WO2017008681A1 - Dérivé d'amide, son procédé de préparation et son utilisation pharmaceutique - Google Patents

Dérivé d'amide, son procédé de préparation et son utilisation pharmaceutique Download PDF

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WO2017008681A1
WO2017008681A1 PCT/CN2016/089134 CN2016089134W WO2017008681A1 WO 2017008681 A1 WO2017008681 A1 WO 2017008681A1 CN 2016089134 W CN2016089134 W CN 2016089134W WO 2017008681 A1 WO2017008681 A1 WO 2017008681A1
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group
cycloalkyl
phenyl
alkyl
compound
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PCT/CN2016/089134
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Chinese (zh)
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关东亮
盛首一
汤小伟
白骅
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浙江海正药业股份有限公司
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Priority to CN201680020686.8A priority Critical patent/CN107428682B/zh
Publication of WO2017008681A1 publication Critical patent/WO2017008681A1/fr

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    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/423—Oxazoles condensed with carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/02—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof
    • C07C303/22—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of sulfonic acids or halides thereof from sulfonic acids, by reactions not involving the formation of sulfo or halosulfonyl groups; from sulfonic halides by reactions not involving the formation of halosulfonyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/01—Sulfonic acids
    • C07C309/02—Sulfonic acids having sulfo groups bound to acyclic carbon atoms
    • C07C309/03—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C309/13—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton
    • C07C309/14—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton containing amino groups bound to the carbon skeleton
    • C07C309/15—Sulfonic acids having sulfo groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton containing amino groups bound to the carbon skeleton the nitrogen atom of at least one of the amino groups being part of any of the groups, X being a hetero atom, Y being any atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/56—Benzoxazoles; Hydrogenated benzoxazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D263/57—Aryl or substituted aryl radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/81—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
    • C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
    • C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D319/18—Ethylenedioxybenzenes, not substituted on the hetero ring

Definitions

  • the present invention relates to a novel amide derivative, a process for its preparation and a pharmaceutical composition containing the same and its use as a therapeutic agent, in particular as a GCGR antagonist.
  • Glucagon is a linear polypeptide consisting of 29 amino acids secreted by islet alpha cells with a molecular weight of 3485; a concentration of 50-100 ng/L in serum and a half-life of 5-10 minutes in plasma.
  • Glucagon specifically binds to the type B G-protein coupled receptor (glucagon receptor, GCGR) on the surface of target cells such as liver and kidney, activates downstream signal transduction pathways, and exerts physiological effects. Contrary to the action of insulin, it is a hormone that promotes catabolism, and has a strong promotion of glycogenolysis and gluconeogenesis, resulting in a marked increase in blood sugar. 1 mol/L of hormone can rapidly decompose 3 ⁇ 10 6 mol / L of glucose from glycogen.
  • the glucagon receptor is located on the cell surface and is a G-protein coupled receptor with seven transmembrane sequences, mainly distributed in the liver, and also distributed in the kidney, heart, muscle, and the like.
  • the main target organ for glucagon action is the liver.
  • the receptor When bound to the receptor, it interacts with the guanine nucleotide to regulate the protein Gs, causing the release of the A subunit of Gs to activate adenylate cyclase, which catalyzes the conversion of ATP to cAMP to exert its biological effects.
  • Pharmacological doses of glucagon can increase cAMP content in cardiomyocytes and increase myocardial contraction.
  • a glucagon receptor antagonist can compete with glucagon for the receptor, thereby blocking its action.
  • Diabetes is a disease characterized by high levels of plasma glucose. Uncontrolled hyperglycemia is associated with an increased risk of microvascular and macrovascular disease, including kidney disease, retinopathy, hypertension, stroke, and heart disease. The control of glucose homeostasis is the primary method of treating diabetes. It has been shown in healthy animals and animal models of type I and type II diabetes that removal of circulating glucagon with selective and specific antibodies results in a decrease in blood glucose levels. Thus a potential treatment for diabetes and other diseases involving abnormal blood glucose is that the glucagon receptor antagonist blocks the glucagon receptor to increase the insulin response, to reduce the rate of gluconeogenesis and/or to reduce the patient's The hepatic glucose output rate is used to lower plasma glucose levels.
  • GCGR antagonists have been published, and not all compounds that are GCGR antagonists have properties that are useful therapeutic agents. Some of these properties include high affinity for the glucagon receptor, duration of receptor activation, oral bioavailability and stability (eg, ability to formulate or crystallize, shelf life). Such properties can lead to improvements in safety, tolerability, effectiveness, therapeutic index, patient compliance, cost effectiveness, ease of preparation, and the like. Surprisingly, it has been found that the specific stereochemistry and functional groups of the compounds of the invention exhibit one or more of these desirable properties, including significantly improved receptor binding properties, oral bioavailability, and/or other enhancements for therapeutic use. An advantageous feature of the suitability of the use.
  • the present invention provides a novel GCGR receptor antagonist designed to have a compound represented by the general formula (I), and the compound of the present invention has a large structural difference with the compound specifically disclosed in the prior art, and exhibits excellent resistance. Diabetes effects and effects.
  • R 1 is selected from aryl, wherein said aryl group is further optionally further selected from one or more selected from the group consisting of alkyl, alkoxy, halogen, hydroxy, cyano, nitro, cycloalkyl, heterocyclic, aryl a substituent of a heteroaryl group, -NR 10 R 11 , -C(O)NR 10 R 11 , -C(O)R 12 , -C(O)OR 12 or -NR 10 C(O)R 11 Substituted, wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl group is further further selected from one or more selected from the group consisting of alkyl, halogen, hydroxy, cyano, nitro, Cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR 10 R 11 , -C(O)NR 10 R 11 , -C(O)R 12 , -C(O
  • R 2 is selected from the group consisting of:
  • a phenyl group wherein said phenyl group is further selected from the group consisting of an alkynyl group, a heterocyclic group,
  • alkynyl group is further substituted by one or more substituents selected from cycloalkyl or alkoxy; preferably substituted by cyclopropyl;
  • the heterocyclic group described therein is preferably a tetrahydropyrrolyl group, a piperidinyl group, a morpholinyl group, a piperazinyl group,
  • R 3 is selected from a hydrogen atom, a halogen, an alkyl group or an alkoxy group, wherein the alkyl group or alkoxy group is further further selected from one or more selected from the group consisting of an alkyl group, an alkoxy group, a halogen group, a hydroxyl group, and a cyano group.
  • R 4 are each independently selected from a hydrogen atom, an alkyl group, an alkoxy group, a halogen, a hydroxyl group, a cyano group or a nitro group, preferably selected from F or Cl, wherein the alkyl group or alkoxy group is optionally further one or Substituting a plurality of substituents selected from -NR 10 R 11 , -C(O)NR 10 R 11 , -C(O)R 12 , -C(O)OR 12 or -NR 10 C(O)R 11 ;
  • R 8 is each independently selected from the group consisting of:
  • alkyl group wherein said alkyl group is further selected from one or more selected from the group consisting of alkoxy, halogen, hydroxy, cyano, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, - Substituted by a substituent of NR 10 R 11 , -C(O)NR 10 R 11 , -C(O)R 12 , -C(O)OR 12 or -NR 10 C(O)R 11 ;
  • R 9 is each independently selected from the group consisting of alkyl, halogen, hydroxy, cyano, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, -C(O)NR 10 R 11 , -C(O) R 12 , -C(O)OR 12 , preferably a tert-butyl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group or heteroaryl group is further further selected from one or more selected from an alkyl group , alkoxy, halogen, hydroxy, cyano, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR 10 R 11 , -C(O)NR 10 R 11 , -C(O Substituting a substituent of R 12 , -C(O)OR 12 or -NR 10 C(O)R 11 ;
  • R 10 , R 11 and R 12 are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group Or a heteroaryl group optionally further selected from one or more selected from the group consisting of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR 14 R 15, -C (O) NR 14 R 15, -C (O) R 16, -C (O) oR 16 or -NR 14 C (O) R 15, substituted with a substituent;
  • R 10 and R 11 together with the N atom to which they are attached form a 4 to 8 membered heterocyclic group, wherein the 4 to 8 membered heterocyclic ring contains one or more N, O, S(O) n atoms, and 4
  • R 14 , R 15 and R 16 are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group Or a heteroaryl group optionally further selected from one or more selected from the group consisting of hydroxyl, halogen, nitro, cyano, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, carboxylic acid or carboxy Substituted by a substituent of the acid ester;
  • X is selected from halogen, preferably F;
  • n is selected from 1, 2, 3 or 4;
  • n is selected from 0, 1 or 2;
  • p is selected from 0, 1, 2, 3 or 4.
  • the compound of the formula (I), or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof is a compound of the formula (II) or Stereoisomers, tautomers or pharmaceutically acceptable salts thereof:
  • R 1 to R 4 and p are as defined in the formula (I).
  • the compound of the formula (I), or a stereoisomer, tautomer or a pharmaceutically acceptable salt thereof is a compound of the formula (III) or Stereoisomers, tautomers or pharmaceutically acceptable salts thereof:
  • R 1 to R 4 and p are as defined in the formula (I).
  • R 1 is selected From phenyl, wherein said phenyl group is optionally further substituted with a substituent selected from an alkyl group or a halogen, preferably substituted with methyl, ethyl, propyl, butyl, F, Cl, Br or I, It is preferably substituted by methyl, F or Cl, and the remaining groups are as defined in the general formula (I).
  • R 1 is selected from phenyl, wherein said phenyl group is optionally further substituted with a substituent selected from an alkyl group or a halogen, preferably methyl, ethyl, propyl, butyl, F, Cl, Br or I. Substituted, more preferably substituted with methyl, F or Cl;
  • R 2 is selected from a phenyl group, and the phenyl group is further Replace
  • R 5 and R 6 , or R 6 and R 7 together with the carbon atom to which they are bonded form a 5- to 7-membered cycloalkyl or heterocyclic group, wherein said cycloalkyl or heterocyclic group is optionally further substituted by one or A plurality of substituents selected from an alkyl group, a halogen, a hydroxyl group, a cyano group, a nitro group, a cycloalkyl group or a heterocyclic group are substituted, and the remaining groups are as defined in the formula (I).
  • R 1 is selected from phenyl, wherein said phenyl group is optionally further substituted with a substituent selected from an alkyl group or a halogen, preferably methyl, ethyl, propyl, butyl, F, Cl, Br or I. Substituted, more preferably substituted with methyl, F or Cl;
  • R 2 is selected from a phenyl group, and the phenyl group is further Replace
  • R 8 is selected from fluorine
  • R 1 is selected from phenyl, wherein said phenyl group is optionally further substituted with a substituent selected from an alkyl group or a halogen, preferably methyl, ethyl, propyl, butyl, F, Cl, Br or I. Substituted, more preferably substituted with methyl, F or Cl;
  • R 2 is selected from a phenyl group, and the phenyl group is further Substituted, the remaining groups are as defined in the general formula (I).
  • R 1 is selected from phenyl, wherein said phenyl group is optionally further substituted with a substituent selected from an alkyl group or a halogen, preferably methyl, ethyl, propyl, butyl, F, Cl, Br or I. Substituted, more preferably substituted with methyl, F or Cl;
  • R 2 is selected from a phenyl group, and the phenyl group is further Replace
  • R 8 is selected from cycloalkyl, wherein the cycloalkyl group is further substituted with an alkyl group.
  • R 1 is selected from phenyl, wherein said phenyl group is optionally further substituted with a substituent selected from an alkyl group or a halogen, preferably methyl, ethyl, propyl, butyl, F, Cl, Br or I. Substituted, more preferably substituted with methyl, F or Cl;
  • R 2 is selected from a phenyl group, and the phenyl group is further Replace
  • R 8 is selected from cyclopropyl, wherein the cyclopropyl group is further substituted with an alkyl group.
  • R 1 is selected from phenyl, wherein said phenyl group is optionally further substituted with a substituent selected from an alkyl group or a halogen, preferably methyl, ethyl, propyl, butyl, F, Cl, Br or I. Substituted, more preferably substituted with methyl, F or Cl;
  • R 2 is selected from a phenyl group, and the phenyl group is further Substituted, the remaining groups are as defined in the general formula (I).
  • R 1 is selected from phenyl, wherein said phenyl group is optionally further substituted with a substituent selected from an alkyl group or a halogen, preferably methyl, ethyl, propyl, butyl, F, Cl, Br or I. Substituted, more preferably substituted with methyl, F or Cl;
  • R 2 is selected from a phenyl group, and the phenyl group is further Replace
  • R 8 is selected from an alkyl group, preferably a tert-butyl group
  • R 1 is selected from phenyl, wherein said phenyl group is optionally further substituted with a substituent selected from an alkyl group or a halogen, preferably methyl, ethyl, propyl, butyl, F, Cl, Br or I. Substituted, more preferably substituted with methyl, F or Cl;
  • R 2 is selected from a phenyl group, and the phenyl group is further Replace
  • R 13 are each independently selected from the group consisting of alkyl, halogen, hydroxy, cyano, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, NR 10 R 11 , -C(O)NR 10 R 11 , -C(O)R 12 , -C(O)OR 12 or -NR 10 C(O)R 11 wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group Further selected from one or more selected from the group consisting of alkyl, halogen, hydroxy, cyano, nitro, cycloalkyl, heterocyclyl, NR 10 R 11 , -C(O)NR 10 R 11 , -C(O) Substituted with a substituent of R 12 , -C(O)OR 12 or -NR 10 C(O)R 11 ; R 13 is preferably an alkyl group;
  • n 0, 1, 2 or 3, and n is preferably 0 or 1; the remaining groups are as defined in the formula (I).
  • R 1 is selected from phenyl, wherein said phenyl group is optionally further substituted with a substituent selected from an alkyl group or a halogen, preferably methyl, ethyl, propyl, butyl, F, Cl, Br or I. Substituted, more preferably substituted with methyl, F or Cl;
  • R 2 is selected from a phenyl group, and the phenyl group is further Replace
  • R 13 is each independently selected from the group consisting of alkyl, halogen, hydroxy, cyano, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR 10 R 11 , -C(O)NR 10 R 11 , —C(O)R 12 , —C(O)OR 12 or —NR 10 C(O)R 11 , wherein said alkyl group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group Optionally further selected from one or more selected from the group consisting of alkyl, halogen, hydroxy, cyano, nitro, cycloalkyl, heterocyclyl, -NR 10 R 11 , -C(O)NR 10 R 11 , -C ( O) is substituted with a substituent of R 12 , -C(O)OR 12 or -NR 10 C(O)R 11 ; R 13 is preferably an alkyl group;
  • n 0, 1, 2 or 3; n is preferably 0 or 1;
  • R 2 is selected From the phenyl group, the phenyl group is further substituted with an alkynyl group which is further substituted with a substituent selected from a cycloalkyl group or an alkoxy group.
  • R 2 is selected From the phenyl group, the phenyl group is further substituted by an ethynyl group or a propynyl group, preferably by an ethynyl group, wherein the ethynyl group or propynyl group is further substituted with a cyclopropyl group.
  • R 2 is :
  • R 13 is each independently selected from the group consisting of alkyl, halogen, hydroxy, cyano, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR 10 R 11 , -C(O)NR 10 R 11 , —C(O)R 12 , —C(O)OR 12 or —NR 10 C(O)R 11 , wherein said alkyl group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group Optionally further selected from one or more selected from the group consisting of alkyl, halogen, hydroxy, cyano, nitro, cycloalkyl, heterocyclyl, -NR 10 R 11 , -C(O)NR 10 R 11 , -C ( O) is substituted with a substituent of R 12 , -C(O)OR 12 or -NR 10 C(O)R 11 ; R 13 is preferably an alkyl group;
  • n 0, 1, 2 or 3; n is preferably 0 or 1;
  • Typical compounds of the invention include, but are not limited to:
  • the present invention provides a process for the preparation of a compound of the formula (I), which comprises:
  • condensation reagent is preferably (2-oxo-3-oxazolidinyl)phosphoryl chloride
  • R 1 to R 4 and p are as defined in the formula (I).
  • the present invention provides a process for the preparation of a compound of the formula (II), which comprises:
  • condensation reagent is preferably (2-oxo-3-oxazolidinyl)phosphoryl chloride
  • R 1 to R 4 and p are as defined in the formula (II).
  • the present invention provides a process for the preparation of a compound of the formula (III), which comprises:
  • condensation reagent is preferably (2-oxo-3-oxazolidinyl)phosphoryl chloride
  • R 1 to R 4 and p are as defined in the formula (III).
  • the invention also provides a method of preparing the general formula (IA), the method comprising:
  • R 1 to R 4 , R 12 and p are as defined in the formula (I).
  • the invention also provides a method of preparing the general formula (IIA), the method comprising:
  • R 1 to R 4 , R 12 and p are as defined in the formula (II).
  • the invention also provides a method of preparing the general formula (IIIA), the method comprising:
  • R 1 to R 4 , R 12 and p are as defined in the formula (III).
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of a compound of the formula (I), (II) or (III) or a stereoisomer thereof, tautomerism thereof Or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or a combination thereof.
  • the present invention also provides a method for inhibiting a glucagon receptor in vitro or in vivo, which comprises the glucagon receptor as described in formula (I), (II) or (III) or Its stereoisomer, tautomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is contacted.
  • the present invention also provides a compound of the formula (I), (II) or (III), or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof Use in the preparation of a medicament for the treatment of type 2 diabetes, hyperglycemia, obesity or insulin resistance.
  • the present invention also provides a compound of the formula (I), (II) or (III), or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof Use in the preparation of a glucagon receptor inhibitor.
  • the present invention also provides a compound of the formula (I), (II) or (III), or a stereoisomer, tautomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof Use in the treatment of type 2 diabetes, hyperglycemia, obesity or insulin resistance.
  • alkyl as a group or part of a group is meant to include C 1 -C 20 linear or branched aliphatic hydrocarbon group with a chain. It is preferably a C 1 -C 10 alkyl group, more preferably a C 1 -C 6 alkyl group.
  • alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl, n-pentyl, 1,1-di Methylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1 -ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethyl Butyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl Wait.
  • the alkyl group may optionally be substituted or unsubstituted.
  • Alkynyl as a group or part of a group refers to an aliphatic hydrocarbon group containing a carbon-carbon triple bond, which may be straight or branched. Preference is given to C 2 -C 10 alkynyl groups, more preferably C 2 -C 6 alkynyl groups, most preferably C 2 -C 4 alkynyl groups. Examples of alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, and the like. The alkynyl group may optionally be substituted or unsubstituted.
  • Cycloalkyl means a saturated or partially saturated monocyclic, fused, bridged, and spiro carbon ring, ie, comprising a monocyclic cycloalkyl, a fused cycloalkyl, a bridged cycloalkyl, and a spirocycloalkyl. It is preferably a C 3 -C 12 cycloalkyl group, more preferably a C 3 -C 8 cycloalkyl group, and most preferably a C 3 -C 6 cycloalkyl group.
  • Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene
  • the alkenyl group, the cyclooctyl group and the like are preferably a cyclopropyl group or a cyclohexenyl group.
  • “Spirocycloalkyl” means a polycyclic group of 5 to 18 members, two or more cyclic structures, and a single ring sharing a carbon atom (referred to as a spiro atom), and the ring contains one or more A double bond, but none of the rings have a fully conjugated ⁇ -electron aromatic system. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • the spirocycloalkyl group is classified into a monospiro, a spiro- or a spirocycloalkyl group, preferably a mono- and bi-spirocycloalkyl group, preferably 4 yuan/5 yuan, 4, depending on the number of common spiro atoms between the rings. Yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan.
  • spirocycloalkyl include, but are not limited to, spiro[4.5]decyl, spiro[4.4]decyl, spiro[3.5]decyl, spiro[2.4]heptyl.
  • “Fused cycloalkyl” means 5 to 18 members, an all-carbon polycyclic group containing two or more cyclic structures that share a carbon atom with each other, and one or more rings may contain one or more double bonds, However, none of the rings have a fully conjugated ⁇ -electron aromatic system, preferably 6 to 12 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyl group, preferably a bicyclic or tricyclic ring, more preferably a 5-membered/5-membered or 5-membered/6-membered bicycloalkyl group.
  • fused cycloalkyl include, but are not limited to, bicyclo[3.1.0]hexyl, bicyclo[3.2.0]hept-1-enyl, bicyclo[3.2.0]heptyl, Decalinyl or tetradecafluorophenanyl.
  • “Bridge cycloalkyl” means 5 to 18 members, containing two or more cyclic structures, sharing two all-carbon polycyclic groups that are not directly bonded to each other, and one or more rings may contain one or A plurality of double bonds, but none of the rings have a fully conjugated ⁇ -electron aromatic system, preferably 6 to 12 members, more preferably 7 to 10 members. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl group preferably a bicyclic ring, a tricyclic ring or a tetracyclic ring, and more preferably a bicyclic ring or a tricyclic ring.
  • bridged cycloalkyl include, but are not limited to: (1s, 4s)-bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, (1s,5s)-di Ring [3.3.1] fluorenyl, bicyclo [2.2.2] octyl, (1r, 5r)-bicyclo[3.3.2] fluorenyl.
  • the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocyclyl ring, wherein the ring to which the parent structure is attached is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthalene Base, benzocycloheptyl and the like.
  • the cycloalkyl group may optionally be substituted or unsubstituted.
  • Heterocyclyl “heterocyclic” or “heterocyclic” are used interchangeably herein to refer to a non-aromatic heterocyclic group wherein one or more of the ring-forming atoms are heteroatoms such as oxygen,
  • the nitrogen, sulfur atom and the like include a monocyclic ring, a fused ring, a bridged ring and a spiro ring, that is, a monocyclic heterocyclic group, a fused heterocyclic group, a bridged heterocyclic group and a spiroheterocyclic group.
  • heterocyclyl includes, but are not limited to, morpholinyl, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxo-thiomorpholinyl, piperidinyl, 2-oxo- Piperidinyl, pyrrolidinyl, 2-oxo-pyrrolidinyl, piperazin-2-one, 8-oxa-3-aza-bicyclo[3.2.1]octyl and piperazinyl.
  • the heterocyclic group may optionally be substituted or unsubstituted.
  • “Spiroheterocyclyl” means a polycyclic group of 5 to 18 members, two or more cyclic structures, and a single ring sharing one atom with each other, and the ring contains one or more double bonds, but no An aromatic system having a fully conjugated ⁇ -electron, wherein one or more ring atoms are selected from the group consisting of nitrogen, oxygen or S(O) m (where m is selected from 0, 1 or 2), and the remaining ring atoms are carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • the spiroheterocyclyl group is classified into a monospiroheterocyclic group, a dispiroheterocyclic group or a polyspirocyclic group according to the number of shared spiro atoms between the ring and the ring, and is preferably a monospiroheterocyclic group and a dispiroheterocyclic group. More preferably, it is 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6-membered monospiroheterocyclic group.
  • spiroheterocyclyl include, but are not limited to, 1,7-dioxaspiro[4.5]fluorenyl, 2-oxa-7-azaspiro[4.4]decyl, 7-oxo Heterospiro[3.5]decyl and 5-oxaspiro[2.4]heptyl.
  • “Fused heterocyclic group” means an all-carbon polycyclic group containing two or more cyclic structures that share a pair of atoms with each other, and one or more rings may contain one or more double bonds, but none of the rings have complete A conjugated ⁇ -electron aromatic system in which one or more ring atoms are selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), and the remaining ring atoms are carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members.
  • bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group preferably a bicyclic or tricyclic ring, more preferably a 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group.
  • fused heterocyclic groups include, but are not limited to, octahydropyrrolo[3,4-c]pyrrolyl, octahydro-1H-isoindenyl, 3-azabicyclo[3.1. 0] hexyl, octahydrobenzo[b][1,4]dioxine.
  • “Bridge heterocyclyl” means 5 to 14 members, 5 to 18 members, containing two or more cyclic structures, sharing two polycyclic groups which are not directly connected to each other, and one or more rings may be used.
  • bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic group preferably a bicyclic ring, a tricyclic ring or a tetracyclic ring, and more preferably a bicyclic ring or a tricyclic ring.
  • fused heterocyclic groups include, but are not limited to, 2-azabicyclo[2.2.1]heptyl, 2-azabicyclo[2.2.2]octyl and 2-aza-di Ring [3.3.2] sulfhydryl.
  • the heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring wherein the ring to which the parent structure is attached is a heterocyclic group.
  • the heterocyclic group may optionally be substituted or unsubstituted.
  • Aryl means a carbocyclic aromatic system containing one or two rings wherein the rings may be joined together in a fused manner.
  • aryl includes aryl groups such as phenyl, naphthyl, tetrahydronaphthyl.
  • the aryl group is a C 6 -C 10 aryl group, more preferably the aryl group is a phenyl group and a naphthyl group, and most preferably a phenyl group.
  • the aryl group may optionally be substituted or unsubstituted.
  • the "aryl” may be fused to a heteroaryl, heterocyclyl or cycloalkyl group, wherein the parent structure is attached to an aryl ring, and non-limiting examples include, but are not limited to:
  • Heteroaryl means an aromatic 5 to 6 membered monocyclic or 9 to 10 membered bicyclic ring which may contain from 1 to 4 atoms selected from nitrogen, oxygen and/or sulfur.
  • heteroaryl include, but are not limited to, furyl, pyridyl, 2-oxo-1,2-dihydropyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl , oxazolyl, oxadiazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl, benzo-di Oxolyl, benzimidazolyl, fluorenyl, isodecyl, 1,3-dioxo-isoindolyl, quinolyl,
  • the heteroaryl group can optionally be substituted or unsubstituted.
  • the heteroaryl ring can be fused to an aryl, heterocyclic or cycloalkyl ring wherein the ring to which the parent structure is attached is a heteroaryl ring, non-limiting examples include, but are not limited to:
  • Alkoxy means a group of (alkyl-O-). Among them, the alkyl group is defined in the relevant definition herein. Alkoxy groups of C 1 -C 6 are preferred. Examples thereof include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy and the like.
  • Hydrophilicity refers to an -OH group.
  • Halogen means fluoro, chloro, bromo and iodo, preferably chloro, bromo and iodo.
  • Amino means -NH 2 .
  • Niro means -NO 2 .
  • Benzyl refers to -CH 2 - phenyl.
  • Carboxy refers to -C(O)OH.
  • Carboxylic acid ester group means -C(O)O(alkyl) or (cycloalkyl) wherein alkyl, cycloalkyl are as defined above.
  • Substituted refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3, hydrogen atoms, independently of each other, substituted by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amino group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.
  • substituted or “substituted”, unless otherwise indicated, means that the group may be substituted by one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy.
  • R 10 , R 11 and R 12 are as defined in the formula (I).
  • “Pharmaceutically acceptable salt” refers to certain salts of the above compounds which retain their original biological activity and are suitable for pharmaceutical use.
  • the pharmaceutically acceptable salt of the compound represented by the formula (I) may be a metal salt, an amine salt formed with a suitable acid, a metal salt preferably an alkali metal or an alkaline earth metal salt, and a suitable acid including an inorganic acid and an organic acid such as acetic acid.
  • benzenesulfonic acid benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, malic acid, maleic acid , mandelic acid, methanesulfonic acid, nitric acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, and the like.
  • Particularly preferred are hydrochloric acid, hydrobromic acid, phosphoric acid and sulfuric acid, and most preferred is the hydrochloride salt.
  • “Pharmaceutical composition” means a mixture comprising one or more of the compounds described herein, or a physiologically pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiologically pharmaceutically acceptable carriers and Shape agent.
  • the purpose of the pharmaceutical composition is to promote the administration of the organism, which facilitates the absorption of the active ingredient and thereby exerts biological activity.
  • the preparation method of the compound of the formula (I) or a salt thereof of the present invention comprises the following steps:
  • the compound of the formula (IC) and (ID) are subjected to a condensation reaction in the presence of a condensation reagent under basic conditions to obtain a compound of the formula (IB); the compound of the formula (IB) is further hydrolyzed to obtain a compound of the formula ( IA); the compound of the formula (IA) and 2-aminoethanesulfonic acid are reacted in the presence of a condensation reagent to obtain To the compound of formula (I).
  • R 1 to R 4 , R 12 and p are as defined in the formula (I).
  • the preparation method of the compound of the formula (II) or a salt thereof of the present invention comprises the following steps:
  • the compound of the formula (IIC) and the (IID) are subjected to a condensation reaction in the presence of a condensation reagent under basic conditions to obtain a compound of the formula (IIB); the compound of the formula (IIB) is further hydrolyzed to obtain a compound of the formula (IIB) IIA); the compound of the formula (IIA) and 2-aminoethanesulfonic acid are reacted in the presence of a condensation reagent to give a compound of the formula (II).
  • R 1 to R 4 , R 12 and p are as defined in the formula (II).
  • the preparation method of the compound of the formula (III) or a salt thereof of the present invention comprises the following steps:
  • the compound of the formula (IIIC) and the (IID) are subjected to a condensation reaction in the presence of a condensation reagent under basic conditions to obtain a compound of the formula (IIIB); the compound of the formula (IIIB) is further hydrolyzed to obtain a compound of the formula (IIIB).
  • IIIA) the compound of the formula (IIIA) and 2-aminoethanesulfonic acid are reacted in the presence of a condensing reagent to give a compound of the formula (III).
  • R 1 to R 4 , R 12 and p are as defined in the formula (III).
  • the basic condition is provided by an organic base or an inorganic base selected from the group consisting of diisopropylethylamine, pyridine, triethylamine, piperidine, N-methylpiperazine, 4-dimethylaminopyridine, Preferred are diisopropylethylamine and triethylamine;
  • the inorganic base is selected from the group consisting of sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, potassium hydride, preferably sodium carbonate and sodium hydride.
  • the condensation reagent includes, but is not limited to, bis(2-oxo-3-oxazolidinyl)phosphoryl chloride, N,N-dicyclohexylcarbodiimide, N,N-diisopropyl Alkyl carbodiimide, o-benzotriazole-N,N,N'N'-tetramethyluronium borate (TBTU), preferably bis(2-oxo-3-oxazolidinyl) Phosphorus chloride.
  • TBTU o-benzotriazole-N,N,N'N'-tetramethyluronium borate
  • Mass spectrometry was measured by an LC/MS instrument, and the ionization method was electrospray (ESI) or atmospheric pressure chemical ionization (APCI).
  • ESI electrospray
  • APCI atmospheric pressure chemical ionization
  • Thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao Ocean Chemical GF254 silica gel plate.
  • the specification of silica gel plate used for thin layer chromatography (TLC) is 0.15mm ⁇ 0.2mm.
  • the specifications for thin layer chromatography separation and purification are 0.4mm to 0.5mm.
  • CD 3 OD Deuterated methanol.
  • the argon atmosphere means that the reaction flask is connected to an argon balloon having a volume of about 1 L.
  • the solution in the reaction means an aqueous solution.
  • the reaction solution was filtered while hot, and the filter cake was washed with ethyl acetate (50 mL ⁇ 2), and the THF was evaporated.
  • the organic phase was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. Purification of 15:1 and 10:1) to give ethyl 2-(4-(2,3-dihydrobenzofuran-5-yl)acetate 1c (8.4 g, pale yellow oil). .
  • reaction mixture was added with 10 mL of water, EtOAc (3 mL, EtOAc) 4-(3-((2',4',6'-Trimethyl-[1,1'-diphenyl]-4-yl)amino)-2-(4-(2,3-dihydro) Benzofuran-5-yl)phenyl)-3-oxopropyl)benzoic acid 2e (500 mg, yellow solid), yield: 78%.
  • Benzo[d][1,3]diox-5-ylboronic acid 3a (16.6 g, 100 mmol), ethyl 2-(4-bromophenyl)acetate 1b (22 g, 91 mmol), sodium carbonate (38.6 g, 364 mmol), bis(tris(p-methylphenyl)phosphine)palladium chloride (3.6 g, 4.55 mmol) was dissolved in a mixed solvent of 240 mL of tetrahydrofuran, 120 mL of ethanol and 60 mL of water, and the mixture was heated to reflux for 3 hours.
  • diaminoethanesulfonic acid 125 mg, 1 mmol was added thereto, and the resulting mixture was added to the above reaction mixture, and stirred at room temperature overnight, and the reaction was monitored by TLC.
  • 4,4-Difluorocyclohexanone 8a (26.8 g, 0.2 mol) and p-methylbenzenesulfonyl hydrazide 8b (37.2 g, 0.2 mol) were dissolved in 150 mL of ethanol and heated to reflux for 3 hours. The reaction solution was cooled to room temperature, filtered, and the filtered cake was washed with EtOAc EtOAc EtOAc EtOAc .
  • 2-(4,4-Difluorocyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane 8c (15.1 g, 0.05 mol) was dissolved in 150 mL of tetrahydrofuran, and tetramethylethylenediamine (154 mL, 1 mol) was added with stirring, and the mixture was cooled to -78 ° C dropwise with n-butyllithium (80 mL, 0.2 mol). After the completion of the dropwise addition, the mixture was further stirred at -78 ° C for 30 minutes, and then allowed to warm to room temperature.
  • 4-(1-Methylcyclopropyl)cyclohexanone 9a (2.7 g, 17.7 mmol, prepared according to the published patent application WO2010039789) was dissolved in 80 mL of dry tetrahydrofuran, and the reaction was cooled to -78 ° C. Lithium bis(trimethylsilyl)amide (36 mL, 35.5 mmol) was added with stirring, and the mixture was stirred at -78 °C for 30 minutes.
  • reaction solution was added dropwise to a solution of 20 mL of 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (6.3 g, 17.7 mmol) in tetrahydrofuran at room temperature. Stir under 3 hours. The reaction mixture was quenched with EtOAc EtOAc (EtOAc m.
  • reaction solution was concentrated under reduced pressure to drynessnessnessnessnessnessnessssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssss
  • the acid chloride (340 mg, 1.34 mmol), N,N-diisopropylethylamine (0.9 mL, 5.34 mmol) was stirred at room temperature for 10 min, then added to the reaction flask, and diaminoethanesulfonic acid (123 mg, 0.98) was added with stirring. Mmol), the obtained mixture was added to the above reaction solution, and stirred at room temperature for 24 hours, and the reaction was monitored by TLC.
  • Di(tris(p-methylphenyl)phosphine)palladium chloride (79 mg, 0.1 mmol) and sodium carbonate (424 mg, 4.0 mmol) were dissolved in a mixed solvent of 16 mL of dimethyl ether, 8 mL of ethanol and 4 mL of water. Heat to reflux for 6 hours. The reaction mixture was quenched with EtOAc EtOAc (EtOAc m. The sodium was dried, filtered, and concentrated under reduced pressure. EtOAc m.
  • 2-(1,4-Dioxaspiro[4.5]decane-8-yl)propan-2-ol 15b (43 g, 75 mmol) was dissolved in 100 mL of dry tetrahydrofuran, and the reaction mixture was reduced to -78 ° C, Methylmagnesium chloride (100 mL, 0.3 mol) was added dropwise, and the temperature was controlled at -78 ° C. After the completion of the dropwise addition, the mixture was allowed to warm to room temperature and stirred overnight.
  • 4-Oxopiperidin-1-carboxylic acid tert-butyl ester 23a (4.00 g, 20.00 mmol) was dissolved in 30 mL of tetrahydrofuran, argon-protected, cooled to -78 ° C, and lithium diisopropylamide (12.0 mL) , 24.00 mmol), reacted at -78 ° C for 1 hour. Then N-(5-chloropyridin-2-yl)-1,1,1-trifluoro-N-((trifluoromethyl)sulfonyl)methanesulfonamide (8.60 g, 22.00 mmol) was added dropwise in 10 mL.
  • reaction solution was filtered through celite, and the filtrate was evaporated to dryness to remove the organic solvent, and the organic solvent was adjusted to pH 3 to 4 with 2M hydrochloric acid, and extracted with ethyl acetate (100 mL ⁇ 3).
  • Test Example 1 Inhibition of glucagon-induced intracellular cAMP production by the compound of the present invention
  • the method uses a HEK293 cell line (purchasing the Cell Resource Center of the Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences) with high expression of human glucagon receptor (hGCGR) as a test model to test the test compound at the cellular level for glucagon. Receptor antagonism.
  • HEK293-hGCGR cells were supplemented with 10% fetal calf serum (FBS, GIBCO Cat. No. 10099141) in F12 medium (Invitrogen Cat. No. #11765047) and cultured at 37 ° C, 5% CO 2 .
  • the cells were seeded in a suitable concentration (3000 cells/well) in a 384-well plate (OptiPlate-384, white, PerkinElmer Cat. No. 6007290).
  • Compounds were first dissolved in DMSO and then serially diluted to the desired concentration. Each compound was set at 10 concentrations of 50 ⁇ M, 16.7 ⁇ M, 5.56 ⁇ M, 1.85 ⁇ M, 0.62 ⁇ M, 0.21 ⁇ M, 69 nM, 23 nM, 7.5 nM. And 2.5nM.
  • the cells were administered to the cells, the cells were stimulated by adding an appropriate concentration of Glucagon (purchased in Sigma, 0.05 nM) and incubated for 1 hour at room temperature.
  • test solution was added according to the Lance cAMP384 Kit Kit (PerkinElmer, #AD0263) operating instructions, and incubation was continued for 1 hour at room temperature and intracellular cyclic adenosine monophosphate (cAMP) levels were determined according to the kit instructions.
  • cAMP cyclic adenosine monophosphate
  • hGLP-1R human glucagon-like peptide 1 receptor
  • GIPR gastrin inhibitory peptide receptor
  • IC 50 values for inhibition of GCGR compounds of the invention as shown in Table 2, wherein the range of IC 50 ⁇ 500nM (range indicated by A):
  • the compounds of the present invention have a significant inhibitory effect on GCGR and have a selective inhibitory effect on GCGR.
  • Test Example 2 Effect of single oral administration of the compound of the present invention on random blood glucose in db/db mice
  • mice 50 male db/db mice, 9-10 weeks, were provided by the Institute of Model Animals, Nanjing University, license number: SCXK (Su) 2010-0001, and a solvent control group was set up.
  • Example 9 The compounds of Example 9 and Example 18 were formulated with 20% Solutol (polyethylene glycol stearate) to the desired concentration.
  • Solutol polyethylene glycol stearate
  • Oral gavage was administered, and the solvent control group was administered with the same volume of 20% Solutol (polyethylene glycol stearate), and the administration group was administered at a volume of 10 ml/kg at a dose of 30 mg/kg.
  • Solutol polyethylene glycol stearate
  • mice Male db/db mice were grouped according to non-fasting blood glucose and body weight (tail blood collection, blood collection was 5-10 ⁇ L, and blood glucose was detected in time with a stable blood glucose meter and blood glucose test paper, and the weight of the mice was weighed and made. The corresponding records were recorded, and then the mice were screened according to the blood glucose level, and the body weight was used as a reference index. Six groups in each group were the solvent control group and the administration group of different compounds.
  • Each group of animals was given a single oral administration of the test drug and solvent, and blood glucose was measured before administration and 1 h, 2 h, 4 h, 6 h, 8 h, 12 h and 24 h after administration, and the hypoglycemic effect and maintenance time of the test substance were observed. And draw a 24-hour blood glucose curve.
  • the modulation of blood glucose by the compounds was determined by comparison to the blood glucose of db/db mice administered only vehicle control.
  • the compounds of the invention have a good hypoglycemic effect.
  • the other compounds of the present invention were tested, and the GCGR was significantly inhibited and selectively inhibited, and both had good hypoglycemic effects.

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Abstract

La présente invention concerne un dérivé d'amide, son procédé de préparation et son utilisation pharmaceutique. En particulier, la présente invention concerne ledit dérivé aminé tel que représenté par la formule générale (I), son procédé de préparation et un sel pharmaceutiquement acceptable de celui-ci, et l'utilisation de celui-ci en tant qu'agent thérapeutique, en particulier, l'utilisation de celui-ci en tant qu'antagoniste du récepteur du glucagon.
PCT/CN2016/089134 2015-07-10 2016-07-07 Dérivé d'amide, son procédé de préparation et son utilisation pharmaceutique WO2017008681A1 (fr)

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WO2019160940A1 (fr) * 2018-02-13 2019-08-22 Ligand Pharmaceuticals Incorporated Antagonistes de récepteur de glucagon

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CN111138366B (zh) * 2018-11-06 2023-03-28 天津药物研究院有限公司 吡唑氨基甲酰类衍生物、及其制备方法和用途

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CN101610995A (zh) * 2007-02-09 2009-12-23 症变治疗公司 新颖的胰高血糖素受体拮抗剂
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