WO2024104250A1 - 作为gpr75激活剂的多环化合物、包含其的药物组合物及其用途 - Google Patents

作为gpr75激活剂的多环化合物、包含其的药物组合物及其用途 Download PDF

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WO2024104250A1
WO2024104250A1 PCT/CN2023/130796 CN2023130796W WO2024104250A1 WO 2024104250 A1 WO2024104250 A1 WO 2024104250A1 CN 2023130796 W CN2023130796 W CN 2023130796W WO 2024104250 A1 WO2024104250 A1 WO 2024104250A1
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alkyl
alkylene
cycloalkyl
membered heterocycloalkyl
halogen
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PCT/CN2023/130796
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English (en)
French (fr)
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郭春龙
衡杰
胡远东
张鹏
张丰盈
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水木未来(北京)科技有限公司
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/335Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/335Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/341Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00Drugs for disorders of the urinary system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/28Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/08Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D263/00Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/32Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D307/00Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/04Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D307/06Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to ring carbon atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D405/00Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D405/00Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • the present invention belongs to the field of pharmaceutical chemistry and relates to a compound used as a GPR75 activator, a pharmaceutical composition containing the compound, a preparation method thereof and medical uses thereof.
  • GPR75 G protein coupled receptor 75
  • G protein coupled receptor 75 is a member of the G protein coupled receptor family. Its endogenous agonist ligands include the metabolite 20HETE and the chemokine CCL5/RANTES6.
  • GPR75 is expressed in a large number of cell types. GPR75 expressed in the pancreatic islets regulates insulin release through the activation of CCL5 and participates in regulating glucose homeostasis in the human body. GPR75 expressed in neurons prevents neuronal cell death mediated by amyloid ⁇ and human immunodeficiency virus viral proteins gp120 and Tau through the activation of CCL5. GPR75 expressed in the kidneys reduces glomerular protein permeability through 20-HETE activation.
  • GPR75 is a potential target for treating obesity, diabetes, high-consumption metabolic diseases caused by primary and malignant tumors, neurodegenerative diseases, kidney damage and other diseases, and has become a hot topic in the field of drug research and development.
  • the main agonists of GPR75 reported in the literature are 20-HETE and CCL5, both of which are endogenous ligands.
  • the 20-HETE molecule is extremely unstable and has a very short half-life, making it difficult to develop into a drug.
  • CCL5 is a polypeptide and also has the problem of poor drugability.
  • the downstream G protein signaling pathway and arrestin signaling pathway affect physiological and pathological processes after 20-HETE and CCL5 activate GPR75.
  • the object of the present invention is to provide a class of compounds with novel structures as GPR75 activators, pharmaceutical compositions containing the same, preparation methods thereof, and use thereof in the preparation of drugs for preventing or treating diseases regulated by GPR75.
  • the present invention provides a compound having a structure of formula (1) or a pharmaceutically acceptable form thereof:
  • W 1 , W 2 , W 3 and W 4 are each independently selected from CR 1 or N; provided that W 1 , W 2 , W 3 and W 4 are not N at the same time and there are no three consecutive N atoms;
  • X is selected from -OH
  • Y is selected from NH, O or S;
  • L 1 , L 2 , L 3 and L 4 are each independently selected from a bond, CR 4 R 5 , NR 3 , O or S, provided that L 1 , L 2 , L 3 and L 4 are not simultaneously a bond;
  • R4 and R5 are each independently selected from a bond, H, halogen, OH, SH, NH2 , CN, carboxyl, C1-6 alkyl, -OC1-6 alkyl, -SC1-6 alkyl, C3-8 cycloalkyl, 5-10 membered heterocycloalkyl, -OC3-8 cycloalkyl, -SC3-8 cycloalkyl, -NH( C1-6 alkyl), -N( C1-6 alkyl) 2 , -NH( C3-8 cycloalkyl), -NH(5-10 membered heterocycloalkyl), -N( C1-6 alkyl)( C3-8 cycloalkyl), -N( C1-6 alkyl)(5-10 membered heterocycloalkyl), -( C1-6 alkylene)-NH( C1-6 alkyl), -( C1-6 alkylene)-CONH( C1-6 alkyl), -( C1-6 alkylene)-NHCO( C1-6
  • the alkyl, alkylene, cycloalkyl, aryl, heteroaryl or heterocycloalkyl in R e is each optionally substituted with one or more substituents selected from halogen, OH, NH 2 , SH, ⁇ O, CN, carboxyl, —C 1-6 alkyl, —OC 1-6 alkyl, C 3-8 cycloalkyl, 5-10 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , —NH(C 3-8 cycloalkyl), —NH(5-10 membered heterocycloalkyl), —N(C 1-6 alkyl)(C 3-8 cycloalkyl) or —N(C 1-6 alkyl)(5-10 membered heterocycloalkyl);
  • n is each independently selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8;
  • any two of L 1 , L 2 , L 3 and L 4 together with the atoms to which they are attached form a C 3-8 cycloalkyl, a 5-10 membered heterocycloalkyl, a C 6-10 aryl or a 5-10 membered heteroaryl, wherein each of the cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally substituted with one or more R f ;
  • V is selected from 5-membered heteroaryl or -C ⁇ C-;
  • the pharmaceutically acceptable form is selected from pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotopically labeled substances, metabolites or prodrugs.
  • each R 1 is independently selected from H, halogen, carboxyl, OH, CN, C 1-6 alkyl, C 3-8 cycloalkyl, -OC 3-8 cycloalkyl, -NR a R b , 5-10 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, -OC 1-6 alkyl, -C( ⁇ O)R a , -S( ⁇ O) 2 R a , -C( ⁇ O)NR a R b , -NR a C( ⁇ O)R b , -S( ⁇ O) 2 NR a R b , -NR a S( ⁇ O) 2 R b , -S( ⁇ O)( ⁇ NH)R a , -P( ⁇ O)R a R b , -P( ⁇ NH)R a R b , -P( ⁇ O)(OR a )(OR b
  • R 1 is each independently selected from H, F, Cl, Br, CN, -CH 3 or -OCH 3 .
  • R 2 and R 3 are each independently selected from H or -CH 3 .
  • Y is selected from NH or O.
  • R 4 and R 5 are each independently selected from H, halogen, OH, SH, NH 2 , CN, carboxyl, C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, -NH(C 1-6 alkyl), -NH(C 3-8 cycloalkyl), -NH(5-10 membered heterocycloalkyl), -(C 1-6 alkylene)-NH(C 1-6 alkyl), -(C 1-6 alkylene)-CONH(C 1-6 alkyl), -(C 1-6 alkylene)-NHCO(C 1-6 alkyl), or -NHCO(C 1-6 alkyl); the alkyl, cycloalkyl, heterocycloalkyl are each optionally substituted with one or more Re ;
  • R 4 and R 5 are each independently selected from H, halogen, OH, SH, NH 2 , CN, carboxyl, C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, -NH(C 1-6 alkyl), -NH(5-10 membered heterocycloalkyl), -N(C 1-6 alkyl)(C 3-8 cycloalkyl), -N(C 1-6 alkyl)(5-10 membered heterocycloalkyl); said alkyl, cycloalkyl, heterocycloalkyl are each optionally substituted with one or more Re ;
  • R4 and R5 are each independently selected from H, -CH3 , -CH2OH , -CH2CH ( CH3 ) 2 , - ( CH2 ) mNH2 , -( CH2 ) mSH , - ( CH2 ) mSCH3 , -( CH2 ) mNHCOCH3 , -( CH2 )mNHSO2CH3, - ( CH2 )mNHSO2( CH2 ) 3 , -CH2NH (CH2) 2N ( CH3 ) 2 , -( CH2 ) mNH ( CH2COOH ) 2 , -CH2O ( CH2CH2O ) nCH2COOH , -CH2O ( CH2CH2O ) nCH2CH2OH , -CH2O ( CH2CH2O ) nCH2CH 2 OCH 3 ⁇ -CH 2 NH(CH 2 CH 2 O) n CH 2 COOH ⁇ -(CH 2 CH 2 CO
  • Each n is independently selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8
  • each m is independently selected from 1, 2, 3, 4, 5, 6, 7 or 8
  • each o is independently selected from 0, 1, 2 or 3.
  • R 4 and R 5 are each independently selected from H, CN, carboxyl or C 1-6 alkyl; the alkyl is optionally substituted with one or more substituents selected from halogen, OH, -NH 2 , CN or -NH-(C 1-6 alkylene)-N(C 1-6 alkyl) 2 .
  • R 4 and R 5 are each independently selected from H or C 1-6 alkyl; the alkyl is optionally substituted with one or more substituents selected from OH, -NH 2 or -NH-(C 1-3 alkylene)-N(C 1-3 alkyl) 2 .
  • R4 and R5 are each independently selected from H, -CH3 , -CH2OH , -CH2CH ( CH3 ) 2 , -( CH2 ) 4NH2 , or -CH2NH ( CH2 ) 2N ( CH3 ) 2 .
  • R 4 and R 5 are taken together to form ⁇ O.
  • R4 and R5 together with the atoms to which they are attached form
  • L3 is -NH-.
  • L 4 is selected from CR 4 R 5 , R 4 and R 5 are each independently selected from H or C 1-6 alkyl; the alkyl is optionally substituted with one or more substituents selected from OH, -NH 2 or -NH-(C 1-3 alkylene)-N(C 1-3 alkyl) 2 .
  • any two of L 1 , L 2 , L 3 and L 4 together with the atoms to which they are attached form a C 3-8 cycloalkyl, a 5-10 membered heterocycloalkyl, a C 6-10 aryl or a 5-10 membered heteroaryl, each of which is optionally substituted with one or more R f ;
  • L 1 and L 2 together with the atoms to which they are attached form a 5-10 membered heteroaryl, each of which is optionally substituted with one or more R f ;
  • L 1 and L 2 together with the atoms to which they are attached form a 5-10 membered heteroaryl, each of which is optionally substituted with one or more R f ;
  • L1 and L2 together with the atoms to which they are attached form a pyrimidinyl or pyridinyl group, wherein the pyrimidinyl group and the pyridinyl group are each optionally substituted with one or more selected from -CH3 , -NHCH3 , -NH( CH2 ) 2N ( CH3 ) 2 , -NH( CH2 ) 2NH2 , -NH( CH2 ) 2OH , substituted by a substituent.
  • L 1 and L 2 together with the atoms to which they are attached, form a C 3-8 cycloalkyl, a 5-10 membered heterocycloalkyl, a C 6-10 aryl, or a 5-10 membered heteroaryl, each of which is optionally substituted with one or more substituents selected from halogen, OH, -NH 2 , CN, -C 1-6 alkyl, -OC 1-6 alkyl, -SC 1-6 alkyl, -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -NH-(C 1-6 alkylene)-NH 2 , -NH-(C 1-6 alkylene)-OH, or -NH-(C 1-6 alkylene)-N(C 1-6 alkyl) 2 .
  • L1 and L2 together with the atoms to which they are attached, form a C5-8 cycloalkyl, a 5-8 membered heterocycloalkyl, a phenyl, or a 5-10 membered heteroaryl, each of which is optionally substituted with one or more substituents selected from halogen, OH, -NH2 , CN, -C1-3 alkyl, -OC1-3 alkyl, -SC1-3 alkyl, -NH( C1-3 alkyl), -N( C1-3 alkyl ) 2 , -NH-( C1-3 alkylene) -NH2 , -NH-( C1-3 alkylene)-OH, or -NH-( C1-3 alkylene)-N( C1-3 alkyl) 2 .
  • substituents selected from halogen, OH, -NH2 , CN, -C1-3 alkyl, -OC1-3 alkyl, -SC1-3 alkyl, -NH( C1-3 alkyl
  • L 1 and L 2 together with the atoms to which they are attached, form a C 5-6 cycloalkyl, a 5-6 membered heterocycloalkyl, or a 6 membered heteroaryl, each of which is optionally substituted with one or more substituents selected from halogen, OH, -NH 2 , CN, -C 1-3 alkyl, -OC 1-3 alkyl, -SC 1-3 alkyl, -NH(C 1-3 alkyl), -N(C 1-3 alkyl) 2 , -NH-(C 1-3 alkylene)-NH 2 , -NH-(C 1-3 alkylene)-OH, or -NH-(C 1-3 alkylene)-N(C 1-3 alkyl) 2 .
  • L1 and L2 together with the atoms to which they are attached form a pyrimidinyl, pyridinyl, pyrazinyl, cyclohexyl, or tetrahydrofuranyl group, each of which is optionally substituted with one or more selected from -CH3 , -NHCH3 , -NH( CH2 ) 2N (CH3) 2 , -NH( CH2 ) 2NH2 , -NH( CH2 ) 2OH , -S( CH2 )2N( CH3 ) 2 , -S (CH2)2NH2, -S(CH2)2OH, -NH(CH2)3N(CH3)2 , -NH ( CH2 ) 3NH2 , -NH ( CH2 ) 3OH , -NH ( CH2 ) 3NHCOCH3 ⁇ -NH(CH 2 ) 2 NHSO 2 CH 3 ⁇ -NH(CH 2 ) 3 NHSO 2 CH 3 ⁇ -NH(CH 2
  • L 1 and L 2 together with the atoms to which they are attached form
  • L 1 and L 2 together with the atoms to which they are attached form
  • L2 and L3 together with the atoms to which they are attached form
  • V is selected from furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, or -C ⁇ C-.
  • V is selected from Or -C ⁇ C-.
  • Ar is selected from C 6-10 aryl or 5-8 membered heteroaryl, each of which is optionally substituted with one or more substituents selected from halogen, OH, NH 2 , CN, -C 1-3 alkyl, -OC 1-3 alkyl, -NH(C 1-3 alkyl) or -N(C 1-3 alkyl) 2 .
  • Ar is selected from phenyl or pyridinyl, each of which is optionally substituted with one or more substituents selected from F, Cl, Br, OH, NH2 , CN, -C1-3 alkyl, or -OC1-3 alkyl.
  • Ar is selected from phenyl or pyridinyl, each of which is optionally substituted with one or more substituents selected from F, Cl, Br, CN, -CH 3 or -OCH 3 .
  • Ar is selected from
  • the present invention provides a compound having a structure of Formula (1-2) or Formula (1-3) or a pharmaceutically acceptable form thereof:
  • W 14 is selected from CR 1 or N, and the other variables are as defined in formula (1).
  • the compound represented by formula (1) of the present invention has a structure represented by formula (2):
  • W 5 , W 6 , W 7 and W 8 are each independently selected from CR 6 or N; provided that W 5 , W 6 , W 7 and W 8 are not N at the same time and there are no three consecutive N atoms;
  • Z is selected from O or S
  • U2 and U3 are independently selected from CH or N;
  • W 9 , W 10 , W 11 , W 12 and W 13 are each independently selected from CR 7 or N; provided that W 9 , W 10 , W 11 , W 12 and W 13 are not N at the same time and there are no three consecutive N atoms;
  • R 7 is each independently selected from halogen, OH, NH 2 , CN, carboxyl, -C 1-6 alkyl, -OC 1-6 alkyl, C 3-8 cycloalkyl, 5-10 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, -NH(C 1-6 alkyl), -NH(C 3-8 cycloalkyl), -NH(5-10 membered heterocycloalkyl), -N(C 1-6 alkyl)(C 3-8 cycloalkyl) or -N(C 1-6 alkyl)(5-10 membered heterocycloalkyl) or -N(C 1-6 alkyl) 2 ;
  • W 1 , W 2 , W 3 , W 4 and X are as defined in formula (1).
  • the present invention provides a compound having a structure shown in formula (2-1) or formula (2-2):
  • each variable is defined as in formula (2).
  • the compound represented by formula (1) of the present invention has a structure represented by formula (3):
  • Z is selected from O or S
  • U2 and U3 are independently selected from CH or N;
  • W 9 , W 10 , W 11 , W 12 and W 13 are each independently selected from CR 7 or N; provided that W 9 , W 10 , W 11 , W 12 and W 13 are not N at the same time and there are no three consecutive N atoms;
  • R 7 is each independently selected from halogen, OH, NH 2 , CN, carboxyl, -C 1-6 alkyl, -OC 1-6 alkyl, C 3-8 cycloalkyl, 5-10 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl, -NH(C 1-6 alkyl), -NH(C 3-8 cycloalkyl), -NH(5-10 membered heterocycloalkyl), -N(C 1-6 alkyl)(C 3-8 cycloalkyl) or -N(C 1-6 alkyl)(5-10 membered heterocycloalkyl) or -N(C 1-6 alkyl) 2 ;
  • W 1 , W 2 , W 3 , W 4 , X, R 4 and R 5 are as defined in formula (1).
  • the compound represented by formula (2) of the present invention has a structure represented by formula (4):
  • W 1 , W 2 , W 3 , W 4 , R 6 , R 7 , U 2 and U 3 are as defined in formula (2).
  • the compound represented by formula (3) of the present invention has a structure represented by formula (5):
  • W 1 , W 2 , W 3 , W 4 , W 9 , W 10 , W 11 , W 12 , W 13 , R 4 , R 5 , U 2 and U 3 are as defined in formula (3).
  • the present invention provides a compound having a structure shown in formula (5-1) or formula (5-2):
  • each variable is defined as in formula (5).
  • the compound represented by formula (3) of the present invention has a structure represented by formula (6):
  • W 1 , W 2 , W 3 , W 4 , R 7 , U 2 and U 3 are as defined in formula (3).
  • the present invention provides a compound having a structure shown in formula (7):
  • each variable is defined as in formula (2).
  • the present invention provides a compound having a structure shown in formula (7-1) or formula (7-2):
  • each variable is defined as in formula (2).
  • the present invention also provides compounds or pharmaceutically acceptable salts, esters, stereoisomers thereof. isomer, tautomer, solvate, N-oxide, isotope-labeled, metabolite or prodrug, the compound is selected from:
  • the compounds of the present invention may be prepared by any method known in the art. Reagents and starting materials are readily available to one of ordinary skill in the art. Individual isomers, enantiomers and diastereomers may be separated or resolved at any convenient point in the synthesis by methods such as selective crystallization techniques or chiral chromatography (See for example, J. Jacques, et al., “Enantiomers, Racemates, and Resolutions", John Wiley and Sons, Inc., 1981, and E. L. Eliel and S. H. Wilen).
  • the present invention provides a method for preparing a compound represented by formula (4), comprising:
  • step 1
  • the organic solvent in the above step (1-a) is selected from isopropanol, tert-butanol, dimethyl sulfoxide, or N,N-dimethylformamide; preferably isopropanol or N,N-dimethylformamide;
  • the base is selected from triethylamine, N,N-diisopropylethylamine, DBU, potassium carbonate, cesium carbonate, or sodium tert-butoxide; preferably triethylamine or N,N-diisopropylethylamine.
  • the organic solvent in the above step (1-b) is selected from dichloromethane, ethanol, acetonitrile, methanol, or tetrahydrofuran; preferably dichloromethane or ethanol;
  • the reducing agent is selected from zinc powder or iron powder; preferably zinc powder;
  • the acid is selected from acetic acid, ammonium chloride, dilute hydrochloric acid or trifluoroacetic acid; preferably acetic acid.
  • Step 2 Compound SMB and compound INT3-A react in the presence of an organic solvent, a base and a catalyst to obtain compound INT3;
  • the organic solvent in the above step 2 is selected from 1,4-dioxane/water, dimethyl sulfoxide, N,N-dimethylformamide, or toluene/water; preferably 1,4-dioxane/water;
  • the base is selected from potassium carbonate, cesium carbonate, sodium tert-butoxide, or potassium tert-butoxide; preferably potassium carbonate or cesium carbonate;
  • the catalyst is selected from Pd(PPh 3 ) 4 , Pd(dppf)Cl 2 , Pd(OAc) 2 or Pd 2 (dba) 3 ; preferably Pd(PPh 3 ) 4 or Pd 2 (dba) 3 .
  • the organic solvent in the above step (3-a) is selected from dichloromethane, ethyl acetate, tetrahydrofuran, acetonitrile, chloroform, or 1,2-dichloroethane; preferably dichloromethane or 1,2-dichloroethane;
  • the reducing agent is selected from sodium cyanoborohydride, sodium triacetoxyborohydride, sodium borohydride, lithium borohydride, or zinc borohydride; preferably sodium cyanoborohydride or sodium triacetoxyborohydride;
  • the catalyst is selected from titanium tetrachloride, tetraisopropyl titanate, bismuth trichloride, scandium trifluoromethanesulfonate, or anhydrous zinc chloride; preferably titanium tetrachloride or bismuth trichloride.
  • the base in the above step (3-b) is selected from lithium hydroxide, sodium hydroxide, or potassium hydroxide; preferably lithium hydroxide.
  • the present invention provides a method for preparing a compound represented by formula (5), comprising:
  • step 1
  • the organic solvent in the above step (1-a) is selected from N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile, tetrahydrofuran, or dichloromethane; preferably N,N-dimethylformamide, tetrahydrofuran, or a mixed solvent of the two;
  • the base is selected from N,N-diisopropylethylamine, triethylamine; preferably N,N-diisopropylethylamine.
  • the deprotection conditions in the above step (1-b) are selected from methanol/acetyl chloride, HCl/methanol solution, HCl/1,4-dioxane solution, trifluoroacetic acid/dichloromethane, or methanol/methanesulfonic acid; preferably methanol/acetyl chloride, or trifluoroacetic acid/dichloromethane.
  • the organic solvent in the above step (2-a) is selected from N,N-dimethylformamide, acetonitrile, dichloromethane, or tetrahydrofuran; preferably N,N-dimethylformamide or dichloromethane;
  • the reducing agent is selected from sodium cyanoborohydride, sodium triacetoxyborohydride, sodium borohydride, lithium borohydride, zinc borohydride, or triethylsilane; preferably sodium cyanoborohydride or sodium triacetoxyborohydride.
  • the base in the above step (2-b) is selected from lithium hydroxide, sodium hydroxide, or potassium hydroxide; preferably lithium hydroxide.
  • W1 , W2 , W3 , W4 , R6 , R7 , W9 , W10 , W11 , W12 , W13 , R4 , R5 , U2 and U3 are as defined above.
  • one or more steps in the above-described preparation method may be omitted, and the order of the reaction steps may be appropriately adjusted as well as protection/deprotection reaction steps may be added or omitted as needed.
  • compositions preparations and kits
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising at least one of the above compounds or a pharmaceutically acceptable form thereof, and one or more pharmaceutically acceptable carriers, wherein the pharmaceutically acceptable form is selected from pharmaceutically acceptable salts, esters, stereoisomers, tautomers, polymorphs, solvates, N-oxides, isotope labels, metabolites or prodrugs.
  • a further object of the present invention is to provide a method for preparing the pharmaceutical composition of the present invention, which comprises combining at least one of the above compounds or a pharmaceutically acceptable form thereof or a mixture thereof with one or more pharmaceutically acceptable carriers.
  • Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, sterile liquids.
  • Pharmaceutically acceptable carriers include pharmaceutical excipients. Examples of suitable pharmaceutically acceptable carriers are described in Remington’s Pharmaceutical Sciences (2005).
  • the pharmaceutical composition can be administered in any form as long as it prevents, alleviates, prevents or cures the symptoms of a human or animal patient.
  • various suitable dosage forms can be prepared according to the administration route.
  • the pharmaceutical composition When administered orally, the pharmaceutical composition can be prepared into any oral acceptable preparation form.
  • the pharmaceutical composition When applied percutaneously or topically, the pharmaceutical composition may be formulated in a suitable ointment, lotion or liniment, wherein the active ingredient may be suspended or dissolved in one or more carriers.
  • the pharmaceutical composition can also be used in the form of injections, including injection solutions, sterile powders for injections and concentrated solutions for injections.
  • Another aspect of the present invention also relates to a pharmaceutical preparation comprising at least one of the above compounds, a pharmaceutically acceptable form thereof or a mixture thereof as an active ingredient, or a pharmaceutical composition of the present invention.
  • the preparation is in the form of a solid preparation, a semi-solid preparation, a liquid preparation or a gaseous preparation.
  • a further object of the present invention is to provide an article, for example, provided in the form of a kit.
  • Articles used herein are intended to include, but are not limited to, kits and packaging.
  • the article of the present invention comprises: (a) a first container; (b) a pharmaceutical composition located in the first container, wherein the composition comprises: a first therapeutic agent, including at least one of the above compounds or a pharmaceutically acceptable form thereof, or a mixture thereof; and (c) an optional package insert, which indicates that the pharmaceutical composition can be used to treat a disease or condition regulated by GPR75, for example: lipodystrophy, anorexia, diabetes, malignancy, glomerulonephritis, or a neurodegenerative disease (such as Alzheimer's disease).
  • a disease or condition regulated by GPR75 for example: lipodystrophy, anorexia, diabetes, malignancy, glomerulonephritis, or a neurodegenerative disease (such as Alzheimer's disease).
  • the package insert is a trademark, label, label, or the like, which lists information related to the pharmaceutical composition located in the first container.
  • the listed information is usually determined by the regulatory agency (e.g., the U.S. Food and Drug Administration) that governs the area where the product is to be sold.
  • the package insert specifically lists the indications for which the pharmaceutical composition is approved.
  • the package insert can be made of any material from which the information contained therein or thereon can be read.
  • the package insert is a printable material (e.g., paper, plastic, cardboard, foil, adhesive paper or plastic, etc.) on which the desired information can be formed (e.g., printed or applied).
  • Another object of the present invention is to provide a method for preventing or treating diseases or conditions regulated by GPR75, which comprises administering to an individual in need thereof an effective amount of at least one of the above-mentioned compounds or their pharmaceutically acceptable forms or mixtures thereof, or the pharmaceutical composition of the present invention.
  • the present invention provides the use of at least one of the above compounds or a pharmaceutically acceptable form thereof or the above pharmaceutical composition in the preparation of a medicament for preventing and/or treating a disease or condition modulated by GPR75.
  • the present invention provides at least one of the above compounds or a pharmaceutically acceptable form thereof or the above pharmaceutical composition for use in preventing and/or treating a disease or condition modulated by GPR75.
  • the disease or condition modulated by GPR75 includes, but is not limited to, lipodystrophy, anorexia, diabetes, malignancy, glomerulonephritis or a neurodegenerative disease (such as Alzheimer's disease).
  • the dosage regimen can be adjusted to provide the best desired response.
  • a single push, a bolus injection, and/or a continuous infusion, etc. can be administered.
  • several divided doses can be administered over time, or the dose can be proportionally reduced or increased as indicated by the urgency of the treatment situation.
  • the dosage value may vary with the type and severity of the condition to be alleviated, and may include single or multiple doses.
  • the dosage of treatment varies, depending on considerations such as: the age, sex, and general health of the patient to be treated; the frequency of treatment and the nature of the desired effect; the degree of tissue damage; the duration of symptoms; and other variables that can be adjusted by individual physicians.
  • the specific dosage regimen should be adjusted over time according to individual needs and the professional judgment of the person administering the composition or supervising the administration of the composition.
  • the dosage and administration regimen of the pharmaceutical composition can be easily determined by a person of ordinary skill in the clinical field.
  • the composition or compound of the present invention can be administered 4 times a day to once every 3 days in divided doses, and the dosage can be, for example, 0.01 to 1000 mg/time.
  • the required dose may be administered in one or more doses to achieve the desired result.
  • the pharmaceutical composition according to the present invention may also be provided in unit dosage form.
  • any number or sub-range falling within the range is intended to be Specifically disclosed.
  • each numerical range of a parameter disclosed herein e.g., in the form of "about a to b", or equivalently “about a to b”, or equivalently “about ab”
  • C 1-6 should be understood to cover any sub-range therein and each point value, such as C 2-5 , C 3-4, C 1-2, C 1-3, C 1-4, C 1-5, etc., as well as C 1, C 2, C 3, C 4, C 5, C 6, etc.
  • 5-10 yuan should be understood to cover any sub-range therein and each point value, such as 5-7 yuan , 5-8 yuan , 5-9 yuan , 6-7 yuan, 6-8 yuan, 6-9 yuan, etc., as well as 5 , 6, 7, 8, 9, 10 yuan, etc.
  • alkyl refers to a straight or branched saturated aliphatic hydrocarbon group.
  • C 1-6 alkyl used in the present invention refers to a saturated straight or branched hydrocarbon group having 1 to 6 carbon atoms (e.g., 1, 2, 3, 4, 5 or 6 carbon atoms).
  • C 1-6 alkyl can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or n-hexyl, etc.
  • alkylene refers to a saturated straight or branched divalent hydrocarbon group.
  • C 1-6 alkylene used herein refers to a saturated straight or branched divalent hydrocarbon group having 1 to 6 carbon atoms, such as methylene, ethylene, propylene or butylene.
  • cycloalkyl refers to a saturated or partially saturated, monocyclic or polycyclic (such as a bicyclic) non-aromatic hydrocarbon group; for example, a monocyclic ring such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclobutene, cyclopentene, cyclohexene; or a bicyclic ring, including a spirocyclic ring, a fused ring or a bridged ring (such as a bicyclo[1.1.1]pentyl, a bicyclo[2.2.1]heptyl, a bicyclo[3.2.1]octyl, a bicyclo[5.2.0]nonyl or a decahydronaphthyl group, etc.).
  • C3-8 cycloalkyl C3-8 cycl
  • heterocycloalkyl refers to a saturated or partially saturated, monocyclic or polycyclic (e.g., bicyclic) non-aromatic group having one or more carbon atoms (e.g., 1, 2, 3, 4, 5, 6, 7, 8, or 9) and one or more (e.g., 1, 2, 3, or 4) heteroatoms independently selected from N, O, P, and S in the ring.
  • the ring system in the heterocycloalkyl may be a fused ring, a bridged ring, or a spiro ring system. If the valence bond requirements are met, the heterocycloalkyl may be connected to other groups (or fragments) through any one of the carbon atoms or heteroatoms in the ring.
  • heterocycloalkyl group examples include oxirane, azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, dioxolanyl, tetrahydrothiophenyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, morpholinyl, thiomorpholinyl, homopiperazinyl and the like.
  • aryl refers to an all-carbon monocyclic or fused polycyclic (eg, bicyclic) aromatic group having a conjugated ⁇ electron system.
  • C 6-10 aryl refers to an aromatic group containing 6 to 10 carbon atoms, such as phenyl or naphthyl.
  • heteroaryl refers to an aromatic group of a monocyclic or condensed ring with a conjugated ⁇ electron system, having one or more carbon atoms (such as 1, 2, 3, 4, 5, 6, 9 or 10 carbon atoms) and one or more (such as 1, 2, 3 or 4) heteroatoms independently selected from N, O, P and S in the ring.
  • Heteroaryl can be characterized by the number of ring atoms.
  • a 5-10 yuan heteroaryl can contain 5-10 (such as 5, 6, 7, 8, 9 or 10) ring atoms, particularly containing 5, 6, 9, 10 ring atoms.
  • heterocycloalkyl can be connected to the parent molecular part by any one of the ring atoms.
  • heteroaryl include thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, etc.
  • the term also encompasses the situation where the heteroaryl group can be optionally further fused to the aryl or heteroaryl ring to form a fused ring system.
  • halo or halogen group refers to F, Cl, Br or I.
  • substituent X and substituent Y are each independently hydrogen, halogen, hydroxyl, -CN, alkyl or aryl.
  • substituent Y can be either hydrogen, or halogen, hydroxyl, -CN, alkyl or aryl; similarly, when substituent Y is hydrogen, substituent X can be either hydrogen, or halogen, hydroxyl, -CN, alkyl or aryl.
  • substituted and its variant forms herein refers to one or more (eg, 1, 2, 3 or 4) atoms or groups of atoms (such as hydrogen atoms) are replaced by other equivalents, provided that the normal valence of the specified atoms or groups of atoms in the current situation is not exceeded and stable compounds can be formed. If an atom or group of atoms is described as "optionally substituted by", it can be substituted or unsubstituted. Unless otherwise specified, the attachment site of the substituent herein can be from any suitable position of the substituent. When the connecting bond in the substituent is shown as a chemical bond between two atoms connected to each other in the ring system, it means that the substituent can be connected to any ring-forming atom in the ring system.
  • pharmaceutically acceptable salt refers to a salt of a compound of the present invention that is substantially non-toxic to an organism.
  • Pharmaceutically acceptable salts generally include (but are not limited to) salts formed by reacting a compound of the present invention with a pharmaceutically acceptable inorganic acid/organic acid/acidic amino acid or inorganic base/organic base/basic amino acid, which are also referred to as acid addition salts or base addition salts.
  • suitable salts see, for example, Jusiak, Soczewinski, et al., Remington’s Pharmaceutical Sciences [M], Mack Publishing Company, 2005 and Stahl, Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection, and Use [M], Wiley-VCH, 2002. Methods for preparing pharmaceutically acceptable salts of the compounds of the present invention are known to those skilled in the art.
  • pharmaceutically acceptable ester refers to an ester which is substantially non-toxic to an organism and is hydrolyzed in vivo to form a compound of the present invention or a salt thereof.
  • the compound of the present invention itself may also be an ester.
  • isomers refers to compounds that have the same molecular weight because they have the same number of atoms and types of atoms, but differ in the arrangement or configuration of the atoms in space.
  • stereoisomer refers to a stable isomer that has a vertical asymmetric plane due to at least one chiral factor (including chiral center, chiral axis, chiral plane, etc.), thereby being able to rotate plane polarized light. Since the compounds of the present invention may have asymmetric centers and other chemical structures that may cause stereoisomerism, the present invention also includes these stereoisomers and mixtures thereof. Since the compounds of the present invention (or their pharmaceutically acceptable salts) include asymmetric carbon atoms, they can exist in the form of single stereoisomers, racemates, enantiomers, and mixtures of diastereomers.
  • these compounds can be prepared in the form of racemates. However, if desired, such compounds may be prepared or isolated as pure stereoisomers, i.e., single enantiomers or diastereomers, or mixtures enriched in a single stereoisomer (purity ⁇ 99%, ⁇ 98%, ⁇ 97%, ⁇ 96%, ⁇ 95%, ⁇ 90%, ⁇ 85%, ⁇ 80%, ⁇ 75%, ⁇ 70%, ⁇ 65%, or ⁇ 60%).
  • single stereoisomers of a compound may be prepared synthetically from optically active starting materials containing the desired chiral center, or by preparing a mixture of enantiomeric products followed by separation or resolution, e.g., conversion to a mixture of diastereomers followed by separation or recrystallization, chromatography, use of a chiral resolving agent, or direct separation of the enantiomers on a chiral chromatographic column.
  • Starting compounds of a particular stereochemistry may be either commercially available or prepared as described below and resolved by methods well known in the art.
  • the term "enantiomer" refers to a pair of stereoisomers that have non-superimposable mirror images of each other.
  • racemic mixture or “racemate” refers to a mixture containing equal parts of a single enantiomer (i.e., an equimolar mixture of two R and S enantiomers).
  • non-racemic mixture refers to a mixture containing unequal parts of a single enantiomer. Unless otherwise indicated, all stereoisomeric forms of the compounds of the present invention are within the scope of the present invention.
  • Solid wedge Virtual wedge To depict the covalent chemical bonds of the compounds of the invention.
  • all possible stereoisomers e.g., a specific enantiomer, a racemic mixture, etc.
  • stereoisomer shown is present.
  • stereoisomers of the compounds of the invention may encompass specific enantiomers, diastereomers, racemates, or mixtures thereof in any ratio.
  • tautomer refers to structural isomers with different energies that can be interconverted via a low energy barrier. If tautomerism is possible (such as in solution), a chemical equilibrium of the tautomers can be achieved.
  • proton tautomers include (but are not limited to) interconversions via proton migration, such as keto-enol isomerization, imine-enamine isomerization, amide-imino alcohol isomerization, nitroso-oxime isomerization, etc. Etc. Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are within the scope of the present invention.
  • polymorph refers to a solid crystalline form of a compound or complex.
  • the present invention encompasses all possible crystalline forms or polymorphs of the compounds of the present invention, which may be a single polymorph or a mixture of multiple polymorphs in any proportion.
  • solvate refers to a substance formed by the combination of a compound of the present invention (or a pharmaceutically acceptable salt thereof) and at least one solvent molecule by non-covalent intermolecular forces.
  • the compounds of the present invention may exist in the form of a solvate, which contains a polar solvent as a lattice structural element.
  • the amount of the polar solvent may be present in a stoichiometric or non-stoichiometric ratio.
  • isotope label refers to a derivative compound formed by replacing a specific atom in the compound of the present invention with its isotope atom.
  • the compound of the present invention includes various isotopes of H, C, N, O, F, P, S, and Cl, such as 2 H (D), 3 H (T), 13 C, 14 C, 13 N, 15 N, 17 O, 18 O, 18 F, 31 P, 32 P, 34 S, 35 S, 36 S, 37 Cl, and 125 I.
  • 12 C can be replaced by 13 C or 14 C
  • 1 H can be replaced by 2 H (D, deuterium) or 3 H (T, tritium)
  • 16 O can be replaced by 18 O, etc.
  • nitrogen-containing heterocycles can form N-oxides.
  • nitrogen-containing heterocycles that can form N-oxides.
  • tertiary amines can form N-oxides.
  • Synthetic methods for preparing N-oxides of heterocycles and tertiary amines are well known to those skilled in the art, including oxidation of heterocycles and tertiary amines with peroxyacids such as peracetic acid and metachloroperbenzoic acid (mCPBA), hydrogen peroxide, alkyl hydroperoxides such as tert-butyl hydroperoxide, sodium perborate and dioxirane such as dimethyl dioxirane.
  • peroxyacids such as peracetic acid and metachloroperbenzoic acid (mCPBA)
  • hydrogen peroxide alkyl hydroperoxides such as tert-butyl hydroperoxide
  • sodium perborate and dioxirane such as dimethyl dioxirane.
  • metabolite refers to a derivative compound formed after metabolism of a compound of the present invention, for example, produced by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc.
  • the present invention covers all possible metabolite forms of the compounds of the present invention, that is, substances formed in the body of an individual to whom the compounds of the present invention are administered.
  • the metabolites of the compounds can be identified by known techniques in the art, and their activity can be characterized by experiments.
  • prodrug refers to a derivative compound that can directly or indirectly provide a compound of the present invention after administration to an individual.
  • Particularly preferred derivative compounds or prodrugs are compounds that can increase the bioavailability of the compound of the present invention when administered to an individual (e.g., more easily absorbed into the blood), or compounds that promote the delivery of the parent compound to the site of action (e.g., the lymphatic system).
  • all prodrug forms of the compounds of the present invention are within the scope of the present invention, and various prodrug forms are known in the art, for example, see T. Higuchi, V. Stella, Pro-drugs as Novel Drug Delivery Systems [J], American Chemical Society, Vol. 14, 1975.
  • the present invention also covers compounds of the present invention containing protecting groups.
  • protecting groups In any process for preparing the compounds of the present invention, it may be necessary and/or desirable to protect sensitive groups or reactive groups on any related molecules, thereby forming a chemically protected form of the compounds of the present invention. This can be achieved by conventional protecting groups, for example those described in T. W. Greene, P. G. M. Wuts, Protective Groups in Organic Synthesis [M], John Wiley & Sons, 2006. These protecting groups can be removed at an appropriate subsequent stage using methods known in the art.
  • the present invention also encompasses methods for preparing the compounds described herein. It should be understood that the compounds of the present invention can be synthesized using the methods described below and synthetic methods known in the field of synthetic organic chemistry or variations thereof known to those skilled in the art. Preferred methods include (but are not limited to) those described below.
  • the reaction can be carried out in a solvent or solvent mixture suitable for the reagents and materials used and suitable for achieving the transformation.
  • active ingredient refers to a chemical entity that is effective in To treat one or more symptoms of a target disorder or condition.
  • the term "effective amount” refers to the amount of active ingredient that, after administration, will achieve the desired effect to some extent, such as alleviating one or more symptoms of the condition being treated or preventing the occurrence of the condition or its symptoms.
  • prevention refers to inhibiting and delaying the onset of a disease, and includes not only prevention before the development of the disease but also prevention of recurrence of the disease after treatment.
  • “individual” includes human or non-human animals.
  • Exemplary human individuals include human individuals (referred to as patients) suffering from diseases (e.g., diseases described herein) or normal individuals.
  • Non-human animals in the present invention include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and/or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).
  • FIG1 shows the effects of compounds and 20-HETE on ERK phosphorylation levels.
  • MS Mass spectrometry
  • Nuclear magnetic resonance (NMR) measurements were performed using a Bruker nuclear magnetic resonance spectrometer, manufacturer: Bruker, model: AVANCE NEO HD-400.
  • the preparative high performance liquid chromatography (HPLC) method was performed using a Huachuang Meixi LC2060 preparative liquid chromatograph (Suyan technologies, ODS, HPLCONE 10C18A, 250*10mm*10um column & Suyan technologies, ODS, HPLCONE 10C18A, 250*30mm*10um column).
  • Thin layer chromatography purification was performed using Yantai Yinlong GF 254 (5-20 ⁇ m) silica gel plates.
  • the reaction is monitored by thin layer chromatography (TLC) or liquid chromatography-mass spectrometry (LC-MS), and the developing solvent system used includes but is not limited to: dichloromethane and methanol system, n-hexane and ethyl acetate system, and petroleum ether and ethyl acetate system.
  • the volume ratio of the solvent is adjusted according to the polarity of the compound, or adjusted by adding triethylamine, acetic acid or formic acid.
  • the eluent system includes but is not limited to the dichloromethane and methanol system and the petroleum ether and ethyl acetate system.
  • the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of triethylamine, acetic acid or formic acid can also be added for adjustment.
  • reaction temperature is room temperature (20°C to 30°C).
  • the reagents used in the examples were purchased from Acros Organics, Aldrich Chemical Company, Nanjing Yaoshi Technology, Titan Technology, Shanghai BiDe, Leyan, Anhui Zesheng or Beijing Inokai.
  • reaction solution was quenched with an aqueous solution of ammonium chloride (20 ml) under an ice bath, the aqueous phase was extracted with ethyl acetate (50 mL * 3), the combined organic phases were washed with an aqueous solution of sodium chloride (50 mL * 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was dried by spin drying.
  • N-Boc- ⁇ -amino acid (2.45 g, 14.01 mmol, 1 eq.) and SMA or SMC (10.78 mmol, 0.77 eq.) were dissolved in DMF (45 mL), and DIPEA (2.79 g, 21.55 mmol, 1.55 eq.) and HATU (6.15 g, 16.16 mmol, 1.15 eq.) were added. After stirring at room temperature for 1 hour, the mixture was heated to 45°C and reacted for 24 hours. LC-MS and TLC showed that the reaction was basically complete.
  • the intermediate 9 (0.19 mmol, 1 eq.) was dissolved in THF/MeOH (2 ml/2 ml), and an aqueous solution (1 ml) of lithium hydroxide (80 mg, 1.9 mmol, 10 eq.) was added dropwise. The reaction was stirred at room temperature for 6 hours. After the reaction was completed under TLC monitoring, the reaction solution was adjusted to pH ⁇ 3 with 1 M HCl solution, extracted with EA (20 mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried. The residue was separated by prep-HPLC (TFA condition, column: HPLCONE 10C18A 250*30mm*10um; Mobile Phase: [water(TFA)-ACN]: 10%-70%, 25 min) to obtain the target compound.
  • the first three steps of the synthesis method refer to Compound A9, and the subsequent steps of the synthesis method refer to Compound A4 to synthesize the following example compounds.
  • the intermediate 10 (0.19 mmol, 1 eq.) was dissolved in THF/MeOH (2 ml/2 ml), and an aqueous solution (1 ml) of lithium hydroxide (80 mg, 1.9 mmol, 10 eq.) was added dropwise. The temperature was raised to 50°C and stirred for reaction for 2 hours.
  • N-tert-Butyloxycarbonyl acetaldehyde amine (100 mg, 0.54 mmol) was dissolved in anhydrous methanol (5 mL). At 0 ° C, 2-amino-5-chloro-benzoic acid methyl ester (103 mg, 0.65 mmol) and acetic acid (32 mg, 0.54 mmol) were added in sequence. After stirring at room temperature for 20 min, sodium cyanoborohydride (102 mg, 1.62 mmol) was added and stirred for 5 hours. LCMS showed that the reaction was basically complete. After the reaction solution was concentrated under reduced pressure, water (20 mL) was added, and ethyl acetate was extracted (20 mL*2).
  • LCMS (HCOOH): m/z 376.8(M+H).
  • the crude compound 4 (0.5 g, 1.36 mmol) was dissolved in N, N-dimethylformamide (10 mL), and compound 5 (393 mg, 1.64 mmol), potassium acetate (401 mg, 4.08 mmol) and acetic acid (81.97 mg, 1.36 mmol) were added, and stirred at 25 ° C for 0.5 hours. Then sodium cyanoborohydride (257.4 mg, 4.08 mmol) was added in batches at 0 ° C, and stirred at 35 ° C for 1 hour. After TLC showed that the reaction was completed, the reaction solution was added to an aqueous solution (30 mL) and extracted with ethyl acetate (15 mL ⁇ 3).
  • the GTPase-Glo kit was used to detect the agonist activity of the compound on the GPR75 protein (the protein expression and purification method refers to the patent PCT/CN2022/117816 Test Example 1).
  • the experimental buffer was 20mM HEPES pH 7.5, 100mM NaCl, 0.01% MNG, 0.0006% CHS, 100 ⁇ M TCEP and 5mM MgCl 2.
  • the test compound and the control compound 20-HETE (a known GPR75 small molecule agonist) were diluted 10 times with 100% DMSO, and 4 concentration gradients were diluted continuously. The compound was then further diluted with buffer to 3 ⁇ working concentration, and 2.5 ⁇ L of the compound solution was added to the corresponding wells of the experimental plate.
  • the starting concentration of the test compound was 40 ⁇ M, the starting concentration of 20-HETE was 200 ⁇ M, and the working concentration of DMSO was 1%.
  • Dilute 1X GTPase-Glo and 5mM ADP with GTPase-Glo buffer add 7.5 ⁇ L of the solution to the test plate and incubate at room temperature. After 30 minutes, add 15 ⁇ L of detection reagent to the test plate and incubate at room temperature. Read the chemiluminescent signal on the BMG ClarioStar after 10 minutes.
  • %Effect 1-100%*(Signal-Bottom)/(Top-Bottom), where Signal represents the signal of the compound, Bottom represents the signal corresponding to 200 ⁇ M 20-HETE, and Top represents the signal of blank 1% DMSO.
  • CHO cells were diluted to 1.25 ⁇ 10 5 cells/ml using a double-antibody culture medium containing 88% DMEM, 10% FBS, 1% GlutaMax, and 1%, and 1 ml was inoculated into a 12-well plate per well.
  • the cells were cultured in a cell culture incubator at 5% CO 2 and 37°C for 24 hours. When the cells grew to 80%, the GPR75 plasmid transfection experiment could be performed.
  • Transfection reagent was prepared with Opti-MEM.
  • the total volume of transfection reagent per well in the 12-well plate was 250ul, including Opti-MEM, 200ng GPR75 plasmid, and 0.6ul Fugene HD (mass-volume ratio: 1:3), and the cells were allowed to stand at room temperature for 15min.
  • the old culture medium in the 12-well plate was removed, and the cells were washed with 1mL DPBS per well.
  • the DPBS was discarded and 1ml Opti-MEM culture medium was added.
  • 250ul transfection reagent was evenly added to each well. After gently shaking, the cells were placed in a cell culture incubator at 5% CO 2 and 37°C for 24h.
  • the compound of the present invention can activate GPR75, activate G protein and downstream pathway, and lead to an increase in the phosphorylation level of ERK.
  • DMEM complete medium 88% DMEM, 10% FBS (ExCell Bio), 1% GlutaMax (Gibco) and 1% double antibody (Gibco)), trypsin (Gibco) and DPBS (Gibco) in a 37°C water bath.
  • DMEM complete medium 88% DMEM, 10% FBS (ExCell Bio), 1% GlutaMax (Gibco) and 1% double antibody (Gibco)
  • trypsin Gibco
  • DPBS DPBS
  • plasmids GPR75, LgBit-Gq, Sm-G ⁇ 1, and G ⁇ 2, were co-transfected at 500 ng/plasmid.
  • the mass volume ratio of plasmid to transfection reagent Fugene was 1 ⁇ g:3 ⁇ l.
  • the plasmid and Fugene mixture was mixed with 250 ⁇ l Opti-MEM and allowed to stand at room temperature for 15 minutes. During the standing period, the cell culture medium in the 6-well plate was discarded and each well was added Wash once with 2 ml of DPBS, discard the DPBS, and add 2 ml of Opti-MEM to each well. After 15 minutes, evenly drop 250 ⁇ l of transfection reagent into each well, shake gently, and place in a cell culture incubator for 24 hours.
  • the detection buffer for diluting the cell samples to be tested prepare the detection buffer of 1 ⁇ HBSS and 10mM HEPES with deionized water, and adjust the pH to 7.4. Remove the opti-MEM containing the transfection reagent from the 6-well plate, rinse the cells with 2ml DPBS, add 250 ⁇ l of trypsin to the 6-well plate, gently shake and aspirate the trypsin, and incubate in the cell culture incubator for 3 minutes.
  • the substrate luciferin (Nano- Live Cell Substrate, Promega) and buffer (Nano- The luciferase detection reagent working solution was prepared with LCS Dilution Buffer, promega) at a volume ratio of 1:20. 5 ⁇ l of the detection reagent working solution was added to each well of the 384-well cell sample plate, the plate was sealed, centrifuged at 1000 rpm for 10 s, and incubated at room temperature for 2 hours. After 2 hours, the baseline chemiluminescence signal value was detected using an ELISA reader as the baseline data.
  • Small molecule compounds were diluted in a 384-well compound dilution plate with a maximum concentration of 125 ⁇ M, 5-fold dilution, and 8 gradients. The concentration of small molecule compounds in the dilution plate was 2.5 times the final concentration of the total system after adding cells. 10 ⁇ l of small molecule compounds were transferred from the 384-well compound dilution plate to the 384-well cell sample plate, sealed, centrifuged at 1000 rpm for 10 s, and allowed to stand at room temperature for 10 min. Chemiluminescent signals were detected on an enzyme reader and the curves were fitted using GraphPad Prism.
  • the agonist activity of each compound on GPR75 is shown in the following table: **** indicates EC50 ⁇ 10 ⁇ M; *** indicates 10 ⁇ M ⁇ EC50 ⁇ 50 ⁇ M.

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Abstract

一种作为GPR75激活剂的多环化合物、包含其的药物组合物及其用途。具体地,涉及一种具有式(1)结构的化合物或其药学上可接受的形式、包含其的药物组合物、其制备方法、及其在制备用于预防或治疗由GPR75调节的疾病的药物中的用途。

Description

作为GPR75激活剂的多环化合物、包含其的药物组合物及其用途 技术领域
本发明属于药物化学领域,涉及一种作为GPR75激活剂的化合物、包含其的药物组合物、其制备方法及医药用途。
背景技术
GPR75(G蛋白偶联受体75,G protein coupled receptor 75)属于G蛋白偶联受体家族成员,其内源性激动剂配体包括代谢产物20HETE以及趋化因子CCL5/RANTES6。GPR75在大量细胞类型中具有表达分布,其中在胰岛中表达的GPR75,通过CCL5的激活,调控胰岛素释放,参与调控人体内的葡萄糖稳态。在神经元表达的GPR75,通过CCL5的激活,防止由淀粉样蛋白β和人类免疫缺陷病毒病毒蛋白gp120和Tau介导的神经元细胞死亡。在肾脏中表达的GPR75,通过20-HETE激活,降低肾小球蛋白渗透率,20-HETE水平过低与蛋白尿和肾小球损伤有关。另外,发表于科学杂志的大数据研究表明,GPR75基因参与调节小鼠的肥胖。GPR75是颇具潜力的治疗肥胖、糖尿病、原发及恶性肿瘤引起的高消耗代谢疾病、神经退行性疾病、肾损伤等多种疾病靶点,已成为药物研发领域的热点。
GPR75目前文献报道的激动剂主要有20-HETE和CCL5,均属于内源性配体。其中20-HETE分子极不稳定,半衰期很短,难以开发成为药物。而CCL5是一种多肽,也存在成药性差的问题。另外,目前并不清楚,20-HETE和CCL5激活GPR75后,下游的G蛋白信号通路和arrestin信号通路分别如何影响生理和病理过程。因此,亟需开发稳定性良好的新型小分子激动剂,或具有偏向性激动效果的激动剂,一方面用于GPR75下游的信号传递机制及生物功能研究,另一方面用于治疗由GPR75调节的疾病或病症。
发明内容
本发明的目的是提供一类结构新颖的作为GPR75激活剂的化合物、包含其的药物组合物、其制备方法、及其在制备用于预防或治疗由GPR75调节的疾病的药物中的用途。
化合物
本发明提供了一种具有式(1)结构的化合物或其药学上可接受的形式:
其中,
W1、W2、W3和W4各自独立地选自CR1或N;条件是W1、W2、W3和W4不同时为N且不存在三个连续的N原子;
R1各自独立地选自H、卤素、羧基、OH、CN、C1-6烷基、C3-8环烷基、-OC3-8环烷基、-NRaRb、5-10元杂环烷基、C6-10芳基、5-10元杂芳基、-OC1-6烷基、-C(=O)Ra、-S(=O)Ra、-S(=O)2Ra、-C(=O)NRaRb、-NRaC(=O)Rb、-S(=O)NRaRb、-NRaS(=O)Rb、-S(=O)2NRaRb、-NRaS(=O)2Rb、-C(=O)ORa、-S(=O)(=NH)Ra、-P(=O)RaRb、-P(=NH)RaRb、-P(=O)(ORa)(ORb)-P(=O)(NRaRb)(ORc)或-P(=O)(NRaRb)(NRcRd);所述烷基、环烷基、杂环烷基、芳基、杂芳基各自任选地被一个或多个选自氘、卤素、OH、=O、CN、羧基、-C1-6烷基、-OC1-6烷基、C3-8环烷基、5-10元杂环烷基、C6-10芳基、5-10元杂芳基、-NRcRd、-C(=O)Rc、 -S(=O)Rc、-S(=O)2Rc、-S(=O)(=NH)Rc、-P(=O)RcRd、-P(=NH)RcRd、-P(=O)(ORc)(ORd)、-P(=O)(NRaRb)(ORc)、-P(=O)(NRaRb)(NRcRd)、-C(=O)NRcRd、-NRcC(=O)Rd、-S(=O)NRcRd、-NRcS(=O)Rd、-S(=O)2NRcRd、-NRcS(=O)2Rd、-C(=O)ORc、-NRcP(=O)RaRb、-NRcP(=O)(ORa)(ORb)、-NRcP(=O)(NRaRb)(ORc)或-NRcP(=O)(NRaRb)(NRcRd)的取代基取代,
Ra、Rb、Rc和Rd各自独立地选自H、C1-6烷基、C3-8环烷基、5-10元杂环烷基、C6-10芳基或5-10元杂芳基;或者,Ra和Rb、Rc和Rd与其所连接的原子一起形成5-10元杂环烷基;所述烷基、环烷基、杂环烷基、芳基或杂芳基各自任选地被一个或多个选自卤素、OH、NH2、=O、CN、羧基、-C1-6烷基、-OC1-6烷基、C3-8环烷基、5-10元杂环烷基、C6-10芳基、5-10元杂芳基、-NH(C1-6烷基)、-N(C1-6烷基)2、-NH(C3-8环烷基)、-NH(5-10元杂环烷基)、-N(C1-6烷基)(C3-8环烷基)或-N(C1-6烷基)(5-10元杂环烷基)的取代基取代;
X选自-OH;
Y选自NH、O或S;
L1、L2、L3和L4各自独立地选自键、CR4R5、NR3、O或S,条件是L1、L2、L3和L4不同时为键;
R2和R3各自独立地选自H、C3-8环烷基或C1-6烷基;所述环烷基或烷基各自任选地被一个或多个选自卤素、OH、=O、CN、羧基、-C1-6烷基、-OC1-6烷基、C3-8环烷基、5-10元杂环烷基、C6-10芳基、5-10元杂芳基、-NRcRd、-C(=O)Rc、-S(=O)Rc、-S(=O)2Rc、-S(=O)(=NH)Rc、-P(=O)RaRb、-P(=O)(ORa)(ORb)、-P(=O)(NRaRb)(ORc)、-P(=O)(NRaRb)(NRcRd)、-C(=O)NRcRd、-NRcC(=O)Rd、-S(=O)NRcRd、-NRcS(=O)Rd、-S(=O)2NRcRd、-NRcS(=O)2Rd、-NRcP(=O)RaRb、-NRcP(=O)(ORa)(ORb)、-NRcP(=O)(NRaRb)(ORc)、-NRcP(=O)(NRaRb)(NRcRd)、或-C(=O)ORc的取代基取代;
R4和R5各自独立地选自键、H、卤素、OH、SH、NH2、CN、羧基、C1-6烷基、-OC1-6烷基、-SC1-6烷基、C3-8环烷基、5-10元杂环烷基、-OC3-8环烷基、-SC3-8环烷基、-NH(C1-6烷基)、-N(C1-6烷基)2、-NH(C3-8环烷基)、-NH(5-10元杂环烷基)、-N(C1-6烷基)(C3-8环烷基)、-N(C1-6烷基)(5-10元杂环烷基)、-(C1-6亚烷基)-NH(C1-6烷基)、-(C1-6亚烷基)-CONH(C1-6烷基)、-(C1-6亚烷基)-NHCO(C1-6烷基)、-(C1-6亚烷基)-NHCO(C3-8环烷基)、-NHCO(C1-6烷基)或-NHCO(C3-8烷基);所述烷基、环烷基、杂环烷基各自任选地被一个或多个Re取代;
Re各自独立地选自卤素、OH、=O、CN、羧基、-C1-6烷基、-OC1-6烷基、C3-8环烷基、-OC3-8环烷基、5-10元杂环烷基、C6-10芳基、5-10元杂芳基、-NRcRd、-C(=O)Rc、-S(=O)Rc、-S(=O)2Rc、-S(=O)(=NH)Rc、-P(=O)RaRb、-P(=O)(ORa)(ORb)、-P(=O)(NRaRb)(ORc)、-P(=O)(NRaRb)(NRcRd)、-C(=O)NRcRd、-NRcC(=O)Rd、-S(=O)NRcRd、-NRcS(=O)Rd、-S(=O)2NRcRd、-NRcS(=O)2Rd、-NRcP(=O)RaRb、-NRcP(=O)(ORa)(ORb)、-NRcP(=O)(NRaRb)(ORc)、-NRcP(=O)(NRaRb)(NRcRd)、-C(=O)ORc、-O(C1-6亚烷基-O)n(C1-6烷基)、-NH(C1-6亚烷基-O)n(C1-6烷基)、-NHCOO(C1-6亚烷基-O)n(C1-6烷基)、-NHC(=NH)NH2或-NH-(C1-6亚烷基)-N(C1-6烷基)2
Re中的所述烷基、亚烷基、环烷基、芳基、杂芳基或杂环烷基各自任选地被一个或多个选自卤素、OH、NH2、SH、=O、CN、羧基、-C1-6烷基、-OC1-6烷基、C3-8环烷基、5-10元杂环烷基、C6-10芳基、5-10元杂芳基、-NH(C1-6烷基)、-N(C1-6烷基)2、-NH(C3-8环烷基)、-NH(5-10元杂环烷基)、-N(C1-6烷基)(C3-8环烷基)或-N(C1-6烷基)(5-10元杂环烷基)的取代基取代;
n各自独立地选自0、1、2、3、4、5、6、7或8;
或者,R4和R5一起形成=O;
或者,R4和R5与其所连接的原子一起形成C3-8环烷基或5-10元杂环烷基,所述环烷基或杂环烷基各自任选地被一个或多个选自卤素、OH、NH2、=O、CN、羧基、-C1-6烷基、-OC1-6烷基、C3-8环烷基、5-10元杂环烷基、C6-10芳基、5-10元杂芳基、-NRcRd、-C(=O)Rc、 -S(=O)Rc、-S(=O)2Rc、-S(=O)(=NH)Rc、-P(=O)RaRb、-P(=NH)RaRb、-P(=O)(ORa)(ORb)、-P(=O)(NRaRb)(ORc)、-P(=O)(NRaRb)(NRcRd)、-C(=O)NRcRd、-NRcC(=O)Rd、-S(=O)NRcRd、-NRcS(=O)Rd、-S(=O)2NRcRd、-NRcS(=O)2Rd、-NRcP(=O)RaRb、-NRcP(=O)(ORa)(ORb)、-NRcP(=O)(NRaRb)(ORc)、-NRcP(=O)(NRaRb)(NRcRd)、-C(=O)ORc或-NH-(C1-6亚烷基)-N(C1-6烷基)2的取代基取代;
或者,L1、L2、L3和L4中的任意两者与其所连接的原子一起形成C3-8环烷基、5-10元杂环烷基、C6-10芳基或者5-10元杂芳基,所述环烷基、杂环烷基、芳基或杂芳基各自任选地被一个或多个Rf取代;
Rf各自独立地选自卤素、=O、OH、SH、-NH2、CN、-C1-8烷基、C3-8环烷基、5-10元杂环烷基、-OC1-8烷基、-SC1-8烷基、-NH(C1-8烷基)、-N(C1-8烷基)2、-NH(C3-8环烷基)、-NH(5-10元杂环烷基)、-N(C1-6烷基)(C3-8环烷基)、-N(C1-6烷基)(5-10元杂环烷基)、-NH(C1-6亚烷基-O)n(C1-6烷基)、-NH-(C1-6亚烷基)-NHCOO(C1-6亚烷基-O)n(C1-6烷基)、-NH-(C1-6亚烷基)-CONH(C1-6亚烷基-O)n(C1-6烷基)、-NH-(C1-6亚烷基)-NHCO-(5-10元杂环烷基)、-NH-(C1-6亚烷基)-OCO-(C1-6烷基)、-NH-(C1-6亚烷基)-NHCO-(C1-6烷基)、-NH-(C1-6亚烷基)-CONH-(C1-6烷基)、-NH-(C1-6亚烷基)-CONH-(C1-6亚烷基)-OC1-6烷基、-NH-(C1-6亚烷基)-NHS(=O)2(C1-6烷基)、-NH-(C1-6亚烷基)-NHS(=O)2(C3-8环烷基)、-NH-(C1-6亚烷基)-S(=O)2(C1-6烷基)、-NH-(C1-6亚烷基)-S(=O)(=NH)(C1-6烷基)、-NHP(=O)(C1-6烷基)2、-NHP(=O)(ORa)(ORb)、-NHP(=O)(ORa)(C1-6烷基)、-NH-(C1-6亚烷基)-NH(C1-6烷基)或-NH-(C1-6亚烷基)-N(C1-6烷基)2
Rf中的所述烷基、亚烷基、环烷基或杂环烷基各自任选地被一个或多个选自卤素、OH、=O、CN、-NH2、-CONH2、-NHC(=NH)NH2、-N=C(NH2)2、羧基、-C1-6烷基、-(C1-6亚烷基)-NH2、-CONH(C1-6亚烷基-O)n(C1-6亚烷基)-NH2、-CONH(C1-6亚烷基-O)n(C1-6亚烷基)-OH、-CONH(C1-6亚烷基-O)n(C1-6烷基)、-CONH(C1-6亚烷基-O)n(C1-6亚烷基)-COOH、-O(C1-6亚烷基-O)n(C1-6亚烷基)-NH2、-O(C1-6亚烷基-O)n(C1-6亚烷基)-OH、-O(C1-6亚烷基-O)n(C1-6烷基)、-O(C1-6亚烷基-O)n(C1-6亚烷基)-COOH、-NH(C1-6亚烷基-O)n(C1-6亚烷基)-NH2、-NH(C1-6亚烷基-O)n(C1-6亚烷基)-OH、-NH(C1-6亚烷基-O)n(C1-6烷基)、-NH(C1-6亚烷基-O)n(C1-6亚烷基)-COOH、-NHCOO(C1-6亚烷基-O)n(C1-6亚烷基)-NH2、-NHCOO(C1-6亚烷基-O)n(C1-6亚烷基)-OH、-NHCOO(C1-6亚烷基-O)n(C1-6烷基)、-NHCOO(C1-6亚烷基-O)n(C1-6亚烷基)-COOH、-OC1-6烷基、C3-8环烷基、5-10元杂环烷基、C6-10芳基、5-10元杂芳基、-NH(C1-6烷基)、-N(C1-6烷基)2、-NH(C3-8环烷基)、-NH(5-10元杂环烷基)、-N(C1-6烷基)(C3-8环烷基)或-N(C1-6烷基)(5-10元杂环烷基)的取代基取代;
V选自5元杂芳基或-C≡C-;
Ar选自C6-10芳基、或者5-10元杂芳基,所述芳基或杂芳基各自任选地被一个或多个选自氘、卤素、OH、=O、CN、羧基、-C1-6烷基、-OC1-6烷基、C3-8环烷基、5-10元杂环烷基、C6-10芳基、5-10元杂芳基、-NRaRb、-C(=O)Ra、-S(=O)Ra、-S(=O)2Ra、-S(=O)(=NH)Ra、-P(=O)RaRb、-P(=NH)RaRb、-P(=O)(ORa)(ORb)、-P(=O)(NRaRb)(ORc)、-P(=O)(NRaRb)(NRcRd)、-C(=O)NRaRb、-NRaC(=O)Rb、-S(=O)2NRaRb、-NRaS(=O)2Rb或-C(=O)ORa的取代基取代;
所述药学上可接受的形式选自药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂化物、N-氧化物、同位素标记物、代谢物或前药。
在一些实施方案中,选自
在一些实施方案中,选自
在一些实施方案中,R1各自独立地选自H、卤素、羧基、OH、CN、C1-6烷基、C3-8环烷基、-OC3-8环烷基、-NRaRb、5-10元杂环烷基、C6-10芳基、5-10元杂芳基、-OC1-6烷基、-C(=O)Ra、-S(=O)2Ra、-C(=O)NRaRb、-NRaC(=O)Rb、-S(=O)2NRaRb、-NRaS(=O)2Rb、-S(=O)(=NH)Ra、-P(=O)RaRb、-P(=NH)RaRb、-P(=O)(ORa)(ORb)、-P(=O)(NRaRb)(ORc)、-P(=O)(NRaRb)(NRcRd)或-C(=O)ORa;所述烷基、环烷基、杂环烷基、芳基、杂芳基各自任选地被一个或多个选自氘、卤素、OH、=O、CN、羧基、-C1-6烷基、-OC1-6烷基、C3-8环烷基、5-10元杂环烷基、C6-10芳基、5-10元杂芳基、-NRcRd、-S(=O)Rc、-S(=O)2Rc、-C(=O)NRcRd、-NRcC(=O)Rd、-S(=O)NRcRd、-NRcS(=O)Rd、-S(=O)2NRcRd、-NRcS(=O)2Rd或-C(=O)ORc的取代基取代,
Ra、Rb、Rc和Rd各自独立地选自H、C1-6烷基、C3-8环烷基、5-10元杂环烷基、C6-10芳基或5-10元杂芳基;或者,Ra和Rb、Rc和Rd与其所连接的原子一起形成5-10元杂环烷基;所述烷基、环烷基、杂环烷基、芳基或杂芳基各自任选地被一个或多个选自卤素、OH、=O、CN、羧基、-C1-6烷基、-OC1-6烷基、C3-8环烷基、5-10元杂环烷基、C6-10芳基、5-10元杂芳基、-NH(C1-6烷基)、-N(C1-6烷基)2、-NH(C3-8环烷基)、-NH(5-10元杂环烷基)、-N(C1-6烷基)(C3-8环烷基)或-N(C1-6烷基)(5-10元杂环烷基)的取代基取代。
在一些实施方案中,R1各自独立地选自H、卤素、羧基、OH、CN、C1-6烷基、C3-8环烷基、-OC3-8环烷基、-NRaRb、5-10元杂环烷基、C6-10芳基、5-10元杂芳基或-OC1-6烷基;所述烷基、环烷基、杂环烷基、芳基、杂芳基各自任选地被一个或多个选自氘、卤素、OH、=O、CN、羧基、-C1-6烷基、-OC1-6烷基、C3-8环烷基、5-10元杂环烷基、C6-10芳基、5-10元杂芳基或-NRcRd的取代基取代,
Ra、Rb、Rc和Rd各自独立地选自H、C1-6烷基、C3-8环烷基或5-10元杂环烷基;或者,Ra和Rb、Rc和Rd与其所连接的原子一起形成5-10元杂环烷基;所述烷基、环烷基、杂环烷基各自任选地被一个或多个选自卤素、OH、=O、CN、羧基、-C1-6烷基、-OC1-6烷基、C3-8环烷基、5-10元杂环烷基、5-10元杂芳基、-NH(C1-6烷基)、-N(C1-6烷基)2、-NH(C3-8环烷基)、-NH(5-10元杂环烷基)、-N(C1-6烷基)(C3-8环烷基)或-N(C1-6烷基)(5-10元杂环烷基)的取代基取代。
在一些实施方案中,R1各自独立地选自H、卤素、CN、C1-6烷基或-OC1-6烷基;所述烷基各自任选地被一个或多个选自卤素、OH、=O、NH2、CN、-C1-6烷基或-OC1-6烷基的 取代基取代。
在一些实施方案中,R1各自独立地选自H、卤素、CN、C1-3烷基、或者-OC1-3烷基;所述烷基各自任选地被一个或多个选自卤素、OH、=O、NH2、CN、-C1-3烷基或-OC1-3烷基的取代基取代。
在一些优选的实施方案中,R1各自独立地选自H、F、Cl、Br、CN、-CH3或-OCH3
在一些实施方案中,R2和R3各自独立地选自H、C3-8环烷基或C1-6烷基;所述环烷基或烷基各自任选地被一个或多个选自卤素、OH、=O、CN、羧基、-C1-6烷基、-OC1-6烷基、C3-8环烷基、5-10元杂环烷基、C6-10芳基、5-10元杂芳基、-NRcRd、-C(=O)Rc、-S(=O)Rc、-S(=O)2Rc、-C(=O)NRcRd、-NRcC(=O)Rd、-S(=O)NRcRd、-NRcS(=O)Rd、-S(=O)2NRcRd、-NRcS(=O)2Rd或-C(=O)ORc的取代基取代。
在一些实施方案中,R2和R3各自独立地选自H、C3-6环烷基或C1-6烷基;所述环烷基或烷基各自任选地被一个或多个选自卤素、OH、=O、CN、羧基、-C1-6烷基、-OC1-6烷基、C3-8环烷基或5-10元杂环烷基的取代基取代。
在一些实施方案中,R2和R3各自独立地选自H或C1-6烷基;所述烷基任选地被一个或多个选自卤素、OH、=O或-C1-6烷基的取代基取代;
在一些实施方案中,R2和R3各自独立地选自H或C1-3烷基;所述烷基任选地被一个或多个选自卤素、OH、=O或-C1-3烷基的取代基取代;
在一些实施方案中,R2和R3各自独立地选自H或-CH3
在一些实施方案中,Y选自NH或O。
在一些实施方案中,R4和R5各自独立地选自H、卤素、OH、SH、NH2、CN、羧基、C1-6烷基、-OC1-6烷基、-SC1-6烷基、-NH(C1-6烷基)、-NH(C3-8环烷基)、-NH(5-10元杂环烷基)、-(C1-6亚烷基)-NH(C1-6烷基)、-(C1-6亚烷基)-CONH(C1-6烷基)、-(C1-6亚烷基)-NHCO(C1-6烷基)或-NHCO(C1-6烷基);所述烷基、环烷基、杂环烷基各自任选地被一个或多个Re取代;
Re各自独立地选自卤素、OH、=O、CN、羧基、-C1-6烷基、-OC1-6烷基、C3-8环烷基、5-10元杂环烷基、C6-10芳基、5-10元杂芳基、-NRcRd、-S(=O)Rc、-S(=O)2Rc、-C(=O)NRcRd、-NRcC(=O)Rd、-S(=O)NRcRd、-NRcS(=O)Rd、-S(=O)2NRcRd、-NRcS(=O)2Rd、-S(=O)(=NH)Rc、-P(=O)RcRd、-P(=O)(ORc)(ORd)、-P(=O)(NRaRb)(ORc)、-P(=O)(NRaRb)(NRcRd)、-NRcP(=O)RaRb、-NRcP(=O)(ORa)(ORb)、-NRcP(=O)(NRaRb)(ORc)、-NRcP(=O)(NRaRb)(NRcRd)、-O(C1-6亚烷基-O)n(C1-6烷基)、-NH(C1-6亚烷基-O)n(C1-6烷基)、-NHCOO(C1-6亚烷基-O)n(C1-6烷基)、-NHC(=NH)NH2或-NH-(C1-6亚烷基)-N(C1-6烷基)2
Re中的所述烷基、亚烷基、环烷基、芳基、杂芳基或杂环烷基各自任选地被一个或多个选自卤素、OH、=O、CN、-NH2、羧基、-C1-6烷基、-OC1-6烷基、C3-8环烷基、5-10元杂环烷基、C6-10芳基、5-10元杂芳基、-NH(C1-6烷基)、-N(C1-6烷基)2、-NH(C3-8环烷基)、-NH(5-10元杂环烷基)、-N(C1-6烷基)(C3-8环烷基)或-N(C1-6烷基)(5-10元杂环烷基)的取代基取代;
或者,R4和R5一起形成=O;
或者,R4和R5与其所连接的原子一起形成C3-8环烷基或5-10元杂环烷基,所述环烷基或杂环烷基各自任选地被一个或多个选自卤素、OH、=O、CN、羧基、-C1-6烷基、-OC1-6烷基、C3-8环烷基、5-10元杂环烷基、C6-10芳基、5-10元杂芳基、-NRcRd、-C(=O)Rc、-S(=O)Rc、-S(=O)2Rc、-C(=O)NRcRd、-NRcC(=O)Rd、-S(=O)NRcRd、-NRcS(=O)Rd、-S(=O)2NRcRd、-NRcS(=O)2Rd、-C(=O)ORc或-NH-(C1-6亚烷基)-N(C1-6烷基)2的取代基取代。
在一些实施方案中,R4和R5各自独立地选自H、卤素、OH、SH、NH2、CN、羧基、C1-6烷基、-OC1-6烷基、-SC1-6烷基、-NH(C1-6烷基)、-NH(5-10元杂环烷基)、-N(C1-6烷基)(C3-8环烷基)、-N(C1-6烷基)(5-10元杂环烷基);所述烷基、环烷基、杂环烷基各自任选地被一个或多个Re取代;
Re各自独立地选自卤素、OH、=O、CN、羧基、-C1-6烷基、-OC1-6烷基、C3-8环烷基、5-10元杂环烷基、C6-10芳基、5-10元杂芳基、-NRcRd、-S(=O)Rc、-S(=O)2Rc、-C(=O)NRcRd、-NRcC(=O)Rd、-S(=O)NRcRd、-S(=O)(=NH)Rc、-P(=O)RcRd、-P(=O)(ORc)(ORd)、-P(=O)(NRaRb)(ORc)、-P(=O)(NRaRb)(NRcRd)、-NRcP(=O)RaRb、-NRcP(=O)(ORa)(ORb)、-NRcP(=O)(NRaRb)(ORc)、-NRcP(=O)(NRaRb)(NRcRd)、-NRcS(=O)Rd、-S(=O)2NRcRd、-NRcS(=O)2Rd、-O(C1-3亚烷基-O)n(C1-3烷基)、-NH(C1-3亚烷基-O)n(C1-3烷基)、-NHCOO(C1-3亚烷基-O)n(C1-3烷基)、-NHC(=NH)NH2或-NH-(C1-3亚烷基)-N(C1-3烷基)2
Re中的所述烷基、亚烷基、环烷基、芳基、杂芳基或杂环烷基各自任选地被一个或多个选自卤素、OH、=O、CN、-NH2、SH、羧基、-OC1-6烷基、C3-8环烷基、5-10元杂环烷基、C6-10芳基、5-10元杂芳基、-NH(C1-6烷基)、-N(C1-6烷基)2、-NH(C3-8环烷基)、-NH(5-10元杂环烷基)、-N(C1-6烷基)(C3-8环烷基)或-N(C1-6烷基)(5-10元杂环烷基)的取代基取代;
或者,R4和R5一起形成=O;
或者,R4和R5与其所连接的原子一起形成C3-8环烷基或5-10元杂环烷基,所述环烷基或杂环烷基各自任选地被一个或多个选自卤素、OH、=O、CN、羧基、-C1-6烷基、-OC1-6烷基、C3-8环烷基、5-10元杂环烷基、C6-10芳基、5-10元杂芳基、-NRcRd或-NH-(C1-6亚烷基)-N(C1-6烷基)2的取代基取代。
在一些实施方案中,R4和R5各自独立地选自H、-CH3、-CH2OH、-CH2CH(CH3)2、-(CH2)mNH2、-(CH2)mSH、-(CH2)mSCH3、-(CH2)mNHCOCH3、-(CH2)mNHSO2CH3、-(CH2)mNHSO2(CH2)3、-CH2NH(CH2)2N(CH3)2、-(CH2)mNH(CH2COOH)2、-CH2O(CH2CH2O)nCH2COOH、-CH2O(CH2CH2O)nCH2CH2OH、-CH2O(CH2CH2O)nCH2CH2OCH3、-CH2NH(CH2CH2O)nCH2COOH、-(CH2)mSCH2CH(OH)CH2OH、-CH2NH(CH2CH2O)nCH2CH2OH、-CH2NH(CH2CH2O)nCH2CH2OCH3、-CH2CH2NHCOO(CH2CH2O)nCH2COOH、-CH2CH2NH(CH2CH2O)nCH2CH2OH、-CH2CH2NHCOO(CH2CH2O)nCH2CH2OCH3、-(CH2)mNHCH2CH(OH)CH2OH、-(CH2)mOCH2CH(OH)CH2OH、-(CH2)2COOH、-CH2COOH、、-(CH2)2CONH2、-CH2CONH2、-CH2CONHCH2CH(OH)CH2OH、-(CH2)2CONHCH2CH(OH)CH2OH、-CH2CONHCH2CH2NHCH(OH)CH2OH、-CH2CH2CONHCH2CH2NHCH(OH)CH2OH、-CH2CONHCH2CH2NH(CH2CH2O)nCH2COOH、-CH2CONHCH2CH2NH(CH2CH2O)nCH2CH2OH、-CH2CONHCH2CH2NH(CH2CH2O)nCH2CH2OCH3、-CH2CONHCH2CH2O(CH2CH2O)nCH2COOH、-CH2CONHCH2CH2O(CH2CH2O)nCH2CH2OH、-CH2CONHCH2CH2O(CH2CH2O)nCH2CH2OCH3、-CH2CH2CONHCH2CH2NH(CH2CH2O)nCH2COOH、-CH2CH2CONHCH2CH2NH(CH2CH2O)nCH2CH2OH、-CH2CH2CONHCH2CH2NH(CH2CH2O)nCH2CH2OCH3、-CH2CH2CONHCH2CH2O(CH2CH2O)nCH2COOH、-CH2CH2CONHCH2CH2O(CH2CH2O)nCH2CH2OH、 -CH2CH2CONHCH2CH2O(CH2CH2O)nCH2CH2OCH3
n各自独立地选自0、1、2、3、4、5、6、7或8,m各自独立地选自1、2、3、4、5、6、7或8,o各自独立地选自0、1、2或3。
在一些实施方案中,R4和R5各自独立地选自H、CN、羧基或C1-6烷基;所述烷基任选地被一个或多个选自卤素、OH、-NH2、CN或-NH-(C1-6亚烷基)-N(C1-6烷基)2的取代基取代。
在一些实施方案中,R4和R5各自独立地选自H或C1-6烷基;所述烷基任选地被一个或多个选自OH、-NH2或-NH-(C1-3亚烷基)-N(C1-3烷基)2的取代基取代。
在一些实施方案中,R4和R5各自独立地选自H、-CH3、-CH2OH、-CH2CH(CH3)2、-(CH2)4NH2或-CH2NH(CH2)2N(CH3)2
在一些实施方案中,R4和R5一起形成=O。
在一些实施方案中,R4和R5与其所连接的原子一起形成
在一些实施方案中,L3为-NH-。
在一些实施方案中,L4选自CR4R5,R4和R5各自独立地选自H或C1-6烷基;所述烷基任选地被一个或多个选自OH、-NH2或-NH-(C1-3亚烷基)-N(C1-3烷基)2的取代基取代。
在一些实施方案中,选自
在一些实施方案中,L1、L2、L3和L4各自独立地选自键、-O-、-NH-、-CH2-、-C(=O)-、 -CH(CH3)-、-CH(CH2OH)-、-CH(CH2CH(CH3)2)-、-CH((CH2)4NH2)-或-CH(CH2NH(CH2)2N(CH3)2)-,条件是L1、L2、L3和L4不同时为键。
在一些实施方案中,选自
在一些实施方案中,L1、L2、L3和L4中的任意两者与其所连接的原子一起形成C3-8环烷基、5-10元杂环烷基、C6-10芳基或者5-10元杂芳基,所述环烷基、杂环烷基、芳基或杂芳基各自任选地被一个或多个Rf取代;
Rf各自独立地选自卤素、=O、OH、-NH2、CN、-C1-8烷基、5-10元杂环烷基、-OC1-8烷基、-SC1-8烷基、-NH(C1-8烷基)、-N(C1-8烷基)2、-NH(C3-8环烷基)、-NH(5-10元杂环烷基)、-N(C1-6烷基)(C3-8环烷基)、-N(C1-6烷基)(5-10元杂环烷基)、-NH(C1-6亚烷基-O)n(C1-6烷基)、-NH-(C1-6亚烷基)-NHCOO(C1-6亚烷基-O)n(C1-6烷基)、-NH-(C1-6亚烷基)-NHCO-(5-10元杂环烷基)、-NH-(C1-6亚烷基)-NHCO-(C1-6烷基)、-NH-(C1-6亚烷基)-CONH-(C1-6烷基)、-NH-(C1-6亚烷基)-CONH-(C1-6亚烷基)-OC1-6烷基、-NH-(C1-6亚烷基)-NHS(=O)2(C1-6烷基)、-NH-(C1-6亚烷基)-NHS(=O)2(C3-8环烷基)、-NH-(C1-6亚烷基)-S(=O)2(C1-6烷基)、-NHP(=O)(C1-6烷基)2、-NHP(=O)(ORa)(ORb)、-NHP(=O)(ORa)(C1-6烷基)、-NH-(C1-6亚烷基)-S(=O)(=NH)(C1-6烷基)、-NH-(C1-6亚烷基)-NH(C1-6烷基)或-NH-(C1-6亚烷基)-N(C1-6烷基)2
Rf中的所述烷基、亚烷基、环烷基或杂环烷基各自任选地被一个或多个选自卤素、OH、=O、CN、-NH2、-CONH2、-NHC(=NH)NH2、-N=C(NH2)2、羧基、-C1-6烷基、-CONH(C1-6亚烷基-O)n(C1-6亚烷基)-NH2、-CONH(C1-6亚烷基-O)n(C1-6亚烷基)-OH、-CONH(C1-6亚烷基-O)n(C1-6烷基)、-CONH(C1-6亚烷基-O)n(C1-6亚烷基)-COOH、-O(C1-6亚烷基-O)n(C1-6亚烷基)-NH2、-O(C1-6亚烷基-O)n(C1-6亚烷基)-OH、-O(C1-6亚烷基-O)n(C1-6烷基)、-O(C1-6亚烷基-O)n(C1-6亚烷基)-COOH、-NH(C1-6亚烷基-O)n(C1-6亚烷基)-NH2、-NH(C1-6亚烷基-O)n(C1-6亚烷基)-OH、-NH(C1-6亚烷基-O)n(C1-6烷基)、-NH(C1-6亚烷基-O)n(C1-6亚烷基)-COOH、-OC1-6烷基、C3-8环烷基、5-10元杂环烷基、C6-10芳基、5-10元杂芳基、-NH(C1-6烷基)、-N(C1-6烷基)2、-NH(C3-8环烷基)、-NH(5-10元杂环烷基)、-N(C1-6烷基)(C3-8环烷基)或-N(C1-6烷基)(5-10元杂环烷基)的取代基取代。
在一些实施方案中,L1和L2与其所连接的原子一起形成5-10元杂芳基,所述杂芳基各自任选地被一个或多个Rf取代;
Rf各自独立地选自卤素、=O、OH、-NH2、CN、-C1-8烷基、-OC1-8烷基、-NH(C1-8烷基)、-N(C1-8烷基)2、-NH(C1-6亚烷基-O)n(C1-6烷基)、-NH-(C1-6亚烷基)-NHCOO(C1-6亚烷基-O)n(C1-6烷基)、-NH-(C1-6亚烷基)-NHCO-(C1-6烷基)、-NH-(C1-6亚烷基)-CONH-(C1-6烷基)、-NH-(C1-6亚烷基)-CONH-(C1-6亚烷基)-OC1-6烷基、-NH-(C1-6亚烷基)-NH(C1-6烷基)或 -NH-(C1-6亚烷基)-N(C1-6烷基)2
Rf中的所述烷基、亚烷基各自任选地被一个或多个选自卤素、OH、=O、CN、-NH2、-CONH2、-NHC(=NH)NH2、-N=C(NH2)2、羧基、-C1-6烷基、-(C1-6亚烷基)-NH2、-CONH(C1-6亚烷基-O)n(C1-6亚烷基)-NH2、-CONH(C1-6亚烷基-O)n(C1-6亚烷基)-OH、-CONH(C1-6亚烷基-O)n(C1-6烷基)、-O(C1-6亚烷基-O)n(C1-6亚烷基)-NH2、-O(C1-6亚烷基-O)n(C1-6亚烷基)-OH、-O(C1-6亚烷基-O)n(C1-6烷基)、-NH(C1-6亚烷基-O)n(C1-6亚烷基)-NH2、-NH(C1-6亚烷基-O)n(C1-6亚烷基)-OH、-NH(C1-6亚烷基-O)n(C1-6烷基)、-OC1-6烷基、-NH(C1-6烷基)、-N(C1-6烷基)2或-NH(C3-8环烷基)的取代基取代。
在一些实施方案中,L1和L2与其所连接的原子一起形成5-10元杂芳基,所述杂芳基各自任选地被一个或多个Rf取代;
Rf各自独立地选自卤素、=O、OH、-NH2、CN、-C1-8烷基、-NH(C1-8烷基)、-NH(C1-6亚烷基-O)n(C1-6烷基)、-NH-(C1-6亚烷基)-NHCO-(C1-6烷基)或-NH-(C1-6亚烷基)-N(C1-6烷基)2
Rf中的所述烷基、亚烷基各自任选地被一个或多个选自卤素、OH、=O、CN、-NH2、-CONH2、-NHC(=NH)NH2或-N=C(NH2)2的取代基取代。
在一些实施方案中,L1和L2与其所连接的原子一起形成嘧啶基或吡啶基,所述嘧啶基、吡啶基各自任选地被一个或多个选自-CH3、-NHCH3、-NH(CH2)2N(CH3)2、-NH(CH2)2NH2、-NH(CH2)2OH、 的取代基取代。
在一些实施方案中,L1和L2与其所连接的原子一起形成C3-8环烷基、5-10元杂环烷基、C6-10芳基或5-10元杂芳基,所述环烷基、杂环烷基、芳基或杂芳基各自任选地被一个或多个选自卤素、OH、-NH2、CN、-C1-6烷基、-OC1-6烷基、-SC1-6烷基、-NH(C1-6烷基)、-N(C1-6烷基)2、-NH-(C1-6亚烷基)-NH2、-NH-(C1-6亚烷基)-OH或-NH-(C1-6亚烷基)-N(C1-6烷基)2的取代基取代。
在一些实施方案中,L1和L2与其所连接的原子一起形成C5-8环烷基、5-8元杂环烷基、苯基或5-10元杂芳基,所述环烷基、杂环烷基、苯基或杂芳基各自任选地被一个或多个选自卤素、OH、-NH2、CN、-C1-3烷基、-OC1-3烷基、-SC1-3烷基、-NH(C1-3烷基)、-N(C1-3烷基)2、-NH-(C1-3亚烷基)-NH2、-NH-(C1-3亚烷基)-OH或-NH-(C1-3亚烷基)-N(C1-3烷基)2的取代基取代。
在一些实施方案中,L1和L2与其所连接的原子一起形成C5-6环烷基、5-6元杂环烷基或6元杂芳基,所述环烷基、杂环烷基或杂芳基各自任选地被一个或多个选自卤素、OH、-NH2、CN、-C1-3烷基、-OC1-3烷基、-SC1-3烷基、-NH(C1-3烷基)、-N(C1-3烷基)2、-NH-(C1-3亚烷基)-NH2、-NH-(C1-3亚烷基)-OH或-NH-(C1-3亚烷基)-N(C1-3烷基)2的取代基取代。
在一些实施方案中,L1和L2与其所连接的原子一起形成嘧啶基、吡啶基、吡嗪基、环己基或四氢呋喃基,所述嘧啶基、吡啶基、吡嗪基、环己基或四氢呋喃基各自任选地被一个或多个选自-CH3、-NHCH3、-NH(CH2)2N(CH3)2、-NH(CH2)2NH2、-NH(CH2)2OH、-S(CH2)2N(CH3)2、-S(CH2)2NH2、-S(CH2)2OH、-NH(CH2)3N(CH3)2、-NH(CH2)3NH2、-NH(CH2)3OH、-NH(CH2)3NHCOCH3、-NH(CH2)2NHSO2CH3、-NH(CH2)3NHSO2CH3、-NH(CH2)2NHSO2(CH2)3、-NH(CH2)3NHSO2(CH2)3、-NH(CH2)2O(CH2CH2O)nCH2COOH、-NH(CH2)2O(CH2CH2O)nCH2CH2OH、-NH(CH2)3COOH、-NH(CH2)2NHPO(OCH2CH3)2、-NH(CH2)3NHPO(OCH2CH3)2、-NH(CH2)2NHPO(CH2CH2OH)2、-NH(CH2)3NHPO(CH2CH2OH)2、-NH(CH2)2O(CH2CH2O)nCH2CH2OCH3、-NH(CH2)2O(CH2CH2O)nCH2CH2NH2、-NH(CH2)2SO2CH3、-NH(CH2)3SO2CH3、-NH(CH2)2PO(OH)2、-NH(CH2)3PO(OH)2、-NH(CH2)2NHPO(OH)2、-NH(CH2)3NHPO(OH)2、-NH(CH2)2NH(CH2CH2O)nCH2CH2OH、-NH(CH2)2NH(CH2CH2O)nCH2CH2OCH3、-NH(CH2)2NH(CH2CH2O)nCH2COOH、-NH(CH2)2NHCOO(CH2CH2O)nCH2COOH、-NHCH2CH2NHCOO(CH2CH2O)nCH2CH2OCH3、-NHCH2CH2NHCOO(CH2CH2O)nCH2CH2OH、-NHCH2CH2NHCH2CH(OH)CH2OH、-NHCH2CH2OCH2CH(OH)CH2OH、-NHCH2CH2SCH2CH(OH)CH2OH、-S(CH2)2NHSO2CH3、-S(CH2)2NHSO2(CH2)3、-S(CH2)2O(CH2CH2O)nCH2COOH、-S(CH2)2O(CH2CH2O)nCH2CH2OH、-S(CH2)2NHPO(OCH2CH3)2、-S(CH2)2NHPO(CH2CH2OH)2、-S(CH2)2O(CH2CH2O)nCH2CH2OCH3、-S(CH2)2O(CH2CH2O)nCH2CH2NH2、-S(CH2)2NHPO(OH)2、-S(CH2)3NHPO(OH)2、-S(CH2)2NH(CH2CH2O)nCH2CH2OH、-S(CH2)2NH(CH2CH2O)nCH2CH2OCH3、-S(CH2)2NH(CH2CH2O)nCH2COOH、-S(CH2)2NHCOO(CH2CH2O)nCH2COOH、-SCH2CH2NHCOO(CH2CH2O)nCH2CH2OCH3、-SCH2CH2NHCOO(CH2CH2O)nCH2CH2OH、-SCH2CH2NHCH2CH(OH)CH2OH、-SCH2CH2OCH2CH(OH)CH2OH、-O(CH2)2NHSO2CH3、-O(CH2)2NHSO2(CH2)3、-O(CH2)2O(CH2CH2O)nCH2COOH、-O(CH2)2O(CH2CH2O)nCH2CH2OH、-O(CH2)2NHPO(OCH2CH3)2、-O(CH2)2NHPO(CH2CH2OH)2、-O(CH2)2O(CH2CH2O)nCH2CH2OCH3、-O(CH2)2O(CH2CH2O)nCH2CH2NH2、-O(CH2)2NHPO(OH)2、-O(CH2)3NHPO(OH)2、-O(CH2)2NH(CH2CH2O)nCH2CH2OH、-O(CH2)2NH(CH2CH2O)nCH2CH2OCH3、-O(CH2)2NH(CH2CH2O)nCH2COOH、-O(CH2)2NHCOO(CH2CH2O)nCH2COOH、-OCH2CH2NHCOO(CH2CH2O)nCH2CH2OCH3、-OCH2CH2NHCOO(CH2CH2O)nCH2CH2OH、-OCH2CH2NHCH2CH(OH)CH2OH、-OCH2CH2OCH2CH(OH)CH2OH、-OCH2CH2SCH2CH(OH)CH2OH、-NHCH2CONHCH2CH2OH、-NHCH2CONHCH2CH2NH2、-NHCH2CONH(CH2CH2O)nCH2CH2OH、-NHCH2CONH(CH2CH2O)nCH2CH2OCH3、-NHCH2CONH(CH2CH2O)nCH2COOH、-NHCH2CONH2、-NHCH2CH2NH(CH2COOH)2 的取代基取代。
在一些实施方案中,L1和L2与其所连接的原子一起形成
在一些实施方案中,L1和L2与其所连接的原子一起形成
在一些实施方案中,L2和L3与其所连接的原子一起形成C5-10环烷基或5-10元杂环烷基,所述环烷基、杂环烷基各自任选地被一个或多个选自=O、卤素、OH、-NH2、CN、-C1-6烷基、-NH(C1-6烷基)或-N(C1-6烷基)2的取代基取代。
在一些实施方案中,L2和L3与其所连接的原子一起形成C5-8环烷基或5-8元杂环烷基,所述环烷基、杂环烷基各自任选地被一个或多个选自=O、卤素、OH、-NH2、CN、-C1-3烷基、-NH(C1-3烷基)或-N(C1-3烷基)2的取代基取代。
在一些实施方案中,L2和L3与其所连接的原子一起形成5-8元杂环烷基,所述杂环烷基任选地被一个或多个选自=O、卤素、OH、-NH2、CN或-C1-3烷基的取代基取代。
在一些实施方案中,L2和L3与其所连接的原子一起形成
在一些实施方案中,V选自呋喃基、噻吩基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、噁二唑基、噻二唑基、三唑基或-C≡C-。
在一些实施方案中,V选自 或-C≡C-。
在一些实施方案中,Ar选自C6-10芳基或5-10元杂芳基,所述芳基或杂芳基各自任选地被一个或多个选自氘、卤素、OH、=O、CN、羧基、-C1-6烷基、-OC1-6烷基、C3-8环烷基、5-10元杂环烷基、C6-10芳基、5-10元杂芳基、-NRaRb、-C(=O)Ra、-S(=O)Ra、-S(=O)2Ra、-C(=O)NRaRb、-NRaC(=O)Rb、-S(=O)2NRaRb、-NRaS(=O)2Rb或-C(=O)ORa的取代基取代。
在一些实施方案中,Ar选自C6-10芳基或5-10元杂芳基,所述芳基或杂芳基各自任选地被一个或多个选自氘、卤素、OH、=O、CN、羧基、-C1-6烷基、-OC1-6烷基、C3-8环烷基、5-10元杂环烷基、C6-10芳基、5-10元杂芳基或-NRaRb的取代基取代。
在一些实施方案中,Ar选自C6-10芳基或5-8元杂芳基,所述芳基或杂芳基各自任选地被一个或多个选自卤素、OH、NH2、CN、-C1-3烷基、-OC1-3烷基、-NH(C1-3烷基)或-N(C1-3烷基)2的取代基取代。
在一些实施方案中,Ar选自苯基或吡啶基,所述苯基或吡啶基各自任选地被一个或多个选自F、Cl、Br、OH、NH2、CN、-C1-3烷基或-OC1-3烷基的取代基取代。
在一些实施方案中,Ar选自苯基或吡啶基,所述苯基或吡啶基各自任选地被一个或多个选自F、Cl、Br、CN、-CH3或-OCH3的取代基取代。
在一些实施方案中,Ar选自
在一些实施方案中,本发明提供一种具有式(1-2)或式(1-3)结构的化合物或其药学上可接受的形式:
其中,W14选自CR1或N,其他各变量如式(1)中所定义。
在一些实施方案中,本发明的式(1)所示的化合物具有式(2)所示的结构:
其中,
W5、W6、W7和W8各自独立地选自CR6或N;条件是W5、W6、W7和W8不同时为N且不存在三个连续的N原子;
R6各自独立地选自卤素、OH、-NH2、CN、-C1-6烷基、-NH(C1-6烷基)、-N(C1-6烷基)2、-NH-(C1-6亚烷基)-NH2、-NH-(C1-6亚烷基)-OH、-NH(C1-6亚烷基-O)n(C1-6烷基)、-NH-(C1-6亚烷基)-NHCO-(C1-6烷基)或-NH-(C1-6亚烷基)-N(C1-6烷基)2,所述烷基、亚烷基各自任选地被一个或多个选自卤素、OH、=O、CN、-NH2、-CONH2、-NHC(=NH)NH2或-N=C(NH2)2的取代基取代;
Z选自O或S;
U2和U3独立地选自CH或N;
W9、W10、W11、W12和W13各自独立地选自CR7或N;条件是W9、W10、W11、W12和W13不同时为N且不存在三个连续的N原子;
R7各自独立地选自卤素、OH、NH2、CN、羧基、-C1-6烷基、-OC1-6烷基、C3-8环烷基、5-10元杂环烷基、C6-10芳基、5-10元杂芳基、-NH(C1-6烷基)、-NH(C3-8环烷基)、-NH(5-10元杂环烷基)、-N(C1-6烷基)(C3-8环烷基)或-N(C1-6烷基)(5-10元杂环烷基)或-N(C1-6烷基)2
W1、W2、W3、W4、X如式(1)中所定义。
在一些实施方案中,本发明提供了具有式(2-1)或式(2-2)所示的结构的化合物:
其中,各变量如式(2)中所定义。
在一些实施方案中,本发明的式(1)所示的化合物具有式(3)所示的结构:
其中,
Z选自O或S;
U2和U3独立地选自CH或N;
W9、W10、W11、W12和W13各自独立地选自CR7或N;条件是W9、W10、W11、W12和W13不同时为N且不存在三个连续的N原子;
R7各自独立地选自卤素、OH、NH2、CN、羧基、-C1-6烷基、-OC1-6烷基、C3-8环烷基、5-10元杂环烷基、C6-10芳基、5-10元杂芳基、-NH(C1-6烷基)、-NH(C3-8环烷基)、-NH(5-10元杂环烷基)、-N(C1-6烷基)(C3-8环烷基)或-N(C1-6烷基)(5-10元杂环烷基)或-N(C1-6烷基)2
W1、W2、W3、W4、X、R4和R5如式(1)中所定义。
在一些实施方案中,本发明的式(2)所示的化合物具有式(4)所示的结构:
其中,W1、W2、W3、W4、R6、R7、U2和U3如式(2)中所定义。
在一些实施方案中,本发明的式(3)所示的化合物具有式(5)所示的结构:
其中,W1、W2、W3、W4、W9、W10、W11、W12、W13、R4、R5、U2和U3如式(3)中所定义。
在一些实施方案中,本发明提供了具有式(5-1)或式(5-2)所示的结构的化合物:
其中,各变量如式(5)中所定义。
在一些实施方案中,本发明的式(3)所示的化合物具有式(6)所示的结构:
其中,W1、W2、W3、W4、R7、U2和U3如式(3)中所定义。
在一些实施方案中,本发明提供了具有式(7)所示的结构的化合物:
其中,各变量如式(2)中所定义。
在一些实施方案中,本发明提供了具有式(7-1)或式(7-2)所示的结构的化合物:
其中,各变量如式(2)中所定义。
本领域技术人员应当理解,本发明涵盖针对各个实施方案进行任意组合所得的化合物。由一个实施方案中的技术特征或优选技术特征与另外的实施方案中的技术特征或优选技术特征组合得到的实施方案也包括在本发明的范围内。
在一些实施方案中,本发明还提供了化合物或其药学上可接受的盐、酯、立体异构 体、互变异构体、溶剂化物、N-氧化物、同位素标记物、代谢物或前药,所述化合物选自:












制备方法
本发明的化合物可以通过本领域已知的任何方法制备。试剂和起始材料对于本领域普通技术人员来说是容易获得的。单独的异构体、对映异构体和非对映异构体可以在合成中的任何方便点通过诸如选择性结晶技术或手性色谱法的方法进行分离或拆分(参见例如selective crystallization techniques or chiral chromatography(See for example,J.Jacques,et al.,"Enantiomers,Racemates,and Resolutions",John Wiley and Sons,Inc.,1981,and E.L.Eliel and S.H.Wilen)。
在一些实施方案中,本发明提供式(4)所示的化合物的制备方法,其包括:
步骤1:
(1-a)化合物SMA和化合物INT1-A在有机溶剂和碱存在下反应得到化合物INT1-B;
(1-b)化合物INT1-B在还原剂、酸和有机溶剂存在下反应得到化合物INT1;
在一些实施方案中,上述步骤(1-a)中的所述有机溶剂选自异丙醇、叔丁醇、二甲基亚砜、或N,N-二甲基甲酰胺;优选异丙醇或N,N-二甲基甲酰胺;所述碱选自三乙胺、N,N-二异丙基乙胺、DBU、碳酸钾、碳酸铯、或叔丁醇钠;优选三乙胺或N,N-二异丙基乙胺。
在一些实施方案中,上述步骤(1-b)中的所述有机溶剂选自二氯甲烷、乙醇、乙腈、甲醇、或四氢呋喃;优选二氯甲烷或乙醇;所述还原剂选自锌粉或铁粉;优选锌粉;所 述酸选自乙酸、氯化铵、稀盐酸或三氟乙酸;优选乙酸。
步骤2:化合物SMB和化合物INT3-A在有机溶剂、碱和催化剂存在下反应得到化合物INT3;
在一些实施方案中,上述步骤2中的所述有机溶剂选自1,4-二氧六环/水、二甲基亚砜、N,N-二甲基甲酰胺、或甲苯/水;优选1,4-二氧六环/水;所述碱选自碳酸钾、碳酸铯、叔丁醇钠、或叔丁醇钾;优选碳酸钾或碳酸铯;所述催化剂选自Pd(PPh3)4、Pd(dppf)Cl2、Pd(OAc)2或Pd2(dba)3;优选Pd(PPh3)4或Pd2(dba)3
步骤3:
(3-a)化合物INT1和化合物INT3在有机溶剂、还原剂和催化剂存在下反应得到化合物INT9;
(3-b)化合物INT9在有机溶剂和碱存在下反应得到式(4)所示的化合物;
在一些实施方案中,上述步骤(3-a)中的所述有机溶剂选自二氯甲烷、乙酸乙酯、四氢呋喃、乙腈、氯仿、或1,2-二氯乙烷;优选二氯甲烷、或1,2-二氯乙烷;所述还原剂选自氰基硼氢化钠、三乙酰氧基硼氢化钠、硼氢化钠、硼氢化锂、或硼氢化锌;优选氰基硼氢化钠、或三乙酰氧基硼氢化钠;所述催化剂选自四氯化钛、钛酸四异丙酯、三氯化铋、三氟甲磺酸钪、或无水氯化锌;优选四氯化钛、或三氯化铋。
在一些实施方案中,上述步骤(3-b)中的所述碱选自氢氧化锂、氢氧化钠、或氢氧化钾;优选氢氧化锂。
在一些实施方案中,本发明提供式(5)所示的化合物的制备方法,其包括:
步骤1:
(1-a)化合物SMA和化合物INT6-A在有机溶剂和碱存在下反应得到化合物INT6-1;
(1-b)化合物INT6-1在脱保护条件下反应得到化合物INT6;
在一些实施方案中,上述步骤(1-a)中的所述有机溶剂选自N,N-二甲基甲酰胺、二甲基亚砜、N,N-二甲基甲酰胺、乙腈、四氢呋喃、或二氯甲烷;优选N,N-二甲基甲酰胺、四氢呋喃、或两者的混合溶剂;所述碱选自N,N-二异丙基乙胺、三乙胺;优选N,N-二异丙基乙胺。
在一些实施方案中,上述步骤(1-b)中的所述脱保护条件选自甲醇/乙酰氯、HCl/甲醇溶液、HCl/1,4-二氧六环溶液、三氟乙酸/二氯甲烷、或甲醇/甲磺酸;优选甲醇/乙酰氯、或三氟乙酸/二氯甲烷。
步骤2:
(2-a)化合物INT3和化合物INT6在有机溶剂和还原剂存在下反应得到化合物INT10;
(2-b)化合物INT10在碱存在下反应得到式(5)所示的化合物;
在一些实施方案中,上述步骤(2-a)中的所述有机溶剂选自N,N-二甲基甲酰胺、乙腈、二氯甲烷、或四氢呋喃;优选N,N-二甲基甲酰胺、或二氯甲烷;所述还原剂选自氰基硼氢化钠、三乙酰氧基硼氢化钠、硼氢化钠、硼氢化锂、硼氢化锌、或三乙基硅烷;优选氰基硼氢化钠、或三乙酰氧基硼氢化钠。
在一些实施方案中,上述步骤(2-b)中的所述碱选自氢氧化锂、氢氧化钠、或氢氧化钾;优选氢氧化锂。
在上述制备方法中,W1、W2、W3、W4、R6、R7、W9、W10、W11、W12、W13、R4、R5、U2和U3如上述所定义。
本领域技术人员应当理解,根据期望获得的产物结构,可以省略上述制备方法中的一个或多个步骤,也可根据需要适当地调整反应步骤的顺序以及增加或省略保护/脱保护反应步骤。
药物组合物、制剂和试剂盒
本发明还提供一种药物组合物,其包含至少一种上述化合物或其药学上可接受的形式、以及一种或多种药学上可接受的载体,所述药学上可接受的形式选自药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂化物、N-氧化物、同位素标记物、代谢物或前药。
本发明的进一步的目的在于提供一种制备本发明的药物组合物的方法,所述方法包括将至少一种上述化合物或其药学上可接受的形式或者它们的混合物、与一种或多种药学上可接受的载体组合。
在本发明的药物组合物中可使用的药学上可接受的载体包括但不限于无菌液体。药学上可接受的载体包括药物赋形剂。适合的药学上可接受的载体的实例如在Remington’s Pharmaceutical Sciences(2005)中所述。
药物组合物可以以任意形式施用,只要其实现预防、减轻、防止或者治愈人类或动物患者的症状。例如,可根据给药途径制成各种适宜的剂型。
当口服用药时,所述药物组合物可制成任意口服可接受的制剂形式。
当经皮或局部施用时,所述药物组合物可制成适当的软膏、洗剂或搽剂形式,其中活性成分可以悬混或溶解于一种或多种载体中。
所述药物组合物还可以注射剂形式用药,包括注射液、注射用无菌粉末与注射用浓溶液。
本发明的另一方面还涉及一种药物制剂,其包含至少一种上述化合物、其药学上可接受的形式或它们的混合物作为活性成分、或者本发明的药物组合物。在一些实施方案中,所述制剂的形式为固体制剂、半固体制剂、液体制剂或气态制剂。
本发明的进一步的目的在于提供一种制品,例如以试剂盒形式提供。本文所用的制品意图包括但不限于药盒和包装。本发明的制品包含:(a)第一容器;(b)位于第一容器中的药物组合物,其中所述组合物包含:第一治疗剂,包括至少一种上述化合物或其药学上可接受的形式、或者它们的混合物;和(c)任选存在的包装说明书,其说明所述药物组合物可用于治疗由GPR75调节的疾病或病症,例如:脂肪营养不良、厌食症、糖尿病、恶性肿瘤、肾小球肾炎或神经退行性疾病(如阿尔兹海默症)。
所述包装说明书为商标、标签、标示等,其列举了与位于所述第一容器内的药物组合物相关的信息。所列出的信息通常由管辖待销售所述制品的区域的管理机构(例如美国食品与药品管理局)决定。优选所述包装说明书具体列出了所述药物组合物获准用于的适应症。所述包装说明书可由任何材料制成,可从所述材料上读取包含于其中或其上的信息。优选所述包装说明书为可印刷材料(例如纸、塑料、卡纸板、箔、胶粘纸或塑料等),其上可形成(例如印刷或施涂)所需信息。
治疗方法和用途
本发明的另一目的在于提供一种预防或治疗由GPR75调节的疾病或病症的方法,所述方法包括向有此需要的个体给药有效量的至少一种上述化合物或其药学可接受的形式或者它们的混合物、或者本发明的药物组合物。
在本发明的实施方案中,本发明提供至少一种上述化合物或其药学上可接受的形式或者上述药物组合物在制备用于预防和/或治疗由GPR75调节的疾病或病症的药物中的用途。
在本发明的实施方案中,本发明提供至少一种上述化合物或其药学上可接受的形式或者上述药物组合物,其用于预防和/或治疗由GPR75调节的疾病或病症。
根据本发明的一些实施方案,所述由GPR75调节的疾病或病症包括但不限于脂肪营养不良、厌食症、糖尿病、恶性肿瘤、肾小球肾炎或神经退行性疾病(如阿尔兹海默症)。
可调整给药方案以提供最佳所需响应。例如,以注射剂形式用药时,可给药单次推注、团注和/或连续输注等。例如,可随时间给药数个分剂量,或可如治疗情况的急需所表明而按比例减少或增加剂量。要注意,剂量值可随要减轻的病况的类型及严重性而变化,且可包括单次或多次剂量。一般地,治疗的剂量是变化的,这取决于所考虑的事项,例如:待治疗患者的年龄、性别和一般健康状况;治疗的频率和想要的效果的性质;组织损伤的程度;症状的持续时间;以及可由各个医师调整的其它变量。要进一步理解,对于任何特定个体,具体的给药方案应根据个体需要及给药组合物或监督组合物的给药的人员的专业判断来随时间调整。可以通过临床领域的普通技术人员容易地确定所述药物组合物的施用量和施用方案。例如,本发明的组合物或化合物可以以分剂量每天4次至每3天给药1次,给药量可以是例如0.01~1000mg/次。可以以一次或多次施用需要的剂量,以获得需要达到的结果。也可以以单位剂量形式提供根据本发明的药物组合物。
一般术语和定义
除非另有定义,本文中所使用的术语的含义与本领域技术人员通常所理解的相同。本文中所使用的技术意图是指本领域中通常所理解的技术,包括对于本领域技术人员显而易见的技术的变化或等效替换。虽然下列术语对于本领域技术人员容易理解,但仍然阐述如下,以便更好地解释本发明。
术语“包括”、“包含”、“具有”或“涉及”及其在本文中的其它变体形式是指包含性的或开放式的集合概念,且不排除其它未列举的元素或方法步骤。本领域技术人员应当理解,上述术语如“包括”涵盖“由…组成”的含义。
当数值范围的下限和上限被公开时,落入该范围中的任何数值或任何亚范围都表示 被具体公开。特别地,本文中所公开的参数的每一个数值范围(例如,以“约a至b”,或同等的“大约a至b”,或同等的“约a-b”的形式)均应理解为涵盖其中的每一个数值和亚范围。例如,“C1-6”应理解为涵盖其中的任意亚范围以及每一个点值,如C2-5、C3-4、C1-2、C1-3、C1-4、C1-5等,以及C1、C2、C3、C4、C5、C6等。又例如,“5-10元”应理解为涵盖其中的任意亚范围以及每一个点值,例如5-7元、5-8元、5-9元、6-7元、6-8元、6-9元等,以及5、6、7、8、9、10元等。
术语“烷基”是指直链或支链的饱和脂肪族烃基。例如,本发明中所使用的术语“C1-6烷基”是指具有1-6个碳原子(例如1、2、3、4、5或6个碳原子)的饱和直链或支链烃基。例如“C1-6烷基”可以是甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基或正己基等。
术语“亚烷基”指饱和的直链或支链的二价烃基。例如,本文中所使用的术语“C1-6亚烷基”指具有1-6个碳原子的饱和的直链或支链的二价烃基,例如亚甲基、亚乙基、亚丙基或亚丁基等。
术语“环烷基”是指饱和的或部分饱和的、单环或多环(诸如双环)的非芳香族烃基;例如单环,如环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基、环丁烯、环戊烯、环己烯;或双环,包括螺环、稠环或桥环(诸如双环[1.1.1]戊基、双环[2.2.1]庚基、双环[3.2.1]辛基、双环[5.2.0]壬基或十氢化萘基等)。例如,术语“C3-8环烷基”指具有5-10个(如5、6、7、8、9或10个)环碳原子的环烷基。
术语“杂环烷基”是指饱和或部分饱和的、单环或多环(如双环)的非芳香族基团,其环中具有一个或多个碳原子(如1、2、3、4、5、6、7、8或9个)以及一个或多个(如1、2、3或4个)各自独立地选自N、O、P和S的杂原子。该术语还涵盖下述情况,其中环中的C原子、N原子和/或P原子可以被氧代基(=O)取代和/或环中的S原子可以被1个或2个氧代基(=O)取代。杂环烷基中的环系可以是稠环、桥环或螺环体系。如果满足价键要求,杂环烷基可以通过环中的任意一个碳原子或杂原子连接至其它基团(或片段)。杂环烷基例如为环氧乙烷基、氮杂环丁烷基、氧杂环丁烷基、硫杂环丁烷基、四氢呋喃基、二氧杂环戊烷基、四氢噻吩基、吡咯烷基、吡咯烷酮基、哌啶基、吗啉基、硫吗啉基、高哌嗪基等。
术语“芳基”是指具有共轭π电子系统的全碳单环或稠合多环(如双环)芳香族基团。如本文中所使用,术语“C6-10芳基”指含有6-10个碳原子的芳香族基团,例如苯基或萘基等。
术语“杂芳基”是指具有共轭π电子系统的单环或稠环的芳香族基团,其环中具有一个或多个碳原子(如1、2、3、4、5、6、9或10个碳原子)以及一个或多个(例如1、2、3或4个)各自独立地选自N、O、P和S的杂原子。杂芳基可以用环原子的数目表征。例如,5-10元杂芳基可以含有5-10个(例如5、6、7、8、9或10个)环原子,特别是含有5、6、9、10个环原子。如果满足价键要求,杂环烷基可以通过任意一个环原子连接至母体分子部分。例如,杂芳基的实例有噻吩基、呋喃基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、噁二唑基、三唑基、噻二唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基等。该术语还涵盖下述情况,杂芳基可任选地进一步稠合于芳基或杂芳基环上,形成稠合环系。
术语“卤代”或“卤素”基团,表示F、Cl、Br或I。
术语“羧基”表示-COOH。
术语“各自独立地”或“独立地”是指结构中存在的取值范围相同或相近的至少两个基团(或片段)可以在特定情形下具有相同或不同的含义。例如,取代基X和取代基Y各自独立地为氢、卤素、羟基、-CN、烷基或芳基,则当取代基X为氢时,取代基Y既可以为氢,也可以为卤素、羟基、-CN、烷基或芳基;同理,当取代基Y为氢时,取代基X既可以为氢,也可以为卤素、羟基、-CN、烷基或芳基。
术语“取代”及其在本文中的其它变体形式是指所指定的原子上的一个或多个(如1、2、 3或4个)原子或原子团(如氢原子)被其它等同物代替,条件是未超过所指定的原子或原子团在当前情况下的正常化合价,并且能够形成稳定的化合物。如果某一原子或原子团被描述为“任选地被……取代”,则其既可以被取代,又可以未被取代。除非另有说明,本文中取代基的连接位点可以来自取代基的任意适宜位置。当取代基中的连接键显示为穿过环系中相互连接的两个原子之间的化学键时,则表示该取代基可以连接该环系中的任意一个成环原子。
术语“药学上可接受的盐”是指对生物体基本上无毒性的、本发明的化合物的盐。药学上可接受的盐通常包括(但不限于)本发明的化合物与药学上可接受的无机酸/有机酸/酸性氨基酸或无机碱/有机碱/碱性氨基酸反应而形成的盐,此类盐又被称为酸加成盐或碱加成盐。适合的盐的综述参见,例如,Jusiak,Soczewinski,et al.,Remington’s Pharmaceutical Sciences[M],Mack Publishing Company,2005和Stahl,Wermuth,Handbook of Pharmaceutical Salts:Properties,Selection,and Use[M],Wiley-VCH,2002。用于制备本发明的化合物的药学上可接受的盐的方法是本领域技术人员已知的。
术语“药学上可接受的酯”是指对生物体基本上无毒性的、在生物体体内水解成本发明的化合物或其盐的酯。另外,本发明的化合物本身也可以是酯。
术语“异构体”是指因具有相同的原子数和原子类型而具有相同的分子量,但原子的空间排列或构型不同的化合物。
术语“立体异构体”(或称“旋光异构体”)是指由于具有至少一个手性因素(包括手性中心、手性轴、手性面等)而导致具有垂直的不对称平面,从而能够使平面偏振光旋转的稳定异构体。由于本发明的化合物存在可能导致立体异构的不对称中心以及其它化学结构,因此本发明也包括这些立体异构体及其混合物。由于本发明的化合物(或其药学上可接受的盐)包括不对称碳原子,因而能够以单一立体异构体形式、外消旋物、对映异构体和非对映异构体的混合物形式存在。通常,这些化合物能够以外消旋物的形式制备。然而,如果需要的话,可以将这类化合物制备或分离后得到纯的立体异构体,即单一对映异构体或非对映异构体,或者单一立体异构体富集化(纯度≥99%、≥98%、≥97%、≥96%、≥95%、≥90%、≥85%、≥80%、≥75%、≥70%、≥65%或≥60%)的混合物。如下文中所述,化合物的单一立体异构体是由含有所需手性中心的旋光起始原料合成制备得到的,或者是通过制备得到对映异构体产物的混合物之后再分离或拆分制备得到的,例如转化为非对映异构体的混合物之后再进行分离或重结晶、色谱处理、使用手性拆分试剂,或者在手性色谱柱上将对映异构体进行直接分离。具有特定立体化学的起始化合物既可以商购得到,也可以按照下文中描述的方法制备再通过本领域熟知的方法拆分得到。术语“对映异构体”是指彼此具有不能重叠的镜像的一对立体异构体。术语“非对映异构体”或“非对映体”是指彼此不构成镜像的旋光异构体。术语“外消旋混合物”或“外消旋物”是指含有等份的单一对映异构体的混合物(即两种R和S对映体的等摩尔量混合物)。术语“非外消旋混合物”是指含有不等份的单一对映异构体的混合物。除非另外指出,本发明的化合物的所有立体异构体形式都在本发明的范围之内。
本文中使用实线实楔形或虚楔形以描绘本发明的化合物的共价化学键。当使用实线以描绘键连至手性原子的键时,表示包括该手性原子处的所有可能的立体异构体(例如,特定的对映异构体、外消旋混合物等)。当使用实或虚楔形以描绘键连至手性原子的键时,表示存在所示的立体异构体。除非另外指明,本发明的化合物的立体异构体可以涵盖特定的对映异构体、非对映异构体、外消旋体或其任意比例的混合物。
术语“互变异构体”(或称“互变异构形式”)是指具有不同能量的、可通过低能垒互相转化的结构异构体。若互变异构是可能的(如在溶液中),则可以达到互变异构体的化学平衡。例如,质子互变异构体(或称质子转移互变异构体)包括(但不限于)通过质子迁移来进行的互相转化,如酮-烯醇异构化、亚胺-烯胺异构化、酰胺-亚胺醇异构化、亚硝基-肟异构化 等。除非另外指出,本发明的化合物的所有互变异构体形式都在本发明的范围之内。
术语“多晶型物”(或称“多晶型形式”)是指化合物或复合物的固体晶体形式。本发明涵盖本发明的化合物的所有可能的结晶形式或多晶型物,其可以为单一的多晶型物或多种多晶型物以任意比例混合而得的混合物。
术语“溶剂化物”是指由本发明的化合物(或其药学上可接受的盐)与至少一种溶剂分子通过非共价分子间作用力结合而形成的物质。本发明的化合物可以溶剂化物的形式存在,其中包含作为晶格结构要素的极性溶剂。极性溶剂的量可以化学计量比或非化学计量比的形式存在。
术语“同位素标记物”是指将本发明的化合物中的特定原子替换为其同位素原子而形成的衍生化合物。除非另外指出,本发明的化合物包括H、C、N、O、F、P、S、Cl的各种同位素,如2H(D)、3H(T)、13C、14C、13N、15N、17O、18O、18F、31P、32P、34S、35S、36S、37Cl和125I。例如,12C可被13C或14C替代;1H可被2H(D,氘)或3H(T,氚)替代;16O可被18O替代等。
本领域技术人员会理解,由于氮需要可用的孤对电子来氧化成氧化物,因此并非所有的含氮杂环都能够形成N-氧化物。本领域技术人员会识别能够形成N-氧化物的含氮杂环。本领域技术人员还会认识到叔胺能够形成N-氧化物。用于制备杂环和叔胺的N-氧化物的合成方法是本领域技术人员熟知的,包括用过氧酸如过氧乙酸和间氯过氧苯甲酸(mCPBA)、过氧化氢、烷基过氧化氢如叔丁基过氧化氢、过硼酸钠和双环氧乙烷(dioxirane)如二甲基双环氧乙烷来氧化杂环和叔胺。这些用于制备N-氧化物的方法已在文献中得到广泛描述和综述,参见例如:T.L.Gilchrist,Comprehensive Organic Synthesis,vol.7,pp748-750(A.R.Katritzky和A.J.Boulton,Eds.,Academic Press);以及G.W.H.Cheeseman和E.S.G.Werstiuk,Advances in Heterocyclic Chemistry,vol.22,pp 390-392(A.R.Katritzky和A.J.Boulton,Eds.,Academic Press)。
术语“代谢物”是指本发明的化合物经代谢后形成的衍生化合物,例如经过氧化、还原、水解、酰胺化、脱酰胺化、酯化、酶解等反应而产生。关于代谢的进一步信息参见Goodman and Gilman's:The Pharmacological Basis of Therapeutics[M],McGraw-Hill International Editions,1996。本发明涵盖本发明的化合物的所有可能的代谢物形式,即在施用本发明的化合物的个体体内形成的物质。化合物的代谢物可以通过所属领域的公知技术来鉴定,其活性可以通过试验来表征。
术语“前药”是指在施用于个体后能够直接或间接地提供本发明的化合物的衍生化合物。特别优选的衍生化合物或前药是在施用于个体时可以提高本发明的化合物的生物利用度的化合物(例如,更易吸收入血),或者促进母体化合物向作用位点(例如,淋巴系统)递送的化合物。除非另外指出,本发明的化合物的所有前药形式都在本发明的范围之内,且各种前药形式是本领域已知的,例如参见T.Higuchi,V.Stella,Pro-drugs as Novel Drug Delivery Systems[J],American Chemical Society,Vol.14,1975。此外,本发明还涵盖含有保护基的本发明的化合物。在制备本发明的化合物的任何过程中,保护在任何有关分子上的敏感基团或反应基团可能是必需的和/或期望的,由此形成本发明的化合物的化学保护的形式。这可以通过常规的保护基实现,例如在T.W.Greene,P.G.M.Wuts,Protective Groups in Organic Synthesis[M],John Wiley&Sons,2006中描述的保护基。使用本领域已知的方法,在适当的后续阶段可以移除这些保护基。
本发明还涵盖本文所述化合物的制备方法。应当理解,本发明的化合物可使用下文描述的方法以及合成有机化学领域中已知的合成方法或本领域技术人员所了解的其变化形式来合成。优选方法包括(但不限于)下文所述那些。反应可在适于所使用的试剂和材料且适合于实现转化的溶剂或溶剂混合物中进行。
术语“活性成分”、“治疗剂”、“活性物质”或“活性剂”是指一种化学实体,它可以有效 地治疗目标病症或病况的一种或多种症状。
如本文中所使用的术语“有效量”(例如“治疗有效量”或“预防有效量”)指给药后会在一定程度上实现预期效果的活性成分的量,例如缓解所治疗病症的一种或多种症状或预防病症或其症状的出现。
除非另外说明,否则如本文中所使用,术语“治疗”意指逆转、减轻、改善这样的术语所应用的病症或病况或者这样的病症或病况的一种或多种症状的进展。
术语“预防”指抑制和延迟疾病的发作,不仅包括在发展疾病之前的预防,还包括在治疗后预防疾病的复发。
如本文所使用的“个体”包括人或非人动物。示例性人个体包括患有疾病(例如本文所述的疾病)的人个体(称为患者)或正常个体。本发明中“非人动物”包括所有脊椎动物,例如非哺乳动物(例如鸟类、两栖动物、爬行动物)和哺乳动物,例如非人灵长类、家畜和/或驯化动物(例如绵羊、犬、猫、奶牛、猪等)。
附图说明
图1示出化合物和20-HETE对ERK磷酸化水平的影响。
具体实施方式
以下列举实施例和试验例,进而详细地说明本发明,但它们不限制本发明的范围,另外在不脱离本发明的范围下可进行变化。
质谱(MS)的测定使用Waters(ESI)质谱仪,生产商:Waters,型号:SQ Detector。
核磁(NMR)的测定使用Bruker核磁共振波谱仪,生产商:Bruker,型号:AVANCE NEO HD-400。
制备高效液相色谱法(HPLC)使用华创美析LC2060制备液相色谱仪(Suyan technologies,ODS,HPLCONE 10C18A,250*10mm*10um色谱柱&Suyan technologies,ODS,HPLCONE 10C18A,250*30mm*10um色谱柱)。
薄层色谱法纯化采用烟台银龙GF 254(5~20μm)硅胶板。
反应的监测采用薄层色谱法(TLC)或液相色谱质谱联用(LC-MS),使用的展开剂体系包括但不限于:二氯甲烷和甲醇体系、正己烷和乙酸乙酯体系以及石油醚和乙酸乙酯体系,溶剂的体积比根据化合物的极性不同而进行调节,或者加入三乙胺、乙酸或甲酸等进行调节。
柱色谱法一般使用青岛海洋200~300目硅胶为固定相。洗脱剂体系包括但不限于二氯甲烷和甲醇体系以及石油醚和乙酸乙酯体系,溶剂的体积比根据化合物的极性不同而进行调节,也可以加入少量的三乙胺、乙酸或甲酸等进行调节。
如实施例中无特殊说明,则反应的温度为室温(20℃~30℃)。
除非特别指明,实施例中所使用的试剂购自Acros Organics、Aldrich Chemical Company、南京药石科技、泰坦科技、上海毕得、乐研、安徽泽升或者北京伊诺凯等公司。
本文中所使用的缩写具有以下含义:

实施例1:中间体1合成
Step 1:化合物INT1-1的合成
将2-甲基-4,6-二氯-5-硝基嘧啶(5.00g,24mmol)溶于异丙醇(60mL)中,加入甲胺盐酸盐(1.78g,26.4mmol,1.1eq.)、三乙胺(1mL,7.2mmol,3eq.),90℃搅拌6小时。TLC监控反应完成后,将反应液旋干,残余物用硅胶柱纯化(MeOH:CH2Cl2=0~20%),得到3.24g黄色固体化合物INT1-1,收率66.8%。LCMS(FA):m/z=202.9(M+H)。
Step 2:化合物INT1-2的合成
将INT1-1(1.6mmol,1.0eq.)溶于异丙醇(5mL)中,加入SMA(1.68mmol,1.05eq.)、三乙胺(0.69mL,4.8mmol,3eq.),90℃搅拌10小时。TLC监控反应完成后,将反应液旋干,残余物用硅胶柱纯化(甲醇:二氯甲烷=0~20%),最终得到化合物INT1-2。
Step 3:中间体1的合成
将INT1-2(0.37mmol,1.0eq.)溶于二氯甲烷(10mL)中,加入锌粉(3.7mmol,10eq.)、乙酸(1.85mmol,5eq),搅拌反应3小时。TLC监控反应完成后,硅藻土过滤反应液,滤渣用二氯甲烷冲洗三次,所得滤液用饱和碳酸氢钠溶液洗涤(20mL*3),无水硫酸钠干燥,过滤,旋干,残余物用硅胶柱纯化(CH2Cl2:MeOH=30~10:1),得到中间体1。

实施例2:中间体2的合成
将2-甲基-4,6-二氯-5-硝基嘧啶(2.08g,10.0mmol,1eq.)、SMA(10.0mmol,1eq.)溶于i-PrOH(30mL),加入三乙胺(3.03g,30mmol,1eq.),加热至90℃搅拌7小时后冷却至室温。减压浓缩,浓缩后的残余物用硅胶柱纯化(PE:EA=99~30:1),得到中间体2。

实施例3:中间体3的合成
将5-溴-2-糠醛(1g,5.71mmol,1.0eq.)和SMB(6.86mmol,1.2eq.)溶于1,4-二氧六环(25mL)和H2O(5mL),加入碳酸钾(2.37g,17.14mmol,3.0eq.)和Pd(PPh3)4(330mg,0.29mmol,0.05eq.),氩气保护下加热至90℃,搅拌反应4小时,LC-MS和TLC显示反应完全后冷却至室温,加入40mL水,乙酸乙酯萃取(30mL*3),合并有机相用饱和氯化钠溶液洗涤,硫酸钠干燥,减压浓缩,残余物用硅胶柱纯化(PE:EA=40:1),得到中间体3,收率74%。
实施例4:中间体4的合成
Step 1:化合物INT4-1的合成
将2,5-二氯苯甲酸(1.12g,5.86mmol)溶于DMF(15mL),加入HATU(3.34g,8.80mmol)和DIPEA(1.52g,11.73mmol),室温搅拌15min后加入炔丙胺(646mg,11.73mmol),室温搅拌反应1小时,LC-MS和TLC显示反应完全。加入50mL水将反应淬灭后,乙酸乙 酯萃取(20mL*3),合并的有机相用饱和氯化钠溶液洗涤,硫酸钠干燥后,减压浓缩,残余物用硅胶柱纯化(PE:EA=10~3:1),得到1.3g白色固体化合物INT4-1,收率97%。
LCMS(HCOOH):m/z=227.85(M+H).
1H NMR(400MHz,CDCl3)δ9.01(t,J=5.4Hz,1H),7.57-7.52(m,1H),7.51-7.49(m,1H),4.04(d,J=2.5Hz,1H),4.02(d,J=2.5Hz,1H),3.18(t,J=2.5Hz,1H)。
Step 2:中间体4的合成
将化合物INT4-1(1.12g,4.91mmol)溶于MeCN(20mL),依次加入二苯基二硒醚(153mg,0.49mmol)、H2O(89mg,4.91mmol)和1-氯甲基-4-氟-1,4-重氮化二环2.2.2辛烷双(四氟硼酸)盐(3.83g,10.80mmol),室温搅拌反应12小时,LC-MS和TLC显示反应完全。减压浓缩,残余物用硅胶柱纯化(PE:EA=10~4:1),得到480mg白色固体化合物中间体4,收率40%。1H NMR(400MHz,CDCl3)δ9.87(s,1H),8.42(s,1H),8.11(d,J=2.1Hz,1H),7.77-7.72(m,2H)。
实施例5:中间体5的合成
Step 1:化合物INT5-1的合成
将2,5-二氯苯甲醛(800mg,4.57mmol)加入到无水甲醇(20mL)中,然后加入TosMIC(936mg,4.80mmol)和碳酸钾(1.26g,9.14mmol),70℃搅拌反应5小时,LCMS监测原料反应完毕。将反应液旋干,加水(20mL),水相用乙酸乙酯萃取(30mL*3),合并有机相用氯化钠水溶液洗涤(50mL*3),无水硫酸钠干燥,过滤,旋干滤液,残余物用硅胶柱纯化(乙酸乙酯:石油醚=0~20%)得到900mg白色固体INT5-1,收率91.9%。
LCMS(HCOOH):m/z=213.9(M+H).
1HNMR(400MHz,DMSO-d6)δ8.62(s,1H),7.90(s,1H),7.85(d,J=2.6Hz,1H),7.67(d,J=8.6Hz,1H),7.51(dd,J=8.6,2.6Hz,1H)。
Step 2:中间体5的合成
将化合物INT5-1(500mg,2.34mmol)溶于THF(10mL),氩气保护,0℃下滴加LiHMDS(4.7mL,1M in THF),0℃反应30min,滴加DMF(341.47mg,4.67mmol)的THF(1mL)溶液,室温反应3小时,LCMS监测原料反应完毕。将反应液在冰浴下用氯化铵水溶液(20ml)淬灭,水相用乙酸乙酯萃取(50mL*3),合并有机相用氯化钠水溶液洗涤(50mL*3),无水硫酸钠干燥,过滤,旋干滤液,残余物用硅胶柱纯化(EA:PE=0~50%)得到150mg黄色固体中间体5,收率26.53%。
LCMS(HCOOH):m/z=241.9(M+H).
1HNMR(400MHz,DMSO-d6)δ10.10(s,1H),7.90(s,1H),7.85(d,J=2.6Hz,1H),7.67(d,J=8.6Hz,1H),7.51(dd,J=8.6,2.6Hz,1H)。
实施例6:中间体6的合成
Step 1:化合物INT6-1的合成
将N-Boc-α-氨基酸(2.45g,14.01mmol,1eq.)和SMA或SMC(10.78mmol,0.77eq.)溶于DMF(45mL),加入DIPEA(2.79g,21.55mmol,1.55eq.)和HATU(6.15g,16.16mmol,1.15eq.),室温搅拌1小时后加热至45℃反应24小时,LC-MS和TLC显示基本反应完全。加入150mL水将反应淬灭后,乙酸乙酯萃取(50mL*4),合并的有机相用饱和氯化钠溶液洗涤,硫酸钠干燥后,减压浓缩,残余物用硅胶柱纯化(PE:EA=10~3:1),得到化合物INT6-1。
Step 2:中间体6的合成
将化合物INT6-1(4.87mmol,1eq.)溶于甲醇(20mL),冷却至0℃后缓慢加入乙酰氯(1.53g,19.49mmol,4eq.),反应5分钟后升至35℃,搅拌反应18小时,LC-MS和TLC显示基本反应完全。蒸干甲醇后,加入20mL饱和碳酸氢钠溶液,乙酸乙酯萃取(20mL*3),合并的有机相用饱和氯化钠溶液洗涤,硫酸钠干燥后,减压浓缩,残余物用硅胶柱纯化(CH2Cl2:MeOH=20~10:1),得到中间体6。
实施例7:中间体7的合成
Step 1:INT7-1的合成
将5-溴-2-糠醛(1.5g,8.57mmol)溶于甲醇(10mL),加入原甲酸三甲酯(1.82g,17.14mmol)和PPTS(215mg,0.86mmol),加热至70℃回流4小时,LC-MS和TLC显示基本反应完全。冷却至室温后加入5mL饱和碳酸氢钠溶液将反应淬灭,加入30mL水后乙酸乙酯萃取(15mL*3),合并有机相,饱和氯化钠溶液洗涤,硫酸钠干燥,减压浓缩,残余物用硅胶柱纯化(PE:EA=99~60:1),得到1.6g得到无色液体化合物INT7-1,收率84%。
1H NMR(400MHz,CDCl3)δ6.32(d,J=3.2Hz,1H),6.22(d,J=3.3Hz,1H),5.31(s,1H),3.28(s,6h)。
Step 2:化合物INT7-2的合成
将4-吡啶硼酸(401mg,3.26mmol)和化合物INT7-1(555mg,2.51mmol)溶于1,4-二氧六环(4mL)和H2O(1mL),加入碳酸钾(1.04g,7.53mmol)和Pd(PPh3)4(145mg,0.13mmol),在氩气保护下加热至90℃,搅拌反应12小时,LC-MS和TLC显示基本反应完全。冷却至室温后,加入20mL水,EA萃取(20mL*3),合并有机相,饱和氯化钠溶液洗涤,Na2SO4干燥,减压浓缩,残余物用硅胶柱纯化(PE:EA=3:1~2),得到410mg淡黄色液体化合物INT7-2,收率75%。LCMS(HCOOH):m/z=220.4(M+H)。
Step 3:中间体7的合成
将化合物INT7-2(396mg,1.81mmol)溶于THF(4mL),加入1M HCl(2mL),室温搅拌4小时,LC-MS和TLC显示基本反应完全。加入10mL饱和碳酸钠溶液将反应淬灭后再加入10mL水,乙酸乙酯萃取(20mL*3),合并有机相,饱和氯化钠溶液洗涤,硫酸钠干燥,减压浓缩得到300mg白色固体化合物中间体7,收率96%。
LCMS(HCOOH):m/z=174.0(M+H)。
实施例8:中间体8的合成
Step 1:化合物INT8-1的合成
将3-吡啶硼酸(416mg,3.39mmol)和化合物INT7-1(576mg,2.61mmol)溶于1,4-二氧六环(4mL)和H2O(1mL),加入碳酸钾(1.04g,7.53mmol)和Pd(PPh3)4(145mg,0.13mmol),在氩气保护下加热至90℃,搅拌反应12小时,LC-MS和TLC显示基本反应完全。冷却至室温后,加入20mL水,EA萃取(20mL*3),合并有机相,饱和氯化钠溶液洗涤,Na2SO4干燥,减压浓缩,残余物用硅胶柱纯化(PE:EA=3~2:1),得到410mg淡黄色液体化合物INT8-1,收率84%。LCMS(HCOOH):m/z=220.4(M+H)。
Step 2:中间体8的合成
将化合物INT8-1(480mg,2.19mmol)溶于THF(4mL),加入1M HCl(2mL),室温搅拌4小时,LC-MS和TLC显示基本反应完全。加入10mL饱和碳酸钠溶液将反应淬灭后再加入10mL水,乙酸乙酯萃取(20mL*3),合并有机相,饱和氯化钠溶液洗涤,硫酸钠干燥,减压浓缩得到360mg白色固体化合物中间体8,收率95%。LCMS(HCOOH):m/z=174.4(M+H)。
实施例9-1:化合物A1~A5的合成
Step 1:中间体9的合成
将中间体1(0.50mmol,1eq.),中间体3/4/5/7/8(0.50mmol,1eq)溶于CH2Cl2溶液(15mL)中,然后冰浴下加入TiCl4(94mg,0.50mmol,1eq)室温下反应1小时,向混合液中加入NaBH3CN(88mg,1.0mmol,2eq),室温下反应6小时。TLC监控反应完成后,向反应液中加入碳酸氢钠溶液(30mL)淬灭,分液,水相用二氯甲烷萃取(20mL*3),合并有机相,无水硫酸钠干燥,过滤,减压浓缩,残余物用硅胶柱纯化(MeOH:CH2Cl2=0~10%),得到中间体9。
Step 2:目标化合物的合成
将中间体9(0.19mmol,1eq.)溶于THF/MeOH(2ml/2ml)中,滴加氢氧化锂(80mg,1.9mmol,10eq.)的水溶液(1ml),常温搅拌反应6小时,TLC监控反应完成后,将反应液用1M HCl溶液调pH≈3,EA萃取(20mL*3),合并有机相,无水硫酸钠干燥,过滤,旋干滤液,残留物经prep-HPLC(TFA condition,column:HPLCONE 10C18A 250*30mm*10um;Mobile Phase:[water(TFA)-ACN]:10%-70%,25min)分离得到目标化合物。

实施例9-2:化合物A6-A10的合成
化合物A6的合成
Step 1:化合物A6-1的合成
将中间体2-2(90mg,0.25mmol)溶于异丙醇(5mL),加入2-氨基乙醇(19mg,0.30mmol)和三乙胺(77mg,0.76mmol),加热至85℃搅拌1小时后LC-MS和TLC显示反应完全,蒸干溶剂得到110mg化合物A6-1。LCMS(HCOOH):m/z=382.53(M+H)。
Step 2:化合物A6-2的合成
将上述所得化合物A6-1(110mg)溶于DCM(4mL),加入锌粉(514mg,7.86mmol)和冰醋酸(79mg,1.31mmol),在室温下搅拌反应30~90分钟,LC-MS和TLC显示反应完全。硅藻土过滤,滤渣用DCM冲洗三次,合并滤液减压浓缩,残余物用硅胶柱纯化(DCM:MeOH=30~10:1),得到64mg黄色油状化合物A6-2,两步收率72%。LCMS(HCOOH):m/z=352.38(M+H)。
Step 3:化合物A6-3的合成
将化合物A6-2(64mg,0.18mmol)和中间体3-2(44mg,0.18mmol)溶于DCM(3mL)和THF(1.5mL),冷却至0℃,加入TiCl4(35mg,0.18mmol),搅拌1小时后加入NaBH3CN(34mg,0.55mmol),搅拌5分钟后升至室温反应2小时,LC-MS和TLC显示反应完全。加入2mL饱和碳酸氢钠溶液淬灭反应,再加入20mL水,乙酸乙酯萃取(20mL*3),合并有机相,饱和氯化钠溶液洗涤,Na2SO4干燥,减压浓缩,残余物用硅胶柱纯化(PE:EA=4~1:2),得到68mg淡黄色固体化合物A6-3,收率65%。LCMS(HCOOH):m/z=576.33(M+H)。
Step 4:化合物A6的合成
将化合物A6-3(68mg,0.12mmol)溶于MeOH(2mL)和H2O(1mL),加入NaOH(47mg,1.18mmol),室温搅拌30min后升至45℃,搅拌反应15小时,LC-MS和TLC显示反应完全。加入3mL 1M稀盐酸淬灭反应,再加入20mL水,乙酸乙酯萃取(30mL*4),合并有机相,饱和氯化钠溶液洗涤,硫酸钠干燥,减压浓缩,残余物用硅胶柱纯化(CH2Cl2:MeOH=30~12:1),得到29mg淡黄色固体化合物A6,收率44%。
采用类似的方法,分别从中间体2-1和中间体2-2起始,2-氨基乙醇、N,N-二甲基-乙二胺、N-叔丁氧羰基乙二胺作为Step 1取代试剂,得到化合物A7、A8、A9。
化合物A10的合成
将化合物A8(50mg)溶于CH2Cl2(1mL)中,0℃下滴加氯化氢的二氧六环溶液(0.5mL),室温下搅拌反应6小时,TLC显示反应完全。将反应液旋干,残留物经prep-HPLC纯化(TFA condition,column:HPLCONE 10C18A 250*30mm*10um;Mobile Phase:[water(TFA)-ACN];10%-45%,25min),得到8mg化合物A10。

实施例9-3化合物A11的合成
合成路线:
制备方法:
第一步:合成化合物3
将化合物1(1g,5.79mmol)和化合物2(875.9mg,5.79mmol)溶于甲苯(15mL)中,加入醋酸钯(65mg,0.29mmol)、2,2'-双二苯膦基-1,1'-联萘(360mg,0.578mmol)、 碘化钠(174mg,1.156mmol)、碳酸钾(1.6g,11.58mmol),在氮气保护下110℃搅拌1小时。TLC显示反应结束后,将反应液加入水(40mL)中,过滤除去固体后,用乙酸乙酯(30mL×3)萃取。合并的有机相经无水硫酸钠干燥,过滤,减压除去溶剂,残余物用硅胶柱层析纯化(石油醚:乙酸乙酯=1:0~5:1)纯化得到化合物3(600mg,黄色油状液体,产率36.04%)。MS(ESI):m/z 288.1[M+1]+
后续参考化合物A4的合成方法得到化合物A11(17.7mg,黄色固体)。MS(ESI):m/z467.9 469.9[M+1]+1H NMR(400MHz,DMSO-d6)δ(ppm)13.11(br.s,1H),10.60(br.s,1H),8.45(dd,J=8.6,1.1Hz,1H),7.94(dd,J=7.9,1.8Hz,1H),7.82(d,J=2.6Hz,1H),7.56(d,J=8.6Hz,1H),7.44(ddd,J=8.7,7.1,1.8Hz,1H),7.36(dd,J=8.6,2.6Hz,1H),7.17(d,J=3.4Hz,1H),7.06(d,J=7.8Hz,1H),6.90-6.80(m,1H),6.70(d,J=7.8Hz,1H),6.58(d,J=3.5Hz,1H),5.39-5.28(m,1H),4.36(d,J=5.7Hz,2H),2.31(s,3H)。
参照化合物A4的合成方法,合成下列的实施例化合物。


参照化合物A9的合成方法,合成下列的实施例化合物。

参照化合物A9和化合物A4的合成方法,前三步合成方法参考化合物A9,后续步骤合成方法参考化合物A4,合成下列的实施例化合物。

实施例10-1:化合物B1-B13的合成
Step 1:中间体10的合成
将中间体6(0.24mmol,1eq.),中间体3/4/5/7/8(0.24mmol,1eq)溶于DMF(2mL)中,加入冰醋酸(72mg,1.20mmol,5eq.)和NaBH3CN(15mg,0.24mmol,1eq.),室温搅拌反应2小时,LC-MS和TLC显示基本反应完全。加入5mL饱和碳酸钠溶液淬灭反应,加入10mL水,乙酸乙酯萃取(10mL*3),合并有机相,饱和氯化钠溶液洗涤,无水硫酸钠干燥,减压浓缩后,加入10mL乙醇溶解,加热至80℃回流8小时,蒸干溶剂,残余物用PTLC纯化(CH2Cl2:MeOH=20:1),得到中间体10。
Step 2:目标化合物的合成
将中间体10(0.19mmol,1eq.)溶于THF/MeOH(2ml/2ml)中,滴加氢氧化锂(80mg,1.9mmol,10eq.)的水溶液(1ml),升温至50℃搅拌反应2小时,TLC监控反应完成后,将反应液用1M HCl溶液调pH≈3,EA萃取(20mL*3),合并有机相,无水硫酸钠干燥,过滤,旋干滤液,残留物用PTLC纯化(CH2Cl2:MeOH:AcOH=150:15:1),得到目标化合物。


实施例10-2:化合物B14-B17的合成
将化合物B1(11.63mg,25.63μmol,1eq.)溶于DMF(0.5mL),0℃条件依次加入HATU(14.62mg,38.45μmol)、三乙胺(22.32μL,128.17μmol),升至室温,搅拌20min后,加入氯化铵/甲胺盐酸盐(76.90μmol,3eq.),室温反应5小时,TLC监测反应完全。加入10mL水,乙酸乙酯萃取(10mL*2),合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,减压旋干残余物用硅胶柱纯化(MeOH:CH2Cl2=0~10%),得到化合物B14和化合物B15。
其余酰胺或N-烷基酰胺类化合物合成方法类似。

实施例10-3:化合物B19的合成
Step 1:化合物B19-1的合成
将中间体3-2(77mg,0.32mmol)溶于乙醇(3.0mL),冰浴条件下加入硼氢化钠(18.12mg,0.48mmol),缓慢升至室温,反应2小时,TLC显示反应完全。冰浴条件下加入饱和碳酸氢钠溶液5mL淬灭反应,加入10mL水稀释,乙酸乙酯萃取(15mL*2),合并有机相, 饱和食盐水洗涤,无水硫酸钠干燥,减压旋干,得到73mg淡黄色固体化合物B19-1,收率94%。
LCMS(HCOOH):m/z=224.85(M+H-H2O);
1H NMR(400MHz,DMSO-d6)δ7.84(d,J=2.6Hz,1H),7.59(d,J=8.6Hz,1H),7.39(dd,J=8.6,2.6Hz,1H),7.18(d,J=3.4Hz,1H),6.50(d,J=3.4Hz,1H),5.38(t,J=5.9Hz,1H),4.49(d,J=5.9Hz,2H)。
Step 2:化合物B19-2的合成
将化合物B19-1(73mg,0.42mmol)溶于THF(2mL),0℃条件下,加入氢化钠(60%,32.1mg,0.84mmol),搅拌10min后,升温至回流并反应1小时,降至室温,加入溴乙酸乙酯(210.0mg,1.26mmol,139μL),回流反应1小时后补加氢化钠(60%,32.1mg,0.84mmol),继续回流反应1小时,TLC显示反应基本完全。冰浴条件下加入15mL水淬灭反应,乙酸乙酯萃取(15mL*3),合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,减压旋干,残余物用硅胶柱纯化(EA:PE=0~10%),得到43mg淡黄色油状物化合物B19-2,收率39.4%。
1H NMR(400MHz,CDCl3)δ7.80(d,J=2.5Hz,1H),7.28(d,J=8.5Hz,1H),7.12-7.04(m,2H),6.44(d,J=3.4Hz,1H),4.60(s,2H),4.16(q,J=7.1Hz,2H),4.07(s,2H),1.22(t,J=7.2Hz,3H)。
Step 3:化合物B19-3的合成
将化合物B19-2(43mg,0.13mmol)溶于甲醇(3mL)/水(0.6mL),加入氢氧化锂水合物(54.81mg,1.31mmol),室温反应1小时,TLC显示反应完全。加入适量醋酸调pH≈6,加入15mL水稀释,乙酸乙酯萃取(15mL*2),合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,减压旋干,得到31mg类白色固体化合物B19-3,收率78.81%。
LCMS(HCOOH):m/z=298.8(M-H)。
Step 4:化合物B19-4的合成
0℃条件下,将化合物B19-3(23.1mg,0.12mmol)溶于氯化亚砜(0.5mL),加热回流反应1小时,减压浓缩得到淡黄色油状物,加入无水THF(1.0mL)溶解,0℃条件下,加入2-氨基-5-氯苯甲酸甲酯(23.1mg,0.124mmol),升至室温,搅拌反应1小时,TLC显示反应完全。加入10mL水稀释,乙酸乙酯萃取(10mL*2),合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,减压旋干,残余物用硅胶柱纯化(EA:PE=0~10%),得到16mg白色固体化合物B19-4,收率41.1%。LCMS(HCOOH):m/z=465.72(M-H)。
Step 4:化合物B19的合成
将化合物B19-4(14mg,29.9μmol)溶于甲醇(2mL)/THF(1mL)/水(0.6mL),0℃条件下,加入氢氧化锂水合物(12.5mg,0.30mmol),搅拌10min后升温至50℃反应2小时,TLC显示反应完全。冰浴条件下,加入适量乙酸调pH≈5,减压旋干,加入2mL二氯甲烷打浆,抽滤,水洗,干燥,得到8.3mg白色固体化合物B19,收率61.4%。
LCMS(HCOOH):m/z=451.8(M-H);
1H NMR(400MHz,Methanol-d4)δ8.56(d,J=9.0Hz,1H),7.91(d,J=2.6Hz,1H),7.76(d,J=2.6Hz,1H),7.44(dd,J=9.0,2.6Hz,1H),7.37(d,J=8.5Hz,1H),7.21(dd,J=8.6,2.5Hz,1H),7.11(d,J=3.5Hz,1H),6.66(d,J=3.4Hz,1H),4.76(s,2H),4.20(s,2H)。
实施例10-4:化合物B20的合成
Step 1:化合物INT11-1的合成
将N-叔丁氧羰基乙醛胺(100mg,0.54mmol)溶于无水甲醇(5mL),0℃条件下,依次加入2-氨基-5-氯-苯甲酸甲酯(103mg,0.65mmol)、醋酸(32mg,0.54mmol),升至室温搅拌20min后,加入氰基硼氢化钠(102mg,1.62mmol),搅拌反应5小时,LCMS显示反应基本完全。反应液减压浓缩后加入水(20mL),乙酸乙酯萃取(20mL*2),合并有机相,无水硫酸钠干燥,过滤,减压浓缩,残余物用硅胶柱分离纯化(EA:PE=0~30%),得到192mg白色固体INT11-1,收率93.2%。LCMS(HCOOH):m/z=329.11(M+H)。
Step 2:中间体11的合成
0℃条件下,将化合物INT11-1(168mg,0.51mmol)溶于DCM/TFA(5mL/1mL),升至室温反应3小时,TLC显示反应完全。减压浓缩,加入饱和碳酸氢钠溶液20mL,乙酸乙酯萃取(20mL*2),合并有机相,无水硫酸钠干燥,过滤,减压浓缩,得到118mg白色固体中间体11,收率100%,直接用于下一步反应。
Step 3:化合物B20-1的合成
将中间体11(118mg,0.51mmol)溶于DMF(4mL),降温至0℃,依次加入中间体3-2(135mg,0.56mmol)、醋酸(61mg,1.02mmol),升至室温搅拌20分钟后,加入氰基硼氢化钠(126mg,2.05mmol),室温搅拌反应30分钟,TLC显示反应基本完全。加入水(20mL)淬灭反应,乙酸乙酯萃取(20mL*2),合并有机相,无水硫酸钠干燥,过滤,减压浓缩,残余物用硅胶柱纯化(MeOH:CH2Cl2=0~8%),得到26mg白色固体化合物B20-1,收率11.2%。
LCMS(HCOOH):m/z=453.1(M+H)。
Step 4:化合物B20的合成
将化合物22-1(26mg,57.30μmol)溶于甲醇(2mL)/水(0.4mL),加入氢氧化锂一水合物(24.0mg,0.57mmol),升至40℃反应5小时,TLC显示反应基本完全。冰浴条件下,加入适量乙酸调pH≈5,加入水(10mL),乙酸乙酯萃取(10mL*3),合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,减压旋干,残余物用硅胶柱纯化(MeOH:CH2Cl2=0~10%),得到7.8mg白色固体化合物B20,收率31.0%。
LCMS(HCOOH):m/z=438.92(M+H);
1H NMR(400MHz,DMSO-d6)δ7.95(d,J=2.6Hz,1H),7.77(d,J=2.7Hz,1H),7.65(d,J=8.6Hz,1H),7.43(m,2H),7.25(d,J=3.4Hz,1H),6.86(d,J=9.1Hz,1H),6.67(d,J=3.4Hz,1H),4.08(s,2H),3.46-3.41(m,2H),2.98(t,J=6.2Hz,2H)。
实施例10-5:化合物B21的合成
Step 1:化合物B21-1的合成
将中间体6-1(30mg,0.14mmol),3-(2,5-二氯)苯基丙炔醛(14.0mg,0.07mmol,0.5eq)溶于CH2Cl2(10mL),冰浴下加入乙酸(9mg,0.14mmol,1eq),室温下反应1小时,向混合液中加入NaBH(AcO)3(61mg,0.42mmol,3eq),室温下反应6小时,TLC显示反应基本完全。加入碳酸氢钠溶液(20mL)淬灭反应,分液后水相再用二氯甲烷萃取(20mL*3),合并有机相,无水硫酸钠干燥,过滤,减压浓缩,残余物硅胶柱纯化(MeOH:CH2Cl2=0~8%),得到15.4mg白色固体化合物B21-1,收率为28.2%。LCMS(FA):m/z=391.0(M+H)。
Step 2:化合物B21的合成
将化合物B21-1(15.4mg,39.5μmol)溶于THF/MeOH(0.5ml/0.5ml)中,滴加氢氧化锂(17mg,0.40mmol,10eq)的水溶液(0.5ml),室温搅拌反应6小时,TLC显示反应完全。将反应液用1M HCl溶液调pH≈3,乙酸乙酯萃取(20mL*3),合并有机相,无水硫酸钠干燥,过滤,旋干滤液,残余物硅胶柱纯化(MeOH:CH2Cl2=0~10%),得到7.7mg白色固体化合物B21,收率51.6%。LCMS(HCOOH):m/z=376.8(M+H).
1H NMR(400MHz,Methanol-d4)δ8.51(d,J=8.4Hz,1H),7.98(d,J=7.9Hz,1H),7.41(d,J=7.4Hz,1H),7.35(d,J=2.5Hz,1H),7.28(d,J=8.6Hz,1H),7.20(d,J=8.6Hz,1H),7.07-7.00(m,1H),3.81(s,2H),3.66(s,2H)。
参照化合物B1-B21的合成方法,合成下列的实施例化合物。

实施例11-1化合物C1的合成
合成路线:
制备方法:
第一步:合成化合物3
将化合物1(2.0g,11.8mmol)和化合物2(2.5g,11.8mmol)溶于吡啶(40mL)中,在冰浴下滴加三氯氧磷(1.8g,14.0mmol),然后在氮气保护下0℃搅拌30分钟。TLC显示反应结束后,将反应液倒入冰水(50mL)中,用乙酸乙酯(50mL×3)萃取。合并的有机相用稀盐酸(50mL×2,1N)洗涤,无水硫酸钠干燥,过滤,减压脱溶剂,残余物用硅胶柱层析纯化(石油醚:乙酸乙酯=1:0至5:1),得到化合物3(1.7g,黄色油状,产率39.0%)。MS(ESI):m/z 367.2[M+1]+
第二步:合成化合物4
将化合物3(1.5g,4.3mmol)溶于盐酸乙酸乙酯溶液(20mL)中,在室温下搅拌30分钟。TLC显示反应结束后,将反应液旋干得到粗品化合物4(1.2g,白色固体,盐酸盐)。MS(ESI):m/z 267.2[M+1]+
第三步:合成化合物5
将化合物5a(7.5g,42.9mmol)和化合物5b(9.0g,47.2mmol)溶于1,4-二氧六环(75mL)和水(7.5mL)中,加入碳酸钾(11.9g,85.8mmol)和1,1-双(二苯基膦)二荗铁二氯化钯(2.1g,2.15mmol)。加料完毕后,反应液在氮气保护下100℃搅拌16小时。TLC显示反应结束后,将反应液缓慢倒入水(150mL)中,用乙酸乙酯(100mL×3)萃取。合并的有机相用饱和食盐水(80mL×2)洗涤,无水硫酸钠干燥,过滤,减压脱溶剂,残余物用硅胶柱层析纯化(洗脱剂:石油醚/乙酸乙酯/二氯甲烷=1:0:0到10:1:1(体积比))得到粗品化合物。粗品化合物用甲醇(20mL)打浆得到化合物5(4.0g,棕黄色固体)。MS(ESI):m/z 241.0 243.0[M+1]+
第四步:合成化合物6
将化合物4(300mg,1.12mmol)和化合物5(240mg,1.12mmol)溶于甲醇(10ml)中,依次加入醋酸(60mg,1.12mmol)和醋酸钾(292mg,3.36mmol),室温下搅拌30分钟。随后冰浴下向反应液中缓慢加入氰基硼氢化钠(187mg,3.36mmol),随后室温下搅拌30分钟。TLC显示反应结束后,将反应液倒入碳酸氢钠水溶液(50mL)中,用乙酸乙酯(30mL×2)萃取。合并的有机相用无水硫酸钠干燥,过滤,减压脱溶剂,残余物用硅胶柱层析纯化(石油醚:乙酸乙酯=1:0至5:1)粗品化合物,粗品化合物再通过HPLC纯化得到化合物6(29.4mg,橙色胶体)。MS(ESI):m/z 491.1[M+1]+
1H NMR(400MHz,DMSO-d6)δ(ppm)11.80(s,1H),8.26(d,J=12.3Hz,1H),7.77(s,1H),7.63-7.48(m,2H),7.34(s,1H),6.99-6.74(m,2H),6.50(s,1H),4.02(d,J=14.1Hz,1H),3.82(s,3H),3.73(d,J=14.2Hz,1H),3.30-3.25(m,2H),2.72-2.61(m,1H),2.28-2.16(m,1H),1.90-1.66(m,3H)。
第五步:合成化合物C1
将化合物6(280mg,0.57mmol)溶于甲醇(5mL)和水(5mL),加入一水合氢氧化锂(120mg,2.85mmol),在室温下搅拌16小时。TLC显示反应结束后,将反应液用稀盐酸(1N)调节pH=5~6,用乙酸乙酯(20mL×4)萃取。合并的有机相用无水硫酸钠干燥,过滤,减压脱溶剂,残余物用HPLC纯化得到化合物C1(72.6mg,类白色固体)。
MS(ESI):m/z 477.1[M+1]+
1H NMR(400MHz,DMSO-d6)δ(ppm)12.27(s,1H),8.25(dd,J=12.5,2.7Hz,1H),7.87(dd,J=8.9,6.8Hz,1H),7.72-7.55(m,2H),7.33(dd,J=8.6,2.2Hz,1H),6.97(d,J=3.4Hz,1H),6.84(td,J=8.4,2.8Hz,1H),6.52(d,J=3.4Hz,1H),3.96(d,J=14.3Hz,1H),3.79(d,J=14.3Hz,1H),3.27-3.21(m,2H),2.70-2.63(m,1H),2.25-2.12(m,1H),1.86-1.71(m,3H)。
实施例11-2化合物C2的合成
合成路线:
制备方法:
第一步:合成化合物3
将粗品化合物1(100mg,0.35mmol)溶于甲醇(5mL)中,加入化合物2(119.2mg,0.53mmol)、醋酸钾(104mg,1.06mmol)和醋酸(21.3mg,0.35mmol),在室温下搅拌0.5小时。然后在冰浴下分批次加入氰基硼氢化钠(66.8mg,1.06mmol),并在35℃下搅拌1小时。TLC显示反应结束后,将反应减压浓缩后加入水(10mL)、乙酸乙酯(15mL×3)萃取。合并的有机相用无水硫酸钠干燥,过滤,减压浓缩,残余物用HPLC纯化得到化合物3(17mg,浅黄色胶体)。
1H NMR(400MHz,DMSO-d6)δ(ppm)11.60(s,1H),8.42(d,J=9.1Hz,1H),7.60(d,J=2.5Hz,1H),7.51-7.34(m,3H),7.20(dd,J=8.0,4.0Hz,1H),6.60(t,J=3.3Hz,1H),6.49(d,J=3.2Hz,1H),4.02(d,J=14.0Hz,1H),3.87(s,3H),3.72(d,J=14.0Hz,1H),3.30-3.26(m,2H),2.71-2.60(m,1H),2.26-2.12(m,1H),1.87-1.67(m,3H)。
第二步:合成化合物C2
将粗品化合物3(200mg,0.41mmol)溶于甲醇(5mL)和水(5mL),加入一水合氢氧化锂(51.2mg,1.22mmol),在室温下搅拌1小时。TLC显示反应结束后,反应液减压浓缩用1N盐酸水溶液调节pH=5-6,乙酸乙酯(10mL×3)萃取。合并的有机相用无水硫酸钠干燥,过滤,减压浓缩,残余物用HPLC纯化得到化合物C2(33.1mg,类白色固体)。
MS(ESI):m/z 476.9[M+1]+
1H NMR(400MHz,DMSO-d6)δ(ppm)12.01(s,1H),8.42(d,J=9.0Hz,1H),7.69(d,J=2.7Hz,1H),7.55-7.36(m,3H),7.19(dd,J=8.5,2.0Hz,1H),6.65(t,J=3.5Hz,1H),6.51(d,J=3.3Hz,1H),3.98(d,J=14.2Hz,1H),3.77(d,J=14.2Hz,1H),3.31-3.29(m,1H),3.25-3.22(m,1H),2.68-2.60(m,1H),2.23-2.12(m,1H),1.83-1.72(m,3H)。
实施例11-3化合物C3的合成
合成路线:
制备方法:
第一步:合成化合物3
将粗品化合物1的盐酸盐(1.2g,4.24mmol)溶于甲醇(10mL)中,加入化合物2(1.52g,6.36mmol)、醋酸钾(295mg,12.72mmol)和醋酸(254mg,4.24mmol),在室温下搅拌0.5小时,然后0℃下分批次加入氰基硼氢化钠(800mg,12.72mmol),并在室温下搅拌0.5小时。TLC显示反应结束后,将反应液倒入碳酸氢钠水溶液(50mL)中,用乙酸乙酯(50mL×3)萃取。合并的有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,过滤,减压脱溶剂,残余物用硅胶柱层析纯化(石油醚:乙酸乙酯=1:0至5:1)得到粗品化合物3(1g,黄色油状,产率83%)。粗品化合物3(150mg)通过HPLC纯化得到化合物3(26.4mg,棕色胶体)。
1H NMR(400MHz,DMSO-d6)δ(ppm)11.61(s,1H),8.43(d,J=9.0Hz,1H),7.61-7.44(m,4H),7.33(dd,J=8.6,2.2Hz,1H),6.90(d,J=3.4Hz,1H),6.50(d,J=3.4Hz,1H),4.02(d,J=14.0Hz,1H),3.85(s,3H),3.71(d,J=14.0Hz,1H),3.31-3.26(m,2H),2.69-2.62(m,1H),2.27-2.16(m,1H),1.84-1.70(m,3H)。
第二步:合成化合物C3
将化合物3(850mg,1.67mmol)溶于甲醇(5mL)和水(5mL),加入一水合氢氧化锂(345mg,2.75mmol),在室温下搅拌16小时。TLC显示反应结束后,反应液用1N稀盐酸调节pH=5-6,乙酸乙酯(20mL×4)萃取。合并的有机相用无水硫酸钠干燥,过滤,减压脱溶剂,残余物用HPLC纯化得到化合物C3(182.8mg,白色固体)。
MS(ESI):m/z 493.0 494.9[M+1]+
1H NMR(400MHz,DMSO-d6)δ(ppm)13.74(br.s,1H),12.09(s,1H),8.44(d,J=9.0Hz,1H),7.69(d,J=2.7Hz,1H),7.63-7.53(m,2H),7.46(dd,J=9.0,2.7Hz,1H),7.33(dd,J=8.6,2.2Hz,1H),6.96(d,J=3.4Hz,1H),6.52(d,J=3.4Hz,1H),3.97(d,J=14.2Hz,1H),3.77(d,J=14.2Hz,1H),3.27-3.20(m,2H),2.69-2.61(m,1H),2.24-2.13(m,1H),1.86-1.68(m,3H)。
实施例11-4化合物C4的合成
合成路线:
制备方法:
第一步:合成化合物3
将化合物1(2.0g,10.8mmol)和化合物2(3.5g,16.2mmol)溶于吡啶(40mL)中,氮气置换三次后,在-10℃~-5℃下滴加三氯氧磷(1.2mL,13.0mmol)。滴加完毕后,在-5℃下继续搅拌30分钟。TLC显示反应结束后,将反应液缓慢倒入水(100mL)中,用乙酸乙酯(80mL×3)萃取。合并的有机相用盐酸水溶液(40mL×3,1N)洗涤,再无水硫酸钠干燥,过滤,减压脱溶剂,残余物用硅胶柱层析纯化(洗脱剂:石油醚/乙酸乙酯=5:1到1:1(体积比)),得到化合物3(3.4g,淡黄色油,产率:78.69%)。
MS(ESI):m/z 283.0[M-100+1]+
第二步:合成化合物4
将化合物3(2.9g,7.57mmol)溶于盐酸乙醇溶液(30mL,30%)中,室温下搅拌16小时。LCMS显示反应结束后,将反应液减压脱溶剂,得到粗品化合物4(2.9g,淡黄色固体)。MS(ESI):m/z 283.0[M+1]+
第三步:合成化合物5
将化合物5a(7.5g,42.9mmol)和化合物5b(9.0g,47.2mmol)溶于1,4-二氧六环(75mL)和水(7.5mL)中,加入碳酸钾(11.9g,85.8mmol)和1,1-双(二苯基膦)二茂铁二氯化钯(2.1g,2.15mmol)。加料完毕后,反应液在氮气保护下100℃搅拌16小时。TLC显示反应结束后,将反应液缓慢倒入水(150mL)中,用乙酸乙酯(100mL×3)萃取。合并的有机相用饱和食盐水(80mL×2)洗涤,无水硫酸钠干燥,过滤,减压脱溶剂,残余物用硅胶柱层析纯化(洗脱剂:石油醚/乙酸乙酯/二氯甲烷=1:0:0到10:1:1(体积比))得到粗品化合物。粗品化合物用甲醇(20mL)打浆得到化合物5(4.0g,棕黄色固体)。MS(ESI):m/z 241.0 243.0[M+1]+
第四步:合成化合物6
将化合物4(2.1g,7.57mmol)溶于N,N-二甲基甲酰胺(20mL)中,依次加入化 合物5(2.2g,9.08mmol)、醋酸钾(2.2g,22.7mmol)和醋酸(455mg,7.57mmol)。然后室温下搅拌30分钟,随后将反应液冷却至0℃,分批加入氰基硼氢化钠(1.4g,22.7mmol)。加料完毕后,在35℃下搅拌1小时。TLC显示反应结束后,将反应液缓慢倒入水(100mL)中,用乙酸乙酯(80mL×3)萃取。合并有机相,然后用饱和食盐水(40mL×3)洗涤,无水硫酸钠干燥,过滤,减压脱溶剂,残余物用硅胶柱层析纯化(洗脱剂:石油醚/乙酸乙酯=1:0到3:1(体积比))得到粗品化合物(4g,黄色油)。300mg粗品通过HPLC纯化得到化合物6(26.1mg,棕色固体)。
1H NMR(400MHz,DMSO-d6)δ(ppm)11.61(s,1H),8.44(d,J=9.1Hz,1H),7.62-7.45(m,4H),7.34(dd,J=8.6,2.2Hz,1H),6.90(d,J=3.4Hz,1H),6.50(d,J=3.4Hz,1H),4.02(d,J=13.9Hz,1H),3.85(s,3H),3.71(d,J=13.9Hz,1H),3.29(dd,J=10.4,3.6Hz,2H),2.69-2.61(m,1H),2.28-2.14(m,1H),1.86-1.71(m,3H).
第五步:合成化合物C4
将化合物6(700mg,1.38mmol)溶于甲醇/四氢呋喃/水(5mL/5mL/5mL)的混合溶剂中,加入一水合氢氧化锂(116mg,2.76mmol),室温下搅拌16小时。TLC显示反应结束后,减压浓缩,除去溶剂,残余物中加入水(30mL),然后用盐酸水溶液(1N)调节pH=5~6,再用乙酸乙酯(50mL×3)萃取。合并有机相然后用饱和食盐水(20mL×3)洗涤,无水硫酸钠干燥,过滤,减压脱溶剂,残余物通过HPLC纯化得到化合物C4(113.3mg,浅黄色固体)。
MS(ESI):m/z 492.9 495.0[M+1]+
1H NMR(400MHz,DMSO-d6)δ(ppm)13.70(br.s,1H),12.00(s,1H),8.43(d,J=9.0Hz,1H),7.68(d,J=2.7Hz,1H),7.62-7.53(m,2H),7.48(dd,J=9.0,2.7Hz,1H),7.32(dd,J=8.6,2.2Hz,1H),6.95(d,J=3.4Hz,1H),6.52(d,J=3.4Hz,1H),3.98(d,J=14.2Hz,1H),3.77(d,J=14.2Hz,1H),3.28-3.20(m,2H),2.69-2.62(m,1H),2.34-2.12(m,1H),1.86-1.70(m,3H)。
实施例11-5化合物C5的合成
合成路线:
制备方法:
第一步:合成化合物3
将化合物1(500mg,1.94mmol)溶于二氧六环(10ml)和水(1ml)中,加入化合物2(354.6mg,2.53mmol)、碳酸钾(538mg,3.88mmol)和双三苯基膦氯化钯(68.4mg,0.097mmol),然后在氮气保护下100℃搅拌16小时。TLC显示反应结束后,反应液倒入水(30mL)中,乙酸乙酯(50mL×3)萃取。合并的有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,过滤,减压脱溶剂,残余物用硅胶柱层析纯化(石油醚:乙酸乙酯=1:0至5:1)得到化合物3(460mg,黄色油状,产率92%)。MS(ESI):m/z 225.0[M+1]+
第二步:合成化合物5
将粗品化合物4的盐酸盐(286mg,1.01mmol)溶于甲醇(40mL)中,加入化合物3(340mg,1.65mmol)、醋酸钾(297mg,3.03mmol)和醋酸(61mg,1.01mmol),在室温下搅拌0.5小时后,在冰浴下分批次加入氰基硼氢化钠(190mg,3.03mmol),并在室温下搅拌0.5小时。TLC显示反应结束后,将反应液倒入碳酸氢钠水溶液(30mL)中,用乙酸乙酯(30mL×3)萃取。合并的有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,过滤,减压脱溶剂,残余物用硅胶柱层析纯化(石油醚:乙酸乙酯=1:0至5:1)得到粗品化合物5(320mg,黄色油状,产率94%)。粗品化合物(150mg)通过HPLC纯化得到化合物5(25.1mg,类白色固体)。
1H NMR(400MHz,DMSO-d6)δ(ppm)11.63(s,1H),8.46(d,J=9.1Hz,1H),7.64-7.44(m,3H),7.39(d,J=8.3Hz,1H),7.15(d,J=8.7Hz,1H),6.82(d,J=3.6Hz,1H),6.47(d,J=3.5Hz,1H),4.01(d,J=14.0Hz,1H),3.85(s,3H),3.71(d,J=14.0Hz,1H),3.27-3.20(m,2H),2.70-2.63(m,1H),2.26-2.17(m,1H),1.86-1.68(m,3H)。
第三步:合成化合物C5
将化合物5(200mg,0.40mmol)溶于甲醇(5mL)和水(5mL)中,加入一水合氢氧化锂(277mg,2mmol),在室温下搅拌16小时。TLC显示反应结束后,反应液用1N稀盐酸调节pH=5-6,乙酸乙酯(20mL×4)萃取。合并的有机相用无水硫酸钠干燥,过滤,减压脱溶剂,残余物用HPLC纯化得到化合物C5(52.4mg,白色固体)。
MS(ESI):m/z 476.9[M+1]+
1H NMR(400MHz,DMSO-d6)δ(ppm)12.07(br.s,1H),8.45(d,J=9.0Hz,1H),7.71(d,J=2.7Hz,1H),7.61(dd,J=8.9,6.2Hz,1H),7.48(dd,J=9.0,2.7Hz,1H),7.42(dd,J=8.8,2.6Hz,1H),7.15(td,J=8.5,2.7Hz,1H),6.87(d,J=3.3Hz,1H),6.50(d,J=3.4Hz,1H),3.96(d,J=14.2Hz,1H),3.77(d,J=14.3Hz,1H),3.26-3.10(m,2H),2.69-2.61(m,1H),2.23-2.13(m,1H),1.83-1.71(m,3H)。
实施例11-6化合物C6的合成
合成路线:
制备方法:
第一步:合成化合物3
将化合物1(500mg,2.4mmol)溶解在二氧六环(10ml)和水(1ml)中,加入化合物2(546mg,2.8mmol)、碳酸钾(718.6mg,4.8mmol)和[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(112mg,0.12mmol)。然后在氮气保护下100℃搅拌16小时。TLC显示反应结束后,将反应液倒入水(50mL)中,乙酸乙酯(50mL×3)萃取,无水硫酸钠干燥,过滤,减压脱溶剂,残余物用硅胶柱层析纯化(石油醚:乙酸乙酯=1:0至5:1)得到化合物3(390mg,黄色固体,产率78%)。MS(ESI):m/z 258.0[M+1]+
第二步:合成化合物5
将粗品化合物4的盐酸盐(245mg,0.86mmol)溶于甲醇(4mL)中,加入化合物3(340mg,1.29mmol)、醋酸钾(264mg,2.58mmol)和醋酸(59mg,0.86mmol),在室温下搅拌0.5小时后,在冰浴下分批次加入氰基硼氢化钠(176mg,2.58mmol),并在室温下搅拌0.5小时。TLC显示反应结束后,将反应液倒入碳酸氢钠水溶液(20mL)中,用乙酸乙酯(30mL×3)萃取。合并的有机相用饱和食盐水(30mL)洗涤,无水硫酸钠干燥,过滤,减压脱溶剂,残余物用硅胶柱层析纯化(石油醚:乙酸乙酯=1:0至5:1)得到粗品化合物5(250mg,黄色油状,产率73%)。粗品化合物(150mg)用HPLC纯化得到化合物5(13.2mg,类白色固体)。
1H NMR(400MHz,DMSO-d6)δ(ppm)11.72(s,1H),8.56(d,J=9.1Hz,1H),8.08(d,J=8.6Hz,1H),7.95-7.86(m,2H),7.78(d,J=2.2Hz,1H),7.61(dd,J=9.0,2.7Hz,1H),7.53(dd,J=8.6,2.2Hz,1H),4.13(s,2H),3.91(s,3H),3.27-3.21(m,2H),2.64-2.59(m,1H),2.27-2.17(m,1H),1.88-1.71(m,3H)。
第三步:合成化合物C6
将化合物5(250mg,0.47mmol)溶于甲醇(5mL)和水(5mL)中,加入一水合氢氧化锂(277mg,2mmol),在室温下搅拌16小时。TLC显示反应结束后,反应液用1N稀盐酸调节pH=5-6,乙酸乙酯(20mL×4)萃取。合并的有机相用无水硫酸钠干燥,过滤,减压脱溶剂,残余物用HPLC纯化得到化合物C6(34.6mg,白色固体)。
MS(ESI):m/z 509.8[M+1]+
1H NMR(400MHz,DMSO-d6)δ(ppm)12.31(br.s,1H),8.54(d,J=9.0Hz,1H),8.08(d,J=8.6Hz,1H),7.98-7.87(m,2H),7.77(d,J=2.1Hz,1H),7.53(dt,J=8.6,2.5Hz,2H),4.12(s,2H),3.24-3.16(m,2H),2.63-2.57(m,1H),2.23-2.13(m,1H),1.88-1.70(m,3H)。
实施例11-7化合物C7的合成
合成路线:
制备方法:
第一步:合成化合物3
将化合物1(500mg,3.2mmol)溶于乙二醇二甲醚溶液(10ml)中,加入化合物2(371.4mg,4.16mmol)、碳酸钾(1.33g,9.6mmol)和双三苯基膦氯化钯(64.3mg,0.16mmol)。然后在氮气保护下100℃搅拌16小时。TLC显示反应结束后,反应液倒入冰水(20mL)中,乙酸乙酯(30mL×3)萃取。合并的有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,过滤,减压脱溶剂,残余物用硅胶柱层析纯化(石油醚:乙酸乙酯=1:0至5:1)得到化合物3(280mg,黄色油状,产率56%)。MS(ESI):m/z 257.0[M+1]+
第二步:合成化合物5
将粗品化合物4的盐酸盐(205mg,0.72mmol)溶于甲醇(40mL)中,加入化合物3(280mg,1.08mmol)、醋酸钾(213mg,2.14mmol)和醋酸(45mg,0.72mmol),在室温下搅拌0.5小时后,冰浴下分批次加入氰基硼氢化钠(139mg,2.14mmol),并在室温下搅拌0.5小时。TLC显示反应结束后,将反应液倒入碳酸氢钠水溶液(10mL)中,用乙酸乙酯(15mL×2)萃取。合并的有机相用饱和食盐水(20mL)洗涤,无水硫酸钠干燥,过滤,减压脱溶剂,残余物用硅胶柱层析纯化(石油醚:乙酸乙酯=1:0至5:1)得到粗品化合物5(300mg,黄色油状,产率79%)。粗品化合物(150mg)用HPLC纯化得到化合物5(16.7mg,类白色胶体)。
1H NMR(400MHz,DMSO-d6)δ(ppm)11.70(s,1H),8.58(d,J=9.1Hz,1H),7.89(d,J=2.7Hz,1H),7.68(t,J=1.3Hz,1H),7.63(dd,J=9.1,2.7Hz,1H),7.41(d,J=1.6Hz,2H),7.24(d,J=3.7Hz,1H),7.07(d,J=3.7Hz,1H),4.02(s,2H),3.89(s,3H),3.31-3.22(m,2H),2.65-2.58(m,1H),2.27-2.16(m,1H),1.89-1.69(m,3H)。
第三步:合成化合物C7
将化合物5(300mg,0.57mmol)溶于甲醇(5mL)和水(5mL)中,加入一水合氢氧化锂(277mg,2mmol),在室温下搅拌16小时。TLC显示反应结束后,将反应液用1N稀盐酸调节pH=5-6,用乙酸乙酯(20mL×4)萃取。合并的有机相用无水硫酸钠干燥,过滤,减压脱溶剂,残余物用HPLC纯化得到化合物C7(70.2mg,浅黄色固体)。
MS(ESI):m/z 508.9[M+1]+
1H NMR(400MHz,DMSO-d6)δ12.16(s,1H),8.57(d,J=9.0Hz,1H),7.90(d,J=2.7Hz,1H),7.68(d,J=1.8Hz,1H),7.59(dd,J=9.0,2.8Hz,1H),7.41(d,J=3.1Hz,2H),7.24(d,J=3.7Hz,1H),7.09(d,J=3.7Hz,1H),4.08-3.97(m,2H),3.24-3.18(m,2H),2.64-2.57(m,1H),2.24-2.13(m,1H),1.88-1.71(m,3H)。
实施例11-8化合物C8的合成
合成路线:
制备方法:
第一步:合成化合物3
将化合物2(1.23g,5.83mmol)溶于无水四氢呋喃(10mL)中,加入三乙胺(942mg,9.33mmol),冰浴下加入三甲基乙酰氯(1.03g,17.5mmol)。在冰浴下搅拌30分钟后,向反应液中加入化合物1(1.0g,5.83mmol),并在65℃下搅拌16小时。TLC显示反应结束后,将反应液中加入水(30mL)中,乙酸乙酯(30mL×3)萃取。合并的有机相用饱和碳酸氢钠溶液(50mL×3)洗涤,无水硫酸钠干燥,过滤,减压脱溶剂,残余物用硅胶柱层析纯化(石油醚:乙酸乙酯=1:0至5:1)得到化合物3(1.23g,黄色油状,产率57.7%)。MS(ESI):m/z=397.1[M+1]+
第二步:合成化合物4
将化合物3(100mg,0.25mmol)溶于盐酸乙酸乙酯溶液(10mL,2.5mol/L)中,在室温下搅拌1小时。TLC显示反应结束后,将反应液旋干得到粗品化合物4(100mg,黄色油状,盐酸盐)。MS(ESI):m/z=296.9[M+1]+
第三步:合成化合物6
将粗品化合物4(100mg,0.25mmol)和化合物5(72.9mg,0.30mmol)溶于甲醇(5mL)中,依次加入醋酸钾(74mg,0.76mmol)和醋酸(15mg,0.25mmol),在室温下搅拌0.5小时后,在冰浴下分批次加入氰基硼氢化钠(47mg,0.76mmol),并在35℃下搅拌16小时。TLC显示反应结束后,将反应液倒入水(10mL)中,乙酸乙酯(15mL×3)萃取。合并的有机相用无水硫酸钠干燥,过滤,减压脱溶剂,粗品化合物再通过HPLC纯化得到化合物6(18.1mg,浅粉色固体)。
1H NMR(400MHz,DMSO-d6)δ(ppm)11.46(s,1H),8.58(d,J=9.1Hz,1H),7.81(d,J=2.7Hz,1H),7.60-7.75(m,3H),7.40(dd,J=8.6,2.2Hz,1H),7.04(d,J=3.4Hz,1H),6.50(d,J=3.4Hz,1H),3.80(s,3H),3.73(dd,J=20.0,12.0Hz,2H),3.07-3.00(m,1H),2.98-2.92(m,1H),2.56-2.35(m,1H),1.95-1.83(m,1H),1.75-1.53(m,3H),1.51-1.40(m,1H),1.34-1.21(m,1H)。
第四步:合成化合物C8
将化合物6(200mg,0.38mmol)溶于甲醇(5mL)和水(5mL),加入一水合氢氧化锂(48.25mg,1.15mmol),在25℃下搅拌1小时。TLC显示反应结束后,将反应液用1N稀盐酸调节pH=1-2,有固体析出,过滤得到残余物用HPLC纯化得到化合物C8(33.6mg,白色固体)。MS(ESI):m/z 506.8[M+1]+
1H NMR(400MHz,DMSO-d6)δ(ppm)11.94(s,1H),8.59(d,J=8.9Hz,1H),7.89(d,J=2.7Hz,1H),7.72(d,J=8.6Hz,1H),7.67(d,J=2.1Hz,1H),7.63(dd,J=9.0,2.7Hz,1H),7.42(dd,J=8.6,2.2Hz,1H),7.08(d,J=3.4Hz,1H),6.54(d,J=3.2Hz,1H),3.80(d,J=14.8Hz,1H),3.70(d,J=14.9Hz,1H),3.04-2.95(m,2H),2.38-2.22(m,1H),1.96-1.82(m,1H),1.72-1.53(m,3H),1.50-1.37(m,1H),1.34-1.25(m,1H)。
实施例11-9化合物C9的合成
合成路线:
制备方法:
第一步:合成化合物3
将化合物1(2.0g,11.8mmol)和化合物2(2.5g,11.8mmol)溶于吡啶(40mL)中,在0℃下加入三氯氧磷(2.2g,14.2mmol),然后在25℃下搅拌30分钟。TLC显示反应结束后,反应液倒入冰水(50mL)中,乙酸乙酯(50mL×3)萃取,合并的有机相使用稀盐酸(50mL×3,1N)洗涤,无水硫酸钠干燥,过滤,减压脱溶剂,残余物用硅胶柱层析纯化(石油醚:乙酸乙酯=1:0至5:1)得到化合物3(3.2g,黄色油状,产率73.87%)。MS(ESI):m/z 389.1[M+23]+
第二步:合成化合物4
将化合物3(3.0g,8.19mmol)溶于盐酸乙醇溶液(30mL),在25℃下搅拌16小时。TLC显示反应结束后,将反应液旋干得到粗品化合物4(2.0g,黄色胶体,盐酸盐)。
MS(ESI):m/z 267.1[M+1]+
第三步:合成化合物6
将粗品化合物4(0.5g,1.36mmol)溶于N,N-二甲基甲酰胺(10mL)中,加入化合物5(393mg,1.64mmol)、醋酸钾(401mg,4.08mmol)和醋酸(81.97mg,1.36mmol),在25℃下搅拌0.5小时。然后在0℃下分批次加入氰基硼氢化钠(257.4mg,4.08mmol),并在35℃下搅拌1小时。TLC显示反应结束后,将反应液加入水溶液(30mL)中,乙酸乙酯(15mL×3)萃取。合并的有机相用饱和食盐水(10mL×3)洗涤,无水硫酸钠干燥,过滤,减压脱溶剂,粗品化合物再通过HPLC纯化得到化合物6(38.7mg,红棕色胶体)。
MS(ESI):m/z 490.9[M+1]+
1H NMR(400MHz,DMSO-d6)δ(ppm)11.55(s,1H),8.46(dd,J=9.3,5.2Hz,1H),7.61-7.51(m,2H),7.45-7.29(m,3H),6.93(d,J=3.4Hz,1H),6.51(d,J=3.4Hz,1H),4.00(d,J=14.2Hz,1H),3.84(s,3H),3.76(d,J=14.1Hz,1H),3.31-3.26(m,2H),2.69-2.63(dd,J=9.6,6.0Hz,1H),2.28-2.16(m,1H),1.86-1.70(m,3H)。
第四步:合成化合物C9
将化合物6(300mg,610.57μmol)溶于甲醇(5mL)和水(5mL),加入一水合氢氧化锂(1.83mg,77mmol),在25℃下搅拌16小时。TLC显示反应结束后,将反应液用 1N稀盐酸调节pH=5-6,乙酸乙酯(20mL×4)萃取。合并的有机相用无水硫酸钠干燥,过滤,减压浓缩,残余物用HPLC纯化得到化合物C9(67.8mg,橙黄色固体)。
MS(ESI):m/z 477.1[M+1]+
1H NMR(400MHz,DMSO-d6)δ(ppm)13.69(br.s,1H),11.94(s,1H),8.46(dd,J=9.3,5.2Hz,1H),7.67-7.55(m,2H),7.51(dd,J=9.4,3.2Hz,1H),7.41-7.25(m,2H),6.98(d,J=3.4Hz,1H),6.53(d,J=3.4Hz,1H),3.96(d,J=14.3Hz,1H),3.81(d,J=14.3Hz,1H),3.23(t,J=7.4Hz,2H),2.69-2.61(m,1H),2.24-2.12(m,1H),1.85-1.68(m,3H)。
实施例11-10化合物C10的合成
合成路线:
制备方法:
第一步:合成化合物3
将化合物1(3.0g,19.8mmol)溶于N,N-二甲基甲酰胺(30mL)中,加入化合物2(5.1g,23.76mmol)、N,N-二异丙基乙胺(7.6g,59.4mmol),在0℃下加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(11.3g,29.7mmol),然后在25℃下搅拌16小时。TLC显示反应结束后,将反应液倒入冰水(70mL)中,用乙酸乙酯(50mL×3) 萃取,合并的有机相用饱和食盐水(50mL×3)洗涤,无水硫酸钠干燥,过滤,减压脱溶剂,残余物用硅胶柱层析纯化(石油醚:乙酸乙酯=1:0至5:1)得到化合物3(6.0g,黄色油状,产率86.8%)。MS(ESI):m/z 349.2[M+1]+
第二步:合成化合物4
将化合物3(6.0g,17.2mmol)溶于盐酸乙醇溶液(60mL),在25℃下搅拌16小时。TLC显示反应结束后,将反应液旋干得到粗品化合物4(6.0g,黄色胶体,盐酸盐)。
MS(ESI):m/z 249.1[M+1]+
第三步:合成化合物6
将粗品化合物4(466mg,1.88mmol)溶于N,N-二甲基甲酰胺(7mL),加入化合物5(448mg,1.88mmol)、醋酸钾(549mg,5.64mmol)和醋酸(112mg,1.88mmol),在25℃下搅拌0.5小时,然后0℃下分批次加入氰基硼氢化钠(354mg,5.64mmol),并在25℃下搅拌16小时。TLC显示反应结束后,将反应液倒入饱和碳酸氢钠水溶液(30mL)中,乙酸乙酯(15mL×3)萃取。合并的有机相用饱和食盐水(10mL×3)洗涤,无水硫酸钠干燥,过滤,减压脱溶剂,残余物用硅胶柱层析纯化(石油醚:乙酸乙酯=1:0至5:1)得到粗品化合物,粗品化合物再通过HPLC纯化得到化合物6(96.5mg,类白色固体)。MS(ESI):m/z 473.0 475.1[M+1]+
1H NMR(400MHz,DMSO-d6)δ(ppm)9.81(s,1H),7.76-7.53(m,6H),7.45-7.36(m,1H),6.97(d,J=3.3Hz,1H),6.52(d,J=3.4Hz,1H),3.94(d,J=14.3Hz,1H),3.81(s,3H),3.77(d,J=14.3Hz,1H),3.32-3.18(m,2H),2.66-2.57(m,1H),2.24-2.11(m,1H),1.86-1.73(m,3H)。
第四步:合成化合物C10
将化合物6(500mg,1.06mmol)溶于甲醇(5mL)和水(5mL),加入一水合氢氧化锂(222mg,5.3mmol),在25℃下搅拌16小时。TLC显示反应结束后,将反应液用1N稀盐酸调节pH=5-6,乙酸乙酯(20mL×4)萃取。合并的有机相用无水硫酸钠干燥,过滤,减压脱溶剂,残余物用HPLC纯化得到化合物C10(26.7mg,浅绿色固体)。
MS(ESI):m/z 459.0 461.0[M+1]+
1H NMR(400MHz,DMSO-d6)δ(ppm)9.80(s,1H),7.72(t,J=9.3Hz,3H),7.67-7.58(m,3H),7.41(dd,J=8.6,2.2Hz,1H),6.99(d,J=3.3Hz,1H),6.53(d,J=3.4Hz,1H),3.92(d,J=14.3Hz,1H),3.79(d,J=14.3Hz,1H),3.31-3.29(m,1H),3.25-3.20(m,1H),2.65-2.57(m,1H),2.21-2.12(m,1H),1.86-1.72(m,3H)。
参照化合物C1-C10的合成方法,合成下列实施例化合物。


实施例12:化合物对GPR75受体的激动活性测试
利用GTPase-Glo试剂盒检测化合物对GPR75蛋白(蛋白表达纯化方法参考专利PCT/CN2022/117816测试例1)的激动活性,实验缓冲液为20mM HEPES pH 7.5,100mM NaCl,0.01%MNG,0.0006%CHS,100μM TCEP和5mM MgCl2。用100%DMSO对待测化合物及对照化合物20-HETE(一种已知的GPR75小分子激动剂)进行10倍稀释,连续稀释4个浓度梯度。然后用缓冲液进一步稀释化合物至3×工作浓度,并取2.5μL化合物溶液加入实验板相应孔中,待测化合物起始浓度为40μM,20-HETE起始浓度为200μM,DMSO工作浓度为1%。用缓冲液稀释GPR75蛋白(工作浓度为0.5μM)和GTP(工作浓度为5μM),并取2.5μL溶液加入实验板中。用缓冲液稀释Gq蛋白(工作浓度为1μM),并取2.5μL溶液加入实验板中,室温孵育18小时。用GTPase-Glo缓冲液稀释得到1X GTPase-Glo和5mM ADP,并取7.5μL溶液加入实验板中,室温孵育。30分钟后向实验板中加入15μL检测试剂,室温孵育。10分钟后在BMG ClarioStar上读取化学发光信号。
数据分析:
计算%Effect并拟合化合物EC50;
%Effect=1-100%*(Signal-Bottom)/(Top-Bottom),其中Signal表示化合物的信号,Bottom表示200μM 20-HETE对应的信号,Top表示空白1%DMSO的信号。
各化合物对GPR75的激动活性具体见下表:
实施例13:化合物对G蛋白通路下游ERK蛋白磷酸化水平的影响的测试
瞬转细胞过表达GPR75
使用含有88%DMEM、10%FBS、1%GlutaMax和1%的双抗培养基稀释CHO细胞至1.25×105个/ml,每孔1ml接种于12孔板,于5%CO2、37℃的细胞培养箱中培养24小时,观察细胞长至8成即可以进行GPR75质粒转染实验。用Opti-MEM配置转染试剂,12孔板中每孔转染试剂总体积为250ul,包括opti-MEM、200ng GPR75质粒和0.6ul Fugene HD(质量体积比:1:3),室温静置15min。移除12孔板中的旧培养基,每孔使用1mL DPBS清洗细胞,弃掉DPBS加入1ml Opti-MEM培养基,随即向每孔中均匀滴加250ul转染试剂,轻轻晃动后放入5%CO2、37℃细胞培养箱中培养24h。
磷酸化ERK蛋白样品制备
移除12孔板中的含有转染试剂的opti-MEM,用1ml PBS漂洗细胞,弃掉PBS后每孔加入新的1ml PBS,置于5%CO2、37℃的细胞培养箱中饥饿处理1h。用PBS配制终浓度为0.2~5000nM的待测化合物或对照化合物20-HETE工作液,移除12孔板中PBS,每孔加入1ml待测化合物或对照化合物工作液,空白对照组加入等量的含有0.1%DMSO的PBS,室温孵育10min。移除12孔板中的含有化合物的PBS以及对照组的含有0.1%DMSO的PBS,每孔加入200ul细胞裂解液,冰浴1-2分钟,用移液器吹打细胞至全部脱落,移至EP管中,冰上裂解30分钟。4℃12000RCF条件离心15分钟,收集上清液体为抽提的总蛋白,用总蛋白稀释5×蛋白上样缓冲液(50mM Tris-HCl(pH 6.8),2%(W/V)十二烷基硫酸钠,0.1%(W/V)溴酚蓝,10%(V/V)丙三醇,10%(V/V)β-巯基乙醇的超纯水溶液)至含有蛋白样本的1×上样缓冲液,于100℃金属浴加热10分钟后冷却,即得待检测的蛋白样品。
磷酸化ERK蛋白含量分析
取10μL蛋白样品,用10%SDS-PAGE凝胶电泳分离蛋白样品。电泳分离总蛋白条件为60V恒压30分钟,120V恒压将蛋白分离至溴酚蓝指示剂至玻璃板底端。电泳结束后,在4℃下,凝胶中蛋白湿转至PVDF膜上(120V恒压,70分钟),转膜结束后,用5%牛奶封闭1小时,使用一抗4℃孵育过夜,PBST洗三次,每次10分钟。室温孵育一抗相对应的兔/鼠二抗1小时,PBST洗膜三次,每次10分钟,化学发光液ECL滴加在载有待检测蛋白的PVDF膜上,在凝胶成像设备上检测化学发光信号。
本发明的化合物能激活GPR75,活化G蛋白及下游通路,导致ERK磷酸化水平升高。
10nM化合物和20-HETE对ERK磷酸化水平的影响结果如图1所示。
实施例14:小分子化合物对GPR75与G蛋白相互作用影响的测试
1.细胞培养
在37℃水浴锅中预热DMEM完全培养基(88%DMEM,10%FBS(ExCell Bio),1%GlutaMax(Gibco)和1%双抗(Gibco))、胰酶(Gibco)和DPBS(Gibco)。CHO细胞长至90%,密度为107/ml时,弃掉DMEM完全培养基,向培养瓶中加入适量DPBS,轻轻晃动清洗细胞,弃掉DPBS。向培养瓶中加入适量胰酶,轻轻晃动培养瓶后移除胰酶,放入CO2细胞培养箱中孵育约3min,轻轻拍打培养瓶,显微镜下观察90%以上细胞变圆后,用DMEM完全培养基悬浮细胞。取10μL悬浮细胞悬液,与10μL台盼蓝混匀,然后取10μL与台盼蓝混合的细胞悬液计数,将CHO细胞悬液稀释至2.5×105/ml,向6孔板中每孔中加入2mL定量后的细胞悬液,置于CO2细胞培养箱中培养24h。
2.细胞转染
GPR75、LgBit-Gq、Sm-Gβ1、Gγ2四个质粒,按照500ng/每个质粒,进行四质粒共转染。质粒与转染试剂Fugene的质量体积比为1μg:3μl,用250μl的Opti-MEM混匀质粒与Fugene混合物,室温静置15分钟,静置期间将6孔板中细胞培养液弃掉,每孔加 入2ml的DPBS清洗一遍,弃掉DPBS,每孔加入2ml的opti-MEM。15分钟后向每孔中均匀滴加250μl的转染试剂,轻轻晃动后放入细胞培养箱中培养24h。
3.小分子化合物对GPR75与G蛋白相互作用影响实验(NanoBiT assay)
3.1收集转染细胞样品铺384孔板
配制稀释待检测细胞样品的检测缓冲液:用去离子水配制成1×HBSS、10mM HEPES的检测缓冲液,调节pH至7.4。移除6孔板中的含有转染试剂的opti-MEM,用2ml DPBS漂洗细胞,向6孔板中加入250μl胰酶,轻轻晃动后吸出胰酶,放入细胞培养箱中孵育3分钟。轻轻拍打6孔板,显微镜下观察90%以上细胞变圆后,用1ml检测缓冲液重悬细胞,取10μl细胞悬液与10μl台盼蓝混匀,然后取10μl细胞台盼蓝混合悬液计数,调整细胞悬液密度至1.0×106/ml,向384optiplate每孔中加入10μl定量后的细胞悬液,1000rpm离心10s,封板备用。
3.2 NanoBiT检测试剂、化合物的配制及化学发光信号检测
3.2.1配制Nano-Glo检测试剂
按照底物荧光素(Nano-Live Cell Substrate,promega)与缓冲液(Nano-LCS Dilution Buffer,promega)体积比1:20配制荧光素酶检测试剂工作液,向384孔细胞样品板每孔细胞中加入5μl的检测试剂工作液,封板,1000rpm离心10s,室温孵育2小时,2小时后使用酶标仪检测baseline化学发光信号值,作为baseline数据。
3.2.2小分子化合物配制及化合物处理细胞后化学发光信号检测
3.2.2.1 GPR75激动剂评价模型
在384孔化合物稀释板中稀释小分子化合物,最高浓度125μM,5倍稀释,8个梯度,稀释板中的小分子化合物浓度为加入细胞后总体系终浓度的2.5倍,从384孔化合物稀释板中转移10μl小分子化合物至384孔细胞样品板中,封板,1000rpm离心10s,室温静置10分钟,于酶标仪上检测化学发光信号,用GraphPad Prism拟合曲线。
各化合物对GPR75的激动活性具体见下表:





****表示EC50≤10μM;***表示10μM<EC50≤50μM。

Claims (15)

  1. 一种具有式(1)结构的化合物或其药学上可接受的形式:
    其中,
    W1、W2、W3和W4各自独立地选自CR1或N;条件是W1、W2、W3和W4不同时为N且不存在三个连续的N原子;
    R1各自独立地选自H、卤素、羧基、OH、CN、C1-6烷基、C3-8环烷基、-OC3-8环烷基、-NRaRb、5-10元杂环烷基、C6-10芳基、5-10元杂芳基、-OC1-6烷基、-C(=O)Ra、-S(=O)Ra、-S(=O)2Ra、-C(=O)NRaRb、-NRaC(=O)Rb、-S(=O)NRaRb、-NRaS(=O)Rb、-S(=O)2NRaRb、-NRaS(=O)2Rb、-C(=O)ORa、-S(=O)(=NH)Ra、-P(=O)RaRb、-P(=NH)RaRb、-P(=O)(ORa)(ORb)-P(=O)(NRaRb)(ORc)或-P(=O)(NRaRb)(NRcRd);所述烷基、环烷基、杂环烷基、芳基、杂芳基各自任选地被一个或多个选自氘、卤素、OH、=O、CN、羧基、-C1-6烷基、-OC1-6烷基、C3-8环烷基、5-10元杂环烷基、C6-10芳基、5-10元杂芳基、-NRcRd、-C(=O)Rc、-S(=O)Rc、-S(=O)2Rc、-S(=O)(=NH)Rc、-P(=O)RcRd、-P(=NH)RcRd、-P(=O)(ORc)(ORd)、-P(=O)(NRaRb)(ORc)、-P(=O)(NRaRb)(NRcRd)、-C(=O)NRcRd、-NRcC(=O)Rd、-S(=O)NRcRd、-NRcS(=O)Rd、-S(=O)2NRcRd、-NRcS(=O)2Rd、-C(=O)ORc、-NRcP(=O)RaRb、-NRcP(=O)(ORa)(ORb)、-NRcP(=O)(NRaRb)(ORc)或-NRcP(=O)(NRaRb)(NRcRd)的取代基取代,
    Ra、Rb、Rc和Rd各自独立地选自H、C1-6烷基、C3-8环烷基、5-10元杂环烷基、C6-10芳基或5-10元杂芳基;或者,Ra和Rb、Rc和Rd与其所连接的原子一起形成5-10元杂环烷基;所述烷基、环烷基、杂环烷基、芳基或杂芳基各自任选地被一个或多个选自卤素、OH、NH2、=O、CN、羧基、-C1-6烷基、-OC1-6烷基、C3-8环烷基、5-10元杂环烷基、C6-10芳基、5-10元杂芳基、-NH(C1-6烷基)、-N(C1-6烷基)2、-NH(C3-8环烷基)、-NH(5-10元杂环烷基)、-N(C1-6烷基)(C3-8环烷基)或-N(C1-6烷基)(5-10元杂环烷基)的取代基取代;
    X选自-OH;
    Y选自NH、O或S;
    L1、L2、L3和L4各自独立地选自键、CR4R5、NR3、O或S,条件是L1、L2、L3和L4不同时为键;
    R2和R3各自独立地选自H、C3-8环烷基或C1-6烷基;所述环烷基或烷基各自任选地被一个或多个选自卤素、OH、=O、CN、羧基、-C1-6烷基、-OC1-6烷基、C3-8环烷基、5-10元杂环烷基、C6-10芳基、5-10元杂芳基、-NRcRd、-C(=O)Rc、-S(=O)Rc、-S(=O)2Rc、-S(=O)(=NH)Rc、-P(=O)RaRb、-P(=O)(ORa)(ORb)、-P(=O)(NRaRb)(ORc)、-P(=O)(NRaRb)(NRcRd)、-C(=O)NRcRd、-NRcC(=O)Rd、-S(=O)NRcRd、-NRcS(=O)Rd、-S(=O)2NRcRd、-NRcS(=O)2Rd、-NRcP(=O)RaRb、-NRcP(=O)(ORa)(ORb)、-NRcP(=O)(NRaRb)(ORc)、-NRcP(=O)(NRaRb)(NRcRd)、或-C(=O)ORc的取代基取代;
    R4和R5各自独立地选自键、H、卤素、OH、SH、NH2、CN、羧基、C1-6烷基、-OC1-6烷基、-SC1-6烷基、C3-8环烷基、5-10元杂环烷基、-OC3-8环烷基、-SC3-8环烷基、-NH(C1-6烷基)、-N(C1-6烷基)2、-NH(C3-8环烷基)、-NH(5-10元杂环烷基)、-N(C1-6烷基)(C3-8环烷基)、-N(C1-6烷基)(5-10元杂环烷基)、-(C1-6亚烷基)-NH(C1-6烷基)、-(C1-6亚烷基)-CONH(C1-6烷基)、-(C1-6亚烷基)-NHCO(C1-6烷基)、-(C1-6亚烷基)-NHCO(C3-8环烷基)、-NHCO(C1-6烷基)或-NHCO(C3-8烷基);所述烷基、环烷基、杂环烷基各自任选地被一个或多个Re取代;
    Re各自独立地选自卤素、OH、=O、CN、羧基、-C1-6烷基、-OC1-6烷基、C3-8环烷基、-OC3-8环烷基、5-10元杂环烷基、C6-10芳基、5-10元杂芳基、-NRcRd、-C(=O)Rc、-S(=O)Rc、-S(=O)2Rc、-S(=O)(=NH)Rc、-P(=O)RaRb、-P(=O)(ORa)(ORb)、-P(=O)(NRaRb)(ORc)、-P(=O)(NRaRb)(NRcRd)、-C(=O)NRcRd、-NRcC(=O)Rd、-S(=O)NRcRd、-NRcS(=O)Rd、-S(=O)2NRcRd、-NRcS(=O)2Rd、-NRcP(=O)RaRb、-NRcP(=O)(ORa)(ORb)、-NRcP(=O)(NRaRb)(ORc)、-NRcP(=O)(NRaRb)(NRcRd)、-C(=O)ORc、-O(C1-6亚烷基-O)n(C1-6烷基)、-NH(C1-6亚烷基-O)n(C1-6烷基)、-NHCOO(C1-6亚烷基-O)n(C1-6烷基)、-NHC(=NH)NH2或-NH-(C1-6亚烷基)-N(C1-6烷基)2
    Re中的所述烷基、亚烷基、环烷基、芳基、杂芳基或杂环烷基各自任选地被一个或多个选自卤素、OH、NH2、SH、=O、CN、羧基、-C1-6烷基、-OC1-6烷基、C3-8环烷基、5-10元杂环烷基、C6-10芳基、5-10元杂芳基、-NH(C1-6烷基)、-N(C1-6烷基)2、-NH(C3-8环烷基)、-NH(5-10元杂环烷基)、-N(C1-6烷基)(C3-8环烷基)或-N(C1-6烷基)(5-10元杂环烷基)的取代基取代;
    n各自独立地选自0、1、2、3、4、5、6、7或8;
    或者,R4和R5一起形成=O;
    或者,R4和R5与其所连接的原子一起形成C3-8环烷基或5-10元杂环烷基,所述环烷基或杂环烷基各自任选地被一个或多个选自卤素、OH、NH2、=O、CN、羧基、-C1-6烷基、-OC1-6烷基、C3-8环烷基、5-10元杂环烷基、C6-10芳基、5-10元杂芳基、-NRcRd、-C(=O)Rc、-S(=O)Rc、-S(=O)2Rc、-S(=O)(=NH)Rc、-P(=O)RaRb、-P(=NH)RaRb、-P(=O)(ORa)(ORb)、-P(=O)(NRaRb)(ORc)、-P(=O)(NRaRb)(NRcRd)、-C(=O)NRcRd、-NRcC(=O)Rd、-S(=O)NRcRd、-NRcS(=O)Rd、-S(=O)2NRcRd、-NRcS(=O)2Rd、-NRcP(=O)RaRb、-NRcP(=O)(ORa)(ORb)、-NRcP(=O)(NRaRb)(ORc)、-NRcP(=O)(NRaRb)(NRcRd)、-C(=O)ORc或-NH-(C1-6亚烷基)-N(C1-6烷基)2的取代基取代;
    或者,L1、L2、L3和L4中的任意两者与其所连接的原子一起形成C3-8环烷基、5-10元杂环烷基、C6-10芳基或者5-10元杂芳基,所述环烷基、杂环烷基、芳基或杂芳基各自任选地被一个或多个Rf取代;
    Rf各自独立地选自卤素、=O、OH、SH、-NH2、CN、-C1-8烷基、C3-8环烷基、5-10元杂环烷基、-OC1-8烷基、-SC1-8烷基、-NH(C1-8烷基)、-N(C1-8烷基)2、-NH(C3-8环烷基)、-NH(5-10元杂环烷基)、-N(C1-6烷基)(C3-8环烷基)、-N(C1-6烷基)(5-10元杂环烷基)、-NH(C1-6亚烷基-O)n(C1-6烷基)、-NH-(C1-6亚烷基)-NHCOO(C1-6亚烷基-O)n(C1-6烷基)、-NH-(C1-6亚烷基)-CONH(C1-6亚烷基-O)n(C1-6烷基)、-NH-(C1-6亚烷基)-NHCO-(5-10元杂环烷基)、-NH-(C1-6亚烷基)-OCO-(C1-6烷基)、-NH-(C1-6亚烷基)-NHCO-(C1-6烷基)、-NH-(C1-6亚烷基)-CONH-(C1-6烷基)、-NH-(C1-6亚烷基)-CONH-(C1-6亚烷基)-OC1-6烷基、-NH-(C1-6亚烷基)-NHS(=O)2(C1-6烷基)、-NH-(C1-6亚烷基)-NHS(=O)2(C3-8环烷基)、-NH-(C1-6亚烷基)-S(=O)2(C1-6烷基)、-NH-(C1-6亚烷基)-S(=O)(=NH)(C1-6烷基)、-NHP(=O)(C1-6烷基)2、-NHP(=O)(ORa)(ORb)、-NHP(=O)(ORa)(C1-6烷基)、-NH-(C1-6亚烷基)-NH(C1-6烷基)或-NH-(C1-6亚烷基)-N(C1-6烷基)2
    Rf中的所述烷基、亚烷基、环烷基或杂环烷基各自任选地被一个或多个选自卤素、OH、=O、CN、-NH2、-CONH2、-NHC(=NH)NH2、-N=C(NH2)2、羧基、-C1-6烷基、-(C1-6亚烷基)-NH2、-CONH(C1-6亚烷基-O)n(C1-6亚烷基)-NH2、-CONH(C1-6亚烷基-O)n(C1-6亚烷基)-OH、-CONH(C1-6亚烷基-O)n(C1-6烷基)、-CONH(C1-6亚烷基-O)n(C1-6亚烷基)-COOH、-O(C1-6亚烷基-O)n(C1-6亚烷基)-NH2、-O(C1-6亚烷基-O)n(C1-6亚烷基)-OH、-O(C1-6亚烷基-O)n(C1-6烷基)、-O(C1-6亚烷基-O)n(C1-6亚烷基)-COOH、-NH(C1-6亚烷基-O)n(C1-6亚烷基)-NH2、-NH(C1-6亚烷基-O)n(C1-6亚烷基)-OH、-NH(C1-6亚烷基-O)n(C1-6烷基)、-NH(C1-6亚烷基-O)n(C1-6亚烷基)-COOH、-NHCOO(C1-6亚烷基-O)n(C1-6亚烷基)-NH2、-NHCOO(C1-6 亚烷基-O)n(C1-6亚烷基)-OH、-NHCOO(C1-6亚烷基-O)n(C1-6烷基)、-NHCOO(C1-6亚烷基-O)n(C1-6亚烷基)-COOH、-OC1-6烷基、C3-8环烷基、5-10元杂环烷基、C6-10芳基、5-10元杂芳基、-NH(C1-6烷基)、-N(C1-6烷基)2、-NH(C3-8环烷基)、-NH(5-10元杂环烷基)、-N(C1-6烷基)(C3-8环烷基)或-N(C1-6烷基)(5-10元杂环烷基)的取代基取代;
    V选自5元杂芳基或-C≡C-;
    Ar选自C6-10芳基、或者5-10元杂芳基,所述芳基或杂芳基各自任选地被一个或多个选自氘、卤素、OH、=O、CN、羧基、-C1-6烷基、-OC1-6烷基、C3-8环烷基、5-10元杂环烷基、C6-10芳基、5-10元杂芳基、-NRaRb、-C(=O)Ra、-S(=O)Ra、-S(=O)2Ra、-S(=O)(=NH)Ra、-P(=O)RaRb、-P(=NH)RaRb、-P(=O)(ORa)(ORb)、-P(=O)(NRaRb)(ORc)、-P(=O)(NRaRb)(NRcRd)、-C(=O)NRaRb、-NRaC(=O)Rb、-S(=O)2NRaRb、-NRaS(=O)2Rb或-C(=O)ORa的取代基取代;
    所述药学上可接受的形式选自药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂化物、N-氧化物、同位素标记物、代谢物或前药。
  2. 根据权利要求1所述的化合物或其药学上可接受的形式,其中:
    选自
    优选地,R1各自独立地选自H、卤素、羧基、OH、CN、C1-6烷基、C3-8环烷基、-OC3-8环烷基、-NRaRb、5-10元杂环烷基、C6-10芳基、5-10元杂芳基、-OC1-6烷基、-C(=O)Ra、-S(=O)2Ra、-C(=O)NRaRb、-NRaC(=O)Rb、-S(=O)2NRaRb、-NRaS(=O)2Rb、-S(=O)(=NH)Ra、-P(=O)RaRb、-P(=NH)RaRb、-P(=O)(ORa)(ORb)、-P(=O)(NRaRb)(ORc)、-P(=O)(NRaRb)(NRcRd)或-C(=O)ORa;所述烷基、环烷基、杂环烷基、芳基、杂芳基各自任选地被一个或多个选自氘、卤素、OH、=O、CN、羧基、-C1-6烷基、-OC1-6烷基、C3-8环烷基、5-10元杂环烷基、C6-10芳基、5-10元杂芳基、-NRcRd、-S(=O)Rc、-S(=O)2Rc、-C(=O)NRcRd、-NRcC(=O)Rd、-S(=O)NRcRd、-NRcS(=O)Rd、-S(=O)2NRcRd、-NRcS(=O)2Rd或-C(=O)ORc的取代基取代,
    Ra、Rb、Rc和Rd各自独立地选自H、C1-6烷基、C3-8环烷基、5-10元杂环烷基、C6-10芳基或5-10元杂芳基;或者,Ra和Rb、Rc和Rd与其所连接的原子一起形成5-10元杂环烷基;所述烷基、环烷基、杂环烷基、芳基或杂芳基各自任选地被一个或多个选自卤素、OH、=O、CN、羧基、-C1-6烷基、-OC1-6烷基、C3-8环烷基、5-10元杂环烷基、C6-10芳基、5-10元杂芳基、-NH(C1-6烷基)、-N(C1-6烷基)2、-NH(C3-8环烷基)、-NH(5-10元杂环烷基)、-N(C1-6烷基)(C3-8环烷基)或-N(C1-6烷基)(5-10元杂环烷基)的取代基取代;
    优选地,R1各自独立地选自H、卤素、羧基、OH、CN、C1-6烷基、C3-8环烷基、-OC3-8环烷基、-NRaRb、5-10元杂环烷基、C6-10芳基、5-10元杂芳基或-OC1-6烷基;所述烷基、环烷基、杂环烷基、芳基、杂芳基各自任选地被一个或多个选自氘、卤素、OH、=O、CN、羧基、-C1-6烷基、-OC1-6烷基、C3-8环烷基、5-10元杂环烷基、C6-10芳基、5-10元杂芳基或-NRcRd的取代基取代,
    Ra、Rb、Rc和Rd各自独立地选自H、C1-6烷基、C3-8环烷基或5-10元杂环烷基;或者,Ra和Rb、Rc和Rd与其所连接的原子一起形成5-10元杂环烷基;所述烷基、环烷基、杂环烷基各自任选地被一个或多个选自卤素、OH、=O、CN、羧基、-C1-6烷基、-OC1-6烷基、C3-8环烷基、5-10元杂环烷基、5-10元杂芳基、-NH(C1-6烷基)、-N(C1-6烷基)2、-NH(C3-8环烷基)、-NH(5-10元杂环烷基)、-N(C1-6烷基)(C3-8环烷基)或-N(C1-6烷基)(5-10元杂环烷基)的取代基取代;
    优选地,R1各自独立地选自H、卤素、CN、C1-6烷基或-OC1-6烷基;所述烷基各自任 选地被一个或多个选自卤素、OH、=O、NH2、CN、-C1-6烷基或-OC1-6烷基的取代基取代;
    优选地,R1各自独立地选自H、卤素、CN、C1-3烷基、或者-OC1-3烷基;所述烷基各自任选地被一个或多个选自卤素、OH、=O、NH2、CN、-C1-3烷基或-OC1-3烷基的取代基取代;
    更优选地,R1各自独立地选自H、F、Cl、Br、CN、-CH3或-OCH3
  3. 根据权利要求1或2所述的化合物或其药学上可接受的形式,其中:
    R2和R3各自独立地选自H、C3-8环烷基或C1-6烷基;所述环烷基或烷基各自任选地被一个或多个选自卤素、OH、=O、CN、羧基、-C1-6烷基、-OC1-6烷基、C3-8环烷基、5-10元杂环烷基、C6-10芳基、5-10元杂芳基、-NRcRd、-C(=O)Rc、-S(=O)Rc、-S(=O)2Rc、-C(=O)NRcRd、-NRcC(=O)Rd、-S(=O)NRcRd、-NRcS(=O)Rd、-S(=O)2NRcRd、-NRcS(=O)2Rd或-C(=O)ORc的取代基取代;
    优选地,R2和R3各自独立地选自H、C3-6环烷基或C1-6烷基;所述环烷基或烷基各自任选地被一个或多个选自卤素、OH、=O、CN、羧基、-C1-6烷基、-OC1-6烷基、C3-8环烷基或5-10元杂环烷基的取代基取代;
    优选地,R2和R3各自独立地选自H或C1-6烷基;所述烷基任选地被一个或多个选自卤素、OH、=O或-C1-6烷基的取代基取代;
    优选地,R2和R3各自独立地选自H或C1-3烷基;所述烷基任选地被一个或多个选自卤素、OH、=O或-C1-3烷基的取代基取代;
    更优选地,R2和R3各自独立地选自H或-CH3
  4. 根据权利要求1-3中任一项所述的化合物或其药学上可接受的形式,其中:
    R4和R5各自独立地选自H、卤素、OH、SH、NH2、CN、羧基、C1-6烷基、-OC1-6烷基、-SC1-6烷基、-NH(C1-6烷基)、-NH(C3-8环烷基)、-NH(5-10元杂环烷基)、-(C1-6亚烷基)-NH(C1-6烷基)、-(C1-6亚烷基)-CONH(C1-6烷基)、-(C1-6亚烷基)-NHCO(C1-6烷基)或-NHCO(C1-6烷基);所述烷基、环烷基、杂环烷基各自任选地被一个或多个Re取代;
    Re各自独立地选自卤素、OH、=O、CN、羧基、-C1-6烷基、-OC1-6烷基、C3-8环烷基、5-10元杂环烷基、C6-10芳基、5-10元杂芳基、-NRcRd、-S(=O)Rc、-S(=O)2Rc、-C(=O)NRcRd、-NRcC(=O)Rd、-S(=O)NRcRd、-NRcS(=O)Rd、-S(=O)2NRcRd、-NRcS(=O)2Rd、-S(=O)(=NH)Rc、-P(=O)RcRd、-P(=O)(ORc)(ORd)、-P(=O)(NRaRb)(ORc)、-P(=O)(NRaRb)(NRcRd)、-NRcP(=O)RaRb、-NRcP(=O)(ORa)(ORb)、-NRcP(=O)(NRaRb)(ORc)、-NRcP(=O)(NRaRb)(NRcRd)、-O(C1-6亚烷基-O)n(C1-6烷基)、-NH(C1-6亚烷基-O)n(C1-6烷基)、-NHCOO(C1-6亚烷基-O)n(C1-6烷基)、-NHC(=NH)NH2或-NH-(C1-6亚烷基)-N(C1-6烷基)2
    Re中的所述烷基、亚烷基、环烷基、芳基、杂芳基或杂环烷基各自任选地被一个或多个选自卤素、OH、=O、CN、-NH2、羧基、-C1-6烷基、-OC1-6烷基、C3-8环烷基、5-10元杂环烷基、C6-10芳基、5-10元杂芳基、-NH(C1-6烷基)、-N(C1-6烷基)2、-NH(C3-8环烷基)、-NH(5-10元杂环烷基)、-N(C1-6烷基)(C3-8环烷基)或-N(C1-6烷基)(5-10元杂环烷基)的取代基取代;
    或者,R4和R5一起形成=O;
    或者,R4和R5与其所连接的原子一起形成C3-8环烷基或5-10元杂环烷基,所述环烷基或杂环烷基各自任选地被一个或多个选自卤素、OH、=O、CN、羧基、-C1-6烷基、-OC1-6烷基、C3-8环烷基、5-10元杂环烷基、C6-10芳基、5-10元杂芳基、-NRcRd、-C(=O)Rc、-S(=O)Rc、-S(=O)2Rc、-C(=O)NRcRd、-NRcC(=O)Rd、-S(=O)NRcRd、-NRcS(=O)Rd、-S(=O)2NRcRd、-NRcS(=O)2Rd、-C(=O)ORc或-NH-(C1-6亚烷基)-N(C1-6烷基)2的取代基取代;
    优选地,R4和R5各自独立地选自H、卤素、OH、SH、NH2、CN、羧基、C1-6烷基、 -OC1-6烷基、-SC1-6烷基、-NH(C1-6烷基)、-NH(5-10元杂环烷基)、-N(C1-6烷基)(C3-8环烷基)、-N(C1-6烷基)(5-10元杂环烷基);所述烷基、环烷基、杂环烷基各自任选地被一个或多个Re取代;
    Re各自独立地选自卤素、OH、=O、CN、羧基、-C1-6烷基、-OC1-6烷基、C3-8环烷基、5-10元杂环烷基、C6-10芳基、5-10元杂芳基、-NRcRd、-S(=O)Rc、-S(=O)2Rc、-C(=O)NRcRd、-NRcC(=O)Rd、-S(=O)NRcRd、-S(=O)(=NH)Rc、-P(=O)RcRd、-P(=O)(ORc)(ORd)、-P(=O)(NRaRb)(ORc)、-P(=O)(NRaRb)(NRcRd)、-NRcP(=O)RaRb、-NRcP(=O)(ORa)(ORb)、-NRcP(=O)(NRaRb)(ORc)、-NRcP(=O)(NRaRb)(NRcRd)、-NRcS(=O)Rd、-S(=O)2NRcRd、-NRcS(=O)2Rd、-O(C1-3亚烷基-O)n(C1-3烷基)、-NH(C1-3亚烷基-O)n(C1-3烷基)、-NHCOO(C1-3亚烷基-O)n(C1-3烷基)、-NHC(=NH)NH2或-NH-(C1-3亚烷基)-N(C1-3烷基)2
    Re中的所述烷基、亚烷基、环烷基、芳基、杂芳基或杂环烷基各自任选地被一个或多个选自卤素、OH、=O、CN、-NH2、SH、羧基、-OC1-6烷基、C3-8环烷基、5-10元杂环烷基、C6-10芳基、5-10元杂芳基、-NH(C1-6烷基)、-N(C1-6烷基)2、-NH(C3-8环烷基)、-NH(5-10元杂环烷基)、-N(C1-6烷基)(C3-8环烷基)或-N(C1-6烷基)(5-10元杂环烷基)的取代基取代;
    或者,R4和R5一起形成=O;
    或者,R4和R5与其所连接的原子一起形成C3-8环烷基或5-10元杂环烷基,所述环烷基或杂环烷基各自任选地被一个或多个选自卤素、OH、=O、CN、羧基、-C1-6烷基、-OC1-6烷基、C3-8环烷基、5-10元杂环烷基、C6-10芳基、5-10元杂芳基、-NRcRd或-NH-(C1-6亚烷基)-N(C1-6烷基)2的取代基取代;
    优选地,R4和R5各自独立地选自H、-CH3、-CH2OH、-CH2CH(CH3)2、-(CH2)mNH2、-(CH2)mSH、-(CH2)mSCH3、-(CH2)mNHCOCH3、-(CH2)mNHSO2CH3、-(CH2)mNHSO2(CH2)3、-CH2NH(CH2)2N(CH3)2、-(CH2)mNH(CH2COOH)2、-CH2O(CH2CH2O)nCH2COOH、-CH2O(CH2CH2O)nCH2CH2OH、-CH2O(CH2CH2O)nCH2CH2OCH3、-CH2NH(CH2CH2O)nCH2COOH、-(CH2)mSCH2CH(OH)CH2OH、-CH2NH(CH2CH2O)nCH2CH2OH、-CH2NH(CH2CH2O)nCH2CH2OCH3、-CH2CH2NHCOO(CH2CH2O)nCH2COOH、-CH2CH2NH(CH2CH2O)nCH2CH2OH、-CH2CH2NHCOO(CH2CH2O)nCH2CH2OCH3、-(CH2)mNHCH2CH(OH)CH2OH、-(CH2)mOCH2CH(OH)CH2OH、-(CH2)2COOH、-CH2COOH、、-(CH2)2CONH2、-CH2CONH2、-CH2CONHCH2CH(OH)CH2OH、-(CH2)2CONHCH2CH(OH)CH2OH、-CH2CONHCH2CH2NHCH(OH)CH2OH、-CH2CH2CONHCH2CH2NHCH(OH)CH2OH、-CH2CONHCH2CH2NH(CH2CH2O)nCH2COOH、-CH2CONHCH2CH2NH(CH2CH2O)nCH2CH2OH、-CH2CONHCH2CH2NH(CH2CH2O)nCH2CH2OCH3、-CH2CONHCH2CH2O(CH2CH2O)nCH2COOH、-CH2CONHCH2CH2O(CH2CH2O)nCH2CH2OH、-CH2CONHCH2CH2O(CH2CH2O)nCH2CH2OCH3、-CH2CH2CONHCH2CH2NH(CH2CH2O)nCH2COOH、-CH2CH2CONHCH2CH2NH(CH2CH2O)nCH2CH2OH、-CH2CH2CONHCH2CH2NH(CH2CH2O)nCH2CH2OCH3、-CH2CH2CONHCH2CH2O(CH2CH2O)nCH2COOH、-CH2CH2CONHCH2CH2O(CH2CH2O)nCH2CH2OH、-CH2CH2CONHCH2CH2O(CH2CH2O)nCH2CH2OCH3
    n各自独立地选自0、1、2、3、4、5、6、7或8,m各自独立地选自1、2、3、4、5、6、7或8,o各自独立地选自0、1、2或3;
    或者,R4和R5一起形成=O;
    或者,R4和R5与其所连接的原子一起形成
  5. 根据权利要求1-4中任一项所述的化合物或其药学上可接受的形式,其中:
    选自
  6. 根据权利要求1-4中任一项所述的化合物或其药学上可接受的形式,其中:
    L1、L2、L3和L4中的任意两者与其所连接的原子一起形成C3-8环烷基、5-10元杂环烷基、C6-10芳基或者5-10元杂芳基,所述环烷基、杂环烷基、芳基或杂芳基各自任选地被一个或多个Rf取代;
    Rf各自独立地选自卤素、=O、OH、-NH2、CN、-C1-8烷基、5-10元杂环烷基、-OC1-8烷基、-SC1-8烷基、-NH(C1-8烷基)、-N(C1-8烷基)2、-NH(C3-8环烷基)、-NH(5-10元杂环烷基)、-N(C1-6烷基)(C3-8环烷基)、-N(C1-6烷基)(5-10元杂环烷基)、-NH(C1-6亚烷基-O)n(C1-6烷基)、-NH-(C1-6亚烷基)-NHCOO(C1-6亚烷基-O)n(C1-6烷基)、-NH-(C1-6亚烷基)-NHCO-(5-10元杂环烷基)、-NH-(C1-6亚烷基)-NHCO-(C1-6烷基)、-NH-(C1-6亚烷基)-CONH-(C1-6烷基)、-NH-(C1-6亚烷基)-CONH-(C1-6亚烷基)-OC1-6烷基、-NH-(C1-6亚烷基)-NHS(=O)2(C1-6烷基)、-NH-(C1-6亚烷基)-NHS(=O)2(C3-8环烷基)、-NH-(C1-6亚烷基)-S(=O)2(C1-6烷基)、-NHP(=O)(C1-6烷基)2、-NHP(=O)(ORa)(ORb)、-NHP(=O)(ORa)(C1-6烷基)、-NH-(C1-6亚烷基)-S(=O)(=NH)(C1-6烷基)、-NH-(C1-6亚烷基)-NH(C1-6烷基)或-NH-(C1-6亚烷基)-N(C1-6烷基)2
    Rf中的所述烷基、亚烷基、环烷基或杂环烷基各自任选地被一个或多个选自卤素、OH、=O、CN、-NH2、-CONH2、-NHC(=NH)NH2、-N=C(NH2)2、羧基、-C1-6烷基、-CONH(C1-6亚烷基-O)n(C1-6亚烷基)-NH2、-CONH(C1-6亚烷基-O)n(C1-6亚烷基)-OH、-CONH(C1-6亚烷基-O)n(C1-6烷基)、-CONH(C1-6亚烷基-O)n(C1-6亚烷基)-COOH、-O(C1-6亚烷基-O)n(C1-6亚烷基)-NH2、-O(C1-6亚烷基-O)n(C1-6亚烷基)-OH、-O(C1-6亚烷基-O)n(C1-6烷基)、-O(C1-6亚烷基-O)n(C1-6亚烷基)-COOH、-NH(C1-6亚烷基-O)n(C1-6亚烷基)-NH2、-NH(C1-6亚烷基-O)n(C1-6亚烷基)-OH、-NH(C1-6亚烷基-O)n(C1-6烷基)、-NH(C1-6亚烷基-O)n(C1-6亚烷基)-COOH、-OC1-6烷基、C3-8环烷基、5-10元杂环烷基、C6-10芳基、5-10元杂芳基、-NH(C1-6烷基)、-N(C1-6烷基)2、-NH(C3-8环烷基)、-NH(5-10元杂环烷基)、-N(C1-6烷基)(C3-8环烷基)或-N(C1-6烷基)(5-10元杂环烷基)的取代基取代;
    优选地,L1和L2与其所连接的原子一起形成5-10元杂芳基,所述杂芳基各自任选地被一个或多个Rf取代;
    Rf各自独立地选自卤素、=O、OH、-NH2、CN、-C1-8烷基、-OC1-8烷基、-NH(C1-8烷基)、-N(C1-8烷基)2、-NH(C1-6亚烷基-O)n(C1-6烷基)、-NH-(C1-6亚烷基)-NHCOO(C1-6亚烷基-O)n(C1-6烷基)、-NH-(C1-6亚烷基)-NHCO-(C1-6烷基)、-NH-(C1-6亚烷基)-CONH-(C1-6烷基)、-NH-(C1-6亚烷基)-CONH-(C1-6亚烷基)-OC1-6烷基、-NH-(C1-6亚烷基)-NH(C1-6烷基)或-NH-(C1-6亚烷基)-N(C1-6烷基)2
    Rf中的所述烷基、亚烷基各自任选地被一个或多个选自卤素、OH、=O、CN、-NH2、-CONH2、-NHC(=NH)NH2、-N=C(NH2)2、羧基、-C1-6烷基、-(C1-6亚烷基)-NH2、-CONH(C1-6亚烷基-O)n(C1-6亚烷基)-NH2、-CONH(C1-6亚烷基-O)n(C1-6亚烷基)-OH、-CONH(C1-6亚烷基-O)n(C1-6烷基)、-O(C1-6亚烷基-O)n(C1-6亚烷基)-NH2、-O(C1-6亚烷基-O)n(C1-6亚烷基)-OH、-O(C1-6亚烷基-O)n(C1-6烷基)、-NH(C1-6亚烷基-O)n(C1-6亚烷基)-NH2、-NH(C1-6亚烷基-O)n(C1-6亚烷基)-OH、-NH(C1-6亚烷基-O)n(C1-6烷基)、-OC1-6烷基、-NH(C1-6烷基)、-N(C1-6烷基)2或-NH(C3-8环烷基)的取代基取代;
    优选地,L1和L2与其所连接的原子一起形成C3-8环烷基、5-10元杂环烷基、C6-10芳基或5-10元杂芳基,所述环烷基、杂环烷基、芳基或杂芳基各自任选地被一个或多个选自卤素、OH、-NH2、CN、-C1-6烷基、-OC1-6烷基、-SC1-6烷基、-NH(C1-6烷基)、-N(C1-6烷基)2、-NH-(C1-6亚烷基)-NH2、-NH-(C1-6亚烷基)-OH或-NH-(C1-6亚烷基)-N(C1-6烷基)2的取代基取代;
    优选地,L1和L2与其所连接的原子一起形成C5-8环烷基、5-8元杂环烷基、苯基或5-10元杂芳基,所述环烷基、杂环烷基、苯基或杂芳基各自任选地被一个或多个选自卤素、OH、-NH2、CN、-C1-3烷基、-OC1-3烷基、-SC1-3烷基、-NH(C1-3烷基)、-N(C1-3烷基)2、-NH-(C1-3亚烷基)-NH2、-NH-(C1-3亚烷基)-OH或-NH-(C1-3亚烷基)-N(C1-3烷基)2的取代基取代;
    优选地,L1和L2与其所连接的原子一起形成C5-6环烷基、5-6元杂环烷基或6元杂芳基,所述环烷基、杂环烷基或杂芳基各自任选地被一个或多个选自卤素、OH、-NH2、CN、-C1-3烷基、-OC1-3烷基、-SC1-3烷基、-NH(C1-3烷基)、-N(C1-3烷基)2、-NH-(C1-3亚烷基)-NH2、-NH-(C1-3亚烷基)-OH或-NH-(C1-3亚烷基)-N(C1-3烷基)2的取代基取代;
    优选地,L1和L2与其所连接的原子一起形成嘧啶基、吡啶基、吡嗪基、环己基或四氢呋喃基,所述嘧啶基、吡啶基、吡嗪基、环己基或四氢呋喃基各自任选地被一个或多个选自-CH3、-NHCH3、-NH(CH2)2N(CH3)2、-NH(CH2)2NH2、-NH(CH2)2OH、-S(CH2)2N(CH3)2、-S(CH2)2NH2、-S(CH2)2OH、-NH(CH2)3N(CH3)2、-NH(CH2)3NH2、-NH(CH2)3OH、-NH(CH2)3NHCOCH3、-NH(CH2)2NHSO2CH3、-NH(CH2)3NHSO2CH3、-NH(CH2)2NHSO2(CH2)3、-NH(CH2)3NHSO2(CH2)3、-NH(CH2)2O(CH2CH2O)nCH2COOH、 -NH(CH2)2O(CH2CH2O)nCH2CH2OH、-NH(CH2)3COOH、-NH(CH2)2NHPO(OCH2CH3)2、-NH(CH2)3NHPO(OCH2CH3)2、-NH(CH2)2NHPO(CH2CH2OH)2、-NH(CH2)3NHPO(CH2CH2OH)2、-NH(CH2)2O(CH2CH2O)nCH2CH2OCH3、-NH(CH2)2O(CH2CH2O)nCH2CH2NH2、-NH(CH2)2SO2CH3、-NH(CH2)3SO2CH3、-NH(CH2)2PO(OH)2、-NH(CH2)3PO(OH)2、-NH(CH2)2NHPO(OH)2、-NH(CH2)3NHPO(OH)2、-NH(CH2)2NH(CH2CH2O)nCH2CH2OH、-NH(CH2)2NH(CH2CH2O)nCH2CH2OCH3、-NH(CH2)2NH(CH2CH2O)nCH2COOH、-NH(CH2)2NHCOO(CH2CH2O)nCH2COOH、-NHCH2CH2NHCOO(CH2CH2O)nCH2CH2OCH3、-NHCH2CH2NHCOO(CH2CH2O)nCH2CH2OH、-NHCH2CH2NHCH2CH(OH)CH2OH、-NHCH2CH2OCH2CH(OH)CH2OH、-NHCH2CH2SCH2CH(OH)CH2OH、-S(CH2)2NHSO2CH3、-S(CH2)2NHSO2(CH2)3、-S(CH2)2O(CH2CH2O)nCH2COOH、-S(CH2)2O(CH2CH2O)nCH2CH2OH、-S(CH2)2NHPO(OCH2CH3)2、-S(CH2)2NHPO(CH2CH2OH)2、-S(CH2)2O(CH2CH2O)nCH2CH2OCH3、-S(CH2)2O(CH2CH2O)nCH2CH2NH2、-S(CH2)2NHPO(OH)2、-S(CH2)3NHPO(OH)2、-S(CH2)2NH(CH2CH2O)nCH2CH2OH、-S(CH2)2NH(CH2CH2O)nCH2CH2OCH3、-S(CH2)2NH(CH2CH2O)nCH2COOH、-S(CH2)2NHCOO(CH2CH2O)nCH2COOH、-SCH2CH2NHCOO(CH2CH2O)nCH2CH2OCH3、-SCH2CH2NHCOO(CH2CH2O)nCH2CH2OH、-SCH2CH2NHCH2CH(OH)CH2OH、-SCH2CH2OCH2CH(OH)CH2OH、-O(CH2)2NHSO2CH3、-O(CH2)2NHSO2(CH2)3、-O(CH2)2O(CH2CH2O)nCH2COOH、-O(CH2)2O(CH2CH2O)nCH2CH2OH、-O(CH2)2NHPO(OCH2CH3)2、-O(CH2)2NHPO(CH2CH2OH)2、-O(CH2)2O(CH2CH2O)nCH2CH2OCH3、-O(CH2)2O(CH2CH2O)nCH2CH2NH2、-O(CH2)2NHPO(OH)2、-O(CH2)3NHPO(OH)2、-O(CH2)2NH(CH2CH2O)nCH2CH2OH、-O(CH2)2NH(CH2CH2O)nCH2CH2OCH3、-O(CH2)2NH(CH2CH2O)nCH2COOH、-O(CH2)2NHCOO(CH2CH2O)nCH2COOH、-OCH2CH2NHCOO(CH2CH2O)nCH2CH2OCH3、-OCH2CH2NHCOO(CH2CH2O)nCH2CH2OH、-OCH2CH2NHCH2CH(OH)CH2OH、-OCH2CH2OCH2CH(OH)CH2OH、-OCH2CH2SCH2CH(OH)CH2OH、-NHCH2CONHCH2CH2OH、-NHCH2CONHCH2CH2NH2、-NHCH2CONH(CH2CH2O)nCH2CH2OH、-NHCH2CONH(CH2CH2O)nCH2CH2OCH3、-NHCH2CONH(CH2CH2O)nCH2COOH、-NHCH2CONH2、-NHCH2CH2NH(CH2COOH)2 的取代基取代;
    优选地,L1和L2与其所连接的原子一起形成
  7. 根据权利要求1-4中任一项所述的化合物或其药学上可接受的形式,其中:
    L2和L3与其所连接的原子一起形成C5-10环烷基或5-10元杂环烷基,所述环烷基、杂环烷基各自任选地被一个或多个选自=O、卤素、OH、-NH2、CN、-C1-6烷基、-NH(C1-6烷基)或-N(C1-6烷基)2的取代基取代;
    优选地,L2和L3与其所连接的原子一起形成C5-8环烷基或5-8元杂环烷基,所述环烷基、杂环烷基各自任选地被一个或多个选自=O、卤素、OH、-NH2、CN、-C1-3烷基、-NH(C1-3烷基)或-N(C1-3烷基)2的取代基取代;
    优选地,L2和L3与其所连接的原子一起形成5-8元杂环烷基,所述杂环烷基任选地被一个或多个选自=O、卤素、OH、-NH2、CN或-C1-3烷基的取代基取代;
    更优选地,L2和L3与其所连接的原子一起形成
  8. 根据权利要求1-7中任一项所述的化合物或其药学上可接受的形式,其中:
    V选自呋喃基、噻吩基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、噁二唑基、噻二唑基、三唑基或-C≡C-;
    优选地,V选自 或-C≡C-。
  9. 根据权利要求1-8中任一项所述的化合物或其药学上可接受的形式,其中:
    Ar选自C6-10芳基或5-10元杂芳基,所述芳基或杂芳基各自任选地被一个或多个选自氘、卤素、OH、=O、CN、羧基、-C1-6烷基、-OC1-6烷基、C3-8环烷基、5-10元杂环烷基、C6-10芳基、5-10元杂芳基、-NRaRb、-C(=O)Ra、-S(=O)Ra、-S(=O)2Ra、-C(=O)NRaRb、-NRaC(=O)Rb、-S(=O)2NRaRb、-NRaS(=O)2Rb或-C(=O)ORa的取代基取代;
    优选地,Ar选自C6-10芳基或5-10元杂芳基,所述芳基或杂芳基各自任选地被一个或多个选自氘、卤素、OH、=O、CN、羧基、-C1-6烷基、-OC1-6烷基、C3-8环烷基、5-10元杂环烷基、C6-10芳基、5-10元杂芳基或-NRaRb的取代基取代;
    优选地,Ar选自C6-10芳基或5-8元杂芳基,所述芳基或杂芳基各自任选地被一个或多个选自卤素、OH、NH2、CN、-C1-3烷基、-OC1-3烷基、-NH(C1-3烷基)或-N(C1-3烷基)2的取代基取代;
    优选地,Ar选自苯基或吡啶基,所述苯基或吡啶基各自任选地被一个或多个选自F、Cl、Br、OH、NH2、CN、-C1-3烷基或-OC1-3烷基的取代基取代;
    优选地,Ar选自苯基或吡啶基,所述苯基或吡啶基各自任选地被一个或多个选自F、Cl、Br、CN、-CH3或-OCH3的取代基取代;
    更优选地,Ar选自
  10. 根据权利要求1所述的化合物或其药学上可接受的形式,其具有式(2)所示的结构:
    其中,
    W5、W6、W7和W8各自独立地选自CR6或N;条件是W5、W6、W7和W8不同时为N且不存在三个连续的N原子;
    R6各自独立地选自卤素、OH、-NH2、CN、-C1-6烷基、-NH(C1-6烷基)、-N(C1-6烷基)2、-NH-(C1-6亚烷基)-NH2、-NH-(C1-6亚烷基)-OH、-NH(C1-6亚烷基-O)n(C1-6烷基)、-NH-(C1-6亚烷基)-NHCO-(C1-6烷基)或-NH-(C1-6亚烷基)-N(C1-6烷基)2,所述烷基、亚烷基各自任选地被一个或多个选自卤素、OH、=O、CN、-NH2、-CONH2、-NHC(=NH)NH2或-N=C(NH2)2的取代基取代;
    Z选自O或S;
    U2和U3独立地选自CH或N;
    W9、W10、W11、W12和W13各自独立地选自CR7或N;条件是W9、W10、W11、W12和W13不同时为N且不存在三个连续的N原子;
    R7各自独立地选自卤素、OH、NH2、CN、羧基、-C1-6烷基、-OC1-6烷基、C3-8环烷基、5-10元杂环烷基、C6-10芳基、5-10元杂芳基、-NH(C1-6烷基)、-NH(C3-8环烷基)、-NH(5-10元杂环烷基)、-N(C1-6烷基)(C3-8环烷基)或-N(C1-6烷基)(5-10元杂环烷基)或-N(C1-6烷基)2
    W1、W2、W3、W4、X如权利要求1中所定义。
  11. 根据权利要求1所述的化合物或其药学上可接受的形式,其具有式(3)所示的结构:
    其中,
    Z选自O或S;
    U2和U3独立地选自CH或N;
    W9、W10、W11、W12和W13各自独立地选自CR7或N;条件是W9、W10、W11、W12和W13不同时为N且不存在三个连续的N原子;
    R7各自独立地选自卤素、OH、NH2、CN、羧基、-C1-6烷基、-OC1-6烷基、C3-8环烷基、5-10元杂环烷基、C6-10芳基、5-10元杂芳基、-NH(C1-6烷基)、-NH(C3-8环烷基)、-NH(5-10元杂环烷基)、-N(C1-6烷基)(C3-8环烷基)或-N(C1-6烷基)(5-10元杂环烷基)或-N(C1-6烷基)2
    W1、W2、W3、W4、X、R4和R5如权利要求1中所定义。
  12. 一种具有式(1-2)或式(1-3)结构的化合物或其药学上可接受的形式:
    其中,W1、W2、W3、W4和W14各自独立地选自CR1或N;条件是W1、W2、W3、W4和W14不同时为N且不存在三个连续的N原子;
    R1各自独立地选自H、卤素、羧基、OH、CN、C1-6烷基、C3-8环烷基、-OC3-8环烷基、-NRaRb、5-10元杂环烷基、C6-10芳基、5-10元杂芳基、-OC1-6烷基、-C(=O)Ra、-S(=O)Ra、-S(=O)2Ra、-C(=O)NRaRb、-NRaC(=O)Rb、-S(=O)NRaRb、-NRaS(=O)Rb、-S(=O)2NRaRb、-NRaS(=O)2Rb、-C(=O)ORa、-S(=O)(=NH)Ra、-P(=O)RaRb、-P(=NH)RaRb、-P(=O)(ORa)(ORb)-P(=O)(NRaRb)(ORc)或-P(=O)(NRaRb)(NRcRd);所述烷基、环烷基、杂环烷基、芳基、杂芳基各自任选地被一个或多个选自氘、卤素、OH、=O、CN、羧基、-C1-6烷基、-OC1-6烷基、C3-8环烷基、5-10元杂环烷基、C6-10芳基、5-10元杂芳基、-NRcRd、-C(=O)Rc、 -S(=O)Rc、-S(=O)2Rc、-S(=O)(=NH)Rc、-P(=O)RcRd、-P(=NH)RcRd、-P(=O)(ORc)(ORd)、-P(=O)(NRaRb)(ORc)、-P(=O)(NRaRb)(NRcRd)、-C(=O)NRcRd、-NRcC(=O)Rd、-S(=O)NRcRd、-NRcS(=O)Rd、-S(=O)2NRcRd、-NRcS(=O)2Rd、-C(=O)ORc、-NRcP(=O)RaRb、-NRcP(=O)(ORa)(ORb)、-NRcP(=O)(NRaRb)(ORc)或-NRcP(=O)(NRaRb)(NRcRd)的取代基取代,
    Ra、Rb、Rc和Rd各自独立地选自H、C1-6烷基、C3-8环烷基、5-10元杂环烷基、C6-10芳基或5-10元杂芳基;或者,Ra和Rb、Rc和Rd与其所连接的原子一起形成5-10元杂环烷基;所述烷基、环烷基、杂环烷基、芳基或杂芳基各自任选地被一个或多个选自卤素、OH、NH2、=O、CN、羧基、-C1-6烷基、-OC1-6烷基、C3-8环烷基、5-10元杂环烷基、C6-10芳基、5-10元杂芳基、-NH(C1-6烷基)、-N(C1-6烷基)2、-NH(C3-8环烷基)、-NH(5-10元杂环烷基)、-N(C1-6烷基)(C3-8环烷基)或-N(C1-6烷基)(5-10元杂环烷基)的取代基取代;
    X选自-OH;
    Y选自NH、O或S;
    L1、L2、L3和L4各自独立地选自键、CR4R5、NR3、O或S,条件是L1、L2、L3和L4不同时为键;
    R2和R3各自独立地选自H、C3-8环烷基或C1-6烷基;所述环烷基或烷基各自任选地被一个或多个选自卤素、OH、=O、CN、羧基、-C1-6烷基、-OC1-6烷基、C3-8环烷基、5-10元杂环烷基、C6-10芳基、5-10元杂芳基、-NRcRd、-C(=O)Rc、-S(=O)Rc、-S(=O)2Rc、-S(=O)(=NH)Rc、-P(=O)RaRb、-P(=O)(ORa)(ORb)、-P(=O)(NRaRb)(ORc)、-P(=O)(NRaRb)(NRcRd)、-C(=O)NRcRd、-NRcC(=O)Rd、-S(=O)NRcRd、-NRcS(=O)Rd、-S(=O)2NRcRd、-NRcS(=O)2Rd、-NRcP(=O)RaRb、-NRcP(=O)(ORa)(ORb)、-NRcP(=O)(NRaRb)(ORc)、-NRcP(=O)(NRaRb)(NRcRd)、或-C(=O)ORc的取代基取代;
    R4和R5各自独立地选自键、H、卤素、OH、SH、NH2、CN、羧基、C1-6烷基、-OC1-6烷基、-SC1-6烷基、C3-8环烷基、5-10元杂环烷基、-OC3-8环烷基、-SC3-8环烷基、-NH(C1-6烷基)、-N(C1-6烷基)2、-NH(C3-8环烷基)、-NH(5-10元杂环烷基)、-N(C1-6烷基)(C3-8环烷基)、-N(C1-6烷基)(5-10元杂环烷基)、-(C1-6亚烷基)-NH(C1-6烷基)、-(C1-6亚烷基)-CONH(C1-6烷基)、-(C1-6亚烷基)-NHCO(C1-6烷基)、-(C1-6亚烷基)-NHCO(C3-8环烷基)、-NHCO(C1-6烷基)或-NHCO(C3-8烷基);所述烷基、环烷基、杂环烷基各自任选地被一个或多个Re取代;
    Re各自独立地选自卤素、OH、=O、CN、羧基、-C1-6烷基、-OC1-6烷基、C3-8环烷基、-OC3-8环烷基、5-10元杂环烷基、C6-10芳基、5-10元杂芳基、-NRcRd、-C(=O)Rc、-S(=O)Rc、-S(=O)2Rc、-S(=O)(=NH)Rc、-P(=O)RaRb、-P(=O)(ORa)(ORb)、-P(=O)(NRaRb)(ORc)、-P(=O)(NRaRb)(NRcRd)、-C(=O)NRcRd、-NRcC(=O)Rd、-S(=O)NRcRd、-NRcS(=O)Rd、-S(=O)2NRcRd、-NRcS(=O)2Rd、-NRcP(=O)RaRb、-NRcP(=O)(ORa)(ORb)、-NRcP(=O)(NRaRb)(ORc)、-NRcP(=O)(NRaRb)(NRcRd)、-C(=O)ORc、-O(C1-6亚烷基-O)n(C1-6烷基)、-NH(C1-6亚烷基-O)n(C1-6烷基)、-NHCOO(C1-6亚烷基-O)n(C1-6烷基)、-NHC(=NH)NH2或-NH-(C1-6亚烷基)-N(C1-6烷基)2
    Re中的所述烷基、亚烷基、环烷基、芳基、杂芳基或杂环烷基各自任选地被一个或多个选自卤素、OH、NH2、SH、=O、CN、羧基、-C1-6烷基、-OC1-6烷基、C3-8环烷基、5-10元杂环烷基、C6-10芳基、5-10元杂芳基、-NH(C1-6烷基)、-N(C1-6烷基)2、-NH(C3-8环烷基)、-NH(5-10元杂环烷基)、-N(C1-6烷基)(C3-8环烷基)或-N(C1-6烷基)(5-10元杂环烷基)的取代基取代;
    n各自独立地选自0、1、2、3、4、5、6、7或8;
    或者,R4和R5一起形成=O;
    或者,R4和R5与其所连接的原子一起形成C3-8环烷基或5-10元杂环烷基,所述环烷基或杂环烷基各自任选地被一个或多个选自卤素、OH、NH2、=O、CN、羧基、-C1-6烷基、-OC1-6烷基、C3-8环烷基、5-10元杂环烷基、C6-10芳基、5-10元杂芳基、-NRcRd、-C(=O)Rc、 -S(=O)Rc、-S(=O)2Rc、-S(=O)(=NH)Rc、-P(=O)RaRb、-P(=NH)RaRb、-P(=O)(ORa)(ORb)、-P(=O)(NRaRb)(ORc)、-P(=O)(NRaRb)(NRcRd)、-C(=O)NRcRd、-NRcC(=O)Rd、-S(=O)NRcRd、-NRcS(=O)Rd、-S(=O)2NRcRd、-NRcS(=O)2Rd、-NRcP(=O)RaRb、-NRcP(=O)(ORa)(ORb)、-NRcP(=O)(NRaRb)(ORc)、-NRcP(=O)(NRaRb)(NRcRd)、-C(=O)ORc或-NH-(C1-6亚烷基)-N(C1-6烷基)2的取代基取代;
    或者,L1、L2、L3和L4中的任意两者与其所连接的原子一起形成C3-8环烷基、5-10元杂环烷基、C6-10芳基或者5-10元杂芳基,所述环烷基、杂环烷基、芳基或杂芳基各自任选地被一个或多个Rf取代;
    Rf各自独立地选自卤素、=O、OH、SH、-NH2、CN、-C1-8烷基、C3-8环烷基、5-10元杂环烷基、-OC1-8烷基、-SC1-8烷基、-NH(C1-8烷基)、-N(C1-8烷基)2、-NH(C3-8环烷基)、-NH(5-10元杂环烷基)、-N(C1-6烷基)(C3-8环烷基)、-N(C1-6烷基)(5-10元杂环烷基)、-NH(C1-6亚烷基-O)n(C1-6烷基)、-NH-(C1-6亚烷基)-NHCOO(C1-6亚烷基-O)n(C1-6烷基)、-NH-(C1-6亚烷基)-CONH(C1-6亚烷基-O)n(C1-6烷基)、-NH-(C1-6亚烷基)-NHCO-(5-10元杂环烷基)、-NH-(C1-6亚烷基)-OCO-(C1-6烷基)、-NH-(C1-6亚烷基)-NHCO-(C1-6烷基)、-NH-(C1-6亚烷基)-CONH-(C1-6烷基)、-NH-(C1-6亚烷基)-CONH-(C1-6亚烷基)-OC1-6烷基、-NH-(C1-6亚烷基)-NHS(=O)2(C1-6烷基)、-NH-(C1-6亚烷基)-NHS(=O)2(C3-8环烷基)、-NH-(C1-6亚烷基)-S(=O)2(C1-6烷基)、-NH-(C1-6亚烷基)-S(=O)(=NH)(C1-6烷基)、-NHP(=O)(C1-6烷基)2、-NHP(=O)(ORa)(ORb)、-NHP(=O)(ORa)(C1-6烷基)、-NH-(C1-6亚烷基)-NH(C1-6烷基)或-NH-(C1-6亚烷基)-N(C1-6烷基)2
    Rf中的所述烷基、亚烷基、环烷基或杂环烷基各自任选地被一个或多个选自卤素、OH、=O、CN、-NH2、-CONH2、-NHC(=NH)NH2、-N=C(NH2)2、羧基、-C1-6烷基、-(C1-6亚烷基)-NH2、-CONH(C1-6亚烷基-O)n(C1-6亚烷基)-NH2、-CONH(C1-6亚烷基-O)n(C1-6亚烷基)-OH、-CONH(C1-6亚烷基-O)n(C1-6烷基)、-CONH(C1-6亚烷基-O)n(C1-6亚烷基)-COOH、-O(C1-6亚烷基-O)n(C1-6亚烷基)-NH2、-O(C1-6亚烷基-O)n(C1-6亚烷基)-OH、-O(C1-6亚烷基-O)n(C1-6烷基)、-O(C1-6亚烷基-O)n(C1-6亚烷基)-COOH、-NH(C1-6亚烷基-O)n(C1-6亚烷基)-NH2、-NH(C1-6亚烷基-O)n(C1-6亚烷基)-OH、-NH(C1-6亚烷基-O)n(C1-6烷基)、-NH(C1-6亚烷基-O)n(C1-6亚烷基)-COOH、-NHCOO(C1-6亚烷基-O)n(C1-6亚烷基)-NH2、-NHCOO(C1-6亚烷基-O)n(C1-6亚烷基)-OH、-NHCOO(C1-6亚烷基-O)n(C1-6烷基)、-NHCOO(C1-6亚烷基-O)n(C1-6亚烷基)-COOH、-OC1-6烷基、C3-8环烷基、5-10元杂环烷基、C6-10芳基、5-10元杂芳基、-NH(C1-6烷基)、-N(C1-6烷基)2、-NH(C3-8环烷基)、-NH(5-10元杂环烷基)、-N(C1-6烷基)(C3-8环烷基)或-N(C1-6烷基)(5-10元杂环烷基)的取代基取代;
    V选自5元杂芳基或-C≡C-;
    Ar选自C6-10芳基、或者5-10元杂芳基,所述芳基或杂芳基各自任选地被一个或多个选自氘、卤素、OH、=O、CN、羧基、-C1-6烷基、-OC1-6烷基、C3-8环烷基、5-10元杂环烷基、C6-10芳基、5-10元杂芳基、-NRaRb、-C(=O)Ra、-S(=O)Ra、-S(=O)2Ra、-S(=O)(=NH)Ra、-P(=O)RaRb、-P(=NH)RaRb、-P(=O)(ORa)(ORb)、-P(=O)(NRaRb)(ORc)、-P(=O)(NRaRb)(NRcRd)、-C(=O)NRaRb、-NRaC(=O)Rb、-S(=O)2NRaRb、-NRaS(=O)2Rb或-C(=O)ORa的取代基取代;
    所述药学上可接受的形式选自药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂化物、N-氧化物、同位素标记物、代谢物或前药。
  13. 化合物或其药学上可接受的形式,其中所述化合物选自:












    所述药学上可接受的形式选自药学上可接受的盐、酯、立体异构体、互变异构体、多晶型物、溶剂化物、N-氧化物、同位素标记物、代谢物或前药。
  14. 一种药物组合物,其包含权利要求1至13中任一项所述的化合物或其药学上可接受的形式、以及一种或多种药学上可接受的载体。
  15. 根据权利要求1至13中任一项所述的化合物或其药学上可接受的形式、或者根据权利要求14所述的药物组合物在制备用于预防或治疗由GPR75调节的疾病或病症的药物中的用途,
    优选地,所述由GPR75调节的疾病选自脂肪营养不良、厌食症、糖尿病、恶性肿瘤、肾小球肾炎或神经退行性疾病。
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