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WO2015000412A1 - Dérivé benzocyclobutène et procédé de préparation et application pharmaceutique associée - Google Patents

Dérivé benzocyclobutène et procédé de préparation et application pharmaceutique associée Download PDF

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Publication number
WO2015000412A1
WO2015000412A1 PCT/CN2014/081474 CN2014081474W WO2015000412A1 WO 2015000412 A1 WO2015000412 A1 WO 2015000412A1 CN 2014081474 W CN2014081474 W CN 2014081474W WO 2015000412 A1 WO2015000412 A1 WO 2015000412A1
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Prior art keywords
group
methyl
salt
compound
fluorenyl
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PCT/CN2014/081474
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English (en)
Chinese (zh)
Inventor
张晨
王健民
黄安邦
雷鸣
何平
徐立宁
魏用刚
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Sichuan Haisco Pharmaceutical Co Ltd
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Sichuan Haisco Pharmaceutical Co Ltd
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Priority to CN201480000823.2A priority Critical patent/CN104507921B/zh
Publication of WO2015000412A1 publication Critical patent/WO2015000412A1/fr
Anticipated expiration legal-status Critical
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    • 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
    • C07D307/80—Radicals substituted by oxygen atoms
    • 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
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic 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
    • 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
    • A61P3/06—Antihyperlipidemics
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems

Definitions

  • the present invention relates to a benzocyclobutene derivative, a preparation method thereof and its use in medicine, in particular to a novel benzo compound having a G protein-coupled receptor 40 (GPR40) receptor function regulating function.
  • GPR40 G protein-coupled receptor 40
  • Type II diabetes is the most common type of diabetes, mainly in adulthood, mainly due to insufficient insulin secretion or insulin resistance (ie, the body tissue can not effectively respond to endogenous insulin), genetic and environmental factors can be Causes insulin resistance.
  • hypoglycemic agents currently approved for marketing include sulfonylureas, biguanides, thiazolidinediones (TZDs), a-glucosidase inhibitors, amylin analogues, dipeptidyl peptidase inhibitors (DPP- IV), sodium-glucose cotransporter 2 (SGLT-2) inhibitors and other drugs.
  • these hypoglycemic agents have side effects such as hypoglycemia, weight gain, cardiovascular risk, and genitourinary tract infections (Vinod S. Deshmukh et al. (2013). International Journal of Basic & Clinical Pharmacology, 2, 4-11 These side effects further increase the burden on diabetic patients. Therefore, it is necessary to develop a new generation of hypoglycemic agents with a novel mechanism of action.
  • G-protein coupled receptor 40 is a novel target with hypoglycemic potential and is highly expressed in islet beta cells.
  • GPR40 also known as fatty acid receptor 1 (FFAR1), is a membrane receptor belonging to the homologous G protein-coupled receptor superfamily and is highly conserved among many species.
  • FFAR1 fatty acid receptor 1
  • G protein-coupled receptors have seven transmembrane structures that can sense extracellular signals, activate intracellular signal transduction pathways, and ultimately cause cellular responses.
  • GPR40 can be activated by medium-long-chain free fatty acid CFFAs (Itoh Y et al. (2003) ). Nature, 422, 173-176).
  • FFAs are also an important signaling molecule that promotes insulin secretion, a function that is primarily achieved through GPR40.
  • the interaction of FFAs with GPR40 increases Ca 2+ flux through PLC or L-type Ca 2+ channel signaling pathways in islet beta cells, which in turn leads to cellular responses (Fujiwara et al. (2005). Am J Physiol Endocrinol Metab, 289, E670 -E677).
  • Studies have shown that in animal models, agonistic GPR40 is effective in lowering blood glucose; in clinical trials, short-term and long-term treatment with GPR40 agonists promotes glucose-induced insulin secretion and increases glucose tolerance (K Nagasumi et al.
  • Fasiglifam hemihydrates (TAK-875) is a GPR40 agonist that has now entered Phase III clinical and proven effective. Studies have shown that: in the animal model of diabetes, fasiglifam hemihydrate CTAK-875) promotes insulin secretion and can effectively control blood glucose, but does not promote insulin secretion in normal rats (Tsujihata Y et al. (2010).
  • fasiglifam hemihydrates also showed significant hypoglycemic effects with a lower risk of hypoglycemia (T. Araki et al. (2012). Diabetes, Obesity and Metabolisml 4, 271-278) .
  • Other GPR40 agonists have also been developed, such as JTT-851, LY-2881835 and the like.
  • GPR40 is a safe and feasible new target for oral hypoglycemic agents.
  • the development of GPR40 agonists has very important research value and application prospects.
  • a number of research literatures related to GPR40 agonists are currently published.
  • the cyclic group of the optionally substituted substituent of Ar the cyclic group of the optional substituent of A, and not substituted by thiazole, oxazole, imidazole and pyrazole, each independently selected from a bond or containing 1 a chain of -5 atoms
  • Xc is selected from 0, S, SO or S0 2
  • Xd is selected from a bond, CH or CH 2
  • D is selected from a benzene ring, a thiophene or a thiazole
  • B is selected from a ring of 5 to 7 members
  • R 1 is selected from a hydroxyl group.
  • CN101616913 describes a fused ring compound which can function as an insulin secretion promoting agent and a GPR40 receptor function regulating effect of diabetes prevention and/or therapeutic drugs, and has the following structural formula:
  • R 1 is selected from -S0 2 -R 6
  • R 6 is selected from d- 6 fluorenyl or optionally substituted 1,1-dioxotetrahydrothiopyranyl
  • X is selected from a bond or a divalent hydrocarbon group
  • R 2 and R 3 are selected from H, a halogen atom, a substituted hydrocarbon group or a substituted hydroxyl group
  • R 4 and R 5 are selected from d- 6 fluorenyl substituted by a hydroxy group
  • A is selected from a benzene ring
  • B is selected from 5 to A 7-membered ring
  • Y is selected from a bond or CH 2
  • R is selected from a hydroxyl group.
  • Ar is optionally a cyclic group of a substituent, and is not substituted by a 4-piperidinyl group
  • B is optionally a ring of a substituent, and is not substituted by a thiazole or an oxazole
  • W is selected from a bond or d- 6 ⁇ a group
  • X, Xa is selected from CH or N
  • Y is selected from O or CR 6 R 7
  • R 1 and R la are selected from H, halogen, d- 6 fluorenyl or d- 6 methoxy
  • R 2 is selected from H a d- 6 fluorenyl or an optionally substituted acyl group
  • R 3 and R 4 are selected from H or halogen
  • R 5 is selected from a substituted hydroxy group or a substituted amine group, and the compound specifically described in
  • WO2010143733 describes a GPR40 receptor modulator which can be used as an insulin secretion promoting agent and a preventive and/or therapeutic drug for diabetes, and has the following structural formula:
  • R 1 is selected from halogen, hydroxy, optionally substituted d- 6 fluorenyl or optionally substituted d- 6 fluorenyloxy;
  • R 2 is selected from substituted hydroxy,
  • R 3 is selected from H, halogen or optionally substituted D- 6 fluorenyl,
  • X is CH 2
  • Y is selected from CH 2
  • Z is selected from CH or N, and
  • A is selected from halogen, optionally substituted amine or 4-13 membered ring.
  • the present invention relates to a compound of the formula or a stereoisomer, hydrate, ester, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug thereof,
  • R is selected from H or d- 8 fluorenyl
  • R 1 and R 4 are each independently selected from the group consisting of F, Cl, Br, I, hydroxy, amino, nitro, cyano, carboxy, d- 8 fluorenyl or
  • R 5 and R 6 may form a 4 to 8 membered carbocyclic ring or a 5 to 8 membered heterocyclic ring, and the carbocyclic or heterocyclic ring may be further optionally further selected from 0 to 4 selected from the group consisting of F, Cl, Br, and I.
  • R 7 , 1 and R 7b are each independently selected from the group consisting of H, hydroxy, amino, carboxy, d- 8 fluorenyl, d- 8 methoxy, C 2 -8 alkenyl,
  • C 2 .8 alkynyl, 3 to 10 membered carbocyclic group, 4 to 10 membered heterocyclic group, 3 to 10 membered carbocyclyloxy group or 4 to 10 membered heterocyclic oxy group, said amino group, fluorenyl group , methoxy, alkenyl, alkynyl, carbocyclyl, heterocyclyl, carbocyclyloxy or heterocyclyloxy optionally further selected from 0 to 4 selected from F, Cl, Br, I, 0 , hydroxy, amino, nitro, cyano, carboxy, d- 8 alkyl with, d_ 8 embankment group, C 2 - 8 alkenyl, C 2 - 8 alkynyl group, 3-10 yuan carbocyclyl, 4-10 Substituted by a heterocyclic group, a 3- to 10-membered carbocyclyloxy group or a 4- to 10-membered heterocyclic oxy group, and the heterocyclic group contains 1
  • p is selected from 0, 1, 2 or 3;
  • q is selected from 0, 1, 2, 3 or 4;
  • t is selected from 0, 1 or 2 (when t is 0, it means that -COOR is directly attached to ring A; when t is 2, there are two identical or different R 2 and two identical or different in the compound R 3 ) ;
  • n is selected from 0, 1, 2, 3, 4 or 5;
  • n is selected from 0, 1 or 2.
  • the phrase "as a selection” means that the scheme after "as a selection” is a side-by-side selection relationship with the scheme before “as a selection”, rather than a further selection in the foregoing scheme.
  • R is selected from H or d- 4 fluorenyl, preferably H or d- 2 fluorenyl, more preferably H;
  • N rS ⁇ Y , S ring A is selected from , ⁇ , ⁇ , ⁇ , , or ' U, preferred Hey. , ⁇ . ⁇
  • Ring B comprising an atom attached to the benzene ring to form a four-membered ring, and ring B may optionally further be from 0 to 4 selected from F,
  • R 1 and R 4 are each independently selected from the group consisting of F, Cl, Br, I, hydroxy, amino, nitro, cyano, carboxy, d- 4- indenyl or -4- decyloxy, preferably F, C1 or d- 4 ⁇ Further, the amino group, thiol group or decyloxy group is further optionally selected from 0 to 3
  • R 5 and R 6 are each independently selected from H, F, Cl, Br, I, hydroxy, amino, nitro, cyano, carboxy, d- 4- indenyl or d- 4 decyloxy, preferably H, F, Cl , Br, I, hydroxy or -4 fluorenyl, more preferably H, F, Cl, hydroxy or d 4 fluorenyl, further preferably H, C1 or d- 4 fluorenyl, said fluorenyl or decyloxy optionally Further 0 to 3 selected from F,
  • the base is further selected from 0 to 4 selected from the group consisting of F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , cyano, hydroxy,
  • R 7 and R 7a are each independently selected from H, hydroxy, amino, carboxy, d- 4 alkyl with, d- 4 embankment group, C 2 - 8 alkenyl, C 2 - 8 alkynyl, carbocycle 3-8 yuan a 4- to 8-membered heterocyclic group, a 3- to 8-membered carbocyclic oxy group or a 4- to 8-membered heterocyclic oxy group, preferably H, hydroxy, amino, d- 4- indenyl or -4- decyloxy, further Preference is given to hydroxy or d- 4- indenyl, said amino, indolyl, decyloxy, alkenyl, alkynyl, carbocyclyl, heterocyclyl, carbocyclyloxy or heterocyclooxy optionally further 0 to 4 choices g F, Cl, Br, I , hydroxy, amino, nitro, cyano, carboxy, d- 4 alkyl with, d
  • p is selected from 0, 1 or 2;
  • q is selected from 0, 1 or 2;
  • n is selected from 0, 1, 2, 3, 4 or 5;
  • n is selected from 0, 1 or 2.
  • R 1 and R 4 are each independently selected from the group consisting of F, Cl, Br, I, hydroxy, amino, nitro, cyano, carboxy, d- 4- indenyl or -4- methoxy, preferably F, C1 or methyl. Said amino, thiol or decyloxy group is optionally further substituted by 0 to 3 substituents selected from F, Cl, Br, I or hydroxy;
  • R 5 and R 6 are each independently selected from H, F, Cl, Br, I, hydroxy, amino, nitro, cyano, carboxy, d- 4- indenyl or CM methoxy, preferably H, F, Cl, Br Or I or d- 4 fluorenyl, more preferably H, F, CI or d- 4 fluorenyl, further preferably H or d-4 fluorenyl, said amino, fluorenyl or decyloxy optionally further being 0 to Substituting three substituents selected from the group consisting of F, Cl, Br, I, hydroxy, d- 4 fluorenyl or -4- methoxy;
  • R 7 and R 7a are each independently selected from H, hydroxy, amino, carboxy, d- 4 alkyl with, d- 4 embankment group, C 2 - 8 alkenyl, C 2 - 8 alkynyl, carbocycle 3-8 yuan a 4- to 8-membered heterocyclic group, a 3- to 8-membered carbocyclic oxy group or a 4- to 8-membered heterocyclic oxy group, preferably H, hydroxy, amino, d- 4- indenyl or -4- decyloxy, further Preference is given to hydroxy or d- 4- indenyl, said amino, indolyl, decyloxy, alkenyl, alkynyl, carbocyclyl, heterocyclyl, carbocyclyloxy or heterocyclooxy optionally further is selected from 0-4 g F, Cl, Br, I , hydroxy, amino, nitro, cyano, carboxy, d- 4 alkyl with,
  • p is selected from 0, 1 or 2;
  • q is selected from 0, 1 or 2;
  • n is selected from 0, 1, 2, 3, 4 or 5;
  • n is selected from 0, 1 or 2.
  • a preferred embodiment of the invention a compound of the formula (II) or a stereoisomer, hydrate, ester, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug thereof,
  • R is selected from H ;
  • Ring B including atoms attached to the benzene ring, together form a four-membered ring, and Ring B may optionally be further from 0 to 4 selected from the group consisting of F, Cl, Br, I, hydroxy, d-4 fluorenyl or ⁇ -4 Substituted by a substituent of an oxy group;
  • R 1 and R 4 are each independently selected from the group consisting of F, Cl, Br, I, hydroxy or -4 -yl, preferably F, CI or methyl;
  • R 5 and R 6 are each independently selected from H, F, Cl, Br, I, hydroxy, amino, nitro, cyano, carboxy, d- 4- indenyl or CM methoxy, preferably H, F, Cl, Br , I or d- 4 thiol, more preferably H, F, CI or C M thiol, further Preferably H or d- 4 fluorenyl;
  • Y is selected from a single bond, -0-, -NR 7 -, -d_ 4 fluorenylene or -O-CM fluorenylene, preferably a single bond, -0- or -NR 7 -, more preferably -0-
  • the fluorenylene group is optionally further substituted with 0 to 4 substituents selected from the group consisting of F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , hydroxy, CM thiol or -4- decyloxy.
  • R 7 is selected from H, hydroxyl, amino, carboxyl, d- 4 alkyl with, d- 4 embankment group, C 2 - 8 alkenyl, C 2 - 8 alkynyl group, 3-8 yuan carbocyclyl or 4-8 a heterocyclic group, preferably H, amino, d- 4 fluorenyl or -4- decyloxy, more preferably d- 4 fluorenyl, and the heterocyclic group contains 1 to 4 selected from N, 0 or S Hetero atom
  • p is selected from 0 or 1 ;
  • q is selected from 0 or 1 ;
  • n is selected from 0, 1, 2, 3, 4 or 5, preferably 3 or 4, more preferably 3;
  • n is selected from 0, 1 or 2.
  • the compound or a compound thereof a stereoisomer, a hydrate, an ester, a metabolite, a solvate, a pharmaceutically acceptable salt, a eutectic III):
  • - ring B including the atom attached to the phenyl ring, together form a four-membered ring, and ring B may be optionally further substituted with from 0 to 4 substituents selected from F or C1;
  • R 5 and R 6 are each independently selected from H, F, Cl, Br, I, hydroxy or d- 4 fluorenyl, preferably H, F, CI or d- 4 fluorenyl, more preferably H, C1 or d- 4 ⁇ Further, preferably H or d- 2 fluorenyl;
  • Y is selected from a single bond, -0 or -NR 7 -, preferably -0-;
  • R 7 is selected from H, hydroxy, amino, d- 4 fluorenyl or d- 4 decyloxy, preferably d- 4 fluorenyl, further preferably d- 2 fluorenyl; m is selected from 0, 1, 2, 3 or 4 , preferably 3 or 4, more preferably 3;
  • n is selected from 0, 1 or 2.
  • R 5 and R 6 are each independently selected from H, F, Cl, hydroxy or d 4 fluorenyl, preferably H, C 1 or d 4 fluorenyl, more preferably H or d 2 fluorenyl;
  • R 7 is selected from a hydroxyl group or a CM fluorenyl group, preferably a d- 4 fluorenyl group, more preferably a d- 2 fluorenyl group;
  • n is selected from 2, 3 or 4, preferably 3 or 4, more preferably 3;
  • n is selected from 0, 1 or 2.
  • a preferred embodiment of the invention a compound of the formula (IV) or a stereoisomer, hydrate, ester, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug thereof, wherein:
  • R 5 and R 6 are each independently selected from H or d- 4 fluorenyl, preferably H or d- 2 fluorenyl;
  • R 7 is selected from the group consisting of d- 4 fluorenyl, preferably d- 2 fluorenyl;
  • n is selected from 0, 1 or 2.
  • a preferred embodiment of the invention a compound of the formula (IV) or a stereoisomer, hydrate, ester, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug thereof, wherein:
  • R 5 and R 6 are each independently selected from H, methyl, ethyl, n-propyl or isopropyl, preferably H, methyl or ethyl;
  • R 7 is selected from methyl, ethyl, n-propyl or isopropyl, preferably methyl.
  • a preferred embodiment of the invention a compound of the formula (IV) or a stereoisomer, hydrate, ester, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug thereof, wherein:
  • R 5 and R 6 are each independently selected from H, methyl or ethyl, eumethyl;
  • R 7 is selected from methyl or ethyl, preferably methyl.
  • a preferred embodiment of the invention a compound of the formula (I) or a stereoisomer, hydrate, ester, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug thereof, wherein the compound is selected From the compound of the formula (II):
  • R is selected from H or d- 4 fluorenyl, preferably H;
  • Ring B comprising atoms connected to the benzene ring to form a four-membered ring
  • R 1 and R 4 are each independently selected from F, Cl, Br or d-4, preferably F, CI or methyl;
  • R 5 and R 6 are each independently selected from H, F, Cl, Br or d-4, preferably H or methyl;
  • R 7 is selected from H or d- 4 fluorenyl, preferably H or d- 2 fluorenyl, more preferably methyl;
  • p is selected from 0, 1 or 2;
  • q is selected from 0, 1 or 2;
  • n is selected from 0, 1, 2, 3, 4 or 5;
  • n is selected from 0, 1 or 2.
  • the compound is selected from the compounds of the formula (III):
  • Ring B comprising atoms connected to the benzene ring to form a four-membered ring
  • R 5 and R 6 are each independently selected from H, F, Cl, Br or d- 4 , preferably! ! Or ⁇ - 2 fluorenyl, more preferably H or methyl;
  • Y is selected from -0- or -O-CM fluorenylene, preferably -0-;
  • R 7 is selected from H or d- 4 fluorenyl
  • n is selected from 0, 1, 2, 3 or 4;
  • n is selected from 0, 1 or 2.
  • a preferred embodiment of the invention a compound of the formula (III) or a stereoisomer, hydrate, ester, metabolite, solvate, pharmaceutically acceptable, eutectic or prodrug thereof, wherein the compound is selected from the group consisting of Compounds of formula 0V):
  • R 5 is selected from H or d- 4 fluorenyl, preferably H or d- 2 fluorenyl, more preferably H or methyl;
  • R 6 is H
  • R 7 is selected from the group consisting of CM thiol, preferably d- 2 fluorenyl, more preferably methyl;
  • n is selected from 2, 3 or 4, preferably 3;
  • n is selected from 0, 1 or 2.
  • a preferred embodiment of the invention a compound of the formula (IV) or a stereoisomer, hydrate, ester, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug thereof, wherein:
  • R 5 is selected from H, methyl, ethyl, n-propyl or isopropyl, preferably H or methyl;
  • R 6 is H
  • R 7 is selected from methyl, ethyl, n-propyl or isopropyl, preferably methyl-
  • R 7 is selected from methyl, ethyl, n-propyl or isopropyl, preferably methyl-
  • R 5 is selected from H, methyl or ethyl, preferably methyl
  • R 6 is H
  • R 7 is a methyl group.
  • R 4 is selected from H, F, CI or methyl
  • R 5 is selected from H or d- 4 fluorenyl, preferably H or d- 2 fluorenyl, more preferably H or methyl;
  • R 7 is selected from H or d- 4 fluorenyl, preferably H or d- 2 fluorenyl, more preferably methyl;
  • n is selected from 0, 1, 2, 3 or 4, preferably 3;
  • n is selected from 0, 1 or 2.
  • a preferred embodiment of the invention a compound of the formula (V) or a stereoisomer, hydrate, ester, metabolite, solvate, pharmaceutically acceptable salt, eutectic or prodrug thereof, wherein:
  • R 4 is selected from H, F, CI or methyl
  • R 5 is H or methyl, preferably H ;
  • the invention relates to a compound selected from, but not limited to:
  • a compound according to the invention or a stereoisomer, hydrate, ester, metabolite, solvate, pharmaceutically acceptable salt, co-crystal or prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein
  • the salt described in the pharmaceutically acceptable salt is selected from, but not limited to, sodium salt, potassium salt, aluminum salt, lithium salt, zinc salt, calcium salt, magnesium salt, barium salt, ammonium salt, trimethylamine salt, tetramethyl Base ammonium salt, Diethylamine salt, triethylamine salt, isopropylamine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, cyclohexylamine salt, dicyclohexylamine salt, pyridinium salt, methylpyridine salt, 2,6- Dimethylpyridine salt, caffeine salt, procaine salt, choline salt, betaine salt, theobromine salt, sulfonium salt, piperazine salt, piperidine salt, N-ethyl piperidine salt
  • the invention also relates to a method of synthesizing the compounds.
  • the compounds of the present invention can be synthesized by a variety of methods of preparation. Preferred methods include, but are not limited to, the methods described below.
  • the functionality exhibited on the molecule should be consistent with the planned transformation. In order to obtain the desired compound of the present invention, a judgment is sometimes required to change the order of the synthesis steps or to select a particular process scheme.
  • Reasonable protecting groups are selected for the protection of reactive functional groups present in the compounds described herein.
  • the present invention relates to a process for the preparation of the compound of the formula ⁇ , which may be selected from the first or second method comprising the following steps, the method 1 comprising:
  • the general formula (Ia-aO compound is obtained by Clemson reduction, modified Clemson reduction, Wolf-Keithner reduction, Huangminglong reduction or reduction of carbonyl by reducing agent-Lewis acid combination method to obtain the general formula (Ia) a compound (when the ring B carries a substituent, the carbonyl group may be first reduced to introduce a substituent to obtain a compound of the formula (Ia), or the substituent may be introduced and then reduced to obtain (Ia));
  • the compound of the formula (Ia 2 ) is reduced to give a compound of the formula (Ia); or the compound of the formula (1) is reduced to give a compound of the formula (Ia);
  • the compound of the formula (I-a) is subjected to a suzuki coupling reaction with the compound of the formula (I-b), and the obtained product is further hydrogenated under a reducing agent to obtain a compound of the formula (I-c);
  • R 9 or R 12 are each independently selected from the group consisting of H, F, Cl, Br, I, hydroxy, cT eF3 or ⁇
  • R 1U is selected from the group consisting of ruthenium, F, Cl, Br, I, hydroxy, d- 6 fluorenyl or d- 6 methoxy, X, Y, ring B, R, R 1 , R 2 , R 3 , R 4 ,
  • the definitions of R 5 , R 6 , p, q and t are consistent with the definition of formula (I).
  • the formula (Ia reduces the carbonyl group to obtain the compound of the formula (Ia); or ethylene glycol, ethylene glycol dimethyl ether, poly Ethylene glycol as a solvent, in the presence of potassium hydroxide, sodium hydroxide, potassium t-butoxide, sodium t-butoxide, hydrazine hydrate, anhydrous hydrazine, the carbonyl group is reduced by the formula (I- ai ) to obtain a compound of the formula (Ia) Or by using hydrazine, hydrazine-dimethylformamide, tetrahydrofuran or dimethyl sulfoxide as solvent, in the presence of aluminum trichloride and zinc dichloride, the general formula (I-aO reduced carbonyl group) a compound of the formula (Ia).
  • the compound of the formula (Ia) is subjected to a suzuki coupling reaction with the compound of the formula (Ib), and the obtained product is further hydrogenated under a reducing agent to obtain a compound of the formula (Ic), wherein the palladium catalyst is selected from the group consisting of four Palladium triphenylphosphine, palladium dichloride, palladium acetate or Bis(triphenylphosphine)palladium dichloride, the reducing agent is selected from the group consisting of sodium borohydride, potassium borohydride, zinc borohydride, cyanide Sodium borohydride, potassium cyanoborohydride, sodium triacetoxyborohydride, lithium aluminum hydride, sodium thioborohydride or lithium
  • Method two includes:
  • the compound of the formula (Ia) is subjected to a suzuki coupling reaction with a compound of the formula (Ib), and the obtained product is further hydrogenated under a reducing agent to obtain a compound of the formula (Ic), wherein the palladium catalyst is selected from tetratriphenyl Phospho palladium, palladium dichloride, palladium acetate or bis(triphenylphosphine)palladium dichloride, the reducing agent is selected from sodium borohydride, boron hydride Potassium, zinc borohydride, sodium cyanoborohydride, potassium cyanoborohydride, sodium triacetoxyborohydride, lithium aluminum hydride, sodium thioborohydride or lithium tri
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising: an effective amount of a compound of the formula (I) or all stereoisomers, hydrates, solvates, esters, metabolites, co-crystals thereof, A pharmaceutically acceptable salt or prodrug and a pharmaceutically acceptable carrier, diluent, adjuvant or excipient; the composition may further comprise one or more additional therapeutic agents.
  • additional therapeutic agents described therein include:
  • glucagon receptor antagonist or a pharmaceutically acceptable salt
  • a drug for improving lipid distribution in a patient selected from the group consisting of HMG-CoA reductase inhibitors, bile acid sequestrants, nicotine, niacin or a salt thereof, ? Enter!
  • An agonist a cholesterol absorption inhibitor, an acyl-CoA (cholesterol acyltransferase (ACAT)) inhibitor, a CETP inhibitor or a phenolic antioxidant or a pharmaceutically acceptable salt, and/or
  • the GPR40 agonist is selected from the group consisting of fasiglifam hemihydrates (TAK-875) or a pharmaceutical thereof An acceptable salt or prodrug.
  • the DDP-IV inhibitor is selected from the group consisting of linagliptin (lilastetine), omarigliptin
  • MK-3102 sitagliptin (sitagliptin), vildagliptin (vildagliptin), alogliptin (alogliptin), saxagliptin (saxagliptin), denagliptin (digagliptin), Carmegliptin ( ⁇ Lenin), Melogliptin (Merolidine), Dutogliptin (Digliptin), Teneligliptin (Teliglitin), Gemigliptin (Ziglitin) or Trelagliptin (Tragliptin).
  • the SGLT-2 inhibitor is selected from the group consisting of Dapagliflozin, Canagliflozin, Atigliflozin, Empagliflozin, Ipragliflozin, Ipragliflozin, Tofogliflozin, Luseogliflozin, Remogliflozin, Sergliflozin or Ertugliflozin;
  • PPAR Y agonists include Ciglitazone (cycloglitazone) ), Troglitazone (troglitazone), Pioglitazone (pioglitazone), Rosiglitazone (Rosiglitazone), Englitazone (englitazone), Darglitazoan (daglitazone), the PPAR ⁇ dual agonist including mulaglitazar Gutazole or aleglitazar, the PPAR S agonist comprises pioglitazone (pioglitazone;) or rosiglitazone (rosiglit
  • the biguanide therapeutic agent is selected from the group consisting of metformin or dibiguanidine.
  • the thiazolidinedione therapeutic agent is selected from the group consisting of ciglitazone, pioglitazone, rosiglitazone, troglitazone, faglitazone or dapaglitazone.
  • the sulfonylurea therapeutic agent is selected from the group consisting of glimepiride, glibenclamide, glibenclamide, gliclazone, glipizide, or gliclazide.
  • the levonide therapeutic agent is selected from the group consisting of nateglinide, repaglinide or mitiglinide.
  • the (X-glucosidase inhibitor is selected from the group consisting of acarbose, voglibose or miglitol.
  • the GLP-1 analogue is selected from Exenatide or Liraglutide. Larupeptide).
  • the invention further relates to the use of the compound or a stereoisomer, hydrate, solvate, ester, metabolite, co-crystal, pharmaceutically acceptable salt or prodrug thereof, or medical use thereof Specifically, in the preparation of a G protein coupled receptor 40 agonist, in particular as a G protein coupled receptor 40 agonist, in the preparation of a pharmaceutical preparation, preferably for the treatment and/or prevention of metabolic diseases Use in applications.
  • the metabolic diseases include diabetes, type II diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, diabetic complications, hypercholesterolemia, hyperglycemia, hyperinsulinemia, hyperlipidemia, high glycerol Acidemia, hypertension, hyperlipoproteinemia, high LDL cholesterol, low HDL cholesterol, hypoglycemia, dyslipidemia, thrombotic disease, cardiovascular disease, kidney disease, ketoacidosis, fatty acid or glycerol High levels, lipoatrophy, lipotoxicity, obesity, metabolic syndrome, X syndrome, insulin resistance, insulin allergy, glucose intolerance, skin disease, atherosclerosis and its sequelae angina, limp, heart disease One or more of seizures or strokes, further preferably including type II diabetes.
  • the present invention also relates to a method of treating and/or preventing the above metabolic diseases, which comprises administering to a subject an effective amount of a compound of the present invention or a stereoisomer, hydrate, ester, solvate, co-crystal thereof. , a metabolite, a pharmaceutically acceptable salt or prodrug or a pharmaceutical composition of the invention.
  • carbon, hydrogen, oxygen, sulfur, nitrogen or halogen involved in the groups and compounds of the present invention include their isotopic conditions, and the carbon, hydrogen, oxygen, sulfur involved in the groups and compounds of the present invention. Or nitrogen optionally further one or more of them correspond Substituted by isotopes, carbon isotopes include 12 C, 13 C, and 14 C.
  • Hydrogen isotopes include helium (H), helium (D, also known as heavy hydrogen), helium (T, also known as super heavy hydrogen; I, oxygen
  • the isotopes include 16 0, 17 0 and 18
  • the sulfur isotopes include 32 S, 33 S, 34 S and 36 S
  • the nitrogen isotopes include 14 N and 15 N
  • the fluorine isotopes include 17 F and 19 F, chlorine.
  • Isotopes include 35 C1 and 37 C1
  • the isotopes include 7 3 ⁇ 4r and 81 Br.
  • Mercapto refers to a linear or branched saturated aliphatic hydrocarbon group having 1 to 20 carbon atoms, preferably a fluorenyl group of 1 to 8 carbon atoms, more preferably a fluorenyl group of 1 to 6 carbon atoms, further A fluorenyl group of 1 to 4 carbon atoms is preferred.
  • R 11 and R la are each independently selected from H, hydroxy, amino, carboxy, d— alkyl with 8, 8 embankment D- group, C 2 - 8 alkenyl, C 2 - 8 alkynyl group, 3-10 yuan carbocyclyl 4 to 10-membered heterocyclic, 3-10 yuan carbocyclyl group Or a 4- to 10-membered heterocyclyloxy group, m is selected from 0, 1, 2, 3, 4 or 5, and n is selected from 0, 1 or 2.
  • the thiol group, R 11 ⁇ R lla
  • Alkoxy means -0-fluorenyl, non-limiting examples include methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-methyl- 1-propoxy, 2-butoxy, 2-methyl-2-propoxy, 1-pentyloxy, 2-pentyloxy, 3-pentyloxy, 2-methyl-2-butoxy Base, 3-methyl-2-butoxy, 3-methyl-1-butoxy and 2-methyl-1-butoxy.
  • Alkenyl means a straight or branched unsaturated aliphatic hydrocarbon group having from 1 to 3 carbon-carbon double bonds, consisting of 2 to 20 carbon atoms, preferably an alkenyl group of 2 to 12 carbon atoms, more preferably Alkenyl of 2-8 carbon atoms.
  • Non-limiting examples include vinyl, propen-2-yl, buten-2-yl, penten-2-yl, penten-4-yl, hexen-2-yl, hexen-3-yl, Hepten-2-yl, hepten-3-yl, hept-4-yl, oct-3-yl, nonen-3-yl, nonen-4-yl and undecen-3-yl.
  • the alkenyl group may be further optionally further selected from 0 to 4 selected from the group consisting of F, Cl, Br, I, decyl, decyloxy, linear alkenyl, linear alkynyl, amino, nitro, cyano, fluorenyl Substituted by a substituent of an amide group, a carbocyclic group or a heterocyclic group.
  • Alkynyl means an alkynyl group having 1 to 3 carbon-carbon triple bonds, a linear or branched unsaturated aliphatic hydrocarbon group consisting of 2 to 20 carbon atoms, preferably 2 to 12 carbon atoms, more preferably Alkynyl group of 2-8 carbon atoms.
  • Non-limiting examples include ethynyl, propyn-1-yl, butyn-1-yl, butyn-3-yl, pentyn-1-yl, hexyn-1-yl, heptyn-1-yl , heptyn-3-yl, heptyn-4-yl, octyn-3-yl, decyn-3-yl, decyn-4-yl, undecyn-3-yl, dodecyn-4- base.
  • the alkynyl group may be further optionally 0 to 4 selected from the group consisting of F, Cl, Br, I, decyl, decyloxy, linear alkenyl, linear alkynyl, amino, nitro, cyano, fluorenyl Substituted by a substituent of an amide group, a carbocyclic group or a heterocyclic group.
  • Carbocyclyl means a saturated or unsaturated aromatic or non-aromatic ring, and an aromatic or non-aromatic ring may be 3 to 10 a monocyclic, 4 to 12 membered bicyclic or 10 to 15 membered tricyclic ring system, a carbocyclic group may be bonded to a bridged ring or a spiro ring, and non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, 1 -cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, phenyl, 1-cyclohexyl-2-alkenyl, 1- Cyclohexyl-3-alkenyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, decyl, cyclodecyl, cyclodode
  • the heterocyclic group can be attached to a hetero atom or a carbon atom, and the heterocyclic group can be bonded to a bridged or spiro ring, non-limiting examples include epoxy ethyl, epoxy Propyl, azacyclopropyl, oxetanyl, azetidinyl, thiot-butyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3 - dioxolyl, azepanyl, oxetanyl, thiaheptyl, oxazepine, diazepine, thiazepine, pyridyl, piperidinyl, High piperidinyl, furyl, thienyl, pyranyl, N-fluorenylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, homopiperaziny
  • Isocyano refers to divination G_ .
  • Neitro means -N0 2 .
  • Carboxy means -COOH.
  • Haldroxymethane means a fluorenyl group substituted by 1, 2 or 3 hydroxy groups, and the fluorenyl group is preferably a C1-4 fluorenyl group.
  • Non-limiting examples include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxypropyl, 1,3-dihydroxypropyl, and 2,3-dihydroxypropyl.
  • “Pharmaceutically acceptable salt” or “pharmaceutically acceptable salt thereof” means that the compound of the present invention retains the biological effectiveness and properties of the free acid, and the free acid is reacted with a non-toxic inorganic or organic base. The salt obtained.
  • Non-limiting examples of the inorganic base include sodium, potassium, aluminum, lithium, zinc, calcium, magnesium, strontium; non-limiting examples of the organic base include ammonia, trimethylamine, tetramethylammonium, Diethylamine, triethylamine, isopropylamine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, pyridine, picoline, 2,6-lutidine, caffeine, proca Cause, choline, betaine, theobromine, hydrazine, piperazine, piperidine, N-ethylpiperidine, polyamine resin, phenicillin salt.
  • Carrier means a material that does not cause significant irritation to the organism and does not eliminate the biological activity and properties of the administered compound.
  • Excipient means an inert substance that is added to a pharmaceutical composition to facilitate administration of the compound.
  • Non-limiting examples include calcium carbonate, calcium phosphate, sugar, starch, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, bonding Agent and disintegrant.
  • an “adjuvant” is a non-specific immunopotentiator that, when injected with an antigen or pre-injected into the body, enhances the body's immune response to the antigen or alters the type of immune response.
  • “Diluent” is also called “filler”. When the original drug is processed into a powder, or to facilitate the spraying of the added inert substance to be diluted.
  • a powder or to facilitate the spraying of the added inert substance to be diluted.
  • Prodrug means a compound of the invention that can be converted to biological activity by metabolism in vivo.
  • Prodrugs of the invention are prepared by modifying functional groups in the compounds of the invention which can be removed by conventional procedures or in vivo to provide the parent compound.
  • Prodrugs include compounds formed by attachment of a carboxy group of any of the compounds of the present invention to any group. When a prodrug of the invention is administered to a mammalian subject, the prodrug is cleaved to form a free carboxyl group, respectively.
  • Examples of prodrugs include, but are not limited to, A compound formed by a carboxyl functional group in the compound of the present invention and methanol, ethanol or benzyl alcohol.
  • Eutectic refers to a crystal in which an active pharmaceutical ingredient and a eutectic formation are combined by hydrogen bonding or other non-covalent bond, wherein the pure state of API (active pharmaceutical ingredient) and CCF (eutectic formation) They are all solid at room temperature and there is a fixed stoichiometric ratio between the components.
  • Eutectic is a multi-component crystal that contains both a binary eutectic formed between two neutral solids and a multi-eutectoid formed from a neutral solid with a salt or solvate.
  • Non-limiting examples of the "eutectic former" include alanine, valine, leucine, isoleucine, valine, phenylalanine, tryptophan, methionine, glycine, serine, Threonine, cysteine, tyrosine, asparagine, glutamine, lysine, arginine, histidine, aspartic acid, aspartic acid, glutamic acid, pyroglutamic acid Acid, sulfuric acid, phosphoric acid, nitric acid, hydrobromic acid, hydrochloric acid, formic acid, acetic acid, propionic acid, benzenesulfonic acid, benzoic acid, phenylacetic acid, salicylic acid, alginic acid, anthranilic acid, camphoric acid, citric acid, vinyl sulfonate Acid, formic acid, fumaric acid, citric acid, gluconic acid, glucuronic acid, glutamic acid, glycolic acid, is
  • Stepoisomer refers to isomers resulting from the arrangement of atoms in a molecule in a spatial arrangement, including cis-trans isomers, enantiomers, and conformational isomers.
  • heterocyclic group optionally substituted by a thiol group means that the fluorenyl group may, but does not necessarily exist, the description including the case where the heterocyclic group is substituted by a thiol group, and wherein the heterocyclic group is not substituted by a thiol group happening.
  • “Pharmaceutical composition” means a combination of one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, or/and one or more additional therapeutic agents, and a pharmaceutically acceptable form. Agents, adjuvants, diluents and carriers.
  • the “EC 50 " half effective concentration refers to the concentration at which half of the maximum efficacy is reached. Detailed ways
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). NMR shift ( ⁇ ) to
  • NMR NMR was measured using a (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDC1 3 ), deuterated methanol (CD 3 OD). ), the internal standard is tetramethylsilane (TMS).
  • MS Alent 6120B (ESI) and Agilent 6120B (APCI)).
  • the HPLC was measured using an Agilent 1260 DAD high pressure liquid chromatograph (Zorbax SB-C18 100 4.6 mm).
  • the thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate.
  • the silica gel plate used for thin layer chromatography (TLC) has a specification of 0.15 mm ⁇ 0.20 mm, and the thin layer chromatography separation and purification product adopts a specification of 0.4 mm.
  • ⁇ 0.5 Column chromatography generally uses Yantai Huanghai silica gel 200 ⁇ 300 mesh silica gel as carrier.
  • the known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from Titan Technology, Anheji Chemical, Shanghai Demer, Chengdu Kelon Chemical, Suiyuan Chemical Technology, and Belling Technology. And other companies.
  • the nitrogen atmosphere means that the reaction flask is connected to a nitrogen balloon of about 1 L volume.
  • the hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume.
  • the hydrogenation reaction is usually evacuated, charged with hydrogen, and operated three times.
  • reaction was carried out under a nitrogen atmosphere.
  • the solution means an aqueous solution.
  • reaction temperature is room temperature.
  • Room temperature is the optimum reaction temperature, which is 20 ° C ⁇ 30 ° C.
  • Ts p-toluenesulfonyl
  • TBS tert-butyldimethylsilyl.
  • Intermediate 1 5-[3-(Hydroxymethyl)phenyl]-4-methyl-bicyclo [4.2.0] octyl-1,3,5-tris-2-propanol (lm)
  • Iron powder (10.39 g, 186 mmol) and ammonium chloride (2.16 g, 40 mmol) were dissolved in a mixed solution of ethanol (150 mL) and water (150 mL), heated to reflux for 15 minutes, and added to the reaction flask.
  • EtOAc EtOAc
  • Step 5 5-Benzyloxy-3-methyl-bicyclo[4.2.0]octyl-1,3,5-trien-7-one (lg) 5-benzyloxy-3-methyl-bicyclo[4.2.0]o 7-one
  • Step 8 3-(2-Benzyloxy-4-methyl-5-bicyclo[4.2.0]octyl-1,3,5-triene)-benzaldehyde (lj)
  • Step 10 5-[3-(Hydroxymethyl)phenyl]-4-methyl-bicyclo[4.2.0]octyl-1,3,5-trien-2-ol (lm)
  • Step 4 3-Methylbicyclo [4.2.0] octyl-1,3,5-triene-5-ol (3d)
  • Ethyl chloroformate (28.00 g, 170 mmol) was dissolved in concentrated sulfuric acid at 0 ° C, resorcinol 1E (17.62 g, 160 mmol) was added, and reacted at room temperature for 2 hours, and the reaction solution was poured into ice. In water, the mixture was filtered, and the filter cake was washed with water (100 mL x 3) and dried. The filter cake was dissolved in 1M sodium hydroxide solution (1 L), heated to reflux for 2 hours, cooled to room temperature, and concentrated with sulfuric acid to dissolve the reaction mixture.
  • EtOAc mjjjjjj Methyl 3-dihydrobenzofuran-3-yl)acetate 1H (4.50 g, yield 60.0%).
  • Step 7 2-[6-[[3-[4-Methyl-2-(3-methylsulfonylpropoxy)-5-cyclo[4.2.0]octyl-1,3,5- Methyltriphenyl]phenyl]methoxy]-2,3-dihydrobenzofuran-3-yl]acetate (II)
  • Step 8 2-[6-[[3-[4-Methyl-2-(3-methylsulfonylpropoxy)-5-cyclo[4.2.0]octyl-1,3,5- Triene]phenyl]methoxy]-2,3-dihydrobenzofuran-3-yl]acetic acid (Compound 1)
  • Step 7 2-[3-(Hydroxymethyl)phenyl)-cyclo[4.2.0]octyl-1,3,5-triene]-5-ol (3H)
  • Step 8 [3-[5-(3-Methanesulfonylpropoxy)-2-cyclo[4.2.0]octyl-1,3,5-triene]phenyl]methanol (31)
  • Step 9 2-[6-[[3-[5-(3-Methanesulfonylpropoxy)-2-cyclo[4.2.0]octyl-1,3,5-triene]phenyl] Methyl methoxy]-2,3-dihydrobenzofuran-3-yl]acetate (3J)
  • Step 10 2-[6-[[3-[5-(3-Methanesulfonylpropoxy)-2-cyclo[4.2.0]octyl-1,3,5-triene]phenyl] Methoxy]-2,3-dihydrobenzofuran-3-yl]acetic acid (compound 3)
  • the third step 2-[(3S)-6-[[3-[2-[[(3aS,6aR)-2,3,3a,4,5,6a-hexahydrofuran [2,3-b] Furan-4-yl]oxy]-4-methyl-5-bicyclo[4.2.0]octyl-1,3,5-triene]phenyl]methoxy]-2,3-dihydrobenzofuran Methyl-3-methylacetate (5D)
  • the third step 2-[(3S)-6-[[3-[4-methyl-2-[(3S)-tetrahydrofuran-3-yl]oxy-5-bicyclo[4.2.0]oct-1, Methyl 3,5-trienyl]phenyl] methoxy]-2,3-dihydrobenzofuran-3-yl]acetate (6D)
  • Methyl 2-chloroisonicotinate 7A (523 mg, 3 mmol) was dissolved in dioxane (5 mL), sodium methoxide (247 mg, 4.5 mmol) was added, and the mixture was stirred under nitrogen. After the system was cooled, the mixture was cooled to dryness (50 mL). EtOAc (EtOAc) Methyl 2-methoxyisonicotinate 7B (0.39 g, yield 69%) as a pale yellow liquid.
  • Step 5 (S)- 2-6-((3-(5-((2-methoxypyridin-4-yl)methoxy)-3-methylbicyclo[4.2.0]oct-1 ,3,5-trien-2-benzyl)oxy)-2,3-dihydrobenzofuran-3-yl)acetate (7F)
  • Step 6 (S)-2-(6-((3-(5-((2-methoxypyridin-4-yl)methoxy)-3-methylbicyclo[4.2.0] s- 1,3,5-Trien-2-yl)benzyl)oxy)-2,3-dihydrobenzofuran-3-yl)acetic acid (Compound 7)
  • Example 8 2-(3S)-6-(( 2 -fluoro-5-( 4 -methyl- 2- (3-(methylsulfonyl)propoxy)-5-bicyclo[ 4 . 2 . Octyl-1,3,5-triene)benzyloxy)-2,3-dihydrobenzofuran-3-yl)acetic acid (compound 8)
  • Step 6 2-(3S)-6-((2-Fluoro-5-(4-methyl-2-(3-(methylsulfonylpropoxy))-5-bicyclo[4.2.0] s- Methyl 1,3,5-triene)phenyl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate (8G)
  • Step 7 2-(3S)-6-((2-Fluoro-5-(4-methyl-2-(3-(methylsulfonylpropoxy))-5-bicyclo[4.2.0] s- 1,3,5-triene)phenyl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic acid (compound 8)
  • Step 5 2-[(3S)-6-[[3-[2-(4-Acetoxytetrahydrofuran-3-yl)oxy-4-methyl-5-bicyclo[4.2.0]oct-1 ,3,5-triene]phenyl]methoxy]-2,3-dihydrobenzofuran-3-yl]acetate methyl ester (10E)
  • Tributylphosphine (0.51 mL, 2.03 mmol) and hydrazine, hydrazine-(azodicarbonyl)dipiperidine (512 mg, 2.03 mmol) were added sequentially and stirred at room temperature for 3 hr.
  • Step 6 2-((S)-6-((3-(5-((3,4-S,S/R,R)-hydroxytetrahydrofuran-3-yl)oxy)-3-methyl Bicyclo[4.2.0]octyl-1,3,5-trien-2-yl)phenyl)oxy)-2,3-dihydrobenzofuran-3-yl)acetic acid (Compound 10)
  • the magnesium powder (8.9 g, 0.36 mol) was mixed with the catalytic amount of elemental iodine, and a solution of dibromoethane (46 g, 0.24 mol) in tetrahydrofuran (200 mL) was added to the mixture under nitrogen atmosphere at 40-55 °C. .
  • Step 5 2-[(3S)-6-[[3-[2-[2-(Cyclopropoxy)ethoxy]-4-methyl-5-bicyclo[4.2.0]oct-1 (6), 2,4-triene]phenyl]methoxy]-2,3-dihydrobenzofuran-3-yl]acetate methyl ester (11F)
  • Step 6 2-[(3S)-6-[[3-[2-[2-(Cyclopropoxy)ethoxy]-4-methyl-5-bicyclo[4.2.0]oct-1 (6), 2,4-triene]phenyl]methoxy]- 2 ,3-dihydrobenzofuran-3-yl]acetic acid (Compound 11)
  • Example 12 2-[(3S)-6-[[3-(2-hydroxy-4-methyl-bicyclo[4.2.0]oct-1(6), 2,4-tris)phenyl] Methoxy]-2,3-dihydrobenzofuran-3-yl]acetic acid (compound 12) 2-[(3S)-6-[[3-(2-hydroxy-4-methyl-5-bicyclo[4.2.0]octa-l(6),2,4-trienyl]phenyl]methoxyl]-2, 3- dihydrobenzofuran-3-yl] acetic acid
  • Step 5 2-[(3S)-6-[[3-(2-Hydroxy-4-methyl-bicyclo[4.2.0]oct-1(6),2,4-triene)phenyl] Methoxy]-2,3-dihydrobenzofuran-3-yl]acetic acid (compound 12)
  • Step 5 2-(3S)-6-((2-Chloro-5-(4-methyl-2-(3-(methylsulfonyl)propoxy)-5-bicyclo[4.2.0] octyl Methyl-1,3,5-triene)benzyloxy)-2,3-dihydrobenzofuran-3-yl)acetate (13E)
  • Step 6 (S)-2-(6-((2-Chloro-5-(3-methyl-5-(3-(methylsulfonyl))propoxy)bicyclo[4.2.0]oct-1 (6), 2,4-Trien-2-yl)benzyl)oxy)-2,3-dihydrobenzofuran-3-yl)acetic acid (Compound 13)
  • Step 2 5-(3-(Hydroxymethyl)-4-methylphenyl)-4-methyl-cyclo[4.2.0]oct-1,3,5-trien-2-ol (14C )
  • Step 5 (S)-2-(6-((2-Methyl-5-(3-methyl-5-(3-(methylsulfonyl)propoxy)bicyclo[4.2.0] octyl -1,3,5-trien-2-yl)benzyl)oxy)-2,3-dihydrobenzofuran-3-yl)acetic acid (Compound 14)
  • the compound was formulated into a 10 mM stock solution in DMSO and diluted in 3 folds for use.
  • the stable expression strain HEK293/GPR40/5x Gal4UAS-Luc+/Gal4-Elkl was seeded at a suitable density in 96-well plates. The next day, waiting for the cells to meet The degree reached about 70%, replaced with serum-free medium, and starved overnight. On the third day, adding test compounds containing different concentrations
  • DMEM medium 200 ⁇ l per well, was incubated in a cell culture incubator for 5 hours. Luciferase activity was detected using the Luciferase Assay System kit. The fluorescence data was fitted and analyzed using Origin 7 software, and the EC 5Q of each compound was calculated. The test results are shown in Table 1.
  • the compound of the present invention exhibits superior pharmacodynamic activity as a GPR40 agonist as compared with the positive control. 2. Oral glucose tolerance test
  • the hypoglycemic effect of the compounds prepared by the various examples of the present invention in sugar-loaded mice was evaluated by oral glucose tolerance test (OGTT).
  • OGTT oral glucose tolerance test
  • mice SPF grade ICR mice, 18-22 g, female, purchased from Beijing Huakangkang Biotechnology Co., Ltd., Animal Production Certificate No.: SCXK (Beijing) 2009-0004.
  • SCXK Beijing 2009-0004.
  • the purchased mice were induced with high fat diet for 25 days and fasted overnight.
  • the basic blood glucose values after fasting 10 groups in each group.
  • the test compound was formulated into a 2 mg/ml suspension in 5% DMSO-15% solutol-80% physiological saline.
  • the drug was administered by intragastric administration at a dose of 20 mg/kg.
  • the blank control group was given 5% DMSO-15% solutol-80% saline.
  • the compounds of the present invention have a good hypoglycemic effect.

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Abstract

La présente invention concerne un dérivé benzocyclobutène et un procédé de préparation et une application pharmaceutique associée. Plus particulièrement, la présente invention concerne un composé représenté par la formule (I) ou un stéréoisomère, un hydrate, un métabolite, un solvate, un sel pharmaceutiquement acceptable, un eutectique, ou un promédicament correspondant, des procédés de préparation associés, une composition pharmaceutique associée, et un objectif pharmaceutique du composé ou de la composition pharmaceutique selon la présente invention, en particulier un objectif d'action comme agoniste du récepteur GPR40 (récepteur couplé à la protéine G). Les définitions des groupes substituants dans la formule (I) sont identiques à celles données dans la description.
PCT/CN2014/081474 2013-07-02 2014-07-02 Dérivé benzocyclobutène et procédé de préparation et application pharmaceutique associée Ceased WO2015000412A1 (fr)

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CN111808089A (zh) * 2019-04-10 2020-10-23 四川大学华西医院 一种治疗糖尿病的药物依格列净或其衍生物的制备方法
US10899735B2 (en) 2018-04-19 2021-01-26 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
CN112391159A (zh) * 2020-11-27 2021-02-23 太原理工大学 一种同时检测铝离子和锌离子的荧光探针、制备和应用
CN113666958A (zh) * 2020-05-13 2021-11-19 成都百裕制药股份有限公司 大麻素衍生物及其制备方法和在医药上的应用
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CN108178751A (zh) * 2018-01-30 2018-06-19 扬州工业职业技术学院 一种恩格列净中间体的合成方法
US11555029B2 (en) 2018-02-13 2023-01-17 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US10710986B2 (en) 2018-02-13 2020-07-14 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US12338233B2 (en) 2018-02-13 2025-06-24 Gilead Sciences, Inc. PD-1/Pd-L1 inhibitors
US10899735B2 (en) 2018-04-19 2021-01-26 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US10774071B2 (en) 2018-07-13 2020-09-15 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US12269812B2 (en) 2018-07-13 2025-04-08 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US11236085B2 (en) 2018-10-24 2022-02-01 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
CN111808089B (zh) * 2019-04-10 2023-04-11 四川大学华西医院 一种治疗糖尿病的药物依格列净或其衍生物的制备方法
CN111808089A (zh) * 2019-04-10 2020-10-23 四川大学华西医院 一种治疗糖尿病的药物依格列净或其衍生物的制备方法
US11512065B2 (en) 2019-10-07 2022-11-29 Kallyope, Inc. GPR119 agonists
US12264171B2 (en) 2020-02-28 2025-04-01 Kallyope, Inc. GPR40 agonists
CN113666958A (zh) * 2020-05-13 2021-11-19 成都百裕制药股份有限公司 大麻素衍生物及其制备方法和在医药上的应用
US11279702B2 (en) 2020-05-19 2022-03-22 Kallyope, Inc. AMPK activators
US11851429B2 (en) 2020-05-19 2023-12-26 Kallyope, Inc. AMPK activators
US11407768B2 (en) 2020-06-26 2022-08-09 Kallyope, Inc. AMPK activators
JP2023540636A (ja) * 2020-09-10 2023-09-25 上海愛博医薬科技有限公司 ベンゾ酸素含有複素環化合物及びその医薬用途
CN112391159A (zh) * 2020-11-27 2021-02-23 太原理工大学 一种同时检测铝离子和锌离子的荧光探针、制备和应用

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