WO2022199458A1 - 噻吩类glp-1受体激动剂及其用途 - Google Patents

噻吩类glp-1受体激动剂及其用途 Download PDF

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WO2022199458A1
WO2022199458A1 PCT/CN2022/081466 CN2022081466W WO2022199458A1 WO 2022199458 A1 WO2022199458 A1 WO 2022199458A1 CN 2022081466 W CN2022081466 W CN 2022081466W WO 2022199458 A1 WO2022199458 A1 WO 2022199458A1
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group
membered
alkyl
alkoxy
halogen
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French (fr)
Inventor
翟文强
张智敏
郭刘斌
刘东舟
潘豪
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Hangzhou Zhongmei Huadong Pharmaceutical Co Ltd
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Hangzhou Zhongmei Huadong Pharmaceutical Co Ltd
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Priority to CN202280019401.4A priority Critical patent/CN116940561A/zh
Priority to US18/283,465 priority patent/US20240208952A1/en
Priority to EP22774119.6A priority patent/EP4317142A4/en
Publication of WO2022199458A1 publication Critical patent/WO2022199458A1/zh
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/14—Ortho-condensed systems
    • C07D491/147—Ortho-condensed systems the condensed system containing one ring with oxygen as ring hetero atom and two rings with nitrogen as ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/20—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention relates to the technical field of medicine, in particular to GLP-1 receptor agonist compounds and preparation methods, as well as the use of the compounds in the preparation of medicines for the treatment or prevention of GLP-1 mediated diseases and related diseases.
  • Diabetes mellitus is a chronic comprehensive disease mainly caused by glucose metabolism disorder caused by absolute or relative shortage of insulin or decreased sensitivity of target cells to insulin. It is divided into type I diabetes mellitus and type II diabetes mellitus. Among them, type II diabetes is adult-onset diabetes mellitus, an endocrine disease mainly manifested by chronic hyperglycemia caused by insulin resistance and/or insulin secretion defect. Type II diabetes patients account for more than 90% of diabetic patients. According to the Global Diabetes Map, there were approximately 425 million diabetic patients in the world in 2017, of which China ranked first in the world with approximately 114.4 million diabetic patients. It is estimated that by 2045, there will be 629 million people with diabetes worldwide. It can be seen that diabetes is a very common chronic disease all over the world.
  • insulin secretagogues mainly the following classes of drugs: insulin secretagogues, metformin, ⁇ -glucosidase inhibitors, insulin sensitizers, sodium-glucose cotransporter 2 inhibitors, dipeptidyl peptidase -4 (DPP-4) inhibitors, GLP-1 receptor agonists, insulin and its similar drugs, etc.
  • DPP-4 dipeptidyl peptidase -4
  • GLP-1 receptor agonists are one of the most effective diabetes treatment drugs, and insulin preparations are still the global The most used diabetes drug, about 30-40% of type 2 diabetes patients eventually need to use insulin.
  • GLP-1 preparations mainly include exenatide, liraglutide, semaglutide, etc., suitable for metformin, sulfonic acid Patients with type 2 diabetes who cannot adequately control blood sugar when combined with ureides.
  • insulin preparations and GLP-1 preparations are basically polypeptide drugs and injection preparations. Even oral semaglutide still has many limitations in drug use. Therefore, it is still necessary to further develop small molecules of GLP-1 receptors. Agonist drugs.
  • GLP-1 stimulates insulin secretion in a glucose-dependent manner, and inhibits glucagon secretion in a glucose-dependent manner, so there is no risk of hypoglycemia.
  • GLP-1 can increase the amount of insulin produced by beta cells and improve the responsiveness of beta cells to glucose.
  • GLP-1 can delay gastric emptying, reduce food intake, and thus have the effect of weight loss.
  • GLP-1 also has the unique effect of cardiovascular and cerebrovascular benefits.
  • GLP-1 receptor agonists are positioned in the transition stage between oral hypoglycemic drugs and insulin in clinical application, and can be used in combination with other drugs, becoming the fastest growing in the past five years and the fastest growing in the future. Potential hypoglycemic drugs.
  • diabetic nephropathy diabetic eye complications (diabetic retinopathy, diabetes-related uveitis, diabetic cataracts), diabetic foot, diabetic cardiovascular complications, diabetic cerebrovascular disease , diabetic neuropathy, obesity, hypertension.
  • diabetic eye complications diabetes-related uveitis, diabetic cataracts
  • diabetic foot diabetic cardiovascular complications
  • diabetic cerebrovascular disease diabetic neuropathy, obesity, hypertension.
  • GLP-1 receptor agonists are currently mostly in the form of injection.
  • the current progress in the development of known GLP-1 receptor agonist small molecules is as follows:
  • WO2009111700A2 discloses a series of oxadiazepine GLP-1 receptor agonist compounds
  • WO2010114824A1 discloses a series of substituted azoanthracene derivatives GLP-1 receptor agonist compounds
  • WO2017078352A1 discloses a series of ring GLP-1 receptor agonist compounds of hexene derivatives
  • KR1020180101671A discloses a series of GLP-1 receptor agonist compounds of heteroaryl substituted pyridine[1,2-a]imidazole derivatives
  • WO2018056453A1 discloses A series of GLP-1 receptor agonist compounds of pyrazolopyridine derivatives
  • WO2018109607A1 discloses a series of GLP-1 receptor agonist compounds similar to the present application, and the like.
  • T 1 and T 2 are each independently selected from CH 2 , NH, O, S;
  • W 1 is selected from O, S, CH 2 , NH;
  • W 2 is selected from O, NH, CH 2 , CR y ;
  • Z 1 , Z 2 , Z 3 , Z 4 are each independently selected from CH, N or C;
  • X 1 , X 2 , X 3 are independently selected from CH, N or C, and at most two of X 1 , X 2 , and X 3 are N;
  • Ring B is selected from benzene ring or 5-7 membered heteroaromatic ring;
  • Ring C is selected from benzene ring, 4-8 membered heterocycle, 5-10 membered spiro ring, 5-10 membered bridged ring and 5-7 membered heteroaromatic ring;
  • R 2 is independently selected from hydrogen, oxo, halogen, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 1-6 alkoxy, -C 1- 6 -cycloalkoxy, cyano, 3-8-membered cycloalkyl, 3-8-membered heterocyclic group, phenyl, 5-8-membered heteroaryl, wherein the halogen, alkyl, alkenyl, alkyne in R 2 group, amino group, alkoxy group, cycloalkoxy group, cycloalkyl group, heterocyclyl group, phenyl group, heteroaryl group can be optionally substituted 1 to 3 times by a substituent independently selected from R x ;
  • R 3 is independently selected from hydrogen, oxo, halogen, -CN, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 1-6 alkoxy, amine group, amide group, sulfonyl group, sulfonamide group, -OH, -C 3-8 cycloalkyl, 3-8-membered heterocyclic group, 6-10-membered aryl, 5-8-membered heteroaryl, wherein R 3 Under the conditions allowed by the valence, it can be optionally substituted 1-3 times by a substituent independently selected from R y ;
  • R 4 is independently selected from hydrogen, halogen, -C 1-3 alkyl, -C 1-3 haloalkyl, -C 1-3 alkoxy, cyano, hydroxyl, amino, amido, sulfonyl, sulfonyl amide group;
  • R 5 is independently selected from hydrogen, halogen, hydroxyl, -CN, -C 1-3 alkyl, -C 1-3 alkoxy, -C 1-3 cycloalkyl, wherein the alkyl group in R 5 , alkoxy, cycloalkyl can be optionally composed of halogen, hydroxyl, -NR z , -CN, -C 1-3 alkyl, -C 1-3 alkoxy, -C 1 under the conditions allowed by the valence ⁇ 3 cycloalkyl substituted 1 to 3 times;
  • R 6 is selected from -R z , -OR z , -SR z , -C 1-3 alkyl, -C 1-3 alkylene-R z , -C 0-3 alkylene-amino-R z , -C 0-3 alkylene-carbonyl-R z , -C 0-3 alkylene-amide-R z , -C 0-3 alkylene-sulfonyl-R z , -C 0-3 Alkylene-phosphoryl-R z , -C 0-3 alkylene-sulfonamido-R z , wherein the alkyl, amine, amide, sulfonyl, sulfonamido, phosphorus in the R 6
  • the acyl group can be optionally substituted 1 to 3 times by halogen or 1 time by R w under the conditions allowed by the valence;
  • R7 is selected from -COOH, -C( Ry ) n0 -COOH, -N( Rz ) n0 -COOH, -SO2 -COOH and -SO2 -NH-COOH, the -C( Ry ) n0 R y in - can be connected to C in the form of main chain and/or branched chain, and R z in -N(R z ) n0 - can be connected to N in the form of main chain and/or branched chain , wherein n 0 is an integer selected from 0, 1 or 2; when n 0 is 2, two R y or R z can be further cyclized into a 3-8 membered carbocyclic or heterocyclic ring;
  • n is an integer selected from 0, 1, 2 or 3;
  • n is an integer selected from 0, 1 or 2;
  • o is an integer selected from 0, 1, 2, 3 or 4;
  • p is an integer selected from 0, 1, 2, 3 or 4;
  • any two R 1 can be further cyclized into a 3- to 8-membered carbocycle, aromatic ring, heterocycle or aromatic heterocycle. It is selected to be substituted 1-3 times by C 1-3 alkyl, C 1-3 haloalkyl, halogen, cyano, and C 1-3 alkoxy;
  • the two R 3 can be further cyclized into a 3- to 8-membered carbocyclic or heterocyclic ring;
  • R 1 and R 3 can be further cyclized into a 3- to 8-membered carbocyclic or heterocyclic ring;
  • any two R 5 can be further cyclized with ring C to form a 6- to 10-membered spiro or bridged ring, and the formed spiro and bridged rings can be optionally composed of C 1 ⁇ 3 alkyl, C 1-3 haloalkyl, halogen, cyano, C 1-3 alkoxy substituted 1 to 3 times;
  • any R 4 and R 5 can be further cyclized into a 5-8 membered ring, and the formed ring can optionally have C 1-3 alkyl, C 1-3 haloalkyl, halogen, cyano, oxo, C 1-3 alkoxy substituted 1-3 times;
  • R w is independently selected from -CN, -CH 2 CN, -C 1-3 alkyl, -OH, -C 1-3 alkoxy, amido, sulfonyl, sulfonamido, -NH 2 , -NH -C 1-3 alkyl group, wherein the alkyl group in R w can be optionally composed of C 1-3 alkyl group, C 1-3 haloalkyl group, halogen, cyano, oxo, C 1-3 alkoxy substituted 1-3 times;
  • R x is independently selected from hydrogen, halogen, oxo, C 1-6 alkoxy, cyano, hydroxyl, carboxyl, amino, amido, sulfonyl, sulfonamido, -C 1-6 alkyl, - C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-6 cycloalkyl, 3-6 membered heterocyclyl, 6-8 membered aryl, 5-8 membered heteroaryl, wherein the The alkyl group, alkoxy group, cycloalkyl group, heterocyclic aryl group and heteroaryl group in R x can be optionally composed of C 1-3 alkyl, C 1-3 haloalkyl, halogen, Cyano, oxo, C 1-3 alkoxy are substituted 1 to 3 times or optionally substituted once by hydroxyl;
  • R y is independently selected from hydrogen, halogen, oxo, -C 1-3 alkoxy, cyano, hydroxyl, amino, carboxyl, amido, sulfonyl, sulfonamido, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-6 cycloalkyl, 3-6 membered heterocyclyl, 5-6 membered heteroaryl, wherein the R y in the alkyl, Alkenyl, alkynyl, amino, amido, alkoxy, cycloalkyl, heterocyclic, and heteroaryl can be optionally composed of C 1-3 alkyl, C 1-3 haloalkanes under the conditions allowed by the valence base, halogen, cyano, oxo, C 1-3 alkoxy substituted 1-3 times;
  • R z is independently selected from hydrogen, C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, aryl, 5-6 membered heteroaryl, Wherein R z can be optionally composed of C 1-3 alkyl, C 1-3 haloalkyl, halogen, cyano, oxo, C 1-3 alkoxy, 3-6 membered heterocycle under the conditions allowed by the valence The base is substituted 1 to 3 times.
  • the ring B can be further selected from:
  • ring B is preferably
  • the ring C can be further selected from:
  • ring C is preferably
  • Z 1 and Z 4 are independently selected from CH, N;
  • X 1 , X 2 , X 3 are independently selected from CH, N or C, and at most two of X 1 , X 2 , and X 3 are N;
  • Y 1 is selected from CH or N;
  • Y 2 is selected from CH, N or C;
  • Y 3 is selected from CH or N;
  • R 2 is independently selected from hydrogen, oxo, halogen, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 1-6 alkoxy, -C 1- 6 -cycloalkoxy, cyano, 3-8-membered cycloalkyl, 3-8-membered heterocyclic group, phenyl, 5-8-membered heteroaryl, wherein the halogen, alkyl, alkenyl, alkyne in R 2 group, amino group, alkoxy group, cycloalkoxy group, cycloalkyl group, heterocyclyl group, phenyl group, heteroaryl group can be optionally substituted 1 to 3 times by a substituent independently selected from R x ;
  • R 3 is independently selected from hydrogen, oxo, halogen, -CN, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 1-6 alkoxy, amine group, amide group, sulfonyl group, sulfonamide group, -OH, -C 3-8 cycloalkyl, 3-8-membered heterocyclic group, 6-10-membered aryl, 5-8-membered heteroaryl, wherein R 3 Under the conditions allowed by the valence, it can be optionally substituted 1-3 times by a substituent independently selected from R y ;
  • R 4 is independently selected from hydrogen, halogen, -C 1-3 alkyl, -C 1-3 haloalkyl, -C 1-3 alkoxy, cyano, hydroxyl, amino, amido, sulfonyl, sulfonyl amide group;
  • R 5 is independently selected from hydrogen, halogen, hydroxyl, -CN, -C 1-3 alkyl, -C 1-3 alkoxy, -C 1-3 cycloalkyl, wherein the alkyl group in R 5 , alkoxy, cycloalkyl can be optionally composed of halogen, hydroxyl, -NR z , -CN, -C 1-3 alkyl, -C 1-3 alkoxy, -C 1 under the conditions allowed by the valence ⁇ 3 cycloalkyl substituted 1 to 3 times;
  • R 6 is selected from -R z , -OR z , -SR z , -C 1-3 alkyl, -C 1-3 alkylene-R z , -C 0-3 alkylene-amino-R z , -C 0-3 alkylene-carbonyl-R z , -C 0-3 alkylene-amide-R z , -C 0-3 alkylene-sulfonyl-R z , -C 0-3 Alkylene-phosphoryl-R z , -C 0-3 alkylene-sulfonamido-R z , wherein the alkyl, amine, amide, sulfonyl, sulfonamido, phosphorus in the R 6
  • the acyl group can be optionally substituted 1 to 3 times by halogen or 1 time by R w under the conditions allowed by the valence;
  • R7 is selected from -COOH, -C( Ry ) n0 -COOH, -N( Rz ) n0 -COOH, -SO2 -COOH and -SO2 -NH-COOH, the -C( Ry ) n0 R y in - can be connected to C in the form of main chain and/or branched chain, and R z in -N(R z ) n0 - can be connected to N in the form of main chain and/or branched chain , wherein n 0 is an integer selected from 0, 1 or 2; when n 0 is 2, two R y or R z can be further cyclized into a 3-8 membered carbocyclic or heterocyclic ring;
  • n is an integer selected from 0, 1, 2 or 3;
  • o is an integer selected from 0, 1, 2, 3 or 4;
  • p is an integer selected from 0, 1, 2, 3 or 4;
  • any two R 1 can be further cyclized into a 3- to 8-membered carbocycle, aromatic ring, heterocycle or aromatic heterocycle. It is selected to be substituted 1-3 times by C 1-3 alkyl, C 1-3 haloalkyl, halogen, cyano, and C 1-3 alkoxy;
  • any two R 5 can be further cyclized with ring C to form a 6- to 10-membered spiro or bridged ring, and the formed spiro and bridged rings can be optionally composed of C 1 ⁇ 3 alkyl, C 1-3 haloalkyl, halogen, cyano, C 1-3 alkoxy substituted 1 to 3 times;
  • any R 4 and R 5 can be further cyclized into a 5-8 membered ring, and the formed ring can optionally have C 1-3 alkyl, C 1-3 haloalkyl, halogen, cyano, oxo, C 1-3 alkoxy substituted 1-3 times;
  • R w is independently selected from -CN, -CH 2 CN, -C 1-3 alkyl, -OH, -C 1-3 alkoxy, amido, sulfonyl, sulfonamido, -NH 2 , -NH -C 1-3 alkyl, wherein the alkyl group in R w can be optionally composed of C 1-3 alkyl, C 1-3 haloalkyl, halogen, cyano, C 1- 3 alkoxy is substituted 1 to 3 times;
  • R x is independently selected from hydrogen, halogen, oxo, C 1-6 alkoxy, cyano, hydroxyl, carboxyl, amino, amido, sulfonyl, sulfonamido, -C 1-6 alkyl, - C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-6 cycloalkyl, 3-6 membered heterocyclyl, 6-8 membered aryl, 5-8 membered heteroaryl, wherein the The alkyl, alkoxy, cycloalkyl, heterocyclylaryl and heteroaryl groups in R x can be optionally substituted 1 to 3 times by halogen or 0 to 1 times by hydroxy under the condition that the valence allows ;
  • R y is independently selected from hydrogen, halogen, oxo, -C 1-3 alkoxy, cyano, hydroxyl, amino, carboxyl, amido, sulfonyl, sulfonamido, -C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, -C 3-6 cycloalkyl, 3-6 membered heterocyclic group, wherein in the R y , alkyl, alkoxy, cycloalkyl, The heterocyclyl group can be optionally substituted 1 to 3 times with halogen under the conditions allowed by the valence;
  • R z is independently selected from hydrogen, C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, 4-6 membered heterocycle, 5-6 membered aryl or 5-6 membered heterocycle Aryl, wherein R z can be optionally halogen, cyano, C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, 3-6 membered hetero- The cyclic group is substituted 1 to 3 times.
  • any adjacent R 4 and R 5 can be further cyclized into a 5- to 8-membered ring;
  • the 5- to 8-membered ring includes C 5-6 carbon ring, 5-8 membered heterocycle, benzene ring, 5-8 membered heteroaromatic ring,
  • the formed ring can be optionally composed of alkyl, haloalkyl, halogen, cyano, alkane under the conditions allowed by the compound Oxygen is substituted 1 to 3 times.
  • any adjacent R 4 and R 5 can be further cyclized into a 5-8 membered ring, and the 5-8 membered ring can be selected from
  • the formed 5- to 8-membered ring can be optionally substituted by C 1-3 alkyl, C 1-3 haloalkyl, halogen, cyano, oxo, C 1-3 alkoxy under the conditions allowed by the valence ⁇ 3 times.
  • any adjacent R 4 and R 5 can be further cyclized into a 5- to 8-membered ring, and the 5- to 8-membered ring is preferably:
  • the formed 5- to 8-membered ring can be optionally substituted by C 1-3 alkyl, C 1-3 haloalkyl, halogen, cyano, oxo, C 1-3 alkoxy under the conditions allowed by the valence ⁇ 3 times.
  • any adjacent R 4 and R 5 can be further cyclized into a 5-8 membered ring, and the 5-8 membered ring can be selected from :
  • the formed 5- to 8-membered ring can be optionally substituted by C 1-3 alkyl, C 1-3 haloalkyl, halogen, cyano, oxo, C 1-3 alkoxy under the conditions allowed by the valence ⁇ 3 times.
  • the structural unit Can be further selected from:
  • the compound of formula I described in the present invention can have the following sub-general formula,
  • the n is selected from 1, 2 or 3.
  • the p is selected from 0, 1 or 2.
  • the R 1 can be further independently selected from -F, -Cl, -CN, -OCH 3 , -OCH 2 CH 3 , -O-cyclopropyl, -CH 3 , - CH2CH3 , -CH2CH2CH3 , - ( CH ) 2CH3 , -COCH3 , -CONH2 , -CF3 , -CHF2 , -CH2F , -CH2CH2F , - CO-cyclopropyl, 5-6 membered heterocyclyl, 5-6 membered heteroaryl.
  • the R 3 can be further selected from -F, -Cl, -CH 3 , -OCH 3 , -NH 2 , -OH, -CH 2 CH 3 , -CH 2 OH, - NHCH3 , -COCH3 , -SO2CH3 , -OCH2CH3 , -CF3 , -CHF2 , -CH2F , isopropyl , cyclopropyl, fluorocyclopropyl .
  • the R y can be further selected from -F, -Cl, methyl, ethyl, trifluoromethyl, difluoromethyl, fluoromethyl, fluoroethyl, methoxy , amino, hydroxyl, propyl, isopropyl, cyclopropyl, cyclobutyl.
  • R y in -C(R y ) n0 -COOH of R 7 can be connected to C in the form of main chain and/or branched chain; when R y is connected in the form of main chain When it is on C of R 7 , R y exists in the form of a corresponding subunit; when R y is connected to C of R 7 in a branched form, R y exists in the form of a corresponding saturated group.
  • R z in -N(R z ) n0 -COOH of R 7 can be connected to N in the form of main chain and/or branched chain; when R z is connected in the form of main chain When on C of R 7 , R z exists in the form of the corresponding subunit; when R y is connected to the N of R 7 in the form of a branched chain, R z exists in the form of the corresponding saturated group.
  • R y in the -C(R y ) n -COOH of R 7 is a methyl group
  • the connecting on C in the form of the main chain refers to the The structure is connected (that is, R 7 is -CH 2 - at this time)
  • the described connection on C in the form of a branched chain refers to the The structure is connected (that is, R 7 is -CH 3 at this time).
  • the R 6 is selected from -R z , -OR z , -SR z , -C 1-3 alkylene-R z , -C 0-3 alkylene-amine -R z , -C 0-3 alkylene-carbonyl-R z , wherein the alkyl group, amine group, amide group, sulfonyl group, sulfonamide group and phosphoryl group in the R 6 can be used under the conditions allowed by the valence Optionally substituted 1 to 3 times by halogen or 1 time by R w .
  • the R z can be further selected from: methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, methoxy, ethoxy, R z can be optionally substituted 1 with halogen, cyano, C 1-3 alkyl, C 1-3 alkoxy, C 3-6 cycloalkyl, 3-6 membered heterocyclic group under the conditions allowed by the valence ⁇ 3 times.
  • the R 1 can be further independently selected from -F, -Cl, -CN, -OCH 3 , -OCH 2 CH 3 , -CH 3 , -CH 2 CH 3 , -COCH 3 , -CONH 2 , -CF 3 , -CHF 2 , -CH 2 F, -CH 2 CH 2 F, -CO-cyclopropyl, 5-6 membered heterocyclic group, 5-6 membered heteroaryl group.
  • the R 2 can be further independently selected from -H, -CH 3 , -CHF 2 , -CH 2 F, -CF 3 , -CH 2 CH 3 , -CH 2 CH 2 F, -NH 2 , cyclopropyl, 5-6 membered heterocyclic group, 5-6 membered heteroaryl group.
  • the R 3 can be further selected from -F, -Cl, -CH 3 , -OCH 3 , -NH 2 , -OH, -CH 2 CH 3 , -CH 2 OH, - NHCH3 , -COCH3 , -SO2CH3 , -OCH2CH3 , -CF3 , -CHF2 , -CH2F , isopropyl , cyclopropyl, fluorocyclopropyl .
  • the R 4 can be further selected from -CN, -CH 3 , -OH, -CH 2 OH, -CH 2 OCH 3 , -OCH 3 , -NH 2 , -NHCH 3 , -COCH 3 , -OCH 2 CH 3 .
  • the R 5 is selected from -F, -Cl, -CN, -CH 3 , -CH 2 CH 3 , -CF 3 , -CHF 2 , -CH 2 F, -CH 2 OH , -OH , -CH2OCH3 , -OCH3 , -CH2CH2OH , -CH2CH2OCH3 , isopropyl or cyclopropyl .
  • the R 7 is selected from -COOH, -CH 2 COOH, -CH 2 CH 2 COOH, -CH(CH 3 )COOH, wherein the R 7 can be valence-allowed Optionally substituted 1-3 times by halogen.
  • the present invention provides a series of compounds, which are independently selected from one of the following compounds or any combination thereof:
  • the present invention provides a series of compounds, which are independently selected from one of the following compounds or any combination thereof:
  • the compounds provided herein, and pharmaceutically acceptable salts thereof, can be used alone or in combination with at least one other therapeutic agent in therapy.
  • the present invention provides a pharmaceutical composition, which contains a compound represented by formula I and a pharmaceutically acceptable salt thereof, and one or more other therapeutically active ingredients.
  • the present invention also provides a pharmaceutical preparation, which contains the compound shown in formula I and a pharmaceutically acceptable salt thereof, and one or more than two pharmaceutically acceptable carriers; the pharmaceutical preparation is any clinically acceptable A formulation dosage form.
  • the compounds provided by the present invention and their pharmaceutically acceptable salts can be formed into solid dosage forms, such as capsules, tablets, pills, lozenges, sugar coatings, granules, powders, ointments, creams, drops, etc.; the present invention
  • the provided compounds and pharmaceutically acceptable salts thereof can be in liquid dosage forms such as elixirs, syrups, emulsions, dispersions, suspensions, solutions, sprays and the like.
  • the pharmaceutically acceptable carriers and/or pharmaceutically acceptable diluents usable in the pharmaceutical compositions or pharmaceutical formulations of the present invention may be any conventional carriers and/or diluents in the field of pharmaceutical formulations.
  • the pharmaceutically acceptable salts of the present invention include acid salts and base salts.
  • the pharmaceutically acceptable salts of the present invention can exist in unsolvated as well as solvated forms.
  • the present invention also provides compounds of formula I and pharmaceutically acceptable salts thereof, which are used in the preparation of medicaments for the treatment and/or metabolism-related diseases.
  • Said metabolism-related diseases include GLP-1 mediation.
  • diseases and related diseases including but not limited to: diabetes mellitus, hyperglycemia, insulin resistance, glucose intolerance, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, adipocyte dysfunction, obesity, dyslipidemia, hyperlipidemia Insulinemia, etc.; wherein, the diabetes includes, but is not limited to, T1D and/or T2DM, idiopathic T1D, early-onset T2D, latent autoimmune diabetes, juvenile atypical diabetes, gestational diabetes and the like.
  • the present invention also provides a method for treating a disease, comprising administering to a patient in need a therapeutically effective amount of a compound represented by formula I and a pharmaceutically acceptable salt thereof, wherein the disease is GLP -1-mediated diseases and related diseases; such diseases include but are not limited to: diabetes, hyperglycemia, insulin resistance, glucose intolerance, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, adipocyte dysfunction, Obesity, dyslipidemia, hyperinsulinemia, etc.; wherein, the diabetes includes, but is not limited to, T1D and/or T2DM, idiopathic T1D, early-onset T2D, latent autoimmune diabetes, juvenile SARS type diabetes, gestational diabetes, etc.
  • diseases include but are not limited to: diabetes, hyperglycemia, insulin resistance, glucose intolerance, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, adipocyte dysfunction, Obesity, dyslipidemia, hyperinsulinemia
  • the compounds of formula I and pharmaceutically acceptable salts thereof provided by the present invention have excellent GLP-1 receptor agonistic activity, and can treat and/or prevent GLP-1-mediated diseases and related diseases.
  • the compounds of formula I and pharmaceutically acceptable salts thereof provided by the present invention have excellent GLP-1 receptor agonistic activity, and can treat and/or prevent GLP-1-mediated diseases and related diseases.
  • the present invention also provides the use of the above-mentioned compounds or their pharmaceutically acceptable salts in the preparation of medicines related to GLP-1 receptor agonists.
  • the GLP-1 receptor agonist-related drug is for the treatment of Type II diabetes, Type I diabetes and obesity.
  • the compounds described in the present invention are named according to the chemical structural formula. If the name of the compound is inconsistent with the chemical structural formula when it represents the same compound, the chemical structural formula shall prevail.
  • the compounds provided by the present invention and their pharmaceutically acceptable salts can exist in a chiral form, ie, S configuration or R configuration.
  • the compounds provided by the present invention and their pharmaceutically acceptable salts may exist in an achiral form.
  • the compounds of the present invention include stereoisomers of the compounds.
  • the stereoisomers mentioned in the present invention refer to enantiomers when the compound represented by formula I has an asymmetric carbon atom; when the compound has a carbon-carbon double bond or a cyclic structure, a cis Trans-isomers; tautomers are produced when compounds are present in the presence of a ketone or oxime.
  • the stereoisomers described in the present invention include but are not limited to: enantiomers, diastereomers, racemates, cis-trans isomers, tautomers isomers, geometric isomers, epimers and mixtures thereof.
  • the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and racemic mixtures thereof and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which belong to this within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
  • enantiomers or “optical isomers” refer to stereoisomers that are mirror images of each other.
  • cis-trans isomer or “geometric isomer” result from the inability to rotate freely due to double bonds or single bonds to ring carbon atoms.
  • diastereomer refers to a stereoisomer in which the molecule has two or more chiral centers and the molecules are in a non-mirror-image relationship.
  • Optically active (R)- and (S)-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting mixture of diastereomers is separated and the auxiliary group is cleaved to provide pure desired enantiomer.
  • a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereomeric salt is formed by conventional methods known in the art.
  • the method performs the resolution of diastereomers, followed by recovery of the pure enantiomers.
  • separation of enantiomers and diastereomers is usually accomplished by the use of chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (eg from amine to amine carboxylate).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound.
  • compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C).
  • deuterated drugs can be formed by replacing hydrogen with deuterium, and the bonds formed by deuterium and carbon are stronger than those formed by ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs can reduce toxic side effects and increase drug stability. , enhance the efficacy, prolong the biological half-life of drugs and other advantages. All transformations of the isotopic composition of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissues, without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • salts of the present invention refers to salts of the compounds of the present invention, prepared from compounds with specific substituents discovered by the present invention and relatively non-toxic acids or bases.
  • base addition salts can be obtained by contacting such compounds with a sufficient amount of base in neat solution or in a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts.
  • acid addition salts can be obtained by contacting such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts including, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, and methanesulfonic acids; also include salts of amino acids such as arginine, etc. , and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain both basic and acidic functional groups and thus can be converted into either base
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the acid or base containing parent compound by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of the two.
  • substituted in the present invention means that any one or more hydrogen atoms on a specified atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence of the specified atom is normal and the substitution Compounds are stable.
  • Oxygen substitution does not occur on aromatic groups.
  • optionally substituted means that it may or may not be substituted. Unless otherwise specified, the kind and number of substituents can be arbitrary on the basis of chemical realization.
  • any variable eg, R
  • its definition in each case is independent.
  • the group may optionally be substituted with up to two Rs, with independent options for R in each case.
  • combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • linking group When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
  • substituent R can be substituted at any position on cyclohexyl or cyclohexadiene.
  • substituents do not indicate through which atom it is attached to the substituted group, such substituents may be bonded through any of its atoms, for example, pyridyl as a substituent may be through any one of the pyridine ring The carbon atom is attached to the substituted group.
  • the direction of attachment is arbitrary, for example,
  • the linking group L in the middle is -MW-, at this time -MW- can connect ring A and ring B in the same direction as the reading order from left to right. It is also possible to connect ring A and ring B in the opposite direction to the reading order from left to right.
  • Combinations of the linking groups, substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • any one or more sites in the group can be linked to other groups by chemical bonds.
  • connection method of the chemical bond is not located, and there is an H atom at the linkable site, when the chemical bond is connected, the number of H atoms at the site will be correspondingly reduced with the number of chemical bonds connected to the corresponding valence. the group.
  • the chemical bond connecting the site to other groups can be represented by straight solid line bonds straight dotted key or wavy lines express.
  • a straight solid bond in -OCH 3 indicates that it is connected to other groups through the oxygen atom in this group;
  • the straight dashed bond in the group indicates that it is connected to other groups through the two ends of the nitrogen atom in the group;
  • the wavy line in the phenyl group indicates that it is connected to other groups through the 1 and 2 carbon atoms in the phenyl group;
  • the number of atoms in a ring is generally defined as the number of ring members, eg, "5-7 membered ring” refers to a “ring” of 5-7 atoms arranged around it.
  • halogen atom in the present invention means a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like.
  • Preferred halogen atoms as substituents of the aryl group of the present invention are fluorine atoms and chlorine atoms.
  • Preferred halogen atoms as substituents of the alkyl group of the present invention are fluorine atoms and chlorine atoms.
  • C 1-6 alkyl groups having halogen atoms as substituents include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, pentafluoroethyl, 2-fluoroethyl, 2,2, 2-trifluoroethyl, 2-chloroethyl, heptafluoropropyl, 3,3,3-trifluoropropyl, 2,3-dichloropropyl, 1-fluoro-3-bromopropyl, 4- bromobutyl, 3,3,3,4,4-pentafluorobutyl, 4,4-dichlorobutyl, 5-iodopentyl, 5,5-difluoropentyl, 6-chlorohexyl and 6, 6,6-Trifluorohexyl.
  • C 1-6 alkyl in the present invention is a straight or branched chain alkyl group having 1 to 6 carbons, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl , isobutyl, sec-butyl, tert-butyl, 1-methylpropyl, n-pentyl, isopentyl, 2-methylbutyl, 1,1-dimethylpropyl, 1-ethylpropyl , n-hexyl, 4-methylpentyl and 2-ethylbutyl.
  • C 1-6 alkoxy in the present invention means a group C 1-6 alkyl-O-, including but not limited to methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, 1-methylpropoxy, n-pentyloxy, isopentyloxy, 2-methylbutoxy, 1, 1-dimethylpropoxy, 1-ethylpropoxy, n-hexyloxy, 4-methylpentyloxy and 2-ethylbutoxy.
  • aryl in the present invention refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (ie, rings sharing adjacent pairs of carbon atoms) groups having a conjugated pi-electron system, preferably 6 to 14 10-membered rings such as phenyl and naphthyl, more preferably phenyl.
  • the aryl ring can be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, including benzo 3-8 membered cycloalkyl, benzo 3-8 membered heterocyclyl, wherein the heterocyclyl It is a heterocyclic group containing 1-3 nitrogen atoms, oxygen atoms and sulfur atoms; or a three-membered nitrogen-containing fused ring containing a benzene ring.
  • heteroaryl refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen.
  • Heteroaryl is preferably 5 to 10-membered, more preferably 5- or 6-membered, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl , pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably triazolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, pyrimidinyl or thiazolyl.
  • the heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is a
  • Heteroaryl groups can be optionally substituted or unsubstituted.
  • the substituents are preferably one or more independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano , cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate group.
  • 5-6 membered heteroaryl ring and “5-6 membered heteroaryl” are used interchangeably herein.
  • the term “5-6 membered heteroaryl” refers to a monocyclic group consisting of 5 to 6 ring atoms with a conjugated ⁇ -electron system, wherein 1, 2, 3 or 4 ring atoms are independently selected from O, S and N heteroatoms, the remainder being carbon atoms, where the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (ie, NO and S(O) p , p is 1 or 2).
  • a 5-6 membered heteroaryl group can be attached to the remainder of the molecule through a heteroatom or a carbon atom.
  • the 5-6 membered heteroaryl groups include 5- and 6-membered heteroaryl groups.
  • Examples of the 5-6 membered heteroaryl group include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrrolyl and 3-pyrrolyl, etc.) azolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5- oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1,
  • alkoxy refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above.
  • alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
  • Alkoxy can be optionally substituted or unsubstituted, when substituted, the substituents are preferably one or more independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkyl Amine, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkane A thio, carboxyl or carboxylate group.
  • haloalkyl refers to an alkyl group substituted with one or more halogens.
  • 3- to 8-membered heterocyclic group in the present invention means a non-aromatic cyclic group containing one or more heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom, and which may be fully saturated or partially unsaturated.
  • the ring may be a 3- to 8-membered monocyclic, bicyclic or spirocyclic ring.
  • oxetanyl Including, but not limited to, oxetanyl, azetidinyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, pyrazolidinyl, thiacyclohexyl, oxanyl, thiaoxanyl, indoline, isodihydro Indolyl, tetrahydroindolyl, quinuclidinyl, azepinyl, etc.
  • heterocyclyl ring can be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is a heterocyclyl, non-limiting examples of which include:
  • C 3-8 cycloalkyl in the present invention means a monovalent group obtained by removing any single hydrogen atom from a cyclic saturated aliphatic hydrocarbon having 3 to 8 carbons, ie, a ring of 3 to 8 carbons alkyl. Including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • the resulting group may be divalent, such as cyclopropane-1,1-diyl, cyclobutane-1,1-diyl, cyclopentane Alkane-1,1-diyl, cyclohexane-1,1-diyl, cycloheptane-1,1-diyl and cyclooctane-1,1-diyl.
  • the cycloalkane rings, carbocyclic rings, and cyclic hydrocarbons in the cycloalkyl group may be cross-linked rings.
  • fused ring refers to a 5- to 20-membered all-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings Can contain one or more double bonds, but none of the rings have a fully conjugated pi electron system.
  • the fused ring is preferably 6 to 14 membered, more preferably 7 to 10 membered.
  • fused rings can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicycloalkyl . It includes but is not limited to:
  • Carbon atoms in fused rings may be optionally replaced by heteroatoms of O, S, N, ie, "fused heterocycles" are also included.
  • fused heterocycle refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, wherein one or more rings may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system, wherein one or more ring atoms are selected from nitrogen, oxygen, or S(O) t (where t is an integer from 0 to 2) heteroatoms, the rest of the ring atoms are carbon.
  • the fused heterocycle is preferably 6 to 14 membered, more preferably 7 to 10 membered.
  • fused heterocycles can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 5-membered/3-membered, 5-membered/4-membered or 5-membered Member/5-membered bicyclic fused heterocyclic group.
  • Fused heterocycles include but are not limited to:
  • bridged ring in the present invention refers to a 5- to 20-membered all-carbon polycyclic group, wherein any two rings share two carbon atoms that are not directly connected, and the bridged ring may contain one or more double bonds, but None of the rings have a fully conjugated pi electron system.
  • the bridged ring is preferably 6 to 14 membered, more preferably 7 to 10 membered. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged ring groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.
  • Bridge rings include but are not limited to:
  • the carbon atoms in the bridged ring may be optionally replaced by heteroatoms of O, S, N, ie "bridged heterocycles" are also included.
  • bridged heterocycle in the present invention refers to a 5- to 14-membered polycyclic heterocycle group, any two rings share two atoms that are not directly connected, and the bridged heterocycle may contain one or more double bonds, but None of the rings has a fully conjugated pi-electron system, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2) and the remaining ring atoms are carbon.
  • the bridged heterocycle is preferably 6 to 14 membered, more preferably 7 to 10 membered.
  • Bridged heterocycles can be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic bridged heterocycles, more preferably bicyclic or tricyclic bridged heterocycles .
  • Bridged heterocycles include, but are not limited to:
  • spirocycle in the present invention refers to a 5- to 20-membered polycyclic group in which a single carbon atom (called a spiro atom) is shared between the single rings, and the spiro ring may contain one or more double bonds, but none
  • the ring has a fully conjugated pi electron system.
  • the spiro ring is preferably 6 to 14 membered, more preferably 7 to 10 membered.
  • spirocycloalkyl groups are classified into mono-spirocycloalkyl groups, double-spirocycloalkyl groups or poly-spirocycloalkyl groups, preferably mono-spirocycloalkyl groups and double-spirocycloalkyl groups. More preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospirocycloalkyl. It includes but is not limited to:
  • the carbon atoms in the spiro rings can be optionally replaced by heteroatoms of O, S, N, ie "spiroheterocycles" are also included.
  • spiroheterocycle in the present invention refers to a 5- to 20-membered polycyclic heterocyclic group, wherein one atom (called a spiro atom) is shared between the single rings, and one or more ring atoms are selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2) heteroatoms and the remaining ring atoms are carbon. Spiroheterocycles can contain one or more double bonds, but none of the rings have a fully conjugated pi electron system.
  • the spiroheterocycle is preferably 6 to 14 membered, more preferably 7 to 10 membered.
  • spiroheterocyclyls are classified into mono-spiroheterocyclyl, bis-spiroheterocyclyl or poly-spiroheterocyclyl, preferably mono-spiroheterocyclyl and bis-spiroheterocyclyl. More preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospiroheterocyclyl. It includes but is not limited to:
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments enumerated below, embodiments formed in combination with other chemical synthesis methods, and those well known to those skilled in the art equivalent replacement. Preferred embodiments include, but are not limited to, the embodiments of the present invention.
  • the compounds described in the present invention are named according to the chemical structural formula. If the name of the compound is inconsistent with the chemical structural formula when it represents the same compound, the chemical structural formula shall prevail.
  • the mass spectrum of the present invention is obtained by measuring with LC/MS instrument, and the ionization mode can be ESI or APCI.
  • GLP-1R-mediated agonist activity was determined by a cell-based functional assay using a homogeneous time-resolved fluorescence (ie, HTRF) cAMP detection kit that measures cAMP levels in cells.
  • the method is a competitive immunoassay. It enables direct pharmacological characterization of compounds acting on Gs-coupled receptors in adherent or suspension cells.
  • Cell-generated native cAMP or unlabeled cAMP standard curves compete with the D2-labeled cAMP red acceptor for binding to the monoclonal anti-cAMP cryptate europium donor, with a specific signal that is inversely proportional to the concentration of cAMP in the standard or experimental sample.
  • the human GLP-1R coding sequence (NCBI reference sequence NP_002053.3) was subcloned into pEGFP-N1 (tsingke), and a cell line stably expressing the receptor was isolated, and GLP-1R was confirmed by observing GFP expression under a fluorescence microscope expression density.
  • GFP-GLP-1R cells were cultured in DMEM growth medium, 10% heat-inactivated fetal bovine serum (GEMINI Cat#900-108), 1% Pen-3Trep (Sangom Biotech Cat#E607011-0100)] and incubated in Incubate in a humidified and 5% CO2 incubator at 37 °C.
  • DMEM growth medium 10% heat-inactivated fetal bovine serum (GEMINI Cat#900-108), 1% Pen-3Trep (Sangom Biotech Cat#E607011-0100)
  • Cells were harvested from T25 tissue culture flasks and centrifuged at 1000 rpm for 5 minutes at room temperature. The cell pellet was then resuspended in 1 ml of stimulation buffer. A 20 ⁇ L sample of cell suspension was counted on a counter STAR IC1000 to determine cell viability and cell count per milliliter. The remaining cell suspension was then adjusted with stimulation buffer to deliver 2000 viable cells per well using a multichannel pipette. Add 5 ⁇ L of cell suspension to each well of the assay plate already containing compound. The plate was sealed and incubated at 37 °C with 5% CO for 30 min.
  • d2-labeled cAMP and 5 ⁇ L of anti-cAMP cryptate were added to each well of the assay plate.
  • the plate was then incubated at room temperature, and after 60 minutes, the change in HTRF signal was read with a Tecan Spark plate reader with excitation at 340 nm/emission at 615 nm and 665 nm absorbance.
  • the raw data were converted to nM cAMP by interpolation from the cAMP standard curve and the percent effect was determined relative to the saturating concentration of the full agonist GLP-17-37 (400 nM) contained on each plate.
  • EC50 determinations were made from agonist dose-response curves analyzed with a curve fitting program using a 4-parameter logistic dose-response equation.
  • This assay demonstrates that the compounds of the present invention activate GLP-1R signaling through the cAMP pathway and thus act as GLP-1R agonists.
  • Experimental data are presented as geometric mean ( EC50s ) based on the number of repetitions listed.
  • Experimental material stable cell line HEK-hERG, strain: HEK 293, source: Academy of Military Medical Sciences;
  • Extracellular fluid mM: N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES) 10, NaCl 145, KCl 4, CaCl 2 2, MgCl 2 1, Glucose 10, with hydroxide Adjust pH to 7.3-7.4 with sodium; adjust osmotic pressure to 290-310mOsm; store at 4°C after filtration.
  • HEPES N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid
  • EGTA ethylene glycol-bis( ⁇ -aminoethyl ether)-N,N,N',N'-tetraacetic acid
  • HEPES 10 HEPES 10
  • Na 2 -ATP 4 adjust the pH to 7.2-7.3 with potassium hydroxide
  • adjust the osmotic pressure to 290-310mOsm
  • Preparation of vehicle control add a certain volume of DMSO to the extracellular solution to make it contain the same content of DMSO as the final test solution (if the test solution contains different DMSO contents, the maximum DMSO content shall prevail) to exclude Interference of DMSO on the cell's own currents.
  • Preparation of the test product The above-mentioned 10 mM stock solution is prepared in proportion to the DMSO stock solution of the required concentration (generally 1000/3 times the actual administration concentration), and finally the stock solution is diluted with extracellular fluid to the required concentration for the experiment. Dosing concentration.
  • Preparation of positive control solution Weigh an appropriate amount of positive control substance and place it in a suitable container, add a certain volume of DMSO, fully stir or shake to dissolve it, and prepare a 10 mM stock solution, and then prepare a stock solution of the required concentration in proportion. Finally, the stock solution was diluted with extracellular fluid to the dosing concentration required for the experiment.
  • the cells were washed with PBS (or DPBS), digested and separated with Tryple solution, and the cells were resuspended with medium and stored in a centrifuge tube, and the supernatant was discarded after centrifugation. , the cells were resuspended with extracellular fluid for use, and stored at 2-8°C. Before patch-clamp recordings, drop cells into the dish to ensure that the cells are at a certain density and that the cells are individually isolated.
  • PBS or DPBS
  • Test article/positive control Concentration ( ⁇ M) Compounds of the present invention 1. 10 Amitriptyline or Terfenadine 1
  • hERG currents were recorded using whole-cell patch-clamp technique.
  • the cell suspension was added to a small petri dish and placed on an inverted microscope stage. After the cells have adhered, perfuse with extracellular fluid.
  • the recommended flow rate is 1–2 mL/min.
  • the glass micro-electrode is drawn by a micro-electrode drawing apparatus in two steps, and the resistance value of the glass micro-electrode is 2-5M ⁇ after filling with the liquid in the electrode.
  • the drug was administered by continuous extracellular perfusion from low concentration to high concentration. Start from a low concentration, continue perfusion until the drug effect is stable, and then proceed to the next concentration.
  • the blocking effect of each test article and positive control on hERG tail current (N ⁇ 2) will be tested respectively; the actual concentration can be adjusted according to the actual solubility and effect, and it is not regarded as a deviation from the protocol.
  • the stable drug effect is defined as: the last 5 stimulation strip current values of each concentration administration period change less than 10% of the mean value (when the current is greater than or equal to 200pA) or less than 30% of the mean value (when the current is less than 200pA), it can be considered that is stable, if not, the concentration data will not be taken.
  • IR 100% ⁇ (peak tail current before administration-peak tail current after administration)/peak tail current before administration.
  • Detection method LC-MS/MS-11 (8050), internal standard: tolbutamide, MS conditions are testosterone and test compound positive ion ESI; tolbutamide negative ion ESI; mobile phase: mobile phase A is 0.1% FA and water, mobile phase B is 0.1% FA in ACN; column and specifications: ACQUITY UPLC HSS T3 1.8um 2.1*50mm.
  • the intermediate reaction materials used in the preparation process were prepared with reference to the preparation method described in WO2018109607A1.
  • NBS (279 mg, 1.57 mmol) was added to a mixture of compound 1-1 (200 mg, 1.43 mmol) and BPO (7 mg, 0.03 mmol) in CCl 4 (5 mL), and then the reaction solution was stirred at 80° C. for 8 hours , after which the reaction mixture was quenched with saturated Na2S2O3 solution ( 5 mL ) .
  • the solution was extracted with water (20 mL) and DCM (20 mL x 3), the combined organic phases were washed with brine (20 mL), dried ( Na2SO4 ) , filtered and concentrated. Flash chromatography ( SiO2 , 20% EtOAc-hexanes) gave 1-(5-(bromomethyl)thiophen-2-yl)ethan-1-one as compound 1-2 (260 mg, 83%).
  • 6-5 (168 mg, 0.380 mmol) was dissolved in a solvent with TsOH.H2O (216.8 mg, 1.140 mmol) in EA (10 mL). The mixture was stirred at 60 °C for 1 h under N2 atmosphere. The mixture was stirred at room temperature for 16 h under N2 atmosphere. Filter, wash the filter cake with EA (5 mL*3), and dry the filter cake to give 6-6 (130 mg).

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Abstract

提供了一系列噻吩类GLP-1受体激动剂化合物，其制备方及制药用途，所述的化合物（I）能用于制备治疗或预防GLP-1介导的疾病及相关疾病。

Description

噻吩类GLP-1受体激动剂及其用途 技术领域
本发明涉及医药技术领域，具体涉及GLP-1受体激动剂化合物及制备方法，以及所述化合物在用于制备治疗或预防GLP-1介导的疾病及相关疾病的药物中的用途。
背景技术
糖尿病是一种因胰岛素绝对或相对不足，或者靶细胞对胰岛素敏感性降低引起的以糖代谢紊乱为主的慢性综合性疾病，分为I型糖尿病和II型糖尿病。其中，II型糖尿病是成人发病型糖尿病，由于胰岛素抵抗和/或胰岛素分泌缺陷引起的以慢性血糖升高为主要表现的内分泌疾病。II型糖尿病患者占糖尿病患者90％以上。根据全球糖尿病地图显示，2017年全球约有4.25亿糖尿病患者，其中中国糖尿病患者位居世界第一，数量约为1.144亿。预计到2045年，全球将有6.29亿糖尿病患者。可见，糖尿病是全球都十分普遍的慢性病。
目前可用于治疗II型糖尿病的主要有以下几类药物：促胰岛素分泌剂，二甲双胍类，α-糖苷酶抑制剂，胰岛素增敏剂，钠-葡萄糖协同转运蛋白2抑制剂，二肽基肽酶-4(DPP-4)抑制剂，GLP-1受体激动剂，胰岛素及其类似药物等，其中胰岛素及GLP-1受体激动剂是最有效的糖尿病治疗药物之一，胰岛素制剂仍然是全球使用量最多的糖尿病用药，约有30-40％的2型糖尿病患者最终需要使用胰岛素，GLP-1制剂主要有艾塞那肽，利拉鲁肽，索马鲁肽等，适用于二甲双胍、磺酰脲类等联合应用不能充分控制血糖的2型糖尿病人。但是目前胰岛素制剂和GLP-1制剂基本上都是多肽类药物及注射制剂，即便是口服索玛鲁肽，在用药上仍有诸多限制，因此仍有必要进一步开发GLP-1受体的小分子激动剂药物。
GLP-1以葡萄糖依赖的方式刺激胰岛素分泌，并且以葡萄糖依赖的方式抑制胰高糖素分泌，因而没有低血糖风险。GLP-1能够增加β细胞产生胰岛素的量，提高β细胞对葡萄糖的反应性。GLP-1可以延缓胃排空，减少食物摄入，因而具有减轻体重的功效。此外，GLP-1还具有心脑血管获益的独特效果。GLP-1受体激动剂在临床应用中被定位于介于口服降糖药和胰岛素之间的过渡阶段使用，并且可与其它药物联用，成为过去五年增长最快，也是未来最具成长潜力的降糖药物。
和II型糖尿病相关的其他病症包括糖尿病肾病、糖尿病眼部并发症(糖尿病性视网膜病变、与糖尿病相关的葡萄膜炎、糖尿病性白内障)、糖尿病足、糖尿病心血管并发症、糖尿病性脑血管病、糖尿病神经病变、肥胖症、高血压。
GLP-1受体激动剂作为一款极具潜力的药物，目前市面多数是注射给药的形式。开发口服小分子GLP-1受体激动剂，可以改善患者依从性，是未来GLP-1受体激动剂的发展趋势。目前已知的GLP-1受体激动剂小分子研发进展如下：
文献WO2009111700A2公开了一系列氧杂二氮杂蒽类GLP-1受体激动剂化合物；WO2010114824A1公开了一系列取代的偶氮蒽衍生物的GLP-1受体激动剂化合物；WO2017078352A1公开了一系列环己烯衍生物的GLP-1受体激动剂化合物；KR1020180101671A公开了一系列杂芳基取代的吡啶[1,2-a]并咪唑类衍生物的GLP-1受体激动剂化合物；WO2018056453A1公开了一系列吡唑并吡啶衍生物的GLP-1受体激动剂化合物；以及WO2018109607A1公开了一系列与本申请相似的GLP-1受体激动剂化合物等。
发明内容
本发明提供了一系列如式I所示的化合物，
Figure PCTCN2022081466-appb-000001
及其药学上可接受的盐，其中
T 1和T 2分别独立地选自CH 2、NH、O、S；
W 1选自O、S、CH 2、NH；
W 2选自O、NH、CH 2、CR y；
Z 1、Z 2、Z 3、Z 4分别独立地选自CH、N或C；
X 1、X 2、X 3分别独立地选自CH、N或C，且X 1、X 2、X 3中至多有两个为N；
环B选自苯环或5～7元杂芳环；
环C选自苯环、4～8元杂环、5～10元螺环、5～10元桥环及5～7元杂芳环；
R 1独立地选自R 2、-羰基-R 2、-羰基-胺基-R 2，-磺酰基-R 2，-酰胺基-R 2，-氧磷基-R 2，-胺基-R 2，-O-R 2，其中R 1中的R 2、胺基、酰胺基、磺酰基、氧磷基可任选地由独立选自R x的取代基取代1～3次；
R 2独立地选自氢、氧代、卤素、-C 1～6烷基、-C 2～6烯基、-C 2～6炔基、-C 1～6烷氧基、-C 1～6环烷氧基、氰基、3～8元环烷基、3～8元杂环基、苯基、5～8元杂芳基，其中R 2中的卤素、烷基、烯基、炔基、胺基、烷氧基、环烷氧基、环烷基、杂环基、苯基、杂芳基可任选地由独立选自R x的取代基取代1～3次；
R 3独立地选自氢、氧代、卤素、-CN、-C 1～6烷基、-C 2～6烯基、-C 2～6炔基、-C 1～6烷氧基、胺基、酰胺基、磺酰基、磺酰胺基、-OH、-C 3～8环烷基、3～8元杂环基、6～10元芳基、5～8元杂芳基，其中R 3在化合价允许的条件下可任选地由独立选自R y的取代基取代1～3次；
R 4独立地选自氢、卤素、-C 1～3烷基、-C 1～3卤代烷基、-C 1～3烷氧基、氰基、羟基、胺基、酰胺基、磺酰基、磺酰胺基；
R 5独立地选自氢、卤素、羟基、-CN、-C 1～3烷基、-C 1～3烷氧基、-C 1～3环烷基，其中所述R 5中的烷基、烷氧基、环烷基在化合价允许的条件下可任选地由卤素、羟基、-NR z、-CN、-C 1～3烷基、-C 1～3烷氧基、-C 1～3环烷基取代1～3次；
R 6选自-R z、-O-R z、-S-R z、-C 1～3烷基、-C 1～3亚烷基-R z、-C 0～3亚烷基-胺基-R z、-C 0～3亚烷基-羰基-R z、-C 0～3亚烷基-酰胺基-R z、-C 0～3亚烷基-磺酰基-R z、-C 0～3亚烷基-磷酰基-R z、-C 0～3亚烷基-磺酰胺基-R z，其中所述R 6中的烷基、胺基、酰胺基、磺酰基、磺酰胺基、磷酰基在化合价允许的条件下可任选地由卤素取代1～3次或由R w取代1次；
R 7选自-COOH、-C(R y) n0-COOH、-N(R z) n0-COOH、-SO 2-COOH和-SO 2-NH-COOH，所述-C(R y) n0-中的R y可以以主链和/或支链的形式连接在C上，所述-N(R z) n0-中的R z可以以主链和/或支链的形式连接在N上，其中n 0是选自0，1或2的整数；当n 0为2时，两个R y或R z可进一步环化为3～8元碳环或杂环；
n是选自0、1、2或3的整数；
m是选自0、1或2的整数；
o是选自0、1、2、3或4的整数；
p是选自0、1、2、3或4的整数；
当n大于等于2时，任意两个R 1可进一步环化为3～8元碳环、芳环、杂环或芳杂环，所形成的碳环和杂环在化合价允许的条件下可任选由C 1～3烷基、C 1～3卤代烷基、卤素、氰基、C 1～3烷氧基取代1～3次；
当m为2时，其中两个R 3可进一步环化为3～8元碳环或杂环；
当m为1或2时，R 1和R 3可进一步环化为3～8元的碳环或杂环；
当p大于等于2时，任意两个R 5可进一步与环C环化成6～10元螺环或桥环，所形成的螺环和桥环在化合价允许的条件下可任选由C 1～3烷基、C 1～3卤代烷基、卤素、氰基、C 1～3烷氧基取代1～3次；
当o不为0且p不为0时，任意R 4和R 5可进一步环化成5～8元环，所形成的环在化合价允许的条件下可任选地有C 1～3烷基、C 1～3卤代烷基、卤素、氰基、氧代、C 1～3烷氧基取代1～3次；
R w独立地选自-CN、-CH 2CN、-C 1～3烷基、-OH、-C 1～3烷氧基、酰胺基、磺酰基、磺酰胺基、-NH 2、-NH-C 1～3烷基，其中所述R w中的烷基在化合价允许的条件下可任选地由C 1～3烷基、C 1～3卤代烷基、卤素、氰基、氧代、C 1～3烷氧基取代1～3次；
R x独立地选自氢、卤素、氧代、C 1～6烷氧基、氰基、羟基、羧基、胺基、酰胺基、磺酰基、磺酰胺基、-C 1～6烷基、-C 2～6烯基、-C 2～6炔基、-C 3～6环烷基、3～6元杂环基、6～8元芳基、5～8元杂芳基，其中所述R x中烷基、烷氧基、环烷基、杂环基芳基和杂芳基在化合价允许的条件下可任选地由C 1～3烷基、C 1～3卤代烷基、卤素、氰基、氧代、C 1～3烷氧基取代1～3次或任选由羟基取代1次；
R y独立地选自氢、卤素、氧代、-C 1～3烷氧基、氰基、羟基、胺基、羧基、酰胺基、磺酰基、磺酰胺基、-C 1～6烷基、-C 2～6烯基、-C 2～6炔基、-C 3～6环烷基、3～6元杂环基，5～6元杂芳基，其中所述R y中烷基、烯基、炔基、胺基、酰胺基、烷氧基、环烷基、杂环基、杂芳基在化合价允许的条件下可任选地由C 1～3烷基、C 1～3卤代烷基、卤素、氰基、氧代、C 1～3烷氧基取代1～3次；
R z独立地选自氢、C 1～3烷基、C 1～3烷氧基、C 3～6环烷基、3～6元杂环基、芳基、5～6元杂芳基，其中R z在化合价允许的条件下可任选地由C 1～3烷基、C 1～3卤代烷基、卤素、氰基、氧代、C 1～3烷氧基、3～6元杂环基取代1～3次。
作为一种具体的实施方式，所述的环B可进一步的选自：
Figure PCTCN2022081466-appb-000002
Figure PCTCN2022081466-appb-000003
其中环B优选为
Figure PCTCN2022081466-appb-000004
作为一种具体的实施方式，所述的环C可进一步的选自：
Figure PCTCN2022081466-appb-000005
Figure PCTCN2022081466-appb-000006
其中环C优选为
Figure PCTCN2022081466-appb-000007
Figure PCTCN2022081466-appb-000008
进一步的，本发明提供一系列如式I-2所示的化合物，
Figure PCTCN2022081466-appb-000009
及其药学上可接受的盐，其中
------表示存在或不存在键；
Z 1、Z 4分别独立地选自CH、N；
X 1、X 2、X 3分别独立地选自CH、N或C，且X 1、X 2、X 3中至多有两个为N；
Y 1选自CH或N；
Y 2选自CH、N或C；
Y 3选自CH或N；
R 1独立地选自R 2、-羰基-R 2、-羰基-胺基-R 2，-磺酰基-R 2，-酰胺基-R 2，-氧磷基-R 2，-胺基-R 2，-O-R 2，其中R 1中的R 2、胺基、酰胺基、磺酰基、氧磷基可任选地由独立选自R x的取代基取代1～3次；
R 2独立地选自氢、氧代、卤素、-C 1～6烷基、-C 2～6烯基、-C 2～6炔基、-C 1～6烷氧基、-C 1～6环烷氧基、氰基、3～8元环烷基、3～8元杂环基、苯基、5～8元杂芳基，其中R 2中的卤素、烷基、烯基、炔基、胺基、烷氧基、环烷氧基、环烷基、杂环基、苯基、杂芳基可任选地由独立选自R x的取代基取代1～3次；
R 3独立地选自氢、氧代、卤素、-CN、-C 1～6烷基、-C 2～6烯基、-C 2～6炔基、-C 1～6烷氧基、胺基、酰胺基、磺酰基、磺酰胺基、-OH、-C 3～8环烷基、3～8元杂环基、6～10元芳基、5～8元杂芳基，其中R 3在化合价允许的条件下可任选地由独立选自R y的取代基取代1～3次；
R 4独立地选自氢、卤素、-C 1～3烷基、-C 1～3卤代烷基、-C 1～3烷氧基、氰基、羟基、胺基、酰胺基、磺酰基、磺酰胺基；
R 5独立地选自氢、卤素、羟基、-CN、-C 1～3烷基、-C 1～3烷氧基、-C 1～3环烷基，其中所述R 5中的烷基、烷氧基、环烷基在化合价允许的条件下可任选地由卤素、羟基、-NR z、-CN、-C 1～3烷基、-C 1～3烷氧基、-C 1～3环烷基取代1～3次；
R 6选自-R z、-O-R z、-S-R z、-C 1～3烷基、-C 1～3亚烷基-R z、-C 0～3亚烷基-胺基-R z、-C 0～3亚烷基-羰基-R z、-C 0～3亚烷基-酰胺基-R z、-C 0～3亚烷基-磺酰基-R z、-C 0～3亚烷基-磷酰基-R z、-C 0～3亚烷基-磺酰胺基-R z，其中所述R 6中的烷基、胺基、酰胺基、磺酰基、磺酰胺基、磷酰基在化合价允许的条件下可任选地由卤素取代1～3次或由R w取代1次；
R 7选自-COOH、-C(R y) n0-COOH、-N(R z) n0-COOH、-SO 2-COOH和-SO 2-NH-COOH，所述-C(R y) n0-中的R y可以以主链和/或支链的形式连接在C上，所述-N(R z) n0-中的R z可以以主链和/或支链的形式连接在N上，其中n 0是选自0，1或2的整数；当n 0为2时，两个R y或R z可进一步环化为3～8元碳环或杂环；
n是选自0、1、2或3的整数；
o是选自0、1、2、3或4的整数；
p是选自0、1、2、3或4的整数；
当n大于等于2时，任意两个R 1可进一步环化为3～8元碳环、芳环、杂环或芳杂环，所形成的碳环和杂环在化合价允许的条件下可任选由C 1～3烷基、C 1～3卤代烷基、卤素、氰基、C 1～3烷氧基取代1～3次；
当p大于等于2时，任意两个R 5可进一步与环C环化成6～10元螺环或桥环，所形成的螺环和桥环在化合价允许的条件下可任选由C 1～3烷基、C 1～3卤代烷基、卤素、氰基、C 1～3烷氧基取代1～3次；
当o不为0且p不为0时，任意R 4和R 5可进一步环化成5～8元环，所形成的环在化合价允许的条件下可任选地有C 1～3烷基、C 1～3卤代烷基、卤素、氰基、氧代、C 1～3烷氧基取代1～3次；
R w独立地选自-CN、-CH 2CN、-C 1～3烷基、-OH、-C 1～3烷氧基、酰胺基、磺酰基、磺酰胺基、-NH 2、-NH-C 1～3烷基，其中所述R w中的烷基在化合价允许的条件下可任选地由C 1～3烷基、C 1～3卤代烷基、卤素、氰基、C 1～3烷氧基取代1～3次；
R x独立地选自氢、卤素、氧代、C 1～6烷氧基、氰基、羟基、羧基、胺基、酰胺基、磺酰基、磺酰胺基、-C 1～6烷基、-C 2～6烯基、-C 2～6炔基、-C 3～6环烷基、3～6元杂环基、6～8元芳基、5～8元杂芳基，其中所述R x中烷基、烷氧基、环烷基、杂环基芳基和杂芳基在化合价允许的条件下可任选地由卤素取代1～3次或任选由羟基取代0～1次；
R y独立地选自氢、卤素、氧代、-C 1～3烷氧基、氰基、羟基、胺基、羧基、酰胺基、磺酰基、磺酰胺基、-C 1～6烷基、-C 2～6烯基、-C 2～6炔基、-C 3～6环烷基、3～6元杂环基，其中所述R y中烷基、烷氧基、环烷基、杂环基在化合价允许的条件下可任选地用卤素取代1～3次；
R z独立地选自氢、C 1～3烷基、C 1～3烷氧基、C 3～6环烷基、4～6元杂环、5～6元芳基或5～6元杂芳基，其中R z在化合价允许的条件下可任选地用卤素、氰基、C 1～3烷基、C 1～3烷氧基、C 3～6环烷基、3～6元杂环基取代1～3次。
作为一种具体的实施方式，当o不为0且p不为0时，任意相邻的R 4和R 5可进一步环化为5～8元环；所述的5～8元环包括C 5～6碳环、5～8元杂环、苯环、5～8元杂芳环，形成的环在化合物允许的条件下可任选地由烷基、卤代烷基、卤素、氰基、烷氧基取代1～3次。
作为一种具体的实施方式，当o不为0且p不为0时，任意相邻的R 4和R 5可进一步环化成5～8元环，所述的5～8元环可选自
Figure PCTCN2022081466-appb-000010
Figure PCTCN2022081466-appb-000011
Figure PCTCN2022081466-appb-000012
所成的5～8元环在化合价允许的条件下可任选地由C 1-3烷基、C 1-3卤代烷基、卤素、氰基、氧代、C 1-3烷氧基取代1～3次。
作为一种具体的实施方式，当o不为0且p不为0时，任意相邻的R 4和R 5可进一步环化成5～8 元环，所述的5～8元环优选为：
Figure PCTCN2022081466-appb-000013
Figure PCTCN2022081466-appb-000014
Figure PCTCN2022081466-appb-000015
所成的5～8元环在化合价允许的条件下可任选地由C 1-3烷基、C 1-3卤代烷基、卤素、氰基、氧代、C 1-3烷氧基取代1～3次。
作为一种具体的实施方式，当o不为0且p不为0时，任意相邻的R 4和R 5可进一步环化成5～8元环，所述的5～8元环可选自：
Figure PCTCN2022081466-appb-000016
Figure PCTCN2022081466-appb-000017
Figure PCTCN2022081466-appb-000018
所成的5～8元环在化合价允许的条件下可任选地由C 1-3烷基、C 1-3卤代烷基、卤素、氰基、氧代、C 1-3烷氧基取代1～3次。
作为一种具体的实施方式，结构单元
Figure PCTCN2022081466-appb-000019
可进一步选自：：
Figure PCTCN2022081466-appb-000020
Figure PCTCN2022081466-appb-000021
作为一种具体的实施方式，本发明所述的式I化合物可以有以下子通式，
Figure PCTCN2022081466-appb-000022
作为一种具体的实施方式，所述的n选自1、2或3。
作为一种具体的实施方式，所述的p选自0、1或2。
作为一种具体的实施方式，所述的R 1可进一步独立地选自-F、-Cl、-CN、-OCH 3、-OCH 2CH 3、-O-环丙基、-CH 3、-CH 2CH 3、-CH 2CH 2CH 3、-(CH) 2CH 3、-COCH 3、-CONH 2、-CF 3、-CHF 2、-CH 2F、-CH 2CH 2F、-CO-环丙基、5～6元杂环基、5～6元杂芳基。
作为一种具体的实施方式，所述的R 3可进一步选自-F、-Cl、-CH 3、-OCH 3、-NH 2、-OH、-CH 2CH 3、-CH 2OH、-NHCH 3、-COCH 3、-SO 2CH 3、-OCH 2CH 3、-CF 3、-CHF 2、-CH 2F、异丙基、环丙基、氟代环丙基。
作为一种具体的实施方式，所述的R y可进一步选自-F、-Cl、甲基、乙基、三氟甲基、二氟甲基、氟甲基、氟乙基、甲氧基、氨基、羟基、丙基、异丙基、环丙基、环丁基。
作为一种具体的实施方式，所述R 7的-C(R y) n0-COOH中的R y可以以主链和/或支链的形式连接在C上；当R y以主链形式连接在R 7的C上时，R y以对应的亚基形式存在；当R y以支链形式连接在R 7的C上时，R y以对应的饱和基形式存在。
作为一种具体的实施方式，所述R 7的-N(R z) n0-COOH中的R z可以以主链和/或支链的形式连接在N上；当R z以主链形式连接在R 7的C上时，R z以对应的亚基形式存在；当R y以支链形式连接在R 7的N上时，R z以对应的饱和基形式存在。
作为一种具体的实施方式，所述的R 7的-C(R y) n-COOH中的R y为甲基时，所述的以主链形式连接在C上是指以
Figure PCTCN2022081466-appb-000023
的结构相连(即此时R 7为-CH 2-)，所述的以支链形式连接在C上是指以
Figure PCTCN2022081466-appb-000024
的结构相连(即此时R 7为-CH 3)。
作为一种具体的实施方式，所述的R 6选自-R z、-O-R z、-S-R z、-C 1～3亚烷基-R z、-C 0～3亚烷基-胺基-R z、-C 0～3亚烷基-羰基-R z，其中所述R 6中的烷基、胺基、酰胺基、磺酰基、磺酰胺基、磷酰基在化合价允许的条件下可任选地由卤素取代1～3次或由R w取代1次。
作为一种具体的实施方式，所述的R z可进一步选自：甲基，乙基，异丙基，环丙基，环丁基，甲氧基，乙氧基，
Figure PCTCN2022081466-appb-000025
Figure PCTCN2022081466-appb-000026
R z在化合价允许的条件下可任选地用卤素、氰基、C 1～3烷基、C 1～3烷氧基、C 3～6环烷基、3～6元杂环基取代1～3次。
作为一种具体的实施方式，所述的R 1可进一步独立地选自-F、-Cl、-CN、-OCH 3、-OCH 2CH 3、-CH 3、-CH 2CH 3、-COCH 3、-CONH 2、-CF 3、-CHF 2、-CH 2F、-CH 2CH 2F、-CO-环丙基、5～6元杂环基、5～6元杂芳基。
作为一种具体的实施方式，所述的R 2可进一步独立地选自-H、-CH 3、-CHF 2、-CH 2F、-CF 3、-CH 2CH 3、-CH 2CH 2F、-NH 2、环丙基、5～6元杂环基、5～6元杂芳基。
作为一种具体的实施方式，所述的R 3可进一步选自-F、-Cl、-CH 3、-OCH 3、-NH 2、-OH、-CH 2CH 3、-CH 2OH、-NHCH 3、-COCH 3、-SO 2CH 3、-OCH 2CH 3、-CF 3、-CHF 2、-CH 2F、异丙基、环丙基、氟代环丙基。
作为一种具体的实施方式，所述的R 4可进一步选自-CN、-CH 3、-OH、-CH 2OH、-CH 2OCH 3、-OCH 3、-NH 2、-NHCH 3、-COCH 3、-OCH 2CH 3。
作为一种具体的实施方式，所述的R 5选自-F、-Cl、-CN、-CH 3、-CH 2CH 3、-CF 3、-CHF 2、-CH 2F、-CH 2OH、-OH、-CH 2OCH 3、-OCH 3、-CH 2CH 2OH、-CH 2CH 2OCH 3、异丙基或环丙基。
作为一种具体的实施方式，所述的R 7选自-COOH、-CH 2COOH、-CH 2CH 2COOH、-CH(CH 3)COOH，其中所述R 7在化合价允许的条件下可任选地由卤素取代1～3次。
作为一种具体的实施方式，本发明提供的一系列化合物，其独立地选自下列化合物之一或其任何组合：
Figure PCTCN2022081466-appb-000027
Figure PCTCN2022081466-appb-000028
Figure PCTCN2022081466-appb-000029
及其药学上可接受的盐。
作为一种具体的实施方式，本发明提供的一系列化合物，其独立地选自下列化合物之一或其任何组合：
Figure PCTCN2022081466-appb-000030
Figure PCTCN2022081466-appb-000031
及其药学上可接受的盐。
本发明提供的化合物及其药学上可接受的盐在治疗中可以单独使用或与至少一种其他治疗剂结 合使用。
本发明提供了一种药物组合物，其含有式I所示的化合物及其药学上可接受的盐，以及一种或两种以上其他治疗活性成分。
本发明还提供了一种药物制剂，其含有式I所示的化合物及其药学上可接受的盐，及一种或两种以上药用载体；所述的药物制剂为临床上可接受的任一种制剂剂型。
本发明提供的化合物及其药学上可接受的盐可以组成固体剂型，如胶囊、片剂、丸剂、锭剂、糖衣剂、颗粒剂、粉末剂、软膏剂、乳膏剂、滴剂等；本发明提供的化合物及其药学上可接受的盐可以是液体剂型，如酏剂、糖浆剂、乳剂、分散剂、悬浮剂、溶液剂、喷雾剂等。
本发明的药物组合物或药物制剂中可用的药用载体和/或药用稀释剂可以使药物制剂领域中任何常规的载体和/或稀释剂。
本发明所述的药学上可接受的盐包括酸价成盐及碱盐。
本发明所述的药学上可接受的盐可呈非溶剂化及溶剂化形式存在。
本发明还提供了如式I所示的化合物及其药学上可接受的盐，在制备用于治疗和/或代谢相关疾病的药物中的用途了所述的代谢相关疾病包括GLP-1介导的疾病及相关疾病，包括但不限于：糖尿病、高血糖症、胰岛素抗性、葡萄糖耐受不良、糖尿病肾病、糖尿病神经疾病、糖尿病视网膜病变、脂肪细胞功能障碍、肥胖症、血脂异常症、高胰岛素血症、等；其中，所述的糖尿病包含但不限于，T1D和/或T2DM、特发性T1D、早发性T2D、潜伏性自身免疫性糖尿病、青少年非典型性糖尿病、妊娠糖尿病等。
本发明还提供了一种疾病的治疗方法，该方法包括向有需要的患者给药治疗有效量的如式I所示的化合物及其药学上可接受的盐，其中，所述的疾病为GLP-1介导的疾病及相关疾病；所述的疾病包括但不限于：糖尿病、高血糖症、胰岛素抗性、葡萄糖耐受不良、糖尿病肾病、糖尿病神经疾病、糖尿病视网膜病变、脂肪细胞功能障碍、肥胖症、血脂异常症、高胰岛素血症、等；其中，所述的糖尿病包含但不限于，T1D和/或T2DM、特发性T1D、早发性T2D、潜伏性自身免疫性糖尿病、青少年非典型性糖尿病、妊娠糖尿病等。
本发明提供的如式I所示的化合物及其药学上可接受的盐，具有优秀的GLP-1受体激动活性，能够治疗和/或预防GLP-1介导的疾病及相关疾病。
本发明提供的如式I所示的化合物及其药学上可接受的盐，具有优秀的GLP-1受体激动活性，能够治疗和/或预防GLP-1介导的疾病及相关疾病。
本发明还提供上述的化合物或其药学上可接受的盐在制备GLP-1受体激动剂相关药物中的应用。
在本发明的一些实施方案中，所述GLP-1受体激动剂相关药物是用于治疗II型糖尿病、I型糖尿病和肥胖。
本发明所表述的化合物，是依据化学结构式命名的，如果表示同一化合物时化合物的命名与化学结构式不符，则以化学结构式为准。
本发明中，除有另外说明，则本文中使用的科学和技术名词具有本领域技术人员通常理解的含义，然而为了更好地理解本发明，下面提供了部分术语的定义。当本发明所提供的术语的定义和解释与本领域技术人员通常理解的含义不同时，以本发明所提供的术语的定义和解释为准。
本发明提供的化合物及其药学上可接受的盐可以是以手性形态存在的，即S构型或R构型。本发明提供的化合物及其药学上可接受的盐可以是以非手性形态存在的。本发明所表述的化合物，当以其中一种构型例举结构时，也表示公开了其另一种构型或非手性形式的结构。
本发明所述的化合物包括化合物的立体异构体。本发明所述的立体异构体是指当如式I所示的化合物存在不对称碳原子时，会产生对映异构体；当化合物存在碳碳双键或环状结构时，会产生顺反异构体；当化合物存在酮或肟时，会产生互变异构体。作为一种具体的实施方案，本发明所述的立体异构体包括但不限于：对映异构体、非对映异构体、消旋异构体、顺反异构体、互变异构体、几何异构体、差向异构体及其混合物。
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括 顺式和反式异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。
除非另有说明，术语“对映异构体”或者“旋光异构体”是指互为镜像关系的立体异构体。
除非另有说明，术语“顺反异构体”或者“几何异构体”系由因双键或者成环碳原子单键不能自由旋转而引起。
除非另有说明，术语“非对映异构体”是指分子具有两个或多个手性中心，并且分子间为非镜像的关系的立体异构体。
除非另有说明，“(+)”表示右旋，“(-)”表示左旋，“(±)”表示外消旋。
除非另有说明，用楔形实线键
Figure PCTCN2022081466-appb-000032
和楔形虚线键
Figure PCTCN2022081466-appb-000033
表示一个立体中心的绝对构型，用直形实线键
Figure PCTCN2022081466-appb-000034
和直形虚线键
Figure PCTCN2022081466-appb-000035
表示立体中心为绝对构型，但是不确定具体为楔形实线键
Figure PCTCN2022081466-appb-000036
还是楔形虚线键
Figure PCTCN2022081466-appb-000037
用波浪线
Figure PCTCN2022081466-appb-000038
表示楔形实线键
Figure PCTCN2022081466-appb-000039
或楔形虚线键
Figure PCTCN2022081466-appb-000040
或用波浪线
Figure PCTCN2022081466-appb-000041
表示直形实线键
Figure PCTCN2022081466-appb-000042
或直形虚线键
Figure PCTCN2022081466-appb-000043
可以通过手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如胺基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成胺基甲酸盐)。
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚( 3H)，碘-125( 125I)或C-14( 14C)。又例如，可用重氢取代氢形成氘代药物，氘与碳构成的键比普通氢与碳构成的键更坚固，相比于未氘化药物，氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。
本发明的术语“药学上可接受的”是指针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
本发明的术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机胺或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸、碳酸氢根、磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等；以及有机酸盐，所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸；还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。
本发明的术语“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该 描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。
本发明的术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，可以包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧(即＝O)时，意味着两个氢原子被取代。氧取代不会发生在芳香基上。术语“任选被取代的”是指可以被取代，也可以不被取代。除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。
本发明的术语“任选地被取代”意指“被取代”和“未被取代”两种情形。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
当一个连接基团的数量为0时，比如-(CRR) 0-，表示该连接基团为单键。
当一个取代基数量为0时，表示该取代基是不存在的，比如-A-(R) 0表示该结构实际上是-A。
当一个取代基为空缺时，表示该取代基是不存在的，比如A-X中X为空缺时表示该结构实际上是A。
当其中一个变量选自单键时，表示其连接的两个基团直接相连，比如A-L-Z中L代表单键时表示该结构实际上是A-Z。
当一个取代基的键可以交叉连接到一个环上的两个或两个以上原子时，这种取代基可以与这个环上的任意原子相键合，例如，结构单元
Figure PCTCN2022081466-appb-000044
表示其取代基R可在环己基或者环己二烯上的任意一个位置发生取代。当所列举的取代基中没有指明其通过哪一个原子连接到被取代的基团上时，这种取代基可以通过其任何原子相键合，例如，吡啶基作为取代基可以通过吡啶环上任意一个碳原子连接到被取代的基团上。
当所列举的连接基团没有指明其连接方向，其连接方向是任意的，例如，
Figure PCTCN2022081466-appb-000045
中连接基团L为-M-W-，此时-M-W-既可以按与从左往右的读取顺序相同的方向连接环A和环B构成
Figure PCTCN2022081466-appb-000046
也可以按照与从左往右的读取顺序相反的方向连接环A和环B构成
Figure PCTCN2022081466-appb-000047
所述连接基团、取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
除非另有规定，当某一基团具有一个或多个可连接位点时，该基团的任意一个或多个位点可以通过化学键与其他基团相连。当该化学键的连接方式是不定位的，且可连接位点存在H原子时，则连接化学键时，该位点的H原子的个数会随所连接化学键的个数而对应减少变成相应价数的基团。所述位点与其他基团连接的化学键可以用直形实线键
Figure PCTCN2022081466-appb-000048
直形虚线键
Figure PCTCN2022081466-appb-000049
或波浪线
Figure PCTCN2022081466-appb-000050
表示。例如-OCH 3中的直形实线键表示通过该基团中的氧原子与其他基团相连；
Figure PCTCN2022081466-appb-000051
中的直形虚线键表示通过该基团中的氮原子的两端与其他基团相连；
Figure PCTCN2022081466-appb-000052
中的波浪线表示通过该苯基基团中的1和2位碳原子与其他基团相连；
Figure PCTCN2022081466-appb-000053
表示该哌啶基上的任意可连接位点可以通过1个化学键与 其他基团相连，至少包括
Figure PCTCN2022081466-appb-000054
这4种连接方式，即使-N-上画出了H原子，但是
Figure PCTCN2022081466-appb-000055
仍包括
Figure PCTCN2022081466-appb-000056
这种连接方式的基团，只是在连接1个化学键时，该位点的的H会对应减少1个变成相应的一价哌啶基。
除非另有规定，环上原子的数目通常被定义为环的元数，例如，“5-7元环”是指环绕排列5-7个原子的“环”。
本发明中的术语“卤素原子”意指氟原子、氯原子、溴原子、碘原子等。优选作为本发明的芳基的取代基的卤素原子是氟原子和氯原子。优选作为本发明的烷基的取代基的卤素原子是氟原子和氯原子。具有卤素原子作为取代基的C 1-6烷基包括但不限于氟甲基、二氟甲基、三氟甲基、氯甲基、五氟乙基、2-氟乙基、2,2,2-三氟乙基、2-氯乙基、七氟丙基、3,3,3-三氟丙基、2,3-二氯丙基、1-氟-3-溴丙基、4-溴丁基、3,3,3,4,4-五氟丁基、4,4-二氯丁基、5-碘戊基、5,5-二氟戊基、6-氯己基和6,6,6-三氟己基。
本发明中的术语“C 1～6烷基”是具有1至6个碳的直链或支链烷基，包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、1-甲基丙基、正戊基、异戊基、2-甲基丁基、1,1-二甲基丙基、1-乙基丙基、正己基、4-甲基戊基和2-乙基丁基。
本发明中的术语“C 1～6烷氧基”意指基团C 1-6烷基-O-，包括但不限于甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基、叔丁氧基、1-甲基丙氧基、正戊基氧基、异戊基氧基、2-甲基丁氧基、1,1-二甲基丙氧基、1-乙基丙氧基、正己基氧基、4-甲基戊基氧基和2-乙基丁氧基。
本发明中的术语“芳基”是指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，优选为6至10元环，例如苯基和萘基，更优选苯基。所述芳基环可以稠合于杂芳基、杂环基或环烷基环上，包括苯并3-8元环烷基、苯并3-8元杂环基，其中所述杂环基为含1-3个氮原子、氧原子、硫原子的杂环基；或者还包含含苯环的三元含氮稠环。
本发明的术语“杂芳基”是指包含1至4个杂原子、5至14个环原子的杂芳族体系，其中杂原子选自氧、硫和氮。杂芳基优选为5至10元，更优选为5元或6元，例如咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、三唑基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基等，优选为三唑基、噻吩基、咪唑基、吡唑基、噁唑基、嘧啶基或噻唑基。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，包括但不限于：
Figure PCTCN2022081466-appb-000057
杂芳基可以是任选取代的或非取代的。当被取代时，取代基优选为一个或多个独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基胺基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基的基团。
除非另有规定，本发明的术语“5-6元杂芳环”和“5-6元杂芳基”可以互换使用。术语“5-6元杂芳基”表示由5至6个环原子组成的具有共轭π电子体系的单环基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子，其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O) p，p是1或2)。5-6元杂芳基可通过杂原子或碳原子连接到分子的其余部分。所述5-6元杂芳基包括5元和6元杂芳基。所述5-6元杂芳基的实例包括但不限于吡咯基(包括N-吡咯基、 2-吡咯基和3-吡咯基等)、吡唑基(包括2-吡唑基和3-吡唑基等)、咪唑基(包括N-咪唑基、2-咪唑基、4-咪唑基和5-咪唑基等)、噁唑基(包括2-噁唑基、4-噁唑基和5-噁唑基等)、三唑基(1H-1,2,3-三唑基、2H-1,2,3-三唑基、1H-1,2,4-三唑基和4H-1,2,4-三唑基等)、四唑基、异噁唑基(3-异噁唑基、4-异噁唑基和5-异噁唑基等)、噻唑基(包括2-噻唑基、4-噻唑基和5-噻唑基等)、呋喃基(包括2-呋喃基和3-呋喃基等)、噻吩基(包括2-噻吩基和3-噻吩基等)、吡啶基(包括2-吡啶基、3-吡啶基和4-吡啶基等)、吡嗪基或嘧啶基(包括2-嘧啶基和4-嘧啶基等)。
本发明的术语“烷氧基”是指-O-(烷基)和-O-(非取代的环烷基)，其中烷基的定义如上所述。烷氧基的非限制性实例包括：甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基。烷氧基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基胺基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基的基团。
本发明的术语“卤代烷基”是指被一个或多个卤素取代的烷基。
本发明中的术语“3～8元杂环基”意指包含一个或多个选自氮原子、氧原子和硫原子的杂原子的非芳族环状基团，并且其可以是完全饱和的或部分不饱和的。环可以是3至8元的单环、二环或螺环。包括但不限于，氧杂环丁烷基、氮杂环丁烷基、哌嗪基、哌啶基、吗啉基、硫代吗啉基、吡咯烷基、四氢吡喃基、四氢呋喃基、噁唑烷基、噻唑烷基、咪唑烷基、吡唑烷基、硫杂环己烷基、氧杂环己烷基、硫杂氧杂环己烷基、二氢吲哚基、异二氢吲哚基、四氢二氢吲哚基、奎宁环基、氮杂卓基等。
所述杂环基环可以稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接在一起的环为杂环基，其非限制性实例包括：
Figure PCTCN2022081466-appb-000058
本发明的术语“C 3～8环烷基”意指从具有3至8个碳的环状饱和脂族烃除去任何单个氢原子得到的一价基团，即，3至8个碳的环烷基。包括但不限于，环丙基、环丁基、环戊基、环己基、环庚基和环辛基。当两个基团一起形成C 3～8环烷环时，得到的基团可以是二价的，例如环丙烷-1,1-二基、环丁烷-1,1-二基、环戊烷-1,1-二基、环己烷-1,1-二基、环庚烷-1,1-二基和环辛烷-1,1-二基。此外，环烷基中的环烷环、碳环、环烃可以是交叉连接的环。
本发明的术语“稠环”是指5至20元的全碳多环基团，其中该体系中的每个环与体系中的其他环共享毗邻的一对碳原子，其中一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。稠环优选为6至14元，更优选为7至10元的。根据组成环的数目，稠环可以分为双环、三环、四环或多环稠环烷基，优选为双环或三环，更优选为5元/5元或5元/6元双环烷基。其包括但不限于：
Figure PCTCN2022081466-appb-000059
稠环中的碳原子可任选地被O、S、N的杂原子替代，即也包括“稠杂环”。
本发明的术语“稠杂环”是指5至20元的多环杂环基团，其中该体系中的每个环与体系中的其他环共享毗邻的一对原子，其中一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，其中一个或多个环原子为选自氮、氧或S(O) t(其中t是整数0至2)的杂原子，其余环原子为碳。稠杂环优选为6至14元，更优选为7至10元的。根据组成环的数目，稠杂环可以分为双环、三环、四环或多环稠杂环基，优选为双环或三环，更优选为5元/3元、5元/4元或5元/5元双环稠杂环基。稠杂环包括但不限于：
Figure PCTCN2022081466-appb-000060
Figure PCTCN2022081466-appb-000061
本发明的术语“桥环”指5至20元的全碳多环基团，其中任意两个环共用两个不直接连接的碳原子，所述桥环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。桥环优选为6至14元，更优选为7至10元的。根据组成环的数目可以分为双环、三环、四环或多环桥环基，优选为双环、三环或四环，更优选为双环或三环。桥环包括但不限于：
Figure PCTCN2022081466-appb-000062
桥环中的碳原子可任选地被O、S、N的杂原子替代，即也包括“桥杂环”。
本发明的术语“桥杂环”指5至14元的多环杂环基团，任意两个环共用两个不直接连接的原子，所述桥杂环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，其余环原子为碳。桥杂环优选为6至14元，更优选为7至10元的。根据组成环的数目，桥杂环可以分为双环、三环、四环或多环桥杂环基，优选为双环、三环或四环桥杂环，更优选为双环或三环桥杂环。桥杂环包括但不限于：
Figure PCTCN2022081466-appb-000063
本发明的术语“螺环”指5至20元的多环基团，其中单环之间共用一个碳原子(称螺原子)，所述螺环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。螺环优选为6至14元，更优选为7至10元的。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基或多螺环烷基，优选为单螺环烷基和双螺环烷基。更优选4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺环烷基。其包括但不限于：
Figure PCTCN2022081466-appb-000064
螺环中的碳原子可任选地被O、S、N的杂原子替代，即也包括“螺杂环”。
本发明的术语“螺杂环”指5至20元的多环杂环基团，其中单环之间共用一个原子(称螺原子)，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，其余环原子为碳。螺杂环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。螺杂环优选为6至14元，更优选为7至10元的。根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环基、双螺杂环基或多螺杂环基，优选为单螺杂环基和双螺杂环基。更优选4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺杂环基。其包括但不限于：
Figure PCTCN2022081466-appb-000065
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式。优选的实施方式包括但不限于本发明的实施例。
本发明所表述的化合物，是依据化学结构式命名的，如果表示同一化合物时化合物的命名与化学结构式不符，则以化学结构式为准。
本发明中，除有另外说明，则本文中使用的科学和技术名词具有本领域技术人员通常理解的含义，然而为了更好地理解本发明，下面提供了部分术语的定义。当本发明所提供的术语的定义和解释与本领域技术人员通常理解的含义不同时，以本发明所提供的术语的定义和解释为准。
具体实施方式
下面结合具体实施例对本发明作进一步的详细说明。以下实施例用于理解本发明的方法和核心思想，对于本领域的技术人员来说，在不脱离本发明构思的前提下，进行任何可能的变化或替换，均属于本发明的保护范围。本发明实施例中未注明具体条件的实验方法，通常为常规条件，或按照原料或商品制造厂商所建议的条件；未注明来源的试剂，通常为通过商业途径可购得的常规试剂。
实验1-化合物鉴定与表征
本发明的 1H NMR谱是用Bruker仪器(400MHz)测定而得，化学位移用ppm表示。使用四甲基硅烷内标准(0.00ppm)。 1H NMR的表示方法：s＝单峰，d＝双重峰，t＝三重峰，m＝多重峰，br＝变宽的，dd＝双重峰的双重峰，dt＝三重峰的双重峰。若提供偶合常数时，其单位为Hz。
本发明的质谱是用LC/MS仪测定得到，离子化方式可为ESI或APCI。
Figure PCTCN2022081466-appb-000066
Figure PCTCN2022081466-appb-000067
Figure PCTCN2022081466-appb-000068
实验2-生物测试方法
(1)测试仪器及试剂
试剂/仪器 供应商 型号
cAMP-GS DYNAMIC kit CisBio 62AM4PEC
DMEM CellMax CGN101.5
FBS Gemini 900-108
1％Pen-3trep Sangom biotech E607011-0100
IBMX Meilunbio MB5226
384well plate Corning 3824
Incubator Thermo 3111
Microscope 江南 XD-202
Cell counter Counter Star Star IC1000
Plate reader Tecan Tecan Spark
(2)GLP-1R试剂盒
GLP-1R介导的激动剂活性是利用均相时间分辨荧光(即HTRF)的cAMP检测试剂盒，通过基于细胞的功能测定来测定的，所述试剂盒测量细胞中的cAMP水平。该方法是竞争性免疫测定。它使得能够直接药理学表征在贴壁或悬浮细胞中作用于Gs-偶联受体的化合物。
细胞产生的天然cAMP或未标记的cAMP标准曲线与d2标记的cAMP红色受体竞争结合单克隆抗cAMP穴状化合物铕供体，特异性信号与标准或实验样品中cAMP的浓度成反比。
将人GLP-1R编码序列(NCBI参考序列NP_002053.3)亚克隆到pEGFP-N1(tsingke)中，并分离稳定表达该受体的细胞系，通过在荧光显微镜下观察GFP的表达证实GLP-1R表达密度。
(3)GLP-1R-GFP-293A细胞培养
293A GFP-GLP-1R细胞在DMEM生长培养基，10％热灭活胎牛血清(GEMINI Cat#900-108)，1％Pen-3Trep(Sangom Biotech Cat#E607011-0100)]中培养，并在37℃下在湿润和5％CO 2培养箱中培养。
(4)cAMP水平测试方法
将不同浓度的各待测化合物(在DMSO中)在刺激缓冲液中用蒸馏水中1:5稀释，加入500μM3-异丁基-1-甲基黄质(IBMX；Meilunbiocat#MB5226)以获得2X化合物工作溶液，然后用多通道移液管将5μL化合物加入白色384孔测定板(Corning3824)中。测定缓冲液混合物中的最终DMSO浓度为1‰。
从T25组织培养瓶中收集细胞，并在室温下以1000rpm离心5分钟。然后将细胞沉淀重悬1ml刺激缓冲液。在计数器STAR IC1000上对20μL细胞悬浮液样品进行计数，以确定细胞存活力和每毫升细胞计数。然后用刺激缓冲液调节剩余的细胞悬浮液，以使用多通道移液管每孔递送2000个活细胞。将5μL细胞悬浮液加入到已经含有化合物的测定板的每个孔中。将板密封并在37℃下用5％CO 2温育30分钟。
在30分钟温育后，将5μL d2标记的cAMP和5μL抗cAMP穴状化合物(两者均在细胞裂解缓冲液中以1:20稀释)加入到测定板的每个孔中。然后将板在室温下温育，60分钟后，用Tecan Spark读板机读取HTRF信号的变化，激发340nm/发射615nm和665nm的吸光值。通过从cAMP标准曲线内插法将原始数据转化为nM cAMP，并相对于每个板上包含的完全激动剂GLP-17～37(400nM)的饱和浓度确定百分比效果。EC 50测定是从激动剂剂量-反应曲线进行的，所述曲线是使用4参数逻辑剂量-反应方程用曲线拟合程序分析的。
本试验证明本发明的化合物通过cAMP途径激活GLP-1R信号传导，因此起GLP-1R激动剂的作用。试验数据以基于所列重复次数的几何平均值(EC 50s)的形式呈现结果。
实验结果：
化合物编号 EC 50(nM)
1 4.67
2 88.78
3 121
4 1.0
5 0.56
6 0.03
7 0.02
8 0.05
9 0.08
10 0.05
11 0.1
12 0.5
13 0.47
实验3-hERG钾离子通道的抑制试验
1.实验材料：稳定细胞株HEK-hERG，品系：HEK 293，来源：军事医学科学院；
Figure PCTCN2022081466-appb-000069
2.电生理溶液
细胞外液(mM)：N-2-羟乙基哌嗪-N'-2-乙磺酸(HEPES)10、NaCl 145、KCl 4、CaCl 2 2、MgCl 2 1、Glucose 10，用氢氧化钠调节pH至7.3～7.4；渗透压调至290-310mOsm；过滤后4℃保存。
电极内液(mM)：KCl 120、KOH 31.25、CaCl 2 5.374、MgCl 2 1.75、乙二醇-双(β-胺基乙醚)-N,N,N',N'-四乙酸(EGTA)10、HEPES 10、Na 2-ATP 4，用氢氧化钾调节pH至7.2～7.3；渗透压调至290-310mOsm；过滤后分装，-20℃保存。
3.阳性对照化合物：
阳性对照品：阿米替林(Amitriptyline hydrochloride)或特非那定(Terfenadine)
来源：Sigma-Aldrich
4.给药制剂的制备
溶媒对照配制：在细胞外液中加入一定体积的DMSO，使其与最终供试品溶液含有同等含量的DMSO(若供试品溶液含有不同DMSO含量，以最大DMSO含量为准)，用以排除DMSO对细胞自身电流的干扰。
供试品配制：将上述10mM储液母液按比例配制成所需浓度的DMSO储备液(一般为实际给药浓度的1000/3倍)，最后将储备液用细胞外液稀释成实验所需的给药浓度。
阳性对照溶液配制：称取适量阳性对照品置于合适容器中，加入一定体积的DMSO，充分搅拌或振荡使全部溶解，配制成10mM的储备溶液，接着按比例配制成所需浓度的储备液，最后将储备液用细胞外液稀释成实验所需的给药浓度。
工作浓度溶液使用前应检查有无沉淀析出，如果有沉淀析出，将稀释储备液，提高细胞外液中DMSO终浓度，但细胞外液中DMSO最终浓度不超过0.5％。实验中采用从低浓度到高浓度连续灌流的方式。实验结束后，剩余供试品和阳性对照品的给药溶液以废液处理。
5.实验方案
细胞准备：
HEK-293-hERG细胞传代培养至合适状态后，将细胞用PBS(或DPBS)进行冲洗，用Tryple溶液进行消化分离，用培养基使细胞再次悬浮并存于离心管中，离心后弃去上清，用细胞外液使细胞再次悬浮备用，2-8℃保存。膜片钳记录之前，将细胞滴加于培养皿中，确保细胞具有一定密度且 细胞呈单个分离状态。
浓度设置：
供试品/阳性对照品 浓度(μM)
本发明化合物 1、10
阿米替林或特非那定 1
电生理实验：
采用全细胞膜片钳技术记录hERG电流。取细胞悬液加于小培养皿中，置于倒置显微镜载物台上。待细胞贴壁后，用细胞外液灌流，推荐流速为1–2mL/min。玻璃微电极由微电极拉制仪两步拉制，充灌电极内液后其入水电阻值为2-5MΩ。
建立全细胞记录模式后，保持钳制电位为-80mV。给予去极化电压至+60mV持续850ms，然后复极化至-50mV维持1275ms引出hERG尾电流。这样一组脉冲程序每15秒钟重复一次，贯穿整个实验。
电流稳定后采用从低浓度到高浓度胞外连续灌流给药的方式。从低浓度开始，持续灌流至药效稳定，然后进行下一浓度的灌流。本实验将分别测试各供试品和阳性对照对hERG尾电流的阻断效应(N≥2)；具体实际浓度可根据实际溶解度和效应进行调节，不视为方案偏离。
药效稳定的定义为：每个浓度给药阶段的最后5个刺激条电流值变化小于均值的10％(当电流大于等于200pA时)或小于均值的30％(当电流小于200pA时)可认为是稳定的，若不稳定，将不采取该浓度数据。
6.数据分析
在数据处理中，判断对hERG的阻断效应时，将尾电流的峰值和其基线进行校正。用尾流的抑制率(inhibition rate，IR)表示不同浓度下各化合物的作用。所有细胞各个浓度的％IR的SD≤15，作为可接受标准(除异常数据外)。
IR＝100％×(给药前尾电流峰值-给药后尾电流峰值)/给药前尾电流峰值。
7.实验结果：
Figure PCTCN2022081466-appb-000070
8.实验结论：本发明化合物未显示hERG抑制活性。
实验4-(人)肝微粒体代谢稳定性
1.实验设计：测定浓度：1μM；对照化合物：睾酮；培养条件：于37℃下培养0,5,15,30,45分钟；测定法发：LC-MS/MS；计算方法：T 1/2＝0.693/K(K是ln[浓度]相对于温育时间图的速率常数)，Cl int＝(0.693/T 1/2)×(1/(微粒体蛋白浓度(0.5mg/mL)))×比例因子。
其中，下表为人微粒体中内在清除预测的比例因子：
Figure PCTCN2022081466-appb-000071
2.实验方法：1.预热0.1M K-buffer，5nM MgCl 2，pH＝7.4；2.测试化合物和参比化合物的实验 溶液，500μM添加溶液：将5μL10mM储备溶液加入95μL ACN中，1.5μM微粒体中的掺加溶液(0.75mg/mL)：将1.5μL的500μM的添加溶液和18.75μL的20Mg/mL肝微粒体加入到479.75μL的K/Mg缓冲液中；3.3×NADPH的原液(6mM，5mg/mL)是将NADPH溶解于缓冲液中；4.将30μL含有0.75mg/mL微粒体溶液的1.5μM的添加溶液分配到指定用于不同时间点(0，5，15，30，45分钟)的测定板上；5.在0分钟时，将150μL含IS的ACN加入平板的孔中，然后加入15μL NADPH储备溶液(6mM，步骤3)；6.将所有其它板在37℃下预孵育5分钟；7.向板中加入15μL NADPH储备溶液以开始反应和计时；8.在5分钟、15分钟、30分钟和45分钟时，分别向相应板的孔中加入150μL含有IS的ACN以终止反应；9.淬灭后，在振动器上将板摇动10分钟(600rpm/分钟)，然后在6000rpm下离心15分钟；10.将80μL上清液从每个孔转移到含有140μL水的96孔样品板中，用于LC/MS分析。
3.分析方法：
检测方法：LC-MS/MS-11(8050)，内标：甲苯磺丁脲，MS条件为睾酮和待测化合物正离子ESI；甲苯磺丁脲负离子ESI；流动相：流动相A为0.1％FA与水中，流动相B为0.1％FA于ACN中；柱及规格：ACQUITY UPLC HSS T3 1.8um 2.1*50mm。
LC条件：
Figure PCTCN2022081466-appb-000072
4.实验结果(人微粒体)：
化合物编号 LMS(t 1/2min)
1 114.9
4 132.3
5 37.33
7 21.25
10 22.54
12 59.84
5.实验结论：本发明化合物肝微粒体稳定性良好
制备实施例
制备过程中所用中间体反应物料是参考WO2018109607A1所述的制备方法制得的。
中间体制备方法
中间体Int-2，(S)-2-(氯甲基)-1-(氧杂环丁-2-基甲基)-1H-苯并[d]咪唑-6-羧酸甲酯的制备方法如下：
Figure PCTCN2022081466-appb-000073
(1)化合物1-2C的制备
Figure PCTCN2022081466-appb-000074
在60℃氩气气氛下，向t-BuOK(170g，1520mmol，2.5eq)在t-BuOH(500mL)中的搅拌溶液中分批加入Me 3SO +I -(335g，1520mmol，2.5eq)，30分钟后向上述混合物中滴加(S)-2-((苄氧基)甲基)环氧乙烷1-1C(100g，610mmol，1.00eq)。将所得混合物在60℃下再搅拌13小时。将混合物冷却至室温，然后过滤，滤饼用EtOAc(3×200mL)洗涤。合并的有机层用盐水(200mL)洗涤，用Na 2SO 4干燥并减压浓缩，得到残余物，将其通过硅胶柱色谱法纯化，用PE/EtOAc(10:1)洗脱，得到(S)-2-((苄氧基)甲基)氧杂环丁，为1-2C(50.0g，46％收率)。
1H NMR(400MHz,CDCl3)δ＝7.39–7.26(m,5H),5.04–4.90(m,1H),4.73–4.50(m,4H),3.64(qd,J＝11.0,4.3Hz,2H),2.72–2.45(m,2H).
(2)化合物1-3C的制备
Figure PCTCN2022081466-appb-000075
将(S)-2-((苄氧基)甲基)氧杂环丁烷1-2C(50g，280.9mmol，1.0eq)和Pd/C(20g，湿)在THF(200mL)中的溶液在H 2(4MPa)下在50℃搅拌16小时。将混合物冷却至室温，然后过滤，用THF(100mL)洗涤滤饼。滤液减压浓缩得到(S)-氧杂环丁烷-2-基甲醇，为1-3C(28g，粗产物)，其直接用于下一步骤。
(3)化合物1-4C的制备
Figure PCTCN2022081466-appb-000076
在25℃下，向(S)-氧杂环丁烷-2-基甲醇1-3C(28g，317.8mmol，1eq)的THF(200mL)溶液中加入TsCl(66.6g，349.6mmol，1.1eq)和TEA(48.2g，476.7mmol，1.5eq)。将混合物在室温下搅拌2小时。用H 2O(100mL)稀释混合物，用DCM(100mL×3)萃取。合并的有机层用Na 2SO 4干燥，过滤并浓缩，得到残余物，将其通过柱色谱法在硅胶上纯化，用(EA/PE＝0-10％)洗脱，得到(S)-氧杂环丁烷-2-基甲基4-甲基苯磺酸酯，为1-4C(56g，72.7％收率)。
1H NMR(400MHz,CDCl3)δ＝7.85–7.79(m,2H),7.35(dd,J＝8.6,0.6Hz,2H),5.00–4.83(m,1H),4.68–4.38(m,2H),4.16(d,J＝4.0Hz,2H),2.78–2.64(m,1H),2.58(d,J＝9.0Hz,1H),2.45(s,3H).
(4)化合物1-5C的制备
Figure PCTCN2022081466-appb-000077
向(S)-氧杂环丁烷-2-基甲基-4-甲基苯磺酸酯1-4C(56g，231mmol，1eq)的DMF(200mL)溶液中加入NaN 3(22.5g，346.7mmol，1.5eq)。将混合物在60℃下搅拌12小时。用H 2O(100mL)稀释混合物，用EtOAc(100mL×3)萃取。合并的有机层用Na 2SO 4干燥，过滤并浓缩，得到(S)-2-(叠氮甲基)氧杂环丁烷，为1-5C(20g，粗产物)，其直接用于下一步骤。
(5)化合物1-6C的制备
Figure PCTCN2022081466-appb-000078
将(S)-2-(叠氮甲基)氧杂环丁烷1-5C(20g，粗产物)和Pd/C(8g)的THF(100mL)溶液在H 2(15Psi)下于25℃搅拌16小时。过滤所得混合物，用THF(3×100mL)洗涤滤饼。滤液直接浓缩得到(S)-氧杂环丁烷-2-基甲胺，为1-6C(3.8g，粗品)。
1H NMR(400MHz,DMSO)δ＝4.60(dq,J＝6.5,5.2Hz,1H),4.52–4.43(m,1H),4.40–4.30(m,1H),2.67(t,J＝5.5Hz,2H),2.57–2.51(m,1H),2.38(ddt,J＝10.8,9.0,7.0Hz,2H).
(6)化合物1-7C的制备
Figure PCTCN2022081466-appb-000079
在25℃下，向(S)-氧杂环丁烷-2-基甲胺1-6C(3.8g，43.6mmol，1eq)的THF(80mL)溶液中加入3-氟-4-硝基苯甲酸甲酯1-6D(8.69g，43.6mmol，1.0eq)和TEA(8.83g，87.2mmol，2eq)。将混合物在40℃下搅拌6小时。浓缩混合物，得到残余物，将其通过硅胶柱色谱纯化，用(EtOAc/石油醚＝0-80％)洗脱，得到(S)-4-硝基-3-((氧杂环丁烷-2-基甲基)胺基)苯甲酸甲酯，为1-7C(6.2g，53.4％收率)。
1H NMR(400MHz,CDCl3)δ＝8.36(s,1H),8.23(d,J＝8.9Hz,1H),7.63(d,J＝1.4Hz,1H),7.26(dd,J＝8.8,1.7Hz,1H),5.16(tt,J＝7.4,4.5Hz,1H),4.81–4.55(m,2H),3.94(s,3H),3.71–3.55(m,2H),2.84–2.72(m,1H),2.70–2.52(m,1H).
(7)化合物1-8C的制备
Figure PCTCN2022081466-appb-000080
将(S)-4-硝基-3-((氧杂环丁烷-2-基甲基)胺基)苯甲酸甲酯1-7C(6.2g，23.3mmol，1.0eq)和Pd/C(1.0g，湿)的MeOH(100mL)溶液在25℃下在H 2(1atm)下搅拌12小时。过滤混合物，滤饼用MeOH(3×20mL)洗涤。将滤液直接浓缩，得到(S)-4-胺基-3-((氧杂环丁烷-2-基甲基)胺基)苯甲酸甲酯，为1-8C(5.2g，94.5％收率)。
LCMS:r.t.＝1.201min,[M+1] +＝237.1，纯度：89.7％。
(8)化合物Int-2的制备
Figure PCTCN2022081466-appb-000081
向(S)-4-胺基-3-((氧杂环丁烷-2-基甲基)胺基)苯甲酸甲酯1-8C(1.0g，4.23mmol，1eq)的THF(20mL)溶液中加入2-氯-1,1,1-三甲氧基乙烷1-8D(0.98g，6.35mmol，1.5eq)和TsOH·H 2O(0.08g，0.423mmol，0.1eq)。将混合物在50℃下搅拌8小时。用饱和碳酸氢钠溶液稀释混合物。NaHCO 3(20mL)并用EtOAc(10mL×3)萃取。合并的有机层用Na 2SO 4干燥，过滤并浓缩，得到残余物，将其通过硅胶柱色谱法纯化，用(EtOAc/石油醚＝0-80％)洗脱，得到(S)-2-(氯甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯，为Int-2(1.1g，88％收率)。
1H NMR(400MHz,CDCl3)δ8.12(d,J＝0.9Hz,1H),8.01(dd,J＝8.5,1.5Hz,1H),7.79(d,J＝8.5Hz,1H),5.21(ddd,J＝9.6,7.3,2.7Hz,1H),5.03(s,2H),4.69–4.45(m,3H),4.34(d,J＝9.2Hz,1H),3.96(s,3H),2.76(dtd,J＝11.5,8.1,6.0Hz,1H),2.42(ddt,J＝11.5,9.2,7.3Hz,1H).
中间体Int-3，4-(6-羟基吡啶-2-基)哌啶-1-甲酸叔丁酯的制备方法如下：
Figure PCTCN2022081466-appb-000082
(1)化合物i-2A的制备
Figure PCTCN2022081466-appb-000083
在0℃下向6-氯吡啶-2-醇i-1A(30.00g，231.58mmol)的DMF(200mL)混合物中加入NaH。将反应混合物在0℃与Ar 2搅拌半小时。然后加入BnBr(43.57g，254.74mmol)到上述溶液中，然后在室温下与Ar 2一起搅拌一小时。通过TLC确定反应完成后，将反应混合物用水(200mL)稀释，用乙酸乙酯(100mL×3)萃取。合并的有机层用饱和NaCl洗涤，用无水Na 2SO 4干燥并通过过滤器过滤。浓缩滤液，得到残余物，将其通过柱色谱法在硅胶上纯化，用(PE/EA＝0-20％)洗脱，得到2-(苄氧基)-6-氯吡啶，为i-2A(25g，47.18％)。
1H NMR(400MHz,CDCl 3)δ7.54–7.44(m,3H),7.40–7.30(m,3H),6.91(dd,J＝7.5,0.6Hz,1H),6.70(dd,J＝8.2,0.6Hz,1H),5.36(s,2H).
(2)化合物i-4A的制备
Figure PCTCN2022081466-appb-000084
向4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-3,6-二氢吡啶-1(2H)-甲酸叔丁酯i-3A(35.19g，113.81mmol)、6-氯吡啶-2-醇i-2A(25.00g，113.81mmol)和Cs 2CO 3(55.62g，170.71mmol)在二噁烷(200mL)中的混合物中加入Pd(dppf)Cl 2(8.25g，11.38mmol)。在N 2气氛下，在100℃下搅拌反应混合物16小时。通过LCMS确定反应完成后，浓缩混合物，得到残余物，将其通过硅胶柱色谱法纯化，用(EA/PE＝0-10％)洗脱，得到6-(苄氧基)-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-羧酸叔丁酯，为i-4A(47.00g，59.9％)。
LCMS:r.t.＝2.368min,[M+1] +＝367，纯度：75.78％.
(3)化合物Int-3的制备
Figure PCTCN2022081466-appb-000085
向6-(苄氧基)-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-羧酸叔丁酯i-4A(23g，62.76mmol)在THF(200ml)中的混合物中加入Pd/C(4g，湿)。将混合物在室温下与H 2搅拌过夜。将反应混合物通过硅藻土过滤，滤饼用EA(50mL×3)洗涤。将合并的滤液浓缩，得到残余物，将其通过硅胶柱色谱法纯化，用(MeOH/DCM＝0-5％)洗脱，得到4-(6-羟基吡啶-2-基)哌啶-1-甲酸叔丁酯，为Int-3(9.2g，53％)。
LCMS:r.t.＝0.94min,[M-55] +＝223，纯度：60％.
1H NMR(400MHz,CDCl 3)δ11.32(s,1H),7.38(dd,J＝9.1,6.9Hz,1H),6.42(d,J＝8.5Hz,1H),6.03(d,J＝6.8Hz,1H),4.25(s,2H),2.83(s,2H),2.61(dd,J＝13.8,10.5Hz,1H),1.92(d,J＝12.0Hz,2H),1.48(s,9H),1.25(s,2H).
中间体Int-5，4-(((6-(1-(叔丁氧基羰基)哌啶-4-基)吡啶-2-基)氧基)甲基)-3-氟苯甲酸的制备方法如下：
(1)化合物i-2的制备
Figure PCTCN2022081466-appb-000086
在0℃下，向4-(6-羟基吡啶-2-基)哌啶-1-甲酸叔丁酯Int-3(1.4g，5.0mmol，1eq)的DMF(20mL)溶液中加入NaH(0.26g，6.5mmol，1.3eq)。在0℃下搅拌混合物30分钟。然后将4-(溴甲基)-3-氟苯甲酸甲酯i-1(1.6g，6.5mmol，1.3eq)加入上述溶液中，在25℃下搅拌2小时。TLC显示起始原料完全消耗，发现新的斑点。用H 2O(10mL)稀释反应混合物，用EtOAc(3×10mL)萃取。合并的有机层用盐水(100mL)洗涤，用Na 2SO 4干燥并减压浓缩，得到残余物，将其通过硅胶柱色谱纯化，用(PE/EA＝0-20％)洗脱，得到4-(6-((2-氟-4-(甲氧基羰基)苄基)氧基)吡啶-2-基)哌啶-1-甲酸叔丁酯i-2(1.1g，50％)。
1H NMR(400MHz,CDCl 3)δ＝7.81(dd,J＝8.0,1.5Hz,1H),7.73(dd,J＝10.4,1.5Hz,1H),7.62–7.44(m,2H),6.73(d,J＝7.3Hz,1H),6.65(d,J＝8.1Hz,1H),5.49(s,2H),4.20(s,1H),3.92(s,3H),2.77(d,J＝43.3Hz,3H),2.05(s,1H),1.85(d,J＝12.6Hz,2H),1.49(s,9H).
(2)化合物Int-5的制备
Figure PCTCN2022081466-appb-000087
在25℃下，向4-(6-((2-氟-4-(甲氧基羰基)苄基)氧基)吡啶-2-基)哌啶-1-甲酸叔丁酯i-2(1.4g，3.15mmol，1eq)的THF(10mL)溶液中加入H 2O(10mL)中的LiOH(0.378g，15.7mmol，5.0eq)。将混合物在室温下搅拌2小时。用HCl(1N)将混合物调节至pH＝7。用H 2O(100mL)稀释反应混合物，用EtOAc(3×50mL)萃取。合并的有机层用盐水(100mL)洗涤，用Na 2SO 4干燥并减压浓缩，得到4-(((6-(1-(叔丁氧基羰基)哌啶-4-基)吡啶-2-基)氧基)甲基)-3-氟苯甲酸，为Int-5(0.47g，34.7％收率)。
LCMS:r.t＝2.177min,[M+1]+＝431.2，纯度：69.7％。
中间体Int-7，4-(6-((2-氟-4-(甲氧基(甲基)胺基甲酰基)苄基)氧基)吡啶-2-基)哌啶-1-甲酸叔丁酯的制备方法如下：
(1)化合物Int-7的制备
Figure PCTCN2022081466-appb-000088
将4-(((6-(1-(叔丁氧基羰基)哌啶-4-基)吡啶-2-基)氧基)甲基)-3-氟苯甲酸Int-5(0.470g，1.09mmol，1.0eq)、N,O-二甲基羟胺盐酸盐(0.214g，2.18mmol，2.0eq)、DIEA(0.564g，4.37mmol，4.0eq)和HATU(0.623g，1.64mmol，1.5eq)的DMF(6mL)溶液在25℃下搅拌2小时。用EtOAc(50mL)稀释混合物，用H 2O(80mL)洗涤，用EtOAc(30mL×3)萃取。合并的有机层用盐水(100mL)洗涤，用Na 2SO 4干燥并减压浓缩，得到残余物，将其通过硅胶柱色谱法纯化，用PE/EtOAc(3:1)洗脱，得到4-(6-((2-氟-4-(甲氧基(甲基)胺基甲酰基)苄基)氧基)吡啶-2-基)哌啶-1-甲酸叔丁酯，为Int-7(0.440g，85.4％收率)。
LCMS:r.t＝2.262min,[M+1]+＝474.3，纯度：98％。
中间体Int-2A，(S)-2-(氯甲基)-3-(氧杂环丁烷-2-基甲基)-3H-咪唑并[4,5-b]吡啶-5-甲酸甲酯的制备方法
Figure PCTCN2022081466-appb-000089
向6-氯-5-硝基吡啶甲酸甲酯2A-1(2.2g，10.34mmol)在20mL THF中的溶液中加入(S)-氧杂环丁烷-2-基甲胺(900mg，10.34mmol)和TEA(2.0g，20mmol)。将反应混合物在氮气下在40℃搅拌16小时。将反应混合物浓缩成粗产物，将其通过柱层析(MeOH/DCM＝0-3％)进一步纯化，得到(S)-5-硝基-6-((氧杂环丁烷-2-基甲基)胺基)吡啶甲酸甲酯2A-2(1.2g，45％)。向得到的2A-2(1.2g，4.49mmol)的5mL MeOH溶液中加入乙酸乙酯,加入Pd/C(500mg)，在H 2气氛下，在室温下搅拌16小时。将反应混合物通过过滤进一步纯化并浓缩，得到(S)-5-胺基-6-((氧杂环丁烷-2-基甲基)胺基)吡啶甲酸甲酯2A-3的粗产物(840mg，78.9％)。向2A-3(840mg，3.54mmol)在10mL THF中的溶液中加入2-氯乙酸酐(667mg，3.9mmol)，并在50℃下搅拌16小时，通过加入饱和NaHCO 3水溶液淬灭反应混合物，用EA(40mL×3)萃取，用盐水洗涤，浓缩得到粗产物，通过柱层析进一步纯化(PE/EA＝10-51％)，得到(S)-2-(氯甲基)-3-(氧杂环丁烷-2-基甲基)-3H-咪唑并[4,5-b]吡啶-5-甲酸甲酯，为Int-2A(422mg，43％)。
LCMS:r.t.＝1.694min,[M+H] +＝296，纯度：98％.
实施例1
(S)-2-((4-(6-((5-乙酰基噻吩-2-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸(化合物1)
Figure PCTCN2022081466-appb-000090
(1)化合物1-2的制备
Figure PCTCN2022081466-appb-000091
将NBS(279mg，1.57mmol)加入到化合物1-1(200mg，1.43mmol)和BPO(7mg，0.03mmol)在CCl 4(5mL)中的混合物中，然后将反应溶液在80℃下搅拌8小时，之后将反应混合物用Na 2S 2O 3饱和溶液(5mL)猝灭。用水(20mL)和DCM(20mL×3)萃取该溶液，用盐水(20mL)洗涤合并的有机相，干燥(Na 2SO 4)，过滤并浓缩。快速色谱法(SiO 2，20％EtOAc-己烷)处理得到1-(5-(溴甲基)噻吩-2-基)乙-1-酮，为化合物1-2(260mg，83％)。
1H NMR(400MHz,CDCl 3)δ7.53(d,J＝3.8Hz,1H),7.12(d,J＝3.8Hz,1H),4.67(s,2H),2.54(s,3H).
(2)化合物1-3的制备
Figure PCTCN2022081466-appb-000092
将化合物1-2(2g，9.13mmol)，化合物1-2-1(3.05g，10.95mmol)和K 2CO 3(2.52g，18.26mmol)在DMF(30mL)中的混合物在50℃下搅拌16小时。加入H 2O(100mL)，反应溶液用EtOAc(3×100mL)萃取。合并的有机相用盐水(10mL)洗涤，干燥(Na 2SO 4)，过滤并浓缩。快速色谱法(SiO 2，25％EtOAc-己烷)处理得到4-(6-((5-乙酰基噻吩-2-基)甲氧基)吡啶-2-基)哌啶-1-甲酸叔丁酯，为化合物1-3(2g，53％)。
1H NMR(400MHz,CDCl 3)δ7.58(d,J＝3.8Hz,1H),7.52(dd,J＝8.1,7.5Hz,1H),7.12(d,J＝3.8Hz,1H),6.75(d,J＝7.3Hz,1H),6.62(d,J＝8.1Hz,1H),5.56(s,2H),4.22(s,2H),2.92–2.69(m,3H),2.53(s,3H),1.90(d,J＝13.5Hz,2H),1.74(qd,J＝12.6,3.8Hz,2H),1.48(s,9H).
(3)化合物1-4的制备
Figure PCTCN2022081466-appb-000093
将HCl/二噁烷(2mL)加入到化合物1-3(45mg，0.11mmol)的EtOAc(2mL)溶液中，将该混合物 在室温搅拌1小时，然后将该混合物浓缩，得到固体。将固体溶解在H 2O(5mL)中，用NaHCO 3(eq)调节至pH＞7，用EtOAc(10mL×3)萃取。合并的有机相用盐水(10mL)洗涤，干燥(Na 2SO 4)，过滤并浓缩，得到1-(5-(((6-(哌啶-4-基)吡啶-2-基)氧基)甲基)噻吩-2-基)乙烷-1-酮，为化合物1-4(20mg，58.8％)
1H NMR(400MHz,DMSO-d6)δ7.82(d,J＝3.8Hz,1H),7.68–7.61(m,1H),7.29(d,J＝3.8Hz,1H),6.88(d,J＝7.0Hz,1H),6.66(d,J＝8.2Hz,1H),5.58(s,2H),3.01(d,J＝9.4Hz,1H),2.80–2.52(m,4H),2.51(s,3H),1.77(d,J＝11.6Hz,2H),1.69–1.52(m,2H),1.24(s,1H).
LCMS(ESI)m/z:317.0[M+H] +.
(4)化合物1-5的制备
Figure PCTCN2022081466-appb-000094
将K 2CO 3(175mg，1.26mmol)加入到化合物1-4(100mg，0.32mmol)和化合物1-4-1(98.2mg，0.32mmol)在二噁烷(2mL)和CH 3CN(1mL)中的混合物中。将混合物在60℃下搅拌16小时。加入水(10mL)，溶液用DCM(10mL×3)萃取，合并的有机相用盐水(30mL)洗涤，干燥(Na 2SO 4)，过滤并浓缩。快速色谱法(硅胶，用0-10％MeOH/DCM洗脱)得到(S)-2-((4-(6-((5-乙酰基噻吩-2-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯，为化合物1-5(50mg，27.6％)。
1H NMR(400MHz,CDCl 3)δ8.17(s,1H),7.97(d,J＝8.7Hz,1H),7.75(d,J＝8.5Hz,1H),7.56(d,J＝3.8Hz,1H),7.51(t,J＝7.8Hz,1H),7.12(d,J＝3.7Hz,1H),6.75(d,J＝7.3Hz,1H),6.60(d,J＝8.2Hz,1H),5.56(s,2H),5.27–5.19(m,1H),4.74(qd,J＝15.5,4.2Hz,2H),4.61(dd,J＝14.0,7.8Hz,1H),4.40(dt,J＝9.2,6.0Hz,1H),3.96(d,J＝11.2Hz,5H),2.97(d,J＝15.4Hz,2H),2.88(s,1H),2.79–2.60(m,2H),2.52(s,3H),2.30(dd,J＝25.1,12.1Hz,2H),1.98–1.79(m,4H).
LC-MS(ESI)m/z:576.0[M+H] +.
(5)化合物1的制备
Figure PCTCN2022081466-appb-000095
将LiOH(2mL)加入到化合物1-5(50mg，0.08mmol)的THF(0.5mL)和MeOH(0.5mL)溶液中，将混合物在室温下搅拌3小时，然后减压除去溶剂，得到粗产物，粗产物通过HPLC纯化(梯度：10％MeCN/90％H 2O，0.1％NH 3·H2O至100％MeCN)，得到(S)-2-((4-(6-((5-乙酰基噻吩-2-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸，为化合物1(14.93mg，29.2％)。
1H NMR(400MHz,DMSO-d6)δ8.04(s,1H),7.81(d,J＝3.8Hz,1H),7.75(d,J＝8.1Hz,1H),7.67–7.60(m,1H),7.41(s,1H),7.29(d,J＝3.8Hz,1H),6.91(d,J＝7.2Hz,1H),6.67(d,J＝8.4Hz,1H),5.58(s,2H),5.09(s,1H),4.69(s,1H),4.59(d,J＝13.7Hz,1H),4.44(s,1H),4.37(d,J＝9.1Hz,1H),3.90(d,J＝13.5Hz,1H),3.75(d,J＝13.2Hz,1H),2.99(s,1H),2.87(s,1H),2.67(s,2H),2.48(s,3H),2.34–2.12(m,3H),1.82(d,J＝12.1Hz,4H).
LC-MS(ESI)m/z:561.3[M+H] +.
实施例2
(S)-2-((4-(6-((4-乙酰基噻吩-2-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸(化合物2)
Figure PCTCN2022081466-appb-000096
(1)化合物2-2的制备
Figure PCTCN2022081466-appb-000097
向化合物2-1(1g，3.52mmol)和N,O-二甲基羟胺(750mg，3.87mmol)在无水DMF(20mL)中的溶液中加入HATU(4g，5.28mmol)、DIEA(4.54g，17.6mmol)。将反应混合物在室温搅拌16小时，将反应混合物在水(50mL)和EtOAc(50mL×3)之间分配。合并的有机相用盐水(50mL)洗涤，干燥(Na 2SO 4)，过滤并浓缩。快速色谱法(SiO 2，0-100％EtOAc-己烷)得到N-甲氧基-N,5-二甲基噻吩-3-甲酰胺，为化合物2-2(1.1g，84.6％)。
1H NMR(400MHz,DMSO-d 6)δ7.90(1H,d,J＝1.4),7.20–7.10(1H,m),3.64(3H,s),3.23(3H,s),2.45(3H,d,J＝1.1).
LCMS:(ESI)m/z:186.0[M+H] +
(2)化合物2-3的制备
Figure PCTCN2022081466-appb-000098
在氮气、0℃下，向CH 3MgBr(1.8mL，5.4mmol)的THF溶液中滴加化合物2-2(500mg，2.7mmol)的无水THF(3mL)溶液。在用NH 4Cl(eq)猝灭反应混合物后，将反应混合物在室温搅拌2小时。用水(10mL)和EtOAc(10mL×3)萃取溶液，用盐水洗涤有机相，干燥(Na 2SO 4)。过滤后，减压浓缩溶剂，得到1-(5-甲基噻吩-3-基)乙-1-酮，为化合物2-3(310mg，82.0％)。
1H NMR(400MHz,DMSO-d6)δ8.24(1H,d,J＝1.4),7.17(1H,s),2.45(3H,d,J＝0.9),2.44(3H,s).
LCMS:(ESI)m/z:141.0[M+H] +
(3)化合物2-4的制备
Figure PCTCN2022081466-appb-000099
将化合物2-3(310mg，2.21mmol)、AIBN(7mg，0.044mmol)和NBS(434mg，2.43mmol)在 CCl 4(6mL)中的混合物在80℃下搅拌16小时，然后用Na 2S 2O 3(eq)猝灭反应混合物。用水(20mL)和DCM(20mL×3)萃取该溶液，用盐水(20mL)洗涤合并的有机相，干燥(Na 2SO 4)，过滤并浓缩。快速色谱法(SiO 2，0-100％EtOAc-己烷)处理得到1-(5-(溴甲基)噻吩-3-基)乙-1-酮，为化合物2-4(280mg，57.9％)。
1H NMR(400MHz,DMSO-d6)δ8.44(1H,s),7.50(1H,s),4.95(2H,s),2.41(3H,s).
LC-MS:(ESI)m/z:219.0[M+H] +
(4)化合物2-5的制备
Figure PCTCN2022081466-appb-000100
将化合物2-4(280mg，1.28mmol)，化合物2-4-1(427mg，1.53mmol)和K 2CO 3(353mg，2.56mmol)在DMF(5mL)中的混合物在50℃下搅拌16小时，将反应混合物在水(10mL)和EtOAc(10mL×3)之间分配。合并的有机相用盐水(10mL)洗涤，干燥(Na 2SO 4)，过滤并浓缩。快速色谱法(SiO2，0-100％EtOAc-己烷)处理得到4-(6-((4-乙酰基噻吩-2-基)甲氧基)吡啶-2-基)哌啶-1-甲酸叔丁酯，为化合物2-5(220mg，41.3％)。
1H NMR(400MHz,DMSO)δ8.42(1H,d,J＝1.5),7.65(1H,dd,J＝8.1,7.4),7.56(1H,d,J＝1.3),6.90(1H,d,J＝7.2),6.66(1H,d,J＝8.0),5.53(2H,s),4.06–4.02(2H,m),2.94–2.74(3H,m),2.46(3H,s),1.85(2H,d,J＝12.8),1.71–1.59(2H,m),1.41(9H,s).
LCMS:(ESI)m/z:417.0[M+H] +
(5)化合物2-6的制备
Figure PCTCN2022081466-appb-000101
将化合物2-5(220mg，0.53mmol)和HCl/二噁烷(1mL)的EtOAc(1.5mL)溶液在室温搅拌1小时，然后将该混合物浓缩得到固体，将其用水(5mL)溶解。用NaHCO 3(eq)调节溶液pH＞7，用EtOAc(5mL×3)萃取。合并有机相，用盐水洗涤(10mL)，干燥(Na 2SO 4)，过滤，浓缩，得到1-(5-(((6-(哌啶-4-基)吡啶-2-基)氧基)甲基)噻吩-3-基)乙烷-1-酮，为化合物2-6(120mg，71.8％)。
1H NMR(400MHz,DMSO-d6)δ8.42(1H,d,J＝1.4),7.67–7.61(1H,m),7.57(1H,d,J＝1.2),7.21(1H,dd,J＝27.2,7.3),6.86(1H,d,J＝7.3),6.63(1H,d,J＝8.1),5.54(2H,s),3.02(2H,d,J＝12.0),2.68(1H,ddd,J＝11.9,8.3,3.7),2.62–2.54(2H,m),2.46(3H,s),1.78(2H,d,J＝12.0),1.64(2H,dd,J＝12.3,3.8).
LCMS:(ESI)m/z:316.0[M+H] +
(6)化合物2-7的制备
Figure PCTCN2022081466-appb-000102
将化合物2-6(120mg，0.379mmol)、化合物2-6-1(123mg，0.417mmol)和K 2CO 3(209mg，1.516mmol)在二噁烷(12mL)和CH 3CN(6mL)中的混合物在60℃下搅拌16小时，用水(30mL)和DCM(30mL×3)萃取该溶液，将合并的有机相用盐水(30mL)洗涤，干燥(Na 2SO 4)，过滤并浓缩。快速色谱法 (SiO 2，0-100％EtOAc-己烷)处理得到(S)-2-((4-(6-((4-乙酰基噻吩-2-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸酯，为化合物2-7(140mg，64.2％)。
1H NMR(400MHz,DMSO-d6)δ8.41(1H,d,J＝1.5),8.29(1H,s),7.82(1H,dd,J＝8.4,1.5),7.73–7.60(2H,m),7.56(1H,d,J＝1.4),6.90(1H,d,J＝7.2),6.64(1H,d,J＝8.2),5.54(2H,d,J＝1.6),5.11(1H,d,J＝7.1),4.82(1H,dd,J＝15.2,7.2),4.67(1H,dd,J＝15.1,2.6),4.49–4.32(2H,m),4.01(1H,dd,J＝13.2,6.1),3.87(3H,s),3.79(1H,d,J＝13.3),3.03(1H,d,J＝11.5),2.88(1H,d,J＝10.7),2.74–2.61(2H,m),2.44(4H,s),2.23(2H,d,J＝29.5),1.84(4H,d,J＝17.5).
LC-MS:(ESI)m/z:575.4[M+H] +
(7)化合物2的制备
Figure PCTCN2022081466-appb-000103
将化合物2-7(100mg，0.17mmol)、LiOH(2mL)的THF(0.5mL)溶液和MeOH(0.5mL)溶液在室温下搅拌3小时。然后减压除去溶剂得到粗产物，粗产物用HPLC纯化(梯度：10％MeCN/90％H 2O，0.1％NH 3·H 2O至100％MeCN)，得到(S)-2-((4-(6-((4-乙酰基噻吩-2-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸，为化合物2(10.67mg，10.9％)。
1H NMR(400MHz,DMSO-d6)δ8.41(1H,d,J＝1.4),8.25(1H,s),7.80(1H,dd,J＝8.4,1.5),7.63(2H,dd,J＝12.1,5.7),7.56(1H,d,J＝1.3),6.90(1H,d,J＝7.2),6.64(1H,d,J＝8.1),5.61–5.49(2H,m),5.11(1H,dt,J＝7.0,4.4),4.79(1H,dd,J＝15.2,7.2),4.65(1H,dd,J＝15.2,2.7),4.39(2H,ddt,J＝11.8,8.9,5.9),3.96(1H,d,J＝13.5),3.78(1H,d,J＝13.5),3.03(1H,d,J＝10.5),2.88(1H,d,J＝11.5),2.74–2.61(2H,m),2.44(4H,s),2.31–2.15(2H,m),1.92–1.73(4H,m).
LC-MS:MC21-01-042R1,(ESI)m/z:561.1[M+H] +
实施例3
(S)-2-((4-(6-((5-乙酰基噻吩-3-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸(化合物3)
Figure PCTCN2022081466-appb-000104
(1)化合物3-2的制备
Figure PCTCN2022081466-appb-000105
将NBS(139mg，0.78mmol)加入到化合物3-1(100mg，0.71mmol)和BPO(3.5mg，0.01mmol)在CCl 4(2mL)中的混合物中，然后将反应溶液在80℃下搅拌16小时，之后将反应混合物用Na 2S 2O 3饱和溶液(5mL)猝灭。用水(20mL)和DCM(20mL×3)萃取该溶液，用盐水(20mL)洗涤合并的有机相，干燥(Na 2SO 4)，过滤并浓缩。快速色谱法(SiO 2，20％EtOAc-己烷)处理得到1-(4-(溴甲基)噻吩-2-基)乙-1-酮，为化合物3-2(40mg，25.8％)。
1H NMR(400MHz,CDCl 3)δ7.69(d,J＝1.3Hz,1H),7.57(d,J＝0.6Hz,1H),4.48(s,2H),2.56(s,3H).
(2)化合物3-3的制备
Figure PCTCN2022081466-appb-000106
将化合物3-2(40mg，0.18mmol)，化合物3-2-1(61mg，0.22mmol)和K 2CO 3(50.5mg，0.37mmol)在DMF(2mL)中的混合物在50℃下搅拌16小时。加入水(5mL)，反应溶液用EtOAc(3×10mL)萃取。合并的有机相用盐水(10mL)洗涤，干燥(Na 2SO 4)，过滤并浓缩。快速色谱法(SiO 2，25％EtOAc-己烷)处理得到4-(6-((5-乙酰基噻吩-3-基)甲氧基)吡啶-2-基)哌啶-1-羧酸叔丁酯，为化合物3-3(22mg，29％)。
1H NMR(400MHz,CDCl 3)δ7.76(s,1H),7.62(s,1H),7.52(t,J＝7.7Hz,1H),6.74(d,J＝7.3Hz,1H),6.61(d,J＝8.2Hz,1H),5.36(s,2H),4.24(s,2H),2.94–2.67(m,3H),2.56(d,J＝2.7Hz,4H),1.89(d,J＝15.0Hz,2H),1.76(t,J＝11.4Hz,2H),1.48(s,9H).
(3)化合物3-4的制备
Figure PCTCN2022081466-appb-000107
将HCl/二噁烷(5mL)加入到化合物3-3(230mg，0.55mmol)的EtOAc(5mL)溶液中，将该混合物在室温搅拌1小时，然后将该混合物浓缩，得到固体。将固体溶解在水(5mL)中，用NaHCO 3(eq)调节至pH＞7，用EtOAc(10mL×3)萃取。合并的有机相用盐水(10mL)洗涤，干燥(Na 2SO 4)，过滤并浓缩，得到1-(4-(((6-(哌啶-4-基)吡啶-2-基)氧基)甲基)噻吩-2-基)乙烷-1-酮，为化合物3-4(140mg，80％)。
1H NMR(400MHz,CDCl 3)δ7.78(d,J＝1.3Hz,1H),7.71–7.64(m,1H),7.55–7.49(m,1H),6.75(d,J＝7.2Hz,1H),6.62(d,J＝8.2Hz,1H),5.38(s,2H),3.32(d,J＝12.4Hz,2H),2.88–2.70(m,3H),2.56(d,J＝2.3Hz,3H),2.02–1.83(m,4H),1.25(s,1H).
LCMS:(ESI)m/z:317.0[M+H] +
(4)化合物3-5的制备
Figure PCTCN2022081466-appb-000108
将K 2CO 3(175mg，1.26mmol)加入到化合物3-4(100mg，0.32mmol)和化合物3-4-1(93mg，0.32 mmol)在二噁烷(6mL)和CH 3CN(3mL)中的混合物中。将混合物在60℃下搅拌16小时。加入水(10mL)，溶液用DCM(10mL×3)萃取，合并的有机相用盐水(20mL)洗涤，干燥(Na 2SO 4)，过滤并浓缩。快速色谱法(硅胶，用0-10％MeOH/DCM洗脱)得到(S)-2-((4-(6-((5-乙酰基噻吩-3-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯，为化合物3-5(100mg，55.1％)。
1H NMR(400MHz,CDCl 3)δ8.16(s,1H),7.97(d,J＝9.5Hz,1H),7.76(s,2H),7.63(s,1H),7.51(dd,J＝9.6,6.0Hz,1H),6.75(d,J＝7.3Hz,1H),6.60(d,J＝8.2Hz,1H),5.37(s,2H),5.23(s,1H),4.74(d,J＝8.8Hz,2H),4.62(dd,J＝14.7,7.2Hz,1H),4.40(s,1H),3.96(d,J＝10.5Hz,5H),3.00(t,J＝12.3Hz,2H),2.73(s,1H),2.64(s,1H),2.54(s,3H),2.47(d,J＝5.7Hz,1H),2.30(dd,J＝25.5,12.1Hz,2H),1.95–1.80(m,4H).
LC-MS:(ESI)m/z:575.3[M+H] +
(5)化合物3的制备
Figure PCTCN2022081466-appb-000109
将LiOH(5mL)加入到化合物3-5(150mg，0.26mmol)的THF(2mL)和MeOH(2mL)溶液中，将混合物在室温下搅拌3小时，然后减压除去溶剂得到粗产物，粗产物通过HPLC纯化(梯度：10％MeCN/90％H 2O，0.1％NH 3·H 2O至100％MeCN)，得到(S)-2-((4-(6-((5-乙酰基噻吩-3-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸，为化合物3(62.17mg，43.6％)。
1H NMR(400MHz,DMSO-d6)δ8.13(s,1H),7.98(d,J＝5.2Hz,2H),7.80(d,J＝8.3Hz,1H),7.63(t,J＝7.7Hz,1H),7.47(d,J＝8.3Hz,1H),6.88(d,J＝7.3Hz,1H),6.66(d,J＝8.2Hz,1H),5.36–5.29(m,2H),5.17–5.06(m,1H),4.66(ddd,J＝17.8,15.2,4.7Hz,2H),4.51–4.32(m,2H),3.92(d,J＝13.4Hz,1H),3.77(d,J＝13.4Hz,1H),2.95(dd,J＝45.6,11.0Hz,2H),2.67(dt,J＝26.5,9.7Hz,2H),2.48(s,3H),2.47–2.40(m,1H),2.30–2.12(m,2H),1.90–1.65(m,4H).
LC-MS:(ESI)m/z:561.3[M+H] +
实施例4
(S)-2-((4-(6-((5-氰基噻吩-2-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸(化合物4)
Figure PCTCN2022081466-appb-000110
(1)化合物4-2的制备
Figure PCTCN2022081466-appb-000111
将化合物4-1(200mg，9.13mmol)，化合物4-1-1(331mg，1.19mmol)和K 2CO 3(274g，1.98mmol)在DMF(5mL)中的混合物在50℃下搅拌16小时。加入水(20mL)，反应溶液用EtOAc(3×20mL)萃取。合并的有机相用盐水(20mL)洗涤，干燥(Na 2SO 4)，过滤并浓缩。快速色谱法(SiO 2，25％EtOAc-己烷)处理，得到4-(6-((5-氰基噻吩-2-基)甲氧基)吡啶-2-基)哌啶-1-羧酸叔丁酯，为化合物4-2(270mg，68.4％)。
1H NMR(400MHz,CDCl3)δ7.60–7.44(m,2H),7.11(d,J＝3.8Hz,1H),6.78(d,J＝7.3Hz,1H),6.62(d,J＝8.1Hz,1H),5.57(s,2H),4.23(s,2H),2.94–2.68(m,3H),1.90(d,J＝12.4Hz,2H),1.82–1.61(m,2H),1.49(s,9H).
LC-MS:(ESI)m/z:344.1[M+H] +
(2)化合物4-3的制备
Figure PCTCN2022081466-appb-000112
将HCl/二噁烷(5mL)加入到化合物4-2(270mg，0.68mmol)的EtOAc(3mL)溶液中，将该混合物在室温搅拌1小时，然后将该混合物浓缩，得到固体。将固体溶解在水(10mL)中，用NaHCO 3(eq)调节至pH＞7，用EtOAc(10mL×3)萃取。合并的有机相用盐水(10mL)洗涤，干燥(Na 2SO 4)，过滤并浓缩，得到(S)-2-((4-(6-((5-氰基噻吩-2-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯，为化合物4-3(190mg，94％).
1H NMR(400MHz,DMSO-d6)δ7.88(d,J＝3.8Hz,1H),7.74–7.62(m,1H),7.39(d,J＝3.8Hz,1H),6.91(d,J＝7.3Hz,1H),6.69(d,J＝8.2Hz,1H),5.62(s,2H),3.11(dd,J＝8.8,6.1Hz,2H),2.83–2.63(m,3H),1.84(d,J＝11.9Hz,2H),1.70(m,J＝12.3,4.1Hz,2H).
(3)化合物4-4的制备
Figure PCTCN2022081466-appb-000113
将K 2CO 3(369mg，2.67mmol)加入到化合物4-3(190mg，0.67mmol)和化合物4-3-1(200mg，0.67mmol)在二噁烷(6mL)和CH 3CN(3mL)中的混合物中。将混合物在60℃下搅拌16小时。加入水(20mL)，溶液用DCM(10mL×3)萃取，合并的有机相用盐水(30mL)洗涤，干燥(Na 2SO 4)，过滤并浓缩。快速色谱法(硅胶，用0-10％的MeOH/DCM洗脱)得到(S)-2-((4-(6-((5-氰基噻吩-2-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯，为化合物4-4(240mg，64.4％)。
1H NMR(400MHz,CDCl 3)δ8.16(s,1H),7.97(d,J＝9.0Hz,1H),7.75(d,J＝8.5Hz,1H),7.56–7.49(m,2H),7.11(d,J＝3.1Hz,1H),6.79(d,J＝7.4Hz,1H),6.60(d,J＝8.4Hz,1H),5.57(s,2H),5.23(s,1H),4.74(d,J＝8.5Hz,2H),4.61(td,J＝8.1,6.2Hz,1H),4.47–4.35(m,1H),3.97(d,J＝14.9Hz,5H),3.01(t,J＝12.3Hz,2H),2.79–2.61(m,2H),2.40(m,3H),1.89(dd,J＝28.0,11.6Hz,4H).
LC-MS:(ESI)m/z:558.3[M+H] +
(4)化合物4的制备
Figure PCTCN2022081466-appb-000114
将LiOH(2mL)加入到化合物4-4(50mg，0.09mmol)的THF(1mL)和MeOH(1mL)溶液中，将混合物在室温下搅拌2小时，然后减压除去溶剂得到粗产物，粗产物用HPLC纯化(梯度：10％MeCN/90％H 2O，0.1％NH 3·H 2O至100％MeCN)，得到(S)-2-((4-(6-((5-氰基噻吩-2-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸，为化合物4(10.73mg，22.0％)。
1H NMR(400MHz,DMSO-d6)δ8.15(s,1H),7.88(d,J＝3.8Hz,1H),7.80(dd,J＝8.4,1.2Hz,1H),7.67(t,J＝7.8Hz,1H),7.51(d,J＝8.4Hz,1H),7.37(d,J＝3.8Hz,1H),6.93(d,J＝7.3Hz,1H),6.68(d,J＝8.2Hz,1H),5.62(s,2H),5.11(qd,J＝7.1,3.2Hz,1H),4.69(ddd,J＝18.0,15.2,5.0Hz,2H),4.50–4.34(m,2H),3.94(d,J＝13.4Hz,1H),3.78(d,J＝13.4Hz,1H),3.02(d,J＝11.4Hz,1H),2.90(d,J＝11.1Hz,1H),2.68(m,2H),2.48–2.39(m,1H),2.30–2.13(m,2H),1.92–1.69(m,4H).
LC-MS:(ESI)m/z:544.3[M+H] +
实施例5
(S)-2-((4-(6-((5-乙酰基-3-氯噻吩-2-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸(化合物5)
Figure PCTCN2022081466-appb-000115
(1)化合物5-2的制备
Figure PCTCN2022081466-appb-000116
向化合物5-1(1g，5.08mmol)和N,O-二甲基羟胺(541mg，5.58mmol)的无水DMF(20mL)溶液中加入HATU(2.89g，7.62mmol)、DIEA(3.28g，25.40mmol)。将反应混合物在室温搅拌16小时，将反应混合物在水(50mL)和EtOAc(50mL×3)之间混合。合并的有机相用盐水(50mL)洗涤，干燥(Na 2SO 4)，过滤并浓缩。快速色谱法(SiO 2，0-100％EtOAc-己烷)处理得到4,5-二氯-N-甲氧基-N-甲基噻吩-2-甲酰胺，为化合物5-2(900mg，75.0％)。
1H NMR(400MHz,DMSO-d 6)δ7.76(1H,s),3.80(3H,s),3.29(3H,s).
LCMS:(ESI)m/z:240.0[M+H] +
(2)化合物5-3的制备
Figure PCTCN2022081466-appb-000117
将化合物5-2(900mg，3.75mmol)，化合物5-2-1(3.96mL，13.87mmol)，K 2CO 3(1.6g，11.62mmol)和(Ph 3P) 4Pd(433mg，0.37mmol)在二噁烷(10mL)中的混合物在106℃下搅拌3小时，然后冷却至室温。将混合物通过硅藻土过滤，并将滤液减压浓缩。残余物通过硅胶色谱(SiO 2，40％EtOAc-己烷)纯化，得到4-氯-N-甲氧基-N,5-二甲基噻吩-2-甲酰胺，为化合物5-3(700mg，85.3％)。
1H NMR(400MHz,DMSO-d6)δ7.62(1H,s),3.76(3H,s),3.27(3H,s),2.41(3H,s).
LCMS:MF12-MC21-01-066R1,(ESI)m/z:220.0[M+H] +
(3)化合物5-4的制备
Figure PCTCN2022081466-appb-000118
在氮气、0℃下，向CH 3MgBr(2.1mL，6.4mmol)的THF溶液中滴加化合物5-3(700mg，3.2mmol)的无水THF(5mL)溶液。在用NH 4Cl(eq)猝灭反应混合物后，将反应混合物在室温搅拌2小时。用水(15mL)和EtOAc(15mL×3)萃取溶液，用盐水洗涤有机相，干燥(Na 2SO 4)。过滤后，减压浓缩溶剂，得到1-(4-氯-5-甲基噻吩-2-基)乙-1-酮，为化合物5-4(450mg，80.9％)。
1H NMR(400MHz,DMSO-d6)δ7.93(1H,s),2.50(3H,s),2.44(3H,s).
LCMS:(ESI)m/z:175.1[M+H] +
(4)化合物5-5的制备
Figure PCTCN2022081466-appb-000119
将化合物5-4(450mg，2.58mmol)、AIBN(8mg，0.052mmol)和NBS(505mg，2.84mmol)在CCl 4(10mL)中的混合物在80℃下搅拌16小时，然后将反应混合物用Na 2S 2O 3猝灭。用水(20mL)和DCM(20mL×3)萃取该溶液，用盐水(20mL)洗涤合并的有机相，干燥(Na 2SO 4)，过滤并浓缩。快速色谱法(SiO 2，0-100％EtOAc-己烷)处理，得到1-(5-(溴甲基)-4-氯噻吩-2-基)乙-1-酮，为化合物5-5(550mg，84.3％)。
1H NMR(400MHz,DMSO-d6)δ8.00(1H,s),4.94(2H,s),2.55(3H,s).
LC-MS:(ESI)m/z:253.0[M+H] +
(5)化合物5-6的制备
Figure PCTCN2022081466-appb-000120
将化合物5-5(530mg，1.98mmol)，化合物5-5-1(702mg，2.38mmol)和K 2CO 3(580mg，3.97mmol)在DMF(10mL)中的混合物在50℃下搅拌16小时，将反应混合物在水(20mL)和EtOAc(20mL×3)之间混合。合并的有机相用盐水(20mL)洗涤，干燥(Na 2SO 4)，过滤并浓缩。快速色谱法(SiO 2，0-100％EtOAc-己烷)处理，得到4-(6-((5-乙酰基-3-氯噻吩-2-基)甲氧基)吡啶-2-基)哌啶-1-甲酸叔丁酯，为化合物5-6(350mg，36.9％)。
1H NMR(400MHz,DMSO-d6)δ7.96(1H,s),7.70–7.60(1H,m),6.92(1H,d,J＝7.3),6.71(1H,d,J＝8.1),5.56(2H,s),4.09–4.02(2H,m),2.96–2.75(3H,m),2.52(3H,s),1.80(2H,d,J＝11.0),1.61(2H,dd,J＝12.3,3.8),1.41(9H,s).
LCMS:(ESI)m/z:451.1[M+H] +
(6)化合物5-7的制备
Figure PCTCN2022081466-appb-000121
将化合物5-6(340mg，0.76mmol)和HCl/二噁烷(7mL)的EtOAc(3mL)溶液在室温搅拌3小时，然后将该混合物浓缩得到固体，将其用水(10mL)溶解。用NaHCO 3(eq)调节溶液pH＞7，用EtOAc(10mL×3)萃取。合并有机相，用盐水洗涤(10mL)，干燥(Na 2SO 4)，过滤，浓缩，得到1-(4-氯-5-(((6-(哌啶-4-基)吡啶-2-基)氧基)甲基)噻吩-2-基)乙烷-1-酮，为化合物5-7(200mg，75.7％)。
1H NMR(400MHz,DMSO-d6)δ7.98(1H,d,J＝6.8),7.67(1H,t,J＝7.8),6.89(1H,d,J＝7.3),6.70(1H,d,J＝8.2),5.57(2H,s),3.04(2H,d,J＝12.1),2.68(1H,dd,J＝9.5,5.8),2.61(2H,dd,J＝12.1,10.1),2.52(3H,s),1.78(2H,d,J＝11.2),1.62(2H,qd,J＝12.3,3.9).
LCMS:(ESI)m/z:351.1[M+H] +
(7)化合物5-8的制备
Figure PCTCN2022081466-appb-000122
将化合物5-7(200mg，0.57mmol)，化合物5-7-1(185mg，0.63mmol)和K 2CO 3(315mg，2.28mmol)在二噁烷(10mL)和CH3CN(5mL)中的混合物在60℃下搅拌16小时，用水(30mL)和DCM(30mL×3)萃取该溶液，将合并的有机相用盐水(30mL)洗涤，干燥(Na 2SO 4)，过滤并浓缩。快速色谱法(SiO 2，0-100％EtOAc-己烷)处理，得到(S)-2-((4-(6-((5-乙酰基-3-氯噻吩-2-基)甲氧基)吡啶-2-基)哌啶-1-基) 甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯，为化合物5-8(200mg，57.8％)。
1H NMR(400MHz,DMSO-d6)δ8.30(1H,d,J＝1.2),7.97(1H,s),7.83–7.77(1H,m),7.71–7.61(2H,m),6.92(1H,d,J＝7.3),6.70(1H,d,J＝8.1),5.56(2H,s),5.11(1H,dd,J＝7.2,2.3),4.83(1H,dd,J＝15.2,7.2),4.68(1H,dd,J＝15.2,2.6),4.46(1H,dd,J＝10.6,4.8),4.36(1H,dt,J＝9.0,5.9),4.07–3.91(1H,m),3.87(3H,s),3.79(1H,d,J＝13.5),3.01(1H,d,J＝11.5),2.86(1H,d,J＝11.4),2.75–2.58(2H,m),2.50(3H,s),2.44(1H,s),2.22(2H,dd,J＝27.9,2.8),1.89–1.68(4H,m).
LC-MS:(ESI)m/z:609.2[M+H] +
(8)化合物5的制备
Figure PCTCN2022081466-appb-000123
将化合物5-8(177mg，0.29mmol)、LiOH(4mL)的THF(2.5mL)溶液和MeOH(1.5mL)溶液在室温下搅拌3小时。然后减压除去溶剂得到粗产物，粗产物用HPLC纯化(梯度：10％MeCN/90％H 2O，0.1％NH 3·H 2O至100％MeCN)，得到(S)-2-((4-(6-((5-乙酰基-3-氯噻吩-2-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸，为化合物5(79.71mg，46.2％)。
1H NMR(400MHz,DMSO-d6)δ8.10(1H,s),7.97(1H,s),7.80(1H,d,J＝8.4),7.66(1H,t,J＝7.7),7.44(1H,d,J＝8.3),6.92(1H,d,J＝7.3),6.70(1H,d,J＝8.2),5.56(2H,s),5.17–5.03(1H,m),4.73(1H,dd,J＝15.2,6.9),4.64–4.56(1H,m),4.47(1H,dd,J＝13.9,7.3),4.38(1H,dt,J＝11.8,5.9),3.91(1H,d,J＝13.3),3.76(1H,d,J＝13.3),2.99(1H,d,J＝10.8),2.88(1H,d,J＝10.9),2.66(2H,dd,J＝13.1,5.5),2.50(3H,s),2.46(1H,d,J＝8.8),2.27–2.10(2H,m),1.79(4H,dd,J＝16.6,10.3).
LC-MS:(ESI)m/z:595.2[M+H] +
实施例6
(S)-2-((4-(6-((5-(环丙烷羰基)噻吩-2-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸(化合物6)
Figure PCTCN2022081466-appb-000124
(1)化合物6-2的制备
Figure PCTCN2022081466-appb-000125
在0℃和N 2下，向6-1(5.0g，39.6mmol)在无水THF(50mL)中的溶液中滴加环丙基溴化镁(1.0M的THF溶液，47.6mL，47.6mmol)。在该温度下搅拌混合物0.5小时，然后在N 2下室温搅拌混合物2.5小时。用H 2O(100mL)猝灭反应溶液，用EtOAc(3×100mL)萃取。合并的有机相用盐水(100mL) 洗涤，干燥(Na 2SO 4)，过滤并浓缩。快速色谱法(SiO 2，EtOAc-己烷)处理得到6-2(7g，99.9％)。
1H NMR(400MHz,DMSO-d6)δ6.72(d,J＝3.3Hz,1H),6.63–6.55(m,1H),5.37(d,J＝4.9Hz,1H),4.08(dd,J＝7.3,5.0Hz,1H),2.38(d,J＝0.6Hz,3H),1.06(qt,J＝7.9,5.0Hz,1H),0.47–0.42(m,2H),0.41–0.36(m,1H),0.28(ddd,J＝9.3,4.2,1.4Hz,1H).
(2)化合物6-3的制备
Figure PCTCN2022081466-appb-000126
将6-2(8.6g，51.12mmol)加入到氧化锰(44.44g，511.1mmol)在DCE(172mL)中的溶液中。将混合物在70℃下搅拌3小时。将混合物滤出，并将滤液浓缩。快速色谱法(SiO 2，16％EtOAc-己烷)处理，得到6-3(7g，83.8％)。
1H NMR(400MHz,CDCl 3)δ7.63(d,J＝4.0Hz,1H),6.81-2-6.79(m,1H),2.53(d,J＝0.6Hz,3H),2.50-2.42(m,1H),1.23–1.17(m,2H),1.01-0.94(m,2H).
(3)化合物6-4的制备
Figure PCTCN2022081466-appb-000127
将6-3(700mg，4.211mmol)加入到BPO(20.4mg，0.0842mmol)和NBS(824.4mg，4.632mmol)的CCl 4(14mL)溶液中。将混合物在80℃下搅拌16小时。用EA稀释后，用EA(200mL×3)和H 2O萃取。真空浓缩有机层。快速色谱法(SiO 2，16％EtOAc-己烷)处理得到6-4(700mg，收率：67.9％)。
1H NMR(400MHz,CDCl 3)δ7.67–7.63(m,1H),7.14(d,J＝3.8Hz,1H),4.68(s,2H),2.53-2.45(m,1H),1.29–1.21(m,2H),1.08–1.00(m,2H).
(4)化合物6-5的制备
Figure PCTCN2022081466-appb-000128
向6-4(200mg，0.816mmol)和6-5-1(340.6mg，1.224mmol)在DMF(2ml)中的溶剂中，然后加入Cs 2CO 3(798mg，2.448mmol)。将混合物在N 2下于室温搅拌12小时。用H 2O(5mL)和EA(10mL*3)萃取。有机相用H 2O(10mL*3)和盐水(10mL)洗涤，并在Na 2SO 4上干燥。浓缩，残余物通过快速柱色谱法纯化，得到化合物6-5(168mg，收率：74.4％)。
1H NMR(400MHz,DMSO-d 6)δ7.66-7.54(m,2H),7.28(d,J＝9.4Hz,2H),6.86(d,J＝7.2Hz,1H),6.69(d,J＝8.0Hz,1H),5.39(s,2H),4.74(q,J＝7.2Hz,4H),4.06–4.00(m,2H),3.03(s,3H),2.90–2.70(m,3H),1.74(d,J＝12.0Hz,2H),1.57(d,J＝12.1Hz,2H),1.42(s,9H).
(5)化合物6-6的制备
Figure PCTCN2022081466-appb-000129
将6-5(168mg，0.380mmol)溶于和TsOH·H 2O(216.8mg，1.140mmol)在EA(10mL)中的溶剂中。在N 2气氛下于60℃搅拌该混合物1小时。在N 2气氛下，将混合物在室温下搅拌16小时。过滤，用EA(5mL*3)洗涤滤饼，干燥滤饼，得到6-6(130mg)。
LC-MS:(ESI)m/z:343.1[M+H] +
(6)化合物6-7的制备
Figure PCTCN2022081466-appb-000130
将混合物6-6(130mg，0.380mmol)和6-7-1(112mg，0.380mmol)加入到溶剂二噁烷(9ml)和MeCN(6ml)中，然后加入K 2CO 3(419mg)。将混合物在65℃搅拌16小时，用EA(100ml*3)和H 2O(100ml)萃取反应溶液，用盐水(100ml)洗涤有机相，并在Na 2SO 4上干燥。残余物通过柱色谱法(PE：EA＝5:1)纯化，得到6-7(112mg，收率：49.1％)。
LC-MS:(ESI)m/z:601.3[M+H] +
(7)化合物6的制备
Figure PCTCN2022081466-appb-000131
将7-7(40mg，0.0666mmol)和1M LiOH(0.5mL)加入到MeOH(0.5mL)和THF(0.5mL)中，在室温下搅拌16小时，同时减压除去溶剂，得到粗产物，粗产物通过HPLC纯化。粗产物通过HPLC纯化，得到5.78mg化合物6。
1H NMR(400MHz,DMSO-d 6)δ8.13(s,1H),8.00(d,J＝3.8Hz,1H),7.78(d,J＝8.4Hz,1H),7.65(t,J＝7.8Hz,1H),7.49(d,J＝8.4Hz,1H),7.32(d,J＝3.8Hz,1H),6.90(d,J＝7.2Hz,1H),6.67(d,J＝8.2Hz,1H),5.59(s,2H),5.13-5.06(m,1H),4.78-4.69(m,1H),4.65-4.55(m,1H),4.49-4.41(m,1H),4.40-4.32(m,1H),3.92(d,J＝13.4Hz,1H),3.76(d,J＝13.4Hz,1H),3.17(s,1H),3.00(d,J＝11.2Hz,1H),2.87(d,J＝11.2Hz,1H),2.80-2.73(m,1H),2.69–2.62(m,2H),2.46–2.40(m,1H),2.21(m,2H),1.78(m,4H),1.00–0.95(m,4H).
实施例7
(S)-2-((4-(6-((3-氯-5-氰基噻吩-2-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸(化合物7)
Figure PCTCN2022081466-appb-000132
(1)化合物7-2的制备
Figure PCTCN2022081466-appb-000133
向7-1(3.4g，17.26mmol)的DMF(50mL)溶液中加入DIEA(11.15g，86.3mmol)。然后加入HATU(9.86g，25.89mmol)。将混合物在室温搅拌0.5小时。然后加入NH 4Cl(1g，18.98mmol)。将混合物在室温搅拌16小时。加入H 2O(100mL)，反应溶液用EtOAc(3×100mL)萃取。用H 2O(3×100mL)和盐水(100mL)洗涤合并的有机相，干燥(Na 2SO 4)，过滤并浓缩。快速色谱法(SiO 2，己烷)得到2.6g化合物7-2，产率：76.9％。
1H NMR(400MHz,DMSO-d6)δ8.14(s,1H),7.80(s,1H),7.75(s,1H).
(2)化合物7-3的制备
Figure PCTCN2022081466-appb-000134
将混合物7-2(1.0g，5.10mmol)和2,4,6-三甲基-1,3,5,2,4,6-三氧三硼杂环己烷(3.5M在THF中，5.4mL，18.87mmol)加入到溶剂二噁烷(10mL)中。然后加入K 2CO 3(2.2g，15.81mmol)和Pd(PPh 3) 4(589mg，0.51mmol)。将反应溶液在106℃搅拌3小时。加入H 2O(10mL)，反应溶液用EtOAc(3×10mL)萃取。合并的有机相用盐水(10mL)洗涤，干燥(Na 2SO 4)，过滤并浓缩。快速色谱法(SiO 2，EtOAc-己烷)纯化，得到300mg化合物7-3，产率：33.4％。
δH(400MHz,DMSO-d6)7.96(1H,s),7.66(1H,s),7.49(1H,s),2.38(3H,s).
(3)化合物7-4的制备
Figure PCTCN2022081466-appb-000135
向7-3(530mg，3.03mmol)的DCM(30mL)溶液中加入Burgess试剂(2.2g，9.08mmol)。在N 2气氛下，将混合物于室温搅拌16小时。加入H 2O(30mL)，用DCM(3×30mL)萃取反应溶液。合并的有机相用盐水(30mL)洗涤，干燥(Na 2SO 4)，过滤并浓缩。快速色谱法(SiO 2，EtOAc-己烷)处理得到390mg化合物7-4，产率：81.9％。
1H NMR(400MHz,DMSO-d6)δ8.00(s,1H),2.46(s,3H).
(4)化合物7-5的制备
Figure PCTCN2022081466-appb-000136
向7-4(390mg，2.48mmol)在CCl 4(8mL)中的溶液中加入NBS(483g，2.73mmol)，然后加入AIBN(6mg，0.05mmol)。在N 2气氛下，在80℃下搅拌该混合物16小时。加入H 2O(10mL)，用DCM(3×10mL)萃取反应溶液。合并的有机相用盐水(10mL)洗涤，干燥(Na 2SO 4)，过滤并浓缩。快速色谱法(SiO 2，EtOAc-己烷)纯化，得到416mg化合物7-5，产率：71.2％。
δH(400MHz,DMSO-d6)8.08(1H,s),4.98(2H,s).
(5)化合物7-6的制备
Figure PCTCN2022081466-appb-000137
将混合物7-5(416mg，1.76mmol)和4-(6-羟基吡啶-2-基)哌啶-1-甲酸叔丁酯(590mg，2.11mmol)加入到溶剂DMF(8mL)中。然后加入K 2CO 3(482mg，3.52mmol)。将反应溶液在50℃下搅拌16小时。加入H 2O(10mL)，反应溶液用EtOAc(3×10mL)萃取。合并的有机相用盐水(10mL)洗涤，干燥(Na 2SO 4)，过滤并浓缩。快速色谱法(SiO 2，EtOAc-己烷)纯化，得到300mg化合物7-6，产率：39.1％。
δH(400MHz,DMSO-d6)8.12(1H,s),7.75(1H,dd,J＝8.1,7.4),7.00(1H,d,J＝7.2),6.78(1H,d,J＝8.1),5.63(2H,s),4.17–4.04(2H,m),2.88(3H,ddd,J＝11.7,8.2,3.6),1.87(2H,d,J＝10.9),1.68(2H,td,J＝12.5,4.1),1.47(10H,s).
(6)化合物7-7的制备
Figure PCTCN2022081466-appb-000138
向7-6(300mg，0.692mmol)在EtOAc(2mL)中的溶液中加入HCl·二噁烷(4mL)。将混合物在室温搅拌1小时。浓缩反应溶液，得到160mg化合物7-7，产率：69.2％
δH(400MHz,DMSO-d6)8.07(1H,s),7.68(1H,t,J＝7.8),6.91(1H,d,J＝7.3),6.70(1H,d,J＝8.2),5.58(2H,s),3.03(2H,d,J＝11.7),2.70(1H,t,J＝11.8),2.59(2H,t,J＝11.6),1.78(2H,d,J＝1.2),1.62(2H,td,J＝12.2,3.8).
(7)化合物7-8的制备
Figure PCTCN2022081466-appb-000139
将混合物7-7(160mg，0.479mmol)和(S)-2-(氯甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6- 甲酸甲酯(155mg，0.527mmol)加入到溶剂二噁烷(6mL)和MeCN(3mL)中，然后加入K 2CO 3(265mg，1.917mmol)。将反应溶液在60℃下搅拌16小时。加入H 2O(10mL)，反应溶液用EtOAc(3×10mL)萃取。合并的有机相用盐水(10mL)洗涤，干燥(Na 2SO 4)，过滤并浓缩。快速色谱法(SiO 2，EtOAc-己烷)纯化，得到190mg化合物7-8，产率：66.9％。
δH(400MHz,DMSO-d6)8.29(1H,s),8.07(1H,s),7.82(1H,dd,J＝8.5,1.4),7.73–7.64(2H,m),6.94(1H,d,J＝7.3),6.71(1H,d,J＝8.1),5.58(2H,s),5.11(1H,d,J＝4.9),4.83(1H,dd,J＝15.2,7.2),4.68(1H,dd,J＝15.2,2.6),4.47(1H,d,J＝5.8),4.42–4.33(1H,m),4.01–3.93(1H,m),3.87(3H,s),3.80(1H,d,J＝13.6),3.01(1H,d,J＝11.4),2.87(1H,d,J＝11.0),2.79–2.59(2H,m),2.43(1H,dd,J＝18.9,8.2),2.31–2.16(2H,m),1.88–1.66(4H,m).
(8)化合物7的制备
Figure PCTCN2022081466-appb-000140
向7-8(90mg，0.152mmol)在MeOH(2mL)和THF(1mL)中的溶液中加入1M LiOH(3mL)。将反应溶液在室温搅拌2小时，浓缩反应溶液，通过制备性HPLC纯化，得到3.26mg化合物7，产率：18.6％。
δH(400MHz,DMSO-d6)8.38(1H,s),8.23(1H,s),8.06(1H,s),7.82(1H,d,J＝8.4),7.68(1H,t,J＝7.8),7.58(1H,d,J＝8.3),6.94(1H,d,J＝7.3),6.71(1H,d,J＝8.1),5.58(2H,s),5.11(1H,d,J＝4.2),4.79(1H,dd,J＝15.0,6.9),4.65(1H,d,J＝13.1),4.47(1H,dd,J＝13.5,7.4),4.41–4.32(1H,m),3.94(1H,d,J＝13.5),3.83–3.73(2H,m),3.00(2H,d,J＝11.5),2.88(1H,d,J＝11.8),2.67(2H,d,J＝8.0),2.45(1H,s),2.29–2.12(2H,m),1.78(4H,dd,J＝37.9,13.2).
LC-MS:(ESI)m/z:578.2[M +H] +
实施例8
(S)-2-((4-(6-((4-氯-5-氰基噻吩-2-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸(化合物8)
Figure PCTCN2022081466-appb-000141
(9)化合物8-2的制备
Figure PCTCN2022081466-appb-000142
将8-1(1.0g，5.84mmol)在6N HCl(5ml)中的混合物冷却至0℃，滴加亚硝酸钠(403mg，5.84mmol)在水(1ml)中的溶液，并将该混合物在0℃下搅拌60分钟。然后将该混合物加入到氯化铜(578 mg，5.84mmol)的浓溶液中。HCl(5ml)在0℃下，将反应混合物在室温下搅拌，然后温热至65℃，直到气体逸出停止。将反应混合物用水稀释，用EtOAc萃取，用水、盐水洗涤，用硫酸钠干燥，过滤并蒸发。残余物通过快速柱色谱法(12％EtOAc/庚烷)纯化，得到780mg 8-2，收率70.9％。
1H NMR(400MHz,CDCl3)δ6.72(d,J＝0.8Hz,1H),3.86(s,3H),2.47(s,3H).
LC-MS:MC21-306-011-P(ESI)m/z:191.0[M+H] +
(10)化合物8-3的制备
Figure PCTCN2022081466-appb-000143
将LiOH(196mg，8.18mmol)在1mL H 2O中的溶液加入8-2(780mg，4.09mmol)在MeOH(4mL)中的溶液中，将混合物在室温下搅拌2小时，然后减压除去溶剂，得到粗产物，将粗产物溶于水中，用1mol/L盐酸调节到PH＝2。过滤混合物，得到8-3(470mg，粗产物)。
1H NMR(400MHz,DMSO-d6)δ6.96(s,1H),2.46(s,3H).
(11)化合物8-4的制备
Figure PCTCN2022081466-appb-000144
将NH 4Cl(100mg，1.87mmol)加入到8-3(300mg，1.70mmol)在DMF(5ml)中的溶液中，然后将HATU(969mg，2.55mmol)和DIEA(1.10g，8.49mmol)分别加入到该混合物中。在N 2气氛下，将混合物于室温搅拌16小时。加入水(20mL)，溶液用乙酸乙酯(10mL×3)萃取，合并的有机相用盐水(30mL)洗涤，用Na 2SO 4干燥，过滤并浓缩。残余物通过快速柱色谱法(28％EtOAc的庚烷溶液)纯化，得到120mg 8-4，收率40.2％。
1H NMR(400MHz,DMSO-d6)δ7.78(s,1H),7.37(s,1H),6.94(s,1H),2.49(s,3H).
LC-MS:MC21-306-018-P,(ESI)m/z:176.0[M+H] +
(12)化合物8-5的制备
Figure PCTCN2022081466-appb-000145
将Burgess试剂(651mg，2.73mmol)加入到8-4(160mg，0.91mmol)的DCM(5mL)溶液中，将该混合物在室温下搅拌16小时。加入水(10mL)，溶液用DCM(10mL×3)萃取，合并的有机相用盐水(30mL)洗涤，用Na 2SO 4干燥，过滤并浓缩。残余物通过快速柱色谱法(25％EtOAc的庚烷溶液)纯化，得到100mg 8-5，收率69.9％。
1H NMR(400MHz,DMSO-d6)δ7.16(d,J＝1.0Hz,1H),2.53(d,J＝0.9Hz,3H).
(13)化合物8-6的制备
Figure PCTCN2022081466-appb-000146
将NBS(124mg，0.20mmol)加入到CCl 4(10mL)中的8-5(100mg，0.63mmol)和AIBN(2mg， 0.01mmol)的混合物中，然后将反应溶液在80℃下搅拌16小时，之后将反应混合物用Na 2S 2O 3饱和溶液(5mL)猝灭。用水(20mL)和DCM(20mL×3)萃取溶液，用盐水(20mL)洗涤合并的有机相，用Na 2SO 4干燥，过滤并浓缩。快速色谱法(SiO 2，0-50％EtOAc/己烷)，得到8-6(50mg，收率33.6％)。
1H NMR(400MHz,DMSO-d6)δ7.51(s,1H),5.02(s,2H).
(14)化合物8-7的制备
Figure PCTCN2022081466-appb-000147
将8-6(50mg，0.21mmol)，8-6-1(71mg，0.25mmol)和K 2CO 3(59mg，0.42mmol)在DMF(3mL)中的混合物在50℃下搅拌16小时，完成后，加入H 2O(10mL)，并将反应溶液用EtOAc(3×10mL)萃取。合并的有机相用盐水(10mL)洗涤，干燥(Na 2SO 4)，过滤并浓缩。快速色谱法(SiO 2，25％EtOAc-己烷)处理得到8-7(40mg，收率44％)。
1H NMR(400MHz,DMSO-d6)δ7.75–7.65(m,1H),7.50(s,1H),6.95(d,J＝7.3Hz,1H),6.72(d,J＝8.1Hz,1H),5.58(s,2H),4.14–3.98(m,2H),2.83(t,J＝11.7Hz,3H),1.84(d,J＝12.7Hz,2H),1.60(qd,J＝12.6,4.2Hz,2H),1.41(s,9H).
(15)化合物8-8的制备
Figure PCTCN2022081466-appb-000148
将HCl/二噁烷(2mL)加入到8-7(40mg，0.09mmol)的EtOAc(2mL)溶液中，将该混合物在室温搅拌1小时，然后将该混合物浓缩，得到固体。将固体溶解在H 2O(3mL)中，用NaHCO 3(eq)调节至pH＞7，用EtOAc(5mL×3)萃取。合并的有机相用盐水(10mL)洗涤，干燥(Na 2SO 4)，过滤并浓缩，得到8-8(35mg，粗产物)。
1H NMR(400MHz,DMSO-d6)δ7.73–7.63(m,1H),7.52(s,1H),6.91(d,J＝7.3Hz,1H),6.70(d,J＝8.1Hz,1H),5.59(s,2H),3.03(d,J＝12.0Hz,2H),2.74–2.54(m,3H),1.78(d,J＝13.0Hz,2H),1.60(qd,J＝12.3,3.9Hz,2H).
(16)化合物8-9的制备
Figure PCTCN2022081466-appb-000149
将K 2CO 3(58mg，0.42mmol)加入到8-8(35mg，0.10mmol)和8-8-1(31mg，0.10mmol)在二噁 烷(2mL)和CH 3CN(1mL)中的混合物中。将混合物在60℃下搅拌16小时。加入水(5mL)，溶液用DCM(5mL×3)萃取，合并的有机相用盐水(10mL)洗涤，干燥(Na 2SO 4)，过滤并浓缩。快速色谱法(硅胶，用0-10％MeOH/DCM洗脱)，得到8-9(34mg，收率54.8％)。
LC-MS:MC21-306-030-P,(ESI)m/z:592.2[M+H] +
(17)化合物8的制备
Figure PCTCN2022081466-appb-000150
将LiOH(2mL)加入到8-9(34mg，0.06mmol)的THF(2mL)溶液中，将混合物在室温下搅拌3小时，然后减压除去溶剂得到粗产物，粗产物通过HPLC纯化(梯度：10％MeCN/90％H 2O，0.1％NH 3·H2O至100％MeCN)，得到化合物8,(3.11mg，收率9.3％)。
1H NMR(400MHz,DMSO-d6)δ8.06(s,1H),7.77(d,J＝7.6Hz,1H),7.72–7.64(m,1H),7.50(s,1H),7.42(d,J＝8.2Hz,1H),6.94(d,J＝7.3Hz,1H),6.70(d,J＝8.2Hz,1H),5.58(s,2H),5.16–5.05(m,1H),4.72(dd,J＝15.3,7.1Hz,1H),4.60(dd,J＝15.6,3.2Hz,1H),4.47(dd,J＝13.7,7.7Hz,1H),4.36(dt,J＝8.8,5.9Hz,1H),3.91(d,J＝13.3Hz,1H),3.77(d,J＝13.3Hz,1H),3.00(d,J＝10.2Hz,1H),2.90(d,J＝11.4Hz,1H),2.67(dt,J＝13.4,7.0Hz,2H),2.43(dd,J＝18.9,7.9Hz,1H),2.29–2.13(m,2H),1.90–1.69(m,4H).
LC-MS:MC21-306-037-P(ESI)m/z:578.0[M+H] +
实施例9
(S)-1-(氧杂环丁烷-2-基甲基)-2-((4-(6-((5-(三氟甲基)噻吩-2-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-甲酸(化合物9)
Figure PCTCN2022081466-appb-000151
(1)化合物9-2的制备
Figure PCTCN2022081466-appb-000152
向9-1(2g，10.2mmol)和K 2CO 3(1.41g，10.2mmol)在DMF(80mL)中的溶液中，在0℃和N 2下滴加CH 3I(2.895g，20.4mmol)。将反应物在室温搅拌2小时。用EA和H 2O(100mL×3)萃取。合并的有机层用盐水洗涤，在无水Na 2SO 4下干燥并过滤。残余物通过柱色谱纯化，得到9-2(2g，95.2％)。
1H NMR(400MHz,DMSO-d 6)δ7.89-7.85(m,1H),7.82(d,J＝4.0Hz,1H),3.90(s,3H).
(2)化合物9-3的制备
Figure PCTCN2022081466-appb-000153
在N 2下，在0℃下，向9-2(2g，9.5mmol)的THF(60mL)溶液中滴加LiAlH 4(9.5mL，9.5mmol)。将反应物在室温搅拌2小时。之后，用硫酸钠十水合物淬灭反应。通过过滤除去固体。将滤液浓缩至干，得到粗产物。残余物通过柱色谱纯化，得到9-3(1.4g，82.4％)。
1H NMR(400MHz,DMSO-d 6)δ7.55-7.50(m,1H),7.05-7.00(m,1H),5.84-5.78(m,1H),4.70(d,J＝5.6Hz,2H).
(3)化合物9-4的制备
Figure PCTCN2022081466-appb-000154
向9-3(1.4g，7.686mmol)、pph 3(2.416g，9.22mmol)和NBS(1.641g，9.22mmol)的DCM(35mL)溶液混合。将混合物在室温搅拌5小时，将混合物用DCM稀释，然后用DCM(20mL×3)和H 2O萃取。粗残余物通过SGC纯化，得到产物9-4(1.3g，71.5％)。
1H NMR(400MHz,DMSO-d 6)δ7.58(s,1H),7.37–7.30(m,1H),5.06(s,2H).
(4)化合物9-5的制备
Figure PCTCN2022081466-appb-000155
将混合物9-4(220mg，0.898mmol)和9-5-1(375mg，1.347mmol)加入到溶剂DMF(10ml)中，然后加入Cs 2CO 3(878mg，2.693mmol)。将混合物在N 2中于室温搅拌12小时。用H 2O(50mL)和EA(100mL×3)进行萃取。有机相用H 2O(100mL×3)和盐水(100mL)洗涤，并Na 2SO 4干燥。浓缩，残留物用柱色谱纯化，得到9-5(200mg，65.1％)。
1H NMR(400MHz,DMSO-d 6)δ7.70–7.63(m,1H),7.60-7.57(m,1H),7.30(d,J＝2.6Hz,1H),6.92(d,J＝7.2Hz,1H),6.68(d,J＝8.0Hz,1H),5.59(s,2H),4.15–3.97(m,2H),2.95-2.70(m,3H),1.84(s,2H),1.73–1.54(m,2H),1.40(s,9H).1H NMR(400MHz,DMSO)
(5)化合物9-6的制备
Figure PCTCN2022081466-appb-000156
将混合物9-5(200mg，0.0678mmol)与TsOH·H 2O(255mg，0.204mmol)添加至溶剂EA(4ml)中。将混合物在N 2中在60℃搅拌1小时。将混合物在N 2中于室温搅拌16小时。过滤，用EA(5mL*3)洗涤滤饼，干燥滤饼，得到产物9-6(132.2mg)。
LC-MS:(ESI)m/z:343.0[M+H] +
(6)化合物9-7的制备
Figure PCTCN2022081466-appb-000157
将混合物9-6(132mg，0.380mmol)和9-7-1(113.2mg，0.380mmol)加入到溶剂二噁烷(3ml)和MeCN(2ml)中，然后加入K 2CO 3(425.3mg)。将混合物在65℃搅拌12小时，用EA(100ml×3)和H 2O(100ml)萃取反应溶液，用盐水(100ml)洗涤有机相，并在Na 2SO 4上干燥。残余物用柱色谱纯化，得到9-7(140mg，65.1％)。
LC-MS:(ESI)m/z:601.1[M+H] +
(7)化合物9的制备
Figure PCTCN2022081466-appb-000158
将9-7(140mg，0.233mmol)和1M LiOH(1mL)加入MeOH(1mL)和THF(1mL)中，并在室温下搅拌16小时，粗产物通过HPLC纯化，得到标题产物(S)-1-(氧杂环丁烷-2-基甲基)-2-((4-(6-((5-(三氟甲基)噻吩-2-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-甲酸(化合物9)，64.94mg。
1H NMR(400MHz,DMSO-d 6)δ8.06(s,1H),7.76(d,J＝8.2Hz,1H),7.68–7.62(m,1H),7.62–7.59(m,1H),7.42(d,J＝8.0Hz,1H),7.32(s,1H),6.92(d,J＝7.2Hz,1H),6.67(d,J＝8.0Hz,1H),5.60(s,2H),5.10(d,J＝4.2Hz,1H),4.75-4.67(m,1H),4.63–4.55(m,1H),4.49-4.42(m 1H),4.40-4.32(m,1H),3.91(d,J＝13.4Hz,1H),3.76(d,J＝13.4Hz,1H),3.01(d,J＝11.0Hz,1H),2.90(d,J＝7.6Hz,1H),2.71–2.61(m,2H),2.47–2.38(m,1H),2.30–2.12(m,2H),1.80(m,4H).
LC-MS:MC21-238-081(ESI)m/z:587.3[M+H] +
实施例10
1-(氧杂环丁烷-2-基甲基)-2-((4-(6-(噻吩并[2,3-c]吡啶-2-基甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-羧酸(化合物10)
Figure PCTCN2022081466-appb-000159
(1)化合物10-2的制备
Figure PCTCN2022081466-appb-000160
在氮气氛下，向10-1(1.0g，3.78mmol)、Cs 2CO 3(1.4g，4.16mmol)在无水THF(20mL)中的溶液中加入2-巯基乙酸甲酯(401mg，3.78mmol)，将混合物在60℃下搅拌2小时，反应完成后，过滤并浓缩，用EA萃取三次，将合并的有机层用水和盐水洗涤，用无水Na 2SO 4干燥，过滤并浓缩，得到10-2(1.0g，粗品)。
1H NMR(400MHz,CDCl 3)δ9.08(s,1H),8.65(s,1H),8.16(s,1H),4.01(s,3H).
LC-MS:(ESI)m/z:273.9[M+H]+
(2)化合物10-3的制备
Figure PCTCN2022081466-appb-000161
向10-2(1.0g，3.67mmol)在无水THF/MeOH(3:1，20mL)中的溶液中加入TEA(1.1g，11.01mmol)、Pd/C(300mg，10％Pd)，将混合物在H 2气氛下在50℃下搅拌24小时，反应完成后，过滤并浓缩，得到10-3(825mg，粗产物)。
1H NMR(400MHz,CDCl 3)δ9.21(s,1H),8.57(d,J＝5.5Hz,1H),8.06(s,1H),7.76(d,J＝5.5Hz,1H),3.98(s,3H).
LC-MS:(ESI)m/z:194.2[M+H]+
(3)化合物10-4的制备
Figure PCTCN2022081466-appb-000162
向10-3(2.5g，12.9mmol)的无水THF(25mL)溶液中滴加LiAlH 4(13mL，1.0M的THF溶液)，同时在0℃下搅拌，将混合物在相同温度下搅拌0.5小时，反应完成后，将Na 2SO 4.10H 2O缓慢加入到反应混合物中，然后过滤和浓缩，将所得残余物通过SGC(MeOH的DCM 0～10％)纯化，得到10-4(410mg，收率19％)。
1H NMR(400MHz,DMSO)δ9.15(s,1H),8.42(d,J＝5.4Hz,1H),7.74(dd,J＝5.4,0.9Hz,1H),7.35(d,J＝0.8Hz,1H),5.85(t,J＝5.8Hz,1H),4.82(dd,J＝5.8,1.1Hz,2H).
LC-MS:(ESI)m/z:166.2[M+H]+
(4)化合物10-5的制备
Figure PCTCN2022081466-appb-000163
向10-4(100mg，0.6mmol)在无水DCM(5mL)中的溶液中加入MsCl(83mg，0.72mmol)和TEA(0.84mL，6.05mmol)。将反应混合物在0℃下搅拌30分钟，然后用水淬灭。用DCM萃取后，用盐水洗涤有机层，用无水Na 2SO 4干燥，并真空浓缩，得到147mg粗品10-5。
(5)化合物10-6的制备
Figure PCTCN2022081466-appb-000164
将10-5(147mg，0.6mmol)，2-((4-(6-羟基吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸甲酯(50mg，0.12mmol)，和Cs 2CO 3(217mg，0.66mmol)在DMF(10ml)中的混合物在50℃下搅拌过夜，将反应用H 2O(10ml)猝灭，用DCM(10ml×3)萃取后，将有机层用盐水洗涤，用无水Na 2SO 4干燥，并真空浓缩，得到残余物。粗产物通过HPLC纯化(梯度：10％MeCN/90％H 2O，H 2O至100％MeCN)，得到10-6(30mg)。
LC-MS:MC21-231-109-P,(ESI)m/z:584.2[M+H]+
(6)化合物10的制备
Figure PCTCN2022081466-appb-000165
将10-6(30mg，0.05mmol)、LiOH(0.5mL)的THF(0.5mL)溶液在室温下搅拌2小时。然后减压除去溶剂，得到粗产物，粗产物用HPLC纯化(梯度：10％MeCN/90％H 2O，0.1％NH 3·H 2O至100％MeCN)，得到1.62mg化合物10。
1H NMR(400MHz,DMSO)δ9.16(s,1H),8.41(d,J＝5.4Hz,1H),8.06(s,1H),7.76(d,J＝6.5Hz,2H),7.69–7.64(m,1H),7.59(s,1H),7.41(d,J＝8.3Hz,1H),6.92(d,J＝7.3Hz,1H),6.71(d,J＝8.2Hz,1H),5.74(s,2H),5.11(m,J＝6.9,3.2Hz,1H),4.70(dd,J＝15.2,6.8Hz,1H),4.58(dd,J＝15.1,3.1Hz,1H),4.47–4.31(m,2H),3.90(d,J＝13.4Hz,1H),3.75(d,J＝13.4Hz,1H),3.00(d,J＝11.0Hz,1H),2.89(d,J＝11.4Hz,1H),2.69–2.62(m,2H),2.42(dd,J＝11.1,4.1Hz,1H),2.27–2.13(m,2H),1.90–1.72(m,4H).
LC-MS:MC21-231-114-P,(ESI)m/z:570.2[M+H] +
实施例11
(S)-2-((4-(6-((5-氰基-3-甲基噻吩-2-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸(化合物11)
Figure PCTCN2022081466-appb-000166
(1)化合物11-2的制备
Figure PCTCN2022081466-appb-000167
将化合物7(60mg，0.101mmol)和三氟(甲基)硼酸钾(124mg，1.015mmol)加入溶剂甲苯(20mL)和H 2O(2mL)中，然后加入cataCXium-A-Pd-G3(4mg，0.005mmol)和Cs 2CO 3(100mg，0.304mmol)。将反应溶液在90℃下搅拌16小时。加入H 2O(20mL)，反应溶液用EtOAc(3×20mL)萃取。合并的有机相用盐水(20mL)洗涤，干燥(Na 2SO 4)，过滤并浓缩。快速色谱法(SiO 2，EtOAc-己烷)纯化得到30mg化合物11-2，产率：51.7％。
1H NMR(400MHz,CDCl 3)δ8.10(d,J＝1.1Hz,1H),7.90(dd,J＝8.5,1.5Hz,1H),7.68(d,J＝8.5Hz,1H),7.45(dd,J＝8.1,7.5Hz,1H),7.27(s,1H),6.70(d,J＝7.3Hz,1H),6.51(d,J＝8.0Hz,1H),5.42(s,2H),5.23(s,1H),5.17(m,1H),4.67(m,2H),4.55(td,J＝7.9,6.1Hz,1H),4.33(dt,J＝9.1,5.9Hz,1H),3.92(s,2H),3.88(s,3H),3.41(s,1H),2.94(t,J＝13.0Hz,2H),2.73–2.54(m,2H),2.43–2.36(m,1H),2.25(s,3H),1.95(d,J＝4.0Hz,4H).
(2)化合物11的制备
Figure PCTCN2022081466-appb-000168
向11-2(30mg，0.05mmol)的THF(5mL)溶液中加入1M LiOH(0.5mL)。将反应溶液在室温搅拌3小时，浓缩反应溶液，通过制备型HPLC纯化，得到1mg化合物11，产率：3.4％。
1H NMR(400MHz,DMSO-d6)δ8.32(s,1H),8.24(s,1H),7.81(d,J＝8.3Hz,1H),7.74(s,1H),7.67–7.59(m,2H),6.91(d,J＝7.4Hz,1H),6.67(d,J＝8.2Hz,1H),5.55(s,2H),5.11(q,J＝8.5Hz,1H),4.80(dd,J＝15.4,6.9Hz,1H),4.66(d,J＝13.3Hz,1H),4.47(dd,J＝13.6,7.4Hz,1H),4.37(m,1H),3.95(d,J＝13.5Hz,1H),3.79(d,J＝13.4Hz,1H),3.00(s,1H),2.89(s,1H),2.74–2.60(m,4H),2.46(s,1H),2.29(s,3H),1.84-1.71(m,4H).
LC-MS:(ESI)m/z:558.2[M+H] +
实施例12
(S-2-((2-((5-氰基噻吩-2-基)甲氧基)-5,8,10,11-四氢氧杂环庚三烯并[4,3-b:6,5-c’]二吡啶-9(7H)-基)甲基)-1-(氧杂环丁烷-2-基甲基)-1H-苯并[d]咪唑-6-甲酸(化合物12)
Figure PCTCN2022081466-appb-000169
其中中间体2-羟基-5,8,10,11-四氢氧杂环庚三烯并[4,3-b:6,5-c’]联吡啶-9(7H)-甲酸酯(12-i)的制备路线如下，
Figure PCTCN2022081466-appb-000170
向2-氯-6-羟基烟酸12-1a(5.0g，29mmol)在MeOH(40mL)中的混合物中加入硫酸(10mL)。将混合物在80℃下搅拌16小时。用冰水猝灭反应混合物，用EA萃取混合物，用盐水洗涤合并的有机层(50mL)，用Na 2SO 4干燥并减压浓缩，得到2-氯-6-羟基烟酸甲酯，12-2a(4.5g，83％收率)。
加入2-氯-6-羟基烟酸甲酯12-2a(3.4g，18.2mmol)、PMB-Cl(3.4g，21.2mmol)和K 2CO 3(3.76g，27.3mmol)在DMF(50mL)中的反应混合物。在80℃下用Ar 2搅拌混合物2小时。通过LC-MS检测反应混合物完全。通过加入水将反应混合物猝灭。水相用EtOAc(100mL×3)萃取，用盐水洗涤。合并的有机层用Na 2SO 4干燥。浓缩并通过洗脱纯化(PE/EA＝0-20％)，得到2-氯-6-((4-甲氧基苄基)氧基)烟酸甲酯12-3a(2.9g，52％收率)。
加入2-氯-6-((4-甲氧基苄基)氧基)烟酸甲酯12-3a(2.9g，9.4mmol)、4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-5,6-二氢吡啶-1,3(2H)-二羧酸1-4甲酯(4.16g，11.3mmol)、Cs 2CO 3(6.16g，18.8mmol)和Pd(dppf)Cl 2(0.69g，0.94mmol)在1,4-二噁烷(80mL)中的反应混合物。在110℃下用Ar 2搅拌该混合物16小时。通过LC-MS检测反应混合物完全。浓缩并通过洗脱纯化(PE/EA＝0-20％)，得到1'-(叔丁基)3,3'-二甲基-6-((4-甲氧基苄基)氧基)-5',6'-二氢-[2,4'-联吡啶]-1',3,3'(2'H)-三羧酸酯12-4a(2.5g，53.2％收率)。
将12-4a(1.5g，2.9mmol)溶于无水THF(15mL)中，然后在0℃分批加入LiAlH 4(0.222g，5.8mmol)。10分钟后，通过LC-MS检测反应混合物完全。用冰水(0.5mL)猝灭反应混合物。过滤混合物并浓缩，得到3,5'-二(羟甲基)-6-((4-甲氧基苄基)氧基)-3',6'-二氢-[2,4'-联吡啶]-1'(2'H)-羧酸叔丁酯12-5a(1.2g，92％收率)。
加入12-5a(1.1g，2.4mmol)、樟脑磺酸(3.24g，9.6mmol)在TOL(20mL)中的反应混合物。将混合物在110℃加热1小时。通过LC-MS检测反应混合物完全。浓缩并通过洗脱纯化(MeOH/DCM＝0-20％)，得到5,7,8,9,10,11-六羟基氧杂环庚三烯并[4,3-b:6,5-c']联吡啶-2-醇12-6a(0.4g，76％收率)。
将12-6a(0.35g，1.6mmol)在DCM(15mL)中的溶液中加入(Boc) 2O(0.42g，1.9mmol)和TEA(0.2mL)。将混合物在室温下搅拌1小时。通过LC-MS检测反应混合物完全。浓缩并通过洗脱(MeOH/DCM＝0-10％)纯化，得到2-羟基-5,8,10,11-四氢氧杂环庚三烯酮[4,3-b:6,5-c']联吡啶-9(7H)-甲酸酯12-i(350mg，70％收率)。 1H NMR(400MHz,CDCl 3)δ12.63(s,1H),7.43(d,J＝9.2Hz,1H),6.49(d,J＝9.1Hz,1H),4.17(s,4H),3.80(s,2H),3.67(t,J＝5.5Hz,2H),2.72(s,2H),1.51(s,9H).
(1)化合物12-1的制备
Figure PCTCN2022081466-appb-000171
向12-i(200mg，0.65mmol)中分批加入NaH(32.7mg，0.85mmol)。搅拌反应混合物5分钟后， 加入5-(溴甲基)噻吩-2-腈(131.5mg，0.65mmol)，并在室温下搅拌10分钟。通过加入H 2O猝灭反应混合物。水相用EtOAc(30mL×3)萃取，用盐水(30mL×2)洗涤。合并的有机层用Na 2SO 4干燥并浓缩。将残余物通过洗脱纯化，得到12-1(210mg，71.7％收率)。
LCMS:r.t.＝2.189min,[M+H]+＝440.
(2)化合物12-2的制备
Figure PCTCN2022081466-appb-000172
将12-1(200mg，0.47mmol)的EtOAc/HCl(10mL)溶液混合。将混合物在室温下搅拌2小时。通过LCMS检测反应混合物完全。浓缩反应溶液，得到12-2(200mg，粗产品)。
LCMS:r.t.＝1.391min,[M+H]+＝340
(3)化合物12-3的制备
Figure PCTCN2022081466-appb-000173
将12-2(200mg，0.589mmol)、DIEA(117.23mg，0.531mmol)在10mL CH 3CN中的反应混合物在室温下搅拌10分钟。然后加入Int-2(111.5mg，0.358mmol)并在60℃加热12小时浓缩该反应混合物，并通过洗脱(MeOH/DCM＝0-5％)纯化，得到12-3(160mg，45％收率)。
LCMS:r.t＝1.388min,[M+H]+＝598
(4)化合物12的制备
Figure PCTCN2022081466-appb-000174
向12-3(160mg，0.27mmol)在THF(5mL)中的混合物中，加入氢氧化锂溶液(1N，5mL)。将混合物在室温下搅拌2小时。将混合物浓缩，通过预HPLC纯化，冷冻干燥，得到化合物12(19.65mg，12.58％收率)。
LCMS:r.t＝1.224min,[M+H]+＝584
1H NMR(400MHz,MeOD)δ8.18(s,1H),7.95(dd,J＝8.4,1.5Hz,1H),7.65–7.57(m,3H),7.23(d,J＝3.8Hz,1H),6.70(d,J＝8.2Hz,1H),5.64(s,2H),5.27(d,J＝6.7Hz,1H),4.72(dd,J＝15.3,3.0Hz,3H),4.61(dd,J＝13.7,7.9Hz,2H),4.46(dd,J＝5.9,3.1Hz,1H),4.37(s,2H),4.12(dd,J＝34.0, 13.6Hz,2H),3.90(s,2H),2.85(s,4H),2.75(d,J＝6.5Hz,1H),2.57–2.49(m,1H).
实施例13
(S)-1-(氧杂环丁烷-2-基甲基)-2-((4-(6-((5-(嘧啶-5-基)噻吩-2-基)甲氧基)吡啶-2-基)哌啶-1-基)甲基)-1H-苯并[d]咪唑-6-甲酸(化合物13)
Figure PCTCN2022081466-appb-000175
(1)化合物13-2的制备
Figure PCTCN2022081466-appb-000176
将13-1(871mg，4.52mmol)、5-(三丁基甲锡烷基)嘧啶(2.2mL，6.77mmol)、Pd 2(dba 3) 2(828mg，0.90mmol)和Cy 3P(253mg，0.90mmol)在干燥DME(20mL)中的混合物在90℃下搅拌16小时，用DCM/MeOH(3×20mL)萃取反应溶液。合并的有机相用盐水(20mL)洗涤，干燥(Na 2SO 4)，过滤并浓缩。快速色谱法(SiO 2，EtOAc-己烷)，得到360mg化合物13-2。
1H NMR(400MHz,CDCl 3)9.09(1H,s),9.08(2H,s),7.61(1H,d,J＝3.6),7.06(1H,d,J＝3.7),5.64(1H,t,J＝5.7),4.69(2H,d,J＝5.7).
LC-MS:(ESI)m/z:193[M+H] +
(2)化合物13-3的制备
Figure PCTCN2022081466-appb-000177
向13-2(360mg，1.87mmol)在无水DCM(5mL)中的溶液中加入MsCl(257mg，2.24mmol)和TEA(2.6mL，18.7mmol)。将反应混合物在0℃下搅拌30分钟，然后用水淬灭。用DCM萃取后，用盐水洗涤有机层，用无水Na 2SO 4干燥，真空浓缩，得到13-3，(500mg，粗产物)。
(3)化合物13-4的制备
Figure PCTCN2022081466-appb-000178
将13-3(500mg，1.84mmol)和Cs2CO3(663mg，2.03mmol)在DMF(10ml)中的混合物在50℃下搅拌过夜，将反应用H 2O(10ml)猝灭，用DCM(10ml×3)萃取后，将有机层用盐水洗涤，用无水Na 2SO 4干燥，并真空浓缩，得到残余物。粗品用HPLC纯化(梯度：10％MeCN/90％H 2O，H 2O至 100％MeCN)，得到194mg化合物13-4。
LC-MS:MC21-663-034-P,(ESI)m/z:611.4[M+H] +
(4)化合物13的制备
Figure PCTCN2022081466-appb-000179
将13-4(197mg，0.32mmol)，LiOH 0.5mL的THF(0.5mL)溶液在室温下搅拌2小时。然后减压除去溶剂，得到粗产物，粗产物用HPLC纯化(梯度：10％MeCN/90％H 2O，0.1％NH 3·H 2O至100％MeCN)，得到64.79mg化合物13。
LC-MS:MC21-663-037-P,(ESI)m/z:597.3[M+H] +
1H NMR(400MHz,DMSO)δ9.09(s,1H),9.06(s,2H),8.26(s,1H),7.81(dd,J＝8.0Hz,1H),7.65(m,3H),7.32(d,J＝4.0Hz,1H),6.91(d,J＝8.0Hz,1H),6.66(d,J＝8.0Hz,1H),5.67–5.54(m,2H),5.11(m,1H),4.79(dd,J 1＝8.0Hz,J 2＝16.0Hz 1H),4.65(dd,J＝12.0Hz,1H),4.44(m,1H),4.36(m,1H),3.97(d,J＝16.0Hz,1H),3.82(d,J＝16.0Hz,1H),3.04(d,J＝12.0Hz,1H),2.89(d,J＝12.0Hz,1H),2.69(m,2H),2.42(m,1H),2.31–2.15(m,2H),1.96–1.72(m,4H).
以上本发明所提供的GLP-1受体激动剂及其应用进行了详细的介绍。本文中应用了具体实施例对本发明的原理及实施方式进行了阐述，以上实施例的说明只是用于帮助理解本发明的方法及其中心思想。应当指出，对于本领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以对本发明进行若干改进和修饰，这些改进和修饰也落入本发明权利要求的保护。

Claims (14)

  1. 式I的化合物
    Figure PCTCN2022081466-appb-100001
    及其药学上可接受的盐，其中
    T 1和T 2分别独立地选自CH 2、NH、O、S；
    W 1选自O、S、CH 2、NH；
    W 2选自O、NH、CH 2、CR y；
    Z 1、Z 2、Z 3、Z 4分别独立地选自CH、N或C；
    X 1、X 2、X 3分别独立地选自CH、N或C，且X 1、X 2、X 3中至多有两个为N；
    环B选自苯环或5～7元杂芳环；
    环C选自苯环、4～8元杂环、5～10元螺环、5～10元桥环及5～7元杂芳环；
    R 1独立地选自R 2、-羰基-R 2、-羰基-胺基-R 2，-磺酰基-R 2，-酰胺基-R 2，-氧磷基-R 2，-胺基-R 2，-O-R 2，其中R 1中的R 2、胺基、酰胺基、磺酰基、氧磷基可任选地由独立选自R x的取代基取代1～3次；
    R 2独立地选自氢、氧代、卤素、-C 1～6烷基、-C 2～6烯基、-C 2～6炔基、-C 1～6烷氧基、-C 1～6环烷氧基、氰基、3～8元环烷基、3～8元杂环基、苯基、5～8元杂芳基，其中R 2中的卤素、烷基、烯基、炔基、胺基、烷氧基、环烷氧基、环烷基、杂环基、苯基、杂芳基可任选地由独立选自R x的取代基取代1～3次；
    R 3独立地选自氢、氧代、卤素、-CN、-C 1～6烷基、-C 2～6烯基、-C 2～6炔基、-C 1～6烷氧基、胺基、酰胺基、磺酰基、磺酰胺基、-OH、-C 3～8环烷基、3～8元杂环基、6～10元芳基、5～8元杂芳基，其中R 3在化合价允许的条件下可任选地由独立选自R y的取代基取代1～3次；
    R 4独立地选自氢、卤素、-C 1～3烷基、-C 1～3卤代烷基、-C 1～3烷氧基、氰基、羟基、胺基、酰胺基、磺酰基、磺酰胺基；
    R 5独立地选自氢、卤素、羟基、-CN、-C 1～3烷基、-C 1～3烷氧基、-C 1～3环烷基，其中所述R 5中的烷基、烷氧基、环烷基在化合价允许的条件下可任选地由卤素、羟基、-NR z、-CN、-C 1～3烷基、-C 1～3烷氧基、-C 1～3环烷基取代1～3次；
    R 6选自-R z、-O-R z、-S-R z、-C 1～3烷基、-C 1～3亚烷基-R z、-C 0～3亚烷基-胺基-R z、-C 0～3亚烷基-羰基-R z、-C 0～3亚烷基-酰胺基-R z、-C 0～3亚烷基-磺酰基-R z、-C 0～3亚烷基-磷酰基-R z、-C 0～3亚烷基-磺酰胺基-R z，其中所述R 6中的烷基、胺基、酰胺基、磺酰基、磺酰胺基、磷酰基在化合价允许的条件下可任选地由卤素取代1～3次或由R w取代1次；
    R 7选自-COOH、-C(R y) n0-COOH、-N(R z) n0-COOH、-SO 2-COOH和-SO 2-NH-COOH，所述-C(R y) n0-中的R y可以以主链和/或支链的形式连接在C上，所述-N(R z) n0-中的R z可以以主链和/或支链的形式连接在N上，其中n 0是选自0，1或2的整数；当n 0为2时，两个R y或R z可进一步环化为3～8元碳环或杂环；
    n是选自0、1、2或3的整数；
    m是选自0、1或2的整数；
    o是选自0、1、2、3或4的整数；
    p是选自0、1、2、3或4的整数；
    当m为2时，其中两个R 3可进一步环化为3～8元碳环或杂环；
    当m为1或2时，R 1和R 3可进一步环化为3～8元的碳环或杂环；
    当n大于等于2时，任意两个R 1可进一步环化为3～8元碳环、芳环、杂环或芳杂环，所形成的碳环和杂环在化合价允许的条件下可任选由C 1～3烷基、C 1～3卤代烷基、卤素、氰基、C 1～3烷氧基取代1～3次；
    当p大于等于2时，任意两个R 5可进一步与环C环化成6～10元螺环或桥环，所形成的螺环和桥环在化合价允许的条件下可任选由C 1～3烷基、C 1～3卤代烷基、卤素、氰基、C 1～3烷氧基取代1～3次；
    当o不为0且p不为0时，任意R 4和R 5可进一步环化成5～8元环，所形成的环在化合价允许的条件下可任选地有C 1～3烷基、C 1～3卤代烷基、卤素、氰基、氧代、C 1～3烷氧基取代1～3次；
    R w独立地选自-CN、-CH 2CN、-C 1～3烷基、-OH、-C 1～3烷氧基、酰胺基、磺酰基、磺酰胺基、-NH 2、-NH-C 1～3烷基，其中所述R w中的烷基在化合价允许的条件下可任选地由C 1～3烷基、C 1～3卤代烷基、卤素、氰基、氧代、C 1～3烷氧基取代1～3次；
    R x独立地选自氢、卤素、氧代、C 1～6烷氧基、氰基、羟基、羧基、胺基、酰胺基、磺酰基、磺酰胺基、-C 1～6烷基、-C 2～6烯基、-C 2～6炔基、-C 3～6环烷基、3～6元杂环基、6～8元芳基、5～8元杂芳基，其中所述R x中烷基、烷氧基、环烷基、杂环基芳基和杂芳基在化合价允许的条件下可任选地由C 1～3烷基、C 1～3卤代烷基、卤素、氰基、氧代、C 1～3烷氧基取代1～3次或任选由羟基取代1次；
    R y独立地选自氢、卤素、氧代、-C 1～3烷氧基、氰基、羟基、胺基、羧基、酰胺基、磺酰基、磺酰胺基、-C 1～6烷基、-C 2～6烯基、-C 2～6炔基、-C 3～6环烷基、3～6元杂环基，5～6元杂芳基，其中所述R y中烷基、烯基、炔基、胺基、酰胺基、烷氧基、环烷基、杂环基、杂芳基在化合价允许的条件下可任选地由C 1～3烷基、C 1～3卤代烷基、卤素、氰基、氧代、C 1～3烷氧基取代1～3次；
    R z独立地选自氢、C 1～3烷基、C 1～3烷氧基、C 3～6环烷基、3～6元杂环基、芳基、5～6元杂芳基，其中R z在化合价允许的条件下可任选地由C 1～3烷基、C 1～3卤代烷基、卤素、氰基、氧代、C 1～3烷氧基、3～6元杂环基取代1～3次。
  2. 根据权利要求1所述的式I化合物，
    所述的环B选自：
    Figure PCTCN2022081466-appb-100002
    Figure PCTCN2022081466-appb-100003
    其中环B优选为
    Figure PCTCN2022081466-appb-100004
    和/或，
    所述的环C选自：
    Figure PCTCN2022081466-appb-100005
    Figure PCTCN2022081466-appb-100006
    其中环C优选为
    Figure PCTCN2022081466-appb-100007
  3. 根据权利要求1所述的式I化合物，该化合物为式I-2或式I-2’的化合物
    Figure PCTCN2022081466-appb-100008
    及其药学上可接受的盐，其中，进一步地，
    Figure PCTCN2022081466-appb-100009
    表示存在或不存在键；
    Z 1、Z 4分别独立地选自CH、N；
    X 1、X 2、X 3分别独立地选自CH、N或C，且X 1、X 2、X 3中至多有两个为N；
    Y 1选自CH或N；
    Y 2选自CH、N或C；
    Y 3选自CH或N；
    R 1独立地选自R 2、-羰基-R 2、-羰基-胺基-R 2，-磺酰基-R 2，-酰胺基-R 2，-氧磷基-R 2，-胺基-R 2，-O-R 2，其中R 1中的R 2、胺基、酰胺基、磺酰基、氧磷基可任选地由独立选自R x的取代基取代1～3次；
    R 2独立地选自氢、氧代、卤素、-C 1～6烷基、-C 2～6烯基、-C 2～6炔基、-C 1～6烷氧基、-C 1～6环烷氧基、氰基、3～8元环烷基、3～8元杂环基、苯基、5～8元杂芳基，其中R 2中的卤素、烷基、烯基、炔基、胺基、烷氧基、环烷氧基、环烷基、杂环基、苯基、杂芳基可任选地由独立选自R x的取代基取代1～3次；
    R 3独立地选自氢、氧代、卤素、-CN、-C 1～6烷基、-C 2～6烯基、-C 2～6炔基、-C 1～6烷氧基、胺基、酰胺基、磺酰基、磺酰胺基、-OH、-C 3～8环烷基、3～8元杂环基、6～10元芳基、5～8元杂芳基，其中R 3在化合价允许的条件下可任选地由独立选自R y的取代基取代1～3次；
    R 4独立地选自氢、卤素、-C 1～3烷基、-C 1～3卤代烷基、-C 1～3烷氧基、氰基、羟基、胺基、酰胺基、磺酰基、磺酰胺基；
    R 5独立地选自氢、卤素、羟基、-CN、-C 1～3烷基、-C 1～3烷氧基、-C 1～3环烷基，其中所述R 5中的烷基、烷氧基、环烷基在化合价允许的条件下可任选地由卤素、羟基、-NR z、-CN、-C 1～3烷基、-C 1～3烷氧基、-C 1～3环烷基取代1～3次；
    R 6选自-R z、-O-R z、-S-R z、-C 1～3烷基、-C 1～3亚烷基-R z、-C 0～3亚烷基-胺基-R z、-C 0～3亚烷基-羰基-R z、-C 0～3亚烷基-酰胺基-R z、-C 0～3亚烷基-磺酰基-R z、-C 0～3亚烷基-磷酰基-R z、-C 0～3亚烷基-磺酰胺基-R z，其中所述R 6中的烷基、胺基、酰胺基、磺酰基、磺酰胺基、磷酰基在化合价允许的条件下可任选地由卤素取代1～3次或由R w取代1次；
    R 7选自-COOH、-C(R y) n0-COOH、-N(R z) n0-COOH、-SO 2-COOH和-SO 2-NH-COOH，所述-C(R y) n0-中的R y可以以主链和/或支链的形式连接在C上，所述-N(R z) n0-中的R z可以以主链和/或支链的形式连接在N上，其中n 0是选自0，1或2的整数；当n 0为2时，两个R y或R z可进一步环化为3～8元碳环或杂环；
    n是选自0、1、2或3的整数；
    o是选自0、1、2、3或4的整数；
    p是选自0、1、2、3或4的整数；
    当n大于等于2时，任意两个R 1可进一步环化为3～8元碳环、芳环、杂环或芳杂环，所形成的碳环和杂环在化合价允许的条件下可任选由C 1～3烷基、C 1～3卤代烷基、卤素、氰基、C 1～3烷氧基取代1～3次；
    当p大于等于2时，任意两个R 5可进一步与环C环化成6～10元螺环或桥环，所形成的螺环和桥环在化合价允许的条件下可任选由C 1～3烷基、C 1～3卤代烷基、卤素、氰基、C 1～3烷氧基取代1～3次；
    当o不为0且p不为0时，任意R 4和R 5可进一步环化成5～8元环，所形成的环在化合价允许的条件下可任选地有C 1～3烷基、C 1～3卤代烷基、卤素、氰基、氧代、C 1～3烷氧基取代1～3次；
    R w独立地选自-CN、-CH 2CN、-C 1～3烷基、-OH、-C 1～3烷氧基、酰胺基、磺酰基、磺酰胺基、-NH 2、-NH-C 1～3烷基，其中所述R w中的烷基在化合价允许的条件下可任选地由C 1～3烷基、C 1～3卤代烷基、卤素、氰基、C 1～3烷氧基取代1～3次；
    R x独立地选自氢、卤素、氧代、C 1～6烷氧基、氰基、羟基、羧基、胺基、酰胺基、磺酰基、磺酰胺基、-C 1～6烷基、-C 2～6烯基、-C 2～6炔基、-C 3～6环烷基、3～6元杂环基、6～8元芳基、5～8元杂芳基，其中所述R x中烷基、烷氧基、环烷基、杂环基芳基和杂芳基在化合价允许的条件下可任选地由卤素取代1～3次或任选由羟基取代0～1次；
    R y独立地选自氢、卤素、氧代、-C 1～3烷氧基、氰基、羟基、胺基、羧基、酰胺基、磺酰基、磺酰胺基、-C 1～6烷基、-C 2～6烯基、-C 2～6炔基、-C 3～6环烷基、3～6元杂环基，其中所述R y中烷基、烷氧基、环烷基、杂环基在化合价允许的条件下可任选地用卤素取代1～3次；
    R z独立地选自氢、C 1～3烷基、C 1～3烷氧基、C 3～6环烷基、4～6元杂环、5～6元芳基或5～6元杂芳基，其中R z在化合价允许的条件下可任选地用卤素、氰基、C 1～3烷基、C 1～3烷氧基、C 3～6环烷基、3～6元杂环基取代1～3次。
  4. 根据权利要求1所述的式I化合物，当o不为0且p不为0时，任意相邻的R 4和R 5可进一步环化为5～8元环；所述的5～8元环包括C 5～6碳环、5～8元杂环、苯环、5～8元杂芳环，形成的环在化合物允许的条件下可任选地由烷基、卤代烷基、卤素、氰基、烷氧基取代1～3次；
    其中，当o不为0且p不为0时，任意相邻的R 4和R 5可进一步环化成5～8元环，所述的5～8元环可选自：
    Figure PCTCN2022081466-appb-100010
    Figure PCTCN2022081466-appb-100011
    Figure PCTCN2022081466-appb-100012
    所成的5～8元环在化合价允许的条件下可任选地由C 1-3烷基、C 1-3卤代烷基、卤素、氰基、氧代、C 1-3烷氧基取代1～3次；
    和/或，当o不为0且p不为0时，任意相邻的R 4和R 5可进一步环化成5～8元环，所述的5～8 元环优选为：
    Figure PCTCN2022081466-appb-100013
    Figure PCTCN2022081466-appb-100014
    Figure PCTCN2022081466-appb-100015
    所成的5～8元环在化合价允许的条件下可任选地由C 1-3烷基、C 1-3卤代烷基、卤素、氰基、氧代、C 1-3烷氧基取代1～3次；
    和/或，当o不为0且p不为0时，任意相邻的R 4和R 5可进一步环化成5～8元环，所述的5～8元环可选自：
    Figure PCTCN2022081466-appb-100016
    Figure PCTCN2022081466-appb-100017
    Figure PCTCN2022081466-appb-100018
    所成的5～8元环在化合价允许的条件下可任选地由C 1-3烷基、C 1-3卤代烷基、卤素、氰基、氧代、C 1-3烷氧基取代1～3次。
  5. 根据权利要求1所述的式I化合物，所述的结构单元
    Figure PCTCN2022081466-appb-100019
    可进一步选自：
    Figure PCTCN2022081466-appb-100020
    Figure PCTCN2022081466-appb-100021
  6. 根据权利要求1所述的式I化合物，所述的I化合物可以有以下子通式
    Figure PCTCN2022081466-appb-100022
  7. 根据权利要求1所述的式I化合物，所述的n选自1、2或3；和/或，所述的p选自0、1或2。
  8. 根据权利要求1所述的式I化合物，所述的R 1可进一步独立地选自-F、-Cl、-CN、-OCH 3、-OCH 2CH 3、-O-环丙基、-CH 3、-CH 2CH 3、-CH 2CH 2CH 3、-(CH) 2CH 3、-COCH 3、-CONH 2、-CF 3、-CHF 2、-CH 2F、-CH 2CH 2F、-CO-环丙基、5～6元杂环基、5～6元杂芳基；
    和/或，所述的R 3可进一步选自-F、-Cl、-CH 3、-OCH 3、-NH 2、-OH、-CH 2CH 3、-CH 2OH、-NHCH 3、-COCH 3、-SO 2CH 3、-OCH 2CH 3、-CF 3、-CHF 2、-CH 2F、异丙基、环丙基、氟代环丙基；
    和/或，所述的R 2可进一步独立地选自-H、-CH 3、-CHF 2、-CH 2F、-CF 3、-CH 2CH 3、-CH 2CH 2F、-NH 2、环丙基、5～6元杂环基、5～6元杂芳基；
    和/或，所述的R 4可进一步选自-CN、-CH 3、-OH、-CH 2OH、-CH 2OCH 3、-OCH 3、-NH 2、-NHCH 3、-COCH 3、-OCH 2CH 3；
    和/或，所述的R 5选自-F、-Cl、-CN、-CH 3、-CH 2CH 3、-CF 3、-CHF 2、-CH 2F、-CH 2OH、-OH、-CH 2OCH 3、-OCH 3、-CH 2CH 2OH、-CH 2CH 2OCH 3、异丙基或环丙基；
    和/或，所述的R 6选自-R z、-O-R z、-S-R z、-C 1～3亚烷基-R z、-C 0～3亚烷基-胺基-R z、-C 0～3亚烷基-羰基-R z，其中所述R 6中的烷基、胺基、酰胺基、磺酰基、磺酰胺基、磷酰基在化合价允许的条件下可任选地由卤素取代1～3次或由R w取代1次；
    和/或，R 7选自-COOH、-CH 2COOH、-CH 2CH 2COOH、-CH(CH 3)COOH，其中所述R 7在化合价允许的条件下可任选地由卤素取代1～3次。
  9. 根据权利要求1所述的式I化合物，所述的R z可进一步选自：甲基，乙基，异丙基，环丙基，环丁基，甲氧基，乙氧基，
    Figure PCTCN2022081466-appb-100023
    Figure PCTCN2022081466-appb-100024
    R z在化合价允许的条件下可任选地用卤素、氰基、C 1～3烷基、C 1～3烷氧基、C 3～6环烷基、3～6元杂环基取代1～3次；
    和/或，所述的R y可进一步选自-F、-Cl、甲基、乙基、三氟甲基、二氟甲基、氟甲基、氟乙基、甲氧基、氨基、羟基、丙基、异丙基、环丙基、环丁基。
  10. 根据权利要求1所述的式I化合物，所述的化合物为
    Figure PCTCN2022081466-appb-100025
    Figure PCTCN2022081466-appb-100026
    Figure PCTCN2022081466-appb-100027
    及其药学上可接受的盐。
  11. 根据权利要求1所述的式I化合物，所述的化合物为
    Figure PCTCN2022081466-appb-100028
    Figure PCTCN2022081466-appb-100029
    Figure PCTCN2022081466-appb-100030
    Figure PCTCN2022081466-appb-100031
    及其药学上可接受的盐。
  12. 一种药物组合物，其包含权利要求1～11中任一项的式I化合物及其药学上可接受的盐及药学上可接受的药用载体。
  13. 根据权利要求1～11任一项所述的式I化合物或其药学上可接受的盐在制备治疗GLP-1受体激动剂介导的疾病或相关疾病的药物中的应用。
  14. 一种用于预防和/或治疗GLP-1介导的疾病和相关疾病的方法，包括对受试者给与治疗有效量的如权利要求1～11中任一项所述的式I化合物或其药学上可接受的盐，其中所述的GLP-1介导的疾病和相关疾病包括但不限于，防糖尿病、高血糖症、胰岛素抗性、葡萄糖耐受不良、糖尿病肾病、糖尿病神经疾病、糖尿病视网膜病变、脂肪细胞功能障碍、肥胖症、血脂异常症、高胰岛素血症。
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Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023111144A1 (en) 2021-12-16 2023-06-22 Astrazeneca Ab Certain 3-azabicyclo[3.1.0]hexanes as glp-1 receptor modulators
WO2023111145A1 (en) 2021-12-16 2023-06-22 Astrazeneca Ab Certain 3-azabicyclo[3.1.0]hexanes as glp-1 receptor modulators
CN116574084A (zh) * 2023-04-17 2023-08-11 华南理工大学 一种噻吩衍生物及其合成方法与应用
US11897851B2 (en) 2020-08-06 2024-02-13 Gasherbrum Bio, Inc. Heterocyclic GLP-1 agonists
US11926626B2 (en) 2020-08-28 2024-03-12 Gasherbrum Bio, Inc. Heterocyclic GLP-1 agonists
WO2024063143A1 (ja) 2022-09-22 2024-03-28 塩野義製薬株式会社 Ｇｌｐ－１受容体アゴニスト作用を有する縮合環化合物
WO2024102625A1 (en) 2022-11-11 2024-05-16 Eli Lilly And Company Glucagon-like peptide 1 receptor agonists
WO2024107781A1 (en) 2022-11-16 2024-05-23 Eli Lilly And Company Glucagon-like peptide 1 receptor agonists
US12234236B1 (en) 2023-09-14 2025-02-25 Ascletis Pharma (China) Co., Limited GLP-1R agonist and therapeutic method thereof
US12291530B1 (en) 2023-11-24 2025-05-06 Ascletis Pharma (China) Co., Limited GLP-1R agonist and therapeutic method thereof
WO2025158275A1 (en) 2024-01-24 2025-07-31 Pfizer Inc. Combination therapy using glucose-dependent insulinotropic polypeptide receptor antagonist compounds and glp-1 receptor agonist compounds
US12378236B2 (en) 2021-09-27 2025-08-05 Terns Pharmaceuticals, Inc. Compounds as GLP-1R agonists
US12410163B2 (en) 2022-02-23 2025-09-09 Terns Pharmaceuticals, Inc. Compounds as GLP-IR agonists
WO2025189141A1 (en) 2024-03-08 2025-09-12 Annapurna Bio, Inc. Methods for treating obesity and increasing weight loss
US12485118B2 (en) 2023-04-07 2025-12-02 Terns Pharmaceuticals, Inc. Combinations of GLP-1R and THRβ agonists and methods of use thereof
US12552791B2 (en) 2020-04-29 2026-02-17 Gasherbrum Bio, Inc. Heterocyclic GLP-1 agonists

Citations (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009111700A2 (en) 2008-03-07 2009-09-11 Transtech Pharma, Inc. Oxadiazoanthracene compounds for the treatment of diabetes
WO2010114824A1 (en) 2009-03-30 2010-10-07 Transtech Pharma Inc Substituted azoanthracene derivatives, pharmaceutical compositions, and methods of use thereof
WO2017078352A1 (en) 2015-11-04 2017-05-11 Hyundai Pharm Co., Ltd. Cyclohexene derivative, preparation method thereof, and pharmaceutical composition for preventing or treating metabolic disease comprising the same as active ingredient
WO2018056453A1 (ja) 2016-09-26 2018-03-29 中外製薬株式会社 Ｇｌｐ－１受容体アゴニスト作用を持つピラゾロピリジン誘導体
WO2018109607A1 (en) 2016-12-16 2018-06-21 Pfizer Inc. Glp-1 receptor agonists and uses thereof
KR20180101671A (ko) 2017-03-03 2018-09-13 한국화학연구원 헤테로아릴이 치환된 2-페닐이미다조[1,2-a]피리딘 유도체, 이의 제조방법 및 이를 유효성분으로 포함하는 GLP-1 수용체 활성 관련 질환의 예방 또는 치료용 약학적 조성물
WO2020103815A1 (en) 2018-11-22 2020-05-28 Qilu Regor Therapeutics Inc. Glp-1r agonists and uses thereof
WO2020207474A1 (en) 2019-04-12 2020-10-15 Qilu Regor Therapeutics Inc. Glp-1r agonists and uses thereof
WO2021018023A1 (zh) 2019-08-01 2021-02-04 济南泰达领创医药技术有限公司 小分子glp-1受体调节剂
WO2021096304A1 (en) * 2019-11-15 2021-05-20 Ildong Pharmaceutical Co., Ltd. Glp-1 receptor agonist and use thereof
CN113480534A (zh) * 2021-07-23 2021-10-08 广州必贝特医药技术有限公司 苯并咪唑或氮杂苯并咪唑-6-羧酸类化合物及其应用
CN113493447A (zh) * 2020-04-03 2021-10-12 山东轩竹医药科技有限公司 Glp-1受体激动剂
WO2022040600A1 (en) * 2020-08-21 2022-02-24 Terns Pharmaceuticals, Inc. Compounds as glp-1r agonists

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA3157525A1 (en) * 2019-10-25 2021-04-29 Gilead Sciences, Inc. Glp-1r modulating compounds
WO2022068772A1 (zh) * 2020-09-29 2022-04-07 深圳信立泰药业股份有限公司 一种苯并咪唑类衍生物及其制备方法和医药用途
EP4304711A1 (en) * 2021-03-11 2024-01-17 Gilead Sciences, Inc. Glp-1r modulating compounds

Patent Citations (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009111700A2 (en) 2008-03-07 2009-09-11 Transtech Pharma, Inc. Oxadiazoanthracene compounds for the treatment of diabetes
WO2010114824A1 (en) 2009-03-30 2010-10-07 Transtech Pharma Inc Substituted azoanthracene derivatives, pharmaceutical compositions, and methods of use thereof
WO2017078352A1 (en) 2015-11-04 2017-05-11 Hyundai Pharm Co., Ltd. Cyclohexene derivative, preparation method thereof, and pharmaceutical composition for preventing or treating metabolic disease comprising the same as active ingredient
WO2018056453A1 (ja) 2016-09-26 2018-03-29 中外製薬株式会社 Ｇｌｐ－１受容体アゴニスト作用を持つピラゾロピリジン誘導体
WO2018109607A1 (en) 2016-12-16 2018-06-21 Pfizer Inc. Glp-1 receptor agonists and uses thereof
KR20180101671A (ko) 2017-03-03 2018-09-13 한국화학연구원 헤테로아릴이 치환된 2-페닐이미다조[1,2-a]피리딘 유도체, 이의 제조방법 및 이를 유효성분으로 포함하는 GLP-1 수용체 활성 관련 질환의 예방 또는 치료용 약학적 조성물
WO2020103815A1 (en) 2018-11-22 2020-05-28 Qilu Regor Therapeutics Inc. Glp-1r agonists and uses thereof
WO2020207474A1 (en) 2019-04-12 2020-10-15 Qilu Regor Therapeutics Inc. Glp-1r agonists and uses thereof
WO2021018023A1 (zh) 2019-08-01 2021-02-04 济南泰达领创医药技术有限公司 小分子glp-1受体调节剂
WO2021096304A1 (en) * 2019-11-15 2021-05-20 Ildong Pharmaceutical Co., Ltd. Glp-1 receptor agonist and use thereof
CN113493447A (zh) * 2020-04-03 2021-10-12 山东轩竹医药科技有限公司 Glp-1受体激动剂
WO2022040600A1 (en) * 2020-08-21 2022-02-24 Terns Pharmaceuticals, Inc. Compounds as glp-1r agonists
CN113480534A (zh) * 2021-07-23 2021-10-08 广州必贝特医药技术有限公司 苯并咪唑或氮杂苯并咪唑-6-羧酸类化合物及其应用

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP4317142A4

Cited By (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12552791B2 (en) 2020-04-29 2026-02-17 Gasherbrum Bio, Inc. Heterocyclic GLP-1 agonists
US12528781B2 (en) 2020-08-06 2026-01-20 Gasherbrum Bio, Inc. Heterocyclic GLP-1 agonists
US11897851B2 (en) 2020-08-06 2024-02-13 Gasherbrum Bio, Inc. Heterocyclic GLP-1 agonists
US11926626B2 (en) 2020-08-28 2024-03-12 Gasherbrum Bio, Inc. Heterocyclic GLP-1 agonists
US12221442B2 (en) 2020-08-28 2025-02-11 Gasherbrum Bio, Inc. Heterocyclic GLP-1 agonists
US12378239B2 (en) 2021-09-27 2025-08-05 Terns Pharmaceuticals, Inc. Compounds as GLP-1R agonists
US12522596B2 (en) 2021-09-27 2026-01-13 Terns Pharmaceuticals, Inc. Compounds as GLP-1R agonists
US12378238B2 (en) 2021-09-27 2025-08-05 Terns Pharmaceuticals, Inc. Compounds as GLP-1R agonists
US12378237B2 (en) 2021-09-27 2025-08-05 Terns Pharmaceuticals, Inc. Compounds as GLP-1R agonists
US12378236B2 (en) 2021-09-27 2025-08-05 Terns Pharmaceuticals, Inc. Compounds as GLP-1R agonists
WO2023111145A1 (en) 2021-12-16 2023-06-22 Astrazeneca Ab Certain 3-azabicyclo[3.1.0]hexanes as glp-1 receptor modulators
WO2023111144A1 (en) 2021-12-16 2023-06-22 Astrazeneca Ab Certain 3-azabicyclo[3.1.0]hexanes as glp-1 receptor modulators
US12410163B2 (en) 2022-02-23 2025-09-09 Terns Pharmaceuticals, Inc. Compounds as GLP-IR agonists
WO2024063143A1 (ja) 2022-09-22 2024-03-28 塩野義製薬株式会社 Ｇｌｐ－１受容体アゴニスト作用を有する縮合環化合物
JP2025537254A (ja) * 2022-11-11 2025-11-14 イーライ リリー アンド カンパニー グルカゴン様ペプチド１受容体アゴニスト
WO2024102625A1 (en) 2022-11-11 2024-05-16 Eli Lilly And Company Glucagon-like peptide 1 receptor agonists
WO2024107781A1 (en) 2022-11-16 2024-05-23 Eli Lilly And Company Glucagon-like peptide 1 receptor agonists
US12485118B2 (en) 2023-04-07 2025-12-02 Terns Pharmaceuticals, Inc. Combinations of GLP-1R and THRβ agonists and methods of use thereof
CN116574084A (zh) * 2023-04-17 2023-08-11 华南理工大学 一种噻吩衍生物及其合成方法与应用
US12234236B1 (en) 2023-09-14 2025-02-25 Ascletis Pharma (China) Co., Limited GLP-1R agonist and therapeutic method thereof
US12291530B1 (en) 2023-11-24 2025-05-06 Ascletis Pharma (China) Co., Limited GLP-1R agonist and therapeutic method thereof
WO2025158275A1 (en) 2024-01-24 2025-07-31 Pfizer Inc. Combination therapy using glucose-dependent insulinotropic polypeptide receptor antagonist compounds and glp-1 receptor agonist compounds
WO2025189141A1 (en) 2024-03-08 2025-09-12 Annapurna Bio, Inc. Methods for treating obesity and increasing weight loss

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