咯基、咪唑基、吡唑基和三氮唑基，所述环戊烷基、吡咯基、咪唑基、吡唑基和三氮唑基任选被1、2或3个Rb取代，其他变量如本发明所定义。In some aspects of the invention, the above-mentioned Ring A is selected from cyclopentyl, pyrrolidyl, pyrrolyl, imidazolyl, pyrazolyl and triazolyl, and the cyclopentyl, pyrrolyl, imidazolyl, Pyrazolyl and triazolyl are optionally substituted by 1, 2 or 3 R b , and other variables are as defined in the present invention.
在本发明的一些方案中，上述环A选自 其他变量如本发明所定义。In some aspects of the present invention, the above-mentioned ring A is selected from Other variables are as defined in the present invention.
在本发明的一些方案中，上述环A选自 其他变量如本发明所定义。In some aspects of the present invention, the above-mentioned ring A is selected from Other variables are as defined in the present invention.
在本发明的一些方案中，上述环A选自 其他变量如本发明所定义。In some aspects of the present invention, the above-mentioned ring A is selected from Other variables are as defined in the present invention.
在本发明的一些方案中，上述环A选自 其他变量如本发明所定义。In some aspects of the present invention, the above-mentioned ring A is selected from Other variables are as defined in the present invention.
在本发明的一些方案中，上述环A选自 其他变量如本发明所定义。In some aspects of the present invention, the above-mentioned ring A is selected from Other variables are as defined in the present invention.
在本发明的一些方案中，上述环A选自 其他变量如本发明所定义。In some aspects of the present invention, the above-mentioned ring A is selected from Other variables are as defined in the present invention.
在本发明的一些方案中，上述环C选自二氢噁唑基、环戊二烯基、 其他变量如本发明所定义。In some aspects of the invention, the above-mentioned ring C is selected from dihydroxazolyl, cyclopentadienyl, Other variables are as defined in the present invention.
在本发明的一些方案中，上述环C选自噁唑基、二氢噁唑基、噁唑酮基、吡咯基、咪唑基、咪唑酮基、吡唑基、环戊二烯基、其他变量如本发明所定义。In some aspects of the invention, the above-mentioned ring C is selected from oxazolyl, dihydroxazolyl, oxazolonyl, pyrrolyl, imidazolyl, imidazolone, pyrazolyl, cyclopentadienyl, Other variables are as defined in the present invention.
在本发明的一些方案中，上述环C选自噁唑基、二氢噁唑基、吡咯基、咪唑基、环戊二烯基、 其他变量如本发明所定义。In some aspects of the invention, the above-mentioned ring C is selected from oxazolyl, dihydroxazolyl, pyrrolyl, imidazolyl, cyclopentadienyl, Other variables are as defined in the present invention.
在本发明的一些方案中，上述环C选自噁唑基、其他变量如本发明所定义。In some aspects of the invention, the above-mentioned ring C is selected from oxazolyl, Other variables are as defined in the present invention.
在本发明的一些方案中，上述环B选自 其他变量如本发明所定义。 In some aspects of the invention, the above-mentioned ring B is selected from Other variables are as defined in the present invention.
在本发明的一些方案中，上述环B选自 其他变量如本发明所定义。In some aspects of the invention, the above-mentioned ring B is selected from Other variables are as defined in the present invention.
在本发明的一些方案中，上述环B选自 其他变量如本发明所定义。In some aspects of the invention, the above-mentioned ring B is selected from Other variables are as defined in the present invention.
在本发明的一些方案中，上述环B选自 其他变量如本发明所定义。In some aspects of the invention, the above-mentioned ring B is selected from Other variables are as defined in the present invention.
本发明还有一些方案由上述变量任意组合而来。There are also some solutions of the present invention derived from any combination of the above variables.
本发明提供了下式所示化合物、其立体异构体或其药学上可接受的盐，




The present invention provides compounds represented by the following formula, their stereoisomers or pharmaceutically acceptable salts thereof,




在本发明的一些方案中，上述化合物、其立体异构体或其药学上可接受的盐，其选自：











In some aspects of the present invention, the above compounds, their stereoisomers or their pharmaceutically acceptable salts are selected from:











本发明还提供了上述化合物、其立体异构体或其药学上可接受的盐在制备治疗TYK2抑制剂相关药物上的应用。The present invention also provides the use of the above compounds, their stereoisomers or their pharmaceutically acceptable salts in the preparation of drugs related to the treatment of TYK2 inhibitors.
本发明还提供了下述合成方法：The invention also provides the following synthesis method:
方法1：
method 1:
技术效果Technical effect
本发明化合物对TYK2具有很强的抑制作用；本发明化合物具有优异的药代动力学性质。The compound of the present invention has a strong inhibitory effect on TYK2; the compound of the present invention has excellent pharmacokinetic properties.
定义和说明Definition and Description
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。Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered uncertain or unclear in the absence of a specific definition, but should be understood in its ordinary meaning. Where a trade name appears herein, it is intended to refer to its corresponding trade name or its active ingredient.
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。As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue. , without undue toxicity, irritation, allergic reactions, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
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。The term "pharmaceutically acceptable salts" refers to salts of compounds of the present invention prepared from compounds having specific substituents found in the present invention and relatively non-toxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting such compounds with a sufficient amount of base in pure solution or in a suitable inert solvent. When the compound of the present invention contains a relatively basic functional group, Acid addition salts may be obtained by contacting such compounds with a sufficient amount of acid in pure solution or in a suitable inert solvent. Certain specific compounds of the present invention contain both basic and acidic functional groups and thus can be converted into either base or acid addition salts.
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。The pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid groups or bases. In general, 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 the two.
除非另有说明，术语“异构体”意在包括几何异构体、顺反异构体、立体异构体、对映异构体、旋光异构体、非对映异构体和互变异构体。Unless otherwise stated, the term "isomer" is intended to include geometric isomers, cis-trans isomers, stereoisomers, enantiomers, optical isomers, diastereomers and tautomers isomer.
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。The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereoisomers isomer, the (D)-isomer, the (L)-isomer, as well as their racemic mixtures and other mixtures, such as enantiomeric or diastereomerically enriched mixtures, all of which belong to the present invention. 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.
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。Unless otherwise stated, the terms "enantiomers" or "optical isomers" refer to stereoisomers that are mirror images of each other.
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。Unless otherwise stated, the term "cis-trans isomers" or "geometric isomers" refers to the inability of the double bonds or single bonds of the carbon atoms in the ring to rotate freely.
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。Unless otherwise stated, the term "diastereomer" refers to stereoisomers whose molecules have two or more chiral centers and are in a non-mirror image relationship between the molecules.
除非另有说明，“(+)”表示右旋，“(-)”表示左旋，“(±)”表示外消旋。Unless otherwise stated, "(+)" means right-handed, "(-)" means left-handed, and "(±)" means racemic.
除非另有说明，用楔形实线键和楔形虚线键表示一个立体中心的绝对构型，用直形实线键和直形虚线键表示立体中心的相对构型，用波浪线表示楔形实线键或楔形虚线键或用波浪线表示直形实线键或直形虚线键 Unless otherwise stated, use wedge-shaped solid line keys and wedge-shaped dotted keys Represents the absolute configuration of a three-dimensional center, using straight solid line keys and straight dotted keys Represent the relative configuration of the three-dimensional center with a wavy line Represents wedge-shaped solid line key or wedge-shaped dotted key or use tilde Represents a straight solid line key or straight dotted key
除非另有说明，当化合物中存在双键结构，如碳碳双键、碳氮双键和氮氮双键，且双键上的各个原子均连接有两个不同的取代基时(包含氮原子的双键中，氮原子上的一对孤对电子视为其连接的一个取代基)，如果该化合物中双键上的原子与其取代基之间用波浪线连接，则表示该化合物的(Z)型异构体、(E)型异构体或两种异构体的混合物。例如下式(A)表示该化合物以式(A-1)或式(A-2)的单一异构体形式存在或以式(A-1)和式(A-2)两种异构体的混合物形式存在；下式(B)表示该化合物以式(B-1)或式(B-2)的单一异构体形式存在或以式(B-1)和式(B-2)两种异构体的混合物形式存在。下式(C)表示该化合物以式(C-1)或式(C-2)的单一异构体形式存在或以式(C-1)和式(C-2)两种异构体的混合物形式存在。

Unless otherwise stated, when there are double bond structures in the compound, such as carbon-carbon double bonds, carbon-nitrogen double bonds, and nitrogen-nitrogen double bonds, and each atom on the double bond is connected to two different substituents (including nitrogen atoms In a double bond, a lone pair of electrons on the nitrogen atom is regarded as a substituent connected to it), if a wavy line is used between the atom on the double bond and its substituent in the compound If connected, it means the (Z) isomer, (E) isomer or a mixture of the two isomers of the compound. For example, the following formula (A) indicates that the compound exists as a single isomer of formula (A-1) or formula (A-2) or as two isomers of formula (A-1) and formula (A-2) exists in the form of a mixture; the following formula (B) indicates that the compound exists in the form of a single isomer of formula (B-1) or formula (B-2) or in the form of both formula (B-1) and formula (B-2) Exists as a mixture of isomers. The following formula (C) indicates that the compound exists in the form of a single isomer of formula (C-1) or formula (C-2) or in the form of two isomers of formula (C-1) and formula (C-2). Exists in mixture form.

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。Unless otherwise stated, the term "tautomer" or "tautomeric form" means that at room temperature, isomers with different functional groups are in dynamic equilibrium and can quickly convert into each other. If tautomers are possible (eg in solution), a chemical equilibrium of tautomers can be achieved. For example, proton tautomers (also called proton transfer tautomers) include interconversions by proton migration, such as keto-enol isomerization and imine-enol isomerization. Amine isomerization. Valence tautomers include interconversions through the reorganization of some bonding electrons. A specific example of keto-enol tautomerization is the tautomerization between pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
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％。Unless otherwise stated, the terms "enriched in an isomer," "enantiomerically enriched," "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%.
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％。Unless otherwise stated, the term "isomeric excess" or "enantiomeric excess" refers 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 content of the other isomer or enantiomer is 10%, then the isomer or enantiomeric excess (ee value) is 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)。The optically active (R)- and (S)-isomers as well as the 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 auxiliaries, in which the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with a suitable optically active acid or base, and then the salt is formed by conventional methods 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 combined with chemical derivatization methods (e.g., generation of amino groups from amines). formate).
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。The compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound. For example, compounds can be labeled with radioactive isotopes, such as tritium ( 3 H), iodine-125 ( 125 I), or C-14 ( 14 C). For another example, deuterated drugs can be replaced by heavy hydrogen to form deuterated drugs. The bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs can reduce side effects and increase drug stability. , enhance efficacy, extend drug biological half-life and other advantages. All variations in the isotopic composition of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
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。The terms "optionally" or "optionally" mean that the subsequently described event or condition may, but need not, occur, and that the description includes instances in which the stated event or condition occurs and instances in which it does not. .
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。氧取代不会发生在芳香基上。 The term "substituted" means that any one or more hydrogen atoms on a specific atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence state of the specific atom is normal and the substituted compound is stable. When the substituent is oxygen (i.e. =O), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups.
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。The term "optionally substituted" means that it may or may not be substituted. Unless otherwise specified, the type and number of substituents may be arbitrary on the basis of chemical achievability.
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。When any variable (e.g., R) occurs more than once in the composition or structure of a compound, its definition in each instance is independent. Thus, for example, if a group is substituted by 0-2 R, then said group may optionally be substituted by up to two R's, with independent options for R in each case. Furthermore, combinations of substituents and/or variants thereof are permitted only if such combinations result in stable compounds.
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。When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
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。When the number of a substituent is 0, it means that the substituent is not present. For example, -A-(R) 0 means that the structure is actually -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。When a substituent is vacant, it means that the substituent does not exist. For example, when X in A-X is vacant, it means that the structure is actually 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。When one of the variables is selected from a single bond, it means that the two groups it is connected to are directly connected. For example, when L in A-L-Z represents a single bond, it means that the structure is actually A-Z.
当一个取代基的键可以交叉连接到两个环上的任意一个原子时，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。When the bond of a substituent can be cross-linked to any atom on both rings, the substituent can be bonded to any atom on the ring, e.g., structural unit It means that the substituent R can be substituted at any position on the cyclohexyl or cyclohexadiene. When the listed substituent does not specify which atom it is connected to the substituted group through, the substituent can be bonded through any atom thereof. For example, a pyridyl group as a substituent can be bonded through any one of the pyridine rings. The carbon atom is attached to the substituted group.
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，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。When the listed linking groups do not specify the direction of connection, the direction of connection is arbitrary, for example, The middle linking group L is -MW-. At this time, -MW- can be connected to ring A and ring B in the same direction as the reading order from left to right. You can also connect ring A and ring B in the opposite direction to the reading order from left to right. Combinations of the linking groups, substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
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直形虚线键或波浪线表示。例如-OCH3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；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；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； 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 这4种连接方式，即使-N-上画出了H原子，但是仍包括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。Unless otherwise specified, when a certain group has one or more attachable sites, any one or more sites of the group can be connected to other groups through chemical bonds. When the connection mode of the chemical bond is non-positioned and there are H atoms at the connectable site, when the chemical bond is connected, the number of H atoms at the site will be reduced correspondingly with the number of connected chemical bonds and become the corresponding valence. group. The chemical bond connecting the site to other groups can be a straight solid line bond straight dashed key or wavy lines express. For example, the straight solid line bond in -OCH 3 means that it is connected to other groups through the oxygen atom in the group; The straight dotted bond in means that it is connected to other groups through both ends of the nitrogen atoms in the group; The wavy lines in indicate that the phenyl group is connected to other groups through the 1 and 2 carbon atoms in the phenyl group; Indicates that any connectable site on the piperidinyl group can be connected to other groups through a chemical bond, including at least In these four connection methods, even if H atoms are drawn on -N-, still includes For groups with this type of connection, only when a chemical bond is connected, the H at that position will be reduced by one and become the corresponding monovalent piperidinyl group.
除非另有规定，环上原子的数目通常被定义为环的元数，例如，“5-7元环”是指环绕排列5-7个原子的“环”。Unless otherwise specified, the number of atoms in a ring is usually defined as the number of ring members. For example, a "5- to 7-membered ring" refers to a "ring" with 5 to 7 atoms arranged around it.
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。Unless otherwise specified, the term "halogen" or "halogen" by itself or as part of another substituent means a fluorine, chlorine, bromine or iodine atom.
除非另有规定，术语“C1-3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C1-3烷基包括C1-2和C2-3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)。C1- 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。Unless otherwise specified, the term "C 1-3 alkyl" is used to mean 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 groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n - propyl and isopropyl), and the like.
除非另有规定，术语“C1-4烷基”用于表示直链或支链的由1至4个碳原子组成的饱和碳氢基团。所述C1-4烷基包括C1-2、C1-3和C2-3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)。C1-4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)、丁基(包括n-丁基，异丁基，s-丁基和t-丁基)等。Unless otherwise specified, the term "C 1-4 alkyl" is used to mean a straight or branched chain saturated hydrocarbon group consisting of 1 to 4 carbon atoms. The C 1-4 alkyl group includes C 1-2 , C 1-3 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 1-4 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl , s-butyl and t-butyl), etc.
除非另有规定，术语“C1-3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C1-3烷氧基包括C1-2、C2-3、C3和C2烷氧基等；其可以是一价、二价或者多价。C1- 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。Unless otherwise specified, the term "C 1-3 alkoxy" means those alkyl groups containing 1 to 3 carbon atoms that are attached to the remainder 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, etc.; it can be monovalent, divalent or multivalent. Examples of C 1-3 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
除非另有规定，“C3-5环烷基”表示由3至5个碳原子组成的饱和环状碳氢基团，其为单环体系，所述C3-5环烷基包括C3-4和C4-5环烷基等；其可以是一价、二价或者多价。C3-5环烷基的实例包括，但不限于，环丙基、环丁基、环戊基等。Unless otherwise specified, "C 3-5 cycloalkyl" means a saturated cyclic hydrocarbon group composed of 3 to 5 carbon atoms, which is a single ring system, and the C 3-5 cycloalkyl group includes C 3 -4 and C 4-5 cycloalkyl, etc.; it can be monovalent, divalent or polyvalent. Examples of C 3-5 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and the like.
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，氮和硫杂原子可任选被氧化(即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。其可以是一价、二价或者多价。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)。Unless otherwise specified, the terms "5-6 membered heteroaromatic ring" and "5-6 membered heteroaryl" may be used interchangeably in the present invention, and the term "5-6 membered heteroaryl" means 5 to 6 ring atoms. It consists of a monocyclic group with a conjugated π electron system, in which 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. The nitrogen atoms are optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) p , p is 1 or 2). A 5-6 membered heteroaryl group can be attached to the rest of the molecule through a heteroatom or a carbon atom. The 5-6 membered heteroaryl group includes 5-membered and 6-membered heteroaryl groups. It can be monovalent, bivalent or polyvalent. Examples of the 5-6 membered heteroaryl include but are not limited to pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrrolyl). azolyl group, etc.), imidazolyl group (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl) 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.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl , 4-thiazolyl and 5-thiazolyl, etc.), furyl (including 2-furyl and 3-furyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (including 2-thienyl, etc.) -pyridyl, 3-pyridyl and 4-pyridyl, etc.), pyrazinyl or pyrimidinyl (including 2-pyrimidinyl, 4-pyrimidinyl, etc.).
除非另有规定，术语“5-6元杂环烷基”本身或者与其他术语联合分别表示由5至6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，氮和硫杂原子可任选被氧化(即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。此外，就该“5-6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5-6元杂环烷基包括5元和6元杂环烷基。其可以是一价、二价或者多价。5-6元杂环烷基的实例包括但不限于吡咯烷基、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、六氢哒嗪基等。Unless otherwise specified, the term "5-6 membered heterocycloalkyl" by itself or in combination with other terms means a saturated cyclic group consisting of 5 to 6 ring atoms, with 1, 2, 3 or 4 ring atoms. are heteroatoms independently selected from O, S and N, and the remainder are carbon atoms, in which the nitrogen atoms are optionally quaternized, and the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O) p , p is 1 or 2). It includes single-ring and double-ring systems, of which double-ring Ring systems include spiro rings, parallel rings and bridged rings. Furthermore, in the case of the "5- to 6-membered heterocycloalkyl", a heteroatom may occupy the attachment position of the heterocycloalkyl to the rest of the molecule. The 5-6 membered heterocycloalkyl group includes 5-membered and 6-membered heterocycloalkyl groups. It can be monovalent, bivalent or polyvalent. Examples of 5-6 membered heterocycloalkyl include but are not limited to pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, etc.) , tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidyl (including 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, etc.), piperazinyl (including 1 -piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazole Alkyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, etc.
除非另有规定，术语“5-6元杂环烯基”本身或者与其他术语联合分别表示包含至少一个碳-碳双键的由5至6个环原子组成的部分不饱和的环状基团，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，氮和硫杂原子可任选被氧化(即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，此体系的任意环都是非芳香性的。其可以是一价、二价或者多价。此外，就该“5-6元杂环烯基”而言，杂原子可以占据杂环烯基与分子其余部分的连接位置。所述5-6元杂环烯基包括5元和6元杂环烯基等。5-6元杂环烯基的实例包括但不限于 Unless otherwise specified, the term "5-6 membered heterocycloalkenyl" by itself or in combination with other terms means a partially unsaturated cyclic group consisting of 5 to 6 ring atoms containing at least one carbon-carbon double bond. , 1, 2, 3 or 4 of its ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, in which the nitrogen atoms are optionally quaternized, and the nitrogen and sulfur heteroatoms can be optionally quaternized. Oxidation (i.e. NO and S(O) p , p is 1 or 2). It includes single-ring and bicyclic systems. The bicyclic system includes spiro ring, paracyclic ring and bridged ring. Any ring in this system is non-aromatic. It can be monovalent, bivalent or polyvalent. In addition, in the case of the "5- to 6-membered heterocycloalkenyl group", a heteroatom may occupy the attachment position of the heterocycloalkenyl group to the rest of the molecule. The 5-6 membered heterocyclic alkenyl group includes 5-membered and 6-membered heterocyclic alkenyl groups. Examples of 5-6 membered heterocyclenyl groups include, but are not limited to
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：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。The structure of the compound of the present invention can be confirmed by conventional methods well 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, single crystal X-ray diffraction (SXRD) uses a Bruker D8 venture diffractometer to collect diffraction intensity data on the cultured single crystal. The light source is CuKα radiation. The scanning method is: After scanning and collecting relevant data, the direct method (Shelxs97) is further used to analyze the crystal structure, and the absolute configuration can be confirmed.
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。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, embodiments formed by combining them with other chemical synthesis methods, and methods well known to those skilled in the art. Equivalent alternatives and preferred embodiments include, but are not limited to, embodiments of the present invention.
本发明所使用的溶剂可经市售获得。The solvent used in the present invention is commercially available.
本发明采用下述缩略词：aq代表水；eq代表当量、等量；DCM代表二氯甲烷；PE代表石油醚；DMSO代表二甲亚砜；EtOAc代表乙酸乙酯；EtOH代表乙醇；MeOH代表甲醇；DMF代表N,N-二甲基甲酰胺；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；r.t.代表室温；O/N代表过夜；THF代表四氢呋喃；Boc2O代表二叔丁基二碳酸酯；TFA代表三氟乙酸；HCl代表盐酸；mp代表熔点；Pd(dppf)Cl2代表[1,1'-双(二苯膦基)二茂铁]二氯化钯；Pd(dppf)Cl2.CH2Cl2代表[1,1'-双(二苯膦基)二茂铁]二氯化钯二氯甲烷复合物；TEA代表三乙胺；Xantphos代表4,5-双二苯基膦-9,9-二甲基氧杂蒽；Pd2(dba)3代表三(二亚苄基丙酮)二钯；EDCI代表1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐；HOBt代表1-羟基苯并三唑；NMP代表N-甲基吡咯烷酮；DIPEA代表N,N-二异丙基乙胺；HATU代表2-(7-偶氮苯并三氮唑)-四甲基脲六氟磷酸酯。The present invention adopts the following abbreviations: aq represents water; eq represents equivalent, equivalent amount; DCM represents dichloromethane; PE represents petroleum ether; DMSO represents dimethyl sulfoxide; EtOAc represents ethyl acetate; EtOH represents ethanol; MeOH represents Methanol; DMF represents N,N-dimethylformamide; Cbz represents benzyloxycarbonyl, which is an amine protecting group; Boc represents tert-butoxycarbonyl, which is an amine protecting group; rt represents room temperature; O/N represents Overnight; THF represents tetrahydrofuran; Boc 2 O represents di-tert-butyl dicarbonate; TFA represents trifluoroacetic acid; HCl represents hydrochloric acid; mp represents melting point; Pd(dppf)Cl 2 represents [1,1'-bis(diphenylphosphine) base)ferrocene]palladium dichloride; Pd(dppf)Cl 2 .CH 2 Cl 2 represents [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane complex; TEA represents triethylamine; -(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; HOBt represents 1-hydroxybenzotriazole; NMP represents N-methylpyrrolidone; DIPEA represents N,N-diisopropyl Ethylamine; HATU stands for 2-(7-azobenzotriazole)-tetramethylurea hexafluorophosphate.
化合物依据本领域常规命名原则或者使用软件命名，市售化合物采用供应商目录名称。Compounds are named according to conventional naming principles in the field or use For software naming, commercially available compounds adopt supplier catalog names.
具体实施方式Detailed ways
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。本文已经详细地描述了本发明，其中也公开了其具体实施例方式，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。 The present invention is described in detail below through examples, which do not mean any adverse limitations to the present invention. The present invention has been described in detail herein, and its specific embodiments are also disclosed. For those skilled in the art, various changes and improvements can be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention. will be obvious.
参考例1
Reference example 1
步骤1：化合物A-1的合成Step 1: Synthesis of Compound A-1
将化合物A-1-1(1g,5.46mmol)溶于二氯甲烷(10mL)中，加入二溴亚砜(3.40g,16.38mmol,1.27mL)，在15℃搅拌1hr。向反应液中加入饱和碳酸氢钠水溶液(20mL)调至pH＝8后加入二氯甲烷(10mL)和水(10mL)萃取一次，有机相用无水硫酸钠干燥后浓缩，得到化合物A-1。1HNMR(400MHz,CDCl3)δ：7.90(d,J＝2.4Hz,1H),7.60-7.57(m,1H),7.08(d,J＝8.4Hz,1H),4.48(s,2H),3.98(s,3H)。Compound A-1-1 (1g, 5.46mmol) was dissolved in dichloromethane (10mL), dibromoxysulfoxide (3.40g, 16.38mmol, 1.27mL) was added, and the mixture was stirred at 15°C for 1 hr. Saturated sodium bicarbonate aqueous solution (20 mL) was added to the reaction solution to adjust pH=8, dichloromethane (10 mL) and water (10 mL) were added for extraction once, the organic phase was dried over anhydrous sodium sulfate and concentrated to obtain compound A-1. . 1 HNMR (400MHz, CDCl 3 ) δ: 7.90 (d, J = 2.4Hz, 1H), 7.60-7.57 (m, 1H), 7.08 (d, J = 8.4Hz, 1H), 4.48 (s, 2H), 3.98(s,3H).
参考例2
Reference example 2
步骤1：化合物A-2-2的合成Step 1: Synthesis of Compound A-2-2
将化合物A-2-1(10g,118.88mmol)溶于无水二氯甲烷(250mL)，向体系中加入叔丁基二苯基氯硅烷(39.21g,142.66mmol,36.65mL)及咪唑(19.42g,285.32mmol)。加料完毕后体系25℃搅拌16hr。加水(200mL)稀释反应液，分液后有机相经饱和食盐水(150mL*3)洗涤，再经无水硫酸钠干燥过滤，滤液减压浓缩，粗品经硅胶柱层析分离纯化(乙酸乙酯：石油醚＝0-5％)得到化合物A-2-2。1H NMR(400MHz,CDCl3)δ:8.05-7.69(m,4H),7.64-7.36(m,6H),5.67(s,2H),4.87-4.45(m,1H),2.94-2.31(m,4H),1.27-1.03(m,9H)。Compound A-2-1 (10g, 118.88mmol) was dissolved in anhydrous dichloromethane (250mL), and tert-butyldiphenylsilyl chloride (39.21g, 142.66mmol, 36.65mL) and imidazole (19.42mL) were added to the system. g, 285.32mmol). After the addition is completed, the system is stirred at 25°C for 16 hours. Add water (200mL) to dilute the reaction solution. After separation, the organic phase was washed with saturated brine (150mL*3), then dried and filtered over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (ethyl acetate). : Petroleum ether = 0-5%) to obtain compound A-2-2. 1 H NMR (400MHz, CDCl 3 )δ:8.05-7.69(m,4H),7.64-7.36(m,6H),5.67(s,2H),4.87-4.45(m,1H),2.94-2.31(m ,4H),1.27-1.03(m,9H).
步骤2：化合物A-2-3的合成Step 2: Synthesis of Compound A-2-3
将化合物A-2-2(36g,111.62mmol)溶于无水二氯甲烷(300mL)，降温至0℃后体系加入间氯过氧苯甲酸(21.19g，85％含量)。加料完毕体系自然升温至25℃搅拌16hr。体系加入氢氧化钙(30g)，搅拌10min后过滤，滤液减压浓缩得到粗品。粗品经硅胶柱层析分离纯化(乙酸乙酯：石油醚＝0-10％)得到化合物A-2-3。1H NMR(400MHz,CDCl3)δ:7.56(ddd,J＝15.76,7.88,1.50Hz,4H),7.39-7.21(m,6H),4.33(t,J＝7.4Hz,0.5H),3.99(quin,J＝7.1Hz,0.5H),3.41-3.20(m,2H),2.18(dd,J＝7.3,14.1Hz,1H),1.96(dd,J＝1.0,15.1Hz,1H),1.78(dd,J＝7.4,15.1Hz,1H),1.62(dd,J＝14.2,6.8Hz,1H),0.96(d,J＝5.0Hz,9H)。Compound A-2-2 (36g, 111.62mmol) was dissolved in anhydrous dichloromethane (300mL). After cooling to 0°C, m-chloroperoxybenzoic acid (21.19g, 85% content) was added to the system. After the addition is completed, the system is naturally heated to 25°C and stirred for 16 hours. Calcium hydroxide (30g) was added to the system, stirred for 10 minutes and then filtered. The filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-10%) to obtain compound A-2-3. 1 H NMR (400MHz, CDCl 3 ) δ: 7.56 (ddd, J＝15.76, 7.88, 1.50Hz, 4H), 7.39-7.21 (m, 6H), 4.33 (t, J＝7.4Hz, 0.5H), 3.99 (quin,J＝7.1Hz,0.5H),3.41-3.20(m,2H),2.18(dd,J＝7.3,14.1Hz,1H),1.96(dd,J＝1.0,15.1Hz,1H),1.78 (dd, J=7.4, 15.1Hz, 1H), 1.62 (dd, J=14.2, 6.8Hz, 1H), 0.96 (d, J=5.0Hz, 9H).
步骤3：化合物A-2-4的合成Step 3: Synthesis of Compound A-2-4
将化合物A-2-3(1.00g,2.95mmol)溶于乙醇(38mL)和水(11mL)中，在20℃下加入氯化铵(584.67mg,10.93mmol)，叠氮钠(672.16mg,10.34mmol)升温至80℃搅拌17hr。向反应液中加入2mol/L氢氧化钠水溶液调至pH＝10后将其减压浓缩，向浓缩后的粗品中加入乙酸乙酯(10mL)萃取一次，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得粗品化合物A-2-4。LCMS m/z＝382.2[M+H]+。Compound A-2-3 (1.00g, 2.95mmol) was dissolved in ethanol (38mL) and water (11mL), and ammonium chloride (584.67mg, 10.93mmol) and sodium azide (672.16mg, 10.34mmol) was heated to 80°C and stirred for 17 hours. Add 2 mol/L sodium hydroxide aqueous solution to the reaction solution to adjust to pH=10, and then concentrate it under reduced pressure. Add ethyl acetate (10 mL) to the concentrated crude product and extract once. The organic phase is dried with anhydrous sodium sulfate and filtered. , the filtrate was concentrated under reduced pressure to obtain crude compound A-2-4. LCMS m/z=382.2[M+H] + .
步骤4：化合物A-2的合成 Step 4: Synthesis of Compound A-2
将化合物A-2-4(0.5g)溶于乙酸乙酯(10mL)中，加入湿钯碳(0.25g,含量10％)，在20℃，40psi氢气氛围下搅拌2hr。将反应液过滤，滤液浓缩，得到化合物A-2。1HNMR(400MHz,CDCl3)δ:7.66-7.63(m,4H),7.43-7.38(m,6H),4.39-4.32(m,1H),4.12-4.07(m,0.5H),3.74-3.70(m,0.5H),3.58-3.50(m,0.5H),2.98-2.90(m,0.5H),2.26-2.07(m,2.5H),1.74-1.66(m,0.5H),1.58-1.50(m,0.5H),1.41-1.32(m,0.5H),1.06(d,J＝2.8Hz,9H)。Compound A-2-4 (0.5g) was dissolved in ethyl acetate (10 mL), wet palladium on carbon (0.25g, content 10%) was added, and the mixture was stirred for 2 hr at 20°C and 40 psi hydrogen atmosphere. The reaction liquid was filtered, and the filtrate was concentrated to obtain compound A-2. 1 HNMR (400MHz, CDCl 3 )δ:7.66-7.63(m,4H),7.43-7.38(m,6H),4.39-4.32(m,1H),4.12-4.07(m,0.5H),3.74-3.70 (m,0.5H),3.58-3.50(m,0.5H),2.98-2.90(m,0.5H),2.26-2.07(m,2.5H),1.74-1.66(m,0.5H),1.58-1.50 (m,0.5H),1.41-1.32(m,0.5H),1.06(d,J＝2.8Hz,9H).
实施例1
Example 1
步骤1：化合物1-2的合成Step 1: Synthesis of Compound 1-2
将化合物1-1(20g,128.90mmol)，丙二酸二乙酯(30.97g,193.36mmol,29.22mL)溶于乙醇(300mL)中，加入叔丁醇钾(28.93g,257.81mmol)，在80℃下搅拌12hr。冷却至室温后，向反应液中加入水(1L)后，搅拌，过滤，收集滤饼。将滤饼用乙腈(200mL)和甲基叔丁基醚(200mL)的混合溶剂20℃搅拌0.5小时后过滤，滤饼真空干燥得到化合物1-2。LCMS m/z＝224.2[M+H]+。Compound 1-1 (20g, 128.90mmol) and diethyl malonate (30.97g, 193.36mmol, 29.22mL) were dissolved in ethanol (300mL), and potassium tert-butoxide (28.93g, 257.81mmol) was added. Stir at 80°C for 12 hours. After cooling to room temperature, water (1L) was added to the reaction solution, stirred, filtered, and the filter cake was collected. The filter cake was stirred with a mixed solvent of acetonitrile (200 mL) and methyl tert-butyl ether (200 mL) at 20°C for 0.5 hours, and then filtered. The filter cake was dried under vacuum to obtain compound 1-2. LCMS m/z=224.2[M+H] + .
步骤2：化合物1-3的合成Step 2: Synthesis of Compounds 1-3
将化合物1-2(24g,107.53mmolq)溶于乙腈(120mL)中，在50℃下加入三氯氧磷(49.47g,322.60mmol,29.98mL)，吡啶(8.51g,107.53mmol,8.68mL)，在100℃下搅拌5hr。将反应液冷却至室温，将其缓慢的倒入到搅拌的冰水混合物(200mL)中，继续搅拌。淬灭结束后，有固体析出，将其过滤，滤饼真空干燥得到化合物1-3。LCMS m/z＝259.9[M+H]+。Compound 1-2 (24g, 107.53mmolq) was dissolved in acetonitrile (120mL), and phosphorus oxychloride (49.47g, 322.60mmol, 29.98mL) and pyridine (8.51g, 107.53mmol, 8.68mL) were added at 50°C. , stir at 100°C for 5 hr. The reaction solution was cooled to room temperature, slowly poured into the stirring ice-water mixture (200 mL), and continued stirring. After quenching, a solid precipitated, which was filtered, and the filter cake was dried under vacuum to obtain compound 1-3. LCMS m/z=259.9[M+H] + .
步骤3：化合物1-4的合成 Step 3: Synthesis of Compounds 1-4
将化合物1-3(7g,26.92mmol)溶于二氧六环(56mL)中，加入4-甲氧基-N-甲基苄胺(4.23g,27.99mmol)，DIPEA(6.96g,53.83mmol,9.38mL)，在15℃下搅拌1hr。向反应液中加入水(50mL)，用乙酸乙酯(50mL*2)萃取，合并后的有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得到化合物1-4。1HNMR(400MHz,CDCl3)δ：8.45(s,1H),7.18-7.16(m,2H),6.89-6.83(m,2H),6.13(s,1H),5.25(s,2H),4.44-4.37(m,2H),3.81(s,3H),3.13(s,3H),1.42(t,J＝7.2Hz,3H)；LCMS m/z＝375.2[M+H]+。Dissolve compound 1-3 (7g, 26.92mmol) in dioxane (56mL), add 4-methoxy-N-methylbenzylamine (4.23g, 27.99mmol), DIPEA (6.96g, 53.83mmol) ,9.38mL), stir at 15℃ for 1hr. Water (50 mL) was added to the reaction solution, and extracted with ethyl acetate (50 mL*2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 1-4. 1 HNMR (400MHz, CDCl 3 ) δ: 8.45 (s, 1H), 7.18-7.16 (m, 2H), 6.89-6.83 (m, 2H), 6.13 (s, 1H), 5.25 (s, 2H), 4.44 -4.37(m,2H),3.81(s,3H),3.13(s,3H),1.42(t,J=7.2Hz,3H); LCMS m/z=375.2[M+H] + .
步骤4：化合物1-5的合成Step 4: Synthesis of Compounds 1-5
将化合物1-4(5g,13.34mmol)溶于二氧六环(50mL)中，加入氢氧化钠(1M,18.68mL)水溶液在50℃下搅拌5hr。将反应液用稀盐酸(3M)调节pH＝3后加入水(50mL)，用乙酸乙酯(50mL*2)萃取，合并后的有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得到化合物1-5。LCMS m/z＝347.0[M+H]+。Compound 1-4 (5g, 13.34mmol) was dissolved in dioxane (50mL), aqueous sodium hydroxide (1M, 18.68mL) was added and stirred at 50°C for 5 hr. Adjust the pH=3 of the reaction solution with dilute hydrochloric acid (3M), add water (50mL), and extract with ethyl acetate (50mL*2). The combined organic phase is dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to obtain Compounds 1-5. LCMS m/z=347.0[M+H] + .
步骤5：化合物1-6的合成Step 5: Synthesis of Compounds 1-6
将化合物1-5(0.95g,2.74mmol)溶于DMF(10mL)，加入化合物(1R,2R)-2-氨基环戊醇盐酸盐(490.08mg,3.56mmol)，加入HOBt(444.21mg,3.29mmol)，加入EDCI(787.77mg,4.11mmol)，三乙胺(831.66mg,8.22mmol,1.14mL)，在40℃下反应1hr。向反应体系中加入(20mL)水，用乙酸乙酯(15mL*3)萃取，合并有机相，用饱和食盐水(10mL*3)清洗，无水硫酸钠干燥，过滤，滤液减压浓缩得粗品。粗品经硅胶柱层析分离纯化(乙酸乙酯/石油醚＝0～100％)得到化合物1-6。LCMS m/z＝430.1[M+H]+。Compound 1-5 (0.95g, 2.74mmol) was dissolved in DMF (10mL), compound (1R, 2R)-2-aminocyclopentanol hydrochloride (490.08mg, 3.56mmol) was added, and HOBt (444.21mg, 3.29mmol), add EDCI (787.77mg, 4.11mmol), triethylamine (831.66mg, 8.22mmol, 1.14mL), and react at 40°C for 1 hr. Add (20mL) water to the reaction system, extract with ethyl acetate (15mL*3), combine the organic phases, wash with saturated brine (10mL*3), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain crude product . The crude product was separated and purified by silica gel column chromatography (ethyl acetate/petroleum ether = 0-100%) to obtain compound 1-6. LCMS m/z=430.1[M+H] + .
步骤7：化合物1-7的合成Step 7: Synthesis of Compounds 1-7
将化合物1-6(0.16g,372.18μmol)，化合物A-1(119.05mg,483.83μmol)溶于四氢呋喃(8mL)中，在0℃下加入钠氢(29.77mg,744.36μmol,60％含量)，自然升温至15℃搅拌16hr。向反应液中滴加饱和氯化铵水溶液(2mL)后，加入水(10mL)，用乙酸乙酯(10mL)萃取。有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得粗品。粗品经硅胶柱层析分离纯化(乙酸乙酯/石油醚＝0～50％)得到化合物1-7。1HNMR(400MHz,CDCl3)δ：8.53(s,1H),7.97(d,J＝7.6Hz,1H),7.87-7.85(m,1H),7.58(dd,J＝8.8,2.0Hz,1H),7.19-7.16(m,2H),7.04(d,J＝8.4Hz,1H),6.90-6.84(m,2H),6.05(s,1H),5.31(s,1H),4.79-4.76(m,1H),4.66-4.63(m,1H),4.50-4.45(m,1H),4.00-3.97(m,1H),3.94(s,3H),3.81(s,3H),3.18(s,3H),2.30-2.22(m,1H),2.07-2.01(m,1H),1.94-1.78(m,4H),1.76-1.63(m,1H)；LCMS m/z＝595.3[M+H]+。Compound 1-6 (0.16g, 372.18μmol) and compound A-1 (119.05mg, 483.83μmol) were dissolved in tetrahydrofuran (8mL), and sodium hydrogen (29.77mg, 744.36μmol, 60% content) was added at 0°C. , naturally raise the temperature to 15°C and stir for 16 hours. After a saturated aqueous ammonium chloride solution (2 mL) was added dropwise to the reaction solution, water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude product. The crude product was separated and purified by silica gel column chromatography (ethyl acetate/petroleum ether = 0-50%) to obtain compound 1-7. 1 HNMR (400MHz, CDCl 3 ) δ: 8.53 (s, 1H), 7.97 (d, J = 7.6Hz, 1H), 7.87-7.85 (m, 1H), 7.58 (dd, J = 8.8, 2.0Hz, 1H ),7.19-7.16(m,2H),7.04(d,J＝8.4Hz,1H),6.90-6.84(m,2H),6.05(s,1H),5.31(s,1H),4.79-4.76( m,1H),4.66-4.63(m,1H),4.50-4.45(m,1H),4.00-3.97(m,1H),3.94(s,3H),3.81(s,3H),3.18(s, 3H),2.30-2.22(m,1H),2.07-2.01(m,1H),1.94-1.78(m,4H),1.76-1.63(m,1H); LCMS m/z=595.3[M+H] + .
步骤8：化合物1-8的合成Step 8: Synthesis of Compounds 1-8
将化合物1-7(0.18g,302.50μmol)溶于乙醇(18mL)和水(1.8mL)中，加入铁粉(168.93mg,3.02mmol)，氯化铵(161.81mg,3.02mmol)，在85℃下搅拌1hr。将反应液过滤，滤液浓缩。得到粗品化合物1-8。LCMS m/z＝565.2[M+H]+。粗品未经纯化直接用于下一步反应。Compound 1-7 (0.18g, 302.50μmol) was dissolved in ethanol (18mL) and water (1.8mL), iron powder (168.93mg, 3.02mmol) and ammonium chloride (161.81mg, 3.02mmol) were added, at 85 Stir for 1 hour at ℃. The reaction solution was filtered, and the filtrate was concentrated. Crude compound 1-8 was obtained. LCMS m/z=565.2[M+H] + . The crude product was used directly in the next reaction without purification.
步骤9：化合物1-9的合成Step 9: Synthesis of Compounds 1-9
将化合物1-8(176mg,311.47μmol)，碳酸铯(202.97mg,622.94μmol)，1,1’-联萘-2,2’-双二苯膦(19.39mg,31.15μmol)溶于二氧六环(18mL)中，氮气置换三次后加入Pd2(dba)3(28.52mg,31.15μmol)，在110℃搅拌下1.5hr。向反应液中加入水(15mL)和乙酸乙酯(20mL)萃取一次，有机相用无水硫酸钠干燥后浓缩。粗品经硅胶柱层析分离纯化(乙酸乙酯/石油醚＝0～50％)得到化合物1-9。LCMS m/z＝529.4[M+H]+。Compound 1-8 (176mg, 311.47μmol), cesium carbonate (202.97mg, 622.94μmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (19.39mg, 31.15μmol) were dissolved in dioxygen In six rings (18 mL), Pd 2 (dba) 3 (28.52 mg, 31.15 μmol) was added after three nitrogen replacements, and the mixture was stirred at 110°C for 1.5 hr. Water (15 mL) and ethyl acetate (20 mL) were added to the reaction solution for extraction once. The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was separated and purified by silica gel column chromatography (ethyl acetate/petroleum ether = 0-50%) to obtain compound 1-9. LCMS m/z=529.4[M+H] + .
步骤10：化合物001的合成Step 10: Synthesis of Compound 001
将化合物1-9(50mg,94.59μmol)溶于二氯甲烷(5mL)中，加入三氟乙酸(1.54g,13.51mmol,1.00mL)，在20℃下搅拌5分钟。向反应液中加入饱和碳酸氢钠水溶液(10mL)淬灭反应后，加入二氯甲烷(5mL)萃取，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得到粗品。粗品经过硅胶柱层析分离纯化(甲醇/二氯甲烷＝0～10％)得到化合物001。1HNMR(400MHz,CDCl3)δ：8.74-8.72(m,1H),8.57(s,1H),8.29 (s,1H),7.10(s,1H),6.87-6.82(m,2H),6.22-6.20(m,1H),5.35(s,1H),4.88(d,J＝14.4Hz,1H),4.39-4.36(m,1H),3.95-3.87(m,4H),3.86-3.75(m,1H),3.07(d,J＝5.2Hz,3H),2.66-2.58(m,1H),2.11-2.06(m,1H),1.89-1.78(m,1H),1.61-1.52(m,1H),1.33-1.23(m,2H)；LCMS m/z＝409.3[M+H]+。Compound 1-9 (50 mg, 94.59 μmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1.54 g, 13.51 mmol, 1.00 mL) was added, and the mixture was stirred at 20°C for 5 minutes. After adding saturated sodium bicarbonate aqueous solution (10 mL) to the reaction solution to quench the reaction, dichloromethane (5 mL) was added for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (methanol/dichloromethane=0-10%) to obtain compound 001. 1 HNMR (400MHz, CDCl 3 ) δ: 8.74-8.72 (m, 1H), 8.57 (s, 1H), 8.29 (s,1H),7.10(s,1H),6.87-6.82(m,2H),6.22-6.20(m,1H),5.35(s,1H),4.88(d,J＝14.4Hz,1H), 4.39-4.36(m,1H),3.95-3.87(m,4H),3.86-3.75(m,1H),3.07(d,J＝5.2Hz,3H),2.66-2.58(m,1H),2.11- 2.06(m,1H),1.89-1.78(m,1H),1.61-1.52(m,1H),1.33-1.23(m,2H); LCMS m/z=409.3[M+H] + .
实施例2
Example 2
步骤1：化合物2-2的合成Step 1: Synthesis of Compound 2-2
将化合物2-1(2g,13.68mmol)溶于DMF(20mL)中，加入碘代丁二酰亚胺(3.08g,13.68mmol)，在20℃下搅拌1hr。向反应液中加入水(60mL)，有固体析出，过滤，将滤饼真空干燥得到化合物2-2。LCMS m/z＝273.0[M+H]+。Compound 2-1 (2g, 13.68mmol) was dissolved in DMF (20mL), iodosuccinimide (3.08g, 13.68mmol) was added, and the mixture was stirred at 20°C for 1 hr. Water (60 mL) was added to the reaction solution, a solid precipitated, filtered, and the filter cake was vacuum dried to obtain compound 2-2. LCMS m/z=273.0[M+H] + .
步骤2：化合物2-3的合成Step 2: Synthesis of Compound 2-3
将化合物2-2(3g,11.03mmol)溶于DMF(48mL)中，依次加入碳酸钾(2.29g,16.54mmol)和异丙基溴(1.36g,11.03mmol,1.04mL)，在80℃下搅拌4hr。冷却至室温后，向反应液中加入水(50mL)，用乙酸乙酯(50mL)萃取，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得到粗品。粗品经硅胶柱层析分离纯化(乙酸乙酯/石油醚＝0～33％)得到化合物2-3。1HNMR(400MHz,CDCl3)δ：10.17(s,1H),8.82(d,J＝1.6Hz, 1H),8.25-8.22(m,1H),7.53(s,1H),5.31-5.24(m,1H),1.56(d,J＝6.8Hz,6H)；LCMS m/z＝315.0[M+H]+。Compound 2-2 (3g, 11.03mmol) was dissolved in DMF (48mL), potassium carbonate (2.29g, 16.54mmol) and isopropyl bromide (1.36g, 11.03mmol, 1.04mL) were added successively, and the mixture was heated at 80°C. Stir for 4 hours. After cooling to room temperature, water (50 mL) was added to the reaction solution, extracted with ethyl acetate (50 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (ethyl acetate/petroleum ether = 0-33%) to obtain compound 2-3. 1 HNMR (400MHz, CDCl 3 ) δ: 10.17 (s, 1H), 8.82 (d, J = 1.6Hz, 1H),8.25-8.22(m,1H),7.53(s,1H),5.31-5.24(m,1H),1.56(d,J＝6.8Hz,6H); LCMS m/z＝315.0[M+H ] + .
步骤3：化合物2-4的合成Step 3: Synthesis of Compounds 2-4
将化合物2-3(1g,3.18mmol)，双联嚬哪醇硼酸脂(1.62g,6.37mmol)，乙酸钾(937.30mg,9.55mmol)溶于DMF(25mL)中，氮气置换三次后加入Pd(dppf)Cl2·CH2Cl2(259.97mg,318.35μmol)，在90℃下搅拌1hr。冷却至室温后，向反应液中加入水(20mL)，用乙酸乙酯(20mL)萃取，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得到粗品。粗品经硅胶柱层析分离纯化(乙酸乙酯/石油醚＝0～33％)得到化合物2-4。LCMS m/z＝315.2[M+H]+。Compound 2-3 (1g, 3.18mmol), bis-zalcohol boronic acid ester (1.62g, 6.37mmol), and potassium acetate (937.30mg, 9.55mmol) were dissolved in DMF (25mL). After nitrogen replacement three times, Pd was added. (dppf)Cl 2 ·CH 2 Cl 2 (259.97 mg, 318.35 μmol), stirred at 90°C for 1 hr. After cooling to room temperature, water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (ethyl acetate/petroleum ether = 0-33%) to obtain compound 2-4. LCMS m/z=315.2[M+H] + .
步骤4：化合物2-5的合成Step 4: Synthesis of Compounds 2-5
将化合物2-4(0.6g,1.91mmol)，化合物1-4(572.63mg,1.53mmol)，碳酸钠(506.02mg,4.77mmol)溶于水(3mL)和二氧六环(27mL)中，氮气置换三次后加入Pd(dppf)Cl2(139.73mg,190.97μmol)，在110℃下搅拌2hr。冷却至室温后，向反应液中加入水(20mL)，用乙酸乙酯(20mL*2)萃取，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得粗品。粗品经硅胶柱层析分离纯化(乙酸乙酯/石油醚＝0～50％)得到化合物2-5。Compound 2-4 (0.6g, 1.91mmol), compound 1-4 (572.63mg, 1.53mmol), sodium carbonate (506.02mg, 4.77mmol) were dissolved in water (3mL) and dioxane (27mL), After nitrogen replacement three times, Pd(dppf)Cl 2 (139.73 mg, 190.97 μmol) was added, and the mixture was stirred at 110°C for 2 hr. After cooling to room temperature, water (20 mL) was added to the reaction solution, extracted with ethyl acetate (20 mL*2), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (ethyl acetate/petroleum ether = 0-50%) to obtain compound 2-5.
LCMS m/z＝527.2[M+H]+。LCMS m/z=527.2[M+H] + .
步骤5：化合物2-6的合成Step 5: Synthesis of Compounds 2-6
将化合物2-5(0.47g,892.54μmol)溶于四氢呋喃(25mL)中，加入硼氢化钠(33.77mg,892.54μmol)，在0℃下搅拌0.5hr。向反应液中缓慢加入饱和氯化铵水溶液(10mL)，用乙酸乙酯(10mL)萃取，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得到粗品化合物2-6。LCMS m/z＝529.3[M+H]+。粗品未经纯化直接用于下一步反应。Compound 2-5 (0.47g, 892.54 μmol) was dissolved in tetrahydrofuran (25 mL), sodium borohydride (33.77 mg, 892.54 μmol) was added, and the mixture was stirred at 0°C for 0.5 hr. Slowly add saturated aqueous ammonium chloride solution (10 mL) to the reaction solution, extract with ethyl acetate (10 mL), dry the organic phase over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain crude compound 2-6. LCMS m/z=529.3[M+H] + . The crude product was used directly in the next reaction without purification.
步骤6：化合物2-7的合成Step 6: Synthesis of Compounds 2-7
将化合物2-6(0.48g,908.06μmol)溶于四氢呋喃(48mL)中，加入三溴化磷(368.70mg,1.36mmol)，在20℃下搅拌0.5hr。向反应液中加入水(15mL)，用乙酸乙酯(20mL)萃取，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得到粗品。粗品经硅胶柱层析分离纯化(乙酸乙酯/石油醚＝0～50％)得到化合物2-7。LCMS m/z＝591.0[M+H]+。Compound 2-6 (0.48g, 908.06 μmol) was dissolved in tetrahydrofuran (48 mL), phosphorus tribromide (368.70 mg, 1.36 mmol) was added, and the mixture was stirred at 20°C for 0.5 hr. Water (15 mL) was added to the reaction solution, extracted with ethyl acetate (20 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (ethyl acetate/petroleum ether = 0-50%) to obtain compound 2-7. LCMS m/z=591.0[M+H] + .
步骤7：化合物2-8的合成Step 7: Synthesis of Compounds 2-8
将化合物2-7(0.49g,828.41μmol)和N-(叔丁氧羰基)乙醇胺(200.31mg,1.24mmol,192.60μL)溶于四氢呋喃(20mL)中，在0℃下加入钠氢(66.27mg,1.66mmol,60％含量)，然后在20℃下搅拌3.5hr。向反应液中加入饱和氯化铵水溶液(10mL)，用乙酸乙酯(10mL)萃取，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得到粗品。粗品经硅胶柱层析分离纯化(乙酸乙酯/石油醚＝0～50％)得到化合物2-8。LCMS m/z＝672.5[M+H]+。Compound 2-7 (0.49g, 828.41μmol) and N-(tert-butoxycarbonyl)ethanolamine (200.31mg, 1.24mmol, 192.60μL) were dissolved in tetrahydrofuran (20mL), and sodium hydrogen (66.27mg) was added at 0°C. ,1.66mmol, 60% content), and then stirred at 20°C for 3.5hr. Saturated ammonium chloride aqueous solution (10 mL) was added to the reaction solution, extracted with ethyl acetate (10 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (ethyl acetate/petroleum ether = 0-50%) to obtain compound 2-8. LCMS m/z=672.5[M+H] + .
步骤8：化合物2-9的合成Step 8: Synthesis of Compounds 2-9
将化合物2-8(0.18g,267.94μmol)溶于二氯甲烷(18mL)中，加入三氟乙酸(3.60mL,48.62mmol)，在20℃下搅拌0.5hr。向反应液中加入饱和碳酸氢钠水溶液(30mL)淬灭反应，然后用二氯甲烷(20mL)萃取，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得到粗品化合物2-9。LCMS m/z＝572.2[M+H]+。粗品未经纯化直接用于下一步反应。Compound 2-8 (0.18g, 267.94 μmol) was dissolved in dichloromethane (18 mL), trifluoroacetic acid (3.60 mL, 48.62 mmol) was added, and the mixture was stirred at 20°C for 0.5 hr. Saturated sodium bicarbonate aqueous solution (30 mL) was added to the reaction solution to quench the reaction, and then extracted with dichloromethane (20 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude compound 2-9. LCMS m/z=572.2[M+H] + . The crude product was used directly in the next reaction without purification.
步骤9：化合物2-10的合成Step 9: Synthesis of Compounds 2-10
将化合物2-9(0.145g,253.64μmol)溶于乙醇(7mL)中，加入氢氧化钠(2M,634.11μL)，在70℃下搅拌1hr。向反应液中加入1mol/L稀盐酸，调至pH＝3后减压浓缩得到粗品化合物2-10。LCMS m/z＝544.2[M+H]+。粗品未经纯化直接用于下一步反应。 Compound 2-9 (0.145g, 253.64 μmol) was dissolved in ethanol (7 mL), sodium hydroxide (2M, 634.11 μL) was added, and the mixture was stirred at 70°C for 1 hr. 1 mol/L dilute hydrochloric acid was added to the reaction solution, adjusted to pH=3, and then concentrated under reduced pressure to obtain crude compound 2-10. LCMS m/z=544.2[M+H] + . The crude product was used directly in the next reaction without purification.
步骤10：化合物2-11的合成Step 10: Synthesis of Compound 2-11
将化合物2-10(0.1g,183.95μmol)溶于二氯甲烷(10mL)中，加入HATU(69.94mg,183.95μmol)，TEA(55.84mg,551.86μmol,76.81μL)，在20℃下搅拌1hr。向反应液中加入水(5mL)静置分液，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得到到粗品。粗品经硅胶柱层析分离纯化(甲醇/二氯甲烷＝0～10％)得到化合物2-11。LCMS m/z＝526.2[M+H]+。Dissolve compound 2-10 (0.1g, 183.95 μmol) in dichloromethane (10 mL), add HATU (69.94 mg, 183.95 μmol), TEA (55.84 mg, 551.86 μmol, 76.81 μL), and stir at 20°C for 1 hr. . Water (5 mL) was added to the reaction solution and allowed to stand for liquid separation. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (methanol/dichloromethane=0-10%) to obtain compound 2-11. LCMS m/z=526.2[M+H] + .
步骤11：化合物002的合成Step 11: Synthesis of Compound 002
将化合物2-11(10mg,19.03μmol)溶于二氯甲烷(1mL)中，加入三氟乙酸(0.2mL,2.70mmol)，在20℃下搅拌10min。向反应液中加入饱和碳酸氢钠水溶液(10mL)，用二氯甲烷(10mL)萃取，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得到粗品。粗品经制备薄层色谱硅胶板分离纯化(二氯甲烷：甲醇＝10:1)得到化合物002。1HNMR(400MHz,CDCl3)δ：9.43(d,J＝0.8Hz,1H),8.73-8.70(m,1H),8.47(s,1H),8.22(d,J＝1.6Hz,1H),7.86(s,1H),6.43-6.40(m,1H),6.27(s,1H),5.29-5.22(m,1H),4.88(s,2H),3.93-3.91(m,2H),3.81-3.78(m,2H),3.24(d,J＝5.3Hz,3H),1.65(d,J＝5.0Hz,6H)；LCMS m/z＝406.1[M+H]+。Compound 2-11 (10 mg, 19.03 μmol) was dissolved in dichloromethane (1 mL), trifluoroacetic acid (0.2 mL, 2.70 mmol) was added, and the mixture was stirred at 20°C for 10 min. Saturated sodium bicarbonate aqueous solution (10 mL) was added to the reaction solution, extracted with dichloromethane (10 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by preparative thin layer chromatography on silica gel plate (dichloromethane: methanol = 10:1) to obtain compound 002. 1 HNMR (400MHz, CDCl 3 ) δ: 9.43 (d, J = 0.8 Hz, 1H), 8.73-8.70 (m, 1H), 8.47 (s, 1H), 8.22 (d, J = 1.6 Hz, 1H), 7.86(s,1H),6.43-6.40(m,1H),6.27(s,1H),5.29-5.22(m,1H),4.88(s,2H),3.93-3.91(m,2H),3.81- 3.78 (m, 2H), 3.24 (d, J = 5.3Hz, 3H), 1.65 (d, J = 5.0Hz, 6H); LCMS m/z = 406.1 [M+H] + .
实施例3
Example 3
步骤1：化合物3-2的合成Step 1: Synthesis of compound 3-2
将化合物3-1(204.16mg,1.01mmol)溶于四氢呋喃(15mL)中，在0℃下加入钠氢(40.57mg,1.01mmol,60％含量)，然后加入化合物2-7(0.3g,507.19μmol)，在20℃下搅拌3hr。向反应液中缓慢滴加饱和氯化铵水溶液(10mL)后加入乙酸乙酯(10mL)萃取，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得到粗品。粗品经硅胶柱层析分离纯化(乙酸乙酯/石油醚＝0～50％)得到化合物3-2。LCMS m/z＝712.2[M+H]+。Compound 3-1 (204.16 mg, 1.01 mmol) was dissolved in tetrahydrofuran (15 mL), sodium hydrogen (40.57 mg, 1.01 mmol, 60% content) was added at 0°C, and then compound 2-7 (0.3 g, 507.19 μmol), stir at 20°C for 3 hr. A saturated aqueous ammonium chloride solution (10 mL) was slowly added dropwise to the reaction solution, and then ethyl acetate (10 mL) was added for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (ethyl acetate/petroleum ether = 0-50%) to obtain compound 3-2. LCMS m/z=712.2[M+H] + .
步骤2：化合物3-3的合成Step 2: Synthesis of compound 3-3
将化合物3-2(0.17g,238.82μmol)溶于二氯甲烷(17mL)中，加入三氟乙酸(3.40mL)在20℃下搅拌10min。向反应液中加入饱和碳酸氢钠水溶液(30mL)调至pH＝8，加入二氯甲烷(20mL)萃取，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得到化合物3-3。粗品未经纯化直接用于下一步反应。LCMS m/z＝612.5[M+H]+。Compound 3-2 (0.17g, 238.82μmol) was dissolved in dichloromethane (17mL), trifluoroacetic acid (3.40mL) was added and stirred at 20°C for 10min. Saturated sodium bicarbonate aqueous solution (30 mL) was added to the reaction solution to adjust pH=8, dichloromethane (20 mL) was added for extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 3-3. The crude product was used directly in the next reaction without purification. LCMS m/z=612.5[M+H] + .
步骤3：化合物3-4的合成 Step 3: Synthesis of Compound 3-4
将化合物3-3(0.15g,245.21μmol)溶于乙醇(7.5mL)中，加入氢氧化钠(2M,613.01μL)在70℃下搅拌2.5hr。向反应液中加入1mol/L稀盐酸(2mL)调至pH＝3后加入水(6mL)，用二氯甲烷(10mL)萃取，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得到化合物3-4。粗品未经纯化直接用于下一步反应。LCMS m/z＝584.4[M+H]+。Compound 3-3 (0.15g, 245.21 μmol) was dissolved in ethanol (7.5 mL), sodium hydroxide (2M, 613.01 μL) was added, and the mixture was stirred at 70°C for 2.5 hr. Add 1 mol/L dilute hydrochloric acid (2 mL) to the reaction solution to adjust pH=3, add water (6 mL), and extract with dichloromethane (10 mL). The organic phase is dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to obtain Compound 3-4. The crude product was used directly in the next reaction without purification. LCMS m/z=584.4[M+H] + .
步骤4：化合物3-5的合成Step 4: Synthesis of Compounds 3-5
将化合物3-4(155mg,265.56μmol)溶于二氯甲烷(16mL)中，加入HATU(100.97mg,265.56μmol)，TEA(0.11mL)在20℃下搅拌0.5hr。向反应液中加入水(10mL)静置分液，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得到粗品。粗品经硅胶柱层析分离纯化(甲醇/二氯甲烷＝0～10％)得到化合物3-5。LCMS m/z＝566.2[M+H]+。Compound 3-4 (155 mg, 265.56 μmol) was dissolved in dichloromethane (16 mL), HATU (100.97 mg, 265.56 μmol) and TEA (0.11 mL) were added and stirred at 20°C for 0.5 hr. Water (10 mL) was added to the reaction solution and allowed to stand for liquid separation. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (methanol/dichloromethane=0-10%) to obtain compound 3-5. LCMS m/z=566.2[M+H] + .
步骤5：化合物003的合成Step 5: Synthesis of Compound 003
将化合物3-5(70mg,123.75μmol)溶于二氯甲烷(6mL)中，加入三氟乙酸(0.81mL)在20℃下搅拌5min。向反应液中加入饱和碳酸氢钠水溶液(10mL)调至pH＝8后，加入二氯甲烷(10mL)萃取，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得到粗品。粗品经制备薄层色谱硅胶板纯化(二氯甲烷：甲醇＝10:1)得到化合物003。1HNMR(400MHz,CDCl3)δ：9.40(s,1H),8.97(d,J＝3.6Hz,1H),8.45(s,1H),8.20(d,J＝1.6Hz,1H),7.86(s,1H),6.45-6.41(m,1H),6.25(s,1H),5.29-5.22(m,1H),5.15-5.10(m,1H),4.73-4.69(m,1H),4.21-4.15(m,1H),4.11-4.05(m,1H),3.24(d,J＝5.2Hz,3H),2.75-2.67(m,1H),2.14-2.08(m,1H),1.90-1.82(m,2H),1.76-1.71(m,2H),1.66(d,J＝6.8Hz,3H),1.61(d,J＝6.8Hz,3H)；LCMS m/z＝446.4[M+H]+。Compound 3-5 (70 mg, 123.75 μmol) was dissolved in dichloromethane (6 mL), trifluoroacetic acid (0.81 mL) was added and stirred at 20°C for 5 min. Saturated aqueous sodium bicarbonate solution (10 mL) was added to the reaction solution to adjust the pH to 8, and dichloromethane (10 mL) was added for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative thin layer chromatography on silica gel plate (dichloromethane: methanol = 10:1) to obtain compound 003. 1 HNMR (400MHz, CDCl 3 ) δ: 9.40 (s, 1H), 8.97 (d, J = 3.6 Hz, 1H), 8.45 (s, 1H), 8.20 (d, J = 1.6 Hz, 1H), 7.86 ( s,1H),6.45-6.41(m,1H),6.25(s,1H),5.29-5.22(m,1H),5.15-5.10(m,1H),4.73-4.69(m,1H),4.21- 4.15(m,1H),4.11-4.05(m,1H),3.24(d,J＝5.2Hz,3H),2.75-2.67(m,1H),2.14-2.08(m,1H),1.90-1.82( m,2H),1.76-1.71(m,2H),1.66(d,J＝6.8Hz,3H),1.61(d,J＝6.8Hz,3H); LCMS m/z＝446.4[M+H] + .
实施例4
Example 4
步骤1：化合物4-2的合成Step 1: Synthesis of compound 4-2
将化合物4-1(75.64mg,431.66μmol)溶于四氢呋喃(5mL)中，在0℃下搅拌5分钟后加入钠氢(40.57mg,863.31μmol,60％含量)，然后加入化合物2-7(170.22mg,287.77μmol)，在20℃下搅拌2hr。向反应液中缓慢滴加饱和氯化铵水溶液(50mL)后加入乙酸乙酯(30mL)萃取，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得到粗品。粗品经硅胶柱层析分离纯化(甲醇/二氯甲烷＝0～3％)得到化合物4-2。LCMS  m/z＝686.5[M+H]+。Compound 4-1 (75.64 mg, 431.66 μmol) was dissolved in tetrahydrofuran (5 mL), stirred at 0°C for 5 minutes, then sodium hydrogen (40.57 mg, 863.31 μmol, 60% content) was added, and then compound 2-7 ( 170.22 mg, 287.77 μmol), stir at 20°C for 2 hr. A saturated aqueous ammonium chloride solution (50 mL) was slowly added dropwise to the reaction solution, and ethyl acetate (30 mL) was added for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (methanol/dichloromethane=0-3%) to obtain compound 4-2. LCMS m/z=686.5[M+H] + .
步骤2：化合物4-3的合成Step 2: Synthesis of compound 4-3
将化合物4-2(142mg,207.05μmol)溶于二氯甲烷(6mL)中，加入三氟乙酸(1.24mL)在20℃下搅拌30min。向反应液中加入饱和碳酸氢钠水溶液(8mL)调至pH＝8，加入二氯甲烷(20mL)萃取，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得到化合物4-3。LCMS m/z＝608.3[M+Na]+。Compound 4-2 (142 mg, 207.05 μmol) was dissolved in dichloromethane (6 mL), trifluoroacetic acid (1.24 mL) was added, and the mixture was stirred at 20°C for 30 min. Saturated sodium bicarbonate aqueous solution (8 mL) was added to the reaction solution to adjust pH=8, dichloromethane (20 mL) was added for extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 4-3. LCMS m/z=608.3[M+Na] + .
步骤3：化合物4-4的合成Step 3: Synthesis of compound 4-4
将化合物4-3(121.24mg,207.05μmol)溶于乙醇(4mL)中，加入氢氧化钠溶液(2M,517.50μL)在70℃下搅拌3hr。向反应液中加入1mol/L稀盐酸(2mL)调至pH＝2后加入水(20mL)，用二氯甲烷(10mL)萃取，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得到化合物4-4。LCMS m/z＝558.0[M+H]+。Compound 4-3 (121.24 mg, 207.05 μmol) was dissolved in ethanol (4 mL), sodium hydroxide solution (2M, 517.50 μL) was added, and the mixture was stirred at 70°C for 3 hr. Add 1 mol/L dilute hydrochloric acid (2 mL) to the reaction solution to adjust pH=2, add water (20 mL), extract with dichloromethane (10 mL), dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain Compound 4-4. LCMS m/z=558.0[M+H] + .
步骤4：化合物4-5的合成Step 4: Synthesis of Compounds 4-5
将化合物4-4(66mg,118.36μmol)溶于二氯甲烷(6mL)中，加入TEA(49.42μL,335.07μmol)，HATU(54mg,142.03μmol)，在20℃下搅拌1hr。向反应液中加入水(20mL)，用二氯甲烷(10mL)萃取，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得到粗品。粗品经硅胶柱层析分离纯化(甲醇/二氯甲烷＝0～5％)得到化合物4-5。LCMS m/z＝540.3[M+H]+。Compound 4-4 (66 mg, 118.36 μmol) was dissolved in dichloromethane (6 mL), TEA (49.42 μL, 335.07 μmol), HATU (54 mg, 142.03 μmol) were added, and the mixture was stirred at 20°C for 1 hr. Water (20 mL) was added to the reaction solution, extracted with dichloromethane (10 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (methanol/dichloromethane=0~5%) to obtain compound 4-5. LCMS m/z=540.3[M+H] + .
步骤5：化合物004的合成Step 5: Synthesis of Compound 004
将化合物4-5(10mg,18.53μmol)溶于二氯甲烷(0.7mL)中，加入三氟乙酸(0.14mL)在20℃下搅30min。向反应液中加入饱和碳酸氢钠水溶液(5mL)调至pH＝8后，加入二氯甲烷(10mL)萃取，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得到粗品。粗品经制备高效液相色谱分离纯化(色谱柱:Phenomenex C18 80*40mm*3μm；流动相:[水(氨水+碳酸氢铵)-乙腈]；梯度:乙腈40％-70％，8min)纯化得到化合物004。1HNMR(400MHz,CDCl3)δ:9.55(s,1H),8.68–8.62(m,1H),8.49(s,1H),8.25(s,1H),7.87(s,1H),6.42(m,1H),6.28(m,1H),5.32–5.25(m,1H),4.99(d,J＝14.56Hz,1H),4.77(d,J＝15.06Hz,1H),4.39(m,1H),3.70-3.78(m,2H),3.26(d,J＝5.27Hz,3H),1.61-1.70(m,6H),1.33-1.41(m,3H)；LCMS m/z＝420.1[M+H]+。Compound 4-5 (10 mg, 18.53 μmol) was dissolved in dichloromethane (0.7 mL), trifluoroacetic acid (0.14 mL) was added and stirred at 20°C for 30 min. Saturated sodium bicarbonate aqueous solution (5 mL) was added to the reaction solution to adjust the pH to 8, and methylene chloride (10 mL) was added for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by preparative high performance liquid chromatography (chromatographic column: Phenomenex C18 80*40mm*3μm; mobile phase: [water (ammonia + ammonium bicarbonate)-acetonitrile]; gradient: acetonitrile 40%-70%, 8min). Compound 004. 1 HNMR(400MHz, CDCl 3 )δ:9.55(s,1H),8.68–8.62(m,1H),8.49(s,1H),8.25(s,1H),7.87(s,1H),6.42(m ,1H),6.28(m,1H),5.32–5.25(m,1H),4.99(d,J＝14.56Hz,1H),4.77(d,J＝15.06Hz,1H),4.39(m,1H) ,3.70-3.78(m,2H),3.26(d,J＝5.27Hz,3H),1.61-1.70(m,6H),1.33-1.41(m,3H); LCMS m/z＝420.1[M+H ] + .
实施例5
Example 5
步骤1：化合物5-2的合成Step 1: Synthesis of compound 5-2
将化合物5-1(5g,23.99mmol)溶于乙醇(58mL)中，加入2-氯-3-醛基丙酸乙酯(5.78g,38.38mmol)，在80℃下搅拌17hr。将溶剂减压浓缩，向反应液中加入水(50mL)和乙酸乙酯(50mL)萃取一次，有机相加入无水硫酸钠干燥，过滤，滤液减压浓缩得粗品。粗品经硅胶柱层析分离纯化(乙酸乙酯/石油醚＝0～50％)得到化合物5-2。LCMS m/z＝305.9[M+H]+。Compound 5-1 (5 g, 23.99 mmol) was dissolved in ethanol (58 mL), ethyl 2-chloro-3-aldehyde propionate (5.78 g, 38.38 mmol) was added, and the mixture was stirred at 80°C for 17 hr. The solvent was concentrated under reduced pressure. Water (50 mL) and ethyl acetate (50 mL) were added to the reaction solution for extraction once. The organic phase was dried by adding anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (ethyl acetate/petroleum ether = 0-50%) to obtain compound 5-2. LCMS m/z=305.9[M+H] + .
步骤2：化合物5-3的合成Step 2: Synthesis of compound 5-3
将化合物5-2(3.9g,12.81mmol)，1-(4-甲氧基苯基)-N-甲基-甲胺(2.52g,16.65mmol)，DIPEA(3.31g,25.61mmol,4.46mL)溶于二氧六环(19.5mL)，在90℃下搅拌1hr。向反应液中加入水(40mL)和乙酸乙酯(40mL)萃取一次，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得粗品。粗品经硅胶柱层析分离纯化(乙酸乙酯/石油醚＝0～50％)得到化合物5-3。LCMS m/z＝375.0[M+H]+。Compound 5-2 (3.9g, 12.81mmol), 1-(4-methoxyphenyl)-N-methyl-methylamine (2.52g, 16.65mmol), DIPEA (3.31g, 25.61mmol, 4.46mL ) was dissolved in dioxane (19.5 mL) and stirred at 90°C for 1 hr. Water (40 mL) and ethyl acetate (40 mL) were added to the reaction solution for extraction once, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (ethyl acetate/petroleum ether = 0-50%) to obtain compound 5-3. LCMS m/z=375.0[M+H] + .
步骤3：化合物5-4的合成Step 3: Synthesis of compound 5-4
将化合物5-3(0.95g,2.53mmol)，2-4(796.32mg,2.53mmol)，碳酸钠(2M,5.07mL)溶于二氧六环(40mL)中，氮气置换三次后加入氯(2-二环己基膦基-2’,4’,6’-三异丙基-1,1’-联苯基[2-(2’-氨基-1,1’-联苯)]钯(199.42mg,253.45μmol)在110℃下搅拌1.5hr。向反应液中加入水(20mL)和乙酸乙酯(20mL)萃取一次，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得粗品。粗品经硅胶柱层析分离纯化(乙酸乙酯/石油醚＝0～50％)得到化合物5-4。LCMS m/z＝527.1[M+H]+。Compound 5-3 (0.95g, 2.53mmol), 2-4 (796.32mg, 2.53mmol), sodium carbonate (2M, 5.07mL) were dissolved in dioxane (40mL), replaced with nitrogen three times and then added chlorine ( 2-Dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl[2-(2'-amino-1,1'-biphenyl)]palladium ( 199.42 mg, 253.45 μmol) and stirred at 110°C for 1.5 hr. Add water (20 mL) and ethyl acetate (20 mL) to the reaction solution and extract once. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude product. The crude product was separated and purified by silica gel column chromatography (ethyl acetate/petroleum ether = 0-50%) to obtain compound 5-4. LCMS m/z = 527.1 [M+H] + .
步骤4：化合物5-5的合成Step 4: Synthesis of Compound 5-5
将化合物5-4(0.8g,1.52mmol)溶于四氢呋喃(48mL)中，在0℃下加入硼氢化钠(57.48mg,1.52mmol)在20℃下搅拌2hr。向反应液中缓慢加入饱和氯化铵水溶液(10mL)后加入水(10mL)和乙酸乙 酯(20mL)萃取一次，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得粗品。粗品经硅胶柱层析分离纯化(乙酸乙酯/石油醚＝0～50％)，得到化合物5-5。LCMS m/z＝529.4[M+H]+。Compound 5-4 (0.8g, 1.52mmol) was dissolved in tetrahydrofuran (48mL), sodium borohydride (57.48mg, 1.52mmol) was added at 0°C and stirred at 20°C for 2 hr. Slowly add saturated aqueous ammonium chloride solution (10 mL) to the reaction solution, then add water (10 mL) and ethyl acetate. The ester (20 mL) was extracted once, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude product. The crude product was separated and purified by silica gel column chromatography (ethyl acetate/petroleum ether = 0-50%) to obtain compound 5-5. LCMS m/z=529.4[M+H] + .
步骤5：化合物5-6的合成Step 5: Synthesis of Compounds 5-6
将化合物5-5(0.6g,1.14mmol)溶于四氢呋喃(60mL)中，加入三溴化磷(460.87mg,1.70mmol)在20℃下搅拌5min。向反应液中加入水(30mL)，加入乙酸乙酯(30mL)萃取一次，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得粗品。粗品经硅胶柱层析分离纯化(乙酸乙酯/石油醚＝0～33％)得到化合物5-6。LCMS m/z＝591.4[M+H]+。Compound 5-5 (0.6 g, 1.14 mmol) was dissolved in tetrahydrofuran (60 mL), phosphorus tribromide (460.87 mg, 1.70 mmol) was added and stirred at 20°C for 5 min. Water (30 mL) was added to the reaction solution, and ethyl acetate (30 mL) was added for extraction once. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (ethyl acetate/petroleum ether = 0-33%) to obtain compound 5-6. LCMS m/z=591.4[M+H] + .
步骤6：化合物5-7的合成Step 6: Synthesis of Compounds 5-7
将化合物5-6(35.73mg,177.52μmol)溶于四氢呋喃(3mL)中，在0℃下加入钠氢(9.47mg,236.69μmol,60％含量)，化合物3-1(70mg,118.34μmol)在20℃下搅拌1hr。向反应液中加入饱和氯化铵水溶液(2mL)后，加入水(5mL)和乙酸乙酯(5mL)萃取一次，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得到粗品化合物5-7。LCMS m/z＝684.4[M+H]+。Compound 5-6 (35.73 mg, 177.52 μmol) was dissolved in tetrahydrofuran (3 mL), sodium hydrogen (9.47 mg, 236.69 μmol, 60% content) was added at 0°C, and compound 3-1 (70 mg, 118.34 μmol) was added in Stir at 20°C for 1 hr. After adding saturated ammonium chloride aqueous solution (2mL) to the reaction solution, water (5mL) and ethyl acetate (5mL) were added for extraction once. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude compound 5- 7. LCMS m/z=684.4[M+H] + .
步骤7：化合物5-8的合成Step 7: Synthesis of Compounds 5-8
将化合物5-7(0.12g,175.49μmol)溶于二氯甲烷(12mL)中，加入三氟乙酸(1.84g,16.15mmol,1.20mL)在20℃下搅拌20min。向反应液中加入饱和碳酸氢钠水溶液调至pH＝8后，加入二氯甲烷(10mL)萃取一次，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得粗品。粗品经制备薄层色谱硅胶板纯化(展开剂：二氯甲烷：甲醇＝5:1)得到化合物5-8。LCMS m/z＝464.2[M+H]+。Compound 5-7 (0.12g, 175.49μmol) was dissolved in dichloromethane (12mL), trifluoroacetic acid (1.84g, 16.15mmol, 1.20mL) was added and stirred at 20°C for 20min. Add saturated sodium bicarbonate aqueous solution to the reaction solution to adjust pH to 8, add methylene chloride (10 mL) for extraction once, dry the organic phase over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a crude product. The crude product was purified by preparative thin layer chromatography on silica gel plate (developing solvent: dichloromethane: methanol = 5:1) to obtain compound 5-8. LCMS m/z=464.2[M+H] + .
步骤8：化合物005的合成Step 8: Synthesis of Compound 005
将化合物5-8(7mg,15.10μmol)溶于二氯甲烷(0.5mL)中，加入HATU(5.74mg,15.10μmol)，TEA(4.58mg,45.30μmol,6.31μL)在20℃下搅拌16hr。向反应液中加入水(1mL)静置分液，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得粗品。粗品经制备薄层色谱硅胶板纯化(二氯甲烷：甲醇＝10:1)，得到化合物005。1HNMR(400MHz,CDCl3)δ:9.28(d,J＝5.2Hz,1H),9.14(s,1H),8.22(d,J＝2.0Hz,1H),8.19(s,1H),7.82(s,1H),6.38(s,1H),6.25(d,J＝2.8Hz,1H),5.31-5.23(m,1H),5.15(d,J＝14.4Hz,1H),4.68(d,J＝14.4Hz,1H),4.32-4.25(m,1H),4.05-3.99(m,1H),3.18(d,J＝4.8Hz,3H),2.69-2.61(m,1H),2.15-2.08(m,1H),1.89-1.82(m,2H),1.75-1.71(m,2H),1.67(d,J＝6.8Hz,3H),1.62(d,J＝6.8Hz,3H)，LCMS m/z＝446.1[M+H]+。Compound 5-8 (7 mg, 15.10 μmol) was dissolved in dichloromethane (0.5 mL), HATU (5.74 mg, 15.10 μmol) and TEA (4.58 mg, 45.30 μmol, 6.31 μL) were added and stirred at 20°C for 16 hr. Water (1 mL) was added to the reaction solution and allowed to stand for liquid separation. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative thin layer chromatography on silica gel plate (dichloromethane: methanol = 10:1) to obtain compound 005. 1 HNMR (400MHz, CDCl 3 ) δ: 9.28 (d, J = 5.2 Hz, 1H), 9.14 (s, 1H), 8.22 (d, J = 2.0 Hz, 1H), 8.19 (s, 1H), 7.82 ( s,1H),6.38(s,1H),6.25(d,J＝2.8Hz,1H),5.31-5.23(m,1H),5.15(d,J＝14.4Hz,1H),4.68(d,J ＝14.4Hz,1H),4.32-4.25(m,1H),4.05-3.99(m,1H),3.18(d,J＝4.8Hz,3H),2.69-2.61(m,1H),2.15-2.08( m,1H),1.89-1.82(m,2H),1.75-1.71(m,2H),1.67(d,J＝6.8Hz,3H),1.62(d,J＝6.8Hz,3H),LCMS m/ z=446.1[M+H] + .
实施例6
Example 6
步骤1：化合物6-1的合成Step 1: Synthesis of compound 6-1
将化合物1-6(2g,5.77mmol)溶于DMF(20mL)中，加入EDCI(1.33g,6.92mmol)，HOBt(935.20mg,6.92mmol)，化合物A-2(2.46g,6.92mmol)，TEA(1.75g,17.30mmol,2.41mL)在20℃下搅拌1hr。向反应液中加入水(20mL)和乙酸乙酯(20mL)萃取一次，有机相用饱和食盐水(20mL)清洗一次，用无水硫酸钠干燥，过滤，滤液减压浓缩得粗品。粗品经硅胶柱层析分离纯化(乙酸乙酯/石油醚＝0～50％)，得到化合物6-1。LCMS m/z＝684.2[M+H]+。Dissolve compound 1-6 (2g, 5.77mmol) in DMF (20mL), add EDCI (1.33g, 6.92mmol), HOBt (935.20mg, 6.92mmol), compound A-2 (2.46g, 6.92mmol), TEA (1.75g, 17.30mmol, 2.41mL) was stirred at 20°C for 1 hr. Water (20 mL) and ethyl acetate (20 mL) were added to the reaction solution for extraction once. The organic phase was washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (ethyl acetate/petroleum ether = 0-50%) to obtain compound 6-1. LCMS m/z=684.2[M+H] + .
步骤2：化合物6-2的合成Step 2: Synthesis of compound 6-2
将化合物A-1(503.41mg,2.05mmol)，化合物6-1(1.4g,2.05mmol)溶于四氢呋喃(20mL)中，0℃加入钠氢(163.66mg,4.09mmol,60％含量)在20℃下搅拌17hr。向反应液中滴加饱和氯化铵水溶液(10mL)后，加入水(10mL)和乙酸乙酯(10mL)萃取一次，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩。粗品经硅胶柱层析分离纯化(乙酸乙酯/石油醚＝0～50％)，得到化合物6-2。LCMS m/z＝849.4[M+H]+。 Compound A-1 (503.41 mg, 2.05 mmol) and compound 6-1 (1.4 g, 2.05 mmol) were dissolved in tetrahydrofuran (20 mL), and sodium hydrogen (163.66 mg, 4.09 mmol, 60% content) was added at 0°C at 20 Stir for 17 hours at ℃. After adding saturated ammonium chloride aqueous solution (10 mL) dropwise to the reaction solution, water (10 mL) and ethyl acetate (10 mL) were added for extraction once. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (ethyl acetate/petroleum ether = 0-50%) to obtain compound 6-2. LCMS m/z=849.4[M+H] + .
步骤3：化合物6-3的合成Step 3: Synthesis of compound 6-3
将化合物6-2(1g,1.18mmol)溶于乙醇(20mL)和水(2mL)中，加入铁粉(657.43mg,11.77mmol)，氯化铵(629.72mg,11.77mmol)在85℃下搅拌0.5hr。将反应液过滤，滤液浓缩后加入乙酸乙酯(10mL)和水(10mL)萃取一次，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得粗品化合物6-3。LCMS m/z＝819.4[M+H]+。Dissolve compound 6-2 (1g, 1.18mmol) in ethanol (20mL) and water (2mL), add iron powder (657.43mg, 11.77mmol), and ammonium chloride (629.72mg, 11.77mmol) and stir at 85°C. 0.5hr. The reaction solution was filtered, and after the filtrate was concentrated, ethyl acetate (10 mL) and water (10 mL) were added for extraction once. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude compound 6-3. LCMS m/z=819.4[M+H] + .
步骤4：化合物6-4的合成Step 4: Synthesis of compound 6-4
将化合物6-3(1g,1.22mmol)，碳酸铯(795.20mg,2.44mmol)，1,1’-联萘-2,2’-双二苯膦(75.99mg,122.03μmol)溶于二氧六环(20mL)中，氮气置换三次后加入Pd2(dba)3(111.75mg,122.03μmol)在110℃下搅拌2hr。向反应液中加入水(20mL)和乙酸乙酯(20mL)萃取一次，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得粗品。粗品经硅胶柱层析分离纯化(乙酸乙酯/石油醚＝0～50％)得到化合物6-4。LCMS m/z＝783.4[M+H]+。Compound 6-3 (1g, 1.22mmol), cesium carbonate (795.20mg, 2.44mmol), 1,1'-binaphthyl-2,2'-bisdiphenylphosphine (75.99mg, 122.03μmol) were dissolved in dioxygen Six rings (20 mL) were replaced with nitrogen three times, then Pd 2 (dba) 3 (111.75 mg, 122.03 μmol) was added, and the mixture was stirred at 110°C for 2 hr. Water (20 mL) and ethyl acetate (20 mL) were added to the reaction solution for extraction once. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (ethyl acetate/petroleum ether = 0-50%) to obtain compound 6-4. LCMS m/z=783.4[M+H] + .
步骤5：化合物6-5的合成Step 5: Synthesis of Compound 6-5
将化合物6-4(0.36g,459.77μmol)溶于四氢呋喃(3.6mL)中，加入四丁基氟化铵(1M,919.54μL)在20℃下搅拌15hr。将反应液浓缩。得到的粗品经制备薄层色谱硅胶板纯化(二氯甲烷：甲醇＝10:1)，得到化合物6-5。LCMS m/z＝545.3[M+H]+。Compound 6-4 (0.36g, 459.77μmol) was dissolved in tetrahydrofuran (3.6mL), tetrabutylammonium fluoride (1M, 919.54μL) was added and stirred at 20°C for 15hr. The reaction solution was concentrated. The obtained crude product was purified by preparative thin layer chromatography on silica gel plate (dichloromethane: methanol = 10:1) to obtain compound 6-5. LCMS m/z=545.3[M+H] + .
步骤6：化合物006的合成Step 6: Synthesis of Compound 006
将化合物6-5(155mg,284.61μmol)溶于二氯甲烷(15.5mL)中，加入三氟乙酸(4.76g,41.73mmol,3.10mL)在20℃下搅拌10min。向反应液中加入饱和碳酸钾水溶液(15mL)调至pH＝8后加入水(5mL)和二氯甲烷(5mL)萃取一次，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得粗品。粗品经制备薄层色谱硅胶板分离纯化(二氯甲烷：甲醇＝10:1)，得到化合物006。LCMS m/z＝425.2[M+H]+。Compound 6-5 (155 mg, 284.61 μmol) was dissolved in dichloromethane (15.5 mL), trifluoroacetic acid (4.76 g, 41.73 mmol, 3.10 mL) was added and stirred at 20°C for 10 min. Add saturated potassium carbonate aqueous solution (15 mL) to the reaction solution to adjust pH=8, add water (5 mL) and dichloromethane (5 mL) for extraction once, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain crude product. . The crude product was separated and purified by preparative thin layer chromatography on silica gel plate (dichloromethane: methanol = 10:1) to obtain compound 006. LCMS m/z=425.2[M+H] + .
步骤7：化合物006A、006B、006C和006D的合成Step 7: Synthesis of Compounds 006A, 006B, 006C and 006D
化合物006经过手性HPLC进行拆分(柱子：DAICEL CHIRALPAK AD-H(250mm*30mm,5μm)；流动相：A(正庚烷)和B(乙醇)；梯度：B％＝50％-50％，得到化合物006A，006B，006C和006D。Compound 006 was resolved by chiral HPLC (column: DAICEL CHIRALPAK AD-H (250mm*30mm, 5μm); mobile phase: A (n-heptane) and B (ethanol); gradient: B%=50%-50% , obtaining compounds 006A, 006B, 006C and 006D.
006A：1HNMR(400MHz,CDCl3)δ:8.74(d,J＝2.4Hz,1H),8.52(s,1H),8.29(s,1H),7.13(s,1H),6.88-6.83(m,2H),6.26-6.24(m,1H),5.37(s,1H),4.89(d,J＝14.0Hz,1H),4.36(d,J＝14.0Hz,1H),4.31-4.28(m,2H),3.92(s,3H),3.82-3.75(m,1H),3.09(d,J＝5.2Hz,3H),2.71-2.66(m,1H),2.59-2.52(m,1H),1.71-1.64(m,2H),1.62-1.56(m,1H)。LCMS m/z＝425.2[M+H]+。手性HPLC(柱子：Chiralpak AD-3,150×4.6mm,I.D.,3um；流动相：A(正庚烷)和B(乙醇，含0.1％异丙胺)；梯度：B％＝50～50％，18min；流速:1mL/min)；Rt＝5.157min，手性异构体过量100％。006A: 1 HNMR (400MHz, CDCl 3 ) δ: 8.74 (d, J = 2.4Hz, 1H), 8.52 (s, 1H), 8.29 (s, 1H), 7.13 (s, 1H), 6.88-6.83 (m ,2H),6.26-6.24(m,1H),5.37(s,1H),4.89(d,J＝14.0Hz,1H),4.36(d,J＝14.0Hz,1H),4.31-4.28(m, 2H),3.92(s,3H),3.82-3.75(m,1H),3.09(d,J＝5.2Hz,3H),2.71-2.66(m,1H),2.59-2.52(m,1H),1.71 -1.64(m,2H),1.62-1.56(m,1H). LCMS m/z=425.2[M+H] + . Chiral HPLC (column: Chiralpak AD-3, 150×4.6mm, ID, 3um; mobile phase: A (n-heptane) and B (ethanol, containing 0.1% isopropylamine); gradient: B%=50~50%, 18min ;Flow rate: 1mL/min); Rt=5.157min, chiral isomer excess 100%.
006B：1HNMR(400MHz,CDCl3)δ：8.79(s,1H),8.55-8.47(m,1H),8.27(s,1H),7.14-7.12(m,1H),6.90-6.84(m,2H),6.28-6.26(m,1H),5.37(s,1H),4.88(d,J＝14.0Hz,1H),4.48-4.45(m,1H),4.38(d,J＝14.0Hz,1H),4.12-4.06(m,1H),3.96-3.88(m,4H),3.11-3.07(m,1H),3.01(s,3H),2.17-2.10(m,1H),1.89-1.81(m,1H),1.47-1.43(m,2H)。LCMS m/z＝425.2[M+H]+。手性HPLC(柱子：Chiralpak AD-3,150×4.6mm,I.D.,3um；流动相：A(正庚烷)和B(乙醇，含0.1％异丙胺)；梯度：B％＝50～50％，18min；流速:1mL/min)；Rt＝6.897min，手性异构体过量93.32％。006B: 1 HNMR (400MHz, CDCl 3 ) δ: 8.79 (s, 1H), 8.55-8.47 (m, 1H), 8.27 (s, 1H), 7.14-7.12 (m, 1H), 6.90-6.84 (m, 2H),6.28-6.26(m,1H),5.37(s,1H),4.88(d,J＝14.0Hz,1H),4.48-4.45(m,1H),4.38(d,J＝14.0Hz,1H ),4.12-4.06(m,1H),3.96-3.88(m,4H),3.11-3.07(m,1H),3.01(s,3H),2.17-2.10(m,1H),1.89-1.81(m ,1H),1.47-1.43(m,2H). LCMS m/z=425.2[M+H] + . Chiral HPLC (column: Chiralpak AD-3, 150×4.6mm, ID, 3um; mobile phase: A (n-heptane) and B (ethanol, containing 0.1% isopropylamine); gradient: B%=50~50%, 18min ; Flow rate: 1mL/min); Rt=6.897min, chiral isomer excess 93.32%.
006C：1HNMR(400MHz,CDCl3)δ:8.72(s,1H),8.47-8.40(m,1H),8.21-8.20(m,1H),7.07-7.04(m,1H),6.83-6.77(m,2H),6.22-6.11(m,1H),5.37(s,1H),4.80(d,J＝14.0Hz,1H),4.39-4.37(m,1H),4.30(d,J＝14.0Hz,1H),4.06-3.98(m,1H),3.88(s,3H),3.68-3.63(m,1H),3.05-2.88(m,4H),2.10-2.03(m,1H),1.81 -1.68(m,3H)。LCMS m/z＝425.2[M+H]+。手性HPLC(柱子：Chiralpak AD-3,150×4.6mm,I.D.,3um；流动相：A(正庚烷)和B(乙醇，含0.1％异丙胺)；梯度：B％＝50～50％，18min；流速:1mL/min)；Rt＝8.638min，手性异构体过量85.98％。006C: 1 HNMR (400MHz, CDCl 3 ) δ: 8.72 (s, 1H), 8.47-8.40 (m, 1H), 8.21-8.20 (m, 1H), 7.07-7.04 (m, 1H), 6.83-6.77 ( m,2H),6.22-6.11(m,1H),5.37(s,1H),4.80(d,J＝14.0Hz,1H),4.39-4.37(m,1H),4.30(d,J＝14.0Hz ,1H),4.06-3.98(m,1H),3.88(s,3H),3.68-3.63(m,1H),3.05-2.88(m,4H),2.10-2.03(m,1H),1.81 -1.68(m,3H). LCMS m/z=425.2[M+H] + . Chiral HPLC (column: Chiralpak AD-3, 150×4.6mm, ID, 3um; mobile phase: A (n-heptane) and B (ethanol, containing 0.1% isopropylamine); gradient: B%=50~50%, 18min ; Flow rate: 1mL/min); Rt=8.638min, chiral isomer excess 85.98%.
006D：1HNMR(400MHz,CDCl3)δ：8.75(d,J＝2.4Hz,1H),8.52(s,1H),8.27(s,1H),7.12(s,1H),6.88-6.83(m,2H),6.25-6.23(m,1H),5.37(s,1H),4.89(d,J＝14.0Hz,1H),4.36(d,J＝14.0Hz,1H),4.31-4.24(m,2H),3.92(s,3H),3.82-3.77(m,1H),3.09(d,J＝5.2Hz,3H),2.69-2.64(m,1H),2.59-2.52(m,1H),1.71-1.64(m,2H),1.61-1.55(m,1H)。LCMS m/z＝425.2[M+H]+。手性HPLC(柱子：Chiralpak AD-3,150×4.6mm,I.D.,3um；流动相：A(正庚烷)和B(乙醇，含0.1％异丙胺)；梯度：B％＝50～50％，18min；流速:1mL/min)；Rt＝12.299min，手性异构体过量87.84％。006D: 1 HNMR (400MHz, CDCl 3 ) δ: 8.75 (d, J = 2.4Hz, 1H), 8.52 (s, 1H), 8.27 (s, 1H), 7.12 (s, 1H), 6.88-6.83 (m ,2H),6.25-6.23(m,1H),5.37(s,1H),4.89(d,J＝14.0Hz,1H),4.36(d,J＝14.0Hz,1H),4.31-4.24(m, 2H),3.92(s,3H),3.82-3.77(m,1H),3.09(d,J＝5.2Hz,3H),2.69-2.64(m,1H),2.59-2.52(m,1H),1.71 -1.64(m,2H),1.61-1.55(m,1H). LCMS m/z=425.2[M+H] + . Chiral HPLC (column: Chiralpak AD-3, 150×4.6mm, ID, 3um; mobile phase: A (n-heptane) and B (ethanol, containing 0.1% isopropylamine); gradient: B%=50~50%, 18min ; Flow rate: 1mL/min); Rt=12.299min, chiral isomer excess 87.84%.
实施例7
Example 7
步骤1：化合物7-1的合成Step 1: Synthesis of compound 7-1
将化合物6-5(0.2g,367.24μmol)溶于二氯甲烷(20mL)中，在0℃下加入二乙胺基三氟化硫(88.79mg,550.86μmol,72.78μL)搅拌5min。向反应液中加入饱和碳酸氢钠水溶液(5mL)调至pH＝7后加入水(10mL)静置分液，有机相用无水硫酸钠干燥,过滤，滤液减压除去溶剂得粗品。粗品经硅胶柱层析分离纯化(乙酸乙酯/石油醚＝0～100％)，得到化合物7-1。LCMS m/z＝547.3[M+H]+。Compound 6-5 (0.2g, 367.24 μmol) was dissolved in dichloromethane (20 mL), and diethylamine sulfur trifluoride (88.79 mg, 550.86 μmol, 72.78 μL) was added at 0°C and stirred for 5 min. Add saturated sodium bicarbonate aqueous solution (5 mL) to the reaction solution to adjust pH=7, then add water (10 mL) and let stand for liquid separation. The organic phase is dried over anhydrous sodium sulfate and filtered. The solvent is removed from the filtrate under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (ethyl acetate/petroleum ether = 0-100%) to obtain compound 7-1. LCMS m/z=547.3[M+H] + .
步骤2：化合物007的合成Step 2: Synthesis of Compound 007
将化合物7-1(0.13g,237.84μmol)溶于二氯甲烷(13mL)中，加入三氟乙酸(4.30g,37.69mmol,2.80mL)在20℃下搅拌10min。向反应液中加入饱和碳酸钠水溶液调至pH＝8后，加入二氯甲烷(10mL)萃取一次，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得粗品。粗品经制备薄层色谱硅胶板分离纯化(二氯甲烷：甲醇＝10:1，Rf＝0.35)得到化合物007。LCMS m/z＝427.4[M+H]+。Compound 7-1 (0.13g, 237.84μmol) was dissolved in dichloromethane (13mL), trifluoroacetic acid (4.30g, 37.69mmol, 2.80mL) was added and stirred at 20°C for 10min. Add saturated aqueous sodium carbonate solution to the reaction solution to adjust pH to 8, add methylene chloride (10 mL) for extraction once, dry the organic phase over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain a crude product. The crude product was separated and purified by preparative thin layer chromatography on silica gel plate (dichloromethane: methanol = 10:1, Rf = 0.35) to obtain compound 007. LCMS m/z=427.4[M+H] + .
步骤3：化合物007A、007B、007C和007D的合成Step 3: Synthesis of Compounds 007A, 007B, 007C and 007D
化合物007经过SFC进行拆分(柱子：ChiralPak IH,250*30mm,10μm；流动相：A(超临界CO2)和B(MeOH,含0.1％氨水)；梯度：B％＝50％-50％)，得到007A&007B混合物，007C和007D。其中007A&007B混合物继续经过SFC进行拆分(柱子：ChiralPak IH,250*30mm,10μm；流动相：A(超临界CO2)和B(异丙醇,含0.1％氨水)；梯度：B％＝45％-45％)，得到007A和007B。Compound 007 was resolved by SFC (column: ChiralPak IH, 250*30mm, 10μm; mobile phase: A (supercritical CO 2 ) and B (MeOH, containing 0.1% ammonia); gradient: B%=50%-50% ), resulting in 007A&007B mixture, 007C and 007D. The 007A&007B mixture continues to be separated by SFC (column: ChiralPak IH, 250*30mm, 10μm; mobile phase: A (supercritical CO 2 ) and B (isopropanol, containing 0.1% ammonia); gradient: B%=45 %-45%), obtain 007A and 007B.
007A：1HNMR(400MHz,CD3OD)δ：9.05-9.04(m,1H),8.28(s,1H),8.09(s,1H),7.00-6.98(m,1H),6.93- 6.91(m,1H),5.30-5.00(m,1H),4.82(d,J＝13.6Hz,1H),4.40(d,J＝13.6Hz,1H),3.97-3.90(m,4H),3.83-3.75(m,1H),3.06-2.96(m,1H),2.94(s,3H),2.49-2.39(m,1H),1.83-1.52(m,2H)。LCMS m/z＝427.0[M+H]+。SFC(柱子：Chiralpak IH-3,100×4.6mm I.D.,3μm；流动相：A(超临界CO2)和B(i-PrOH，含0.1％异丙胺)；梯度：B％＝5～40％，3.5min；流速:4mL/min；波长:220nm；压力:100bar)，Rt＝1.521min，手性异构体过量100％。007A: 1 HNMR (400MHz, CD 3 OD) δ: 9.05-9.04(m,1H),8.28(s,1H),8.09(s,1H),7.00-6.98(m,1H),6.93- 6.91(m,1H),5.30-5.00(m,1H),4.82(d,J＝13.6Hz,1H),4.40(d,J＝13.6Hz,1H),3.97-3.90(m,4H),3.83 -3.75(m,1H),3.06-2.96(m,1H),2.94(s,3H),2.49-2.39(m,1H),1.83-1.52(m,2H). LCMS m/z=427.0[M+H] + . SFC (column: Chiralpak IH-3, 100×4.6mm ID, 3μm; mobile phase: A (supercritical CO 2 ) and B (i-PrOH, containing 0.1% isopropylamine); gradient: B%=5~40%, 3.5 min; flow rate: 4mL/min; wavelength: 220nm; pressure: 100bar), Rt=1.521min, chiral isomer excess 100%.
007B：1HNMR(400MHz,CDCl3)δ：8.72(d,J＝1.2Hz,1H),8.53(s,1H),8.30(s,1H),7.11(s,1H),6.89-6.83(m,2H),6.22-6.21(m,1H),5.12-4.98(m,1H),4.92(d,J＝14.0Hz,1H),4.35(d,J＝14.0Hz,1H),4.31-4.23(m,1H),3.93(s,3H),3.83-3.79(m,1H),3.10(d,J＝5.2Hz,3H),3.06-2.97(m,1H),2.66-2.53(m,1H),2.02-1.88(m,1H),1.57-1.41(m,1H)。LCMS m/z＝427.0[M+H]+。SFC(柱子：Chiralpak IH-3,100×4.6mm I.D.,3μm；流动相：A(超临界CO2)和B(i-PrOH，含0.1％异丙胺)；梯度：B％＝5～40％，3.5min；流速:4mL/min；波长:220nm；压力:100bar)，Rt＝2.029min，手性异构体过量95.88％。007B: 1 HNMR (400MHz, CDCl 3 ) δ: 8.72 (d, J = 1.2 Hz, 1H), 8.53 (s, 1H), 8.30 (s, 1H), 7.11 (s, 1H), 6.89-6.83 (m ,2H),6.22-6.21(m,1H),5.12-4.98(m,1H),4.92(d,J＝14.0Hz,1H),4.35(d,J＝14.0Hz,1H),4.31-4.23( m,1H),3.93(s,3H),3.83-3.79(m,1H),3.10(d,J＝5.2Hz,3H),3.06-2.97(m,1H),2.66-2.53(m,1H) ,2.02-1.88(m,1H),1.57-1.41(m,1H). LCMS m/z=427.0[M+H] + . SFC (column: Chiralpak IH-3, 100×4.6mm ID, 3μm; mobile phase: A (supercritical CO 2 ) and B (i-PrOH, containing 0.1% isopropylamine); gradient: B%=5~40%, 3.5 min; flow rate: 4mL/min; wavelength: 220nm; pressure: 100bar), Rt=2.029min, chiral isomer excess 95.88%.
007C：1HNMR(400MHz,CD3OD)δ：8.97(d,J＝3.2Hz,1H),8.28(d,J＝1.6Hz,1H),8.10(s,1H),6.95-6.93(m,1H),6.88-6.86(m,1H),5.12-4.92(m,1H),4.79(d,J＝13.6Hz,1H),4.34(d,J＝13.6Hz,1H),4.12-4.07(m,1H),3.91(s,3H),3.79-3.73(m,1H),3.00(s,3H),2.83-2.57(m,2H),1.88-1.72(m,1H),1.39-1.33(m,1H)。LCMS m/z＝427.0[M+H]+。SFC(柱子：Chiralpak IH-3,50×4.6mm I.D.,3μm；流动相：A(超临界CO2)和B(MeOH，含0.1％异丙胺)；梯度：B％＝5～50％，3min；流速:3.4mL/min；波长:220nm；压力:100bar)，Rt＝1.665min，手性异构体过量99.68％。007C: 1 HNMR (400MHz, CD 3 OD) δ: 8.97 (d, J = 3.2 Hz, 1H), 8.28 (d, J = 1.6 Hz, 1H), 8.10 (s, 1H), 6.95-6.93 (m, 1H),6.88-6.86(m,1H),5.12-4.92(m,1H),4.79(d,J＝13.6Hz,1H),4.34(d,J＝13.6Hz,1H),4.12-4.07(m ,1H),3.91(s,3H),3.79-3.73(m,1H),3.00(s,3H),2.83-2.57(m,2H),1.88-1.72(m,1H),1.39-1.33(m ,1H). LCMS m/z=427.0[M+H] + . SFC (column: Chiralpak IH-3, 50×4.6mm ID, 3μm; mobile phase: A (supercritical CO 2 ) and B (MeOH, containing 0.1% isopropylamine); gradient: B%=5～50%, 3min ; Flow rate: 3.4mL/min; Wavelength: 220nm; Pressure: 100bar), Rt = 1.665min, chiral isomer excess 99.68%.
007D：1HNMR(400MHz,CD3OD)δ：8.99-8.94(m,1H),8.25(s,1H),8.06(d,J＝4.4Hz,1H),6.98-6.96(m,1H),6.91-6.89(m,1H),5.20-5.00(m,1H),4.80(d,J＝13.6Hz,1H),4.38(d,J＝13.6Hz,1H),3.97-3.91(m,4H),3.82-3.75(m,1H),3.05-2.91(m,1H),2.87(d,J＝10.8Hz,3H),2.48-2.38(m,1H),1.80-1.58(m,2H)。LCMS m/z＝427.0[M+H]+。SFC(柱子：Chiralpak IH-3,50×4.6mm I.D.,3μm；流动相：A(CO2)和B(MeOH，含0.1％异丙胺)；梯度：B％＝5～50％，3min；流速:3.4mL/min；波长:220nm；压力:100bar)，Rt＝2.006min，手性异构体过量86.80％。007D: 1 HNMR (400MHz, CD 3 OD) δ: 8.99-8.94 (m, 1H), 8.25 (s, 1H), 8.06 (d, J = 4.4Hz, 1H), 6.98-6.96 (m, 1H), 6.91-6.89(m,1H),5.20-5.00(m,1H),4.80(d,J＝13.6Hz,1H),4.38(d,J＝13.6Hz,1H),3.97-3.91(m,4H) ,3.82-3.75(m,1H),3.05-2.91(m,1H),2.87(d,J=10.8Hz,3H),2.48-2.38(m,1H),1.80-1.58(m,2H). LCMS m/z=427.0[M+H] + . SFC (column: Chiralpak IH-3, 50×4.6mm ID, 3μm; mobile phase: A (CO 2 ) and B (MeOH, containing 0.1% isopropylamine); gradient: B%=5～50%, 3min; flow rate :3.4mL/min; wavelength: 220nm; pressure: 100bar), Rt=2.006min, excess chiral isomer 86.80%.
生物测试部分Biological testing section
实验例1：化合物对Ba/F3-FL-TYK2-E957D细胞增殖的抑制活性Experimental Example 1: Inhibitory activity of compounds on Ba/F3-FL-TYK2-E957D cell proliferation
三磷酸腺苷(Adenosine Tri-Phosphate,ATP)是自然界中各种生命活动中共用的能量载体，是能量储存和转移的最小单位。CellTiter-GloTM活细胞检测试剂盒采用萤光素酶作检测物，发光过程中萤光素酶需要ATP的参与。向细胞培养基中加入CellTiter-GloTM试剂，测量发光值，光信号和体系中ATP量成正比，而ATP又和活细胞数正相关。因此通过使用CellTiter-Glo试剂盒检测ATP含量，可以检测出细胞的增殖情况。本测试中，细胞系为Ba/F3-FL-TYK2-E957D，它能够稳定表达外源导入的人TYK2-E957D基因，TYK2-E957D基因序列包含有JH1和JH2结构域。Adenosine Tri-Phosphate (ATP) is a common energy carrier in various life activities in nature and is the smallest unit of energy storage and transfer. CellTiter-Glo TM live cell detection kit uses luciferase as the detection substance, and luciferase requires the participation of ATP during the luminescence process. Add CellTiter-Glo TM reagent to the cell culture medium and measure the luminescence value. The light signal is directly proportional to the amount of ATP in the system, and ATP is positively correlated with the number of viable cells. Therefore, by using the CellTiter-Glo kit to detect ATP content, cell proliferation can be detected. In this test, the cell line is Ba/F3-FL-TYK2-E957D, which can stably express the exogenously introduced human TYK2-E957D gene. The TYK2-E957D gene sequence contains JH1 and JH2 domains.
IC50测定过程：IC 50 determination process:
1)细胞培养1) Cell culture
将细胞系在培养条件37℃，5％CO2的培养箱中进行培养。定期传代，取处于对数生长期的细胞用于铺板。The cell lines were cultured in an incubator with culture conditions of 37°C and 5% CO2 . Passage regularly and use cells in the logarithmic growth phase for plating.
2)化合物存储板制备2) Compound storage plate preparation
a)用DMSO将待测化合物配置成10mM溶液，再用DMSO将待测化合物稀释至0.3或1mM。 a) Use DMSO to prepare the compound to be tested into a 10mM solution, and then use DMSO to dilute the compound to be tested to 0.3 or 1mM.
b)制备1000×化合物存储板(管)：用DMSO从最高浓度3倍梯度稀释至最低浓度，9个浓度(Ba/F3-FL-TYK2-E957D细胞系最高浓度为1μM或300nM)。b) Prepare 1000× compound storage plate (tube): Use DMSO to dilute 3-fold gradient from the highest concentration to the lowest concentration, 9 concentrations (the highest concentration for Ba/F3-FL-TYK2-E957D cell line is 1 μM or 300 nM).
c)20×化合物工作液的配制:在平底的96孔透明药板中加入49μL细胞培养液，从1000×化合物存储板中吸取1μL化合物加入96孔透明药板的细胞培养液中。在溶媒对照中加入1μL DMSO。加入化合物或DMSO后用排枪吹打混匀。c) Preparation of 20× compound working solution: Add 49 μL of cell culture medium to a flat-bottomed 96-well transparent medicine plate, and add 1 μL of compound from the 1000× compound storage plate to the cell culture medium of the 96-well transparent medicine plate. Add 1 μL DMSO to the vehicle control. Add the compound or DMSO and mix with pipette.
3)细胞铺板与给药3) Cell plating and drug administration
a)用台盼兰进行细胞染色并计数活细胞，要求细胞活率90％以上。a) Use trypan blue to stain cells and count viable cells. The cell viability rate is required to be above 90%.
b)在化合物检测细胞板中每孔加入95μL细胞悬液(2000cells/well)，在Min对照孔中加入不含细胞(含0.1％DMSO)的培养液。b) Add 95 μL of cell suspension (2000 cells/well) to each well of the compound detection cell plate, and add culture medium without cells (containing 0.1% DMSO) to the Min control well.
c)化合物检测细胞板加药：取5μL的20×化合物工作液按表1所示加入到细胞培养板中。在Max对照中加入5μL DMSO-细胞培养液混合液。DMSO终浓度为0.1％。c) Compound detection cell plate addition: Take 5 μL of 20× compound working solution and add it to the cell culture plate as shown in Table 1. Add 5 μL of DMSO-cell culture medium mixture to the Max control. The final DMSO concentration is 0.1%.
d)将培养板在37℃，5％CO2培养箱中培养72小时。d) Incubate the culture plate in a 37°C, 5% CO2 incubator for 72 hours.
4)CellTiter-Glo发光法细胞活性检测4)CellTiter-Glo luminescence method cell viability detection
以下步骤按照Promega CellTiter-Glo发光法细胞活性检测试剂盒(Promega-G7573)的说明书来进行。The following steps are carried out according to the instructions of Promega CellTiter-Glo Luminescence Cell Viability Detection Kit (Promega-G7573).
a)将CellTiter-Glo缓冲液融化并放置至室温。a) Melt CellTiter-Glo buffer and bring to room temperature.
b)将CellTiter-Glo底物放置至室温。b) Let CellTiter-Glo substrate come to room temperature.
c)在一瓶CellTiter-Glo底物中加入CellTiter-Glo缓冲液以溶解底物，从而配制CellTiter-Glo工作液。c) Add CellTiter-Glo buffer to a bottle of CellTiter-Glo substrate to dissolve the substrate to prepare CellTiter-Glo working solution.
d)缓慢涡旋震荡使充分溶解。d) Vortex slowly to fully dissolve.
e)取出细胞培养板放置10分钟使其平衡至室温。e) Take out the cell culture plate and let it equilibrate to room temperature for 10 minutes.
f)在每孔中加入50μL(等于每孔中细胞培养液一半体积)的CellTiter-Glo工作液。f) Add 50 μL (equal to half the volume of cell culture medium in each well) of CellTiter-Glo working solution into each well.
g)将培养板在轨道摇床上振摇2分钟以诱导细胞裂解。g) Shake the plate on an orbital shaker for 2 minutes to induce cell lysis.
h)培养板在室温放置10分钟以稳定发光信号。h) Place the culture plate at room temperature for 10 minutes to stabilize the luminescence signal.
i)在SpectraMax Paradigm读板器上检测发光信号。i) Detect luminescence signal on SpectraMax Paradigm plate reader.
5)数据处理5)Data processing
SpectraMax Paradigm读数得出对应的每孔荧光值RLU。SpectraMax Paradigm readings yield the corresponding fluorescence value RLU for each well.
细胞增殖抑制率(Inhibition Rate)数据采用下列公式来处理：Cell proliferation inhibition rate (Inhibition Rate) data is processed using the following formula:
Inhibition Rate(Inh％)＝100-(RLUDrug-RLUMin)/(RLUMax-RLUMin)*100％。在EXCEL中计算不同浓度化合物对应的抑制率，然后用GraphPad Prism软件分析数据，利用非线性S曲线回归来拟合数据得出剂量-效应曲线，并由此计算IC50值，数据见表1。Inhibition Rate (Inh%)=100-(RLU Drug -RLU Min )/(RLU Max -RLU Min )*100%. Calculate the inhibition rates corresponding to different concentrations of compounds in EXCEL, then use GraphPad Prism software to analyze the data, and use nonlinear S-curve regression to fit the data to obtain a dose-effect curve, from which the IC 50 value is calculated. The data are shown in Table 1.
表1细胞半数抑制浓度IC50(nM)

Table 1 Cell half inhibitory concentration IC 50 (nM)

结果表明：本发明化合物对转染人TYK2-E957D基因的Ba/F3细胞的增殖具有较强的抑制活性，本发明化合物是活性较高的TYK2抑制剂。The results show that the compound of the present invention has strong inhibitory activity on the proliferation of Ba/F3 cells transfected with human TYK2-E957D gene, and the compound of the present invention is a highly active TYK2 inhibitor.
实验例2：化合物在小鼠体内的药代动力学测试Experimental Example 2: Pharmacokinetic test of compounds in mice
实验目的：Purpose:
以7-9周雄性CD-1小鼠为受试动物，应用LC/MS/MS法测定单次静脉注射(IV)及灌胃(PO)给予化合物后，不同时刻血浆中化合物的药物浓度，研究本发明的化合物在小鼠体内的药代动力学行为，评价其药动学特征。Using 7-9 week old male CD-1 mice as test animals, the LC/MS/MS method was used to determine the drug concentration of the compound in the plasma at different times after a single intravenous injection (IV) and oral administration (PO) of the compound. Study the pharmacokinetic behavior of the compound of the present invention in mice and evaluate its pharmacokinetic characteristics.
实验操作：Experimental operation:
以标准方案测试化合物静脉注射及口服给药后的啮齿类动物药代特征。受试动物给药前禁食10-14小时，给药4小时后进食。化合物均以相应溶媒配成澄清溶液用于IV(静注)和PO(灌胃)组给药。溶媒为10％DMSO+10％solutol+80％(10％HP-β-CD水溶液)。收集24小时内的全血样品，6000g离心3分钟，分离上清得血浆样品，加入4倍体积含内标的乙腈溶液沉淀蛋白，离心取上清液加入等倍体积的水再离心取上清进样，以LC-MS/MS分析方法定量分析血药浓度，并计算药代参数，如达峰浓度，达峰时间，清除率，半衰期，药时曲线下面积，生物利用度等。The pharmacokinetic profile of the compounds in rodents after intravenous and oral administration was tested using standard protocols. The test animals were fasted for 10-14 hours before administration and fed 4 hours after administration. The compounds were formulated into clear solutions with corresponding solvents for administration in IV (intravenous injection) and PO (gastric administration) groups. The solvent is 10% DMSO+10% solutol+80% (10% HP-β-CD aqueous solution). Collect whole blood samples within 24 hours, centrifuge at 6000g for 3 minutes, separate the supernatant to obtain the plasma sample, add 4 times the volume of acetonitrile solution containing the internal standard to precipitate the protein, centrifuge the supernatant, add an equal volume of water, and centrifuge to obtain the supernatant. Sample, quantitatively analyze the plasma drug concentration using LC-MS/MS analysis method, and calculate pharmacokinetic parameters, such as peak concentration, peak time, clearance rate, half-life, area under the drug-time curve, bioavailability, etc.
药代动力学参数结果见表2：The results of pharmacokinetic parameters are shown in Table 2:
表2小鼠体内药代动力学测试结果
Table 2 In vivo pharmacokinetic test results in mice
结论：本发明化合物在小鼠中展现了优异的药代动力学特性。 Conclusion: The compounds of the present invention exhibit excellent pharmacokinetic properties in mice.

Claims (14)

  1. 式(I)所示化合物、其立体异构体或其药学上可接受的盐，
    The compound represented by formula (I), its stereoisomer or its pharmaceutically acceptable salt,
    其中，in,
    L1选自单键和NH；L 1 is selected from single bond and NH;
    L2选自-NH-C(＝O)-；L 2 is selected from -NH-C(=O)-;
    L3选自-O-、-NH-、-C1-3烷基-O-、-C1-3烷基-NH-和-C1-3烷基-O-C1-3烷基-，所述-C1-3烷基-O-、-C1-3烷基-NH-和-C1-3烷基-O-C1-3烷基-任选被1、2或3个Rc取代；L 3 is selected from -O-, -NH-, -C 1-3 alkyl-O-, -C 1-3 alkyl-NH- and -C 1-3 alkyl-OC 1-3 alkyl-, The -C 1-3 alkyl-O-, -C 1-3 alkyl-NH- and -C 1-3 alkyl-OC 1-3 alkyl- are optionally substituted by 1, 2 or 3 R c replace;
    R1选自-NH-C1-3烷基，R2选自H；R 1 is selected from -NH-C 1-3 alkyl, R 2 is selected from H;
    或者，R1和R2与它们相连的原子共同构成5-6元杂环烯基；Alternatively, R 1 and R 2 and the atoms to which they are connected together constitute a 5-6 membered heterocyclic alkenyl group;
    R3选自H、F、Cl、Br、I、OH、CN、NH2、C1-4烷基、C1-3烷氧基和6元杂芳基，所述C1-4烷基、C1-3烷氧基和6元杂芳基任选被1、2或3个Ra取代；R 3 is selected from H, F, Cl, Br, I, OH, CN, NH 2 , C 1-4 alkyl, C 1-3 alkoxy and 6-membered heteroaryl, the C 1-4 alkyl , C 1-3 alkoxy group and 6-membered heteroaryl group are optionally substituted by 1, 2 or 3 R a ;
    环A不存在；Ring A does not exist;
    或者，环A选自C3-5环烷基、5-6元杂环烷基和5-6元杂芳基，所述C3-5环烷基、5-6元杂环烷基和5-6元杂芳基任选被1、2或3个Rb取代；Alternatively, Ring A is selected from C 3-5 cycloalkyl, 5-6 membered heterocycloalkyl and 5-6 membered heteroaryl, said C 3-5 cycloalkyl, 5-6 membered heterocycloalkyl and The 5-6 membered heteroaryl group is optionally substituted by 1, 2 or 3 R b ;
    环B选自苯基、5-6元杂芳基、5-6元杂环烷基、吡啶并吡咯基、苯并噁唑基、苯并吡咯基、苯并咪唑基、苯并吡唑基和 Ring B is selected from phenyl, 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl, pyridopyrrolyl, benzoxazolyl, benzopyrrolyl, benzimidazolyl, benzopyrazolyl and
    环C选自C5-6环烷基、C5-6环烷烯基、5-6元杂环烷基和5-6元杂环烯基；Ring C is selected from C 5-6 cycloalkyl, C 5-6 cycloalkenyl, 5-6 membered heterocycloalkyl and 5-6 membered heterocycloalkenyl;
    结构单元选自 Structural units Selected from
    各Ra分别独立地选自F、Cl、Br、I、CH3和OCH3；Each R a is independently selected from F, Cl, Br, I, CH 3 and OCH 3 ;
    各Rb分别独立地选自F、Cl、Br、I、OH、C1-3烷基和C1-3烷氧基，所述C1-3烷基和C1-3烷氧基任选被1、2或3个卤素取代；Each R b is independently selected from F, Cl, Br, I, OH, C 1-3 alkyl and C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are optional Choose to be replaced by 1, 2 or 3 halogens;
    或者，2个Rb与它们相连的碳原子共同构成C3-5环烷基；Alternatively, 2 R b and the carbon atoms to which they are connected together constitute a C 3-5 cycloalkyl group;
    各Rc分别独立地选自C1-3烷基和苯基；Each R c is independently selected from C 1-3 alkyl and phenyl;
    条件是：1)环A不存在时，环B选自吡啶并吡咯基； The conditions are: 1) When ring A does not exist, ring B is selected from pyridopyrrolyl;
    或者，2)结构单元选自时，环A不为环丙基或环丁基；Or, 2) structural unit Selected from When, ring A is not cyclopropyl or cyclobutyl;
    所述5-6元杂芳基、6元杂芳基、5-6元杂环烷基和5-6元杂环烯基的“杂”分别独立地表示1、2或3个选自N、O、S、C(＝O)和NH的原子或原子团。The "hetero" of the 5-6-membered heteroaryl, 6-membered heteroaryl, 5-6-membered heterocycloalkyl and 5-6-membered heterocycloalkenyl independently represents 1, 2 or 3 selected from N , O, S, C (=O) and NH atoms or atomic groups.
  2. 根据权利要求1所述化合物、其立体异构体或其药学上可接受的盐，其选自：
    The compound according to claim 1, its stereoisomer or its pharmaceutically acceptable salt, which is selected from:
    L3、R3和环A如权利要求1所定义。L 3 , R 3 and ring A are as defined in claim 1.
  3. 根据权利要求1或2所述化合物、其立体异构体或其药学上可接受的盐，其中，各Rb分别独立地选自F、Cl、Br、I、OH、CH3、CF3和OCH3。The compound according to claim 1 or 2, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein each R b is independently selected from F, Cl, Br, I, OH, CH 3 , CF 3 and OCH 3 .
  4. 根据权利要求1或2所述化合物、其立体异构体或其药学上可接受的盐，其中，L3选自-O-、-NH-、-CH2-O-、-CH2CH2-O-、-CH(CH3)-O-、-CH2-NH-、-CH2CH2-NH-、-CH2-O-CH2-、-CH2-O-CH2CH2-、-CH2-O-CH2C(CH3)2-、-CH2-O-CH2CH(CH3)-、 The compound according to claim 1 or 2, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein L 3 is selected from -O-, -NH-, -CH 2 -O-, -CH 2 CH 2 -O-, -CH(CH 3 )-O-, -CH 2 -NH-, -CH 2 CH 2 -NH-, -CH 2 -O-CH 2 -, -CH 2 -O -CH 2 CH 2 -, -CH 2 -O-CH 2 C(CH 3 ) 2 -, -CH 2 -O-CH 2 CH(CH 3 )-,
  5. 根据权利要求1或2所述化合物、其立体异构体或其药学上可接受的盐，其中，R1选自-NH-CH3，R2选自H。The compound according to claim 1 or 2, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from -NH-CH 3 and R 2 is selected from H.
  6. 根据权利要求1或2所述化合物、其立体异构体或其药学上可接受的盐，其中，R1和R2与它们相连的原子一起使结构单元为 The compound according to claim 1 or 2, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 together with the atoms to which they are connected form a structural unit for
  7. 根据权利要求1或2所述化合物、其立体异构体或其药学上可接受的盐，其中，R3选自H、F、Cl、Br、I、OH、CN、NH2、CH3、CH2CH3、CH(CH3)2、CH2CH2CH2CH3、C(CH3)3、OCH3、OCH2CH3、吡啶基和嘧啶基，所述CH3、CH2CH3、CH(CH3)2、CH2CH2CH2CH3、C(CH3)3、OCH3、OCH2CH3、吡啶基和嘧啶基任选被1、2或3个Ra取代。The compound according to claim 1 or 2, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from H, F, Cl, Br, I, OH, CN, NH 2 , CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 CH 2 CH 2 CH 3 , C(CH 3 ) 3 , OCH 3 , OCH 2 CH 3 , pyridyl and pyrimidinyl, the CH 3 , CH 2 CH 3. CH(CH 3 ) 2 , CH 2 CH 2 CH 2 CH 3 , C(CH 3 ) 3 , OCH 3 , OCH 2 CH 3 , pyridyl and pyrimidinyl are optionally substituted by 1, 2 or 3 R a .
  8. 根据权利要求7所述化合物、其立体异构体或其药学上可接受的盐，其中，R3选自H、F、Cl、Br、 I、OH、CN、NH2、CH3、CH2CH3、CH(CH3)2、OCH3、OCH2CH3、C(CH3)3、 The compound according to claim 7, its stereoisomer or its pharmaceutically acceptable salt, wherein R3 is selected from H, F, Cl, Br, I, OH, CN, NH 2 , CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , OCH 3 , OCH 2 CH 3 , C(CH 3 ) 3 ,
  9. 根据权利要求1或2所述化合物、其立体异构体或其药学上可接受的盐，其中，环A选自环丙基、环丁基、环戊基、吡咯烷基、四氢呋喃基、吡咯基、咪唑基、吡唑基和三氮唑基，所述环丙基、环丁基、环戊基、吡咯烷基、四氢呋喃基、吡咯基、咪唑基、吡唑基和三氮唑基任选被1、2或3个Rb取代。The compound according to claim 1 or 2, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein ring A is selected from cyclopropyl, cyclobutyl, cyclopentyl, pyrrolidinyl, tetrahydrofuryl, pyrrole base, imidazolyl, pyrazolyl and triazolyl, the cyclopropyl, cyclobutyl, cyclopentyl, pyrrolidinyl, tetrahydrofuranyl, pyrrolyl, imidazolyl, pyrazolyl and triazolyl are any Choose to be replaced by 1, 2 or 3 R b .
  10. 根据权利要求9所述化合物、其立体异构体或其药学上可接受的盐，其中，环A选自 The compound according to claim 9, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein ring A is selected from
  11. 根据权利要求1或2所述化合物、其立体异构体或其药学上可接受的盐，其中，环C选自二氢噁唑基、环戊二烯基、 The compound according to claim 1 or 2, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein ring C is selected from dihydroxazolyl, cyclopentadienyl,
  12. 根据权利要求1或2所述化合物、其立体异构体或其药学上可接受的盐，其中，环B选自 The compound according to claim 1 or 2, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein ring B is selected from
  13. 下式所示化合物、其立体异构体或其药学上可接受的盐，




    The compound represented by the following formula, its stereoisomer or its pharmaceutically acceptable salt,




  14. 根据权利要求13所述化合物、其立体异构体或其药学上可接受的盐，其选自：











    The compound according to claim 13, its stereoisomer or its pharmaceutically acceptable salt, which is selected from:











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