WO2014187343A1 - Dérivé benzofurane, son procédé de préparation, et son application médicale - Google Patents

Dérivé benzofurane, son procédé de préparation, et son application médicale Download PDF

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WO2014187343A1
WO2014187343A1 PCT/CN2014/078156 CN2014078156W WO2014187343A1 WO 2014187343 A1 WO2014187343 A1 WO 2014187343A1 CN 2014078156 W CN2014078156 W CN 2014078156W WO 2014187343 A1 WO2014187343 A1 WO 2014187343A1
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group
fluorenyl
compound
formula
salt
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Chinese (zh)
Inventor
张晨
王健民
何平
雷鸣
叶飞
魏用刚
邓炳初
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Sichuan Haisco Pharmaceutical Co Ltd
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Sichuan Haisco Pharmaceutical Co Ltd
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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
    • C07D307/94—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom spiro-condensed with carbocyclic rings or ring systems, e.g. griseofulvins
    • 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
    • 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
    • A61P3/08—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
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
    • 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
    • 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
    • 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
    • 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
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • 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
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/83—Oxygen atoms

Definitions

  • the present invention relates to a benzofuran derivative, a preparation method thereof and its use in medicine, in particular to a novel benzofuran derivative having a G protein-coupled receptor 40 (GPR40) receptor function regulating function. Or a stereoisomer, hydrate, solvate, co-crystal, pharmaceutically acceptable salt or prodrug thereof, a process for the preparation thereof, and a pharmaceutical composition comprising the same, and its use in medicine.
  • GPR40 G protein-coupled receptor 40
  • Type II diabetes is the most common type of diabetes, mainly in adulthood, mainly characterized by insufficient insulin secretion or insulin resistance (ie, the body tissue cannot respond effectively to endogenous insulin), genetic and environmental factors, etc. Causes insulin resistance.
  • hypoglycemic agents currently approved for marketing include sulfonylureas, biguanides, thiazolyldione CTZD S ; » a-glucosidase inhibitors, amylin analogues, dipeptidyl peptidase inhibitors (DPP) -IV), sodium-glucose cotransporter 2 GLT-2) inhibitors and the like.
  • 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 hemihydrate (TAK-875) is a GPR40 agonist that has now entered Phase III clinical practice and has proven effective. Studies have shown that fasiglifam hemihydrate (TAK-875) promotes insulin secretion and effectively controls blood glucose in an animal model of diabetes, but does not promote insulin secretion in normal rats (Tsujihata Y et al. (2010).
  • 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.
  • US2006258722 describes a GPR40 receptor modulator which can be used as an insulin secretion promoter and a preventive and/or therapeutic agent for diabetes, and its structural formula is as follows:
  • 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 a preventive and/or therapeutic drug for diabetes, 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 hydroxy group or substituted hydrocarbyl
  • R 4 and R 5 is selected from substituted with hydroxy ⁇ - 6 alkyl with
  • a is selected from a benzene ring
  • B 5 is selected from To a 7-membered ring
  • Y is selected from a bond or CH2, and R is selected from a hydroxyl group.
  • X, Xa is selected from CH or N
  • Y is selected from 0 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, d- 6 fluorenyl or optionally substituted acyl
  • R 3 and R 4 are selected from H or halogen
  • R 5 is selected from substituted hydroxy or substituted amine groups, and the compounds specifically described in US7786165 are not considered to be the present invention. a part of.
  • WO2010143733 describes a GPR40 receptor modulator which can be used as an insulin secretion promoter and a preventive and/or therapeutic drug for diabetes, and its structural formula is as follows:
  • 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 the embankment d_ 6-yl,
  • X is CH 2
  • Y is selected from CH 2
  • Z is selected from CH or N,
  • a is selected from halogen, an optionally substituted amino group or 4-13 membered ring.
  • the present invention provides a novel structure of a compound represented by the formula ⁇ , which has been shown to exhibit excellent pharmacodynamic activity as a GPR40 agonist.
  • a preferred embodiment of the invention a compound of the formula (I) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof:
  • R is selected from H, d- 8 fluorenyl or PEG, preferably H or d- 6 fluorenyl, more preferably 11 or -4- mercapto, further preferably H;
  • ring Q is selected from a 5- to 8-membered carbocyclic or heterocyclic group.
  • R 1, R 2, R 3 and R 4 are each independently optionally selected from H, F, Cl, Br, I, cyano, isocyano, amino, nitro, hydroxy, carboxy, alkyl with 8 or 8 embankment D- Oxy group, preferably H, F, Cl, Br, I, cyano, amino, nitro, hydroxy, d- 6 fluorenyl or d- 6 methoxy, more preferably H, F, Cl, Br, I, cyanide Further, H, F, Cl, cyano, hydroxy, d- 3 fluorenyl or d- 3 decyloxy, more preferably H, F, Cl, a hydroxyl group, a d- 4 fluorenyl group or a d- 4 methoxy group.
  • any one of R 6 and R 7 , R and R 8 , R and R 9 , R 7 and R 8 , R 7 and R 9 , R 8 and R 9 may form a 3 to 8 membered carbocyclic ring or a 3 to 8 membered heterocyclic ring, preferably forming a 3 to 6 membered carbocyclic ring or a 3 to 6 membered heterocyclic ring, more preferably R 6 and R 7 , any of R 8 and R 9 may form a 3 to 6 membered carbocyclic ring.
  • each R 12a may be The same or different preferably 0 to 3 in the range is selected from 0 to 3 R 12a , more preferably 0 to 2 R 12a ;
  • R 12a when two R 12a are attached to the same atom, they can form a 3 to 8 together with the atoms to which they are attached.
  • R i2 , R i2b, Ri 3 and R i3a are selected from the group consisting of H , F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , cyano, decyl, isocyano, amino, nitro, hydroxy , a carboxyl group, a d- 8 fluorenyl group, a d- 8 methoxy group, a 3 to 10 membered carbocyclic group or a 3 to 10 membered heterocyclic group, preferably H, F, Cl, Br, I, hydroxy, decyl, cyano, Amino group, d- 6 fluorenyl group, d- 6 methoxy group, 3 to 6 membered carbocyclic group or 3 to 6 membered heterocyclic group, more preferably H, F, Cl, Br, hydroxy, decyl, cyano, amino, D- 4 fluorenyl, d- 4 methoxy, 3
  • oxy group is selected from the group consisting of F, Cl, Br, -CF 3 , d- 3 fluorenyl or d- 3 methoxy, preferably 0 to 1 selected from F, d- 2 fluorenyl or this ⁇ —2 methoxy;
  • p is selected from 0, 1, 2 or 3, preferably 0, 1 or 2, more preferably 0 or 1, further preferably 0;
  • q is selected from 0, 1, 2, 3 or 4, preferably 0, 1 or 2, more preferably 0 or 1, further preferably 0;
  • t is selected from 0, 1 or 2, preferably 0 or 1, more preferably 1;
  • n is selected from 0, 1, 2, 3 or 4, preferably 0, 1, 2 or 3, more preferably 0, 1 or 2;
  • 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.
  • Preferred embodiments of the invention include a compound of the formula (I) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein:
  • R 1 , R 2 , R 3 and R 4 are each independently selected from the group consisting of H, F, Cl, Br, I, cyano, amino, nitro, hydroxy, d- 6 fluorenyl Or d- 6 methoxy, preferably H, F, Cl, Br, I, cyano, hydroxy, d- 4 fluorenyl or d- 4 methoxy, more preferably H, F, cyano, hydroxy, d- 3 fluorenyl or d-3 methoxy, further preferably H, d- 2 fluorenyl or d- 2 decyloxy, further preferably H, wherein the fluorenyl, decyloxy or amino group are each independently optionally further 0 to 3 substituents selected from the group consisting of F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , cyano, nitro, hydroxy, d- 6 fluorenyl or d- 6 fluorenyl
  • R 5 , R 1Q and R 11 are each independently selected from H, F, Cl, Br, I, cyano, hydroxy, d- 6 fluorenyl, d- 6 methoxy or 6 fluorenyl-Od- 6 fluorenyl
  • H, F, Cl, Br, I, d- 4 fluorenyl or d- 4 fluorenyloxy more preferably H, F, d- 3 fluorenyl or d- 3 decyloxy, further preferably H, F, d - 2 fluorenyl or d - 2 decyloxy, further preferably H or d - 2 fluorenyl
  • the fluorenyl and decyloxy groups each independently optionally further from 0 to 3 selected from F, Cl, Br, Substituting for a substituent of I, -CH 2 F, -CHF 2 , -CF 3 , 6 fluorenyl or d- 6 methoxy, preferably 0
  • Preferred embodiments of the invention include a compound of the formula (I) or all stereoisomers, hydrates, esters, solvates, pharmaceutically acceptable salts or prodrugs thereof, wherein:
  • R 1 , R 2 , R 3 and R 4 are each independently selected from H, F, Cl, Br, I, cyano, hydroxy, d- 4 fluorenyl or d- 4 decyloxy, preferably H, F, cyanide a hydroxy group, a d- 3 fluorenyl group or a d- 3 methoxy group, more preferably H, d- 2 fluorenyl or d- 2 methoxy, more preferably H, wherein the fluorenyl or decyloxy group is independently Optionally further substituted by 0 to 3 substituents selected from the group consisting of F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , d- 4 fluorenyl or -4- methoxy, preferably 0-2 is selected from F, Cl, -CF 3, d- 3 ⁇ alkyl with or --3 embankment group, more preferably F, d- 2-yl or embankment
  • R 5 , R 1Q and R 11 are each independently selected from H, F, Cl, Br, I, d 4 fluorenyl or d 4 methoxy, preferably H, F, 3 decyl or d- 3 decyloxy, More preferably, H, F, d- 2- indenyl or d- 2- nonyloxy, further preferably H or d- 2- indenyl, each independently optionally further selected from 0 to 2 Substituted with a substituent of F, Cl, Br, I, d- 4 fluorenyl or d- 4 methoxy, preferably 0 to 2 are selected from F, d- 3 fluorenyl or -3- decyloxy, more preferably F , or alkyl with d- 2 ⁇ - 2 embankment group, more preferably d- 2 embankment group.
  • Preferred embodiments of the invention include a compound of the formula (I) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein:
  • R 1 , R 5 , R 1Q and R 11 are each independently selected from the group consisting of H, F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, butyl, methoxy, ethoxy, Propyloxy, methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl or ethoxyethyl, preferably H, F, methyl, ethyl, methoxy, B Oxy, methoxymethyl, methoxyethyl, ethoxymethyl or ethoxyethyl, more preferably H, methyl, ethyl, methoxy or ethoxy, further preferably H or A base.
  • Preferred embodiments of the invention include a compound of the formula (I) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein:
  • any one of R 6 and R 7 , R 6 and R 8 , R 6 and R 9 , R 7 and R 8 , R 7 and R 9 , R 8 and R 9 may form a 3 to 6-membered carbon.
  • a ring or a 3 to 6 membered heterocyclic ring preferably any group of R 6 and R 7 , R 8 and R 9 may form a 3 to 6 membered carbocyclic ring or a 3 to 6 membered heterocyclic ring, more preferably a 3 to 4 membered carbon ring.
  • R 12 , R 13 and R 13a are selected from the group consisting of H, F, Cl, Br, I, hydroxy, decyl, cyano, amino, d- 6 fluorenyl, d- 6 methoxy, (3 to 6-membered carbocyclic) Or a 3 to 6 membered heterocyclic group, preferably H, F, Cl, Br, hydroxy, decyl, cyano, amino, d- 4 fluorenyl, CM methoxy, 3 to 6 membered carbocyclyl or 3 to 6
  • the heterocyclic group is more preferably H, F, Cl, Br, d- 4 fluorenyl, d- 4 decyloxy, 3 to 6-membered carbocyclic or 3- to 6-membered heterocyclic group, further preferably H, F, Cl , Br, d 4 fluorenyl, d 4 methoxy, 3 to 5 membered carbocyclic or 3 to 5 membered heterocyclic group, further preferably
  • n is selected from 0, 1, or 2.
  • Preferred embodiments of the invention include a compound of the formula (I) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein:
  • R 6 , R 7 , R 8 and R 9 are each independently selected from the group consisting of H, F, Cl, Br, I, hydroxy, cyano, d 4 fluorenyl, d 4 methoxy,
  • the Cw fluorenyl group is further preferably H, d 2 decyloxy or -d 2 fluorenyl-O-Cw fluorenyl, and the fluorenyl and decyloxy groups are each independently optionally further 0 to 3 selected from -CH 2 Substituted with a substituent of F, -CHF 2 , -CF 3 , cyano, amino, nitro, hydroxy, carboxy or d
  • any of R 6 and R 7 , R 8 and R 9 may form a 3 to 6 membered carbocyclic ring or a 3 to 6 membered heterocyclic ring, preferably a 3 to 4 membered carbocyclic ring or a 3 to 4 membered heterocyclic ring.
  • it is a 3-membered carbocyclic ring or a 3-membered heterocyclic ring, further preferably a 3-membered carbocyclic ring containing 1 to 3 hetero atoms selected from N, 0 or S, preferably 1 to 2 selected from N, 0 or a hetero atom of S, and the carbocyclic or heterocyclic ring formed may be optionally further substituted with 0 to 3 substituents of R 12a , preferably 0 to 2 R 12a ;
  • the methoxy group is further optionally further selected from 0 to 3 selected from the group consisting of F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , cyano, amino, nitro, hydroxy, carboxy, d - 4 ⁇ Substituted with a substituent of a 4- methoxy group, preferably 0 to 3 are selected from the group consisting of F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , d- 4 fluorenyl, CM ⁇ The oxy group, more preferably 0 to 3, is selected from the group consisting of F, Cl, Br, -CH 2 F, -CHF 2 , - -CF 3 , d- 4 fluorenyl, CM ⁇ The oxy group, more preferably 0 to 3, is selected from the group consisting of F, Cl, Br, -CH 2 F, -CHF 2 , - -CF 3 , d
  • n is selected from 0, 1, 2, 3 or 4, preferably 0, 1, 2 or 3, more preferably 0, 1 or 2;
  • n is selected from 0, 1, or 2.
  • Preferred embodiments of the invention include a compound of the formula (I) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein: R 6 , R 7 , R 8 and R 9 are each independently selected from the group consisting of H, F, methyl, ethyl, propyl, isopropyl, butyl, methoxy, ethoxy, propoxy, methoxy Methyl, methoxyethyl, methoxypropyl, ethoxymethyl or ethoxyethyl, preferably H, methyl, methoxy, ethoxy, methoxymethyl, ethoxy Methyl, methoxyethyl or ethoxyethyl, more preferably H, methoxy, ethoxy, methoxymethyl or ethoxymethyl, further preferably H;
  • R 6 and any of R 7 , R 8 and R 9 may form a 3 to 4 membered carbocyclic ring or a 3 to 4 membered heterocyclic ring, preferably a 3 membered carbon ring or a 3 membered heterocyclic ring, more preferably a 3 membered carbon.
  • a ring said heterocyclic ring containing 1 to 3 heteroatoms of 0, N or S, preferably 1 to 2 heteroatoms selected from N, 0 or S, and the resulting carbocyclic or heterocyclic ring may optionally be further From 0 to 3 selected from the group consisting of F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, butyl, methoxy, ethoxy, propoxy, methoxymethyl, A Substituted by a substituent of an oxyethyl group, a methoxypropyl group, an ethoxymethyl group or an ethoxyethyl group, preferably 0 to 2 are selected from the group consisting of F, methyl, ethyl, propyl, isopropyl, Methoxy, ethoxy, methoxymethyl, methoxyethyl, ethoxymethyl or ethoxyethyl, more preferably 0 to 1 selected from F,
  • Preferred embodiments of the invention include a compound of the formula (I) or a stereoisomer, hydrate, ester, solvate, co-crystal, or a derivative thereof.
  • Preferred embodiments of the invention include a compound of the formula (I) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolic salt or prodrug thereof, wherein:
  • Ring Q is selected from .
  • a preferred embodiment of the invention a compound of the formula (II) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof:
  • R is selected from H or d 6 fluorenyl, preferably H or d 4 fluorenyl, more preferably H;
  • R 1 is selected from H, F, Cl, Br, I, cyano, amino, nitro, hydroxy, d- 6 fluorenyl or d- 6 methoxy, preferably H, F, Cl, Br, cyano, amino a hydroxyl group, a d- 4 fluorenyl group or a d- 4 methoxy group, more preferably H, F, Cl, Br, a cyano group, an amino group, a hydroxyl group, a 3 fluorenyl group or a d- 3 methoxy group, further preferably H, F, d - 2 fluorenyl or d - 2 decyloxy, further preferably H, wherein the fluorenyl, decyloxy or amino group is each independently optionally further from 0 to 3 selected from F, Cl, Br, I, - Substituted with a substituent of CH 2 F, -CHF 2 , -CF 3 , cyano, nitro, hydroxy,
  • R 5 , R 1Q and R 11 are each independently selected from H, F, Cl, Br, I, cyano, hydroxy, d- 6 fluorenyl, d- 6 methoxy or 6 fluorenyl-Od- 6 fluorenyl
  • H, F, Cl, Br, d- 4 fluorenyl or d- 4 decyloxy more preferably H, F, Cl, Br, d- 3 fluorenyl or d- 3 decyloxy, further preferably H, F, Cl, Br, d- 2 fluorenyl or d- 2- decyloxy, further preferably H, F, d 2 fluorenyl or d-2-decyloxy, the fluorenyl or decyloxy group being independently optional Further substituted by 0 to 3 substituents selected from the group consisting of F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , d- 6 fluorenyl
  • R 6 , R 7 , R 8 and R 9 are each independently selected from the group consisting of H, F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , cyano, hydroxy,
  • any one of R 6 and R 7 , R 7 and R 8 , R 8 and R 9 , R 6 and R 8 , R 6 and R 9 may form a 3 to 6 carbon ring or 3 to 6 member.
  • the heterocyclic ring preferably any of R 6 and R 7 , R 8 and R 9 may form a 3 to 6 membered carbocyclic ring or a 3 to 6 membered heterocyclic ring, more preferably a 3 to 4 membered carbon ring or a 3 to 4 membered heterocyclic ring.
  • the ring is further preferably a 3-membered carbocyclic ring or a 3-membered heterocyclic ring, further preferably a 3-membered carbocyclic ring, and the heterocyclic ring contains 1 to 3 N, 0 or S atoms, preferably 1 to 2 selected from N, 0 or S. a hetero atom, the carbocyclic or heterocyclic ring optionally further substituted by 0 to 3 substituents of R 12a , preferably 0 to 2
  • a 3 to 6 membered carbocyclic ring or a 3 to 6 membered heterocyclic ring may be formed, preferably a 3 to 6 membered heterocyclic ring containing 1 to 3 a hetero atom selected from N, 0 or S, preferably 1 to 2 heteroatoms selected from N, 0 or S, optionally further 0 to 3 selected from F, Cl, Br , I, CF 3, hydroxy, cyano, or alkyl with 6 ⁇ - 6 embankment group substituents, preferably 0 to 2 groups selected from F, Cl, Br, CF 3 , hydroxy, cyano, d- 4 fluorenyl or -4- yloxy, more preferably 0 to 2 selected from F, d- 3 fluorenyl or d- 3 methoxy, more preferably 0 to 1 selected from F, d 2 fluorenyl or d_ 2 ⁇ oxy;
  • R 12 , R 13 and R 13a are selected from H, F, Cl, Br, I, hydroxy, decyl, cyano, amino, d- 6 fluorenyl, d- 6 decyloxy, 3 to 6 membered carbocyclyl or a 3- to 6-membered heterocyclic group, preferably H, F, Cl, Br, hydroxy, decyl, cyano, amino, d- 4 fluorenyl, CM methoxy, 3 to 6-membered carbocyclic or 3 to 6-membered
  • the cyclo group is more preferably H, F, Cl, Br, d_ 4 fluorenyl, d 4 methoxy, 3 to 6-membered carbocyclic or 3- to 6-membered heterocyclic group, further preferably H, F, Cl, Br, D- 4 fluorenyl, d- 4 methoxy, 3 to 5 membered carbocyclyl or 3 to 5 membered heterocyclic group, further preferably d-
  • p is selected from 0, 1 or 2, preferably 0 or 1, more preferably 0;
  • n is selected from 0, 1, 2, 3 or 4, preferably 0, 1, 2 or 3, more preferably 0, 1 or 2;
  • n is selected from 0, 1, or 2.
  • Preferred embodiments of the invention include a compound of the formula (II) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein:
  • R 1 is selected from H, F, Cl, Br, cyano, amino, hydroxy, d- 4 fluorenyl or d- 4 methoxy, preferably H, F, Cl, Br, cyano, amino, hydroxy, d- 3 fluorenyl or d-3 methoxy, more preferably H, F, d-2 fluorenyl or d-2-decyloxy, further preferably H, wherein the flu
  • R 5 , R 1Q and R 11 are each independently selected from H, F, Cl, Br, d 4 fluorenyl or d 4 methoxy, preferably H, F, Cl, Br, d- 3 decyl or d- 3 a decyloxy group, more preferably H, F, Cl, Br, d- 2- indenyl or d- 2- nonyloxy, further preferably H, F, d- 2- indenyl or d- 2- indolyl, said fluorenyl Or the methoxy groups are each independently optionally further substituted with from 0 to 3 selected from the group consisting of F, Cl, Br, -CH 2 F, -CHF 2 , -CF 3 , d- 4 fluorenyl or d- 4 methoxy.
  • Substituted preferably 0 to 2 substituents selected from the group consisting of F, Cl, Br, d-4 fluorenyl or -4-methoxy, more preferably 0 to 2 selected from F, Cl, Br, d — 3 ⁇ or d— 3 ⁇ oxy, more preferably 0 to 1 selected from F, d— 2 fluorenyl or d ⁇ 2 fluorenyl;
  • any of R 6 and R 7 , R 8 and R 9 may form a 3 to 6 membered carbocyclic ring or a 3 to 6 membered heterocyclic ring, preferably a 3 to 4 membered carbocyclic ring or a 3 to 4 membered heterocyclic ring.
  • the heterocyclic ring contains 1 to 3 ⁇ , 0 or S atoms, preferably 1 to 2 hetero atoms selected from N, 0 or S, optionally further 0 to 3 R 12a Substituted by a substituent, preferably 0 to 2 R 12a ;
  • R 12 , R 13 and R 13a are selected from H, F, Cl, Br, hydroxy, decyl, cyano, amino, d- 4 fluorenyl, d- 4- decyloxy, 3 to 6-membered carbocyclyl or 3 to a 6-membered heterocyclic group, preferably H, F, Cl, Br, d- 4 fluorenyl, d- 4 methoxy, 3 to 6-membered carbocyclic or 3- to 6-membered heterocyclic group, more preferably H, F, Cl, Br, d- 4 fluorenyl, d- 4 decyloxy, 3 to 5 membered carbocyclic group or 3 to 5 membered heterocyclic group, further preferably d- 3 fluorenyl, d- 3 methoxy, 3 to a 5-membered carbocyclic group or a 3- to 5-membered heterocyclic group, further preferably a 2 fluorenyl group or a d- 2 fluoren
  • p is selected from 0, 1 or 2, preferably 0 or 1, more preferably 0;
  • n is selected from 0, 1, 2, 3 or 4, preferably 0, 1, 2 or 3, more preferably 0, 1 or 2;
  • n is selected from 0, 1, or 2.
  • Preferred embodiments of the invention include a compound of the formula (III) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof:
  • R 5 , R 1U and R 11 are each independently selected from H, F, Cl, Br, d 4 fluorenyl or d 4 methoxy, preferably H, F, Cl, Br, d- 3 decyl or d- 3 a decyloxy group, more preferably H, F, Cl, Br, d- 2- indenyl or d- 2- nonyloxy, further preferably H, F, d-2-indenyl or d-2-indolyl, said fluorenyl Or the methoxy groups are each independently optionally further substituted with 0 to 2 substituents selected from the group consisting of F, Cl, Br, d-4 fluorenyl or -4-methoxy, preferably 0 to 2 selected from F, Cl, Br, d- 3 fluorenyl or -3-decyloxy, more preferably 0 to 1 selected from F, d- 2 fluorenyl or -2- decyloxy;
  • any one of R 6 and R 7 , R 8 and R 9 may form a 3- to 4-membered carbocyclic ring or a 3- to 4-membered heterocyclic ring, preferably a 3-membered carbocyclic ring or a 3-membered heterocyclic ring, more preferably 3 yuan.
  • a carbocyclic ring containing 1 to 2 heteroatoms selected from N, 0 or S, and the carbocyclic or heterocyclic ring formed may be optionally further substituted with 0 to 2 substituents of R 12a ;
  • R 12 is selected from the group consisting of H, F, Cl, Br, d- 4 fluorenyl, d- 4- decyloxy, 3 to 6-membered carbocyclic or 3- to 6-membered heterocyclic, preferably H, F, Cl, Br, D_ 4 fluorenyl, d 4 methoxy, 3 to 5 membered carbocyclic or 3 to 5 membered heterocyclic group, more preferably d 3 fluorenyl, 3 methoxy, 3 to 5 valent carbocyclyl or 3 to 5 a heterocyclic group, further preferably d- 2 fluorenyl or d- 2 fluorenyloxy;
  • n is selected from 0, 1, 2, 3 or 4, preferably 0, 1, 2 or 3, more preferably 0, 1 or 2;
  • n is selected from 0, 1, or 2.
  • Preferred embodiments of the invention include a compound of the formula (III) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein:
  • R 5 , R 1Q and R 11 are each independently selected from H, F, methyl or ethyl.
  • Preferred embodiments of the present invention include a compound represented by the formula (IV) or a stereoisomer, hydrate, ester, solvate, cocrystal, metabolite, pharmaceutical thereof among them:
  • any one of R 6 and R 7 , R 8 and R 9 may form a 3- to 4-membered carbocyclic ring or a 3- to 4-membered heterocyclic ring, preferably a 3-membered carbocyclic ring or a 3-membered heterocyclic ring, more preferably 3 yuan.
  • a carbocyclic ring containing from 1 to 3 heteroatoms selected from N, 0 or S, and the carbocyclic or heterocyclic ring formed may be optionally further substituted with from 0 to 3 substituents of R 12a ;
  • R 12 is selected from the group consisting of H, F, Cl, Br, d- 4 fluorenyl, d- 4- decyloxy, 3 to 6-membered carbocyclic or 3- to 6-membered heterocyclic, preferably
  • n is selected from 0, 1, 2, 3 or 4, preferably 0, 1, 2 or 3, more preferably 0, 1 or 2;
  • n is selected from 0, 1, or 2.
  • Preferred embodiments of the invention include a compound of the formula 0V) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein:
  • any one of R 6 and R 7 , R 8 and R 9 may form a 3- to 4-membered carbocyclic ring or a 3- to 4-membered heterocyclic ring, preferably a 3-membered carbocyclic ring or a 3-membered heterocyclic ring, more preferably 3 yuan.
  • a carbocyclic ring containing 1 to 2 heteroatoms selected from N, 0 or S, and the carbocyclic or heterocyclic ring formed may be optionally further substituted with 0 to 2 substituents of R 12a ;
  • R 12 is selected from the group consisting of H, F, Cl, Br, d 4 fluorenyl, d 4 methoxy, 3 to 5 membered carbocyclic or 3 to 5 membered heterocyclic, preferably d 3 fluorenyl, d 3 ⁇ An oxy group, a 3- to 5-membered carbocyclic group or a 3- to 5-membered heterocyclic group, more preferably a d- 2 fluorenyl group or a d- 2 fluorenyloxy group; m is selected from 0, 1, 2, 3 or 4, preferably 0, 1, 2 or 3, more preferably 0, 1 or 2;
  • n is selected from 0, 1, or 2.
  • Preferred embodiments of the invention include a compound of the formula (IV) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein:
  • R 6 and R 7 are each independently selected from H, d 4 fluorenyl, d 4 methoxy or -d 4 fluorenyl-O-CM fluorenyl, preferably H, d 3 decyl, 3 decyloxy or -d --3 alkyl with - Od- 3 embankment group, more preferably H, d- 3 embankment group or alkyl with -d- 3 - Od- 3 embankment group, more preferably H, d- 2 embankment group or -d- 2 Mercapto-Od- 2 fluorenyl, further preferably H;
  • R 8 and R 9 are each independently selected from H, d- 4 alkyl with, d- 4 group or -d- 4 embankment embankment embankment -Od- 4-yl group, preferably H, d_ 3 alkyl with, d- 3 embankment Oxy or -d-3indolyl-Od- 3 fluorenyl, more preferably H, d- 2 fluorenyl, d- 2 -nonyloxy or -d-2indolyl-O-Cw fluorenyl, further preferably H, d_ 2 methoxy or -d 2 fluorenyl-O-Cw fluorenyl;
  • R 8 and R 9 may form a 3-membered carbon ring.
  • Preferred embodiments of the invention include a compound of the formula ⁇ ) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein:
  • R 6 and R 7 are each independently selected from g H, d_ 3 fluorenyl, d 3 methoxy or -d 3 fluorenyl-O-Cw fluorenyl, preferably H, d 3 methoxy or - 3 fluorenyl- Od- 3 embankment group, more preferably H, d- 2 embankment embankment -d- 2-yl group or - Od- 2 embankment group, more preferably H;
  • R 8 and R 9 are each independently selected from H, d. 3 fluorenyl, 3 decyloxy or -d-3indolyl-indole-d- 3 fluorenyl, preferably H, decyl, d 2 decyloxy or -d_ 2 fluorenyl-O-Cw fluorenyl, more preferably H, d 2 methoxy or -d 2 fluorenyl-O-Cw fluorenyl;
  • R 8 and R 9 may form a 3-membered carbon ring.
  • Preferred embodiments of the invention include a compound of the formula ⁇ ) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein:
  • R 6 and R 7 are each independently selected from H, methyl, methoxy, ethoxy, methoxymethyl, ethoxymethyl, methoxyethyl or ethoxyethyl, preferably H, Methoxy or ethoxy, more preferably H;
  • R 8 and R 9 are each independently selected from H, methyl, methoxy, ethoxy, methoxymethyl, ethoxymethyl or methoxyethyl, preferably H, methyl, methoxy Methyl or ethoxymethyl, more preferably H, methoxymethyl or ethoxymethyl; alternatively, R 8 and R 9 form a 3-membered carbocyclic ring.
  • Preferred embodiments of the invention include a compound of the formula (IV) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein:
  • R 8 and R 9 are each independently selected from H, methoxymethyl or ethoxymethyl; or, alternatively, R 8 and R 9 may form a 3-membered carbocyclic ring.
  • R is selected from 11 or - 8 fluorenyl
  • R 6 and R 7 can be formed ( ⁇ ( ⁇ or two ⁇ 12 ! ⁇ 215 ;
  • 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;
  • 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 (I) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein:
  • R 1 and R 4 are each independently selected from F, Cl, Br or d 4 alkyl, preferably F or CI;
  • R 2 and R 3 are each independently selected from H, F, Cl, Br or d 4 fluorenyl, preferably H;
  • R 5 , R 1Q and R 11 are each independently selected from H, F, Cl, Br, I or d- 4 , preferably H, F or methyl.
  • a preferred embodiment of the invention a compound of the formula (I) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein:
  • R 6 , R 7 , R 8 and R 9 are each independently selected from H, -CH 2 OH, d 4 fluorenyl, d 4 methoxy, -d 4 fluorenyl-OC ⁇ -(CH 2 ) m -NR 13 R 13a , preferably H, -CH 2 OH, methyl, methoxy, ethoxy, " ⁇ O ⁇ , 0, ' ⁇ Q , or
  • any one of R 6 and R 7 , R 6 and R 8 , R 6 and R 9 , R 7 and R 8 , R 7 and R 9 , R 8 and R 9 may form a 3 to 6-membered carbon.
  • a ring preferably a 3- to 4-membered carbocyclic ring, more preferably a 3-membered carbocyclic ring;
  • R 11 or R 12 is selected from ⁇ - 6 alkyl with, preferably H or methyl;
  • n is selected from 0, 1, 2, 3 or 4;
  • n is selected from 0, 1, or 2.
  • a compound of the formula (I) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof which is of the general formula (II) a compound or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof:
  • R is selected from 11 or - 4 fluorenyl groups, preferably H:
  • R 1 is selected from F, C1 or Br, preferably F or C1;
  • R 5 , R 1Q and R 11 are each independently selected from H, F, Cl, Br or d 4 alkyl, preferably H, F or methyl;
  • R 6 , R 7 , R 8 and R 9 are each independently selected from H, —CH 2 OH, d 4 fluorenyl, d 4 methoxy, —d 4 fluorenyl-O-CM ⁇ -(CH 2 ) m -NR 13 R 13a , preferably H, -CH 2 OH, methyl, methoxy, ethoxy, 3 ⁇ 4 ⁇ C ⁇ , ⁇ 0, ⁇ Q , or
  • any one of R 6 and R 7 , R 6 and R 8 , R 6 and R 9 , R 7 and R 8 , R 7 and R 9 , R 8 and R 9 may form a 3 to 6-membered carbon.
  • a ring preferably a 3- to 4-membered carbocyclic ring, more preferably a 3-membered carbocyclic ring;
  • R 12 is selected from the group consisting of 11 or 4 - 4 , preferably H or methyl;
  • p is selected from 0, 1 or 2;
  • n is selected from 0, 1, 2, 3 or 4;
  • n is selected from 0, 1, or 2.
  • the compound of the formula (I) or a stereoisomer, hydrate, ester, solvate, eutectic thereof a compound, a metabolite, a pharmaceutically acceptable salt or a prodrug, which is a compound of the formula (in) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable Accepted salt or prodrug:
  • R 5 , R 1Q and R 11 are each independently selected from H, F, Cl, Br or d 4 alkyl, preferably H, F or methyl;
  • R 6 , R 7 , R 8 and R 9 are each independently selected from H, —CH 2 OH, d 4 fluorenyl, d 4 methoxy, —d 4 fluorenyl-OC —(CH 2 ) m —NR 13 R 13a , preferably H, -CH 2 OH, methyl, methoxy, ethoxy, , 0
  • R 8 and R 9 may form a 3-membered carbon ring with the carbon atom to which they are attached;
  • R 12 is selected from H or d 4 alkyl, preferably H or methyl;
  • n is selected from 0, 1, 2, 3 or 4;
  • n is selected from 0, 1, or 2.
  • a compound of the formula ⁇ or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof which is of the formula (IV) a compound or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof:
  • R 6 , R 7 , R 8 and R 9 are each independently selected from H, -CH 2 OH, d 4 fluorenyl, d 4 methoxy, -d 4 fluorenyl-0-C -1-4 - (CH 2 ) m -NR 13 R 13a , preferably H, -CH 2 OH, methyl, methoxy, ethoxy, 0
  • R 8 and R 9 may form a water 3-membered carbon ring with the carbon atom to which they are attached;
  • R 12 is selected from the group consisting of 11 or 4 - 4, preferably H or methyl;
  • 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 (IV): or a stereoisomer, hydrate, ester, solvate, eutectic, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein:
  • R 6 and R 7 are each independently selected from the group consisting of H, methyl, methoxy, ethoxy, W or N , ⁇ S ⁇ ;
  • R 8 and R 9 are each independently selected from the group consisting of H, -CH 2 OH, methyl, Or 0;
  • R 8 and R 9 may form a 3-membered carbocyclic ring with the carbon atom to which they are attached.
  • a compound of the compound of the formula (I) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof which is a formula a compound represented by (V): or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof:
  • R 4 is selected from H, F or Cl, preferably H or F;
  • R 5 , R 1Q and R 11 are each independently selected from H, F, CI or d 4 alkyl, preferably H, F or methyl;
  • R 6 , R 7 , R 8 and R 9 are each independently selected from H, -CH 2 OH, d 4 fluorenyl, d 4 methoxy, -d 4 fluorenyl-O-CM -(CH 2 ) m - NR 13 R 13a , preferably H, -CH 2 OH, methyl, methoxy, ethoxy, . , , , ⁇ 0 ,
  • R 8 and R 9 may form a water 3-membered carbon ring with the carbon atom to which they are attached;
  • R 12 is selected from the group consisting of 11 or 4 - 4 , preferably H or methyl;
  • 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 (V) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein: R 4 is selected from H, F or Cl, preferably H or F;
  • R 5 and R 11 are methyl
  • R 1Q is selected from H or F, preferably H;
  • R 8 and R 9 are each independently selected from the group consisting of H, -CH 2 OH, methyl, ⁇ . ⁇ or ' ⁇ . ⁇ , or R 8 and R 9 form a 3-membered carbocyclic ring with the carbon atom to which they are attached, preferably R 8 and R 9 form a 3-membered carbocyclic ring with the carbon atom to which they are attached; a preferred embodiment of the invention, formula (V) The compound or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein:
  • R 8 and R 9 may form a 3-membered carbocyclic ring with the carbon atom to which they are attached.
  • Suitable pharmaceutically acceptable salts of the compounds of the formula ⁇ include, but are not limited to, sodium salts, potassium salts, aluminum salts, lithium salts, zinc salts, calcium salts, magnesium salts, barium salts, ammonium salts, Trimethylamine salt, tetramethylammonium salt, diethylamine salt, triethylamine salt, isopropylamine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, cyclohexylamine salt, dicyclohexylamine salt, pyridinium salt , methylpyridine salt, 2,6-lutidine salt, caffeine salt, procaine salt, choline salt, betaine salt, theobromine salt, sulfonium salt, piperazine salt, piperidine salt, hydrazine -ethylpiperidine salt, polyamine resin salt, phenamine penicillin salt, hydrochloride, hydrobromide, sulfate, nitrate, phosphate, formate,
  • the present invention also relates to a process for the preparation of the compound of the formula (I), and it is known to those skilled in the art that the compound of the present invention can be synthesized by various preparation methods. Preferred methods include, but are not limited to, the methods described below. Those skilled in the art will appreciate that 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 synthetic 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. Specifically, the method for producing the compound of the formula (I) of the present invention is selected from one of the following methods:
  • the compound of the formula (Ia) is sequentially converted into a compound of the formula (Ib) by a Homer-Wadsworth-Emmons reaction (or wittig reaction), a reduction reaction and a thiolation reaction; or the compound of the formula (Ia) is converted into a pass by a reduction elimination reaction.
  • a compound of formula (Ib) is sequentially converted into a compound of formula (Ib) by a Homer-Wadsworth-Emmons reaction (or wittig reaction), a reduction reaction and a thiolation reaction; or the compound of the formula (Ia) is converted into a pass by a reduction elimination reaction.
  • a compound of formula (Ib) is sequentially converted into a compound of the formula (Ib) by a Homer-Wadsworth-Emmons reaction (or wittig reaction), a reduction reaction and a thiolation reaction; or the compound of the formula (Ia) is converted into a pass by a reduction elimination reaction
  • the compound of the formula (I-b) is converted into a compound of the formula (I-c) by a suzuki coupling reaction and a reduction reaction;
  • the compound of the formula (I-c) is converted into a compound of the formula (I) by a Mitsunobu condensation reaction and a hydrolysis reaction; the compound of the formula (I-c) is converted into a compound of the formula (I) by a Mitsunobu condensation reaction;
  • the compound of the formula (I-e) is converted into a compound of the formula (I-f) by an epoxidation reaction and a ring-opening reaction; or the compound of the formula (I-e) is converted into a compound of the formula (I-f) by a nucleophilic substitution reaction;
  • a compound of the formula (If) is converted to a compound of the formula (lc) by a suzuki coupling reaction; or a compound of the formula (If) is converted into a compound of the formula (lc) by a suzuki coupling reaction and a hydrogenation reduction reaction; a compound of the formula (Ic) is converted to a compound of the formula (I) by a Mitsimobu condensation reaction and a hydrolysis reaction; a compound of the formula (Ic) is converted into a compound of the formula (I) by a Mitsimobu condensation reaction;
  • a compound of the formula (Ig) is converted to a compound of the formula (Ia) by an Adol reaction; or a compound of the formula (Ig) is converted to a compound of the formula (Ia) by a nucleophilic substitution reaction;
  • the compound of the formula (I-a) is converted into a compound of the formula (I-f) by a reduction reaction; or the compound of the formula (I-a) is converted into a compound of the formula (I-f) by a reduction reaction and a dehydroxylation reaction;
  • the compound of the formula (I-f) is subjected to a suzuki coupling reaction to a compound of the formula (I-c); or the compound of the formula (I-f) is converted into a compound of the formula (I-c) by a suzuki coupling reaction and a hydrogenation reduction reaction.
  • a compound of the formula (Ic) is converted to a compound of the formula (I) by a Mitsimobu condensation reaction and a hydrolysis reaction; a compound of the formula (Ic) is converted into a compound of the formula (I) by a Mitsimobu condensation reaction;
  • the compound of the formula (I-a) is converted into a compound of the formula (I-h) by a suzuki coupling reaction; or the compound of the formula (I-a) is converted into a compound of the formula (I-h) by a suzuki coupling reaction and a hydrogenation reduction reaction;
  • the compound of the formula (1-i) is converted into a compound of the formula (I) by a nucleophilic substitution reaction, a Mitsimobu condensation reaction and a hydrolysis reaction, or a compound of the formula (1-i) is converted into a compound of the formula (I) by a Mitsimobu condensation reaction. ; among them:
  • L is selected from F, Cl, Br or I
  • R, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R u , Q, p, q and t are as defined in the present invention; 16.
  • R 17 and R 18 are selected from H, hydroxy, methyl or ethyl.
  • preparation method of the compound of the general formula (I) of the present invention is selected from one of the following methods:
  • the compound of the formula (Ia) is reacted with diethoxycyanomethyl phosphate under basic conditions using tetrahydrofuran as a solvent, and then the cyano group is reduced to an aldehyde group with diisobutylaluminum hydride, and further with a reducing agent.
  • the reaction is then further reacted with a thiolation reagent under basic conditions to obtain a compound of the formula (Ib); or the compound of the formula (Ia) is reacted with a reducing agent, and further, in the presence of concentrated sulfuric acid, a elimination reaction is carried out to obtain a general formula.
  • the palladium catalyst is selected from the group consisting of [ ⁇ , ⁇ -bis(; diphenyl) Phosphine) ferrocene] palladium dichloride, [ ⁇ , ⁇ -bis(diphenylphosphino)ferrocene] palladium dichloromethane ruthenium complex, tetrakis(triphenylphosphine) palladium, two Palladium chloride, palladium acetate or bistriphenylphosphine palladium dichloride, the group consisting of [ ⁇ , ⁇ -bis(; diphenyl) Phosphine) ferrocene] palladium dichloride, [ ⁇ , ⁇ -bis(diphenylphosphino)ferrocene] palladium dichloromethane ruthenium complex, tetrakis(triphenylphosphine) palladium, two Palladium chloride, palladium acetate or bistriphenylphosphine palladium dichloride,
  • the compound of the formula (Id) is substituted with 3-bromopropene in the presence of potassium carbonate in the presence of acetonitrile, tetrahydrofuran, toluene or 1,2-dichloroacetic acid as a solvent, and then at 180 ° C, through Clay Reordering to obtain a compound of the formula (Ie);
  • the compound of the formula (Ie) is epoxidized with m-chloroperoxybenzoic acid by using methylene chloride or 1,2-dichloroacetic acid as a solvent, and then heated to reflux with 1,2-dichloroethane as a solvent.
  • the compound of the formula (Ig) is reacted with formaldehyde to obtain a compound of the formula (Ia) in the presence of methanol and water as a solvent in the presence of potassium carbonate; or tetrahydrofuran, hydrazine, hydrazine-dimethylformamide as a solvent, in sodium hydrogen
  • a nucleophilic substitution reaction with iodoformamidine or 1,2-dibromoacetamidine gives a compound of the formula (Ia);
  • the compound of the formula (Ia) is reacted with lithium tetrahydroaluminum to obtain a compound of the formula (If) in the presence of tetrahydrofuran as a solvent in the presence of aluminum trichloride; or the compound of the formula (Ia) is hydrogenated under the action of a reducing agent, and further Dehydroxylation gives a compound of the formula (If) wherein the dehydroxylation agent is selected from the group consisting of triethylsilyl, palladium/carbon, TMSCl/Nal or CS 2 /NaH, and TMSC1 refers to trimethylsilyl silane, wherein The reducing agent is as described above;
  • a compound of the formula (If) undergoes a suzuki coupling reaction with 3-formylbenzeneboronic acid in the presence of a palladium catalyst, and then a hydrogenation reduction reaction is carried out under the action of a reducing agent.
  • a compound of (Ic) wherein the palladium catalyst and the reducing agent are as defined above;
  • the Mitsunobu reaction gives a compound of the formula (I); or the compound of the formula (I-c) is converted into a compound of the formula ⁇ by a Mitsimobu condensation reaction and a hydrolysis reaction under the above conditions;
  • the compound of the formula (Ia) is subjected to a suzuki coupling reaction with 3-formylbenzeneboronic acid in the presence of a palladium catalyst, and then hydrogenated to reduce the formula under the action of a reducing agent.
  • R, R ⁇ R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R u , Q, p, q and t are as defined in the present invention Consistent; R 16 , R 17 , R 18 are selected from H, hydroxy, methyl or ethyl.
  • 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 other Therapeutic agent.
  • Other 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 hemihydrate or a pharmaceutically acceptable salt or prodrug thereof.
  • the DDPIV inhibitor is selected from the group consisting of linagliptin (Lilatripin), omarigliptin (MK-3102), sitagliptin (sitagliptin), vildagliptin (vidatripin), alogliptin (alogliptin), saxagliptin (sand Gliptin), denagliptin (digagliptin), Carmegliptin, Melogliptin (Merrolidine), Dutogliptin, Teneligliptin (Teliglitin), Gemigliptin or Trelagliptin.
  • the SGLT-2 inhibitor is selected from the group consisting of dapagliflozin, propanediol, empagliflozin, ertugliflozin, ipragliflozin, tofogliflozin, canagliflozinlus or eogliflozin.
  • the PARP inhibitor is selected from the group consisting of bezafibrate, feno fib rate, pioglitazone, azelaic acid ⁇ rosiglitazone or saroglitazar.
  • 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, Tolglybutamide, glibenclamide, glibenclamide, gliclazone, glipizide, or gliclazide.
  • the levonide therapeutic agent is selected from the group consisting of nateglinide, repaglinide or mitiglinide.
  • Said (X-glucosidase inhibitor is selected from the group consisting of acarbose, Voglibose or miglitol.
  • the GLP-1 analogue is selected from the group consisting of exenatide or liraglutide.
  • the present invention also relates to a compound of the formula (I) or a stereoisomer, hydrate, solvate, ester, metabolite, co-crystal, pharmaceutically acceptable salt or prodrug thereof as a G protein conjugation
  • a compound of the formula (I) or a stereoisomer, hydrate, solvate, ester, metabolite, co-crystal, pharmaceutically acceptable salt or prodrug thereof as a G protein conjugation
  • the use of the body 40 agonist in medicine and also relates to the compound of the formula (I) or a stereoisomer, hydrate, solvate, ester, metabolite, co-crystal, pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition of a prodrug for medical use preferably a compound of the formula (I) of the present invention or a stereoisomer, hydrate, solvate, ester, metabolite, co-crystal thereof, pharmaceutically acceptable
  • the salt or prodrug is used as a G protein coupled receptor 40 agonist for the preparation of a pharmaceutical preparation for the treatment and/or prevention of metabolic diseases.
  • the metabolic diseases may include, for example, diabetes, type II diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, diabetic complications, hypercholesterolemia, hyperglycemia, hyperinsulinemia, hyperlipidemia.
  • high triglycerideemia hypertension, hyperlipoproteinemia, high LDL cholesterol, low HDL cholesterol, hypoglycemia, dyslipidemia, thrombotic disease, cardiovascular disease, kidney disease, ketoacidosis, fatty acids Or elevated levels of glycerol, lipoatrophy, lipotoxicity, obesity, metabolic syndrome, syndrome X, insulin resistance, insulin allergy, glucose intolerance, skin disease, atherosclerosis and its sequelae, angina, One or more of limp, heart attack or stroke.
  • the compound of the formula (I) of the present invention or a stereoisomer, hydrate, solvate, ester, metabolite, co-crystal, pharmaceutically acceptable salt or prodrug thereof thereof is used as a G protein couple.
  • a conjugated 40 agonist is used to prepare a pharmaceutical preparation for the treatment and/or prevention of type 2 diabetes.
  • the invention also relates to a method of treating and/or preventing the metabolic disease, the method comprising administering to a subject an effective amount of a compound of the formula ⁇ according to the invention or a stereoisomer, hydrate or ester thereof A solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug, or a pharmaceutical composition comprising the same.
  • the 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.
  • the nitrogen is optionally further replaced by one or more of their corresponding isotopes, wherein the carbon isotopes include 12 C, 13 C, and 14 C, and the hydrogen isotopes include helium (H), helium (D, also known as heavy hydrogen), ⁇ (T, also known as super heavy hydrogen; I, oxygen isotopes include 16 0, 17 0 and 18 0, sulfur isotopes include 32 S, 33 S, 34 S and 36 S, nitrogen isotopes include 14 N and 15 N,
  • the fluorine isotopes include 17 F and 19 F
  • the chlorine isotopes include 35 C1 and 37 C1
  • the bromine 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.
  • 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, hexene-3-yl, g Alken-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, propyn-2-yl, butyn-1-yl, butyn-2-yl, butyn-3-yl, 3,3-dimethyl Butyrynyl-2-yl, pentyn-1-yl, pentyn-2-yl, hexyn-1-yl, 1-heptyn-1-yl, heptyn-3-yl, heptyne-4- Base, octyn-3-yl, decyn-3-yl, decyn-4-yl, undecy-3-yl, dodecyn-4-yl.
  • 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.
  • the aromatic or non-aromatic ring may be a 3 to 10 membered monocyclic ring, a 4 to 12 membered bicyclic ring or a 10 to 15 membered tricyclic ring system.
  • the ring group may be attached to a bridged ring or a spiro ring, and non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, phenyl, 1-cyclopentyl-2 -alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexenyl, cyclohexadienyl, ring Heptyl, ring Octyl, cyclodecyl, cyclodecyl, cyclodecyl, cyclododedecyl, ⁇ , *w.
  • Heterocyclyl means a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring, and the aromatic or non-aromatic ring may be a 3 to 10 membered monocyclic ring, a 4 to 12 membered bicyclic ring or 10 to 15 a tricyclic ring system, and comprising 1 to 4 hetero atoms selected from N, 0 or S, preferably a 3 to 8 membered heterocyclic group, and optionally substituted N, S in the ring of the heterocyclic group can be oxidized into various Oxidation state.
  • the heterocyclic group may be bonded to a hetero atom or a carbon atom, and the heterocyclic group may be bonded to a bridged ring or a spiro ring, and non-limiting examples include an epoxy group, a propylene group, an aziridine group, and an oxygen hetero ring.
  • PEG means a polymer containing ⁇ , wherein n is an integer in the range of from 2 to about 1,000, preferably from 2 to about 500, more preferably from 2 to about 250, still more preferably from 2 to about 125, still more preferably from 2 to about 50. Further, an integer in the range of 2 to about 25 is further preferable.
  • Amino means -NH 2 .
  • Mercaptoalkyl refers to an amino group having one or two mercapto substituents.
  • Neitro means -N0 2 .
  • Carboxy means -COOH.
  • Carboxylic acid ester means COOR 15 wherein R 15 is a fluorenyl group.
  • 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 invention retains the biological effectiveness and properties of the free acid or free base, and the free acid is passed through with a non-toxic inorganic base or An organic base, a salt obtained by reacting a free base with a non-toxic inorganic or organic acid.
  • 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
  • Non-limiting examples of the inorganic acid and organic acid choline, betaine, theobromine, hydrazine, piperazine, piperidine, N-ethylpiperidine, polyamine resin, phenicillin salt; Hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, glycolic acid, propionic acid, 2-hydroxypropionic acid, malonic acid, trifluoroacetic acid, methanesulfonic
  • 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.
  • the prodrugs of the present invention are prepared by modifying functional groups in the compounds of the present invention, which can be removed by conventional procedures or in vivo to give the parent compound.
  • a prodrug includes a compound formed by attaching a hydroxyl group, an amino group or a thiol group to any group in the compound of the present invention.
  • the prodrug of the present invention is administered to a mammalian individual, the prodrug is cleaved to form a free hydroxyl group, respectively. Amino or free sulfhydryl.
  • Examples of prodrugs include, but are not limited to, compounds formed by the hydroxyl or amino functional groups of the compounds of the invention with formic acid, acetic acid or benzoic acid.
  • eutectic refers to a crystal in which an active pharmaceutical ingredient and a eutectic formation are combined by hydrogen bonding or other non-covalent bonds, wherein the active pharmaceutical ingredient (API) and the eutectic formation (CCF) are in a pure state. 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 eutectic formations include alanine, valine, leucine, isoleucine, valine, phenylalanine, tryptophan, methionine, glycine, serine, threonine, and half Cystine, tyrosine, asparagine, glutamine, lysine, arginine, histidine, aspartic acid, aspartic acid, glutamic acid, pyroglutamic 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 sulfonic acid, formic acid, Fumaric acid, citric acid, gluconic acid, glucuronic acid, glutamic acid, glycolic acid,
  • 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.
  • 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 nuclear magnetic resonance
  • MS mass spectrometry
  • ⁇ is given in units of 10 - 6 (ppm).
  • the 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).
  • the HPLC was measured using an Agilent 1260 DAD high pressure liquid chromatograph (Zorbax SB-C18 100 x 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 the specification of 0.4 mm. ⁇ 0.5 mm.
  • 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.
  • the optimum reaction temperature at room temperature is 20 ° C ⁇ 30 ° C.
  • Resorcinol 1A (17.62 g, 160.02 mmol) was added in small portions to concentrated sulfuric acid (60 mL) containing ethyl chloroformate (28.00 g 170.12 mmol) at 0 ° C, and the reaction was stirred at room temperature 2 hour. The reaction mixture was poured into ice water, and the mixture was filtered. Step 2: 2-(6-Hydroxybenzofuran-3-yl)acetic acid (1C)
  • Step 5 2-(6-((3-(3-methoxy-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy) -2,3-dihydrobenzofuran-3-yl)acetic acid (Compound 1)
  • Step 5 2-(6-((3-(3-ethoxy-2,2,4,6-tetramethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy) -2,3-dihydrobenzofuran-3-yl)acetic acid (compound 2)
  • diethoxycyanomethyl phosphate (1.1 g, 6.22 mmol) was slowly added dropwise to a solution of sodium hydride (149 mg, 6.22 mmol) in tetrahydrofuran (20 mL). After stirring for 10 minutes, a solution of 5-bromo-4,6-dimethylbenzofuran-3(2H)-one 2E (1.0 g, 4.15 mmol) in tetrahydrofuran was slowly added dropwise to the mixture and the mixture was warmed to 35 ° C. The reaction was stirred for 3 hours.
  • Step 7 (3-(3-(2-methoxyethyl)-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)phenyl)methanol (3g)
  • Step 8 2-(6-((3-(3-(2-methoxyethyl)-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl) Methyl oxy)-2,3-dihydrobenzofuran-3-yl)acetate (3h) Methyl 2-(6-((3-(3-(2-methoxyethyl)-4,6-dimethyl-2 -dihydrobenzofuran-5-yl) benzyl)oxy)- 2,3-dihydrobenzofuran-3-yl)acetate
  • Step 9 2-(6-((3-(3-(2-methoxyethyl)-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl) Oxy)) 2,3-dihydrobenzofuran-3-yl)acetic acid (compound 3)
  • Step 6 2-(6-((3-(4,6-Dimethyl-2,3-dihydrobenzofuran-5-yl;)benzyl)oxy)-2,3-dihydro Benzofuran-3-yl;) methyl acetate (4f) Methyl 2-(6-((3-(4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2,3-dihydrobenzofura n-3-yl)acetate
  • Step 7 2-(6-((3-(4,6-Dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2,3-dihydrobenzene And furan-3-yl)acetic acid (compound 4)
  • reaction solution was concentrated to remove a solvent, diluted with water (50 mL), and extracted with ethyl acetate (60 mL x 3), and the organic phase was combined with saturated brine (100 mL x 2) and water (100 mL x 2) )washing. The residue was dried over anhydrous sodium sulfate (MgSO4).
  • Step 5 3-(2,2-bis(methoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)benzaldehyde (5e)
  • Tetrakis(triphenylphosphine)palladium (93.6 mg, 0.08 mmol) was added to the reaction system under a nitrogen atmosphere, the temperature was raised to 80 ° C, and the reaction was stirred for 18 hours. After completion of the reaction, water (10 mL) was added to the reaction mixture, which was diluted with ethyl acetate (50 mL). The organic layer was washed with brine (20 mL EtOAc). The residue was purified by silica gel column chromatography (EtOAc(EtOAc)
  • Step 6 (3-(2,2-bis(methoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl alcohol (5f)
  • Step 7 2-(6-((3-(2,2-bis(methoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl) )oxy) -2,3-dihydrobenzofuran-3-yl;) methyl acetate (5g)
  • Step 7 2-(6-((3-(2-(methoxy))-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy -2,3-dihydrobenzofuran Methyl-3-yl;) methyl acetate (6g)
  • Tributylphosphine (0.13 mL, 0.52 mmol) and azodiyldipiperidine (130.9 mg, 0.52 mmol) were added to (3-(2-(methylmethoxy)-4,6-) under a nitrogen atmosphere.
  • EtOAc mjjjjjjjjj
  • Step 8 2-(6-((3-(2-(methoxy))-(4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy -2,3-dihydrobenzofuran-3-yl)acetic acid (compound 6)
  • Tributylphosphine (0.41 mL, 1.64 mmol) and azodiyldipiperidine (413.8 mg, 1.64 mmol) were added to 5-(3-hydroxymethylphenyl)-4,6-dimethyl Methyl-benzofuran-3(2H)-one 9a (200 mg, 0.75 mmol) and methyl 2-(6-hydroxy-2,3-dihydrobenzofuran-3-yl)acetate 1E (186.1 mg, 0.89 mmol) in dry dichloromethane (15 mL). The reaction solution was stirred at room temperature for 2 hours.
  • the third step 2-(6-((3-(4,6-dimethyl-3-oxo-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2, 3-dihydrobenzofuran-3-yl)acetic acid (compound 9)
  • Step 4 (S) 2-(6-((3-(4,6-Dimethyl-3-oxo-3H-spiro-[benzofuran-2,1'-cyclopropyl]-5) -yl)benzyl)oxy)-2,3-dihydrobenzofuran-3-yl;)methyl acetate (1 Od)
  • Tributylphosphine 0.3 mL, 1.20 mmol
  • azodiyldipiperidine 302 mg, 1.20 mmoL
  • 5-(3-hydroxymethylphenyl)-4,6-dimethyl in a nitrogen atmosphere.
  • -3H-spiro [benzofuran-2, fluorenyl-cyclopropyl]-3-one 10c 160 mg, 0.54 mmol
  • S) 2-(6-hydroxy-2,3-dihydrobenzofuran -3-yl)methyl acetate 3D 136 mg, 0.65 mmoL
  • dry dichloromethane 15 mL
  • Step 5 (S) 2-(6-((3-(4,6-Dimethyl-3-oxo-3H-spiro[benzofuran-2,1'-cyclopropyl]-5-) Benzyl)oxy)-2,3-dihydrobenzofuran-3-yl)acetic acid (Compound 10)
  • Second step (S) 2-(6-((3-(2,2-bis(methoxymethyl)-4,6-dimethyl-3-oxo-2,3-dihydrobenzene) Methyl furan-5-yl)benzyl)oxy)-2,3-dihydrobenzofuran-3-yl)acetate (lib)
  • Tributylphosphine (0.34 mL, 1.36 mmol) and azodiyldipiperidine (343 mg, 1.36 mmol) were added to 5-(3-(hydroxymethyl)phenyl)-2,2- under a nitrogen atmosphere.
  • Bis(methoxymethyl)-4,6-dimethylbenzofuran-3(2H)-one 11a (220 mg, 0.62 mmol) and (S) 2-(6-hydroxy-2,3-di Methyl hydrobenzofuran-3-yl)acetate 3D (154 mg, 0.74 mmol) in dry methylene chloride (15 mL). The reaction solution was stirred at room temperature for 1 hour.
  • the third step (S) 2-(6-((3-(2,2-bis(methoxymethyl))-4,6-dimethyl-3-oxo-2,3-dihydrobenzene And furan-5-yl)benzyl)oxy)-2,3-dihydrobenzofuran-3-yl)acetic acid (Compound 11)
  • Tributylphosphine 0.3 mL, 1.23 mmol
  • azodiyldipiperidine 317 mg, 1.23 mmol
  • Dihydrobenzofuran-5-yl)phenylmethanol 13c
  • (S) 2-(6-hydroxy-2,3-dihydrobenzofuran-3-yl)acetate Ester 3D 129 mg, 0.62 mmol
  • dry methylene chloride 12 mL
  • Step 5 (3S) 2-(6-((3-(2,4,6-Trimethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy)-2, 3-dihydrobenzofuran-3-yl)acetic acid (compound 13)
  • Step 6 (S) 2-(6-((3-(2,2-bis(ethoxymethyl)-4,6-dimethyl-2,3-dihydrobenzofuran-5-) Methyl)benzyl)oxy)-2,3-dihydrobenzofuran-3-yl;)methyl acetate (14f)
  • Tributylphosphine (0.21 mL, 0.83 mmol) and azodiyldipiperidine (214 mg, 0.83 mmol) were added to 3-(2,2-bis(ethoxymethyl)-4 under nitrogen atmosphere.
  • 6-Dimethyl-2,3-dihydrobenzofuran-5-yl)benzyl alcohol 14e 140 mg, 0.38 mmol
  • (S) 2-(6-hydroxy-2,3-dihydrobenzofuran Methyl 3-methyl)acetate 3D (94 mg, 0.45 mmoL) in dry dichloromethane (12 mL).
  • the reaction solution was stirred at room temperature for 2 hours. A small amount of n-hexane was added to the reaction mixture, and the insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting product was directly subjected to the next reaction.
  • Step 7 (3S) 2-(6-((3-(2,2-Diethoxymethyl-4,6-dimethyl-2,3-dihydrobenzofuran-5-yl)) Benzyl)oxy)-2,3-dihydrobenzofuran-3-yl)acetic acid (Compound 14)
  • Step 3 ( S) 2-(6-((3-(4,6-Dimethyl-3H-spiro[benzofuran-2, fluorenyl-cyclopropyl]-5-yl)benzyl)oxy)-2, Methyl 3-dihydrobenzofuran-3-yl)acetate (15c)
  • tributylphosphine (0.34 mL, 1.34 mmol) and azodiyldipiperidine (338 mg, 1.34 mmol) were added (3-(4,6-dimethyl-3H-spiro[benzo Furan-2, fluorenyl-cyclopropyl]-5-yl)benzyl alcohol 15b (170 mg, 0.61 mmol) and (S) 2-(6-hydroxy-2,3-dihydrobenzofuran-3-yl) Methyl acetate 3D (139 mg, 0.67 mmoL) in dry methylene chloride (12 mL). The reaction mixture was stirred at room temperature for 2 hours.
  • Step 5 (S) 2-(6-((3-(3,3,4,6-tetramethyl-2,3-dihydrobenzofuran-5-yl)benzyl)oxy) - 2,3-dihydrobenzofuran-3-yl)acetic acid (compound 16)
  • Step 8 Methyl 2-[(3S)-6-[[3-(7-fluoro-4,6-dimethyl-3-oxo-spiro[benzofuran-2,1'-cyclopropane embankment] -5-yl) phenyl] methoxy] - 2, 3-dihydro-benzofuran-3-yl] acetate (18i)
  • Tributylphosphine (0.39 mL, 1.56 mmol) and hydrazine, hydrazine-(azo-dicarbonyl)dipiperidine (393 mg, 1.56 mmol) were added in vacuo, and stirred at room temperature for 3 hr.
  • Step 9 2-[(3S 6-[[3-(7-Fluoro-4,6-dimethyl-3-oxo-spiro[benzofuran-2,1'-cyclopropene]-5 -yl;)phenyl]methoxy]-2,3-dihydrobenzofuran-3-yl]acetic acid (compound 18)
  • Second step 2,2-bis[tert-butyl(dimethyl)methylsilyl]oxymethyl]-5-[3-(hydroxymethyl)phenyl]-4,6-dimethyl -benzofuran-3-one (19b) 2,2-bis[[tert-butyl(dimethyl)silyl]oxymethyl]-5-[3-(hydroxymethyl)phenyl]-4,6-dimethyl-benzofUran -3-one
  • Step 3 Methyl -2-[(3S)-6-[[3-[2,2-bis[[tert-butyl(dimethyl)methylsilyl)oxymethyl]-4,6-dimethyl-3 -oxo-benzofuran-5-yl]phenyl]methoxy]-2,3-dihydrobenzofuran-3-yl]acetic acid (19c)
  • Tributylphosphine (1.04 ml, 4.15 mmol) and hydrazine, hydrazine-(azodicarbonyl)dipiperidine (1.05 g, 4.15 mmol) were added, and then stirred at room temperature for 3 hr.
  • the residue was purified by silica gel column chromatography (EtOAc (EtOAc/EtOAc) - bis[[tert-butyl(dimethyl)methylsilyl]oxymethyl]-4,6-dimethyl-3-oxo-benzofuran-5-yl]phenyl]methoxy ]-2,3-Dihydrobenzofuran-3-yl]acetic acid 19c (1.2 g, yield 87%).
  • Step 5 2-[(3S)-6-[[3-[2,2-bis(hydroxymethyl)-4,6-dimethyl-3-oxo-benzofuran-5-yl] Phenyl]methoxy]-2,3-dihydrobenzofuranpyridin-3-yl]acetic acid (Compound 19)
  • the third step 4,6-dimethyl-N-(3-methanesulfonylpropyl)-5-[3-(tetrahydropyran-2-yloxymethyl)phenyl]-2,3- Dihydrobenzofuran-3-amine (20c)
  • Step 5 Methyl 2-[(3S)-6-[[3-[4,6-dimethyl-3-(3-methylsulfonylpropylamino)-2,3-dihydrobenzofuran) -5-yl]phenyl] Methyl methoxy]-2,3-dihydrobenzofuranpyridin-3-yl]acetate (20e)
  • tributylphosphine (0.24 mL, 0.94 mmol) and hydrazine, hydrazine-(azodicarbonyl)dipiperidine (238 mg, 0.94 mmol) were sequentially added and stirred at room temperature for 2 hr.
  • Step 6 2-[(3S)-6-[[3-[4,6-Dimethyl-3-(3-methanesulfonylpropylamino)-2,3-dihydrobenzofuran-5 -yl]phenyl]methoxy]-2,3-dihydrobenzofuranpyridin-3-yl]acetic acid (compound 20)
  • Step 5 Methyl 2-[(3S)-6-[[5-(4,6-dimethyl-3-oxo-spiro[benzofuran-2,1'-cyclopropene]-5 -yl)-2-fluoro-phenyl]methoxy]-2,3-dihydrobenzofuran-3-yl]acetic acid methyl ester (21f)

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Abstract

La présente invention concerne un dérivé benzofurane, son procédé de préparation, et son application médicale, et concerne plus particulièrement un composé représenté par la formule générale (I), un stéréoisomère associé, un hydrate associé, un solvate associé, un composé eutectique associé, un sel ou promédicament associé pharmaceutiquement acceptable, son procédé de préparation, une composition pharmaceutique comprenant ledit dérivé benzofurane, et une application médicale dudit composé ou de ladite composition pharmaceutique, en particulier comme agoniste du récepteur GPR40 (récepteur couplé à la protéine G), les définitions des groupes substituants dans la formule générale (I) étant identiques aux définitions données dans la description.
PCT/CN2014/078156 2013-05-22 2014-05-22 Dérivé benzofurane, son procédé de préparation, et son application médicale Ceased WO2014187343A1 (fr)

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WO2018113800A1 (fr) * 2016-12-22 2018-06-28 上海宣创生物科技有限公司 Sel de glycine bétaïne de pyrroloquinoléine quinone
US10710986B2 (en) 2018-02-13 2020-07-14 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
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CN112641776A (zh) * 2019-10-12 2021-04-13 江苏晶立信医药科技有限公司 一种以二甲双胍或其可药用盐和澳格列汀或其可药用盐为活性成分的药用组合物
CN113717135A (zh) * 2021-01-07 2021-11-30 贵州省中国科学院天然产物化学重点实验室(贵州医科大学天然产物化学重点实验室) 羰基取代的苯并二氢呋喃、苯并二氢吡喃化合物的合成方法
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US11236085B2 (en) 2018-10-24 2022-02-01 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US11279702B2 (en) 2020-05-19 2022-03-22 Kallyope, Inc. AMPK activators
CN114262250A (zh) * 2021-12-24 2022-04-01 乐威医药（江苏）股份有限公司 芳香环苄基邻位双烷基的合成方法
US11407768B2 (en) 2020-06-26 2022-08-09 Kallyope, Inc. AMPK activators
US11512065B2 (en) 2019-10-07 2022-11-29 Kallyope, Inc. GPR119 agonists
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US12264171B2 (en) 2020-02-28 2025-04-01 Kallyope, Inc. GPR40 agonists
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CN103524466A (zh) * 2012-07-03 2014-01-22 上海昀怡健康管理咨询有限公司 二氢苯并呋喃类衍生物、其制备方法、中间体及其应用

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WO2018113800A1 (fr) * 2016-12-22 2018-06-28 上海宣创生物科技有限公司 Sel de glycine bétaïne de pyrroloquinoléine quinone
US12590062B2 (en) 2017-04-20 2026-03-31 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
CN107540648A (zh) * 2017-08-09 2018-01-05 江苏工程职业技术学院 一种达格列净的制备方法
US10710986B2 (en) 2018-02-13 2020-07-14 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
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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
US11512065B2 (en) 2019-10-07 2022-11-29 Kallyope, Inc. GPR119 agonists
CN112641776A (zh) * 2019-10-12 2021-04-13 江苏晶立信医药科技有限公司 一种以二甲双胍或其可药用盐和澳格列汀或其可药用盐为活性成分的药用组合物
US12264171B2 (en) 2020-02-28 2025-04-01 Kallyope, Inc. GPR40 agonists
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
CN113717135A (zh) * 2021-01-07 2021-11-30 贵州省中国科学院天然产物化学重点实验室(贵州医科大学天然产物化学重点实验室) 羰基取代的苯并二氢呋喃、苯并二氢吡喃化合物的合成方法
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