WO2015010655A1 - Triadic fused cyclic carboxylic acids derivatives, preparation method therefor and pharmaceutical use thereof - Google Patents

Triadic fused cyclic carboxylic acids derivatives, preparation method therefor and pharmaceutical use thereof Download PDF

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WO2015010655A1
WO2015010655A1 PCT/CN2014/083061 CN2014083061W WO2015010655A1 WO 2015010655 A1 WO2015010655 A1 WO 2015010655A1 CN 2014083061 W CN2014083061 W CN 2014083061W WO 2015010655 A1 WO2015010655 A1 WO 2015010655A1
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group
salt
alkyl
pharmaceutically acceptable
compound
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PCT/CN2014/083061
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French (fr)
Chinese (zh)
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张晨
雷鸣
何平
魏用刚
邓炳初
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四川海思科制药有限公司
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Priority to CN201480020721.7A priority Critical patent/CN105143181B/en
Publication of WO2015010655A1 publication Critical patent/WO2015010655A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/16—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C317/18—Sulfones; Sulfoxides having sulfone or sulfoxide groups and singly-bound oxygen atoms bound to the same carbon skeleton with sulfone or sulfoxide groups bound to acyclic carbon atoms of the carbon skeleton
    • 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
    • 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
    • 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
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with 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 ring carbon atoms
    • C07D307/20—Oxygen atoms
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2603/00—Systems containing at least three condensed rings
    • C07C2603/02—Ortho- or ortho- and peri-condensed systems
    • C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
    • C07C2603/06—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members
    • C07C2603/10—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings
    • C07C2603/12—Ortho- or ortho- and peri-condensed systems containing three rings containing at least one ring with less than six ring members containing five-membered rings only one five-membered ring

Definitions

  • the present invention relates to a ternary cyclocarboxylic acid derivative, a preparation method thereof and its use in medicine, in particular to a novel three 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, etc. Causes insulin resistance.
  • Oral hypoglycemic agents currently approved for marketing include sulfonylureas, biguanides, thiazolidinediones (TZDs), alpha-glucosidase inhibitors, amylin analogues, dipeptidyl peptidase inhibitors (DPP- IV), sodium-glucose cotransporter 2
  • G-protein coupled receptor 40 (GPR40) 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. G protein-coupled receptors have 7 transmembrane structures, can sense extracellular signals, activate intracellular signal transduction pathways, and ultimately cause cellular responses. GPR40 can be activated by medium long-chain free fatty acids (FFAs) (Itoh Y et al ( 2003) . Nature, 422, 173-176). In addition to being an energy source, FFAs are also an important signaling molecule that promotes insulin secretion, a function that is primarily achieved through GPR40.
  • FFAs medium long-chain free fatty acids
  • Fasiglifam hemihydrate (TAK-875) is a GPR40 agonist that has now entered Phase III clinical and proven effective. Studies have shown that fasiglifam hemihydrate (TAK-875) promotes insulin secretion and can effectively control blood glucose in an animal model of diabetes, but does not promote insulin secretion in normal rats (Ts yihata Y et al. (2010). Diabetes, 59 , A165); In clinical trials, fasiglifam hemihydrate (TAK-875) also showed significant hypoglycemic effects with a lower risk of hypoglycemia (T. Araki et al. (2012). Diabetes, Obesity and Metabolisml4, 271- 278). Other GPR40 agonists have also been developed, such as JTT-851, LY-2881835 and so on.
  • 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.
  • 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, wherein R 1 is selected from -S0 2 -R 6 and R 6 is selected from D 6 fluorenyl or optionally substituted U-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 a 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 a 5- to 7-membered ring, Y is selected from a bond or CH 2 , and R is selected from a hydroxyl group.
  • R 1 is selected from -S0 2 -R 6 and R
  • V is selected from a bond or
  • the present invention provides a compound represented by the formula (I) or a stereoisomer, hydrate, ester, solvate, eutectic, metabolite, or pharmaceutically thereof thereof:
  • R is selected from H or d. 8 fluorenyl
  • R b , R bl , R e and R el are each independently selected from H, F, Cl, Br, I, hydroxy, C 1-8 fluorenyl or C 1-8 decyloxy, wherein the fluorenyl or hydrazine
  • R a and R al are each independently selected from H, F, Cl, Br, I, cyano, amino, nitro, hydroxy, carboxy, d. 8 alkyl or d 8 methoxy, wherein the fluorenyl, hydrazine
  • the oxy or amino group is each independently optionally further selected from 0 to 4 selected from the group consisting of F, C1, Br, I, cyano, nitro, hydroxy, d. 8 decyl, d. 8 decyloxy, C 2 .
  • R 1 and R 2 are each independently selected from H, F, Cl, Br, I, cyano, amino, nitro, hydroxy, carboxy, d. 8 fluorenyl or d 8 decyloxy, wherein the fluorenyl, hydrazine
  • the oxy or amino group is each independently optionally further selected from 0 to 4 selected from the group consisting of F, C1, Br, I, cyano, nitro, hydroxy, d. 8 decyl, d. 8 decyloxy, C 2 .
  • G is selected from the group consisting of H, F, Cl, Br, I, fluorenyl, hydroxy, nitro, cyano, d. 8 fluorenyl, d. 8 decyloxy, C 2 . 8 alkenyl
  • t is 0 or 1;
  • k 0, 1 or 2;
  • p 0, 1, 2 or 3;
  • q 0, 1, 2 or 3;
  • n 0, 1, or 2.
  • Preferred embodiments of the invention include a compound of the formula (A) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof,
  • R is selected from H or d. 4 fluorenyl, preferably H ;
  • R b and R bl are each independently selected from H, F, hydroxy, d. 4 fluorenyl or d. 4 alkoxy, preferably H or d. 4 decyloxy, wherein the fluorenyl or decyloxy are each independently Optionally further substituted with 0 to 3 substituents selected from F, —CF 3 , d 4 fluorenyl or d 4 alkoxy;
  • R 3 and R 3a are each independently selected from H, hydroxy, d 4 fluorenyl or d 4 methoxy, preferably H or d 4 fluorenyl, more preferably d 2 fluorenyl, wherein the fluorenyl or decyloxy are each independently Optionally optionally substituted by 0 to 2 substituents selected from the group consisting of F, Cl, Br, C 1-4 fluorenyl or d 4 methoxy;
  • p 0, 1, 2 or 3;
  • q 0, 1, 2 or 3;
  • n 0, 1, or 2.
  • Preferred embodiments of the invention include a compound of the formula (A) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein:
  • R is selected from H or d. 2 fluorenyl, preferably H;
  • R b is selected from H or d 4 fluorenyl, preferably H or d 2 fluorenyl, more preferably H, wherein the fluorenyl group is further substituted by 0 to 2 selected from F, -CF 3 or d. 2 fluorenyl;
  • R bl is selected from H, F or CM fluorenyl groups, preferably H, F or fluorenyl, more preferably H or fluorenyl, wherein the fluorenyl group is further 0 to 2 selected from F, -CF 3 or d 2 fluorenyl Replaced
  • R 1 and R 2 are each independently selected from H, F, Cl, Br, -CH 2 F, -CHF 2 , -CF 3 , C 1-4 fluorenyl or C 1-4 decyloxy, preferably H, F, Cl, Br, -CH 2 F, -CHF 2 , -CF 3 or C 1-2 fluorenyl;
  • G is selected from H, F, Cl, Br, I, CM thiol, CM methoxy, 3 to 6 membered carbocyclic or 4 to 6 membered heterocyclic, preferably H, F, Cl, Br, alkyl or a 5- to 6-membered carbocyclic group, more preferably H, F, Cl, Br, fluorenyl or 6-membered carbocyclic group, further preferably F, d 2 alkyl or 6-membered carbocyclic group, further preferably 6-membered carbocyclic group,
  • the heterocyclic group contains 1 to 2 heteroatoms selected from N, 0 or S; the fluorenyl, decyloxy, carbocyclyl or heterocyclic group are each independently optionally further 0 to 3 selected from F , Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , C 1-3 fluorenyl, C 1-3 decyloxy, -0-C 1-3 alkyl-O-
  • R 3 is selected from H or C 1-3 fluorenyl, preferably C 1-3 fluorenyl;
  • p is 0, 1, 2 or 3, preferably 0;
  • q is 0, 1, 2 or 3, preferably 0;
  • n 0, 1 or 2, more preferably 2.
  • Preferred embodiments of the invention include a compound of the formula (A) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein:
  • R is H
  • R b is H
  • R bl is selected from! ! or. ⁇ , ⁇ ! ! or. ⁇ ; R 1 and R 2 are each independently selected from H or F ;
  • R 3 is selected from! ! Or ⁇ , preferably d. 3 ⁇ ;
  • the atom or group preferably has 1 to 2 0 hetero atoms, more preferably 1 0 hetero atom, and the heterocyclic group is optionally further substituted by 0 to 3 d 2 methoxy groups, preferably 0 to Substituted by two hydroxyl groups;
  • p 0, 1, 2 or 3;
  • q 0, 1, 2 or 3;
  • n 0, 1 or 2, preferably 2.
  • Preferred embodiments of the invention include compounds represented by the formula ( ⁇ ) or stereoisomers, hydrates, esters, solvates thereof
  • R is H
  • R b is H
  • R bl is selected from H or methyl, preferably H ;
  • R 1 and R 2 are each independently selected from H or F;
  • p 0, 1, 2 or 3;
  • q 0, 1, 2 or 3.
  • R b is selected from H ;
  • R bl is selected from! ! or. ⁇ , ⁇ ! ! or. ⁇ ;
  • R 3 is selected from! ! Or ⁇ , preferably d. 3 ⁇ ;
  • n 0, 1 or 2, preferably 2.
  • a preferred embodiment of the invention a compound of the formula ( ⁇ ) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof:
  • R b is selected from H
  • R bl is selected from H or methyl, preferably H ;
  • - R is selected from H or d. 8 fluorenyl
  • R b , R bl , R e and R el are each independently selected from H, F, Cl, Br, I, hydroxy, C 1-8 fluorenyl or C 1-8 decyloxy, wherein the fluorenyl or hydrazine
  • R a and R al are each independently selected from H, F, Cl, Br, I, cyano, amino, nitro, hydroxy, carboxy, d. 8 alkyl or d 8 methoxy, wherein the fluorenyl, hydrazine
  • the oxy or amino group is each independently optionally further selected from 0 to 4 selected from the group consisting of F, C1, Br, I, cyano, nitro, hydroxy, d. 8 decyl, d. 8 decyloxy, C 2 .
  • R 1 and R 2 are each independently selected from H, F, Cl, Br, I, cyanide a base, an amino group, a nitro group, a hydroxyl group, a carboxyl group, an alkyl group or a d- 8 methoxy group, wherein the fluorenyl group, the decyloxy group or the amino group are each independently optionally further from 0 to 4 selected from the group consisting of F, C1, Br, I, cyano, nitro, hydroxy, d.
  • the thiol or fluorenyl group is each independently optionally further selected from 0 to 4 selected from the group consist
  • R 3 and R 3a are each independently selected from H, hydroxy, d- 8 fluorenyl or d 8 decyloxy, wherein the fluorenyl or alkoxy are each independently optionally further 0 to 4 selected from the group consisting of F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , cyano, nitro, hydroxy, Cl-8, cl-8, oxy, C 2 - 8 Alkenyl,
  • t is 0 or 1;
  • k 0, 1 or 2 ;
  • p 0, 1, 2 or 3;
  • q 0, 1, 2 or 3;
  • n 0, 1, or 2. According to a preferred embodiment of the present invention, there is provided a compound of the formula ( ⁇ ) or a stereoisomer, hydrate, oxime solvate, eutectic or metabolite thereof.
  • - R is selected from H or d. 4 fluorenyl, preferably H;
  • R b and R bl are each independently selected from H or CM thiol, preferably H or methyl;
  • R 1 and R 2 are each independently selected from H, F, Cl, C 1-4 fluorenyl or C 1-4 fluorenyloxy;
  • R 3 is selected from H or CM thiol, preferably CM thiol, more preferably methyl;
  • p 0, 1, 2 or 3;
  • q 0, 1, 2 or 3;
  • n 0, 1, or 2.
  • R is selected from H or a mercapto group, preferably H;
  • R B is selected from H
  • R BL is selected from H or a thiol group, preferably H or methyl;
  • R 1 and R 2 are each independently selected from H, F, Cl, CM thiol or C w decyloxy;
  • R 3 is selected from H or d 2 alkyl, preferably methyl
  • the heterocyclic group is optionally further substituted with 0 to 3 substituents selected from the group consisting of d 2 methoxy groups;
  • p 0, 1, 2 or 3;
  • q 0, 1, 2 or 3;
  • n 0, 1, or 2.
  • the compound of the formula ( ⁇ ) or a stereoisomer, hydrate or ester thereof is a compound of the formula ( ⁇ ) or a stereoisomer, hydrate or ester thereof
  • R is selected from H or d. 2 fluorenyl
  • R B is selected from H
  • R BL is selected from alkyl with ffi3 ⁇ 4d 2.
  • R 3 is selected from H or a thiol group
  • n 0, 1, or 2. According to a preferred embodiment of the present invention, there is provided a compound of the formula ( ⁇ ) or a stereoisomer, hydrate, oxime solvate, co-crystal, or metabolite thereof.
  • R b is selected from H
  • R bl is selected from H or a thiol group, preferably H or methyl;
  • R 3 is selected from H or decyl, preferably methyl;
  • n 0, 1, or 2.
  • a preferred embodiment of the invention a compound of the formula (A) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein:
  • R b is selected from H
  • R bl is selected from H or methyl
  • a preferred embodiment of the invention a compound of the formula (A) or a stereoisomer, hydrate, cerium crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof,
  • R b is selected from H
  • R bl H or methyl
  • Suitable pharmaceutically acceptable salts of the present invention include, but are not limited to, sodium, potassium, aluminum, lithium, zinc, calcium, magnesium, strontium, ammonium, 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, phenicillin salt, hydrochloride, hydrobromide, sulfate, nitrate, phosphate, formate, acetate, glycolate , propionate, 2-hydroxypropionate, malonate, trifluoroacetate, methanesulfonate, ethanesulfonate, triflate, ethylene sulfonate, besylate, P-toluenesulfonate, benzoate, phenylacetate, alginate, anthranilate, camphorate, maleate, tartrate, citrate, succinate, mandelate, rich Citrate, malate, oxalate, salicylate, glu
  • the invention also relates to the system
  • the compound of the formula (Ia) is sequentially converted into a compound of the formula (Ib) by protecting a hydroxyl group reaction, a reduction reaction and a elimination reaction; or the compound of the formula -a) is sequentially converted into a pass by protecting a hydroxyl group reaction, a wittig reaction and a double bond transposition reaction.
  • a compound of formula -b) is sequentially converted into a compound of formula (Ib) by protecting a hydroxyl group reaction, a reduction reaction and a elimination reaction; or the compound of the formula -a) is sequentially converted into a pass by protecting a hydroxyl group reaction, a wittig reaction and a double bond transposition reaction.
  • the compound is converted to the compound of the formula (Ic) by a simmons-simth reaction and a deprotection group reaction;
  • the compound of the formula -c) and the compound of the formula -d) are converted to the compound of the formula (I) by a Mistunobo condensation reaction; wherein - R, R 1 , RR al , R b , R bl , R c , R cl , R 2 , G, Q, Wi, W 2 , W 3 , t, p, k and q are as defined above in the present invention.
  • the invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising: an effective amount of a compound of the invention or all stereoisomers, hydrates, solvates, esters, metabolites, co-crystals thereof, pharmaceutically acceptable Accepted salts or prodrugs, and pharmaceutically acceptable carriers, diluents, adjuvants or excipients.
  • the composition may further comprise one or more additional therapeutic agents.
  • the other therapeutic agents described therein may include:
  • PTP-1B protein tyrosine phosphatase-IB
  • glucagon receptor antagonist or a pharmaceutically acceptable salt, and/or
  • a drug for improving lipid distribution in a patient selected from the group consisting of an HMG-CoA reductase inhibitor, a bile acid sequestrant, nicotine, nicotinic acid or a salt thereof, ? ⁇ 0 ( agonist, cholesterol absorption inhibitor, acyl-CoA (cholesterol acyltransferase) (ACAT) an inhibitor, a CETP inhibitor or a phenolic antioxidant or a pharmaceutically acceptable salt, and/or (q) a biguanide, a thiazolidinedione, a linoleum, or a pharmaceutically acceptable thereof Salt or prodrug.
  • the GPR40 agonist is selected from the group consisting of fasiglifam hemihydrate or a pharmaceutically acceptable salt or prodrug thereof.
  • the DDP-IV inhibitor is selected from the group consisting of lmagliptin (lilastectin;), sitagliptin (sitagliptin;), vildagliptm (vildagliptin), alogliptin (alogliptin), saxagliptm (saxagliptin) ), denagliptm (digagliptin), Carmegliptin, Melogliptin, or Dutogliptin, Teneligliptin, Gemigliptin or Trelaglitpt.
  • the SGLT-2 inhibitor is selected from the group consisting of dapagliflozm, propanediol, empagliflozin, ertugliflozin, ipragliflozin, tofogliflozin, canagliflozinlus or eogliflozin.
  • the PPAR is excited to be selected from bezafibrate, fenofibrate, 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 daglitazone.
  • the sulfonylurea therapeutic agent is selected from the group consisting of glimepiride, Tolglybutamide, glibenclamide, glibenclamide, gliclazide, gliprazine, or gliclazide.
  • the levonide therapeutic agent is selected from the group consisting of nateglinide, repaglinide or mitiglinide.
  • the a-glucosidase inhibitor is selected from the group consisting of acarbose, voglibose or miglitol.
  • the GLP-1 analogue is selected from exenatide or liraglutide.
  • the invention further relates to a compound of the invention or a stereoisomer, hydrate, solvate, ester, metabolite, co-crystal, pharmaceutically acceptable salt or prodrug thereof thereof as a G protein-coupled receptor 40
  • an agonist in medicine also relates to the medicament comprising a compound of the invention or a stereoisomer, hydrate, solvate, ester, metabolite, co-crystal, pharmaceutically acceptable salt or prodrug thereof
  • the composition preferably a compound of the invention, or a stereoisomer, hydrate, solvate, ester, metabolite, co-crystal, pharmaceutically acceptable salt or prodrug thereof, or
  • the pharmaceutical composition 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, sputum type 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, X syndrome, insulin resistance, insulin allergy, glucose intolerance, skin disease, atherosclerosis and its sequelae, angina, One or more of limp, heart attack or stroke.
  • diabetes sputum type diabetes
  • diabetic retinopathy diabetic neuropathy
  • diabetic nephropathy diabetic complications
  • hypercholesterolemia hyperglycemia
  • hyperinsulinemia hyperlipidemia.
  • the compound 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-coupled receptor 40
  • Agonists are used in the preparation of pharmaceutical preparations for the treatment and/or prevention of diabetes.
  • the invention also provides a method of treating and/or preventing a metabolic disease, the method comprising administering any of the preceding items a compound of the formula (1), formula ( ⁇ ) and formula (III) or a stereoisomer, hydrate, hydrate, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof or Said pharmaceutical composition.
  • 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 ytterbium (H) and yttrium (D, also known as heavy hydrogen; , ⁇ CT, also called super heavy hydrogen;), 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 79 Br and 81 Br.
  • “Mercapto” refers to a straight or branched saturated aliphatic hydrocarbon group having 1 to 20 carbon atoms, preferably a fluorenyl group of 1 to 10 carbon atoms, more preferably a fluorenyl group of 1 to 8 carbon atoms, further A fluorenyl group of 1 to 6 carbon atoms is preferred.
  • “Amidino” means a straight or branched saturated aliphatic fluorenyl group having 1 to 20 carbon atoms, preferably a fluorenyl group of 1 to 10 carbon atoms, more preferably a fluorenyl group of 1 to 8 carbon atoms. Further preferred is a fluorenyl group of 1 to 6 carbon atoms.
  • Non-limiting examples include methylene, ethylene, propylene, methylmethylene, ethylethylene, 1,2-dimethylethylene, 1,1,2,2-tetra Methylethylene; the fluorenyl group may be further optionally 0 to 5 selected from the group consisting of F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , amino group, hydroxyl group, d. 8 Substituted by a substituent of fluorenyl, d.
  • 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, 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, -CH 2 F, -CHF 2 , -CF 3 , hydroxy, decyl, nitro, cyano, carboxy, olefin.
  • 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.
  • 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 base can be connected with a bridge ring or a spiral ring.
  • Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl , cyclohexyl, phenyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexenyl, cyclohexadienyl
  • 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.
  • Carboxy means -COOH.
  • Neitro means -N0 2 .
  • “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 A salt obtained by an organic base reaction, a salt obtained by reacting the free base with a non-toxic inorganic acid or an 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, tetramethyl Ammonium, diethylamine, triethylamine, isopropylamine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, pyridine, picoline, 2,6-lutidine, caffeine, general Rucaine, choline, betaine, theobromine, hydrazine, piperazine, piperidine, N-ethylpiperidine, polyamine resin, phenicillin salt; non-limiting of the inorganic and organic acids Examples 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 abrogate 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”.
  • the diluted inert substance is added. Such as: clay, kaolin, clay, talcum powder, etc.
  • 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 provide 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, free 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 bond, wherein the pure state of API and CCF is solid at room temperature, and each component There is a fixed stoichiometric ratio between them.
  • 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 spatial arrangement of atoms in a molecule, 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 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. 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 judgement 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 the reactive functional groups present in the compounds described herein.
  • the process for the preparation of the compounds of the formula I) according to the invention comprises:
  • the compound of the formula -e) is reduced to a compound of the formula -d) by a reducing agent under anhydrous and anaerobic conditions using methanol as a solvent; wherein the reducing agent is selected from the group consisting of sodium borohydride, potassium borohydride and lithium aluminum hydride. , sodium thioborohydride or lithium tri-sec-butyl borohydride;
  • the compound of the formula (Ia) and the protecting group are reacted with a protective hydroxyl group, and the obtained product is reduced by a reducing agent under anhydrous anaerobic conditions, and the reduced product is again
  • the elimination reaction occurs under acidic conditions to obtain a compound of the formula (Ib); or under basic conditions, using dry dichloromethane as a solvent, the compound of the formula (Ia) and the protecting group are protected by a hydroxyl group, and the obtained product is alkaline.
  • a compound of formula -b) is reacted with iodomethyl hydrazine to obtain a silk ring compound, which is then deprotected under basic conditions to give a compound of formula -c).
  • the acid and base are as described above; in the presence of dichloromethane or tetrahydrofuran as solvent, tri-tert-butylphosphine, diisopropyl azodicarboxylate or 1,1-(azodicarbonyl)dipiperidine a compound of formula (c) is subjected to a Mistunobo condensation reaction with a compound of the formula (Id) to give a compound of the formula (I); or a compound of the formula -c) is subjected to a Mistunobo condensation reaction with a compound of the formula (Id) and the hydrolysis reaction is converted into a pass.
  • R, R 1 , R 2 , RR al , R b , R bl , R c , R cl , Q, G, Wi, W 2 , W 3 , k, t, p and q are as defined above in the present invention . detailed description
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). NMR shifts ([delta]) are given in units of 10_ 6 (ppm) a.
  • 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 deuterated dimethyl sulfoxide
  • CDC1 3 deuterated chloroform
  • CD 3 deuterated methanol
  • OD 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 has a 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.
  • TBS tert-butyldimethylsilyl.
  • the third step 2-[3-[tert-butyl(dimethyl)silyl]oxy-l,la,6,6a-tetrahydrocyclopropane[a]indol-6-yl]methyl acetate ( 3C) methyl 2-[3-[tert-butyl(dimethyl)silyl]oxy-l,la,6,6a-tetrahydrocyclopropa[a]inden-6-yl]acetate
  • Step 3 2-[3-[tert-Butyl(dimethyl))silyl]oxy-la-methyl-6,6a-dihydro-1H-cyclopropene[a] ⁇ -6-yl Ethyl acetate (5C)
  • Tetrabutylammonium fluoride (610 mg, 2.33 mmol) was added to the above product 2-[3-[tert-butyl(dimethyl))silyl]oxy-la-methyl-6,6a-dihydrogen -1H-cyclopropanone [a] ⁇ -6-yl] ethyl acetate 5C in a crude product in tetrahydrofuran (10 mL). The reaction was stirred at room temperature for 1 hour, monitored by TLC plate, and the reaction was completed.
  • Second step 2-[3-[[3-[2,6-dimethyl-4-(3-methylsulfonylpropoxy))phenyl]phenyl]methoxy]-l,la, 6,6a-tetrahydrocyclopropane [a] indol-6-yl]acetic acid (compound 3)
  • Second step 2-[3-[[3-[2,6-Dimethyl-4-[(3R)-tetrahydrofuran-3-yl]oxy-phenyl]phenyl]methoxy]-l ,la,6,6a-tetrahydrocyclopropene[a]indol-6-yl]acetic acid (compound 4) 2-[3-[[3-[2,6-dimethyl-4-[(3R)-tetrahydrofuran -3-yl]oxy-phenyl]phenyl]methoxy]-l,la,6,6a-tetrahydrocyclopropa[a]inden-6-yl]acetic acid
  • Tributylphosphine (404 mg, 2.00 mmol) was added dropwise to the mixture, and the reaction was further stirred at 0 ° C for 0.5 hour. The reaction solution was allowed to warm to room temperature, and the reaction was stirred for 3 hours, and the TLC plate was followed to complete the reaction. The reaction mixture was concentrated under reduced pressure.
  • EtOAc EtOAc mjjjjjj 6-Dimethyl-4-(3-methanesulfonylpropoxy)phenyl]phenyl]methoxy]-la-methyl-6,6a-dihydro-1H-cyclopropene[a] ⁇ -6-yl]methyl acetate 5a (302 mg, yield 53.7%).
  • Step 5 2-[(laS,6R,6aR)-3-[[3-[4-[[(3R,3aR,6S,6aR)-3-methoxy-2,3,3a,5, 6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy]-2,6-dimethylphenyl]phenyl]methoxy]-Ua,6,6a-tetra Hydrogen cyclopropenyl[a]indol-6-yl]acetate methyl ester (6D
  • Step 6 2-[3-[[3-[4-[[(3R,3aR,6S,6aR)-3-methoxy-2,3,3a,5,6,6a-hexahydrofuran [3,2-b]furan-6-yl]oxy -2,6-dimethylphenyl]phenyl]methoxy]-l,la,6,6a-tetrahydrocyclopropenyl[a]indol-6-yl]acetic acid (compound 6)
  • the activity of the compounds prepared in the various examples of the present invention was tested using the GPR40 luciferase reporter assay.
  • the test procedure is as follows:
  • the compound was formulated into a 10 mM stock solution in DMSO and diluted to a 3-fold gradient 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, the cell confluence reached about 70%, replaced with serum-free medium, and starved overnight. On the third day, DMEM medium containing different concentrations of the test compound was added, 200 ⁇ l per well, and incubated in a cell culture incubator for 5 hours. Luciferase activity was detected using the Luciferase Assay System kit. Ongm 7 software using fluorescence analysis to fit the data to calculate EC 5 for each compound. The test results are shown in Table 1. Table 1 luciferase reporter gene test results
  • the compounds of the present invention exhibit excellent pharmacodynamic activity as GPR40 agonists.

Abstract

Triadic fused cyclic carboxylic acids derivatives, preparation method therefor and pharmaceutical use thereof, particularly relating to compounds represented by general formula (I), stereoisomers, hydrates, solvates, metabolites, eutectics, pharmaceutically acceptable salts or prodrugs thereof, preparation method therefor or pharmaceutical compositions comprising same, and the pharmaceutical use of said compounds or pharmaceutical compositions, especially the use as GPR40 receptors (G protein-coupled receptors) agonist. The definition of each substituent in general formula (I) is the same as that in description.

Description

三元并环羧酸类衍生物、 其制备方法及其在医药上的应用 技术领域  Ternary cyclocarboxylic acid derivative, preparation method thereof and application thereof in medicine
本发明涉及一种三元并环羧酸类衍生物、 其制备方法及其在医药上的应用， 具体涉及 —种具有 G蛋白偶联受体 40 (GPR40) 受体功能调节作用的新颖的三元并环羧酸类衍生物 或其立体异构体、 水合物、 溶剂化物、 共晶体、 药学上可接受的盐或者前药、 其制备方法 及包含其的药物组合物以及其在医药上的应用。 背景技术  The present invention relates to a ternary cyclocarboxylic acid derivative, a preparation method thereof and its use in medicine, in particular to a novel three having a G protein-coupled receptor 40 (GPR40) receptor function regulating function. a carboxylic acid derivative or a stereoisomer, hydrate, solvate, cocrystal, pharmaceutically acceptable salt or prodrug thereof, a process for the preparation thereof, and a pharmaceutical composition comprising the same, and a pharmaceutical composition thereof application. Background technique
糖尿病及其并发症严重影响了人们的生活质量， 并成为导致死亡的重要原因之一， 糖 尿病中过高的血糖水平导致患者出现多尿、 多饮和多食的典型症状， 糖尿病的并发症如肾 损伤、 糖尿病酮酸中毒和心脏病等可危及生命。 II型糖尿病是最常见的一类糖尿病， 主要 发生在成年阶段， 主要表现为胰岛素分泌不足或胰岛素抵抗 （即机体组织不能有效对内源 性胰岛素做出反应） ， 遗传和环境等诸多因素均可导致胰岛素抵抗。  Diabetes and its complications seriously affect people's quality of life and become one of the important causes of death. Excessive blood sugar levels in diabetes lead to typical symptoms of polyuria, polydipsia and polyphagia. Diabetes complications such as Kidney damage, diabetic ketoacidosis and heart disease can be life threatening. 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, etc. Causes insulin resistance.
糖尿病患者如果通过饮食和锻炼不能有效控制血糖， 则需注射激素类药物或口服降糖 药。 目前已批准上市的口服降糖药包括磺酰脲类、 双胍类、 噻唑垸二酮类 （TZDs ) 、 α-葡 萄糖苷酶抑制剂、 糊精类似物、 二肽基肽酶抑制剂 （DPP-IV ) 、 钠-葡萄糖协同转运蛋白 2 If diabetics cannot effectively control their blood sugar through diet and exercise, they should be given hormonal drugs or oral hypoglycemic agents. Oral hypoglycemic agents currently approved for marketing include sulfonylureas, biguanides, thiazolidinediones (TZDs), alpha-glucosidase inhibitors, amylin analogues, dipeptidyl peptidase inhibitors (DPP- IV), sodium-glucose cotransporter 2
( SGLT-2 ) 抑制剂等类药物。 然而， 以上这些降糖药均有副作用， 如低血糖、 体重增加、 心血管风险和泌尿生殖道感染等 （Vinod S. Deshmukh等 （2013 ) . International Journal of Basic & Clinical Pharmacology, 2， 4-11 ) ， 这些副作用进一步加重了糖尿病患者的负担， 因此， 需要开发具有新型作用机制的新一代降糖药。 G蛋白偶联受体 40 (GPR40)是一个具 有降糖尿潜力的新靶点， 在胰岛 β细胞中高表达。 GPR40又称脂肪酸受体 1 ( FFAR1 ) ， 是 一个属于同源 G蛋白偶联受体超家族的膜受体， 在多种物种中高度保守。 G蛋白偶联受体有 7次跨膜结构， 可感受胞外信号， 激活胞内信号转导通路， 并最终引起细胞应答， GPR40可 被中长链游离脂肪酸 (FFAs ) 激活 （Itoh Y等 (2003 ) . Nature, 422， 173-176) 。 FFAs除 了作为能量来源外， 也是一种重要的信号分子， 可促进胰岛素分泌， 该功能主要是通过 GPR40实现的。 FFAs与 GPR40相互作用后，可通过胰岛 β细胞中的 PLC或 L型 Ca2+通道信号通 路提高 Ca2+流量，进而引起细胞应答（Fujiwara等（2005 ) . Am J Physiol Endocrinol Metab, 289, E670-E677) 。 研究表明， 在动物模型中， 激动 GPR40可有效降低血糖； 临床试验中， 患者 短期和长期使用 GPR40激动剂进行治疗均可促进葡萄糖诱导的胰岛素分泌， 并可提高葡萄 糖耐量 （K Nagasumi等 （2009) . Diabetes, 58， 1067-1076 ) ， 且由于 GPR40只有在高水平 血糖的情况下才可促进胰岛素分泌， 因此产生低血糖的风险低。 (SGLT-2) Inhibitors and other drugs. However, 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 (GPR40) 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. G protein-coupled receptors have 7 transmembrane structures, can sense extracellular signals, activate intracellular signal transduction pathways, and ultimately cause cellular responses. GPR40 can be activated by medium long-chain free fatty acids (FFAs) (Itoh Y et al ( 2003) . Nature, 422, 173-176). In addition to being an energy source, 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. (2009) Diabetes, 58, 1067-1076), and because GPR40 is only at a high level In the case of blood sugar, insulin secretion is promoted, so the risk of hypoglycemia is low.
Fasiglifam hemihydrate (TAK-875 ) 是目前已进入三期临床并被证明有效的 GPR40激动 剂。 研究表明： 在糖尿病动物模型中， fasiglifam hemihydrate (TAK-875 ) 可促进胰岛素分 泌并可有效控制血糖， 而在正常大鼠中则不会促进胰岛素分泌 （Ts yihata Y等 （2010 ) . Diabetes, 59， A165 )； 在临床试验中， fasiglifam hemihydrate (TAK-875 )也表现出明显的 降糖效果， 同时具有较低的低血糖风险 （T. Araki等 （2012 ) . Diabetes, Obesity and Metabolisml4, 271-278 )。 其它一些 GPR40激动剂也相继被开发， 如 JTT-851、 LY-2881835 等。  Fasiglifam hemihydrate (TAK-875) is a GPR40 agonist that has now entered Phase III clinical and proven effective. Studies have shown that fasiglifam hemihydrate (TAK-875) promotes insulin secretion and can effectively control blood glucose in an animal model of diabetes, but does not promote insulin secretion in normal rats (Ts yihata Y et al. (2010). Diabetes, 59 , A165); In clinical trials, fasiglifam hemihydrate (TAK-875) also showed significant hypoglycemic effects with a lower risk of hypoglycemia (T. Araki et al. (2012). Diabetes, Obesity and Metabolisml4, 271- 278). Other GPR40 agonists have also been developed, such as JTT-851, LY-2881835 and so on.
综上所述， GPR40是一个安全可行的口服降糖药新靶点， GPR40激动剂的开发具有十分 重要的研究价值和应用前景。 目前一些关于 GPR40激动剂相关的研究文献相继公开。  In summary, 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.
(1) US7820837描述了可作为胰岛素分泌促进剂及糖尿病的预防和 /或治疗药的 GPR40 受体调节剂， 其中， Ar任选取代基的环状基团， A任选取代基的环状基团， 且不被噻唑、 噁 唑、 咪唑和吡唑所取代， Xa和 Xb各自独立选自键或包含 1-5个原子的链， Xc选自 0、 S、 SO 或 S02， Xd选自键、 CH或 CH2， D选自苯环、 噻吩或噻唑， B选自 5至 7元的环， R1选自羟基 。 不认为此专利中 述是本发明的一部分， 其结构式如下：
Figure imgf000004_0001
(1) US Pat. No. 7,820,837 describes GPR40 receptor modulators which are useful as inhibitors of insulin secretion and a preventive and/or therapeutic agent for diabetes, wherein a cyclic group of an optionally substituted Ar group, a cyclic group of an optionally substituted substituent a group, and not substituted by thiazole, oxazole, imidazole and pyrazole, Xa and Xb are each independently selected from a bond or a chain containing 1-5 atoms, Xc is selected from 0, S, SO or S0 2 , and Xd is selected from The bond, CH or CH 2 , D is selected from the group consisting of a benzene ring, a thiophene or a thiazole, B is selected from the group consisting of 5 to 7 members, and R 1 is selected from the group consisting of hydroxyl groups. It is not considered that this patent is part of the invention and its structural formula is as follows:
Figure imgf000004_0001
(2) CN101616913描述了可作为胰岛素分泌促进剂及糖尿病的预防和 /或治疗药的 GPR40受体功能调节作用的稠环化合物， 其中， R1选自 -S02-R6， R6选自 d_6垸基或任选被取 代的 U-二氧代四氢噻喃基， X选自键或二价烃基； R2和 R3选自 H、 卤原子、 被取代的烃基 或被取代的羟基； R4和 R5选自被羟基取代的 d_6垸基； A选自苯环， B选自 5至 7元环， Y选自 键或 CH2， R选自羟基。 一部分， 其结构式如下： (2) 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, wherein R 1 is selected from -S0 2 -R 6 and R 6 is selected from D 6 fluorenyl or optionally substituted U-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 a 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 a 5- to 7-membered ring, Y is selected from a bond or CH 2 , and R is selected from a hydroxyl group. In part, its structural formula is as follows:
Figure imgf000004_0002
Figure imgf000004_0002
(3) US7786165描述了 GPR40受体功能调节剂， 其中， Ar任选取代基的环状基团， 且 不被 4-哌啶基取代， B任选取代基的环状基团，且不被噻唑或噁唑取代， V选自键或含有 1-3 个原子的链， 且此链不为 -N=N-基团， W选自键或 Cw垸基， X、 Xa选自 CH或 N， Y选自 0或 CR6R7， R1和 Rla选自 H、 卤素、 垸基或 垸氧基， R2选自 H、 垸基或任选取代的酰 基， R3和 R4选自 H或卤素， R5选自取代的羟基或取代的胺基， 不认为 US7786165中具体描述 的化合物是本发明的一部分， 其结构式如下：
Figure imgf000005_0001
(3) US7786165 describes a GPR40 receptor function modulator, wherein the cyclic group of the optional substituent of Ar is not substituted by 4-piperidinyl, and the cyclic group of B is optionally substituted, and is not Substituted by thiazole or oxazole, V is selected from a bond or a chain containing 1-3 atoms, and this chain is not a -N=N- group, W is selected from a bond or a C w fluorenyl group, and 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, fluorenyl or decyloxy, and R 2 is selected from H, fluorenyl or optionally substituted acyl, R 3 and R 4 It is selected from H or halogen, and R 5 is selected from a substituted hydroxy group or a substituted amine group. The compound specifically described in US Pat. No. 7,876,165 is not considered to be part of the present invention, and its structural formula is as follows:
Figure imgf000005_0001
发明内容 Summary of the invention
本发明提供了一种通式 (I)所示的化合物或其立体异构体、 水合物、 酯、 溶剂化物、 共 晶体、 代谢产物、 药学上 ：  The present invention provides a compound represented by the formula (I) or a stereoisomer, hydrate, ester, solvate, eutectic, metabolite, or pharmaceutically thereof thereof:
Figure imgf000005_0002
其中-
Figure imgf000005_0002
among them-
R选自 H或者 d.8垸基； R is selected from H or d. 8 fluorenyl;
Rb、 Rbl、 Re和 Rel各自独立选自 H、 F、 Cl、 Br、 I、 羟基、 C1-8垸基或 C1-8垸氧基， 其 中所述垸基或垸氧基各自独立地任选进一步被 0至 4个选自 F、 Cl、 Br、 I、 -CH2F、 -CHF2 、 -CF3、 Ci-8 垸基、 C1-8 垸氧基、 C2-8 烯基、 C2-8 炔基、 -C(=0)-R3、 -C(=0)-0-R3、 -C(=0)-NR3R3\ -S(=0)n-R3, -0-C(=0)-0-R3或者 -NR3R3a的取代基所取代（其中当具有多个 取代基时， 各取代基可相同或不同， 下文中类似的描述具有相同的含义， 不再赘述)； R b , R bl , R e and R el are each independently selected from H, F, Cl, Br, I, hydroxy, C 1-8 fluorenyl or C 1-8 decyloxy, wherein the fluorenyl or hydrazine The groups are each independently optionally further selected from 0 to 4 selected from the group consisting of F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , Ci -8 fluorenyl, C 1-8 decyloxy, C 2-8 alkenyl, C 2-8 alkynyl, -C(=0)-R 3 , -C(=0)-0-R 3 , -C(=0)-NR 3 R 3 \ -S( =0) n -R 3 , -0-C(=0)-0-R 3 or a substituent of -NR 3 R 3a (wherein, when having a plurality of substituents, each substituent may be the same or different, The similar descriptions below have the same meanings and will not be described again);
Ra和 Ral各自独立选自 H、 F、 Cl、 Br、 I、 氰基、 氨基、 硝基、 羟基、 羧基、 d.8烷基 或 d_8垸氧基，其中所述垸基、 垸氧基或氨基各自独立地任选进一步被 0至 4个选自 F、 C1 、 Br、 I、 氰基、 硝基、 羟基、 d.8垸基、 d.8垸氧基、 C2.8烯基、 C2.8炔基、 -C(=0)-R3、 -C(=0)-0-R3、 -C(=0)-NR3R3a、 -S(=0)n-R3、 -0-C(=0)-0-R3或者 -NR3R3a的取代基所取代；R a and R al are each independently selected from H, F, Cl, Br, I, cyano, amino, nitro, hydroxy, carboxy, d. 8 alkyl or d 8 methoxy, wherein the fluorenyl, hydrazine The oxy or amino group is each independently optionally further selected from 0 to 4 selected from the group consisting of F, C1, Br, I, cyano, nitro, hydroxy, d. 8 decyl, d. 8 decyloxy, C 2 . 8 Alkenyl, C 2 .8 alkynyl, -C(=0)-R 3 , -C(=0)-0-R 3 , -C(=0)-NR 3 R 3a , -S(=0) Substituted by a substituent of n -R 3 , -0-C(=0)-0-R 3 or -NR 3 R 3a ;
R1和 R2各自独立选自 H、 F、 Cl、 Br、 I、 氰基、 氨基、 硝基、 羟基、 羧基、 d.8垸基 或 d_8垸氧基，其中所述垸基、 垸氧基或氨基各自独立地任选进一步被 0至 4个选自 F、 C1 、 Br、 I、 氰基、 硝基、 羟基、 d.8垸基、 d.8垸氧基、 C2.8烯基、 C2.8炔基、 -C(=0)-R3、 -C(=0)-0-R3、 -C(=0)-NR3R3a、 -S(=0)n-R3、 -0-C(=0)-0-R3或者 -NR3R3a的取代基所取代；R 1 and R 2 are each independently selected from H, F, Cl, Br, I, cyano, amino, nitro, hydroxy, carboxy, d. 8 fluorenyl or d 8 decyloxy, wherein the fluorenyl, hydrazine The oxy or amino group is each independently optionally further selected from 0 to 4 selected from the group consisting of F, C1, Br, I, cyano, nitro, hydroxy, d. 8 decyl, d. 8 decyloxy, C 2 . 8 Alkenyl, C 2 .8 alkynyl, -C(=0)-R 3 , -C(=0)-0-R 3 , -C(=0)-NR 3 R 3a , -S(=0) Substituted by a substituent of n -R 3 , -0-C(=0)-0-R 3 or -NR 3 R 3a ;
Wi, W2 禾口 W3 各自独立选自单键、 -0-、 - R3-、 -S(=0)n -、 Ci-8 垸基、 -C(=0)-、 -C(=C -C 垸基-、 -O-C^烷基-或 -C^垸基 -0-， 所述垸基各自独立地任选进一步被 0至 4 个选 Θ F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 羟基、 d.8垸基、 d.8垸氧基、 -C2.8烯基、 -C2-8炔基或者 -NR3R3a的取代基所取代； Wi, W 2 and W 3 are each independently selected from a single bond, -0-, -R 3 -, -S(=0) n -, Ci -8 fluorenyl, -C(=0)-, -C( =C -C fluorenyl-, -OC^alkyl- or -C^ fluorenyl--0-, each of which is optionally independently further selected from 0 to 4 F, Cl, Br, I, - CH 2 F, -CHF 2 , -CF 3 , hydroxy, d. 8 fluorenyl, d. 8 decyloxy, -C 2 .8 alkenyl, Substituted with a C 2-8 alkynyl group or a substituent of -NR 3 R 3a ;
环 Q选自 5至 8元碳环或 5至 8元杂环， 所述杂环含有 1至 4个选自 N、 0或 S(=0)n 的杂原子或基团 （其中当具有多个杂原子或基团时， 各杂原子或基团可相同或不同， 下文 中类似的描述具有相同的含义， 不再赘述)； Ring Q is selected from a 5- to 8-membered carbocyclic ring or a 5- to 8-membered heterocyclic ring containing from 1 to 4 heteroatoms or groups selected from N, 0 or S(=0) n (wherein When a hetero atom or a group is present, each hetero atom or group may be the same or different, and similar descriptions have the same meanings hereinafter, and are not described again);
G选自 H、 F、 Cl、 Br、 I、 巯基、 羟基、 硝基、 氰基、 d.8垸基、 d.8垸氧基、 C2.8烯基G is selected from the group consisting of H, F, Cl, Br, I, fluorenyl, hydroxy, nitro, cyano, d. 8 fluorenyl, d. 8 decyloxy, C 2 . 8 alkenyl
、 C2-8炔基、 -C(=0)-R3、 -C(=0)-OR3、 -C(=0)-NR3R3 a、 -NR3R3 a、 -S(=0)n-R3、 -0-C(=0)-C1-8垸基、 -0-C(=0)-0-C1-8垸基、 -0-C(=0)-NR3R3a、 3至 10元碳环基、 3至 10 元杂环基、 -C(=0)-R4或 -0-R4，所述杂环基含 1至 4个选自 N、 0或 S(=0)n杂原子或基团， 所述巯基、 羟基、 垸基、 垸氧基、 烯基、 炔基、 碳环基或杂环基任选进一步被 0至 4个选 g F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 巯基、 羟基、 硝基、 氰基、 C1-8垸基、 C2-8烯基、 C2-8炔基、 -OR3 , -C(=0)-R3、 -C(=0)-OR3、 -C(=0)-NR3R3a、 -NR3R3a、 -S(=0)n-R3、 -0-C(=0)-Ci-8垸基、 -0-C(=0)-0-Ci-8垸基、 -0-C(=0)-NR3R3a、 -C1-8垸基 -S(=0)n-R3、 -O-C 垸基 -S(=0)N-R3、 3至 10元碳环基、 3至 10元杂环基、 或 -0-R4的取代基所取代； R3和 R3a各自独立选自 H、 羟基、 d_8垸基或 d_8垸氧基， 其中所述垸基或烷氧基各自 独立地任选进一步被 0至 4个选自 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 氰基、 硝基、 羟 基、 Cl—8院基、 Cl-8院氧基、 C2-8烯基、 C2-8块基、 -C(=0)-Cl-8院基、 -C(=0)-0- Cl—8院基、, C 2-8 alkynyl, -C(=0)-R 3 , -C(=0)-OR 3 , -C(=0)-NR 3 R 3 a , -NR 3 R 3 a , -S (=0) n -R 3 , -0-C(=0)-C 1-8垸 base, -0-C(=0)-0-C 1-8垸 base, -0-C(=0 -NR 3 R 3a , a 3 to 10 membered carbocyclic group, a 3 to 10 membered heterocyclic group, -C(=0)-R 4 or -0-R 4 , said heterocyclic group having 1 to 4 From N, 0 or S(=0) n heteroatoms or groups, the fluorenyl, hydroxy, decyl, decyloxy, alkenyl, alkynyl, carbocyclic or heterocyclic group is optionally further from 0 to 4 Selected as g F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , fluorenyl, hydroxy, nitro, cyano, C 1-8 fluorenyl, C 2-8 alkenyl, C 2 -8 alkynyl, -OR 3 , -C(=0)-R 3 , -C(=0)-OR 3 , -C(=0)-NR 3 R 3a , -NR 3 R 3a , -S( =0) n -R 3 , -0-C(=0)-Ci -8垸, -0-C(=0)-0-Ci -8垸, -0-C(=0)-NR 3 R 3a , -C 1-8 fluorenyl-S(=0) n -R 3 , -OC thiol-S(=0) N -R 3 , 3 to 10 membered carbocyclic group, 3 to 10 membered Substituted by a ring group, or a substituent of -0-R 4 ; each of R 3 and R 3a is independently selected from H, hydroxy, d- 8 fluorenyl or d- 8 methoxy, wherein the fluorenyl or alkoxy are each independently Ground Is further selected from 0 to 4 substituents selected from F, Cl, Br, I, -CH 2 F, -CHF 2, -CF 3, cyano, nitro, hydroxy, Cl-8-yl hospital, Cl-8 alkoxy homes , C 2 -8 alkenyl, C 2 - 8 block, -C(=0)-Cl- 8 , and -C(=0)-0- Cl-8,
-S(=0)n-C1-8垸基或者 -0-C(=0)-0-C 垸基的取代基所取代； -S(=0) n -C 1-8 fluorenyl or a substituent substituted with -0-C(=0)-0-C fluorenyl;
R4选自 3至 10元碳环基或 3至 10元杂环基，所述杂环基含 1至 4个选自 N、 0或 S(=0)n 杂原子或基团， 所述碳环基或杂环基任选进一步被 0至 4个选自 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 巯基、 羟基、 硝基、 氰基、 d.8垸基、 d.8垸氧基、 C2.8烯基、 C2.8炔基、 -C(=0)-R3、 -C(=0)-OR3、 -C(=0)-NR3R3a、 -NR3R3a、 -S(=0)n-R3、 -0-C(=0)-C1-8 垸基、 -0-C(=0)-0-C1-8垸基、 -0-C(=0)-NR3R3A、 -0-C1-8垸基- S(=0)n-R3、 3至 10元碳环基或 3至 10元杂环基的取代基所取代； R 4 is selected from a 3 to 10 membered carbocyclic group or a 3 to 10 membered heterocyclic group having 1 to 4 hetero atoms or groups selected from N, 0 or S(=0) n , said Carbocyclyl or heterocyclyl optionally further selected from 0 to 4 selected from the group consisting of F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , fluorenyl, hydroxy, nitro, cyano, d. 8 fluorenyl, d. 8 decyloxy, C 2 .8 alkenyl, C 2 .8 alkynyl, -C(=0)-R 3 , -C(=0)-OR 3 , -C(=0 )-NR 3 R 3a , -NR 3 R 3a , -S(=0) n -R 3 , -0-C(=0)-C 1-8 fluorenyl, -0-C(=0)-0 -C 1-8 fluorenyl, -0-C(=0)-NR 3 R 3A , -0-C 1-8 fluorenyl-S(=0) n -R 3 , 3 to 10 membered carbocyclic group or Substituted by a substituent of a 3- to 10-membered heterocyclic group;
t为 0或者 1 ;  t is 0 or 1;
k为 0、 1或者 2;  k is 0, 1 or 2;
p为 0、 1、 2或者 3 ;  p is 0, 1, 2 or 3;
q为 0、 1、 2或者 3 ;  q is 0, 1, 2 or 3;
n为 0、 1或者 2。  n is 0, 1, or 2.
本发明优选方案， 包括通式（Π)所示的化合物或其立体异构体、 水合物、 酯、 溶剂化 物、 共晶体、 代谢产物、 药学上可接受的盐或者前药，
Figure imgf000007_0001
Preferred embodiments of the invention include a compound of the formula (A) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof,
Figure imgf000007_0001
(II)  (II)
其中- among them-
R选自 H或者 d.4垸基， 优选 H; R is selected from H or d. 4 fluorenyl, preferably H ;
Rb和 Rbl各自独立选自 H、 F、 羟基、 d.4垸基或 d.4烷氧基， 优选 H或 d.4垸氧基， 其中所述垸基或垸氧基各自独立地任选进一步被 0至 3个选自 F、 -CF3、 d_4垸基或 d_4烷 氧基的取代基所取代； R b and R bl are each independently selected from H, F, hydroxy, d. 4 fluorenyl or d. 4 alkoxy, preferably H or d. 4 decyloxy, wherein the fluorenyl or decyloxy are each independently Optionally further substituted with 0 to 3 substituents selected from F, —CF 3 , d 4 fluorenyl or d 4 alkoxy;
R1和 R2各自独立选自 H、 F、 Cl、 Br、 氰基、 氨基、 硝基、 d.4垸基或 d.4垸氧基， 其 中所述垸基、 垸氧基或氨基各自独立地任选进一步被 0至 3个选自 F、 d_4垸基、 d_4烷氧 基、 -C(=0)-NR3R3a、 -S(=0)n-R3或者 -NR3R3a的取代基所取代； R 1 and R 2 are each independently selected from H, F, Cl, Br, cyano, amino, nitro, d. 4 fluorenyl or d. 4 decyloxy, wherein each of the fluorenyl, decyl or amino groups Optionally optionally further from 0 to 3 selected from the group consisting of F, d_ 4 decyl, d- 4 alkoxy, -C(=0)-NR 3 R 3a , -S(=0) n -R 3 or -NR Substituting 3 substituents of R 3a ;
G 选自 H、 F、 Cl、 Br、 I、 C1-6 垸基、 C1-6 垸氧基、 -C(=0)-NR3R3a、 -S(=0)n-R3、 -0-C(=0)- R3R3\ 3至 8元碳环基或 4至 8元杂环基，优选 3至 8元碳环基，更优选 5至 6 元碳环基， 所述杂环基含 1至 3个选自 N、 0或 S杂原子， 所述垸基、 垸氧基、 碳环基或 杂环基任选进一步被 0至 3个选自 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 羟基、 硝基、 CM 垸基、 -OR3、 -C(=0)-R3、 -C(=0)-OR3、 -C(=0)- R3R3a、 - R3R3a、 -S(=0)n-R3、 G is selected from the group consisting of H, F, Cl, Br, I, C 1-6 fluorenyl, C 1-6 decyloxy, -C(=0)-NR 3 R 3a , -S(=0) n -R 3 , -0-C(=0)-R 3 R 3 \ 3 to 8 membered carbocyclic group or 4 to 8 membered heterocyclic group, preferably 3 to 8 membered carbocyclic group, more preferably 5 to 6 membered carbocyclic group, The heterocyclic group contains 1 to 3 heteroatoms selected from N, 0 or S, and the fluorenyl, decyloxy, carbocyclyl or heterocyclic group is optionally further selected from 0 to 3 selected from F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , hydroxy, nitro, CM thiol, -OR 3 , -C(=0)-R 3 , -C(=0)-OR 3 , -C(=0)- R 3 R 3a , - R 3 R 3a , -S(=0) n -R 3 ,
-0-C(=0)-Ci-4 垸基、 -0-C(=0)-0-C1-4 垸基、 -0-C(=0)-NR3R3a、 -C1-4 垸基 -S(=0)n-R3、 -O-Cw垸基- S(=0)n-R3, 3至 8元碳环基、 4至 8元杂环基或 -O-R4的取代基所取代，优选被 0到 3个选自 CM垸基、 -O-CM垸基- S(=0)N-R3或 -O-R4的取代基所取代； -0-C(=0)-Ci -4 fluorenyl, -0-C(=0)-0-C 1-4 fluorenyl, -0-C(=0)-NR 3 R 3a , -C 1 -4 fluorenyl-S(=0) n -R 3 , -O-Cw fluorenyl-S(=0) n -R 3 , 3 to 8 membered carbocyclic group, 4 to 8 membered heterocyclic group or -OR Substituted by a substituent of 4 , preferably substituted by 0 to 3 substituents selected from CM fluorenyl, -O-CM fluorenyl-S(=0) N- R 3 or -OR 4 ;
R3和 R3a各自独立选自 H、 羟基、 d_4垸基或 d_4垸氧基， 优选 H或 d_4垸基， 更优选 d_2垸基， 其中所述垸基或垸氧基各自独立地任选进一步被 0至 2个选自 F、 Cl、 Br、 C1-4 垸基或 d_4垸氧基的取代基所取代； R 3 and R 3a are each independently selected from H, hydroxy, d 4 fluorenyl or d 4 methoxy, preferably H or d 4 fluorenyl, more preferably d 2 fluorenyl, wherein the fluorenyl or decyloxy are each independently Optionally optionally substituted by 0 to 2 substituents selected from the group consisting of F, Cl, Br, C 1-4 fluorenyl or d 4 methoxy;
R4选自 3至 8元碳环基或 4至 8元杂环基，优选 4至 8元杂环基，所述杂环基含 1至 3 个选自 N、 0、 S、 S(=0)或 S(=0)2杂原子或基团，所述碳环基或杂环基任选进一步被 0至 3 个选自 F、 羟基、 d_4垸基、 d_4垸氧基、 -C(=0)-R3、 -C(=0)-OR3、 -S(=0)n-R3或 -0-C1-4烷 基- S(=0)n-R3的取代基所取代； R 4 is selected from a 3 to 8 membered carbocyclic group or a 4 to 8 membered heterocyclic group, preferably a 4 to 8 membered heterocyclic group, and the heterocyclic group has 1 to 3 selected from N, 0, S, S (= 0) or S(=0) 2 heteroatoms or groups, optionally further 0 to 3 selected from the group consisting of F, hydroxy, d 4 fluorenyl, d 4 methoxy, C(=0)-R 3 , -C(=0)-OR 3 , -S(=0) n -R 3 or -0-C 1-4 alkyl-S(=0) n -R 3 Substituted by a substituent;
p为 0、 1、 2或者 3 ;  p is 0, 1, 2 or 3;
q为 0、 1、 2或者 3 ;  q is 0, 1, 2 or 3;
n为 0、 1或者 2。 本发明优选方案， 包括通式 (Π)所示的化合物或其立体异构体、 水合物、 酯、 溶剂化物 、 共晶体、 代谢产物、 药学上可接受的盐或者前药， 其中： n is 0, 1, or 2. Preferred embodiments of the invention include a compound of the formula (A) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein:
R选自 H或者 d.2垸基， 优选 H; R is selected from H or d. 2 fluorenyl, preferably H;
Rb选自 H或 d_4垸基， 优选 H或 d_2垸基， 更优选 H, 其中所述垸基进一步被 0至 2 个选自 F、 -CF3或 d.2垸基所取代； R b is selected from H or d 4 fluorenyl, preferably H or d 2 fluorenyl, more preferably H, wherein the fluorenyl group is further substituted by 0 to 2 selected from F, -CF 3 or d. 2 fluorenyl;
Rbl选自 H、 F或 CM垸基， 优选 H、 F或 垸基， 更优选 H或 垸基， 其中所述 垸基进一步被 0至 2个选自 F、 -CF3或 d_2垸基所取代； R bl is selected from H, F or CM fluorenyl groups, preferably H, F or fluorenyl, more preferably H or fluorenyl, wherein the fluorenyl group is further 0 to 2 selected from F, -CF 3 or d 2 fluorenyl Replaced
R1和 R2各自独立选自 H、 F、 Cl、 Br、 -CH2F、 -CHF2、 -CF3、 C1-4垸基或 C1-4垸氧基， 优选 H、 F、 Cl、 Br、 -CH2F、 -CHF2、 -CF3或 C1-2垸基； R 1 and R 2 are each independently selected from H, F, Cl, Br, -CH 2 F, -CHF 2 , -CF 3 , C 1-4 fluorenyl or C 1-4 decyloxy, preferably H, F, Cl, Br, -CH 2 F, -CHF 2 , -CF 3 or C 1-2 fluorenyl;
G选自 H、 F、 Cl、 Br、 I、 CM垸基、 CM垸氧基、 3至 6元碳环基或 4至 6元杂环基， 优选 H、 F、 Cl、 Br、 烷基或 5至 6元碳环基， 更优选 H、 F、 Cl、 Br、 垸基或 6元 碳环基， 进一步优选 F、 d_2烷基或 6元碳环基， 进一步优选 6元碳环基， 所述杂环基含 1 至 2个选自 N、 0或 S杂原子； 所述垸基、 垸氧基、 碳环基或杂环基各自独立地任选进一 步被 0至 3个选自 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 C1-3垸基、 C1-3垸氧基、 -0-C1-3烷 基 -O- Cw垸基、 -Cw垸基 -S(=0)n-R3、 -O-Cw垸基 - S(=0)n-R3或 -O-R4的取代基所取代， 优 选被 0至 3个选自 F、 Cl、 Br、 垸基、 垸氧基、 -O-Cw垸基 -O- Cw垸基、 -0-C1-3烷 基 -S(=0)n-R3或 -O-R4的取代基所取代，更优选被 0至 3个选自 F、 C1-3垸基、 -O-Cw垸基 -O- Ci-3烷基、 -O-Cw烷基 -S(=0)n-R3或 -O-R4的取代基所取代，进一步优选被 0至 3个选自 垸基、 -O-Cw垸基 -S(=0)n-R3或 -O-R4的取代基所取代； G is selected from H, F, Cl, Br, I, CM thiol, CM methoxy, 3 to 6 membered carbocyclic or 4 to 6 membered heterocyclic, preferably H, F, Cl, Br, alkyl or a 5- to 6-membered carbocyclic group, more preferably H, F, Cl, Br, fluorenyl or 6-membered carbocyclic group, further preferably F, d 2 alkyl or 6-membered carbocyclic group, further preferably 6-membered carbocyclic group, The heterocyclic group contains 1 to 2 heteroatoms selected from N, 0 or S; the fluorenyl, decyloxy, carbocyclyl or heterocyclic group are each independently optionally further 0 to 3 selected from F , Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , C 1-3 fluorenyl, C 1-3 decyloxy, -0-C 1-3 alkyl-O-Cw fluorenyl Substituted with a substituent of -Cw fluorenyl-S(=0) n -R 3 , -O-Cw fluorenyl-S(=0) n -R 3 or -OR 4 , preferably 0 to 3 F, Cl, Br, fluorenyl, decyloxy, -O-Cw fluorenyl-O-Cw fluorenyl, -0-C 1-3 alkyl-S(=0) n -R 3 or -OR 4 substituents, more preferably substituted with 0 to 3 substituents selected from F, C 1-3 alkyl with, -O-Cw alkyl with -O- Ci -3 alkyl, -O-Cw alkyl group -S (= 0) Substituted by a substituent of n -R 3 or -OR 4 , further preferably from 0 to 3 selected from fluorenyl, -O-Cw fluorenyl-S(=0) n -R Substituted by a substituent of 3 or -OR 4 ;
R3选自 H或 C1-3垸基， 优选 C1-3垸基； R 3 is selected from H or C 1-3 fluorenyl, preferably C 1-3 fluorenyl;
R4选自 3至 6元碳环基或 5至 8元杂环基，优选 5至 8元杂环基，更优选 5元杂环基， 所述杂环基含 1至 2个选自 N、 0、 S、 S(=0)或 S(=0)2杂原子或基团， 优选含 1至 2个 0 杂原子，更优选含 1个 0杂原子，所述的杂环基任选进一步被 0至 3个选自羟基、 d_3垸基 、 d_3垸氧基的取代基所取代， 优选被 0至 3个 d_2垸氧基所取代； R 4 is selected from a 3- to 6-membered carbocyclic group or a 5- to 8-membered heterocyclic group, preferably a 5- to 8-membered heterocyclic group, more preferably a 5-membered heterocyclic group, and the heterocyclic group has 1 to 2 selected from N , 0, S, S(=0) or S(=0) 2 heteroatoms or groups, preferably having 1 to 2 0 heteroatoms, more preferably 1 heteroatom, said heterocyclic optionally Further substituted by 0 to 3 substituents selected from the group consisting of a hydroxyl group, a d- 3 fluorenyl group, and a d- 3 methoxy group, preferably substituted with 0 to 3 d 2 methoxy groups;
p为 0、 1、 2或者 3， 优选 0;  p is 0, 1, 2 or 3, preferably 0;
q为 0、 1、 2或者 3， 优选 0;  q is 0, 1, 2 or 3, preferably 0;
n为 0、 1或者 2， 更优选 2。  n is 0, 1 or 2, more preferably 2.
本发明优选方案， 包括通式 (Π)所示的化合物或其立体异构体、 水合物、 酯、 溶剂化物 、 共晶体、 代谢产物、 药学上可接受的盐或者前药， 其中：  Preferred embodiments of the invention include a compound of the formula (A) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein:
R为 H;  R is H;
Rb为 H; R b is H;
Rbl选自！！或。^垸基， 优选！！或。^垸基； R1和 R2各自独立选自 H或 F; R bl is selected from! ! or. ^垸基,优选! ! or. ^垸基; R 1 and R 2 are each independently selected from H or F ;
G选自 H、 F、 Cl、 Br、 C1-3垸基或 5至 6元碳环基， 优选 H、 F、 Cl、 Br、 C1-2垸基或 6元碳环基， 更优选 F、 d_2垸基或 6元碳环基， 进一步优选 6元碳环基； 所述垸基或碳环 基各自独立地任选进一步被 0至 3个选自 F、 Cl、 Br、 烷基、 垸氧基、 -O-Cw垸基 -O- C1-3垸基、 -O-Cw垸基 -S(=0)n-R3或 -O-R4的取代基所取代，优选进一步被 0至 3个选自 F、 C1-3垸基、 -O-Cw垸基 -0- C1-3垸基、 -O-Cw垸基 -S(=0)n-R3或 -O-R4的取代基所取代， 更优选进一步被 0至 3个选自 垸基、 -O-Cw垸基 -S(=0)n-R3或 -O-R4的取代基所取代；G is selected from H, F, Cl, Br, C 1-3 fluorenyl or a 5- to 6-membered carbocyclic group, preferably H, F, Cl, Br, C 1-2 fluorenyl or 6-membered carbocyclic group, more preferably F, d 2 fluorenyl or 6-membered carbocyclic group, further preferably 6-membered carbocyclic group; each of the fluorenyl or carbocyclic groups is independently independently optionally 0 to 3 selected from F, Cl, Br, alkyl Substituted with a substituent of an methoxy group, -O-Cw fluorenyl-O-C 1-3 fluorenyl group, -O-Cw fluorenyl-S(=0) n -R 3 or -OR 4 , preferably further 0 to 3 selected from F, C 1-3 fluorenyl, -O-Cw fluorenyl-0-C 1-3 fluorenyl, -O-Cw fluorenyl-S(=0) n -R 3 or -OR 4 substituents, further more preferably from 0 to 3 groups selected from the embankment, -O-Cw alkyl with -S (= 0) n -R 3 or -OR 4, substituted with a substituent;
R3选自！！或^^垸基， 优选 d.3垸基； R 3 is selected from! ! Or ^^垸基, preferably d. 3垸;
R4选自 5至 8元杂环基，优选 5元杂环基，所述杂环基含 1至 2个选自 N、 0、 S、 S(=0) 或 S(=0)2杂原子或基团， 优选含 1至 2个 0杂原子， 更优选含 1个 0杂原子， 所述的杂环 基任选进一步被 0至 3个 d_2垸氧基所取代， 优选被 0至 2个羟基所取代； R 4 is selected from a 5- to 8-membered heterocyclic group, preferably a 5-membered heterocyclic group, and the heterocyclic group has 1 to 2 selected from N, 0, S, S (=0) or S (=0) 2 The atom or group preferably has 1 to 2 0 hetero atoms, more preferably 1 0 hetero atom, and the heterocyclic group is optionally further substituted by 0 to 3 d 2 methoxy groups, preferably 0 to Substituted by two hydroxyl groups;
p为 0、 1、 2或者 3 ;  p is 0, 1, 2 or 3;
q为 0、 1、 2或者 3 ;  q is 0, 1, 2 or 3;
n为 0、 1或者 2， 优选 2。  n is 0, 1 or 2, preferably 2.
本发明优选方案， 包括通式 (Π)所示的化合物或其立体异构体、 水合物、 酯、 溶剂化物 Preferred embodiments of the invention include compounds represented by the formula (Π) or stereoisomers, hydrates, esters, solvates thereof
、 共晶体、 代谢产物、 药学上可接受的盐或者前药， 其中： a eutectic, a metabolite, a pharmaceutically acceptable salt or a prodrug, wherein:
R为 H;  R is H;
Rb为 H; R b is H;
Rbl选自 H或甲基， 优选 H; R bl is selected from H or methyl, preferably H ;
R1和 R2各自独立选自 H或 F; R 1 and R 2 are each independently selected from H or F;
更优选 , 优选
Figure imgf000009_0001
More preferably, preferably
Figure imgf000009_0001
p为 0、 1、 2或者 3 ;  p is 0, 1, 2 or 3;
q为 0、 1、 2或者 3。  q is 0, 1, 2 or 3.
本发明优选方案，提供了一种通式 （ΠΙ)所示的化合物或者其立体异构体、 水合物、 酉 I 、 溶剂化物、 共晶体、 代谢产物、 药学上可接受的盐或前药：
Figure imgf000010_0001
According to a preferred embodiment of the present invention, there is provided a compound of the formula (ΠΙ) or a stereoisomer, hydrate, oxime I, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof:
Figure imgf000010_0001
Rb选自 H; R b is selected from H ;
Rbl选自！！或。^垸基， 优选！！或。^垸基； R bl is selected from! ! or. ^垸基,优选! ! or. ^垸基;
R8选自 -Cw垸基 -O-Cw垸基、 -Cw垸基 -S(=0)n-R3或 5至 8元杂环基， 优选 -Cw垸基 -S(=0)n-R3或 5至 8元杂环基， 更优选 -d_3垸基 -S(=0)n-R3或 5元杂环基， 所述杂环基含 1 至 2个选自 N、 0、 S、 S(=0)或 S(=0)2杂原子或基团， 优选含 1至 2个 0杂原子， 更优选 含 1个 0杂原子， 所述的杂环基任选进一步被 0至 2个 d_2垸氧基所取代； R 8 is selected from -Cw fluorenyl-O-Cw fluorenyl, -Cw decyl-S(=0) n -R 3 or a 5- to 8-membered heterocyclic group, preferably -Cw fluorenyl-S(=0) n a -R 3 or 5 to 8 membered heterocyclic group, more preferably a -d- 3 mercapto-S(=0) n -R 3 or 5 membered heterocyclic group, the heterocyclic group having 1 to 2 selected from N, 0, S, S (=0) or S (=0) 2 heteroatoms or groups, preferably having 1 to 2 0 heteroatoms, more preferably 1 heteroatom, said heterocyclic group optionally further Substituted by 0 to 2 d 2 alkyloxy groups;
R3选自！！或^^垸基， 优选 d.3垸基； R 3 is selected from! ! Or ^^垸基, preferably d. 3垸;
n为 0、 1或者 2， 优选 2。  n is 0, 1 or 2, preferably 2.
本发明优选方案， 一种通式 (ΙΠ) 所示的化合物或者其立体异构体、 水合物、 酯、 溶剂 化物、 共晶体、 代谢产物、 药学上可接受的盐或前药：  A preferred embodiment of the invention, a compound of the formula (ΙΠ) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof:
Rb选自 H; R b is selected from H;
Rbl选自 H或甲基， 优选 H; R bl is selected from H or methyl, preferably H ;
Figure imgf000010_0002
本发明优选方案， 通式 （I) 所示的化合物或其立体异构体、 水合物、 酯、 溶剂化物、 共晶体、 代谢产物、 药 上可接受的盐或前药:
Figure imgf000010_0002
Preferred embodiments of the invention, the compound of the formula (I) or a stereoisomer, hydrate, ester or solvate thereof, Co-crystals, metabolites, pharmaceutically acceptable salts or prodrugs:
Figure imgf000011_0001
Figure imgf000011_0001
(I)  (I)
其中- R选自 H或者 d.8垸基； Wherein - R is selected from H or d. 8 fluorenyl;
Rb、 Rbl、 Re和 Rel各自独立选自 H、 F、 Cl、 Br、 I、 羟基、 C1-8垸基或 C1-8垸氧基， 其 中所述垸基或垸氧基各自独立地任选进一步被 0至 4个选自 F、 Cl、 Br、 I、 -CH2F、 -CHF2 、 -CF3、 Ci-8 垸基、 C1-8 垸氧基、 C2-8 烯基、 C2-8 炔基、 -C(=0)-R3、 -C(=0)-0-R3、 -C(=0)-NR3R3a、 -S(=0)n-R3、 -0-C(=0)-0-R3或者 -NR3R3a的取代基所取代； R b , R bl , R e and R el are each independently selected from H, F, Cl, Br, I, hydroxy, C 1-8 fluorenyl or C 1-8 decyloxy, wherein the fluorenyl or hydrazine The groups are each independently optionally further selected from 0 to 4 selected from the group consisting of F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , Ci -8 fluorenyl, C 1-8 decyloxy, C 2-8 alkenyl, C 2-8 alkynyl, -C(=0)-R 3 , -C(=0)-0-R 3 , -C(=0)-NR 3 R 3a , -S( =0) substituted with n -R 3 , -0-C(=0)-0-R 3 or a substituent of -NR 3 R 3a ;
Ra和 Ral各自独立选自 H、 F、 Cl、 Br、 I、 氰基、 氨基、 硝基、 羟基、 羧基、 d.8烷基 或 d_8垸氧基，其中所述垸基、 垸氧基或氨基各自独立地任选进一步被 0至 4个选自 F、 C1 、 Br、 I、 氰基、 硝基、 羟基、 d.8垸基、 d.8垸氧基、 C2.8烯基、 C2.8炔基、 -C(=0)-R3、 -C(=0)-0-R3、 -C(=0)-NR3R3a、 -S(=0)n-R3、 -0-C(=0)-0-R3或者 -NR3R3a的取代基所取代； R1和 R2各自独立选自 H、 F、 Cl、 Br、 I、 氰基、 氨基、 硝基、 羟基、 羧基、 烷基 或 d_8垸氧基，其中所述垸基、 垸氧基或氨基各自独立地任选进一步被 0至 4个选自 F、 C1 、 Br、 I、 氰基、 硝基、 羟基、 d.8垸基、 d.8垸氧基、 C2.8烯基、 C2.8炔基、 -C(=0)-R3、 -C(=0)-0-R3、 -C(=0)-NR3R3a、 -S(=0)n-R3、 -0-C(=0)-0-R3或者 -NR3R3a的取代基所取代； Wi, W2 禾口 W3 各自独立选自单键、 -0-、 - R3-、 -S(=0)n -、 Ci-8 垸基、 -C(=0)-、 -C(=0)-C1-8垸基-、 -0-C1-8垸基-或 -d_8垸基 -0-，所述垸基或垸基各自独立地任选进一步被 0 至 4个选自 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 羟基、 C1-8垸基、 C1-8垸氧基、 -C2-8烯基 、 -C2_8炔基或者 -NR3R3a的取代基所取代； R a and R al are each independently selected from H, F, Cl, Br, I, cyano, amino, nitro, hydroxy, carboxy, d. 8 alkyl or d 8 methoxy, wherein the fluorenyl, hydrazine The oxy or amino group is each independently optionally further selected from 0 to 4 selected from the group consisting of F, C1, Br, I, cyano, nitro, hydroxy, d. 8 decyl, d. 8 decyloxy, C 2 . 8 Alkenyl, C 2 .8 alkynyl, -C(=0)-R 3 , -C(=0)-0-R 3 , -C(=0)-NR 3 R 3a , -S(=0) Substituted by a substituent of n -R 3 , -0-C(=0)-0-R 3 or -NR 3 R 3a ; R 1 and R 2 are each independently selected from H, F, Cl, Br, I, cyanide a base, an amino group, a nitro group, a hydroxyl group, a carboxyl group, an alkyl group or a d- 8 methoxy group, wherein the fluorenyl group, the decyloxy group or the amino group are each independently optionally further from 0 to 4 selected from the group consisting of F, C1, Br, I, cyano, nitro, hydroxy, d. 8 decyl, d. 8 decyloxy, C 2 .8 alkenyl, C 2 .8 alkynyl, -C(=0)-R 3 , -C( =0)-0-R 3 , -C(=0)-NR 3 R 3a , -S(=0) n -R 3 , -0-C(=0)-0-R 3 or -NR 3 R Substituted by a substituent of 3a ; Wi, W 2 and W 3 are each independently selected from a single bond, -0-, -R 3 -, -S(=0) n -, Ci -8 thiol, -C(=0)-, -C(=0)-C 1-8 fluorenyl-, -0-C 1-8 fluorenyl- or -d_ 8 mercapto--0-, The thiol or fluorenyl group is each independently optionally further selected from 0 to 4 selected from the group consisting of F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , hydroxy, C 1-8 fluorenyl, C Substituted with a substituent of 1-8 methoxy, -C 2-8 alkenyl, -C 2 -8 alkynyl or -NR 3 R 3a ;
环 Q选自 5至 8元碳环或 5至 8元杂环， 所述杂环含有 1至 4个选自 N、 0或 S(=0)n 的杂原子或基团； Ring Q is selected from a 5- to 8-membered carbocyclic ring or a 5- to 8-membered heterocyclic ring containing from 1 to 4 heteroatoms or groups selected from N, 0 or S(=0) n ;
G选自 H、 F、 Cl、 Br、 I、 巯基、 羟基、 硝基、 氰基、 d.8垸基、 d.8垸氧基、 C2.8烯基 、 C2-8 炔基、 -C(=0)-R3、 -C(=0)-OR3、 -C(=0)-NR3R3a、 -NR3R3a、 -S(=0)n-R3、G is selected from the group consisting of H, F, Cl, Br, I, fluorenyl, hydroxy, nitro, cyano, d. 8 fluorenyl, d. 8 decyloxy, C 2 .8 alkenyl, C 2-8 alkynyl, -C(=0)-R 3 , -C(=0)-OR 3 , -C(=0)-NR 3 R 3a , -NR 3 R 3a , -S(=0) n -R 3 ,
-0-C(=0)-C1-8垸基、 -0-C(=0)-0-C1-8垸基、 -0-C(=0)-NR3R3a、 3至 10元碳环基、 3至 10 元杂环基、 -C(=0 R4或 -0-R4，所述杂环基含 1至 4个选自 N、 0或 S(=0)n杂原子或基团， 所述巯基、 羟基、 垸基、 垸氧基、 烯基、 炔基、 碳环基或杂环基任选进一步被 0至 4个选 g F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 巯基、 羟基、 硝基、 氰基、 垸基、 C2-8烯基、 C2-8 炔基、 -OR3、 -C(=0)-R3、 -C(=0)-OR3、 -C(=0)-NR3R3a、 -NR3R3a、 -S(=0)n-R3、-0-C(=0)-C 1-8 fluorenyl, -0-C(=0)-0-C 1-8 fluorenyl, -0-C(=0)-NR 3 R 3a , 3 to a 10-membered carbocyclic group, a 3 to 10 membered heterocyclic group, -C(=0 R 4 or -0-R 4 , the heterocyclic group having 1 to 4 selected from N, 0 or S(=0) n a hetero atom or a group, the fluorenyl, hydroxy, decyl, decyloxy, alkenyl, alkynyl, carbocyclic or heterocyclic group optionally further selected from 0 to 4 g F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , fluorenyl, hydroxy, nitro, cyano, fluorenyl, C 2-8 alkenyl, C 2-8 alkynyl, - OR 3 , -C(=0)-R 3 , -C(=0)-OR 3 , -C(=0)-NR 3 R 3a , -NR 3 R 3a , -S(=0) n -R 3 ,
-0-C(=0)-Ci-8 垸基、 -0-C(=0)-0-C1-8 垸基、 -0-C(=0)-NR3R3a、 -C1-8 垸基 -S(=0)n-R3、 -O-C 垸基 -S(=0)N-R3、 3至 10元碳环基、 3至 10元杂环基、 或 -0-R4的取代基所取代； R3和 R3a各自独立选自 H、 羟基、 d_8垸基或 d_8垸氧基， 其中所述垸基或烷氧基各自 独立地任选进一步被 0至 4个选自 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 氰基、 硝基、 羟 基、 Cl—8院基、 Cl-8院氧基、 C2-8烯基、 C2-8块基、 -C(=0)-Cl-8院基、 -C(=0)-0- Cl—8院基、-0-C(=0)-Ci -8垸, -0-C(=0)-0-C 1-8垸, -0-C(=0)-NR 3 R 3a , -C 1 -8 fluorenyl-S(=0) n -R 3 , -OC thiol-S(=0) N -R 3 , 3 to 10 membered carbocyclic group, 3 to 10 membered heterocyclic group, or -0- Substituents of R 4 are substituted; R 3 and R 3a are each independently selected from H, hydroxy, d- 8 fluorenyl or d 8 decyloxy, wherein the fluorenyl or alkoxy are each independently optionally further 0 to 4 selected from the group consisting of F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , cyano, nitro, hydroxy, Cl-8, cl-8, oxy, C 2 - 8 Alkenyl, C 2-8 block, -C(=0)-Cl- 8 , and -C(=0)-0- Cl-8,
-s(=o)n-c1-8垸基或者 -o-q=o)-o-c^垸基的取代基所取代； -s(=o) n -c 1-8 fluorenyl or -oq=o) substituted with a substituent of the -oc^ group;
R4选自 3至 10元碳环基或 3至 10元杂环基，所述杂环基含 1至 4个选自 N、 0或 S(=0)n 杂原子或基团， 所述碳环基或杂环基任选进一步被 0至 4个选自 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 巯基、 羟基、 硝基、 氰基、 d.8垸基、 d.8垸氧基、 C2.8烯基、 C2.8炔基、 -C(=0)-R3、 -C(=0)-OR3、 -C(=0)-NR3R3a、 -NR3R3a、 -S(=0)n-R3、 -0-C(=0)-C1-8 垸基、 -0-C(=0)-0-C1-8垸基、 -0-C(=0)-NR3R3A、 -0-C1-8垸基- S(=0)n-R3、 3至 10元碳环基或 3至 10元杂环基的取代基所取代； R 4 is selected from a 3 to 10 membered carbocyclic group or a 3 to 10 membered heterocyclic group having 1 to 4 hetero atoms or groups selected from N, 0 or S(=0) n , said Carbocyclyl or heterocyclyl optionally further selected from 0 to 4 selected from the group consisting of F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , fluorenyl, hydroxy, nitro, cyano, d. 8 fluorenyl, d. 8 decyloxy, C 2 .8 alkenyl, C 2 .8 alkynyl, -C(=0)-R 3 , -C(=0)-OR 3 , -C(=0 )-NR 3 R 3a , -NR 3 R 3a , -S(=0) n -R 3 , -0-C(=0)-C 1-8 fluorenyl, -0-C(=0)-0 -C 1-8 fluorenyl, -0-C(=0)-NR 3 R 3A , -0-C 1-8 fluorenyl-S(=0) n -R 3 , 3 to 10 membered carbocyclic group or Substituted by a substituent of a 3- to 10-membered heterocyclic group;
t为 0或者 1 ;  t is 0 or 1;
k为 0、 1或者 2; k is 0, 1 or 2 ;
p为 0、 1、 2或者 3 ;  p is 0, 1, 2 or 3;
q为 0、 1、 2或者 3 ;  q is 0, 1, 2 or 3;
n为 0、 1或者 2。 本发明优选方案， 提供了一种通式 （Π) 所述的化合物或其立体异构体、 水合物、 酉 溶剂化物、 共晶体、 代谢产  n is 0, 1, or 2. According to a preferred embodiment of the present invention, there is provided a compound of the formula (Π) or a stereoisomer, hydrate, oxime solvate, eutectic or metabolite thereof.
Figure imgf000012_0001
Figure imgf000012_0001
(Π)  (Π)
其中- R选自 H或者 d.4垸基， 优选 H; Wherein - R is selected from H or d. 4 fluorenyl, preferably H;
Rb和 Rbl各自独立选自 H或 CM垸基， 优选 H或甲基； R b and R bl are each independently selected from H or CM thiol, preferably H or methyl;
R1和 R2各自独立选自 H、 F、 Cl、 C1-4垸基或 C1-4垸氧基； R 1 and R 2 are each independently selected from H, F, Cl, C 1-4 fluorenyl or C 1-4 fluorenyloxy;
G选自 3至 8元碳环基， 所述碳环基任选进一步被 0至 3个选自 d_4垸基、 -0-Cw烷 基 -S(=C N-R3或 -O-R4的取代基所取代； G is selected from a 3 to 8 membered carbocyclic group, and the carbocyclic group is optionally further 0 to 3 selected from the group consisting of d- 4 fluorenyl, -0-C w alkane Substituted by a substituent of the group -S (=C N -R 3 or -OR 4 ;
R3选自 H或 CM垸基， 优选 CM垸基， 更优选甲基； R 3 is selected from H or CM thiol, preferably CM thiol, more preferably methyl;
R4选自 4至 8元杂环基， 优选 5至 8元杂环基， 所述杂环基含 1至 3个选自 N、 0、 S 、 S(=0)或 S(=0)2杂原子或基团，所述杂环基任选进一步被 0至 3个选自 d_4垸氧基的取代 基所取代； R 4 is selected from a 4- to 8-membered heterocyclic group, preferably a 5- to 8-membered heterocyclic group, and the heterocyclic group has 1 to 3 selected from N, 0, S, S (=0) or S (=0). a hetero atom or a group, which is optionally further substituted with 0 to 3 substituents selected from the group consisting of d- 4 methoxy groups;
p为 0、 1、 2或者 3 ;  p is 0, 1, 2 or 3;
q为 0、 1、 2或者 3 ;  q is 0, 1, 2 or 3;
n为 0、 1或者 2。 本发明优选方案， 通式 （Π) 所述的化合物所述的化合物或其立体异构体、 水合物、 酯 、 溶剂化物、 共晶体、 代谢产物、 药学上可接受的盐或者前药， 其中：  n is 0, 1, or 2. A preferred embodiment of the invention, a compound of the formula (Π), or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein :
R选自 H或者 垸基， 优选 H;  R is selected from H or a mercapto group, preferably H;
RB选自 H; R B is selected from H;
RBL选自 H或 垸基， 优选 H或甲基； R BL is selected from H or a thiol group, preferably H or methyl;
R1和 R2各自独立选自 H、 F、 Cl、 CM垸基或 Cw垸氧基； R 1 and R 2 are each independently selected from H, F, Cl, CM thiol or C w decyloxy;
G选自 6元碳环基，所述碳环基进一步被 0至 3个选自 d.2垸基、 -O-Cw垸基 -S(=0)N-R3 或 -O-R4的取代基所取代； G is selected from a 6-membered carbocyclic group further substituted by 0 to 3 substituents selected from the group consisting of d. 2 fluorenyl, -O-Cw fluorenyl-S(=0) N- R 3 or -OR 4 Substituted by
R3选自 H或 d_2烷基， 优选甲基； R 3 is selected from H or d 2 alkyl, preferably methyl;
R4选自 5至 8元杂环基， 所述杂环基含 1至 2个选自 N、 0、 S、 S(=0)或 S(=0)2杂原 子或基团， 所述的杂环基任选进一步被 0至 3个选自 d_2垸氧基的取代基所取代； R 4 is selected from a 5- to 8-membered heterocyclic group containing 1 to 2 heteroatoms or groups selected from N, 0, S, S (=0) or S (=0) 2 , The heterocyclic group is optionally further substituted with 0 to 3 substituents selected from the group consisting of d 2 methoxy groups;
p为 0、 1、 2或者 3 ;  p is 0, 1, 2 or 3;
q为 0、 1、 2或者 3 ;  q is 0, 1, 2 or 3;
n为 0、 1或者 2。  n is 0, 1, or 2.
本发明优选方案， 通式 （Π) 所述的化合物所述的化合物或其立体异构体、 水合物、 酯 According to a preferred embodiment of the present invention, the compound of the formula (Π) or a stereoisomer, hydrate or ester thereof
、 溶剂化物、 共晶体、 代谢产物、 药学上可接受的盐或者前药， 其中- R1和 R2各自独立选自 H; a solvate, a eutectic, a metabolite, a pharmaceutically acceptable salt or a prodrug, wherein -R 1 and R 2 are each independently selected from H;
R选自 H或者 d.2垸基； R is selected from H or d. 2 fluorenyl;
RB选自 H; R B is selected from H;
RBL选自 ffi¾d.2垸基； R BL is selected from alkyl with ffi¾d 2.;
G选自 6元碳环基， 所述碳环基进一步被 0至 3个选自 d_2垸基、 -0-d_3垸基 -S(=0)N-R3或 -O-R4的取代基所取代； G is selected from a 6-membered carbocyclic group, which is further substituted by 0 to 3 selected from d 2 fluorenyl, -0-d 3 fluorenyl-S(=0) N -R 3 or -OR 4 Substituted by
R3选自 H或 垸基； R4选自 5至 8元杂环基， 所述杂环基含 1至 2个选自 N、 0、 S、 S(=0)或 S(=0)2杂原子或基 团， 所述的杂环基任选进一步被 0至 3个选自 d_2院氧基的取代基所取代； R 3 is selected from H or a thiol group; R 4 is selected from a 5- to 8-membered heterocyclic group containing 1 to 2 heteroatoms or groups selected from N, 0, S, S (=0) or S (=0) 2 , The heterocyclic group is optionally further substituted with 0 to 3 substituents selected from the group consisting of d- 2 ;
p为 0;  p is 0;
q为 0;  q is 0;
n为 0、 1或者 2。 本发明优选方案，提供了一种通式 （ΠΙ)所述的化合物或其立体异构体、 水合物、 酉 溶剂化物、 共晶体、 代谢产  n is 0, 1, or 2. According to a preferred embodiment of the present invention, there is provided a compound of the formula (ΠΙ) or a stereoisomer, hydrate, oxime solvate, co-crystal, or metabolite thereof.
Figure imgf000014_0001
Figure imgf000014_0001
(in)  (in)
其中  among them
Rb选自 H; R b is selected from H;
Rbl选自 H或 垸基， 优选 H或甲基； R bl is selected from H or a thiol group, preferably H or methyl;
R8选自 -Cw垸基 -S(=0)n-R3或 5至 8元杂环基， 所述杂环基含 1至 2个选自 N、 0、 S 、 S(=0)或 S(=0)2杂原子或基团， 所述的杂环基仟选进一步被 0至 2个 d_2垸氧基所取代； R3选自 H或 垸基， 优选甲基； R 8 is selected from -Cw decyl-S(=0) n -R 3 or a 5- to 8-membered heterocyclic group, and the heterocyclic group has 1 to 2 selected from N, 0, S, S (=0) Or S(=0) 2 heteroatoms or groups, said heterocyclic group being further substituted by 0 to 2 d 2 methoxy groups; R 3 is selected from H or decyl, preferably methyl;
n为 0、 1或者 2。 本发明优选方案，通式 （ΠΙ)所述的化合物或其立体异构体、 水合物、 酯、 溶剂化物、 共晶体、 代谢产物、 药学上可接受的盐或者前药， 其中：  n is 0, 1, or 2. A preferred embodiment of the invention, a compound of the formula (A) or a stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof, wherein:
Rb选自 H; R b is selected from H;
Rbl选自 H或甲基； R bl is selected from H or methyl;
Figure imgf000014_0002
选
Figure imgf000015_0001
本发明优选方案，通式 （ΠΙ)所述的化合物或其立体异构体、 水合物、 酉 晶体、 代谢产物、 药学上可接受的盐或者前药，
Figure imgf000014_0002
selected
Figure imgf000015_0001
A preferred embodiment of the invention, a compound of the formula (A) or a stereoisomer, hydrate, cerium crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof,
其中- among them-
Rb选自 H; R b is selected from H;
Rbl H或甲基； R bl H or methyl;
Figure imgf000015_0002
Figure imgf000015_0002
更优选
Figure imgf000016_0001
本发明涉及通式 ) 所示化合物的合适的药学上可接受的盐包括， 但不限于钠盐、 钾 盐、 铝盐、 锂盐、 锌盐、 钙盐、 镁盐、 钡盐、 铵盐、 三甲胺盐、 四甲基铵盐、 二乙胺盐、 三乙胺盐、 异丙基胺盐、 乙醇胺盐、 二乙醇胺盐、 三乙醇胺盐、 环己胺盐、 二环己基胺盐More preferred
Figure imgf000016_0001
Suitable pharmaceutically acceptable salts of the present invention relating to the compounds of formula () include, but are not limited to, sodium, potassium, aluminum, lithium, zinc, calcium, magnesium, strontium, ammonium, Trimethylamine salt, tetramethylammonium salt, diethylamine salt, triethylamine salt, isopropylamine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, cyclohexylamine salt, dicyclohexylamine salt
、 吡啶盐、 甲基吡啶盐、 2,6-二甲基吡啶盐、 咖啡碱盐、 普鲁卡因盐、 胆碱盐、 甜菜碱盐 、 可可碱盐、 嘌吟盐、 哌嗪盐、 哌啶盐、 Ν-乙基哌啶盐、 聚胺树脂盐、 苯明青霉素盐、 盐 酸盐、 氢溴酸盐、 硫酸盐、 硝酸盐、 磷酸盐、 甲酸盐、 乙酸盐、 羟乙酸盐、 丙酸盐、 2-羟 基丙酸盐、 丙二酸盐、 三氟乙酸盐、 甲磺酸盐、 乙磺酸盐、 三氟甲磺酸盐、 乙烯磺酸盐、 苯磺酸盐、 对甲苯磺酸盐、 苯甲酸盐、 苯乙酸盐、 褐藻酸盐、 氨茴酸盐、 樟脑酸盐、 马来 酸盐、 酒石酸盐、 柠檬酸盐、 琥珀酸盐、 扁桃酸盐、 富马酸盐、 苹果酸盐、 草酸盐、 水杨 酸盐、 葡萄糖醛酸盐、 半乳糖醛酸盐、 枸橼酸盐、 天冬氨酸盐、 谷氨酸盐、 肉桂酸盐或它 们的组合。 优选钠盐、 钾盐、 铵盐、 三乙胺盐、 乙醇胺盐、 二乙醇胺盐、 盐酸盐、 氢溴酸 盐、 硫酸盐、 磷酸盐、 三氟乙酸盐、 乙酸盐、 马来酸盐、 天冬氨酸盐、 谷氨酸盐、 苹果酸 盐或它们的组合。 , 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, phenicillin salt, hydrochloride, hydrobromide, sulfate, nitrate, phosphate, formate, acetate, glycolate , propionate, 2-hydroxypropionate, malonate, trifluoroacetate, methanesulfonate, ethanesulfonate, triflate, ethylene sulfonate, besylate, P-toluenesulfonate, benzoate, phenylacetate, alginate, anthranilate, camphorate, maleate, tartrate, citrate, succinate, mandelate, rich Citrate, malate, oxalate, salicylate, glucuronide, galacturonate, citrate, aspartate, glutamate, cinnamate or their combination. Preferred are sodium salt, potassium salt, ammonium salt, triethylamine salt, ethanolamine salt, diethanolamine salt, hydrochloride salt, hydrobromide salt, sulfate salt, phosphate salt, trifluoroacetate salt, acetate salt, maleic acid Salt, aspartate, glutamate, malate or a combination thereof.
本发明还涉及制  The invention also relates to the system
Figure imgf000016_0002
通式 (I-a)化合物依次通过保护羟基反应、 还原反应和消除反应转化为通式 (I-b)化合物； 或者通式 -a)化合物依次通过保护羟基反应、 wittig反应和双键转位反应转化为通式 -b)化 合物；
Figure imgf000016_0002
The compound of the formula (Ia) is sequentially converted into a compound of the formula (Ib) by protecting a hydroxyl group reaction, a reduction reaction and a elimination reaction; or the compound of the formula -a) is sequentially converted into a pass by protecting a hydroxyl group reaction, a wittig reaction and a double bond transposition reaction. a compound of formula -b);
Figure imgf000016_0003
-b)化合物依次通过 simmons-simth反应和脱保护基反应转化为通式 (I-c)化合物;
Figure imgf000016_0003
-b) the compound is converted to the compound of the formula (Ic) by a simmons-simth reaction and a deprotection group reaction;
Figure imgf000017_0001
Figure imgf000017_0001
通式 -c)化合物与通式 -d)化合物通过 Mistunobo缩合反应转化为通式 (I)化合物； 其中- R、 R1, R Ral、 Rb、 Rbl、 Rc、 Rcl、 R2、 G、 Q、 Wi, W2、 W3、 t、 p、 k禾口 q如同本发 明前述所定义。 The compound of the formula -c) and the compound of the formula -d) are converted to the compound of the formula (I) by a Mistunobo condensation reaction; wherein - R, R 1 , RR al , R b , R bl , R c , R cl , R 2 , G, Q, Wi, W 2 , W 3 , t, p, k and q are as defined above in the present invention.
本发明还涉及一种药物组合物， 所述的组合物包括： 有效剂量的本发明所述化合物或 其所有立体异构体、 水合物、 溶剂化物、 酯、 代谢产物、 共晶体、 药学上可接受的盐或前 药， 及药学上可接受的载体、 稀释剂、 佐剂或赋形剂。 所述的组合物还可进一步包括一种 或多种其他治疗剂。  The invention further relates to a pharmaceutical composition comprising: an effective amount of a compound of the invention or all stereoisomers, hydrates, solvates, esters, metabolites, co-crystals thereof, pharmaceutically acceptable Accepted salts or prodrugs, and pharmaceutically acceptable carriers, diluents, adjuvants or excipients. The composition may further comprise one or more additional therapeutic agents.
具体地， 其中所述的其他治疗剂可包括：  Specifically, the other therapeutic agents described therein may include:
(a) GPR40激动剂或药学上可接受的盐， 和 /或  (a) a GPR40 agonist or a pharmaceutically acceptable salt, and/or
(b) DPP-IV抑制剂或药学上可接受的盐， 和 /或  (b) a DPP-IV inhibitor or a pharmaceutically acceptable salt, and/or
(c) SGLT-2抑制剂或药学上可接受的盐， 和 /或  (c) an SGLT-2 inhibitor or a pharmaceutically acceptable salt, and/or
((！ ？^激动剂和部分激动剂或药学上可接受的盐， 和 /或  ((! ?^ agonist and partial agonist or pharmaceutically acceptable salt, and / or
(e) PPARa/Y双重激动剂或药学上可接受的盐， 和 /或 (e) a PPAR a/Y dual agonist or pharmaceutically acceptable salt, and/or
(f) PPA 激动剂或药学上可接受的盐， 和 /或  (f) a PPA agonist or a pharmaceutically acceptable salt, and/or
fe)胰岛素或拟胰岛素或药学上可接受的盐， 和 /或  Fe) insulin or pseudo insulin or a pharmaceutically acceptable salt, and/or
Oi)蛋白酪氨酸磷酸酶 -IB (PTP-1B ) 抑制剂或药学上可接受的盐， 和 /或  Oi) a protein tyrosine phosphatase-IB (PTP-1B) inhibitor or a pharmaceutically acceptable salt, and/or
«磺酰脲类抑制剂或药学上可接受的盐， 和 /或  «sulfonylurea inhibitors or pharmaceutically acceptable salts, and/or
(ί) α-葡糖苷酶抑制剂或药学上可接受的盐， 和 /或  (ί) an alpha-glucosidase inhibitor or a pharmaceutically acceptable salt, and/or
(k)GLP- GLP-1类似物、 GIP-1、 HSD-1或药学上可接受的盐， 禾口 /或  (k) GLP-GLP-1 analogue, GIP-1, HSD-1 or a pharmaceutically acceptable salt, and/or
①胰高血糖素受体拮抗剂或药学上可接受的盐， 和 /或  a glucagon receptor antagonist or a pharmaceutically acceptable salt, and/or
(m)抗炎药， 和 /或  (m) anti-inflammatory drugs, and / or
(n)回肠胆汁酸转运蛋白抑制剂或药学上可接受的盐， 和 /或  (n) an ileal bile acid transporter inhibitor or a pharmaceutically acceptable salt, and/or
(0；)减肥药， 和 /或  (0;) diet pills, and / or
(P)改善患者脂质分布的药物， 所述药物选自 HMG-CoA还原酶抑制剂、 胆汁酸螯合剂 、 烟碱、 烟酸或其盐、 ？?^0(激动剂、 胆固醇吸收抑制剂、 酰基 CoA (胆固醇酰基转移酶 (ACAT) ) 抑制剂、 CETP抑制剂或酚类抗氧剂或药学上可接受的盐， 和 /或 (q)双胍类、 噻唑垸二酮类、 列奈类、 或其药学上可接受的盐或前药。 (P) A drug for improving lipid distribution in a patient selected from the group consisting of an HMG-CoA reductase inhibitor, a bile acid sequestrant, nicotine, nicotinic acid or a salt thereof, ?^ 0 ( agonist, cholesterol absorption inhibitor, acyl-CoA (cholesterol acyltransferase) (ACAT) an inhibitor, a CETP inhibitor or a phenolic antioxidant or a pharmaceutically acceptable salt, and/or (q) a biguanide, a thiazolidinedione, a linoleum, or a pharmaceutically acceptable thereof Salt or prodrug.
本发明优选方案， 所述的 GPR40激动剂选自 fasiglifam hemihydrate或其药学上可接受 的盐或前药。 所述的 DDP-IV 抑制剂选自 lmagliptin (利拉列汀；)、 sitagliptin (西他列汀；)、 vildagliptm (维达列汀）、 alogliptin (阿格列汀）、 saxagliptm (沙格列汀）、 denagliptm (地格列汀） 、 Carmegliptin, Melogliptin (美罗禾 J汀)、 Dutogliptin, Teneligliptin (特力禾 J汀)、 Gemigliptin 或者 Trelagliptm。 所述的 SGLT-2抑制剂选自 dapagliflozm、 propanediol, empagliflozin, ertugliflozin、 ipragliflozin、 tofogliflozin、 canagliflozinlus或 eogliflozin。 所述的 PPAR激动 齐 ll选自 bezafibrate、 fenofibrate 、 pioglitazone、 azelaic acid、 rosiglitazone或 saroglitazar。  In a preferred embodiment of the invention, the GPR40 agonist is selected from the group consisting of fasiglifam hemihydrate or a pharmaceutically acceptable salt or prodrug thereof. The DDP-IV inhibitor is selected from the group consisting of lmagliptin (lilastectin;), sitagliptin (sitagliptin;), vildagliptm (vildagliptin), alogliptin (alogliptin), saxagliptm (saxagliptin) ), denagliptm (digagliptin), Carmegliptin, Melogliptin, or Dutogliptin, Teneligliptin, Gemigliptin or Trelaglitpt. The SGLT-2 inhibitor is selected from the group consisting of dapagliflozm, propanediol, empagliflozin, ertugliflozin, ipragliflozin, tofogliflozin, canagliflozinlus or eogliflozin. The PPAR is excited to be selected from bezafibrate, fenofibrate, pioglitazone, azelaic acid, rosiglitazone or saroglitazar.
本发明优选方案， 所述的双胍类治疗剂选自二甲双胍或者二乙双胍。 所述的噻唑垸二 酮类治疗剂选自环格列酮、 吡咯列酮、 罗格列酮、 曲格列酮、 法格列酮或者达格列酮。 所 述的磺酰脲类治疗剂选自格列美脲、 Tolglybutamide、 格列波脲、 格列苯脲、 格列喹酮、 格 列吡嗪、 或格列齐特。 所述的列奈类治疗剂选自那格列奈、 瑞格列奈或者米格列奈。 所述 的 a-葡萄糖苷酶抑制剂选自阿卡波糖、 伏格列波糖或者米格列醇。 所述的 GLP-1类似物选 自艾赛那肽或者利拉鲁肽。  In a preferred embodiment of the invention, 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 daglitazone. The sulfonylurea therapeutic agent is selected from the group consisting of glimepiride, Tolglybutamide, glibenclamide, glibenclamide, gliclazide, gliprazine, or gliclazide. The levonide therapeutic agent is selected from the group consisting of nateglinide, repaglinide or mitiglinide. The a-glucosidase inhibitor is selected from the group consisting of acarbose, voglibose or miglitol. The GLP-1 analogue is selected from exenatide or liraglutide.
本发明还涉及本发明所述的化合物或其立体异构体、 水合物、 溶剂化物、 酯、 代谢产 物、 共晶体、 药学上可接受的盐或前药作为一种 G蛋白偶联受体 40激动剂在医学上的应用， 还涉及所述包括本发明所述化合物或其立体异构体、 水合物、 溶剂化物、 酯、 代谢产物、 共晶体、 药学上可接受的盐或前药的药物组合物在医学上的应用， 优选本发明的所述的化 合物或其立体异构体、 水合物、 溶剂化物、 酯、 代谢产物、 共晶体、 药学上可接受的盐或 前药或者所述的药物组合物是作为一种 G蛋白偶联受体 40激动剂用于制备用于治疗和 /或 预防代谢性疾病的药物制剂。  The invention further relates to a compound of the invention or a stereoisomer, hydrate, solvate, ester, metabolite, co-crystal, pharmaceutically acceptable salt or prodrug thereof thereof as a G protein-coupled receptor 40 The use of an agonist in medicine also relates to the medicament comprising a compound of the invention or a stereoisomer, hydrate, solvate, ester, metabolite, co-crystal, pharmaceutically acceptable salt or prodrug thereof For medical use of the composition, preferably a compound of the invention, or a stereoisomer, hydrate, solvate, ester, metabolite, co-crystal, pharmaceutically acceptable salt or prodrug thereof, or The pharmaceutical composition 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.
所述的代谢性疾病例如可以是包括糖尿病、 Π 型糖尿病、 糖尿病性视网膜病、 糖尿病 件神经病、 糖尿病件肾病、 糖尿病并发症、 高胆固醇血症、 高血糖、 高胰岛素血症、 高脂 血症、 高甘油三酸脂血症、 高血压、 高脂蛋白血症、 高 LDL胆固醇、 低 HDL胆固醇、 低 血糖症、 血脂异常、 血栓性疾病、 心血管疾病、 肾脏疾病、 酮症酸中毒、 脂肪酸或甘油的 升高的水平、 脂肪萎缩、 脂肪毒性、 肥胖症、 代谢综合症、 X 综合症、 胰岛素抗性、 胰岛 素过敏症、 葡萄糖耐受不良、 皮肤病、 动脉粥样硬化及其后遗症心绞痛、 跛行、 心脏病发 作或中风中的一种或多种。 进一步优选本发明的所述的化合物或其立体异构体、 水合物、 溶剂化物、 酯、 代谢产物、 共晶体、 药学上可接受的盐或前药是作为一种 G蛋白偶联受体 40激动剂用于制备用于治疗和 /或预防 Π型糖尿病的药物制剂。  The metabolic diseases may include, for example, diabetes, sputum type 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, X syndrome, insulin resistance, insulin allergy, glucose intolerance, skin disease, atherosclerosis and its sequelae, angina, One or more of limp, heart attack or stroke. Further preferably, the compound 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-coupled receptor 40 Agonists are used in the preparation of pharmaceutical preparations for the treatment and/or prevention of diabetes.
本发明还提供一种治疗和 /或预防代谢疾病的方法， 所述方法包括给药前面任意一项所 述的式 (1)、 式 (Π)和式 (III)的化合物或其立体异构体、 水合物、 酉旨、 溶剂化物、 共晶体、 代 谢产物、 药学上可接受的盐或前药或者所述的药物组合物。 The invention also provides a method of treating and/or preventing a metabolic disease, the method comprising administering any of the preceding items a compound of the formula (1), formula (Π) and formula (III) or a stereoisomer, hydrate, hydrate, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug thereof or Said pharmaceutical composition.
除非有相反的陈述， 在本发明中使用的术语具有下述含义。  Unless otherwise stated, the terms used in the present invention have the following meanings.
本发明所述基团和化合物中所涉及的碳、 氢、 氧、 硫、 氮或卤素均包括它们的同位素 情况， 及本发明所述基团和化合物中所涉及的碳、 氢、 氧、 硫或氮任选进一步被一个或多 个它们对应的同位素所替代， 其中碳的同位素包括 12C、 13C和 14C， 氢的同位素包括氕（H) 、 氘 （D， 又叫重氢；)、 氚 CT, 又叫超重氢；)， 氧的同位素包括160、 170和180， 硫的同位素 包括 32S、 33S、 34S和 36S， 氮的同位素包括 14N和 15N， 氟的同位素包括 17F和 19F， 氯的同 位素包括 35C1和 37C1， 溴的同位素包括 79Br和 81Br。 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. Or 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 ytterbium (H) and yttrium (D, also known as heavy hydrogen; , 氚CT, also called super heavy hydrogen;), 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, and the bromine isotopes include 79 Br and 81 Br.
"垸基"是指含 1至 20个碳原子的直链或支链饱和脂肪族烃基，优选为 1至 10个碳原子 的垸基， 更优选为 1至 8个碳原子的垸基， 进一步优选为 1至 6个碳原子的垸基。 非限制 性实施例包括甲基、 乙基、 正丙基、 异丙基、 正丁基、 仲丁基、 叔丁基、 正戊基、 2-戊基 、 3-戊基、 2-甲基 -2-戊基、 3-甲基 -2-戊基、 4-甲基 -2-戊基、 3-甲基 -3-戊基、 2-甲基 -3-戊基 、 2,3-二甲基 -2-丁基、 3,3-二甲基 -2-丁基、 正庚基、 正辛基及其各种支链异构体； 所述的垸 基可以任选进一步被 0至 5个选自 F、 Cl、 Br、 I、 =0、 -CH2F、 -CHF2、 -CF3、 羟基、 巯基 、 硝基、 氰基、 羧基、 C2.8 烯基、 C2.8 炔基、 d.8 垸基、 d.8 垸氧基、 -SR5、 -S(=0)R5、 -S(=0)2R5、 -C(=0)-R3、 -C(=0)-0-R3、 -C(=0)- R3R3a、 -NR3R3a、 -0-C(=0)-C1-8 垸基、 -0-C(=0)-0-R3、 -0-C(=0)-NR3R3a、 -0-C1-3烷基 -O- C1-3烷基、 -0-C1-8烷基- S(=0)n-R3、 -d_8垸基 -S(=0)n-R3、 -0-R4、 3至 10元碳环基或 3至 10元杂环基的取代基所取代，其中 R5 选自 1至 8个碳原子的烷基、 3至 10个碳原子的碳环基或者 3至 10个碳原子的杂环基， R3 、 R3a和 R4如同本发明前述所定义， 本文中出现的垸基， 其定义如上所述。 "Mercapto" refers to a straight or branched saturated aliphatic hydrocarbon group having 1 to 20 carbon atoms, preferably a fluorenyl group of 1 to 10 carbon atoms, more preferably a fluorenyl group of 1 to 8 carbon atoms, further A fluorenyl group of 1 to 6 carbon atoms is preferred. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl -2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3- Dimethyl-2-butyl, 3,3-dimethyl-2-butyl, n-heptyl, n-octyl and various branched isomers thereof; the thiol group may optionally be further Up to 5 selected from the group consisting of F, Cl, Br, I, =0, -CH 2 F, -CHF 2 , -CF 3 , hydroxy, decyl, nitro, cyano, carboxy, C 2 .8 alkenyl, C 2 .8 alkynyl, d. 8 fluorenyl, d. 8 decyloxy, -SR 5 , -S(=0)R 5 , -S(=0) 2 R 5 , -C(=0)-R 3 , -C(=0)-0-R 3 , -C(=0)- R 3 R 3a , -NR 3 R 3a , -0-C(=0)-C 1-8垸, -0- C(=0)-0-R 3 , -0-C(=0)-NR 3 R 3a , -0-C 1-3 alkyl-O-C 1-3 alkyl, -0-C 1- 8- alkyl-S(=0) n -R 3 , -d_ 8 fluorenyl-S(=0) n -R 3 , -0-R 4 , 3 to 10 membered carbocyclic group or 3 to 10 membered heterocyclic ring Substituted by a substituent wherein R 5 is selected from an alkyl group of 1 to 8 carbon atoms, and a carbon of 3 to 10 carbon atoms A cyclic group or a heterocyclic group of 3 to 10 carbon atoms, R 3 , R 3a and R 4 are as defined above in the present invention, and the fluorenyl group appearing herein is as defined above.
其中可以理解的是， 当表达中垸基右边出现键时， 譬如 "-O-C^垸基 -" ， 则表示其中 的 "d_8垸基"两端各有一连接键与其相邻的取代基进行连接， 也可称为 "亚垸基"， 其他 还譬如 " -C1-8垸基 -0- " 、 " -C(=0)-Ci-8垸基- "、 " -C1-8垸基 -S(=0)n-R3 "和 " -0-C1-8垸基 - S(=0)n-R3 " ， 均做同样理解。 Which it will be appreciated that, when expressed in the embankment group appears to the right key, such as "-OC ^ alkyl with -", which indicates that the both ends of the "d_ 8 alkyl with" each have adjacent thereto a linkage connected substituents , also known as "Acryl", others such as "-C 1-8垸--0-", "-C(=0)-Ci -8垸--, "-C 1-8垸The base -S(=0) n -R 3 " and " -0-C 1-8 fluorenyl-S(=0) n -R 3 " are equally understood.
"垸氧基"是指 -0-垸基，非限制性实施例包括甲氧基、 乙氧基、 1-丙氧基、 2-丙氧基、 1- 丁氧基、 2-甲基 -1-丙氧基、 2-丁氧基、 2-甲基 -2-丙氧基、 1-戊氧基、 2-戊氧基、 3-戊氧基、 2-甲基 -2-丁氧基、 3-甲基 -2-丁氧基、 3-甲基- i -丁氧基和 2-甲基- i -丁氧基； 所述的垸基可以 任选进一步被 0至 5个选自 F、 Cl、 Br、 I、 =0、 -CH2F、 -CHF2、 -CF3、 羟基、 巯基、 硝基 、 氰基、 羧基、 C2-8烯基、 C2-8炔基、 C1-8垸基、 C1-8垸氧基、 -SR5、 -S(=0)R5、 -S(=0)2R5 、 -C(=0)-R3、 -C(=0)-0-R3、 -C(=0)-NR3R3a、 - R3R3a、 -0-C(=0)-C1-8 烷基、 -0-C(=0)-0-R3、 -0-C(=0)- R3R3a、 -0-C1-3垸基 -O- C1-3垸基、 -0-C1-8垸基- S(=0)n-R3、 -d_8垸基 -S(=0)n-R3、 -0-R4、 3至 10元碳环基或 3至 10元杂环基的取代基所取代，其中 R5 选自 1至 8个碳原子的烷基、 3至 10个碳原子的碳环基或者 3至 10个碳原子的杂环基， R3 、 R3a和 R4如同本发明前述所定义， 本文中出现的垸基， 其定义如上所述。 "Alkoxy" means -0-fluorenyl, and 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 , 3 -methyl- 2 -butoxy, 3 -methyl-i-butoxy and 2 -methyl-i-butoxy; the thiol group may optionally be further selected from 0 to 5 From F, Cl, Br, I, =0, -CH 2 F, -CHF 2 , -CF 3 , hydroxy, decyl, nitro, cyano, carboxy, C 2-8 alkenyl, C 2-8 alkynyl , C 1-8 fluorenyl, C 1-8 decyloxy, -SR 5 , -S(=0)R 5 , -S(=0) 2 R 5 , -C(=0)-R 3 , C(=0)-0-R 3 , -C(=0)-NR 3 R 3a , - R 3 R 3a , -0-C(=0)-C 1-8 alkyl, -0-C( =0)-0-R 3 , -0-C(=0)- R 3 R 3a , -0-C 1-3 fluorenyl-O- C 1-3 fluorenyl group, -0-C 1-8垸Base - S(=0) n -R 3 , -d_ 8 alkyl with -S (= 0) n -R 3 , -0-R 4, 3 to 10 membered carbocyclic group or 3 to 10-membered heterocyclic group substituents, wherein R 5 is selected from 1 to An alkyl group of 8 carbon atoms, a carbocyclic group of 3 to 10 carbon atoms or a heterocyclic group of 3 to 10 carbon atoms, R 3 , R 3a and R 4 are as defined in the foregoing, and 垸 appearing herein Base, which is defined as described above.
"垸基"是指含 1至 20个碳原子的直链或支链饱和脂肪族垸基，优选为 1至 10个碳原子 的垸基， 更优选为 1至 8个碳原子的垸基， 进一步优选为 1至 6个碳原子的垸基。 非限制 性实施例包括亚甲基、 亚乙基、 亚丙基、 甲基亚甲基、 乙基亚乙基、 1,2-二甲基亚乙基、 1,1,2,2-四甲基亚乙基； 所述的垸基可以任选进一步被 0至 5个选自 F、 Cl、 Br、 I、 -CH2F 、 -CHF2、 -CF3、 氨基、 羟基、 d.8垸基、 d.8垸氧基、 C2.8烯基、 C2.8炔基或者 -NR3R3a的取 代基所取代， 其中 R3和 R3a如同本发明前述所定义， 本文中出现的垸基， 其定义如上所述。 "Amidino" means a straight or branched saturated aliphatic fluorenyl group having 1 to 20 carbon atoms, preferably a fluorenyl group of 1 to 10 carbon atoms, more preferably a fluorenyl group of 1 to 8 carbon atoms. Further preferred is a fluorenyl group of 1 to 6 carbon atoms. Non-limiting examples include methylene, ethylene, propylene, methylmethylene, ethylethylene, 1,2-dimethylethylene, 1,1,2,2-tetra Methylethylene; the fluorenyl group may be further optionally 0 to 5 selected from the group consisting of F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , amino group, hydroxyl group, d. 8 Substituted by a substituent of fluorenyl, d. 8 methoxy, C 2 .8 alkenyl, C 2 .8 alkynyl or —NR 3 R 3a wherein R 3 and R 3a are as defined above in the present invention, The thiol group that appears is defined as described above.
"烯基 "是指含有 1至 3个碳-碳双键， 由 2-20个碳原子组成的直链或者支链不饱和脂肪 族烃基， 优选 2-12个碳原子的烯基， 更优选 2-8个碳原子的烯基。 非限制性实施例包括乙 烯基、 丙烯 -2-基、 丁烯 -2-基、 戊烯 -2-基、 戊烯 -4-基、 己烯 -2-基、 己烯 -3 基、 庚烯 -2-基、 庚烯 -3-基、 庚烯 -4-基、 辛烯 -3-基、 壬烯 -3-基、 癸烯 -4-基和十一烯 -3-基。 所述的烯基可以 任选进一步被 0至 4个选自 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 羟基、 巯基、 硝基、 氰 基、 羧基、 烯基、 炔基、 C 垸基、 C 垸氧基、 -C(=0)-R3、 -C(=0)-0-R3、 -C(=0)-NR3R3a、 -NR3R3a、 -0-C(=0)-C1-8垸基、 -0-C(=0)-0-R3、 -0-C(=0)-NR3R3a、 -0-C1-3 垸基 -O- Cw垸基、 -O-C 烷基 - S(=0)N-R3、 -C1-8垸基 -S(=0)N-R3、 -0-R4、 3至 10元碳环基 或 3至 10元杂环基的取代基所取代， 其中 R3、 R3a和 R4如同本发明前述所定义， 本文中出 现的垸基， 其定义如上所述。 "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, 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, -CH 2 F, -CHF 2 , -CF 3 , hydroxy, decyl, nitro, cyano, carboxy, olefin. Base, alkynyl, C decyl, C methoxy, -C(=0)-R 3 , -C(=0)-0-R 3 , -C(=0)-NR 3 R 3a , -NR 3 R 3a , -0-C(=0)-C 1-8 fluorenyl, -0-C(=0)-0-R 3 , -0-C(=0)-NR 3 R 3a , -0 -C 1-3 fluorenyl-O-Cw fluorenyl, -OC alkyl-S(=0) N -R 3 , -C 1-8 fluorenyl-S(=0) N -R 3 , -0- Substituted by a substituent of R 4 , 3 to 10 membered carbocyclyl or 3 to 10 membered heterocyclyl, wherein R 3 , R 3a and R 4 are as defined above in the present invention, and the fluorenyl group represented herein is as defined above Said.
"炔基 "是指含有 1至 3个碳-碳叁键， 由 2-20个碳原子组成的直链或者支链不饱和脂肪 族烃基， 优选 2-12个碳原子的炔基， 更优选 2-8个碳原子的炔基。 非限制性实施例包括乙 炔基、 丙炔 -1-基、 丙炔 -2-基、 丁炔 -1-基、 丁炔 -2-基、 丁炔 -3-基、 3,3-二甲基丁炔 -2-基、 戊炔 -1-基、 戊炔 -2-基、 己炔 -1-基、 1-庚炔 -1-基、 庚炔 -3-基、 庚炔 -4-基、 辛炔 -3-基、 壬炔 -3-基、 癸炔 -4-基、 十一炔 -3-基、 十二炔 -4-基。 所述的炔基可以任选进一步被 0至 4个选自 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 羟基、 巯基、 硝基、 氰基、 羧基、 C2-8烯基、 C2-8炔 基、 C1-8 垸基、 C1-8 垸氧基、 -C(=0)-R3、 -C(=0)-0-R3、 -C(=0)-NR3R3a、 -NR3R3a、 -0-C(=0)-C1-8垸基、 -0-C(=0)-0-R3、 -0-C(=0)- R3R3a、 -0-C1-3垸基 -O- C1-3垸基、 -0-C1-8 垸基- S(=0)n-R3、 -C1-8垸基 -S(=0)n-R3、 -0-R4、 3至 10元碳环基或 3至 10元杂环基的取代 基所取代， 其中 R3、 R3a和 R4如同本发明前述所定义， 本文中出现的垸基， 其定义如上所 述。 "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, -CH 2 F, -CHF 2 , -CF 3 , hydroxy, decyl, nitro, cyano, carboxy, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 fluorenyl, C 1-8 decyloxy, -C(=0)-R 3 , -C(=0)-0-R 3 , -C(=0)-NR 3 R 3a , -NR 3 R 3a , -0-C(=0)-C 1-8 fluorenyl, -0-C(=0)-0-R 3 , -0 -C(=0)- R 3 R 3a , -0-C 1-3 fluorenyl-O- C 1-3 fluorenyl, -0-C 1-8 fluorenyl-S(=0) n -R 3 Substituted with a substituent of -C 1-8 fluorenyl-S(=0) n -R 3 , -0-R 4 , a 3 to 10 membered carbocyclic group or a 3 to 10 membered heterocyclic group, wherein R 3 , R 3a and R 4 are as defined above in the present invention, and the fluorenyl groups appearing herein are as defined above.
"碳环基"是指饱和或者不饱和的芳香环或者非芳香环， 芳香环或者非芳香环可以是 3 至 10元的单环、 4至 12元双环或者 10至 15元三环体系，碳环基可以连接有桥环或者螺环， 非限制性实施例包括环丙基、 环丁基、 环戊基、 1-环戊基 -1-烯基、 1-环戊基 -2-烯基、 1-环 戊基 -3-烯基、 环己基、 苯基、 1-环己基 -2-烯基、 1-环己基 -3-烯基、 环己烯基、 环己二烯基"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 base can be connected with a bridge ring or a spiral ring. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl , cyclohexyl, phenyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexenyl, cyclohexadienyl
、 环 基、 环十一垸基、 环十二垸基、 苯基、 萘基、 蒽基、 菲
Figure imgf000021_0001
； 所述的碳环基可以任选进一步被 0至 8个选自 F、 C1 、 Br、 I、 =0、 -CH2F、 -CHF2、 -CF3、 羟基、 巯基、 硝基、 氰基、 羧基、 C2-8烯基、 C2-8炔 基、 C1-8 垸基、 C1-8 垸氧基、 -SR5、 -S(=0)R5、 -S(=0)2R5、 -C(=0)-R3、 -C(=0)-0-R3、 -C(=0)-NR3R3a、 -NR3R3a、 -0-C(=0)-C1-8垸基、 -0-C(=0)-0-R3、 -0-C(=0)-NR3R3a、 -0-C1-3 垸基 -O- Cw垸基、 -O-C 烷基 - S(=0)N-R3、 -C1-8垸基 -S(=0)N-R3、 -0-R4、 3至 10元碳环基 或 3至 10元杂环基的取代基所取代， 其中 R5选自 1至 8个碳原子的烷基、 3至 10个碳原 子的碳环基或者 3至 10个碳原子的杂环基， R3、 R3a和 R4如同本发明前述所定义， 本文中 出现的垸基， 其定义如上所述。 , ring group, ring eleven fluorenyl, cyclododedecyl, phenyl, naphthyl, anthracenyl, phenanthrene
Figure imgf000021_0001
The carbocyclic group may be further optionally 0 to 8 selected from the group consisting of F, C1, Br, I, =0, -CH 2 F, -CHF 2 , -CF 3 , hydroxy, decyl, nitro, cyanide Base, carboxyl group, C 2-8 alkenyl group, C 2-8 alkynyl group, C 1-8 fluorenyl group, C 1-8 decyloxy group, -SR 5 , -S(=0)R 5 , -S(= 0) 2 R 5 , -C(=0)-R 3 , -C(=0)-0-R 3 , -C(=0)-NR 3 R 3a , -NR 3 R 3a , -0-C (=0)-C 1-8 fluorenyl, -0-C(=0)-0-R 3 , -0-C(=0)-NR 3 R 3a , -0-C 1-3 fluorenyl- O-Cw fluorenyl, -OC alkyl-S(=0) N -R 3 , -C 1-8 fluorenyl-S(=0) N -R 3 , -0-R 4 , 3 to 10 carbon Substituted by a substituent of a cyclic group or a 3- to 10-membered heterocyclic group, wherein R 5 is selected from an alkyl group of 1 to 8 carbon atoms, a carbocyclic group of 3 to 10 carbon atoms or a hetero atom of 3 to 10 carbon atoms The cyclic group, R 3 , R 3a and R 4 are as defined above in the present invention, and the fluorenyl groups appearing herein are as defined above.
"杂环基"是指取代的或未取代的饱和或不饱和的芳香环或者非芳香环， 芳香环或者非 芳香环可以是 3至 10元的单环、 4至 12元双环或者 10至 15元三环体系，且包含 1至 4个 选自 N、 0或 S的杂原子， 优选 3至 8元杂环基， 杂环基的环中选择性取代的 N、 S可被氧 化成各种氧化态。 杂环基可以连接在杂原子或者碳原子上， 杂环基可以连接有桥环或者螺 环， 非限制性实施例包括环氧乙基、 环氧丙基、 氮杂环丙基、 氧杂环丁基、 氮杂环丁基、 硫杂环丁基、 1,3-二氧戊环基、 1,4-二氧戊环基、 1,3-二氧六环基、 氮杂环庚基、 氧杂环庚 基、 硫杂环庚基、 氧氮杂卓基、 二氮杂卓基、 硫氮杂卓基、 吡啶基、 哌啶基、 高哌啶基、 呋喃基、 噻吩基、 吡喃基、 N-垸基吡咯基、 嘧啶基、 吡嗪基、 哒嗪基、 哌嗪基、 高哌嗪基 、 咪唑基、 哌啶基、 哌叮基、 吗啉基、 硫代吗啉基、 、 噻噁垸基、 1,3-二噻基、 二氢呋喃 基、 二氢吡喃基、 二噻戊环基、 四氢呋喃基、 四氢噻吩基、 四氢吡喃基、 四氢噻喃基、 四 氢吡咯基、 四氢咪唑基、 四氢噻唑基、 四氢吡喃基、 苯并咪唑基、 苯并吡啶基、 吡咯并吡 啶基、 苯并二氢呋喃基、 2-吡咯啉基、 3-吡咯啉基、 二氢吲哚基、 2H-吡喃基、 4H-吡喃基 、 二氧杂环己基、 1,3-二氧戊基、 吡唑啉基、 二噻烷基、 二噻茂垸基、 二氢噻吩基、 吡唑 垸基咪唑啉基、 咪唑垸基、 1,2,3,4-四氢异喹啉基、 3-氮杂双环 [3.1.0]己基、 3-氮杂双环  "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. Butyl, azetidinyl, thiat-butyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxolyl, azepanyl , oxetanyl, thiaheptyl, oxazepine, diazepine, thiazepine, pyridyl, piperidinyl, homopiperidinyl, furyl, thienyl, pyridyl Cyclol, N-fluorenylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperazinyl, homopiperazinyl, imidazolyl, piperidinyl, piperidinyl, morpholinyl, thiomorpholinyl , thiaxanthyl, 1,3-dithia, dihydrofuranyl, dihydropyranyl, dithiapentyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyran , tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridinyl, benzodihydrofuranyl, 2- Porolinyl, 3-pyrroline, indanyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxopentyl, pyrazolinyl, dithiat Alkyl, dithiadecyl, dihydrothienyl, pyrazolyl imidazolinyl, imidazolium, 1,2,3,4-tetrahydroisoquinolinyl, 3-azabicyclo[3.1.0 Hexyl, 3-azabicyclo
[4.1.0]庚基、 氮杂双环 [2.2.2]己基、 3H-吲哚基喹嗪基、 N-吡啶基尿素、 1,1-二氧硫代吗啉 基、 氮杂二环 [3.2.1]辛垸基、 氮杂二环 [5.2.0]壬垸基、 氧杂三环 [5.3.1.1]十二垸基、 氮杂金 [4.1.0]heptyl, azabicyclo[2.2.2]hexyl, 3H-decylquinazinyl, N-pyridylurea, 1,1-dioxythiomorpholinyl, azabicyclo[ 3.2.1] Octyl, azabicyclo[5.2.0]fluorenyl, oxatricyclo[5.3.1.1]dodecyl, aza gold
刚垸基、 氧 螺 [3.3]庚垸基、
Figure imgf000021_0002
。 所述 的杂环基可以任选进一步被 0至 8个选自 F、 Cl、 Br、 I、 =0、 -CH2F、 -CHF2、 -CF3、 羟基 、 巯基、 硝基、 氰基、 羧基、 C2.8烯基、 C2.8炔基、 d.8垸基、 d.8垸氧基、 -SR5、 -S(=0)R5 、 -S(=0)2R5、 -C(=0)-R3、 -C(=0)-0-R3、 -C(=0)-NR3R3a、 -NR3R3a、 -0-C(=0)-C1-8 垸基、 -0-C(=0)-0-R3、 -0-C(=0)- R3R3a、 -0-C1-3垸基 -O- C1-3垸基、 -0-C1-8垸基- S(=0)n-R3、 -d_8垸基 -S(=0)n-R3、 -0-R4、 3至 10元碳环基或 3至 10元杂环基的取代基所取代，其中 R5 选自 1至 8个碳原子的烷基、 3至 10个碳原子的碳环基或者 3至 10个碳原子的杂环基， R3 、 R3a和 R4如同本发明前述所定义， 本文中出现的垸基， 其定义如上所述。 Gangyl, oxo[3.3]heptanyl,
Figure imgf000021_0002
. The heterocyclic group may be further optionally 0 to 8 selected from the group consisting of F, Cl, Br, I, =0, -CH 2 F, -CHF 2 , -CF 3 , hydroxyl , fluorenyl, nitro, cyano, carboxy, C 2 .8 alkenyl, C 2 .8 alkynyl, d. 8 decyl, d. 8 decyloxy, —SR 5 , —S(=0)R 5 -S(=0) 2 R 5 , -C(=0)-R 3 , -C(=0)-0-R 3 , -C(=0)-NR 3 R 3a , -NR 3 R 3a , -0-C(=0)-C 1-8垸, -0-C(=0)-0-R 3 , -0-C(=0)- R 3 R 3a , -0-C 1 -3 fluorenyl-O-C 1-3 fluorenyl, -0-C 1-8 fluorenyl-S(=0) n -R 3 , -d_ 8 fluorenyl-S(=0) n -R 3 , Substituted by a substituent of -0-R 4 , a 3 to 10 membered carbocyclic group or a 3 to 10 membered heterocyclic group, wherein R 5 is selected from an alkyl group of 1 to 8 carbon atoms, and a carbon of 3 to 10 carbon atoms A cyclic group or a heterocyclic group of 3 to 10 carbon atoms, R 3 , R 3a and R 4 are as defined above in the present invention, and the fluorenyl group appearing herein is as defined above.
"羧基 "是指 -COOH。  "Carboxy" means -COOH.
"氰基 "是指 N。 "Cyano" means N.
"硝基 "是指 -N02。 "Nitro" means -N0 2 .
"羟基 "是指 -OH。  "Hydroxy" means -OH.
"巯基 "是指 -SH。  "巯基" means -SH.
"=0"为本领域通常习惯用法， 是指以双键相连的氧原子， 譬如羰基中与碳原子相连的 双键氧原子。  "=0" is a commonly used practice in the art and refers to an oxygen atom connected by a double bond, such as a double bond oxygen atom to a carbon atom in a carbonyl group.
"药学上可接受的盐 "或者 "其药学上可接受的盐"是指本发明化合物保持游离酸或者游 离碱的生物有效性和特性， 且所述的游离酸通过与无毒的无机碱或者有机碱反应获得的盐， 所述的游离碱通过与无毒的无机酸或者有机酸反应获得的盐。 所述的无机碱的非限制性实 施例包括钠、 钾、 铝、 锂、 锌、 钙、 镁、 钡的碱； 所述的有机碱的非限制性实施例包括氨 、 三甲胺、 四甲基铵、 二乙胺、 三乙胺、 异丙基胺、 乙醇胺、 二乙醇胺、 三乙醇胺、 环己 胺、 二环己基胺、 吡啶、 甲基吡啶、 2,6-二甲基吡啶、 咖啡碱、 普鲁卡因、 胆碱、 甜菜碱 、 可可碱、 嘌吟、 哌嗪、 哌啶、 N-乙基哌啶、 聚胺树脂、 苯明青霉素盐； 所述的无机酸和 有机酸的非限制性实施例盐酸、 氢溴酸、 硫酸、 硝酸、 磷酸、 甲酸、 乙酸、 羟乙酸、 丙酸 、 2-羟基丙酸、 丙二酸、 三氟乙酸、 甲磺酸、 乙磺酸、 三氟甲磺酸、 乙烯磺酸、 苯磺酸、 对甲苯磺酸、 苯甲酸、 苯乙酸、 褐藻酸、 氨茴酸、 樟脑酸、 马来酸、 酒石酸、 柠檬酸、 琥 珀酸、 扁桃酸、 富1 ¾酸、 苹果酸、 草酸、 水杨酸、 葡萄糖醛酸、 半乳糖醛酸、 枸橼酸、 天 冬氨酸、 谷氨酸、 肉桂酸。 "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 A salt obtained by an organic base reaction, a salt obtained by reacting the free base with a non-toxic inorganic acid or an 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, tetramethyl Ammonium, diethylamine, triethylamine, isopropylamine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, pyridine, picoline, 2,6-lutidine, caffeine, general Rucaine, choline, betaine, theobromine, hydrazine, piperazine, piperidine, N-ethylpiperidine, polyamine resin, phenicillin salt; non-limiting of the inorganic and organic acids Examples 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 acid, ethanesulfonic acid, trifluoromethanesulfonate acid, vinylsulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, benzoic acid, phenylacetic acid, alginic acid, anthranilic acid, camphoric acid, maleic acid, tartaric acid, citric acid, succinic acid, mandelic acid, fumaric acid 1 ¾ , malic acid, oxalic acid, salicylic acid, glucuronic acid Galacturonic acid, citric acid, aspartic acid, glutamic acid, cinnamic acid.
"载体 "是指不会对生物体产生明显剌激且不会消除所给予化合物的生物活性和特性的 材料。  "Carrier" means a material that does not cause significant irritation to the organism and does not abrogate the biological activity and properties of the administered compound.
"赋形剂"是指加入到药物组合物中以促进化合物给药的惰性物质。 非限制性实施例包 括碳酸钙、 磷酸钙、 糖、 淀粉、 纤维素衍生物 （包括微晶纤维素)、 明胶、 植物油、 聚乙二 醇类、 稀释剂、 成粒剂、 润滑剂、 粘合剂和崩解剂。  "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.
"佐剂 "是非特异性免疫增强剂， 当与抗原一起注射或预先注入机体时， 可增强机体对抗 原的免疫应答或改变免疫应答类型。 "稀释剂"也叫"填充剂"。 把原药加工成粉剂时，或为了使其便于喷施所加入的进行稀释 的惰性物质。 如： 粘土、 高岭土、 陶土、 滑石粉等。 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 for the purpose of facilitating the spraying, the diluted inert substance is added. Such as: clay, kaolin, clay, talcum powder, etc.
"前药 "是指可经体内代谢转化为具有生物活性的本发明化合物。 本发明的前药通过修 饰本发明化合物中的功能基团来制备， 该修饰可以通过常规的操作或者在体内被除去， 而 得到母体化合物。 前药包括本发明化合物中的一个羟基、 氨基或者巯基连接在任何集团上 所形成的化合物， 当本发明的前药被施予哺乳动物个体时， 前药被割裂而分别形成游离的 羟基、 游离的氨基或者游离的巯基。 前药的例子包括但不限于， 本发明化合物中的羟基或 氨基功能基团与甲酸、 乙酸或苯甲酸所形成的化合物。  "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 provide 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. When the prodrug of the present invention is administered to a mammalian individual, the prodrug is cleaved to form a free hydroxyl group, free 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.
"共晶 "是指活性药物成分和共晶形成物在氢键或其他非共价键的作用下结合而成的晶 体， 其中 API和 CCF的纯态在室温下均为固体， 并且各组分间存在固定的化学计量比。 共 晶是一种多组分晶体， 既包含两种中性固体之间形成的二元共晶， 也包含中性固体与盐或 溶剂化物形成的多元共晶。 所述"共晶形成物"的非限定性实例包括丙氨酸、 缬氨酸、 亮氨 酸、 异亮氨酸、 脯氨酸、 苯丙氨酸、 色氨酸、 蛋氨酸、 甘氨酸、 丝氨酸、 苏氨酸、 半胱氨 酸、 酪氨酸、 天冬酰胺、 谷氨酰胺、 赖氨酸、 精氨酸、 组氨酸、 天冬氨酸、 门冬氨酸、 谷 氨酸、 焦谷氨酸、 硫酸、 磷酸、 硝酸、 氢溴酸、 盐酸、 甲酸、 乙酸、 丙酸、 苯磺酸、 苯甲 酸、 苯乙酸、 水杨酸、 褐藻酸、 氨茴酸、 樟脑酸、 柠檬酸、 乙烯磺酸、 蚁酸、 富马酸、 糠 酸、 葡萄糖酸、 葡萄糖醛酸、 谷氨酸、 乙醇酸、 羟乙磺酸、 乳酸、 马来酸、 苹果酸、 扁桃 酸、 粘液酸、 双羟萘酸、 泛酸、 硬脂酸、 琥珀酸、 磺胺酸、 酒石酸、 对甲苯磺酸、 丙二酸 、 2-羟基丙酸、 草酸、 羟乙酸、 葡萄糖醛酸、 半乳糖醛酸、 枸橼酸、 肉桂酸、 对甲苯磺酸 、 甲磺酸、 乙磺酸或三氟甲磺酸、 氨、 异丙基胺、 三甲基胺、 二乙胺、 三乙胺、 三丙基胺 、 二乙醇胺、 乙醇胺、 二甲基乙醇胺、 2-二甲基氨基乙醇、 2-二乙基氨基乙醇、 二环己基 胺、 咖啡碱、 普鲁卡因、 胆碱、 甜菜碱、 苯明青霉素、 乙二胺、 葡萄糖胺、 甲基葡糖胺、 可可碱、 三乙醇胺、 氨丁三醇、 嘌吟、 哌嗪、 哌啶和 N-乙基哌啶。  "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 and CCF is solid at room temperature, and each component There is a fixed stoichiometric ratio between them. 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, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, mucic acid, pamoic acid , pantothenic acid, stearic acid, succinic acid, sulfamic acid, tartaric acid, p-toluenesulfonic acid, malonic acid, 2-hydroxypropionic acid, oxalic acid, glycolic acid, glucuronic acid, galacturonic acid, citric acid, cinnamic acid , p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid Trifluoromethanesulfonic acid, ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2 -diethylaminoethanol, dicyclohexylamine, caffeine, procaine, choline, betaine, phenylpheniticin, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine Triol, hydrazine, piperazine, piperidine and N-ethylpiperidine.
"立体异构体 "是指由分子中原子在空间上排列方式不同所产生的异构体，包括顺反异构 体、 对映异构体和构象异构体。  "Stereoisomer" refers to isomers resulting from the spatial arrangement of atoms in a molecule, including cis-trans isomers, enantiomers, and conformational isomers.
"任选 "或"任选地 "或"选择性的"或"选择性地"是指随后所述的事件或状况可以但未必 发生， 该描述包括其中发生该事件或状况的情况及其中未发生的情况。 例如， "选择性地被 垸基取代的杂环基"是指该垸基可以但未必存在， 该描述包括其中杂环基被垸基取代的情况， 及其中杂环基未被垸基取代的情况。 "药物组合物 "表示一种或多种本文所述化合物或其生 理学 /药学上可接受的盐或前体药物的组合或 /和一种或多种其它治疗剂以及药学上可接受 的赋形剂、 佐剂、 稀释剂和载体。  "Optional" or "optionally" or "optional" or "optionally" means that the subsequently described event or condition may, but does not necessarily, occur, including where the event or condition occurred and What happened. For example, "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.
"EC50" 半数有效浓度， 指达到最大药效一半时的浓度。 本发明化合物的合成方法 "EC 50 " Half effective concentration, which is the concentration at which half of the maximum efficacy is reached. Method for synthesizing the compound of the present invention
本领域技术人员知道本发明的化合物可以通过多种制备方法合成。 优选的方法包括 ， 但不限于以下所描述的方法。 本领域的技术人员能够理解在分子上表现出的功能性应当与 所计划的转化一致。 为了得到本发明的所需化合物， 有时需要一种判断以改变合成步骤的 顺序或者选择一种特定的工艺方案。 为了对本发明所描述的化合物中存在的反应性功能基 团进行保护而选择合理的保护基团。  Those skilled in the art will recognize that 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. 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 judgement 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 the reactive functional groups present in the compounds described herein.
根据本发明的具体实施方案， 本发明的通式I)化合物的制备方法包括：  According to a particular embodiment of the invention, the process for the preparation of the compounds of the formula I) according to the invention comprises:
Figure imgf000024_0001
Figure imgf000024_0001
在无水无氧条件下， 以甲醇为溶剂， 通式 -e)化合物被还原剂还原为通式 -d)化合物； 其中所述的还原剂选自硼氢化钠、 硼氢化钾、 氢化铝锂、 硫代硼氢化钠或者三仲丁基硼氢 化锂；  The compound of the formula -e) is reduced to a compound of the formula -d) by a reducing agent under anhydrous and anaerobic conditions using methanol as a solvent; wherein the reducing agent is selected from the group consisting of sodium borohydride, potassium borohydride and lithium aluminum hydride. , sodium thioborohydride or lithium tri-sec-butyl borohydride;
在碱性条件下， 以干燥的二氯甲垸为溶剂， 通式 (I-a)化合物与保护基发生保护羟基的反 应， 所得产物在无水无氧条件下被还原剂还原， 此还原产物再在酸性条件下发生消除反应 得到通式 (I-b)化合物； 或者在碱性条件下， 以干燥的二氯甲烷为溶剂， 通式 (I-a)化合物与保 护基发生保护羟基的反应， 所得产物在碱性条件下与甲基三苯基溴化膦发生 witting反应， 所得产物再在酸性条件下发生双键转位反应得到通式 (I-b)化合物；其中所述的碱选自咪唑、 吡啶、 二乙胺、 二甲胺、 苯胺、 丁基锂、 苯基锂、 叔丁醇甲、 二异丙基胺基锂、 六甲基二 硅胺基锂、 甲醇钠、 乙醇钾或叔丁醇钾； 保护基选自叔丁基二甲基硅基、 叔丁基二苯基硅 基、 三甲基硅基、 三乙基硅基、 三甲基硅氧基、 三乙基硅氧基、 叔丁基二甲基硅氧基、 苄 基醚或对甲氧基苄基； 还原剂选自硼氢化钠、 硼氢化钾、 氢化铝锂、 硫代硼氢化钠或者三 仲丁基硼氢化锂； 酸选自对甲苯磺酸、 三氟乙酸、 苯甲酸、 乙二胺四乙酸、 水杨酸、 乙酸 、 酒石酸、 马来酸或草酸； Under basic conditions, with the dry methylene chloride as solvent, the compound of the formula (Ia) and the protecting group are reacted with a protective hydroxyl group, and the obtained product is reduced by a reducing agent under anhydrous anaerobic conditions, and the reduced product is again The elimination reaction occurs under acidic conditions to obtain a compound of the formula (Ib); or under basic conditions, using dry dichloromethane as a solvent, the compound of the formula (Ia) and the protecting group are protected by a hydroxyl group, and the obtained product is alkaline. Under the condition, a fitting reaction occurs with methyltriphenylphosphonium bromide, and the obtained product undergoes double bond translocation reaction under acidic conditions to obtain a compound of the formula (Ib); wherein the base is selected from the group consisting of imidazole, pyridine and diethylamine. , dimethylamine, aniline, butyl lithium, phenyl lithium, tert-butanol methyl, lithium diisopropylamide, lithium hexamethyldisilazide, sodium methoxide, potassium ethoxide or potassium t-butoxide; Selected from tert-butyldimethylsilyl, tert-butyldiphenylsilyl, trimethylsilyl, triethylsilyl, trimethylsiloxy, triethylsiloxy, tert-butyl Methylsilyloxy, benzyl ether or p-methoxybenzyl; reducing agent selection From sodium borohydride, potassium borohydride, lithium aluminum hydride, sodium thioborohydride or lithium tri-sec-butylborohydride; acid selected from p-toluenesulfonic acid, trifluoroacetic acid, benzoic acid, ethylenediaminetetraacetic acid, water Acid, acetic acid , tartaric acid, maleic acid or oxalic acid;
在酸性条件下， 通式 -b)化合物与碘甲垸发生 simmos-smith反应得到绸环化合物， 此 绸环化合物再在碱性条件下脱去羟基保护基得到通式 -c)化合物， 所述的酸和碱如上所述； 以二氯甲垸或者四氢呋喃为溶剂，三叔丁基膦条件下，偶氮二甲酸二异丙酯或者 1,1- (偶 氮二羰基)二哌啶存在下，通式 -c)化合物与通式 (I-d)化合物发生 Mistunobo缩合反应得到通 式 (I)化合物； 或者通式 -c)化合物与通式 (I-d)化合物发生 Mistunobo缩合反应以及水解反应 转化为通式 (I)化合物；  Under acidic conditions, a compound of formula -b) is reacted with iodomethyl hydrazine to obtain a silk ring compound, which is then deprotected under basic conditions to give a compound of formula -c). The acid and base are as described above; in the presence of dichloromethane or tetrahydrofuran as solvent, tri-tert-butylphosphine, diisopropyl azodicarboxylate or 1,1-(azodicarbonyl)dipiperidine a compound of formula (c) is subjected to a Mistunobo condensation reaction with a compound of the formula (Id) to give a compound of the formula (I); or a compound of the formula -c) is subjected to a Mistunobo condensation reaction with a compound of the formula (Id) and the hydrolysis reaction is converted into a pass. a compound of formula (I);
其中- among them-
R、 R1, R2、 R Ral、 Rb、 Rbl、 Rc、 Rcl、 Q、 G、 Wi, W2、 W3、 k、 t、 p禾口 q如同本 发明中前述所定义。 具体实施方式 R, R 1 , R 2 , RR al , R b , R bl , R c , R cl , Q, G, Wi, W 2 , W 3 , k, t, p and q are as defined above in the present invention . detailed description
以下结合附图及实施例详细说明本发明的技术方案，但本发明的保护范围包括但是 不限于此。  The technical solutions of the present invention are described in detail below with reference to the accompanying drawings and embodiments, but the scope of the present invention includes but is not limited thereto.
本发明中， 化合物的结构是通过核磁共振 （NMR) 或 （和） 质谱 （MS) 来确定的。 NMR位移 （δ) 以 10_6 (ppm) 的单位给出。 NMR的测定是用 （Bruker Avance III 400 禾口 Bruker Avance 300) 核磁仪， 测定溶剂为氘代二甲基亚砜 （DMSO-d6)， 氘代氯仿 (CDC13)， 氘代甲醇 （CD3OD)， 内标为四甲基硅垸 (TMS)。 In the present invention, the structure of the compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). NMR shifts ([delta]) are given in units of 10_ 6 (ppm) a. 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).
MS的测定用 (Agilent 6120B(ESI)禾口 Agilent 6120B(APCI))。  For the measurement of MS (Agilent 6120B (ESI) and Agilent 6120B (APCI)).
HPLC的测定使用安捷伦 1260DAD高压液相色谱仪 （Zorbax SB-C18 100x4.6 mm)。 薄层层析硅胶板使用烟台黄海 HSGF254 或青岛 GF254 硅胶板， 薄层色谱法 （TLC) 使用的硅胶板采用的规格是 0.15 mm~0.20 mm, 薄层层析分离纯化产品采用的规格是 0.4 mm〜0.5 mm。  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 has a specification of 0.4 mm. ~0.5 mm.
柱层析一般使用烟台黄海硅胶 200~300目硅胶为载体。  Column chromatography generally uses Yantai Huanghai silica gel 200~300 mesh silica gel as the carrier.
本发明的己知的起始原料可以采用或按照本领域已知的方法来合成， 或可购买于泰坦 科技、 安耐吉化学、 上海德默、 成都科龙化工、 韶远化学科技、 百灵威科技等公司。  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.
氮气氛是指反应瓶连接一个约 1L容积的氮气气球。  The nitrogen atmosphere means that the reaction flask is connected to a nitrogen balloon of about 1 L volume.
氢气氛是指反应瓶连接一个约 1L容积的氢气气球。  The hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume.
氢化反应通常抽真空， 充入氢气， 反复操作 3次。  The hydrogenation reaction is usually evacuated, charged with hydrogen, and operated three times.
实施例中无特殊说明， 反应在氮气氛下进行。  Unless otherwise stated in the examples, the reaction was carried out under a nitrogen atmosphere.
实施例中无特殊说明， 溶液是指水溶液。  There is no particular description in the examples, and the solution means an aqueous solution.
实施例中无特殊说明， 反应的温度为室温。 室温为最适宜的反应温度， 为 20°C ~ 30°C。 There is no particular description in the examples, and the reaction temperature is room temperature. The optimum reaction temperature at room temperature is 20 ° C ~ 30 ° C.
本文所用的其他符号具有下列意义：  Other symbols used in this article have the following meanings:
s: 单峰  s: single peak
d: 二重峰  d: doublet
t: 三重峰  t: triple peak
q: 四重峰  q: Quadruple peak
m: 多重峰  m: multiple peak
br: 宽峰 Br : wide peak
J: 耦合常数  J: coupling constant
Hz: 赫兹  Hz: Hertz
Bn: 苄基  Bn: benzyl
Me: 甲基  Me: methyl
Et: 乙基  Et: ethyl
TBS: 叔丁基二甲基硅基。  TBS: tert-butyldimethylsilyl.
中间体 1: Intermediate 1:
[3-[2,6-二甲基 -4-(3-甲磺酰基丙氧基)苯基]苯基]甲醇 （1G)  [3-[2,6-Dimethyl-4-(3-methanesulfonylpropoxy)phenyl]phenyl]methanol (1G)
[3-[2,6-dimethyl-4-(3-methylsulfonylpropoxy)phenyl]phenyl]methanol [3-[2,6-dimethyl-4-(3-methylsulfonylpropoxy)phenyl]phenyl]methanol
Figure imgf000026_0001
第一步： 3-(4-羟基 -2,6-二甲基-苯基；)苯甲醛（1B)
Figure imgf000026_0001
First step: 3- (4-hydroxy-2,6-dimethyl-phenyl;) benzaldehyde (1B)
3-(4-hydroxy-2,6-dimethyl-phenyl)benzaldehyde
Figure imgf000027_0001
3-(4-hydroxy-2,6-dimethyl-phenyl)benzaldehyde
Figure imgf000027_0001
将 4-溴 -3,5-二甲基苯酚 1A (17.44 g, 86.74 mmol) 和 3-甲酰基苯硼酸 （13.02 g, 86.83 mmol)溶于碳酸钠溶液（210 mL, 1 M)、 乙醇 （90 mL) 和甲苯（210 mL) 的混合溶剂中。 氮气置换反应体系， 并鼓泡 0.5小时， 加入四 (三苯基膦；)钯（5 g, 43.26 mmol)。 氮气氛围下 加热至 80°C，搅拌反应 24小时。 将反应液冷却至室温，加入水（200 mL)和乙酸乙酯 （200 mL), 用硅藻土过滤， 滤液分层， 有机层用饱和食盐水 （200 mL 2)洗涤。 乙酸乙酯层用 无水硫酸钠干燥， 过滤， 滤液减压浓缩。 残留物用硅胶柱层析法分离纯化 (石油醚 /乙酸乙酯 (ν/ν)= 15/1) , 得到类白色固体状的 3-(4-羟基 -2,6-二甲基-苯基；)苯甲醛 1B (16.22 g, 产率 82.6%) 第二步： 3-甲硫基丙基 4-甲基苯磺酸酯 (1D)  4-Bromo-3,5-dimethylphenol 1A (17.44 g, 86.74 mmol) and 3-formylbenzeneboronic acid (13.02 g, 86.83 mmol) were dissolved in sodium carbonate solution (210 mL, 1 M), ethanol ( Mixture of 90 mL) and toluene (210 mL). The reaction system was replaced with nitrogen, and was bubbled for 0.5 hour, and tetrakis(triphenylphosphine;)palladium (5 g, 43.26 mmol) was added. The mixture was heated to 80 ° C under a nitrogen atmosphere, and the reaction was stirred for 24 hours. The reaction solution was cooled to room temperature, water (EtOAc) (EtOAc)EtOAc. The ethyl acetate layer was dried over anhydrous sodium sulfate and filtered and evaporated. The residue was purified by silica gel column chromatography (EtOAc (EtOAc/EtOAc) Base;) benzaldehyde 1B (16.22 g, yield 82.6%) Step 2: 3-methylthiopropyl 4-methylbenzenesulfonate (1D)
3 -methylsulfanylpropyl 4-methylbenzenesulfonate
Figure imgf000027_0002
3-methylsulfanylpropyl 4-methylbenzenesulfonate
Figure imgf000027_0002
冰浴下， 将对甲苯磺酰氯 （54.0 g, 0.28 mol) 的甲苯 （100 mL)溶液滴入 3-甲硫基丙醇 1C (20.0 g, 0.19 mol)、 三乙醇胺 （40 mL,0.28 mol)和 Ν,Ν,Ν',Ν'-四甲基 -1,6-己二胺 （3.3 g, 18.9 mmol) 的甲苯（100 mL)溶液中。 冰浴下搅拌反应 3小时， TLC板监测， 反应结束。 向反应液中加水（30 mL)，搅拌 20分钟，静置分液。 水层加入乙酸乙酯 （400 mL),用水（400 mL x 1)洗涤， 合并有机相， 用无水硫酸钠干燥， 过滤， 滤液减压浓缩。 残留物用硅胶柱层 析法分离纯化 (石油醚 /乙酸乙酯 (v/v)= 12/1)，得到棕色油状物 3-甲硫基丙基 4-甲基苯磺酸酯 1D (48.8 g, 产率 99.6%)。 第三步： 3-甲磺酰基丙基 4-甲基苯磺酸酯 (1E)  Under ice bath, p-toluenesulfonyl chloride (54.0 g, 0.28 mol) in toluene (100 mL) was added dropwise to 3-methylthiopropanol 1C (20.0 g, 0.19 mol), triethanolamine (40 mL, 0.28 mol) And hydrazine, hydrazine, hydrazine, Ν'-tetramethyl-1,6-hexanediamine (3.3 g, 18.9 mmol) in toluene (100 mL). The reaction was stirred for 3 hours under ice bath, monitored by TLC plate, and the reaction was completed. Water (30 mL) was added to the reaction mixture, and the mixture was stirred for 20 minutes, and the mixture was allowed to stand. The aqueous layer was combined with EtOAc (EtOAc)EtOAc. The residue was purified by silica gel column chromatography (EtOAc (EtOAc/EtOAc) g, yield 99.6%). Step 3: 3-Methanesulfonylpropyl 4-methylbenzenesulfonate (1E)
3 -methylsulfonylpropyl 4-methylbenzenesulfonate
Figure imgf000027_0003
3-methylsulfonylpropyl 4-methylbenzenesulfonate
Figure imgf000027_0003
冰浴下， 将过氧化氢钾 （229.7 g, 0.37 mol) 的水溶液（900 mL) 缓慢加入 3-甲硫基丙基 4-甲基苯磺酸酯 1D (48.8 g, 0.19 mol) 的甲醇 （900 mL) 溶液中。 滴加完毕， 将混合物升至 室温搅拌反应 20小时， TLC板监测反应结束。 向反应液中加入水（2000 mL)， 用乙酸乙酯 (1500 mL x 1)萃取， 有机层用饱和食盐水（200 mL x l) 洗涤， 无水硫酸钠干燥， 过滤， 滤 液减压浓缩， 得到白色结晶状固体 3-甲磺酰基丙基 4-甲基苯磺酸酯 1E (44.8 g, 产率 99.0%) 第四步： 3-[2,6-二甲基 -4-(3-甲磺酰基丙基)苯基]苯甲醛 （1F) Under ice bath, an aqueous solution of potassium hydrogen peroxide (229.7 g, 0.37 mol) (900 mL) was slowly added to 3-methylthiopropyl 4-methylbenzenesulfonate 1D (48.8 g, 0.19 mol) in methanol ( 900 mL) in solution. After the dropwise addition was completed, the mixture was allowed to warm to room temperature and stirred for 20 hours, and the TLC plate was used to monitor the end of the reaction. Add water (2000 mL) to the reaction solution with ethyl acetate (1500 mL x 1), the organic layer was washed with EtOAc EtOAc (EtOAc) Benzene sulfonate 1E (44.8 g, yield 99.0%). Step 4: 3-[2,6-Dimethyl-4-(3-methanesulfonylpropyl)phenyl]benzaldehyde (1F)
3-[2,6-dimethyl-4-(3-methylsulfonylpropoxy)phenyl]benzaldehyde
Figure imgf000028_0001
3-[2,6-dimethyl-4-(3-methylsulfonylpropoxy)phenyl]benzaldehyde
Figure imgf000028_0001
室温下， 将 3-(4-羟基 -2,6-二甲基-苯基)苯甲醛 1B (16.22 g, 0.072 mol)、 3-甲磺酰基丙基 4-甲基苯磺酸酯 1E (30.98 g, 0.11 mol)及碳酸钾 （15.86 g, 0.11 mol)溶于 Ν,Ν-二甲基甲酰 胺 （150 mL) 中，将混合物加热至 90°C，搅拌反应 24小时。 向反应液中加入冰水（300 mL) 稀释， 用乙酸乙酯 （500 mL x l)萃取， 合并有机相， 饱和食盐水（300 mL x 2) 洗涤， 无水 硫酸钠干燥， 过滤， 减压浓縮得油状物。 油状物用乙酸乙酯 /正己垸混合液（乙酸乙酯 /正己 垸 (v/v)= 1/2 ) 重结晶， 得到类白色固体 3-[2,6-二甲基 -4-(3-甲磺酰基丙基)苯基]苯甲醛 1F (11.38 g, 产率 45.8%)。  3-(4-Hydroxy-2,6-dimethyl-phenyl)benzaldehyde 1B (16.22 g, 0.072 mol), 3-methanesulfonylpropyl 4-methylbenzenesulfonate 1E (at room temperature) 30.98 g, 0.11 mol) and potassium carbonate (15.86 g, 0.11 mol) were dissolved in hydrazine, hydrazine-dimethylformamide (150 mL), and the mixture was heated to 90 ° C, and the reaction was stirred for 24 hours. The reaction mixture was diluted with ice water (300 mL), and extracted with ethyl acetate (500 mL×l). The organic phase was combined, washed with saturated brine (300 mL×2), dried over anhydrous sodium sulfate Reduced oil. The oil was recrystallized from ethyl acetate / n-hexanes (ethyl acetate / hexanes (v/v) = 1/2) to afford white crystals of 3-[2,6-dimethyl-4-(3) -Methanesulfonylpropyl)phenyl]benzaldehyde 1F (11.38 g, yield 45.8%).
第五步： [3-[2,6-二甲基 -4-(3-甲磺酰基)苯基]苯基]甲醇 (1G) Step 5: [3-[2,6-Dimethyl-4-(3-methylsulfonyl)phenyl]phenyl]methanol (1G)
[3-[2,6-dimethyl-4-(3-methylsulfonylpropoxy)phenyl]phenyl]methanol  [3-[2,6-dimethyl-4-(3-methylsulfonylpropoxy)phenyl]phenyl]methanol
Figure imgf000028_0002
Figure imgf000028_0002
冰浴下， 分批将硼氢化钠 （1.47 g, 38.86 mmol) 加入 3-[2,6-二甲基 -4-(3-甲磺酰基丙基) 苯基]苯甲醛 1F (11.38 g, 32.85 mmol) 的四氢呋喃 （100 mL)和甲醇 （100 mL) 混合溶剂中， 室温搅拌反应 3小时， TLC板监测反应完全。 用浓盐酸调节 pH为 3-4左右，加入水（500 mL) 稀释反应液， 用乙酸乙酯 （300 mL X 1)萃取， 有机层用饱和食盐水（200mL χ 1) 洗涤， 无 水硫酸钠干燥， 过滤， 减压浓缩。 残留物用乙酸乙酯 /正己垸混合液 (乙酸乙酯 /正己垸 (ν/ν)= 20/50)重结晶，得到类白色固体 [3-[2,6-二甲基 -4-(3-甲磺酰基)苯基]苯基]甲醇 lG (10.70 g, 产 率 93.5%)。 中间体 2:  Sodium borohydride (1.47 g, 38.86 mmol) was added in portions to 3-[2,6-dimethyl-4-(3-methanesulfonylpropyl)phenyl]benzaldehyde 1F (11.38 g, 32.85 mmol) of a mixture of tetrahydrofuran (100 mL) and methanol (100 mL) was stirred at room temperature for 3 hours, and the reaction was monitored by TLC. Adjust the pH to 3-4 with concentrated hydrochloric acid, dilute the reaction solution with water (500 mL), extract with ethyl acetate (300 mL X 1), and wash the organic layer with saturated brine (200 mL χ 1) Dry, filter, and concentrate under reduced pressure. The residue was recrystallized from ethyl acetate / hexanes (EtOAc / EtOAc (EtOAc) 3-Methanesulfonyl)phenyl]phenyl]methanol 1G (10.70 g, yield 93.5%). Intermediate 2:
2-[5- [叔丁基(二甲基)硅基]氧基 -3-氧代 -茚满 -1-基]乙酸甲酯 (2G) 2-[5-[tert-Butyl(dimethyl)silyl]oxy-3-oxo-indan-1-yl]acetate methyl ester (2G)
methyl 2-[5-[tert-butyl(dimethyl)silyl]oxy-3-oxo-indan-l-yl]acetate Methyl 2-[5-[tert-butyl(dimethyl)silyl]oxy-3-oxo-indan-l-yl]acetate
Figure imgf000029_0001
第一步： 2,4-二乙酰基 -3-(4-甲氧基苯基；)戊二酸二乙酯 (2B)
Figure imgf000029_0001
First step: 2,4-diacetyl-3-(4-methoxyphenyl;) diethyl glutarate (2B)
diethyl 2,4-diacetyl-3 -(4-methoxyphenyl)pentanedioate Diethyl 2,4-diacetyl-3 -(4-methoxyphenyl)pentanedioate
Figure imgf000029_0002
Figure imgf000029_0002
在 0°C下， 将 3-羰基丁酸乙酯 （42.3 g, 325 mmol) 溶于对甲氧基苯甲醛 2A (21.0 g, 154 mmol) 中， 滴加二异丙醇胺 （4 mL)， 升至室温继续搅拌反应 5天。 将反应混合物过滤， 滤 饼减压干燥， 得到淡黄色固体 2,4-二乙酰基 -3-(4-甲氧基苯基;)戊二酸二乙酯 2B (23.89 g, 产 率 40.9%)。  Ethyl 3-carbonylbutyrate (42.3 g, 325 mmol) was dissolved in p-methoxybenzaldehyde 2A (21.0 g, 154 mmol) at 0 ° C, diisopropyl alcoholamine (4 mL) The reaction was stirred for 5 days at room temperature. The reaction mixture was filtered, and the filtered cake was evaporated to dryness crystals crystals crystalssssssssssssssssssssssssss ).
第二步： 3-(4-甲氧基苯基)戊二酸 (2C) Second step: 3-(4-methoxyphenyl)glutaric acid (2C)
3 -(4-methoxyphenyl)pentanedioic acid 3-(4-methoxyphenyl)pentanedioic acid
Figure imgf000029_0003
Figure imgf000029_0003
将氢氧化钾溶液（2 mL, 41.02 mmol, 20 M) 加入 2,4-二乙酰基 -3-(4-甲氧基苯基；)戊二酸 二乙酯 2B (3.01 g, 7.96 mmol) 中， 室温下搅拌反应 17小时。 向反应体系中加入冰块， 降温 至 0°C， 用二氯甲垸（lO mLx l)萃取， 水层用浓盐酸调节 PH为 1， 沉淀物析出， 过滤， 滤 饼减压干燥， 得到淡黄色固体 3-(4-甲氧基苯基)戊二酸 2C (1.23 g, 产率 64.7%)。 第三步： 2-(5-甲氧基 -3-氧代 -茚满 -1-基;)乙酸 (2D) Add potassium hydroxide solution (2 mL, 41.02 mmol, 20 M) to diethyl 2,4-diacetyl-3-(4-methoxyphenyl;) glutarate 2B (3.01 g, 7.96 mmol) The reaction was stirred at room temperature for 17 hours. Ice cubes were added to the reaction system, the temperature was lowered to 0 ° C, extracted with dichloromethane (10 mL×1), the aqueous layer was adjusted to pH 1 with concentrated hydrochloric acid, and the precipitate was precipitated, filtered, and the filter cake was dried under reduced pressure to obtain Pale yellow solid 3-(4-methoxyphenyl)glutaric acid 2C (1.23 g, yield 64.7%). The third step: 2-(5-methoxy-3-oxo-indan-1-yl;) acetic acid (2D)
2-(5-methoxy-3 -oxo-indan- 1 -yl)acetic acid 2-(5-methoxy-3 -oxo-indan- 1 -yl)acetic acid
Figure imgf000030_0001
Figure imgf000030_0001
将多聚磷酸 （60.01 g, 177.58 mmol) 加入 3-(4-甲氧基苯基)戊二酸 2C (4.02 g, 16.87 mmol) 中，搅拌均匀，加热至 100°C反应 4小时。 搅拌下缓慢地向反应体系中加入冰水至反 应体系不再粘稠。 用乙酸乙酯 （5 mLx3)萃取， 合并有机层， 用无水硫酸钠干燥， 过滤， 滤 液减压浓缩。 残留物用硅胶柱层析法分离纯化 (石油醚 /乙酸乙酯 (v/v)= 1/1-1/2), 得到淡黄色 粉末 2-(5-甲氧基 -3-氧代 -茚满 -1-基)乙酸 2D (1.41 g, 产率 38.0%)。  Polyphosphoric acid (60.01 g, 177.58 mmol) was added to 3-(4-methoxyphenyl)glutaric acid 2C (4.02 g, 16.87 mmol), stirred well, and heated to 100 ° C for 4 hours. Ice water was slowly added to the reaction system while stirring until the reaction system was no longer viscous. The mixture was extracted with EtOAc (EtOAc m. The residue was purified by silica gel column chromatography (EtOAc (EtOAc/EtOAc) Indole-1-yl)acetic acid 2D (1.41 g, yield 38.0%).
第四步： 2-(5-甲氧基 -3-氧代 -茚满 -1-基)乙酸甲酯 (2E) Step 4: Methyl 2-(5-methoxy-3-oxo-indan-1-yl)acetate (2E)
methyl 2-(5 -methoxy-3 -oxo-indan- 1 -yl)acetate Methyl 2-(5 -methoxy-3 -oxo-indan- 1 -yl)acetate
Figure imgf000030_0002
Figure imgf000030_0002
0°C下， 将 2-(5-甲氧基 -3-氧代 -茚满 -1-基)乙酸 2D (1.04 g, 4.72 mmol)溶于 10 mL甲醇 中，缓慢滴加 5滴浓硫酸，升至室温反应 4小时。 将反应体系减压浓缩，加入水（10 mL) 稀 释， 用二氯甲垸（10 mLx3) 萃取， 合并有机层， 饱和食盐水（5 mLx l)洗涤， 无水硫酸钠 干燥， 过滤， 滤液减压浓缩。 残留物用硅胶柱层析法分离纯化 (石油醚 /乙酸乙酯 (v/v)= 10/1 →8/1), 得到白色固体 2-(5-甲氧基 -3-氧代 -茚满 -1-基;)乙酸甲酯 2E (1.01 g, 产率 91.0%)。 第五步： 2-(5-羟基 -3-氧代 -茚满 -1-基)乙酸甲酯 （2F) 2-(5-Methoxy-3-oxo-indan-1-yl)acetic acid 2D (1.04 g, 4.72 mmol) was dissolved in 10 mL of methanol at 0 ° C, and 5 drops of concentrated sulfuric acid were slowly added dropwise. It was allowed to react to room temperature for 4 hours. The reaction system was concentrated under reduced pressure, diluted with water (10 mL), and extracted with dichloromethane (10 mL×3). The organic layer was combined, washed with saturated brine (5 mL×l), dried over anhydrous sodium sulfate, filtered Concentrated by pressure. The residue was purified by silica gel column chromatography (EtOAc (EtOAc/EtOAc) Full-1-yl;) methyl acetate 2E (1.01 g, yield 91.0%). Step 5 : Methyl 2-( 5 -hydroxy- 3 -oxo-indan-1-yl)acetate ( 2 F)
methyl 2-(5 -hydroxy-3 -oxo-indan- 1 -yl)acetate Methyl 2-(5-hydroxy-3 -oxo-indan- 1 -yl)acetate
Figure imgf000030_0003
Figure imgf000030_0003
氮气氛围， 将三氯化铝 （200 mg， 1.50 mmol) 加入到 2-(5-甲氧基 -3-氧代 -茚满 -1-基;)乙 酸甲酯 2E (0.23 g， 0.98 mmol) 的甲苯（10 mL)溶液中， 加热回流 0.5小时。 向反应液中加 入水（5 mL) 终止反应。 用乙酸乙酯 （15 mLx2)萃取反应液，合并有机相，饱和食盐水 （50 mLx l) 洗涤。 乙酸乙酯层用无水硫酸钠干燥， 过滤， 滤液减压浓缩。 残留物用硅胶柱层析 法分离纯化 (石油醚 /乙酸乙酯 (vA = 4/1), 得到淡黄色固体 2-(5-羟基 -3-氧代 -茚满 -1-基；)乙酸 甲酯 2F (198 mg, 产率 91.7%)。 第六步： 2-[5- [叔丁基(二甲基)硅基]氧基 -3-氧代 -茚满 -1-基]乙酸甲酯 (2G) Add aluminum trichloride (200 mg, 1.50 mmol) to 2-(5-methoxy-3-oxo-indan-1-yl;) methyl acetate 2E (0.23 g, 0.98 mmol). The solution in toluene (10 mL) was heated to reflux for 0.5 h. Water (5 mL) was added to the reaction solution to terminate the reaction. The reaction mixture was extracted with ethyl acetate (15 mL×2). The ethyl acetate layer was dried over anhydrous sodium sulfate and filtered and evaporated. The residue was purified by silica gel column chromatography (EtOAc (EtOAc) (EtOAc (EtOAc) Methyl ester 2F (198 mg, yield 91.7%). Step 6: 2-[5-[tert-Butyl(dimethyl)silyl]oxy-3-oxo-indan-1-yl]acetate (2G)
methyl 2-[5-[tert-butyl(dimethyl)silyl]oxy-3-oxo-indan-l-yl]acetate Methyl 2-[5-[tert-butyl(dimethyl)silyl]oxy-3-oxo-indan-l-yl]acetate
Figure imgf000031_0001
Figure imgf000031_0001
向 2-(5-羟基 -3-氧代 -茚满 -1-基；)乙酸甲酯 2F (1.8 g, 8.17 mmol)在干燥二氯甲垸（30 mL) 中的溶液中加入叔丁基二甲基氯硅垸（2.4 g, 15.92 mmol) 及咪唑 (1.2 g, 17.63 mmol), 室温 搅拌反应 1 小时。 将混合物过滤除去不溶物， 滤液加水 （30 mL) 稀释， 用二氯甲垸 （30 mLx3)萃取， 合并有机相， 饱和食盐水（100 m x l) 洗涤， 无水硫酸钠干燥有机相， 过滤， 滤液减压浓缩。 残留物用硅胶柱层析分离纯化 (石油醚 /乙酸乙酯 (v/v)= 12/1)， 得到淡黄色油 状物 2-[5- [叔丁基(二甲基)硅基]氧基 -3-氧代 -茚满 -1-基]乙酸甲酯 2G (2.58 g, 产率 94.5%)。 中间体 3: (消旋体）  To a solution of 2-(5-hydroxy-3-oxo-indan-1-yl;)methyl acetate 2F (1.8 g, 8.17 mmol) in dry dichloromethane (30 mL) Dimethylsilyl silane (2.4 g, 15.92 mmol) and imidazole (1.2 g, 17.63 mmol) were stirred at room temperature for 1 hour. The mixture was filtered to remove the insoluble material, and the filtrate was diluted with water (30 mL), and extracted with dichloromethane (30 mL×3). The organic phase was combined, washed with saturated brine (100 m×l), dried over anhydrous sodium sulfate and filtered. Concentrate under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc (EtOAc/EtOAc) Methyl 3-oxo-indan-1-yl]acetate 2G (2.58 g, yield 94.5%). Intermediate 3: (racemic)
2-(3-羟基 -l,la,6,6a-四氢环丙垸 [a]茚 -6-基;)乙酸甲酯 （3D)  2-(3-hydroxy-l,la,6,6a-tetrahydrocyclopropene [a] 茚 -6-yl;) methyl acetate (3D)
meth -(3 -hydroxy- 1 , 1 a,6,6a-tetrahydrocyclopropa[a]inden-6-yl)acetate Meth -(3 -hydroxy- 1 , 1 a,6,6a-tetrahydrocyclopropa[a]inden-6-yl)acetate
Figure imgf000031_0002
Figure imgf000031_0002
第一步： 2-[5- [叔丁基(二甲基)硅基]氧基 -3-羟基 -茚满 -1-基]乙酸甲酯 (3A) First step: 2-[5-[tert-Butyl(dimethyl)silyl]oxy-3-hydroxy-indan-1-yl]acetate (3A)
methyl 2- [5 - [tert-butyl(dimethyl)silyl]oxy-3 -hydroxy-indan- 1 -yl] acetate
Figure imgf000032_0001
Methyl 2- [5 - [tert-butyl(dimethyl)silyl]oxy-3 -hydroxy-indan- 1 -yl] acetate
Figure imgf000032_0001
无水无氧条件下， 将 2-[5- [叔丁基(二甲基)硅基]氧基 -3-氧代 -茚满 -1-基]乙酸甲酯 2G (2.10 g, 6.29 mmol) 溶于甲醇 （20 mL) 中， 搅拌 15分钟。 冰水下， 分小份向混合物中加入 硼氢化钠 （0.24 g, 6.29 mmol)， 升至室温搅拌反应 20分钟， 反应完全。 向反应液中加入乙 酸乙酯 （50 mL)和水（50 mL), 搅拌 10分钟， 分液。 有机相用水（20 mLx3)洗涤， 合并 有机相并用无水硫酸钠干燥， 过滤， 滤液减压浓缩， 得到无色液体 2-[5- [叔丁基 (二甲基)硅 基]氧基 -3-羟基 -茚满 -1-基]乙酸甲酯 3A (2.07 g,产率 97.6%)。  Methyl 2-[5-[tert-butyl(dimethyl)silyl]oxy-3-oxo-indan-1-yl]acetate 2G (2.10 g, 6.29 mmol) ) Dissolved in methanol (20 mL) and stirred for 15 minutes. Under ice, sodium borohydride (0.24 g, 6.29 mmol) was added to the mixture, and the mixture was stirred at room temperature for 20 minutes, and the reaction was completed. Ethyl acetate (50 mL) and water (50 mL) were added to the mixture and stirred for 10 min. The organic phase was washed with water (20 mL×3), EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Methyl 3-hydroxy-indan-1-yl]acetate 3A (2.07 g, yield 97.6%).
第二步： 2-[5- [叔丁基(二甲基)硅基]氧基 -1H-茚小基]乙酸甲酯 (3B) Second step: 2-[5-[tert-butyl(dimethyl)silyl]oxy-1H-indenyl]methyl acetate (3B)
methyl 2- [5 - [tert-butyl(dimethyl)si Methyl 2- [5 - [tert-butyl(dimethyl)si
Figure imgf000032_0002
Figure imgf000032_0002
2-[5- [叔丁基 (二甲基；)硅基]氧基 -3-羟基 -茚满 -1-基]乙酸甲酯 3A (2.07g, 6.15 mmol) 溶于 甲苯（20 mL) 中， 室温下搅拌 5分钟， 加入对甲苯磺酸 （0.52g, 3.02 mmol)。 升温至 110°C 搅拌反应 0.5小时， 反应完全。 向反应液中加入乙酸乙酯 （50 mL)和水（50 mL)， 搅拌 5分 钟， 分液。 有机相用水（20 mLx3)洗涤， 用无水硫酸钠干燥， 过滤， 滤液减压浓缩。 残留 物用硅胶柱层析分离纯化 (石油醚 /乙酸乙酯 (v/v)= 60/1),得到无色液体 2-[5- [叔丁基 (二甲基) 硅基]氧基 -1H-茚 -1-基]乙酸甲酯 3B (1.6 g, 产率 81.6%)。  2-[5-[tert-Butyl(dimethyl))silyl]oxy-3-hydroxy-indan-1-yl]acetate methyl ester 3A (2.07 g, 6.15 mmol) dissolved in toluene (20 mL) After stirring at room temperature for 5 minutes, p-toluenesulfonic acid (0.52 g, 3.02 mmol) was added. The temperature was raised to 110 ° C and the reaction was stirred for 0.5 hours, and the reaction was completed. Ethyl acetate (50 mL) and water (50 mL) were added to the mixture and stirred for 5 min. The organic phase was washed with EtOAcq. The residue was purified by silica gel column chromatography (EtOAc/EtOAc (EtOAc/EtOAc) -1H-indol-1-yl]methyl acetate 3B (1.6 g, yield 81.6%).
第三步： 2-[3- [叔丁基(二甲基)硅基]氧基 -l,la,6,6a-四氢环丙垸 [a]茚 -6-基]乙酸甲酯 (3C) methyl 2-[3-[tert-butyl(dimethyl)silyl]oxy-l,la,6,6a-tetrahydrocyclopropa[a]inden-6-yl]acetate The third step: 2-[3-[tert-butyl(dimethyl)silyl]oxy-l,la,6,6a-tetrahydrocyclopropane[a]indol-6-yl]methyl acetate ( 3C) methyl 2-[3-[tert-butyl(dimethyl)silyl]oxy-l,la,6,6a-tetrahydrocyclopropa[a]inden-6-yl]acetate
Figure imgf000032_0003
Figure imgf000032_0003
无水无氧， -5 °C下， 将二乙基锌 （5 mL, 5.02 mmol) 溶于二氯甲垸（20 mL) 中， 搅拌 5 分钟， 滴入碘甲垸（1.33 g, 5.02 mmol), 搅拌 30分钟。 再滴入 2-[5- [叔丁基 (二甲基；)硅基]氧 基- m -茚 -1-基]乙酸甲酯 3B (400 mg, 1.26 mmol) 的二氯甲烷（20 mL)溶液， 升至室温搅拌 反应过夜。 向反应液中加入饱和氯化铵溶液 pO mL),搅拌，浓缩。 向浓缩液中加入乙酸乙 酯 (40 mL)， 搅拌， 分液， 有机相用水（20 mLx3)洗涤， 无水硫酸钠干燥， 过滤， 滤液减压 浓缩。 残留物用硅胶柱层析分离纯化 (石油醚 /乙酸乙酯 (v/v)= 30/1), 得到无色液体 2-[3- [叔 丁基 (二甲基；)硅基]氧基 -Ua,6,6a-四氢环丙垸 [a]茚 -6-基]乙酸甲酯 3C (207 mg, 产率 49%)。 第四步： 2-(3-羟基 -l,la,6,6a-四氢环丙垸 [a]茚 -6-基;)乙酸甲酯 (3D) Anhydrous and anaerobic, diethylzinc (5 mL, 5.02 mmol) was dissolved in dichloromethane (20 mL) at -5 °C, stirred for 5 min, and iodine (1.33 g, 5.02 mmol) ), stir for 30 minutes. Add 2-[5-[tert-butyl(dimethyl))silyl]oxy- m -indol-1-yl]acetate methyl ester 3B (400 mg, 1.26 mmol) in dichloromethane (20 mL) The solution was allowed to warm to room temperature and stirred overnight. A saturated ammonium chloride solution (pO mL) was added to the reaction mixture, stirred, and concentrated. Ethyl acetate (40 mL) was added to the mixture, the mixture was stirred and evaporated, and the organic phase was washed with water (20 mL×3), dried over anhydrous sodium sulfate Concentrated. The residue was purified by silica gel column chromatography (EtOAc/EtOAc (EtOAc/EtOAc) Methyl-Ua,6,6a-tetrahydrocyclopropane[a]indol-6-yl]methyl acetate 3C (207 mg, yield 49%). The fourth step: 2-(3-hydroxy-l,la,6,6a-tetrahydrocyclopropene[a]indol-6-yl;) methyl acetate (3D)
methyl 2-(3 -hydroxy- 1 , 1 a,6,6a-tetrahydrocyclopropa[a]inden-6-yl)acetate Methyl 2-(3 -hydroxy- 1 , 1 a,6,6a-tetrahydrocyclopropa[a]inden-6-yl)acetate
Figure imgf000033_0001
Figure imgf000033_0001
2-[3- [叔丁基(二甲基)硅基]氧基 -l,la,6,6a-四氢环丙垸 [a]茚 -6-基]乙酸甲酯 3C (517 mg, 1.55 mmol)溶于四氢呋喃 （20 mL) 中， 室温下加入四丁基氟化铵 （517 mg, 1.98 mmol)， 搅 拌反应 0.5小时， 反应完全。 向反应液中加水（20 mL)， 用乙酸乙酯 （20 mLx3)萃取， 合并 有机相， 用水（lO mLx l) 洗涤， 无水硫酸钠干燥， 过滤， 滤液减压浓缩。 用硅胶柱层析分 离纯化 (石油醚 /乙酸乙酯 (v/v)= 10/1), 得到无色液体的 2-(3-羟基 -l,la,6,6a-四氢环丙垸 [a]茚 -6-基)乙酸甲酯 3D (221 mg, 产率 65.4%)。  2-[3-[tert-Butyl(dimethyl)silyl]oxy-l,la,6,6a-tetrahydrocyclopropene[a]indol-6-yl]methyl acetate 3C (517 mg, 1.55 mmol) was dissolved in tetrahydrofuran (20 mL), tetrabutylammonium fluoride (517 mg, 1.98 mmol) was added at room temperature, and the reaction was stirred for 0.5 hr. Water (20 mL) was added to EtOAc EtOAc (EtOAc)EtOAc. Separation and purification by silica gel column chromatography (petroleum ether / ethyl acetate (v/v) = 10/1) to give 2-(3-hydroxy-l,la,6,6a-tetrahydrocyclopropane as a colorless liquid. [a] Indole-6-yl) methyl acetate 3D (221 mg, yield 65.4%).
再进一步通过手性 HPLC拆分 （CHIRALCEL OJ-H， 柱型： 0.46 cm I.D. χ 25 cm L， 流 动相： 正己垸 /无水乙醇 = 80/20(v/v)， 流速： lmL/mm， 波长： UV 214 nm， 柱温： 35 °C ) 得到黄色固体 3E (异构体 1 ) (108.7mg, ee: 99.97%, RT: 7.04 mm)和黄色固体 3F (异构 体 2) (110.2 mg, ee: 99.63%, RT: 10+ 18 mm)。 中间体 4:  Further resolution by chiral HPLC (CHIRALCEL OJ-H, column type: 0.46 cm ID χ 25 cm L, mobile phase: n-hexane/anhydrous ethanol = 80/20 (v/v), flow rate: lmL/mm, Wavelength: UV 214 nm, column temperature: 35 ° C) Yellow solid 3E (isomer 1) (108.7 mg, ee: 99.97%, RT: 7.04 mm) and yellow solid 3F (isomer 2) (110.2 mg) , ee: 99.63%, RT: 10+ 18 mm). Intermediate 4:
[3-[2,6-二甲基 -4-[(3R)-四氢呋喃 -3-基]氧基-苯基]苯基]甲醇 （4D)  [3-[2,6-Dimethyl-4-[(3R)-tetrahydrofuran-3-yl]oxy-phenyl]phenyl]methanol (4D)
[3-[2,6-dimethyl-4-[ 3R -tetrahydrofuran-3-yl]oxy-phenyl]phenyl]methanol [3-[2,6-dimethyl-4-[ 3R -tetrahydrofuran-3-yl]oxy-phenyl]phenyl]methanol
Figure imgf000033_0002
第一步： [(3S)-四氢呋喃 -3-基] 4-甲基苯磺酸酯 (4B)
Figure imgf000033_0002
First step: [(3S)-tetrahydrofuran-3-yl] 4-methylbenzenesulfonate (4B)
[(3 S)-tetrahydrofuran-3 -yl] 4-methylbenzenesulfonate
Figure imgf000034_0001
[(3 S)-tetrahydrofuran-3 -yl] 4-methylbenzenesulfonate
Figure imgf000034_0001
无水无氧氛围， 将 (S)-(+)-3-羟基四氢呋喃 4A (660.8 mg, 7.5 mmol)、 四甲基己二胺 （1.6 mL, 7.5 mmol)和二乙胺 （1.6 mL, 11.3 mmol) 溶于甲苯（15 mL) 中。 冰浴下，滴加对甲苯磺 酰氯 （2.1 g, 11.25 mmol) 的甲苯溶液（10 mL 保持在 0°C、 氮气氛围继续反应 2小时， TLC板监测反应完全。 向反应液中加入水（50 mL) 淬灭反应，用乙酸乙酯 （50 mL ) 萃取， 合并有机相， 用饱和食盐水 （50 mLx2;)洗涤， 无水硫酸钠干燥有机相， 过滤， 滤液减压浓 缩。 残留物用硅胶柱层析分离纯化 (石油醚 /乙酸乙酯 (vA =4: 1)， 得到淡黄色油状液体 [(3S)- 四氢呋喃 -3-基] 4-甲基苯磺酸酯 4B (1.34 g, 产率 75%)。  Anhydrous anaerobic atmosphere, (S)-(+)-3-hydroxytetrahydrofuran 4A (660.8 mg, 7.5 mmol), tetramethylhexamethylenediamine (1.6 mL, 7.5 mmol) and diethylamine (1.6 mL, 11.3) Methyl) is dissolved in toluene (15 mL). Under ice-cooling, a toluene solution of p-toluenesulfonyl chloride (2.1 g, 11.25 mmol) was added dropwise (10 mL was kept at 0 ° C, and the reaction was continued for 2 hours under a nitrogen atmosphere, and the reaction was monitored by TLC plate. Water was added to the reaction mixture. The reaction was quenched with EtOAc EtOAc (EtOAc)EtOAc. Separation and purification by column chromatography (petroleum ether / ethyl acetate (vA = 4: 1) to give a pale yellow oily liquid [(3S)-tetrahydrofuran-3-yl] 4-methylbenzenesulfonate 4B (1.34 g, yield Rate 75%).
第二步： 3-[2,6-二甲基 -4-[(3R)-四氢呋喃 -3-基]氧基-苯基]苯甲醛（4C) Second step: 3-[2,6-Dimethyl-4-[(3R)-tetrahydrofuran-3-yl]oxy-phenyl]benzaldehyde (4C)
3-[2,6-dimethyl-4-[(3R)-tetrahydro aldehyde
Figure imgf000034_0002
3-[2,6-dimethyl-4-[(3R)-tetrahydro aldehyde
Figure imgf000034_0002
将 [(3S)-四氢呋喃 -3-基] 4-甲基苯磺酸酯 4B (1.28 g, 5.28 mmol), 4'-羟基 -2',6'-二甲基 -1,1'-二苯基 -3-醛 1B (1.00 g, 4.42 mmol)和碳酸铯 （1.73 g, 5.30 mmol)溶于 Ν,Ν-二甲基甲酰 胺 （15 mL)中， 氮气氛围， 升温至 90°C搅拌反应 3小时。 向反应液中加入水（50 mL) 淬灭 反应， 用乙酸乙酯 （50 mLx3)萃取， 有机层分别用 1M氢氧化钠水溶液（100 mLx l) 和饱 和氯化钠水溶液（100 mLx l) 洗涤， 有机层用无水硫酸钠干燥。 过滤， 滤液减压浓缩， 残留 物用硅胶柱层析分离纯化 (石油醚 /乙酸乙酯 (v/v)= 10/1) ， 得到黄色油状 3-[2,6-二甲基 -4-[(3R)-四氢呋喃 -3-基]氧基-苯基]苯甲醛 4C (1.15 g, 产率 88%)。  [(3S)-Tetrahydrofuran-3-yl] 4-methylbenzenesulfonate 4B (1.28 g, 5.28 mmol), 4'-hydroxy-2',6'-dimethyl-1,1'-di Phenyl-3-aldehyde 1B (1.00 g, 4.42 mmol) and cesium carbonate (1.73 g, 5.30 mmol) were dissolved in hydrazine, hydrazine-dimethylformamide (15 mL), and heated to 90 ° C under stirring. Reaction for 3 hours. The reaction mixture was quenched with water (50 mL). The organic layer was dried over anhydrous sodium sulfate. Filtration, the filtrate was concentrated under reduced pressure. EtOAcjjjjjjjjjjjjj [(3R)-Tetrahydrofuran-3-yl]oxy-phenyl]benzaldehyde 4C (1.15 g, yield 88%).
第三步： [3-[2,6-二甲基 -4-[(3R)-四氢呋喃 -3-基]氧基-苯基]苯基]甲醇 （4D) Third step: [3-[2,6-Dimethyl-4-[(3R)-tetrahydrofuran-3-yl]oxy-phenyl]phenyl]methanol (4D)
[3-[2,6-dimethyl-4-[(3R)-tetrahydrofuran-3-yl]oxy-phenyl]phenyl]methanol
Figure imgf000034_0003
[3-[2,6-dimethyl-4-[(3R)-tetrahydrofuran-3-yl]oxy-phenyl]phenyl]methanol
Figure imgf000034_0003
无水无氧氛围， 将 3-[2,6-二甲基 -4-[(3R)-四氢呋喃 -3-基]氧基-苯基]苯甲醛 4C (1.15 g, 3.88 mmol)溶于甲醇 （30 mL)溶液中， 冰浴下， 分批向体系中加入硼氢化钠 （734.53 mg, 19.42 mmol 升至室温搅拌反应 15分钟， 向反应液中加水（20 mL) 淬灭反应。 浓缩反应 液， 加入盐酸 （20 mL, 1 M)， 用乙酸乙酯 （30 mL><3) 萃取， 合并有机相并用无水硫酸钠干 燥， 过滤， 将滤液减压浓缩。 残留物用硅胶柱层析分离纯化 (石油醚 /乙酸乙酯 (v/v)= 4/1)， 得到无色透明油状液体 [3-[2,6-二甲基 -4-[(3R)-四氢呋喃 -3-基]氧基-苯基]苯基]甲醇 4D (1.1 g, 产率 98%)。 中间体 5: 3-[2,6-Dimethyl-4-[(3R)-tetrahydrofuran-3-yl]oxy-phenyl]benzaldehyde 4C (1.15 g, 3.88 mmol) was dissolved in methanol. (30 mL), in an ice bath, add sodium borohydride (734.53 mg, 19.42 mmol) to room temperature and stir for 15 minutes, and add water (20 mL) to the reaction solution to quench the reaction. Hydrochloric acid (20 mL, 1 M) was added, EtOAc (EtOAc m. Purification (petroleum ether/ethyl acetate (v/v) = 4/1) afforded as a colorless oily liquid [3-[2,6-dimethyl-4-[(3R)-tetrahydrofuran-3-yl] Oxy-phenyl]phenyl]methanol 4D (1.1 g, yield 98%). Intermediate 5:
2-(3-羟基 -la-甲基 -6,6a-二氢 -1H-环丙垸 [a]茚 -6-基)乙酸甲酯 （5D)  2-(3-Hydroxy-la-methyl-6,6a-dihydro-1H-cyclopropanone [a] 茚-6-yl)acetic acid methyl ester (5D)
methyl 2- -hydroxy- 1 a-methyl-6,6a-dihydro- 1 H-cyclopropa[a] inden-6-yl) acetate Methyl 2- -hydroxy- 1 a-methyl-6,6a-dihydro- 1 H-cyclopropa[a] inden-6-yl) acetate
Figure imgf000035_0001
Figure imgf000035_0001
第一步： 2-[5- [叔丁基(二甲基)硅基]氧基 -3-亚甲基 -茚满小基]乙酸甲酯 （5A) First step: 2-[5-[tert-butyl(dimethyl)silyl]oxy-3-methylene-indanyl]methyl acetate (5A)
methyl 2-[5-[tert-butyl(dimethyl)silyl]oxy-3-methylene-indan-l-yl]acetate Methyl 2-[5-[tert-butyl(dimethyl)silyl]oxy-3-methylene-indan-l-yl]acetate
Figure imgf000035_0002
Figure imgf000035_0002
氮气氛围， 在 0°C下， 将叔丁醇钾 （0.98 g, 8.71 mmol)的四氢呋喃溶液缓慢加入到甲基 三苯基溴化膦（3.11 g, 8.71 mmol) 的干燥四氢呋喃 （20 mL)中的溶液中， 保持 0°C条件反应 0.5小时。 缓慢向反应体系中滴加 2-[5- [叔丁基(二甲基)硅基]氧基 -3-氧代 -茚满 -1-基]乙酸甲 酯 2G (1.94 g, 5.80 mmol) 的四氢呋喃溶液中， 升至室温， 继续搅拌反应 1小时。 TLC板跟 踪， 反应结束， 缓缓加入饱和氯化铵水溶液（30 mL)， 搅拌 5分钟。 混合物用乙酸乙酯 （30 mLx3)萃取， 合并有机相， 饱和食盐水（100 mLx l) 洗涤， 无水硫酸钠干燥， 过滤， 滤液 减压浓缩。 残留物用硅胶柱层析法分离纯化 (石油醚 /乙酸乙酯 (v/v)= 20/1)， 得到淡黄色油状 物 2-[5- [叔丁基 (二甲基)硅基]氧基 -3-亚甲基 -茚满 -1-基]乙酸甲酯 5A (1.53 g,产率 79.3%)。 第二步： 2-[5- [叔丁基(二甲基)硅基]氧基 -3-甲基 -1H-茚 -1-基]乙酸甲酯 （5B)  A solution of potassium tert-butoxide (0.98 g, 8.71 mmol) in tetrahydrofuran was slowly added to methyltriphenylphosphonium bromide (3.11 g, 8.71 mmol) in dry tetrahydrofuran (20 mL). The solution was kept at 0 ° C for 0.5 hour. 2-[5-[tert-Butyl(dimethyl)silyl]oxy-3-oxo-indan-1-yl]acetate methyl ester 2G (1.94 g, 5.80 mmol) was added dropwise slowly to the reaction system. In a tetrahydrofuran solution, the temperature was raised to room temperature, and the reaction was further stirred for 1 hour. The TLC plate was followed and the reaction was completed. Saturated aqueous ammonium chloride (30 mL) was added slowly and stirred for 5 min. The mixture was extracted with EtOAc (EtOAc) (EtOAc)EtOAc. The residue was purified by silica gel column chromatography (EtOAc (EtOAc/EtOAc) Methyloxy-3-methylene-indan-1-yl]acetate 5A (1.53 g, yield 79.3%). Step 2: 2-[5-[tert-Butyl(dimethyl)silyl]oxy-3-methyl-1H-indol-1-yl]acetate (5B)
methyl 2- [5 - [tert-butyl(dimethyl)silyl]oxy-3 -methyl- 1 H-inden- 1 -yl] acetate Methyl 2- [5 - [tert-butyl(dimethyl)silyl]oxy-3 -methyl- 1 H-inden- 1 -yl] acetate
Figure imgf000035_0003
Figure imgf000035_0003
将 2-[5- [叔丁基 (二甲基)硅基]氧基 -3-亚甲基 -茚满 -1-基]乙酸甲酯 5A (0.97 g, 2.92 mmol) 和三氟乙酸 （0.1 g, 0.88 mmol)溶于二氯甲垸（10 mL) 中。 升温至 40°C下搅拌反应 1小时， TLC点板跟踪反应结束。 将反应液浓缩旋干，残留物用硅胶柱层析分离纯化 (石油醚 /乙酸乙 酯 (v/v)= 20/1), 得到无色液体 2-[5- [叔丁基(二甲基)硅基]氧基 -3-甲基 -1H-茚 -1-基]乙酸甲酯 5B (0.71 g,产率 73.2%)。 2-[5-[tert-Butyl(dimethyl)silyl]oxy-3-methylene-indan-1-yl]acetate methyl ester 5A (0.97 g, 2.92 mmol) Trifluoroacetic acid (0.1 g, 0.88 mmol) was dissolved in dichloromethane (10 mL). The reaction was stirred at 40 ° C for 1 hour, and the TLC dot plate was followed to complete the reaction. The reaction mixture was concentrated to dryness (EtOAc mjjjjjjjjjjjjj Methyl) methoxy-3-methyl-1H-indol-1-yl]methyl acetate 5B (0.71 g, yield 73.2%).
第三步： 2-[3- [叔丁基 (二甲基;)硅基]氧基 -la-甲基 -6,6a-二氢 -1H-环丙垸 [a]茚 -6-基]乙酸乙酯 (5C) Step 3: 2-[3-[tert-Butyl(dimethyl))silyl]oxy-la-methyl-6,6a-dihydro-1H-cyclopropene[a]茚-6-yl Ethyl acetate (5C)
methyl 2-[3-[tert-butyl(dimethyl)silyl]oxy-la-methyl-6,6a-dihydro-lH-cyclopropa[a]inden-6-yl] acetate Methyl 2-[3-[tert-butyl(dimethyl)silyl]oxy-la-methyl-6,6a-dihydro-lH-cyclopropa[a]inden-6-yl] acetate
Figure imgf000036_0001
Figure imgf000036_0001
氮气氛围， 将二乙基锌 （0.53 g, 4.27 mmol) 溶于二氯甲垸（20 mL) 中， 降温至 -78°C， 滴加碘甲垸（2.29 g, 8.56 mmol)， 搅拌 10分钟， 再加入三氟乙酸 （0.49 g, 4.28 mmol)， 继续 搅拌 20分钟。 向混合物中滴加 2-[5- [叔丁基(二甲基)硅基]氧基 -3-甲基 -1H-茚 -1-基]乙酸甲酯 5B (0.71 g, 2.41 mmol) 的二氯甲垸溶液（20 mL),缓慢升至室温，继续搅拌反应 2小时， TLC 板监测反应结束。 向反应液中加入饱和氯化铵溶液（10 mL)， 分液， 有机相用水（10 mLx2) 洗涤， 无水硫酸钠干燥， 过滤， 将滤液减压浓缩， 得到 2-[3- [叔丁基 (二甲基)硅基]氧基 -la- 甲基 -6,6a-二氢 -1H-环丙垸 [a]茚 -6-基]乙酸乙酯 5C的粗产品， 直接用于下一步反应。  Diethylzinc (0.53 g, 4.27 mmol) was dissolved in dichloromethane (20 mL) under nitrogen atmosphere, cooled to -78 ° C, and ethyl iodothymidine (2.29 g, 8.56 mmol) was added dropwise and stirred for 10 min. Further trifluoroacetic acid (0.49 g, 4.28 mmol) was added and stirring was continued for 20 minutes. To the mixture was added dropwise 2-[5-[tert-butyl(dimethyl)silyl]oxy-3-methyl-1H-inden-1-yl]acetate methyl ester 5B (0.71 g, 2.41 mmol). The solution of methylene chloride (20 mL) was slowly warmed to room temperature, and the reaction was further stirred for 2 hours, and the TLC plate was used to monitor the end of the reaction. Saturated ammonium chloride solution (10 mL) was added to the reaction mixture, and the organic layer was washed with water (10 mL×2), dried over anhydrous sodium sulfate, filtered, A crude product of ethyl (dimethyl)silyl]oxy-la-methyl-6,6a-dihydro-1H-cyclopropane[a]indol-6-yl]ethyl acetate 5C, used directly under One step reaction.
第四步： 2-(3-羟基 -la-甲基 -6,6a-二氢 -1H-环丙垸 [a]茚 -6-基 1)乙酸甲酯 （5D) Step 4: 2-(3-Hydroxy-la-methyl-6,6a-dihydro-1H-cyclopropanil [a]茚-6-yl 1) methyl acetate (5D)
methyl 2-(3 -hydroxy- 1 a-methyl-6,6a-dihydro- 1 H-cyclopropa[a] inden-6-yl) acetate Methyl 2-(3 -hydroxy- 1 a-methyl-6,6a-dihydro- 1 H-cyclopropa[a] inden-6-yl) acetate
Figure imgf000036_0002
Figure imgf000036_0002
将四丁基氟化铵 （610 mg, 2.33 mmol)加入上步产物 2-[3- [叔丁基 (二甲基；)硅基]氧基 -la- 甲基 -6,6a-二氢 -1H-环丙垸 [a]茚 -6-基]乙酸乙酯 5C的粗产品的四氢呋喃 （10 mL)溶液中。 室温下搅拌反应 1小时， TLC板监测， 反应结束。 将反应液直接浓缩旋干， 残留物用硅胶 柱层析分离纯化 (石油醚 /乙酸乙酯 (vA = 6/1) , 得到无色液体 2-P-羟基 -la-甲基 -6,6a-二氢 -1H-环丙垸 [a]茚 -6-基 1)乙酸甲酯 5D (230 mg, 产率 56.2%)。 实施例 1  Tetrabutylammonium fluoride (610 mg, 2.33 mmol) was added to the above product 2-[3-[tert-butyl(dimethyl))silyl]oxy-la-methyl-6,6a-dihydrogen -1H-cyclopropanone [a] 茚-6-yl] ethyl acetate 5C in a crude product in tetrahydrofuran (10 mL). The reaction was stirred at room temperature for 1 hour, monitored by TLC plate, and the reaction was completed. The reaction mixture was directly concentrated to dryness, and the residue was purified eluting with silica gel column chromatography - Dihydro-1H-cyclopropanil [a] indol-6-yl 1) methyl acetate 5D (230 mg, yield 56.2%). Example 1
2-[3-[[3-[2,6-二甲基 -4- 3-甲磺酰基丙氧基；)苯基]苯基]甲氧基] -l,la,6,6a-四氢环丙垸 [a]茚 -6- 基]乙酸 （化合物 1) 2-[3-[[3-[2,6-dimethyl-4-(3-methylsulfonylpropoxy)phenyl]phenyl]methoxy]-l,la,6,6a-tetrahydro cyclopropa[a inden-6- l acetic acid 2-[3-[[3-[2,6-dimethyl-4- 3-methanesulfonylpropoxy;)phenyl]phenyl]methoxy]-l,la,6,6a-tetra Hydrogen oxime [a] 茚-6-yl] acetic acid (compound 1) 2-[3-[[3-[2,6-dimethyl-4-(3-methylsulfonylpropoxy)phenyl]phenyl]methoxy]-l,la,6,6a-tetrahydro cyclopropa[a inden-6- l acetic acid
Figure imgf000037_0001
Figure imgf000037_0001
第一步： 2-[3-[[3-[2，6-二甲基 -4-(3-甲磺酰基丙氧基)苯基]苯基]甲氧基] -l,la,6,6a-四氢环丙烷 [a]茚 -6-基]乙酸甲酯 （la) First step: 2-[3-[[3-[2,6-dimethyl-4-(3-methylsulfonylpropoxy)phenyl]phenyl]methoxy]-l,la,6 , 6a-tetrahydrocyclopropane [a] indol-6-yl] methyl acetate (la)
methyl 2-[3-[[3-[2,6-dimethyl-4-(3-methylsulfonylpropoxy)phenyl]phenyl]methoxy]-l,la,6,6a- tetrahydrocyclopropa[a]inden-6-yl]acetate Methyl 2-[3-[[3-[2,6-dimethyl-4-(3-methylsulfonylpropoxy)phenyl]phenyl]methoxy]-l,la,6,6a-tetrahydrocyclopropa[a]inden-6-yl]acetate
Figure imgf000037_0002
Figure imgf000037_0002
氮气氛围，在 0°C下， [3-[2,6-二甲基 -4-(3-甲磺酰基丙氧基)苯基]苯基]甲醇 lG (383 mg, 1.10 mmol)和2-(3-羟基-Ua,6,6a-四氢环丙垸[a]茚-6-基)乙酸甲酯3D (221 mg, 1.01 mmol) 溶 于干燥的二氯甲垸（30 mL) 中， 将三丁基膦（445 mg, 2.20 mmol)和 1,Γ-(偶氮二羰基;)二哌 啶 （555 mg, 2.20 mmol) 加入混合物中。 保持冰浴搅拌 5分钟， 升至室温继续搅拌反应 1.5 小时， TLC板跟踪反应结束。 反应液用水（10 mLx2) 洗涤， 有机相用无水硫酸钠干燥， 过 滤， 滤液减压浓缩。 残留物用硅胶柱层析分离纯化 (石油醚 /乙酸乙酯 (v/v)= 1/1)， 得到无色 液体状的 2-[3-[[3-[2,6-二甲基 -4-(3-甲磺酰基丙氧基)苯基]苯基]甲氧基] -Ua,6,6a-四氢环丙 垸 [a]茚 -6-基]乙酸甲酯 la (197 mg, 产率 35.9%)。  [3-[2,6-Dimethyl-4-(3-methanesulfonylpropoxy)phenyl]phenyl]methanol 1G (383 mg, 1.10 mmol) and 2 at 0 ° C -(3-Hydroxy-Ua,6,6a-tetrahydrocyclopropane[a]indol-6-yl)acetic acid methyl ester 3D (221 mg, 1.01 mmol) dissolved in dry dichloromethane (30 mL) Tributylphosphine (445 mg, 2.20 mmol) and 1, hydrazine-(azodicarbonyl;)dipiperidine (555 mg, 2.20 mmol) were added to the mixture. The mixture was kept in an ice bath for 5 minutes, and the reaction was further stirred at room temperature for 1.5 hours, and the TLC plate was followed to complete the reaction. The reaction mixture was washed with EtOAcq. The residue was purified by silica gel column chromatography (EtOAc/EtOAc (EtOAc/EtOAc) 4-(3-methanesulfonylpropoxy)phenyl]phenyl]methoxy]-Ua,6,6a-tetrahydrocyclopropene[a]indol-6-yl]methyl acetate la (197 Mg, yield 35.9%).
第二步： 2-[3-[[3-[2,6-二甲基 -4-(3-甲磺酰基丙氧基)苯基]苯基]甲氧基] -l,la,6,6a-四氢环丙烷 [a]茚 -6-基]乙酸 （化合物 1) The second step: 2-[3-[[3-[2,6-dimethyl-4-(3-methanesulfonylpropoxy)phenyl]phenyl]methoxy]-l,la,6 ,6a-tetrahydrocyclopropane [a]茚-6 -yl]acetic acid (Compound 1)
2-[3-[[3-[2,6-dimethyl-4-(3-methylsulfonylpropoxy)phenyl]phenyl]methoxy]-l,la,6,6a-tetrahydro cyclopropa[a] inden-6-yl] acetic acid 2-[3-[[3-[2,6-dimethyl-4-(3-methylsulfonylpropoxy)phenyl]phenyl]methoxy]-l,la,6,6a-tetrahydro cyclopropa[a] inden-6-yl] acetic acid Acid
将 2-[3-[[3-[2,6-二甲基 -4-(3-甲磺酰基丙氧基)苯基]苯基]甲氧基] -Ua,6,6a-四氢环丙垸 [a]茚 -6-基]乙酸甲酯 la (150 mg, 0.27 mmol) 溶于甲醇 (10 mL) 中，滴加氢氧化钠 (108 mg, 2.7 M)溶液于混合物中。 室温搅拌反应过夜， TLC点板跟踪反应结束。 反应液用稀盐酸调 节 pH小于 4， 用乙酸乙酯 （10 mLx2)萃取， 合并有机相， 用水（10 mLx l)洗涤。 将有机 相浓缩， 溶于氢氧化钠溶液 (10 mL, 1M)中， 用乙酸乙酯 （10 mLx2)萃取， 有机相用无水硫 酸钠干燥， 过滤， 滤液减压浓缩， 得到白色固体的 2-[3-[[3-[2,6-二甲基 -4-P-甲磺酰基丙氧 基)苯基]苯基]甲氧基 ]-l,la,6,6a-四氢环丙垸 [a]茚 -6-基]乙酸化合物 1 (80mg, 产率 54.8%)。  2-[3-[[3-[2,6-Dimethyl-4-(3-methanesulfonylpropoxy)phenyl]phenyl]methoxy]-Ua,6,6a-tetrahydro The cyanohydrazide [a] 茚-6-yl] methyl acetate la (150 mg, 0.27 mmol) was dissolved in methanol (10 mL) and a solution of sodium hydroxide (108 mg, 2.7 M) was added dropwise. The reaction was stirred at room temperature overnight, and the TLC spot plate was followed to complete the reaction. The reaction mixture was adjusted to pH 4 with dilute aqueous hydrochloric acid, extracted with ethyl acetate (10 mL×2), and the organic phase was combined and washed with water (10 mL×l). The organic phase was concentrated, dissolved in EtOAc EtOAc (EtOAc (EtOAc) -[3-[[3-[2,6-Dimethyl-4-P-methylsulfonylpropoxy)phenyl]phenyl]methoxy]-l,la,6,6a-tetrahydrocyclo Propionanium [a] indole-6-yl]acetic acid compound 1 (80 mg, yield 54.8%).
MS [M-1]- (ESI): 533.2 ο  MS [M-1]- (ESI): 533.2 ο
¾ MR (400 MHz, CDC13) 57.40(m,2H), 7.17(s,lH), 7.06(d,lH), 6.93(m,2H), 6.73(dd,lH),3⁄4 MR (400 MHz, CDC1 3 ) 57.40 (m, 2H), 7.17 (s, lH), 7.06 (d, lH), 6.93 (m, 2H), 6.73 (dd, lH),
6.64(s,2H), 5.08(s,2H), 4.13(t,2H), 3.87(m,lH), 3.28(m,2H), 2.97(s,3H), 2.81(dd,lH), 2.50(dd,lH), 2.35(m,3H), 2.05(m,lH), 1.99(s,6H), 0.92(m,lH), 0.09(m,lH)。 实施例 2 6.64(s,2H), 5.08(s,2H), 4.13(t,2H), 3.87(m,lH), 3.28(m,2H), 2.97(s,3H), 2.81(dd,lH), 2.50 (dd, lH), 2.35 (m, 3H), 2.05 (m, lH), 1.99 (s, 6H), 0.92 (m, lH), 0.09 (m, lH). Example 2
2-[3-[[3-[2,6-二甲基 -4-(3-甲磺酰基丙氧基；)苯基]苯基]甲氧基] -Ua,6,6a-四氢环丙垸 [a]茚 -6- 基]乙酸 （化合物 2)  2-[3-[[3-[2,6-Dimethyl-4-(3-methanesulfonylpropoxy))phenyl]phenyl]methoxy]-Ua,6,6a-tetrahydro Cyclopropanil [a] 茚-6-yl]acetic acid (compound 2)
2-[3-[[3-[2,6-dimethyl-4-(3-methylsulfonylpropoxy)phenyl]phenyl]methoxy]-l,la,6,6a-tetrahydro cyclopropa[a inden-6- l acetic acid  2-[3-[[3-[2,6-dimethyl-4-(3-methylsulfonylpropoxy)phenyl]phenyl]methoxy]-l,la,6,6a-tetrahydro cyclopropa[a inden-6- l acetic acid
Figure imgf000038_0002
Figure imgf000038_0002
第一步： 2-[3-[[3-[2,6-二甲基 -4-(3-甲磺酰基丙氧基)苯基]苯基]甲氧基] -l,la,6,6a-四氢环丙烷 [a]茚 -6-基]乙酸甲酯 （2a) methyl 2-[3-[[3-[2,6-dimethyl-4-(3-methylsulfonylpropoxy)phenyl]phenyl]methoxy]-l,la,6,6a- tetrahydrocyclopropa[a]inden-6-yl]acetate First step: 2-[3-[[3-[2,6-dimethyl-4-(3-methylsulfonylpropoxy)phenyl]phenyl]methoxy]-l,la,6 , 6a-tetrahydrocyclopropane [a] indol-6-yl] methyl acetate (2a) Methyl 2-[3-[[3-[2,6-dimethyl-4-(3-methylsulfonylpropoxy)phenyl]phenyl]methoxy]-l,la,6,6a-tetrahydrocyclopropa[a]inden-6-yl]acetate
Figure imgf000039_0001
Figure imgf000039_0001
室温下，氮气氛围， 2-(3-羟基 -l,la,6,6a-四氢环丙并 [a]茚 -6-基；)乙酸甲酯 3E (43.6 mg, 0.20 mmol), [3-[2,6-二甲基 -4-(3-甲磺酰基丙氧基)苯基]苯基]甲醇 lG (69.7 mg， 0.20 mmol) 溶于 干燥的二氯甲垸（20 mL)中，加入 U 偶氮二羰基;)二哌啶 G00.9 mg, 0.40 mmol)。 将混合物 降至 0°C， 滴加三丁基膦（80.9 mg, 0.40 mmol), 冰浴下继续搅拌 3小时， TLC板跟踪反应 结束。 将反应液直接减压浓縮， 残留物用硅胶柱层析分离纯化 (石油醚 /乙酸乙酯 (v/v)= 1/1), 得到白色固体 2-[3-[[3-[2,6-二甲基 -4-(3-甲磺酰基丙氧基)苯基]苯基]甲氧基] -Ua,6,6a-四氢 环丙垸 [a]茚 -6-基]乙酸甲酯 2a (91 mg, 产率 83.0%)。  At room temperature, nitrogen atmosphere, 2-(3-hydroxy-l,la,6,6a-tetrahydrocyclopropyl[a]indol-6-yl;)methyl acetate 3E (43.6 mg, 0.20 mmol), [3 -[2,6-Dimethyl-4-(3-methanesulfonylpropoxy)phenyl]phenyl]methanol 1G (69.7 mg, 0.20 mmol) dissolved in dry dichloromethane (20 mL) , U azodicarbonyl;) Dipiperidine G00.9 mg, 0.40 mmol). The mixture was lowered to 0 ° C, tributylphosphine (80.9 mg, 0.40 mmol) was added dropwise, and stirring was continued for 3 hours in an ice bath, and the TLC plate was followed to complete the reaction. The reaction mixture was concentrated under reduced pressure. EtOAc mjjjjjjjjjj ,6-Dimethyl-4-(3-methanesulfonylpropoxy)phenyl]phenyl]methoxy]-Ua,6,6a-tetrahydrocyclopropene [a]茚-6-yl] Methyl acetate 2a (91 mg, yield 83.0%).
第二步： 2-[3-[[3-[2,6-二甲基 -4-(3-甲磺酰基丙氧基)苯基]苯基]甲氧基] -l,la,6,6a-四氢环丙烷 [a]茚 -6-基]乙酸 （化合物 2) The second step: 2-[3-[[3-[2,6-dimethyl-4-(3-methanesulfonylpropoxy)phenyl]phenyl]methoxy]-l,la,6 ,6a-tetrahydrocyclopropane [a]茚-6 -yl]acetic acid (Compound 2 )
2-[3-[[3-[2,6-dimethyl-4-(3-methylsulfonylpropoxy)phenyl]phenyl]methoxy]-l,la,6,6a-tetrahydro cyclopropa[a] inden-6-yl] acetic acid  2-[3-[[3-[2,6-dimethyl-4-(3-methylsulfonylpropoxy)phenyl]phenyl]methoxy]-l,la,6,6a-tetrahydro cyclopropa[a] inden-6-yl] acetic acid Acid
Figure imgf000039_0002
Figure imgf000039_0002
将 2-[3-[[3-[2,6-二甲基 -4-(3-甲磺酰基丙氧基)苯基]苯基]甲氧基] -Ua,6,6a-四氢环丙垸 [a]茚 -6-基]乙酸甲酯 2a (91 mg, 0.17 mmol)溶于甲醇 (10 mL) 中，滴加氢氧化钠 (133 mg, 6.64 M)溶液，室温下搅拌反应过夜， TLC点板跟踪反应结束。 将反应液浓缩至 l mL，加水 （20 mL)稀释， 用乙酸乙酯 (10 mLx2)萃取， 合并有机相， 用水（10 mL><2)洗涤。 有机相用无 水硫酸钠干燥，过滤，将滤液减压浓缩。 残留物用硅胶柱层析分离纯化 (二氯甲院 /甲醇 (v/v)= 10/1),得到白色固体 2-[3-[[3-[2,6-二甲基 -4-(3-甲磺酰基丙氧基)苯基]苯基]甲氧基] -l,la,6,6a- 四氢环丙垸 [a]茚 -6-基]乙酸化合物 2 (67 mg, 产率 75.3%)。  2-[3-[[3-[2,6-Dimethyl-4-(3-methanesulfonylpropoxy)phenyl]phenyl]methoxy]-Ua,6,6a-tetrahydro Cyclopropanol [a] 茚-6-yl] methyl acetate 2a (91 mg, 0.17 mmol) was dissolved in methanol (10 mL), and sodium hydroxide (133 mg, 6.64 M) was added dropwise and stirred at room temperature. Overnight, the TLC dot plate tracks the end of the reaction. The reaction mixture was concentrated to EtOAc (EtOAc) (EtOAc) The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by silica gel column chromatography (dichlorobenzene/methanol (v/v) = 10/1) to give 2-[3-[[3-[2,6-dimethyl-4- (3-methanesulfonylpropoxy)phenyl]phenyl]methoxy]-l,la,6,6a-tetrahydrocyclopropene[a]indol-6-yl]acetic acid compound 2 (67 mg, The yield was 75.3%).
MS [M-1]- (ESI): 533.2 ο  MS [M-1]- (ESI): 533.2 ο
¾ MR (400 MHz, CDC13) 57.40(m,2H), 7.17(s,lH), 7.06(d,lH), 6.93(m,2H), 6.73(dd,lH),3⁄4 MR (400 MHz, CDC1 3 ) 57.40 (m, 2H), 7.17 (s, lH), 7.06 (d, lH), 6.93 (m, 2H), 6.73 (dd, lH),
6.64(s,2H), 5.08(s,2H), 4.13(t,2H), 3.87(m,lH), 3.28(m,2H), 2.97(s,3H), 2.81(dd,lH), 2.50(dd,lH), 2.35(m,3H), 2.05(m,lH), 1.99(s,6H), 0.92(m,lH), 0.09(m,lH)。 实施例 3 6.64(s,2H), 5.08(s,2H), 4.13(t,2H), 3.87(m,lH), 3.28(m,2H), 2.97(s,3H), 2.81(dd,lH), 2.50 (dd, lH), 2.35 (m, 3H), 2.05 (m, lH), 1.99 (s, 6H), 0.92 (m, lH), 0.09 (m, lH). Example 3
2-[3-[[3-[2,6-二甲基 -4-(3-甲磺酰基丙氧基；)苯基]苯基]甲氧基] -l,la,6,6a-四氢环丙垸 [a]茚 -6- 基]乙酸 （化合物 3)  2-[3-[[3-[2,6-Dimethyl-4-(3-methanesulfonylpropoxy))phenyl]phenyl]methoxy]-l,la,6,6a- Tetrahydrocyclopropane [a] indol-6-yl]acetic acid (compound 3)
2-[3-[[3-[2,6-dimethyl-4-(3-methylsulfonylpropoxy)phenyl]phenyl]methoxy]-l,la,6,6a-tetrahydro cyclopropa[a inden-6- l acetic acid  2-[3-[[3-[2,6-dimethyl-4-(3-methylsulfonylpropoxy)phenyl]phenyl]methoxy]-l,la,6,6a-tetrahydro cyclopropa[a inden-6- l acetic acid
Figure imgf000040_0001
Figure imgf000040_0001
第一步： 2-[3-[[3-[2,6-二甲基 -4-(3-甲磺酰基丙氧基)苯基]苯基]甲氧基] -l,la,6,6a-四氢环丙烷 [a]茚 -6-基]乙酸甲酯 3a) methyl 2-[3-[[3-[2,6-dimethyl-4-(3-methylsulfonylpropoxy)phenyl]phenyl]methoxy]-l,la,6,6a- tetrahydrocyclopropa[a]inden-6-yl]acetate First step: 2-[3-[[3-[2,6-dimethyl-4-(3-methylsulfonylpropoxy)phenyl]phenyl]methoxy]-l,la,6 , 6a-tetrahydrocyclopropane [a] 茚-6-yl] methyl acetate 3a) methyl 2-[3-[[3-[2,6-dimethyl-4-(3-methylsulfonylpropoxy)phenyl]phenyl]methoxy ]-l,la,6,6a-tetrahydrocyclopropa[a]inden-6-yl]acetate
Figure imgf000040_0002
Figure imgf000040_0002
氮气氛围， 2-(3-羟基 -Ua,6,6a-四氢环丙垸 [a]茚 -6-基)乙酸甲酯 3F (43.6 mg, 0.20 mmol) 禾口 [3-[2,6-二甲基 -4-(3-甲磺酰基丙氧基)苯基]苯基]甲醇 1G (69.7 mg, 0.20 mmol) 溶于干燥 二氯甲烷（20 mL) 中， 再加入 U 偶氮二羰基；)二哌啶 (100.9 mg, 0.40 mmol)。 将混合物降 温至 0°C， 滴加三丁基膦（80.9 mg, 0.40 mmol), 冰浴下继续搅拌 3小时， TLC板跟踪反应 结束。 将反应液直接减压浓縮， 残留物用硅胶柱层析分离纯化 (石油醚 /乙酸乙酯 (v/v)= 1/1)， 得到白色固体 2-[3-[[3-[2,6-二甲基 -4-(3-甲磺酰基丙氧基)苯基]苯基]甲氧基] -Ua,6,6a-四氢 环丙垸 [a]茚 -6-基]乙酸甲酯 3a (94 mg, 产率 85.7%)。  Nitrogen atmosphere, 2-(3-hydroxy-Ua,6,6a-tetrahydrocyclopropane[a]indol-6-yl)acetate methyl ester 3F (43.6 mg, 0.20 mmol) and [3] -Dimethyl-4-(3-methanesulfonylpropoxy)phenyl]phenyl]methanol 1G (69.7 mg, 0.20 mmol) dissolved in dry dichloromethane (20 mL), then U azo Carbonyl;) Dipiperidine (100.9 mg, 0.40 mmol). The mixture was cooled to 0 ° C, tributylphosphine (80.9 mg, 0.40 mmol) was added dropwise, and stirring was continued for 3 hours under ice bath, and the TLC plate was followed to complete the reaction. The reaction mixture was concentrated under reduced pressure. EtOAc mjjjjjjjjjj ,6-Dimethyl-4-(3-methanesulfonylpropoxy)phenyl]phenyl]methoxy]-Ua,6,6a-tetrahydrocyclopropene [a]茚-6-yl] Methyl acetate 3a (94 mg, yield 85.7%).
第二步： 2-[3-[[3-[2,6-二甲基 -4-(3-甲磺酰基丙氧基；)苯基]苯基]甲氧基] -l,la,6,6a-四氢环丙烷 [a]茚 -6-基]乙酸 （化合物 3) Second step: 2-[3-[[3-[2,6-dimethyl-4-(3-methylsulfonylpropoxy))phenyl]phenyl]methoxy]-l,la, 6,6a-tetrahydrocyclopropane [a] indol-6-yl]acetic acid (compound 3)
2-[3-[[3-[2,6-dimethyl-4-(3-methylsulfonylpropoxy)phenyl]phenyl]methoxy]-l,la,6,6a-tetrahydro
Figure imgf000041_0001
2-[3-[[3-[2,6-dimethyl-4-(3-methylsulfonylpropoxy)phenyl]phenyl]methoxy]-l,la,6,6a-tetrahydro
Figure imgf000041_0001
将 2-[3-[[3-[2,6-二甲基 -4-(3-甲磺酰基丙氧基)苯基]苯基]甲氧基] -Ua,6,6a-四氢环丙垸 [a]茚 -6-基]乙酸甲酯 3a (94 mg, 0.17 mmol) 溶于甲醇 （10 mL) 中， 滴加氢氧化钠 （133 mg, 6.64 M)水溶液， 室温搅拌反应过夜， TLC点板跟踪反应结束。 将反应液浓缩至 lmL， 加水 (20 mL)稀释， 用乙酸乙酯 （10 mLx2)萃取， 合并有机相， 用水（10 mL><2)洗涤。 有机相 用无水硫酸钠干燥， 过滤， 将滤液减压浓缩。 残留物用硅胶柱层析分离纯化 (二氯甲院 /甲醇 (v/v)= 10/1) ， 得到白色固体 2-[3-[[3-[2,6-二甲基 -4-P-甲磺酰基丙氧基)苯基]苯基]甲氧 基] -l,la,6,6a-四氢环丙垸 [a]茚 -6-基]乙酸 3 (71 mg,产率 78.0%)。  2-[3-[[3-[2,6-Dimethyl-4-(3-methanesulfonylpropoxy)phenyl]phenyl]methoxy]-Ua,6,6a-tetrahydro Methyl chloroformate [a] 茚-6-yl]methyl acetate 3a (94 mg, 0.17 mmol) dissolved in methanol (10 mL), aqueous sodium hydroxide (133 mg, 6.64 M) , TLC point plate tracking reaction is over. The reaction mixture was concentrated to EtOAc (EtOAc) (EtOAc) The organic phase was dried over anhydrous sodium sulfate and filtered and evaporated. The residue was purified by silica gel column chromatography (dichlorobenzene/methanol (v/v) = 10/1) to give 2-[3-[[3-[2,6-dimethyl-4- P-Methanesulfonylpropoxy)phenyl]phenyl]methoxy]-l,la,6,6a-tetrahydrocyclopropene[a]indol-6-yl]acetic acid 3 (71 mg, yield 78.0%).
MS [M-1]- (ESI): 533.2 ο  MS [M-1]- (ESI): 533.2 ο
¾ MR (400 MHz, CDC13) 57.40(m,2H), 7.17(s,lH), 7.06(d,lH), 6.93(m,2H), 6.73(dd,lH), 6.64(s,2H), 5.08(s,2H), 4.13(t,2H), 3.87(m,lH), 3.28(m,2H), 2.97(s,3H), 2.81(dd,lH), 2.50(dd,lH), 2.35(m,3H), 2.05(m,lH), 1.99(s,6H), 0.92(m,lH), 0.09(m,lH)。 实施例 4 3⁄4 MR (400 MHz, CDC1 3 ) 57.40 (m, 2H), 7.17 (s, lH), 7.06 (d, lH), 6.93 (m, 2H), 6.73 (dd, lH), 6.64 (s, 2H) , 5.08(s,2H), 4.13(t,2H), 3.87(m,lH), 3.28(m,2H), 2.97(s,3H), 2.81(dd,lH), 2.50(dd,lH), 2.35 (m, 3H), 2.05 (m, lH), 1.99 (s, 6H), 0.92 (m, lH), 0.09 (m, lH). Example 4
2-[3-[[3-[2,6-二甲基 -4-[(3R 四氢呋喃 -3-基]氧基-苯基]苯基]甲氧基] -l,la,6,6a-四氢环丙烷 [a] 茚 -6-基]乙酸 （化合物 4) 2-[3-[[3-[2,6-Dimethyl-4-[(3Rtetrahydrofuran-3-yl)oxy-phenyl]phenyl]methoxy]-l,la,6,6a -tetrahydrocyclopropane [a] 茚-6 -yl]acetic acid (compound 4 )
2-[3-[[3-[2,6-dimethyl-4-[(3R)-tetrahydrofuran-3-yl]oxy-phenyl]phenyl]methoxy]-l,la,6,6a- tetrahydrocyclopropa[a]inden- -yl]acetic acid  2-[3-[[3-[2,6-dimethyl-4-[(3R)-tetrahydrofuran-3-yl]oxy-phenyl]phenyl]methoxy]-l,la,6,6a-tetrahydrocyclopropa[a] Inden- -yl]acetic acid
Figure imgf000041_0002
Figure imgf000041_0002
笫一步： 2-[3-[[3-[2,6-二甲基 -4-[(3R)-四氢呋喃 -3-基]氧基-苯基]苯基]甲氧基] -l,la,6,6a-四氢 环丙垸 [a]茚 -6-基]乙酸甲酯 （化合物 4a) Further: 2-[3-[[3-[2,6-Dimethyl-4-[(3R)-tetrahydrofuran-3-yl]oxy-phenyl]phenyl]methoxy]-l, La,6,6a-tetrahydrogen Cyclopropanil [a] 茚- 6 -yl]methyl acetate (compound 4 a)
Methyl 2-[3-[[3-[2,6-dimethyl-4-[(3R)-tetrahydrofuran-3-yl]oxy-phenyl]phenyl]methoxy]-l,la,6. 6a-tetrahydrocyclopropa[a]inden-6-yl] acetate  Methyl 2-[3-[[3-[2,6-dimethyl-4-[(3R)-tetrahydrofuran-3-yl]oxy-phenyl]phenyl]methoxy]-l,la,6. 6a-tetrahydrocyclopropa[a ]inden-6-yl] acetate
Figure imgf000042_0001
Figure imgf000042_0001
[3-[2,6-二甲基 -4-[(3R)-四氢呋喃 -3-基]氧基-苯基]苯基]甲醇 4D (298 mg, 1.00 mmol， 中 间体 4)和 2-(3-羟基 -l,la,6,6a-四氢环丙垸 [a]茚 -6-基)乙酸甲酯 3D(218 mg, 1.00 mmol)溶于干 燥二氯甲垸（20 mL) 中。 将混合物降温至 0°C，加入 1,1'-(偶氮二羰基；)二哌啶 （504 mg, 2.00 mmol)和滴入三丁基膦（404 mg, 2.00 mmol), 保持 0°C搅拌反应 15分钟。 将反应液缓慢升 至室温继续反应 3小时， TLC板跟踪反应结束。 反应液用硅藻土过滤， 滤液减压浓缩。 残 留物用硅胶柱层析分离纯化 (石油醚 /乙酸乙酯 i 、= 3/1), 得到无色液体 2-[3-[[3-[2,6-二甲 基—4-[(3R)-四氢呋喃 -3-基]氧基-苯基]苯基]甲氧基] -l,la,6,6a-四氢环丙垸 [a]茚 -6-基]乙酸甲酯 4a(408 mg, 产率 81.9%)。  [3-[2,6-Dimethyl-4-[(3R)-tetrahydrofuran-3-yl]oxy-phenyl]phenyl]methanol 4D (298 mg, 1.00 mmol, Intermediate 4) and 2- (3-Hydroxy-l,la,6,6a-tetrahydrocyclopropane[a]indol-6-yl)acetic acid methyl ester 3D (218 mg, 1.00 mmol) dissolved in dry dichloromethane (20 mL) . The mixture was cooled to 0 ° C, 1,1 '-(azodicarbonyl;)dipiperidine (504 mg, 2.00 mmol) was added and tributylphosphine (404 mg, 2.00 mmol) was added dropwise, maintaining 0 ° C The reaction was stirred for 15 minutes. The reaction solution was slowly warmed to room temperature and the reaction was continued for 3 hours, and the TLC plate was followed to complete the reaction. The reaction solution was filtered through celite, and evaporated. The residue was purified by silica gel column chromatography ( petroleum ether / ethyl acetate i, = 3/1) to give colorless liquid 2-[3-[[3-[2,6-dimethyl- 4-[( 3R)-tetrahydrofuran-3-yl]oxy-phenyl]phenyl]methoxy]-l,la,6,6a-tetrahydrocyclopropene[a]indol-6-yl]methyl acetate 4a ( 408 mg, yield 81.9%).
第二步： 2-[3-[[3-[2,6-二甲基 -4-[(3R)-四氢呋喃 -3-基]氧基-苯基]苯基]甲氧基] -l,la,6,6a-四氢 环丙垸 [a]茚 -6-基]乙酸 （化合物 4) 2-[3-[[3-[2,6-dimethyl-4-[(3R)-tetrahydrofuran-3-yl]oxy-phenyl]phenyl]methoxy]-l,la,6,6a- tetrahydrocyclopropa[a]inden-6-yl]acetic acid Second step: 2-[3-[[3-[2,6-Dimethyl-4-[(3R)-tetrahydrofuran-3-yl]oxy-phenyl]phenyl]methoxy]-l ,la,6,6a-tetrahydrocyclopropene[a]indol-6-yl]acetic acid (compound 4) 2-[3-[[3-[2,6-dimethyl-4-[(3R)-tetrahydrofuran -3-yl]oxy-phenyl]phenyl]methoxy]-l,la,6,6a-tetrahydrocyclopropa[a]inden-6-yl]acetic acid
Figure imgf000042_0002
Figure imgf000042_0002
将 2-[3-[[3-[2,6-二甲基 -4-[(3R)-四氢呋喃 -3-基]氧基-苯基]苯基]甲氧基] -l,la,6,6a-四氢环 丙垸 [a]茚 -6-基]乙酸甲酯 4a (408 mg, 0.82 mmoL)悬浮于甲醇 (40 mL) 中， 滴加氢氧化钠 (656 mg, 16.40 M) 水 溶液， 室温下搅拌反应过夜。 将反应液减压浓缩， 加水（10 mL)， 用 1M稀盐酸酸化混合物至 PH小于 4。 用乙酸乙酯（20 mLx3)萃取， 合并有机相， 用水 （10 mLx2) 洗涤， 无水硫酸钠干燥， 过滤， 将滤液浓缩。 残留物用硅胶柱层析分离纯化 （二氯 甲院 /甲醇 (v/v)= 50/1)，得到白色固体 2-[3-[[3-[2,6-二甲基 -4-[(3R)-四氢呋喃 -3-基]氧基-苯基] 苯基]甲氧基] -Ua,6,6a-四氢环丙垸 [a]茚 -6-基]乙酸 化合物 4 (292 mg, 产率 73.6%)。  2-[3-[[3-[2,6-Dimethyl-4-[(3R)-tetrahydrofuran-3-yl]oxy-phenyl]phenyl]methoxy]-l,la, 6,6a-tetrahydrocyclopropane [a] 茚-6-yl] methyl acetate 4a (408 mg, 0.82 mmoL) was suspended in methanol (40 mL) and sodium hydroxide (656 mg, 16.40 M) was added dropwise. The aqueous solution was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure. water (10 mL) was evaporated, The mixture was extracted with EtOAc (EtOAc)EtOAc. The residue was purified by silica gel column chromatography (dichlorobenzene/methanol (v/v) = 50/1) to afford 2-[3-[[3-[2,6-dimethyl-4- [(3R)-tetrahydrofuran-3-yl]oxy-phenyl]phenyl]methoxy]-Ua,6,6a-tetrahydrocyclopropene[a]indol-6-yl]acetic acid compound 4 (292 Mg, yield 73.6%).
MS [M-1]- (ESI): 483.1。  MS [M-1]- (ESI): 483.1.
¾ MR (400 MHz, CDC13) δ7.43(ηι,2Η), 7.18(s,lH), 7.08(d,lH), 6.90(m,2H), 6.73(dd,lH), 6.62(s,2H), 5.08(s,2H), 4.95(m,lH), 4.03(m,3H), 3.87(m,2H), 2.85(dd,lH), 2.48(dd,lH), 2.32(m,lH), 2.20(m,2H), 2.07(m,lH), 1.99(s,6H), 0.93(m,lH), 0.09(m,lH)。 实施例 5 3⁄4 MR (400 MHz, CDC1 3 ) δ 7.43 (ηι, 2Η), 7.18 (s, lH), 7.08 (d, lH), 6.90 (m, 2H), 6.73 (dd, lH), 6.62 (s, 2H), 5.08(s,2H), 4.95(m,lH), 4.03(m,3H), 3.87(m,2H), 2.85(dd,lH), 2.48(dd,lH), 2.32(m,lH), 2.20(m,2H), 2.07(m,lH), 1.99(s,6H), 0.93(m,lH), 0.09(m,lH). Example 5
2-[3-[[3-[2,6-二甲基 -4-(3-甲磺酰基丙氧基；)苯基]苯基]甲氧基] -la-甲基 -6,6a-二氢 -1H-环丙烷 [a]茚 -6-基]乙酸 （化合物 5) 2-[3-[[3-[2,6-Dimethyl-4-(3-methylsulfonylpropoxy))phenyl]phenyl]methoxy]-la-methyl-6,6a -Dihydro-1H-cyclopropane [a] 茚-6 -yl]acetic acid (Compound 5 )
2-[3-[[3-[2,6-dimethyl-4-(3-methylsulfonylpropoxy)phenyl]phenyl]methoxy]-la-methyl-6,6a- dihydro- 1 H-cyclopropa[a] inden-6-yl] acetic acid  2-[3-[[3-[2,6-dimethyl-4-(3-methylsulfonylpropoxy)phenyl]phenyl]methoxy]-la-methyl-6,6a- dihydro- 1 H-cyclopropa[a] inden-6 -yl] acetic acid
Figure imgf000043_0001
Figure imgf000043_0001
第一歩 2-[3-[[3-[2,6-二甲基 -4-(3-甲磺酰基丙氧基；)苯基]苯基]甲氧基] -la-甲基 -6,6a-二氢 -1H- 环丙垸 [a]茚 -6-基]乙酸甲酯 （化合物 First 歩2-[3-[[3-[2,6-dimethyl-4-(3-methylsulfonylpropoxy))phenyl]phenyl]methoxy]-la-methyl- 6,6a-dihydro-1H-cyclopropene[a]fluorenyl- 6 -yl]acetate (compound)
Methyl 2-[3-[[3-[2,6-dimethyl-4-(3-methylsulfonylpropoxy)phenyl]phenyl]methoxy]-la-methyl-6 ,6a-dihydro-lH-cyclopropa[a]inden-6-yl]acetic acid  Methyl 2-[3-[[3-[2,6-dimethyl-4-(3-methylsulfonylpropoxy)phenyl]phenyl]methoxy]-la-methyl-6 ,6a-dihydro-lH-cyclopropa[a]inden-6 -yl]acetic acid
Figure imgf000043_0002
Figure imgf000043_0002
2-(3-羟基 -la-甲基 -6,6a-二氢 -1H-环丙烷 [a]茚 -6-基)乙酸甲酯 5D(230 mg, 0.99 mmol)和 [3-[2,6-二甲基 -4-(3-甲磺酰基丙氧基；)苯基]苯基]甲醇 1G (348 mg, 1.00 mmol) 溶于干燥二 氯甲垸（20 mL) 中。 将混合物降温至 0°C， 搅拌 5分钟， 再加入 1,1'-(偶氮二羰基)二哌啶 (502 mg, 2.00 mmol), 继续搅拌 5分钟。 向混合物中滴入三丁基膦（404 mg, 2.00 mmol), 保 持 0°C继续搅拌反应 0.5小时。 将反应液升至室温继续搅拌反应 3小时， TLC板跟踪反应结 束。 将反应液直接减压浓缩， 残留物用硅胶柱层析分离纯化 (石油醚 /乙酸乙酯 (v/v)= 2/1)， 得到白色固体 2-[3-[[3-[2,6-二甲基 -4-(3-甲磺酰基丙氧基)苯基]苯基]甲氧基] -la-甲基 -6,6a-二 氢 -1H-环丙垸 [a]茚 -6-基]乙酸甲酯 5a (302 mg, 产率 53.7%)。  Methyl 2-(3-hydroxy-la-methyl-6,6a-dihydro-1H-cyclopropane[a]indol-6-yl)acetate 5D (230 mg, 0.99 mmol) and [3-[2, 6-Dimethyl-4-(3-methanesulfonylpropoxy;)phenyl]phenyl]methanol 1G (348 mg, 1.00 mmol) was dissolved in dry dichloromethane (20 mL). The mixture was cooled to 0 ° C, stirred for 5 min, then additional 1,1'-(azodicarbonyl)dipiperidine (502 mg, 2.00 mmol) was added and stirring was continued for 5 min. Tributylphosphine (404 mg, 2.00 mmol) was added dropwise to the mixture, and the reaction was further stirred at 0 ° C for 0.5 hour. The reaction solution was allowed to warm to room temperature, and the reaction was stirred for 3 hours, and the TLC plate was followed to complete the reaction. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc mjjjjjjj 6-Dimethyl-4-(3-methanesulfonylpropoxy)phenyl]phenyl]methoxy]-la-methyl-6,6a-dihydro-1H-cyclopropene[a]茚-6-yl]methyl acetate 5a (302 mg, yield 53.7%).
第二歩 2-[3-[[3-[2,6-二甲基 -4-(3-甲磺酰基丙氧基；)苯基]苯基]甲氧基] -la-甲基 -6,6a-二氢 -1H- 环丙垸 [a]茚 -6-基]乙酸 （化合物 5) The second hydrazine 2-[3-[[3-[2,6-dimethyl-4-(3-methylsulfonylpropoxy))phenyl]phenyl]methoxy]-la-methyl- 6,6a-dihydro-1H- Cyclopropanil [a]茚-6 -yl]acetic acid (compound 5 )
2-[3-[[3-[2,6-dimethyl-4-(3-methylsulfonylpropoxy)phenyl]phenyl]methoxy]-la-methyl-6,6a- dihydro- 1 H-cyclopropa[a] inden-6-yl] acetic acid  2-[3-[[3-[2,6-dimethyl-4-(3-methylsulfonylpropoxy)phenyl]phenyl]methoxy]-la-methyl-6,6a- dihydro- 1 H-cyclopropa[a] inden-6 -yl] acetic acid
Figure imgf000044_0001
Figure imgf000044_0001
将 2-[3-[[3-[2,6-二甲基 -4-(3-甲磺酰基丙氧基；)苯基]苯基]甲氧基] -la-甲基 -6,6a-二氢 -1Η- 环丙垸 [a]茚 -6-基]乙酸甲 5a (302 mg, 0.54 mmol) 溶于甲醇 （10 mL) 中，滴加氢氧化钠 （302 mg, 15.1 M)水溶液，在 40Ό下搅拌反应 2小时， TLC点板跟踪反应结束。 将反应液浓缩至 3 mL，加水（10 mL)稀释，用 1M稀盐酸调节反应液 pH = 3。 用乙酸乙酯 （20 mL><3) 萃取， 合并有机相， 用水（10 mLx2)洗涤， 无水硫酸钠干燥， 过滤， 将滤液减压浓缩。 残留物用 硅胶柱层析分离纯化 (石油醚 /乙酸乙酯 (νΛ = 2/1), 得到白色固体 2-[3-[[3-[2,6-二甲基 -4-(3- 甲磺酰基丙氧基)苯基]苯基]甲氧基 ]-la-甲基 -6,6a-二氢 -1H-环丙垸 [a]茚 -6-基]乙酸 化合物 5 (187 mg, 产率 63.6%)。  2-[3-[[3-[2,6-Dimethyl-4-(3-methanesulfonylpropoxy))phenyl]phenyl]methoxy]-la-methyl-6, 6a-Dihydro-1Η-cyclopropane [a] 茚-6-yl]acetic acid methyl 5a (302 mg, 0.54 mmol) dissolved in methanol (10 mL), sodium hydroxide (302 mg, 15.1 M) The aqueous solution was stirred at 40 Torr for 2 hours, and the TLC dot plate was followed to end the reaction. The reaction solution was concentrated to 3 mL, diluted with water (10 mL), and the mixture was adjusted to pH = 3 with 1M diluted hydrochloric acid. The mixture was extracted with EtOAc (EtOAc (EtOAc)EtOAc. The residue was purified by silica gel column chromatography (EtOAc (EtOAc) (EtOAc (EtOAc) Methanesulfonylpropoxy)phenyl]phenyl]methoxy]-la-methyl-6,6a-dihydro-1H-cyclopropene[a]indol-6-yl]acetic acid compound 5 (187 mg , yield 63.6%).
MS [M-1]" (ESI): 547.2。  MS [M-1]" (ESI): 547.2.
¾ NMR (400 MHz, CDC13) 57.40(m,2H), 7.18(s,lH), 7.06(m,lH), 6.92(d,lH), 6.86(m,lH), 6.73(m,lH), 6.65(s,2H), 5.09(s,2H), 4.11(m,2H), 3.85(m,lH), 3.28(t,2H), 2.97(s,3H), 2.82(dd,lH), 2.46(m,lH), 2.37(m,2H), 1.99(s,6H), 1.88(m,lH), 1.49(m,3H), 0.81(m,lH), 0.22(m,lH)。 实施例 6 3⁄4 NMR (400 MHz, CDC1 3 ) 57.40 (m, 2H), 7.18 (s, lH), 7.06 (m, lH), 6.92 (d, lH), 6.86 (m, lH), 6.73 (m, lH) , 6.65(s,2H), 5.09(s,2H), 4.11(m,2H), 3.85(m,lH), 3.28(t,2H), 2.97(s,3H), 2.82(dd,lH), 2.46 (m, lH), 2.37 (m, 2H), 1.99 (s, 6H), 1.88 (m, lH), 1.49 (m, 3H), 0.81 (m, lH), 0.22 (m, lH). Example 6
2-[(laS,6R,6aR)-3-[[3-[4-[[(3R,3aR,6S,6aR)-3-甲氧基 -2,3,3a,5,6,6a-六氢呋喃并 [3,2-b]呋喃 -6- 基]氧] -2,6-二甲氧基苯基]苯基]甲氧基] -Ua,6,6a-四氢环丙烯并 [a]茚 -6-基]乙酸 （化合物 6) 2-[(laS,6R,6aR)-3-[[3-[4-[[(3R,3aR,6S,6aR)-3-methoxy-2,3,3a,5,6,6a- Hexahydrofuro[3,2-b]furan-6-yl]oxy]-2,6-dimethoxyphenyl]phenyl]methoxy]-Ua,6,6a-tetrahydrocyclopropene [a] 茚-6-yl]acetic acid (compound 6)
2-[(laS,6R,6aR)-3-[[3-[4-[[(3R,3aR,6S,6aR)-3-methoxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan -6-yl]oxy]-2,6-dimethyl-phenyl]phenyl]methoxy]-l,la,6,6a-tetrahydrocyclopropa[a]inden-6-yl] acetic acid 2-[(laS,6R,6aR)-3-[[3-[4-[[(3R,3aR,6S,6aR)-3-methoxy-2,3,3a,5,6,6a-hexahydrofuro[ 3,2-b]furan -6-yl]oxy]-2,6-dimethyl-phenyl]phenyl]methoxy]-l,la,6,6a-tetrahydrocyclopropa[a]inden-6-yl] acetic acid
Figure imgf000044_0002
Figure imgf000044_0002
Figure imgf000045_0001
Figure imgf000045_0001
第一步： （3R,3aR,6R,6aR)-6-甲氧基 -2,3,3a,5,6,6a-六氢呋喃并 [3,2-b]呋喃 -3-醇 （6b) First step: (3R, 3aR, 6R, 6aR)-6-methoxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol (6b )
(3R,3aR,6R,6aR)-6-methoxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol (3R,3aR,6R,6aR)-6-methoxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol
Figure imgf000045_0002
Figure imgf000045_0002
将 (31 ,301 ,61^601 )-2,3,3&,5,6,6&-六氢呋喃并 [3,2-b]呋喃 -3,6-二醇 6a (2.0 g, 16.38 mmol) 溶于二氯甲垸（30 mL) 中，加入碘甲垸（2.3 g, 16.42 mmol) 和氧化银（4.76 g, 20.53 mmol) , 室温避光反应 24 小时。 过滤， 将滤液减压浓缩， 残留物用硅胶柱层析分离提纯 （石油醚 / 乙酸乙酯 (v/v)= 1/2),得到白色固体状的 （3R,3aR,6R,6aR)-6-甲氧基 -2,3,3a,5,6,6a-六氢呋喃并 [3,2-b]呋喃 -3-醇化合物 6b (187 mg, 产率 36%)。 第二步： [(3R,3aR,6R,6aS)-3-甲氧基 -2,3,3a,5,6,6a-六氢呋喃并 [3,2-b]呋喃 -6-基] 4-甲基苯磺酸 酯 (6c)  (31,301 ,61^601 )-2,3,3&,5,6,6&-hexahydrofuro[3,2-b]furan-3,6-diol 6a (2.0 g, 16.38 mmol) Dissolved in dichloromethane (30 mL), adding iodothymidine (2.3 g, 16.42 mmol) and silver oxide (4.76 g, 20.53 mmol), and allowed to react at room temperature for 24 hours. Filtration, and the filtrate was concentrated under reduced pressure. EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjj 6-Methoxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol compound 6b (187 mg, yield 36%). Second step: [(3R,3aR,6R,6aS)-3-methoxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl] 4-methylbenzenesulfonate (6c)
[(3R,3 aR,6R,6aS)-3 -methoxy-2,3 ,3 a,5,6,6a-hexahydrofuro[3 ,2-b]furan-6-yl] 4-methylbenzenesulfonate
Figure imgf000046_0001
[(3R,3 aR,6R,6aS)-3 -methoxy-2,3 ,3 a,5,6,6a-hexahydrofuro[3 ,2-b]furan-6-yl] 4-methylbenzenesulfonate
Figure imgf000046_0001
将 (3R,3aR,6R,6aR)-6-甲氧基 -2,3,3a,5,6,6a-六氢呋喃并 [3,2-b]呋喃 -3-醇 6b (900 mg, 5.62 mmol)溶于二氯甲垸（30 mL) 中，冰浴下，依次加入 4-二甲氨基吡啶 （343 mg， 2.81 mmol), 三乙胺 (1.71 g， 16.86 mmol) 和对甲苯磺酰氯 (1.61 g， 8.43 mmol),升至室温反应 17小时， 向反应液中加水 pO rnL),搅拌 20分钟，静置分液，水层加入二氯甲垸（30 mL)，用水 （100 mL x 1)洗涤， 合并有机相， 用无水硫酸钠干燥， 过滤， 将滤液减压浓缩， 残留物用硅胶柱 层析法分离提纯 （石油醚 /乙酸乙酯 (v/v)= 4/1)， 得到无色油状的 [(3R,3aR,6R,6aS)-3-甲氧基 -2,3,3a,5,6,6a-六氢呋喃并 [3,2-b]呋喃 -6-基] 4-甲基苯磺酸酯 6c (1.3 g, 产率 73%)。 第三步 ： 3-[4-[[(3R,3aR,6S,6aR)-3-甲氧基 -2,3,3a,5,6,6a-六氢呋喃并 [3,2-b]呋喃 -6-基]氧 基] -2,6-二甲基苯基]苯甲醛 （6d)  (3R,3aR,6R,6aR)-6-methoxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol 6b (900 mg, 5.62 mmol) was dissolved in dichloromethane (30 mL). EtOAc (EtOAc: EtOAc, (1.61 g, 8.43 mmol), raise to room temperature for 17 hours, add water to the reaction solution, pO rnL), stir for 20 minutes, let stand for separation, add water to the layer to dichloromethane (30 mL), water (100 mL x 1) Washing, the organic phase is combined, dried with anhydrous sodium sulfate, filtered, and the filtrate is evaporated. The residue is purified by silica gel column chromatography ( petroleum ether / ethyl acetate (v/v) = 4/1) , [(3R,3aR,6R,6aS)-3-methoxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6- 4-methylbenzenesulfonate 6c (1.3 g, yield 73%). The third step: 3-[4-[[(3R,3aR,6S,6aR)-3-methoxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b] Furan-6-yl]oxy]-2,6-dimethylphenyl]benzaldehyde (6d)
S-l^-I pR^aR^S^al^-S-methoxy-ZASa^ASa-hexahydrofuroP -bjiliran-S-ylJoxyJ-Z^-dimethyl- phenyl]benzaldehyde  S-l^-I pR^aR^S^al^-S-methoxy-ZASa^ASa-hexahydrofuroP -bjiliran-S-ylJoxyJ-Z^-dimethyl- phenyl]benzaldehyde
Figure imgf000046_0002
Figure imgf000046_0002
将 [(3R,3aR,6R,6aS)-3-甲氧基 -2,3,3a,5,6,6a-六氢呋喃并 [3,2-b]呋喃 -6-基] 4-甲基苯磺酸 酉旨 6c (600 mg, 1.91 mmol), 4'-羟基 -2',6'-二甲基 -Ι,Γ-二苯基 -3-醛 1B (475 mg, 2.10 mmol) 和 碳酸铯 （701 mg, 2.29 mmol) 溶于 Ν,Ν-二甲基甲酰胺 （10 mL) 中， 氮气氛围， 升温至 90°C 搅拌反应 3小时。 向反应液中加入水（50 mL) 淬灭反应， 用乙酸乙酯 （50 mL x 3) 萃取， 依次用 1M氢氧化钠水溶液 （100 mL X 1)、 饱和氯化钠水溶液（100 mL χ 1)洗涤， 有机层 用无水硫酸钠干燥。 过滤， 将滤液减压浓缩， 残留物用硅胶柱层析分离纯化 （石油醚 /乙酸 乙酯 (ν/ν)= 4/1) 得到无色油状的 3-[4-[[(3R,3aR,6S,6aR)-3-甲氧基 -2,3,3a,5,6,6a-六氢呋喃并 [3,2-b]呋喃 -6-基]氧基] -2,6-二甲基苯基]苯甲醛 6d (360 mg, 产率 52%)。 第四步 ： [3-[4-[[(3R,3aR,6S,6aR)-3-甲氧基 -2,3,3a,5,6,6a-六氢呋喃并 [3,2-b]呋喃 -6-基]氧 基] -2,6-二甲基苯基]苯基]甲醇 （6e)  [(3R,3aR,6R,6aS)-3-methoxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl] 4-A Benzobenzenesulfonate 6c (600 mg, 1.91 mmol), 4'-hydroxy-2',6'-dimethyl-indole, indole-diphenyl-3-aldehyde 1B (475 mg, 2.10 mmol) and Cesium carbonate (701 mg, 2.29 mmol) was dissolved in hydrazine, hydrazine-dimethylformamide (10 mL), and the mixture was warmed to 90 ° C. Water (50 mL) was added to the reaction mixture to quench the mixture, which was extracted with ethyl acetate (50 mL x 3), and then 1M aqueous sodium hydroxide (100 mL X 1) and saturated aqueous sodium chloride (100 mL χ 1 ) The organic layer was dried over anhydrous sodium sulfate. Filtration, and the filtrate was concentrated under reduced pressure. EtOAcjjjjjjjjjjjjjj ,6S,6aR)-3-methoxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy]-2,6-di Methylphenyl]benzaldehyde 6d (360 mg, yield 52%). Fourth step: [3-[4-[[(3R,3aR,6S,6aR)-3-methoxy-2,3,3a,5,6,6a-hexahydrofuran[3,2-b Furan-6-yl]oxy]-2,6-dimethylphenyl]phenyl]methanol (6e)
P-W-I pR^aR^S^al^-S-methoxy-ZASa S^a-hexahydrofuroP -bJiliran-S-ylJoxyJ-Z^-dimethyl- phenyl]phenyl]methanol
Figure imgf000047_0001
PWI pR^aR^S^al^-S-methoxy-ZASa S^a-hexahydrofuroP -bJiliran-S-ylJoxyJ-Z^-dimethyl- phenyl]phenyl]methanol
Figure imgf000047_0001
无水无氧氛围， 将 3-[4-[[(3R,3aR,6S,6aR)-3-甲氧基 -2,3,3a,5,6,6a-六氢呋喃并 [3,2-b]呋喃 -6-基]氧基] -2,6-二甲基苯基]苯甲醛 6d (360 mg, 0.99 mmol) 溶于甲醇 （30 mL)中， 冰浴下， 分批向体系中加入硼氢化钠 （333 mg, 8.80 mmol)， 升至室温搅拌反应 15分钟， 向反应液中 加水（20 mL) 淬灭反应。 浓缩反应液，加入盐酸（20 mL, 1M)，用乙酸乙酯 （30 mL χ 3) 萃 取， 合并有机相并用无水硫酸钠干燥， 过滤， 将滤液减压浓缩， 残留物用硅胶柱层析分离 纯化 （石油醚 /乙酸乙酯 (ν/ν)= 4/1) , 得到无色透明油状的 [3-[4-[[(3R,3aR,6S,6aR)-3-甲氧基 -2,3,3a,5,6,6a-六氢呋喃并 [3,2-b]呋喃 -6-基]氧基] -2,6-二甲基苯基]苯基]甲醇 6e (360 mg, 产率 98%)。 第五步： 2-[(laS,6R,6aR)-3-[[3-[4-[[(3R,3aR,6S,6aR)-3-甲氧基 -2,3,3a,5,6,6a-六氢呋喃并 [3,2-b] 呋喃 -6-基]氧基] -2,6-二甲基苯基]苯基]甲氧基] -Ua,6,6a-四氢环丙烯并 [a]茚 -6-基]乙酸甲酯 (6D  Anhydrous anaerobic atmosphere, 3-[4-[[(3R,3aR,6S,6aR)-3-methoxy-2,3,3a,5,6,6a-hexahydrofuran [3,2 -b]furan-6-yl]oxy]-2,6-dimethylphenyl]benzaldehyde 6d (360 mg, 0.99 mmol) dissolved in methanol (30 mL), ice-bath, batchwise Sodium borohydride (333 mg, 8.80 mmol) was added thereto, and the mixture was stirred at room temperature for 15 minutes, and water (20 mL) was added to the mixture to quench. The reaction mixture was concentrated, EtOAcjjjjjjjjjjjjjjjjjjjjjjjj Separation and purification (petroleum ether/ethyl acetate (ν/ν) = 4/1) afforded [3-[4-[[(3R,3aR,6S,6aR)-3-methoxy- 2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy]-2,6-dimethylphenyl]phenyl]methanol 6e (360 Mg, yield 98%). Step 5: 2-[(laS,6R,6aR)-3-[[3-[4-[[(3R,3aR,6S,6aR)-3-methoxy-2,3,3a,5, 6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy]-2,6-dimethylphenyl]phenyl]methoxy]-Ua,6,6a-tetra Hydrogen cyclopropenyl[a]indol-6-yl]acetate methyl ester (6D
methyl 2-[(laS,6R,6aR)-3-[[3-[4-[[(3R,3aR,6S,6aR)-3-methoxy-2,3,3a,5,6,6a-hexahydrofuro [3,2-b]furan-6-yl]oxy]-2,6-dimethyl-phenyl]phenyl]methoxy]-l,la,6,6a-tetrahydrocyclopropa[a] inden-6-yl] acetate Methyl 2-[(laS,6R,6aR)-3-[[3-[4-[[(3R,3aR,6S,6aR)-3-methoxy-2,3,3a,5,6,6a-hexahydrofuro [3,2-b]furan-6-yl]oxy]-2,6-dimethyl-phenyl]phenyl]methoxy]-l,la,6,6a-tetrahydrocyclopropa[a] inden-6-yl] acetate
Figure imgf000047_0002
Figure imgf000047_0002
将 [3-[4-[[(3R,3aR,6S,6aR)-3-甲氧基 -2,3,3a,5,6,6a-六氢呋喃并 [3,2-b]呋喃 -6-基]氧基] -2,6- 二甲基苯基]苯基]甲醇 6e (120 mg, 0.32 mmol)和 2-(3-羟基 -l,la,6,6a-四氢环丙垸 [a]茚 -6-基) 乙酸甲酯 3D(78 mg, 0.36 mmol)溶于干燥二氯甲烷（10 mL) 中， 0°C下， 加入 Ι,Γ- (偶氮二 羰基)二哌啶 （178 mg, 0.70 mmol)和三丁基膦（142 mg, 0.70 mmol), 保持 0°C搅拌反应 15 分钟。 将反应液缓慢升至室温继续反应 3 小时， 反应液用硅藻土过滤， 将滤液减压浓缩， 残留物用硅胶柱层析分离纯化 (石油醚 /乙酸乙酯 yl 3/1) ， 得到无色液体 2-[(laS,6R,6aR)-3-[[3-[4-[[(3R,3aR,6S,6aR)-3-甲氧基 -2,3,3a,5,6,6a-六氢呋喃并 [3,2-b]呋喃 -6- 基]氧基] -2,6-二甲基苯基]苯基]甲氧基] -Ua,6,6a-四氢环丙烯并 [a]茚 -6-基]乙酸甲酯 6f (93 mg, 产率 50%)。 第六步： 2-[3-[[3-[4-[[(3R,3aR,6S,6aR)-3-甲氧基 -2,3,3a,5,6,6a-六氢呋喃并 [3,2-b]呋喃 -6-基]氧 基] -2,6-二甲基苯基]苯基]甲氧基] -l,la,6,6a-四氢环丙烯并 [a]茚 -6-基]乙酸 （化合物 6) [3-[4-[[(3R,3aR,6S,6aR)-3-methoxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan- 6-yl]oxy]-2,6-dimethylphenyl]phenyl]methanol 6e (120 mg, 0.32 mmol) and 2-(3-hydroxy-l,la,6,6a-tetrahydrocyclopropane垸[a]茚-6-yl) Methyl acetate 3D (78 mg, 0.36 mmol) was dissolved in dry dichloromethane (10 mL), and then, at 0 ° C, Ι, Γ-(azodicarbonyl) Piperidine (178 mg, 0.70 mmol) and tributylphosphine (142 mg, 0.70 mmol) were stirred at 0 ° C for 15 min. The reaction mixture was slowly warmed to room temperature, and the reaction mixture was stirred for 3 hours. The reaction mixture was filtered over EtOAc (EtOAc)EtOAc. Color liquid 2-[(laS,6R,6aR)-3-[[3-[4-[[(3R,3aR,6S,6aR)-3-methoxy-2,3,3a,5,6, 6a-hexahydrofuro[3,2-b]furan-6-yl]oxy]-2,6-dimethylphenyl]phenyl]methoxy]-Ua,6,6a-tetrahydrocyclo Methyl propylene and [a] indol-6-yl]acetate 6f (93 mg, yield 50%). Step 6: 2-[3-[[3-[4-[[(3R,3aR,6S,6aR)-3-methoxy-2,3,3a,5,6,6a-hexahydrofuran [3,2-b]furan-6-yl]oxy -2,6-dimethylphenyl]phenyl]methoxy]-l,la,6,6a-tetrahydrocyclopropenyl[a]indol-6-yl]acetic acid (compound 6)
2-[3-[[3-[4-[[(3R,3aR,6S,6aR)-3-methoxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy]-2,6- dimethyl-phenyl]phenyl]methoxy]-l,la,6,6a-tetrahydrocyclopropa[a]inden-6-yl] acetic acid 2-[3-[[3-[4-[[(3R,3aR,6S,6aR)-3-methoxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan- 6-yl]oxy]-2,6-dimethyl-phenyl]phenyl]methoxy]-l,la,6,6a-tetrahydrocyclopropa[a]inden-6-yl] acetic acid
Figure imgf000048_0001
Figure imgf000048_0001
将 2-[(laS,6R,6aR)-3-[[3-[4-[[(3R,3aR,6S,6aR)-3-甲氧基 -2,3,3a,5,6,6a-六氢呋喃并 [3,2-b] 呋喃 -6-基]氧基] -2,6-二甲基苯基]苯基]氧甲基] -Ua,6,6a-四氢环丙烯并 [a]茚 -6-基]乙酸甲酯 6f (93 mg, 0.16 mmol) 溶于甲醇 (10 mL) 中， 滴加氢氧化钠溶液 (200 mg, 6.64 M), 室温下搅 拌反应过夜， 减压浓缩反应液， 加水（20 mL)稀释， 用乙酸乙酯 (10 mLx2)萃取， 合并有 机相， 用水（lO mL ) 洗涤， 有机相用无水硫酸钠干燥， 过滤， 将滤液减压浓缩， 残留物 用硅胶柱层析分离纯化 （石油醚 /乙酸乙酯 （vA = 1/1) 得到白色固体状的 2-[3-[[3-[4-[[(3¾3 ,68,601 )-3-甲氧基 -2,3,3a,5,6,6a-六氢呋喃并 [3,2-b]呋喃 -6-基]氧基] -2,6- 二甲基苯基]苯基]氧甲基 ]-l,la,6,6a-四氢环丙烯并 [a]茚 -6-基]乙酸化合物 6 (80 mg, 产率 86%)。  2-[(laS,6R,6aR)-3-[[3-[4-[[(3R,3aR,6S,6aR)-3-methoxy-2,3,3a,5,6,6a -hexahydrofuro[3,2-b]furan-6-yl]oxy]-2,6-dimethylphenyl]phenyl]oxymethyl]-Ua,6,6a-tetrahydrocyclopropene And [a] 茚-6-yl]methyl acetate 6f (93 mg, 0.16 mmol) was dissolved in methanol (10 mL), sodium hydroxide solution (200 mg, 6.64 M) was added dropwise, and the reaction was stirred at room temperature overnight. The reaction mixture was concentrated with EtOAc EtOAc (EtOAc m. The residue was purified by silica gel column chromatography (EtOAc (EtOAc) (EtOAc (EtOAc) -Methoxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]oxy]-2,6-dimethylphenyl]phenyl Oxymethyl]-l,la,6,6a-tetrahydrocyclopropenyl[a]indol-6-yl]acetic acid compound 6 (80 mg, yield 86%).
MS [M+1]+ (ESI): 557.3。 MS [M+1] + (ESI): 557.3.
¾ MR (400 MHz, DMSO-d6) δ 12.18 (s, 1H), 7.45 (s, 1H), 7.39 (d, 1H), 7.15 (s, 1H), 7.063⁄4 MR (400 MHz, DMSO-d 6 ) δ 12.18 (s, 1H), 7.45 (s, 1H), 7.39 (d, 1H), 7.15 (s, 1H), 7.06
(d, 1H), 7.00 (d, 1H), 6.91 (d, 1H), 6.72 (m, 3H), 5.11 (s, 2H), 4.83 (d, 1H), 4.71 (s, 1H), 4.54 (d, 1H), 4.03 (m, 1H), 3.93 (m, 2H), 3.86 (s, 1H), 3.67 (m, 1H), 3.52 (m, 1H), 3.35 (s, 3H), 2.72 (dd, 1H), 2.28 (m, 2H), 1.96 (m, 1H), 1.91 (s, 6H), 0.86 (m, 1H), 0.03 (m, 1H)。 生物测试例 (d, 1H), 7.00 (d, 1H), 6.91 (d, 1H), 6.72 (m, 3H), 5.11 (s, 2H), 4.83 (d, 1H), 4.71 (s, 1H), 4.54 ( d, 1H), 4.03 (m, 1H), 3.93 (m, 2H), 3.86 (s, 1H), 3.67 (m, 1H), 3.52 (m, 1H), 3.35 (s, 3H), 2.72 (dd , 1H), 2.28 (m, 2H), 1.96 (m, 1H), 1.91 (s, 6H), 0.86 (m, 1H), 0.03 (m, 1H). Biological test case
GPR40 荧光素酶报告基因试验 GPR40 luciferase reporter gene assay
利用 GPR40 荧光素酶报告基因试验测试本发明各实施例制备的化合物的活性， 试验 过程如下：  The activity of the compounds prepared in the various examples of the present invention was tested using the GPR40 luciferase reporter assay. The test procedure is as follows:
用 DMSO将化合物配制成 10mM的储存液， 再按 3倍梯度稀释待用。 将稳定表达株 HEK293/GPR40/5x Gal4UAS-Luc+/Gal4-Elkl以适当密度接种于 96孔板。 第二天，待细胞汇 合度达到 70%左右， 更换为无血清培养基， 饥饿过夜。 第三天， 加入含有不同浓度受试化 合物的 DMEM培养基， 每孔 200μ1， 放入细胞培养箱孵育 5小时。 利用 Luciferase Assay System试剂盒检测荧光素酶活性。 使用 Ongm 7软件对荧光数据进行拟合分析， 计算各化 合物的 EC5。， 试验结果见表 1。 表 1荧光素酶报告基因试验结果 The compound was formulated into a 10 mM stock solution in DMSO and diluted to a 3-fold gradient 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, the cell confluence reached about 70%, replaced with serum-free medium, and starved overnight. On the third day, DMEM medium containing different concentrations of the test compound was added, 200 μl per well, and incubated in a cell culture incubator for 5 hours. Luciferase activity was detected using the Luciferase Assay System kit. Ongm 7 software using fluorescence analysis to fit the data to calculate EC 5 for each compound. The test results are shown in Table 1. Table 1 luciferase reporter gene test results
Figure imgf000049_0001
结论： 本发明化合物作为 GPR40激动剂显示出优异的药效活性。
Figure imgf000049_0001
Conclusion: The compounds of the present invention exhibit excellent pharmacodynamic activity as GPR40 agonists.

Claims

权利要求书 claims
1、 一种通式 (I)所示的化合物或其立体异构体、 水合物、 酯、 溶剂化物、 共晶体、 代 谢产物、 药学上可接受 ： 1. A compound represented by general formula (I) or its stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable:
Figure imgf000050_0001
其中：
Figure imgf000050_0001
in:
R选自 H或者 d.8垸基； R is selected from H or d. 8 alkyl;
Rb、 Rbl、 Re和 Rel各自独立选自 H、 F、 Cl、 Br、 I、 羟基、 C1-8垸基或 C1-8垸氧基， 其中 所述垸基或垸氧基各自独立地任选进一步被 0至 4个选自 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 C1-8垸基、 C1-8垸氧基、 C2-8烯基、 C2-8炔基、 -C(=0)-R3、 -C(=0)-0-R3、 Rb , Rbl , Re and Rel are each independently selected from H, F, Cl, Br, I, hydroxyl, C 1-8 alkyl or C 1-8 alkyloxy, wherein the alkyl or alkyloxy Each group is independently optionally further selected from F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , C 1-8 alkyl, C 1-8 alkyloxy, C 2-8 alkenyl, C 2-8 alkynyl, -C(=0)-R 3 , -C(=0)-0-R 3 ,
-C(=0)-NR3R3a、 -S(=0)n-R3、 -0-C(=0)-0-R3或者 -NR3R3a的取代基所取代； -C(=0)-NR 3 R 3a , -S(=0) n -R 3 , -0-C(=0)-0-R 3 or -NR 3 R 3a substituent;
Ra和 Ral各自独立选自 H、 F、 Cl、 Br、 I、 氰基、 氨基、 硝基、 羟基、 羧基、 垸基或 d_8垸氧基， 其中所述垸基、 垸氧基或氨基各自独立地任选进一步被 0至 4个选自 F、 Cl、 Br 、 I、 氰基、 硝基、 羟基、 CL8垸基、 d.8垸氧基、 C2.8烯基、 C2.8炔基、 -C(=0)-R3、 R a and R al are each independently selected from H, F, Cl, Br, I, cyano, amino, nitro, hydroxyl, carboxyl, alkyl or d- 8 alkyloxy, wherein the alkyl, alkyloxy or Each amino group is independently optionally further selected from 0 to 4 F, Cl, Br, I, cyano, nitro, hydroxyl, CL 8 alkyl, d. 8 alkyloxy, C 2. 8 alkenyl, C 2. 8alkynyl , -C(=0)-R 3 ,
-C(=0)-0-R3、 -C(=0)-NR3R3a、 -S(=0)n-R3、 -0-C(=0)-0-R3或者 -NR3R3a的取代基所取代；-C(=0)-0-R 3 , -C(=0)-NR 3 R 3a , -S(=0) n -R 3 , -0-C(=0)-0-R 3 or - Substituted by the substituent of NR 3 R 3a ;
R1和 R2各自独立选自 H、 F、 Cl、 Br、 I、 氰基、 氨基、 硝基、 羟基、 羧基、 d.8垸基或 d_8垸氧基， 其中所述垸基、 垸氧基或氨基各自独立地任选进一步被 0至 4个选自 F、 Cl、 Br 、 I、 氰基、 硝基、 羟基、 CL8垸基、 d.8垸氧基、 C2.8烯基、 C2.8炔基、 -C(=0)-R3、 R 1 and R 2 are each independently selected from H, F, Cl, Br, I, cyano, amino, nitro, hydroxyl, carboxyl, d.8 alkyl or d_8 alkyloxy, wherein the alkyl, alkyl The oxygen group or amino group is each independently optionally further selected from 0 to 4 F, Cl, Br, I, cyano, nitro, hydroxyl, CL 8 alkyl, d. 8 alkyloxy, C 2. 8 alkene Base, C 2. 8 alkynyl group, -C(=0)-R 3 ,
-C(=0)-0-R3、 -C(=0)-NR3R3a、 -S(=0)n-R3、 -0-C(=0)-0-R3或者 -NR3R3a的取代基所取代； Wi, W2和 W3各自独立选自单键、 -0-、 -NR3-、 -S(=0)N -、 C1-8垸基、 -C(=0)-、 -C(=0)-0-R 3 , -C(=0)-NR 3 R 3a , -S(=0) n -R 3 , -0-C(=0)-0-R 3 or - Substituted by the substituent of NR 3 R 3a ; Wi, W 2 and W 3 are each independently selected from single bond, -0-, -NR 3 -, -S(=0) N -, C 1-8 alkyl group, - C(=0)-,
-C(=C -C 垸基-、 -O-C^垸基-或 -C^垸基 -0-，所述垸基各自独立地任选进一步被 0至 4个选 gF、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 羟基、 C1-8垸基、 C1-8垸氧基、 -C2-8烯基、 -C2-8炔 基或者 -NR3R3a的取代基所取代； -C(=C -C alkyl-, -OC, alkyl- or -C alkyl-0-, each of the alkyl groups is optionally further optionally substituted by 0 to 4 selected from F, Cl, Br, I , -CH 2 F, -CHF 2 , -CF 3 , hydroxyl, C 1-8 alkyl, C 1-8 alkyloxy, -C 2-8 alkenyl, -C 2-8 alkynyl or -NR 3 R 3a is substituted by a substituent;
环 Q选自 5至 8元碳环或 5至 8元杂环， 所述杂环含有 1至 4个选自 N、 0或 ^=0)11的杂原子 或基团； Ring Q is selected from a 5- to 8-membered carbocyclic ring or a 5- to 8-membered heterocyclic ring, and the heterocyclic ring contains 1 to 4 heteroatoms or groups selected from N, 0 or (N=0);
G选自 H、 F、 Cl、 Br、 I、 巯基、 羟基、 硝基、 氰基、 d.s烷基、 d.8烷氧基、 C2.8烯基 、 C2-8炔基、 -C(=0)-R3、 -C(=0)-OR3、 -C(=0)- R3R3a、 - R3R3a、 -S(=0)n-R3、 -0-C(=0)-C1-8垸基、 -0-C(=0)-0-C1-8垸基、 -0-C(=0)-NR¾3a、 3至 10元碳环基、 3至 10元杂 环基、 - =0)-R4或 -0-R4,所述杂环基含 1至 4个选自 N、 0或 S(=0)n杂原子或基团，所述巯基 、 羟基、 垸基、 垸氧基、 烯基、 炔基、 碳环基或杂环基任选进一步被 0至 4个选自 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 巯基、 羟基、 硝基、 氰基、 C^8垸基、 C^8烯基、 C^8炔基、 -OR3, -C(=0)-R3、 -C(=0)-OR3、 -C(=0)-NR3R3a、 -NR3R3a、 -S(=0)n-R3、 -0-C(=0)-C1-8烷基 、 -0-C(=0)-0-C1-8垸基、 -0-C(=0)-NR3R3a、 -C1-8垸基 -S(=0)n-R3、 -0-C1-8垸基 -S(=0)n-R3、 3至 10元碳环基、 3至 10元杂环基、 或 -0-R4的取代基所取代； G is selected from H, F, Cl, Br, I , mercapto, hydroxyl, nitro, cyano, d.s alkyl, d.8 alkoxy, C 2.8 alkenyl, C 2-8 alkynyl, -C(=0)-R 3 , -C(=0)-OR 3 , -C(=0)- R 3 R 3a , -R 3 R 3a , -S(=0) n -R 3 , -0-C(=0)-C 1-8 alkyl group, -0-C(=0)-0-C 1-8 alkyl group, -0-C(=0)-NR¾ 3a , 3 to 10 yuan Carbocyclyl, 3 to 10 membered heterocyclyl, -=0)-R 4 or -0-R 4 , the heterocyclyl contains 1 to 4 heteroatoms selected from N, 0 or S(=0) Or group, the thiol group, hydroxyl group, alkyl group, alkyloxy group, alkenyl group, alkynyl group, carbocyclic group or heterocyclic group is optionally further selected from 0 to 4 F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , mercapto group, hydroxyl group, nitro group, cyano group, C^ 8 alkyl group, C ^ 8 alkenyl group, C ^ 8 alkynyl group, -OR 3 , -C(=0)- R 3 , -C(=0)-OR 3 , -C(=0)-NR 3 R 3a , -NR 3 R 3a , -S(=0) n -R 3 , -0-C(=0) -C 1-8 alkyl, -0-C(=0)-0-C 1-8 alkyl, -0-C(=0)-NR 3 R 3a , -C 1-8 alkyl-S( =0) n -R 3 , -0-C 1-8 alkyl-S(=0) n -R 3 , 3 to 10-membered carbocyclyl, 3 to 10-membered heterocyclyl, or -0-R 4 Substituted by substituents;
R3和 R3a各自独立选自 H、 羟基、 d_8垸基或 d_8垸氧基， 其中所述垸基或垸氧基各自独 立地任选进一步被 0至 4个选自 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 氰基、 硝基、 羟基、 C 垸基、 C 垸氧基、 C2-8烯基、 C2-8炔基、 -C(=0)-C1-8垸基、 -C(=0)-0- C1-8垸基、 R 3 and R 3a are each independently selected from H, hydroxyl, d_8 alkyl or d_8 alkyloxy, wherein each of the alkyl or alkyloxy is independently optionally further selected from 0 to 4 from F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , cyano, nitro, hydroxyl, C alkyl, C alkyloxy, C 2-8 alkenyl, C 2-8 alkynyl, -C (=0)-C 1-8 alkyl group, -C(=0)-0- C 1-8 alkyl group,
-s(=o)n-c^垸基或者 -o- =o)-o-c^垸基的取代基所取代； -s(=o) n -c^alkyl or -o- =o)-oc^alkyl substituent;
R4选自 3至 10元碳环基或 3至 10元杂环基， 所述杂环基含 1至 4个选自 N、 0或 S(=0)n杂原 子或基团， 所述碳环基或杂环基任选进一步被 0至 4个选自 F、 Cl、 Br、 I、 -CH2F、 -CHF2、 -CF3、 巯基、 羟基、 硝基、 氰基、 d.8垸基、 d.8垸氧基、 C2.8烯基、 C2.8炔基、 -C(=0)-R3、 -C(=0)-OR3、 -C(=0)-NR3R3a、 -NR3R3a、 -S(=0)n-R3、 -0-C(=0)-C1-8垸基、 -0-C(=0)-0-C1-8 垸基、 -0-C(=0)- R3R3a、 -0-C1-8垸基- S(=0)n-R3、 3至 10元碳环基或 3至 10元杂环基的取代 基所取代； R 4 is selected from a 3 to 10-membered carbocyclyl group or a 3 to 10-membered heterocyclyl group, and the heterocyclyl group contains 1 to 4 heteroatoms or groups selected from N, 0 or S(=0), and the The carbocyclic group or heterocyclic group is optionally further selected from 0 to 4 groups from F, Cl, Br, I, -CH 2 F, -CHF 2 , -CF 3 , mercapto group, hydroxyl, nitro, cyano, d. 8 alkyl group, d. 8 alkyloxy group, C 2. 8 alkenyl group, C 2 . 8 alkynyl group, -C(=0)-R 3 , -C(=0)-OR 3 , -C(=0 )-NR 3 R 3a , -NR 3 R 3a , -S(=0) n -R 3 , -0-C(=0)-C 1-8 alkyl, -0-C(=0)-0 -C 1-8 alkyl group, -0-C(=0)- R 3 R 3a , -0-C 1-8 alkyl group - S(=0) n -R 3 , 3 to 10-membered carbocyclic group or Substituted with substituents of 3 to 10 membered heterocyclic groups;
t为 0或者 1 ; t is 0 or 1;
k为 0、 1或者 2; k is 0, 1 or 2 ;
p为 0、 1、 2或者 3 ; p is 0, 1, 2 or 3;
q为 0、 1、 2或者 3 ; q is 0, 1, 2 or 3;
n为 0、 1或者 2。 n is 0, 1 or 2.
2、 根据权利要求 1所述的化合物或其立体异构体、 水合物、 酯、 溶剂化物、 共晶体、 、 药学上可接受的盐或前药， 其中所述化合物为通式 (Π)所示的化合物： 2. The compound according to claim 1 or its stereoisomer, hydrate, ester, solvate, co-crystal, pharmaceutically acceptable salt or prodrug, wherein the compound is represented by general formula (II) Compounds shown:
Figure imgf000051_0001
Figure imgf000051_0001
R选自 H或者 d.4垸基; RB和 RBL各自独立选自 H或 CM垸基； R is selected from H or d. 4 alkyl; R B and R BL are each independently selected from H or CM alkyl;
R1和 R2各自独立选自 H、 F、 Cl、 CM垸基或 CM垸氧基； R 1 and R 2 are each independently selected from H, F, Cl, CM alkyl or CM alkyloxy;
G选自 3至 8元碳环基， 所述碳环基任选进一步被 0至 3个选自 d_4垸基、 -0-Cw烷 基 -S(=0)N-R3或 -0-R4的取代基所取代； G is selected from 3 to 8-membered carbocyclic groups, and the carbocyclic groups are optionally further substituted by 0 to 3 members selected from d_4 alkyl, -0-C alkyl -S(=0) N -R 3 or - Substituted by 0-R 4 substituent;
R3选自 ffi¾d.4垸基； R 3 is selected from ffi¾d. 4 alkyl;
R4选自 4至 8元杂环基， 所述杂环基含 1至 3个选自 N、 0、 S、 S(=0)或 S(=0)2杂原子或基 团， 所述杂环基任选进一步被 0至 3个选自 d_4垸氧基的取代基所取代； R 4 is selected from 4 to 8-membered heterocyclyl, and the heterocyclyl contains 1 to 3 heteroatoms or groups selected from N, 0, S, S(=0) or S (=0), The heterocyclic group is optionally further substituted by 0 to 3 substituents selected from d_4 alkyloxy;
p为 0、 1、 2或者 3 ; p is 0, 1, 2 or 3;
q为 0、 1、 2或者 3 ; q is 0, 1, 2 or 3;
n为 0、 1或者 2。 n is 0, 1 or 2.
3、 根据权利要求 2所述的化合物或其立体异构体、 水合物、 酯、 溶剂化物、 共晶体、 代谢产物、 药学上可接受的盐或前药， 其中： 3. The compound according to claim 2 or its stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug, wherein:
R1和 R2各自独立选自 H; R 1 and R 2 are each independently selected from H ;
R选自 H或者 d.2垸基； R is selected from H or d. 2 alkyl;
RB选自 H; R B is selected from H;
RBL选自 ffi¾d.2垸基； R BL is selected from ffi¾d. 2 alkyl;
G选自 6元碳环基， 所述碳环基进一步被 0至 3个选自 d_2垸基、 -0-d_3垸基 -S(=0)N-R3或 -0-R4的取代基所取代； G is selected from a 6-membered carbocyclic group, and the carbocyclic group is further selected from 0 to 3 d_2 alkyl, -0- d_3 alkyl-S(=0) N -R 3 or -0-R 4 Substituted by substituents;
R3选自 ffi^C^垸基； R 3 is selected from ffi^C^ alkyl;
R4选自 5至 8元杂环基， 所述杂环基含 1至 2个选自 N、 0、 S、 S(=0)或 S(=0)2杂原子或基 团， 所述的杂环基任选进一步被 0至 3个选自 d_2院氧基的取代基所取代； R 4 is selected from 5 to 8-membered heterocyclyl, and the heterocyclyl contains 1 to 2 heteroatoms or groups selected from N, 0, S, S(=0) or S(=0), The heterocyclyl group is optionally further substituted by 0 to 3 substituents selected from d_ 2- hydroxyl group;
p为 0; p is 0;
q为 0; q is 0;
n为 0、 1或者 2。 n is 0, 1 or 2.
4、 根据权利要求 1所述的化合物或其立体异构体、 水合物、 酯、 溶剂化物、 共晶体、 代谢产物、 药学上可接受的 ΠΙ)所示的化合物： 4. The compound according to claim 1 or its stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable compound represented by II):
Figure imgf000052_0001
Figure imgf000052_0001
(in) 其中 (in) in
Rb选自 H; R b is selected from H;
Rbl选自 ffi¾d.3垸基； R bl is selected from ffi¾d. 3 alkyl;
R8选自 -Cw垸基 -S(=0)n-R3或 5至 8元杂环基，所述杂环基含 1至 2个选自 N、 0、 S、 S(=0) 或 S(=0)2杂原子或基团， 所述的杂环基任选进一步被 0至 2个 d_2垸氧基所取代； R 8 is selected from -C alkyl -S(=0) n -R 3 or 5 to 8-membered heterocyclyl, the heterocyclyl contains 1 to 2 selected from N, 0, S, S(=0) Or S (=0) 2 heteroatoms or groups, the heterocyclic group is optionally further substituted by 0 to 2 d_ 2 alkyloxy groups;
R3选自 ffi¾d.3垸基； R 3 is selected from ffi¾d. 3 alkyl;
n为 0、 1或者 2。 n is 0, 1 or 2.
5、 根据权利要求 4所述的化合物或其立体异构体、 水合物、 酯、 溶剂化物、 共晶体、 代谢产物、 药学上可接受的盐或前药， 其中： 5. The compound according to claim 4 or its stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug, wherein:
Rbl选自 H或甲基； R bl is selected from H or methyl;
Figure imgf000053_0001
Figure imgf000053_0001
6、 根据权利要求 5所述的化合物或其立体异构体、 水合物、 酉旨、 溶剂化物、 共晶体、 代谢产物、 药学上可接受的盐或前药， 6. The compound according to claim 5 or its stereoisomer, hydrate, molecule, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug,
其中- in-
、、。、 ,,. ,
R8选自 、
Figure imgf000053_0002
 R 8 is selected from,
Figure imgf000053_0002
7、 根据权利要求 1所述的化合物或其立体异构体、 水合物、 酯、 溶剂化物、 共晶体、 代 、 药学上可接受的盐或前药， 其中化合 7. The compound according to claim 1 or its stereoisomer, hydrate, ester, solvate, co-crystal, substitute, pharmaceutically acceptable salt or prodrug, wherein the compound
Figure imgf000053_0003
Figure imgf000053_0003
Figure imgf000054_0001
Figure imgf000054_0001
8、 根据权利要求 7所述的化合物或其立体异构体、 水合物、 酯、 溶剂化物、 共晶体、 代谢产物、 药学上可接受的盐或前药， 其中化合物选自： 8. The compound according to claim 7 or its stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug, wherein the compound is selected from:
Figure imgf000054_0002
Figure imgf000054_0002
9、 根据权利要求 8所述的化合物或其立体异构体、 水合物、 酯、 溶剂化物、 共晶体、 代谢产物、 药学上可 9. The compound according to claim 8 or its stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable
Figure imgf000054_0003
Figure imgf000054_0003
10、 根据权利要求 1~9中任一项所述的化合物或其立体异构体、 水合物、 酯、 溶剂化 物、 共晶体、 代谢产物、 药学上可接受的盐或前药， 其中所述的盐选自钠盐、 钾盐、 铝盐 、 锂盐、 锌盐、 钙盐、 镁盐、 钡盐、 铵盐、 三甲胺盐、 四甲基铵盐、 二乙胺盐、 三乙胺盐 、 异丙基胺盐、 乙醇胺盐、 二乙醇胺盐、 三乙醇胺盐、 环己胺盐、 二环己基胺盐、 吡啶盐 、 甲基吡啶盐、 2,6-二甲基吡啶盐、 咖啡碱盐、 普鲁卡因盐、 胆碱盐、 甜菜碱盐、 可可碱 盐、 嘌吟盐、 哌嗪盐、 哌啶盐、 N-乙基哌啶盐、 聚胺树脂盐、 苯明青霉素盐、 盐酸盐、 氢 溴酸盐、 硫酸盐、 硝酸盐、 磷酸盐、 甲酸盐、 乙酸盐、 羟乙酸盐、 丙酸盐、 2-羟基丙酸盐 、 丙二酸盐、 三氟乙酸盐、 甲磺酸盐、 乙磺酸盐、 三氟甲磺酸盐、 乙烯磺酸盐、 苯磺酸盐 、 对甲苯磺酸盐、 苯甲酸盐、 苯乙酸盐、 褐藻酸盐、 氨茴酸盐、 樟脑酸盐、 马来酸盐、 酒 石酸盐、 柠檬酸盐、 琥珀酸盐、 扁桃酸盐、 富马酸盐、 苹果酸盐、 草酸盐、 水杨酸盐、 葡 萄糖醛酸盐、 半乳糖醛酸盐、 枸橼酸盐、 天冬氨酸盐、 谷氨酸盐、 肉桂酸盐或者它们的组 合。 10. The compound according to any one of claims 1 to 9 or its stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug, wherein said The salt is selected from sodium salt, potassium salt, aluminum salt, lithium salt, zinc salt, calcium salt, magnesium salt, barium salt, ammonium salt, trimethylamine salt, tetramethylammonium salt, diethylamine salt, triethylamine salt , isopropylamine salt, ethanolamine salt, diethanolamine salt, triethanolamine salt, cyclohexylamine salt, dicyclohexylamine salt, pyridinium salt, picolinium salt, 2,6-lutidine salt, caffeine salt, Procaine salt, choline salt, betaine salt, theobromine salt, purine salt, piperazine salt, piperidine salt, N-ethylpiperidine salt, polyamine resin salt, benzene penicillin salt, hydrochloric acid Salt, hydrobromide, sulfate, nitrate, phosphate, formate, acetate, glycolate, propionate, 2-hydroxypropionate, malonate, trifluoroacetate , methanesulfonate, ethanesulfonate, trifluoromethanesulfonate, ethylene sulfonate, benzenesulfonate, p-toluenesulfonate, benzoate, phenylacetate, alginate, anisate Acid, camphorate, maleate, alcohol Petrolate, citrate, succinate, mandelate, fumarate, malate, oxalate, salicylate, glucuronate, galacturonate, citrate, Aspartate, glutamate, cinnamate or combinations thereof.
11、 根据权利要求 10所述的化合物或其立体异构体、 水合物、 酯、 溶剂化物、 共晶体11. The compound according to claim 10 or its stereoisomer, hydrate, ester, solvate, or co-crystal
、 代谢产物、 药学上可接受的盐或前药， 其中所述的盐选自钠盐、 钾盐、 铵盐、 三乙胺盐 、 乙醇胺盐、 二乙醇胺盐、 盐酸盐、 氢溴酸盐、 硫酸盐、 磷酸盐、 三氟乙酸盐、 乙酸盐、 马来酸盐、 天冬氨酸盐、 谷氨酸盐、 苹果酸盐或它们的组合。 , metabolites, pharmaceutically acceptable salts or prodrugs, wherein the salt is selected from sodium salt, potassium salt, ammonium salt, triethylamine salt, ethanolamine salt, diethanolamine salt, hydrochloride, hydrobromide , sulfate, phosphate, trifluoroacetate, acetate, maleate, aspartate, glutamate, malate or combinations thereof.
12、 制备权利要 1~9中任一项所述的化合物的方法， 该方法包括： 12. A method for preparing the compound according to any one of claims 1 to 9, which method includes:
Figure imgf000055_0001
Figure imgf000055_0001
l-a l-b l-a l-b
通式 -a)化合物依次通过保护羟基反应、 还原反应和消除反应转化为通式 -b)化合物； 或者通式 (l-a)化合物依次通过保护羟基反应、 wittig反应和双键转位反应转化为通式 (l-b)化 合物； The compound of general formula-a) is converted into a compound of general formula-b) through a hydroxyl protection reaction, a reduction reaction and an elimination reaction in sequence; or the compound of general formula (l-a) is converted into a compound of general formula (l-a) through a hydroxyl protection reaction, wittig reaction and double bond translocation reaction in sequence. Compounds of formula (l-b);
Figure imgf000055_0002
通式 (l-b)化合物依次通过 simmons-simth反应和脱保护基反应转化为通式 (I-c)化合物;
Figure imgf000055_0002
The compound of general formula (lb) is converted into the compound of general formula (Ic) through simmons-simth reaction and deprotection reaction;
Figure imgf000055_0003
Figure imgf000055_0003
通式 (l-c)化合物与通式 (I-d)化合物通过 Mistunobo缩合反应转化为通式 ®化合物； 其中- Compounds of general formula (l-c) and compounds of general formula (I-d) are converted into compounds of general formula ® through Mistunobo condensation reaction; where-
R、 R1, Ra、 Ral、 Rb、 Rbl、 Re、 Rel、 R2、 G、 Q、 Wi, W2、 W3、 p、 t、 k和 q如同与权利 要求 1~9中任一项所定义。 R, R 1 , R a , R al , R b , R bl , Re , R el , R 2 , G , Q, Wi, W 2 , W 3 , p, t, k and q are as in claim 1 defined by any one of ~9.
13、 一种药物组合物， 所述的组合物包括有效剂量的根据权利要求 1~11中任一项所述 的化合物或其立体异构体、 水合物、 酯、 溶剂化物、 共晶体、 代谢产物、 药学上可接受的 盐或前药以及药学上可接受的载体、 稀释剂、 佐剂或赋形剂； 还可以进一步包括一种或多 种其他治疗剂。 13. A pharmaceutical composition, said composition comprising an effective dose of the compound according to any one of claims 1 to 11 or its stereoisomer, hydrate, ester, solvate, co-crystal, metabolism The product, a pharmaceutically acceptable salt or prodrug, and a pharmaceutically acceptable carrier, diluent, adjuvant or excipient; may further include one or more other therapeutic agents.
14、 根据权利要求 13所述的药物组合物， 其中所述的其他治疗剂包括： 14. The pharmaceutical composition according to claim 13, wherein the other therapeutic agents include:
(a) GPR40激动剂或药学上可接受的盐， 和 /或 (a) GPR40 agonist or pharmaceutically acceptable salt, and/or
OD) DPP-IV抑制剂或药学上可接受的盐， 和 /或 OD) DPP-IV inhibitor or pharmaceutically acceptable salt, and/or
(c) SGLT-2抑制剂或药学上可接受的盐， 和 /或 (c) SGLT-2 inhibitor or pharmaceutically acceptable salt, and/or
(d) PPAi S动剂和部分激动剂或药学上可接受的盐， 和 /或 (d) PPAi S agonists and partial agonists or pharmaceutically acceptable salts, and/or
(e) PPAR^双重激动剂或药学上可接受的盐， 和 /或 (e) PPAR^ dual agonist or pharmaceutically acceptable salt, and/or
(f) PPA!U¾动剂或药学上可接受的盐， 和 /或 (f) PPA activators or pharmaceutically acceptable salts, and/or
fe)胰岛素或拟胰岛素或药学上可接受的盐， 和 /或 fe)insulin or insulinomimetic or pharmaceutically acceptable salt, and/or
W蛋白酪氨酸磷酸酶 -IB抑制剂或药学上可接受的盐， 和 /或 W protein tyrosine phosphatase-IB inhibitor or pharmaceutically acceptable salt, and/or
(1)磺酰脲类抑制剂或药学上可接受的盐， 和 /或 (1) Sulfonylurea inhibitors or pharmaceutically acceptable salts, and/or
(ί) α-葡糖苷酶抑制剂或药学上可接受的盐， 和 /或 (ί) alpha-glucosidase inhibitor or pharmaceutically acceptable salt, and/or
(k)GLP- GLP-1类似物、 GIP-1、 HSD-1或药学上可接受的盐， 禾口 /或 (k) GLP- GLP-1 analog, GIP-1, HSD-1 or pharmaceutically acceptable salt, and/or
(1)胰高血糖素受体拮抗剂或药学上可接受的盐， 和 /或 (1) Glucagon receptor antagonist or pharmaceutically acceptable salt, and/or
(m)抗炎药， 和 /或 (m) anti-inflammatory drugs, and/or
(n)回肠胆汁酸转运蛋白抑制剂或药学上可接受的盐， 和 /或 ( n ) Ileal bile acid transporter inhibitor or pharmaceutically acceptable salt, and/or
(o)减肥药， 和 /或 (o) diet pills, and/or
(p)改善患者脂质分布的药物，所述药物选自 HMG-CoA还原酶抑制剂、 胆汁酸螯合剂、 烟碱、 烟酸或其盐、 PPARa激动剂、 胆固醇吸收抑制剂、 酰基 CoA抑制剂、 CETP抑制剂或 酚类抗氧剂或药学上可接受的盐， 和 /或 (p) Drugs that improve the lipid profile of patients, the drugs are selected from the group consisting of HMG-CoA reductase inhibitors, bile acid sequestrants, nicotine, nicotinic acid or its salts, PPAR alpha agonists, cholesterol absorption inhibitors, acyl CoA Inhibitors, CETP inhibitors or phenolic antioxidants or pharmaceutically acceptable salts, and/or
(q)双胍类、 噻唑垸二酮类、 列奈类或其药学上可接受的盐或前药。 (q) Biguanides, thiazolidinediones, lenides or their pharmaceutically acceptable salts or prodrugs.
15、 根据权利要求 14所述的药物组合物， 其中， 所述 GPR40激动剂选自 fasiglifam hemihydrate或其药学上可接受的盐或前药。 15. The pharmaceutical composition according to claim 14, wherein the GPR40 agonist is selected from fasiglifam hemihydrate or its pharmaceutically acceptable salts or prodrugs.
16、 根据权利要求 14所述的药物组合物， 其中， 所述 DDP-IV抑制剂选自利拉列汀、 omangliptin, 西他列汀、 维达列汀、 阿格列汀、 沙格列汀、 地格列汀、 Carmegliptm、 美罗 利汀、 Dutogliptin、 特力利汀、 Gemigliptin或者 Trelagliptin; SGLT-2抑制剂选自 dapagliflozm 、 propanediol empagliflozin、 ertugliflozin、 ipragliflozin、 tofogliflozin、 16. The pharmaceutical composition according to claim 14, wherein the DDP-IV inhibitor is selected from the group consisting of linagliptin, omangliptin, sitagliptin, vildagliptin, alogliptin, and saxagliptin , digagliptin, Carmegliptm, meroliptin, Dutogliptin, tenilliptin, Gemigliptin or Trelagliptin; the SGLT-2 inhibitor is selected from dapagliflozm, propanediol empagliflozin, ertugliflozin, ipragliflozin, tofogliflozin,
canagliflozinluseogliflozin ; PPAR激动剂选自 bezafibrate、 fenofibrate 、 pioglitazone、 azelaic acid、 rosiglitazone或 saroglitazar。 canagliflozinluseogliflozin; PPAR agonist selected from bezafibrate, fenofibrate, pioglitazone, azelaic acid, rosiglitazone or saroglitazar.
17、 根据权利要求 14所述的药物组合物， 其中， 所述双胍类治疗剂选自二甲双胍或者 二乙双胍； 噻唑垸二酮类治疗剂选自环格列酮、 吡咯列酮、 罗格列酮、 曲格列酮、 法格列 酮或者 达格列醌磺酰脲类治疗剂选自格列美脲、 Tolglybutamide、 格列波脲、 格列苯脲、 格列喹酮、 格列吡嗪或格列齐特； 列奈类治疗剂选自那格列奈、 瑞格列奈或者米格列奈； （X- 葡萄糖苷酶抑制剂选自阿卡波糖、 伏格列波糖或者米格列醇； GLP-1 类似物选自艾赛那肽或 者利拉鲁肽。 17. The pharmaceutical composition according to claim 14, wherein the biguanide therapeutic agent is selected from metformin or metformin; the thiazoledione therapeutic agent is selected from cycloglitazone, pioglitazone, rosiglita ketone, troglitazone, faglitazone or dapaglitazone sulfonylurea therapeutic agent selected from glimepiride, Tolglybutamide, glyburide, glibenclamide, glazidione, glipizide or gliclazide; the linide therapeutic agent is selected from nateglinide, repaglinide or mitiglinide; (the X-glucosidase inhibitor is selected from acarbose, voglibose or mitiglinide) Glitol; GLP-1 analog selected from exenatide or liraglutide.
18、 权利要求 1-11中任一项所述的化合物或其立体异构体、 水合物、 酯、 溶剂化物、 共晶体、 代谢产物、 药学上可接受的盐或前药或者权利要求 13-17中任一项所述的药物组合 物在作为一种 G蛋白偶联受体 40激动剂用于制备用于治疗和 /或预防代谢疾病的药物制剂中 的应用。 18. The compound of any one of claims 1-11 or its stereoisomer, hydrate, ester, solvate, co-crystal, metabolite, pharmaceutically acceptable salt or prodrug or claim 13- Use of the pharmaceutical composition described in any one of 17 as a G protein-coupled receptor 40 agonist for the preparation of pharmaceutical preparations for the treatment and/or prevention of metabolic diseases.
19、 根据权利要求 18所述的应用， 其中， 所述代谢疾病包括 I型糖尿病、 II型糖尿病、 糖尿病性视网膜病、 糖尿病性神经病、 糖尿病性肾病、 糖尿病并发症、 高胆固醇血症、 高 血糖、 高胰岛素血症、 高脂血症、 高甘油三酸脂血症、 高血压、 高脂蛋白血症、 高 LDL胆 固醇、 低 HDL胆固醇、 低血糖症、 血脂异常、 血栓性疾病、 心血管疾病、 肾脏疾病、 酮症 酸中毒、 脂肪酸或甘油的升高的水平、 脂肪萎缩、 脂肪毒性、 肥胖症、 代谢综合征、 X综 合 ¾£、 胰岛素抗性、 胰岛素过敏 或葡萄糖耐受不良中的一种或多种。 19. Application according to claim 18, wherein the metabolic diseases include type I diabetes, type II diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, diabetic complications, hypercholesterolemia, and hyperglycemia. , hyperinsulinemia, hyperlipidemia, hypertriglyceridemia, hypertension, hyperlipoproteinemia, high LDL cholesterol, low HDL cholesterol, hypoglycemia, dyslipidemia, thrombotic disease, cardiovascular disease , kidney disease, ketoacidosis, elevated levels of fatty acids or glycerol, lipoatrophy, lipotoxicity, obesity, metabolic syndrome, syndrome X, insulin resistance, insulin sensitivity, or glucose intolerance Kind or variety.
20、 根据权利要求 19所述的应用， 其中， 所述代谢疾病包括 Π型糖尿病。 20. The application according to claim 19, wherein the metabolic disease includes type II diabetes.
21、 一种治疗和 /或预防代谢疾病的方法， 所述方法包括给药权利要求 1-11中任一项所 述的化合物或其立体异构体、 水合物、 酯、 溶剂化物、 共晶体、 代谢产物、 药学上可接受 的盐或前药或者权利要求 13-17中任一项所述的药物组合物。 21. A method for treating and/or preventing metabolic diseases, the method comprising administering the compound of any one of claims 1-11 or its stereoisomer, hydrate, ester, solvate, or co-crystal , metabolites, pharmaceutically acceptable salts or prodrugs or the pharmaceutical composition according to any one of claims 13-17.
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