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WO2024125634A1 - Composé de tétrahydronaphtyridine et son application en médecine - Google Patents

Composé de tétrahydronaphtyridine et son application en médecine Download PDF

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Publication number
WO2024125634A1
WO2024125634A1 PCT/CN2023/139134 CN2023139134W WO2024125634A1 WO 2024125634 A1 WO2024125634 A1 WO 2024125634A1 CN 2023139134 W CN2023139134 W CN 2023139134W WO 2024125634 A1 WO2024125634 A1 WO 2024125634A1
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Prior art keywords
alkyl
carbocycle
compound
cyclopropyl
optionally substituted
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.)
Ceased
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PCT/CN2023/139134
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English (en)
Chinese (zh)
Inventor
张晨
赵晨飞
柴金龙
李凯
马俊杰
唐平明
袁帅
余彦
李瑶
严庞科
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Tibet Haisco Pharmaceutical Co Ltd
Original Assignee
Tibet Haisco Pharmaceutical Co Ltd
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Publication of WO2024125634A1 publication Critical patent/WO2024125634A1/fr
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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
    • A61K31/4375—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 six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present invention specifically relates to a compound described by the general formula (I) or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, and intermediates thereof, as well as their use in ⁇ v ⁇ 1 and ⁇ v ⁇ 6 related diseases such as idiopathic pulmonary fibrosis.
  • Idiopathic pulmonary fibrosis is a fatal disease with an average survival of less than 4 years.
  • Existing standard treatments for IPF have only limited effects on improving lung function and prolonging survival, and are unable to prevent disease progression or improve patients' lives in a sustained manner.
  • TGF- ⁇ transforming growth factor- ⁇
  • One of the characteristics of IPF is upregulated transforming growth factor- ⁇ (TGF- ⁇ ) signaling, which promotes the transformation of fibroblasts to myofibroblasts, the expression of collagen genes, and the deposition of scar tissue, thereby impairing lung function.
  • TGF- ⁇ transforming growth factor- ⁇
  • ⁇ v integrin is considered a key regulator of TGF- ⁇ activation. Therefore, ⁇ v integrin is a potential target for the treatment of IPF.
  • the purpose of the present invention is to provide a novel dual-target inhibitor capable of inhibiting ⁇ v ⁇ 1 and ⁇ v ⁇ 6.
  • the compound of the present invention has selective inhibitory activity on ⁇ v ⁇ 1 and ⁇ v ⁇ 6, weak off-target inhibition on the adhesion of ⁇ v ⁇ 5, and basically no inhibitory activity on ⁇ v ⁇ 3, and has good pharmacokinetic properties and bioavailability, oral performance and good safety.
  • the present invention provides a compound represented by general formula (I) or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein:
  • the compound of formula (I) is selected from the compounds of formula (II),
  • the compound of formula (I) or (II) is selected from the compound of formula (III),
  • A is selected from C 1-6 alkyl, 3 to 15 membered carbocyclic ring or 4 to 15 membered heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted with 1 to 4 Ra ;
  • A is selected from a 3- to 15-membered carbocyclic ring or a 4- to 15-membered heterocyclic ring, which is optionally substituted with 1 to 4 Ra ;
  • A is selected from a 3- to 12-membered carbocyclic ring or a 4- to 12-membered heterocyclic ring, which is optionally substituted with 1 to 4 Ra ;
  • A is selected from 3-6 membered cycloalkyl, 6-10 membered aryl, 5-10 membered heteroaryl, 4-6 membered heteroalkyl, 5-12 membered paracyclic carbocyclyl, 5-12 membered spirocyclic carbocyclyl, 5-12 membered bridged carbocyclyl, 5-12 membered paracyclic heterocyclyl, 5-12 membered spirocyclic heterocyclyl, 5-12 membered bridged heterocyclyl;
  • A is selected from phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, thiazolyl, thienyl, oxazolyl, isoxazolyl, isothiazolyl, furanyl, benzocyclobutenyl, benzocyclopentenyl, benzocyclohexenyl, benzopyrrolyl, benzopyrazoly
  • A is selected from phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, piperidinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, thienyl, oxazolyl, furanyl, benzocyclopentenyl, benzopyrrolyl, benzopyrazolyl, benzopyridinyl, benzopyrimidinyl, benzopyridazinyl, benzothiophenyl, benzofuranyl, pyridopyrrolyl, pyridoimidazolyl, pyridopyridinyl, benzimidazolyl, benzo thiazolyl, benzoxazolyl, pyridopyrimi
  • A is selected from the following substituted or unsubstituted groups: When substituted, it is optionally substituted with 1 to 4 Ra ;
  • A is selected from phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, thiazolyl, thienyl, oxazolyl, isoxazolyl, isothiazolyl, furanyl, benzocyclobutenyl, benzocyclopentenyl, benzocyclohexenyl, benzopyrrolyl, benzopyrazoly
  • A is selected from phenyl, pyrrolidinyl, pyrrolyl, piperidinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, thienyl, furanyl, benzopyrrolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, pyridopyrimidinyl, pyrazolopyrimidinyl, pyrrolopyrimidinyl, thienopyrimidinyl, and A is optionally substituted with 1 to 4 Ra ;
  • A is selected from the following substituted or unsubstituted groups: When substituted, it is optionally substituted with 1 to 4 Ra ;
  • A is selected from C 1-6 alkyl, which is optionally substituted with 1 to 4 Ra ;
  • A is selected from C 1-4 alkyl, which is optionally substituted with 1 to 4 Ra ;
  • A is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, and the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl is optionally substituted with 1 to 4 Ra ;
  • A is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl;
  • A is selected from isopropyl, tert-butyl, and the isopropyl, tert-butyl is optionally substituted with 1 to 4 Ra ;
  • Y is selected from C ⁇ O, C ⁇ S;
  • Y is selected from a bond
  • X1 is selected from -( CRx1aRx1b ) n1- or -NH-;
  • X 1 is selected from a bond, -NH-, -CH 2 -, -CHF-, -CF 2 -, -CH(CH 3 )-, -C(CH 3 ) 2 -,
  • X2 is selected from -( CRx2aRx2b ) n2- ;
  • X2 is selected from -CH2CH2- , -CHFCH2- , -CH2CH2CH2- , -CH2C ( CH3 ) 2- , -C( CH3 ) 2CH2- ,
  • X3 is selected from -( CRx3aRx3b ) n3- ;
  • X3 is selected from -CH2CH2CH2- , -CH2C ( CH3 ) 2CH2- ,
  • X4 is selected from -( CRx4aRx4b ) n4- ;
  • X4 is selected from a bond, -CH2- , -CH2CH2- , -CH ( CH3 )-, -C( CH3 ) 2- , -CF2- ,;
  • X4 is selected from a bond, -CH2CH2- , -CH2- , -CH( CH3 )-, -C( CH3 ) 2- ,
  • R 1 is selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 0-4 alkylene-C 3-6 carbocycle, -C 0-4 alkylene-3 to 7 membered heterocycle, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted with 1 to 4 R 1A ;
  • R 1 is selected from C 1-5 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 carbocycle, 3 to 6 membered heterocycle, wherein the alkyl, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted with 1 to 4 R 1A ;
  • R 1 is selected from methyl, ethyl, propyl, butyl, vinyl, propenyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, thiazolyl, thienyl, oxazolyl, isoxazolyl, isothiazolyl, furanyl, the methyl R 1A is substituted with 1 to 4 R 1A
  • R 1 is selected from methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, wherein the methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl is optionally substituted with 1 to 4 R 1A ;
  • R is selected from
  • two R 2 , R x1a and R x1b , R x2a and R x2b , R 3a and R 3b , R x3a and R x3b , R x4a and R x4b together with the atoms to which they are respectively attached form a cyclopropyl group;
  • n1, n2, n3, n4 are each independently selected from 0, 1, 2, 3, 4 or 5;
  • n1, n2, n4 are each independently selected from 0, 1, 2, 3;
  • n3 is selected from 1, 2, 3, 4 or 5;
  • At least one of R x2a , R x2b , R 3a , and R 3b is not selected from H or deuterium;
  • R x3a and R x3b are not selected from H, deuterium or halogen;
  • R x2a and R x2b , R x3a and R x3b together form a 3- to 8-membered carbocyclic ring or a 4- to 8-membered heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k .
  • A is selected from a 3- to 15-membered carbocyclic ring or a 4- to 15-membered heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted with 1 to 4 R a ;
  • or A is selected from C 1-6 alkyl, said alkyl being optionally substituted with 1 to 4 R a ;
  • X1 is selected from -( CRx1aRx1b ) n1- or -NH-;
  • X2 is selected from -( CRx2aRx2b ) n2- ;
  • X3 is selected from -( CRx3aRx3b ) n3- ;
  • X4 is selected from -( CRx4aRx4b ) n4- ;
  • n1, n2, n3, n4 are each independently selected from 0, 1, 2, 3, 4 or 5;
  • R 1 is selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -C 0-4 alkylene-C 3-6 carbocycle, -C 0-4 alkylene-3 to 7 membered heterocycle, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted by 1 to 4 R 1A ;
  • R 2 , R x1a and R x1b , R x2a and R x2b , R 3a and R 3b , R x3a and R x3b , R x4a and R x4b together with the atoms to which they are respectively attached, form a 3- to 8-membered carbocyclic ring or a 4- to 8-membered heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted with 1 to 4 R k ;
  • At least one of R x2a , R x2b , R 3a , and R 3b is not selected from H or deuterium;
  • R x3a and R x3b are not selected from H, deuterium or halogen;
  • R x2a and R x2b , R x3a and R x3b together form a 3- to 8-membered carbocyclic ring or a 4- to 8-membered heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 R k .
  • A is selected from a 3- to 12-membered carbocyclic ring or a 4- to 12-membered heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted with 1 to 4 R a ;
  • or A is selected from C 1-4 alkyl, which is optionally substituted with 1 to 4 R a ;
  • n1, n2, n4 are each independently selected from 0, 1, 2, 3;
  • n3 is selected from 1, 2, 3, 4 or 5;
  • R 1 is selected from C 1-5 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 carbocycle, 3 to 6 membered heterocycle, wherein the alkyl, alkenyl, alkynyl, carbocycle or heterocycle is optionally substituted by 1 to 4 R 1A ;
  • R a , R 2 , R x1a , R x1b , R x2a , R x2b , R 3a , R 3b , R x3a , R x3b , R x4a , and R x4b are each independently selected from H, deuterium, halogen, OH, ⁇ O, CN, NH 2 , NO 2 , COOH, CONH 2 , C( ⁇ O)NHCH 3 , S( ⁇ O) 2 CH 3 , O-phenyl, C 1-4 alkyl, OC 1-4 alkyl, SC 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, NHC 1-4 alkyl, N(C 1-4 alkyl) 2 , -OC 3-6 carbocycle, -O-3 to 6 membered heterocycle, -NH-C 3-6 carbocycle, -NH-3 to 6 membered heterocycle, -SC 3-6 membered carb
  • R 2 , R x1a and R x1b , R x2a and R x2b , R 3a and R 3b , R x3a and R x3b , R x4a and R x4b together with the atoms to which they are respectively attached, form a 3- to 6-membered carbocyclic ring or a 4- to 6-membered heterocyclic ring, wherein the carbocyclic ring or heterocyclic ring is optionally substituted with 1 to 4 R k ;
  • A is selected from the group consisting of phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, thiazolyl, thienyl, oxazolyl, isoxazolyl, isothiazolyl, furanyl, benzocyclobutenyl, benzocyclopentenyl, benzocyclohexenyl, benzopyrrolyl, benzopyrazo
  • Or A is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, and the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl is optionally substituted with 1 to 4 Ra ;
  • R is selected from methyl, ethyl, propyl, butyl, vinyl, propenyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazine R 1A , R 1B , R 1C , R 1D , R 1E , R 1F , R 1F , R 1F , R 1F , R 1F , R 1B , R 1C , R
  • R 2 , R x1a and R x1b , R x2a and R x2b , R 3a and R 3b , R x3a and R x3b , R x4a and R x4b together with the atoms to which they are respectively attached, form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, or morpholinyl group, wherein the cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, or morpholinyl group is optionally substituted with 1 to 4 R k ;
  • A is selected from the group consisting of phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, piperidinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, thienyl, oxazolyl, furanyl, benzocyclopentenyl, benzopyrrolyl, benzopyrazolyl, benzopyridinyl, benzopyrimidinyl, benzopyridazinyl, benzothiophenyl, benzofuranyl, pyridopyrrolyl, pyridoimidazolyl, pyridopyridinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, pyridopyrimi
  • A is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, and the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl is optionally substituted by 1 to 4 Ra ;
  • R 1 is selected from methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, and the methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl is optionally substituted by 1 to 4 R 1A ;
  • R 2 , R x1a and R x1b , R x2a and R x2b , R 3a and R 3b , R x3a and R x3b , R x4a and R x4b together with the atoms to which they are respectively attached form a cyclopropyl group
  • A is selected from the following substituted or unsubstituted groups: When substituted, it is optionally substituted with 1 to 4 Ra ;
  • A is selected from isopropyl and tert-butyl, and the isopropyl and tert-butyl are optionally substituted by 1 to 4 Ra ;
  • R 1 is selected from
  • X1 is selected from a bond, -NH-, -CH2- , -CHF-, -CF2- , -CH( CH3 )-, -C( CH3 ) 2- ,
  • X2 is selected from -CH2CH2- , -CHFCH2- , -CH2CH2CH2- , -CH2C ( CH3 ) 2- , -C ( CH3 ) 2CH2- ,
  • X3 is selected from -CH2CH2CH2- , -CH2C ( CH3 ) 2CH2- ,
  • X4 is selected from a bond, -CH2- , -CH2CH2- , -CH ( CH3 )-, -C( CH3 ) 2- , -CF2- ;
  • A, X 2 , X 3 , X 4 , R 3a , and R 3b are defined the same as in the first, second, third, fourth, or fifth embodiment of the present invention.
  • the present invention relates to the following compound or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the compound is selected from one of the structures in Table S below:
  • the present invention relates to a pharmaceutical composition, comprising the above compound or its stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, and a pharmaceutically acceptable carrier.
  • 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 drugs for inhibiting ⁇ v ⁇ 1 and ⁇ v ⁇ 6.
  • 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 idiopathic pulmonary fibrosis.
  • 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").
  • the present invention also provides a method for treating a disease in a mammal, comprising administering to the mammal a therapeutically effective amount of the compound of the present invention or its stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal or pharmaceutical composition.
  • the mammal of the present invention includes a human.
  • 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., idiopathic pulmonary fibrosis) 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 an amount of a compound disclosed herein that is required to provide a clinically significant reduction in disease symptoms.
  • therapeutically effective amounts include, but are not limited to, 1-1500 mg, 1-1000 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 -500mg, 2-500mg, 3-500mg, 4-500mg, 5-500mg, 6-500mg, 10-500mg, 20-500mg, 25-500mg, 30-500mg, 40-500mg, 50-500mg, 60-500mg, 70-500mg, 75-500mg, 80-500mg, 90-500mg, 100-500mg, 125-500mg, 150-500mg, 200-500mg, 250-500mg, 300-500mg, 40 0-500mg, 5-
  • the pharmaceutical composition includes but is not limited to 1-1500 mg, 1-1000 mg, 1-800 mg, 1-600 mg, 20-400 mg, 25-200 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg g, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 300 mg of a compound of the present invention or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof.
  • 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 idiopathic pulmonary fibrosis.
  • a method for treating a disease in a mammal comprising administering to a subject a drug compound of the present invention or a stereoisomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof at a daily dose of 1-1500 mg/day
  • the daily dose may be a single dose or divided doses, in some embodiments, the daily dose includes but is not limited to 10-1500 mg/day, 10-1000 mg/day, 10-800 mg/day, 25-800 mg/day, 50-800 mg/day, In some embodiments, the daily dose includes but is not limited to 10 mg/day, 20 mg/day, 25 mg/day, 50 mg/day, 100 mg/day, 125 mg/day, 150 mg/day, 200 mg/day, 400 mg/day, 600 mg/day, 800 mg/day.
  • 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 that 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.
  • Preparation specifications refers to the weight of the main drug contained in each vial, tablet or other unit preparation.
  • 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 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 prot
  • Halogen refers to F, Cl, Br or I.
  • Halogen substituted refers to substitution with F, Cl, Br or I, including but not limited to substitution with 1 to 10 substituents selected from F, Cl, Br or I, substitution with 1 to 6 substituents selected from F, Cl, Br or I, preferably substitution with 1 to 4 substituents selected from F, Cl, Br or I.
  • Halogen substituted is abbreviated as "halo”.
  • Alkyl refers to a substituted or unsubstituted straight or branched chain saturated aliphatic hydrocarbon group, including but not limited to alkyl groups of 1 to 20 carbon atoms, alkyl groups of 1 to 8 carbon atoms, alkyl groups of 1 to 6 carbon atoms, and alkyl groups of 1 to 4 carbon atoms.
  • Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and various branched chain isomers thereof; the alkyl groups appearing in this article have the same definition as this definition.
  • the alkyl group can be monovalent, divalent, trivalent or tetravalent.
  • Heteroalkyl refers to a substituted or unsubstituted alkyl group in which one or more (including but not limited to 2, 3, 4, 5 or 6) carbon atoms are replaced by heteroatoms (including but not limited to N, O or S).
  • Non-limiting examples include -X( CH2 )vX( CH2 )vX( CH2 )vH (v is an integer from 1 to 5, each X is independently selected from a bond or a heteroatom, the heteroatom includes but is not limited to N, O or S, and at least one X is selected from a heteroatom, and the N or S in the heteroatom can be oxidized to various oxidation states).
  • the heteroalkyl group can be monovalent, divalent, trivalent or tetravalent.
  • Alkylene refers to a substituted or unsubstituted straight-chain or branched divalent saturated hydrocarbon group, including -(CH 2 ) v -(v is an integer from 1 to 10). Examples of alkylene include, but are not limited to, methylene, ethylene, propylene, and butylene.
  • Heteroalkylene refers to a substituted or unsubstituted alkylene in which one or more (including but not limited to 2, 3, 4, 5 or 6) carbon atoms are replaced by heteroatoms (including but not limited to N, O or S).
  • Non-limiting examples include -X( CH2 )vX( CH2 )vX( CH2 )v-, v is an integer from 1 to 5, each X is independently selected from a bond, N, O or S, and at least one X is selected from N, O or S.
  • Cycloalkyl refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon group, typically having 3 to 10 carbon atoms, non-limiting examples of which include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Cycloalkyl groups appearing herein are defined as above. Cycloalkyl groups may 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 10 atoms, 3 to 8 atoms, including 1 to 3 heteroatoms selected from N, O or S, and the selectively substituted N and S in the ring of heterocycloalkyl can be oxidized to various oxidation states. Heterocycloalkyl can be connected to a heteroatom or a carbon atom, and heterocycloalkyl can be connected to an aromatic ring or a non-aromatic ring.
  • Heterocycloalkyl can be connected to a bridge ring or a spiro ring, and non-limiting examples include oxirane, aziridine, oxadiazine, azetidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, dioxolane, dioxane, pyrrolidinyl, piperidinyl, imidazolidinyl, oxazolidinyl, oxazolidinyl, morpholinyl, hexahydropyrimidinyl, piperazinyl.
  • Heterocycloalkyl can 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-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene and 1,4-
  • Alkynyl refers to a substituted or unsubstituted straight chain or branched unsaturated hydrocarbon group having at least one, typically one, two or three carbon-carbon triple bonds, with a main chain comprising 2 to 10 carbon atoms, including but not limited to 2 to 6 carbon atoms in the main chain, 2 to 4 carbon atoms in the main chain, examples of alkynyl groups include but are not limited to ethynyl, propargyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 4-butynyl, 5-butynyl, 6-butynyl, 7-butynyl, 8-butynyl, 9-butynyl, 10-butynyl, 11-butynyl, 12-butynyl, 13-butynyl, 14-butynyl, 15-butynyl, 16-butynyl, 15
  • 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.
  • Carbocyclyl or “carbocycle” refers to a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring, which can be a 3-8-membered monocyclic ring, a 4-12-membered bicyclic ring, or a 10-15-membered tricyclic ring system, and the carbocyclyl can be attached to the aromatic or non-aromatic ring, which can be a monocyclic ring, a bridged ring, or a spirocyclic ring.
  • 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 saturated or unsaturated aromatic or non-aromatic ring, which can be a 3-8 membered monocyclic ring, a 4-12 membered bicyclic ring or a 10-15 membered tricyclic ring system, and contains 1 or more (including but not limited to 2, 3, 4 or 5) heteroatoms selected from N, O or S.
  • the N and S selectively substituted in the heterocyclyl ring can be oxidized to various oxidation states.
  • the heterocyclic group may be connected to a heteroatom or a carbon atom, may be connected to an aromatic ring or a non-aromatic ring, may be connected to a bridged ring or a spiro ring, and 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, tetrahydrofur
  • Spirocycle or “spirocyclyl” can be monovalent, divalent, trivalent or tetravalent.
  • the number of ring atoms in the cyclic system includes but is not limited to 5 to 20, 5 to 14, 5 to 12, 5 to 10.
  • Non-limiting examples include: "Bicyclic" or "bicyclic group” can be monovalent, divalent, trivalent or tetravalent.
  • Carbospirocycle refers to a “spirocycle” wherein the ring system consists of only carbon atoms.
  • the "carbospirocycle”, “spirocarbocyclyl”, “spirocarbocyclyl” or “carbospirocyclyl” appearing in this document have the same definition as spirocycle.
  • Carbocyclic ring refers to a “cyclic ring” whose ring system consists of only carbon atoms.
  • Carbocyclic ring refers to a “cyclic ring” whose ring system consists of only carbon atoms.
  • Carbocyclic ring refers to a “cyclic ring” whose ring system consists of only carbon atoms.
  • Carbocyclic ring refers to a "cyclic ring” whose ring system consists of only carbon atoms.
  • Carbocyclic ring refers to a “cyclic ring” whose ring system consists of only carbon atoms.
  • Carbocyclic ring refers to a "cyclic ring” whose ring system consists of only carbon atoms.
  • Carbocyclic ring refers to a "cyclic ring” whose ring system consists of only carbon atoms.
  • Carbocyclic ring refers to a "cyclic
  • Carbobridge ring “bridged ring carbocyclic group”, “bridged carbocyclic group” or “carbon bridged cyclic group” refers to a “bridged ring” whose ring system consists of only carbon atoms. "Carbobridge ring”, “bridged ring carbocyclic group”, “bridged carbocyclic group” or “carbon bridged cyclic group” appearing in this article have the same definition as the bridged ring.
  • Heteromonocycle refers to a “heterocyclic group” or “heterocycle” of a monocyclic ring system.
  • the heterocyclic group, “monocyclic heterocyclyl” or “heteromonocyclic group” appearing in this document has the same definition as heterocycle.
  • Heterocyclic ring refers to a "cyclic ring” containing a heteroatom.
  • the heterocyclic ring, “heterocyclic ring group”, “cyclic heterocyclic group” or “heterocyclic ring group” appearing in this article have the same definition as cyclic ring.
  • Heterospirocycle refers to a "spirocycle” containing a heteroatom. Heterospirocycle, “heterospirocyclyl”, “spiro heterocyclyl” or “heterospirocyclyl” appearing herein have the same definition as spirocycle.
  • Heterobridged ring refers to a “bridged ring” containing a heteroatom.
  • the heterobridged ring, “heterobridged ring group”, “bridged heterocyclic group” or “heterobridged ring group” appearing herein have the same definition as the bridged ring.
  • Aryl or “aromatic ring” refers to a substituted or unsubstituted aromatic hydrocarbon group having a single ring or a fused ring, wherein the number of ring atoms in the aromatic ring includes, but is not limited to, 6 to 18, 6 to 12, or 6 to 10 carbon atoms.
  • the aryl ring may be fused to a saturated or unsaturated carbocyclic or heterocyclic ring, wherein the ring connected to the parent structure is the aryl ring, non-limiting examples of which include benzene ring, naphthalene ring, "Aryl” or “aromatic ring” can be monovalent, divalent, trivalent or tetravalent. When divalent, trivalent or tetravalent, the point of attachment is on the aryl ring.
  • heteroaryl examples include but are not limited to pyridyl, furanyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, benzopyrazole, benzimidazole, benzopyridine, pyrrolopyridine, etc.
  • the heteroaryl ring can be fused to a saturated or unsaturated carbocyclic ring or heterocyclic ring, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples include
  • the heteroaryl groups appearing in this article have the same definition as this definition.
  • the heteroaryl group can be monovalent, divalent, trivalent or tetravalent. When divalent, trivalent or tetravalent, the attachment site is located on the heteroaryl ring.
  • 5-membered ring and 5-membered heteroaromatic ring refers to a 5-membered fused heteroaromatic ring, at least one of the two rings contains one or more heteroatoms (including but not limited to O, S or N), and the whole group is aromatic.
  • Non-limiting examples include pyrrolopyrrole ring, pyrazolopyrrole ring, pyrazolopyrazole ring, pyrrolofuran ring, pyrazolofuran ring, pyrrolothiophene ring, and pyrazolothiophene ring.
  • 5- and 6-membered heteroaromatic ring refers to a 5- and 6-membered fused heteroaromatic ring, where at least one of the two fused rings contains one or more heteroatoms (including but not limited to O, S or N), and the entire group is aromatic.
  • Non-limiting examples include benzo 5-membered heteroaromatic group, 6-membered heteroaromatic ring and 5-membered heteroaromatic ring.
  • Consing 1 to 5 heteroatoms selected from O, S, and N means containing 1, 2, 3, 4 or 5 heteroatoms selected from O, S, and N.
  • “Replaced by 1 to X substituents selected from" means substituted by 1, 2, 3 ....X substituents, X is selected from any integer between 1 and 10.
  • “replaced by 1 to 4 R k” means substituted by 1, 2, 3 or 4 R k .
  • “replaced by 1 to 5 substituents selected from" means substituted by 1, 2, 3, 4 or 5 substituents selected from"
  • “the heterobridged ring is optionally substituted by 1 to 4 substituents selected from D or F” means that the heterobridged ring is optionally substituted by 1, 2, 3 or 4 substituents selected from D or F.
  • X-Y membered rings (3 ⁇ X ⁇ Y, Y is selected from any integer between 4 and 12) include X, X+1, X+2, X+3, X+4...Y membered rings.
  • Rings include heterocyclic rings, carbocyclic rings, aromatic rings, aryl groups, heteroaryl groups, cycloalkyl groups, heteromonocyclic rings, heterocyclic rings, heterospirocyclic rings or heterobridged rings.
  • “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.
  • 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.
  • Carrier refers to a material that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.
  • Excipient refers to an inert substance added to a pharmaceutical composition to facilitate administration of a compound.
  • Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders, and disintegrants.
  • Prodrug refers to a compound of the present invention that can be converted into a biologically active compound through in vivo metabolism.
  • the prodrug of the present invention is prepared by modifying the amino or carboxyl group in the compound of the present invention, and the modification can be removed by conventional operations or in vivo to obtain the parent compound.
  • the prodrug of the present invention is administered to a mammalian subject, the prodrug is cleaved to form a free amino or carboxyl group.
  • Co-crystal refers to a crystal formed by 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 both 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.
  • IC50 is the concentration of a drug or inhibitor required to inhibit a specified biological process (or a component of such a process, such as an enzyme, receptor, cell, etc.) by half.
  • 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);
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF 254 or Qingdao GF 254 silica gel plate.
  • the silica gel plate used in thin layer chromatography (TLC) adopts a specification of 0.15mm-0.20mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm;
  • Boc tert-butoxycarbonyl
  • Ts p-toluenesulfonyl
  • Example 1 Trifluoroacetate salt of 5-((2-methoxyethyl)(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)amino)-3-(quinazolin-4-ylamino)pentanoic acid (Compound 1)
  • the racemate of the trifluoroacetate salt of compound 1 (100 mg) was subjected to chiral separation.
  • the chiral separation method is as follows:
  • the sample was dissolved in acetonitrile to prepare a sample solution with a concentration of 10 mg/mL.
  • the mobile phase consists of A and B system: mobile phase A: CO 2 ; mobile phase B: ethanol/acetonitrile (containing 0.1% NH 3 . H 2 O); b. Isocratic elution, mobile phase B content is 65%; c. Flow rate is 100 mL/min.
  • the preparative liquid was lyophilized to obtain a crude product of compound 6 (610 mg), which was dissolved in dichloromethane (40 mL), washed with water (10 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and lyophilized to obtain compound 6 (360 mg).
  • the mixture was concentrated under reduced pressure, and the concentrate was purified by preparative liquid phase (instrument: waters 2767 preparative liquid phase; chromatographic column: XBridge@Prep C18 (30 mm ⁇ 150 mm); mobile phase composition: mobile phase: acetonitrile/water (containing 0.1% trifluoroacetic acid)) to obtain the trifluoroacetate salt of compound 16 (55 mg).
  • the sample was dissolved in acetonitrile to prepare a sample solution with a concentration of 10 mg/mL.
  • the mobile phase consists of A and B system: mobile phase A: CO 2 ; mobile phase B: ethanol (containing 0.1% NH 3 . H 2 O); b. Isocratic elution, mobile phase B content is 40%; c. Flow rate is 100 mL/min.
  • the sample was dissolved in acetonitrile to prepare a sample solution with a concentration of 10 mg/mL.
  • the mobile phase consists of A and B system: mobile phase A: CO 2 ; mobile phase B: acetonitrile and isopropanol (containing 0.1% NH 3 . H 2 O); b. Isocratic elution, mobile phase B content is 70%; c. Flow rate is 100 mL/min.
  • the sample was dissolved in acetonitrile to prepare a sample solution with a concentration of 10 mg/mL.
  • the mobile phase consists of A and B system: mobile phase A: CO 2 ; mobile phase B: ethanol (containing 0.1% NH 3 . H 2 O); b. Isocratic elution, mobile phase B content is 40%; c. Flow rate is 100 mL/min.
  • the sample was dissolved in acetonitrile to prepare a sample solution with a concentration of 10 mg/mL.
  • the mobile phase consists of A and B system: mobile phase A: CO 2 ; mobile phase B: ethanol (containing 0.1% NH 3 . H 2 O); b. Isocratic elution, mobile phase B content is 40%; c. Flow rate is 100 mL/min.
  • Example 4 the final product was purified by reverse phase preparation (Instrumnent: Waters 2767; Cloumn: C18; Mobile phase: A is acetonitrile, B is 0.1% TFA in H2O; Gradient: Phase A from 5% to 35% in 16 min, Flow rate: 15 mL/min) and the obtained preparation solution was lyophilized to obtain the trifluoroacetate salt of compound 63-1 (retention time 15.91 min, 23 mg) and the trifluoroacetate salt of compound 63-2 (retention time 15.46 min, 19 mg).
  • Test Example 1 Integrin ⁇ v ⁇ 6 ELISA test
  • LAP was prepared with TBS buffer to a final concentration of 0.25 ⁇ g/ml, and 50 ul of the solution was transferred to a 96-well plate and coated overnight at 4°C.
  • the plate was washed 3 times with TBS buffer, and then 150 ul of blocking solution (TBS buffer containing 1% BSA) was added and blocked at 37°C for 1 hour.
  • TBS buffer containing 1% BSA blocking solution
  • the plate was washed 3 times with TBS buffer, 0.1 ⁇ g/ml of ⁇ v ⁇ 6 integrin protein was prepared with TBS buffer containing 0.1% BSA, 50 ul of integrin protein was transferred to a 96-well plate, and 1 ⁇ l of different concentrations of compounds or DMSO was added, and incubated at room temperature for 2 hours.
  • ⁇ g/ml of Biotinylated anti- ⁇ v antibody was prepared with TBS buffer containing 0.1% BSA, the plate was washed 3 times with TBS buffer, 50 ul of antibody was added, and incubated at room temperature for 1 hour. The plate was washed 3 times with TBS buffer, 50 ul of Streptavidin-HRP was added, and incubated at room temperature for 20 minutes. 50 ⁇ l of TMB substrate was added and incubated at room temperature for 20 min. Finally, 25 ⁇ l of stop buffer (2M H 2 SO 4 ) was added and the OD value of the plate was read at 450 nm on a microplate reader. IC 50 values were calculated using GraphPad Prism 6 software.
  • the compounds of the present invention such as the compounds in the examples, have good inhibitory activity against ⁇ v ⁇ 6.
  • Fibronectin was prepared with TBS buffer to a final concentration of 3 ⁇ g/ml, and 50 ul of the solution was transferred to a 96-well plate and coated overnight at 4°C. The plate was washed 3 times with TBS buffer, and then 150 ul of blocking solution (TBS buffer containing 1% BSA) was added and blocked at 37°C for 1 hour. The plate was washed 3 times with TBS buffer, 1 ⁇ g/ml of ⁇ v ⁇ 1 integrin protein was prepared with TBS buffer containing 0.1% BSA, 50 ul of integrin protein was transferred to a 96-well plate, and 1 ⁇ l of different concentrations of compounds or DMSO was added, and incubated at room temperature for 2 hours.
  • 0.5 ug/ml of Biotinylated anti- ⁇ v antibody was prepared with TBS buffer containing 0.1% BSA, the plate was washed 3 times with TBS buffer, 50 ⁇ l of antibody was added, and incubated at room temperature for 1 hour. The plate was washed 3 times with TBS buffer, 50 ⁇ l of Streptavidin-HRP was added, and incubated at room temperature for 20 minutes. 50 ⁇ l of TMB substrate was added and incubated at room temperature for 20 min. Finally, 25 ⁇ l of stop buffer (2M H 2 SO 4 ) was added and the OD value of the plate was read at 450 nm on a microplate reader. IC 50 values were calculated using GraphPad Prism 6 software.
  • the compounds of the present invention such as the compounds in the examples, have good inhibitory activity against ⁇ v ⁇ 1.
  • Test Example 3 Determination of IC50 in CHO a5KO ⁇ v ⁇ 1 Cell Adhesion Assay
  • rhFibronectin (#4305-FNB, R&D systems) was coated on E-plate 96PET and incubated overnight at 4°C. On the day of the assay, the plate was washed twice with 150 ⁇ L/well PBS, blocked with 100 ⁇ L/well blocking buffer at room temperature, and washed once with 150 ⁇ L/well PBS. 50 ⁇ L/well HBSS assay buffer containing the test compound was added to the E-Plate 96PET. Cell parameters were recorded by xCELLigence RTCA MP.
  • %Inhibition 100%-(Signalcmpd-SignalAve_PC)/(SignalAve_VC-SignalAve_PC) ⁇ 100%.
  • Test Example 4 Determination of IC50 in SW480- ⁇ v ⁇ 6 Cell Adhesion Assay
  • Cell counts were performed using Vi-Cell, and the cells were resuspended in assay buffer to a cell density of 4 million cells/mL.
  • 50 ul of cell solution was transferred to the coated plate to a cell density of 200,000 cells/well, 1 ul of compound solution was added using Janus, and incubated at 37°C for 120 minutes.
  • the coated plate was washed twice with assay buffer, and non-adherent cells were removed by BlueWash.
  • 50ul/well of substrate solution was transferred to the wells and incubated at 37°C for 2 hours. Finally, 90 ⁇ L/well of stop solution was added on the SpectraMax 340PC and the absorbance was measured at 405nm.
  • Test Example 5 Determination of IC50 in ⁇ v ⁇ 5PC-3 cell adhesion assay
  • PC-3 cells in logarithmic growth phase and overexpressing ⁇ v ⁇ 5 are ready for use.
  • 50 ⁇ L/well of recombinant human vitronection solution is transferred to a 96-well plate, sealed and incubated overnight at 4°C. The next day, the plate is washed 4 times with buffer, then 150 ⁇ L of detection buffer containing 1% BSA is added to seal the plate for 1 hour at 37°C, and then washed 3 times with 150 ⁇ L TBS buffer.
  • 50 ⁇ L of cell suspension is transferred to the coated plate to a cell density of 2x10 ⁇ 5 cells/well, 1 ⁇ L of compound is added using Janus, and incubated at 37° Incubate at 37°C for 120 minutes.
  • the compounds of the present invention have weak off-target inhibition on ⁇ v ⁇ 5 adhesion and weak inhibition on av ⁇ 6 and av ⁇ 1
  • the adhesion inhibition activity is strong.
  • the av ⁇ 5/ ⁇ v ⁇ 1, av ⁇ 5/ ⁇ v ⁇ 6 selectivity of the compounds of the present invention is higher than the corresponding selectivity of the reference compound 1, especially the av ⁇ 5/ ⁇ v ⁇ 1, av ⁇ 5/ ⁇ v ⁇ 6 selectivity of compounds 6, 58, 59, and 77 are higher than the av ⁇ 5/ ⁇ v ⁇ 1, av ⁇ 5/ ⁇ v ⁇ 6 selectivity of the reference compound 1, and the av ⁇ 5/ ⁇ v ⁇ 1, av ⁇ 5/ ⁇ v ⁇ 6 selectivity of compound 59 is greater than 558 times and 985 times, respectively.
  • mice Male ICR mice, 25-30 g, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.
  • mice On the day of the experiment, ICR 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.
  • Intravenous administration solvent 5% DMA + 5% Solutol + 90% Saline
  • Oral administration solvent 5% DMSO + 95% (0.5% MC)
  • the compounds of the present invention such as the example compounds, especially compound 59, have good pharmacokinetic properties in mice.
  • control compound 1 The structure of the control compound 1 is as follows, and its synthesis refers to patent WO2019173653A1.
  • mice Male SD rats, 200-250 g, purchased from Chengdu Dashuo Experimental Animal Co., Ltd.
  • Intravenous administration solvent 5% DMA + 5% Solutol + 90% Saline
  • Oral administration solvent 5% DMSO + 95% (0.5% MC)
  • the compounds of the present invention such as the compounds in the examples, have good pharmacokinetic properties.
  • mice Male beagle dogs, about 8-10 kg, purchased from Beijing Mas Biotechnology Co., Ltd.
  • Intravenous administration solvent 5% DMA + 5% Solutol + 90% Saline
  • Oral administration solvent 5% DMSO + 95% (0.5% MC)
  • the compounds of the present invention such as the compounds in the examples, especially compound 59, have good pharmacokinetic properties in dogs.
  • the experiment used a monolayer of Caco-2 cells and was incubated in triplicate in a 96-well Transwell plate.
  • a transport buffer solution (HBSS, 10 mM HEPES, pH 7.4 ⁇ 0.05) containing the compound of the present invention (2 ⁇ M) or the control compounds digoxin (10 ⁇ M), nadolol (2 ⁇ M) and metoprolol (2 ⁇ M) was added to the dosing port well on the apical side or the basolateral side.
  • a transport buffer solution containing DMSO was added to the corresponding receiving port well. After incubation at 37 ⁇ 1 ° C for 2 hours, the cell plate was removed and appropriate amounts of samples were taken from the top and bottom ends to a new 96-well plate.
  • acetonitrile containing an internal standard was added to precipitate the protein.
  • the samples were analyzed using LC MS/MS and the concentrations of the compound of the present invention and the control compound were determined. The concentration data were used to calculate the apparent permeability coefficients for transport from the apical side to the basolateral side of the monolayer cells and from the basolateral side to the apical side, thereby calculating the efflux rate.
  • the integrity of the monolayer cells after 2 hours of incubation was evaluated by leakage of fluorescent yellow.
  • the compounds of the present invention have good Caco-2 permeability.
  • Test Example 10 Determination of IC50 in ⁇ v ⁇ 3 SK-MEL-24 cell adhesion assay
  • SK-MEL-24 cells that are in the logarithmic growth phase and overexpress av ⁇ 3 are ready for use.
  • the compounds of the present invention have weak off-target inhibition of ⁇ v ⁇ 3 adhesion.

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Abstract

La présente invention concerne un composé représenté par la formule générale (I), ou un stéréoisomère, un tautomère, un deutérate, un solvate, un promédicament, un métabolite, un sel ou un co-cristal pharmaceutiquement acceptable de celui-ci, et un intermédiaire de celui-ci, ainsi qu'une utilisation dans des maladies associées à αvβ1 et αvβ6, telles que la fibrose pulmonaire idiopathique.
PCT/CN2023/139134 2022-12-16 2023-12-15 Composé de tétrahydronaphtyridine et son application en médecine Ceased WO2024125634A1 (fr)

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WO2025067384A1 (fr) * 2023-09-28 2025-04-03 成都微芯药业有限公司 Inhibiteur d'intégrine d'acide aminé, son procédé de préparation et son utilisation

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CN109476632A (zh) * 2016-07-05 2019-03-15 洛克菲勒大学 四氢萘啶戊酰胺整联蛋白拮抗剂
CN112135612A (zh) * 2018-03-07 2020-12-25 普利安特治疗公司 氨基酸化合物和使用方法
WO2021225912A1 (fr) * 2020-05-07 2021-11-11 Pliant Therapeutics, Inc. Traitement de maladies respiratoires avec des composés acides aminés
CN114173803A (zh) * 2019-04-08 2022-03-11 普利安特治疗公司 氨基酸化合物的剂型和方案

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CN109476632A (zh) * 2016-07-05 2019-03-15 洛克菲勒大学 四氢萘啶戊酰胺整联蛋白拮抗剂
CN112135612A (zh) * 2018-03-07 2020-12-25 普利安特治疗公司 氨基酸化合物和使用方法
CN114173803A (zh) * 2019-04-08 2022-03-11 普利安特治疗公司 氨基酸化合物的剂型和方案
WO2021225912A1 (fr) * 2020-05-07 2021-11-11 Pliant Therapeutics, Inc. Traitement de maladies respiratoires avec des composés acides aminés

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2025067384A1 (fr) * 2023-09-28 2025-04-03 成都微芯药业有限公司 Inhibiteur d'intégrine d'acide aminé, son procédé de préparation et son utilisation

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