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WO2025148997A1 - Dérivé de tétrahydropyridinopyrazole et son utilisation en médecine - Google Patents

Dérivé de tétrahydropyridinopyrazole et son utilisation en médecine

Info

Publication number
WO2025148997A1
WO2025148997A1 PCT/CN2025/071588 CN2025071588W WO2025148997A1 WO 2025148997 A1 WO2025148997 A1 WO 2025148997A1 CN 2025071588 W CN2025071588 W CN 2025071588W WO 2025148997 A1 WO2025148997 A1 WO 2025148997A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
optionally substituted
carbocyclyl
ring
membered heterocyclyl
Prior art date
Legal status (The legal status 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 status listed.)
Pending
Application number
PCT/CN2025/071588
Other languages
English (en)
Chinese (zh)
Inventor
张晨
雷鸣
孟逸飞
李阳光
袁洪媛
李瑶
严庞科
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Haisco Pharmaceutical Group Co Ltd
Original Assignee
Haisco Pharmaceutical Group Co Ltd
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 Haisco Pharmaceutical Group Co Ltd filed Critical Haisco Pharmaceutical Group Co Ltd
Publication of WO2025148997A1 publication Critical patent/WO2025148997A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention belongs to the field of medicine, and specifically relates to a compound described by general formula (I) or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, and intermediates and preparation methods thereof, as well as use of the compounds in the preparation of drugs for treating diabetes or obesity.
  • Diabetes is a group of metabolic diseases characterized by high blood sugar.
  • High blood sugar is caused by defects in insulin secretion or impaired biological action, or both.
  • Long-term high blood sugar in diabetes leads to chronic damage and dysfunction of various tissues, especially the eyes, kidneys, heart, blood vessels, and nerves. It is mainly divided into two types.
  • Type 1 diabetes destruction of pancreatic B cells leads to absolute insulin deficiency.
  • Type 2 diabetes mainly insulin resistance with relative insulin deficiency or impaired insulin secretion with insulin resistance.
  • Drugs for type 2 diabetes can be divided into six major categories (insulin, insulin secretagogues, biguanides, glucosidase inhibitors, thiazolidinediones, and SGLT2 inhibitors), each of which works through a different primary mechanism.
  • GLP-1 is a 30-amino acid incretin hormone that is secreted by L cells in the intestine. GLP-1 stimulates insulin secretion in a physiological and glucose-dependent manner, reduces glucagon secretion, inhibits gastric emptying, reduces appetite, and stimulates beta-cell proliferation. In nonclinical experiments, GLP-1 promotes the sustained capacity of beta cells by stimulating the transcription of important genes for glucose-dependent insulin secretion and promoting beta-cell neogenesis. In healthy people, GLP-1 plays an important role in regulating postprandial blood glucose by stimulating glucose-dependent insulin secretion from the pancreas, which leads to increased peripheral glucose absorption. GLP-1 also inhibits the secretion of glucagon, resulting in a decrease in hepatic glucose output. In addition, GLP-1 delays gastric emptying, slows small intestinal motility, and delays food absorption.
  • GLP-1 receptor agonists have antagonistic effects on neurodegeneration and AD progression.
  • systemic administration of liraglutide for 8 weeks prevented memory impairment, neuronal loss, and deterioration of hippocampal synaptic plasticity.
  • liraglutide can significantly reduce the deposition and inflammation of amyloid plaques.
  • mAbs monoclonal antibodies
  • liraglutide pretreatment significantly protected mAb-induced spatial memory and long-term potentiation impairments.
  • Another GLP-1 analog, exenatide has also shown promising results against neurodegenerative diseases in preclinical studies.
  • the object of the present invention is to provide a compound that can stimulate the GLP-1 receptor or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, and intermediates and preparation methods thereof, as well as use thereof in the preparation of drugs for treating diabetes or obesity.
  • the compound of the invention has good pharmacokinetic properties and bioavailability, oral properties and good safety.
  • the present invention provides a compound or a stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, wherein the compound is selected from the compounds represented by general formula (I), wherein:
  • the compound represented by general formula (I) is selected from the compounds represented by general formula (II-a) or (II-b),
  • the compound represented by general formula (I) is selected from the compounds represented by general formula (II-b-1),
  • the compound represented by general formula (I) is selected from the compound represented by general formula (III),
  • the compound represented by general formula (I) is selected from the compounds represented by general formula (III-1),
  • ring A is selected from phenyl, 5 to 6 membered heteroaryl, C 3-6 monocarbocyclyl, 4 to 8 membered heteromonocyclyl, benzoC 7-8 carbocyclyl, and the ring A is optionally substituted with 1 to 4 Ra ;
  • ring A is selected from one of the following groups optionally substituted with 1 to 4 Ra : phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxolanyl, oxhexyl, 1,3-dioxolanyl, 1,4-dioxhexanyl, piperazinyl, morpholinyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, pyrrolyl, thienyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl,
  • Ring A2 is selected from phenyl optionally substituted with 1 to 3 Ra ;
  • ring B is selected from 5- and 5-membered heteroaryl or 5- and 6-membered heteroaryl, and said ring B is optionally substituted with 1 to 4 R b ;
  • ring B is selected from pyrrolothienyl, pyrrolopyrazolyl, pyrrolopyrrolyl, pyrroloimidazolyl, pyrazolothienyl, imidazothienyl, imidazoimidazolyl, pyrazolopyrazolyl, pyrrolothiazolyl, pyrrolofuranyl, indolyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrrolopyridazinyl, pyrrolopyrazinyl, pyrrolotriazinyl, pyrazolophenyl, pyrazolopyridinyl, pyrazolopyrimidinyl, imidazophenyl, imidazopyridinyl, imidazopyrimidinyl, and said ring B is optionally substituted with 1 to 4 R b ;
  • ring D is selected from one of the following groups optionally substituted with 1 to 4 R d : phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, quinolyl, isoquinolyl, indolyl, benzopyrazolyl, benzimidazolyl, benzothiazolyl, benzisothiazolyl, benzothienyl, benzofuranyl,
  • ring D is selected from the following structures optionally substituted with 1 to 4 R d : phenyl,
  • ring C is selected from one of the following groups optionally substituted with 1 to 4 R c : cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxolanyl, oxhexyl, 1,3-dioxolanyl, 1,4-dioxhexanyl, piperazinyl, morpholinyl;
  • L2 is selected from -CR L1 R L2 - or one of the following groups optionally substituted with 1 to 3 R k :
  • L2 is selected from
  • X is selected from S or O;
  • m is selected from 1, 2, 3 or 4;
  • R4 is selected from
  • R 4a , R 4b , R 4c , R 4d , R 4e , and R 4f are each independently selected from H, deuterium, and C 1-6 alkyl, wherein the alkyl is optionally substituted with 1 to 4 R k ;
  • R 4a , R 4b , R 4c , R 4d , R 4e , and R 4f are each independently selected from H, deuterium, and C 1-4 alkyl, wherein the alkyl is optionally substituted with 1 to 4 R k ;
  • R 4a , R 4b , R 4c , R 4d , R 4e , and R 4f are each independently selected from H, deuterium, methyl, ethyl, propyl, and isopropyl;
  • each R d1 is independently selected from H, deuterium, CD 3 , methyl, ethyl, cyclopropyl, -CH 2 CH 2 OCH 3 , -CF 3 , -CH 2 F, -CHF 2 , -CH 2 CH 2 F, -CH 2 CH 2 CH 2 F, -OCH 2 CH 2 OH,
  • R d1 is independently selected from H, deuterium, CD 3 , methyl, ethyl, cyclopropyl;
  • RA is selected from Ra ;
  • R A1 is selected from methyl, ethyl, propyl, isopropyl substituted with 1 to 3 R A11 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl substituted with 1 to 3 R k , cyclobutylspirocyclobutyl, cyclopentylspirocyclobutyl, cyclopentylspirocyclopentyl, cyclohexylspirocyclobutyl, cyclohexylspirocyclopentyl, cyclohexylspirocyclohexyl optionally substituted with 1 to 3 R k , azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, morpholinylspirocyclohexyl optionally substituted with 1 to 3 R k ;
  • R A11 is selected from deuterium, OH, CN, NH 2 , C 1-4 alkoxy, -NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , C 3-10 carbocyclyl, 4 to 10 membered heterocyclyl;
  • R A11 is selected from deuterium, OH, CN, NH 2 , methoxy, ethoxy, NH(CH 3 ), N(CH 3 ) 2 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, morpholinylspirocyclohexyl;
  • R 5a and R 5b are each independently selected from C 1-4 alkyl and C 3-6 cycloalkyl, and the alkyl and cycloalkyl are optionally substituted with 1 to 4 R k ;
  • R 5a , R 5b are each independently selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, wherein the methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl is optionally substituted with 1 to 3 R k ;
  • R 1 , R 2 , R 3 , RL1 , and RL2 are each independently selected from H, deuterium, halogen, CN, OH, NO 2 , NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OC 1-6 alkyl, and -SC 1-6 alkyl, and the alkyl, alkenyl, and alkynyl are optionally substituted with 1 to 4 R k ;
  • R 1 , R 2 , R 3 , RL1 , and RL2 are each independently selected from H, deuterium, halogen, CN, OH, NO 2 , NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -OC 1-4 alkyl, and -SC 1-4 alkyl, wherein the alkyl, alkenyl, and alkynyl are optionally substituted with 1 to 4 R k ;
  • R 1 , R 2 , R 3 , RL1 , and RL2 are each independently selected from H, deuterium, F, Cl, Br, I, CN, OH, NO 2 , NH 2 , NH(CH 3 ), N(CH 3 ) 2 , or one of the following groups optionally substituted with 1 to 3 R k : methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, isopropoxy, methylthio;
  • R 1 , R 2 , and R 3 are each independently selected from H, deuterium, F, Cl, Br, I, CN, OH, NO 2 , NH 2 , NH(CH 3 ), N(CH 3 ) 2 , CD 3 , OCD 3 , CF 3 , CH 2 F, CHF 2 , CH 2 OH, OCF 3 , OCHF 2 , OCH 2 F, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, isopropoxy, methylthio;
  • RL1 and RL2 are each independently selected from H, deuterium, F, Cl, Br, I, CN, OH, NO2 , NH2 , NH( CH3 ), N( CH3 ) 2 , methyl, ethyl, methoxy, ethoxy, isopropoxy, methylthio;
  • R L1 , R L2 and the atoms to which they are attached together form a C 3-8 carbocyclic ring or a 4- to 8-membered heterocyclic ring, which is optionally substituted with 1 to 4 R k ;
  • R L1 , R L2 and the attached carbon atom together form a C 3-6 carbocyclic ring or a 4- to 6-membered heterocyclic ring, which is optionally substituted with 1 to 4 R k ;
  • R L1 , R L2 and the attached carbon atom together form the following group optionally substituted with 1 to 3 R k : cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl;
  • R 5a , R 5b and the phosphorus atom to which they are attached together form a 5- to 8-membered heterocyclic ring, which is optionally substituted with 1 to 4 R k ;
  • R 5a , R 5b and the attached phosphorus atom together form a 5- to 8-membered monocyclic heterocyclic ring, which is optionally substituted with 1 to 4 R k ;
  • R 5a , R 5b and the attached phosphorus atom together form the following group optionally substituted with 1 to 3 R k :
  • a or b are each independently selected from 0, 1, 2 or 3;
  • ring A is selected from When C 11-15 aryl, 11 to 15 membered heterocyclyl, or 11 to 15 membered heteroaryl, RA is selected from Ra , and the ring A is optionally substituted by 1 to 4 Ras ;
  • RA is selected from RA1
  • RA1 is selected from C 1-6 alkyl substituted by 1 to 3 RA11
  • C 3-6 carbocyclyl substituted by 1 to 3 R k C 7-12 carbocyclyl optionally substituted by 1 to 3 R k
  • the RA11 is selected from deuterium, OH, CN, NH 2 , C 1-6 alkoxy, -NH(C 1-6 alkyl), N(C 1-6 alkyl) 2
  • the ring A is optionally substituted by 1 to 4 R a .
  • Ring A is selected from C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-10 carbocyclyl, 4- to 10-membered heterocyclyl, C 11-15 aryl, 11- to 15-membered heterocyclyl, 11- to 15-membered heteroaryl, and the ring A is optionally substituted by 1 to 4 Ras ;
  • Ring B is selected from C 6-10 aryl, 5- to 6-membered heteroaryl, 5- and 5-membered heteroaryl, 5- and 6-membered heteroaryl, 6- and 6-membered heteroaryl, C 3-10 carbocyclyl, and 4- to 10-membered heterocyclyl, and is optionally substituted by 1 to 4 R b ;
  • Ring D is selected from C 6-12 carbocyclyl, 5 to 12 membered heterocyclyl, and said ring D is optionally substituted by 1 to 4 R d ;
  • Ring C is selected from C 3-12 carbocyclyl, 4 to 12 membered heterocyclyl, and the ring C is optionally substituted by 1 to 4 R c ;
  • L2 is selected from -(CR L1 R L2 ) m -;
  • X is selected from S or O;
  • n is selected from 1, 2, 3 or 4;
  • R 4a , R 4b , R 4c , R 4d , R 4e , and R 4f are each independently selected from H, deuterium, and C 1-6 alkyl, wherein the alkyl is optionally substituted with 1 to 4 R k ;
  • R 5a and R 5b are each independently selected from C 1-6 alkyl and C 3-6 carbocyclyl, wherein the alkyl and carbocyclyl are optionally substituted by 1 to 4 R k ;
  • R 1 , R 2 , R 3 , RL1 , and RL2 are each independently selected from H, deuterium, halogen, CN, OH, NO 2 , NH 2 , NHC 1-6 alkyl, N(C 1-6 alkyl) 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OC 1-6 alkyl, and -SC 1-6 alkyl, wherein the alkyl, alkenyl, and alkynyl are optionally substituted with 1 to 4 R k ;
  • R L1 , R L2 and the atoms to which they are attached together form a C 3-8 carbocyclyl or a 4 to 8 membered heterocyclyl, said carbocyclyl or heterocyclyl being optionally substituted with 1 to 4 R k ;
  • R 5a , R 5b and the phosphorus atom to which they are attached together form a 5- to 8-membered heterocyclic group, which is optionally substituted with 1 to 4 R k ;
  • Ring A is selected from C 6-10 aryl, 5- to 10-membered heteroaryl, C 3-10 carbocyclyl, 4- to 10-membered heterocyclyl
  • RA is selected from RA1
  • RA1 is selected from C 1-6 alkyl substituted by 1 to 3 RA11
  • C 3-6 carbocyclyl substituted by 1 to 3 R k C 7-12 carbocyclyl optionally substituted by 1 to 3 R k
  • 4- to 12-membered heterocyclyl optionally substituted by 1 to 3 R k
  • the RA11 is selected from deuterium, OH, CN, NH 2 , C 1-6 alkoxy, -NH(C 1-6 alkyl), N(C 1-6 alkyl) 2 , C 3-12 carbocyclyl, 4- to 12-membered heterocyclyl
  • the Ring A is optionally substitute
  • Ring B is selected from 5- and 5-membered heteroaryl or 5- and 6-membered heteroaryl, and the ring B is optionally substituted by 1 to 4 R b ;
  • Ring C is selected from C 3-6 monocycloalkyl, 4-7 membered monoheterocyclyl, 6-11 membered spiroheterocyclyl, 5-11 membered bridged heterocyclyl, 7-10 membered heterocyclyl, and the ring C is optionally substituted by 1 to 4 R c ;
  • Ring D is selected from phenyl, naphthyl, benzoC 4-6 carbocyclyl, benzo 4-7 membered heterocyclyl, 5-6 membered heteroaryl or 8-10 membered cycloheteroaryl, and the ring D is optionally substituted by 1 to 4 R d ;
  • Ring A is selected from phenyl, 5- to 6-membered heteroaryl, C 3-6 monocarbocyclyl, 4- to 8-membered heteromonocyclyl, benzoC 7-8 carbocyclyl, and the ring A is optionally substituted by 1 to 4 Ras ;
  • R 4a , R 4b , R 4c , R 4d , R 4e , and R 4f are each independently selected from H, deuterium, and C 1-4 alkyl, wherein the alkyl is optionally substituted with 1 to 4 R k ;
  • R 5a and R 5b are each independently selected from C 1-4 alkyl and C 3-6 cycloalkyl, and the alkyl and cycloalkyl are optionally substituted by 1 to 4 R k ;
  • R 1 , R 2 , R 3 , RL1 , and RL2 are each independently selected from H, deuterium, halogen, CN, OH, NO 2 , NH 2 , NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, -OC 1-4 alkyl, and -SC 1-4 alkyl, wherein the alkyl, alkenyl, and alkynyl are optionally substituted with 1 to 4 R k ;
  • R L1 , R L2 and the attached carbon atom together form a C 3-6 carbocyclic group or a 4 to 6 membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally substituted with 1 to 4 R k ;
  • R 5a , R 5b and the attached phosphorus atom together form a 5- to 8-membered monoheterocyclic group, which is optionally substituted with 1 to 4 R k ;
  • RA11 is selected from deuterium, OH, CN, NH2 , C1-4 alkoxy, -NH( C1-4 alkyl), N( C1-4 alkyl) 2 , C3-10 carbocyclyl, 4 to 10 membered heterocyclyl;
  • Ring B is selected from pyrrolothienyl, pyrrolopyrazolyl, pyrrolopyrrolyl, pyrroloimidazolyl, pyrazolothienyl, imidazothienyl, imidazoimidazolyl, pyrazolopyrazolyl, pyrrolothiazolyl, pyrrolofuranyl, indolyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrrolopyridazinyl, pyrrolopyrazinyl, pyrrolotriazinyl, pyrazolophenyl, pyrazolopyridinyl, pyrazolopyrimidinyl, imidazophenyl, imidazopyridinyl, imidazopyrimidinyl, and said ring B is optionally substituted with 1 to 4 R b ;
  • L2 is selected from -(CR L1 R L2 )-, -(CR L1 R L2 ) 2 -;
  • Ring B is selected from the following groups optionally substituted by 1 to 4 R b : Its right side is connected to ring C;
  • R 4a , R 4b , R 4c , R 4d , R 4e , and R 4f are each independently selected from H, deuterium, methyl, ethyl, propyl, and isopropyl;
  • RA1 is selected from methyl, ethyl, propyl, isopropyl substituted with 1 to 3 RA11 , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl substituted with 1 to 3 R k , cyclobutylspirocyclobutyl, cyclopentylspirocyclobutyl, cyclopentylspirocyclopentyl, cyclohexylspirocyclobutyl, cyclohexylspirocyclopentyl, cyclohexylspirocyclohexyl optionally substituted with 1 to 3 R k , azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, morpholinylspirocyclohexyl optionally substituted with 1 to 3 R k , -P(
  • RA11 is selected from deuterium, OH, CN, NH2 , methoxy, ethoxy, -NH( C1-2 alkyl), N( C1-2 alkyl) 2 , C3-7 carbocyclyl, 4 to 8 membered heterocyclyl;
  • R 1 , R 2 , R 3 , RL1 , and RL2 are each independently selected from H, deuterium, F, Cl, Br, I, CN, OH, NO 2 , NH 2 , NH(CH 3 ), N(CH 3 ) 2 or one of the following groups optionally substituted with 1 to 3 R k : methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, isopropoxy, and methylthio;
  • R L1 , R L2 and the attached carbon atom together form the following group optionally substituted with 1 to 3 R k : cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, tetrahydrofuranyl;
  • R 5a , R 5b and the attached phosphorus atom together form the following group optionally substituted by 1 to 3 R k :
  • Ring A is selected from one of the following groups optionally substituted by 1 to 4 Ra : phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, oxetanyl, oxolanyl, oxhexyl, 1,3-dioxolanyl, 1,4-dioxhexanyl, piperazinyl, morpholinyl, pyrazolyl, imidazolyl, oxazolyl, thiazolyl, pyrrolyl, thienyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl,
  • the present invention relates to the use of the above-mentioned compound or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal or the above-mentioned pharmaceutical composition in preparing a drug for treating diabetes or obesity.
  • the present invention relates to a pharmaceutical composition or pharmaceutical preparation, which comprises a therapeutically effective amount of the compound of the present invention or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal and a pharmaceutical excipient.
  • the pharmaceutical composition can be in the form of a unit preparation (the amount of the main drug in the unit preparation is also referred to as "preparation specification").
  • Effective amount or “therapeutically effective amount” as used herein refers to administering a sufficient amount of a compound disclosed herein that will alleviate one or more symptoms of the disease or condition (e.g., diabetes or obesity) being treated to some extent.
  • the result is a reduction and/or alleviation of the signs, symptoms, or causes of the disease, or any other desired changes in a biological system.
  • an "effective amount” for therapeutic use is the amount of a compound disclosed herein required to provide a clinically significant reduction in disease symptoms.
  • therapeutically effective amounts include, but are not limited to, 1-1500 mg, 1-1000 mg, 1-800 mg, 1-600 mg, 2-600 mg, 3-600 mg, 4-600 mg, 5-600 mg, 6-600 mg, 10-600 mg, 20-600 mg, 25-600 mg, 30-600 mg, 40-600 mg, 50-600 mg, 60-600 mg, 70-600 mg, 75-600 mg, 80-600 mg, 90-600 mg, 100-600 mg, 200-600 mg, 1-500 mg, 2-500 mg, 3-500 mg g, 4-500mg, 5-500mg, 6-500mg, 10-500mg, 20-500mg, 25-500mg, 30-500mg, 40-500mg, 50-500mg, 60-500mg, 70-500mg, 75-500mg, 80-500m g, 90-500mg, 100-500mg, 125-500mg, 150-500mg, 200-500mg, 250-500mg, 300-500mg, 400-500mg, 5-400mg,
  • a method for treating a disease in a mammal comprising administering to a subject a therapeutically effective amount of a compound of the present invention or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, the therapeutically effective amount preferably being 1-1500 mg, and the disease preferably being a disease related to GLP-1R activity or expression (such as diabetes or obesity).
  • the present invention relates to a kit, which may include a composition in a single-dose or multi-dose form, and the kit contains a compound of the present invention or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, and the amount of the compound of the present invention or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal is the same as its amount in the above-mentioned pharmaceutical composition.
  • the amount of the compound of the invention or its stereoisomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal in the present invention is in each case calculated as the free base.
  • the carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds described in the present invention all include their isotopes, and the carbon, hydrogen, oxygen, sulfur or nitrogen involved in the groups and compounds described in the present invention are optionally further replaced by one or more of their corresponding isotopes, wherein carbon isotopes include 12 C, 13 C and 14 C, hydrogen isotopes include protium (H), deuterium (D, also called heavy hydrogen), tritium (T, also called super tritium), oxygen isotopes include 16 O, 17 O and 18 O, sulfur isotopes include 32 S, 33 S, 34 S and 36 S, nitrogen isotopes include 14 N and 15 N, fluorine isotopes include 17 F and 19 F, chlorine isotopes include 35 Cl and 37 Cl, and bromine isotopes include 79 Br and 81 Br.
  • carbon isotopes include 12 C, 13 C and 14 C
  • hydrogen isotopes include pro
  • Halogen refers to F, Cl, Br or I.
  • Cycloalkyl refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon radical, typically having 3 to 12 carbon atoms, and the cycloalkyl radical can be a monocyclic, cyclic, bridged, and spirocyclic ring. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutyl-cyclobutyl, cyclobutyl-spirocyclobutyl, adamantane, etc.
  • the cycloalkyl radical can be monovalent, divalent, trivalent, or tetravalent.
  • Heterocycloalkyl refers to a substituted or unsubstituted saturated cyclic hydrocarbon containing heteroatoms, including but not limited to 3 to 12 atoms, 3 to 8 atoms, including 1 to 3 heteroatoms selected from N, O, S or Se, and the C, N, S on the ring of the heterocycloalkyl can be oxidized to various oxidation states. Heterocycloalkyl can be a monocyclic, cyclic, bridged and spirocyclic.
  • Heterocycloalkyl can be connected to a heteroatom or a carbon atom, and non-limiting examples include oxirane, aziridine, oxadiazine, azetidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, dioxolane, dioxane, pyrrolidinyl, piperidinyl, imidazolidinyl, oxazolidinyl, oxazininyl, morpholinyl, hexahydropyrimidinyl, piperazinyl,
  • the heterocycloalkyl group may be monovalent, divalent, trivalent or tetravalent.
  • alkenyl refers to a substituted or unsubstituted straight chain or branched unsaturated hydrocarbon group having at least one, typically one, two or three carbon-carbon double bonds, with a backbone of 2 to 10, 2 to 6 or 2 to 4 carbon atoms.
  • alkenyl groups include but are not limited to vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 2-methyl-1-butenyl, 2-methyl-2 ...
  • alkenyl group can be monovalent, divalent, trivalent or tetravalent.
  • Alkoxy refers to substituted or unsubstituted -O-alkyl. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropyloxy, and cyclobutyloxy.
  • Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexenyl, benzene ring, naphthalene ring, "Carbocyclyl” or “carbocycle” can be monovalent, divalent, trivalent or tetravalent.
  • Heterocyclyl or “heterocycle” refers to a substituted or unsubstituted aromatic or non-aromatic ring, which can be a 3-8 membered monocyclic ring, a 4-12 membered bicyclic ring, a 10-15 membered tricyclic ring, or a 12-18 membered quaternary system, and contains 1 or more (including but not limited to 2, 3, 4 or 5) heteroatoms selected from N, O, S or Se.
  • the C, N, S or Se selectively substituted in the heterocyclyl ring can be oxidized to various oxidation states.
  • the heterocyclic group can be connected to a heteroatom or a carbon atom, and can be connected to an aromatic ring or a non-aromatic ring.
  • the heterocyclic group is optionally a monocyclic, bridged, fused or spirocyclic ring.
  • Non-limiting examples include oxirane, aziridine, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxhexacyclyl, azepanyl, pyridyl, furanyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, dihydrofuranyl, dihydropyranyl, dithiolanyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridin
  • Heteromonocycle refers to a monocyclic ring system of "heterocyclyl” or “heterocycle”.
  • 4--7 membered heteromonocyclic rings refer to 4-, 5-, 6- or 7-membered heteromonocyclic rings
  • 5--10 membered heterocyclic rings refer to 5-, 6-, 7-, 8-, 9- or 10-membered heterocyclic rings
  • Cxy carbocyclic group (including aryl, cycloalkyl, monocyclic carbocyclic group, spirocyclic carbocyclic group, cyclic carbocyclic group or bridged carbocyclic group) includes Cx , Cx +1 , Cx +2 , Cx +3 , Cx +4 ... Cy -membered ring (x is an integer, and 3 ⁇ x ⁇ y, y is selected from any integer between 4 and 20), for example.
  • C3-6 cycloalkyl refers to C3 , C4 , C5 or C6 cycloalkyl.
  • any one or more sites of the group can be connected to other groups through chemical bonds.
  • the chemical bond connection is non-positional and there are hydrogen atoms at the connectable sites, when the chemical bonds are connected, the number of H atoms at the site will decrease with the number of connected chemical bonds and become a group with the corresponding valence.
  • any connectable site on the piperidine group can be connected to other groups through one chemical bond, including at least These four connection methods, even if the H atom is drawn on -N-, Also included For example Indicates that the R group on the piperidinyl group can be located on C, can be located on N, and at least includes
  • connection directions include connection from left to right and from right to left in reading order, for example, A-L-B, when L is selected from -M-W-, includes A-M-W-B and A-W-M-B.
  • alkyl optionally substituted with F means that alkyl may but need not be substituted with F, and the description includes situations where alkyl is substituted with F and situations where alkyl is not substituted with F.
  • “Pharmaceutically acceptable salt” or “pharmaceutically acceptable salt thereof” refers to a salt of the compound of the present invention that retains the biological effectiveness and properties of the free acid or free base, and the free acid is obtained by reacting with a non-toxic inorganic base or organic base, and the free base is obtained by reacting with a non-toxic inorganic acid or organic acid.
  • “Pharmaceutical composition” refers to a mixture of one or more compounds of the present invention, or stereoisomers, tautomers, deuterated forms, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals thereof and other chemical components, wherein “other chemical components” refers to pharmaceutically acceptable carriers, excipients and/or one or more other therapeutic agents.
  • Preparation specifications refers to the weight of the main drug contained in each vial, tablet or other unit preparation.
  • Co-crystal refers to a crystal formed by the active pharmaceutical ingredient (API) and the co-crystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds, in which the pure state of API and CCF are solid at room temperature and there is a fixed stoichiometric ratio between the components.
  • Co-crystal is a multi-component crystal, including binary eutectics formed between two neutral solids and multi-component eutectics formed between neutral solids and salts or solvates.
  • Animal is meant to include mammals, such as humans, companion animals, zoo animals, and livestock, preferably humans, horses, or dogs.
  • Stepoisomers refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, diastereomers and conformational isomers.
  • Tautomers refer to functional group isomers produced by the rapid movement of an atom in a molecule between two positions, such as keto-enol isomerism and amide-imino alcohol isomerism.
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • HPLC determination was performed using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18 100 ⁇ 4.6mm, 3.5 ⁇ M);
  • Methyltriphenylphosphonium bromide (20.0 g, 55.99 mmol) was dissolved in ultra-dry THF (100 mL) under ice bath conditions, and 1 M potassium tert-butoxide-tetrahydrofuran solution (60.0 mL, 60.0 mmol) was added to the system. The mixture was reacted for 0.5 hour under nitrogen atmosphere, and then 1a (8.0 g, 39.41 mmol) was added. The system was warmed to room temperature and reacted for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by column chromatography to obtain 1b (3.46 g, yield 43.67%).
  • Triethylamine (75 mL) and formic acid (50 mL) were mixed and stirred in an ice bath for 10 min, and 3a (10 g, 46.07 mmol) and McLaughlin's acid (6.64 g, 46.07 mmol) were added in sequence, and then the mixture was reacted at 100 °C for 5 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was separated and purified by column chromatography to obtain 3b (11.2 g, yield 93.10%).
  • the compounds of the present invention have a good agonist effect on the GLP-1 receptor, and their EC 50 values are less than 10 nM.
  • the EC 50 value of compound 1 is less than 1 nM.
  • the compounds of the present invention such as the compounds in the examples, have a good oral hypoglycemic effect on the GLP-1 receptor.
  • mice were randomly divided into groups according to body weight. They were fasted but not watered for 12-14 hours one day before administration and fed 4 hours after administration.
  • the purpose of this study was to evaluate the effects of the test substances on the activities of five isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) of human liver microsomal cytochrome P450 (CYP) using an in vitro test system.
  • CYP human liver microsomal cytochrome P450
  • Specific probe substrates of CYP450 isoenzymes were incubated with human liver microsomes and different concentrations of the test substances, and the reaction was initiated by adding reduced nicotinamide adenine dinucleotide phosphate (NADPH).

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Abstract

L'invention concerne un dérivé de tétrahydropyridinopyrazole et son utilisation en médecine. L'invention concerne spécifiquement un composé tel que représenté dans la formule générale (I) ou un stéréoisomère, un tautomère, une substance deutérée, un solvate, un promédicament, un métabolite, un sel pharmaceutiquement acceptable ou un cristal eutectique de celui-ci, un intermédiaire de celui-ci, son procédé de préparation et son utilisation dans la préparation d'un médicament pour le traitement du diabète ou de l'obésité.
PCT/CN2025/071588 2024-01-10 2025-01-09 Dérivé de tétrahydropyridinopyrazole et son utilisation en médecine Pending WO2025148997A1 (fr)

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CN109790161A (zh) * 2016-09-26 2019-05-21 中外制药株式会社 具有glp-1受体激动剂作用的吡唑并吡啶衍生物
CN115698003A (zh) * 2020-02-07 2023-02-03 加舒布鲁姆生物公司 杂环glp-1激动剂
CN116003403A (zh) * 2022-11-20 2023-04-25 药康众拓(北京)医药科技有限公司 一种氘代吲唑类化合物、药物组合物及其应用
CN116390926A (zh) * 2020-07-20 2023-07-04 上海诚益生物科技有限公司 四氢吡唑并-吡嗪基-二氢咪唑酮或四氢吡唑并-吡啶基-二氢咪唑酮化合物及其使用方法
WO2025002250A1 (fr) * 2023-06-29 2025-01-02 韦恩生物科技有限公司 Agoniste du récepteur glp-1, son procédé de préparation et son utilisation
CN119306743A (zh) * 2023-07-14 2025-01-14 西藏海思科制药有限公司 一种四氢吡啶并吡唑衍生物及其在医药上的应用
WO2025026436A1 (fr) * 2023-08-02 2025-02-06 韦恩生物科技有限公司 Composé cyclique fusionné contenant de l'azote, son procédé de préparation et son utilisation
CN119431365A (zh) * 2023-07-28 2025-02-14 江苏豪森药业集团有限公司 一种含苯基杂环类衍生物调节剂及其制备方法和应用

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109790161A (zh) * 2016-09-26 2019-05-21 中外制药株式会社 具有glp-1受体激动剂作用的吡唑并吡啶衍生物
CN115698003A (zh) * 2020-02-07 2023-02-03 加舒布鲁姆生物公司 杂环glp-1激动剂
CN116390926A (zh) * 2020-07-20 2023-07-04 上海诚益生物科技有限公司 四氢吡唑并-吡嗪基-二氢咪唑酮或四氢吡唑并-吡啶基-二氢咪唑酮化合物及其使用方法
CN116003403A (zh) * 2022-11-20 2023-04-25 药康众拓(北京)医药科技有限公司 一种氘代吲唑类化合物、药物组合物及其应用
WO2025002250A1 (fr) * 2023-06-29 2025-01-02 韦恩生物科技有限公司 Agoniste du récepteur glp-1, son procédé de préparation et son utilisation
CN119306743A (zh) * 2023-07-14 2025-01-14 西藏海思科制药有限公司 一种四氢吡啶并吡唑衍生物及其在医药上的应用
CN119431365A (zh) * 2023-07-28 2025-02-14 江苏豪森药业集团有限公司 一种含苯基杂环类衍生物调节剂及其制备方法和应用
WO2025026436A1 (fr) * 2023-08-02 2025-02-06 韦恩生物科技有限公司 Composé cyclique fusionné contenant de l'azote, son procédé de préparation et son utilisation

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