WO2020156241A1 - 芳环或芳杂环类化合物及其制备方法和医药用途 - Google Patents

芳环或芳杂环类化合物及其制备方法和医药用途 Download PDF

Info

Publication number
WO2020156241A1
WO2020156241A1 PCT/CN2020/072763 CN2020072763W WO2020156241A1 WO 2020156241 A1 WO2020156241 A1 WO 2020156241A1 CN 2020072763 W CN2020072763 W CN 2020072763W WO 2020156241 A1 WO2020156241 A1 WO 2020156241A1
Authority
WO
WIPO (PCT)
Prior art keywords
azabicyclo
cyclopropyl
oxadiazol
isoxazol
methoxy
Prior art date
Application number
PCT/CN2020/072763
Other languages
English (en)
French (fr)
Inventor
殷惠军
闫旭
宗利斌
史建新
刘春艳
张守良
司春枫
路嘉伟
米桢
李�浩
Original Assignee
中国医药研究开发中心有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 中国医药研究开发中心有限公司 filed Critical 中国医药研究开发中心有限公司
Priority to CN202080006066.5A priority Critical patent/CN112955448B/zh
Priority to AU2020214889A priority patent/AU2020214889A1/en
Priority to EP20749262.0A priority patent/EP3919489A4/en
Priority to JP2021544611A priority patent/JP2022518603A/ja
Priority to CA3128416A priority patent/CA3128416A1/en
Priority to KR1020217027636A priority patent/KR20210123337A/ko
Priority to US17/310,432 priority patent/US20220127258A1/en
Publication of WO2020156241A1 publication Critical patent/WO2020156241A1/zh

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • C07D451/06—Oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • 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

Definitions

  • the present invention belongs to the technical field of medicine, and specifically relates to an aromatic ring or aromatic heterocyclic compound, a preparation method thereof, and a pharmaceutical composition containing the same, and its use for regulating Farnesoid X receptor (FXR). ) Activity, and then used to treat and/or prevent diseases related to FXR activity.
  • FXR Farnesoid X receptor
  • Farnesol derivative X receptor (FXR), as a bile acid-activated nuclear receptor, can directly or through the orphan nuclear receptor small heterodimer chaperone (SHP) regulate the expression of a variety of metabolism-related genes.
  • FXR was discovered in 1995, and its name comes from the fact that this receptor can be activated by superphysiological levels of farnesol.
  • BAs bile acids
  • bile acid accumulation is a more important pathogenic factor for non-alcoholic fatty liver.
  • the activation of FXR can reduce the synthesis and uptake of bile acids in the liver, and increase the efflux of bile acids, to achieve the net effect of reducing the accumulation of bile acids in the liver;
  • FXR can up-regulate SHP, and SHP can inhibit the expression of the important enzyme CYP7A1 for bile acid synthesis, and then Inhibit bile acid synthesis (Pharmacol.Ther.2010, 126, 228-243);
  • FXR can induce FGF15/19 to activate FGFR4, which in turn activates the JNK pathway to inhibit the expression of CYP7A1;
  • FXR inhibits the decrease of NTCP by up-regulating BSEP and MRP2
  • the level of bile acid in hepatocytes stimulates the secretion of bile
  • FXR can improve insulin resistance.
  • FXR knockout mice show impaired glucose metabolism clearance, indicating that the mice have peripheral insulin resistance.
  • the improvement effect of FXR activation on insulin resistance may be related to the following mechanism: FXR can reduce lipid accumulation in peripheral tissues (such as muscle cells), thereby reducing lipid-related toxicity, especially for obese patients caused by diet (Acta.Pharmacol.Sin .2015, 36, 44-50); the activation of FXR in the small intestine can promote the release of FGF19 into the portal vein.
  • FGF19 has a certain insulin sensitization effect. It is also reported that FGF19 has a weight reduction effect.
  • FGF19 transgenic mice show strong resistance to diet induction Obesity effect; FXR can reduce gluconeogenesis and glycogen output, cholic acid feeding mice can inhibit the expression of gluconeogenesis-related enzymes, such as PEPCK, G6P and other genes, but have no effect on SHP knockout mice; FXR agonists can Reduce mouse PEPCK and G6P, while reducing glycogen output.
  • FXR can reduce gluconeogenesis and glycogen output
  • cholic acid feeding mice can inhibit the expression of gluconeogenesis-related enzymes, such as PEPCK, G6P and other genes, but have no effect on SHP knockout mice
  • FXR agonists can Reduce mouse PEPCK and G6P, while reducing glycogen output.
  • FXR can reduce the production of triglycerides and fatty acids and promote their metabolism through a variety of ways.
  • FXR can inhibit the expression of SREBP1c, inhibit the synthesis and secretion of triglycerides and fatty acids, promote the expression of VLDLR, increase the clearance of VLDL and chylomicrons, inhibit the expression of APOC and MTP, inhibit the assembly of VLDL, induce PPAR ⁇ , and promote fatty acid production.
  • Beta oxidation induces lipoprotein lipase, which in turn enhances the metabolism of lipoprotein and free fatty acids.
  • FXR positively regulates SRBI, CEH, SCP2, etc. to promote the uptake of HDL and the reverse transport of cholesterol. It can also inhibit the expression and activity of PCSK9, enhance the clearance of LDLR and LDL, and achieve the effect of lowering cholesterol (Curr.Opin.Lipidol.2016) , 27, 295-301).
  • FXR can inhibit inflammation by down-regulating the expression of a variety of inflammation-related genes.
  • FXR is closely related to inflammation.
  • FXR knockout mice have higher levels of pro-inflammatory and pro-fibrocytokines, including TNF ⁇ , ICAM-1, and ⁇ -SMA , TIMP-1, TGF ⁇ , etc.
  • the inhibition of inflammation and fibrosis by FXR may be related to the following mechanisms:
  • the main inflammation inhibitory mechanism of FXR activation is to antagonize the NF ⁇ B signaling pathway; FXR activation can improve bile duct obstruction, intestinal flora overgrowth, mucosal damage, intestinal bacterial translocation, etc.
  • FXR can induce the inhibitor of SOCS3, thereby inhibiting the STAT3 signaling pathway; the activation of FXR can increase MicroRNA mir29a, which can regulate the expression of multiple extracellular matrix proteins.
  • FXR agonists can be used for lipid, especially triglyceride accumulation, and diseases and disorders caused by chronic fat and fibrosis caused by triglyceride accumulation, such as non-alcoholic fatty liver (NAFLD) or non-alcoholic steatohepatitis ( NASH) prevention and treatment (Adv. Ther. 2016, 33, 291-319; Drug Discov. Today, 2012, 17, 988-97).
  • FXR agonists have become one of the hottest topics in global innovative drug research and development.
  • the steroidal FXR agonist obeticholic acid has been successfully approved for use in primary biliary cirrhosis (PBC), and has shown good efficacy in clinical studies (FlINT studies) for the treatment of NASH.
  • Further FXR agonists The rationality for the treatment of PBC and NASH.
  • the drug has poor selectivity as a steroid drug, especially for TGR5, which can easily cause side effects such as severe itching and hyperlipidemia.
  • obeticholic acid has serious hepato-intestinal circulation, which leads to high accumulation of drugs in the body, which has caused safety risks. Therefore, non-steroidal FXR agonists with higher selectivity and better pharmacokinetic properties have attracted more attention (Lancet, 2015, 385, 956-65; N. Engl. J. Med. 2016, 375, 631-643).
  • the non-steroidal FXR agonist researched earlier is GW-4604.
  • This compound has strong in vitro activity, but its pharmacokinetic properties are not good, and due to the safety risk of the diarylethene structure; currently, the research and development progress is the fastest, The most concerned is PX-104.
  • the drug has high FXR agonistic activity and pharmacokinetic properties. It has been shown to significantly reduce liver fat accumulation and damage in preclinical pharmacodynamics models. It has now entered clinical trials for NASH Phase II study (J. Pharmacol. Exp. Ther. 2012, 343, 556-567; J. Med. Chem. 2014, 57, 8035-8055). Nevertheless, the in vitro activity of PX-104 still has room for further improvement, and the clinical dose is relatively high. Therefore, there is a continuing need for new or improved drugs that stimulate FXR for the development of new and more effective drugs to treat NASH, NAFLD, PBC or other FXR-related diseases.
  • the inventors designed and synthesized a series of compounds containing bridging ring group-substituted aromatic rings or aromatic heterocyclic skeletons, and screened them for FXR activity.
  • the research results show that these compounds have outstanding FXR agonistic activity.
  • And can be developed as a drug to treat diseases related to FXR activity.
  • the object of the present invention is to provide a compound represented by the general formula (I) or its meso, racemate, enantiomer, diastereomer, or a mixture form thereof, and Prodrugs or their pharmaceutically acceptable salts,
  • Z is selected from:
  • X is CH, CF, N or NO
  • R 2 is selected from hydrogen, halogen, alkyl, and cycloalkyl, wherein the alkyl or cycloalkyl is optionally further substituted with one or more groups selected from halogen, hydroxy, alkyl, and alkoxy;
  • R 3 and R 4 are each independently selected from hydrogen, halogen, alkyl, and alkoxy, and the alkyl or alkoxy is optionally further substituted with one or more halogens;
  • Ar is 5-membered or 6-membered aryl or heteroaryl
  • Cy is aryl or heteroaryl
  • R 1 is selected from -(CH 2 ) m -R 5 or -O(CH 2 ) m -R 5 ; wherein the -(CH 2 ) m -or -O(CH 2 ) m -group is optionally further One or more groups selected from halogen, cyano, hydroxyl, oxo, alkyl, haloalkyl, alkoxy, haloalkoxy, CO 2 H, SO 3 H;
  • R 5 is selected from hydrogen, halogen, cyano, nitro, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, OR 6 , NR 6 R 7 , -CO 2 R 6 , -C(O )R 6 , -C(O)NR 6 R 7 , -N(R 6 )C(O)R 7 , -C(O)NR 6 SO 2 R 7 , -S(O) p R 6 , -S (O) p NR 6 R 7 , -N(R 6 )S(O) p R 7 , or -S(O) p NR 6 COR 7 ; the alkyl group, cycloalkyl group, heterocyclic group, aryl group Or heteroaryl is optionally further selected from halogen, amino, nitro, cyano, hydroxy, mercapto, carboxy, ester, oxo, alkyl, haloalkyl, alk
  • R 6 and R 7 are each independently selected from hydrogen, halogen, hydroxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl And heteroaryl are optionally further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl , One or more groups of heteroaryl are substituted;
  • the nitrogen-containing heterocyclic group is optionally further selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto , Carboxyl group, ester group, alkyl group, alkoxy group, cycloalkyl group, heterocyclic group, aryl group, heteroaryl group substituted by one or more groups;
  • Each R 8 may be the same or different, and are each independently selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxy, ester, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl , Alkynyl, cycloalkyl, halocycloalkyl, heterocyclyl, aryl, heteroaryl;
  • n 0, 1 or 2;
  • n is an integer from 0 to 6;
  • p 0, 1 or 2;
  • q is an integer from 0 to 4.
  • the compound represented by the general formula (I) according to the present invention or its mesomer, racemate, enantiomer, diastereomer, Or its mixture form, its prodrug or its pharmaceutically acceptable salt which is the compound represented by the general formula (II) or its meso, racemate, enantiomer, diastereomer , Or its mixture form, its prodrug or its pharmaceutically acceptable salt,
  • X 1 , X 2 , and X 3 are each independently selected from C, N, O or S, preferably N, O;
  • Ar is selected from oxazole, isoxazole, thiazole, isothiazole, imidazole, triazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxa Diazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole or 1,3,4-thiadiazole.
  • X is selected from CH or N;
  • R 2 is selected from hydrogen, halogen, alkyl, cycloalkyl, preferably C 1 -C 6 alkyl or C 3 -C 6 cycloalkyl, more preferably cyclopropyl; the alkyl or cycloalkyl optionally further Substituted by one or more groups selected from halogen, hydroxyl, alkyl, and alkoxy;
  • R 3 and R 4 are each independently selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, preferably hydrogen, halogen, C 1 -C 6 haloalkyl and C 1 -C 6 haloalkoxy.
  • n 1.
  • Cy is a C 5 -C 6 aryl group or a 5- to 6-membered heteroaryl group, preferably phenyl, pyridyl, pyrimidinyl, pyrazinyl, thiazolyl, furyl, imidazolyl, and pyrazolyl.
  • R 1 is selected from -(CH 2 ) m -R 5 or -O(CH 2 ) m -R 5 ;
  • R 5 is selected from hydrogen, halogen, alkyl, OR 6 , NR 6 R 7 , -CO 2 R 6 , -C(O)R 6 , -C(O)NR 6 R 7 , -N(R 6 )C (O)R 7 , -C(O)NR 6 SO 2 R 7 , -S(O) p R 6 , -S(O) p NR 6 R 7 , -N(R 6 )S(O) p R 7 , or -S(O) p NR 6 COR 7 , preferably -C(O)R 6 , -C(O)NR 6 R 7 , -S(O) p R 6 , -S(O) p NR 6 R 7 , more preferably -C(O)R 6 or -S(O) p NR 6 R 7 , even more preferably -COOH;
  • R 6 and R 7 are each independently selected from hydrogen, halogen, hydroxy, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl And heteroaryl are optionally further selected from halogen, amino, nitro, cyano, hydroxyl, mercapto, carboxy, ester, oxo, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl , One or more groups of heteroaryl are substituted;
  • the nitrogen-containing heterocyclic group is optionally further selected from halogen, amino, nitro, cyano, oxo, hydroxyl, mercapto ,carboxyl;
  • n is an integer from 0 to 6, preferably 0, 1 or 2; more preferably 0.
  • Each R 8 may be the same or different, and each is independently selected from halogen, alkyl, haloalkyl, alkoxy, and haloalkoxy;
  • q is an integer from 0 to 4; preferably q is 0 or 1.
  • Typical compounds of the present invention include but are not limited to:
  • the present invention further provides a method for preparing the compound represented by the general formula (I) according to the present invention or its mesomer, racemate, enantiomer, diastereomer, or mixture thereof Form, its prodrug or its pharmaceutically acceptable salt method, which comprises the following steps:
  • the compound IE and ID are cyclized to obtain the compound of general formula (I), wherein the condensing agent is preferably zinc chloride;
  • Z, n, Cy, R 1 , R 8 , and q are as defined in the general formula (I).
  • the present invention further provides a method for preparing the compound represented by the general formula (I) according to the present invention or its mesomer, racemate, enantiomer, diastereomer, or mixture thereof Form, its prodrug or its pharmaceutically acceptable salt method, which comprises the following steps:
  • the compound IJ is subjected to a cyclization reaction to obtain a compound of general formula (I), wherein the oxidant is preferably iodobenzene diacetic acid;
  • Z, n, Cy, R 1 , R 8 , and q are as defined in the general formula (I).
  • Another aspect of the present invention provides a pharmaceutical composition, which contains the compound represented by the general formula (I) according to the present invention or its mesomer, racemate, enantiomer, diastereomer Isomers, or mixtures thereof, prodrugs or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers.
  • the present invention further provides the compound represented by the general formula (I) according to the present invention or its meso, racemate, enantiomer, diastereomer, or mixture form thereof, and Use of prodrugs or their pharmaceutically acceptable salts, or pharmaceutical compositions containing them, in the preparation of FXR agonists.
  • the present invention further provides the compound represented by the general formula (I) according to the present invention or its meso, racemate, enantiomer, diastereomer, or mixture form thereof, and Use of a prodrug or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the prodrug in the preparation of a medicine for preventing and/or treating diseases related to FXR activity.
  • the present invention provides a compound represented by the general formula (I) according to the present invention or its mesomer, racemate, enantiomer, diastereomer, or a mixture of its forms, and its former
  • the medicine or its pharmaceutically acceptable salt, or a pharmaceutical composition containing it, is used as an FXR agonist.
  • the present invention further provides the compound represented by the general formula (I) according to the present invention or its meso, racemate, enantiomer, diastereomer, or mixture form thereof, and A prodrug or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, which is used as a medicine for the prevention and/or treatment of diseases related to FXR activity.
  • the present invention further provides a method for preventing and/or treating diseases related to FXR activity, which comprises administering to a subject in need a preventive or therapeutically effective amount of the formula (I) represented by the present invention
  • a preventive or therapeutically effective amount of the formula (I) represented by the present invention The compound or its mesosome, racemate, enantiomer, diastereomer, or mixture form thereof, its prodrug or its pharmaceutically acceptable salt, or a pharmaceutical composition containing it.
  • the diseases related to FXR activity may be: chronic intrahepatic cholestasis or extrahepatic cholestasis, or chronic cholestasis or acute intrahepatic cholestasis Liver fibrosis caused by disease; and/or liver obstructive or chronic inflammation; and/or liver cirrhosis; and/or liver sebaceous gland disease and related syndromes, bile associated with alcohol-induced cirrhosis or viral hepatitis Stagnation or fibrotic effects; and/or liver failure or liver ischemia after liver resection; and/or steatohepatitis-related chemotherapy; and/or acute liver failure; and/or inflammatory bowel disease; and/or lipid And lipid protein disorders; and/or diabetes and clinical complications of diabetes, including diabetic nephropathy, diabetic neuropathy, diabetic retinopathy and other clinical manifestations; and/or lipids, especially triglyceride
  • the compound represented by the general formula (I) of the present invention can form a pharmaceutically acceptable acid addition salt with an acid.
  • the acid includes inorganic acid and organic acid, particularly preferably hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalene disulfonic acid, acetic acid, propionic acid, lactic acid , Trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid, etc.
  • the compound represented by the general formula (I) of the present invention can form a pharmaceutically acceptable basic addition salt with a base.
  • the bases include inorganic bases and organic bases.
  • Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine, etc.
  • acceptable inorganic bases include aluminum hydroxide, hydroxide Calcium, potassium hydroxide, sodium carbonate and sodium hydroxide, etc.
  • the present invention also includes prodrugs of the compounds represented by the general formula (I) of the present invention.
  • the prodrugs of the present invention are derivatives of the compound represented by the general formula (I). They may have weak activity or even no activity by themselves, but after administration, under physiological conditions (such as metabolism, solvolysis) Or another way) is converted into the corresponding biologically active form.
  • the pharmaceutical composition containing the active ingredient may be in a form suitable for oral administration, such as tablets, dragees, lozenges, water or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or Elixirs.
  • the oral composition may be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, coloring agents and preservatives, In order to provide pleasing and delicious medicinal preparations.
  • the tablet contains the active ingredient and non-toxic pharmaceutically acceptable excipients suitable for the preparation of tablets for mixing.
  • excipients can be inert excipients, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, such as microcrystalline cellulose, croscarmellose sodium, corn Starch or alginic acid; binders, such as starch, gelatin, polyvinylpyrrolidone, or gum arabic; and lubricants, such as magnesium stearate, stearic acid, or talc.
  • These tablets may be uncoated or may be coated by known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained release effect over a longer period of time.
  • water-soluble taste-masking substances such as hydroxypropyl methylcellulose or hydroxypropyl cellulose, or extended time substances such as ethyl cellulose, cellulose acetate butyrate can be used.
  • Hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin can also be used, or in which the active ingredient is mixed with a water-soluble carrier such as polyethylene glycol or an oil solvent such as peanut oil, liquid paraffin or olive oil.
  • Soft gelatin capsules provide oral preparations.
  • Aqueous suspensions contain the active substance and excipients suitable for the preparation of aqueous suspensions for mixing.
  • excipients are suspending agents, such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinylpyrrolidone and gum arabic; dispersing or wetting agents, which can be natural Produced phospholipids such as lecithin, or condensation products of alkylene oxides and fatty acids, such as polyoxyethylene stearate, or condensation products of ethylene oxide and long-chain fatty alcohols, such as seventeen-carbon ethyleneoxy whale Heptadecaethyleneoxycetanol, or condensation products of ethylene oxide and partial esters derived from fatty acids and hexitols, such as polyethylene oxide sorbitol monooleate, or ethylene oxide with fatty acids and hexitols Condensation products of anhydride-derived partial esters, such as polyethylene oxide sorbitan monooleate
  • the aqueous suspension may also contain one or more preservatives such as ethyl paraben or n-propyl paraben, one or more coloring agents, one or more flavoring agents and one or more sweeteners.
  • preservatives such as ethyl paraben or n-propyl paraben
  • coloring agents such as ethyl paraben or n-propyl paraben
  • flavoring agents such as sucrose, saccharin or aspartame.
  • Oil suspensions can be formulated by suspending the active ingredients in vegetable oils such as peanut oil, olive oil, sesame oil or coconut oil, or mineral oils such as liquid paraffin. Oil suspensions may contain thickening agents such as beeswax, hard paraffin or cetyl alcohol. The above-mentioned sweeteners and flavoring agents can be added to provide a palatable preparation. These compositions can be preserved by adding antioxidants such as butylated hydroxyanisole or alpha-tocopherol.
  • dispersible powders and granules suitable for preparing aqueous suspensions can provide the active ingredient and a dispersing or wetting agent for mixing, suspending agent or one or more preservatives. Suitable dispersing or wetting agents and suspending agents are as described above. Other excipients such as sweeteners, flavoring agents and coloring agents may also be added. These compositions are preserved by adding antioxidants such as ascorbic acid.
  • the pharmaceutical composition of the invention may also be in the form of an oil-in-water emulsion.
  • the oil phase may be a vegetable oil such as olive oil or peanut oil, or a mineral oil such as liquid paraffin or a mixture thereof.
  • Suitable emulsifiers may be naturally occurring phospholipids, such as soybean lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation of the partial esters and ethylene oxide Products such as polyethylene oxide sorbitol monooleate.
  • the emulsion may also contain sweetening agents, flavoring agents, preservatives and antioxidants.
  • Syrups and elixirs formulated with sweetening agents such as glycerin, propylene glycol, sorbitol or sucrose.
  • Such preparations may also contain a demulcent, a preservative, a coloring agent and an antioxidant.
  • the pharmaceutical composition of the present invention may be in the form of a sterile injectable aqueous solution.
  • Acceptable solvents and solvents that can be used include water, Ringer's solution and isotonic sodium chloride solution.
  • the sterile injection preparation may be a sterile injection oil-in-water microemulsion in which the active ingredient is dissolved in an oil phase.
  • the active ingredient is dissolved in a mixture of soybean oil and lecithin.
  • the oil solution is added to a mixture of water and glycerin to form a microemulsion.
  • the injection or microemulsion can be injected into the patient's bloodstream by local large-scale injection.
  • it is best to administer the solution and microemulsion in a manner that maintains a constant circulating concentration of the compound of the invention.
  • a continuous intravenous delivery device can be used.
  • the pharmaceutical composition of the present invention may be in the form of a sterile injection water or oil suspension for intramuscular and subcutaneous administration.
  • the suspension can be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents mentioned above.
  • the sterile injection preparation may also be a sterile injection solution or suspension prepared in a non-toxic parenterally acceptable diluent or solvent, for example, a solution prepared in 1,3-butanediol.
  • sterile fixed oil can be conveniently used as a solvent or suspension medium. For this purpose, any blended fixed oil including synthetic mono- or diglycerides can be used.
  • fatty acids such as oleic acid can also be used to prepare injections.
  • the compounds of the present invention can be administered in the form of suppositories for rectal administration.
  • These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid in the rectum and thus will melt in the rectum to release the drug.
  • suitable non-irritating excipient include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, polyethylene glycols of various molecular weights and mixtures of fatty acid esters of polyethylene glycol.
  • the dosage of the drug depends on many factors, including but not limited to the following factors: the activity of the specific compound used, the age of the patient, the weight of the patient, the patient’s health, the patient’s clothing, the patient The diet, time of administration, mode of administration, rate of excretion, combination of drugs, etc.
  • the best treatment method such as the treatment mode, the daily dosage of the compound of the general formula or the type of pharmaceutically acceptable salt can be verified according to the traditional treatment plan.
  • the present invention may contain a compound represented by general formula (I), and a pharmaceutically acceptable salt, hydrate or solvate thereof as an active ingredient, mixed with a pharmaceutically acceptable carrier or excipient to prepare a composition, and Prepared into a clinically acceptable dosage form.
  • the derivatives of the present invention can be used in combination with other active ingredients, as long as they do not produce other adverse effects, such as allergic reactions.
  • the compound of the present invention can be used as the sole active ingredient, and can also be used in combination with other drugs for the treatment of diseases related to FXR activity. Combination therapy is achieved by administering each treatment component simultaneously, separately or sequentially.
  • alkyl refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably containing 1 to 6 carbon atoms Atom of the alkyl group.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 , 2-Dimethylpropyl, 2,2-Dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 -Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -Methylhexyl, 3-methylhexyl, 4-methylhe
  • lower alkyl groups containing 1 to 6 carbon atoms More preferred are lower alkyl groups containing 1 to 6 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, and sec-butyl.
  • Alkyl groups may be substituted or unsubstituted.
  • substituents When substituted, substituents may be substituted at any available attachment point.
  • the substituents are preferably one or more of the following groups, which are independently selected from alkanes Group, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkane Oxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxy, or carboxylate.
  • alkenyl refers to an alkyl group as defined above composed of at least two carbon atoms and at least one carbon-carbon double bond, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2-, or 3 -Butenyl etc. Alkenyl groups may be substituted or unsubstituted.
  • the substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio.
  • alkynyl refers to an alkyl group as defined above composed of at least two carbon atoms and at least one carbon-carbon triple bond, such as ethynyl, propynyl, butynyl, and the like.
  • the alkynyl group may be substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent.
  • the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 6 Carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Groups, cyclooctyl groups, etc.; polycyclic cycloalkyls include spiro, fused, and bridged cycloalkyls.
  • spirocycloalkyl refers to a polycyclic group that shares one carbon atom (called a spiro atom) between 5- to 20-membered monocyclic rings, which may contain one or more double bonds, but none of the rings have complete conjugate ⁇ electronic system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan.
  • the spirocycloalkyl group is classified into a single spirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group, preferably a single spirocycloalkyl group and a bispirocycloalkyl group. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered monospirocycloalkyl.
  • spirocycloalkyl groups include:
  • fused cycloalkyl refers to a 5- to 20-membered all-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or Multiple double bonds, but none of the rings have a fully conjugated ⁇ -electron system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyls, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic alkyl.
  • fused cycloalkyl groups include:
  • bridged cycloalkyl refers to a 5- to 20-membered, all-carbon polycyclic group with any two rings sharing two carbon atoms that are not directly connected. It may contain one or more double bonds, but no ring has complete Conjugated ⁇ electron system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyls, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic.
  • bridged cycloalkyl groups include:
  • the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthalene Group, benzocycloheptyl group, etc. Cycloalkyl groups may be optionally substituted or unsubstituted.
  • the substituents are preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, oxo, carboxy, or carboxylate.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent which contains 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) m (where m is an integer of 0 to 2) heteroatoms, but does not include the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. It preferably contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; most preferably contains 3 to 8 ring atoms, of which 1 to 3 are heteroatoms; most preferably contains 5 to 7 ring atoms, of which 1 to 2 or 1 to 3 are heteroatoms.
  • Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidine Group, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, etc., preferably 1, 2, 5-oxadiazolyl, pyranyl or morpholinyl.
  • Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.
  • spiroheterocyclic group refers to a polycyclic heterocyclic group that shares one atom (called a spiro atom) between 5- to 20-membered monocyclic rings, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O ) m (where m is an integer of 0 to 2) heteroatoms, and the remaining ring atoms are carbon. It can contain one or more double bonds, but none of the rings have a fully conjugated ⁇ -electron system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan.
  • the spiro heterocyclic group is classified into a single spiro heterocyclic group, a dispiro heterocyclic group or a polyspiro heterocyclic group, preferably a single spiro heterocyclic group and a dispiro heterocyclic group. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospiro heterocyclic group.
  • Non-limiting examples of spiroheterocyclic groups include:
  • fused heterocyclic group refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system.
  • One or more rings may contain one or more Double bond, but none of the rings have a fully conjugated ⁇ -electron system, one or more of the ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), and the rest of the ring
  • the atom is carbon. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan.
  • bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group.
  • fused heterocyclic groups include:
  • bridged heterocyclic group refers to a 5- to 14-membered polycyclic heterocyclic group with any two rings sharing two atoms that are not directly connected. It may contain one or more double bonds, but none of the rings has a complete common A conjugated ⁇ -electron system in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O) m (where m is an integer of 0 to 2), and the remaining ring atoms are carbon. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan.
  • bridged heterocyclic groups include:
  • the heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclic group, non-limiting examples thereof include:
  • the heterocyclic group may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, oxo, carboxy, or carboxylate.
  • aryl refers to a 6 to 14-membered all-carbon monocyclic or fused polycyclic (that is, rings sharing adjacent pairs of carbon atoms) with a conjugated ⁇ -electron system, preferably 6 to 10 members, such as benzene Base and naphthyl. Phenyl is more preferred.
  • the aryl ring may be fused to a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, non-limiting examples thereof include:
  • the aryl group may be substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio, carboxyl or carboxylate.
  • heteroaryl refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, where the heteroatoms are selected from oxygen, sulfur and nitrogen.
  • Heteroaryl groups are preferably 5 to 10 members, containing 1 to 3 heteroatoms; more preferably 5 or 6 members, containing 1 to 2 heteroatoms; preferably, for example, imidazolyl, furyl, thienyl, thiazolyl, pyridine Azolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably imidazolyl, thiazolyl, pyrazolyl or pyrimidinyl, thiazolyl; more preferably Pyrazolyl or thiazolyl.
  • the heteroaryl ring may be fused on an aryl, heterocyclic or cycloalkyl ring, where
  • the heteroaryl group may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, carboxy or carboxylate.
  • alkoxy refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), where alkyl is defined as described above.
  • alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
  • the alkoxy group may be optionally substituted or unsubstituted.
  • the substituent group is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, carboxy or carboxylate.
  • haloalkyl refers to an alkyl group substituted with one or more halogens, wherein the alkyl group is as defined above.
  • haloalkoxy refers to an alkoxy group substituted with one or more halogens, where alkoxy is as defined above.
  • hydroxyalkyl refers to an alkyl group substituted with a hydroxy group, where the alkyl group is as defined above.
  • hydroxy refers to the -OH group.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • amino refers to -NH 2 .
  • cyano refers to -CN.
  • nitro refers to -NO 2 .
  • mercapto refers to -SH.
  • ester group refers to -C(O)O (alkyl) or -C(O)O (cycloalkyl), where alkyl and cycloalkyl are as defined above.
  • acyl refers to a compound containing a -C(O)R group, where R is an alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl group.
  • sulfonic acid group refers to -S(O) 2 OH.
  • sulfonate group refers to -S(O) 2 O (alkyl) or -S(O) 2 O (cycloalkyl), where alkyl and cycloalkyl are as defined above.
  • sulfonyl refers to a compound of the -S(O) 2 R group, where R is alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl.
  • aminoacyl refers to -C(O)-NRR', wherein R and R'are each independently hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl.
  • aminonosulfonyl or “sulfonylamino” refers to -S(O) 2 -NRR', where R and R'are each independently hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl base.
  • heterocyclic group optionally substituted by an alkyl group means that an alkyl group may but does not have to be present.
  • the description includes the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by an alkyl group. .
  • Substituted refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3 hydrogen atoms independently of each other substituted by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without too much effort. For example, an amino group or a hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (e.g., olefinic) bond.
  • “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein or their physiologically/pharmaceutically acceptable salts or prodrugs and other chemical components, and other components such as physiological/pharmaceutically acceptable carriers And excipients.
  • the purpose of the pharmaceutical composition is to promote the administration to the organism, which is beneficial to the absorption of the active ingredient and thus the biological activity.
  • “Pharmaceutically acceptable salt” refers to the salt of the compound of the present invention, which is safe and effective when used in mammals, and has due biological activity.
  • the present invention adopts the following technical solutions.
  • the compound represented by the general formula (I) of the present invention or its salt can be prepared by the following scheme, and the specific preparation method is as follows.
  • compound IA is reacted with Z-CH 2 -Br to obtain compound IB, wherein the alkaline reagent is preferably potassium tert-butoxide; subsequently, compound IB is deprotected under acidic conditions to obtain compound IC, wherein , The acidic reagent is preferably trifluoroacetic acid; subsequently, under alkaline conditions, the compound IC is reacted with cyanogen bromide to obtain the compound ID, wherein the alkaline reagent is preferably potassium carbonate; then, under the condition of the condensing agent, the compound ID and IE A condensation ring-closing reaction occurs to obtain a compound of general formula (II), wherein the condensing agent is preferably zinc chloride.
  • the condensing agent is preferably zinc chloride.
  • Z, n, Cy, R 1 , R 8 , and q are as defined in the general formula (I).
  • compound IF is condensed with tert-butyl carbazate to obtain compound IG, wherein the alkaline reagent is preferably DMAP, and the condensing agent is preferably EDC; subsequently, compound IG is subjected to acidic conditions Deprotection reaction occurs to obtain compound IH, wherein the acidic reagent is preferably trifluoroacetic acid; subsequently, compound IH and triethyl orthoformate undergo a cyclization reaction to obtain compound II; then, under alkaline conditions, compound II and IC are reacted Condensation reaction yields compound IJ, wherein the basic condition is preferably triethylamine; finally, under the condition of an oxidizing agent, the compound IJ is subjected to a cyclization reaction to obtain a compound of general formula (I), and the oxidizing agent is preferably iodobenzene diacetic acid.
  • the alkaline reagent is preferably DMAP, and the condensing agent is preferably E
  • Z, n, Cy, R 1 , R 8 , and q are as defined in the general formula (I).
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS).
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • the NMR shift is given in units of 10 -6 (ppm).
  • NMR is measured by Brukerdps300 nuclear magnetometer, the solvent is deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard is tetramethyl Silane (TMS).
  • the preparation liquid phase uses lc3000 high performance liquid chromatograph and lc6000 high performance liquid chromatograph (manufacturer: Chuangxintongheng).
  • the chromatographic column is Daisogel C18 10 ⁇ m 60A (20mm ⁇ 250mm).
  • HPLC determination uses Shimadzu LC-20AD high pressure liquid chromatograph (Agilent TC-C18 250 ⁇ 4.6mm 5 ⁇ m column) and Shimadzu LC-2010AHT high pressure liquid chromatograph (Phenomenex C18 250 ⁇ 4.6mm 5 ⁇ m column).
  • the thin layer chromatography silica gel plate uses Qingdao Ocean Chemical GF254 silica gel plate, the size of the silica gel plate used in thin layer chromatography (TLC) is 0.15mm ⁇ 0.2mm, and the specification of thin layer chromatography separation and purification products is 0.4mm ⁇ 0.5 mm.
  • the known starting materials of the present invention can be synthesized by using or according to methods known in the art, or can be purchased from the network shopping mall, Beijing coupling, Sigma, Bailingwei, Yi Shiming, Shanghai Shuya, Yinuokai, Nanjing Yaoshi, Anaiji Chemical and other companies.
  • reaction can all be carried out under an argon atmosphere or a nitrogen atmosphere.
  • the argon atmosphere or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1L.
  • the microwave reaction uses CEM Discover SP type microwave reactor.
  • the solution refers to an aqueous solution.
  • reaction temperature is room temperature, which is 20°C to 30°C.
  • the monitoring of the reaction progress in the examples adopts thin-layer chromatography (TLC), and the developing reagent systems used in the reaction are: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether And ethyl acetate system, D: acetone, the volume ratio of the solvent is adjusted according to the polarity of the compound.
  • TLC thin-layer chromatography
  • the eluent system of column chromatography and the developing solvent system of thin-layer chromatography used to purify compounds include: A: dichloromethane and methanol system, B: petroleum ether, ethyl acetate and dichloromethane system, C: petroleum In the ether and ethyl acetate system, the volume ratio of the solvent is adjusted according to the polarity of the compound. A small amount of basic or acidic reagents such as triethylamine and acetic acid can also be added to adjust.
  • Example 1 4-(5-((1R,3r,5S)-3-((5-cyclopropyl-3-(2,6-dichlorophenyl)-isoxazol-4-yl)methan (Oxy)-8-azabicyclo[3.2.1]octane-8-yl)-1,2,4-oxadiazol-3-yl)benzoic acid (1)
  • Step 1 (1R,3r,5S)-3-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)-8-aza Preparation of bicyclo[3.2.1]octane-8-tert-butyl carboxylate (1B)
  • Step 2 4-((((1R,3r,5S)-8-azabicyclo[3.2.1]oct-3-yl)oxy)methyl)-5-cyclopropyl-3-(2, Preparation of 6-dichlorophenyl)isoxazole (1C)
  • Step 4 4-(5-((1R,3r,5S)-3-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy )-8-Azabicyclo[3.2.1]octane-8-yl)-1,2,4-oxadiazol-3-yl)methyl benzoate (1E)
  • Step 5 4-(5-((1R,3r,5S)-3-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy )-8-Azabicyclo[3.2.1]octane-8-yl)-1,2,4-oxadiazol-3-yl)benzoic acid (1)
  • the preparation method was the same as in Example 1, except that methyl 2-chloro-4-cyanobenzoate was used instead of methyl p-cyanobenzoate to obtain the title compound 2.
  • the preparation method was the same as in Example 1, except that methyl 6-cyanopyridine-2-carboxylate was used instead of methyl p-cyanobenzoate to obtain the title compound 3.
  • the preparation method was the same as in Example 1, except that methyl 5-cyanothiophene-2-carboxylate was used instead of methyl p-cyanobenzoate to obtain the title compound 4.
  • Example 5 4-(5-((1R,3r,5S)-(3-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methan (Oxy)-8-azabicyclo[3.2.1]octane-8-yl)-1,2,4-oxadiazol-3-yl)-3-methylbenzoic acid (5)
  • the preparation method was the same as in Example 1, except that methyl 4-cyano-3-methylbenzoate was used instead of methyl p-cyanobenzoate to obtain the title compound 5.
  • the preparation method was the same as in Example 1, except that methyl meta-cyanobenzoate was used instead of methyl p-cyanobenzoate to obtain the title compound 6.
  • Example 7 4-(5-((1R,3r,5S)-(3-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methan (Oxy)-8-azabicyclo[3.2.1]octane-8-yl)-1,2,4-oxadiazol-3-yl)-2-methylbenzoic acid (7)
  • Example 8 4-(5-((1R,3r,5S)-3-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy (Yl)-8-azabicyclo[3.2.1]oct-8-yl)-1,3,4-oxadiazol-2-yl)benzoic acid (8)
  • Step 4 (Z)-N-((E)-((1R,3r,5S)3-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4- (Yl)methoxy)-8-azabicyclo[3.2.1]octane-8-yl)methylene)4-(methoxycarbonyl)benzylhydrazine (8E)
  • Step 5 4-(5-((1R,3r,5S)3-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) Preparation of methyl 8-azabicyclo[3.2.1]octane-8-yl)1,3,4-oxadiazol-2-yl)benzoate (8F)
  • reaction solution was concentrated under reduced pressure, and the residue was purified by preparative liquid chromatography (eluent: 0%-100% acetonitrile: water) to obtain 0.135 g of the title product as a white solid with a yield of 45.1%.
  • Step 6 4-(5-((1R,3r,5S)3-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) Preparation of -8-azabicyclo[3.2.1]octane-8-yl)1,3,4-oxadiazol-2-yl)benzoic acid (8)
  • the preparation method was the same as in Example 8, except that 2,6-pyridinedicarboxylic acid monomethyl ester was used instead of terephthalic acid monomethyl ester to obtain the title compound 10.
  • the preparation method was the same as that of Example 8, except that methyl 5-carboxythiophene-2-carboxylate was used instead of monomethyl terephthalate to obtain the title compound 11.
  • Example 12 4-(5-((1R,3r,5S)-(3-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methan (Oxy)-8-azabicyclo[3.2.1]octane-8-yl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzoic acid (12)
  • the preparation method was the same as in Example 8, except that 3-fluoro-4-(methoxycarbonyl)benzoic acid was used instead of monomethyl terephthalate to obtain the title compound 12.
  • Example 13 4-(5-((1R,3r,5S)-(3-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methan (Oxy)-8-azabicyclo[3.2.1]octane-8-yl)-1,3,4-oxadiazol-2-yl)-2-methoxybenzoic acid (13)
  • the preparation method was the same as in Example 8, except that 3-methoxy-4-(methoxycarbonyl)benzoic acid was used instead of monomethyl terephthalate to obtain the title compound 13.
  • Example 14 4-(5-((1R,3r,5S)-(3-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methan (Oxy)-8-azabicyclo[3.2.1]octane-8-yl)-1,3,4-oxadiazol-2-yl)-3-methylbenzoic acid (14)
  • the preparation method was the same as in Example 8, except that 2-methyl-4-(methoxycarbonyl)benzoic acid was used instead of monomethyl terephthalate to obtain the title compound 14.
  • the preparation method was the same as in Example 8, except that 3-(methoxycarbonyl)benzoic acid was used instead of monomethyl terephthalate to obtain the title compound 15.
  • Example 16 4-(5-((1R,3r,5S)-(3-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methan (Oxy)-8-azabicyclo[3.2.1]octane-8-yl)-1,3,4-oxadiazol-2-yl)-3-fluorobenzoic acid (16)
  • the preparation method was the same as in Example 8, except that 2-fluoro-4-(methoxycarbonyl)benzoic acid was used instead of monomethyl terephthalate to obtain the title compound 16.
  • Example 17 4-(5-((1R,3r,5S)-(3-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methan (Oxy)-8-azabicyclo[3.2.1]octane-8-yl)-1,3,4-oxadiazol-2-yl)-2-methylbenzoic acid (17)
  • Step 4 (Z)-4-bromo-N-((E)-(((1R,3r,5S)-3-((5-cyclopropyl-3-(2,6-dichlorophenyl) Preparation of isoxazol-4-yl)methoxy)-8-azabicyclo[3.2.1]octane-8-yl)methylene)-3-methylbenzohydrazino acid (17E)
  • Step 5 2-(4-Bromo-3-methylphenyl)-5-((1R,3r,5S)-3-((5-cyclopropyl-3-(2,6-dichlorophenyl) )Isoxazol-4-yl)methoxy)-8azabicyclo[3.2.1]oct-8-yl)-1,3,4-oxadiazole (17F)
  • Step 6 4-(5-((1R,3r,5S)-(3-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy Preparation of methyl)-8-azabicyclo[3.2.1]octane-8-yl)-1,3,4-oxadiazol-2-yl)-2-methylbenzoate (17G)
  • Step 7 4-(5-(((1R,3r,5S)-(3-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methan Oxy)-8-azabicyclo[3.2.1]octane-8-yl)-1,3,4-oxadiazol-2-yl)-2-methylbenzoic acid (17) Preparation of 4 -(5-(((1R,3r,5S)-(3-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)- 8-azabicyclo[3.2.1]octane-8-yl)-1,3,4-oxadiazol-2-yl)-2-methylbenzoic acid methyl ester (0.20g, 0.33mmol), methanol (10mL), water (5mL), THF (15mL), lithium hydroxide (33mg, 1.36mmol)
  • the preparation method was the same as that of Example 8, except that pyridine-2,5-dicarboxy-2-methyl ester was used instead of monomethyl terephthalate to obtain the title compound 18.
  • the preparation method was the same as in Example 8, except that 5-(methoxycarbonyl)-2-pyridinecarboxylic acid was used instead of monomethyl terephthalate to obtain the title compound 19.
  • the preparation method was the same as in Example 17, except that 4-bromothiophene-2-carboxylic acid was used instead of 4-bromo-3-methylbenzoic acid to obtain the title compound 20.
  • Example 21 4-(5-((1R,3r,5S)-(3-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methan (Oxy)-8-azabicyclo[3.2.1]octane-8-yl)-1,3,4-oxadiazol-2-yl)thiophene-2-carboxylic acid (21)
  • the preparation method was the same as in Example 17, except that 5-bromo-3-thiophenecarboxylic acid was used instead of 4-bromo-3-methylbenzoic acid to obtain the title compound 21.
  • Example 22 4-(5-((1R,3r,5S)-3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl )Methoxy)-8-azabicyclo[3.2.1]oct-8-yl)-1,3,4-oxadiazol-2-yl)benzoic acid (22)
  • the preparation method is the same as in Example 8, except that 4-((((1R,3r,5S)-8-azabicyclo[3.2.1]oct-3-yl)oxy)methyl)-5-ring Propyl-3-(2-(trifluoromethoxy)phenyl)isoxazole (prepared according to the method disclosed in WO2012087519) instead of 4-((((1R,3r,5S)-8-azabicyclo[ 3.2.1]oct-3-yl)oxy)methyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole (1C) to obtain the title compound 22.
  • the preparation method is the same as in Example 8, except that 4-((((1R,3r,5S)-8-azabicyclo[3.2.1]oct-3-yl)oxy)methyl)-5-ring Propyl-3-(2-(trifluoromethoxy)phenyl)isoxazole (prepared according to the method disclosed in WO2012087519) instead of 4-((((1R,3r,5S)-8-azabicyclo[ 3.2.1]oct-3-yl)oxy)methyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole (1C) and 3-chloro-4-(methyl (Oxycarbonyl)benzoic acid instead of monomethyl terephthalate, the title compound 23 was prepared.
  • Example 24 6-(5-((1R,3r,5S)-3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl )Methoxy)-8-azabicyclo[3.2.1]octane-8-yl)-1,3,4-oxadiazol-2-yl)pyridine-2-carboxylic acid (24)
  • the preparation method is the same as in Example 8, except that 4-((((1R,3r,5S)-8-azabicyclo[3.2.1]oct-3-yl)oxy)methyl)-5-ring Propyl-3-(2-(trifluoromethoxy)phenyl)isoxazole (prepared according to the method disclosed in WO2012087519) instead of 4-((((1R,3r,5S)-8-azabicyclo[ 3.2.1]oct-3-yl)oxy)methyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole (1C) and 2,6-pyridinedicarboxylic acid Monomethyl ester replaces monomethyl terephthalate to obtain the title compound 24.
  • the preparation method is the same as in Example 8, except that 4-((((1R,3r,5S)-8-azabicyclo[3.2.1]oct-3-yl)oxy)methyl)-5-ring Propyl-3-(2-(trifluoromethoxy)phenyl)isoxazole (prepared according to the method disclosed in WO2012087519) instead of 4-((((1R,3r,5S)-8-azabicyclo[ 3.2.1]oct-3-yl)oxy)methyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole (1C) and 5-carboxythiophene-2-carboxylic acid
  • the methyl ester replaced the monomethyl terephthalate to obtain the title compound 25.
  • Example 26 4-(5-((1R,3r,5S)-(3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazole-4- (Yl)methoxy)-8-azabicyclo[3.2.1]octane-8-yl)-1,3,4-oxadiazol-2-yl)-2-fluorobenzoic acid (26)
  • the preparation method is the same as in Example 8, except that 4-((((1R,3r,5S)-8-azabicyclo[3.2.1]oct-3-yl)oxy)methyl)-5-ring Propyl-3-(2-(trifluoromethoxy)phenyl)isoxazole (prepared according to the method disclosed in WO2012087519) instead of 4-((((1R,3r,5S)-8-azabicyclo[ 3.2.1]oct-3-yl)oxy)methyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole (1C) and 3-fluoro-4-(methyl) (Oxycarbonyl)benzoic acid instead of monomethyl terephthalate, the title compound 26 was prepared.
  • Example 27 4-(5-((1R,3r,5S)-(3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazole-4- Yl)methoxy)-8-azabicyclo[3.2.1]octane-8-yl)-1,3,4-oxadiazol-2-yl)-3-methylbenzoic acid (27) preparation
  • the preparation method is the same as in Example 8, except that 4-((((1R,3r,5S)-8-azabicyclo[3.2.1]oct-3-yl)oxy)methyl)-5-ring Propyl-3-(2-(trifluoromethoxy)phenyl)isoxazole (prepared according to the method disclosed in WO2012087519) instead of 4-((((1R,3r,5S)-8-azabicyclo[ 3.2.1]oct-3-yl)oxy)methyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole (1C) and 2-methyl-4-( Methoxycarbonyl)benzoic acid was substituted for monomethyl terephthalate to obtain the title compound 27.
  • Example 28 3-(5-((1R,3r,5S)-(3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazole-4- (Yl)methoxy)-8-azabicyclo[3.2.1]octane-8-yl)-1,3,4-oxadiazol-2-yl)benzoic acid (28)
  • the preparation method is the same as in Example 8, except that 4-((((1R,3r,5S)-8-azabicyclo[3.2.1]oct-3-yl)oxy)methyl)-5-ring Propyl-3-(2-(trifluoromethoxy)phenyl)isoxazole (prepared according to the method disclosed in WO2012087519) instead of 4-((((1R,3r,5S)-8-azabicyclo[ 3.2.1]oct-3-yl)oxy)methyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole (1C) and 3-(methoxycarbonyl) Benzoic acid was substituted for monomethyl terephthalate to obtain the title compound 28.
  • Example 29 4-(5-((1R,3r,5S)-(3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazole-4- (Yl)methoxy)-8-azabicyclo[3.2.1]octane-8-yl)-1,3,4-oxadiazol-2-yl)-3-fluorobenzoic acid (29)
  • the preparation method is the same as in Example 8, except that 4-((((1R,3r,5S)-8-azabicyclo[3.2.1]oct-3-yl)oxy)methyl)-5-ring Propyl-3-(2-(trifluoromethoxy)phenyl)isoxazole (prepared according to the method disclosed in WO2012087519) instead of 4-((((1R,3r,5S)-8-azabicyclo[ 3.2.1]oct-3-yl)oxy)methyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole (1C) and 2-fluoro-4-(methyl (Oxycarbonyl)benzoic acid instead of monomethyl terephthalate, the title compound 29 was prepared.
  • Example 30 4-(5-((1R,3r,5S)-(3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazole-4- Yl) methoxy)-8-azabicyclo[3.2.1]octane-8-yl)-1,3,4-oxadiazol-2-yl)-2-methylbenzoic acid (30) preparation
  • the preparation method is the same as in Example 17, except that 4-((((1R,3r,5S)-8-azabicyclo[3.2.1]oct-3-yl)oxy)methyl)-5-ring Propyl-3-(2-(trifluoromethoxy)phenyl)isoxazole (prepared according to the method disclosed in WO2012087519) instead of 4-((((1R,3r,5S)-8-azabicyclo[ 3.2.1]oct-3-yl)oxy)methyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole (1C) to obtain the title compound 30.
  • the preparation method is the same as in Example 8, except that 4-((((1R,3r,5S)-8-azabicyclo[3.2.1]oct-3-yl)oxy)methyl)-5-ring Propyl-3-(2-(trifluoromethoxy)phenyl)isoxazole (prepared according to the method disclosed in document WO2012087519) instead of 4-((((1R,3r,5S)-8-azabicyclo[ 3.2.1]oct-3-yl)oxy)methyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole (1C) and pyridine-2,5-dicarboxy Acid-2-methyl ester replaced monomethyl terephthalate to obtain the title compound 31.
  • Example 32 6-(5-((1R,3r,5S)-3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl )Methoxy)-8-azabicyclo[3.2.1]octane-8-yl)-1,3,4-oxadiazol-2-yl)nicotinic acid (32)
  • the preparation method is the same as in Example 8, except that 4-((((1R,3r,5S)-8-azabicyclo[3.2.1]oct-3-yl)oxy)methyl)-5-ring Propyl-3-(2-(trifluoromethoxy)phenyl)isoxazole (prepared according to the method disclosed in WO2012087519) instead of 4-((((1R,3r,5S)-8-azabicyclo[ 3.2.1]oct-3-yl)oxy)methyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole (1C) and 5-(methoxycarbonyl)- 2-pyridinecarboxylic acid was substituted for monomethyl terephthalate to obtain the title compound 32.
  • the preparation method is the same as in Example 17, except that 4-((((1R,3r,5S)-8-azabicyclo[3.2.1]oct-3-yl)oxy)methyl)-5-ring Propyl-3-(2-(trifluoromethoxy)phenyl)isoxazole (prepared according to the method disclosed in WO2012087519) instead of 4-((((1R,3r,5S)-8-azabicyclo[ 3.2.1]oct-3-yl)oxy)methyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole (1C) and 4-bromothiophene-2-carboxylic acid Instead of 4-bromo-3-methylbenzoic acid, the title compound 33 was prepared.
  • Example 34 4-(5-((1R,3r,5S)-(3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazole-4- (Yl)methoxy)-8-azabicyclo[3.2.1]octane-8-yl)-1,3,4-oxadiazol-2-yl)thiophene-2-carboxylic acid (34)
  • the preparation method is the same as in Example 17, except that 4-((((1R,3r,5S)-8-azabicyclo[3.2.1]oct-3-yl)oxy)methyl)-5-ring Propyl-3-(2-(trifluoromethoxy)phenyl)isoxazole (prepared according to the method disclosed in WO2012087519) instead of 4-((((1R,3r,5S)-8-azabicyclo[ 3.2.1]oct-3-yl)oxy)methyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole (1C) and 5-bromo-3-thiophenecarboxylic acid Instead of 4-bromo-3-methylbenzoic acid, the title compound 34 was prepared.
  • Test Example 1 Evaluation of the compounds of the present invention on FXR agonistic activity
  • the luciferase reporter assay was used to evaluate the FXR agonistic activity of the compounds of the present invention.
  • the experimental process includes: transferring luc2P-GAL4-HEK293 stable transfection cell line (HEK293 cells were transfected with pGL4.35 plasmid and established by Hygromycin B screening.
  • the cells contained 9 ⁇ GAL4 UAS and firefly luciferase reporter gene.
  • Ligand activated The LBD-GAL4 DBD fusion protein can enter the nucleus and bind to 9 ⁇ GAL4 UAS and activate the transcription of the downstream luciferase reporter gene) to a 96-well plate with 1 ⁇ 10 4 cells per well.
  • X-tremeGENE HP transfection reagent to transfect pBIND-FXR (insert pFN26A-BIND hRluc-neo from FXR-LBD)
  • the vector is constructed.
  • the plasmid size is 7.5kb, Amp resistant, contains FXR-LBD, can express FXR-LBD and GAL4 DBD fusion protein), the ratio of plasmid and transfection reagent is 1 ⁇ g: 2 ⁇ l, the specific dosage is 100ng plasmid per well, 0.2 ⁇ l X-tremeGENE HP transfection reagent; adding the test compound (the highest concentration of each compound is 30 ⁇ M, 3 times dilution, a total of 10 concentrations) to induce luciferase expression.
  • the measurement sequence of Renilla fluorescence should be the same as that of firefly fluorescence.
  • EC 50 is the half effective concentration
  • Top is the maximum effect
  • Bottom is the blank effect
  • HillSlope is the slope.
  • the activity of the compound is shown in Table 1.
  • Example FXR agonistic activity Example 1 A Example 2 A Example 3 A Example 4 A Example 5 A Example 6 A Example 7 A Example 8 A Example 9 C Example 10 D Example 11 D Example 12 D Example 13 A Example 14 A Example 15 A Example 16 C Example 17 A Example 18 D Example 19 E Example 20 C Example 21 D Example 22 A Example 23 D Example 24 E Example 25 D Example 26 D Example 27 A Example 28 A Example 29 D
  • Example 30 A Example 31 D Example 32 E Example 33 D Example 34 E
  • Test Example 2 The effect of the compound of the present invention on the rat model of bile acid stasis induced by 1-naphthalene isothiocyanate (ANIT)
  • Animals SD rats, male, 7-8 weeks old, weighing 220-240g, purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd., SPF grade, animal production license number: SCXK ( ⁇ ) 2016-0011, Issuing unit: Beijing Municipal Science and Technology Commission.
  • the animals are divided into 20 groups according to their body weight: normal group, model group, Example 8 (3mg/kg/d, 10mg/kg/d) group, Example 11 (3mg/kg/d, 10mg /kg/d) group, Example 12 (3mg/kg/d, 10mg/kg/d) group, Example 14 (3mg/kg/d, 10mg/kg/d) group, Example 20 (3mg/kg /d, 10mg/kg/d) group, Example 22 (3mg/kg/d, 10mg/kg/d) group, Example 26 (3mg/kg/d, 10mg/kg/d) group, Example 28 (3mg/kg/d, 10mg/kg/d) group, Example 29 (3mg/kg/d, 10mg/kg/d) group, 10 rats in each group, start intragastric administration, the administration volume is 10mL/ kg, once a day for 4 days.
  • the curative effect of the compound of the present invention on ANIT-induced bile acid stasis rats is shown in Table 2 below.
  • the blood drug concentration and liver drug concentration of the compound of the present invention in ANIT-induced cholestasis rats administered for 4 days are shown in Table 3, Table 4 and Table 5 below.
  • Example 8 (3mg/kg/d) 164.8 ⁇ 85.0** 401.8 ⁇ 172.8** 2.5 ⁇ 0.7** 100.0 ⁇ 99.8
  • Example 8 (10mg/kg/d) 79.9 ⁇ 98.7** 243.5 ⁇ 192.6** 2.0 ⁇ 0.5** 32.9 ⁇ 68.0**
  • Example 11 (3mg/kg/d) 276.3 ⁇ 118.0 761.3 ⁇ 253.7 4.9 ⁇ 0.9 243.4 ⁇ 72.4
  • Example 11 (10mg/kg/d) 180.3 ⁇ 107.8* 466.1 ⁇ 242.4** 3.7 ⁇ 1.5* 190.3 ⁇ 140.7
  • Example 12 (3mg/kg/d) 122.5 ⁇ 89.7** 314.2 ⁇ 237.9* 2.2 ⁇ 0.8** 69.0 ⁇ 66.7*
  • Example 12 (10mg/kg/d) 54.7 ⁇ 27.3** 139.3 ⁇ 34.6** 1.9 ⁇ 0.5** 25.4 ⁇ 14.3**
  • Example 14 (3mg/kg/d) 220.3 ⁇ 104.0* 643.3 ⁇ 239.3* 4.6 ⁇ 1.3 235.8 ⁇ 80.1
  • Example 14 (10
  • Examples 8, 11, 12, 14, 20, 22, 26, 28, 29 of the present invention significantly reduce the levels of ALT, AST, GGT and TBA in the serum of ANIT rats, indicating that the compound of the present invention can significantly improve ANIT rats Of cholestasis. Moreover, these compounds have high liver targeting.
  • Test Example 3 Effect test of the compound of the present invention on hERG channel
  • Reagent supplier Item No. batch number DMEM Gibco 11995-065 1897371 Fetal Bovine Serum Gibco 10091148 1872295 G418 Amresco E859 17J065302 TrypLE TM Express Gibco 12604021 1810976 Dimethyl sulfoxide Sigma D4540 BCBW5664 Cisapride (Cisapride) Sigma C4740 0000021445 Potassium aspartate Sigma A6558 WXBC4890V Sodium chloride Sigma S5886 SLBS7447 Potassium chloride Sigma P5405 SLBR2609V Ethylene glycol bis(2-aminoethyl ether) Sigma E3889 SLBR7504V 4-hydroxyethylpiperazine ethanesulfonic acid Santa Cruz SC-29097A J3015/C2817 Magnesium chloride Sigma M2393 SLBP9770V glucose Sigma G8270 SLBR5156V Calcium chloride Sigma C7902 SLBV3136
  • Intracellular and extracellular fluid are intracellular and extracellular fluid:
  • the stock solution of the compound of Example 8 of the present invention (30.26 mM DMSO solution) was sequentially diluted with 10 mL of extracellular fluid to prepare 0.3 ⁇ M, 1 ⁇ M, 3 ⁇ M, 0 ⁇ M, and 30 ⁇ M liquids. Visually check the solubility of the sample to be tested, and the sample to be tested is completely dissolved without visible precipitation.
  • 10mg cisapill was prepared into a 10mM stock solution using 2066.29 ⁇ L dimethylsulfoxide (DMSO).
  • DMSO dimethyl sulfoxide
  • 10 ⁇ L of each concentration was added to 10 mL of extracellular fluid to ensure that the DMSO concentration was 0.1%.
  • the final working concentration of cisapride is 1nM, 10nM, 100nM and 1 ⁇ M. Visually inspecting the solubility of cisapride, cisapride was completely dissolved without visible precipitation.
  • the HEK293 cell line stably expressing the hERG potassium channel (supplier Creacell, catalog number A-0302) was cultured in DMEM medium containing 10% fetal bovine serum and 0.8 mg/mL G418 at a temperature of 37°C and a carbon dioxide concentration of 5% .
  • Cell passage Remove the old medium and wash with PBS once, then add 1mL TrypLE TM expression solution, and incubate at 37°C for 0.5 minutes. When the cells detach from the bottom of the dish, add 5 mL of 37°C pre-warmed complete medium (DMEM medium containing 10% fetal calf serum and 0.8 mg/mL G418). The cell suspension was gently pipetted to separate the aggregated cells. The cell suspension was transferred to a sterile centrifuge tube and centrifuged at 1000 rpm for 5 minutes to collect the cells. For expansion or maintenance culture, the cells are seeded in a 6 cm cell culture dish, and each cell culture dish is seeded with 2.5 ⁇ 10 5 cells (final volume: 5 mL).
  • the cell density In order to maintain the electrophysiological activity of cells, the cell density must not exceed 80%.
  • the cells were separated with TrypLE TM expression solution before the experiment, and 3 ⁇ 10 3 cells were spread on a cover glass and cultured in a 24-well plate (final volume: 500 ⁇ L). After 18 hours, the experiment was performed.
  • the whole-cell patch clamp voltage stimulation scheme for recording the whole-cell hERG potassium current is as follows: when the whole-cell seal is formed, the patch clamp is set at -80mV. The clamping voltage is depolarized from -80mV to +30mV for 2.5 seconds, and then quickly maintained at -50mV for 4 seconds, which can excite the tail current of the hERG channel. The experiment uses -50mV as leakage current detection. Collect data repeatedly every 10 seconds to observe the effect of the drug on the hERG tail current. The experimental data is collected by EPC-10 amplifier (HEKA) and stored in PatchMaster (HEKA) software.
  • HEKA EPC-10 amplifier
  • HEKA PatchMaster
  • the capillary glass tube (BF150-86-10, Sutter Instruments) was drawn into a recording electrode with a microelectrode drawing instrument (P97, Sutter Instruments). Operate the microelectrode manipulator (MP285, Sutter Instruments) under an inverted microscope (IX71, Olympus) to touch the recording electrode to the cell, and apply negative pressure suction to form a G ⁇ seal. After forming the G ⁇ seal, perform fast capacitance compensation, and then continue to give negative pressure to suck and break the cell membrane to form a whole-cell recording mode. Then perform slow capacitance compensation and record the film capacitance and series resistance. No leakage compensation is given.
  • the administration is started, and the next concentration is measured after each drug concentration acts for 5 minutes (or the current becomes stable), and multiple concentrations are measured for each test compound.
  • a vacuum pump was used for liquid exchange.
  • the current detected by each cell in the compound-free external fluid serves as its own control group. Three cells were tested independently. All electrophysiological experiments were performed at room temperature.
  • Example 8 of the present invention The compound of Example 8 of the present invention and the inhibition of the hERG channel inhibition concentration (IC 50) The results are shown in Table 6.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Emergency Medicine (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

本发明涉及芳环或芳杂环类化合物及其制备方法和医药用途。特别地，本发明涉及通式(I)所示的化合物、其制备方法及含有该化合物的药物组合物，及其作为法尼醇衍生物X受体(Farnesoid X receptor，FXR)激动剂的用途，该化合物及含有该化合物的药物组合物可以用于治疗和/或预防与FXR活性相关的疾病，例如胆汁郁积病症、糖尿病及其并发症、非酒精性脂肪肝(NAFLD)、非酒精性脂肪肝炎(NASH)、肥胖或代谢综合征(血脂异常、糖尿病和体重指数异常高的合并病症)、心血管疾病等。其中通式(I)中的各取代基的定义与说明书中的定义相同。

Description

芳环或芳杂环类化合物及其制备方法和医药用途 技术领域
本发明属于医药技术领域，具体涉及一种芳环或芳杂环类化合物、其制备方法及含有其的药物组合物，以及其用于调节法尼醇衍生物X受体(Farnesoid X receptor，FXR)活性，进而用于治疗和/或预防与FXR活性相关的疾病的用途。
背景技术
法尼醇衍生物X受体(FXR)作为一种胆汁酸激活的核受体，可直接或通过孤儿核受体小异二聚体伴侣(SHP)调控多种代谢相关基因的表达。FXR于1995年被发现，其命名源于该受体可以被超生理水平的法尼醇激活。近年研究发现，胆汁酸(Bile Acids，BAs)是FXR最主要的生理配体(Drug Discovery Today，2012，17，988)。
异常水平的胆汁酸与肝部炎症和纤维化有关，相比甘油三酯，胆汁酸的蓄积是非酒精性脂肪肝的更重要致病因素。FXR的激活可通过降低肝部胆汁酸的合成和摄取，并提高胆汁酸外排，达到降低肝内胆汁酸蓄积净效应；FXR可上调SHP，SHP可抑制胆汁酸合成重要酶CYP7A1的表达，进而抑制胆汁酸合成(Pharmacol.Ther.2010，126，228-243)；此外，FXR可诱导FGF15/19激活FGFR4，进而启动JNK通路，以抑制CYP7A1的表达；FXR通过上调BSEP和MRP2，抑制NTCP降低肝细胞内胆汁酸水平，刺激胆汁酸在肝细胞小管膜分泌，抑制从门静脉的胆汁酸再摄取；FXR可通过OSTα/β调控胆汁酸转运，促进胆汁酸外排至循环系统，通过肾脏消除。
FXR可改善胰岛素抵抗，FXR基因敲除小鼠表现出了糖代谢清除的受损，表明小鼠存在外周胰岛素抵抗。FXR激活对胰岛素抵抗的改善作用可能与以下机制有关：FXR可降低外周组织(如肌细胞)脂质的蓄积，进而降低脂质相关毒性，特别是针对饮食导致的肥胖患者(Acta.Pharmacol.Sin.2015，36，44-50)；小肠FXR的激活可促进FGF19释放入门静脉，FGF19具有一定的胰岛素增敏作用，另有报道FGF19具有降低体重作用，FGF19转基因小鼠表现了较强抵抗饮食诱导肥胖作用；FXR可降低糖异生和肝糖输出，胆酸喂养小鼠可抑制糖异生相关酶，如PEPCK、G6P等基因的表达，但对于SHP敲除小鼠无作用；FXR激动剂可降低小鼠PEPCK和G6P，同时降低肝糖的输出。
FXR可通过多种途径降低甘油三酯和脂肪酸的产生，并促进其代谢。FXR可通过抑制SREBP1c的表达，抑制甘油三酯和脂肪酸的合成及分泌，促进VLDLR的表达，提升VLDL和乳糜微粒的清除，抑制APOC和MTP的表达，抑制VLDL的组装，诱导PPARα，促进脂肪酸的β氧化，诱导脂蛋白脂肪酶，进而增强脂蛋白和游离脂肪酸的代谢作用。FXR通过正调控SRBI、CEH、SCP2等促进HDL的 摄取和胆固醇的逆转运，还可通过抑制PCSK9的表达和活性，增强LDLR和LDL的清除，达到降低胆固醇的作用(Curr.Opin.Lipidol.2016，27，295-301)。
FXR可通过下调多种炎症相关基因的表达抑制炎症，FXR与炎症反应密切相关，FXR基因敲除小鼠具有较高的促炎症和促纤维细胞因子水平，包括TNFα、ICAM-1、α-SMA、TIMP-1、TGFβ等。FXR对炎症和纤维化的抑制可能与以下机制有关：FXR激活的主要炎症抑制机制是拮抗NFκB信号通路；FXR激活可以改善胆道阻塞、肠道菌群过度生长、粘膜损伤、肠道细菌移位等；FXR可诱导SOCS3的抑制因子，进而抑制STAT3信号通路；FXR的激活可提升MicroRNA mir29a，MicroRNA mir29a可调节多个胞外基质蛋白的表达。此外，另有研究表明，FXR可促进肝组织再生，且抑制干细胞肿瘤的发生。因此，FXR激动剂可用于脂质特别是甘油三酯蓄积，及甘油三酯蓄积导致的慢性脂肪和纤维变性引起的疾病和病症，例如非酒精性脂肪肝(NAFLD)或非酒精性脂肪肝炎(NASH)的预防和治疗(Adv.Ther.2016，33，291-319；Drug Discov.Today，2012，17，988-97)。
目前，FXR激动剂已成为全球创新药物研发的热门之一。其中，甾体类FXR激动剂奥贝胆酸已成功获批用于原发性胆汁性肝硬化(PBC)，并在治疗NASH的临床研究(FlINT研究)表现出较好疗效，进一步FXR激动剂用于PBC和NASH治疗的合理性。但该药物作为甾体药物选择性较差，特别是对TGR5也有一定作用，容易导致严重瘙痒和高脂血症等副作用。此外，奥贝胆酸存在严重的肝肠循环，导致药物在体内存在较高蓄积，已引发安全性风险。因此，选择性更高和药代性质更优的非甾体FXR激动剂更加受到关注(Lancet，2015，385，956-65；N.Engl.J.Med.2016，375，631-643)。
非甾体FXR激动剂研究较早的是GW-4604，该化合物具有较强的体外活性，但药代性质不佳，且由于二芳基乙烯结构具有安全性风险；目前，研发进展最快、最受关注的是PX-104，该药物具有较高的FXR激动活性和药代性质，在临床前药效学模型中表现出显著降低肝脂肪蓄积和损伤的疗效，现已进入针对NASH的临床II期研究(J.Pharmacol.Exp.Ther.2012，343，556-567；J.Med.Chem.2014，57，8035-8055)。尽管如此，PX-104的体外活性仍有进一步提升的空间，临床剂量相对较高。因此，持续地需要激动FXR的新型或改进的药物，以用于开发新的、更有效的药物来治疗NASH、NAFLD、PBC或其它与FXR相关的疾病。
发明内容
本发明人经过潜心研究，设计合成了一系列含有桥环基取代的芳环或芳杂环骨架的化合物，并对其进行了FXR活性的筛选，研究结果显示该类化合物具有突出的FXR激动活性，并且可以被开发为治疗与FXR活性相关的疾病的药物。
因此，本发明的目的为提供一种通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、其前药或其可药用盐，
Figure PCTCN2020072763-appb-000001
其中：
Z选自：
Figure PCTCN2020072763-appb-000002
其中，X为CH、CF、N或NO；
R 2选自氢、卤素、烷基、环烷基，其中所述烷基或环烷基任选进一步被选自卤素、羟基、烷基、烷氧基的一个或多个基团所取代；
R 3和R 4各自独立地选自氢、卤素、烷基、烷氧基，所述烷基或烷氧基任选进一步被一个或多个卤素取代；
Ar为5元或6元芳基或杂芳基；
Cy为芳基或杂芳基；
R 1选自-(CH 2) m-R 5或-O(CH 2) m-R 5；其中所述-(CH 2) m-或-O(CH 2) m-基团任选进一步被选自卤素、氰基、羟基、氧代基、烷基、卤代烷基、烷氧基、卤代烷氧基、CO 2H、SO 3H的一个或多个基团取代；
R 5选自氢、卤素、氰基、硝基、烷基、环烷基、杂环基、芳基、杂芳基、OR 6、NR 6R 7、-CO 2R 6、-C(O)R 6、-C(O)NR 6R 7、-N(R 6)C(O)R 7、-C(O)NR 6SO 2R 7、-S(O) pR 6、-S(O) pNR 6R 7、-N(R 6)S(O) pR 7、或-S(O) pNR 6COR 7；所述烷基、环烷基、杂环基、芳基或杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、卤代烷基、烷氧基、卤代烷氧基、烯基、炔基、环烷基、卤代环烷基、杂环基、芳基、杂芳基的一个或多个基团取代；
R 6和R 7各自独立地选自氢、卤素、羟基、烷基、环烷基、杂环基、芳基、杂芳基，其中所述烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代；
或者R 6和R 7与他们连接的氮原子一起形成含氮杂环基，所述含氮杂环基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代；
每一个R 8可以相同或不同，且各自独立地选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、烷基、卤代烷基、烷氧基、卤代烷氧基、烯基、炔基、环烷基、卤代环烷基、杂环基、芳基、杂芳基；
n为0、1或2；
m为0至6的整数；
p为0、1或2；
q为0至4的整数；
条件是，Ar不为
Figure PCTCN2020072763-appb-000003
其中，*代表与Cy连接位点，#代表与桥环N连接位点。
在本发明一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、其前药或其可药用盐，其为通式(II)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、其前药或其可药用盐，
Figure PCTCN2020072763-appb-000004
其中，
X 1、X 2、X 3各自独立地选自C、N、O或S，优选N，O；
Z、n、Cy、R 1、R 8、q如通式(I)所定义。
在本发明另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、其前药或其可药用盐，
其中，Ar选自噁唑、异噁唑、噻唑、异噻唑、咪唑、三氮唑、1，2，3-噁二唑、1，2，4-噁二唑、1，3，4-噁二唑、1，2，3-噻二唑、1，2，4-噻二唑或1，3，4-噻二唑。
在本发明另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、其前药或其可药用盐，
其中，
Z为
Figure PCTCN2020072763-appb-000005
X选自CH或N；
R 2选自氢、卤素、烷基、环烷基，优选C 1-C 6烷基或C 3-C 6环烷基，更优选环丙基；所述烷基或环烷基任选进一步被选自卤素、羟基、烷基、烷氧基的一个或多个基团所取代；
R 3和R 4各自独立地选自氢、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基，优选氢、卤素、C 1-C 6卤代烷基和C 1-C 6卤代烷氧基。
在本发明另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合 物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、其前药或其可药用盐，
其中，n为1。
在本发明另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、其前药或其可药用盐，
其中，
Cy为C 5-C 6芳基或5至6元杂芳基，优选苯基、吡啶基、嘧啶基、吡嗪基、噻唑基、呋喃基、咪唑基、吡唑基。
在本发明另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、其前药或其可药用盐，
其中，
R 1选自-(CH 2) m-R 5或-O(CH 2) m-R 5；
R 5选自氢、卤素、烷基、OR 6、NR 6R 7、-CO 2R 6、-C(O)R 6、-C(O)NR 6R 7、-N(R 6)C(O)R 7、-C(O)NR 6SO 2R 7、-S(O) pR 6、-S(O) pNR 6R 7、-N(R 6)S(O) pR 7、或-S(O) pNR 6COR 7，优选-C(O)R 6、-C(O)NR 6R 7、-S(O) pR 6、-S(O) pNR 6R 7，更优选-C(O)R 6或-S(O) pNR 6R 7，甚至更优选-COOH；
R 6和R 7各自独立地选自氢、卤素、羟基、烷基、环烷基、杂环基、芳基、杂芳基，其中所述烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代；
或者R 6和R 7与他们连接的氮原子一起形成含氮杂环基，所述含氮杂环基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基；
m为0至6的整数，优选0、1或2；更优选0。
在本发明另一个优选的实施方案中，根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、其前药或其可药用盐，
其中，
每一个R 8可以相同或不同，且各自独立地选自卤素、烷基、卤代烷基、烷氧基、卤代烷氧基；
q为0至4的整数；优选q为0或1。
本发明典型的化合物包括但不限于：
4-(5-((1R，3r，5S)-3-((5-环丙基-3-(2，6-二氯苯基)-异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，2，4-噁二唑-3-基)苯甲酸；
2-氯-4-(5-((1R，3r，5S)-3-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)-8-氮 杂双环[3.2.1]辛-8-基)-1，2，4-噁二唑-3-基)苯甲酸；
6-(5-((1R，3r，5S)-(3-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，2，4-噁二唑-3-基)吡啶-2-甲酸；
5-(5-((1R，3r，5S)-(3-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，2，4-噁二唑-3-基)噻吩-2-甲酸；
4-(5-((1R，3r，5S)-(3-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，2，4-噁二唑-3-基)-3-甲基苯甲酸；
3-(5-((1R，3r，5S)-(3-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，2，4-噁二唑-3-基)苯甲酸；
4-(5-((1R，3r，5S)-(3-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，2，4-噁二唑-3-基)-2-甲基苯甲酸；
4-(5-((1R，3r，5S)-3-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛-8-基)-1，3，4-噁二唑-2-基)苯甲酸；
2-氯-4-(5-((1R，3r，5S)-3-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛-8-基)-1，3，4-噁二唑-2-基)苯甲酸；
6-(5-((1R，3r，5S)-3-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，3，4-噁二唑-2-基)吡啶-2-甲酸；
5-(5-((1R，3r，5S)-(3-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，3，4-噁二唑-2-基)噻吩-2-甲酸；
4-(5-((1R，3r，5S)-(3-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，3，4-噁二唑-2-基)-2-氟苯甲酸；
4-(5-((1R，3r，5S)-(3-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，3，4-噁二唑-2-基)-2-甲氧基苯甲酸；
4-(5-((1R，3r，5S)-(3-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，3，4-噁二唑-2-基)-3-甲基苯甲酸；
3-(5-((1R，3r，5S)-(3-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，3，4-噁二唑-2-基)苯甲酸；
4-(5-((1R，3r，5S)-(3-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，3，4-噁二唑-2-基)-3-氟苯甲酸；
4-(5-((1R，3r，5S)-(3-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，3，4-噁二唑-2-基)-2-甲基苯甲酸；
5-(5-((1R，3r，5S)-3-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，3，4-噁二唑-2-基)吡啶甲酸；
6-(5-((1R，3r，5S)-3-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，3，4-噁二唑-2-基)烟酸；
5-(5-((1R，3r，5S)-(3-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)-8-氮杂双 环[3.2.1]辛烷-8-基)-1，3，4-噁二唑-2-基)噻吩-3-羧酸；
4-(5-((1R，3r，5S)-(3-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，3，4-噁二唑-2-基)噻吩-2-羧酸；
4-(5-((1R，3r，5S)-3-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛-8-基)-1，3，4-噁二唑-2-基)苯甲酸；
2-氯-4-(5-((1R，3r，5S)-3-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛-8-基)-1，3，4-噁二唑-2-基)苯甲酸；
6-(5-((1R，3r，5S)-3-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，3，4-噁二唑-2-基)吡啶-2-甲酸；
5-(5-((1R，3r，5S)-(3-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，3，4-噁二唑-2-基)噻吩-2-甲酸；
4-(5-((1R，3r，5S)-(3-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，3，4-噁二唑-2-基)-2-氟苯甲酸；
4-(5-((1R，3r，5S)-(3-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，3，4-噁二唑-2-基)-3-甲基苯甲酸；
3-(5-((1R，3r，5S)-(3-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，3，4-噁二唑-2-基)苯甲酸；
4-(5-((1R，3r，5S)-(3-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，3，4-噁二唑-2-基)-3-氟苯甲酸；
4-(5-((1R，3r，5S)-(3-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，3，4-噁二唑-2-基)-2-甲基苯甲酸；
5-(5-((1R，3r，5S)-3-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，3，4-噁二唑-2-基)吡啶甲酸；
6-(5-((1R，3r，5S)-3-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，3，4-噁二唑-2-基)烟酸；
5-(5-((1R，3r，5S)-(3-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，3，4-噁二唑-2-基)噻吩-3-羧酸；
4-(5-((1R，3r，5S)-(3-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，3，4-噁二唑-2-基)噻吩-2-羧酸；
或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、其前药或其可药用盐。
本发明进一步提供一种制备根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、其前药或其可药用盐的方法，其包括以下步骤：
当Ar为
Figure PCTCN2020072763-appb-000006
时，其中，*代表与Cy连接位点，#代表与桥环N连接位 点，
Figure PCTCN2020072763-appb-000007
在缩合剂条件下，将化合物IE与ID进行环合反应得到通式(I)化合物，其中，缩合剂优选氯化锌；
其中，Z、n、Cy、R 1、R 8、q如通式(I)所定义。
本发明进一步提供一种制备根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、其前药或其可药用盐的方法，其包括以下步骤：
当Ar为
Figure PCTCN2020072763-appb-000008
时，其中，*代表与Cy连接位点，#代表与桥环N连接位点，
Figure PCTCN2020072763-appb-000009
在氧化剂条件下，将化合物IJ进行环合反应得到通式(I)化合物，其中，氧化剂优选碘苯二乙酸；
其中，Z、n、Cy、R 1、R 8、q如通式(I)所定义。
本发明另一方面提供一种药物组合物，其含有根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、其前药或其可药用盐，以及药学上可接受的载体。
本发明进一步提供根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、其前药或其可药用盐，或者含有其的药物组合物，在制备FXR激动剂中的用途。
本发明进一步提供根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、其前药或其可药用盐，或者含有其的药物组合物，在制备预防和/或治疗与FXR活性相关的疾病的药物中的用途。
本发明提供根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、其前药或其可药用盐，或者含有其的药物组合物，其用作FXR激动剂的用途。
本发明进一步提供根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、其前药或其可药用盐，或者含有其的药物组合物，其用作药物的用途，所述药物用于预防和/或治疗与FXR 活性相关的疾病。
本发明进一步提供一种预防和/或治疗与FXR活性相关的疾病的方法，其包括向有需要的受试者施用预防或治疗有效量的根据本发明所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、其前药或其可药用盐，或者含有其的药物组合物。
在本发明的一个优选的实施方案中，根据本发明所述的与FXR活性相关的疾病可以为：慢性肝内胆汁郁积病症或肝外胆汁郁积病症，或慢性胆汁郁积病症或急性肝内胆汁郁积病症导致的肝纤维化；和/或肝脏梗阻性或慢性炎症；和/或肝硬化；和/或肝皮脂腺病和相关的综合征，与酒精诱导的肝硬变或与病毒性肝炎相关的胆汁郁积或纤维变性作用；和/或肝脏切除后的肝脏衰竭或肝脏缺血；和/或脂肪肝炎相关的化学疗法；和/或急性肝脏衰竭；和/或炎性肠病；和/或脂质和脂质蛋白紊乱；和/或糖尿病及糖尿病临床并发症，包括糖尿病性肾病、糖尿病性神经病、糖尿病视网膜病和其他临床表现；和/或脂质，特别是甘油三酯蓄积，及甘油三酯蓄积导致的慢性脂肪和纤维变性引起的疾病和病症，例如非酒精性脂肪肝或非酒精性脂肪肝炎；和/或肥胖或代谢综合征，例如血脂障碍、糖尿病、体重指数异常高的合并病症；和/或作为慢性梗阻性动脉粥样硬化终末点而产生的急性心肌梗塞、急性中风、或血栓形成；非恶性过度增殖性疾病和恶性过度增殖性疾病，特别是肝细胞癌、结肠腺瘤和息肉病、结肠腺癌、乳腺癌、胰腺癌、巴特氏食管癌和其他形式的胃肠道和肝脏肿瘤性疾病。
按照本发明所属领域的常规方法，本发明通式(I)所示的化合物可以与酸生成药学上可接受的酸式加成盐。所述酸包括无机酸和有机酸，特别优选盐酸、氢溴酸、硫酸、磷酸、甲磺酸、乙磺酸、对甲苯磺酸、苯磺酸、萘二磺酸、乙酸、丙酸、乳酸、三氟乙酸、马来酸、柠檬酸、富马酸、草酸、酒石酸、苯甲酸等。
按照本发明所属领域的常规方法，本发明通式(I)所示的化合物可以与碱生成药学上可接受的碱式加成盐。所述碱包括无机碱和有机碱，可接受的有机碱包括二乙醇胺、乙醇胺、N-甲基葡糖胺、三乙醇胺、氨丁三醇等，可接受的无机碱包括氢氧化铝、氢氧化钙、氢氧化钾、碳酸钠和氢氧化钠等。
此外，本发明还包括本发明通式(I)所示的化合物的前药。本发明所述的前药是通式(I)所示的化合物的衍生物，它们自身可能具有较弱的活性甚至没有活性，但是在给药后，在生理条件下(例如通过代谢、溶剂分解或另外的方式)被转化成相应的生物活性形式。
含活性成分的药物组合物可以是适用于口服的形式，例如片剂、糖锭剂、锭剂、水或油混悬液、可分散粉末或颗粒、乳液、硬或软胶囊，或糖浆剂或酏剂。可按照本领域任何已知制备药用组合物的方法制备口服组合物，此类组合物可含有一种或多种选自以下的成分：甜味剂、矫味剂、着色剂和防腐剂，以提供悦目和可口的药用制剂。片剂含有活性成分和用于混合的适宜制备片剂的无毒的可药 用的赋形剂。这些赋形剂可以是惰性赋形剂，如碳酸钙、碳酸钠、乳糖、磷酸钙或磷酸钠；造粒剂和崩解剂，例如微晶纤维素、交联羧甲基纤维素钠、玉米淀粉或藻酸；粘合剂，例如淀粉、明胶、聚乙烯吡咯烷酮或阿拉伯胶；和润滑剂，例如硬脂酸镁、硬脂酸或滑石粉。这些片剂可以不包衣或可通过掩盖药物的味道或在胃肠道中延迟崩解和吸收，因而在较长时间内提供缓释作用的已知技术将其包衣。例如，可使用水溶性味道掩蔽物质，例如羟丙基甲基纤维素或羟丙基纤维素，或延长时间物质例如乙基纤维素、醋酸丁酸纤维素。
也可用其中活性成分与惰性固体稀释剂例如碳酸钙、磷酸钙或高岭土混合的硬明胶胶囊，或其中活性成分与水溶性载体例如聚乙二醇或油溶媒例如花生油、液体石蜡或橄榄油混合的软明胶胶囊提供口服制剂。
水混悬液含有活性物质和用于混合的适宜制备水混悬液的赋形剂。此类赋形剂是悬浮剂，例如羧基甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、藻酸钠、聚乙烯吡咯烷酮和阿拉伯胶；分散剂或湿润剂，可以是天然产生的磷脂例如卵磷脂，或烯化氧与脂肪酸的缩合产物，例如聚氧乙烯硬脂酸酯，或环氧乙烷与长链脂肪醇的缩合产物，例如十七碳亚乙基氧基鲸蜡醇(heptadecaethyleneoxy cetanol)，或环氧乙烷与由脂肪酸和己糖醇衍生的部分酯的缩合产物，例如聚环氧乙烷山梨醇单油酸酯，或环氧乙烷与由脂肪酸和己糖醇酐衍生的偏酯的缩合产物，例如聚环氧乙烷脱水山梨醇单油酸酯。水混悬液也可以含有一种或多种防腐剂例如尼泊金乙酯或尼泊金正丙酯、一种或多种着色剂、一种或多种矫味剂和一种或多种甜味剂，例如蔗糖、糖精或阿司帕坦。
油混悬液可通过使活性成分悬浮于植物油如花生油、橄榄油、芝麻油或椰子油，或矿物油例如液体石蜡中配制而成。油混悬液可含有增稠剂，例如蜂蜡、硬石蜡或鲸蜡醇。可加入上述的甜味剂和矫味剂，以提供可口的制剂。可通过加入抗氧化剂例如丁羟茴醚或α-生育酚保存这些组合物。
通过加入水，适用于制备水混悬液的可分散粉末和颗粒可以提供活性成分和用于混合的分散剂或湿润剂、悬浮剂或一种或多种防腐剂。适宜的分散剂或湿润剂和悬浮剂如上所述。也可加入其他赋形剂例如甜味剂、矫味剂和着色剂。通过加入抗氧化剂例如抗坏血酸保存这些组合物。
本发明的药物组合物也可以是水包油乳剂的形式。油相可以是植物油例如橄榄油或花生油，或矿物油例如液体石蜡或其混合物。适宜的乳化剂可以是天然产生的磷脂，例如大豆卵磷脂，和由脂肪酸和己糖醇酐衍生的酯或偏酯，例如山梨坦单油酸酯，和所述偏酯和环氧乙烷的缩合产物，例如聚环氧乙烷山梨醇单油酸酯。乳剂也可以含有甜味剂、矫味剂、防腐剂和抗氧剂。可用甜味剂例如甘油、丙二醇、山梨醇或蔗糖配制的糖浆和酏剂。此类制剂也可含有缓和剂、防腐剂、着色剂和抗氧剂。
本发明的药物组合物可以是无菌注射水溶液形式。可以使用的可接受的溶媒 和溶剂有水、林格氏液和等渗氯化钠溶液。无菌注射制剂可以是其中活性成分溶于油相的无菌注射水包油微乳。例如将活性成分溶于大豆油和卵磷脂的混合物中。然后将油溶液加入水和甘油的混合物中处理形成微乳。可通过局部大量注射，将注射液或微乳注入患者的血流中。或者，最好按可保持本发明化合物恒定循环浓度的方式给予溶液和微乳。为保持这种恒定浓度，可使用连续静脉内递药装置。
本发明的药物组合物可以是用于肌内和皮下给药的无菌注射水或油混悬液的形式。可按已知技术，用上述那些适宜的分散剂或湿润剂和悬浮剂配制该混悬液。无菌注射制剂也可以是在无毒肠胃外可接受的稀释剂或溶剂中制备的无菌注射溶液或混悬液，例如在1，3-丁二醇中制备的溶液。此外，可方便地用无菌固定油作为溶剂或悬浮介质。为此目的，可使用包括合成甘油单或二酯在内的任何调和固定油。此外，脂肪酸例如油酸也可以制备注射剂。
可按用于直肠给药的栓剂形式给予本发明化合物。可通过将药物与在普通温度下为固体但在直肠中为液体，因而在直肠中会溶化而释放药物的适宜的无刺激性赋形剂混合来制备这些药物组合物。此类物质包括可可脂、甘油明胶、氢化植物油、各种分子量的聚乙二醇和聚乙二醇的脂肪酸酯的混合物。
本领域技术人员熟知，药物的给药剂量依赖于多种因素，包括但并非限定于以下因素：所用特定化合物的活性、病人的年龄、病人的体重、病人的健康状况、病人的行被、病人的饮食、给药时间、给药方式、排泄的速率、药物的组合等。另外，最佳的治疗方式如治疗的模式、通式化合物的日用量或可药用的盐的种类可以根据传统的治疗方案来验证。
本发明可以含有通式(I)所示的化合物，及其药学上可接受的盐、水合物或溶剂化物作为活性成分，与药学上可接受的载体或赋型剂混合制备成组合物，并制备成临床上可接受的剂型。本发明的衍生物可以与其他活性成分组合使用，只要它们不产生其他不利的作用，例如过敏反应等。本发明化合物可作为唯一的活性成分，也可以与其它治疗与FXR活性相关的疾病的药物联合使用。联合治疗通过将各个治疗组分同时、分开或相继给药来实现。
发明的详细说明
除非有相反陈述，在说明书和权利要求书中使用的术语具有下述含义。
术语“烷基”指饱和脂肪族烃基团，其为包含1至20个碳原子的直链或支链基团，优选含有1至12个碳原子的烷基，更优选含有1至6个碳原子的烷基。非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1，1-二甲基丙基、1，2-二甲基丙基、2，2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1，1，2-三甲基丙基、1，1-二甲基丁基、1，2-二甲基丁基、2，2-二甲基丁基、1，3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2，3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2，3-二甲基戊基、2，4-二甲基戊基、2，2-二甲基戊基、 3，3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2，3-二甲基己基、2，4-二甲基己基、2，5-二甲基己基、2，2-二甲基己基、3，3-二甲基己基、4，4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2，2-二乙基戊基、正癸基、3，3-二乙基己基、2，2-二乙基己基，及其各种支链异构体等。更优选的是含有1至6个碳原子的低级烷基，非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1，1-二甲基丙基、1，2-二甲基丙基、2，2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1，1，2-三甲基丙基、1，1-二甲基丁基、1，2-二甲基丁基、2，2-二甲基丁基、1，3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2，3-二甲基丁基等。烷基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。
术语“烯基”指由至少由两个碳原子和至少一个碳-碳双键组成的如上定义的烷基，例如乙烯基、1-丙烯基、2-丙烯基、1-、2-或3-丁烯基等。烯基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基。
术语“炔基”指由至少由两个碳原子和至少一个碳-碳三键组成的如上定义的烷基，例如乙炔基、丙炔基、丁炔基等。炔基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基。
术语“环烷基”指饱和或部分不饱和单环或多环环状烃取代基，环烷基环包含3至20个碳原子，优选包含3至12个碳原子，更优选包含3至6个碳原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等；多环环烷基包括螺环、稠环和桥环的环烷基。
术语“螺环烷基”指5至20元的单环之间共用一个碳原子(称螺原子)的多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基或多螺环烷基，优选为单螺环烷基和双螺环烷基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺环烷基。 螺环烷基的非限制性实例包括：
Figure PCTCN2020072763-appb-000010
术语“稠环烷基”指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团，其中一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基，优选为双环或三环，更优选为5元/5元或5元/6元双环烷基。稠环烷基的非限制性实例包括：
Figure PCTCN2020072763-appb-000011
术语“桥环烷基”指5至20元，任意两个环共用两个不直接连接的碳原子的全碳多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基，优选为双环、三环或四环，更有选为双环或三环。桥环烷基的非限制性实例包括：
Figure PCTCN2020072763-appb-000012
所述环烷基环可以稠合于芳基、杂芳基或杂环烷基环上，其中与母体结构连接在一起的环为环烷基，非限制性实例包括茚满基、四氢萘基、苯并环庚烷基等。环烷基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。
术语“杂环基”指饱和或部分不饱和单环或多环环状烃取代基，其包含3至20个环原子，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选包含3至12个环原子，其中1～4个是杂原子；最优选包含3至8个环原子，其中1～3个是杂原子；最优选包含5至7个环原子，其中1～2或1～3个是杂原子。单环杂环基的非限制性实例包括吡咯烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基、吡喃基等，优选1、2、5-噁二唑基、吡喃基或吗啉基。多环杂环基包括螺环、稠环和桥环的杂环基。
术语“螺杂环基”指5至20元的单环之间共用一个原子(称螺原子)的多环杂环基团，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，其余环原子为碳。其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环基、双螺杂环基或多螺杂环基，优选为单螺杂环基和双螺杂环基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺杂环基。螺杂环基的非限制性实例包括：
Figure PCTCN2020072763-appb-000013
术语“稠杂环基”指5至20元，系统中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠杂环基，优选为双环或三环，更优选为5元/5元或5元/6元双环稠杂环基。稠杂环基的非限制性实例包括：
Figure PCTCN2020072763-appb-000014
术语“桥杂环基”指5至14元，任意两个环共用两个不直接连接的原子的多环杂环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子系统，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥杂环基，优选为双环、三环或四环，更有选为双环或三环。桥杂环基的非限制性实例包括：
Figure PCTCN2020072763-appb-000015
所述杂环基环可以稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接在一起的环为杂环基，其非限制性实例包括：
Figure PCTCN2020072763-appb-000016
等。
杂环基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。
术语“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，优选为6至10元，例如苯基和萘基。更优选苯基。所述芳基环可以稠合于杂芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为芳基环，其非限制性实例包括：
Figure PCTCN2020072763-appb-000017
芳基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
术语“杂芳基”指包含1至4个杂原子、5至14个环原子的杂芳族体系，其中杂原子选自氧、硫和氮。杂芳基优选为5至10元，含1至3个杂原子；更优选为5元或6元，含1至2个杂原子；优选例如咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基等，优选为咪唑基、噻唑基、吡唑基或嘧啶基、噻唑基；更有选吡唑基或噻唑基。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，其非限制性实例包括：
Figure PCTCN2020072763-appb-000018
杂芳基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
术语“烷氧基”指-O-(烷基)和-O-(非取代的环烷基)，其中烷基的定义如上所述。烷氧基的非限制性实例包括：甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基。烷氧基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷 氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。
术语“卤代烷基”指被一个或多个卤素取代的烷基，其中烷基如上所定义。
术语“卤代烷氧基”指被一个或多个卤素取代的烷氧基，其中烷氧基如上所定义。
术语“羟烷基”指被羟基取代的烷基，其中烷基如上所定义。
术语“羟基”指-OH基团。
术语“卤素”指氟、氯、溴或碘。
术语“氨基”指-NH 2。
术语“氰基”指-CN。
术语“硝基”指-NO 2。
术语“氧代基”指＝O。
术语“羧基”指-C(O)OH。
术语“巯基”指-SH。
术语“酯基”指-C(O)O(烷基)或-C(O)O(环烷基)，其中烷基和环烷基如上所定义。
术语“酰基”指含有-C(O)R基团的化合物，其中R为烷基、环烷基、杂环基、芳基、杂芳基。
术语“磺酸基”指-S(O) 2OH。
术语“磺酸酯基”指-S(O) 2O(烷基)或-S(O) 2O(环烷基)，其中烷基和环烷基如上所定义。
术语“磺酰基”指-S(O) 2R基团的化合物，其中R为烷基、环烷基、杂环基、芳基、杂芳基。
术语“氨基酰基”指-C(O)-NRR’，其中R、R’各自独立地为氢、烷基、环烷基、杂环基、芳基、杂芳基。
术语“氨基磺酰基”或“磺酰氨基”指-S(O) 2-NRR’，其中R、R’各自独立地为氢、烷基、环烷基、杂环基、芳基、杂芳基。
“任选”或“任选地”意味着随后所描述的事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生的场合。例如，“任选被烷基取代的杂环基团”意味着烷基可以但不必须存在，该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。
“取代的”指基团中的一个或多个氢原子，优选为最多5个，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和 (如烯属)键的碳原子结合时可能是不稳定的。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
“可药用盐”是指本发明化合物的盐，这类盐用于哺乳动物体内时具有安全性和有效性，且具有应有的生物活性。
本发明化合物的合成方法
为了完成本发明的目的，本发明采用如下技术方案。
本发明通式(I)所示的化合物或其盐可通过以下方案制备，具体制备方法如下。
(1)当Ar为
Figure PCTCN2020072763-appb-000019
时，其中，*代表与Cy连接位点，#代表与桥环N连接位点；按照方案1的方法，由化合物IA作为起始原料，得到通式(I)化合物。
Figure PCTCN2020072763-appb-000020
方案1
方案1的合成：
在碱性条件下，将化合物IA与Z-CH 2-Br反应得到化合物IB，其中，碱性试剂优选叔丁醇钾；随后，将化合物IB在酸性条件下发生脱保护反应得到化合物IC，其中，酸性试剂优选三氟乙酸；随后，在碱性条件下，将化合物IC与溴化氰反应得到化合物ID，其中，碱性试剂优选碳酸钾；随后，在缩合剂条件下，将化合物ID与IE发生缩合关环反应，得到通式(II)化合物，其中，缩合剂优选氯化锌。
其中，Z、n、Cy、R 1、R 8、q如通式(I)所定义。
(2)当Ar为
Figure PCTCN2020072763-appb-000021
时，其中，*代表与Cy连接位点，#代表与桥环N连接位点；按照方案2的方法，由化合物IF作为起始原料，得到通式(I)化合物。
Figure PCTCN2020072763-appb-000022
方案2
方案2的合成：
在碱性条件和缩合剂的作用下，将化合物IF与肼基甲酸叔丁酯发生缩合反应得到化合物IG，其中，碱性试剂优选DMAP，缩合剂优选EDC；随后，将化合物IG在酸性条件下发生脱保护反应得到化合物IH，其中，酸性试剂优选三氟乙酸；随后，化合物IH与原甲酸三乙酯发生环合反应，得到化合物II；随后，在碱性条件下，将化合物II与IC发生缩合反应，得到化合物IJ，其中，碱性条件优选三乙胺；最后，在氧化剂条件下，将化合物IJ进行环合反应得到通式(I)化合物，氧化剂优选碘苯二乙酸。
其中，Z、n、Cy、R 1、R 8、q如通式(I)所定义。
具体实施方式
以下结合实施例进一步描述本发明，但这些实施例并非限制着本发明的范围。
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移以10 -6(ppm)的单位给出。NMR的测定是用Brukerdps300型核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)、氘代氯仿(CDCl 3)、氘代甲醇(CD 3OD)，内标为四甲基硅烷(TMS)。
MS的测定用1100Series LC/MSD Trap(ESI)质谱仪(生产商：Agilent)。
制备液相使用lc3000高效液相色谱仪以及lc6000高效液相色谱仪(生产商：创新通恒)。色谱柱为Daisogel C18 10μm 60A(20mm×250mm)。
HPLC的测定使用岛津LC-20AD高压液相色谱仪(Agilent TC-C18 250×4.6mm 5μm色谱柱)和岛津LC-2010AHT高压液相色谱仪(Phenomenex C18 250×4.6mm 5μm色谱柱)。
薄层层析硅胶板使用青岛海洋化工GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.2mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。
柱层析一般使用青岛海洋硅胶100～200目、200～300目硅胶为载体。
本发明的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买自网化商城、北京耦合、Sigma、百灵威、易世明、上海书亚、伊诺凯、南京药石、安耐吉化学等公司。
实施例中无特殊说明，反应能够均在氩气氛或氮气氛下进行。
氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。
微波反应使用CEM Discover SP型微波反应器。
实施例中无特殊说明，溶液是指水溶液。
实施例中无特殊说明，反应的温度为室温，为20℃～30℃。
实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂的体系有：A：二氯甲烷和甲醇体系，B：正己烷和乙酸乙酯体系，C：石油醚和乙酸乙酯体系，D：丙酮，溶剂的体积比根据化合物的极性不同而进行调节。
纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂体系包括：A：二氯甲烷和甲醇体系，B：石油醚、乙酸乙酯和二氯甲烷体系，C：石油醚和乙酸乙酯体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和醋酸等碱性或酸性试剂进行调节。
实施例1：4-(5-((1R，3r，5S)-3-((5-环丙基-3-(2，6-二氯苯基)-异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，2，4-噁二唑-3-基)苯甲酸(1)的制备
Figure PCTCN2020072763-appb-000023
步骤1：(1R，3r，5S)-3-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)-8-氮杂二环[3.2.1]辛烷-8-羧酸叔丁酯(1B)的制备
将18-冠醚-6(4.95g，18.7mmol)、(1R，3r，5S)-3-羟基-8-氮杂二环[3.2.1]辛烷-8-羧酸叔丁酯(4.24g，18.7mmol)、THF(90mL)加入至反应瓶中，降温至0℃。向上述混合物中加入叔丁醇钾(2.86g，25.5mmol)，于0℃搅拌5分钟后，将4-(溴 甲基)-5-环丙基-3-(2，6-二氯苯基)异噁唑(根据文献WO2011020615公开的方法制备)(5.90g，17mmol)溶解于10mLTHF中，缓慢滴加至以上混合物中，滴加完毕后，继续室温搅拌2小时。反应完成后，向反应液中加入乙酸乙酯(100mL)和水(100mL)，有机相用饱和食盐水、水各洗涤一次，无水硫酸钠干燥，过滤，滤液减压浓缩，得到9.20g黄色油状的标题产物粗品，直接用于下一步。
步骤2：4-((((1R，3r，5S)-8-氮杂双环[3.2.1]辛-3-基)氧基)甲基)-5-环丙基-3-(2，6-二氯苯基)异噁唑(1C)的制备
将(1R，3r，5S)-3-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)-8-氮杂二环[3.2.1]辛烷-8-羧酸叔丁酯(9.20g，18.7mmol)、二氯甲烷(36mL)、三氟乙酸(18mL)加入至反应瓶中，室温搅拌1小时。反应完成后，用碳酸氢钠水溶液、水各洗涤一次，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物通过硅胶柱层析色谱法(洗脱剂：二氯甲烷-二氯甲烷∶甲醇＝10∶1)纯化，得到4.00g黄色固体状的标题产物，收率：54.6％。
步骤3：(1R，3r，5S)-3-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-甲腈(1D)的制备
将4-((((1R，3r，5S)-8-氮杂双环[3.2.1]辛-3-基)氧基)甲基)-5-环丙基-3-(2，6-二氯苯基)异噁唑(4.00g，10.24mmol)、水(80mL)、碳酸钾(4.30g，30.72mmol)加入至反应瓶中，室温搅拌下将溴化氰(1.20g，11.27mmol)加入至80mL二氯甲烷中，缓慢滴加到反应瓶中，滴加完毕后，继续室温搅拌2小时。反应完成后，用1N盐酸水溶液(90mL)、水(90mL)各洗涤一次，无水硫酸钠干燥，过滤，滤液减压浓缩，得到4.00g黄色油状物的标题产物，收率：94.0％。
步骤4：4-(5-((1R，3r，5S)-3-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，2，4-噁二唑-3-基)苯甲酸甲酯(1E)的制备
将对氰基苯甲酸甲酯(2.00g，12.4mmol)、甲醇(40mL)、盐酸羟胺(0.87g，12.4mmol)、碳酸氢钠(1.13g，13.4mmol)加入至反应瓶中，室温搅拌0.5小时后，升温至75℃继续搅拌3小时。反应完成后，将反应液倾倒入50mL冰水中，搅拌10分钟，过滤，滤饼用水洗涤，干燥得1.50g白色固体状的4-(N-羟基甲脒基)苯甲酸甲酯，收率62.2％。
将4-(N-羟基甲脒基)苯甲酸甲酯(1.00g，2.4mmol)、乙酸乙酯(30mL)、0.5N氯化锌的四氢呋喃溶液(18mL)和(1R，3r，5S)-3-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-甲腈(1.00g，5.15mmol)加入至反应瓶中，于50℃搅拌3小时，然后升温至70℃继续搅拌18小时。反应完成后，向反应液中加入水(100mL)和乙酸乙酯(100mL)，有机相用水、饱和食盐水各洗涤一次，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物通过硅胶柱层析色谱法纯化(洗脱剂：正庚烷∶乙酸乙酯＝5∶1)，得0.60g白色固体状标题产物，收率42.1％。
步骤5：4-(5-((1R，3r，5S)-3-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)-8- 氮杂双环[3.2.1]辛烷-8-基)-1，2，4-噁二唑-3-基)苯甲酸(1)的制备
将4-(5-((1R，3r，5S)-3-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，2，4-噁二唑-3-基)苯甲酸甲酯(0.60g，1mmol)、甲醇(30mL)、2N氢氧化钾水溶液(10mL)加入至反应瓶中，于40℃搅拌18小时。反应完成后，加入100mL水，用盐酸调节至pH＝2～3，析出黄色固体，过滤，干燥得580mg黄色固体，经制备液相色谱法(洗脱剂：0％-100％乙腈∶水溶液)纯化，得到278mg浅黄色固体状标题产物，收率47.5％。
MS：m/z＝581.4[M+H] +。
1H NMR(300MHz，DMSO)：δppm 1.14(m，2H)，1.27(m，2H)，1.81(m，2H)，2.00(m，6H)，2.33(m，1H)，3.55(s，1H)，4.28(s，2H)，4.37(m，2H)，7.36(m，1H)，7.43(m，2H)，8.11(m，2H)，8.17(m，2H)。
实施例2：2-氯-4-(5-((1R，3r，5S)-3-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛-8-基)-1，2，4-噁二唑-3-基)苯甲酸(2)的制备
Figure PCTCN2020072763-appb-000024
与实施例1的制备方法相同，除了用2-氯-4-氰基苯甲酸甲酯替代对氰基苯甲酸甲酯，制得标题化合物2。
MS：m/z＝615.2[M+H] +。
1H NMR(300MHz，DMSO)：δppm 1.11(m，2H)，1.28(m，2H)，1.68(m，2H)，1.75(m，4H)，1.94(m，2H)，2.35(m，1H)，3.50(m，1H)，4.06(m，2H)，4.38(s，2H)，7.63(m，3H)，7.92(m，1H)，8.06(m，2H)。
实施例3：6-(5-((1R，3r，5S)-(3-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，2，4-噁二唑-3-基)吡啶-2-甲酸(3)的制备
Figure PCTCN2020072763-appb-000025
与实施例1的制备方法相同，除了用6-氰基吡啶-2-羧酸甲酯代替对氰基苯甲酸甲酯，制得标题化合物3。
MS：m/z＝582.2[M+H] +。
1H NMR(300MHz，DMSO)：δppm 1.11(m，4H)，1.64(m，2H)，1.80(m，4H)， 1.94(m，2H)，2.36(m，1H)，3.52(m，1H)，4.29(m，2H)，4.37(s，2H)，7.80(m，3H)，8.27(m，3H)。
实施例4：5-(5-((1R，3r，5S)-(3-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，2，4-噁二唑-3-基)噻吩-2-甲酸(4)的制备
Figure PCTCN2020072763-appb-000026
与实施例1的制备方法相同，除了用5-氰基噻吩-2-甲酸甲酯替代对氰基苯甲酸甲酯，制得标题化合物4。
MS：m/z＝587.1[M+H] +。
1H NMR(300MHz，DMSO)：δppm 1.16(m，2H)，1.28(m，2H)，1.66(m，2H)，1.74(m，4H)，1.85(m，2H)，2.34(m，1H)，3.54(m，1H)，4.22(m，2H)，4.28(s，2H)，7.64(m，3H)，7.79(m，1H)，7.90(m，1H)。
实施例5：4-(5-((1R，3r，5S)-(3-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，2，4-噁二唑-3-基)-3-甲基苯甲酸(5)的制备
Figure PCTCN2020072763-appb-000027
与实施例1的制备方法相同，除了用4-氰基-3-甲基苯甲酸甲酯替代对氰基苯甲酸甲酯，制得标题化合物5。
MS：m/z＝595.4[M+H] +。
1H NMR(300MHz，DMSO)：δppm 1.12(m，2H)，1.28(m，2H)，1.78(m，2H)，1.86(m，4H)，1.91(m，2H)，2.31(m，1H)，2.65(s，3H)，3.58(m，1H)，4.06(m，2H)，4.26(s，2H)，7.58(m，1H)，7.66(m，2H)，7.93(m，2H)，8.05(m，1H)。
实施例6：3-(5-((1R，3r，5S)-(3-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，2，4-噁二唑-3-基)苯甲酸(6)的制备
Figure PCTCN2020072763-appb-000028
Figure PCTCN2020072763-appb-000029
与实施例1的制备方法相同，除了用间氰基苯甲酸甲酯替代对氰基苯甲酸甲酯，制得标题化合物6。
MS：m/z＝581.1[M+H] +。
1H NMR(300MHz，DMSO)：δppm 1.11(m，4H)，1.59(m，2H)，1.68(m，4H)，1.98(m，2H)，2.31(m，1H)，2.65(s，3H)，3.48(m，1H)，4.07(m，2H)，4.28(s，2H)，7.59(m，3H)，7.75(m，1H)，8.25(m，2H)，8.57(m，1H)。
实施例7：4-(5-((1R，3r，5S)-(3-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，2，4-噁二唑-3-基)-2-甲基苯甲酸(7)的制备
Figure PCTCN2020072763-appb-000030
与实施例1的制备方法相同，除了用4-氰基-2-甲基苯甲酸甲酯替代对氰基苯甲酸甲酯，制得标题化合物7。
MS：m/z＝595.4[M+H] +。
1H NMR(300MHz，DMSO)：δppm 1.12(m，2H)，1.26(m，2H)，1.78(m，2H)，1.76(m，4H)，1.98(m，2H)，2.34(m，1H)，2.59(s，3H)，3.48(m，1H)，4.08(m，2H)，4.27(s，2H)，7.64(m，3H)，7.95(m，3H)。
实施例8：4-(5-((1R，3r，5S)-3-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛-8-基)-1，3，4-噁二唑-2-基)苯甲酸(8)的合成
Figure PCTCN2020072763-appb-000031
Figure PCTCN2020072763-appb-000032
步骤1：2-(4-(甲氧基羰基)苯甲酰基)肼-1-甲酸叔丁酯(8B)的制备
将对苯二甲酸单甲酯(5.00g，27.8mmol)、二氯甲烷(80mL)、肼基甲酸叔丁酯(4.50g，34.4mmol)、DMAP(13.5g，111mmol)和EDCI(7.50g，38.9mmol)加入至反应瓶中，室温搅拌20小时。反应完成后，加入100mL水、100mL二氯甲烷萃取，有机相用水、饱和食盐水各洗涤一次，无水硫酸钠干燥，过滤，滤液减压浓缩，得到16.30g浅黄色固体状的标题产物，直接用于下一步，收率：100％。
步骤2：4-(肼基甲酰基)苯甲酸甲酯(8C)的制备
将2-(4-(甲氧基羰基)苯甲酰基)肼-1-甲酸叔丁酯(18.94g，64.4mmol)、乙酸乙酯(50mL)加入至反应瓶中，于0℃加入饱和盐酸乙酸乙酯溶液(40mL)，然后于室温搅拌18小时。反应完成后，用饱和碳酸氢钠溶液调节pH至8～9，过滤，干燥，得到4.80g白色固体状标题产物，收率：38.4％。
步骤3：4-(1，3，4-噁二唑-2-基)苯甲酸甲酯(8D)的制备
将4-(肼基甲酰基)苯甲酸甲酯(3.00g，15.5mmol)、原甲酸三乙酯(11.40g，77.3mmol)加入至反应瓶中，于105℃搅拌16小时。反应完成后，将反应液减压浓缩，残余物通过硅胶柱层析色谱法纯化(洗脱剂：正庚烷∶乙酸乙酯＝3∶1)，得到1.00g白色固体状的标题产物，收率31.7％。
步骤4：(Z)-N-((E)-((1R，3r，5S)3-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)亚甲基)4-(甲氧羰基)苯甲肼酸(8E)的制备
将4-(1，3，4-噁二唑-2-基)苯甲酸甲酯(0.50g，2.45mmol)、DMF(10mL)、4-((((1R，3r，5S)-8-氮杂双环[3.2.1]辛-3-基)氧基)甲基)-5-环丙基-3-(2，6-二氯苯基)异噁唑(1C)(4.50g，34.4mmol)、TEA(2mL)加入至反应瓶中，于90℃搅拌18小时。反应完成后，向反应液中加入水(40mL)和二氯甲烷(40mL)，有机相用水、饱和食盐水各洗涤一次，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物通过硅胶柱层析色谱法纯化(洗脱剂：二氯甲烷∶甲醇＝20∶1)，得到0.40g褐色固体 状的标题产物，收率27.4％。
步骤5：4-(5-((1R，3r，5S)3-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)8-氮杂双环[3.2.1]辛烷-8-基)1，3，4-噁二唑-2-基)苯甲酸甲酯(8F)的制备
将(Z)-N-((E)-((1R，3r，5S)3-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)亚甲基)4-(甲氧羰基)苯甲肼酸(8E)(0.30g，0.5mmol)、二氯甲烷(10mL)、碘苯二乙酸(0.24g，0.756mmol)加入至反应瓶中，室温搅拌1小时。反应完成后，将反应液减压浓缩，残余物通过制备液相色谱法(洗脱剂：0％-100％乙腈∶水)纯化，得到0.135g白色固体状标题产物，收率45.1％。
步骤6：4-(5-((1R，3r，5S)3-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)1，3，4-噁二唑-2-基)苯甲酸(8)的制备
将4-(5-((1R，3r，5S)3-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)1，3，4-噁二唑-2-基)苯甲酸甲酯(8F)(0.135g，0.23mmol)、甲醇(10mL)、水(5mL)、THF(15mL)、氢氧化锂(33mg，1.36mmol)加入至反应瓶中，于40℃搅拌24小时。反应完成后，将反应液用盐酸调节至pH＝1～2，加入水(40mL)和乙酸乙酯(40mL)，有机相用水、饱和食盐水各洗涤一次，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物通过制备液相色谱法(洗脱剂：0％-100％乙腈∶水)纯化，得到56mg白色固体状标题产物，收率42.5％。
MS：m/z＝581[M+H] +。
1H NMR(300MHz，DMSO)：δppm 1.11(m，4H)，1.64(m，2H)，1.76(m，4H)，1.91(m，2H)，2.38(m，1H)，3.46(m，1H)，4.04(m，2H)，4.28(s，2H)，7.62(m，3H)，8.18(m，4H)。
实施例9：2-氯-4-(5-((1R，3r，5S)-3-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛-8-基)-1，3，4-噁二唑-2-基)苯甲酸(9)的制备
Figure PCTCN2020072763-appb-000033
与实施例8的制备方法相同，除了用3-氯-4-(甲氧基羰基)苯甲酸替代对苯二甲酸单甲酯，制得标题化合物9。
MS：m/z＝615.2[M+H] +。
1H NMR(300MHz，DMSO)：δppm 1.11(m，4H)，1.64(m，2H)，1.76(m，4H)，1.91(m，2H)，2.36(m，1H)，3.48(m，1H)，4.07(m，2H)，4.27(s，2H)，7.59(m，1H)，7.67(m，2H)，7.92(m，1H)，8.04(m，1H)，8.08(m，1H)。
实施例10：6-(5-((1R，3r，5S)-3-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧 基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，3，4-噁二唑-2-基)吡啶-2-甲酸(10)的制备
Figure PCTCN2020072763-appb-000034
与实施例8的制备方法相同，除了用2，6-吡啶二羧酸单甲酯替代对苯二甲酸单甲酯，制得标题化合物10。
MS：m/z＝582.2[M+H] +。
1H NMR(300MHz，DMSO)：δppm 1.11(m，4H)，1.64(m，2H)，1.75(m，4H)，1.90(m，2H)，2.35(m，1H)，3.48(m，1H)，4.09(m，2H)，4.27(s，2H)，7.72(m，3H)，8.25(m，3H)。
实施例11：5-(5-((1R，3r，5S)-(3-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，3，4-噁二唑-2-基)噻吩-2-甲酸(11)的制备
Figure PCTCN2020072763-appb-000035
与实施例8的制备方法相同，除了用5-羧基噻吩-2-甲酸甲酯替代对苯二甲酸单甲酯，制得标题化合物11。
MS：m/z＝587.1[M+H] +。
1H NMR(300MHz，DMSO)：δppm 1.11(m，4H)，1.60(m，2H)，1.74(m，4H)，1.85(m，2H)，2.35(m，1H)，3.47(m，1H)，4.02(m，2H)，4.26(s，2H)，7.61(m，3H)，7.79(m，1H)，7.90(m，1H)。
实施例12：4-(5-((1R，3r，5S)-(3-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，3，4-噁二唑-2-基)-2-氟苯甲酸(12)的制备
Figure PCTCN2020072763-appb-000036
与实施例8的制备方法相同，除了用3-氟-4-(甲氧基羰基)苯甲酸替代对苯二甲酸单甲酯，制得标题化合物12。
MS：m/z＝599.4[M+H] +。
1H NMR(300MHz，DMSO)：δppm 1.11(m，4H)，1.64(m，2H)，1.75(m，4H)，1.91(m，2H)，2.32(m，1H)，3.49(m，1H)，4.06(m，2H)，4.26(s，2H)，7.63(m，3H)，7.92(m，2H)，8.06(m，1H)。
实施例13：4-(5-((1R，3r，5S)-(3-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，3，4-噁二唑-2-基)-2-甲氧基苯甲酸(13)的制备
Figure PCTCN2020072763-appb-000037
与实施例8的制备方法相同，除了用3-甲氧基-4-(甲氧基羰基)苯甲酸替代对苯二甲酸单甲酯，制得标题化合物13。
MS：m/z＝611.2[M+H] +。
1H NMR(300MHz，DMSO)：δppm 1.11(m，4H)，1.64(m，2H)，1.76(m，4H)，1.91(m，2H)，2.32(m，1H)，3.48(m，1H)，3.92(m，3H)，4.07(m，2H)，4.26(s，2H)，7.61(m，5H)，7.77(m，1H)。
实施例14：4-(5-((1R，3r，5S)-(3-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，3，4-噁二唑-2-基)-3-甲基苯甲酸(14)的制备
Figure PCTCN2020072763-appb-000038
与实施例8的制备方法相同，除了用2-甲基-4-(甲氧基羰基)苯甲酸替代对苯二甲酸单甲酯，制得标题化合物14。
MS：m/z＝595.4[M+H] +。
1H NMR(300MHz，DMSO)：δppm 1.11(m，4H)，1.59(m，2H)，1.76(m，4H)，1.91(m，2H)，2.37(m，1H)，2.65(s，3H)，3.48(m，1H)，4.06(m，2H)，4.28(s，2H)，7.56(m，1H)，7.66(m，2H)，7.90(m，1H)，7.96(m，1H)，8.05(m，1H)。
实施例15：3-(5-((1R，3r，5S)-(3-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，3，4-噁二唑-2-基)苯甲酸(15)的制备
Figure PCTCN2020072763-appb-000039
Figure PCTCN2020072763-appb-000040
与实施例8的制备方法相同，除了用3-(甲氧基羰基)苯甲酸替代对苯二甲酸单甲酯，制得标题化合物15。
MS：m/z＝581.1[M+H] +。
1H NMR(300MHz，DMSO)：δppm 1.11(m，4H)，1.60(m，2H)，1.67(m，4H)，1.88(m，2H)，2.32(m，1H)，3.48(m，1H)，4.09(m，2H)，4.26(s，2H)，7.59(m，3H)，7.77(m，1H)，8.23(m，2H)，8.51(m，1H)。
实施例16：4-(5-((1R，3r，5S)-(3-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，3，4-噁二唑-2-基)-3-氟苯甲酸(16)的制备
Figure PCTCN2020072763-appb-000041
与实施例8的制备方法相同，除了用2-氟-4-(甲氧基羰基)苯甲酸替代对苯二甲酸单甲酯，制得标题化合物16。
MS：m/z＝599.4[M+H] +。
1H NMR(300MHz，DMSO)：δppm 1.11(m，4H)，1.60(m，2H)，1.62(m，4H)，1.75(m，2H)，2.31(m，1H)，3.54(m，1H)，4.04(m，2H)，4.27(s，2H)，7.64(m，4H)，7.81(m，1H)，7.92(m，1H)。
实施例17：4-(5-((1R，3r，5S)-(3-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，3，4-噁二唑-2-基)-2-甲基苯甲酸(17)的制备
Figure PCTCN2020072763-appb-000042
Figure PCTCN2020072763-appb-000043
步骤1：2-(4-溴-3-甲基苯甲酰基)肼-1-羧酸叔丁酯(17B)的制备
将4-溴-3-甲基苯甲酸(5.98g，27.8mmol)、二氯甲烷(80mL)、肼基甲酸叔丁酯(4.50g，34.4mmol)、DMAP(13.5g，111mmol)和EDCI(7.50g，38.9mmol)加入至反应瓶中，室温搅拌20小时。反应完成后，加入100mL水、100mL二氯甲烷萃取，有机相用水、饱和食盐水各洗涤一次，无水硫酸钠干燥，过滤，滤液减压浓缩，得到8.90g浅黄色固体状的标题产物，直接用于下一步，收率：97.1％。
步骤2：4-溴-3-甲基苯甲酰肼(17C)的制备
将2-(4-溴-3-甲基苯甲酰基)肼-1-羧酸叔丁酯(8.90g，27.1mmol)、乙酸乙酯(50mL)加入至反应瓶中，于0℃加入饱和盐酸乙酸乙酯溶液(40mL)，然后于室温搅拌18小时。反应完成后，用饱和碳酸氢钠溶液调节pH至8～9，过滤，干燥，得到5.60g白色固体状标题产物，收率：90.5％。
步骤3：2-(4-溴-3-甲基苯基)-1，3，4-噁二唑(17D)的制备
将4-溴-3-甲基苯甲酰肼(5.60g，24.5mmol)、原甲酸三乙酯(50mL)加入至反应瓶中，于105℃搅拌16小时。反应完成后，将反应液减压浓缩，残余物通过硅胶柱层析色谱法纯化(洗脱剂：正庚烷∶乙酸乙酯＝3∶1)，得到4.20g白色固体状的标题产物，收率71.8％。
步骤4：(Z)-4-溴-N-((E)-(((1R，3r，5S)-3-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)亚甲基)-3-甲基苯并肼基酸(17E)的制备
将2-(4-溴-3-甲基苯基)-1，3，4-噁二唑(0.50g，2.10mmol)、DMF(10mL)、4-((((1R，3r，5S)-8-氮杂双环[3.2.1]辛-3-基)氧基)甲基)-5-环丙基-3-(2，6-二氯苯基)异噁唑(1C)(0.82g，2.10mmol)、DIPEA(5mL)加入至反应瓶中，于110℃搅拌18小时。反应完成后，向反应液中加入水(40mL)和二氯甲烷(40mL)，有机相用水、饱和食盐水各洗涤一次，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物通过硅胶柱层析色谱法纯化(洗脱剂：二氯甲烷∶甲醇＝20∶1)，得到0.40g褐色 固体状的标题产物，收率30.2％。
步骤5：2-(4-溴-3-甲基苯基)-5-((1R，3r，5S)-3-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)-8氮杂双环[3.2.1]辛-8-基)-1，3，4-噁二唑(17F)的制备
将(Z)-4-溴-N-((E)-(((1R，3r，5S)-3-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)亚甲基)-3-甲基苯并肼基酸(0.40g，0.63mmol)、二氯甲烷(10mL)、碘苯二乙酸(0.31g，0.95mmol)加入至反应瓶中，室温搅拌1小时。反应完成后，将反应液减压浓缩，残余物通过硅胶柱层析色谱法纯化(洗脱剂：石油醚∶乙酸乙酯＝2∶1)，得到0.35g黄色油状物标题产物，收率87.8％。
步骤6：4-(5-((1R，3r，5S)-(3-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，3，4-噁二唑-2-基)-2-甲基苯甲酸甲酯(17G)的制备
将2-(4-溴-3-甲基苯基)-5-((1R，3r，5S)-3-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)-8氮杂双环[3.2.1]辛-8-基)-1，3，4-噁二唑(0.35g，0.56mmol)、Pd(dppf)Cl 2(41mg，0.056mmol)、乙酸钠(92mg，1.12mmol)、甲醇(10mL)、DMF(3mL)加入至高压罐(TGYF，华欧)中，一氧化碳排空气三次，0.5mPa，80℃搅拌反应16小时。反应完成后，将反应液减压浓缩，残余物通过硅胶柱层析色谱法纯化(洗脱剂：石油醚∶乙酸乙酯＝2∶1)，得到0.20g黄色油状物标题产物，收率59.0％。
步骤7：4-(5-(((1R，3r，5S)-(3-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，3，4-噁二唑-2-基)-2-甲基苯甲酸(17)的制备将4-(5-(((1R，3r，5S)-(3-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，3，4-噁二唑-2-基)-2-甲基苯甲酸甲酯(0.20g，0.33mmol)、甲醇(10mL)、水(5mL)、THF(15mL)、氢氧化锂(33mg，1.36mmol)加入至反应瓶中，于40℃搅拌24小时。反应完成后，将反应液用盐酸调节至pH＝1～2，加入水(40mL)和乙酸乙酯(40mL)，有机相用水、饱和食盐水各洗涤一次，无水硫酸钠干燥，过滤，滤液减压浓缩，残余物通过制备液相色谱法(洗脱剂：0％-100％乙腈∶水)纯化，得到76mg白色固体状标题产物，收率38.8％。
MS：m/z＝595.3[M+H] +。
1H NMR(300MHz，DMSO)：δppm 1.14(m，4H)，1.65(m，2H)，1.79(m，4H)，1.97(m，2H)，2.36(m，1H)，2.51(m，3H)，3.50(m，1H)，4.18(m，2H)，4.28(s，2H)，7.62(m，5H)，7.92(m，1H)。
实施例18：5-(5-((1R，3r，5S)-3-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，3，4-噁二唑-2-基)吡啶甲酸(18)的制备
Figure PCTCN2020072763-appb-000044
与实施例8的制备方法相同，除了用吡啶-2，5-二羧-2-甲基酯替代对苯二甲酸单甲酯，制得标题化合物18。
MS：m/z＝582.5[M+H] +。
1H NMR(300MHz，DMSO)：δppm 1.14(m，4H)，1.65(m，2H)，1.79(m，4H)，1.95(m，2H)，2.35(m，1H)，3.53(m，1H)，4.19(m，2H)，4.27(s，2H)，7.59(m，3H)，8.15(m，1H)，8.38(m，1H)，9.14(m，1H)。
实施例19：6-(5-((1R，3r，5S)-3-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，3，4-噁二唑-2-基)烟酸(19)的制备
Figure PCTCN2020072763-appb-000045
与实施例8的制备方法相同，除了用5-(甲氧羰基)-2-吡啶羧酸替代对苯二甲酸单甲酯，制得标题化合物19。
MS：m/z＝582.5[M+H] +。
1H NMR(300MHz，DMSO)：δppm 1.11(m，4H)，1.66(m，2H)，1.79(m，4H)，1.95(m，2H)，2.35(m，1H)，3.53(m，1H)，4.20(m，2H)，4.27(s，2H)，7.62(m，3H)，8.12(m，1H)，8.39(m，1H)，9.14(m，1H)。
实施例20：5-(5-((1R，3r，5S)-(3-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，3，4-噁二唑-2-基)噻吩-3-羧酸(20)的制备
Figure PCTCN2020072763-appb-000046
与实施例17的制备方法相同，除了用4-溴噻吩-2-甲酸替代4-溴-3-甲基苯甲酸，制得标题化合物20。
MS：m/z＝587.7[M+H] +。
1H NMR(300MHz，DMSO)：δppm 1.11(m，4H)，1.61(m，2H)，1.76(m，4H)，1.85(m，2H)，2.33(m，1H)，3.47(m，1H)，4.12(m，2H)，4.25(s，2H)，7.58(m，3H)，7.77(m，1H)，8.39(m，1H)。
实施例21：4-(5-((1R，3r，5S)-(3-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，3，4-噁二唑-2-基)噻吩-2-羧酸(21)的制备
Figure PCTCN2020072763-appb-000047
与实施例17的制备方法相同，除了用5-溴-3-噻吩甲酸替代4-溴-3-甲基苯甲酸，制得标题化合物21。
MS：m/z＝587.4[M+H] +。
1H NMR(300MHz，DMSO)：δppm 1.13(m，4H)，1.68(m，2H)，1.77(m，4H)，1.85(m，2H)，2.33(m，1H)，3.47(m，1H)，4.13(m，2H)，4.26(s，2H)，7.64(m，3H)，7.94(m，1H)，8.34(m，1H)。
实施例22：4-(5-((1R，3r，5S)-3-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛-8-基)-1，3，4-噁二唑-2-基)苯甲酸(22)的合成
Figure PCTCN2020072763-appb-000048
与实施例8的制备方法相同，除了用4-((((1R，3r，5S)-8-氮杂双环[3.2.1]辛-3-基)氧基)甲基)-5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑(根据文献WO2012087519公开的方法制备)替代4-((((1R，3r，5S)-8-氮杂双环[3.2.1]辛-3-基)氧基)甲基)-5-环丙基-3-(2，6-二氯苯基)异噁唑(1C)，制得标题化合物22。
MS：m/z＝597.7[M+H] +。
1H NMR(300MHz，DMSO)：δppm 1.13(m，4H)，1.66(m，2H)，1.80(m，4H)，1.95(m，2H)，2.33(m，1H)，3.53(m，1H)，4.17(m，2H)，4.33(s，2H)，7.82(m，4H)，7.96(m，2H)，8.08(m，2H)。
实施例23：2-氯-4-(5-((1R，3r，5S)-3-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛-8-基)-1，3，4-噁二唑-2-基)苯甲酸(23)的制备
Figure PCTCN2020072763-appb-000049
与实施例8的制备方法相同，除了用4-((((1R，3r，5S)-8-氮杂双环[3.2.1]辛-3-基)氧基)甲基)-5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑(根据文献WO2012087519公 开的方法制备)替代4-((((1R，3r，5S)-8-氮杂双环[3.2.1]辛-3-基)氧基)甲基)-5-环丙基-3-(2，6-二氯苯基)异噁唑(1C)及3-氯-4-(甲氧基羰基)苯甲酸替代对苯二甲酸单甲酯，制得标题化合物23。
MS：m/z＝631.5[M+H] +。
1H NMR(300MHz，DMSO)：δppm 1.13(m，4H)，1.66(m，2H)，1.79(m，4H)，1.99(m，2H)，2.33(m，1H)，3.51(m，1H)，4.20(m，2H)，4.33(s，2H)，7.55(m，2H)，7.68(m，2H)，7.89(m，2H)，7.94(m，1H)。
实施例24：6-(5-((1R，3r，5S)-3-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，3，4-噁二唑-2-基)吡啶-2-甲酸(24)的制备
Figure PCTCN2020072763-appb-000050
与实施例8的制备方法相同，除了用4-((((1R，3r，5S)-8-氮杂双环[3.2.1]辛-3-基)氧基)甲基)-5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑(根据文献WO2012087519公开的方法制备)替代4-((((1R，3r，5S)-8-氮杂双环[3.2.1]辛-3-基)氧基)甲基)-5-环丙基-3-(2，6-二氯苯基)异噁唑(1C)及2，6-吡啶二羧酸单甲酯替代对苯二甲酸单甲酯，制得标题化合物24。
MS：m/z＝598.5[M+H] +。
1H NMR(300MHz，DMSO)：δppm 1.13(m，4H)，1.66(m，2H)，1.79(m，4H)，1.98(m，2H)，2.33(m，1H)，3.51(m，1H)，4.20(m，2H)，4.32(s，2H)，7.62(m，4H)，8.25(m，3H)。
实施例25：5-(5-((1R，3r，5S)-(3-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，3，4-噁二唑-2-基)噻吩-2-甲酸(25)的制备
Figure PCTCN2020072763-appb-000051
与实施例8的制备方法相同，除了用4-((((1R，3r，5S)-8-氮杂双环[3.2.1]辛-3-基)氧基)甲基)-5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑(根据文献WO2012087519公开的方法制备)替代4-((((1R，3r，5S)-8-氮杂双环[3.2.1]辛-3-基)氧基)甲基)-5-环丙基-3-(2，6-二氯苯基)异噁唑(1C)及5-羧基噻吩-2-甲酸甲酯替代对苯二甲酸单甲酯，制得标题化合物25。
MS：m/z＝603.4[M+H] +。
1H NMR(300MHz，DMSO)：δppm 1.11(m，4H)，1.65(m，2H)，1.74(m，4H)，1.79(m，2H)，2.33(m，1H)，3.53(m，1H)，4.14(m，2H)，4.32(s，2H)，7.65(m，6H)。
实施例26：4-(5-((1R，3r，5S)-(3-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，3，4-噁二唑-2-基)-2-氟苯甲酸(26)的制备
Figure PCTCN2020072763-appb-000052
与实施例8的制备方法相同，除了用4-((((1R，3r，5S)-8-氮杂双环[3.2.1]辛-3-基)氧基)甲基)-5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑(根据文献WO2012087519公开的方法制备)替代4-((((1R，3r，5S)-8-氮杂双环[3.2.1]辛-3-基)氧基)甲基)-5-环丙基-3-(2，6-二氯苯基)异噁唑(1C)及3-氟-4-(甲氧基羰基)苯甲酸替代对苯二甲酸单甲酯，制得标题化合物26。
MS：m/z＝615.3[M+H] +。
1H NMR(300MHz，DMSO)：δppm 1.11(m，4H)，1.66(m，2H)，1.79(m，4H)，1.95(m，2H)，2.32(m，1H)，3.52(m，1H)，4.15(m，2H)，4.33(s，2H)，7.62(m，2H)，7.80(m，2H)，7.89(m，2H)，8.02(m，1H)。
实施例27：4-(5-((1R，3r，5S)-(3-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，3，4-噁二唑-2-基)-3-甲基苯甲酸(27)的制备
Figure PCTCN2020072763-appb-000053
与实施例8的制备方法相同，除了用4-((((1R，3r，5S)-8-氮杂双环[3.2.1]辛-3-基)氧基)甲基)-5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑(根据文献WO2012087519公开的方法制备)替代4-((((1R，3r，5S)-8-氮杂双环[3.2.1]辛-3-基)氧基)甲基)-5-环丙基-3-(2，6-二氯苯基)异噁唑(1C)及2-甲基-4-(甲氧基羰基)苯甲酸替代对苯二甲酸单甲酯，制得标题化合物27。
MS：m/z＝611.4[M+H] +。
1H NMR(300MHz，DMSO)：δppm 1.16(m，4H)，1.72(m，2H)，1.77(m，4H)，2.00(m，2H)，2.43(m，1H)，2.59(s，3H)，3.54(m，1H)，4.22(m，2H)，4.30(s，2H)， 7.63(m，2H)，7.71(m，2H)，7.95(m，3H)。
实施例28：3-(5-((1R，3r，5S)-(3-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，3，4-噁二唑-2-基)苯甲酸(28)的制备
Figure PCTCN2020072763-appb-000054
与实施例8的制备方法相同，除了用4-((((1R，3r，5S)-8-氮杂双环[3.2.1]辛-3-基)氧基)甲基)-5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑(根据文献WO2012087519公开的方法制备)替代4-((((1R，3r，5S)-8-氮杂双环[3.2.1]辛-3-基)氧基)甲基)-5-环丙基-3-(2，6-二氯苯基)异噁唑(1C)及3-(甲氧基羰基)苯甲酸替代对苯二甲酸单甲酯，制得标题化合物28。
MS：m/z＝597.2[M+H] +。
1H NMR(300MHz，DMSO)：δppm 1.11(m，4H)，1.66(m，2H)，1.79(m，4H)，1.94(m，2H)，2.33(m，1H)，3.53(m，1H)，4.17(m，2H)，4.32(s，2H)，7.65(m，5H)，8.05(m，2H)，8.35(m，1H)。
实施例29：4-(5-((1R，3r，5S)-(3-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，3，4-噁二唑-2-基)-3-氟苯甲酸(29)的制备
Figure PCTCN2020072763-appb-000055
与实施例8的制备方法相同，除了用4-((((1R，3r，5S)-8-氮杂双环[3.2.1]辛-3-基)氧基)甲基)-5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑(根据文献WO2012087519公开的方法制备)替代4-((((1R，3r，5S)-8-氮杂双环[3.2.1]辛-3-基)氧基)甲基)-5-环丙基-3-(2，6-二氯苯基)异噁唑(1C)及2-氟-4-(甲氧基羰基)苯甲酸替代对苯二甲酸单甲酯，制得标题化合物29。
MS：m/z＝615.5[M+H] +。
1H NMR(300MHz，DMSO)：δppm 1.11(m，4H)，1.66(m，2H)，1.79(m，4H)，1.90(m，2H)，2.31(m，1H)，3.52(m，1H)，4.15(m，2H)，4.32(s，2H)，7.57(m，2H)，7.67(m，2H)，7.85(m，2H)，8.02(m，1H)。
实施例30：4-(5-((1R，3r，5S)-(3-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基) 甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，3，4-噁二唑-2-基)-2-甲基苯甲酸(30)的制备
Figure PCTCN2020072763-appb-000056
与实施例17的制备方法相同，除了用4-((((1R，3r，5S)-8-氮杂双环[3.2.1]辛-3-基)氧基)甲基)-5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑(根据文献WO2012087519公开的方法制备)替代4-((((1R，3r，5S)-8-氮杂双环[3.2.1]辛-3-基)氧基)甲基)-5-环丙基-3-(2，6-二氯苯基)异噁唑(1C)，制得标题化合物30。
MS：m/z＝611.4[M+H] +。
1H NMR(300MHz，DMSO)：δppm 1.11(m，4H)，1.67(m，2H)，1.80(m，4H)，2.08(m，2H)，2.33(m，1H)，2.54(m，1H)，3.54(m，1H)，4.19(m，2H)，4.34(s，2H)，7.67(m，6H)，7.93(m，1H)。
实施例31：5-(5-((1R，3r，5S)-3-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，3，4-噁二唑-2-基)吡啶甲酸(31)的制备
Figure PCTCN2020072763-appb-000057
与实施例8的制备方法相同，除了用4-((((1R，3r，5S)-8-氮杂双环[3.2.1]辛-3-基)氧基)甲基)-5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑(根据文献WO2012087519公开的方法制备)替代4-((((1R，3r，5S)-8-氮杂双环[3.2.1]辛-3-基)氧基)甲基)-5-环丙基-3-(2，6-二氯苯基)异噁唑(1C)及吡啶-2，5-二羧酸-2-甲基酯替代对苯二甲酸单甲酯，制得标题化合物31。
MS：m/z＝598.5[M+H] +。
1H NMR(300MHz，DMSO)：δppm 1.10(m，4H)，1.68(m，2H)，1.80(m，4H)，1.98(m，2H)，2.35(m，1H)，3.53(m，1H)，4.20(m，2H)，4.34(s，2H)，7.59(m，4H)，8.15(m，1H)，8.36(m，1H)，9.14(m，1H)。
实施例32：6-(5-((1R，3r，5S)-3-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，3，4-噁二唑-2-基)烟酸(32)的制备
Figure PCTCN2020072763-appb-000058
与实施例8的制备方法相同，除了用4-((((1R，3r，5S)-8-氮杂双环[3.2.1]辛-3-基)氧基)甲基)-5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑(根据文献WO2012087519公开的方法制备)替代4-((((1R，3r，5S)-8-氮杂双环[3.2.1]辛-3-基)氧基)甲基)-5-环丙基-3-(2，6-二氯苯基)异噁唑(1C)及5-(甲氧羰基)-2-吡啶羧酸替代对苯二甲酸单甲酯，制得标题化合物32。
MS：m/z＝598.5[M+H] +。
1H NMR(300MHz，DMSO)：δppm 1.13(m，4H)，1.69(m，2H)，1.81(m，4H)，1.95(m，2H)，2.35(m，1H)，3.53(m，1H)，4.18(m，2H)，4.28(s，2H)，7.63(m，4H)，8.12(m，1H)，8.39(m，1H)，9.14(m，1H)。
实施例33：5-(5-((1R，3r，5S)-(3-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，3，4-噁二唑-2-基)噻吩-3-羧酸(33)的制备
Figure PCTCN2020072763-appb-000059
与实施例17的制备方法相同，除了用4-((((1R，3r，5S)-8-氮杂双环[3.2.1]辛-3-基)氧基)甲基)-5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑(根据文献WO2012087519公开的方法制备)替代4-((((1R，3r，5S)-8-氮杂双环[3.2.1]辛-3-基)氧基)甲基)-5-环丙基-3-(2，6-二氯苯基)异噁唑(1C)及4-溴噻吩-2-甲酸替代4-溴-3-甲基苯甲酸，制得标题化合物33。
MS：m/z＝603.3[M+H] +。
1H NMR(300MHz，DMSO)：δppm 1.13(m，4H)，1.66(m，2H)，1.79(m，4H)，1.85(m，2H)，2.35(m，1H)，3.34(m，1H)，4.15(m，2H)，4.33(s，2H)，7.57(m，4H)，7.79(m，1H)，8.38(m，1H)。
实施例34：4-(5-((1R，3r，5S)-(3-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，3，4-噁二唑-2-基)噻吩-2-羧酸(34)的制备
Figure PCTCN2020072763-appb-000060
与实施例17的制备方法相同，除了用4-((((1R，3r，5S)-8-氮杂双环[3.2.1]辛-3-基)氧基)甲基)-5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑(根据文献WO2012087519公开的方法制备)替代4-((((1R，3r，5S)-8-氮杂双环[3.2.1]辛-3-基)氧基)甲基)-5-环丙基-3-(2，6-二氯苯基)异噁唑(1C)及5-溴-3-噻吩甲酸替代4-溴-3-甲基苯甲酸，制得标题化合物34。
MS：m/z＝603.4[M+H] +。
1H NMR(300MHz，DMSO)：δppm 1.17(m，4H)，1.72(m，2H)，1.85(m，4H)，1.93(m，2H)，2.56(m，1H)，3.53(m，1H)，4.18(m，2H)，4.38(s，2H)，7.61(m，2H)，7.70(m，2H)，8.01(m，1H)，8.41(m，1H)。
本发明化合物的生物学评价
测试例1：本发明化合物对FXR激动活性的评价
采用荧光素酶报告基因实验(luciferase assay)评价本发明化合物对FXR激动活性。
实验过程包括：传luc2P-GAL4-HEK293稳转细胞系(由HEK293细胞转染pGL4.35质粒，经Hygromycin B筛选建立。该细胞含有9×GAL4 UAS和萤火虫荧光素酶报告基因。配体激活的LBD-GAL4 DBD融合蛋白可以入核与9×GAL4 UAS结合并激活下游荧光素酶报告基因的转录)至96孔板，每孔1×10 4细胞。使用X-tremeGENE HP转染试剂转染pBIND-FXR(由FXR-LBD插入pFN26A-BIND hRluc-neo
Figure PCTCN2020072763-appb-000061
载体构建而成。质粒大小7.5kb，Amp抗性，含有FXR-LBD，可表达FXR-LBD和GAL4 DBD融合蛋白)，质粒与转染试剂比例为1μg∶2μl，具体用量为每孔100ng质粒，0.2μl X-tremeGENE HP转染试剂；加入待测化合物(各化合物加药最高浓度为30μM，3倍稀释，共计10个浓度)，诱导荧光素酶表达。24小时后，将含有待测细胞的96孔板从孵箱中取出，置于室温，每孔加入与孔内培养基体积相等的
Figure PCTCN2020072763-appb-000062
Luciferase Reagent(80μl/孔)，混匀，室温孵育20min，让细胞充分裂解，然后将孔板中的所有液体转移至96孔酶标板中，用多功能读板仪(厂家：Bio Tek(USA)；型号：Synergy4)测量萤火虫萤光素值；向每孔中加入与初始培养基体积相等的
Figure PCTCN2020072763-appb-000063
Stop &
Figure PCTCN2020072763-appb-000064
Reagent(80μl/孔)，混匀，室温孵育10min，然后测量海肾萤光素值。海肾萤光的测量顺序应该与萤火虫萤光相同。使用GraphPad Prism 5软件，采用非线性回归方法进行曲线拟合及EC 50计算，拟合方程为：Y＝Bottom+(Top-Bottom)/(1+10^((LogEC 50-X)*HillSlope))。其中，EC 50是半有效浓度，Top为最大效应，Bottom为空白效应，HillSlope为斜率。 化合物的活性如表1所示。
在表1中，A是指化合物激动FXR活性的EC 50＜25nM；B是指EC 50＝25nM至50nM；C是指EC 50＝50nM至100nM；D是指EC 50＝100nM至500nM；E是指EC 50＞500nM。
表1.本发明化合物的FXR激动活性
实施例 FXR激动活性
实施例1 A
实施例2 A
实施例3 A
实施例4 A
实施例5 A
实施例6 A
实施例7 A
实施例8 A
实施例9 C
实施例10 D
实施例11 D
实施例12 D
实施例13 A
实施例14 A
实施例15 A
实施例16 C
实施例17 A
实施例18 D
实施例19 E
实施例20 C
实施例21 D
实施例22 A
实施例23 D
实施例24 E
实施例25 D
实施例26 D
实施例27 A
实施例28 A
实施例29 D
实施例30 A
实施例31 D
实施例32 E
实施例33 D
实施例34 E
结论：如上表1所述，本发明化合物显示出体外FXR的激动活性。
测试例2：本发明化合物对1-萘异硫氰酸酯(ANIT)诱导的大鼠胆汁酸淤积模型的疗效
动物：SD大鼠，雄性，7-8周龄，体重220-240g，购于北京市维通利华实验动物技术有限公司，SPF级，动物生产许可证号：SCXK(京)2016-0011，发证单位：北京市科学技术委员会。
样品配制：将本发明化合物加入至DMSO中，超声至完全溶解。加入0.5％CMC-Na定容(DMSO∶0.5％CMC-Na＝1∶99)后再超声至溶解均一，备用。
动物适应3-5天后，动物按体重分为20组：正常组、模型组、实施例8(3mg/kg/d、10mg/kg/d)组、实施例11(3mg/kg/d、10mg/kg/d)组、实施例12(3mg/kg/d、10mg/kg/d)组、实施例14(3mg/kg/d、10mg/kg/d)组、实施例20(3mg/kg/d、10mg/kg/d)组、实施例22(3mg/kg/d、10mg/kg/d)组、实施例26(3mg/kg/d、10mg/kg/d)组、实施例28(3mg/kg/d、10mg/kg/d)组、实施例29(3mg/kg/d、10mg/kg/d)组，每组10只，开始灌胃给药，给药体积为10mL/kg，每天给药1次，共给药4天。给药第2天，除正常组外每只动物灌胃给予ANIT(1-萘异硫氰酸酯，麦克林，纯度98％，货号：N814658，CAS号：551-06-4，规格：5g/瓶存储条件：2-8度，批号：C10116101。)一次，在给药后4小时给予，剂量为50mg/kg，给药体积5mL/kg，第4天早上禁食。用小动物麻醉机，采用异氟烷吸入麻醉后，用毛细玻璃管，眼球后静脉丛取血放置1小时左右，每只约1ml左右，3500转/分，离心10分钟，取血清，采用AU480全自动生化分析系统(BECKMAN COULTER)测ALT、AST、GGT和TBA指标并测血药浓度。取肝脏，称重，剪碎，加生理盐水(肝脏重量∶生理盐水＝1∶2)，匀浆后冻存测肝药浓度，采用超高效液相色谱仪：Shimadzu，LC 30AD；三重四级杆质谱仪：AB，TQ5500检测。
本发明化合物对ANIT诱导胆汁酸淤积大鼠的疗效如下表2所示。本发明化合物在ANIT诱导胆汁酸淤积大鼠给药4天的血药浓度和肝药浓度如下表3、表4和表5所示。
表2.本发明化合物对ANIT诱导胆汁酸淤积大鼠的疗效
  ALT AST GGT TBA
正常 43.4±7.3** 127.0±11.5** 1.3±0.5** 7.9±2.6**
模型 344.7±131.5 964.0±274.7 5.4±1.7 234.3±82.1
实施例8(3mg/kg/d) 164.8±85.0** 401.8±172.8** 2.5±0.7** 100.0±99.8
实施例8(10mg/kg/d) 79.9±98.7** 243.5±192.6** 2.0±0.5** 32.9±68.0**
实施例11(3mg/kg/d) 276.3±118.0 761.3±253.7 4.9±0.9 243.4±72.4
实施例11(10mg/kg/d) 180.3±107.8* 466.1±242.4** 3.7±1.5* 190.3±140.7
实施例12(3mg/kg/d) 122.5±89.7** 314.2±237.9* 2.2±0.8** 69.0±66.7*
实施例12(10mg/kg/d) 54.7±27.3** 139.3±34.6** 1.9±0.5** 25.4±14.3**
实施例14(3mg/kg/d) 220.3±104.0* 643.3±239.3* 4.6±1.3 235.8±80.1
实施例14(10mg/kg/d) 45.5±11.9** 181.4±20.8** 1.7±0.4** 20.3±12.3**
实施例20(3mg/kg/d) 141.5±101.4* 400.2±304.4* 2.8±1.2* 119.5±124.7
实施例20(10mg/kg/d) 50.9±22.4** 139.8±58.4** 2.6±0.5** 16.1±8.0**
实施例22(3mg/kg/d) 100.8±90.9** 324.8±313.1** 2.7±1.7* 73.3±103.2*
实施例22(10mg/kg/d) 44.5±8.1** 163.3±21.3** 1.8±0.5** 27.4±13.6**
实施例26(3mg/kg/d) 62.2±27.6** 187.7±50.4** 1.9±0.8** 23.2±10.1**
实施例26(10mg/kg/d) 50.0±11.2** 162.3±27.7** 1.4±0.7** 35.3±13.2**
实施例28(3mg/kg/d) 147.1±66.2 342.7±153.6* 2.3±0.5** 66.2±58.4*
实施例28(10mg/kg/d) 46.6±12.1** 150.8±28.7** 1.9±0.5** 20.5±6.0**
实施例29(3mg/kg/d) 82.0±44.5* 256.0±168.8* 2.3±1.1* 51.7±65.2*
实施例29(10mg/kg/d) 77.8±69.5** 189.4±76.9** 1.9±0.4** 26.8±13.6**
注明：*为与模型组比较P＜0.05，**为与模型组比较P＜0.01。
表3.本发明化合物给药4天血药浓度结果
Figure PCTCN2020072763-appb-000065
表4.本发明化合物给药4天肝药浓度结果
Figure PCTCN2020072763-appb-000066
Figure PCTCN2020072763-appb-000067
表5.本发明化合物给药4天肝药浓度/血药浓度结果
Figure PCTCN2020072763-appb-000068
结论：本发明实施例8、11、12、14、20、22、26、28、29显著降低ANIT大鼠血清中的ALT、AST、GGT和TBA水平，说明本发明化合物可显著改善ANIT大鼠的胆汁淤积。而且，这些化合物具有较高的肝脏靶向性。
测试例3：本发明化合物对hERG通道的作用测试
试验试剂：
试剂 供货商 货号 批号
DMEM Gibco 11995-065 1897371
胎牛血清 Gibco 10091148 1872295
G418 Amresco E859 17J065302
TrypLE TM Express Gibco 12604021 1810976
二甲基亚砜 Sigma D4540 BCBW5664
西沙必利(Cisapride) Sigma C4740 0000021445
天冬氨酸钾 Sigma A6558 WXBC4890V
氯化钠 Sigma S5886 SLBS7447
氯化钾 Sigma P5405 SLBR2609V
乙二醇双(2-氨基乙基醚) Sigma E3889 SLBR7504V
4-羟乙基哌嗪乙磺酸 Santa Cruz SC-29097A J3015/C2817
氯化镁 Sigma M2393 SLBP9770V
葡萄糖 Sigma G8270 SLBR5156V
氯化钙 Sigma C7902 SLBV3136
磷酸二氢钠 GENERAL-REAGENT G21298B P1297763
三磷酸腺苷钠盐 Sigma A2383 SLBT7818
磷酸盐缓冲液(PBS) Takara T900 2301
hERG稳定表达细胞系 Creacell A-0320 N/A
试验仪器：
名称 供应商 型号
放大器 HEKA(Germany) EPC10
微操纵器 Sutter Instruments(USA) MP285
电极拉制仪 Sutter Instruments(USA) P97
显微镜 Olympus(Japan) IX71
毛细玻璃管 Sutter Instruments(USA) BF150-86-10
数据采集和分析软件 HEKA(Germany) Patchmaster & IGOR
细胞内外液：
细胞外液：140mM NaCl，3.5mM KCl，1mM MgCl 2，2mM CaCl 2，10mM葡萄糖，10mM HEPES，1.25mM NaH 2PO 4，NaOH调节pH＝7.4。
细胞内液：20mM KCl，115mM K-天冬氨酸，1mM MgCl 2，5mM EGTA，10mM HEPES，2mM Na 2-ATP，KOH调节pH＝7.2。
待测样品配制：
用10mL的细胞外液将本发明实施例8化合物储液(30.26mM的DMSO溶液)依次稀释，配成0.3μM、1μM、3μM、0μM以及30μM液体。目测待测样品的溶解性，待测样品全部溶解没有肉眼可见的沉淀。
西沙必利(阳性对照)配制：
将10mg西沙必利用2066.29μL二甲基亚砜(DMSO)配制成10mM的储液。用二甲基亚砜(DMSO)将西沙必利储液依次稀释为1μM、10μM、100μM以及1mM，共4个浓度。在检测之前，每个浓度各取10μL加入到10mL细胞外液中，确保DMSO浓度为0.1％。西沙必利最终的工作浓度为1nM、10nM、100nM以及1μM。目测西沙必利的溶解性，西沙必利全部溶解没有肉眼可见的沉淀。
细胞培养：
hERG钾通道稳定表达的HEK293细胞系(供应商Creacell，货号A-0302)在含有10％胎牛血清及0.8mg/mL G418的DMEM培养基中培养，培养温度为37℃，二氧化碳浓度为5％。
细胞传代：除去旧培养基并用PBS洗一次，然后加入1mL TrypLE TM表达溶液，37℃孵育0.5分钟。当细胞从皿底脱离，加入5mL 37℃预热的完全培养基(含10％胎牛血清及0.8mg/mL G418的DMEM培养基)。将细胞悬液用吸管轻轻吹打使聚集的细胞分离。将细胞悬液转移至无菌的离心管中，1000rpm离心5分钟收集细胞。扩增或维持培养，将细胞接种于6厘米细胞培养皿，每个细胞培养皿接种细胞量为2.5×10 5个细胞(最终体积：5mL)。为维持细胞的电生理活性，细胞密度必须不 能超过80％。膜片钳检测，实验之前细胞用TrypLE TM表达溶液分离，将3×10 3细胞铺到盖玻片上，在24孔板中培养(最终体积：500μL)，18个小时后，进行实验检测。
电生理记录实验方法：
全细胞膜片钳记录全细胞hERG钾电流的电压刺激方案如下：当形成全细胞封接后膜片钳设置于-80mV。钳制电压由-80mV除极至+30mV维持2.5秒，然后迅速保持在-50mV维持4秒，可以激发出hERG通道的尾电流。实验以-50mV为漏电流检测。每隔10秒重复采集数据，观察药物对hERG尾电流的作用。实验数据由EPC-10放大器(HEKA)进行采集并储存于PatchMaster(HEKA)软件中。
用微电极拉制仪(P97，Sutter Instruments)将毛细玻璃管(BF150-86-10，Sutter Instruments)拉制成记录电极。在倒置显微镜(IX71，Olympus)下操纵微电极操纵仪(MP285，Sutter Instruments)将记录电极接触到细胞上，给予负压抽吸，形成GΩ封接。形成GΩ封接后进行快速电容补偿，然后继续给予负压，吸破细胞膜，形成全细胞记录模式。然后进行慢速电容的补偿并记录膜电容及串联电阻。不给予漏电补偿。
当全细胞记录的hERG电流稳定后开始给药，每个药物浓度作用至5分钟(或者电流至稳定)后检测下一个浓度，每一个测试化合物检测多个浓度。将铺有细胞的盖玻片置于倒置显微中的记录浴槽中，测试化合物以及不含化合物的外液利用重力灌流的方法从低浓度到高浓度依次流经记录小室从而作用于细胞，在记录中利用真空泵进行液体交换。每一个细胞在不含化合物的外液中检测到的电流作为自己的对照组。独立重复检测3个细胞。所有电生理实验在室温下进行。
数据质量标准：
以下标准用来判断数据是否可以接受：
(1)串联电阻≤20MΩ
(2)封接电阻≥1GΩ
(3)起始尾电流峰值≥400pA
(4)起始尾电流峰值大于激活电流峰值
(5)尾电流没有明显的自发性衰减(5分钟内自发性衰减小于5％)
(6)在膜电位为-80mV下无明显的漏电流(漏电流≤100pA)
本发明实施例8化合物对hERG通道抑制作用以及半抑制浓度(IC 50)结果如下表6所示。
表6.本发明实施例8化合物对hERG通道抑制作用以及半抑制浓度(IC 50)
Figure PCTCN2020072763-appb-000069
实验结果表明：本发明实施例8化合物对hERG通道无抑制作用。

Claims (14)

  1. 一种通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、其前药或其可药用盐，
    Figure PCTCN2020072763-appb-100001
    其中：
    Z选自：
    Figure PCTCN2020072763-appb-100002
    其中，X为CH、CF、N或NO；
    R 2选自氢、卤素、烷基、环烷基，其中所述烷基或环烷基任选进一步被选自卤素、羟基、烷基、烷氧基的一个或多个基团所取代；
    R 3和R 4各自独立地选自氢、卤素、烷基、烷氧基，所述烷基或烷氧基任选进一步被一个或多个卤素取代；
    Ar为5元或6元芳基或杂芳基；
    Cy为芳基或杂芳基；
    R 1选自-(CH 2) m-R 5或-O(CH 2) m-R 5；其中所述-(CH 2) m-或-O(CH 2) m-基团任选进一步被选自卤素、氰基、羟基、氧代基、烷基、卤代烷基、烷氧基、卤代烷氧基、CO 2H、SO 3H的一个或多个基团取代；
    R 5选自氢、卤素、氰基、硝基、烷基、环烷基、杂环基、芳基、杂芳基、OR 6、NR 6R 7、-CO 2R 6、-C(O)R 6、-C(O)NR 6R 7、-N(R 6)C(O)R 7、-C(O)NR 6SO 2R 7、-S(O) pR 6、-S(O) pNR 6R 7、-N(R 6)S(O) pR 7、或-S(O) pNR 6COR 7；所述烷基、环烷基、杂环基、芳基或杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、卤代烷基、烷氧基、卤代烷氧基、烯基、炔基、环烷基、卤代环烷基、杂环基、芳基、杂芳基的一个或多个基团取代；
    R 6和R 7各自独立地选自氢、卤素、羟基、烷基、环烷基、杂环基、芳基、杂芳基，其中所述烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代；
    或者R 6和R 7与他们连接的氮原子一起形成含氮杂环基，所述含氮杂环基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基、酯基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代；
    每一个R 8可以相同或不同，且各自独立地选自卤素、氨基、硝基、氰基、羟 基、巯基、羧基、酯基、烷基、卤代烷基、烷氧基、卤代烷氧基、烯基、炔基、环烷基、卤代环烷基、杂环基、芳基、杂芳基；
    n为0、1或2；
    m为0至6的整数；
    p为0、1或2；
    q为0至4的整数；
    条件是，Ar不为
    Figure PCTCN2020072763-appb-100003
    其中，*代表与Cy连接位点，#代表与桥环N连接位点。
  2. 根据权利要求1所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、其前药或其可药用盐，其为通式(II)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、其前药或其可药用盐，
    Figure PCTCN2020072763-appb-100004
    其中，
    X 1、X 2、X 3各自独立地选自C、N、O或S，优选N，O；
    Z、n、Cy、R 1、R 8、q如权利要求1所定义。
  3. 根据权利要求1或2所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、其前药或其可药用盐，
    其中，
    Z为
    Figure PCTCN2020072763-appb-100005
    X选自CH或N；
    R 2选自氢、卤素、烷基、环烷基，优选C 1-C 6烷基或C 3-C 6环烷基，更优选环丙基；所述烷基或环烷基任选进一步被选自卤素、羟基、烷基、烷氧基的一个或多个基团所取代；
    R 3和R 4各自独立地选自氢、卤素、烷基、卤代烷基、烷氧基、卤代烷氧基，优选氢、卤素、C 1-C 6卤代烷基和C 1-C 6卤代烷氧基。
  4. 根据权利要求1至3中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、其前药或其可药用盐，其中，n为1。
  5. 根据权利要求1至4中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、其前药或其可药用盐，其中，
    Cy为C 5-C 6芳基或5至6元杂芳基，优选苯基、吡啶基、嘧啶基、吡嗪基、噻唑基、呋喃基、咪唑基、吡唑基。
  6. 根据权利要求1至5中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、其前药或其可药用盐，
    其中，
    R 1选自-(CH 2) m-R 5或-O(CH 2) m-R 5；
    R 5选自氢、卤素、烷基、OR 6、NR 6R 7、-CO 2R 6、-C(O)R 6、-C(O)NR 6R 7、-N(R 6)C(O)R 7、-C(O)NR 6SO 2R 7、-S(O) pR 6、-S(O) pNR 6R 7、-N(R 6)S(O) pR 7、或-S(O) pNR 6COR 7，优选-C(O)R 6、-C(O)NR 6R 7、-S(O) pR 6、-S(O) pNR 6R 7，更优选-C(O)R 6或-S(O) pNR 6R 7，甚至更优选-COOH；
    R 6和R 7各自独立地选自氢、卤素、羟基、烷基、环烷基、杂环基、芳基、杂芳基，其中所述烷基、环烷基、杂环基、芳基和杂芳基任选进一步被选自卤素、氨基、硝基、氰基、羟基、巯基、羧基、酯基、氧代基、烷基、烷氧基、环烷基、杂环基、芳基、杂芳基的一个或多个基团取代；
    或者R 6和R 7与他们连接的氮原子一起形成含氮杂环基，所述含氮杂环基任选进一步被选自卤素、氨基、硝基、氰基、氧代基、羟基、巯基、羧基；
    m为0至6的整数，优选0、1或2；更优选0。
  7. 根据权利要求1至6中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、其前药或其可药用盐，其中，
    每一个R 8可以相同或不同，且各自独立地选自卤素、烷基、卤代烷基、烷氧基、卤代烷氧基；
    q为0至4的整数；优选q为0或1。
  8. 根据权利要求1至7中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、其前药或其可药用盐，其中，所述化合物选自：
    4-(5-((1R，3r，5S)-3-((5-环丙基-3-(2，6-二氯苯基)-异噁唑-4-基)甲氧基)-8-氮杂双 环[3.2.1]辛烷-8-基)-1，2，4-噁二唑-3-基)苯甲酸；
    2-氯-4-(5-((1R，3r，5S)-3-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛-8-基)-1，2，4-噁二唑-3-基)苯甲酸；
    6-(5-((1R，3r，5S)-(3-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，2，4-噁二唑-3-基)吡啶-2-甲酸；
    5-(5-((1R，3r，5S)-(3-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，2，4-噁二唑-3-基)噻吩-2-甲酸；
    4-(5-((1R，3r，5S)-(3-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，2，4-噁二唑-3-基)-3-甲基苯甲酸；
    3-(5-((1R，3r，5S)-(3-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，2，4-噁二唑-3-基)苯甲酸；
    4-(5-((1R，3r，5S)-(3-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，2，4-噁二唑-3-基)-2-甲基苯甲酸；
    4-(5-((1R，3r，5S)-3-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛-8-基)-1，3，4-噁二唑-2-基)苯甲酸；
    2-氯-4-(5-((1R，3r，5S)-3-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛-8-基)-1，3，4-噁二唑-2-基)苯甲酸；
    6-(5-((1R，3r，5S)-3-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，3，4-噁二唑-2-基)吡啶-2-甲酸；
    5-(5-((1R，3r，5S)-(3-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，3，4-噁二唑-2-基)噻吩-2-甲酸；
    4-(5-((1R，3r，5S)-(3-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，3，4-噁二唑-2-基)-2-氟苯甲酸；
    4-(5-((1R，3r，5S)-(3-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，3，4-噁二唑-2-基)-2-甲氧基苯甲酸；
    4-(5-((1R，3r，5S)-(3-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，3，4-噁二唑-2-基)-3-甲基苯甲酸；
    3-(5-((1R，3r，5S)-(3-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，3，4-噁二唑-2-基)苯甲酸；
    4-(5-((1R，3r，5S)-(3-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，3，4-噁二唑-2-基)-3-氟苯甲酸；
    4-(5-((1R，3r，5S)-(3-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，3，4-噁二唑-2-基)-2-甲基苯甲酸；
    5-(5-((1R，3r，5S)-3-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，3，4-噁二唑-2-基)吡啶甲酸；
    6-(5-((1R，3r，5S)-3-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)-8-氮杂双 环[3.2.1]辛烷-8-基)-1，3，4-噁二唑-2-基)烟酸；
    5-(5-((1R，3r，5S)-(3-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，3，4-噁二唑-2-基)噻吩-3-羧酸；
    4-(5-((1R，3r，5S)-(3-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，3，4-噁二唑-2-基)噻吩-2-羧酸；
    4-(5-((1R，3r，5S)-3-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛-8-基)-1，3，4-噁二唑-2-基)苯甲酸；
    2-氯-4-(5-((1R，3r，5S)-3-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛-8-基)-1，3，4-噁二唑-2-基)苯甲酸；
    6-(5-((1R，3r，5S)-3-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，3，4-噁二唑-2-基)吡啶-2-甲酸；
    5-(5-((1R，3r，5S)-(3-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，3，4-噁二唑-2-基)噻吩-2-甲酸；
    4-(5-((1R，3r，5S)-(3-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，3，4-噁二唑-2-基)-2-氟苯甲酸；
    4-(5-((1R，3r，5S)-(3-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，3，4-噁二唑-2-基)-3-甲基苯甲酸；
    3-(5-((1R，3r，5S)-(3-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，3，4-噁二唑-2-基)苯甲酸；
    4-(5-((1R，3r，5S)-(3-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，3，4-噁二唑-2-基)-3-氟苯甲酸；
    4-(5-((1R，3r，5S)-(3-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，3，4-噁二唑-2-基)-2-甲基苯甲酸；
    5-(5-((1R，3r，5S)-3-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，3，4-噁二唑-2-基)吡啶甲酸；
    6-(5-((1R，3r，5S)-3-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，3，4-噁二唑-2-基)烟酸；
    5-(5-((1R，3r，5S)-(3-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，3，4-噁二唑-2-基)噻吩-3-羧酸；
    4-(5-((1R，3r，5S)-(3-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-基)-1，3，4-噁二唑-2-基)噻吩-2-羧酸。
  9. 一种制备根据权利要求1至8中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、其前药或其可药用盐的方法，其包括以下步骤：
    当Ar为
    Figure PCTCN2020072763-appb-100006
    时，其中，*代表与Cy连接位点，#代表与桥环N连接位点，
    Figure PCTCN2020072763-appb-100007
    在缩合剂条件下，将化合物IE与ID进行环合反应得到通式(I)化合物，其中，缩合剂优选氯化锌；
    其中，Z、n、Cy、R 1、R 8、q如权利要求1所定义。
  10. 一种制备根据权利要求1至8中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、其前药或其可药用盐的方法，其包括以下步骤：
    当Ar为
    Figure PCTCN2020072763-appb-100008
    时，其中，*代表与Cy连接位点，#代表与桥环N连接位点，
    Figure PCTCN2020072763-appb-100009
    在氧化剂条件下，将化合物IJ进行环合反应得到通式(I)化合物，其中，氧化剂优选碘苯二乙酸；
    其中，Z、n、Cy、R 1、R 8、q如权利要求1所定义。
  11. 一种药物组合物，其含有根据权利要求1至8中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、其前药或其可药用盐，以及药学上可接受的载体。
  12. 根据权利要求1至8中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、其前药或其可药用盐，或者根据权利要求11所述的药物组合物，在制备FXR激动剂中的用途。
  13. 根据权利要求1至8中任一项所述的通式(I)所示的化合物或其内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、其前药或其可药用盐，或者根据权利要求11所述的药物组合物，在制备预防和/或治疗与FXR活性相关的疾病的药物中的用途。
  14. 根据权利要求13所述的用途，其中所述与FXR活性相关的疾病选自：慢性肝内胆汁郁积病症或肝外胆汁郁积病症，或慢性胆汁郁积病症或急性肝内胆汁郁积病症导致的肝纤维化；和/或肝脏梗阻性或慢性炎症；和/或肝硬化；和/或肝皮脂腺病和相关的综合征，与酒精诱导的肝硬变或与病毒性肝炎相关的胆汁郁积或纤维变性作用；和/或肝脏切除后的肝脏衰竭或肝脏缺血；和/或脂肪肝炎相关的化学疗法；和/或急性肝脏衰竭；和/或炎性肠病；和/或脂质和脂质蛋白紊乱；和/或糖尿病及糖尿病临床并发症，包括糖尿病性肾病、糖尿病性神经病、糖尿病视网膜病和其他临床表现；和/或脂质，特别是甘油三酯蓄积，及甘油三酯蓄积导致的慢性脂肪和纤维变性引起的疾病和病症，例如非酒精性脂肪肝或非酒精性脂肪肝炎；和/或肥胖或代谢综合征，例如血脂障碍、糖尿病、体重指数异常高的合并病症；和/或作为慢性梗阻性动脉粥样硬化终末点而产生的急性心肌梗塞、急性中风、或血栓形成；非恶性过度增殖性疾病和恶性过度增殖性疾病，特别是肝细胞癌、结肠腺瘤和息肉病、结肠腺癌、乳腺癌、胰腺癌、巴特氏食管癌和其他形式的胃肠道和肝脏肿瘤性疾病。
PCT/CN2020/072763 2019-01-31 2020-01-17 芳环或芳杂环类化合物及其制备方法和医药用途 WO2020156241A1 (zh)

Priority Applications (7)

Application Number Priority Date Filing Date Title
CN202080006066.5A CN112955448B (zh) 2019-01-31 2020-01-17 芳环或芳杂环类化合物及其制备方法和医药用途
AU2020214889A AU2020214889A1 (en) 2019-01-31 2020-01-17 Aromatic ring or heteroaromatic ring compounds, preparation method therefor and medical use thereof
EP20749262.0A EP3919489A4 (en) 2019-01-31 2020-01-17 AROMATIC RING OR HETEROAROMATIC RING COMPOUNDS, PROCESS FOR THEIR PRODUCTION AND MEDICAL USE
JP2021544611A JP2022518603A (ja) 2019-01-31 2020-01-17 芳香環又は芳香族複素環化合物、その製造方法及び医薬使用
CA3128416A CA3128416A1 (en) 2019-01-31 2020-01-17 Aromatic ring or heteroaromatic ring compounds, preparation method therefor and medical use thereof
KR1020217027636A KR20210123337A (ko) 2019-01-31 2020-01-17 방향족 고리 또는 헤테로방향족 고리 화합물, 이의 제조 방법 및 이의 의학 용도
US17/310,432 US20220127258A1 (en) 2019-01-31 2020-01-17 Aromatic ring or heteroaromatic ring compounds, preparation method therefor and medical use thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201910096771 2019-01-31
CN201910096771.8 2019-01-31

Publications (1)

Publication Number Publication Date
WO2020156241A1 true WO2020156241A1 (zh) 2020-08-06

Family

ID=71841921

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2020/072763 WO2020156241A1 (zh) 2019-01-31 2020-01-17 芳环或芳杂环类化合物及其制备方法和医药用途

Country Status (9)

Country Link
US (1) US20220127258A1 (zh)
EP (1) EP3919489A4 (zh)
JP (1) JP2022518603A (zh)
KR (1) KR20210123337A (zh)
CN (1) CN112955448B (zh)
AU (1) AU2020214889A1 (zh)
CA (1) CA3128416A1 (zh)
TW (1) TW202115052A (zh)
WO (1) WO2020156241A1 (zh)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021144330A1 (en) 2020-01-15 2021-07-22 INSERM (Institut National de la Santé et de la Recherche Médicale) Use of fxr agonists for treating an infection by hepatitis d virus
CN114195777A (zh) * 2020-09-18 2022-03-18 凯思凯迪（上海）医药科技有限公司 新型fxr小分子激动剂制备及其用途
CN114195776A (zh) * 2020-09-18 2022-03-18 凯思凯迪（上海）医药科技有限公司 新型fxr小分子激动剂制备及其用途
WO2022068815A1 (zh) * 2020-09-30 2022-04-07 中国科学院上海药物研究所 Fxr小分子激动剂及其制备方法和用途
WO2022152770A1 (en) 2021-01-14 2022-07-21 Enyo Pharma Synergistic effect of a fxr agonist and ifn for the treatment of hbv infection
WO2022229302A1 (en) 2021-04-28 2022-11-03 Enyo Pharma Strong potentiation of tlr3 agonists effects using fxr agonists as a combined treatment

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4245365A1 (en) * 2022-03-16 2023-09-20 Cascade Pharmaceuticals, Inc. A fxr small molecule agonist, the preparation and use thereof
WO2023223257A1 (en) * 2022-05-19 2023-11-23 X-Chem Inc. Amino heteroaromatic compounds

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011020615A1 (en) 2009-08-19 2011-02-24 Phenex Pharmaceuticals Ag Novel fxr (nr1h4 ) binding and activity modulating compounds
WO2012087519A1 (en) 2010-12-20 2012-06-28 Irm Llc Compositions and methods for modulating fxr
CN105431420A (zh) * 2013-05-01 2016-03-23 豪夫迈·罗氏有限公司 二杂芳基化合物及其用途

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2655369A1 (en) * 2010-12-20 2013-10-30 Irm Llc Compositions and methods for modulating farnesoid x receptors
EP2718288B1 (en) * 2011-06-09 2015-03-11 Boehringer Ingelheim International GmbH Substituted piperidines as gpr119 modulators for the treatment of metabolic disorders
TN2017000243A1 (en) * 2014-12-18 2018-10-19 Novartis Ag Azabicyclooctane derivatives as fxr agonists for use in the treatment of liver and gastrointestinal diseases
CN106946867B (zh) * 2016-01-06 2019-11-12 广州市恒诺康医药科技有限公司 Fxr受体调节剂及其制备方法和用途
US10526345B2 (en) * 2016-04-08 2020-01-07 Mankind Pharma Ltd. Compounds as GPR119 agonists
US10292983B2 (en) * 2016-08-03 2019-05-21 Cymabay Therapeutics, Inc. Oxymethylene aryl compounds for treating inflammatory gastrointestinal diseases or gastrointestinal conditions
EP3523298A4 (en) * 2016-10-04 2020-06-24 Enanta Pharmaceuticals, Inc. ISOXAZOLANALOGA AS FXR AGONISTS AND METHOD FOR USE THEREOF
WO2019120088A1 (zh) * 2017-12-22 2019-06-27 四川科伦博泰生物医药股份有限公司 异噁唑衍生物及其制备方法和用途
CN111868056B (zh) * 2018-07-11 2023-02-03 中国医药研究开发中心有限公司 1,2,4-噁二唑类化合物及其制备方法和医药用途

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011020615A1 (en) 2009-08-19 2011-02-24 Phenex Pharmaceuticals Ag Novel fxr (nr1h4 ) binding and activity modulating compounds
WO2012087519A1 (en) 2010-12-20 2012-06-28 Irm Llc Compositions and methods for modulating fxr
CN103443099A (zh) * 2010-12-20 2013-12-11 Irm责任有限公司 调节fxr的组合物和方法
CN105431420A (zh) * 2013-05-01 2016-03-23 豪夫迈·罗氏有限公司 二杂芳基化合物及其用途

Non-Patent Citations (11)

* Cited by examiner, † Cited by third party
Title
ACTA. PHARMACOL. SIN., vol. 36, 2015, pages 44 - 50
ADV. THER., vol. 33, 2016, pages 291 - 319
CAS, no. 551-06-4
CURR. OPIN. LIPIDOL., vol. 27, 2016, pages 295 - 301
DRUG DISCOV. TODAY, vol. 17, 2012, pages 988 - 97
J. MED. CHEM., vol. 57, 2014, pages 8035 - 8055
J. PHARMACOL. EXP. THER., vol. 343, 2012, pages 556 - 567
LANCET, vol. 385, 2015, pages 956 - 65
N. ENGL. J. MED., vol. 375, 2016, pages 631 - 643
PHARMACOL. THER., vol. 126, 2010, pages 228 - 243
See also references of EP3919489A4

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021144330A1 (en) 2020-01-15 2021-07-22 INSERM (Institut National de la Santé et de la Recherche Médicale) Use of fxr agonists for treating an infection by hepatitis d virus
CN114195777A (zh) * 2020-09-18 2022-03-18 凯思凯迪（上海）医药科技有限公司 新型fxr小分子激动剂制备及其用途
CN114195776A (zh) * 2020-09-18 2022-03-18 凯思凯迪（上海）医药科技有限公司 新型fxr小分子激动剂制备及其用途
CN114195776B (zh) * 2020-09-18 2023-06-20 凯思凯迪（上海）医药科技有限公司 新型fxr小分子激动剂制备及其用途
CN114195777B (zh) * 2020-09-18 2023-06-20 凯思凯迪（上海）医药科技有限公司 新型fxr小分子激动剂制备及其用途
WO2022068815A1 (zh) * 2020-09-30 2022-04-07 中国科学院上海药物研究所 Fxr小分子激动剂及其制备方法和用途
WO2022152770A1 (en) 2021-01-14 2022-07-21 Enyo Pharma Synergistic effect of a fxr agonist and ifn for the treatment of hbv infection
WO2022229302A1 (en) 2021-04-28 2022-11-03 Enyo Pharma Strong potentiation of tlr3 agonists effects using fxr agonists as a combined treatment

Also Published As

Publication number Publication date
CA3128416A1 (en) 2020-08-06
AU2020214889A1 (en) 2021-09-02
KR20210123337A (ko) 2021-10-13
US20220127258A1 (en) 2022-04-28
CN112955448A (zh) 2021-06-11
JP2022518603A (ja) 2022-03-15
TW202115052A (zh) 2021-04-16
EP3919489A4 (en) 2022-10-12
EP3919489A1 (en) 2021-12-08
CN112955448B (zh) 2023-02-03

Similar Documents

Publication Publication Date Title
WO2020156241A1 (zh) 芳环或芳杂环类化合物及其制备方法和医药用途
KR102400183B1 (ko) Fxr 작용제
JP7532371B2 (ja) Ｔｈｒβ受容体アゴニスト化合物、およびその製造方法および使用
CN111868056B (zh) 1,2,4-噁二唑类化合物及其制备方法和医药用途
WO2021197464A1 (zh) 稠合咪唑类衍生物、其制备方法及其在医药上的应用
TW201728581A (zh) Ｆｘｒ受體激動劑
JP7243959B2 (ja) イソオキサゾール誘導体、その製造方法、及びその使用
CN113056271B (zh) 法尼醇x受体激动剂及其用途
WO2020030107A1 (zh) 一种含有酰胺类衍生物的药物组合物及其制备方法和应用
WO2021254470A1 (zh) 6-氧代-3,6-二氢吡啶类衍生物、其制备方法及其在医药上的应用
BR112015028399B1 (pt) Derivados 11-hidroxila de ácidos biliares e conjugados de aminoácido dos mesmos como moduladores de receptor farnesoide x, composição farmacêutica e uso dos referidos derivados
CN107021958A (zh) Fxr受体激动剂
WO2020114307A1 (zh) 异噁唑衍生物及其制备方法和用途
TW201934555A (zh) 含氮三環化合物及其在藥物中的應用
CN112334467B (zh) Fxr受体激动剂
WO2019149089A1 (zh) 含有羧酸基团的苯并氮杂环类化合物及其制备方法和用途
WO2020029908A1 (zh) 螺桥环化合物、其药物组合物及其用途
CN110563720B (zh) 磺酰胺类化合物及其制备方法和医药用途
EP4178672A1 (en) MODULATORS OF THR-ß AND METHODS OF USE THEREOF
WO2023205507A1 (en) Androgen receptor modulators and methods for their use

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 20749262

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2021544611

Country of ref document: JP

Kind code of ref document: A

Ref document number: 3128416

Country of ref document: CA

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 20217027636

Country of ref document: KR

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 2020214889

Country of ref document: AU

Date of ref document: 20200117

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 2020749262

Country of ref document: EP

Effective date: 20210831