WO2023208244A1 - Composé macrocyclique et son utilisation - Google Patents

Composé macrocyclique et son utilisation Download PDF

Info

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
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
compound
ring
pharmaceutically acceptable
stereoisomer
Prior art date
Application number
PCT/CN2023/092077
Other languages
English (en)
Chinese (zh)
Inventor
王建非
杨广文
孙继奎
张杨
陈曙辉
Original Assignee
南京明德新药研发有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 南京明德新药研发有限公司 filed Critical 南京明德新药研发有限公司
Publication of WO2023208244A1 publication Critical patent/WO2023208244A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • 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

L'invention concerne un nouveau composé macrocyclique et son utilisation, et en particulier, l'invention concerne un composé représenté par la formule (I) et un sel pharmaceutiquement acceptable de celui-ci.
PCT/CN2023/092077 2022-04-29 2023-05-04 Composé macrocyclique et son utilisation WO2023208244A1 (fr)

Applications Claiming Priority (14)

Application Number Priority Date Filing Date Title
CN202210476383 2022-04-29
CN202210476383.4 2022-04-29
CN202210613430 2022-05-31
CN202210613430.5 2022-05-31
CN202210689548 2022-06-16
CN202210689548.6 2022-06-16
CN202210864278.8 2022-07-20
CN202210864278 2022-07-20
CN202211216969.3 2022-09-30
CN202211216969 2022-09-30
CN202211530422.0 2022-11-30
CN202211530422 2022-11-30
CN202310166839 2023-02-24
CN202310166839.1 2023-02-24

Publications (1)

Publication Number Publication Date
WO2023208244A1 true WO2023208244A1 (fr) 2023-11-02

Family

ID=88517934

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2023/092077 WO2023208244A1 (fr) 2022-04-29 2023-05-04 Composé macrocyclique et son utilisation

Country Status (1)

Country Link
WO (1) WO2023208244A1 (fr)

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102498113A (zh) * 2009-09-21 2012-06-13 弗·哈夫曼-拉罗切有限公司 Jak的大环抑制剂
CN103298794A (zh) * 2010-11-09 2013-09-11 塞尔卓姆有限公司 作为tyk2抑制剂的吡啶化合物及其氮杂类似物
CN107735399A (zh) * 2015-07-02 2018-02-23 Tp生物医药公司 作为蛋白质激酶的调节剂的手性二芳基大环
US20190169208A1 (en) * 2016-07-28 2019-06-06 Tp Therapeutics, Inc. Macrocycle kinase inhibitors
CN110003209A (zh) * 2010-05-20 2019-07-12 阵列生物制药公司 作为trk激酶抑制剂的大环化合物
CN113754682A (zh) * 2020-06-04 2021-12-07 成都倍特药业股份有限公司 具有大环结构的化合物及其用途
CN113811534A (zh) * 2019-03-11 2021-12-17 埃斯克疗法股份有限公司 Tyk2抑制剂和其用途
CN113874021A (zh) * 2019-03-26 2021-12-31 温缇克斯生物科学公司 Tyk2假激酶配体
WO2022060973A1 (fr) * 2020-09-16 2022-03-24 Alumis, Inc. Inhibiteurs de tyk2 et leurs utilisations

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102498113A (zh) * 2009-09-21 2012-06-13 弗·哈夫曼-拉罗切有限公司 Jak的大环抑制剂
CN110003209A (zh) * 2010-05-20 2019-07-12 阵列生物制药公司 作为trk激酶抑制剂的大环化合物
CN103298794A (zh) * 2010-11-09 2013-09-11 塞尔卓姆有限公司 作为tyk2抑制剂的吡啶化合物及其氮杂类似物
CN107735399A (zh) * 2015-07-02 2018-02-23 Tp生物医药公司 作为蛋白质激酶的调节剂的手性二芳基大环
US20190169208A1 (en) * 2016-07-28 2019-06-06 Tp Therapeutics, Inc. Macrocycle kinase inhibitors
CN113811534A (zh) * 2019-03-11 2021-12-17 埃斯克疗法股份有限公司 Tyk2抑制剂和其用途
CN113874021A (zh) * 2019-03-26 2021-12-31 温缇克斯生物科学公司 Tyk2假激酶配体
CN113754682A (zh) * 2020-06-04 2021-12-07 成都倍特药业股份有限公司 具有大环结构的化合物及其用途
WO2022060973A1 (fr) * 2020-09-16 2022-03-24 Alumis, Inc. Inhibiteurs de tyk2 et leurs utilisations

Similar Documents

Publication Publication Date Title
CN108283000A (zh) γ-羟基丁酸的前药及其组合物和用途
WO2020239076A1 (fr) DÉRIVÉS DE PYRIDAZINONE CONSTITUANT DES AGONISTES DU RÉCEPTEUR DE LA THYROXINE DE TYPE β ET LEUR UTILISATION
CN104812748A (zh) 二氢吡唑gpr40调节剂
CN113993860A (zh) 作为kras g12c突变蛋白抑制剂的七元杂环类衍生物
WO2021115335A1 (fr) Composé utile en tant qu'inhibiteur de la kinase 9 dépendante de la cycline et son utilisation
CN114502561A (zh) Lsd1抑制剂
CN112601746B (zh) 吡唑并嘧啶衍生物及其作为pi3k抑制剂的应用
JP7374532B2 (ja) 選択性の高いｒｏｓ１阻害剤としての化合物、及びその使用
KR102500569B1 (ko) 선택적 btk 키나제 억제제로서의 피라졸로피리딘계 화합물
CN114096245B (zh) 作为ccr2/ccr5拮抗剂的杂环烷基类化合物
WO2021129817A1 (fr) Composé à base de pyrimidine ayant un effet inhibiteur de la cétohexokinase (chk)
CN107556366A (zh) 具有突变型异柠檬酸脱氢酶抑制活性的化合物、其制备方法及用途
JP7083436B2 (ja) ピロリジニル尿素誘導体とＴｒｋＡ関連疾患への使用
WO2023208244A1 (fr) Composé macrocyclique et son utilisation
WO2022253335A1 (fr) Composé aryle contenant du sulfonyle et son application
WO2022237797A1 (fr) Composés d'acide alkylcarboxylique et leur application
CN114790176A (zh) 咪唑类化合物及其制备方法和用途
WO2021175223A1 (fr) Composé benzo 2-azaspiro[4,4]nonane et son utilisation
CN109071429A (zh) 丙啶磺酰胺类化合物及其使用方法
CN106336387A (zh) 酰胺类衍生物、其制备方法及其在医药上的用途
WO2024078370A1 (fr) Composé à petite molécule ayant une structure phénylspiro[indoline-3,3'-pyrrolidine] substituée
CN113166055A (zh) ***受体拮抗剂
CN116082259B (zh) 氨基甲酸酯基或氨甲酰基取代的5-ht2b拮抗剂
WO2023274418A1 (fr) Composé chimère ciblant la protéolyse
WO2023241618A1 (fr) Composés aminopyrimidines et leur utilisation

Legal Events

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

Ref document number: 23795676

Country of ref document: EP

Kind code of ref document: A1