WO2020029908A1 - Composé cyclique à pont spiro, composition pharmaceutique de celui-ci et son utilisation - Google Patents

Composé cyclique à pont spiro, composition pharmaceutique de celui-ci et son utilisation Download PDF

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WO2020029908A1
WO2020029908A1 PCT/CN2019/099219 CN2019099219W WO2020029908A1 WO 2020029908 A1 WO2020029908 A1 WO 2020029908A1 CN 2019099219 W CN2019099219 W CN 2019099219W WO 2020029908 A1 WO2020029908 A1 WO 2020029908A1
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alkyl
independently
substituted
heteroaryl
group
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Chinese (zh)
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张健存
邹晴安
陈延维
王坤
张菊福
彭武建
康宁
张礼军
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广州市恒诺康医药科技有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to the field of medicinal chemistry, in particular to a class of spiral bridge compounds as modulators of FXR receptors, pharmaceutical compositions containing said compounds, and the use of said compounds or compositions in medicines for treating FXR-mediated diseases Applications.
  • Farnesoid X receptor is a member of the nuclear receptor superfamily with ligand activity. It was first cloned and found in rat liver cDNA library by Forman et al. In 1995 [Cell.1995; 81 ( 5): 687-93], which is named because its transcriptional activity can be enhanced by farnesyl derivatives at super physiological concentrations. In 1999, Parks, Makishima, and Tang also discovered that physiological levels of bile acid (BA) are endogenous ligands of FXR, so FXR is also known as the BA receptor [Science. 1999; 284, 1362-1365].
  • BA bile acid
  • FXR is mainly expressed at high levels in the liver and intestines, and also at a certain level in the adrenal glands and renal crests. In addition, it is expressed at lower levels in the heart, lung, adipose tissue, and testis [Gene. 2002; 290: 35 -43].
  • FXR as a bile acid nuclear receptor, participates in the regulation of a variety of physiological functions by regulating the expression of a series of genes, including bile acid metabolism, lipid metabolism, and sugar metabolism [Biochim Biophys Acta. 2010; 1802: 363-372]. More importantly, research confirms that FXR plays a key role in protecting the liver and suppressing the development of liver cancer. FXR's protection of the liver is manifested in many aspects, including: maintaining the homeostasis of bile acids, inhibiting hepatocyte apoptosis, reducing tissue oxidative stress responses, reducing liver fibrosis levels, inhibiting inflammatory responses, and promoting liver cell regeneration Wait.
  • FXR prevents liver damage caused by high bile acids by regulating the normal level of bile acids in the body; second, FXR promotes liver by preventing apoptosis of liver cells and cell necrosis caused by acute liver damage Third, FXR can inhibit the secretion of extracellular matrix and reduce the occurrence of fibrosis by reducing the sensitivity of hepatic stellate cells to TGF- ⁇ [J Pharmacol ExpTher.
  • FXR can inhibit the occurrence and development of liver cancer by regulating NF- ⁇ B-mediated liver inflammation [Hepatology.2007; 46: 590-7]; Fifth, in the case of liver damage, bile acids in the body Increased levels, thereby activating FXR in the body and promoting liver repair and regeneration [JHuazhongUnivSciTechnologMedSci, 2010,30 (1): 55-60]; Sixth, FXR activation can inhibit cholesterol regulatory element binding protein-1C (sterol regulatory element-binding protein-1C, SREBP-1C) and fatty acid synthetase (FAS) expression, increase liver cell and adipocyte peroxisome proliferato activated receptors (peroxisome proliferato r activated receptor (PPAR) expression, improve insulin resistance, reduce fat synthesis, thereby reducing liver fat deposition [Hepatol Int 2010; 4: 741-748]. FXR has so many hepatoprotective effects suggesting that
  • FXR agonists have been developed by Intercept Pharmaceuticals, and have made some breakthrough progress, further confirming the feasibility of FXR agonists in the treatment of NAFLD.
  • Obeticholic acid (OCA) a bile acid FXR agonist developed by Intercept Pharmaceuticals, is on the market.
  • the small molecule FXR agonist PX-104 acquired by Gilead Sciences and developed by Phenex Pharmaceuticals is currently in Phase II clinical research.
  • FXR agonists have shown significant clinical application value and are expected to benefit more patients, especially NAFLD patients. Therefore, the development of FXR agonists has broad application prospects and is also urgently needed.
  • the present invention provides a new class of spiral bridge compounds, which have good agonistic activity on FXR.
  • the compound of the invention has excellent medicinal effects, pharmacokinetic properties and / or toxicological properties, and has better clinical application prospects.
  • the present invention provides compositions and methods capable of modulating the activity of farnesyl X receptors (FXRs).
  • the invention provides compounds that are FXR agonists or partial agonists.
  • the present invention provides a new class of compounds with good agonistic activity on FXR, which can be used to prepare and treat diseases mediated by FXR, including non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, chronic liver Intra- or extra-hepatic cholestasis, liver fibrosis caused by chronic cholestasis or acute intrahepatic cholestasis, chronic hepatitis B, gallbladder stones, liver cancer, colon cancer, or intestinal inflammatory diseases.
  • the present invention also provides methods for preparing the compounds of the present invention, methods of using the compounds to treat the above-mentioned diseases in mammals, especially humans, and pharmaceutical compositions comprising the compounds.
  • the present invention provides a new spiro-bridged compound comprising a compound represented by formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomeric compound of compound represented by formula (I) Conformers, tautomers, nitrogen oxides, metabolites, prodrugs, or mixtures:
  • A is C or N
  • P is C (R a ), N, N (R b ), or O;
  • Q is C (R a ), N, N (R b ), or O;
  • M is C or N
  • R 1 is H, F, Cl, Br, I, -CN, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl, wherein R 1 is independently optionally Is replaced by 1, 2, 3 or 4 R 5 ;
  • R 2 is aryl, heteroaryl, cycloalkyl, or heterocyclyl, wherein R 2 is independently optionally substituted with 1, 2, 3, or 4 R 6 ;
  • R 3a and R 3b are each independently H, F, Cl, Br, I, CN, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkylamino, C 1-6 alkoxy Group, halo C 1-6 alkoxy, C 3-6 cycloalkyl, or halo C 3-6 cycloalkyl, or R 3a , R 3b together with the carbon atom to which they are attached form C 3-6 Cycloalkyl, C 3-6 cycloalkenyl, or heterocyclic group consisting of 3-6 atoms; wherein the C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C A 3-6 cycloalkyl group, a C 3-6 cycloalkenyl group, and a 3-6 atom heterocyclic group are independently optionally substituted with 1, 2, 3, or 4 R 7 ;
  • X is:
  • X is independently optionally substituted by 1, 2, 3 or 4 R 8 ;
  • X 2 , X 3 and X 4 are each independently -O-, -S-, -NH-,-(CH 2 ) m1 -NH- (CH 2 ) m2 -,-(CH 2 ) m1 -O- ( CH 2) m2 -, - ( CH 2) m1 -S- (CH 2) m2 -, or - (CH 2) m3 -;
  • Z is an arylene, heteroarylene, or heterocyclic group, wherein Z is independently optionally substituted with 1, 2, 3, or 4 R 10 ;
  • Each R 4a is independently H, alkyl, alkenyl, alkynyl, haloalkyl, cyano-substituted alkyl, hydroxyalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, ring Alkyl, cycloalkylalkyl, heterocyclyl, or heterocyclylalkyl; wherein R 4a is independently optionally substituted with 1, 2, 3, or 4 R 4b ;
  • Each R 11 is independently H, OH, NH 2 , alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cyano-substituted alkyl, alkoxy, haloalkoxy, aryl, aralkyl , Heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, or heterocyclylalkyl; wherein R 11 is independently optionally selected by 1, 2, 3, or 4 R 11a replaced;
  • Each R 12a and R 12b is independently H, alkyl, alkenyl, alkynyl, haloalkyl, cyano-substituted alkyl, hydroxyalkyl, aryl, aralkyl, heteroaryl, heteroarylalkane Group, cycloalkyl, cycloalkylalkyl, heterocyclyl, or heterocyclylalkyl; wherein R 12a and R 12b are each independently optionally substituted with 1, 2, 3, or 4 R 11b ;
  • Each R 13 is independently alkylene, alkenylene, alkynylene, hydroxyalkyl, cyano-substituted alkylene, or haloalkylene;
  • Each R 4b , R 11a and R 11b is independently H, -CN, -NO 2 , -OH, -NH 2 , F, Cl, Br, I, C 1-6 alkyl, C 2-6 alkenyl , C 2-6 alkynyl, halo C 1-6 alkyl, cyano substituted C 1-6 alkyl, C 1-6 hydroxyalkyl, or C 1-6 alkoxy;
  • Each R 1a and R b is independently H, alkyl, alkenyl, alkynyl, cyano-substituted alkyl, hydroxyalkyl, or haloalkyl;
  • Each R a is independently H, -CN, -NO 2 , -OH, -NH 2 , F, Cl, Br, I, alkyl, alkenyl, alkynyl, haloalkyl, cyano-substituted alkyl, Hydroxyalkyl, alkoxy, or haloalkoxy;
  • R 14 , R 14a , R 15 , R 15a , and R 16 is independently H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halo C 1-6 alkane Alkyl, cyano-substituted C 1-6 alkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, or heterocyclylalkyl ;
  • Each R 16a , R 17 , and R 17a is independently H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cyano-substituted C 1-6 alkyl, or Halogenated C 1-6 alkyl;
  • Each m1 is independently 0, 1, 2 or 3;
  • Each m2 is independently 0, 1, 2 or 3;
  • Each m3 is independently 0, 1, 2, or 3.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the present invention or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer Body, nitrogen oxides, metabolites, prodrugs, and pharmaceutically acceptable excipients, diluents or carriers.
  • the pharmaceutical composition of the invention further comprises an additional therapeutic agent.
  • the present invention provides the use of a compound of the present invention or a pharmaceutical composition of the present invention in the manufacture of a medicament for preventing or treating a disease mediated by FXR in a mammal.
  • the FXR-mediated diseases include non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, chronic intrahepatic or extrahepatic cholestasis disorders, caused by chronic cholestasis disorders, or acute intrahepatic cholestasis disorders Of fibrosis, chronic hepatitis B, gallbladder stones, liver cancer, colon cancer, or inflammatory bowel disease.
  • mammal means, for example, a primate (e.g., human, male or female), cow, sheep, goat, horse, pig, dog, cat, rabbit, rat, mouse, fish , Birds, etc.
  • a primate e.g., human, male or female
  • the mammal is a primate.
  • the mammal is a human.
  • Stereoisomers refer to compounds that have the same chemical structure, but differ in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotomers), geometric isomers (cis / trans) isomers, atropisomers, etc. .
  • Enantiomers refer to two isomers of a compound that cannot overlap but mirror image each other.
  • Diastereomer refers to a stereoisomer that has two or more chiral neutrality and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivity. Diastereomeric mixtures can be separated by high resolution analytical operations such as electrophoresis and chromatography, such as HPLC.
  • any asymmetric atom (e.g., carbon, etc.) of a compound disclosed herein can exist in racemic or enantiomerically enriched form, such as (R)-, (S)-, or (R, S) -configuration presence.
  • each asymmetric atom has at least 50% enantiomeric excess in the (R)-or (S) -configuration, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.
  • tautomers or “tautomeric forms” refers to structural isomers with different energies that can be converted to each other through a low energy barrier. If tautomerization is possible (eg in solution), the chemical equilibrium of the tautomers can be reached.
  • protontautomers also known as prototropic tautomers
  • Valence tautomers include interconversions through the reorganization of some bonding electrons.
  • keto-enol tautomerism is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers.
  • tautomerism is phenol-keto tautomerism.
  • a specific example of phenol-keto tautomerization is the interconversion of pyridin-4-ol and pyridin-4 (1H) -one tautomers. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.
  • “Pharmaceutically acceptable” means those compounds, materials, compositions and / or dosage forms which, within the scope of sound medical judgment, are suitable for contact with patient tissues without excessive toxicity, irritation, allergies, or reasonableness The benefit / risk ratio is commensurate with other issues and complications and is effectively used for the intended purpose.
  • the compounds of the present invention may be optionally substituted with one or more substituents, such as the compounds of the general formula above, or like the specific examples, subclasses in the examples, and the present invention includes A class of compounds.
  • substituted means that one or more hydrogen atoms in a given structure are replaced with a particular substituent. Unless otherwise indicated, a substituted group may have one substituent substituted at each substitutable position of the group. When more than one position in the given structural formula can be substituted by one or more substituents selected from a specific group, the substituents may be substituted at the same or different positions.
  • unsubstituted means that the specified group is unsubstituted.
  • C 1-6 alkyl specifically refers to independently disclosed methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, and C 6 alkyl.
  • linking substituents are described.
  • the Markush variables listed for the group should be understood as the linking group.
  • the Marcus definition of the variable enumerates “alkyl” or “aryl”
  • the "alkyl” or “aryl” respectively Represents a connected alkylene or arylene group.
  • alkyl or "alkyl group” used in the present invention means a saturated straight or branched chain monovalent hydrocarbon group containing 1 to 20 carbon atoms, wherein the alkyl group may be optionally Is substituted with one or more substituents described herein. Unless otherwise specified, alkyl groups contain 1-20 carbon atoms. In one embodiment, the alkyl group contains 1-12 carbon atoms; in another embodiment, the alkyl group contains 1-6 carbon atoms; in yet another embodiment, the alkyl group contains 1 -4 carbon atoms; also in one embodiment, the alkyl group contains 1-3 carbon atoms. The alkyl group may be optionally substituted with one or more substituents described herein.
  • alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), n-propyl (n-Pr, -CH 2 CH 2 CH 3 ), Isopropyl (i-Pr, -CH (CH 3 ) 2 ), n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), isobutyl (i-Bu, -CH 2 CH (CH 3 ) 2 ), sec-butyl (s-Bu, -CH (CH 3 ) CH 2 CH 3 ), tert-butyl (t-Bu, -C (CH 3 ) 3 ), n-pentyl (-CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH (CH 3 ) CH 2 CH 2 CH 3 ), 3-pentyl (-CH (CH 2 CH 3 ) 2 ), 2-methyl 2-butyl (-C (CH 3 ) 2 ),
  • alkenyl refers to a straight-chain or branched monovalent hydrocarbon group containing 2-12 carbon atoms, at least one site of unsaturation, that is, a carbon-carbon sp 2 double bond, which includes “cis” and " Reverse ", or” E “and” Z ".
  • the alkenyl group contains 2-8 carbon atoms; in another embodiment, the alkenyl group contains 2-6 carbon atoms; in yet another embodiment, the alkenyl group contains 2 -4 carbon atoms.
  • the alkenyl group may be optionally substituted with one or more substituents described herein.
  • alkynyl refers to a straight or branched chain monovalent hydrocarbon group containing 2 to 12 carbon atoms, which has at least one site of unsaturation, that is, a carbon-carbon sp triple bond.
  • the alkynyl group contains 2-8 carbon atoms; in another embodiment, the alkynyl group contains 2-6 carbon atoms; in yet another embodiment, the alkynyl group contains 2 -4 carbon atoms.
  • alkynyl groups include, but are not limited to, ethynyl (-C ⁇ CH), propargyl (-CH 2 C ⁇ CH), 1-propynyl (-C ⁇ C-CH 3 ), and the like .
  • the alkynyl group may be optionally substituted with one or more substituents described herein.
  • alkoxy means that an alkyl group is connected to the rest of the molecule through an oxygen atom, wherein the alkyl group has the definition as described in the present invention. Unless otherwise specified, the alkoxy group contains 1-12 carbon atoms. In one embodiment, the alkoxy group contains 1-6 carbon atoms; in another embodiment, the alkoxy group contains 1-4 carbon atoms; in yet another embodiment, the alkoxy group The pellet contains 1-3 carbon atoms. The alkoxy group may be optionally substituted with one or more substituents described herein.
  • alkoxy groups include, but are not limited to, methoxy (MeO, -OCH 3 ), ethoxy (EtO, -OCH 2 CH 3 ), 1-propoxy (n-PrO, n- Propoxy, -OCH 2 CH 2 CH 3 ), 2-propoxy (i-PrO, i-propoxy, -OCH (CH 3 ) 2 ), 1-butoxy (n-BuO, n- Butoxy, -OCH 2 CH 2 CH 2 CH 3 ), 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH 2 CH (CH 3 ) 2 ), 2-but Oxy (s-BuO, s-butoxy, -OCH (CH 3 ) CH 2 CH 3 ), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC (CH 3 ) 3 ), 1-pentyloxy (n-pentyloxy, -OCH 2 CH 2 CH 2 CH 3 ), 2-pentyl
  • haloalkyl means an alkyl, alkenyl or alkoxy group substituted with one or more halogen atoms, such examples include, but are not limited to, Trifluoromethyl, trifluoroethyl, 2,2,3,3-tetrafluoropropyl, trifluoromethoxy and the like.
  • hydroxyalkyl used in the present invention means that an alkyl group is substituted with one or more hydroxyl groups, wherein the alkyl group has the definition as described in the present invention, and such examples include, but are not limited to, hydroxy Ethyl, 2-hydroxypropyl, hydroxymethyl, etc.
  • cycloalkyl refers to a monovalent saturated or partially unsaturated (but not aromatic) monocyclic or polycyclic hydrocarbon.
  • the cycloalkyl group can be a bridged or non-bridged, spiro or non-spiro, and / or fused or non-fused bicyclic group.
  • the cycloalkyl group includes 3-10 carbon atoms, ie, C 3 to C 10 cycloalkyl.
  • the cycloalkyl has 3-15 (C 3-15 ), 3-10 (C 3-10 ), or 3-7 (C 3-7 ) carbon atoms.
  • the cycloalkyl group is monocyclic or bicyclic. In some embodiments, the cycloalkyl group is monocyclic. In some embodiments, the cycloalkyl group is bicyclic. In some embodiments, the cycloalkyl group is tricyclic. In some embodiments, the cycloalkyl group is fully saturated. In some embodiments, the cycloalkyl group is partially saturated.
  • the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo [2.1.1] hexyl, bicyclo [2.2.1] heptyl, ten Hydronaphthyl, or adamantyl.
  • a cycloalkyl group When a cycloalkyl group is substituted, it may be on any ring, that is, on any aromatic or non-aromatic ring contained by the cycloalkyl group, and may be independently substituted with one or more substituents described herein.
  • heterocyclyl and “heterocyclic” are used interchangeably in this application and, unless otherwise stated, refer to a monovalent monocyclic nonaromatic ring system and / or polycyclic ring system containing at least one nonaromatic ring; where One or more of the non-aromatic monocyclic atoms (in certain embodiments, 1, 2, 3, or 4) are heteroatoms independently selected from O, S (O) 0-2, and N, and The remaining ring atoms are all carbon atoms; and wherein one or more of the ring atoms of the polycyclic ring system (in some embodiments, 1, 2, 3, or 4) are independently selected from O, S ( O) Heteroatoms of 0-2 and N, and the remaining ring atoms are all carbon atoms.
  • the heterocyclic ring contains 1 or 2 heteroatoms, each of which is a nitrogen atom.
  • the heterocyclyl is polycyclic and contains one heteroatom in a non-aromatic ring, or one heteroatom in an aromatic ring, or two heteroatoms in an aromatic ring, or two One of the heteroatoms is in the aromatic ring and the other is in the non-aromatic ring.
  • the heterocyclyl group has 3-20, 3-15, 3-10, 3-8, 4-7, or 5-6 ring atoms.
  • the heterocyclyl is a monocyclic, bicyclic, tricyclic, or tetracyclic system.
  • the heterocyclyl group can be a bridged or non-bridged, spiro or non-spiro, and / or fused or non-fused bicyclic group.
  • One or more nitrogen and sulfur atoms may be optionally oxidized, one or more nitrogen atoms may be optionally quaternized, and one or more carbon atoms may be optionally replace.
  • Some rings can be partially or fully saturated, or aromatic, provided that the heterocyclic ring is not fully aromatic.
  • the monocyclic and polycyclic heterocycles may be attached to the main structure at any heteroatom or carbon atom that results in a stable compound.
  • the polycyclic heterocyclic group may be connected to the main structure through any of its rings, including any aromatic ring or non-aromatic ring, regardless of whether the ring contains a hetero atom.
  • a heterocyclyl is a "heterocycloalkyl" which is 1) a saturated or partially unsaturated (but not aromatic) monovalent monocyclic group containing at least one ring heteroatom as described herein , Or 2) a saturated or partially unsaturated (but not aromatic) monovalent bicyclic group or tricyclic group, wherein at least one ring contains at least one heteroatom as described in the present invention.
  • heterocyclyl and heterocycloalkyl When heterocyclyl and heterocycloalkyl are substituted, they may be substituted on either ring, that is, on any aromatic or non-aromatic ring contained by heterocyclyl and heterocycloalkyl.
  • such heterocyclyls include, but are not limited to, ethylene oxide, azetidinyl, oxetanyl, thietyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuryl, tetrahydrothienyl, dihydrothienyl, 1,3-dioxopentyl , Dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetra
  • heterocyclic group examples include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolyl, 2-piperidine Keto, 3,5-dioxopiperidinyl and pyrimidinone.
  • sulfur atom in the heterocyclic group being oxidized examples include, but are not limited to, sulfolane, 1,1-dioxothiomorpholinyl.
  • the heterocyclyl group may be optionally substituted with one or more substituents described herein.
  • a heterocyclic group is a heterocyclic group consisting of 3-8 atoms, which means a saturated or partially unsaturated monocyclic ring containing 3-8 ring atoms, wherein at least one ring atom is selected from nitrogen and sulfur And oxygen atoms.
  • Ring sulfur atoms can be optionally oxidized to S-oxides.
  • the ring nitrogen atom can be optionally oxidized to an N-oxygen compound.
  • heterocyclic groups of 3-8 atoms include, but are not limited to: azetidinyl, oxetanyl, thietyl, pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolinyl , Pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuryl, tetrahydrothienyl, dihydrothienyl, 1,3-dioxcyclopentyl, disulfide Cyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine , Dioxanyl, dithiazyl, thiaxanyl, homopiperazinyl, homopiperidinyl,
  • Examples of the sulfur atom in the heterocyclic group being oxidized include, but are not limited to, sulfolane, 1,1-dioxothiomorpholinyl.
  • the 3-8 atom heterocyclic group may be optionally substituted with one or more substituents described in the present invention.
  • a heterocyclic group is a heterocyclic group composed of 3-6 atoms, and refers to a saturated or partially unsaturated monocyclic ring containing 3-6 ring atoms, wherein at least one ring atom is selected from nitrogen and sulfur. And oxygen atoms.
  • Ring sulfur atoms can be optionally oxidized to S-oxides.
  • the ring nitrogen atom can be optionally oxidized to an N-oxygen compound.
  • the 3-6 atom heterocyclic group may be optionally substituted with one or more substituents described in the present invention.
  • a heterocyclic group is a heterocyclic group consisting of 5-6 atoms, which means a saturated or partially unsaturated monocyclic ring containing 5-6 ring atoms, wherein at least one ring atom is selected from nitrogen, Sulfur and oxygen atoms.
  • Ring sulfur atoms can be optionally oxidized to S-oxides.
  • the ring nitrogen atom can be optionally oxidized to an N-oxygen compound.
  • heterocyclic groups of 5-6 atoms include, but are not limited to: pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolinolyl, pyrazolinyl, pyrazolyl, imidazolinyl, imidazolidine Group, tetrahydrofuryl, dihydrofuryl, tetrahydrothienyl, dihydrothienyl, 1,3-dioxocyclopentyl, dithiocyclopentyl, 2-oxopyrrolidyl, oxo-1,3 -Thiazolidinyl, sulfolane, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothianyl, piperidinyl, morpholinyl, thiomorpholine , Piperazinyl, dioxanyl, dithiazyl, thiaxanyl, 2-piperidone
  • spirocyclic group means that one ring originates from a special cyclic carbon on the other ring.
  • ring A and ring B share one carbon atom in two saturated ring systems, and they are called "spiro rings”.
  • Each ring in the spiro ring is either a carbocyclic or a heteroalicyclic.
  • Such examples include, but are not limited to, 2,7-diazaspiro [4.4] nonane-2-yl, 7-oxo-2-azaspiro [4.5] decane-2-yl, 4-aza Spiro [2.4] heptane-5-yl, 4-oxaspiro [2.4] heptane-5-yl, 5-azaspiro [2.4] heptane-5-yl, spiro [2.4] heptyl, spiro [4.4] Nonyl, 7-hydroxy-5-azaspiro [2.4] heptane-5-yl and the like.
  • spirobicyclyl means that a spirobicyclyl system has two points of attachment to the rest of the molecule, where spirobicyclyl has the definition as described herein.
  • spirobicyclo means that one ring originates from a particular cyclic carbon on the other ring. For example, as described above, ring A and ring B share one carbon atom in two saturated ring systems, and are called "spiro rings”.
  • each ring system contains one or more heteroatoms, wherein each ring system contains 3-7 membered rings, that is, contains 1-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S , Where S or P is optionally substituted with one or more oxygen atoms to obtain groups such as SO, SO 2 , PO, PO 2 , such examples include, but are not limited to 4-azaspiro [2.4] Heptane-5-yl, 4-oxaspiro [2.4] heptane-5-yl, 5-azaspiro [2.4] heptane-5-yl, 7-hydroxy-5-azaspiro [2.4] heptane Alk-5-yl, 2,6-diazaspiro [3.3] heptane, 2,6-diazaspiro [3.4] octane, 1,6-diazaspiro [3.4] octane, 2, 7-diazaspiro [3.5] nonane, 1,7-di
  • bridged ring group used in the present invention means a saturated or unsaturated bridged ring system, and refers to a non-aromatic bridged ring system, as shown in formula (a2), that is, ring A1 and ring A2 share an alkane chain or a heterocyclic Alkanes, where j is 1, 2, 3 or 4.
  • Such a system may contain an independent or conjugated unsaturated state, but its core structure does not contain an aromatic ring or an aromatic heterocyclic ring (but an aromatic can be used as a substituent thereon).
  • Each of the bridged rings is either a carbocyclic or heteroalicyclic.
  • bicyclic [2.2.1] heptane 2-azabicyclo [2.2.1] heptane, 1,2,3,4,4a, 5,8,8a-octahydronaphthalene, these are included in the fused bicyclic or bridged ring system.
  • bridged heterocyclyl refers to a saturated or unsaturated bridged ring system and relates to a non-aromatic bridged ring system. Such a system may contain an independent or conjugated unsaturated state, but its core structure does not contain an aromatic ring or an aromatic heterocyclic ring (but an aromatic can be used as a substituent thereon).
  • each ring system contains one or more heteroatoms, wherein each ring system contains 3-7 membered rings, that is, contains 1-6 carbon atoms and 1-3 heteroatoms selected from N, O, P, S , Where S or P is optionally substituted with one or more oxygen atoms to obtain groups such as SO, SO 2 , PO, PO 2 , such examples include, but are not limited to, 2-azabicyclo [2.2. 1] heptane, (1R, 5S) -3,6-diazabicyclo [3.1.1] heptane, 2,5-diazabicyclo [2.2.1] heptane, (1R, 5S) -8 -Azabicyclo [3.2.1] octane and the like.
  • spiro bridge ring group means that one ring originates from a special cyclic carbon on another bridge ring.
  • ring A and bridged ring B share one carbon atom in two saturated ring systems.
  • spiro bridged rings they are called "spiro bridged rings”.
  • Each ring in a helical bridge ring is either a carbocyclic or a heteroalicyclic.
  • Such examples include, but are not limited to (1R, 5S) -spiro [bicyclo [3.2.1] octane-3,1'-cyclobutane], (1'R, 5'S) -8'-azaspiro [Azetane-3,3'-bicyclo [3.2.1] octane], (1R, 5S) -3-azaspiro [Bicyclo [3.2.1] octane-8,1'-cyclobutane Alkane], (1'R, 5'S) -3'-azaspiro [azetidine-3,8'-bicyclo [3.2.1] octane], etc.
  • connection points in the ring system connected to the rest of the molecule there are two connection points in the ring system connected to the rest of the molecule, as shown in formula (a4) or (a5), which means that either the E-terminus or the E'-end is connected to the rest of the molecule That is, the connection methods at both ends can be interchanged.
  • n typically describes the number of ring-forming atoms in a molecule, and the number of ring-forming atoms in the molecule is n.
  • piperidinyl is a 6 atom heterocycloalkyl group
  • 1,2,3,4-tetrahydronaphthalene is a 10 atom cycloalkyl group.
  • unsaturated means that the group contains one or more degrees of unsaturation.
  • heteroatom refers to O, S, N, P, and Si, including any oxidation state of N, S, and P; forms of primary, secondary, tertiary amines, and quaternary ammonium salts; or Hydrogen-substituted forms, for example, N (like N in 3,4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR (like N-substituted pyrrolidin NR).
  • halogen refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).
  • aryl refers to a monovalent C 6 -C 14 carbocyclic ring system containing at least one aromatic ring, wherein the aromatic ring system is monocyclic, bicyclic, or tricyclic .
  • the aryl group may be connected to the main structure through any ring thereof, that is, any aromatic ring or non-aromatic ring.
  • aryl is phenyl, naphthyl, bicyclo [4.2.0] oct-1,3,5-trienyl, indanyl, fluorenyl, or tetrahydronaphthyl.
  • aryl is phenyl, naphthyl, tetrahydronaphthyl, fluorenyl, or indanyl; the phenyl, naphthyl, tetrahydronaphthyl, fluorenyl, and indanyl
  • Each optionally substituted by the aryl group may be independently optionally substituted with one or more substituents described herein, and in some embodiments, includes independently selected from D, F, Cl, Br, I, N 3 , CN, NO 2 , OH, SH, NH 2 , alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, alkylamino, hydroxyalkyl, cyano-substituted alkyl, naphthenic Group, heterocycly
  • arylene used in the present invention means a divalent aryl group obtained by removing two hydrogen atoms from an aryl group, wherein the aryl group has the definition described in the present invention.
  • heteroaryl refers to a monovalent monocyclic or polycyclic aromatic group, wherein said at least one (in certain embodiments, 1, 2, 3, or 4)
  • a ring atom is a heteroatom independently selected from O, S (O) 0-2 and N in the ring.
  • the heteroaryl group is connected to the rest of the molecule through the valence rules of any atom in the ring system.
  • each ring of a heteroaryl group may contain 1 or 2 O atoms, 1 or 2 S atoms, and / or 1 to 4 N atoms, or a combination thereof, provided that each ring The total number of heteroatoms is 4 or less, and each ring contains at least 1 carbon atom.
  • the heteroaryl has 5-20, 5-15, or 5-10 ring atoms. When a heteroaryl group is substituted, it may be substituted on either ring.
  • monocyclic heteroaryl groups include, but are not limited to, furyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, Pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl and triazolyl.
  • bicyclic heteroaryl groups include, but are not limited to, benzofuryl, benzimidazolyl, benzoisoxazolyl, benzopyranyl, benzothiadiazolyl, benzo Thiazolyl, benzothienyl, benzotriazolyl, benzoxazolyl, furanopyridyl, imidazopyridyl, imidazothiazolyl, indazinyl, indolyl, indazolyl, isobenzo Furyl, isobenzothienyl, isoindolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, oxazolopyridyl, phthalazinyl, pteridyl, purinyl, pyridopyridyl, pyrrole Pyridyl, quinolyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimi
  • tricyclic heteroaryl groups include, but are not limited to, acridinyl, benzoindolyl, carbazolyl, dibenzofuranyl, pyridinyl, phenanthroline, phenanthridine And phenazinyl.
  • the heteroaryl is phenylene, naphthylene, pyridylene, pyrimidinyl, pyrazidinyl, pyridazinyl, thiazolyl, benzothiazolyl, benzo [ d] isothiazolyl, imidazo [1,2-a] pyridyl, quinolinyl, 1H-indolyl, pyrrolo [1,2-b] pyridazinyl, benzofuranyl, benzo [b ] Thienyl, 1H-indazolyl, benzo [d] isoxazolyl, quinazolinyl, 1H-pyrrolo [3,2-c] pyridyl, pyrazolo [1,5-a] pyrimidine , Imidazo [1,2-b] pyridazinyl, or pyrazolo [1,5-a] pyridinyl; each of which is optionally defined throughout 1, 2,
  • heteroarylene used in the present invention refers to a divalent heteroaryl group obtained by removing two hydrogen atoms from a heteroaryl group, wherein the heteroaryl group has the definition described in the present invention.
  • alkylamino includes “N-alkylamino” and "N, N-dialkylamino", wherein the amino groups are each independently substituted with one or two alkyl groups. Some of these examples are that the alkylamino group is a lower alkylamino group having one or two C1-6 alkyl groups attached to a nitrogen atom. In other embodiments, the alkylamino group is a lower alkylamino group of C1-3 .
  • Suitable alkylamino groups may be monoalkylamino or dialkylamino, such examples include, but are not limited to, N-methylamino, N-ethylamino, N, N-dimethylamino, N, N -Diethylamino and so on.
  • cyano-substituted alkyl includes C1-10 straight or branched chain alkyl groups substituted with one or more cyano groups.
  • the cyano-substituted alkyl is a C 1-6 "lower cyanoalkyl” substituted with one or more cyano groups
  • the cyano-substituted Alkyl is C 1-4 "lower cyanoalkyl” substituted by one or more cyano groups, examples of which include, but are not limited to, CNCH 2- , CNCH 2 CH 2- , CNCH 2 CH 2 CH 2- , CNCH 2 CHCNCH 2 -and so on.
  • a substituent is a ring system formed by a bond to the central ring (as shown in the figure below) to represent that the substituent may be substituted at any substitutable position on any ring.
  • formula b represents any position that may be substituted on ring A or ring B, such as formula c, d, e, f, g, h, i, j, k, l, m, n, o, p, q and so on.
  • prodrug used in the present invention represents the conversion of a compound into a compound represented by formula (I) in vivo. Such transformations are affected by the prodrug's hydrolysis in the blood or the enzyme's conversion into the parent structure in the blood or tissues.
  • the prodrug compound of the present invention may be an ester.
  • the ester can be used as a prodrug of phenyl esters, aliphatic (C 1 -C 24 ) esters, acyloxymethyl esters, carbonic acid. Esters, carbamates and amino acid esters.
  • a compound in the present invention contains a hydroxyl group, which can be acylated to obtain a compound in the form of a prodrug.
  • prodrug forms include phosphate esters.
  • these phosphate ester compounds are obtained by phosphorylation of hydroxy groups on the parent.
  • prodrugs refer to the following literature: T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the ACSSymposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J.
  • Metal refers to a product obtained by metabolizing a specific compound or a salt thereof in the body.
  • the metabolites of a compound can be identified by techniques well known in the art, and its activity can be characterized by experimental methods as described in the present invention. Such products can be obtained by administering a compound through oxidation, reduction, hydrolysis, amidolation, deamidation, esterification, degreasing, enzymatic cleavage, and the like.
  • the invention includes metabolites of a compound, including metabolites produced by sufficient contact of a compound of the invention with a mammal for a period of time.
  • “Pharmaceutically acceptable salt” as used in the present invention refers to organic and inorganic salts of the compounds of the present invention.
  • Pharmaceutically acceptable salts are well known in the art, as described in the literature: SMBerge et al., Describe acceptable acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19.
  • Salts formed from pharmaceutically acceptable non-toxic acids include, but are not limited to, inorganic acid salts such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, formed by reaction with amino groups, And organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or other methods described in the book literature such as ion exchange method These salts.
  • inorganic acid salts such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, formed by reaction with amino groups
  • organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or other methods described in the book literature such as ion exchange method These salts.
  • salts include adipate, alginate, ascorbate, aspartate, besylate, benzoate, bisulfate, borate, butyrate, and camphoric acid Salt, camphor sulfonate, cyclopentylpropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerol phosphate Salt, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodate, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, Malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pipate, pectate, persulfate, 3 -Phen
  • Salts obtained by reaction with a suitable base include salts of alkali metals, alkaline earth metals, ammonium and N + (C 1 -C 4 alkyl) 4 .
  • the present invention also contemplates the formation of quaternary ammonium salts of any compound containing a group of N.
  • Water-soluble or oil-soluble or dispersed products can be obtained by quaternization.
  • Alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • the pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations formed by anti- counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C 1 -8 sulfonates and aromatic sulfonates.
  • solvate of the present invention means an association formed by one or more solvent molecules and a compound of the present invention.
  • Solvent-forming solvents include, but are not limited to, water, isopropanol, ethanol, methanol, dimethylsulfoxide, ethyl acetate, acetic acid, and aminoethanol.
  • hydrate refers to an association formed by the solvent molecules being water.
  • the term "hydrate” may be used.
  • one molecule of the compound of the present invention may be combined with one water molecule, such as monohydrate; in other embodiments, one molecule of the compound of the present invention may be combined with more than one water molecule, such as dihydrate In some embodiments, one molecule of the compound of the present invention can be combined with less than one water molecule, such as a hemihydrate. It should be noted that the hydrates described herein retain the biological effectiveness of the compounds in a non-hydrated form.
  • any disease or disorder as used herein in some embodiments refers to ameliorating the disease or disorder (ie, slowing or preventing or reducing the development of the disease or at least one clinical symptom thereof). In other embodiments, “treating” refers to alleviating or improving at least one physical parameter, including a physical parameter that may not be perceived by the patient. In other embodiments, “treatment” refers to modulating a disease or condition physically (e.g., stabilizing a perceptible symptom) or physiologically (e.g., a parameter that stabilizes the body) or both. In other embodiments, “treating” refers to preventing or delaying the onset, occurrence or worsening of a disease or disorder.
  • the spiral bridge compound provided by the present invention has a good agonistic activity on FXR, and can be used for preparing and treating diseases mediated by FXR, including non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, chronic intrahepatic or extrahepatic Cholestasis disorders, drugs for liver fibrosis caused by chronic cholestasis disorders or acute intrahepatic cholestasis, chronic hepatitis B, gallstones, liver cancer, colon cancer, or intestinal inflammatory diseases.
  • diseases mediated by FXR including non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, chronic intrahepatic or extrahepatic Cholestasis disorders, drugs for liver fibrosis caused by chronic cholestasis disorders or acute intrahepatic cholestasis, chronic hepatitis B, gallstones, liver cancer, colon cancer, or intestinal inflammatory diseases.
  • the invention provides a compound comprising a compound represented by formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer of a compound represented by formula (I) Body, nitrogen oxide, metabolite, prodrug, or mixture:
  • A is C or N
  • P is C (R a ), N, N (R b ), or O;
  • Q is C (R a ), N, N (R b ), or O;
  • M is C or N
  • R 1 is H, F, Cl, Br, I, -CN, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl, wherein R 1 is independently optionally Is replaced by 1, 2, 3 or 4 R 5 ;
  • R 2 is aryl, heteroaryl, cycloalkyl, or heterocyclyl, wherein R 2 is independently optionally substituted with 1, 2, 3, or 4 R 6 ;
  • R 3a and R 3b are each independently H, F, Cl, Br, I, CN, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkylamino, C 1-6 alkoxy Group, halo C 1-6 alkoxy, C 3-6 cycloalkyl, or halo C 3-6 cycloalkyl, or R 3a , R 3b together with the carbon atom to which they are attached form C 3-6 Cycloalkyl, C 3-6 cycloalkenyl, or heterocyclic group consisting of 3-6 atoms; wherein the C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C A 3-6 cycloalkyl group, a C 3-6 cycloalkenyl group, and a 3-6 atom heterocyclic group are independently optionally substituted with 1, 2, 3, or 4 R 7 ;
  • X is:
  • X is independently optionally substituted by 1, 2, 3 or 4 R 8 ;
  • X 2 , X 3 and X 4 are each independently -O-, -S-, -NH-,-(CH 2 ) m1 -NH- (CH 2 ) m2 -,-(CH 2 ) m1 -O- ( CH 2) m2 -, - ( CH 2) m1 -S- (CH 2) m2 -, or - (CH 2) m3 -;
  • Z is an arylene, heteroarylene, or heterocyclic group, wherein Z is independently optionally substituted with 1, 2, 3, or 4 R 10 ;
  • Each R 4a is independently H, alkyl, alkenyl, alkynyl, haloalkyl, cyano-substituted alkyl, hydroxyalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, ring Alkyl, cycloalkylalkyl, heterocyclyl, or heterocyclylalkyl; wherein R 4a is independently optionally substituted with 1, 2, 3, or 4 R 4b ;
  • Each R 11 is independently H, OH, NH 2 , alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, cyano-substituted alkyl, alkoxy, haloalkoxy, aryl, aralkyl , Heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, or heterocyclylalkyl; wherein R 11 is independently optionally selected by 1, 2, 3, or 4 R 11a replaced;
  • Each R 12a and R 12b is independently H, alkyl, alkenyl, alkynyl, haloalkyl, cyano-substituted alkyl, hydroxyalkyl, aryl, aralkyl, heteroaryl, heteroarylalkane Group, cycloalkyl, cycloalkylalkyl, heterocyclyl, or heterocyclylalkyl; wherein R 12a and R 12b are each independently optionally substituted with 1, 2, 3, or 4 R 11b ;
  • Each R 13 is independently alkylene, alkenylene, alkynylene, hydroxyalkyl, cyano-substituted alkylene, or haloalkylene;
  • Each R 4b , R 11a and R 11b is independently H, -CN, -NO 2 , -OH, -NH 2 , F, Cl, Br, I, C 1-6 alkyl, C 2-6 alkenyl , C 2-6 alkynyl, halo C 1-6 alkyl, cyano substituted C 1-6 alkyl, C 1-6 hydroxyalkyl, or C 1-6 alkoxy;
  • Each R 1a and R b is independently H, alkyl, alkenyl, alkynyl, cyano-substituted alkyl, hydroxyalkyl, or haloalkyl;
  • Each R a is independently H, -CN, -NO 2 , -OH, -NH 2 , F, Cl, Br, I, alkyl, alkenyl, alkynyl, haloalkyl, cyano-substituted alkyl, Hydroxyalkyl, alkoxy, or haloalkoxy;
  • R 14 , R 14a , R 15 , R 15a , and R 16 is independently H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halo C 1-6 alkane Alkyl, cyano-substituted C 1-6 alkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, or heterocyclylalkyl ;
  • Each R 16a , R 17 , and R 17a is independently H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, cyano-substituted C 1-6 alkyl, or Halogenated C 1-6 alkyl;
  • Each m1 is independently 0, 1, 2 or 3;
  • Each m2 is independently 0, 1, 2 or 3;
  • Each m3 is independently 0, 1, 2, or 3.
  • X is
  • X is independently optionally substituted by 1, 2, 3 or 4 R 8 ;
  • Each R 1a is independently H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, cyano-substituted C 1-4 alkyl, C 1-4 hydroxyalkyl, or Halo C 1-4 alkyl;
  • a 0, 1, 2 or 3;
  • b 0, 1, 2 or 3;
  • c 0, 1, 2 or 3.
  • P 1 is N or -C (R a )-;
  • Q 1 is O, or -N (R b )-;
  • R a is H, -CN, -NO 2 , -OH, -NH 2 , F, Cl, Br, I, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halo C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, or halo C 1-4 alkoxy; and
  • R b is H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, cyano substituted C 1-4 alkyl, C 1-4 hydroxyalkyl, or halogenated C 1 -4 alkyl.
  • the compound has a structure represented by formulae (II)-(IV):
  • Z is C 6-10 arylene, C 1-9 heteroarylene, or C 2-7 heterocyclylene, wherein Z is independently optionally 1, 2, 3, or 4 R 10 is replaced.
  • Z is phenylene, naphthylene, pyridylene, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, benzothiazolyl, benzo [d] iso Thiazolyl, imidazo [1,2-a] pyridyl, naphthyl, quinolinyl, 1H-indolyl, pyrrolo [1,2-b] pyridazinyl, benzofuranyl, benzo [b ] Thienyl, 1H-indazolyl, benzo [d] isoxazolyl, quinazolinyl, 1H-pyrrolo [3,2-c] pyridyl, pyrazolo [1,5-a] pyrimidine Group, imidazo [1,2-b] pyridazinyl, or pyrazolo [1,5-a] pyridyl, or Z is one of the following sub-structure formula
  • Z is independently optionally substituted by 1, 2, 3 or 4 R 10 .
  • the compound has a structure represented by any one of formulae (II1a)-(II1e) and (III1a)-(III1d):
  • Z 1 is N or C (R 10 );
  • Each Z 2 is independently O, S, N (R 10 ), or -CHR 10- ;
  • Each Z 3 is independently N or C (R 10 );
  • Z 4 and Z 5 are each independently N, or C (R 10 );
  • n 0, 1, 2 or 3;
  • c 0, 1, 2 or 3.
  • the compound has a structure represented by any one of formulae (IIa)-(IIe) and (IIIa)-(IIId):
  • Z 1 is N or C (R 10 );
  • Each Z 2 is independently O, S, N (R 10 ), or -CHR 10- ;
  • Each Z 3 is independently N or C (R 10 );
  • Z 4 and Z 5 are each independently N, or C (R 10 );
  • n 0, 1, 2 or 3.
  • R 1 is H, F, Cl, Br, I, -CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl , C 1-9 heteroaryl, C 3-8 cycloalkyl, or C 3-7 heterocyclyl, wherein said R 1 is independently optionally substituted with 1, 2, 3 or 4 R 5 .
  • R 1 is phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, isopropyl, or tert-butyl, wherein R 1 is independently optionally 1, 2 , 3 or 4 R 5 substitutions.
  • R 2 is C 6-10 aryl, C 1-9 heteroaryl, C 3-8 cycloalkyl, or C 3-7 heterocyclyl, wherein said R 2 is independently optional Ground is replaced by 1, 2, 3 or 4 R 6 .
  • R 2 is phenyl, or C 1-9 heteroaryl, wherein said R 2 is independently optionally substituted with 1, 2, 3, or 4 R 6 .
  • R 2 is:
  • R 2 is independently optionally substituted with 1, 2, 3 or 4 R 6 .
  • Each R 1a is independently H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, cyano-substituted C 1-4 alkyl, C 1-4 hydroxyalkyl, or halo Substituted C 1-4 alkyl.
  • each R 4a is independently H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halo C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 hydroxyalkyl, C 6-10 aryl, C 6-10 aryl C 1-4 alkyl, C 1-9 heteroaryl, C 1-9 heteroaryl C 1-4 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl C 1-4 alkyl, C 3-7 heterocyclyl, or C 3-7 heterocyclyl C 1-4 alkyl Group; wherein R 4a is independently optionally substituted with 1, 2, 3 or 4 R 4b .
  • each R 11 is independently H, OH, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halo C 1-4 alkyl , Cyano-substituted C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, halo C 1-4 alkoxy, C 6-10 aryl, C 6-10 aryl C 1-4 alkyl, C 1-9 heteroaryl, C 1-9 heteroaryl C 1-4 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl C 1-4 alkyl , C 3-7 heterocyclyl, or C 3-7 heterocyclyl C 1-4 alkyl; wherein R 11 is independently optionally substituted with 1, 2, 3, or 4 R 11a .
  • each of R 12a and R 12b is independently H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halo C 1-4 alkyl, cyano C 1-4 alkyl, C 1-4 hydroxyalkyl, C 6-10 aryl, C 6-10 aryl C 1-4 alkyl, C 1-9 heteroaryl, C 1-9 Heteroaryl C 1-4 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl C 1-4 alkyl, C 3-7 heterocyclyl, or C 3-7 heterocyclyl C 1 -4 alkyl; wherein R 12a and R 12b are each independently optionally substituted with 1, 2, 3 or 4 R 11b .
  • each R 13 is independently C 1-6 alkylene, C 1-6 alkenylene, C 1-6 alkynylene, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkylene, or halogenated C 1-6 alkylene.
  • each of R 4b , R 11a and R 11b is independently H, -CN, -NO 2 , -OH, -NH 2 , F, Cl, Br, I, methyl, ethyl, Propyl, butyl, methoxy, ethoxy, -CH 2 CH 2 CN, -CH 2 CH 2 OH, -CF 3 , or -CH 2 CF 3 .
  • Each R 4a is independently H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halo C 1-4 alkyl, cyano-substituted C 1-4 alkyl, C 1-4 hydroxyalkyl, C 6-10 aryl, C 6-10 aryl C 1-4 alkyl, C 1-9 heteroaryl, C 1-9 heteroaryl C 1-4 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl C 1-4 alkyl, C 3-7 heterocyclyl, or C 3-7 heterocyclyl C 1-4 alkyl; wherein R 4a is independently Is optionally substituted with 1, 2, 3 or 4 R 4b ;
  • Each R 11 is independently H, OH, NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halo C 1-4 alkyl, cyano-substituted C 1 -4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, halo C 1-4 alkoxy, C 6-10 aryl, C 6-10 aryl C 1-4 alkyl , C 1-9 heteroaryl, C 1-9 heteroaryl C 1-4 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl C 1-4 alkyl, C 3-7 hetero A cyclic group, or a C 3-7 heterocyclyl C 1-4 alkyl group; wherein R 11 is independently optionally substituted with 1, 2, 3 or 4 R 11a ;
  • Each R 12a and R 12b is independently H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halo C 1-4 alkyl, cyano-substituted C 1-4 Alkyl, C 1-4 hydroxyalkyl, C 6-10 aryl, C 6-10 aryl C 1-4 alkyl, C 1-9 heteroaryl, C 1-9 heteroaryl C 1-4 Alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl C 1-4 alkyl, C 3-7 heterocyclyl, or C 3-7 heterocyclyl C 1-4 alkyl; where R 12a and R 12b are each independently optionally substituted with 1, 2, 3 or 4 R 11b ;
  • Each R 13 is independently C 1-6 alkylene, C 1-6 alkenylene, C 1-6 alkynylene, C 1-6 hydroxyalkyl, cyano-substituted C 1-6 alkylene , Or halo C 1-6 alkylene;
  • Each of R 4b , R 11a and R 11b is independently H, -CN, -NO 2 , -OH, -NH 2 , F, Cl, Br, I, methyl, ethyl, propyl, butyl, methyl Oxy, ethoxy, -CH 2 CH 2 CN, -CH 2 CH 2 OH, -CF 3 , or -CH 2 CF 3 .
  • R 4b , R 11a and R 11b is independently H, -CN, -NO 2 , -OH, -NH 2 , F, Cl, Br, I, methyl, ethyl, propyl, butyl, methyl Oxy, ethoxy, -CH 2 CH 2 CN, -CH 2 CH 2 OH, -CF 3 , or -CH 2 CF 3 .
  • each R 4a is independently H, methyl, ethyl, propyl, butyl, phenyl, naphthyl, benzyl, C 1-9 heteroaryl, or C 1- 9 heteroaryl C 1-4 alkyl; wherein R 4a is independently optionally substituted with 1,2, 3, or 4 R 4b.
  • each R 11 is independently H, OH, NH 2 , methyl, ethyl, propyl, butyl, phenyl, naphthyl, benzyl, C 1-9 heteroaryl , Or C 1-9 heteroaryl C 1-4 alkyl; wherein R 11 is independently optionally substituted with 1, 2, 3, or 4 R 11a .
  • each of R 12a and R 12b is independently H, methyl, ethyl, propyl, butyl, phenyl, naphthyl, benzyl, C 1-9 heteroaryl, or C 1-9 heteroaryl C 1-4 alkyl; wherein R 12a and R 12b are each independently optionally substituted with 1, 2, 3 or 4 R 11b .
  • each R 13 is independently C 1-4 alkylene, C 1-4 alkenylene, C 1-4 alkynylene, C 1-4 hydroxyalkyl, cyano substituted C 1-4 alkylene, or halo C 1-4 alkylene.
  • each of R 4b , R 11a and R 11b is independently H, -CN, -NO 2 , -OH, -NH 2 , F, Cl, Br, I, methyl, ethyl , Propyl, butyl, methoxy, ethoxy, -CH 2 CH 2 CN, -CH 2 CH 2 OH, -CF 3 , or -CH 2 CF 3 .
  • Each R 4a is independently H, methyl, ethyl, propyl, butyl, phenyl, naphthyl, benzyl, C 1-9 heteroaryl, or C 1-9 heteroaryl C 1-4 Alkyl; wherein R 4a is independently optionally substituted with 1, 2, 3 or 4 R 4b ;
  • Each R 11 is independently H, OH, NH 2 , methyl, ethyl, propyl, butyl, phenyl, naphthyl, benzyl, C 1-9 heteroaryl, or C 1-9 heteroaryl C 1-4 alkyl; wherein R 11 is independently optionally substituted with 1, 2, 3 or 4 R 11a ;
  • Each R 12a and R 12b is independently H, methyl, ethyl, propyl, butyl, phenyl, naphthyl, benzyl, C 1-9 heteroaryl, or C 1-9 heteroaryl C 1-4 alkyl; wherein R 12a and R 12b are each independently optionally substituted with 1, 2, 3 or 4 R 11b ;
  • Each R 13 is independently C 1-4 alkylene, C 1-4 alkenylene, C 1-4 alkynylene, C 1-4 hydroxyalkyl, cyano-substituted C 1-4 alkylene , Or halo C 1-4 alkylene;
  • Each of R 4b , R 11a and R 11b is independently H, -CN, -NO 2 , -OH, -NH 2 , F, Cl, Br, I, methyl, ethyl, propyl, butyl, methyl Oxy, ethoxy, -CH 2 CH 2 CN, -CH 2 CH 2 OH, -CF 3 , or -CH 2 CF 3 .
  • R 3a and R 3b are each independently H, F, Cl, Br, I, CN, methyl, ethyl, propyl, butyl, haloC 1-4 alkyl, C 1-4 alkylamino, C 1-4 alkoxy, or halogenated C 1-4 alkoxy, or R 3a , R 3b together with the carbon atom to which they are attached form a C 3-6 cycloalkyl, C 3 -6 cycloalkenyl, or 3-6 atom heterocyclic group; wherein said C 1-4 alkoxy, C 1-4 alkylamino, C 3-6 cycloalkyl, C 3-6 cycloolefin And a heterocyclic group consisting of 3 to 6 atoms are independently optionally substituted with 1, 2, 3 or 4 R 7 .
  • each of R 14 , R 14a , R 15 , R 15a , and R 16 is independently H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, Halo C 1-4 alkyl, cyano substituted C 1-4 alkyl, C 6-10 aryl, C 6-10 aryl C 1-4 alkyl, C 1-9 heteroaryl, C 1 -9heteroaryl C 1-4 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl C 1-4 alkyl, C 3-7 heterocyclyl, or C 3-7 heterocyclyl C 1-4 alkyl.
  • each of R 16a , R 17 , and R 17a is independently H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, cyano-substituted C 1-4 alkyl, or halo C 1-4 alkyl.
  • Each of R 5 , R 6 , R 7 , R 8 , R 9 and R 10 is independently H, -CN, -NO 2 , -OH, -NH 2 , F, Cl, Br, I, methyl, ethyl Propyl, propyl, butyl, methoxy, ethoxy, propoxy, -CH 2 CN, -CH 2 OH, -CH 2 CH 2 CN, -CH 2 CH 2 OH, -CF 3 , -CH 2 CF 3 , -OCF 3 , or -OCH 2 CF 3 .
  • R 14 , R 14a , R 15 , R 15a , and R 16 is independently H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halo C 1-4 alkane Group, cyano-substituted C 1-4 alkyl, C 6-10 aryl, C 6-10 aryl C 1-4 alkyl, C 1-9 heteroaryl, C 1-9 heteroaryl C 1 -4 alkyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl C 1-4 alkyl, C 3-7 heterocyclyl, or C 3-7 heterocyclyl C 1-4 alkyl; with
  • Each R 16a , R 17 , and R 17a is independently H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, cyano-substituted C 1-4 alkyl, or Halo C 1-4 alkyl.
  • Each of R 5 , R 6 , R 7 , R 8 , R 9 and R 10 is independently H, -CN, -NO 2 , -OH, -NH 2 , F, Cl, Br, I, methyl, ethyl Propyl, propyl, butyl, methoxy, ethoxy, propoxy, -CH 2 CN, -CH 2 OH, -CH 2 CH 2 CN, -CH 2 CH 2 OH, -CF 3 , -CH 2 CF 3 , -OCF 3 , or -OCH 2 CF 3 .
  • the compound of the invention is a compound having one of the following structures:
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound according to the invention, and a pharmaceutically acceptable excipient, diluent, or carrier.
  • the pharmaceutical composition of the invention further comprises an additional therapeutic agent.
  • the composition of the present invention wherein the additional therapeutic agent is for treating dyslipidemia, cholestasis, estrogen-induced cholestasis, drug-induced cholestasis, primary biliary cirrhosis ( PBC), primary sclerosing cholangitis (PSC), progressive familial cholestasis (PFIC), alcohol-induced cirrhosis, cystic fibrosis, gallstone disease, liver fibrosis, atherosclerosis or diabetes, Especially drugs for type II diabetes.
  • the present invention provides the use of a compound of the present invention or a pharmaceutical composition of the present invention in the manufacture of a medicament for the prevention or treatment of a disease mediated by FXR in a mammal.
  • the FXR-mediated diseases include non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, chronic intrahepatic or extrahepatic cholestasis disorders, caused by chronic cholestasis disorders or acute intrahepatic cholestasis disorders Liver fibrosis, chronic hepatitis B, gallbladder stones, liver cancer, colon cancer, or inflammatory bowel disease.
  • a compound of the invention or a pharmaceutical composition thereof may be administered in combination with an additional therapeutic agent.
  • the uses of the invention include administering to a mammal an amount of a compound or pharmaceutical composition of the invention sufficient to achieve the treatment or prevention.
  • the compounds of the invention are generally administered in the form of a pharmaceutical composition.
  • the composition can be prepared in a manner well known in the pharmaceutical technology and comprises at least one compound according to the invention according to formula I, II, III, IV, IIa-IIc, IIIa-IIIc, II1a-II1c, or III1a-III1c.
  • the compounds of the invention are administered in a pharmaceutically effective amount.
  • the amount of a compound of the invention actually administered will generally be determined by the physician based on the circumstances including the condition to be treated, the route of administration chosen, the actual compound of the invention administered, the age, weight and response of the individual patient, the patient's symptoms Severity.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition can be formulated into a formulation suitable for a specific administration route, such as oral administration, parenteral administration, rectal administration, and the like.
  • the pharmaceutical composition of the present invention can be made in solid form (including but not limited to capsules, tablets, pills, granules, powders or suppositories) or liquid form (including but not limited to solutions, suspensions or Emulsion).
  • the pharmaceutical composition may be subjected to conventional pharmaceutical operations such as sterilization and / or may contain conventional inert diluents, lubricants or buffers and adjuvants such as preservatives, stabilizers, wetting agents, emulsifiers, buffers and the like.
  • liquid composition for oral administration pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing an inert diluent such as water or liquid paraffin can be used.
  • the compositions may also include materials other than diluents, and in some embodiments, wetting agents, sweeteners, or flavoring preparations.
  • composition for parenteral administration may be an emulsion or a sterile solution.
  • propylene glycol, polyethylene glycol, vegetable oils, especially olive oil or injectable organic esters can be used as a solvent or carrier, and in some embodiments, ethyl oleate is used as a solvent or carrier.
  • These compositions may also contain adjuvants, especially wetting agents, isotonic agents, emulsifiers, dispersants and stabilizers.
  • Sterilization can be performed in several ways, and in some embodiments, sterilization is performed by radiation or by heating using a bacteriological filter. They can also be prepared in the form of sterile solid compositions, which can be dissolved in sterile water or any other injectable sterile medium when used.
  • compositions for rectal administration are suppositories or rectal capsules which, in addition to the active ingredient, contain excipients such as cocoa butter, semi-synthetic glycerides or polyethylene glycols.
  • the composition provided by the present invention is a pharmaceutical composition or a single unit dosage form.
  • the pharmaceutical composition and single unit dosage form provided by the present invention comprise a prophylactic or therapeutically effective amount of one or more prophylactic or therapeutic agents (for example, a compound provided by the present invention or other prophylactic or therapeutic agents) and a typical one or A variety of pharmaceutically acceptable carriers or excipients.
  • prophylactic or therapeutic agents for example, a compound provided by the present invention or other prophylactic or therapeutic agents
  • pharmaceutically acceptable carriers or excipients for example, a compound provided by the present invention or other prophylactic or therapeutic agents
  • pharmaceutically acceptable means approved by a federal or state government regulatory agency or listed in the United States Pharmacopeia or other generally recognized pharmacopoeia for use in animals, especially for Human drugs.
  • carrier includes a diluent, adjuvant (e.g., Freund's adjuvant (complete and incomplete)), excipient, or vehicle administered with a therapeutic agent.
  • adjuvant e.g., Freund's adjuvant (complete and incomplete)
  • excipient or vehicle administered with a therapeutic agent.
  • Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like.
  • water can be used as a carrier.
  • Saline and dextrose solutions as well as glycerol solutions can also be used as liquid carriers, especially for injection solutions. Examples of suitable pharmaceutical carriers are described in Remington: The Science and Practice of Pharmacy; Pharmaceutical Press; 22 edition (September 15, 2012).
  • Typical pharmaceutical compositions and dosage forms contain one or more excipients.
  • suitable excipients are well known to those skilled in the pharmaceutical arts.
  • suitable excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, Glycerin monostearate, talc, sodium chloride, skimmed milk powder, glycerin, propylene, ethylene glycol, water, ethanol, etc.
  • the suitability of a particular excipient for incorporation into a pharmaceutical composition or dosage form depends on various factors well known in the art, including, but not limited to, the manner in which the dosage form is administered to a subject and the particular active ingredient in the dosage form.
  • the composition or single unit dosage form may also contain small amounts of wetting or emulsifying agents, or pH buffering agents.
  • compositions for oral administration contain an effective amount of a compound of the invention, which may be in the form of tablets, dragees, aqueous or oily suspensions, powders or granules, emulsions, hard or soft capsules or syrups Or tincture.
  • Compositions for oral use may be prepared according to any method known in the art of producing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, colorants, and preservatives. , Thereby providing a pharmacologically beautiful and palatable preparation. Tablets may contain the active ingredients and non-toxic, pharmaceutically acceptable excipients used in combination to produce the tablets.
  • inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate
  • granulating and disintegrating agents such as corn starch or alginic acid
  • binders such as starch, gelatin, or arabic Gums
  • lubricants such as magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated according to known techniques to delay their disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material can be used, such as glyceryl monostearate or glyceryl distearate.
  • the pharmaceutical composition or combination product of the present invention may be a unit dose of the active ingredient of about 1-1000 mg, or about 1-500 mg or about 1-250 mg or about 1-150 mg or about 0.5-100 mg or about 1-50 mg of active ingredient.
  • the therapeutically effective amount of a compound, pharmaceutical composition, or combination thereof depends on the species, weight, age, and health of the individual, the condition or disease to be treated, or the severity of the individual. A physician, clinician or veterinarian can easily determine the effective amount of each active ingredient necessary to prevent, treat, or inhibit the progression of a disease or disorder.
  • the above-mentioned dosage characteristics can be demonstrated by in vitro and in vivo tests using suitable mammals such as mice, rats, dogs, monkeys or isolated organs, tissues and preparations thereof.
  • the compounds of the present invention can be applied in the form of a solution in vitro, such as an aqueous solution; in vivo, such as in the form of a suspension or an aqueous solution, enterally, parenterally (preferably intravenously).
  • In vitro doses range from about 10-3 molar concentrations to 10-9 molar concentrations.
  • a therapeutically effective amount in vivo depends on the route of administration and is in the range of about 0.1-500 mg / kg or about 1-100 mg / kg.
  • the compounds of the invention may be administered simultaneously with, or before or after, one or more other therapeutic ingredients.
  • the compound of the present invention can be administered separately with the other ingredient by the same or different routes of administration, or both can be administered together in the same pharmaceutical composition.
  • the other therapeutic component is for the treatment of dyslipidemia, cholestasis, estrogen-induced cholestasis, drug-induced cholestasis, primary biliary cirrhosis (PBC), primary sclerosing bile ducts Drugs for inflammation (PSC), progressive familial cholestasis (PFIC), alcohol-induced cirrhosis, cystic fibrosis, gallstone disease, liver fibrosis, atherosclerosis or diabetes, especially type II diabetes.
  • the invention provides a compound of the invention or a pharmaceutical composition comprising a compound of the invention for use in medicine.
  • the invention provides a compound of the invention or a pharmaceutical composition comprising a compound of the invention for use in a medicament for the prevention and / or treatment of a disease mediated by FXR in a mammal.
  • the invention also relates to a compound of formula I, II, III, IV, IIa-IIe, IIIa-IIId, II1a-II1e, or III1a-III1d or a pharmaceutical composition containing said compound for use in the treatment of dietary fats and fat-soluble diets Gastrointestinal disorders with reduced vitamin intake, which can be treated by increasing intestinal levels of bile acids and phospholipids.
  • the invention provides a compound of the invention or a pharmaceutical composition comprising a compound of the invention for use in the preparation and prevention of and / or treatment of non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, chronic intrahepatic or Extrahepatic cholestasis, liver fibrosis caused by chronic cholestasis or acute intrahepatic cholestasis, chronic hepatitis B, gallbladder stones, liver cancer, colon cancer, or intestinal inflammatory diseases.
  • the compounds of the invention can be used to beneficially alter lipid characteristics, including but not limited to lowering total cholesterol levels, lowering LDL cholesterol levels, lowering VLDL cholesterol levels, increasing HDL cholesterol levels, and / or lowering triglycerides Level. Accordingly, the invention provides methods for treating FXR-mediated diseases, such as dyslipidemia and diseases associated with dyslipidemia, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the invention.
  • FXR-mediated diseases such as dyslipidemia and diseases associated with dyslipidemia
  • the compound or pharmaceutical composition is used to treat the following diseases: lipid and lipoprotein diseases, such as clinically marked hypercholesterolemia, hypertriglyceridemia, and atherosclerosis,
  • lipid and lipoprotein diseases such as clinically marked hypercholesterolemia, hypertriglyceridemia, and atherosclerosis
  • FXR beneficial effects of FXR: increase HDL cholesterol, decrease serum triglycerides, increase conversion of liver cholesterol to bile acid, increase clearance and metabolic conversion of VLDL and other lipoproteins in the liver.
  • the compound and pharmaceutical composition can be used for the preparation of a medicament, wherein the combined effects of FXR-targeted drugs on reducing lipids, anticholestasis, and anticellulosis can be used to treat liver steatosis and Related syndromes, such as non-alcoholic steatohepatitis (“NASH”), or for the treatment of cholestasis and fibrosis associated with alcohol-induced cirrhosis or viral hepatitis.
  • NASH non-alcoholic steatohepatitis
  • the present invention also relates to a compound of formula I, II, III, IV, IIa-IIe, IIIa-IIId, II1a-II1e, or III1a-III1d or a pharmaceutical composition containing said compound for the prevention of cardiovascular disease and post-traumatic Treatment, such as acute myocardial infarction, acute stroke, or thrombosis that appears as the end point of chronic obstructive atherosclerosis.
  • post-traumatic Treatment such as acute myocardial infarction, acute stroke, or thrombosis that appears as the end point of chronic obstructive atherosclerosis.
  • FXR and FXR agonists were evaluated. From these preliminary results, it seems that FXR agonists may also affect cancer cell lines (Niesor et al., Curr. Pharm. Des. 2001, 7 (4), 231-59) and vascular smooth muscle cells (VSMCs) (Bishop- Bailey et al., Proc. Natl. Acad. Sci. U.
  • the compounds of the present invention can be prepared by the methods described in the present invention, unless further specified, wherein the substituents are defined as formulae I, II, III, IV, IIa-IIe, IIIa-IIId, II1a-II1e , Or III1a-III1d.
  • the following reaction schemes and examples are provided to further illustrate the contents of the present invention.
  • Anhydrous tetrahydrofuran, dioxane, toluene, and diethyl ether were obtained by refluxing and drying the sodium metal.
  • Anhydrous dichloromethane and chloroform were obtained by refluxing drying with calcium hydride.
  • Ethyl acetate, petroleum ether, n-hexane, N, N-dimethylacetamide and N, N-dimethylformamide are dried before use by using anhydrous sodium sulfate.
  • reaction bottle is plugged with a suitable rubber stopper, and the substrate is injected through a syringe. Glassware is dry.
  • the column was a silica gel column.
  • Silica gel 300-400 mesh was purchased from Qingdao Ocean Chemical Plant.
  • 1 H NMR spectra were recorded using a Bruker 400MHz or 600MHz nuclear magnetic resonance spectrometer.
  • the 1 H NMR spectrum uses CDC1 3 , DMSO-d 6 , CD 3 OD, or acetone-d 6 as a solvent (in ppm), and uses TMS (0 ppm) or chloroform (7.26 ppm) as a reference standard.
  • TMS 0. ppm
  • chloroform 7.26 ppm
  • MS mass spectrometry
  • E 1 is selected from halogen, methanesulfonyloxy or p-toluenesulfonyloxy;
  • E 2 is selected from halogen;
  • R is selected from C 1-6 alkyl;
  • Pr 1 is selected from tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, p-methoxy benzyl group;
  • A, P, Q, M , R 1, R 2, R 3a, R 3b, R 11, R 12a, X, Y, Z each have the definition of the present invention.
  • E 1 is selected from halogen, methanesulfonyloxy or p-toluenesulfonyloxy;
  • E 2 is selected from halogen;
  • R is selected from C 1-6 alkyl;
  • Pr 1 is selected from tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, p-methoxy benzyl group;
  • A, P, Q, M , R 1, R 2, R 3a, R 3b, X, Y, Z each have the definition of the present invention.
  • Intermediate 2-1 and Intermediate 1-5 in the presence of a base such as triethylamine, N, N-diisopropylethylamine, potassium carbonate, cesium carbonate
  • Intermediate 2-2 can be obtained through a nucleophilic substitution reaction
  • Intermediate 2-1 and Intermediate 1-5 can be obtained by palladium-catalyzed coupling reaction to obtain Intermediate 2-2;
  • Intermediate 2-2 under acidic conditions such as three Fluoroacetic acid, hydrogen chloride), or palladium-catalyzed hydrogenation, or reaction with trimethyliodosilane to remove the protecting group Pr 1 to obtain intermediate 2-3;
  • intermediate 2-3 and intermediate 1-1 in a base such as Triethylamine, N, N-diisopropylethylamine, potassium carbonate, cesium carbonate, potassium tert-butoxide or sodium tert-butoxide
  • a base such as Triethylamine, N, N-diisopropylethylamine, potassium carbonate, cesium
  • Step 1) Preparation of (1R, 5S) -3-methylene-8-azabicyclo [3.2.1] octane-8-t-butyl formate (1-1)
  • Methyltriphenylphosphine bromide (4g, 11.2mmol) was dissolved in methyl tert-butyl ether (15ml), and potassium tert-butoxide (1.24g, 11.2mmol) was added at zero degrees. The color of the solution changed after the addition. It turns yellow and finishes after half an hour. After the addition, the mixture is warmed to room temperature and stirred for 5h, and then cooled to zero. Then (1R, 5S) -3-oxo-8-azabicyclo [3.2.1] octane-8 -A solution of tert-butyl formate (2 g, 8.88 mmol) in methyl tert-butyl ether, dripping in half an hour.
  • Step 5 Preparation of chloro 2,6-dichlorobenzaldehyde oxime (1-5)
  • Step 6) Preparation of 5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazole-4-carboxylic acid ethyl ester (1-6)
  • Step 7) Preparation of [5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazole 4-yl] methanol (1-7)
  • lithium tetrahydroaluminum 750 mg, 19.8 mmol
  • anhydrous THF 40 mL
  • the intermediate 1-6 4.15 g, 12.7
  • mmol of anhydrous THF solution 40 mL
  • Water (0.8 mL), 15% NaOH solution (0.8 mL), and water (2.4 mL) were added dropwise in this order.
  • Step 8) Preparation of 4- (chloromethyl) -5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazole (1-8)
  • Step 10) Preparation of 2-amino-4-fluorobenzo [d] thiazole-6-carboxylic acid methyl ester (1-10)
  • Step 12 (1R, 5S) -3 '- ⁇ [5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl] methoxy ⁇ -8-aza Preparation of spiro [bicyclo [3.2.1] octane-3,1'-cyclobutane] -8-t-butyl formate (1-12)
  • the aqueous layer was adjusted to a pH of about 10 with a 4M sodium hydroxide aqueous solution, and extracted with ethyl acetate (30 mL ⁇ 2). The layer was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and dried to give a yellow solid.
  • the obtained solid was dissolved in acetic acid (15 mL), and added dropwise to a mixed solution of acetic acid (12 mL), hydrochloric acid (0.76 mL), and paraformaldehyde (550 mg) at 95 ° C. After 30 minutes of addition, the reaction was continued for 1 hour.
  • Step 1) 2-((1R, 5S) -3 '-[((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methyl) (methyl ) Amino] -8-azaspiro [bicyclo [3.2.1] octane-3,1'-cyclobutane] -8-yl ⁇ -4-fluorobenzo [d] thiazole-6-carboxylic acid methyl ester preparation
  • Step 2 2-((1R, 5S) -3 '-[((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methyl) (methyl ) Amino] -8-azaspiro [Bicyclo [3.2.1] octane-3,1'-cyclobutane] -8-yl ⁇ -4-fluorobenzo [d] thiazole-6-carboxylic acid
  • AlphaScreen test Perkins-Elmer's hexahistidine detection kit is used to detect compounds that bind to co-activators of human farnesol receptor protein (hFXR) (SRC1-2), as follows:
  • Donor beads and acceptor beads total 30 ⁇ L / well;
  • the instrument reads the plate (homogeneous luminescence immunoassay system), and the EC 50 is processed by the data processing software GraphPad Prism5.
  • nM is nmol / L
  • A means EC 50 ⁇ 100 nM
  • B means 100 nM ⁇ EC 50 ⁇ 1000 nM
  • C means EC 50 > 1000 nM.
  • the compound of the present invention has very good agonistic activity on FXR, has excellent in vivo and in vitro pharmacological effects and pharmacokinetic properties, and has better clinical application prospects.

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Abstract

L'invention concerne un composé cyclique à pont spiro capable de moduler l'activité d'un récepteur farnésoïde X (FXR), une composition pharmaceutique associée, et l'utilisation du composé et de la composition pour traiter une maladie à médiation par FXR chez des mammifères, le composé ayant une structure représentée dans (I), ou un sel, un hydrate, un solvate, un stéréoisomère, un tautomère, un oxyde d'azote, un métabolite, un promédicament ou un mélange pharmaceutiquement acceptables de celui-ci.
PCT/CN2019/099219 2018-08-08 2019-08-05 Composé cyclique à pont spiro, composition pharmaceutique de celui-ci et son utilisation WO2020029908A1 (fr)

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CN112083113B (zh) * 2020-07-09 2021-06-15 苏州旭辉检测有限公司 一种螺环化合物的生物样品分析方法
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WO2018067704A1 (fr) * 2016-10-04 2018-04-12 Enanta Pharmaceuticals, Inc. Analogues de l'isoxazole en tant qu'agonistes de fxr et leurs procédés d'utilisation
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EP2545964A1 (fr) * 2011-07-13 2013-01-16 Phenex Pharmaceuticals AG Nouveaux composés se liant au fxr (nr1 h4) et modulant son activité
EP3034499A1 (fr) * 2014-12-17 2016-06-22 Gilead Sciences, Inc. Nouveaux composés de modulation (FXR NR1H4)
CN108218852A (zh) * 2016-12-15 2018-06-29 宁波百纳西药业有限公司 一种螺环化合物、其制备方法、组合物及用途
CN106632294A (zh) * 2016-12-15 2017-05-10 宁波百纳西药业有限公司 一种螺环化合物及其药物用途

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CN106146483A (zh) * 2015-04-23 2016-11-23 上海迪诺医药科技有限公司 杂环类法尼酯衍生物x受体调节剂
CN106946867A (zh) * 2016-01-06 2017-07-14 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
WO2018067704A1 (fr) * 2016-10-04 2018-04-12 Enanta Pharmaceuticals, Inc. Analogues de l'isoxazole en tant qu'agonistes de fxr et leurs procédés d'utilisation
WO2018081285A1 (fr) * 2016-10-26 2018-05-03 Enanta Pharmaceuticals, Inc. Dérivés d'isoxazole contenant de l'urée utilisés comme agonistes de fxr et leurs procédés d'utilisation
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