WO2020029908A1 - Spiro bridged ring compound, pharmaceutical composition thereof and use thereof - Google Patents

Spiro bridged ring compound, pharmaceutical composition thereof and use thereof 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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PCT/CN2019/099219
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French (fr)
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

A spiro bridged ring compound capable of modulating the activity of a farnesoid X receptor (FXR), a pharmaceutical composition thereof, and the use of the compound and the composition to treat an FXR-mediated disease in mammals, the compound having a structure shown in (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug or mixture thereof.

Description

螺桥环化合物、其药物组合物及其用途Spiral bridge compound, pharmaceutical composition and use thereof 发明领域Field of invention
本发明涉及药物化学领域，尤其涉及作为FXR受体调节剂的一类螺桥环化合物，包含所述化合物的药物组合物，以及使用所述化合物或组合物在治疗FXR介导的疾病的药物中的应用。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.
发明背景Background of the invention
法尼醇X受体(farnesoid X receptor,FXR)是具有配体活性的核受体超家族成员，最早于1995年由Forman等人在大鼠肝脏cDNA文库中克隆发现[Cell.1995；81(5):687-93]，因其转录活性可被超生理浓度的法尼酯衍生物增强而命名。1999年Parks、Makishima和Tang同时发现生理水平的胆汁酸(bile acid,BA)是FXR的内源性配体，因此FXR又称为BA受体[Science.1999；284,1362-1365]。FXR主要在肝脏和肠道中有高水平表达，在肾上腺以及肾脏屮也有一定水平的表达，另外在心脏、肺、脂肪组织和睾丸等器官中有较低水平的表达[Gene.2002；290:35-43]。Farnesoid X receptor (FXR) 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]. 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].
研究发现，FXR作为一种胆汁酸核受体，通过调控一系列基因的表达，参与了多种生理功能的调节，包括胆汁酸代谢、脂代谢、糖代谢等[Biochim Biophys Acta.2010；1802:363-372]。更重要地是，研究证实，FXR在保护肝脏和抑制肝癌的发生中发挥着关键的作用。FXR对肝脏的保护表现在多个方面，包括：维持胆汁酸的内稳态，抑制肝细胞凋亡，减少组织的氧化应激反应，降低肝脏的纤维化水平，抑制炎症反应，促进肝细胞再生等。具体来说，第一，FXR通过调控体内胆汁酸的正常水平来防御由胆汁酸过高造成的肝损伤；第二，FXR通过阻止肝细胞的凋亡及急性肝损伤造成的细胞坏死，促进肝脏的损伤修复；第三，FXR能通过降低肝星状细胞对TGF-β的敏感性从而抑制细胞外基质的分泌，减少纤维化的发生[J Pharmacol Exp Ther.2005；315:58-68]；第四，FXR可以通过调节NF-κB介导的肝脏的炎症反应从而抑制肝癌的发生及发展[Hepatology.2007；46:590-7]；第五，在肝脏受损的情况下，体内胆汁酸水平增加，从而激活体内FXR，促进肝脏的修复和再生[J Huazhong Univ Sci Technolog Med Sci,2010,30(1):55-60]；第六，FXR激活后可抑制胆固醇调节元件结合蛋白-1C(sterol regulatory element-binding protein-1C,SREBP-1C)和脂肪酸合成酶(fatty acid synthetase,FAS)的表达,增加肝细胞及脂肪细胞过氧化物酶体增生物激活受体(peroxisome proliferator activated receptor,PPAR)的表达，改善胰岛素抵抗，减少脂肪的合成，从而减少肝脏脂肪的沉积[Hepatol Int 2010；4:741-748]。FXR具有如此多的肝脏保护作用提示它可能是NAFLAD的潜在治疗靶点。Studies have found that 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. Specifically, first, 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-β [J Pharmacol ExpTher. 2005; 315: 58-68]; Fourth, FXR can inhibit the occurrence and development of liver cancer by regulating NF-κB-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 it may be a potential therapeutic target for NAFLAD.
近年来，诸多知名国际医药公司开展了FXR激动剂的研究，并且取得了一些突破性的进展，进一步证实了FXR激动剂治疗NAFLD的可行性。由Intercept制药公司开发的胆汁酸类FXR激动剂奥贝胆酸 (obeticholic acid,OCA)已经上市。吉利德科学所收购的由Phenex制药公司所研发的小分子FXR激动剂PX-104目前处于临床II期研究。FXR激动剂已经显示出显著的临床应用价值，有望使更多的患者受益，尤其是NAFLD患者。因此，FXR激动剂的研发具有广阔应用前景并且也是迫切需要的。In recent years, many well-known international pharmaceutical companies have carried out research on FXR agonists, 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.
本发明提供了一类新的螺桥环类化合物，其对FXR具有很好的激动活性。本发明化合物具有优异的药效、药代性质和/或毒理性质，具备较佳的临床应用前景。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.
发明概要Summary of invention
以下仅概括说明本发明的一些方面，但并不局限于此。这些方面和其他部分将在后面有更完整的说明。本说明书中所有参考文献均通过引用其整体并入本文。当本说明书公开内容与引用文献有差异时，以本说明书公开内容为准。The following only outlines some aspects of the present invention, but is not limited thereto. These and other sections are explained more fully later. All references in this specification are incorporated herein by reference in their entirety. When there is a discrepancy between the disclosure of this specification and the cited documents, the disclosure of this specification shall prevail.
本发明提供了能够调节法尼酯X受体(FXRs)活性的组合物和方法。一方面，本发明提供了作为FXR激动剂或部分激动剂的化合物。具体而言，本发明提供了一类新的对FXR具有很好的激动活性的化合物，可用于制备治疗由FXR介导的疾病，包括非酒精性脂肪性肝病，非酒精性脂肪肝炎，慢性肝内或肝外胆汁淤积病症，由慢性胆汁淤积病症或者急性肝内胆汁淤积病症导致的肝纤维化，慢性乙型肝炎，胆囊结石，肝癌，结肠癌，或者肠道炎性疾病的药物。本发明也提供了制备本发明所述化合物的方法，使用这些化合物治疗哺乳动物，尤其是人类的上述疾病的方法以及包含这些化合物的药物组合物。The present invention provides compositions and methods capable of modulating the activity of farnesyl X receptors (FXRs). In one aspect, the invention provides compounds that are FXR agonists or partial agonists. Specifically, 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.
一方面，本发明提供了一种新的螺桥环化合物，其包含式(I)所示化合物，或式(I)所示化合物的药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、氮氧化物、代谢物、前药、或混合物：In one aspect, 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:
Figure PCTCN2019099219-appb-000001
Figure PCTCN2019099219-appb-000001
其中，among them,
A为C或N；A is C or N;
P为C(R a)、N、N(R b)、或O； P is C (R a ), N, N (R b ), or O;
Q为C(R a)、N、N(R b)、或O； Q is C (R a ), N, N (R b ), or O;
M为C或N；M is C or N;
Figure PCTCN2019099219-appb-000002
为单键或双键；
Figure PCTCN2019099219-appb-000002
Single or double bond;
R 1为H、F、Cl、Br、I、-CN、烷基、烯基、炔基、芳基、杂芳基、环烷基、或杂环基，其中所述R 1独立任选地被1、2、3或4个R 5取代； 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为芳基、杂芳基、环烷基、或杂环基，其中所述R 2独立任选地被1、2、3或4个R 6取代； 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和R 3b各自独立地为H、F、Cl、Br、I、CN、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氨基、C 1-6烷氧基、卤代C 1-6烷氧基、C 3-6环烷基、或卤代C 3-6环烷基，或者R 3a、R 3b同与之连接的碳原子一起形成C 3-6环烷基、C 3-6环烯基、或3-6个原子组成的杂环基；其中所述C 1-6烷基、C 1-6烷氧基、C 1-6烷氨基、C 3-6环烷基、C 3-6环烯基、和3-6个原子组成的杂环基独立任选地被1、2、3或4个R 7取代； 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为：X is:
Figure PCTCN2019099219-appb-000003
Figure PCTCN2019099219-appb-000003
其中X独立任选地被1、2、3或4个R 8取代； Wherein X is independently optionally substituted by 1, 2, 3 or 4 R 8 ;
X 1不存在，或X 1为-N(R 1a)-、O、S、-C(＝O)-、-S(＝O)-、-S(＝O) 2-、-C(＝O)N(R 1a)-、-S(＝O)N(R 1a)-、或-S(＝O) 2N(R 1a)-； X 1 does not exist, or X 1 is -N (R 1a )-, O, S, -C (= O)-, -S (= O)-, -S (= O) 2- , -C (= O) N (R 1a )-, -S (= O) N (R 1a )-, or -S (= O) 2 N (R 1a )-;
X 2、X 3和X 4各自独立地为-O-、-S-、-NH-、-(CH 2) m1-NH-(CH 2) m2-、-(CH 2) m1-O-(CH 2) m2-、-(CH 2) m1-S-(CH 2) m2-、或-(CH 2) m3-； 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 -;
Y不存在，或Y为-N(R 1a)-、-O-、-S-、-C(＝O)-、-S(＝O)-、-S(＝O) 2-、-C(＝O)N(R 1a)-、-S(＝O)N(R 1a)-、-S(＝O) 2N(R 1a)-、C 1-6亚烷基、C 2-6亚烯基、C 2-6亚炔基、C 3-8亚环烷基、C 2-9亚杂环基、C 6-10亚芳基、或C 1-9亚杂芳基，其中Y独立任选地被1、2、3或4个R 9取代； Y does not exist, or Y is -N (R 1a )-, -O-, -S-, -C (= O)-, -S (= O)-, -S (= O) 2- , -C (= O) N (R 1a )-, -S (= O) N (R 1a )-, -S (= O) 2 N (R 1a )-, C 1-6 alkylene, C 2-6 Alkenylene, C 2-6 alkynylene, C 3-8 cycloalkylene, C 2-9 heterocyclylene, C 6-10 arylene, or C 1-9 heteroarylene, where Y Independently optionally substituted by 1, 2, 3 or 4 R 9 ;
Z为亚芳基、亚杂芳基、或亚杂环基，其中Z独立任选地被1、2、3或4个R 10取代； Z is an arylene, heteroarylene, or heterocyclic group, wherein Z is independently optionally substituted with 1, 2, 3, or 4 R 10 ;
R 4为杂芳基、-S(＝O) 0-2R 11、-C(＝O)R 11、-S(＝O) 1-2OR 4a、-OS(＝O) 1-2R 4a、-C(＝O)OR 4a、-OC(＝O)R 4a、-C(＝O)NR 12aR 12b、-S(＝O) 1-2NR 12aR 12b、-O-R 13-C(＝O)OR 4a、-O-R 13-S(＝O) 1-2OR 4a、-N(R 12a)-R 13-C(＝O)OR 4a、-C(＝O)N(R 12a)-R 13-OH、-C(＝O)N(R 12a)-R 13-NH 2、-C(＝O)N(R 12a)-R 13-C(＝O)OR 4a、-C(＝O)N(R 12a)-R 13-S(＝O) 1-2OR 4a、-C(＝O)N(R 12a)-S(＝O) 1-2R 11、-N(R 12a)C(＝O)NR 12aR 12b、-N(R 12a)S(＝O) 1-2NR 12aR 12b、-N(R 12a)C(＝O)N(R 12a)-S(＝O) 1-2R 11、或-OC(＝O)N(R 12a)-S(＝O) 1-2R 11； R 4 is heteroaryl, -S (= O) 0-2 R 11 , -C (= O) R 11 , -S (= O) 1-2 OR 4a , -OS (= O) 1-2 R 4a , -C (= O) OR 4a , -OC (= O) R 4a , -C (= O) NR 12a R 12b , -S (= O) 1-2 NR 12a R 12b , -OR 13 -C (= O) OR 4a , -OR 13 -S (= O) 1-2 OR 4a , -N (R 12a ) -R 13 -C (= O) OR 4a , -C (= O) N (R 12a ) -R 13 -OH, -C (= O) N (R 12a ) -R 13 -NH 2 , -C (= O) N (R 12a ) -R 13 -C (= O) OR 4a , -C (= O) N (R 12a ) -R 13 -S (= O) 1-2 OR 4a, -C (= O) N (R 12a) -S (= O) 1-2 R 11, -N ( R 12a ) C (= O) NR 12a R 12b , -N (R 12a ) S (= O) 1-2 NR 12a R 12b , -N (R 12a ) C (= O) N (R 12a ) -S (= O) 1-2 R 11 , or -OC (= O) N (R 12a ) -S (= O) 1-2 R 11 ;
各R 4a分别独立地为H、烷基、烯基、炔基、卤代烷基、氰基取代的烷基、羟烷基、芳基、芳烷基、杂芳基、杂芳基烷基、环烷基、环烷基烷基、杂环基、或杂环基烷基；其中R 4a独立任选地被1、2、3或4个R 4b取代； 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 ;
各R 11分别独立地为H、OH、NH 2、烷基、烯基、炔基、卤代烷基、羟烷基、氰基取代的烷基、烷氧基、卤代烷氧基、芳基、芳烷基、杂芳基、杂芳基烷基、环烷基、环烷基烷基、杂环基、或杂环基烷基；其中R 11独立任选地被1、2、3或4个R 11a取代； 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;
各R 12a和R 12b分别独立地为H、烷基、烯基、炔基、卤代烷基、氰基取代的烷基、羟烷基、芳基、芳烷基、杂芳基、杂芳基烷基、环烷基、环烷基烷基、杂环基、或杂环基烷基；其中R 12a和R 12b分别独立任选地被1、2、3或4个R 11b取代； 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 ;
各R 13分别独立地为亚烷基、亚烯基、亚炔基、羟烷基、氰基取代的亚烷基、或卤代亚烷基； Each R 13 is independently alkylene, alkenylene, alkynylene, hydroxyalkyl, cyano-substituted alkylene, or haloalkylene;
各R 4b、R 11a和R 11b分别独立地为H、-CN、-NO 2、-OH、-NH 2、F、Cl、Br、I、C 1-6烷基、C 2-6烯基、C 2-6炔基、卤代C 1-6烷基、氰基取代的C 1-6烷基、C 1-6羟烷基、或C 1-6烷氧基； 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;
各R 1a和R b分别独立地为H、烷基、烯基、炔基、氰基取代的烷基、羟烷基、或卤代烷基； Each R 1a and R b is independently H, alkyl, alkenyl, alkynyl, cyano-substituted alkyl, hydroxyalkyl, or haloalkyl;
各R a分别独立地为H、-CN、-NO 2、-OH、-NH 2、F、Cl、Br、I、烷基、烯基、炔基、卤代烷基、氰基取代的烷基、羟烷基、烷氧基、或卤代烷氧基； 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;
各R 5、R 6、R 7、R 8、R 9和R 10分别独立地为H、-CN、-NO 2、-OH、-NH 2、F、Cl、Br、I、烷基、烯基、炔基、卤代烷基、氰基取代的烷基、羟烷基、烷氨基、烷氧基、卤代烷氧基、环烷基、-S(＝O) 0-2R 14、-C(＝O)R 15、-OS(＝O) 1-2R 14a、-OC(＝O)R 15a、-N(R 16a)C(＝O)R 16、-OC(＝O)NR 17R 17a、-NR 17R 17a、-N(R 16a)S(＝O) 1-2R 16、或-N(R 16a)C(＝O)NR 17R 17a； 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, alkyl, alkene Alkyl, alkynyl, haloalkyl, cyano-substituted alkyl, hydroxyalkyl, alkamino, alkoxy, haloalkoxy, cycloalkyl, -S (= O) 0-2 R 14 , -C (= O) R 15 , -OS (= O) 1-2 R 14a , -OC (= O) R 15a , -N (R 16a ) C (= O) R 16 , -OC (= O) NR 17 R 17a , -NR 17 R 17a , -N (R 16a ) S (= O) 1-2 R 16 , or -N (R 16a ) C (= O) NR 17 R 17a ;
各R 14、R 14a、R 15、R 15a、和R 16分别独立地为H、C 1-6烷基、C 2-6烯基、C 2-6炔基、卤代C 1-6烷基、氰基取代的C 1-6烷基、芳基、芳烷基、杂芳基、杂芳基烷基、环烷基、环烷基烷基、杂环基、或杂环基烷基； Each of 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 ;
各R 16a、R 17、和R 17a和分别独立地为H、C 1-6烷基、C 2-6烯基、C 2-6炔基、氰基取代的C 1-6烷基、或卤代C 1-6烷基； 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;
各m1分别独立地为0、1、2或3；Each m1 is independently 0, 1, 2 or 3;
各m2分别独立地为0、1、2或3；和Each m2 is independently 0, 1, 2 or 3; and
各m3分别独立地为0、1、2或3。Each m3 is independently 0, 1, 2, or 3.
另一方面，本发明提供了一种药物组合物，所述药物组合物包含本发明所述的化合物或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、氮氧化物、代谢物、前药，以及药学上可以接受的辅料、稀释剂或载体。In another aspect, the present invention provides 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.
在一些实施方案，本发明所述的药物组合物进一步包含附加治疗剂。In some embodiments, the pharmaceutical composition of the invention further comprises an additional therapeutic agent.
另一方面，本发明提供了一种使用本发明所述的化合物或本发明所述的药物组合物在制备用于预防或治疗哺乳动物由FXR介导的疾病的药物中的用途。In another aspect, 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.
在一些实施方案，其中所述FXR介导的疾病包括非酒精性脂肪性肝病，非酒精性脂肪肝炎，慢性肝内或肝外胆汁淤积病症，由慢性胆汁淤积病症或者急性肝内胆汁淤积病症导致的肝纤维化，慢性乙型肝炎， 胆囊结石，肝癌，结肠癌，或者肠道炎性疾病。In some embodiments, wherein 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.
发明详述Detailed description of the invention
定义和一般术语Definitions and general terms
除非另外说明，本发明所使用的所有科技术语具有与本发明所属领域技术人员的通常理解相同的含义。本发明涉及的所有专利和公开出版物通过引用方式整体并入本发明。Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications related to the present invention are incorporated herein by reference in their entirety.
除非另有说明或者上下文中有明显的冲突，本文所使用的冠词“一”、“一个(种)”和“所述”旨在包括“至少一个”或“一个或多个”。因此，本文所使用的这些冠词是指一个或多于一个(即至少一个)宾语的冠词。例如，“一组分”指一个或多个组分，即可能有多于一个的组分被考虑在所述实施方案的实施方式中采用或使用。Unless otherwise stated or there is a clear conflict in context, the articles "a," "an," and "said" as used herein are intended to include "at least one" or "one or more". Thus, as used herein, these articles refer to the articles of one or more (ie, at least one) objects. For example, "a component" means one or more components, that is, more than one component may be considered for adoption or use in an embodiment of the described embodiment.
本发明所使用的术语“哺乳动物”是指，例如灵长类动物(例如人类，男性或女性)、牛、绵羊、山羊、马、猪、犬、猫、兔、大鼠、小鼠、鱼、鸟等。在某些实施方案中，所述哺乳动物是灵长类动物。在其他实施方案中，所述哺乳动物是人。The term "mammal" as used herein means, for example, a primate (e.g., human, male or female), cow, sheep, goat, horse, pig, dog, cat, rabbit, rat, mouse, fish , Birds, etc. In certain embodiments, the mammal is a primate. In other embodiments, the mammal is a human.
“立体异构体”是指具有相同化学构造，但原子或基团在空间上排列方式不同的化合物。立体异构体包括对映异构体、非对映异构体、构象异构体(旋转异构体)、几何异构体(顺/反)异构体、阻转异构体，等等。"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. .
“对映异构体”是指一个化合物的两个不能重叠但互成镜像关系的异构体。"Enantiomers" refer to two isomers of a compound that cannot overlap but mirror image each other.
“非对映异构体”是指有两个或多个手性中性并且其分子不互为镜像的立体异构体。非对映异构体具有不同的物理性质，如熔点、沸点、光谱性质和反应性。非对映异构体混合物可通过高分辨分析操作如电泳和色谱，例如HPLC来分离。"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.
本发明所使用的立体化学定义和规则一般遵循S.P.Parker，Ed.，McGraw-Hill Dictionary of Chemical Terms(1984)McGraw-Hill Book Company，New York；and Eliel，E.and Wilen，S.，“Stereochemistry of Organic Compounds”，John Wiley&Sons，Inc.，New York，1994。The stereochemistry definitions and rules used in the present invention generally follow SPParker, Ed., McGraw-Hill, Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds ", John Wiley & Sons, Inc., New York, 1994.
本发明公开化合物的任何不对称原子(例如，碳等)都可以以外消旋或对映体富集的形式存在，例如(R)-、(S)-或(R,S)-构型形式存在。在某些实施方案中，各不对称原子在(R)-或(S)-构型方面具有至少50％对映体过量，至少60％对映体过量，至少70％对映体过量，至少80％对映体过量，至少90％对映体过量， 至少95％对映体过量，或至少99％对映体过量。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. In certain embodiments, 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.
术语“互变异构体”或“互变异构形式”是指具有不同能量的可通过低能垒(low energy barrier)互相转化的结构异构体。若互变异构是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(protontautomer)(也称为质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。价键互变异构体(valence tautomer)包括通过一些成键电子的重组来进行的互相转化。酮-烯醇互变异构的具体实例是戊烷-2,4-二酮和4-羟基戊-3-烯-2-酮互变异构体的互变。互变异构的另一个实例是酚-酮互变异构。酚-酮互变异构的一个具体实例是吡啶-4-醇和吡啶-4(1H)-酮互变异构体的互变。除非另外指出，本发明化合物的所有互变异构体形式都在本发明的范围之内。The term "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. For example, protontautomers (also known as prototropic tautomers) include interconversions via proton migration, such as keto-enol isomerization and imine-ene Amine isomerization. Valence tautomers include interconversions through the reorganization of some bonding electrons. A specific example of keto-enol tautomerism is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of 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.
“药学上可接受的”是指这样一些化合物、原料、组合物和/或剂型，它们在合理医学判断的范围内，适用于与患者组织接触而无过度毒性、刺激性、变态反应或与合理的利益/风险比相对称的其他问题和并发症，并有效用于既定用途。"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.
像本发明所描述的，本发明的化合物可以任选地被一个或多个取代基所取代，如上面的通式化合物，或者像实施例里面特殊的例子，子类，和本发明所包含的一类化合物。As described in the present invention, 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.
一般而言，术语“取代的”表示所给结构中的一个或多个氢原子被具体取代基所取代。除非其他方面表明，一个取代的基团可以有一个取代基在基团各个可取代的位置进行取代。当所给出的结构式中不只一个位置能被选自具体基团的一个或多个取代基所取代，那么取代基可以相同或不同地在各个位置取代。In general, the term "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.
术语“未取代的”，表示指定基团不带有取代基。The term "unsubstituted" means that the specified group is unsubstituted.
术语“任选地被…….所取代”，可以与术语“未取代或被…..所取代”交换使用，即所述结构是未取代的或者被一个或多个本发明所述的取代基取代，本发明所述的取代基包括，但不限于D、F、Cl、Br、I、N 3、CN、NO 2、OH、SH、NH 2、烷基、卤代烷基、烯基、炔基、烷氧基、烷基氨基、羟烷基、氰基取代的烷基、环烷基、杂环基、芳基、杂芳基、-S(＝O) 0-2R 11、-C(＝O)R 11、-S(＝O) 1-2OR 4a、-OS(＝O) 1-2R 4a、-C(＝O)OR 4a、-OC(＝O)R 4a、-C(＝O)NR 12aR 12b、-S(＝O) 1-2NR 12aR 12b、-O-R 13-C(＝O)OR 4a、-O-R 13-S(＝O) 1-2OR 4a、-N(R 12a)-R 13-C(＝O)OR 4a、-C(＝O)N(R 12a)-R 13-OH、-C(＝O)N(R 12a)-R 13-NH 2、-C(＝O)N(R 12a)-R 13-C(＝O)OR 4a、-C(＝O)N(R 12a)-R 13-S(＝O) 1-2OR 4a、-C(＝O)N(R 12a)-S(＝O) 1-2R 11、-N(R 12a)C(＝O)NR 12aR 12b、-N(R 12a)S(＝O) 1-2NR 12aR 12b、-N(R 12a)C(＝O)N(R 12a)-S(＝O) 1-2R 11、-OC(＝O)N(R 12a)-S(＝O) 1-2R 11等等，其中R 4a、R 11、R 12a、R 12b、和R 13具有本发明所述定义。 The term "optionally substituted with ..." may be used interchangeably with the term "unsubstituted or substituted with ...", ie the structure is unsubstituted or substituted by one or more of the invention The substituents described in the present invention include, but are not limited to, D, F, Cl, Br, I, N 3 , CN, NO 2 , OH, SH, NH 2 , alkyl, haloalkyl, alkenyl, alkyne Alkyl, alkoxy, alkylamino, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -S (= O) 0-2 R 11 , -C (= O) R 11 , -S (= O) 1-2 OR 4a , -OS (= O) 1-2 R 4a , -C (= O) OR 4a , -OC (= O) R 4a ,- C (= O) NR 12a R 12b , -S (= O) 1-2 NR 12a R 12b , -OR 13 -C (= O) OR 4a , -OR 13 -S (= O) 1-2 OR 4a , -N (R 12a ) -R 13 -C (= O) OR 4a , -C (= O) N (R 12a ) -R 13 -OH, -C (= O) N (R 12a ) -R 13 -NH 2 , -C (= O) N (R 12a ) -R 13 -C (= O) OR 4a , -C (= O) N (R 12a ) -R 13 -S (= O) 1-2 OR 4a, -C (= O) N (R 12a) -S (= O) 1-2 R 11, -N (R 12a) C (= O) NR 12a R 12b, -N (R 12a) S ( = O) 1-2 NR 12a R 12b , -N (R 12a ) C (= O) N (R 12a ) -S (= O) 1-2 R 11 , -OC (= O) N (R 12a ) -S (= O) 1-2 R 11 and so on, wherein R 4a , R 11 , R 12a , R 12b , and R 13 have the present invention The definition.
另外，需要说明的是，除非以其他方式明确指出，在本发明中所采用的描述方式“各…独立地为”与“…各自独立地为”和“…独立地为”可以互换，均应做广义理解，其既可以是指在不同基团中，相同符号之间所表达的具体选项之间互相不影响，也可以表示在相同的基团中，相同符号之间所表达的具体选项之间互相 不影响。In addition, it should be noted that unless explicitly stated otherwise, the description methods used in the present invention "each independently are" and "... each independently are" and "... independently are" are interchangeable, both It should be understood in a broad sense. It can mean that the specific options expressed between the same symbols in different groups do not affect each other, or it can mean the specific options expressed between the same symbols in the same group. Do not affect each other.
在本说明书的各部分，本发明公开化合物的取代基按照基团种类或范围公开。特别指出，本发明包括这些基团种类和范围的各个成员的每一个独立的次级组合。例如，术语“C 1-6烷基”特别指独立公开的甲基、乙基、C 3烷基、C 4烷基、C 5烷基和C 6烷基。 In each part of the specification, the substituents of the compounds disclosed in the present invention are disclosed according to the kind or scope of the group. In particular, the invention includes each independent subcombination of each member of these group types and ranges. For example, the term "C 1-6 alkyl" specifically refers to independently disclosed methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, and C 6 alkyl.
在本发明的各部分，描述了连接取代基。当所述结构清楚地需要连接基团时，针对所述基团所列举的马库什变量应理解为连接基团。例如，如果所述结构需要连接基团并且针对所述变量的马库什基团定义列举了“烷基”或“芳基”，则应理解，所述“烷基”或“芳基”分别代表连接的亚烷基基团或亚芳基基团。In the various parts of the invention, linking substituents are described. When the structure clearly requires a linking group, the Markush variables listed for the group should be understood as the linking group. For example, if the structure requires a linking group and the Marcus definition of the variable enumerates "alkyl" or "aryl", it should be understood that the "alkyl" or "aryl" respectively Represents a connected alkylene or arylene group.
本发明使用的术语“烷基”或“烷基基团”，表示含有1至20个碳原子，饱和的直链或支链一价烃基基团，其中，所述烷基基团可以任选地被一个或多个本发明描述的取代基所取代。除非另外详细说明，烷基基团含有1-20个碳原子。在一实施方案中，烷基基团含有1-12个碳原子；在另一实施方案中，烷基基团含有1-6个碳原子；在又一实施方案中，烷基基团含有1-4个碳原子；还在一实施方案中，烷基基团含有1-3个碳原子。所述烷基基团可以任选地被一个或多个本发明描述的取代基所取代。The term "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.
烷基基团的实例包含，但并不限于，甲基(Me、-CH 3)，乙基(Et、-CH 2CH 3)，正丙基(n-Pr、-CH 2CH 2CH 3)，异丙基(i-Pr、-CH(CH 3) 2)，正丁基(n-Bu、-CH 2CH 2CH 2CH 3)，异丁基(i-Bu、-CH 2CH(CH 3) 2)，仲丁基(s-Bu、-CH(CH 3)CH 2CH 3)，叔丁基(t-Bu、-C(CH 3) 3)，正戊基(-CH 2CH 2CH 2CH 2CH 3)，2-戊基(-CH(CH 3)CH 2CH 2CH 3)，3-戊基(-CH(CH 2CH 3) 2)，2-甲基-2-丁基(-C(CH 3) 2CH 2CH 3)，3-甲基-2-丁基(-CH(CH 3)CH(CH 3) 2)，3-甲基-1-丁基(-CH 2CH 2CH(CH 3) 2)，2-甲基-1-丁基(-CH 2CH(CH 3)CH 2CH 3)，正己基(-CH 2CH 2CH 2CH 2CH 2CH 3)，2-己基(-CH(CH 3)CH 2CH 2CH 2CH 3)，3-己基(-CH(CH 2CH 3)(CH 2CH 2CH 3))，2-甲基-2-戊基(-C(CH 3) 2CH 2CH 2CH 3)，3-甲基-2-戊基(-CH(CH 3)CH(CH 3)CH 2CH 3)，4-甲基-2-戊基(-CH(CH 3)CH 2CH(CH 3) 2)，3-甲基-3-戊基(-C(CH 3)(CH 2CH 3) 2)，2-甲基-3-戊基(-CH(CH 2CH 3)CH(CH 3) 2)，2,3-二甲基-2-丁基(-C(CH 3) 2CH(CH 3) 2)，3,3-二甲基-2-丁基(-CH(CH 3)C(CH 3) 3)，正庚基，正辛基，等等。 Examples of 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 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 CH 2 CH 3 ), 3-methyl-2-butyl (-CH (CH 3 ) CH (CH 3 ) 2 ), 3-methyl-1- Butyl (-CH 2 CH 2 CH (CH 3 ) 2 ), 2-methyl-1-butyl (-CH 2 CH (CH 3 ) CH 2 CH 3 ), n-hexyl (-CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-hexyl (-CH (CH 3 ) CH 2 CH 2 CH 2 CH 3 ), 3-hexyl (-CH (CH 2 CH 3 ) (CH 2 CH 2 CH 3 )), 2-methyl-2-pentyl (-C (CH 3 ) 2 CH 2 CH 2 CH 3 ), 3-methyl-2-pentyl (-CH (CH 3 ) CH (CH 3 ) CH 2 CH 3 ), 4-methyl-2-pentyl (-CH (CH 3 ) CH 2 CH (CH 3 ) 2 ), 3-methyl-3-pentyl (-C (CH 3 ) (CH 2 CH 3 ) 2), 2-methyl-3-pentyl (-CH (CH 2 CH 3) CH (CH 3) 2), 2,3- dimethyl 2-butyl (-C (CH 3) 2 CH (CH 3) 2), 3,3- dimethyl-2-butyl (-CH (CH 3) C ( CH 3) 3), n-heptyl Base, n-octyl, etc.
术语“烯基”表示含有2-12个碳原子的直链或支链一价烃基，其中至少有一个不饱和位点，即有一个碳-碳sp 2双键，其包括“顺”和“反”的定位，或者“E”和“Z”的定位。在一实施方案中，烯基基团包含2-8个碳原子；在另一实施方案中，烯基基团包含2-6个碳原子；在又一实施方案中，烯基基团包含2-4个碳原子。烯基基团的实例包括，但并不限于，乙烯基(-CH＝CH 2)、烯丙基(-CH 2CH＝CH 2)等等。所述烯基基团可以任选地被一个或多个本发明描述的取代基所取代。 The term "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 ". In one embodiment, 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. Examples of alkenyl groups include, but are not limited to, vinyl (-CH = CH 2 ), allyl (-CH 2 CH = CH 2 ), and the like. The alkenyl group may be optionally substituted with one or more substituents described herein.
术语“炔基”表示含有2-12个碳原子的直链或支链一价烃基，其中至少有一个不饱和位点，即有一个碳-碳sp三键。在一实施方案中，炔基基团包含2-8个碳原子；在另一实施方案中，炔基基团包含2-6个碳原子；在又一实施方案中，炔基基团包含2-4个碳原子。炔基基团的实例包括，但并不限于，乙炔基(-C≡CH)、 炔丙基(-CH 2C≡CH)、1-丙炔基(-C≡C-CH 3)等等。所述炔基基团可以任选地被一个或多个本发明描述的取代基所取代。 The term "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. In one embodiment, 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. Examples of 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.
术语“烷氧基”表示烷基基团通过氧原子与分子其余部分相连，其中烷基基团具有如本发明所述的定义。除非另外详细说明，所述烷氧基基团含有1-12个碳原子。在一实施方案中，烷氧基基团含有1-6个碳原子；在另一实施方案中，烷氧基基团含有1-4个碳原子；在又一实施方案中，烷氧基基团含有1-3个碳原子。所述烷氧基基团可以任选地被一个或多个本发明描述的取代基所取代。The term "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.
烷氧基基团的实例包括，但并不限于，甲氧基(MeO、-OCH 3)，乙氧基(EtO、-OCH 2CH 3)，1-丙氧基(n-PrO、n-丙氧基、-OCH 2CH 2CH 3)，2-丙氧基(i-PrO、i-丙氧基、-OCH(CH 3) 2)，1-丁氧基(n-BuO、n-丁氧基、-OCH 2CH 2CH 2CH 3)，2-甲基-l-丙氧基(i-BuO、i-丁氧基、-OCH 2CH(CH 3) 2)，2-丁氧基(s-BuO、s-丁氧基、-OCH(CH 3)CH 2CH 3)，2-甲基-2-丙氧基(t-BuO、t-丁氧基、-OC(CH 3) 3)，1-戊氧基(n-戊氧基、-OCH 2CH 2CH 2CH 2CH 3)，2-戊氧基(-OCH(CH 3)CH 2CH 2CH 3)，3-戊氧基(-OCH(CH 2CH 3) 2)，2-甲基-2-丁氧基(-OC(CH 3) 2CH 2CH 3)，3-甲基-2-丁氧基(-OCH(CH 3)CH(CH 3) 2)，3-甲基-l-丁氧基(-OCH 2CH 2CH(CH 3) 2)，2-甲基-l-丁氧基(-OCH 2CH(CH 3)CH 2CH 3)，等等。 Examples of 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 2 CH 3 ), 2-pentyloxy (-OCH (CH 3 ) CH 2 CH 2 CH 3 ), 3-pentyloxy (-OCH (CH 2 CH 3 ) 2 ), 2-methyl-2-butoxy (-OC (CH 3 ) 2 CH 2 CH 3 ), 3-methyl-2-butoxy (-OCH (CH 3 ) CH (CH 3 ) 2 ), 3-methyl-l-butoxy (-OCH 2 CH 2 CH (CH 3 ) 2 ), 2-methyl-l-butoxy (-OCH 2 CH (CH 3 ) CH 2 CH 3 ), and so on.
术语“卤代烷基”，“卤代烯基”或“卤代烷氧基”表示烷基，烯基或烷氧基基团被一个或多个卤素原子所取代，这样的实例包含，但并不限于，三氟甲基、三氟乙基、2,2,3,3-四氟丙基、三氟甲氧基等。The term "haloalkyl", "haloalkenyl" or "haloalkoxy" 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.
本发明使用的术语“羟烷基”表示烷基基团被一个或多个羟基基团所取代，其中烷基基团具有如本发明所述的定义，这样的实例包括，但并不限于羟乙基，2-羟基丙基，羟甲基等。The term "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.
本发明使用的术语“环烷基”，除非另有说明，是指一价饱和或部分不饱和(但非芳香族)的单环或多环烃。在一些实施方案，所述环烷基基团可以是桥接的或非桥接的、螺环的或非螺环的、和/或稠合的或非稠合的双环基团。在一些实施方案，所述环烷基基团包括3-10个碳原子，即C 3至C 10环烷基。在一些实施方案，所述环烷基具有3-15(C 3-15)、3-10(C 3-10)、或3-7(C 3-7)个碳原子。在一些实施方案，所述环烷基基团是单环或双环。在一些实施方案，所述环烷基基团是单环。在一些实施方案，所述环烷基基团是双环。在一些实施方案，所述环烷基基团是三环。在一些实施方案，所述环烷基基团是完全饱和的。在一些实施方案，所述环烷基基团是部分饱和的。在一些实施方案，所述环烷基基团是环丙基、环丁基、环戊基、环己基、环庚基、双环[2.1.1]己基、双环[2.2.1]庚基、十氢萘基、或金刚烷基。当环烷基被取代时，其可在任一环上，即在由环烷基包含的任何芳香环或非芳香环上，可独立地被一个或多个本发明所描述的取代基所取代。 The term "cycloalkyl" as used herein, unless otherwise stated, refers to a monovalent saturated or partially unsaturated (but not aromatic) monocyclic or polycyclic hydrocarbon. In some embodiments, the cycloalkyl group can be a bridged or non-bridged, spiro or non-spiro, and / or fused or non-fused bicyclic group. In some embodiments, the cycloalkyl group includes 3-10 carbon atoms, ie, C 3 to C 10 cycloalkyl. In some embodiments, the cycloalkyl has 3-15 (C 3-15 ), 3-10 (C 3-10 ), or 3-7 (C 3-7 ) carbon atoms. In some embodiments, 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. In some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo [2.1.1] hexyl, bicyclo [2.2.1] heptyl, ten Hydronaphthyl, or adamantyl. 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.
术语“杂环基”和“杂环”在本申请中可交换使用，除非另有说明，是指包含至少一个非芳香环的一价单环非芳香环体系和/或多环体系；其中所述非芳香单环原子中的一个或多个(在某些实施方案，1、2、3或 4个)是独立地选自O、S(O) 0-2和N的杂原子，和所述其余环原子均为碳原子；和其中所述多环体系的环原子中的一个或多个(在某些实施方案，1、2、3或4个)是独立地选自O、S(O) 0-2和N的杂原子，和所述其余环原子均为碳原子。在一些实施方案，所述杂环包含1或2个杂原子，所述杂原子均为氮原子。在一些实施方案，所述杂环基是多环的并且在非芳香环中包含一个杂原子，或者在芳香环中包含一个杂原子，或者在芳香环中包含两个杂原子，或者包含两个杂原子其中一个在芳香环中，而另一个在非芳香环中。在一些实施方案，所述杂环基基团具有3-20、3-15、3-10、3-8、4-7、或5-6个环原子。在一些实施方案，所述杂环基是单环、双环、三环、或四环体系。在一些实施方案，所述杂环基基团可以是桥接的或非桥接的、螺环的或非螺环的、和/或稠合的或非稠合的双环基团。一个或多个氮原子和硫原子可任选地被氧化，一个或多个氮原子可任选地被季铵化，一个或多个碳原子可任选地被
Figure PCTCN2019099219-appb-000004
替换。一些环可以是部分或完全饱和的，或者是芳香族的，条件是杂环是非完全芳香性的。所述单环杂环和多环杂环可在任何导致稳定化合物的杂原子或碳原子上与所述主结构连接。所述多环杂环基可通过其任一环，包括任何芳香环或非芳香环，而不管所述环是否含有杂原子，连接至所述主结构上。在一些实施方案，杂环基为“杂环烷基”，其为1)如本发明所述的含有至少一个环杂原子的饱和或部分不饱和(但非芳香族)一价单环基团，或2)饱和或部分不饱和(但非芳香族)一价双环基团或三环基团，其中至少一个环含有至少一个如本发明所述的杂原子。当杂环基和杂环烷基被取代时，其可在任一环上，即在由杂环基和杂环烷基所包含的任何芳香环或非芳香环上被取代。在一些实施方案，此类杂环基包括，但不限于，环氧乙烷基、氮杂环丁基，氧杂环丁基，硫杂环丁基，吡咯烷基，2-吡咯啉基，3-吡咯啉基，吡唑啉基，吡唑烷基，咪唑啉基，咪唑烷基，四氢呋喃基，二氢呋喃基，四氢噻吩基，二氢噻吩基，1,3-二氧环戊基，二硫环戊基，四氢吡喃基，二氢吡喃基，2H-吡喃基，4H-吡喃基，四氢噻喃基，哌啶基，吗啉基，硫代吗啉基，哌嗪基，二噁烷基，二噻烷基，噻噁烷基，高哌嗪基，高哌啶基，氧杂环庚烷基，硫杂环庚烷基，氧氮杂
Figure PCTCN2019099219-appb-000005
基，二氮杂
Figure PCTCN2019099219-appb-000006
基，硫氮杂
Figure PCTCN2019099219-appb-000007
基，苯并二噁烷基，苯并二氧杂环戊烯基，苯并呋喃酮基，苯并吡喃酮基，苯并吡喃基，二氢苯并呋喃基，苯并四氢噻吩基，苯并噻喃基，苯并噁嗪基，β-咔啉基，苯并二氢吡喃基，色酮基，噌啉基，香豆素基，十氢喹啉基，十氢异喹啉基，二氢苯并异噻嗪基，二氢苯并异噁嗪基，二氢呋喃基，二氢异吲哚基，二氢吡喃基，二氢吡唑基，二氢吡嗪基，二氢吡啶基，二氢嘧啶基，二氢吡咯基，二氧戊环基，1,4-二噻喃基，呋喃酮基，咪唑烷基，2,4-二氧-咪唑烷基，咪唑啉基，吲哚啉基，2-氧-吲哚啉基，异苯并四氢呋喃基，异苯并四氢噻吩基，异苯并二氢吡喃基，异香豆素基，异二氢吲哚基(异吲哚啉基)，1-氧-异二氢吲哚基，1,3-二氧-异二氢吲哚基，异噻唑烷基，异噁唑烷基，3-氧-异噁唑烷基，吗啉基，3,5-二氧-吗啉基，八氢吲哚基，八氢异吲哚基，1-氧-八氢异吲哚基，1,3-二氧-六氢异吲哚基，噁唑烷酮基，噁唑烷基，环氧乙烷基，哌嗪基，2,6-二氧-哌嗪基，哌啶基，2,6-二氧-哌啶基，4-哌啶酮基，2-氧吡咯烷基，2,5-二氧吡咯烷基，奎宁环基，四氢异喹啉基，3,5-二氧-硫代吗啉基，噻唑烷基，2,4-二氧-噻唑烷基，四氢喹啉基，吩噻嗪基， 吩噁嗪基，氧杂蒽基和1,3,5-三硫杂环己烷基。杂环基中-CH 2-基团被-C(＝O)-替代的实例包括，但不限于，2-氧代吡咯烷基、氧代-1,3-噻唑烷基、2-哌啶酮基、3,5-二氧代哌啶基和嘧啶二酮基。杂环基中硫原子被氧化的实例包括，但不限于，环丁砜基、1,1-二氧代硫代吗啉基。所述的杂环基基团可以任选地被一个或多个本发明所描述的取代基所取代。 The terms "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. In some embodiments, the heterocyclic ring contains 1 or 2 heteroatoms, each of which is a nitrogen atom. In some embodiments, 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. In some embodiments, the heterocyclyl group has 3-20, 3-15, 3-10, 3-8, 4-7, or 5-6 ring atoms. In some embodiments, the heterocyclyl is a monocyclic, bicyclic, tricyclic, or tetracyclic system. In some embodiments, 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
Figure PCTCN2019099219-appb-000004
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. In some embodiments, 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. 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. In some embodiments, 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, tetrahydrothyranyl, piperidinyl, morpholinyl, thiomorpholine Group, piperazinyl, dioxanyl, dithiazyl, thiaxanyl, homopiperazinyl, homopiperidinyl, oxecanyl, thiacycloheptyl, oxazepine
Figure PCTCN2019099219-appb-000005
Diaza
Figure PCTCN2019099219-appb-000006
Radical
Figure PCTCN2019099219-appb-000007
, Benzodioxanyl, benzodioxolenyl, benzofuranone, benzopyranone, benzopyranyl, dihydrobenzofuranyl, benzotetrahydrothiophene , Benzothianyl, benzoxazinyl, β-carolinyl, benzodihydropyranyl, chromone, fluorenyl, coumarin, decahydroquinolinyl, decahydroiso Quinolinyl, dihydrobenzoisothiazinyl, dihydrobenzoisoxazinyl, dihydrofuranyl, dihydroisoindolyl, dihydropyranyl, dihydropyrazolyl, dihydropyrazine , Dihydropyridyl, dihydropyrimidinyl, dihydropyrrolyl, dioxolyl, 1,4-dithianyl, furanone, imidazolidinyl, 2,4-dioxo-imidazolyl , Imidazolinyl, indololinyl, 2-oxo-indolyl, isobenzotetrahydrofuryl, isobenzotetrahydrothienyl, isobenzodihydropyranyl, isocoumarin, isodihydro Indolyl (isoindololinyl), 1-oxo-isodihydroindolyl, 1,3-dioxo-isodihydroindolyl, isothiazolyl, isoxazolyl, 3-oxo -Isoxazolidinyl, morpholinyl, 3,5-dioxo-morpholinyl, octahydroindolyl, octahydroisoindolyl, 1-oxo- Hydroisoindolyl, 1,3-dioxo-hexahydroisoindolyl, oxazolidinyl, oxazolidinyl, oxiranyl, piperazinyl, 2,6-dioxo-piperazine , Piperidinyl, 2,6-dioxo-piperidinyl, 4-piperidinone, 2-oxopyrrolidin, 2,5-dioxopyrrolidin, quinuclidinyl, tetrahydroisoquine Phenyl, 3,5-dioxo-thiomorpholinyl, thiazolidinyl, 2,4-dioxo-thiazolidinyl, tetrahydroquinolinyl, phenothiazinyl, phenoxazinyl, xanthene And 1,3,5-trithiacyclohexane. Examples of the -CH 2 -group replaced by -C (= O)-in the heterocyclic group include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolyl, 2-piperidine Keto, 3,5-dioxopiperidinyl and pyrimidinone. Examples of the sulfur atom in the heterocyclic group being oxidized include, but are not limited to, sulfolane, 1,1-dioxothiomorpholinyl. The heterocyclyl group may be optionally substituted with one or more substituents described herein.
在一实施方案中，杂环基为3-8个原子组成的杂环基，是指包含3-8个环原子的饱和或部分不饱和的单环，其中至少一个环原子选自氮、硫和氧原子。除非另外说明，3-8个原子组成的杂环基可以是碳基或氮基，且-CH 2-基团可以任选地被-C(＝O)-替代。环的硫原子可以任选地被氧化成S-氧化物。环的氮原子可以任选地被氧化成N-氧化合物。3-8个原子组成的杂环基的实例包括，但不限于：氮杂环丁基，氧杂环丁基，硫杂环丁基，吡咯烷基，2-吡咯啉基，3-吡咯啉基，吡唑啉基，吡唑烷基，咪唑啉基，咪唑烷基，四氢呋喃基，二氢呋喃基，四氢噻吩基，二氢噻吩基，1,3-二氧环戊基，二硫环戊基，四氢吡喃基，二氢吡喃基，2H-吡喃基，4H-吡喃基，四氢噻喃基，哌啶基，吗啉基，硫代吗啉基，哌嗪基，二噁烷基，二噻烷基，噻噁烷基，高哌嗪基，高哌啶基，氧杂环庚烷基，硫杂环庚烷基，氧氮杂
Figure PCTCN2019099219-appb-000008
基，二氮杂
Figure PCTCN2019099219-appb-000009
基，硫氮杂
Figure PCTCN2019099219-appb-000010
基。杂环基中-CH 2-基团被-C(＝O)-替代的实例包括，但不限于，2-氧代吡咯烷基、氧代-1,3-噻唑烷基、2-哌啶酮基、3,5-二氧代哌啶基和嘧啶二酮基。杂环基中硫原子被氧化的实例包括，但不限于，环丁砜基、1,1-二氧代硫代吗啉基。所述的3-8个原子组成的杂环基基团可以任选地被一个或多个本发明所描述的取代基所取代。 In one embodiment, 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. Unless stated otherwise, a heterocyclic group of 3-8 atoms may be a carbon or nitrogen group, and the -CH 2 -group may be optionally replaced by -C (= O)-. Ring sulfur atoms can be optionally oxidized to S-oxides. The ring nitrogen atom can be optionally oxidized to an N-oxygen compound. Examples of 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, oxepanyl, thietyl, oxazepine
Figure PCTCN2019099219-appb-000008
Diaza
Figure PCTCN2019099219-appb-000009
Radical
Figure PCTCN2019099219-appb-000010
base. Examples of the -CH 2 -group replaced by -C (= O)-in the heterocyclic group include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolyl, 2-piperidine Keto, 3,5-dioxopiperidinyl and pyrimidinone. 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.
在一实施方案中，杂环基为3-6个原子组成的杂环基，是指包含3-6个环原子的饱和或部分不饱和的单环，其中至少一个环原子选自氮、硫和氧原子。除非另外说明，3-6个原子组成的杂环基可以是碳基或氮基，且-CH 2-基团可以任选地被-C(＝O)-替代。环的硫原子可以任选地被氧化成S-氧化物。环的氮原子可以任选地被氧化成N-氧化合物。所述的3-6个原子组成的杂环基基团可以任选地被一个或多个本发明所描述的取代基所取代。 In one embodiment, 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. Unless stated otherwise, a heterocyclic group of 3-6 atoms may be a carbon or nitrogen group, and the -CH 2 -group may be optionally replaced by -C (= O)-. 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.
在另一实施方案中，杂环基为5-6个原子组成的杂环基，是指包含5-6个环原子的饱和或部分不饱和的单环，其中至少一个环原子选自氮、硫和氧原子。除非另外说明，5-6个原子组成的杂环基可以是碳基或氮基，且-CH 2-基团可以任选地被-C(＝O)-替代。环的硫原子可以任选地被氧化成S-氧化物。环的氮原子可以任选地被氧化成N-氧化合物。5-6个原子组成的杂环基的实例包括，但不限于：吡咯烷基，2-吡咯啉基，3-吡咯啉基，吡唑啉基，吡唑烷基，咪唑啉基，咪唑烷基，四氢呋喃基，二氢呋喃基，四氢噻吩基，二氢噻吩基，1,3-二氧环戊基，二硫环戊基、2-氧代吡咯烷基、氧代-1,3-噻唑烷基、环丁砜基、四氢吡喃基，二氢吡喃基，2H-吡喃基，4H-吡喃基，四氢噻喃基，哌啶基，吗啉基，硫代吗啉基，哌嗪基，二噁烷基，二噻烷基，噻噁烷基、2-哌啶酮基、3,5-二氧代哌啶基和嘧啶二酮基、1,1-二氧代硫代吗啉基。所述的5-6个原子组成的杂环基基团可以任选地被一个或多个本发明所描述的取代基所取代。 In another embodiment, 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. Unless stated otherwise, a heterocyclic group of 5-6 atoms may be a carbon group or a nitrogen group, and the -CH 2 -group may be optionally replaced by -C (= O)-. Ring sulfur atoms can be optionally oxidized to S-oxides. The ring nitrogen atom can be optionally oxidized to an N-oxygen compound. Examples of 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, 3,5-dioxopiperidinyl, and pyrimidinone, 1,1-dioxo Thiomorpholinyl. The 5-6 atom heterocyclic group may be optionally substituted with one or more substituents described in the present invention.
术语“螺环基”，“螺环”，“螺双环基”，“螺双环”表示一个环起源于另一个环上特殊的环状碳。例如，环A和环B在两个饱和的环体系中共享一个碳原子，则被称为“螺环”。螺环里面的每一个环要么是碳环要么是杂脂环族。这样的实例包括，但并不限于2,7-二氮杂螺[4.4]壬烷-2-基，7-氧-2-氮杂螺[4.5]癸烷-2-基，4-氮杂螺[2.4]庚烷-5-基，4-氧杂螺[2.4]庚烷-5-基，5-氮杂螺[2.4]庚烷-5-基，螺[2.4]庚烷基，螺[4.4]壬烷基，7-羟基-5-氮杂螺[2.4]庚烷-5-基等。并且所述螺双环基可以是取代或未取代的，其中取代基可以是，但并不限于，D、F、Cl、Br、I、N 3、CN、NO 2、OH、SH、NH 2、烷基、卤代烷基、烯基、炔基、烷氧基、烷基氨基、羟烷基、氰基取代的烷基、环烷基、杂环基、芳基、杂芳基、-S(＝O) 0-2R 11、-C(＝O)R 11、-S(＝O) 1-2OR 4a、-OS(＝O) 1-2R 4a、-C(＝O)OR 4a、-OC(＝O)R 4a、-C(＝O)NR 12aR 12b、-S(＝O) 1-2NR 12aR 12b、-O-R 13-C(＝O)OR 4a、-O-R 13-S(＝O) 1-2OR 4a、-N(R 12a)-R 13-C(＝O)OR 4a、-C(＝O)N(R 12a)-R 13-OH、-C(＝O)N(R 12a)-R 13-NH 2、-C(＝O)N(R 12a)-R 13-C(＝O)OR 4a、-C(＝O)N(R 12a)-R 13-S(＝O) 1-2OR 4a、-C(＝O)N(R 12a)-S(＝O) 1-2R 11、-N(R 12a)C(＝O)NR 12aR 12b、-N(R 12a)S(＝O) 1-2NR 12aR 12b、-N(R 12a)C(＝O)N(R 12a)-S(＝O) 1-2R 11、-OC(＝O)N(R 12a)-S(＝O) 1-2R 11等等，其中R 4a、R 11、R 12a、R 12b、和R 13具有本发明所述定义。 The terms "spirocyclic group", "spirocyclic ring", "spirobicyclic group" and "spirobicyclic group" mean that one ring originates from a special cyclic carbon on the other ring. For example, 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. And the spirobicyclic group may be substituted or unsubstituted, wherein the substituent may be, but is not limited to, D, F, Cl, Br, I, N 3 , CN, NO 2 , OH, SH, NH 2 , Alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, alkylamino, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -S (= O) 0-2 R 11 , -C (= O) R 11 , -S (= O) 1-2 OR 4a , -OS (= O) 1-2 R 4a , -C (= O) OR 4a , -OC (= O) R 4a , -C (= O) NR 12a R 12b , -S (= O) 1-2 NR 12a R 12b , -OR 13 -C (= O) OR 4a , -OR 13- S (= O) 1-2 OR 4a , -N (R 12a ) -R 13 -C (= O) OR 4a , -C (= O) N (R 12a ) -R 13 -OH, -C (= O) N (R 12a ) -R 13 -NH 2 , -C (= O) N (R 12a ) -R 13 -C (= O) OR 4a , -C (= O) N (R 12a ) -R 13 -S (= O) 1-2 OR 4a, -C (= O) N (R 12a) -S (= O) 1-2 R 11, -N (R 12a) C (= O) NR 12a R 12b, -N (R 12a) S (= O) 1-2 NR 12a R 12b, -N (R 12a) C (= O) N (R 12a) -S (= O) 1-2 R 11, - OC (= O) N (R 12a ) -S (= O) 1-2 R 11 and so on, wherein R 4a , R 11 , R 12a , R 12b , and R 13 have the definitions described in the present invention.
Figure PCTCN2019099219-appb-000011
Figure PCTCN2019099219-appb-000011
术语“亚螺双环基”表示螺双环基体系具有两个连接点与分子其余部分相连，其中螺双环基具有如本发明所述的定义。The term "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.
术语“螺杂双环基”表示一个环起源于另一个环上特殊的环状碳。例如，如上面所描述的，环A和环B在两个饱和的环体系中共享一个碳原子，则被称为“螺环”。且至少一个环体系包含一个或多个杂原子，其中每一个环体系包含3-7元环，即包含1-6个碳原子和选自N，O，P，S的1-3个杂原子,在此S或P任选地被一个或多个氧原子所取代得到例如SO，SO 2，PO，PO 2的基团，这样的实例包括，但并不限于4-氮杂螺[2.4]庚烷-5-基，4-氧杂螺[2.4]庚烷-5-基，5-氮杂螺[2.4]庚烷-5-基，7-羟基-5-氮杂螺[2.4]庚烷-5-基，2,6-二氮杂螺[3.3]庚烷，2,6-二氮杂螺[3.4]辛烷，1,6-二氮杂螺[3.4]辛烷，2,7-二氮杂螺[3.5]壬烷，1,7-二氮杂螺[3.5]壬烷，3,9-二氮杂螺[5.5]十一烷等。并且所述螺杂双环基可以是取代或未取代的，其中取代基可以是，但并不限于，D、F、Cl、Br、I、N 3、CN、NO 2、OH、SH、NH 2、烷基、卤代烷基、烯基、炔基、烷氧基、烷基氨基、羟烷基、氰基取代的烷基、环烷基、杂环基、芳基、杂芳基、-S(＝O) 0-2R 11、-C(＝O)R 11、-S(＝O) 1-2OR 4a、-OS(＝O) 1-2R 4a、-C(＝O)OR 4a、-OC(＝O)R 4a、-C(＝O)NR 12aR 12b、-S(＝O) 1-2NR 12aR 12b、-O-R 13-C(＝O)OR 4a、-O-R 13-S(＝O) 1-2OR 4a、-N(R 12a)-R 13-C(＝O)OR 4a、-C(＝O)N(R 12a)-R 13-OH、-C(＝O)N(R 12a)-R 13-NH 2、-C(＝O)N(R 12a)-R 13-C(＝O)OR 4a、-C(＝O)N(R 12a)-R 13-S(＝O) 1-2OR 4a、-C(＝O)N(R 12a)-S(＝O) 1-2R 11、-N(R 12a)C(＝O)NR 12aR 12b、-N(R 12a)S(＝O) 1-2NR 12aR 12b、-N(R 12a)C(＝O)N(R 12a)-S(＝O) 1-2R 11、-OC(＝O)N(R 12a)-S(＝O) 1-2R 11等等，其中R 4a、R 11、R 12a、R 12b、和R 13具有本发明所述定义。 The term "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". And at least one 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-diazaspiro [3.5] nonane, 3,9-diazaspiro [5.5] undecane, etc. And the spiro heterobicyclic group may be substituted or unsubstituted, wherein the substituent may be, but is not limited to, D, F, Cl, Br, I, N 3 , CN, NO 2 , OH, SH, NH 2 , Alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, alkylamino, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -S ( = O) 0-2 R 11 , -C (= O) R 11 , -S (= O) 1-2 OR 4a , -OS (= O) 1-2 R 4a , -C (= O) OR 4a -OC (= O) R 4a , -C (= O) NR 12a R 12b , -S (= O) 1-2 NR 12a R 12b , -OR 13 -C (= O) OR 4a , -OR 13 -S (= O) 1-2 OR 4a , -N (R 12a ) -R 13 -C (= O) OR 4a , -C (= O) N (R 12a ) -R 13 -OH, -C ( = O) N (R 12a ) -R 13 -NH 2 , -C (= O) N (R 12a ) -R 13 -C (= O) OR 4a , -C (= O) N (R 12a )- R 13 -S (= O) 1-2 OR 4a, -C (= O) N (R 12a) -S (= O) 1-2 R 11, -N (R 12a) C (= O) NR 12a R 12b , -N (R 12a ) S (= O) 1-2 NR 12a R 12b , -N (R 12a ) C (= O) N (R 12a ) -S (= O) 1-2 R 11 , -OC (= O) N (R 12a ) -S (= O) 1-2 R 11 and so on, wherein R 4a , R 11 , R 12a , R 12b , and R 13 have the definitions described in the present invention.
本发明使用的术语“桥环基”表示饱和或不饱和的桥环体系，涉及非芳香族的桥环体系，如式(a2) 所示，即环A1与环A2共有一个烷链或一个杂烷链，其中j为1，2，3或4。这样的体系可以包含独立的或共轭的不饱和状态，但其核心结构不包含芳香环或芳杂环(但是芳香族可以作为其上的取代基)。桥接环中的每一个环要么是碳环要么是杂脂环族，这样的实例包括，但并不限于，双环[2.2.1]庚烷，2-氮杂双环[2.2.1]庚烷，1,2,3,4,4a,5,8,8a-八氢萘，这些都包含在稠合双环或桥环的体系之内。并且所述桥环基可以是取代或未取代的，其中取代基可以是，但并不限于，D、F、Cl、Br、I、N 3、CN、NO 2、OH、SH、NH 2、烷基、卤代烷基、烯基、炔基、烷氧基、烷基氨基、羟烷基、氰基取代的烷基、环烷基、杂环基、芳基、杂芳基、-S(＝O) 0-2R 11、-C(＝O)R 11、-S(＝O) 1-2OR 4a、-OS(＝O) 1-2R 4a、-C(＝O)OR 4a、-OC(＝O)R 4a、-C(＝O)NR 12aR 12b、-S(＝O) 1-2NR 12aR 12b、-O-R 13-C(＝O)OR 4a、-O-R 13-S(＝O) 1-2OR 4a、-N(R 12a)-R 13-C(＝O)OR 4a、-C(＝O)N(R 12a)-R 13-OH、-C(＝O)N(R 12a)-R 13-NH 2、-C(＝O)N(R 12a)-R 13-C(＝O)OR 4a、-C(＝O)N(R 12a)-R 13-S(＝O) 1-2OR 4a、-C(＝O)N(R 12a)-S(＝O) 1-2R 11、-N(R 12a)C(＝O)NR 12aR 12b、-N(R 12a)S(＝O) 1-2NR 12aR 12b、-N(R 12a)C(＝O)N(R 12a)-S(＝O) 1-2R 11、-OC(＝O)N(R 12a)-S(＝O) 1-2R 11等的基团取代，其中R 4a、R 11、R 12a、R 12b、和R 13具有本发明所述定义。 The term "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. Examples of such include, but are not limited to, 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. And the bridged ring group may be substituted or unsubstituted, wherein the substituent may be, but is not limited to, D, F, Cl, Br, I, N 3 , CN, NO 2 , OH, SH, NH 2 , Alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, alkylamino, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -S (= O) 0-2 R 11 , -C (= O) R 11 , -S (= O) 1-2 OR 4a , -OS (= O) 1-2 R 4a , -C (= O) OR 4a , -OC (= O) R 4a , -C (= O) NR 12a R 12b , -S (= O) 1-2 NR 12a R 12b , -OR 13 -C (= O) OR 4a , -OR 13- S (= O) 1-2 OR 4a , -N (R 12a ) -R 13 -C (= O) OR 4a , -C (= O) N (R 12a ) -R 13 -OH, -C (= O) N (R 12a ) -R 13 -NH 2 , -C (= O) N (R 12a ) -R 13 -C (= O) OR 4a , -C (= O) N (R 12a ) -R 13 -S (= O) 1-2 OR 4a, -C (= O) N (R 12a) -S (= O) 1-2 R 11, -N (R 12a) C (= O) NR 12a R 12b, -N (R 12a) S (= O) 1-2 NR 12a R 12b, -N (R 12a) C (= O) N (R 12a) -S (= O) 1-2 R 11, - OC (= O) N (R 12a ) -S (= O) 1-2 R 11 and the like, wherein R 4a , R 11 , R 12a , R 12b , and R 13 have the definitions described in the present invention.
Figure PCTCN2019099219-appb-000012
Figure PCTCN2019099219-appb-000012
术语“桥杂环基”表示饱和或不饱和的桥环体系，涉及非芳香族的桥环体系。这样的体系可以包含独立的或共轭的不饱和状态，但其核心结构不包含芳香环或芳杂环(但是芳香族可以作为其上的取代基)。且至少一个环体系包含一个或多个杂原子，其中每一个环体系包含3-7元环，即包含1-6个碳原子和选自N，O，P，S的1-3个杂原子,在此S或P任选地被一个或多个氧原子所取代得到例如SO，SO 2，PO，PO 2的基团，这样的实例包括，但并不限于2-氮杂双环[2.2.1]庚烷，(1R,5S)-3,6-二氮杂双环[3.1.1]庚烷，2,5-二氮杂双环[2.2.1]庚烷，(1R,5S)-8-氮杂双环[3.2.1]辛烷等。并且所述桥杂环基可以是取代或未取代的，其中取代基可以是，但并不限于，D、F、Cl、Br、I、N 3、CN、NO 2、OH、SH、NH 2、烷基、卤代烷基、烯基、炔基、烷氧基、烷基氨基、羟烷基、氰基取代的烷基、环烷基、杂环基、芳基、杂芳基、-S(＝O) 0-2R 11、-C(＝O)R 11、-S(＝O) 1-2OR 4a、-OS(＝O) 1-2R 4a、-C(＝O)OR 4a、-OC(＝O)R 4a、-C(＝O)NR 12aR 12b、-S(＝O) 1-2NR 12aR 12b、-O-R 13-C(＝O)OR 4a、-O-R 13-S(＝O) 1-2OR 4a、-N(R 12a)-R 13-C(＝O)OR 4a、-C(＝O)N(R 12a)-R 13-OH、-C(＝O)N(R 12a)-R 13-NH 2、-C(＝O)N(R 12a)-R 13-C(＝O)OR 4a、-C(＝O)N(R 12a)-R 13-S(＝O) 1-2OR 4a、-C(＝O)N(R 12a)-S(＝O) 1-2R 11、-N(R 12a)C(＝O)NR 12aR 12b、-N(R 12a)S(＝O) 1-2NR 12aR 12b、-N(R 12a)C(＝O)N(R 12a)-S(＝O) 1-2R 11、-OC(＝O)N(R 12a)-S(＝O) 1-2R 11等的基团取代，其中R 4a、R 11、R 12a、R 12b、和R 13具有本发明所述定义。 The term "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). And at least one 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. And the bridged heterocyclic group may be substituted or unsubstituted, wherein the substituent may be, but is not limited to, D, F, Cl, Br, I, N 3 , CN, NO 2 , OH, SH, NH 2 , Alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, alkylamino, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -S ( = O) 0-2 R 11 , -C (= O) R 11 , -S (= O) 1-2 OR 4a , -OS (= O) 1-2 R 4a , -C (= O) OR 4a -OC (= O) R 4a , -C (= O) NR 12a R 12b , -S (= O) 1-2 NR 12a R 12b , -OR 13 -C (= O) OR 4a , -OR 13 -S (= O) 1-2 OR 4a , -N (R 12a ) -R 13 -C (= O) OR 4a , -C (= O) N (R 12a ) -R 13 -OH, -C ( = O) N (R 12a ) -R 13 -NH 2 , -C (= O) N (R 12a ) -R 13 -C (= O) OR 4a , -C (= O) N (R 12a )- R 13 -S (= O) 1-2 OR 4a, -C (= O) N (R 12a) -S (= O) 1-2 R 11, -N (R 12a) C (= O) NR 12a R 12b , -N (R 12a ) S (= O) 1-2 NR 12a R 12b , -N (R 12a ) C (= O) N (R 12a ) -S (= O) 1-2 R 11 , -OC (= O) N (R 12a) -S (= O) 1-2 R 11 such groups, wherein R 4a, R 11, R 12a , R 12b, and R 13 having the definition of the present invention
术语“螺桥环基”表示一个环起源于另一个桥环上特殊的环状碳。例如，环A和桥环B在两个饱和的环体系中共享一个碳原子，如式(a3)所示，则被称为“螺桥环”。螺桥环里面的每一个环要么是碳环要么是杂脂环族。这样的实例包括，但并不限于(1R,5S)-螺[双环[3.2.1]辛烷-3,1'-环丁烷]，(1'R,5'S)-8'-氮杂螺[氮杂环丁烷-3,3'-双环[3.2.1]辛烷]，(1R,5S)-3-氮杂螺[双环[3.2.1]辛烷-8,1'-环丁烷]，(1'R,5'S)-3'-氮杂螺[氮杂环丁烷-3,8'-双环[3.2.1]辛烷]等。并且所述螺桥环基可以是取代或未取代的， 其中取代基可以是，但并不限于，D、F、Cl、Br、I、N 3、CN、NO 2、OH、SH、NH 2、烷基、卤代烷基、烯基、炔基、烷氧基、烷基氨基、羟烷基、氰基取代的烷基、环烷基、杂环基、芳基、杂芳基、-S(＝O) 0-2R 11、-C(＝O)R 11、-S(＝O) 1-2OR 4a、-OS(＝O) 1-2R 4a、-C(＝O)OR 4a、-OC(＝O)R 4a、-C(＝O)NR 12aR 12b、-S(＝O) 1-2NR 12aR 12b、-O-R 13-C(＝O)OR 4a、-O-R 13-S(＝O) 1-2OR 4a、-N(R 12a)-R 13-C(＝O)OR 4a、-C(＝O)N(R 12a)-R 13-OH、-C(＝O)N(R 12a)-R 13-NH 2、-C(＝O)N(R 12a)-R 13-C(＝O)OR 4a、-C(＝O)N(R 12a)-R 13-S(＝O) 1-2OR 4a、-C(＝O)N(R 12a)-S(＝O) 1-2R 11、-N(R 12a)C(＝O)NR 12aR 12b、-N(R 12a)S(＝O) 1-2NR 12aR 12b、-N(R 12a)C(＝O)N(R 12a)-S(＝O) 1-2R 11、-OC(＝O)N(R 12a)-S(＝O) 1-2R 11等的基团取代，其中R 4a、R 11、R 12a、R 12b、和R 13具有本发明所述定义。 The term "spiro bridge ring group" means that one ring originates from a special cyclic carbon on another bridge ring. For example, ring A and bridged ring B share one carbon atom in two saturated ring systems. As shown in formula (a3), 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. And the spiro bridged ring group may be substituted or unsubstituted, wherein the substituent may be, but is not limited to, D, F, Cl, Br, I, N 3 , CN, NO 2 , OH, SH, NH 2 , Alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, alkylamino, hydroxyalkyl, cyano-substituted alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -S ( = O) 0-2 R 11 , -C (= O) R 11 , -S (= O) 1-2 OR 4a , -OS (= O) 1-2 R 4a , -C (= O) OR 4a -OC (= O) R 4a , -C (= O) NR 12a R 12b , -S (= O) 1-2 NR 12a R 12b , -OR 13 -C (= O) OR 4a , -OR 13 -S (= O) 1-2 OR 4a , -N (R 12a ) -R 13 -C (= O) OR 4a , -C (= O) N (R 12a ) -R 13 -OH, -C ( = O) N (R 12a ) -R 13 -NH 2 , -C (= O) N (R 12a ) -R 13 -C (= O) OR 4a , -C (= O) N (R 12a )- R 13 -S (= O) 1-2 OR 4a, -C (= O) N (R 12a) -S (= O) 1-2 R 11, -N (R 12a) C (= O) NR 12a R 12b , -N (R 12a ) S (= O) 1-2 NR 12a R 12b , -N (R 12a ) C (= O) N (R 12a ) -S (= O) 1-2 R 11 , -OC (= O) N (R 12a) -S (= O) 1-2 R 11 such groups, wherein R 4a, R 11, R 12a , R 12b, and R 13 having the definition of the present invention
Figure PCTCN2019099219-appb-000013
Figure PCTCN2019099219-appb-000013
如本发明所描述的，环体系中有两个连接点与分子其余部分相连，如式(a4)或(a5)所示，表示既可以是E端也可以是E’端与分子其余部分相连，即两端的连接方式可以互换。As described in the present invention, 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.
Figure PCTCN2019099219-appb-000014
Figure PCTCN2019099219-appb-000014
术语“n个原子组成的”，其中n是整数，典型地描述分子中成环原子的数目，在所述分子中成环原子的数目是n。例如，哌啶基是6个原子组成的杂环烷基，而1,2,3,4-四氢萘是10个原子组成的环烷基基团。The term "consisting of n atoms", where n is an integer, typically describes the number of ring-forming atoms in a molecule, and the number of ring-forming atoms in the molecule is n. For example, piperidinyl is a 6 atom heterocycloalkyl group, and 1,2,3,4-tetrahydronaphthalene is a 10 atom cycloalkyl group.
在本发明中所使用的术语“不饱和的”表示基团中含有一个或多个不饱和度。The term "unsaturated" as used in the present invention means that the group contains one or more degrees of unsaturation.
术语“杂原子”是指O、S、N、P和Si，包括N、S和P任何氧化态的形式；伯、仲、叔胺和季铵盐的形式；或者杂环中氮原子上的氢被取代的形式，例如，N(像3,4-二氢-2H-吡咯基中的N)，NH(像吡咯烷基中的NH)或NR(像N-取代的吡咯烷基中的NR)。The term "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).
术语“卤素”是指氟(F)、氯(Cl)、溴(Br)或碘(I)。The term "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).
本发明使用的术语“芳基”，除非另有说明，是指包含至少一个芳环的一价C 6-C 14碳环体系，其中所述芳环体系是单环、二环、或三环。所述芳基可通过其任何环即任何芳香环或非芳香环连接至主结构上。在一些实施方案，芳基是苯基、萘基、二环[4.2.0]辛-1,3,5-三烯基、茚满基、芴基、或四氢萘基。当芳基被取代时，其可在任何环上即在由芳基包含的任何芳香环或非芳香环上被取代。在一些或任一实施方案，芳基是苯基、萘基、四氢萘基、芴基、或茚满基；所述苯基、萘基、四氢萘基、芴基、和茚满基各自任选地被所述芳基基团可以独立任选地被一个或多个本发明所描述的取代基所取代，在一些实施方案，包括被独立地选自D、F、Cl、Br、I、N 3、CN、NO 2、OH、SH、NH 2、烷基、卤代烷基、烯基、炔基、烷氧基、烷 基氨基、羟烷基、氰基取代的烷基、环烷基、杂环基、芳基、杂芳基、-S(＝O) 0-2R 11、-C(＝O)R 11、-S(＝O) 1-2OR 4a、-OS(＝O) 1-2R 4a、-C(＝O)OR 4a、-OC(＝O)R 4a、-C(＝O)NR 12aR 12b、-S(＝O) 1-2NR 12aR 12b、-O-R 13-C(＝O)OR 4a、-O-R 13-S(＝O) 1-2OR 4a、-N(R 12a)-R 13-C(＝O)OR 4a、-C(＝O)N(R 12a)-R 13-OH、-C(＝O)N(R 12a)-R 13-NH 2、-C(＝O)N(R 12a)-R 13-C(＝O)OR 4a、-C(＝O)N(R 12a)-R 13-S(＝O) 1-2OR 4a、-C(＝O)N(R 12a)-S(＝O) 1-2R 11、-N(R 12a)C(＝O)NR 12aR 12b、-N(R 12a)S(＝O) 1-2NR 12aR 12b、-N(R 12a)C(＝O)N(R 12a)-S(＝O) 1-2R 11、-OC(＝O)N(R 12a)-S(＝O) 1-2R 11等的基团取代，其中R 4a、R 11、R 12a、R 12b、和R 13具有本发明所述定义。 The term "aryl" as used herein, unless otherwise specified, 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. In some embodiments, aryl is phenyl, naphthyl, bicyclo [4.2.0] oct-1,3,5-trienyl, indanyl, fluorenyl, or tetrahydronaphthyl. When an aryl group is substituted, it may be substituted on any ring, that is, on any aromatic or non-aromatic ring contained by the aryl group. In some or any embodiments, 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, heterocyclyl, aryl, heteroaryl, -S (= O) 0-2 R 11 , -C (= O) R 11 , -S (= O) 1-2 OR 4a , -OS (= O) 1-2 R 4a , -C (= O) OR 4a , -OC (= O) R 4a , -C (= O) NR 12a R 12b , -S (= O) 1-2 NR 12a R 12b , -OR 13 -C (= O) OR 4a , -OR 13 -S (= O) 1-2 OR 4a , -N (R 12a ) -R 13 -C (= O) OR 4a , -C (= O) N (R 12a ) -R 13 -OH, -C (= O) N (R 12a ) -R 13 -NH 2 , -C (= O) N (R 12a ) -R 13 -C (= O ) OR 4a, -C (= O ) N (R 12a) -R 13 -S (= O) 1-2 OR 4a, -C (= O) N (R 12a) -S (= O) 1-2 R 11 , -N (R 12a ) C (= O) NR 12a R 12 b , -N (R 12a ) S (= O) 1-2 NR 12a R 12b , -N (R 12a ) C (= O) N (R 12a ) -S (= O) 1-2 R 11 ,- OC (= O) N (R 12a ) -S (= O) 1-2 R 11 and the like, wherein R 4a , R 11 , R 12a , R 12b , and R 13 have the definitions described in the present invention.
本发明使用的术语“亚芳基”表示从芳基基团中去掉两个氢原子所得到的的二价芳基基团，其中芳基基团具有本发明所述定义。The term "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.
本发明使用的术语“杂芳基”，除非另有说明，是指一价单环或多环芳香基团，其中所述至少一个(在某些实施方案，1、2、3或4个)环原子是独立地选自所述环中的O、S(O) 0-2和N的杂原子。所述杂芳基基团是通过环体系中的任何原子，其化合价规则允许情况下，连接至分子其余部分。在一些实施方案，杂芳基基团的每个环可含有1或2个O原子、1或2个S原子、和/或1至4个N原子、或其组合，条件是每个环中杂原子的总数为4或更少，以及每个环含有至少1个碳原子。在一些实施方案，所述杂芳基具有5-20、5-15、或5-10个环原子。当杂芳基被取代时，其可在任一环上进行取代。在某些实施方案，单环杂芳基基团包括但不限于，呋喃基，咪唑基，异噻唑基，异噁唑基，噁二唑基，噁唑基，吡嗪基，吡唑基，哒嗪基，吡啶基，嘧啶基，吡咯基，噻二唑基，噻唑基，噻吩基，四唑基，三嗪基和三唑基。在某些实施方案，双环杂芳基基团包括，但不限于，苯并呋喃基，苯并咪唑基，苯并异噁唑基，苯并吡喃基，苯并噻二唑基，苯并噻唑基，苯并噻吩基，苯并三唑基，苯并噁唑基，呋喃并吡啶基，咪唑并吡啶基，咪唑并噻唑基，吲嗪基，吲哚基，吲唑基，异苯并呋喃基，异苯并噻吩基，异吲哚基，异喹啉基，异噻唑基，萘啶基，噁唑并吡啶基，酞嗪基，蝶啶基，嘌呤基，吡啶并吡啶基，吡咯并吡啶基，喹啉基，喹喔啉基，喹唑啉基，噻二唑并嘧啶基和噻吩并吡啶基。在某些实施方案，三环杂芳基基团包括，但不限于，吖啶基，苯并吲哚基，咔唑基，二苯并呋喃基，咟啶基，菲咯啉基，菲啶基和吩嗪基。在一些或任一实施方案，杂芳基是亚苯基、亚萘基、亚吡啶基、亚嘧啶基、亚吡嗪基、亚哒嗪基、亚噻唑基、苯并噻唑基、苯并[d]异噻唑基、咪唑并[1,2-a]吡啶基、喹啉基、1H-吲哚基、吡咯并[1,2-b]哒嗪基、苯并呋喃基、苯并[b]噻吩基、1H-吲唑基、苯并[d]异噁唑基、喹唑啉基、1H-吡咯并[3,2-c]吡啶基、吡唑并[1,5-a]嘧啶基、咪唑并[1,2-b]哒嗪基、或吡唑并[1,5-a]吡啶基；其各自任选地被1、2、3或4个本说明书通篇中所定义的基团取代，在一些实施方案，包括被独立地选自D、F、Cl、Br、I、N 3、CN、NO 2、OH、SH、NH 2、烷基、卤代烷基、烯基、炔基、烷氧基、烷基氨基、羟烷基、氰基取代的烷基、环烷基、杂环基、芳基、杂芳基、-S(＝O) 0-2R 11、-C(＝O)R 11、-S(＝O) 1-2OR 4a、-OS(＝O) 1-2R 4a、-C(＝O)OR 4a、-OC(＝O)R 4a、-C(＝O)NR 12aR 12b、-S(＝O) 1-2NR 12aR 12b、-O-R 13-C(＝O)OR 4a、-O-R 13-S(＝O) 1-2OR 4a、-N(R 12a)-R 13-C(＝O)OR 4a、-C(＝O)N(R 12a)-R 13-OH、 -C(＝O)N(R 12a)-R 13-NH 2、-C(＝O)N(R 12a)-R 13-C(＝O)OR 4a、-C(＝O)N(R 12a)-R 13-S(＝O) 1-2OR 4a、-C(＝O)N(R 12a)-S(＝O) 1-2R 11、-N(R 12a)C(＝O)NR 12aR 12b、-N(R 12a)S(＝O) 1-2NR 12aR 12b、-N(R 12a)C(＝O)N(R 12a)-S(＝O) 1-2R 11、-OC(＝O)N(R 12a)-S(＝O) 1-2R 11等的基团取代，其中R 4a、R 11、R 12a、R 12b、和R 13具有本发明所述定义。 The term "heteroaryl" as used herein, unless otherwise specified, 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. In some embodiments, 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. In some embodiments, 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. In certain embodiments, 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. In certain embodiments, 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, thiadiazolopyrimidyl, and thienopyryl. In certain embodiments, tricyclic heteroaryl groups include, but are not limited to, acridinyl, benzoindolyl, carbazolyl, dibenzofuranyl, pyridinyl, phenanthroline, phenanthridine And phenazinyl. In some or any embodiments, 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, 3, or 4 throughout this specification substituted groups, in some embodiments, comprise 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, cycloalkyl, heterocyclyl, aryl, heteroaryl, -S (= O) 0-2 R 11 ,- C (= O) R 11 , -S (= O) 1-2 OR 4a , -OS (= O) 1-2 R 4a , -C (= O) OR 4a , -OC (= O) R 4a , -C (= O) NR 12a R 12b , -S (= O) 1-2 NR 12a R 12b , -OR 13 -C (= O) OR 4a , -OR 13 -S (= O) 1-2 OR 4a , -N (R 12a ) -R 13 -C (= O) OR 4a , -C (= O) N (R 12a ) -R 13 -OH, -C (= O) N (R 12a ) -R 13 -NH 2 , -C (= O) N (R 12a ) -R 13 -C (= O) OR 4a , -C (= O) N (R 12a ) -R 13 -S (= O) 1-2 OR 4a, -C (= O) N (R 12a) -S (= O) 1-2 R 11, -N ( R 12a ) C (= O) NR 12a R 12b , -N (R 12a ) S (= O) 1-2 NR 12a R 12b , -N (R 12a ) C (= O) N (R 12a ) -S (= O) 1-2 R 11 , -OC (= O) N (R 12a ) -S (= O) 1-2 R 11, etc., in which R 4a , R 11 , R 12a , R 12b , And R 13 have the definitions described in the present invention.
本发明使用的术语“亚杂芳基”表示从杂芳基基团中去掉两个氢原子所得到的的二价杂芳基基团，其中杂芳基基团具有本发明所述定义。The term "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.
术语“烷基氨基”包括“N-烷基氨基”和“N,N-二烷基氨基”，其中氨基基团分别独立地被一个或两个烷基基团所取代。其中一些实施例是，烷基氨基是一个或两个C 1-6烷基连接到氮原子上的较低级的烷基氨基基团。另外一些实施例是，烷基氨基是C 1-3的较低级的烷基氨基基团。合适的烷基氨基基团可以是单烷基氨基或二烷基氨基，这样的实例包括，但并不限于，N-甲氨基，N-乙氨基，N,N-二甲氨基，N,N-二乙氨基等等。 The term "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.
术语“氰基取代烷基”包括被一个或多个氰基所取代的C 1-10直链或支链烷基基团。其中一些实施例是，氰基取代的烷基是被一个或多个氰基基团所取代的C 1-6“较低级的氰基烷基”，另一些实施例是，氰基取代的烷基是被一个或多个氰基基团所取代的C 1-4“较低级的氰基烷基”，这样的实例包括，但并不限于，CNCH 2-、CNCH 2CH 2-、CNCH 2CH 2CH 2-、CNCH 2CHCNCH 2-等。 The term "cyano-substituted alkyl" includes C1-10 straight or branched chain alkyl groups substituted with one or more cyano groups. In some examples, the cyano-substituted alkyl is a C 1-6 "lower cyanoalkyl" substituted with one or more cyano groups, and in other examples, 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.
像本发明所描述的，取代基画一个键连接到中心的环上形成的环体系(如下图所示)代表取代基可在任一环上任何可取代的位置取代。例如，式b代表A环或B环上任何可能被取代的位置均可被取代，如式c、d、e、f、g、h、i、j、k、l、m、n、o、p、q等所示。As described in the present invention, 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. For example, 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.
Figure PCTCN2019099219-appb-000015
Figure PCTCN2019099219-appb-000015
本发明所使用的术语“前药”，代表一个化合物在体内转化为式(I)所示的化合物。这样的转化受前体药 物在血液中水解或在血液或组织中经酶转化为母体结构的影响。本发明前体药物类化合物可以是酯，在现有的发明中酯可以作为前体药物的有苯酯类，脂肪族(C 1-C 24)酯类，酰氧基甲基酯类，碳酸酯，氨基甲酸酯类和氨基酸酯类。例如本发明里的一个化合物包含羟基，即可以将其酰化得到前体药物形式的化合物。其他的前体药物形式包括磷酸酯，如这些磷酸酯类化合物是经母体上的羟基磷酸化得到的。关于前体药物完整的讨论可以参考以下文献：T.Higuchi and V.Stella,Pro-drugs as Novel Delivery Systems,Vol.14 of the A.C.S.Symposium Series,Edward B.Roche,ed.,Bioreversible Carriers in Drug Design,American Pharmaceutical Association and Pergamon Press,1987,J.Rautio et al.,Prodrugs:Design and Clinical Applications,Nature Review Drug Discovery,2008,7,255-270,and S.J.Hecker et al.,Prodrugs of Phosphates and Phosphonates,Journal of Medicinal Chemistry,2008,51,2328-2345。 The term "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. In the existing invention, 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. For example, a compound in the present invention contains a hydroxyl group, which can be acylated to obtain a compound in the form of a prodrug. Other prodrug forms include phosphate esters. For example, these phosphate ester compounds are obtained by phosphorylation of hydroxy groups on the parent. For a complete discussion of 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. Rautio et al., Prodrugs: Design and Clinical Applications, Nature Review Drug Discovery, 2008, 7, 255-270, and SJ Hecker et al., Prodrugs of Phosphates and Phosphonates, Journal of Medicinal Chemistry , 2008, 51,2328-2345.
“代谢物”是指具体的化合物或其盐在体内通过代谢作用所得到的产物。一个化合物的代谢产物可以通过所属领域公知的技术来进行鉴定，其活性可以通过如本发明所描述的那样采用试验的方法进行表征。这样的产物可以是通过给药化合物经过氧化，还原，水解，酰氨化，脱酰氨作用，酯化，脱脂作用，酶裂解等等方法得到。相应地，本发明包括化合物的代谢产物，包括将本发明的化合物与哺乳动物充分接触一段时间所产生的代谢产物。"Metabolite" 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. Accordingly, 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.
本发明所使用的“药学上可接受的盐”是指本发明的化合物的有机盐和无机盐。药学上可接受的盐在所属领域是为我们所熟知的，如文献：S.M.Berge et al.,describe pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences,1977,66:1-19.所记载的。药学上可接受的无毒的酸形成的盐包括，但并不限于，与氨基基团反应形成的无机酸盐如盐酸盐，氢溴酸盐，磷酸盐，硫酸盐，高氯酸盐，和有机酸盐如乙酸盐，草酸盐，马来酸盐，酒石酸盐，柠檬酸盐，琥珀酸盐，丙二酸盐，或通过书籍文献上所记载的其他方法如离子交换法来得到这些盐。其他药学上可接受的盐包括己二酸盐，藻酸盐，抗坏血酸盐，天冬氨酸盐，苯磺酸盐，苯甲酸盐，重硫酸盐，硼酸盐，丁酸盐，樟脑酸盐，樟脑磺酸盐，环戊基丙酸盐，二葡萄糖酸盐，十二烷基硫酸盐，乙磺酸盐，甲酸盐，反丁烯二酸盐，葡庚糖酸盐，甘油磷酸盐，葡萄糖酸盐，半硫酸盐，庚酸盐，己酸盐，氢碘酸盐，2-羟基-乙磺酸盐，乳糖醛酸盐，乳酸盐，月桂酸盐，月桂基硫酸盐，苹果酸盐，丙二酸盐，甲磺酸盐，2-萘磺酸盐，烟酸盐，硝酸盐，油酸盐，棕榈酸盐，扑酸盐，果胶酸盐，过硫酸盐，3-苯基丙酸盐，苦味酸盐，特戊酸盐，丙酸盐，硬脂酸盐，硫氰酸盐，对甲苯磺酸盐，十一酸盐，戊酸盐，等等。通过与适当的碱反应得到的盐包括碱金属，碱土金属，铵和N +(C 1-C 4烷基) 4的盐。本发明也拟构思了任何所包含N的基团的化合物所形成的季铵盐。水溶性或油溶性或分散产物可以通过季铵化作用得到。碱金属或碱土金属盐包括钠，锂，钾，钙，镁，等等。药学上可接受的盐进一步包括适当的、无毒的铵，季铵盐和抗平衡离子形成的胺阳离子，如卤化物，氢氧化物，羧化物，硫酸化物，磷酸化物，硝酸化物，C 1-8磺酸化物和芳香磺酸化物。 "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. Other pharmaceutically acceptable 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 -Phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, etc. 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.
本发明的“溶剂化物”是指一个或多个溶剂分子与本发明的化合物所形成的缔合物。形成溶剂化物的溶剂包括，但并不限于，水，异丙醇，乙醇，甲醇，二甲亚砜，乙酸乙酯，乙酸和氨基乙醇。术语“水合物”是指溶剂分子是水所形成的缔合物。The "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. The term "hydrate" refers to an association formed by the solvent molecules being water.
当所述溶剂为水时，可以使用术语“水合物”。在一些实施例中，一个本发明化合物分子可以与一个水分子相结合，比如一水合物；在另外一些实施例中，一个本发明化合物分子可以与多于一个的水分子相结合，比如二水合物，还有一些实施例中，一个本发明化合物分子可以与少于一个的水分子相结合，比如半水合物。应注意，本发明所述的水合物保留有非水合形式的所述化合物的生物有效性。When the solvent is water, the term "hydrate" may be used. In some embodiments, 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.
如本发明所使用的术语“治疗”任何疾病或病症，在其中一些实施方案中指改善疾病或病症(即减缓或阻止或减轻疾病或其至少一种临床症状的发展)。在另一些实施方案中，“治疗”指缓和或改善至少一种身体参数，包括可能不为患者所察觉的身体参数。在另一些实施方案中，“治疗”指从身体上(例如稳定可察觉的症状)或生理学上(例如稳定身体的参数)或上述两方面调节疾病或病症。在另一些实施方案中，“治疗”指预防或延迟疾病或病症的发作、发生或恶化。The term "treating" 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.
发明内容Summary of the invention
本发明提供的螺桥环化合物对FXR具有很好的激动活性的化合物，可用于制备治疗由FXR介导的疾病，包括非酒精性脂肪性肝病，非酒精性脂肪肝炎，慢性肝内或肝外胆汁淤积病症，由慢性胆汁淤积病症或者急性肝内胆汁淤积病症导致的肝纤维化，慢性乙型肝炎，胆囊结石，肝癌，结肠癌，或者肠道炎性疾病的药物。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.
一方面，本发明提供了化合物，其包含式(I)所示化合物，或式(I)所示化合物的药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、氮氧化物、代谢物、前药、或混合物：In one aspect, 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:
Figure PCTCN2019099219-appb-000016
Figure PCTCN2019099219-appb-000016
其中，among them,
A为C或N；A is C or N;
P为C(R a)、N、N(R b)、或O； P is C (R a ), N, N (R b ), or O;
Q为C(R a)、N、N(R b)、或O； Q is C (R a ), N, N (R b ), or O;
M为C或N；M is C or N;
Figure PCTCN2019099219-appb-000017
为单键或双键；
Figure PCTCN2019099219-appb-000017
Single or double bond;
R 1为H、F、Cl、Br、I、-CN、烷基、烯基、炔基、芳基、杂芳基、环烷基、或杂环基，其中所述R 1独立任选地被1、2、3或4个R 5取代； 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为芳基、杂芳基、环烷基、或杂环基，其中所述R 2独立任选地被1、2、3或4个R 6取代； 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和R 3b各自独立地为H、F、Cl、Br、I、CN、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氨基、C 1-6烷氧基、卤代C 1-6烷氧基、C 3-6环烷基、或卤代C 3-6环烷基，或者R 3a、R 3b同与之连接的碳原子一起形成C 3-6环烷基、C 3-6环烯基、或3-6个原子组成的杂环基；其中所述C 1-6烷基、C 1-6烷氧基、C 1-6烷氨基、C 3-6环烷基、C 3-6环烯基、和3-6个原子组成的杂环基独立任选地被1、2、3或4个R 7取代； 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为：X is:
Figure PCTCN2019099219-appb-000018
Figure PCTCN2019099219-appb-000018
其中X独立任选地被1、2、3或4个R 8取代； Wherein X is independently optionally substituted by 1, 2, 3 or 4 R 8 ;
X 1不存在，或X 1为-N(R 1a)-、O、S、-C(＝O)-、-S(＝O)-、-S(＝O) 2-、-C(＝O)N(R 1a)-、-S(＝O)N(R 1a)-、或-S(＝O) 2N(R 1a)-； X 1 does not exist, or X 1 is -N (R 1a )-, O, S, -C (= O)-, -S (= O)-, -S (= O) 2- , -C (= O) N (R 1a )-, -S (= O) N (R 1a )-, or -S (= O) 2 N (R 1a )-;
X 2、X 3和X 4各自独立地为-O-、-S-、-NH-、-(CH 2) m1-NH-(CH 2) m2-、-(CH 2) m1-O-(CH 2) m2-、-(CH 2) m1-S-(CH 2) m2-、或-(CH 2) m3-； 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 -;
Y不存在，或Y为-N(R 1a)-、-O-、-S-、-C(＝O)-、-S(＝O)-、-S(＝O) 2-、-C(＝O)N(R 1a)-、-S(＝O)N(R 1a)-、-S(＝O) 2N(R 1a)-、C 1-6亚烷基、C 2-6亚烯基、C 2-6亚炔基、C 3-8亚环烷基、C 2-9亚杂环基、C 6-10亚芳基、或C 1-9亚杂芳基，其中Y独立任选地被1、2、3或4个R 9取代； Y does not exist, or Y is -N (R 1a )-, -O-, -S-, -C (= O)-, -S (= O)-, -S (= O) 2- , -C (= O) N (R 1a )-, -S (= O) N (R 1a )-, -S (= O) 2 N (R 1a )-, C 1-6 alkylene, C 2-6 Alkenylene, C 2-6 alkynylene, C 3-8 cycloalkylene, C 2-9 heterocyclylene, C 6-10 arylene, or C 1-9 heteroarylene, where Y Independently optionally substituted by 1, 2, 3 or 4 R 9 ;
Z为亚芳基、亚杂芳基、或亚杂环基，其中Z独立任选地被1、2、3或4个R 10取代； Z is an arylene, heteroarylene, or heterocyclic group, wherein Z is independently optionally substituted with 1, 2, 3, or 4 R 10 ;
R 4为杂芳基、-S(＝O) 0-2R 11、-C(＝O)R 11、-S(＝O) 1-2OR 4a、-OS(＝O) 1-2R 4a、-C(＝O)OR 4a、-OC(＝O)R 4a、-C(＝O)NR 12aR 12b、-S(＝O) 1-2NR 12aR 12b、-O-R 13-C(＝O)OR 4a、-O-R 13-S(＝O) 1-2OR 4a、-N(R 12a)-R 13-C(＝O)OR 4a、-C(＝O)N(R 12a)-R 13-OH、-C(＝O)N(R 12a)-R 13-NH 2、-C(＝O)N(R 12a)-R 13-C(＝O)OR 4a、-C(＝O)N(R 12a)-R 13-S(＝O) 1-2OR 4a、-C(＝O)N(R 12a)-S(＝O) 1-2R 11、-N(R 12a)C(＝O)NR 12aR 12b、-N(R 12a)S(＝O) 1-2NR 12aR 12b、-N(R 12a)C(＝O)N(R 12a)-S(＝O) 1-2R 11、或-OC(＝O)N(R 12a)-S(＝O) 1-2R 11； R 4 is heteroaryl, -S (= O) 0-2 R 11 , -C (= O) R 11 , -S (= O) 1-2 OR 4a , -OS (= O) 1-2 R 4a , -C (= O) OR 4a , -OC (= O) R 4a , -C (= O) NR 12a R 12b , -S (= O) 1-2 NR 12a R 12b , -OR 13 -C (= O) OR 4a , -OR 13 -S (= O) 1-2 OR 4a , -N (R 12a ) -R 13 -C (= O) OR 4a , -C (= O) N (R 12a ) -R 13 -OH, -C (= O) N (R 12a ) -R 13 -NH 2 , -C (= O) N (R 12a ) -R 13 -C (= O) OR 4a , -C (= O) N (R 12a ) -R 13 -S (= O) 1-2 OR 4a, -C (= O) N (R 12a) -S (= O) 1-2 R 11, -N ( R 12a ) C (= O) NR 12a R 12b , -N (R 12a ) S (= O) 1-2 NR 12a R 12b , -N (R 12a ) C (= O) N (R 12a ) -S (= O) 1-2 R 11 , or -OC (= O) N (R 12a ) -S (= O) 1-2 R 11 ;
各R 4a分别独立地为H、烷基、烯基、炔基、卤代烷基、氰基取代的烷基、羟烷基、芳基、芳烷基、杂芳基、杂芳基烷基、环烷基、环烷基烷基、杂环基、或杂环基烷基；其中R 4a独立任选地被1、2、3或4个R 4b取代； 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 ;
各R 11分别独立地为H、OH、NH 2、烷基、烯基、炔基、卤代烷基、羟烷基、氰基取代的烷基、烷氧基、卤代烷氧基、芳基、芳烷基、杂芳基、杂芳基烷基、环烷基、环烷基烷基、杂环基、或杂环基烷基；其中R 11独立任选地被1、2、3或4个R 11a取代； 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;
各R 12a和R 12b分别独立地为H、烷基、烯基、炔基、卤代烷基、氰基取代的烷基、羟烷基、芳基、芳烷基、杂芳基、杂芳基烷基、环烷基、环烷基烷基、杂环基、或杂环基烷基；其中R 12a和R 12b分别独立任选地被1、2、3或4个R 11b取代； 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 ;
各R 13分别独立地为亚烷基、亚烯基、亚炔基、羟烷基、氰基取代的亚烷基、或卤代亚烷基； Each R 13 is independently alkylene, alkenylene, alkynylene, hydroxyalkyl, cyano-substituted alkylene, or haloalkylene;
各R 4b、R 11a和R 11b分别独立地为H、-CN、-NO 2、-OH、-NH 2、F、Cl、Br、I、C 1-6烷基、C 2-6烯基、C 2-6炔基、卤代C 1-6烷基、氰基取代的C 1-6烷基、C 1-6羟烷基、或C 1-6烷氧基； 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;
各R 1a和R b分别独立地为H、烷基、烯基、炔基、氰基取代的烷基、羟烷基、或卤代烷基； Each R 1a and R b is independently H, alkyl, alkenyl, alkynyl, cyano-substituted alkyl, hydroxyalkyl, or haloalkyl;
各R a分别独立地为H、-CN、-NO 2、-OH、-NH 2、F、Cl、Br、I、烷基、烯基、炔基、卤代烷基、氰基取代的烷基、羟烷基、烷氧基、或卤代烷氧基； 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;
各R 5、R 6、R 7、R 8、R 9和R 10分别独立地为H、-CN、-NO 2、-OH、-NH 2、F、Cl、Br、I、烷基、烯基、炔基、卤代烷基、氰基取代的烷基、羟烷基、烷氨基、烷氧基、卤代烷氧基、环烷基、-S(＝O) 0-2R 14、-C(＝O)R 15、-OS(＝O) 1-2R 14a、-OC(＝O)R 15a、-N(R 16a)C(＝O)R 16、-OC(＝O)NR 17R 17a、-NR 17R 17a、-N(R 16a)S(＝O) 1-2R 16、或-N(R 16a)C(＝O)NR 17R 17a； 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, alkyl, alkene Alkyl, alkynyl, haloalkyl, cyano-substituted alkyl, hydroxyalkyl, alkamino, alkoxy, haloalkoxy, cycloalkyl, -S (= O) 0-2 R 14 , -C (= O) R 15 , -OS (= O) 1-2 R 14a , -OC (= O) R 15a , -N (R 16a ) C (= O) R 16 , -OC (= O) NR 17 R 17a , -NR 17 R 17a , -N (R 16a ) S (= O) 1-2 R 16 , or -N (R 16a ) C (= O) NR 17 R 17a ;
各R 14、R 14a、R 15、R 15a、和R 16分别独立地为H、C 1-6烷基、C 2-6烯基、C 2-6炔基、卤代C 1-6烷基、氰基取代的C 1-6烷基、芳基、芳烷基、杂芳基、杂芳基烷基、环烷基、环烷基烷基、杂环基、或杂环基烷基； Each of 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 ;
各R 16a、R 17、和R 17a和分别独立地为H、C 1-6烷基、C 2-6烯基、C 2-6炔基、氰基取代的C 1-6烷基、或卤代C 1-6烷基； 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;
各m1分别独立地为0、1、2或3；Each m1 is independently 0, 1, 2 or 3;
各m2分别独立地为0、1、2或3；和Each m2 is independently 0, 1, 2 or 3; and
各m3分别独立地为0、1、2或3。Each m3 is independently 0, 1, 2, or 3.
在一些实施方案，其中，X为In some embodiments, X is
Figure PCTCN2019099219-appb-000019
Figure PCTCN2019099219-appb-000019
其中X独立任选地被1、2、3或4个R 8取代； Wherein X is independently optionally substituted by 1, 2, 3 or 4 R 8 ;
X 1不存在，或X 1为-N(R 1a)-、-O-、-S-、-C(＝O)-、-S(＝O)-、-S(＝O) 2-、-C(＝O)N(R 1a)-、-S(＝O)N(R 1a)-、或-S(＝O) 2N(R 1a)-； X 1 does not exist, or X 1 is -N (R 1a )-, -O-, -S-, -C (= O)-, -S (= O)-, -S (= O) 2- , -C (= O) N (R 1a) -, - S (= O) N (R 1a) -, or -S (= O) 2 N ( R 1a) -;
各R 1a分别独立地为H、C 1-4烷基、C 2-4烯基、C 2-4炔基、氰基取代的C 1-4烷基、C 1-4羟烷基、或卤代C 1-4烷基；和 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; and
a为0、1、2或3；a is 0, 1, 2 or 3;
b为0、1、2或3；和b is 0, 1, 2 or 3; and
c为0、1、2或3。c is 0, 1, 2 or 3.
在一些实施方案，其中，A、P、Q和M以及碳原子组成的环
Figure PCTCN2019099219-appb-000020
为： In some embodiments, wherein A, P, Q, and M and a ring consisting of carbon atoms
Figure PCTCN2019099219-appb-000020
for:
Figure PCTCN2019099219-appb-000021
Figure PCTCN2019099219-appb-000021
其中，P 1为N、或-C(R a)-； Wherein P 1 is N or -C (R a )-;
Q 1为O、或-N(R b)-； Q 1 is O, or -N (R b )-;
R a为H、-CN、-NO 2、-OH、-NH 2、F、Cl、Br、I、C 1-4烷基、C 2-4烯基、C 2-4炔基、卤代C 1-4烷基、氰基取代的C 1-4烷基、C 1-4羟烷基、C 1-4烷氧基、或卤代C 1-4烷氧基；和 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为H、C 1-4烷基、C 2-4烯基、C 2-4炔基、氰基取代的C 1-4烷基、C 1-4羟烷基、或卤代C 1-4烷基。 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.
在一些实施方案，其中，所述化合物具有式(II)-(IV)所示结构：In some embodiments, the compound has a structure represented by formulae (II)-(IV):
Figure PCTCN2019099219-appb-000022
Figure PCTCN2019099219-appb-000022
其中，c为0、1、2或3。Where c is 0, 1, 2 or 3.
在一些实施方案，其中，Z为C 6-10亚芳基、C 1-9亚杂芳基、或C 2-7亚杂环基，其中Z独立任选地被1、2、3或4个R 10取代。 In some embodiments, wherein 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.
在一些实施方案，其中，Z为亚苯基、亚萘基、亚吡啶基、亚嘧啶基、亚吡嗪基、亚哒嗪基、亚噻唑基、苯并噻唑基、苯并[d]异噻唑基、咪唑并[1,2-a]吡啶基、萘基、喹啉基、1H-吲哚基、吡咯并[1,2-b]哒嗪基、苯并呋喃基、苯并[b]噻吩基、1H-吲唑基、苯并[d]异噁唑基、喹唑啉基、1H-吡咯并[3,2-c]吡啶基、吡唑并[1,5-a]嘧啶基、咪唑并[1,2-b]哒嗪基、或吡唑并[1,5-a]吡啶基，或Z为以下子结构式之一：In some embodiments, 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 formulas:
Figure PCTCN2019099219-appb-000023
Figure PCTCN2019099219-appb-000023
其中Z独立任选地被1、2、3或4个R 10取代。 Wherein Z is independently optionally substituted by 1, 2, 3 or 4 R 10 .
在一些实施方案，其中，所述化合物具有式(II1a)-(II1e)和(III1a)-(III1d)任一所示结构：In some embodiments, the compound has a structure represented by any one of formulae (II1a)-(II1e) and (III1a)-(III1d):
Figure PCTCN2019099219-appb-000024
Figure PCTCN2019099219-appb-000024
其中，among them,
Z 1为N、或C(R 10)； Z 1 is N or C (R 10 );
各Z 2分别独立地为O、S、N(R 10)、或-CHR 10-； Each Z 2 is independently O, S, N (R 10 ), or -CHR 10- ;
各Z 3分别独立地为N、或C(R 10)； Each Z 3 is independently N or C (R 10 );
Z 4和Z 5各自独立地为N、或C(R 10)； Z 4 and Z 5 are each independently N, or C (R 10 );
m为0、1、2或3；和m is 0, 1, 2 or 3; and
c为0、1、2或3。c is 0, 1, 2 or 3.
在一些实施方案，其中，所述化合物具有式(IIa)-(IIe)和(IIIa)-(IIId)任一所示结构：In some embodiments, the compound has a structure represented by any one of formulae (IIa)-(IIe) and (IIIa)-(IIId):
Figure PCTCN2019099219-appb-000025
Figure PCTCN2019099219-appb-000025
其中，among them,
Z 1为N、或C(R 10)； Z 1 is N or C (R 10 );
各Z 2分别独立地为O、S、N(R 10)、或-CHR 10-； Each Z 2 is independently O, S, N (R 10 ), or -CHR 10- ;
各Z 3分别独立地为N、或C(R 10)； Each Z 3 is independently N or C (R 10 );
Z 4和Z 5各自独立地为N、或C(R 10)；和 Z 4 and Z 5 are each independently N, or C (R 10 ); and
m为0、1、2或3。m is 0, 1, 2 or 3.
在一些实施方案，其中，R 1为H、F、Cl、Br、I、-CN、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 6-10芳基、C 1-9杂芳基、C 3-8环烷基、或C 3-7杂环基，其中所述R 1独立任选地被1、2、3或4个R 5取代。 In some embodiments, wherein 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 .
在一些实施方案，其中，R 1为苯基、环丙基、环丁基、环戊基、环己基、异丙基、或叔丁基，其中所述R 1独立任选地被1、2、3或4个R 5取代。 In some embodiments, wherein 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.
在一些实施方案，其中，R 2为C 6-10芳基、C 1-9杂芳基、C 3-8环烷基、或C 3-7杂环基，其中所述R 2独立任选地被1、2、3或4个R 6取代。 In some embodiments, wherein 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 .
在一些实施方案，其中，R 2为苯基、或C 1-9杂芳基，其中所述R 2独立任选地被1、2、3或4个R 6取代。 In some embodiments, wherein 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 .
在另一些实施方案，其中，R 2为： In other embodiments, wherein R 2 is:
Figure PCTCN2019099219-appb-000026
Figure PCTCN2019099219-appb-000026
其中所述R 2独立任选地被1、2、3或4个R 6取代。 Wherein said R 2 is independently optionally substituted with 1, 2, 3 or 4 R 6 .
在一些实施方案，其中，Y不存在，或Y为-N(R 1a)-、-O-、-S-、-C(＝O)-、-S(＝O)-、-S(＝O) 2-、-C(＝O)N(R 1a)-、-S(＝O)N(R 1a)-、-S(＝O) 2N(R 1a)-、C 1-4亚烷基、C 2-4亚烯基、或C 2-4亚炔基，其中Y独立任选地被1、2、3或4个R 9取代；和 In some embodiments, wherein Y is absent, or Y is -N (R 1a )-, -O-, -S-, -C (= O)-, -S (= O)-, -S (= O) 2- , -C (= O) N (R 1a )-, -S (= O) N (R 1a )-, -S (= O) 2 N (R 1a )-, C 1-4 Alkyl, C 2-4 alkenylene, or C 2-4 alkynylene, wherein Y is independently optionally substituted with 1, 2, 3, or 4 R 9 ; and
各R 1a分别独立地H、C 1-4烷基、C 2-4烯基、C 2-4炔基、氰基取代的C 1-4烷基、C 1-4羟烷基、或卤代C 1-4烷基。 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.
在一些实施方案，其中，In some embodiments, wherein
R 4为C 1-9杂芳基、-S(＝O) 0-2R 11、-C(＝O)R 11、-S(＝O) 1-2OR 4a、-OS(＝O) 1-2R 4a、-C(＝O)OR 4a、-OC(＝O)R 4a、-C(＝O)NR 12aR 12b、-S(＝O) 1-2NR 12aR 12b、-O-R 13-C(＝O)OR 4a、-O-R 13-S(＝O) 1-2OR 4a、-N(R 12a)-R 13-C(＝O)OR 4a、-C(＝O)N(R 12a)-R 13-OH、-C(＝O)N(R 12a)-R 13-NH 2、-C(＝O)N(R 12a)-R 13-C(＝O)OR 4a、-C(＝O)N(R 12a)-R 13-S(＝O) 1-2OR 4a、-C(＝O)N(R 12a)-S(＝O) 1-2R 11、-N(R 12a)C(＝O)NR 12aR 12b、-N(R 12a)S(＝O) 1-2NR 12aR 12b、-N(R 12a)C(＝O)N(R 12a)-S(＝O) 1-2R 11、或-OC(＝O)N(R 12a)-S(＝O) 1-2R 11。 R 4 is C 1-9 heteroaryl, -S (= O) 0-2 R 11 , -C (= O) R 11 , -S (= O) 1-2 OR 4a , -OS (= O) 1-2 R 4a , -C (= O) OR 4a , -OC (= O) R 4a , -C (= O) NR 12a R 12b , -S (= O) 1-2 NR 12a R 12b ,- OR 13 -C (= O) OR 4a , -OR 13 -S (= O) 1-2 OR 4a , -N (R 12a ) -R 13 -C (= O) OR 4a , -C (= O) N (R 12a ) -R 13 -OH, -C (= O) N (R 12a ) -R 13 -NH 2 , -C (= O) N (R 12a ) -R 13 -C (= O) OR 4a, -C (= O) N (R 12a) -R 13 -S (= O) 1-2 OR 4a, -C (= O) N (R 12a) -S (= O) 1-2 R 11 , -N (R 12a ) C (= O) NR 12a R 12b , -N (R 12a ) S (= O) 1-2 NR 12a R 12b , -N (R 12a ) C (= O) N (R 12a ) -S (= O) 1-2 R 11 or -OC (= O) N (R 12a ) -S (= O) 1-2 R 11 .
在一些实施方案，其中，各R 4a分别独立地为H、C 1-4烷基、C 2-4烯基、C 2-4炔基、卤代C 1-4烷基、氰基取代的C 1-4烷基、C 1-4羟烷基、C 6-10芳基、C 6-10芳基C 1-4烷基、C 1-9杂芳基、C 1-9杂芳基C 1-4烷基、C 3-8环烷基、C 3-8环烷基C 1-4烷基、C 3-7杂环基、或C 3-7杂环基C 1-4烷基；其中R 4a独立任选地被1、2、3或4个R 4b取代。 In some embodiments, wherein 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 .
在一些实施方案，其中，各R 11分别独立地为H、OH、NH 2、C 1-4烷基、C 2-4烯基、C 2-4炔基、卤代C 1-4烷基、氰基取代的C 1-4烷基、C 1-4羟烷基、C 1-4烷氧基、卤代C 1-4烷氧基、C 6-10芳基、C 6-10芳基C 1-4烷基、C 1-9杂芳基、C 1-9杂芳基C 1-4烷基、C 3-8环烷基、C 3-8环烷基C 1-4烷基、C 3-7杂环基、或C 3-7杂环基C 1-4烷基；其中R 11独立任选地被1、2、3或4个R 11a取代。 In some embodiments, wherein 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 .
在一些实施方案，其中，各R 12a和R 12b分别独立地为H、C 1-4烷基、C 2-4烯基、C 2-4炔基、卤代C 1-4烷基、氰基取代的C 1-4烷基、C 1-4羟烷基、C 6-10芳基、C 6-10芳基C 1-4烷基、C 1-9杂芳基、C 1-9杂芳基C 1-4烷基、C 3-8环烷基、C 3-8环烷基C 1-4烷基、C 3-7杂环基、或C 3-7杂环基C 1-4烷基；其中R 12a和R 12b分别独立任选地被1、2、3或4个R 11b取代。 In some embodiments, 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 .
在一些实施方案，其中，各R 13分别独立地为C 1-6亚烷基、C 1-6亚烯基、C 1-6亚炔基、C 1-6羟烷基、氰基取代的C 1-6亚烷基、或卤代C 1-6亚烷基。 In some embodiments, 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.
在一些实施方案，其中，各R 4b、R 11a和R 11b分别独立地为H、-CN、-NO 2、-OH、-NH 2、F、Cl、Br、I、甲基、乙基、丙基、丁基、甲氧基、乙氧基、-CH 2CH 2CN、-CH 2CH 2OH、-CF 3、或-CH 2CF 3。 In some embodiments, 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 .
在一些一些方案，其中，In some programs, where
R 4为C 1-9杂芳基、-S(＝O) 0-2R 11、-C(＝O)R 11、-S(＝O) 1-2OR 4a、-OS(＝O) 1-2R 4a、-C(＝O)OR 4a、-OC(＝O)R 4a、-C(＝O)NR 12aR 12b、-S(＝O) 1-2NR 12aR 12b、-O-R 13-C(＝O)OR 4a、-O-R 13-S(＝O) 1-2OR 4a、-N(R 12a)-R 13-C(＝O)OR 4a、-C(＝O)N(R 12a)-R 13-OH、-C(＝O)N(R 12a)-R 13-NH 2、-C(＝O)N(R 12a)-R 13-C(＝O)OR 4a、-C(＝O)N(R 12a)-R 13-S(＝O) 1-2OR 4a、-C(＝O)N(R 12a)-S(＝O) 1-2R 11、-N(R 12a)C(＝O)NR 12aR 12b、-N(R 12a)S(＝O) 1-2NR 12aR 12b、-N(R 12a)C(＝O)N(R 12a)-S(＝O) 1-2R 11、或-OC(＝O)N(R 12a)-S(＝O) 1-2R 11； R 4 is C 1-9 heteroaryl, -S (= O) 0-2 R 11 , -C (= O) R 11 , -S (= O) 1-2 OR 4a , -OS (= O) 1-2 R 4a , -C (= O) OR 4a , -OC (= O) R 4a , -C (= O) NR 12a R 12b , -S (= O) 1-2 NR 12a R 12b ,- OR 13 -C (= O) OR 4a , -OR 13 -S (= O) 1-2 OR 4a , -N (R 12a ) -R 13 -C (= O) OR 4a , -C (= O) N (R 12a ) -R 13 -OH, -C (= O) N (R 12a ) -R 13 -NH 2 , -C (= O) N (R 12a ) -R 13 -C (= O) OR 4a, -C (= O) N (R 12a) -R 13 -S (= O) 1-2 OR 4a, -C (= O) N (R 12a) -S (= O) 1-2 R 11 , -N (R 12a ) C (= O) NR 12a R 12b , -N (R 12a ) S (= O) 1-2 NR 12a R 12b , -N (R 12a ) C (= O) N (R 12a ) -S (= O) 1-2 R 11 , or -OC (= O) N (R 12a ) -S (= O) 1-2 R 11 ;
各R 4a分别独立地为H、C 1-4烷基、C 2-4烯基、C 2-4炔基、卤代C 1-4烷基、氰基取代的C 1-4烷基、C 1-4羟烷基、C 6-10芳基、C 6-10芳基C 1-4烷基、C 1-9杂芳基、C 1-9杂芳基C 1-4烷基、C 3-8环烷基、C 3-8环烷基C 1-4烷基、C 3-7杂环基、或C 3-7杂环基C 1-4烷基；其中R 4a独立任选地被1、2、3或4个R 4b取代； 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 ;
各R 11分别独立地为H、OH、NH 2、C 1-4烷基、C 2-4烯基、C 2-4炔基、卤代C 1-4烷基、氰基取代的C 1-4烷基、C 1-4羟烷基、C 1-4烷氧基、卤代C 1-4烷氧基、C 6-10芳基、C 6-10芳基C 1-4烷基、C 1-9杂芳基、C 1-9杂芳基C 1-4烷基、C 3-8环烷基、C 3-8环烷基C 1-4烷基、C 3-7杂环基、或C 3-7杂环基C 1-4烷基；其中R 11独立任选地被1、2、3或4个R 11a取代； 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 ;
各R 12a和R 12b分别独立地为H、C 1-4烷基、C 2-4烯基、C 2-4炔基、卤代C 1-4烷基、氰基取代的C 1-4烷基、C 1-4羟烷基、C 6-10芳基、C 6-10芳基C 1-4烷基、C 1-9杂芳基、C 1-9杂芳基C 1-4烷基、C 3-8环烷基、C 3-8环烷基C 1-4烷基、C 3-7杂环基、或C 3-7杂环基C 1-4烷基；其中R 12a和R 12b分别独立任选地被1、2、3或4个R 11b取代； 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 ;
各R 13分别独立地为C 1-6亚烷基、C 1-6亚烯基、C 1-6亚炔基、C 1-6羟烷基、氰基取代的C 1-6亚烷基、或卤代C 1-6亚烷基；和 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; and
各R 4b、R 11a和R 11b分别独立地为H、-CN、-NO 2、-OH、-NH 2、F、Cl、Br、I、甲基、乙基、丙基、丁基、甲氧基、乙氧基、-CH 2CH 2CN、-CH 2CH 2OH、-CF 3、或-CH 2CF 3。在另一些实施方案，其中， 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 . In other embodiments, wherein
R 4为呋喃基、噻唑基、吡唑基、咪唑基、三唑基、四唑基、吡啶基、喹啉基、-S(＝O) 0-2R 11、-C(＝O)R 11、-S(＝O) 1-2OR 4a、-OS(＝O) 1-2R 4a、-C(＝O)OR 4a、-OC(＝O)R 4a、-C(＝O)NR 12aR 12b、-S(＝O) 1-2NR 12aR 12b、-O-R 13-C(＝O)OR 4a、-O-R 13-S(＝O) 1-2OR 4a、-N(R 12a)-R 13-C(＝O)OR 4a、-C(＝O)N(R 12a)-R 13-OH、-C(＝O)N(R 12a)-R 13-NH 2、-C(＝O)N(R 12a)-R 13-C(＝O)OR 4a、-C(＝O)N(R 12a)-R 13-S(＝O) 1-2OR 4a、-C(＝O)N(R 12a)-S(＝O) 1-2R 11、-N(R 12a)C(＝O)NR 12aR 12b、-N(R 12a)S(＝O) 1-2NR 12aR 12b、-N(R 12a)C(＝O)N(R 12a)-S(＝O) 1-2R 11、或-OC(＝O)N(R 12a)-S(＝O) 1-2R 11。 R 4 is furyl, thiazolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, quinolinyl, -S (= O) 0-2 R 11 , -C (= O) R 11 , -S (= O) 1-2 OR 4a , -OS (= O) 1-2 R 4a , -C (= O) OR 4a , -OC (= O) R 4a , -C (= O) NR 12a R 12b , -S (= O) 1-2 NR 12a R 12b , -OR 13 -C (= O) OR 4a , -OR 13 -S (= O) 1-2 OR 4a , -N (R 12a ) -R 13 -C (= O) OR 4a , -C (= O) N (R 12a ) -R 13 -OH, -C (= O) N (R 12a ) -R 13 -NH 2 ,- C (= O) N (R 12a) -R 13 -C (= O) OR 4a, -C (= O) N (R 12a) -R 13 -S (= O) 1-2 OR 4a, -C (= O) N (R 12a ) -S (= O) 1-2 R 11 , -N (R 12a ) C (= O) NR 12a R 12b , -N (R 12a ) S (= O) 1- 2 NR 12a R 12b , -N (R 12a ) C (= O) N (R 12a ) -S (= O) 1-2 R 11 , or -OC (= O) N (R 12a ) -S (= O) 1-2 R 11 .
在另一些实施方案，其中，各R 4a分别独立地为H、甲基、乙基、丙基、丁基、苯基、萘基、苄基、C 1-9杂芳基、或C 1-9杂芳基C 1-4烷基；其中R 4a独立任选地被1、2、3或4个R 4b取代。 In other embodiments, 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.
在另一些实施方案，其中，各R 11分别独立地为H、OH、NH 2、甲基、乙基、丙基、丁基、苯基、萘基、苄基、C 1-9杂芳基、或C 1-9杂芳基C 1-4烷基；其中R 11独立任选地被1、2、3或4个R 11a取代。 In other embodiments, 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 .
在另一些实施方案，其中，各R 12a和R 12b分别独立地为H、甲基、乙基、丙基、丁基、苯基、萘基、苄基、C 1-9杂芳基、或C 1-9杂芳基C 1-4烷基；其中R 12a和R 12b分别独立任选地被1、2、3或4个R 11b取代。 In other embodiments, wherein 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 .
在另一些实施方案，其中，各R 13分别独立地为C 1-4亚烷基、C 1-4亚烯基、C 1-4亚炔基、C 1-4羟烷基、氰基取代的C 1-4亚烷基、或卤代C 1-4亚烷基。 In other embodiments, wherein 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.
在另一些实施方案，其中，各R 4b、R 11a和R 11b分别独立地为H、-CN、-NO 2、-OH、-NH 2、F、Cl、Br、I、甲基、乙基、丙基、丁基、甲氧基、乙氧基、-CH 2CH 2CN、-CH 2CH 2OH、-CF 3、或-CH 2CF 3。 In other embodiments, 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 .
在一些实施方案，其中，In some embodiments, wherein
R 4为呋喃基、噻唑基、吡唑基、咪唑基、三唑基、四唑基、吡啶基、喹啉基、-S(＝O) 0-2R 11、-C(＝O)R 11、-S(＝O) 1-2OR 4a、-OS(＝O) 1-2R 4a、-C(＝O)OR 4a、-OC(＝O)R 4a、-C(＝O)NR 12aR 12b、-S(＝O) 1-2NR 12aR 12b、-O-R 13-C(＝O)OR 4a、-O-R 13-S(＝O) 1-2OR 4a、-N(R 12a)-R 13-C(＝O)OR 4a、-C(＝O)N(R 12a)-R 13-OH、-C(＝O)N(R 12a)-R 13-NH 2、-C(＝O)N(R 12a)-R 13-C(＝O)OR 4a、-C(＝O)N(R 12a)-R 13-S(＝O) 1-2OR 4a、-C(＝O)N(R 12a)-S(＝O) 1-2R 11、-N(R 12a)C(＝O)NR 12aR 12b、-N(R 12a)S(＝O) 1-2NR 12aR 12b、-N(R 12a)C(＝O)N(R 12a)-S(＝O) 1-2R 11、或-OC(＝O)N(R 12a)-S(＝O) 1-2R 11； R 4 is furyl, thiazolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, quinolinyl, -S (= O) 0-2 R 11 , -C (= O) R 11 , -S (= O) 1-2 OR 4a , -OS (= O) 1-2 R 4a , -C (= O) OR 4a , -OC (= O) R 4a , -C (= O) NR 12a R 12b , -S (= O) 1-2 NR 12a R 12b , -OR 13 -C (= O) OR 4a , -OR 13 -S (= O) 1-2 OR 4a , -N (R 12a ) -R 13 -C (= O) OR 4a , -C (= O) N (R 12a ) -R 13 -OH, -C (= O) N (R 12a ) -R 13 -NH 2 ,- C (= O) N (R 12a) -R 13 -C (= O) OR 4a, -C (= O) N (R 12a) -R 13 -S (= O) 1-2 OR 4a, -C (= O) N (R 12a ) -S (= O) 1-2 R 11 , -N (R 12a ) C (= O) NR 12a R 12b , -N (R 12a ) S (= O) 1- 2 NR 12a R 12b , -N (R 12a ) C (= O) N (R 12a ) -S (= O) 1-2 R 11 , or -OC (= O) N (R 12a ) -S (= O) 1-2 R 11 ;
各R 4a分别独立地为H、甲基、乙基、丙基、丁基、苯基、萘基、苄基、C 1-9杂芳基、或C 1-9杂芳基C 1-4烷基；其中R 4a独立任选地被1、2、3或4个R 4b取代； 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 ;
各R 11分别独立地为H、OH、NH 2、甲基、乙基、丙基、丁基、苯基、萘基、苄基、C 1-9杂芳基、或C 1-9杂芳基C 1-4烷基；其中R 11独立任选地被1、2、3或4个R 11a取代； 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 ;
各R 12a和R 12b分别独立地为H、甲基、乙基、丙基、丁基、苯基、萘基、苄基、C 1-9杂芳基、或C 1-9杂芳基C 1-4烷基；其中R 12a和R 12b分别独立任选地被1、2、3或4个R 11b取代； 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 ;
各R 13分别独立地为C 1-4亚烷基、C 1-4亚烯基、C 1-4亚炔基、C 1-4羟烷基、氰基取代的C 1-4亚烷基、或卤代C 1-4亚烷基；和 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; and
各R 4b、R 11a和R 11b分别独立地为H、-CN、-NO 2、-OH、-NH 2、F、Cl、Br、I、甲基、乙基、丙基、丁基、甲氧基、乙氧基、-CH 2CH 2CN、-CH 2CH 2OH、-CF 3、或-CH 2CF 3。 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 .
在一些实施方案，其中，R 3a和R 3b各自独立地为H、F、Cl、Br、I、CN、甲基、乙基、丙基、丁基、卤代C 1-4烷基、C 1-4烷氨基、C 1-4烷氧基、或卤代C 1-4烷氧基，或者R 3a、R 3b同与之连接的碳原子一起形成C 3-6环烷基、C 3-6环烯基、或3-6个原子组成的杂环基；其中所述C 1-4烷氧基、C 1-4烷氨基、C 3-6环烷基、C 3-6环烯基、和3-6个原子组成的杂环基独立任选地被1、2、3或4个R 7取代。 In some embodiments, wherein 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 .
在一些实施方案，其中，In some embodiments, wherein
各R 5、R 6、R 7、R 8、R 9和R 10分别独立地为H、-CN、-NO 2、-OH、-NH 2、F、Cl、Br、I、C 1-6烷基、C 2-6烯基、C 2-6炔基、卤代C 1-6烷基、氰基取代的C 1-6烷基、C 1-6羟烷基、C 1-6烷氨基、C 1-6烷氧基、卤代 C 1-6烷氧基、-S(＝O) 0-2R 14、-C(＝O)R 15、-OS(＝O) 1-2R 14a、-OC(＝O)R 15a、-N(R 16a)C(＝O)R 16、-OC(＝O)NR 17R 17a、-NR 17R 17a、-N(R 16a)S(＝O) 1-2R 16、或-N(R 16a)C(＝O)NR 17R 17a。 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, 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, C 1-6 alkane Amino, C 1-6 alkoxy, halo C 1-6 alkoxy, -S (= O) 0-2 R 14 , -C (= O) R 15 , -OS (= O) 1-2 R 14a , -OC (= O) R 15a , -N (R 16a ) C (= O) R 16 , -OC (= O) NR 17 R 17a , -NR 17 R 17a , -N (R 16a ) S (= O) 1-2 R 16 or -N (R 16a ) C (= O) NR 17 R 17a .
在一些实施方案，其中，各R 14、R 14a、R 15、R 15a、和R 16分别独立地为H、C 1-4烷基、C 2-4烯基、C 2-4炔基、卤代C 1-4烷基、氰基取代的C 1-4烷基、C 6-10芳基、C 6-10芳基C 1-4烷基、C 1-9杂芳基、C 1-9杂芳基C 1-4烷基、C 3-8环烷基、C 3-8环烷基C 1-4烷基、C 3-7杂环基、或C 3-7杂环基C 1-4烷基。 In some embodiments, 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.
在一些实施方案，其中，各R 16a、R 17、和R 17a和分别独立地为H、C 1-4烷基、C 2-4烯基、C 2-4炔基、氰基取代的C 1-4烷基、或卤代C 1-4烷基。 In some embodiments, 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.
在另一一些实施方案，其中，In some other embodiments, wherein
各R 5、R 6、R 7、R 8、R 9和R 10分别独立地为H、-CN、-NO 2、-OH、-NH 2、F、Cl、Br、I、甲基、乙基、丙基、丁基、甲氧基、乙氧基、丙氧基、-CH 2CN、-CH 2OH、-CH 2CH 2CN、-CH 2CH 2OH、-CF 3、-CH 2CF 3、-OCF 3、或-OCH 2CF 3。 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 .
在一些实施方案，其中，In some embodiments, wherein
各R 5、R 6、R 7、R 8、R 9和R 10分别独立地为H、-CN、-NO 2、-OH、-NH 2、F、Cl、Br、I、C 1-6烷基、C 2-6烯基、C 2-6炔基、卤代C 1-6烷基、氰基取代的C 1-6烷基、C 1-6羟烷基、C 1-6烷氨基、C 1-6烷氧基、卤代C 1-6烷氧基、-S(＝O) 0-2R 14、-C(＝O)R 15、-OS(＝O) 1-2R 14a、-OC(＝O)R 15a、-N(R 16a)C(＝O)R 16、-OC(＝O)NR 17R 17a、-NR 17R 17a、-N(R 16a)S(＝O) 1-2R 16、或-N(R 16a)C(＝O)NR 17R 17a； 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, 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, C 1-6 alkane Amino, C 1-6 alkoxy, halo C 1-6 alkoxy, -S (= O) 0-2 R 14 , -C (= O) R 15 , -OS (= O) 1-2 R 14a , -OC (= O) R 15a , -N (R 16a ) C (= O) R 16 , -OC (= O) NR 17 R 17a , -NR 17 R 17a , -N (R 16a ) S (= O) 1-2 R 16 or -N (R 16a ) C (= O) NR 17 R 17a ;
各R 14、R 14a、R 15、R 15a、和R 16分别独立地为H、C 1-4烷基、C 2-4烯基、C 2-4炔基、卤代C 1-4烷基、氰基取代的C 1-4烷基、C 6-10芳基、C 6-10芳基C 1-4烷基、C 1-9杂芳基、C 1-9杂芳基C 1-4烷基、C 3-8环烷基、C 3-8环烷基C 1-4烷基、C 3-7杂环基、或C 3-7杂环基C 1-4烷基；和 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 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
各R 16a、R 17、和R 17a和分别独立地为H、C 1-4烷基、C 2-4烯基、C 2-4炔基、氰基取代的C 1-4烷基、或卤代C 1-4烷基。 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.
在一些实施方案，其中，In some embodiments, wherein
各R 5、R 6、R 7、R 8、R 9和R 10分别独立地为H、-CN、-NO 2、-OH、-NH 2、F、Cl、Br、I、甲基、乙基、丙基、丁基、甲氧基、乙氧基、丙氧基、-CH 2CN、-CH 2OH、-CH 2CH 2CN、-CH 2CH 2OH、-CF 3、-CH 2CF 3、-OCF 3、或-OCH 2CF 3。 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 .
在一些实施方案，本发明所述化合物为具有以下结构之一的化合物：In some embodiments, the compound of the invention is a compound having one of the following structures:
Figure PCTCN2019099219-appb-000027
Figure PCTCN2019099219-appb-000027
Figure PCTCN2019099219-appb-000028
Figure PCTCN2019099219-appb-000028
Figure PCTCN2019099219-appb-000029
Figure PCTCN2019099219-appb-000029
Figure PCTCN2019099219-appb-000030
Figure PCTCN2019099219-appb-000030
Figure PCTCN2019099219-appb-000031
Figure PCTCN2019099219-appb-000031
Figure PCTCN2019099219-appb-000032
Figure PCTCN2019099219-appb-000032
Figure PCTCN2019099219-appb-000033
Figure PCTCN2019099219-appb-000033
Figure PCTCN2019099219-appb-000034
Figure PCTCN2019099219-appb-000034
Figure PCTCN2019099219-appb-000035
Figure PCTCN2019099219-appb-000035
或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、氮氧化物、代谢物、前药、或混合物。Or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, or mixture thereof.
另一方面，本发明提供了药物组合物，所述药物组合物包含本发明所述的化合物，以及药学上可以接受的辅料、稀释剂或载体。In another aspect, the invention provides a pharmaceutical composition comprising a compound according to the invention, and a pharmaceutically acceptable excipient, diluent, or carrier.
在一些实施方案，本发明所述的药物组合物进一步包含附加治疗剂。In some embodiments, the pharmaceutical composition of the invention further comprises an additional therapeutic agent.
在一些实施方案，本发明所述组合物中，其中所述附加治疗剂是用于治疗血脂异常、胆汁淤积、雌激素诱导的胆汁淤积、药物诱导的胆汁淤积、原发性胆汁性肝硬化(PBC)、原发性硬化性胆管炎(PSC)、进行性家族性胆汁淤积(PFIC)、酒精导致的肝硬化、囊性纤维化、胆石病、肝纤维化、动脉粥样硬化症或糖尿病，特别是II型糖尿病的药物。In some embodiments, 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.
另一方面，本发明提供了使用本发明所述的化合物或本发明所述的药物组合物在制备用于预防或治疗哺乳动物由FXR介导的疾病的药物中的用途。In another aspect, 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.
在一些实施方案，所述FXR介导的疾病包括非酒精性脂肪性肝病，非酒精性脂肪肝炎，慢性肝内或肝外胆汁淤积病症，由慢性胆汁淤积病症或者急性肝内胆汁淤积病症导致的肝纤维化，慢性乙型肝炎，胆囊结石，肝癌，结肠癌，或者肠道炎性疾病。In some embodiments, 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.
在一些实施方案，本发明化合物或其药物组合物可与另外的治疗剂组合施用。In some embodiments, a compound of the invention or a pharmaceutical composition thereof may be administered in combination with an additional therapeutic agent.
在一些实施方案，本发明所述用途包括对哺乳动物施用足以实现所述治疗或预防的量的本发明所述化合物或药物组合物。In some embodiments, 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.
药物组合物、制剂和用途Pharmaceutical composition, preparation and use
当用作药物时，本发明化合物通常以药物组合物形式施用。所述组合物可以以制药技术中熟知的方式制备并且包含至少一个根据式I、II、III、IV、IIa-IIc、IIIa-IIIc、II1a-II1c、或III1a-III1c的本发明所述化合 物。通常，本发明化合物以药物有效量施用。实际施用的本发明化合物的量通常将由医师根据相关情形决定，所述情形包括待治疗病症、所选的施用途径、所施用的本发明的实际化合物、个别患者的年龄、体重和响应、患者症状的严重程度等。When used as a medicament, 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. Generally, 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.
本发明提供了包含本发明化合物和可药用载体的药用组合物。所述药用组合物可以制成适合于特定给药途径的制剂，例如口服给药、胃肠外给药和直肠给药等。另外，本发明的药用组合物可以制成固体形式(包括但不限于胶囊剂、片剂、丸剂、颗粒剂、散剂或栓剂)或液体形式(包括但不限于溶液剂、混悬液剂或乳剂)。药用组合物可以进行常规制药操作例如灭菌和/或可以含有常规惰性稀释剂、润滑剂或缓冲剂以及辅助剂，例如防腐剂、稳定剂、润湿剂、乳化剂和缓冲剂等。The invention provides 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. In addition, 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.
作为用于口服给药的液体组合物，可使用含有惰性稀释剂如水或液体石蜡的药学上可接受的溶液、悬浮液、乳液、糖浆剂和酏剂。所述这些组合物还可包含稀释剂以外的物质，在一些实施方案，包含润湿剂、甜味剂或调味剂制品。As the 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.
用于肠胃外给药的组合物可以是乳剂或无菌溶液。在某些实施方案，可使用丙二醇、聚乙二醇、植物油、特别是橄榄油或可注射的有机酯作为溶剂或载体，在一些实施方案，使用油酸乙酯作为溶剂或载体。所述这些组合物还可包含佐剂，特别是润湿剂，等渗剂，乳化剂，分散剂和稳定剂。可以几种方式进行灭菌，在某些实施方案，使用细菌学过滤器，通过辐射或通过加热进行灭菌。它们也可以无菌固体组合物的形式进行制备，其可在使用时溶于无菌水或任何其他可注射的无菌介质中。The composition for parenteral administration may be an emulsion or a sterile solution. In certain embodiments, 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.
用于直肠给药的组合物为栓剂或直肠胶囊，其除了活性成分之外还含有辅料如可可脂、半合成甘油酯或聚乙二醇。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.
在某些实施方案，本发明提供的组合物是药物组合物或单一单位剂型。本发明提供的药物组合物和单一单位剂型包含预防或治疗有效量的一种或多种预防剂或治疗剂(例如，本发明提供的化合物或其他预防剂或治疗剂)以及典型的一种或多种药学上可接受的载体或辅料。在具体实施方案和本发明中，术语“药学上可接受的”是指由联邦或州政府的监管机构批准，或者在美国药典或其他公认的药典中列出的用于动物、特别是用于人类的药物。术语“载体”包括与治疗剂一同施用的稀释剂、佐剂(例如，弗氏佐剂(完全和不完全))、辅料或媒介物。此类药物载体可以是无菌液体，如水和油类，包括石油、动物油、植物油或合成来源的那些，如花生油、大豆油、矿物油、芝麻油等。当静脉内施用药物组合物时，水可用作载体。盐水溶液和葡萄糖水溶液以及甘油溶液也可用作液体载体，特别是用于注射溶液。合适的药物载体的实例记载在Remington:The Science and Practice of Pharmacy；医药出版社(Pharmaceutical Press)；22版(2012年9月15日)中。In certain embodiments, 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. In specific embodiments and the present invention, the term "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. The term "carrier" includes a diluent, 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. When the pharmaceutical composition is administered intravenously, 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).
典型的药物组合物和剂型包含一种或多种辅料。合适的辅料对药学领域的技术人员而言是熟知的，在某些实施方案，合适的辅料包括淀粉、葡萄糖、乳糖、蔗糖、明胶、麦芽、大米、面粉、白垩、硅胶、硬脂酸钠、甘油单硬脂酸酯、滑石粉、氯化钠、脱脂奶粉、甘油、丙烯、乙二醇、水、乙醇等。特定的辅料是否适合掺入药物组合物或剂型，取决于本领域众所周知的各种因素，包括但不限于将所述剂型施用于受试者的方式以及所述剂型中的特定活性成分。若需要，所述组合物或单一单位剂型还可含有少量润湿剂或乳化剂，或pH缓冲剂。Typical pharmaceutical compositions and dosage forms contain one or more excipients. Suitable excipients are well known to those skilled in the pharmaceutical arts. In certain embodiments, 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. If desired, the composition or single unit dosage form may also contain small amounts of wetting or emulsifying agents, or pH buffering agents.
用于口服给药的适当的组合物包含有效量的本发明化合物，它可以为下列形式：片剂、锭剂、水性或油性混悬液、散剂或颗粒剂、乳剂、硬或软胶囊或糖浆或酏剂。口服使用的组合物可以根据药用组合物生产领域中已知的任何方法制备，此类组合物可以含有一或多种选自下列的成分：甜味剂、矫味剂、着色剂和防腐剂，从而提供药学上美观和可口的制剂。片剂可以包含活性成分以及与之组合的用于生产片剂的无毒的、可药用的辅料。这些辅料包括：例如，惰性稀释剂，例如碳酸钙、碳酸钠、乳糖、磷酸钙或磷酸钠；成粒剂和崩解剂，例如玉米淀粉或藻酸；粘合剂，例如淀粉、明胶或阿拉伯胶；润滑剂，例如硬脂酸镁、硬脂酸或滑石粉。片剂可以是未包衣的，或者根据已知技术包衣以延迟其在胃肠道内的崩解和吸收，从而在较长时间内提供持续作用。例如，可以采用延时材料，例如可以采用单硬脂酸甘油酯或二硬脂酸甘油酯。Suitable 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. These include, for example, 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. For example, a time delay material can be used, such as glyceryl monostearate or glyceryl distearate.
对于约50-70kg的个体而言，本发明的药用组合物或组合产品可以为约1-1000mg的活性成分的单位剂量，或约1-500mg或约1-250mg或约1-150mg或约0.5-100mg或约1-50mg的活性成分。化合物、药用组合物或其组合产品的治疗有效量取决于个体的种属、体重、年龄和个体健康情况、待治疗的病症或疾病或其严重程度。医师、临床医生或兽医可以容易地确定预防、治疗疾病或病症或者抑制其进展所必需的各个活性成分的有效量。For an individual of about 50-70 kg, 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.
上述剂量特性可以通过体外和体内试验采用合适的哺乳动物进行论证，所述哺乳动物例如小鼠、大鼠、犬、猴或离体器官、组织及其制品。本发明化合物在体外可以以溶液的形式应用，例如水溶液；在体内以例如混悬液或水溶液的形式在肠内、胃肠外(最好是静脉内)应用。体外剂量范围在约10-3摩尔浓度至10-9摩尔浓度之间。体内治疗有效量取决于给药途径，在约0.1-500mg/kg或约1-100mg/kg的范围内。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.
本发明化合物可以与一或多种其它治疗成分同时给药，或者在其之前或之后给药。本发明化合物可以与另一种成分通过相同或不同给药途径分别给药，或者两者在同一药用组合物中一起给药。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.
在一个实施方案，所述其他治疗成分是用于治疗血脂异常、胆汁淤积、雌激素诱导的胆汁淤积、药物诱导的胆汁淤积、原发性胆汁性肝硬化(PBC)、原发性硬化性胆管炎(PSC)、进行性家族性胆汁淤积(PFIC)、酒精导致的肝硬化、囊性纤维化、胆石病、肝纤维化、动脉粥样硬化症或糖尿病，特别是II型糖尿病的药物。In one embodiment, 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.
另一方面，本发明提供了本发明化合物或包含本发明化合物的药物组合物，其用于医学。在具体实施方案中，本发明提供了本发明化合物或包含本发明化合物的药物组合物，其用于预防和/或治疗哺乳动物由FXR介导的疾病的药物中的用途。In another aspect, the invention provides a compound of the invention or a pharmaceutical composition comprising a compound of the invention for use in medicine. In a specific embodiment, 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.
本发明也涉及式I、II、III、IV、IIa-IIe、IIIa-IIId、II1a-II1e、或III1a-III1d化合物或含有所述化合物的药物组合物，用于治疗具有饮食脂肪和脂溶性饮食维生素摄取降低的胃肠道疾病，通过增加胆酸和磷脂的肠道水平可以治疗该疾病。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.
在一些实施方案，本发明提供了本发明化合物或包含本发明化合物的药物组合物，其用于制备用于预防和/或治疗非酒精性脂肪性肝病，非酒精性脂肪肝炎，慢性肝内或肝外胆汁淤积病症，由慢性胆汁淤积病症或者急性肝内胆汁淤积病症导致的肝纤维化，慢性乙型肝炎，胆囊结石，肝癌，结肠癌，或者肠道炎性疾病。In some embodiments, 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.
在另一实施方案，本发明化合物可以用于有益地改变脂质特征，包括但不限于降低总胆固醇水平、降低LDL胆固醇水平、降低VLDL胆固醇水平、升高HDL胆固醇水平和/或降低甘油三酯水平。因此，本发明提供了治疗FXR介导的疾病的方法，所述疾病例如血脂异常和与血脂异常相关的疾病，该方法包括给予需要的患者治疗有效量的本发明化合物。In another embodiment, 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.
在另一实施方案，所述化合物或药用组合物用于治疗下列疾病：脂质和脂蛋白疾病，例如临床症状明显的高胆固醇血症、高甘油三酯血症和动脉粥样硬化症，通过FXR的下列有益作用可以改善上述疾病：升高HDL胆固醇、降低血清甘油三酯、使得肝脏胆固醇向胆酸的转化增加、提高VLDL和其它脂蛋白在肝脏中的清除率和代谢转化。In another embodiment, the compound or pharmaceutical composition is used to treat the following diseases: lipid and lipoprotein diseases, such as clinically marked hypercholesterolemia, hypertriglyceridemia, and atherosclerosis, The above-mentioned diseases can be improved by the following 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.
在另一个实施方案中，所述化合物和药用组合物可以用于制备药物，其中FXR靶向药物的降低脂质、抗胆汁淤积和抗纤维素化的组合作用可以用于治疗肝脏脂肪变性及相关综合征，例如非酒精性脂肪性肝炎(″NASH″)，或者用于治疗与酒精导致的肝硬化或病毒性肝炎有关的胆汁淤积和纤维素化。In another embodiment, 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.
本发明也涉及式I、II、III、IV、IIa-IIe、IIIa-IIId、II1a-II1e、或III1a-III1d化合物或含有所述化合物的药物组合物，用于心血管疾病的预防和创伤后治疗，例如急性心肌梗塞、急性中风或作为慢性阻塞性动脉粥样硬化症终点出现的血栓形成。在几篇选出的论文中，评价了FXR和FXR激动剂对癌症和非恶性细胞扩散以及细胞凋亡的作用。从这些初步结果似乎可以看出，FXR激动剂可能也会影响癌细胞系(Niesor等，Curr.Pharm.Des.2001，7(4)，231-59)和血管平滑肌细胞(VSMCs)(Bishop-Bailey等，Proc.Natl.Acad.Sci.U S A.2004，101(10)，3668-3673)中的细胞凋亡。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. In several selected papers, the effects of FXR and FXR agonists on the proliferation and apoptosis of cancer and non-malignant cells 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.S.A. 2004, 101 (10), 3668-3673).
具体实施方式detailed description
为描述本发明，以下列出了实施例。但需要理解，本发明不限于这些实施例，只是提供实践本发明的 方法。To describe the invention, the examples are listed below. However, it should be understood that the present invention is not limited to these embodiments, but merely provides a method for practicing the present invention.
一般地，本发明的化合物可以通过本发明所描述的方法制备得到，除非有进一步的说明，其中取代基的定义如式I、II、III、IV、IIa-IIe、IIIa-IIId、II1a-II1e、或III1a-III1d所示。下面的反应方案和实施例用于进一步举例说明本发明的内容。Generally, 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.
所属领域的专业人员将认识到：本发明所描述的化学反应可以用来合适地制备许多本发明的其他化合物，且用于制备本发明的化合物的其它方法都被认为是在本发明的范围之内。例如，根据本发明那些非例证的化合物的合成可以成功地被所属领域的技术人员通过修饰方法完成，如适当的保护干扰基团，通过利用其他已知的试剂除了本发明所描述的，或将反应条件做一些常规的修改。另外，本发明所公开的反应或已知的反应条件也公认地适用于本发明其他化合物的制备。Those skilled in the art will recognize that the chemical reactions described in this invention can be used to suitably prepare many other compounds of the invention, and that other methods for preparing the compounds of this invention are considered to be within the scope of this invention Inside. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art through modification methods, such as appropriate protection of interference groups, by using other known reagents in addition to those described in the present invention, or The reaction conditions are modified in a conventional manner. In addition, the disclosed reactions or known reaction conditions are also generally accepted for the preparation of other compounds of the invention.
下面所描述的实施例，除非其他方面表明所有的温度定为摄氏度。试剂购买于商品供应商如Aldrich Chemical Company,Arco Chemical Company and Alfa Chemical Company，使用时都没有经过进一步纯化，除非其他方面表明。一般的试剂从汕头西陇化工厂，广东光华化学试剂厂，广州化学试剂厂，天津好寓宇化学品有限公司，天津市福晨化学试剂厂，武汉鑫华远科技发展有限公司，青岛腾龙化学试剂有限公司，和青岛海洋化工厂购买得到。The examples described below, unless otherwise indicated, all temperatures are set to degrees Celsius. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company, Alfa Chemical Company, and were used without further purification unless otherwise indicated. General reagents from Shantou Xilong Chemical Factory, Guangdong Guanghua Chemical Reagent Factory, Guangzhou Chemical Reagent Factory, Tianjin Haoyuyu Chemical Co., Ltd., Tianjin Fuchen Chemical Reagent Factory, Wuhan Xinhuayuan Technology Development Co., Ltd., Qingdao Tenglong Chemical Reagent Co., Ltd. and Qingdao Ocean Chemical Plant.
无水四氢呋喃，二氧六环，甲苯，乙醚是经过金属钠回流干燥得到。无水二氯甲烷和氯仿是经过氢化钙回流干燥得到。乙酸乙酯，石油醚，正己烷，N,N-二甲基乙酰胺和N,N-二甲基甲酰胺是经无水硫酸钠事先干燥使用。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.
以下反应一般是在氮气或氩气正压下或在无水溶剂上套一干燥管(除非其他方面表明)，反应瓶都塞上合适的橡皮塞，底物通过注射器打入。玻璃器皿都是干燥过的。The following reactions are generally carried out under a positive pressure of nitrogen or argon or a dry tube over an anhydrous solvent (unless otherwise indicated), the reaction bottle is plugged with a suitable rubber stopper, and the substrate is injected through a syringe. Glassware is dry.
色谱柱是使用硅胶柱。硅胶(300-400目)购于青岛海洋化工厂。The column was a silica gel column. Silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Plant.
1H NMR谱使用Bruker 400MHz或600MHz核磁共振谱仪记录。 1H NMR谱以CDC1 3、DMSO-d 6、CD 3OD或丙酮-d 6为溶剂(以ppm为单位)，用TMS(0ppm)或氯仿(7.26ppm)作为参照标准。当出现多重峰的时候，将使用下面的缩写：s(singlet，单峰)、d(doublet，双峰)、t(triplet，三重峰)、m(multiplet，多重峰)、br(broadened，宽峰)、dd(doublet of doublets，双二重峰)、dt(doublet of triplets，双三重峰)。偶合常数，用赫兹(Hz)表示。 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. When multiple peaks appear, the following abbreviations will be used: s (singlet, singlet), d (doublet, doublet), t (triplet, triplet), m (multiplet, multiplet), br (broadened, broad Peaks), dd (doublet of doublets), dt (doublet of triplets). Coupling constant, expressed in Hertz (Hz).
低分辨率质谱(MS)数据的测定条件是：Agilent 6120四级杆HPLC-M(柱子型号：Zorbax SB-C18,2.1x 30mm,3.5微米,6min,流速为0.6mL/min。流动相：5％-95％((含0.1％甲酸的CH 3CN)在(含0.1％甲酸的H 2O)中的比例)，采用电喷雾电离(ESI)，在210nm/254nm下，用UV检测。 The determination conditions of low resolution mass spectrometry (MS) data are: Agilent 6120 quadrupole HPLC-M (column model: Zorbax SB-C18, 2.1x 30mm, 3.5 microns, 6min, flow rate 0.6mL / min. Mobile phase: 5 % -95% ((the proportion of CH 3 CN containing 0.1% formic acid) in (H 2 O containing 0.1% formic acid)) was detected by UV at 210 nm / 254 nm using electrospray ionization (ESI).
纯的化合物的使用Agilent 1260pre-HPLC或Calesep pump 250pre-HPLC(柱子型号：NOVASEP 50/80mm DAC)，在210nm/254nm用UV检测。Pure compounds were detected using Agilent 1260 pre-HPLC or Calepep pump 250 pre-HPLC (column model: NOVASEP 50 / 80mm DAC) and UV detection at 210nm / 254nm.
下面简写词的使用贯穿本发明：The following abbreviations are used throughout the invention:
CD 3OD 氘代甲醇 CD 3 OD deuterated methanol
CDCl 3 氘代氯仿 CDCl 3 deuterated chloroform
DMF N,N-二甲基甲酰胺DMFN, N-dimethylformamide
DMSO-d 6 氘代二甲基亚砜 DMSO-d 6 deuterated dimethyl sulfoxide
DCM 二氯甲烷DCM
g 克g
h 小时h
mL、ml 毫升mL, ml
RT、rt、r.t. 室温RT, rt, r.t. room temperature
Boc 叔丁氧羰基Boc tert-Butoxycarbonyl
Cbz 苄氧羰基Cbz benzyloxycarbonyl
Pd 2(dba) 3 三(二亚苄基丙酮)二钯 Pd 2 (dba) 3 tris (dibenzylideneacetone) dipalladium
X-Phos 2-二环己基磷-2',4',6'-三异丙基联苯X-Phos 2-dicyclohexyl phosphorus-2 ', 4', 6'-triisopropylbiphenyl
HATU 2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯HATU 2- (7-benzotriazole) -N, N, N ', N'-tetramethylurea hexafluorophosphate
HBTU O-苯并三氮唑-四甲基脲六氟磷酸酯HBTU O-benzotriazole-tetramethylurea hexafluorophosphate
BOP 苯并三氮唑-1-基氧基三(二甲基氨基)磷鎓六氟磷酸盐BOP benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate
PyBOP 六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷PyBOP hexafluorophosphate benzotriazol-1-yl-oxytripyrrolidinyl phosphorus
制备本发明公开化合物的典型合成步骤如下面的合成方案1、2和3所示。Typical synthetic steps for preparing the compounds disclosed herein are shown in the following synthetic schemes 1, 2 and 3.
合成方案1：Synthesis scheme 1:
Figure PCTCN2019099219-appb-000036
Figure PCTCN2019099219-appb-000036
其中，E 1选自卤素、甲磺酰氧基或对甲苯磺酰氧基；E 2选自卤素；R选自C 1-6烷基；Pr 1选自叔丁氧羰基、苄氧羰基、苄基、对甲氧基苄基；A、P、Q、M、R 1、R 2、R 3a、R 3b、R 11、R 12a、X、Y、Z均具有本发明所述定义。 Wherein 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.
将中间体1-1和中间体1-2在碱(如三乙胺、N,N-二异丙基乙胺、碳酸钾、碳酸铯、叔丁醇钾或叔丁醇钠)存在下以及加热(30℃至120℃)条件下，通过亲核取代反应得到中间体1-3；所得中间体1-3在酸性条件(如三氟乙酸、氯化氢)下，或钯催化氢化，或与三甲基碘硅烷反应脱去保护基Pr 1从而得到中间体1-4；将中间体1-4和中间体1-5在碱(如三乙胺、N,N-二异丙基乙胺、碳酸钾、碳酸铯)存在下以及加热(60℃至120℃)条件下，通过亲核取代反应得中间体1-6；或者中间体1-4和中间体1-5通过钯催化的偶联反应得到中间体1-6；中间体1-6在碱性条件下经过水解反应得到式1-7所示的化合物；式1-7所示的化合物在缩合剂如HATU、HBTU、BOP、PyBOP等的作用下，与中间体1-8发生缩合反应得到式1-9所示的化合物。 Intermediate 1-1 and intermediate 1-2 in the presence of a base such as triethylamine, N, N-diisopropylethylamine, potassium carbonate, cesium carbonate, potassium t-butoxide or sodium t-butoxide, and Intermediate 1-3 is obtained through nucleophilic substitution reaction under heating (30 ° C to 120 ° C); the obtained intermediate 1-3 is acidified (such as trifluoroacetic acid, hydrogen chloride), or palladium-catalyzed hydrogenation, or The methyl iodosilane reaction deprotects Pr 1 to obtain intermediate 1-4; intermediate 1-4 and intermediate 1-5 are in a base (such as triethylamine, N, N-diisopropylethylamine, Intermediate 1-6 is obtained by nucleophilic substitution reaction in the presence of potassium carbonate, cesium carbonate) and under heating (60 ° C to 120 ° C); or the coupling of intermediate 1-4 and intermediate 1-5 by palladium Intermediate 1-6 is obtained by reaction; Intermediate 1-6 is subjected to hydrolysis reaction under basic conditions to obtain a compound represented by Formula 1-7; the compound represented by Formula 1-7 is subjected to a condensing agent such as HATU, HBTU, BOP, PyBOP Under the action of condensation, a condensation reaction with the intermediate 1-8 is performed to obtain a compound represented by the formula 1-9.
合成方案2：Synthesis scheme 2:
Figure PCTCN2019099219-appb-000037
Figure PCTCN2019099219-appb-000037
其中，E 1选自卤素、甲磺酰氧基或对甲苯磺酰氧基；E 2选自卤素；R选自C 1-6烷基；Pr 1选自叔丁氧羰基、苄氧羰基、苄基、对甲氧基苄基；A、P、Q、M、R 1、R 2、R 3a、R 3b、X、Y、Z均具有本发明所述定义。 Wherein 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.
将中间体2-1和中间体1-5在碱(如三乙胺、N,N-二异丙基乙胺、碳酸钾、碳酸铯)存在下以及加热(60℃至120℃)条件下，通过亲核取代反应得中间体2-2；或者中间体2-1和中间体1-5通过钯催化的偶联反应得到中间体2-2；中间体2-2在酸性条件(如三氟乙酸、氯化氢)下，或钯催化氢化，或与三甲基碘硅烷反应脱去保护基Pr 1从而得到中间体2-3；将中间体2-3和中间体1-1在碱(如三乙胺、N,N-二异丙基乙胺、碳酸钾、碳酸铯、叔丁醇钾或叔丁醇钠)存在下以及加热(30℃至120℃)条件下，通过亲核取代反应得到中间体1-6；中间体1-6在碱性条件下经过水解反应得到式1-7所示的化合物；式1-7所示的化合物在缩合剂如HATU、HBTU、BOP、PyBOP等的作用下，与中间体1-8发生缩合反应得到式1-9所示的化合物。 Intermediate 2-1 and Intermediate 1-5 in the presence of a base (such as triethylamine, N, N-diisopropylethylamine, potassium carbonate, cesium carbonate) and heating (60 ° C to 120 ° C) Intermediate 2-2 can be obtained through a nucleophilic substitution reaction; or 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) and heating (30 ° C to 120 ° C) through a nucleophilic substitution reaction Intermediate 1-6 is obtained; Intermediate 1-6 is subjected to hydrolysis reaction under basic conditions to obtain compounds represented by formula 1-7; compounds represented by formula 1-7 are subjected to condensation agents such as HATU, HBTU, BOP, PyBOP, etc. Under the action of the compound, a condensation reaction with the intermediate 1-8 is performed to obtain a compound represented by the formula 1-9.
实施例Examples
实施例1Example 1
2-{(1R,5S)-3'-[(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基]-8-氮杂螺[双环[3.2.1]辛烷-3,1'-环丁烷]-8-基}-4-氟苯并[d]噻唑-6-甲酸(1)的制备2-{(1R, 5S) -3 '-[(5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy] -8-azaspiro Preparation of [Bicyclo [3.2.1] octane-3,1'-cyclobutane] -8-yl} -4-fluorobenzo [d] thiazole-6-carboxylic acid (1)
Figure PCTCN2019099219-appb-000038
Figure PCTCN2019099219-appb-000038
步骤1)：(1R,5S)-3-亚甲基-8-氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯(1-1)的制备Step 1): Preparation of (1R, 5S) -3-methylene-8-azabicyclo [3.2.1] octane-8-t-butyl formate (1-1)
将甲基三苯基溴化膦(4g，11.2mmol)溶于甲基叔丁基醚(15ml)中，然后在零度下加入叔丁醇钾(1.24g，11.2mmol)，加入之后溶液颜色变成黄色，半小时加完，加完之后升至室温搅拌5h，然后再冷却至零度，滴加(1R,5S)-3-氧代-8-氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯(2g，8.88mmol)的甲基叔丁基醚溶液，半小时滴完。升至室温过夜，LCMS监测反应完成，将反应液过滤，用石油醚萃取，有机相用硅胶拌样过柱(流动相：石油醚/乙酸乙酯＝10/1)，得到标题化合物为无色油状产物(1.8g，收率95％)。MS(m/z)：223.75[M+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. The temperature was raised to room temperature overnight, and the reaction was monitored by LCMS. The reaction solution was filtered, extracted with petroleum ether, and the organic phase was stirred through silica gel column (mobile phase: petroleum ether / ethyl acetate = 10/1) to give the title compound as colorless. Oily product (1.8 g, yield 95%). MS (m / z): 223.75 [M + 1].
步骤2)：(1R,5S)-3'-氧代-8-氮杂螺[双环[3.2.1]辛烷-3,1'-环丁烷]-8-甲酸叔丁酯(1-2)的制备Step 2): (1R, 5S) -3'-oxo-8-azaspiro [bicyclo [3.2.1] octane-3,1'-cyclobutane] -8-tert-butyl formate (1- 2) Preparation
将中间体1-1(1.8g，8.07mmol)、甲基叔丁基醚(30mL)和锌铜试剂(8.5g，65.9mmol)加入至三口瓶中，氮气保护，降温至零度，然后往反应液中滴加三氯乙酰氯(3.4mL，30.5mmol)的乙二醇二甲醚(5mL)溶液，控制滴加速度保持反应液内温不超过十度，1小时滴加完成之后升温至室温搅拌过夜。降温至负十度，滴加水(13mL)淬灭，保持淬灭时内温不超过十度，三十分钟滴加完成之后再加入甲醇(13mL)，锌粉(4g)和氯化铵(2.2g)，室温搅拌4小时，然后将反应液用硅藻土过滤，用二氯甲烷淋洗，滤液旋干之后用乙酸乙酯溶解，再用氯化钠水溶液洗涤两次，硫酸钠干燥，旋干，经柱层析纯化(流动相：石油醚/乙酸乙酯＝5/1)得到标题化合物为无色油状产物(1.8g，收率84％)。MS(m/z)：265.81[M+1]。Add intermediate 1-1 (1.8g, 8.07mmol), methyl tert-butyl ether (30mL), and zinc-copper reagent (8.5g, 65.9mmol) to a three-necked flask, protected by nitrogen, and cooled to zero. Then proceed to the reaction A solution of trichloroacetyl chloride (3.4 mL, 30.5 mmol) in ethylene glycol dimethyl ether (5 mL) was added dropwise to the solution, and the dropping rate was controlled to keep the internal temperature of the reaction solution not to exceed ten degrees. After the dropwise addition was completed, the temperature was raised to room temperature and stirred. overnight. Cool down to minus ten degrees, quench with dropwise addition of water (13mL), keep the internal temperature not exceeding ten degrees during quenching, and add methanol (13mL), zinc powder (4g), and ammonium chloride (2.2 g), stir at room temperature for 4 hours, then filter the reaction solution through celite, rinse with dichloromethane, spin-dry the filtrate and dissolve it with ethyl acetate, wash twice with sodium chloride aqueous solution, dry with sodium sulfate, and spin Dry and purify by column chromatography (mobile phase: petroleum ether / ethyl acetate = 5/1) to give the title compound as a colorless oily product (1.8 g, yield 84%). MS (m / z): 265.81 [M + 1].
步骤3)：(1R,5S)-3'-羟基-8-氮杂螺[双环[3.2.1]辛烷-3,1'-环丁烷]-8-甲酸叔丁酯(1-3)的制备Step 3): (1R, 5S) -3'-hydroxy-8-azaspiro [bicyclo [3.2.1] octane-3,1'-cyclobutane] -8-t-butyl formate (1-3 ) Preparation
将中间体1-2(1.8g，6.79mmol)溶于甲醇(35mL)，冷却至0℃，然后分批加入硼氢化钠(0.5g，13.5mmol)，加完之后自然升至室温，室温下搅拌1小时，将反应液旋干之后加入水(30mL)，用乙酸乙酯萃取(30mL x 2)，有机层经饱和食盐水洗涤(30mL x 2)，无水硫酸钠干燥，旋干后用石油醚打浆得到标题化合物为白色固体(1.5g，收率83％)。MS(m/z)：267.99[M+1]。Dissolve Intermediate 1-2 (1.8g, 6.79mmol) in methanol (35mL), cool to 0 ° C, and then add sodium borohydride (0.5g, 13.5mmol) in portions. After the addition, the mixture is naturally raised to room temperature. After stirring for 1 hour, the reaction solution was spin-dried, water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 2). The organic layer was washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, and spin-dried. Petroleum ether was slurried to give the title compound as a white solid (1.5 g, yield 83%). MS (m / z): 267.99 [M + 1].
步骤4)：2,6-二氯苯甲醛肟(1-4)的制备Step 4): Preparation of 2,6-dichlorobenzaldehyde oxime (1-4)
将2,6-二氯苯甲醛(5.0g,28.6mmol)溶于无水乙醇(45mL)中，室温下搅拌，依次加入NH 2OH·HCl(2.3g,33.1mmol)，NaOH(1.3g，32.5mmol)和水(20mL)，室温反应过夜。反应液冷却至室温后，旋干溶剂，加入水(100mL)，用乙酸乙酯(2×100mL)萃取，合并有机层，用饱和盐水(2×100mL)洗，无水Na 2SO 4干燥，过滤，旋干，加入石油醚(100mL)，搅匀，过滤，烘干，得到标题化合物为白色固体(3.5g，收率64％)。 Dissolve 2,6-dichlorobenzaldehyde (5.0 g, 28.6 mmol) in absolute ethanol (45 mL), stir at room temperature, and add NH 2 OH · HCl (2.3 g, 33.1 mmol) and NaOH (1.3 g, 32.5 mmol) and water (20 mL) and reacted at room temperature overnight. After the reaction solution was cooled to room temperature, the solvent was spin-dried, water (100 mL) was added, and extracted with ethyl acetate (2 × 100 mL). The organic layers were combined, washed with saturated brine (2 × 100 mL), and dried over anhydrous Na 2 SO 4 . Filter, spin dry, add petroleum ether (100 mL), stir well, filter, and dry to give the title compound as a white solid (3.5 g, yield 64%).
步骤5)：氯代2,6-二氯苯甲醛肟(1-5)的制备Step 5): Preparation of chloro 2,6-dichlorobenzaldehyde oxime (1-5)
将中间体1-4(4.7g，24.7mmol)溶于DMF(40mL)中，加入NCS(3.3g，24.7mmol)，室温搅拌反应1h。将反应液倒入水(100mL)中，用乙醚(2×150mL)萃取，合并有机层，有机层用饱和盐水(3×100mL)洗，无水Na 2SO 4干燥，过滤，旋干，得到标题化合物为黄色油状物(5.5g)，不纯化直接进行 下一步反应。 Intermediate 1-4 (4.7 g, 24.7 mmol) was dissolved in DMF (40 mL), NCS (3.3 g, 24.7 mmol) was added, and the reaction was stirred at room temperature for 1 h. The reaction solution was poured into water (100 mL) and extracted with diethyl ether (2 × 150 mL). The organic layers were combined, the organic layers were washed with saturated brine (3 × 100 mL), dried over anhydrous Na 2 SO 4 , filtered, and spin-dried to obtain The title compound was a yellow oil (5.5 g) and proceeded to the next reaction without purification.
步骤6)：5-环丙基-3-(2,6-二氯苯基)异噁唑-4-甲酸乙酯(1-6)的制备Step 6): Preparation of 5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazole-4-carboxylic acid ethyl ester (1-6)
将中间体1-5(4.8g，21.1mmol)溶于Et 3N(40mL)，加入3-环丙基-3-氧代丙酸乙酯(6.3g，40.6mmol)，再加入THF(20mL)，室温搅拌反应过夜。将反应液倒入水(150mL)中，用乙酸乙酯(2×150mL)萃取，有机层用饱和盐水(2×150ml)洗涤，无水Na 2SO 4干燥，过滤，旋干，柱层析纯化(流动相：PE/EA＝100/1)得到标题化合物为白色固体(4.2g，收率60％)。 Dissolve intermediate 1-5 (4.8 g, 21.1 mmol) in Et 3 N (40 mL), add ethyl 3-cyclopropyl-3-oxopropanoate (6.3 g, 40.6 mmol), and then add THF (20 mL) ), The reaction was stirred overnight at room temperature. The reaction solution was poured into water (150 mL), extracted with ethyl acetate (2 × 150 mL), and the organic layer was washed with saturated brine (2 × 150 ml), dried over anhydrous Na 2 SO 4 , filtered, spin-dried, and column chromatography. Purification (mobile phase: PE / EA = 100/1) gave the title compound as a white solid (4.2 g, yield 60%).
步骤7)：[5-环丙基-3-(2,6-二氯苯基)异噁唑4-基]甲醇(1-7)的制备Step 7): Preparation of [5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazole 4-yl] methanol (1-7)
0℃，氮气保护下于250ml双口瓶中，将四氢锂铝(750mg，19.8mmol)加入无水THF(40mL)中，搅匀后滴加溶有中间体1-6(4.15g，12.7mmol)的无水THF溶液(40mL)，继续0℃反应2h。依次滴加水(0.8mL)、15％NaOH溶液(0.8mL)和水(2.4mL)，升至室温搅拌15分钟后，硅藻土过滤，乙酸乙酯洗涤，旋干溶剂后，经柱层析纯化(流动相：PE/EA＝10/1)得到标题化合物为白色固体(2.8g，收率78％)。In a 250 ml double-necked flask at 0 ° C under nitrogen, lithium tetrahydroaluminum (750 mg, 19.8 mmol) was added to anhydrous THF (40 mL), and the intermediate 1-6 (4.15 g, 12.7) was added dropwise after stirring. mmol) of anhydrous THF solution (40 mL), and continued to react at 0 ° C for 2 h. Water (0.8 mL), 15% NaOH solution (0.8 mL), and water (2.4 mL) were added dropwise in this order. After warming to room temperature and stirring for 15 minutes, it was filtered through celite, washed with ethyl acetate, and the solvent was spin-dried, and then subjected to column chromatography. Purification (mobile phase: PE / EA = 10/1) gave the title compound as a white solid (2.8 g, yield 78%).
步骤8)：4-(氯甲基)-5-环丙基-3-(2,6-二氯苯基)异噁唑(1-8)的制备Step 8): Preparation of 4- (chloromethyl) -5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazole (1-8)
将中间体1-7(180mg，0.63mmol)溶于DCM(5mL)，冰浴冷却，加入氯化亚砜(138μL，1.90mmol)和DMF(3滴)，室温反应1小时。旋干，经柱层析纯化得到标题化合物为淡黄色油状物(173mg，收率91％)。Intermediate 1-7 (180 mg, 0.63 mmol) was dissolved in DCM (5 mL), cooled in an ice bath, and thionyl chloride (138 μL, 1.90 mmol) and DMF (3 drops) were added, and reacted at room temperature for 1 hour. Spin-dried and purified by column chromatography to give the title compound as a pale yellow oil (173 mg, yield 91%).
步骤9)：3-氟-4-氨基苯甲酸甲酯(1-9)的制备Step 9): Preparation of methyl 3-fluoro-4-aminobenzoate (1-9)
将3-氟-4-硝基苯甲酸甲酯(1.0g，5.0mmol)溶于乙酸乙酯(5mL)和甲醇(5mL)中，加入10％Pd/C(150mg)，氢气氛围下室温反应16h。硅藻土过滤，旋干溶剂得到标题化合物为白色固体(830mg，收率：98％)。 1H NMR(400MHz,CDCl 3)δ:7.69(m,1H),7.66(m,1H),6.76(m,1H),4.17(s,2H),3.88(s,3H)。 Dissolve methyl 3-fluoro-4-nitrobenzoate (1.0g, 5.0mmol) in ethyl acetate (5mL) and methanol (5mL), add 10% Pd / C (150mg), and react at room temperature under a hydrogen atmosphere. 16h. It was filtered through celite, and the solvent was spin-dried to give the title compound as a white solid (830 mg, yield: 98%). 1 H NMR (400 MHz, CDCl 3 ) δ: 7.69 (m, 1H), 7.66 (m, 1H), 6.76 (m, 1H), 4.17 (s, 2H), 3.88 (s, 3H).
步骤10)：2-氨基-4-氟苯并[d]噻唑-6-甲酸甲酯(1-10)的制备Step 10): Preparation of 2-amino-4-fluorobenzo [d] thiazole-6-carboxylic acid methyl ester (1-10)
将中间体1-9(830mg,4.9mmol)和硫氰酸钾(1.9mg，19.6mmol)溶于乙酸中(10mL)，10℃下滴加溴(250μL，4.9mmol)的乙酸溶液(5mL)，30min加完，升至30℃反应48h。加入水(30mL)稀释，用氨水调pH至8～9，过滤，用水洗涤，真空干燥得到标题化合物为黄色固体(530mg，收率48％)。 1H NMR(400MHz,DMSO)δ:8.16(m,1H),8.14(s,2H),7.56(m,1H),3.83(s,3H)。 Intermediate 1-9 (830 mg, 4.9 mmol) and potassium thiocyanate (1.9 mg, 19.6 mmol) were dissolved in acetic acid (10 mL), and a solution of bromine (250 μL, 4.9 mmol) in acetic acid (5 mL) was added dropwise at 10 ° C. After 30 min, the temperature was raised to 30 ° C and the reaction was continued for 48 h. Water (30 mL) was added to dilute, the pH was adjusted to 8-9 with aqueous ammonia, filtered, washed with water, and dried under vacuum to give the title compound as a yellow solid (530 mg, yield 48%). 1 H NMR (400 MHz, DMSO) δ: 8.16 (m, 1H), 8.14 (s, 2H), 7.56 (m, 1H), 3.83 (s, 3H).
步骤11)：2-氯-4-氟苯并[d]噻唑-6-甲酸甲酯(1-11)的制备Step 11): Preparation of 2-chloro-4-fluorobenzo [d] thiazole-6-carboxylic acid methyl ester (1-11)
将无水氯化铜(474mg，3.53mmol)和亚硝酸叔丁酯(0.56ml，4.7mmol)加入到乙腈(10mL)中，室温下搅拌10分钟，分批加入中间体1-10(530mg，2.35mmol)，15分钟加完，继续反应16h。硅藻土过滤，滤液加入1N HCl(15mL)搅拌15分钟，分层，水层用乙酸乙酯(15mL×2)萃取，合并有机层，饱和盐水(15mL×2)洗，无水硫酸钠干燥，过滤，旋干，柱层析(流动相：石油醚/乙酸乙酯＝30/1)得到标题化合物为白色固体(350mg，收率60％)。 1H NMR(400MHz,CDCl 3)δ:8.33(d,J＝1.6Hz,1H),7.88(dd,J＝1.6Hz,9.2Hz,1H),3.99(s,3H)。 Anhydrous copper chloride (474 mg, 3.53 mmol) and tert-butyl nitrite (0.56 ml, 4.7 mmol) were added to acetonitrile (10 mL), stirred at room temperature for 10 minutes, and intermediates 1-10 (530 mg, 2.35 mmol), the addition was completed in 15 minutes, and the reaction was continued for 16 h. Filter through diatomaceous earth, add 1N HCl (15 mL) and stir for 15 minutes. The layers are separated. The aqueous layer is extracted with ethyl acetate (15 mL x 2). The organic layers are combined, washed with saturated brine (15 mL x 2), and dried over anhydrous sodium sulfate. , Filtered, spin-dried, and column chromatography (mobile phase: petroleum ether / ethyl acetate = 30/1) to give the title compound as a white solid (350 mg, yield 60%). 1 H NMR (400 MHz, CDCl 3 ) δ: 8.33 (d, J = 1.6 Hz, 1 H), 7.88 (dd, J = 1.6 Hz, 9.2 Hz, 1 H), 3.99 (s, 3 H).
步骤12)：(1R,5S)-3'-{[5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基]甲氧基}-8-氮杂螺[双环[3.2.1]辛烷-3,1'-环丁烷]-8-甲酸叔丁酯(1-12)的制备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)
将中间体1-3(227mg，0.85mmol)溶于乙二醇二甲醚(5mL)，加入叔丁醇钾(168mg，1.5mmol)，室温搅拌20分钟，再加入中间体1-8(361mg，1.12mmol)，继续室温反应过夜。将溶剂旋干，加水(20mL)，用乙酸乙酯(15mL×2)萃取，有机层经无水硫酸钠干燥，旋干，柱层析纯化(流动相：石油醚/乙酸乙酯＝10/1)得到标题化合物为无色浆状物(388mg，收率86％)。MS(m/z)：532.4[M+1]。Dissolve intermediate 1-3 (227 mg, 0.85 mmol) in ethylene glycol dimethyl ether (5 mL), add potassium tert-butoxide (168 mg, 1.5 mmol), stir at room temperature for 20 minutes, and then add intermediate 1-8 (361 mg , 1.12 mmol), and the reaction was continued at room temperature overnight. The solvent was spin-dried, water (20 mL) was added, and extracted with ethyl acetate (15 mL × 2). The organic layer was dried over anhydrous sodium sulfate, spin-dried, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 10 / 1) The title compound was obtained as a colorless slurry (388 mg, yield 86%). MS (m / z): 532.4 [M + 1].
步骤13)：4-{[(1R,5S)-8-氮杂螺[双环[3.2.1]辛烷-3,1'-环丁烷]-3-基氧基]甲基}-5-环丙基-3-(2,6-二氯苯基)异噁唑(1-13)的制备Step 13): 4-{[(1R, 5S) -8-azaspiro [bicyclo [3.2.1] octane-3,1'-cyclobutane] -3-yloxy] methyl} -5 -Cyclopropyl-3- (2,6-dichlorophenyl) isoxazole (1-13)
将中间体(1-12)(388mg，0.73mmol)溶于二氯甲烷(5mL)，加入三氟乙酸(1mL)，室温搅拌2小时后，将反应液旋干，加入饱和碳酸氢钠(15mL)，用二氯甲烷(15mL×2)萃取，有机层经无水硫酸钠干燥，旋干得到标题化合物为泡沫状固体(290mg，收率92％)。不纯化直接进行下一步反应。MS(m/z)：432.2[M+1]。The intermediate (1-12) (388 mg, 0.73 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added, and after stirring at room temperature for 2 hours, the reaction solution was spin-dried and saturated sodium bicarbonate (15 mL) was added. ), Extracted with dichloromethane (15 mL × 2), the organic layer was dried over anhydrous sodium sulfate, and spin-dried to give the title compound as a foamy solid (290 mg, yield 92%). The next reaction was carried out without purification. MS (m / z): 432.2 [M + 1].
步骤14)：2-{(1R,5S)-3'-[(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基]-8-氮杂螺[双环[3.2.1]辛烷-3,1'-环丁烷]-8-基}-4-氟苯并[d]噻唑-6-甲酸甲酯(1-14)的制备Step 14): 2-{(1R, 5S) -3 '-[(5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy] -8 -Azaspiro [Bicyclo [3.2.1] octane-3,1'-cyclobutane] -8-yl} -4-fluorobenzo [d] thiazole-6-carboxylic acid methyl ester (1-14) preparation
将中间体1-13(100mg，0.24mmol)溶于DMF(2mL)，加入中间体1-11(61mg,0.24mmol)和三乙胺(68μL，0.49mmol)，于90℃加热反应2小时。待反应液冷却至室温，将其倒入水(15mL)中，用乙酸乙酯(15mL×2)萃取，有机层用饱和食盐水(15mL×3)洗涤，无水硫酸钠干燥，过滤，旋干，经柱层析纯化(流动相：石油醚/乙酸乙酯＝5/1)得到标题化合物为淡黄色固体(90mg，收率72％)。MS(m/z)：642.2[M+1]。Intermediate 1-13 (100 mg, 0.24 mmol) was dissolved in DMF (2 mL), intermediate 1-11 (61 mg, 0.24 mmol) and triethylamine (68 μL, 0.49 mmol) were added, and the reaction was heated at 90 ° C. for 2 hours. After the reaction solution was cooled to room temperature, it was poured into water (15 mL) and extracted with ethyl acetate (15 mL × 2). The organic layer was washed with saturated brine (15 mL × 3), dried over anhydrous sodium sulfate, filtered, and filtered. Dry and purify by column chromatography (mobile phase: petroleum ether / ethyl acetate = 5/1) to give the title compound as a pale yellow solid (90 mg, yield 72%). MS (m / z): 642.2 [M + 1].
步骤15)：2-{(1R,5S)-3'-[(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基]-8-氮杂螺[双环[3.2.1]辛烷-3,1'-环丁烷]-8-基}-4-氟苯并[d]噻唑-6-甲酸(1)的制备Step 15): 2-{(1R, 5S) -3 '-[(5-Cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy] -8 -Azaspiro [Bicyclo [3.2.1] octane-3,1'-cyclobutane] -8-yl} -4-fluorobenzo [d] thiazole-6-carboxylic acid (1)
将中间体1-14(90mg，0.14mmol)溶于四氢呋喃(2mL)、甲醇(2mL)和水(1mL)中，加入氢氧化锂一水合物(29mg，0.70mmol)，室温反应过夜。旋干，加水(5mL)，用1N HCl调pH至3左右，过滤，烘干，经甲基叔丁基醚和正己烷打浆得到标题化合物为白色固体(50mg，收率57％)。MS(m/z)：628.3[M+1]。 1H NMR(400MHz,CDCl 3)δ:8.15(s,1H),7.77(d,J＝11.2Hz,2H),7.45(m,2H),7.37(m,1H),4.42(m,2H),4.16(m,2H),3.93(m,1H),2.51(m,1H),2.14-2.07(m,3H),1.96(m,3H),1.84(m,4H),1.70(m,1H),1.50(m,1H),1.14(m,2H),0.90(m,2H)。 Intermediate 1-14 (90 mg, 0.14 mmol) was dissolved in tetrahydrofuran (2 mL), methanol (2 mL), and water (1 mL), and lithium hydroxide monohydrate (29 mg, 0.70 mmol) was added, and reacted at room temperature overnight. Spin-dry, add water (5 mL), adjust the pH to about 3 with 1N HCl, filter, dry, and beat with methyl tert-butyl ether and n-hexane to obtain the title compound as a white solid (50 mg, yield 57%). MS (m / z): 628.3 [M + 1]. 1 H NMR (400MHz, CDCl 3 ) δ: 8.15 (s, 1H), 7.77 (d, J = 11.2 Hz, 2H), 7.45 (m, 2H), 7.37 (m, 1H), 4.42 (m, 2H) , 4.16 (m, 2H), 3.93 (m, 1H), 2.51 (m, 1H), 2.14-2.07 (m, 3H), 1.96 (m, 3H), 1.84 (m, 4H), 1.70 (m, 1H ), 1.50 (m, 1H), 1.14 (m, 2H), 0.90 (m, 2H).
实施例2Example 2
3-{(1R,5S)-3'-[(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基]-8-氮杂螺[双环[3.2.1]辛烷-3,1'-环丁烷]-8-基}-4-氟苯甲酸(2)的制备3-{(1R, 5S) -3 '-[(5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy] -8-azaspiro Preparation of [Bicyclo [3.2.1] octane-3,1'-cyclobutane] -8-yl} -4-fluorobenzoic acid (2)
Figure PCTCN2019099219-appb-000039
Figure PCTCN2019099219-appb-000039
步骤1)：3-{(1R,5S)-3'-[(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基]-8-氮杂螺[双环[3.2.1]辛烷-3,1'-环丁烷]-8-基}-4-氟苯甲酸甲酯(2-1)的制备Step 1): 3-{(1R, 5S) -3 '-[(5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy] -8 -Azaspiro [Bicyclo [3.2.1] octane-3,1'-cyclobutane] -8-yl} -4-fluorobenzoic acid methyl ester (2-1)
将中间体1-13(86mg，0.2mmol)、Pd 2(dba) 3(9.1mg，0.01mmol)、X-Phos(9.5mg，0.02mmol)和碳酸铯(130mg，0.4mmol)溶于乙二醇二甲醚，加入3-溴-4-氟苯甲酸甲酯(93mg,0.4mmol)，氮气保护，于90℃反应过夜。待反应液冷至室温，经硅藻土过滤，旋干，柱层析纯化(流动相：石油醚/乙酸乙酯＝8/1)得到标题化合物为浆状物(35mg)。MS(m/z)：585.2[M+1]。 Intermediate 1-13 (86 mg, 0.2 mmol), Pd 2 (dba) 3 (9.1 mg, 0.01 mmol), X-Phos (9.5 mg, 0.02 mmol) and cesium carbonate (130 mg, 0.4 mmol) were dissolved in ethylene glycol Dimethyl ether, methyl 3-bromo-4-fluorobenzoate (93 mg, 0.4 mmol) was added, protected by nitrogen, and reacted at 90 ° C overnight. After the reaction liquid was cooled to room temperature, filtered through celite, spin-dried, and purified by column chromatography (mobile phase: petroleum ether / ethyl acetate = 8/1) to obtain the title compound as a slurry (35 mg). MS (m / z): 585.2 [M + 1].
步骤2)：3-{(1R,5S)-3'-[(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基]-8-氮杂螺[双环[3.2.1]辛烷-3,1'-环丁烷]-8-基}-4-氟苯甲酸(2)的制备Step 2): 3-{(1R, 5S) -3 '-[(5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy] -8 -Azaspiro [Bicyclo [3.2.1] octane-3,1'-cyclobutane] -8-yl} -4-fluorobenzoic acid (2)
将中间体2-1(35mg，0.06mmol)溶于四氢呋喃(1mL)、甲醇(1mL)和水(1mL)中，加入氢氧化锂一水合物(12mg，0.30mmol)，室温反应。TLC显示反应完全后，将反应液旋干，加水(5mL)，用1N HCl调pH至3左右，过滤，烘干得到标题化合物为白色固体(28mg，收率85％)。MS(m/z)：571.4[M+1]。 1H NMR(400MHz,CDCl 3)δ:7.54(m,2H),7.45(m,2H),7.37(m,1H),7.05(m,1H),4.26(m,2H),4.15(m,2H),3.89(m,1H),2.48(m,1H),2.15(m,1H),1.97(m,2H),1.86(m,4H),1.76(m,2H),1.66(m,1H),1.52(m,1H),1.44(m,1H),1.28(m,2H),1.14(m,2H)。 Intermediate 2-1 (35 mg, 0.06 mmol) was dissolved in tetrahydrofuran (1 mL), methanol (1 mL), and water (1 mL), and lithium hydroxide monohydrate (12 mg, 0.30 mmol) was added, and reacted at room temperature. After TLC showed that the reaction was complete, the reaction solution was spin-dried, water (5 mL) was added, and the pH was adjusted to about 3 with 1N HCl, filtered, and dried to obtain the title compound as a white solid (28 mg, yield 85%). MS (m / z): 571.4 [M + 1]. 1 H NMR (400MHz, CDCl 3 ) δ: 7.54 (m, 2H), 7.45 (m, 2H), 7.37 (m, 1H), 7.05 (m, 1H), 4.26 (m, 2H), 4.15 (m, 2H), 3.89 (m, 1H), 2.48 (m, 1H), 2.15 (m, 1H), 1.97 (m, 2H), 1.86 (m, 4H), 1.76 (m, 2H), 1.66 (m, 1H) ), 1.52 (m, 1H), 1.44 (m, 1H), 1.28 (m, 2H), 1.14 (m, 2H).
实施例3Example 3
4-{(1R,5S)-3'-[(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基]-8-氮杂螺[双环[3.2.1]辛烷-3,1'-环丁烷]-8-基}-3-氟苯甲酸(3)的制备4-{(1R, 5S) -3 '-[(5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy] -8-azaspiro Preparation of [Bicyclo [3.2.1] octane-3,1'-cyclobutane] -8-yl} -3-fluorobenzoic acid (3)
Figure PCTCN2019099219-appb-000040
Figure PCTCN2019099219-appb-000040
参考实施例2，用4-溴-3-氟苯甲酸甲酯代替3-溴-4氟苯甲酸甲酯制备得到4-{(1R,5S)-3'-[(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基]-8-氮杂螺[双环[3.2.1]辛烷-3,1'-环丁烷]-8-基}-3-氟苯甲酸。MS(m/z)：571.4[M+1]。 1H NMR(400MHz,CDCl 3)δ:7.75(m,1H),7.69(m,1H),7.43(m,2H),7.36(m,1H),6.76(m,1H),4.41(m,2H),4.14(m,2H),3.89(m,1H),2.50(m,1H),2.14(m,1H),1.99(m,3H),1.84-1.77(m,5H),1.67(m,1H),1.53(m,1H),1.44(m,1H),1.28(m,2H),1.14(m,2H)。 Reference Example 2 Using 4-bromo-3-fluorobenzoic acid methyl ester instead of 3-bromo-4fluorobenzoic acid methyl ester to prepare 4-{(1R, 5S) -3 '-[(5-cyclopropyl- 3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy] -8-azaspiro [bicyclo [3.2.1] octane-3,1'-cyclobutane]- 8-yl} -3-fluorobenzoic acid. MS (m / z): 571.4 [M + 1]. 1 H NMR (400MHz, CDCl 3 ) δ: 7.75 (m, 1H), 7.69 (m, 1H), 7.43 (m, 2H), 7.36 (m, 1H), 6.76 (m, 1H), 4.41 (m, 2H), 4.14 (m, 2H), 3.89 (m, 1H), 2.50 (m, 1H), 2.14 (m, 1H), 1.99 (m, 3H), 1.84-1.77 (m, 5H), 1.67 (m , 1H), 1.53 (m, 1H), 1.44 (m, 1H), 1.28 (m, 2H), 1.14 (m, 2H).
实施例4Example 4
6-{(1R,5S)-3'-[(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基]-8-氮杂螺[双环[3.2.1]辛烷-3,1'-环丁烷]-8-基}苯并[d]异噻唑-3-甲酸(4)的制备6-{(1R, 5S) -3 '-[(5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy] -8-azaspiro [Bicyclo [3.2.1] octane-3,1'-cyclobutane] -8-yl} Preparation of benzo [d] isothiazole-3-carboxylic acid (4)
Figure PCTCN2019099219-appb-000041
Figure PCTCN2019099219-appb-000041
参考实施例2，用6-溴苯并[d]异噻唑-3-甲酸乙酯代替3-溴-4氟苯甲酸甲酯制备得到6-{(1R,5S)-3'-[(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基]-8-氮杂螺[双环[3.2.1]辛烷-3,1'-环丁烷]-8-基}苯并[d]异噻唑-3-甲酸。MS(m/z)：610.3[M+1]。 1H NMR(400MHz,CDCl 3)δ:8.58(m,1H),7.41(m,2H),7.33(m,1H),6.92(m,2H),4.23(m,2H),4.12(m,2H),3.87(m,1H),2.50(m,1H),2.12(m,1H),2.04-1.89(m,3H),1.82-1.67(m,5H),1.60(m,1H),1.48(m,1H),1.36(m,1H),1.26(m,2H),1.12(m,2H)。 Reference Example 2 Preparation of 6-{(1R, 5S) -3 '-[(5 by using 6-bromobenzo [d] isothiazole-3-carboxylic acid ethyl ester instead of 3-bromo-4fluorobenzoic acid methyl ester -Cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy] -8-azaspiro [bicyclo [3.2.1] octane-3,1'- Cyclobutane] -8-yl} benzo [d] isothiazole-3-carboxylic acid. MS (m / z): 610.3 [M + 1]. 1 H NMR (400MHz, CDCl 3 ) δ: 8.58 (m, 1H), 7.41 (m, 2H), 7.33 (m, 1H), 6.92 (m, 2H), 4.23 (m, 2H), 4.12 (m, 2H), 3.87 (m, 1H), 2.50 (m, 1H), 2.12 (m, 1H), 2.04-1.89 (m, 3H), 1.82-1.67 (m, 5H), 1.60 (m, 1H), 1.48 (m, 1H), 1.36 (m, 1H), 1.26 (m, 2H), 1.12 (m, 2H).
实施例5Example 5
2-{(1R,5S)-3'-[(5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基]-8-氮杂螺[双环[3.2.1]辛烷-3,1'-环丁烷]-8-基}-4-氟苯并[d]噻唑-6-甲酸(5)的制备2-{(1R, 5S) -3 '-[(5-cyclopropyl-3- (2- (trifluoromethoxy) phenyl) isoxazol-4-yl) methoxy] -8- Preparation of Azaspiro [Bicyclo [3.2.1] octane-3,1'-cyclobutane] -8-yl} -4-fluorobenzo [d] thiazole-6-carboxylic acid (5)
Figure PCTCN2019099219-appb-000042
Figure PCTCN2019099219-appb-000042
参考实施例1，用2-(三氟甲氧基)苯甲醛代替2,6-二氯苯甲醛制备得到2-{(1R,5S)-3'-[(5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基]-8-氮杂螺[双环[3.2.1]辛烷-3,1'-环丁烷]-8-基}-4-氟苯并[d]噻唑-6-甲酸。MS(m/z)：644.3[M+1]。 1H NMR(400MHz,CDCl 3)δ8.13(d,J＝1.5Hz,1H),7.75(dd,J＝11.1,1.5Hz,1H),7.62-7.47(m,2H),7.39(m,2H),4.40(m,2H),4.20(m,2H),3.90(m,1H),2.53(m,1H),2.14-2.02(m,2H),1.97(m,2H),1.89(m,2H),1.74(m,3H),1.59(m,1H),1.31-1.18(m,4H),1.11(m,2H)。 Reference Example 1, using 2- (trifluoromethoxy) benzaldehyde instead of 2,6-dichlorobenzaldehyde to prepare 2-{(1R, 5S) -3 '-[(5-cyclopropyl-3- (2- (trifluoromethoxy) phenyl) isoxazol-4-yl) methoxy] -8-azaspiro [bicyclo [3.2.1] octane-3,1'-cyclobutane] -8-yl} -4-fluorobenzo [d] thiazole-6-carboxylic acid. MS (m / z): 644.3 [M + 1]. 1 H NMR (400 MHz, CDCl 3 ) δ 8.13 (d, J = 1.5 Hz, 1 H), 7.75 (dd, J = 11.1, 1.5 Hz, 1 H), 7.62-7.47 (m, 2H), 7.39 (m, 2H), 4.40 (m, 2H), 4.20 (m, 2H), 3.90 (m, 1H), 2.53 (m, 1H), 2.14-2.02 (m, 2H), 1.97 (m, 2H), 1.89 (m , 2H), 1.74 (m, 3H), 1.59 (m, 1H), 1.31-1.18 (m, 4H), 1.11 (m, 2H).
实施例6Example 6
6-{(1R,5S)-3'-[(5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基]-8-氮杂螺[双环[3.2.1]辛烷-3,1'-环丁烷]-8-基}苯并[d]异噻唑-3-甲酸(6)的制备6-{(1R, 5S) -3 '-[(5-cyclopropyl-3- (2- (trifluoromethoxy) phenyl) isoxazol-4-yl) methoxy] -8- Preparation of Azaspiro [Bicyclo [3.2.1] octane-3,1'-cyclobutane] -8-yl} benzo [d] isothiazole-3-carboxylic acid (6)
Figure PCTCN2019099219-appb-000043
Figure PCTCN2019099219-appb-000043
参考实施例4，用2-(三氟甲氧基)苯甲醛代替2,6-二氯苯甲醛制备得到6-{(1R,5S)-3'-[(5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基]-8-氮杂螺[双环[3.2.1]辛烷-3,1'-环丁烷]-8-基}苯并[d]异噻唑-3-甲酸。MS(m/z)：626.3[M+1]。 1H NMR(400MHz,CDCl 3)δ8.58(s,1H),7.50(m,2H),7.36(m,2H),6.87(m,2H),4.16(m,4H),3.91-3.78(m,1H),2.51(m,1H),2.16-1.65(m,10H),1.27-1.18(m,4H),1.08(m,2H)。 Reference Example 4: Preparation of 6-{(1R, 5S) -3 '-[(5-cyclopropyl-3-) by using 2- (trifluoromethoxy) benzaldehyde instead of 2,6-dichlorobenzaldehyde (2- (trifluoromethoxy) phenyl) isoxazol-4-yl) methoxy] -8-azaspiro [bicyclo [3.2.1] octane-3,1'-cyclobutane] -8-yl} benzo [d] isothiazole-3-carboxylic acid. MS (m / z): 626.3 [M + 1]. 1 H NMR (400MHz, CDCl 3 ) δ 8.58 (s, 1H), 7.50 (m, 2H), 7.36 (m, 2H), 6.87 (m, 2H), 4.16 (m, 4H), 3.91-3.78 ( m, 1H), 2.51 (m, 1H), 2.16-1.65 (m, 10H), 1.27-1.18 (m, 4H), 1.08 (m, 2H).
实施例7Example 7
3-{(1R,5S)-3'-[(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基]-8-氮杂螺[双环[3.2.1]辛烷-3,1'-环丁烷]-8-基}-5-氟苯甲酸(7)的制备3-{(1R, 5S) -3 '-[(5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy] -8-azaspiro [Bicyclo [3.2.1] octane-3,1'-cyclobutane] -8-yl} -5-fluorobenzoic acid (7)
Figure PCTCN2019099219-appb-000044
Figure PCTCN2019099219-appb-000044
参考实施例2，用4-溴-3-氟苯甲酸甲酯代替3-溴-4氟苯甲酸甲酯制备得到3-{(1R,5S)-3'-[(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基]-8-氮杂螺[双环[3.2.1]辛烷-3,1'-环丁烷]-8-基}-5-氟苯甲酸。MS(m/z):571.4[M+1]. 1H NMR(400MHz,CDCl 3)δ7.45(t,J＝6.4Hz,2H),7.38(d,J＝8.0Hz,1H),7.20(s,1H),7.07(d,J＝8.8Hz,1H),6.59(d,J＝11.6Hz,1H),4.18-4.14(m,4H),3.89(m,1H),2.51(m,1H),2.14(m,1H),2.01-1.89(m,3H),1.81(m,5H),1.61(m,1H),1.43(m,2H),1.28(m,2H),1.13(m,2H)。 Reference Example 2 Using 3-bromo-3-fluorobenzoic acid methyl ester instead of 3-bromo-4fluorobenzoic acid methyl ester to prepare 3-{(1R, 5S) -3 '-[(5-cyclopropyl- 3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy] -8-azaspiro [bicyclo [3.2.1] octane-3,1'-cyclobutane]- 8-yl} -5-fluorobenzoic acid. MS (m / z): 571.4 [M + 1]. 1 H NMR (400MHz, CDCl 3 ) δ7.45 (t, J = 6.4Hz, 2H), 7.38 (d, J = 8.0Hz, 1H), 7.20 (s, 1H), 7.07 (d, J = 8.8 Hz, 1H), 6.59 (d, J = 11.6 Hz, 1H), 4.18-4.14 (m, 4H), 3.89 (m, 1H), 2.51 (m, 1H), 2.14 (m, 1H), 2.01-1.89 (m, 3H), 1.81 (m, 5H), 1.61 (m, 1H), 1.43 (m, 2H), 1.28 (m, 2H), 1.13 (m , 2H).
实施例8Example 8
5-{(1R,5S)-3'-[(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基]-8-氮杂螺[双环[3.2.1]辛烷-3,1'-环丁烷]-8-基}吡嗪-2-甲酸(8)的制备5-{(1R, 5S) -3 '-[(5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy] -8-azaspiro Preparation of [Bicyclo [3.2.1] octane-3,1'-cyclobutane] -8-yl} pyrazine-2-carboxylic acid (8)
Figure PCTCN2019099219-appb-000045
Figure PCTCN2019099219-appb-000045
参考实施例1，用5-氯吡嗪-2-羧酸甲酯代替2-氯-4-氟苯并[d]噻唑-6-甲酸甲酯制备得到5-{(1R,5S)-3'-[(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基]-8-氮杂螺[双环[3.2.1]辛烷-3,1'-环丁烷]-8-基}吡嗪-2-甲酸。MS(m/z)：555.5[M+1]。1H NMR(400MHz,CDCl 3)δ8.84(s,1H),7.83(s,1H),7.45-7.39(m,2H),7.35(m,1H),4.60(m,2H),4.12(m,2H),3.88(m,1H),2.50(m,1H),2.11(m,1H),1.97(m,2H),1.86-1.71(m,5H),1.44(m,1H),1.27(m,5H),1.12(m,2H)。 Reference Example 1 Preparation of 5-{(1R, 5S) -3 by using methyl 5-chloropyrazine-2-carboxylic acid methyl ester instead of 2-chloro-4-fluorobenzo [d] thiazole-6-carboxylic acid methyl ester '-[(5-Cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy] -8-azaspiro [bicyclo [3.2.1] octane- 3,1'-cyclobutane] -8-yl} pyrazine-2-carboxylic acid. MS (m / z): 555.5 [M + 1]. 1H NMR (400MHz, CDCl 3 ) δ8.84 (s, 1H), 7.83 (s, 1H), 7.45-7.39 (m, 2H), 7.35 (m, 1H), 4.60 (m, 2H), 4.12 (m , 2H), 3.88 (m, 1H), 2.50 (m, 1H), 2.11 (m, 1H), 1.97 (m, 2H), 1.86-1.71 (m, 5H), 1.44 (m, 1H), 1.27 ( m, 5H), 1.12 (m, 2H).
实施例9Example 9
2-{(1R,5S)-3'-[(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基]-8-氮杂螺[双环[3.2.1]辛烷-3,1'-环丁烷]-8-基}嘧啶-5-甲酸(9)的制备2-{(1R, 5S) -3 '-[(5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy] -8-azaspiro Preparation of [Bicyclo [3.2.1] octane-3,1'-cyclobutane] -8-yl} pyrimidine-5-carboxylic acid (9)
Figure PCTCN2019099219-appb-000046
Figure PCTCN2019099219-appb-000046
参考实施例1，用2-氯嘧啶-5-羧酸乙酯代替2-氯-4-氟苯并[d]噻唑-6-甲酸甲酯制备得到2-{(1R,5S)-3'-[(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基]-8-氮杂螺[双环[3.2.1]辛烷-3,1'-环丁烷]-8-基}嘧啶-5-甲酸。MS(m/z)：555.2[M+1]。 1H NMR(400MHz,CDCl 3)δ8.86(s,2H),7.45-7.39(m,2H),7.35(m,1H),4.86-4.70(m,2H),4.13(m,2H),3.90(m,1H),2.51(m,1H),2.12(m,1H),2.04-1.87(m,3H),1.78(m,5H),1.69-1.61(m,1H),1.46(m,1H),1.33-1.20(m,3H),1.11(m,2H)。 Reference Example 1 Using 2-chloropyrimidine-5-carboxylic acid ethyl ester instead of 2-chloro-4-fluorobenzo [d] thiazole-6-carboxylic acid methyl ester to prepare 2-{(1R, 5S) -3 ' -[(5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy] -8-azaspiro [bicyclo [3.2.1] octane-3 , 1'-cyclobutane] -8-yl} pyrimidine-5-carboxylic acid. MS (m / z): 555.2 [M + 1]. 1 H NMR (400MHz, CDCl 3 ) δ8.86 (s, 2H), 7.45-7.39 (m, 2H), 7.35 (m, 1H), 4.86-4.70 (m, 2H), 4.13 (m, 2H), 3.90 (m, 1H), 2.51 (m, 1H), 2.12 (m, 1H), 2.04-1.87 (m, 3H), 1.78 (m, 5H), 1.69-1.61 (m, 1H), 1.46 (m, 1H), 1.33-1.20 (m, 3H), 1.11 (m, 2H).
实施例10Example 10
5-{(1R,5S)-3'-[(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基]-8-氮杂螺[双环[3.2.1]辛烷-3,1'-环丁烷]-8-基}吡啶-2-甲酸(10)的制备5-{(1R, 5S) -3 '-[(5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy] -8-azaspiro Preparation of [Bicyclo [3.2.1] octane-3,1'-cyclobutane] -8-yl} pyridine-2-carboxylic acid (10)
Figure PCTCN2019099219-appb-000047
Figure PCTCN2019099219-appb-000047
参考实施例2，用5-溴吡啶-2-羧酸甲酯代替3-溴-4-氟苯甲酸甲酯制备得到5-{(1R,5S)-3'-[(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基]-8-氮杂螺[双环[3.2.1]辛烷-3,1'-环丁烷]-8-基}吡啶-2-甲酸。MS(m/z)：554.2[M+1]。 1H NMR(400MHz,CDCl 3)δ7.99(m,1H),7.40(m,4H),7.00(s,1H),4.27(m,2H),4.13(m,2H),3.88(m,1H),2.50(m,1H),1.99(m,4H),1.56(m,2H),1.31-1.20(m,6H),1.13(m,4H)。 Reference Example 2 Preparation of 5-{(1R, 5S) -3 '-[(5-cyclopropyl) by using methyl 5-bromopyridine-2-carboxylate instead of methyl 3-bromo-4-fluorobenzoate -3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy] -8-azaspiro [bicyclo [3.2.1] octane-3,1'-cyclobutane] -8-yl} pyridine-2-carboxylic acid. MS (m / z): 554.2 [M + 1]. 1 H NMR (400MHz, CDCl 3 ) δ 7.99 (m, 1H), 7.40 (m, 4H), 7.00 (s, 1H), 4.27 (m, 2H), 4.13 (m, 2H), 3.88 (m, 1H), 2.50 (m, 1H), 1.99 (m, 4H), 1.56 (m, 2H), 1.31-1.20 (m, 6H), 1.13 (m, 4H).
实施例11Example 11
5-{(1R,5S)-3'-[(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基]-8-氮杂螺[双环[3.2.1]辛烷-3,1'-环丁烷]-8-基}烟酸(11)的制备5-{(1R, 5S) -3 '-[(5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy] -8-azaspiro [Bicyclo [3.2.1] octane-3,1'-cyclobutane] -8-yl} Preparation of Niacin (11)
Figure PCTCN2019099219-appb-000048
Figure PCTCN2019099219-appb-000048
参考实施例2，用5-溴烟酸甲酯代替3-溴-4-氟苯甲酸甲酯制备得到5-{(1R,5S)-3'-[(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基]-8-氮杂螺[双环[3.2.1]辛烷-3,1'-环丁烷]-8-基}烟酸。MS(m/z)：554.2[M+1]。 1H NMR(400MHz,CDCl 3)δ8.64(m,1H),8.29(m,1H),7.72(m,1H),7.42(m,2H),7.35(m,1H),4.26(m,2H), 4.11(m,2H),3.86(m,1H),2.50(m,1H),2.11(m,1H),1.98(m,3H),1.86-1.70(m,5H),1.61(m,1H),1.49(m,1H),1.36(m,1H),1.25(m,2H),1.11(m,2H)。 Reference Example 2 Using 5-bromonicotinic acid methyl ester instead of 3-bromo-4-fluorobenzoic acid methyl ester to prepare 5-{(1R, 5S) -3 '-[(5-cyclopropyl-3- ( 2,6-dichlorophenyl) isoxazol-4-yl) methoxy] -8-azaspiro [bicyclo [3.2.1] octane-3,1'-cyclobutane] -8-yl }niacin. MS (m / z): 554.2 [M + 1]. 1 H NMR (400MHz, CDCl 3 ) δ 8.64 (m, 1H), 8.29 (m, 1H), 7.72 (m, 1H), 7.42 (m, 2H), 7.35 (m, 1H), 4.26 (m, 2H), 4.11 (m, 2H), 3.86 (m, 1H), 2.50 (m, 1H), 2.11 (m, 1H), 1.98 (m, 3H), 1.86-1.70 (m, 5H), 1.61 (m , 1H), 1.49 (m, 1H), 1.36 (m, 1H), 1.25 (m, 2H), 1.11 (m, 2H).
实施例12Example 12
4-{(1R,5S)-3'-[(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基]-8-氮杂螺[双环[3.2.1]辛烷-3,1'-环丁烷]-8-基}吡啶-2-甲酸(10)的制备4-{(1R, 5S) -3 '-[(5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy] -8-azaspiro Preparation of [Bicyclo [3.2.1] octane-3,1'-cyclobutane] -8-yl} pyridine-2-carboxylic acid (10)
Figure PCTCN2019099219-appb-000049
Figure PCTCN2019099219-appb-000049
参考实施例2，用5-溴烟酸甲酯代替3-溴-4-氟苯甲酸甲酯制备得到4-{(1R,5S)-3'-[(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基]-8-氮杂螺[双环[3.2.1]辛烷-3,1'-环丁烷]-8-基}吡啶-2-甲酸。MS(m/z)：554.2[M+1]。1H NMR(400MHz,CDCl 3)δ8.26(d,J＝6.9Hz,1H),7.52(m,1H),7.43(m,3H),6.58(m,1H),4.51(m,1H),4.31(m,1H),4.13(m,2H),3.88(m,1H),2.52(m,1H),2.10(m,1H),2.02(m,3H),1.90-1.76(m,3H),1.43(m,2H),1.29-1.22(m,5H),1.12(m,2H)。 Reference Example 2 Using 4-bromonicotinic acid methyl ester instead of 3-bromo-4-fluorobenzoic acid to prepare 4-{(1R, 5S) -3 '-[(5-cyclopropyl-3- ( 2,6-dichlorophenyl) isoxazol-4-yl) methoxy] -8-azaspiro [bicyclo [3.2.1] octane-3,1'-cyclobutane] -8-yl } Pyridine-2-carboxylic acid. MS (m / z): 554.2 [M + 1]. 1H NMR (400MHz, CDCl 3 ) δ8.26 (d, J = 6.9Hz, 1H), 7.52 (m, 1H), 7.43 (m, 3H), 6.58 (m, 1H), 4.51 (m, 1H), 4.31 (m, 1H), 4.13 (m, 2H), 3.88 (m, 1H), 2.52 (m, 1H), 2.10 (m, 1H), 2.02 (m, 3H), 1.90-1.76 (m, 3H) , 1.43 (m, 2H), 1.29-1.22 (m, 5H), 1.12 (m, 2H).
实施例13Example 13
2-{(1R,5S)-3'-[(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基]-3-氮杂螺[双环[3.3.1]壬烷-9,1'-环丁烷]-3-基}-4-氟苯并[d]噻唑-6-甲酸(13)的制备2-{(1R, 5S) -3 '-[(5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy] -3-azaspiro Preparation of [Bicyclo [3.3.1] nonane-9,1'-cyclobutane] -3-yl} -4-fluorobenzo [d] thiazole-6-carboxylic acid (13)
Figure PCTCN2019099219-appb-000050
Figure PCTCN2019099219-appb-000050
步骤1)(1R,5S)-3-苄基-3-氮杂双环[3.3.1]壬烷-9-酮的制备Step 1) Preparation of (1R, 5S) -3-benzyl-3-azabicyclo [3.3.1] nonane-9-one
将苄胺(2.14mL,19.6mmol)溶于叔丁醇(5mL)中，0℃下，依次加入多聚甲醛(1.18g,39.2mmol)、浓盐酸(1.8mL,21.6mmol)、环己酮(5.26mL,50.9mmol)，加完后加热至80℃下回流反应3小时。旋干溶剂，加入水(50mL)和乙酸乙酯(50mL)，分层，水层用4M氢氧化钠水溶液调pH至10左右，用乙酸乙酯萃取(30mL×2)，合并有机层，有机层经饱和盐水(30mL)洗，无水硫酸钠干燥，旋干得黄色固体。所得固体用乙酸(15mL)溶解，95℃下，滴加到乙酸(12mL)、盐酸(0.76mL)、多聚甲醛(550mg)的混合液中，30分钟加完，继续反应1小时。旋干溶剂，加入水(20mL)和乙酸乙酯(20mL)，分层，水层用4M氢氧化钠水溶液调pH至10左右，用乙酸乙酯萃取(20mL×2)，合并有机层，有机层经饱和盐水(20mL)洗，无水硫酸钠干燥，过滤，柱层析(石油醚/乙酸乙酯＝100/1)纯化得1.28g黄 色油状物，即为(1R,5S)-3-苄基-3-氮杂双环[3.3.1]壬烷-9-酮。收率：28％。MS(m/z)：230.2[M+H]。Dissolve benzylamine (2.14 mL, 19.6 mmol) in tert-butanol (5 mL), and add paraformaldehyde (1.18 g, 39.2 mmol), concentrated hydrochloric acid (1.8 mL, 21.6 mmol), and cyclohexanone in order at 0 ° C. (5.26 mL, 50.9 mmol). After the addition was completed, the mixture was heated to 80 ° C. and refluxed for 3 hours. The solvent was spin-dried, water (50 mL) and ethyl acetate (50 mL) were added, and the layers were separated. 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. The solvent was spin-dried, water (20 mL) and ethyl acetate (20 mL) were added, and the layers were separated. The aqueous layer was adjusted to a pH of about 10 with a 4M sodium hydroxide aqueous solution, and extracted with ethyl acetate (20 mL × 2). The layer was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and purified by column chromatography (petroleum ether / ethyl acetate = 100/1) to obtain 1.28 g of a yellow oily substance, namely (1R, 5S) -3- Benzyl-3-azabicyclo [3.3.1] nonane-9-one. Yield: 28%. MS (m / z): 230.2 [M + H].
步骤2)(1R,5S)-3-苄基-3-氮杂双环[3.3.1]壬烷-9-醇的制备Step 2) Preparation of (1R, 5S) -3-benzyl-3-azabicyclo [3.3.1] nonane-9-ol
将(1R,5S)-3-苄基-3-氮杂双环[3.3.1]壬烷-9-酮(1.28g,5.5mmol)溶于甲醇(15mL)中，冰浴下分批加入硼氢化钠(0.42g,11.0mmol)，加完升至室温反应1小时。旋干溶剂，加入水(15mL)，用乙酸乙酯萃取(15mL×2)，有机层无水硫酸钠干燥，过滤，旋干，柱层析(石油醚/乙酸乙酯＝10/1)纯化得900mg白色固体，即为(1R,5S)-3-苄基-3-氮杂双环[3.3.1]壬烷-9-醇。(1R, 5S) -3-benzyl-3-azabicyclo [3.3.1] nonane-9-one (1.28g, 5.5mmol) was dissolved in methanol (15mL), and boron was added in portions in an ice bath. Sodium hydride (0.42 g, 11.0 mmol) was added to the room temperature and reacted for 1 hour. The solvent was spin-dried, water (15 mL) was added, and extracted with ethyl acetate (15 mL × 2). The organic layer was dried over anhydrous sodium sulfate, filtered, spin-dried, and purified by column chromatography (petroleum ether / ethyl acetate = 10/1). 900 mg of a white solid was obtained, namely (1R, 5S) -3-benzyl-3-azabicyclo [3.3.1] nonane-9-ol.
步骤3)(1R,5S)-3-氮杂双环[3.3.1]壬烷-9-醇的制备Step 3) Preparation of (1R, 5S) -3-azabicyclo [3.3.1] nonane-9-ol
将(1R,5S)-3-苄基-3-氮杂双环[3.3.1]壬烷-9-醇(900mg,3.85mmol)溶于甲醇(15mL)中，加入Pd/C(180mg)，氢气氛围下室温反应16小时。加硅藻土过滤，洗涤，旋干得640mg白色固体，即为(1R,5S)-3-氮杂双环[3.3.1]壬烷-9-醇，产物不需纯化直接下一步反应。(1R, 5S) -3-benzyl-3-azabicyclo [3.3.1] nonane-9-ol (900 mg, 3.85 mmol) was dissolved in methanol (15 mL), and Pd / C (180 mg) was added, The reaction was carried out at room temperature under a hydrogen atmosphere for 16 hours. Add diatomaceous earth to filter, wash, and spin-dry to obtain 640mg of white solid, which is (1R, 5S) -3-azabicyclo [3.3.1] nonane-9-ol. The product can be directly reacted in the next step without purification.
步骤4)(1R,5S)-9-羟基-3-氮杂双环[3.3.1]-3-甲酸叔丁酯的制备Step 4) Preparation of (1R, 5S) -9-hydroxy-3-azabicyclo [3.3.1] -3-carboxylic acid tert-butyl ester
将(1R,5S)-3-氮杂双环[3.3.1]壬烷-9-醇(640mg,4.5mmol)溶于二氯甲烷(20mL)中，加入Boc酸酐(1.24mL,5.4mmol)和三乙胺(0.94mL,6.75mmol)，室温下反应1小时。加入水(20mL)洗，分层，有机层用无水硫酸钠干燥，过滤，旋干，柱层析(石油醚：乙酸乙酯＝5：1)得480mg白色固体，即为(1R,5S)-9-羟基-3-氮杂双环[3.3.1]-3-甲酸叔丁酯。收率：44％。MS(m/z)：242.2[M+H]。(1R, 5S) -3-azabicyclo [3.3.1] nonane-9-ol (640 mg, 4.5 mmol) was dissolved in dichloromethane (20 mL), and Boc anhydride (1.24 mL, 5.4 mmol) and Triethylamine (0.94 mL, 6.75 mmol) was reacted at room temperature for 1 hour. Water (20 mL) was added for washing, and the layers were separated. The organic layer was dried over anhydrous sodium sulfate, filtered, and spin-dried. Column chromatography (petroleum ether: ethyl acetate = 5: 1) gave 480 mg of a white solid, which was (1R, 5S). ) 9-Hydroxy-3-azabicyclo [3.3.1] -3-carboxylic acid tert-butyl ester. Yield: 44%. MS (m / z): 242.2 [M + H].
步骤5)(1R,5S)-9-氧代-3-氮杂双环[3.3.1]壬烷-3-甲酸叔丁酯的制备Step 5) Preparation of (1R, 5S) -9-oxo-3-azabicyclo [3.3.1] nonane-3-carboxylic acid tert-butyl ester
将(1R,5S)-9-羟基-3-氮杂双环[3.3.1]-3-甲酸叔丁酯(1.8g，7.46mmol)溶于二氯甲烷(50mL)中，加入戴斯-马丁氧化剂(3.5g，8.22mmol)。室温搅拌过夜。反应完全后，蒸干溶剂，加入硫代硫酸钠和石油醚搅拌后硅藻土过滤，滤饼用石油醚和乙酸乙酯的混合溶液(3:1)洗涤，有机相依次用硫代硫酸钠溶液洗涤和饱和氯化钠水溶液洗涤，有机相用硫酸钠干燥，蒸干溶剂得(1R,5S)-9-氧代-3-氮杂双环[3.3.1]壬烷-3-甲酸叔丁酯1.6g，收率：89％。MS(m/z)：240.2[M+H]。(1R, 5S) -9-Hydroxy-3-azabicyclo [3.3.1] -3-carboxylic acid tert-butyl ester (1.8 g, 7.46 mmol) was dissolved in dichloromethane (50 mL), and Dess-Martin was added Oxidant (3.5 g, 8.22 mmol). Stir overnight at room temperature. After the reaction is completed, the solvent is evaporated to dryness, sodium thiosulfate and petroleum ether are added, and the mixture is stirred and filtered through celite. The filter cake is washed with a mixed solution of petroleum ether and ethyl acetate (3: 1), and the organic phase is sequentially washed with sodium thiosulfate. The solution was washed with saturated sodium chloride solution, the organic phase was dried over sodium sulfate, and the solvent was evaporated to give (1R, 5S) -9-oxo-3-azabicyclo [3.3.1] nonane-3-carboxylic acid tert-butyl. 1.6 g of ester, yield: 89%. MS (m / z): 240.2 [M + H].
步骤6)2-{(1R,5S)-3'-[(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基]-3-氮杂螺[双环[3.3.1]壬烷-9,1'-环丁烷]-3-基}-4-氟苯并[d]噻唑-6-甲酸的制备Step 6) 2-{(1R, 5S) -3 '-[(5-Cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy] -3- Preparation of Azaspiro [Bicyclo [3.3.1] nonane-9,1'-cyclobutane] -3-yl} -4-fluorobenzo [d] thiazole-6-carboxylic acid
参照实施例1，用(1R,5S)-9-氧代-3-氮杂双环[3.3.1]壬烷-3-甲酸叔丁酯代替(1R,5S)-3-氧代-8-氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯制备得到2-{(1R,5S)-3'-[(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基]-3-氮杂螺[双环[3.3.1]壬烷-9,1'-环丁烷]-3-基}-4-氟苯并[d]噻唑-6-甲酸。MS(m/z)：642.5[M+1].1H NMR(400MHz,CDCl 3)δ8.17(s,1H),7.78(d,J＝11.2Hz,1H),7.45(m,2H),7.38(m,1H),4.21(s,2H),3.90(m,2H),3.48(m,3H),2.36-2.10(m,4H),1.74(m,2H),1.65(m,4H),1.38(m,1H),1.34-1.21(m,4H),1.16(m,2H)。 Referring to Example 1, (1R, 5S) -9-oxo-3-azabicyclo [3.3.1] nonane-3-carboxylic acid tert-butyl ester was used instead of (1R, 5S) -3-oxo-8- Preparation of azabicyclo [3.2.1] octane-8-t-butyl formate to obtain 2-{(1R, 5S) -3 '-[(5-cyclopropyl-3- (2,6-dichlorophenyl) ) Isoxazol-4-yl) methoxy] -3-azaspiro [bicyclo [3.3.1] nonane-9,1'-cyclobutane] -3-yl} -4-fluorobenzo [ d] Thiazole-6-carboxylic acid. MS (m / z): 642.5 [M + 1] .1H NMR (400MHz, CDCl 3 ) δ8.17 (s, 1H), 7.78 (d, J = 11.2Hz, 1H), 7.45 (m, 2H), 7.38 (m, 1H), 4.21 (s, 2H), 3.90 (m, 2H), 3.48 (m, 3H), 2.36-2.10 (m, 4H), 1.74 (m, 2H), 1.65 (m, 4H) , 1.38 (m, 1H), 1.34-1.21 (m, 4H), 1.16 (m, 2H).
实施例14Example 14
6-{(1R,5S)-3'-[(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基]-3-氮杂螺[双环[3.3.1]壬烷-9,1'-环丁烷]-3-基}苯并[d]异噻唑-3-甲酸(14)的制备6-{(1R, 5S) -3 '-[(5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy] -3-azaspiro [Bicyclo [3.3.1] nonane-9,1'-cyclobutane] -3-yl} preparation of benzo [d] isothiazole-3-carboxylic acid (14)
Figure PCTCN2019099219-appb-000051
Figure PCTCN2019099219-appb-000051
参照实施例4，用(1R,5S)-9-氧代-3-氮杂双环[3.3.1]壬烷-3-甲酸叔丁酯代替(1R,5S)-3-氧代-8-氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯制备得到6-{(1R,5S)-3'-[(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基]-3-氮杂螺[双环[3.3.1]壬烷-9,1'-环丁烷]-3-基}苯并[d]异噻唑-3-甲酸。MS(m/z)：624.38[M+1]。Referring to Example 4, (1R, 5S) -9-oxo-3-azabicyclo [3.3.1] nonane-3-carboxylic acid tert-butyl ester was used instead of (1R, 5S) -3-oxo-8- Preparation of azabicyclo [3.2.1] octane-8-t-butyl formate to obtain 6-{(1R, 5S) -3 '-[(5-cyclopropyl-3- (2,6-dichlorophenyl) ) Isoxazol-4-yl) methoxy] -3-azaspiro [bicyclo [3.3.1] nonane-9,1'-cyclobutane] -3-yl} benzo [d] isothiazole -3-carboxylic acid. MS (m / z): 624.38 [M + 1].
实施例15Example 15
2-{(1R,5S)-3'-[(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基]-3-氮杂螺[双环[3.2.1]辛烷-8,1'-环丁烷]-3-基}-4-氟苯并[d]噻唑-6-甲酸(15)的制备2-{(1R, 5S) -3 '-[(5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy] -3-azaspiro Preparation of [Bicyclo [3.2.1] octane-8,1'-cyclobutane] -3-yl} -4-fluorobenzo [d] thiazole-6-carboxylic acid (15)
(1)3-苄基-3-氮杂双环[3.2.1]-8-酮的制备。(1) Preparation of 3-benzyl-3-azabicyclo [3.2.1] -8-one.
Figure PCTCN2019099219-appb-000052
Figure PCTCN2019099219-appb-000052
步骤1)(1R,5S)-3-苄基-3-氮杂双环[3.2.1]-8-酮的制备Step 1) Preparation of (1R, 5S) -3-benzyl-3-azabicyclo [3.2.1] -8-one
将苄胺(2.68g,25mmol)溶于叔丁醇(6mL)，10℃下加入多聚甲醛(1.5g,50mmol)、浓盐酸(2.37mL,27.5mmol)和环戊酮(5.46g,65mmol)，80℃反应3小时。冷却，旋干，加丙酮(30mL)，过滤得3.58g白色固体。于100mL单口瓶中加入乙酸(20mL)、浓盐酸(1.25mL,13.5mmol)和多聚甲醛，加热至95℃。将上述所得固体溶于乙酸(20mL)并滴加至上述反应液中，半小时加完，并继续反应1小时。冷却，旋除溶剂，加水(30mL)和二氯甲烷(30mL)，用氢氧化钠溶液调pH至10，分层，水层用二氯甲烷(30mL×2)萃取，合并有机层，无水硫酸钠干燥，旋干，柱层析纯化(石油醚：乙酸乙酯＝25：1)得无色油状液体2.21g，即为3-苄基-3-氮杂双环[3.2.1]-8-酮，收率：41％。 1H NMR(400MHz,CDCl 3)δ:7.38-7.26(m,5H),3.62(s,2H),3.00(m,2H),2.57(m,2H),2.18(m,2H),2.09(m,2H),1.88(m,2H)。 Dissolve benzylamine (2.68g, 25mmol) in tert-butanol (6mL), and add paraformaldehyde (1.5g, 50mmol), concentrated hydrochloric acid (2.37mL, 27.5mmol), and cyclopentanone (5.46g, 65mmol) ), Reaction at 80 ° C for 3 hours. Cool, spin dry, add acetone (30 mL), and filter to obtain 3.58 g of a white solid. Into a 100 mL single-necked flask, add acetic acid (20 mL), concentrated hydrochloric acid (1.25 mL, 13.5 mmol) and paraformaldehyde, and heat to 95 ° C. The solid obtained above was dissolved in acetic acid (20 mL) and added dropwise to the above reaction solution, the addition was completed for half an hour, and the reaction was continued for 1 hour. Cool, spin off the solvent, add water (30 mL) and dichloromethane (30 mL), adjust the pH to 10 with sodium hydroxide solution, separate the layers, extract the aqueous layer with dichloromethane (30 mL × 2), combine the organic layers, and dry Dry over sodium sulfate, spin dry, and purify by column chromatography (petroleum ether: ethyl acetate = 25: 1) to obtain 2.21 g of colorless oily liquid, which is 3-benzyl-3-azabicyclo [3.2.1] -8 -Ketone, yield: 41%. 1 H NMR (400MHz, CDCl 3 ) δ: 7.38-7.26 (m, 5H), 3.62 (s, 2H), 3.00 (m, 2H), 2.57 (m, 2H), 2.18 (m, 2H), 2.09 ( m, 2H), 1.88 (m, 2H).
步骤2)(1R,5S)-3-苄基-3-氮杂双环[3.2.1]-8-醇的制备。Step 2) Preparation of (1R, 5S) -3-benzyl-3-azabicyclo [3.2.1] -8-ol.
将(1R,5S)-3-苄基-3-氮杂双环[3.2.1]-8-酮(2.15g,10mmol)溶于甲醇(40mL)，冰浴冷却，分批加入硼氢化钠(570mg,15mmol)，升至室温反应2小时。旋干，加水(50mL)，用乙酸乙酯(50mL×2)萃取，饱和食盐水(50mL×2)洗涤，无水硫酸钠干燥，过滤，旋干得淡黄色固体2.0g，即为(1R,5S)-3-苄基-3-氮杂双环[3.2.1]-8-醇，不纯化直接进行下一步反应。(1R, 5S) -3-benzyl-3-azabicyclo [3.2.1] -8-one (2.15 g, 10 mmol) was dissolved in methanol (40 mL), cooled in an ice bath, and sodium borohydride ( 570 mg, 15 mmol), warmed to room temperature and reacted for 2 hours. Spin-dry, add water (50mL), extract with ethyl acetate (50mL × 2), wash with saturated brine (50mL × 2), dry with anhydrous sodium sulfate, filter, spin-dry to obtain 2.0g of pale yellow solid, which is , 5S) -3-benzyl-3-azabicyclo [3.2.1] -8-alcohol, proceed directly to the next step without purification.
步骤3)(1R,5S)-8-羟基-3-氮杂双环[3.2.1]辛烷-3-甲酸叔丁酯的制备。Step 3) Preparation of (1R, 5S) -8-hydroxy-3-azabicyclo [3.2.1] octane-3-carboxylic acid tert-butyl ester.
将(1R,5S)-3-苄基-3-氮杂双环[3.2.1]-8-醇(2.0g,9.20mmol)溶于甲醇(30mL)，通入氢气，室温反应 过夜。用硅藻土过滤，旋干，将所得物溶于二氯甲烷(30mL)，并加入三乙胺(2.55mL,18.4mmol)和Boc酸酐(2.29mL,11.0mmol)，室温反应4小时。旋干，柱层析纯化得白色固体1.5g，即为8-羟基-3-氮杂双环[3.2.1]辛烷-3-甲酸叔丁酯，收率：72％。 1H NMR(400MHz,CDCl 3)δ:4.06(m,1H),3.71(m,1H),3.57(m,1H),3.39(m,1H),3.31(m,1H),2.01(m,2H),1.74(m,3H),1.63-1.57(m,2H),1.48(s,9H)。 (1R, 5S) -3-benzyl-3-azabicyclo [3.2.1] -8-alcohol (2.0 g, 9.20 mmol) was dissolved in methanol (30 mL), hydrogen was passed in, and the reaction was carried out at room temperature overnight. Filter through celite, spin dry, dissolve the resultant in dichloromethane (30 mL), add triethylamine (2.55 mL, 18.4 mmol) and Boc anhydride (2.29 mL, 11.0 mmol), and react at room temperature for 4 hours. Spin-dry and purify by column chromatography to obtain 1.5 g of white solid, which is 8-hydroxy-3-azabicyclo [3.2.1] octane-3-carboxylic acid tert-butyl ester, yield: 72%. 1 H NMR (400MHz, CDCl 3 ) δ: 4.06 (m, 1H), 3.71 (m, 1H), 3.57 (m, 1H), 3.39 (m, 1H), 3.31 (m, 1H), 2.01 (m, 2H), 1.74 (m, 3H), 1.63-1.57 (m, 2H), 1.48 (s, 9H).
步骤4)(1R,5S)-8-氧代-3-氮杂双环[3.2.1]辛烷-3-甲酸叔丁酯的制备Step 4) Preparation of (1R, 5S) -8-oxo-3-azabicyclo [3.2.1] octane-3-carboxylic acid tert-butyl ester
将(1R,5S)-8-羟基-3-氮杂双环[3.2.1]辛烷-3-甲酸叔丁酯(1.14g，5.00mmol)溶于二氯甲烷(50mL)中，加入戴斯-马丁氧化剂(3.18g，7.50mmol)。室温搅拌过夜。反应完全后，蒸干溶剂，加入硫代硫酸钠和石油醚搅拌后硅藻土过滤，滤饼用石油醚和乙酸乙酯的混合溶液(3:1)洗涤，有机相依次用硫代硫酸钠溶液洗涤和饱和氯化钠水溶液洗涤，有机相用硫酸钠干燥，蒸干溶剂得(1R,5S)-8-氧代-3-氮杂双环[3.2.1]辛烷-3-甲酸叔丁酯0.96g，收率：85％。MS(m/z)：226.2[M+H]。(1R, 5S) -8-Hydroxy-3-azabicyclo [3.2.1] octane-3-carboxylic acid tert-butyl ester (1.14 g, 5.00 mmol) was dissolved in dichloromethane (50 mL), and Dess was added -Martin oxidant (3.18 g, 7.50 mmol). Stir overnight at room temperature. After the reaction is completed, the solvent is evaporated to dryness, sodium thiosulfate and petroleum ether are added, and the mixture is stirred and filtered through celite. The filter cake is washed with a mixed solution of petroleum ether and ethyl acetate (3: 1), and the organic phase is sequentially washed with sodium thiosulfate. The solution was washed with saturated sodium chloride solution, and the organic phase was dried over sodium sulfate. The solvent was evaporated to give (1R, 5S) -8-oxo-3-azabicyclo [3.2.1] octane-3-carboxylic acid tert-butyl 0.96 g of ester, yield: 85%. MS (m / z): 226.2 [M + H].
步骤5)2-{(1R,5S)-3'-[(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基]-3-氮杂螺[双环[3.2.1]辛烷-8,1'-环丁烷]-3-基}-4-氟苯并[d]噻唑-6-甲酸的制备Step 5) 2-{(1R, 5S) -3 '-[(5-Cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy] -3- Preparation of Azaspiro [Bicyclo [3.2.1] octane-8,1'-cyclobutane] -3-yl} -4-fluorobenzo [d] thiazole-6-carboxylic acid
参照实施例1，用(1R,5S)-8-氧代-3-氮杂双环[3.2.1]辛烷-3-甲酸叔丁酯代替(1R,5S)-3-氧代-8-氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯制备得到2-{(1R,5S)-3'-[(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基]-3-氮杂螺[双环[3.2.1]辛烷-8,1'-环丁烷]-3-基}-4-氟苯并[d]噻唑-6-甲酸。MS(m/z)：628.45[M+1]。 1H NMR(400MHz,CDCl 3)δ8.05(t,J＝2.0Hz,1H),7.66(m,1H),7.40(m,2H),7.33(m,1H),4.15(m,2H),3.88(m,1H),3.34(m,4H),2.23(m,1H),2.11(m,1H),2.04-1.84(m,3H),1.84-1.69(m,4H),1.22(m,4H),1.10(m,2H)。 Referring to Example 1, (1R, 5S) -8-oxo-3-azabicyclo [3.2.1] octane-3-carboxylic acid tert-butyl ester was used instead of (1R, 5S) -3-oxo-8- Preparation of azabicyclo [3.2.1] octane-8-t-butyl formate to obtain 2-{(1R, 5S) -3 '-[(5-cyclopropyl-3- (2,6-dichlorophenyl) ) Isoxazol-4-yl) methoxy] -3-azaspiro [bicyclo [3.2.1] octane-8,1'-cyclobutane] -3-yl} -4-fluorobenzo [ d] Thiazole-6-carboxylic acid. MS (m / z): 628.45 [M + 1]. 1 H NMR (400MHz, CDCl 3 ) δ 8.05 (t, J = 2.0 Hz, 1H), 7.66 (m, 1H), 7.40 (m, 2H), 7.33 (m, 1H), 4.15 (m, 2H) , 3.88 (m, 1H), 3.34 (m, 4H), 2.23 (m, 1H), 2.11 (m, 1H), 2.04-1.84 (m, 3H), 1.84-1.69 (m, 4H), 1.22 (m , 4H), 1.10 (m, 2H).
实施例16Example 16
6-{(1R,5S)-3'-[(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基]-3-氮杂螺[双环[3.2.1]辛烷-8,1'-环丁烷]-3-基}苯并[d]异噻唑-3-甲酸(16)的制备6-{(1R, 5S) -3 '-[(5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methoxy] -3-azaspiro [Bicyclo [3.2.1] octane-8,1'-cyclobutane] -3-yl} preparation of benzo [d] isothiazole-3-carboxylic acid (16)
Figure PCTCN2019099219-appb-000053
Figure PCTCN2019099219-appb-000053
参照实施例4，用(1R,5S)-8-氧代-3-氮杂双环[3.2.1]辛烷-3-甲酸叔丁酯代替(1R,5S)-3-氧代-8-氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯制备得到6-{(1R,5S)-3'-[(5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲氧基]-3-氮杂螺[双环[3.2.1]辛烷-8,1'-环丁烷]-3-基}苯并[d]异噻唑-3-甲酸。MS(m/z)：610.3[M+1]。Referring to Example 4, (1R, 5S) -8-oxo-3-azabicyclo [3.2.1] octane-3-carboxylic acid tert-butyl ester was used instead of (1R, 5S) -3-oxo-8- Preparation of azabicyclo [3.2.1] octane-8-t-butyl formate to obtain 6-{(1R, 5S) -3 '-[(5-cyclopropyl-3- (2,6-dichlorophenyl) ) Isoxazol-4-yl) methoxy] -3-azaspiro [bicyclo [3.2.1] octane-8,1'-cyclobutane] -3-yl} benzo [d] isothiazole -3-carboxylic acid. MS (m / z): 610.3 [M + 1].
实施例17Example 17
2-{(1R,5S)-3'-[((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲基)氨基]-8-氮杂螺[双环[3.2.1]辛烷-3,1'-环丁烷]-8-基}-4-氟苯并[d]噻唑-6-甲酸(17)的制备2-{(1R, 5S) -3 '-[((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methyl) amino] -8-nitrogen Preparation of heterospiro [bicyclo [3.2.1] octane-3,1'-cyclobutane] -8-yl} -4-fluorobenzo [d] thiazole-6-carboxylic acid (17)
Figure PCTCN2019099219-appb-000054
Figure PCTCN2019099219-appb-000054
步骤1)(1R,5S)-3'-((甲磺酰基)氧基)-8-氮杂螺[双环[3.2.1]辛烷-3,1'-环丁烷]-8-甲酸叔丁酯的制备Step 1) (1R, 5S) -3 '-((Methanesulfonyl) oxy) -8-azaspiro [bicyclo [3.2.1] octane-3,1'-cyclobutane] -8-carboxylic acid Preparation of tert-butyl ester
将(1R,5S)-3'-羟基-8-氮杂螺[叔丁基[3.2.1]辛烷-3,1'-环丁烷]-8-甲酸叔丁酯(1.1g，4.12mmol)溶于二氯甲烷(15mL)中，氮气保护后，冷却至0℃，加入三乙胺(1.7mL,12.2mmol)，缓慢加入甲磺酰氯(0.38mL，4.94mmol)。升至室温搅拌1小时。反应完全后，蒸干溶剂，加入水(30mL)，用乙酸乙酯(30mL x 2)萃取，合并有机层，经饱和食盐水洗涤，无水硫酸钠干燥，旋干得淡黄色油状物1.35g，收率：95％。MS(m/z)：346.2[M+1]。(1R, 5S) -3'-Hydroxy-8-azaspiro [tert-butyl [3.2.1] octane-3,1'-cyclobutane] -8-t-butyl formate (1.1 g, 4.12 mmol) was dissolved in dichloromethane (15 mL). After protecting with nitrogen, cooled to 0 ° C., triethylamine (1.7 mL, 12.2 mmol) was added, and methanesulfonyl chloride (0.38 mL, 4.94 mmol) was slowly added. Warm to room temperature and stir for 1 hour. After the reaction was completed, the solvent was evaporated, water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL). The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and spin-dried to give 1.35 g of a pale yellow oil. Yield: 95%. MS (m / z): 346.2 [M + 1].
步骤2)(1R,5S)-3'-叠氮基-8-氮杂螺[双环[3.2.1]辛烷-3,1'-环丁烷]-8-甲酸叔丁酯的制备Step 2) Preparation of (1R, 5S) -3'-azido-8-azaspiro [bicyclo [3.2.1] octane-3,1'-cyclobutane] -8-t-butyl formate
将(1R,5S)-3'-((甲磺酰基)氧基)-8-氮杂螺[双环[3.2.1]辛烷-3,1'-环丁烷]-8-甲酸叔丁酯(1.35g,3.91mmol)溶于二甲基甲酰胺(15mL)中，加入叠氮钠(0.76g，11.74mmol)，加热至100℃，搅拌3小时。反应完全后，冷却至室温，将反应液倒入水(30mL)中，用乙酸乙酯(30mL x 3)萃取，合并有机层，用饱和食盐水洗涤，有机层经无水硫酸钠干燥，旋干得淡黄色油状物0.8g，收率：70％。MS(m/z)：293.2[M+1]。(1R, 5S) -3 '-((Methanesulfonyl) oxy) -8-azaspiro [bicyclo [3.2.1] octane-3,1'-cyclobutane] -8-carboxylic acid tert-butyl The ester (1.35 g, 3.91 mmol) was dissolved in dimethylformamide (15 mL), sodium azide (0.76 g, 11.74 mmol) was added, and the mixture was heated to 100 ° C and stirred for 3 hours. After the reaction is completed, cool to room temperature, pour the reaction solution into water (30 mL), and extract with ethyl acetate (30 mL). Combine the organic layers and wash with saturated brine. The organic layer is dried over anhydrous sodium sulfate, Dry to a pale yellow oil, 0.8 g, yield: 70%. MS (m / z): 293.2 [M + 1].
步骤3)(1R,5S)-3'-氨基-8-氮杂螺[双环[3.2.1]辛烷-3,1'-环丁烷]-8-甲酸叔丁酯的制备Step 3) Preparation of (1R, 5S) -3'-amino-8-azaspiro [bicyclo [3.2.1] octane-3,1'-cyclobutane] -8-carboxylic acid tert-butyl ester
将(1R,5S)-3'-叠氮基-8-氮杂螺[双环[3.2.1]辛烷-3,1'-环丁烷]-8-甲酸叔丁酯(0.8g，2.74mmol)溶于甲醇(10mL)中，加入10％钯碳(0.3g)，在氢气下室温搅拌1.5小时。反应完全后，硅藻土过滤，柱层析纯化(甲醇/二氯甲烷＝1/50至1/20)得(1R,5S)-3'-氨基-8-氮杂螺[双环[3.2.1]辛烷-3,1'-环丁烷]-8-甲酸叔丁酯0.51g，收率：71％。MS(m/z)：267.0[M+1]。(1R, 5S) -3'-azido-8-azaspiro [bicyclo [3.2.1] octane-3,1'-cyclobutane] -8-t-butyl formate (0.8g, 2.74 mmol) was dissolved in methanol (10 mL), 10% palladium on carbon (0.3 g) was added, and the mixture was stirred at room temperature under hydrogen for 1.5 hours. After the reaction was completed, the celite was filtered and purified by column chromatography (methanol / dichloromethane = 1/50 to 1/20) to obtain (1R, 5S) -3'-amino-8-azaspiro [bicyclo [3.2. 1] octane-3,1'-cyclobutane] -tert-butyl formate 0.51 g, yield: 71%. MS (m / z): 267.0 [M + 1].
步骤4)(1R,5S)-3'-(((苄氧基)羰基)氨基)-8-氮杂螺[双环[3.2.1]辛烷-3,1'-环丁烷]-8-甲酸叔丁酯的制备Step 4) (1R, 5S) -3 '-(((Benzyloxy) carbonyl) amino) -8-azaspiro [bicyclo [3.2.1] octane-3,1'-cyclobutane] -8 -Preparation of tert-butyl formate
将(1R,5S)-3'-氨基-8-氮杂螺[双环[3.2.1]辛烷-3,1'-环丁烷]-8-甲酸叔丁酯(0.5g，0.18mmol)溶于二氯甲烷(7mL)中，加入二异丙基乙胺(0.54mL，0.54mmol)，氮气保护后，冷却至0℃，滴加氯甲酸苄酯(0.3mL，0.21mmol)，加完后升至室温反应2小时。旋干，经柱层析纯化(石油醚/乙酸乙酯＝5/1)得(1R,5S)-3'-(((苄氧基)羰基)氨基)-8-氮杂螺[双环[3.2.1]辛烷-3,1'-环丁烷]-8-甲酸叔丁酯0.65g，收率：98％。MS(m/z)：401.2[M+1]。(1R, 5S) -3'-Amino-8-azaspiro [bicyclo [3.2.1] octane-3,1'-cyclobutane] -8-formic acid tert-butyl ester (0.5 g, 0.18 mmol) Dissolved in dichloromethane (7mL), added diisopropylethylamine (0.54mL, 0.54mmol), protected by nitrogen, cooled to 0 ° C, and benzyl chloroformate (0.3mL, 0.21mmol) was added dropwise. After warming to room temperature, it was reacted for 2 hours. Spin-dry and purify by column chromatography (petroleum ether / ethyl acetate = 5/1) to obtain (1R, 5S) -3 '-(((benzyloxy) carbonyl) amino) -8-azaspiro [bicyclo [ 3.2.1] octane-3,1'-cyclobutane] -tert-butyl formate 0.65 g, yield: 98%. MS (m / z): 401.2 [M + 1].
步骤5)(1R,5S)-8-氮杂螺[双环[3.2.1]辛烷-3,1'-环丁烷]-3'-基氨基甲酸苄酯的制备Step 5) Preparation of (1R, 5S) -8-azaspiro [bicyclo [3.2.1] octane-3,1'-cyclobutane] -3'-ylcarbamate
将(1R,5S)-3'-(((苄氧基)羰基)氨基)-8-氮杂螺[双环[3.2.1]辛烷-3,1'-环丁烷]-8-甲酸叔丁酯(0.65g，1.63mmol)溶于甲醇(7mL)中，加入2N氯化氢二氧六环溶液(7mL)。室温搅拌1小时，反应完全后蒸干溶剂得产物480mg，收率：99％。MS(m/z)：301.3[M+1]。Put (1R, 5S) -3 '-(((benzyloxy) carbonyl) amino) -8-azaspiro [bicyclo [3.2.1] octane-3,1'-cyclobutane] -8-formic acid Tert-butyl ester (0.65 g, 1.63 mmol) was dissolved in methanol (7 mL), and a 2N hydrogen chloride dioxane solution (7 mL) was added. After stirring at room temperature for 1 hour, the solvent was evaporated to obtain 480 mg of the product after the reaction was completed. The yield was 99%. MS (m / z): 301.3 [M + 1].
步骤6)2-{(1R,5S)-3'-(((苄氧基)羰基)氨基)-8-氮杂螺[双环[3.2.1]辛烷-3,1'-环丁烷]-8-基}-4-氟苯并[d]噻唑-6- 甲酸甲酯的制备Step 6) 2-{(1R, 5S) -3 '-(((Benzyloxy) carbonyl) amino) -8-azaspiro [bicyclo [3.2.1] octane-3,1'-cyclobutane Preparation of methyl] -8-yl} -4-fluorobenzo [d] thiazole-6-carboxylic acid
将(1R,5S)-8-氮杂螺[双环[3.2.1]辛烷-3,1'-环丁烷]-3'-基氨基甲酸苄酯(480mg，1.43mmol)溶于乙腈(10mL)中，加入三乙胺(0.67mL,4.83mmol)和2-氯-4-氟苯并[d]噻唑-6-羧酸甲酯(418mg，1.7mmol)。于80℃反应过夜，待反应液冷却，旋干，经柱层析纯化(石油醚/乙酸乙酯＝3/1)得产物0.8g，收率：98％。MS(m/z)：510.3[M+1]。(1R, 5S) -8-azaspiro [bicyclo [3.2.1] octane-3,1'-cyclobutane] -3'-ylcarbamic acid benzyl ester (480 mg, 1.43 mmol) was dissolved in acetonitrile ( 10 mL), triethylamine (0.67 mL, 4.83 mmol) and 2-chloro-4-fluorobenzo [d] thiazole-6-carboxylic acid methyl ester (418 mg, 1.7 mmol) were added. The reaction was carried out at 80 ° C. overnight. After the reaction solution was cooled, spin-dried, purified by column chromatography (petroleum ether / ethyl acetate = 3/1) to obtain 0.8 g of the product, yield: 98%. MS (m / z): 510.3 [M + 1].
步骤7)2-{(1R,5S)-3'-氨基-8-氮杂螺[双环[3.2.1]辛烷-3,1'-环丁烷]-8-基}-4-氟苯并[d]噻唑-6-甲酸甲酯的制备Step 7) 2-{(1R, 5S) -3'-amino-8-azaspiro [bicyclo [3.2.1] octane-3,1'-cyclobutane] -8-yl} -4-fluoro Preparation of benzo [d] thiazole-6-carboxylic acid methyl ester
将2-{(1R,5S)-3'-(((苄氧基)羰基)氨基)-8-氮杂螺[双环[3.2.1]辛烷-3,1'-环丁烷]-8-基}-4-氟苯并[d]噻唑-6-甲酸甲酯(0.4g，0.79mmol)溶于二氯甲烷(5mL)中，加入三甲基碘硅烷(0.33mL，2.37mmol)，室温搅拌1小时后蒸干溶剂，加入水(10mL)和甲基叔丁基醚(10mL)。分液，水相用固体碳酸氢钠调碱，并用二氯甲烷(10mL x 3)萃取，合并有机层，经饱和食盐水洗涤，无水硫酸钠干燥，旋干得产物250mg，收率：84.7％。MS(m/z)：376.2[M+1]。Add 2-{(1R, 5S) -3 '-(((benzyloxy) carbonyl) amino) -8-azaspiro [bicyclo [3.2.1] octane-3,1'-cyclobutane]- 8-yl} -4-fluorobenzo [d] thiazole-6-carboxylic acid methyl ester (0.4g, 0.79mmol) was dissolved in dichloromethane (5mL), and trimethyliodosilane (0.33mL, 2.37mmol) was added. After stirring at room temperature for 1 hour, the solvent was evaporated, and water (10 mL) and methyl tert-butyl ether (10 mL) were added. The liquid phase was separated, and the aqueous phase was alkalized with solid sodium bicarbonate and extracted with dichloromethane (10 mL). The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and dried to give 250 mg of the product. Yield: 84.7 %. MS (m / z): 376.2 [M + 1].
步骤8)2-{(1R,5S)-3'-[((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲基)氨基]-8-氮杂螺[双环[3.2.1]辛烷-3,1'-环丁烷]-8-基}-4-氟苯并[d]噻唑-6-甲酸甲酯的制备Step 8) 2-{(1R, 5S) -3 '-[((5-Cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methyl) amino]- Preparation of 8-azaspiro [bicyclo [3.2.1] octane-3,1'-cyclobutane] -8-yl} -4-fluorobenzo [d] thiazole-6-carboxylic acid methyl ester
将2-{(1R,5S)-3'-氨基-8-氮杂螺[双环[3.2.1]辛烷-3,1'-环丁烷]-8-基}-4-氟苯并[d]噻唑-6-甲酸甲酯(250mg，0.67mmol)溶于乙腈(10mL)中，加入三乙胺(0.2mL,1.51mmol)和4-(氯甲基)-5-环丙基-3-(2,6-二氯苯基)异噁唑(200mg，0.68mmol)。于80℃反应过夜，待反应液冷却至室温，旋干溶剂，经柱层析纯化(石油醚/乙酸乙酯＝5/1)得产物300mg，收率：70％。MS(m/z)：641.4[M+1]。2-{(1R, 5S) -3'-amino-8-azaspiro [bicyclo [3.2.1] octane-3,1'-cyclobutane] -8-yl} -4-fluorobenzo [d] Thiazole-6-carboxylic acid methyl ester (250mg, 0.67mmol) was dissolved in acetonitrile (10mL), and triethylamine (0.2mL, 1.51mmol) and 4- (chloromethyl) -5-cyclopropyl- 3- (2,6-dichlorophenyl) isoxazole (200 mg, 0.68 mmol). The reaction was carried out at 80 ° C. overnight. After the reaction solution was cooled to room temperature, the solvent was spin-dried and purified by column chromatography (petroleum ether / ethyl acetate = 5/1) to obtain 300 mg of the product, yield: 70%. MS (m / z): 641.4 [M + 1].
步骤9)2-{(1R,5S)-3'-[((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲基)氨基]-8-氮杂螺[双环[3.2.1]辛烷-3,1'-环丁烷]-8-基}-4-氟苯并[d]噻唑-6-甲酸的制备Step 9) 2-((1R, 5S) -3 '-[((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methyl) amino]- Preparation of 8-azaspiro [bicyclo [3.2.1] octane-3,1'-cyclobutane] -8-yl} -4-fluorobenzo [d] thiazole-6-carboxylic acid
将2-{(1R,5S)-3'-[((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲基)氨基]-8-氮杂螺[双环[3.2.1]辛烷-3,1'-环丁烷]-8-基}-4-氟苯并[d]噻唑-6-甲酸甲酯(100mg，0.16mmol)溶于四氢呋喃(1.5mL)、甲醇(1.5mL)和水(1mL)中，加入氢氧化钠(24mg，0.6mmol)。室温反应1小时，反应完全后蒸干有机溶剂，加水(10mL)，用1N盐酸调pH至5左右，再用乙酸乙酯(10mL x 3)萃取，合并有机层，经饱和食盐水洗涤，无水硫酸钠干燥，旋干，经厚制备板纯化得淡黄色固体60mg，收率：62％。MS(m/z)：627.43[M+1]。 1H NMR(400MHz,CDCl 3)δ8.03(s,1H),7.65(m,1H),7.52-7.35(m,3H),4.48(s,1H),4.28(s,1H),3.69(m,2H),3.40(m,1H),2.31(m,2H),1.89(m,8H),1.27(m,5H),1.12(m,2H)。 2-((1R, 5S) -3 '-[((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methyl) amino] -8- Azaspiro [Bicyclo [3.2.1] octane-3,1'-cyclobutane] -8-yl} -4-fluorobenzo [d] thiazole-6-carboxylic acid methyl ester (100mg, 0.16mmol) To tetrahydrofuran (1.5 mL), methanol (1.5 mL) and water (1 mL), sodium hydroxide (24 mg, 0.6 mmol) was added. The reaction was performed at room temperature for 1 hour. After the reaction was completed, the organic solvent was evaporated, water (10 mL) was added, the pH was adjusted to about 5 with 1N hydrochloric acid, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic layers were combined and washed with saturated brine. Dry with sodium sulfate, spin dry, and purify by thick preparation plate to obtain 60 mg of light yellow solid, yield: 62%. MS (m / z): 627.43 [M + 1]. 1 H NMR (400MHz, CDCl 3 ) δ 8.03 (s, 1H), 7.65 (m, 1H), 7.52-7.35 (m, 3H), 4.48 (s, 1H), 4.28 (s, 1H), 3.69 ( m, 2H), 3.40 (m, 1H), 2.31 (m, 2H), 1.89 (m, 8H), 1.27 (m, 5H), 1.12 (m, 2H).
实施例18Example 18
2-{(1R,5S)-3'-[((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲基)(甲基)氨基]-8-氮杂螺[双环[3.2.1]辛烷-3,1'-环丁烷]-8-基}-4-氟苯并[d]噻唑-6-甲酸(18)的制备2-{(1R, 5S) -3 '-[((5-cyclopropyl-3- (2,6-dichlorophenyl) isoxazol-4-yl) methyl) (methyl) amino] Preparation of -8-azaspiro [bicyclo [3.2.1] octane-3,1'-cyclobutane] -8-yl} -4-fluorobenzo [d] thiazole-6-carboxylic acid (18)
Figure PCTCN2019099219-appb-000055
Figure PCTCN2019099219-appb-000055
步骤1)2-{(1R,5S)-3'-[((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲基)(甲基)氨基]-8-氮杂螺[双环[3.2.1]辛烷-3,1'-环丁烷]-8-基}-4-氟苯并[d]噻唑-6-甲酸甲酯的制备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
将2-{(1R,5S)-3'-氨基-8-氮杂螺[双环[3.2.1]辛烷-3,1'-环丁烷]-8-基}-4-氟苯并[d]噻唑-6-甲酸甲酯(200mg，0.31mmol)溶于四氢呋喃(5mL)中，加入钠氢(15mg，0.38mmol)，室温搅拌20分钟后，滴加碘甲烷(0.02mL，0.34mmol)。反应完全后，加入水(10mL)淬灭反应，用乙酸乙酯萃取，合并有机层，经饱和食盐水洗涤，无水硫酸钠干燥，旋干，经柱层析纯化(石油醚/乙酸乙酯＝4/1)得产物180mg，收率：88％。MS(m/z)：655.4[M+1]。2-{(1R, 5S) -3'-amino-8-azaspiro [bicyclo [3.2.1] octane-3,1'-cyclobutane] -8-yl} -4-fluorobenzo [d] Thiazole-6-carboxylic acid methyl ester (200mg, 0.31mmol) was dissolved in tetrahydrofuran (5mL), sodium hydrogen (15mg, 0.38mmol) was added, and after stirring at room temperature for 20 minutes, iodomethane (0.02mL, 0.34mmol) was added dropwise ). After the reaction was completed, water (10 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, spin-dried, and purified by column chromatography (petroleum ether / ethyl acetate). = 4/1) to give 180 mg of product, yield: 88%. MS (m / z): 655.4 [M + 1].
步骤2)2-{(1R,5S)-3'-[((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲基)(甲基)氨基]-8-氮杂螺[双环[3.2.1]辛烷-3,1'-环丁烷]-8-基}-4-氟苯并[d]噻唑-6-甲酸的制备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
将2-{(1R,5S)-3'-[((5-环丙基-3-(2,6-二氯苯基)异噁唑-4-基)甲基)(甲基)氨基]-8-氮杂螺[双环[3.2.1]辛烷-3,1'-环丁烷]-8-基}-4-氟苯并[d]噻唑-6-甲酸甲酯(100mg，0.15mmol)溶于四氢呋喃(1.5mL)、甲醇(1.5mL)和水(1mL)中，加入氢氧化钠(24mg，0.6mmol)。室温反应1小时，反应完全后蒸干有机溶剂，加水(10mL)，用1N盐酸调pH至5左右，再用乙酸乙酯(10mL x 3)萃取，合并有机层，经饱和食盐水洗涤，无水硫酸钠干燥，旋干，经厚制备板纯化得淡黄色固体55mg，收率：57％。MS(m/z)：641.44[M+1]。 1H NMR(400MHz,CDCl 3)δ8.13(m,1H),7.77(m,1H),7.51-7.35(m,3H),4.52(s,1H),4.30(d,J＝7.2Hz,1H),3.45(m,2H),2.84(m,1H),2.19(m,2H),2.09(m,5H),1.80(m,3H),1.66(m,1H),1.55(m,1H),1.47(m,1H),1.37-1.21(m,5H),1.15(m,2H)。 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 (100mg, 0.15 mmol) was dissolved in tetrahydrofuran (1.5 mL), methanol (1.5 mL) and water (1 mL), and sodium hydroxide (24 mg, 0.6 mmol) was added. The reaction was performed at room temperature for 1 hour. After the reaction was completed, the organic solvent was evaporated, water (10 mL) was added, the pH was adjusted to about 5 with 1N hydrochloric acid, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic layers were combined and washed with saturated brine. It was dried with water sodium sulfate, spin-dried, and purified through a thick preparation plate to obtain 55 mg of a pale yellow solid, yield: 57%. MS (m / z): 641.44 [M + 1]. 1 H NMR (400MHz, CDCl 3 ) δ8.13 (m, 1H), 7.77 (m, 1H), 7.51-7.35 (m, 3H), 4.52 (s, 1H), 4.30 (d, J = 7.2Hz, 1H), 3.45 (m, 2H), 2.84 (m, 1H), 2.19 (m, 2H), 2.09 (m, 5H), 1.80 (m, 3H), 1.66 (m, 1H), 1.55 (m, 1H) ), 1.47 (m, 1H), 1.37-1.21 (m, 5H), 1.15 (m, 2H).
生物试验Biological test
体外活性测试In vitro activity test
AlphaScreen测试：采用珀金埃尔默仪器有限公司(Perkins-Elmer)的六聚组氨酸检测试剂盒(hexahistidine detection kit)，检测化合物对人法尼醇受体蛋白(hFXR)结合其共激活因子(SRC1-2)的影响，方法如下：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:
1)制备混合物，包括人法尼醇受体蛋白hFXR(100nM,15μL/孔)、多肽bSRC1-2(50nM,15μL/孔)、10×AlphaScreen缓冲液(15μL/孔)、去离子水(60μL/孔)，转入96孔板，105μL/孔；1) Preparation of mixture, including human farnesol receptor protein hFXR (100 nM, 15 μL / well), peptide bSRC1-2 (50 nM, 15 μL / well), 10 × AlphaScreen buffer (15 μL / well), deionized water (60 μL / Well), transfer to 96-well plate, 105μL / well;
2)上述实施例制备得到的化合物按照2倍倍比稀释12次，15μL/孔；2) The compound prepared in the above example is diluted 12 times at a ratio of 2 times, 15 μL / well;
3)供体微珠、受体微珠一共30μL/孔；3) Donor beads and acceptor beads total 30 μL / well;
4)室温避光孵育2h；4) Incubate at room temperature in the dark for 2h;
5)转384孔板，40μL/孔，3个复孔。瞬时离心1000rpm，1分钟，使液滴充分混合在孔底；5) Spin 384-well plate, 40 μL / well, 3 replicates. Centrifuge briefly at 1000 rpm for 1 minute to fully mix the droplets at the bottom of the well;
6)暗室里，仪器读板(均相发光免疫检测系统)，EC 50由数据处理软件GraphPad Prism5处理得到。 6) In the dark room, the instrument reads the plate (homogeneous luminescence immunoassay system), and the EC 50 is processed by the data processing software GraphPad Prism5.
结果如下表1所示：The results are shown in Table 1 below:
表1 FXR激动活性测试结果Table 1 FXR agonistic activity test results
实施例号Example number EC 50(nM) EC 50 (nM)
实施例1Example 1 AA
实施例2Example 2 AA
实施例3Example 3 AA
实施例4Example 4 AA
实施例5Example 5 BB
实施例6Example 6 BB
实施例7Example 7 BB
实施例8Example 8 AA
实施例9Example 9 AA
实施例10Example 10 AA
实施例11Example 11 AA
实施例12Example 12 BB
实施例13Example 13 AA
实施例14Example 14 AA
实施例15Example 15 AA
实施例16Example 16 AA
实施例17Example 17 BB
实施例18Example 18 BB
注：nM为nmol/L，A代表EC 50<100nM，B代表100nM<EC 50<1000nM，C代表EC 50>1000nM。 Note: nM is nmol / L, A means EC 50 <100 nM, B means 100 nM <EC 50 <1000 nM, and C means EC 50 > 1000 nM.
从上述结果中可以看出，本发明的多个化合物化合物对FXR激动的EC 50达到100nM以下，显示出了非常好的FXR激动活性。 From the above results, it can be seen that the EC 50 of the compounds of the present invention on FXR activation is below 100 nM, and shows very good FXR agonistic activity.
总之，本发明化合物对FXR具有很好的激动活性，具有优异的体内外药效、药代性质，具备较佳的临床应用前景。In a word, 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.
本说明书中引用的所有出版物、专利和专利申请均通过引用并入本文，就如同每个单独的出版物、专利或专利申请被具体地和单独地指出通过引用并入。尽管已根据各种实施例/实施方案描述了所要求保护的 主题，但本领域技术人员将认识到，可在不脱离本发明精神的情况下进行各种修改/修饰、替换、删减和改变/变化。因此，所要求保护的主题的范围旨在仅由所附权利要求的范围限定，包括其等同物。All publications, patents, and patent applications cited in this specification are incorporated herein by reference, as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. Although the claimed subject matter has been described in terms of various examples / implementations, those skilled in the art will recognize that various modifications / modifications, substitutions, deletions and changes may be made without departing from the spirit of the invention /Variety. Accordingly, the scope of the claimed subject matter is intended to be limited only by the scope of the following claims, including equivalents thereof.

Claims (23)

  1. 化合物，其包含式(I)所示化合物，或式(I)所示化合物的药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、氮氧化物、代谢物、前药、或混合物：A compound comprising a compound represented by formula (I), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, nitrogen oxide, metabolism of a compound represented by formula (I) Substance, prodrug, or mixture:
    Figure PCTCN2019099219-appb-100001
    Figure PCTCN2019099219-appb-100001
    其中，among them,
    A为C或N；A is C or N;
    P为C(R a)、N、N(R b)、或O； P is C (R a ), N, N (R b ), or O;
    Q为C(R a)、N、N(R b)、或O； Q is C (R a ), N, N (R b ), or O;
    M为C或N；M is C or N;
    Figure PCTCN2019099219-appb-100002
    为单键或双键；
    Figure PCTCN2019099219-appb-100002
    Single or double bond;
    R 1为H、F、Cl、Br、I、-CN、烷基、烯基、炔基、芳基、杂芳基、环烷基、或杂环基，其中所述R 1独立任选地被1、2、3或4个R 5取代； 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为芳基、杂芳基、环烷基、或杂环基，其中所述R 2独立任选地被1、2、3或4个R 6取代； 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和R 3b各自独立地为H、F、Cl、Br、I、CN、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氨基、C 1-6烷氧基、卤代C 1-6烷氧基、C 3-6环烷基、或卤代C 3-6环烷基，或者R 3a、R 3b同与之连接的碳原子一起形成C 3-6环烷基、C 3-6环烯基、或3-6个原子组成的杂环基；其中所述C 1-6烷基、C 1-6烷氧基、C 1-6烷氨基、C 3-6环烷基、C 3-6环烯基、和3-6个原子组成的杂环基独立任选地被1、2、3或4个R 7取代； 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为：X is:
    Figure PCTCN2019099219-appb-100003
    Figure PCTCN2019099219-appb-100003
    其中X独立任选地被1、2、3或4个R 8取代； Wherein X is independently optionally substituted by 1, 2, 3 or 4 R 8 ;
    X 1不存在，或X 1为-N(R 1a)-、O、S、-C(＝O)-、-S(＝O)-、-S(＝O) 2-、-C(＝O)N(R 1a)-、-S(＝O)N(R 1a)-、或-S(＝O) 2N(R 1a)-； X 1 does not exist, or X 1 is -N (R 1a )-, O, S, -C (= O)-, -S (= O)-, -S (= O) 2- , -C (= O) N (R 1a )-, -S (= O) N (R 1a )-, or -S (= O) 2 N (R 1a )-;
    X 2、X 3和X 4各自独立地为-O-、-S-、-NH-、-(CH 2) m1-NH-(CH 2) m2-、-(CH 2) m1-O-(CH 2) m2-、-(CH 2) m1-S-(CH 2) m2-、或-(CH 2) m3-； 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 -;
    Y不存在，或Y为-N(R 1a)-、-O-、-S-、-C(＝O)-、-S(＝O)-、-S(＝O) 2-、-C(＝O)N(R 1a)-、-S(＝O)N(R 1a)-、-S(＝O) 2N(R 1a)-、C 1-6亚烷基、C 2-6亚烯基、C 2-6亚炔基、C 3-8亚环烷基、C 2-9亚杂环基、C 6-10亚芳基、或C 1-9亚杂芳基，其中Y独立任选地被1、2、3或4个R 9取代； Y does not exist, or Y is -N (R 1a )-, -O-, -S-, -C (= O)-, -S (= O)-, -S (= O) 2- , -C (= O) N (R 1a )-, -S (= O) N (R 1a )-, -S (= O) 2 N (R 1a )-, C 1-6 alkylene, C 2-6 Alkenylene, C 2-6 alkynylene, C 3-8 cycloalkylene, C 2-9 heterocyclylene, C 6-10 arylene, or C 1-9 heteroarylene, where Y Independently optionally substituted by 1, 2, 3 or 4 R 9 ;
    Z为亚芳基、亚杂芳基、或亚杂环基，其中Z独立任选地被1、2、3或4个R 10取代； Z is an arylene, heteroarylene, or heterocyclic group, wherein Z is independently optionally substituted with 1, 2, 3, or 4 R 10 ;
    R 4为杂芳基、-S(＝O) 0-2R 11、-C(＝O)R 11、-S(＝O) 1-2OR 4a、-OS(＝O) 1-2R 4a、-C(＝O)OR 4a、-OC(＝O)R 4a、-C(＝O)NR 12aR 12b、-S(＝O) 1-2NR 12aR 12b、-O-R 13-C(＝O)OR 4a、-O-R 13-S(＝O) 1-2OR 4a、-N(R 12a)-R 13-C(＝O)OR 4a、-C(＝O)N(R 12a)-R 13-OH、-C(＝O)N(R 12a)-R 13-NH 2、-C(＝O)N(R 12a)-R 13-C(＝O)OR 4a、-C(＝O)N(R 12a)-R 13-S(＝O) 1-2OR 4a、-C(＝O)N(R 12a)-S(＝O) 1-2R 11、-N(R 12a)C(＝O)NR 12aR 12b、-N(R 12a)S(＝O) 1-2NR 12aR 12b、-N(R 12a)C(＝O)N(R 12a)-S(＝O) 1-2R 11、或-OC(＝O)N(R 12a)-S(＝O) 1-2R 11； R 4 is heteroaryl, -S (= O) 0-2 R 11 , -C (= O) R 11 , -S (= O) 1-2 OR 4a , -OS (= O) 1-2 R 4a , -C (= O) OR 4a , -OC (= O) R 4a , -C (= O) NR 12a R 12b , -S (= O) 1-2 NR 12a R 12b , -OR 13 -C (= O) OR 4a , -OR 13 -S (= O) 1-2 OR 4a , -N (R 12a ) -R 13 -C (= O) OR 4a , -C (= O) N (R 12a ) -R 13 -OH, -C (= O) N (R 12a ) -R 13 -NH 2 , -C (= O) N (R 12a ) -R 13 -C (= O) OR 4a , -C (= O) N (R 12a ) -R 13 -S (= O) 1-2 OR 4a, -C (= O) N (R 12a) -S (= O) 1-2 R 11, -N ( R 12a ) C (= O) NR 12a R 12b , -N (R 12a ) S (= O) 1-2 NR 12a R 12b , -N (R 12a ) C (= O) N (R 12a ) -S (= O) 1-2 R 11 , or -OC (= O) N (R 12a ) -S (= O) 1-2 R 11 ;
    各R 4a分别独立地为H、烷基、烯基、炔基、卤代烷基、氰基取代的烷基、羟烷基、芳基、芳烷基、杂芳基、杂芳基烷基、环烷基、环烷基烷基、杂环基、或杂环基烷基；其中R 4a独立任选地被1、2、3或4个R 4b取代； 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 ;
    各R 11分别独立地为H、OH、NH 2、烷基、烯基、炔基、卤代烷基、羟烷基、氰基取代的烷基、烷氧基、卤代烷氧基、芳基、芳烷基、杂芳基、杂芳基烷基、环烷基、环烷基烷基、杂环基、或杂环基烷基；其中R 11独立任选地被1、2、3或4个R 11a取代； 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;
    各R 12a和R 12b分别独立地为H、烷基、烯基、炔基、卤代烷基、氰基取代的烷基、羟烷基、芳基、芳烷基、杂芳基、杂芳基烷基、环烷基、环烷基烷基、杂环基、或杂环基烷基；其中R 12a和R 12b分别独立任选地被1、2、3或4个R 11b取代； 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 ;
    各R 13分别独立地为亚烷基、亚烯基、亚炔基、羟烷基、氰基取代的亚烷基、或卤代亚烷基； Each R 13 is independently alkylene, alkenylene, alkynylene, hydroxyalkyl, cyano-substituted alkylene, or haloalkylene;
    各R 4b、R 11a和R 11b分别独立地为H、-CN、-NO 2、-OH、-NH 2、F、Cl、Br、I、C 1-6烷基、C 2-6烯基、C 2-6炔基、卤代C 1-6烷基、氰基取代的C 1-6烷基、C 1-6羟烷基、或C 1-6烷氧基； 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;
    各R 1a和R b分别独立地为H、烷基、烯基、炔基、氰基取代的烷基、羟烷基、或卤代烷基； Each R 1a and R b is independently H, alkyl, alkenyl, alkynyl, cyano-substituted alkyl, hydroxyalkyl, or haloalkyl;
    各R a分别独立地为H、-CN、-NO 2、-OH、-NH 2、F、Cl、Br、I、烷基、烯基、炔基、卤代烷基、氰基取代的烷基、羟烷基、烷氧基、或卤代烷氧基； 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;
    各R 5、R 6、R 7、R 8、R 9和R 10分别独立地为H、-CN、-NO 2、-OH、-NH 2、F、Cl、Br、I、烷基、烯基、炔基、卤代烷基、氰基取代的烷基、羟烷基、烷氨基、烷氧基、卤代烷氧基、环烷基、-S(＝O) 0-2R 14、-C(＝O)R 15、-OS(＝O) 1-2R 14a、-OC(＝O)R 15a、-N(R 16a)C(＝O)R 16、-OC(＝O)NR 17R 17a、-NR 17R 17a、-N(R 16a)S(＝O) 1-2R 16、或-N(R 16a)C(＝O)NR 17R 17a； 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, alkyl, alkene Alkyl, alkynyl, haloalkyl, cyano-substituted alkyl, hydroxyalkyl, alkamino, alkoxy, haloalkoxy, cycloalkyl, -S (= O) 0-2 R 14 , -C (= O) R 15 , -OS (= O) 1-2 R 14a , -OC (= O) R 15a , -N (R 16a ) C (= O) R 16 , -OC (= O) NR 17 R 17a , -NR 17 R 17a , -N (R 16a ) S (= O) 1-2 R 16 , or -N (R 16a ) C (= O) NR 17 R 17a ;
    各R 14、R 14a、R 15、R 15a、和R 16分别独立地为H、C 1-6烷基、C 2-6烯基、C 2-6炔基、卤代C 1-6烷基、氰基取代的C 1-6烷基、芳基、芳烷基、杂芳基、杂芳基烷基、环烷基、环烷基烷基、杂环基、或杂环基烷基； Each of 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 ;
    各R 16a、R 17、和R 17a和分别独立地为H、C 1-6烷基、C 2-6烯基、C 2-6炔基、氰基取代的C 1-6烷基、或卤代C 1-6烷基； 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;
    各m1分别独立地为0、1、2或3；Each m1 is independently 0, 1, 2 or 3;
    各m2分别独立地为0、1、2或3；和Each m2 is independently 0, 1, 2 or 3; and
    各m3分别独立地为0、1、2或3。Each m3 is independently 0, 1, 2, or 3.
  2. 根据权利要求1所述的化合物，其中，X为The compound according to claim 1, wherein X is
    Figure PCTCN2019099219-appb-100004
    Figure PCTCN2019099219-appb-100004
    其中X独立任选地被1、2、3或4个R 8取代； Wherein X is independently optionally substituted by 1, 2, 3 or 4 R 8 ;
    X 1不存在，或X 1为-N(R 1a)-、-O-、-S-、-C(＝O)-、-S(＝O)-、-S(＝O) 2-、-C(＝O)N(R 1a)-、-S(＝O)N(R 1a)-、或-S(＝O) 2N(R 1a)-； X 1 does not exist, or X 1 is -N (R 1a )-, -O-, -S-, -C (= O)-, -S (= O)-, -S (= O) 2- , -C (= O) N (R 1a) -, - S (= O) N (R 1a) -, or -S (= O) 2 N ( R 1a) -;
    各R 1a分别独立地为H、C 1-4烷基、C 2-4烯基、C 2-4炔基、氰基取代的C 1-4烷基、C 1-4羟烷基、或卤代C 1-4烷基；和 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; and
    a为0、1、2或3；a is 0, 1, 2 or 3;
    b为0、1、2或3；和b is 0, 1, 2 or 3; and
    c为0、1、2或3。c is 0, 1, 2 or 3.
  3. 根据权利要求1所述的化合物，其中，A、P、Q和M以及碳原子组成的环
    Figure PCTCN2019099219-appb-100005
    为：     The compound according to claim 1, wherein a ring consisting of A, P, Q, and M and a carbon atom
    Figure PCTCN2019099219-appb-100005
    for:
    Figure PCTCN2019099219-appb-100006
    Figure PCTCN2019099219-appb-100006
    其中，P 1为N、或-C(R a)-； Wherein P 1 is N or -C (R a )-;
    Q 1为O、或-N(R b)-； Q 1 is O, or -N (R b )-;
    R a为H、-CN、-NO 2、-OH、-NH 2、F、Cl、Br、I、C 1-4烷基、C 2-4烯基、C 2-4炔基、卤代C 1-4烷基、氰基取代的C 1-4烷基、C 1-4羟烷基、C 1-4烷氧基、或卤代C 1-4烷氧基；和 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为H、C 1-4烷基、C 2-4烯基、C 2-4炔基、氰基取代的C 1-4烷基、C 1-4羟烷基、或卤代C 1-4烷基。 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.
  4. 根据权利要求1所述的化合物，其中，所述化合物具有式(II)-(IV)任一所示结构：The compound according to claim 1, wherein the compound has a structure represented by any one of formulae (II) to (IV):
    Figure PCTCN2019099219-appb-100007
    Figure PCTCN2019099219-appb-100007
    其中，c为0、1、2或3。Where c is 0, 1, 2 or 3.
  5. 根据权利要求1-4任一项所述的化合物，其中，Z为C 6-10亚芳基、C 1-9亚杂芳基、或C 2-7亚杂环基，其中Z独立任选地被1、2、3或4个R 10取代。 The compound according to any one of claims 1-4, wherein Z is a C 6-10 arylene group, a C 1-9 heteroarylene group, or a C 2-7 heterocyclic group, wherein Z is independently selected Ground is replaced by 1, 2, 3 or 4 R 10 .
  6. 根据权利要求1-4任一项所述的化合物，其中，Z为亚苯基、亚萘基、亚吡啶基、亚嘧啶基、亚吡嗪基、亚哒嗪基、亚噻唑基、苯并噻唑基、苯并[d]异噻唑基、咪唑并[1,2-a]吡啶基、萘基、喹啉基、1H-吲哚基、吡咯并[1,2-b]哒嗪基、苯并呋喃基、苯并[b]噻吩基、1H-吲唑基、苯并[d]异噁唑基、喹唑啉基、1H-吡咯并[3,2-c]吡啶基、吡唑并[1,5-a]嘧啶基、咪唑并[1,2-b]哒嗪基、或吡唑并[1,5-a]吡啶基，或Z为以下子结构式之一：The compound according to any one of claims 1 to 4, wherein Z is a phenylene group, a naphthylene group, a pyridylene group, a pyrimidinyl group, a pyrazinyl group, a pyridazinyl group, a thiazolyl group, a benzo Thiazolyl, benzo [d] isothiazolyl, 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, pyrazole [1,5-a] pyrimidinyl, imidazo [1,2-b] pyridazinyl, or pyrazolo [1,5-a] pyridinyl, or Z is one of the following substructures:
    Figure PCTCN2019099219-appb-100008
    Figure PCTCN2019099219-appb-100008
    其中Z独立任选地被1、2、3或4个R 10取代。 Wherein Z is independently optionally substituted by 1, 2, 3 or 4 R 10 .
  7. 根据权利要求1所述的化合物，其中，所述化合物具有式(IIa)-(IId)和(IIIa)-(IIIc)任一所示结构：The compound according to claim 1, wherein the compound has a structure represented by any one of formulae (IIa)-(IId) and (IIIa)-(IIIc):
    Figure PCTCN2019099219-appb-100009
    Figure PCTCN2019099219-appb-100009
    其中，among them,
    Z 1为N、或C(R 10)； Z 1 is N or C (R 10 );
    Z 2为O、S、N(R 10)、或-CHR 10-； Z 2 is O, S, N (R 10 ), or -CHR 10- ;
    Z 3为N、或C(R 10)； Z 3 is N or C (R 10 );
    Z 4和Z 5各自独立地为N、或C(R 10)；和 Z 4 and Z 5 are each independently N, or C (R 10 ); and
    m为0、1、2或3。m is 0, 1, 2 or 3.
  8. 根据权利要求1-4和7任一项所述的化合物，其中，R 1为H、F、Cl、Br、I、-CN、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 6-10芳基、C 1-9杂芳基、C 3-8环烷基、或C 3-7杂环基，其中所述R 1独立任选地被1、2、3或4个R 5取代。 The compound according to any one of claims 1-4 and 7, wherein 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 1, 2 , 3 or 4 R 5 substitutions.
  9. 根据权利要求1-4和7任一项所述的化合物，其中，R 1为苯基、环丙基、环丁基、环戊基、环己基、异丙基、或叔丁基，其中所述R 1独立任选地被1、2、3或4个R 5取代。 The compound according to any one of claims 1-4 and 7, wherein R 1 is phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, isopropyl, or tert-butyl, wherein Said R 1 is independently optionally substituted with 1, 2, 3 or 4 R 5 .
  10. 根据权利要求1-4和7任一项所述的化合物，其中，R 2为C 6-10芳基、C 1-9杂芳基、C 3-8环烷基、或C 3-7杂环基，其中所述R 2独立任选地被1、2、3或4个R 6取代。 The compound according to any one of claims 1-4 and 7, wherein R 2 is C 6-10 aryl, C 1-9 heteroaryl, C 3-8 cycloalkyl, or C 3-7 hetero A cyclic group, wherein said R 2 is independently optionally substituted with 1, 2, 3 or 4 R 6 .
  11. 根据权利要求1-4和7任一项所述的化合物，其中，R 2为苯基、或C 1-9杂芳基，其中所述R 2独立任选地被1、2、3或4个R 6取代。 The compound according to any one of claims 1-4 and 7, wherein R 2 is phenyl, or C 1-9 heteroaryl, wherein R 2 is independently optionally 1, 2, 3, or 4 R 6 is replaced.
  12. 根据权利要求1-4和7任一项所述的化合物，其中，R 2为： The compound according to any one of claims 1-4 and 7, wherein R 2 is:
    Figure PCTCN2019099219-appb-100010
    Figure PCTCN2019099219-appb-100010
    其中所述R 2独立任选地被1、2、3或4个R 6取代。 Wherein said R 2 is independently optionally substituted with 1, 2, 3 or 4 R 6 .
  13. 根据权利要求1-4和7任一项所述的化合物，其中，Y不存在，或Y为-N(R 1a)-、-O-、-S-、-C(＝O)-、-S(＝O)-、-S(＝O) 2-、-C(＝O)N(R 1a)-、-S(＝O)N(R 1a)-、-S(＝O) 2N(R 1a)-、C 1-4亚烷基、C 2-4亚烯基、或C 2-4亚炔基，其中Y独立任选地被1、2、3或4个R 9取代；和 The compound according to any one of claims 1-4 and 7, wherein Y is absent or Y is -N (R 1a )-, -O-, -S-, -C (= O)-,- S (= O)-, -S (= O) 2- , -C (= O) N (R 1a )-, -S (= O) N (R 1a )-, -S (= O) 2 N (R 1a )-, C 1-4 alkylene, C 2-4 alkenylene, or C 2-4 alkynylene, wherein Y is independently optionally substituted with 1, 2, 3, or 4 R 9 ; with
    各R 1a分别独立地H、C 1-4烷基、C 2-4烯基、C 2-4炔基、氰基取代的C 1-4烷基、C 1-4羟烷基、或卤代C 1-4烷基。 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.
  14. 根据权利要求1-4和7任一项所述的化合物，其中，The compound according to any one of claims 1-4 and 7, wherein:
    R 4为C 1-9杂芳基、-S(＝O) 0-2R 11、-C(＝O)R 11、-S(＝O) 1-2OR 4a、-OS(＝O) 1-2R 4a、-C(＝O)OR 4a、-OC(＝O)R 4a、-C(＝O)NR 12aR 12b、-S(＝O) 1-2NR 12aR 12b、-O-R 13-C(＝O)OR 4a、-O-R 13-S(＝O) 1-2OR 4a、-N(R 12a)-R 13-C(＝O)OR 4a、-C(＝O)N(R 12a)-R 13-OH、-C(＝O)N(R 12a)-R 13-NH 2、-C(＝O)N(R 12a)-R 13-C(＝O)OR 4a、-C(＝O)N(R 12a)-R 13-S(＝O) 1-2OR 4a、-C(＝O)N(R 12a)-S(＝O) 1-2R 11、-N(R 12a)C(＝O)NR 12aR 12b、-N(R 12a)S(＝O) 1-2NR 12aR 12b、-N(R 12a)C(＝O)N(R 12a)-S(＝O) 1-2R 11、或-OC(＝O)N(R 12a)-S(＝O) 1-2R 11； R 4 is C 1-9 heteroaryl, -S (= O) 0-2 R 11 , -C (= O) R 11 , -S (= O) 1-2 OR 4a , -OS (= O) 1-2 R 4a , -C (= O) OR 4a , -OC (= O) R 4a , -C (= O) NR 12a R 12b , -S (= O) 1-2 NR 12a R 12b ,- OR 13 -C (= O) OR 4a , -OR 13 -S (= O) 1-2 OR 4a , -N (R 12a ) -R 13 -C (= O) OR 4a , -C (= O) N (R 12a ) -R 13 -OH, -C (= O) N (R 12a ) -R 13 -NH 2 , -C (= O) N (R 12a ) -R 13 -C (= O) OR 4a, -C (= O) N (R 12a) -R 13 -S (= O) 1-2 OR 4a, -C (= O) N (R 12a) -S (= O) 1-2 R 11 , -N (R 12a ) C (= O) NR 12a R 12b , -N (R 12a ) S (= O) 1-2 NR 12a R 12b , -N (R 12a ) C (= O) N (R 12a ) -S (= O) 1-2 R 11 , or -OC (= O) N (R 12a ) -S (= O) 1-2 R 11 ;
    各R 4a分别独立地为H、C 1-4烷基、C 2-4烯基、C 2-4炔基、卤代C 1-4烷基、氰基取代的C 1-4烷基、C 1-4羟烷基、C 6-10芳基、C 6-10芳基C 1-4烷基、C 1-9杂芳基、C 1-9杂芳基C 1-4烷基、C 3-8环烷基、C 3-8环烷基C 1-4烷基、C 3-7杂环基、或C 3-7杂环基C 1-4烷基；其中R 4a独立任选地被1、2、3或4个R 4b取代； 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 ;
    各R 11分别独立地为H、OH、NH 2、C 1-4烷基、C 2-4烯基、C 2-4炔基、卤代C 1-4烷基、氰基取代的C 1-4烷基、C 1-4羟烷基、C 1-4烷氧基、卤代C 1-4烷氧基、C 6-10芳基、C 6-10芳基C 1-4烷基、C 1-9杂芳基、C 1-9杂芳基 C 1-4烷基、C 3-8环烷基、C 3-8环烷基C 1-4烷基、C 3-7杂环基、或C 3-7杂环基C 1-4烷基；其中R 11独立任选地被1、2、3或4个R 11a取代； 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 ;
    各R 12a和R 12b分别独立地为H、C 1-4烷基、C 2-4烯基、C 2-4炔基、卤代C 1-4烷基、氰基取代的C 1-4烷基、C 1-4羟烷基、C 6-10芳基、C 6-10芳基C 1-4烷基、C 1-9杂芳基、C 1-9杂芳基C 1-4烷基、C 3-8环烷基、C 3-8环烷基C 1-4烷基、C 3-7杂环基、或C 3-7杂环基C 1-4烷基；其中R 12a和R 12b分别独立任选地被1、2、3或4个R 11b取代； 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 ;
    各R 13分别独立地为C 1-6亚烷基、C 1-6亚烯基、C 1-6亚炔基、C 1-6羟烷基、氰基取代的C 1-6亚烷基、或卤代C 1-6亚烷基；和 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; and
    各R 4b、R 11a和R 11b分别独立地为H、-CN、-NO 2、-OH、-NH 2、F、Cl、Br、I、甲基、乙基、丙基、丁基、甲氧基、乙氧基、-CH 2CH 2CN、-CH 2CH 2OH、-CF 3、或-CH 2CF 3。 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 .
  15. 根据权利要求1-4和7任一项所述的化合物，其中，The compound according to any one of claims 1-4 and 7, wherein:
    R 4为呋喃基、噻唑基、吡唑基、咪唑基、三唑基、四唑基、吡啶基、喹啉基、-S(＝O) 0-2R 11、-C(＝O)R 11、-S(＝O) 1-2OR 4a、-OS(＝O) 1-2R 4a、-C(＝O)OR 4a、-OC(＝O)R 4a、-C(＝O)NR 12aR 12b、-S(＝O) 1-2NR 12aR 12b、-O-R 13-C(＝O)OR 4a、-O-R 13-S(＝O) 1-2OR 4a、-N(R 12a)-R 13-C(＝O)OR 4a、-C(＝O)N(R 12a)-R 13-OH、-C(＝O)N(R 12a)-R 13-NH 2、-C(＝O)N(R 12a)-R 13-C(＝O)OR 4a、-C(＝O)N(R 12a)-R 13-S(＝O) 1-2OR 4a、-C(＝O)N(R 12a)-S(＝O) 1-2R 11、-N(R 12a)C(＝O)NR 12aR 12b、-N(R 12a)S(＝O) 1-2NR 12aR 12b、-N(R 12a)C(＝O)N(R 12a)-S(＝O) 1-2R 11、或-OC(＝O)N(R 12a)-S(＝O) 1-2R 11； R 4 is furyl, thiazolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, quinolinyl, -S (= O) 0-2 R 11 , -C (= O) R 11 , -S (= O) 1-2 OR 4a , -OS (= O) 1-2 R 4a , -C (= O) OR 4a , -OC (= O) R 4a , -C (= O) NR 12a R 12b , -S (= O) 1-2 NR 12a R 12b , -OR 13 -C (= O) OR 4a , -OR 13 -S (= O) 1-2 OR 4a , -N (R 12a ) -R 13 -C (= O) OR 4a , -C (= O) N (R 12a ) -R 13 -OH, -C (= O) N (R 12a ) -R 13 -NH 2 ,- C (= O) N (R 12a) -R 13 -C (= O) OR 4a, -C (= O) N (R 12a) -R 13 -S (= O) 1-2 OR 4a, -C (= O) N (R 12a ) -S (= O) 1-2 R 11 , -N (R 12a ) C (= O) NR 12a R 12b , -N (R 12a ) S (= O) 1- 2 NR 12a R 12b , -N (R 12a ) C (= O) N (R 12a ) -S (= O) 1-2 R 11 , or -OC (= O) N (R 12a ) -S (= O) 1-2 R 11 ;
    各R 4a分别独立地为H、甲基、乙基、丙基、丁基、苯基、萘基、苄基、C 1-9杂芳基、或C 1-9杂芳基C 1-4烷基；其中R 4a独立任选地被1、2、3或4个R 4b取代； 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 ;
    各R 11分别独立地为H、OH、NH 2、甲基、乙基、丙基、丁基、苯基、萘基、苄基、C 1-9杂芳基、或C 1-9杂芳基C 1-4烷基；其中R 11独立任选地被1、2、3或4个R 11a取代； 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 ;
    各R 12a和R 12b分别独立地为H、甲基、乙基、丙基、丁基、苯基、萘基、苄基、C 1-9杂芳基、或C 1-9杂芳基C 1-4烷基；其中R 12a和R 12b分别独立任选地被1、2、3或4个R 11b取代； 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 ;
    各R 13分别独立地为C 1-4亚烷基、C 1-4亚烯基、C 1-4亚炔基、C 1-4羟烷基、氰基取代的C 1-4亚烷基、或卤代C 1-4亚烷基；和 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; and
    各R 4b、R 11a和R 11b分别独立地为H、-CN、-NO 2、-OH、-NH 2、F、Cl、Br、I、甲基、乙基、丙基、丁基、甲氧基、乙氧基、-CH 2CH 2CN、-CH 2CH 2OH、-CF 3、或-CH 2CF 3。 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 .
  16. 根据权利要求1-4和7任一项所述的化合物，其中，R 3a和R 3b各自独立地为H、F、Cl、Br、I、CN、甲基、乙基、丙基、丁基、卤代C 1-4烷基、C 1-4烷氨基、C 1-4烷氧基、或卤代C 1-4烷氧基，或者R 3a、R 3b 同与之连接的碳原子一起形成C 3-6环烷基、C 3-6环烯基、或3-6个原子组成的杂环基；其中所述C 1-4烷氧基、C 1-4烷氨基、C 3-6环烷基、C 3-6环烯基、和3-6个原子组成的杂环基独立任选地被1、2、3或4个R 7取代。 The compound according to any one of claims 1-4 and 7, wherein R 3a and R 3b are each independently H, F, Cl, Br, I, CN, methyl, ethyl, propyl, butyl , Halogenated C 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 Forming a C 3-6 cycloalkyl, C 3-6 cycloalkenyl, or 3-6 atom heterocyclic group; wherein the C 1-4 alkoxy, C 1-4 alkylamino, C 3- A 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 .
  17. 根据权利要求1-4和7任一项所述的化合物，其中，The compound according to any one of claims 1-4 and 7, wherein:
    各R 5、R 6、R 7、R 8、R 9和R 10分别独立地为H、-CN、-NO 2、-OH、-NH 2、F、Cl、Br、I、C 1-6烷基、C 2-6烯基、C 2-6炔基、卤代C 1-6烷基、氰基取代的C 1-6烷基、C 1-6羟烷基、C 1-6烷氨基、C 1-6烷氧基、卤代C 1-6烷氧基、-S(＝O) 0-2R 14、-C(＝O)R 15、-OS(＝O) 1-2R 14a、-OC(＝O)R 15a、-N(R 16a)C(＝O)R 16、-OC(＝O)NR 17R 17a、-NR 17R 17a、-N(R 16a)S(＝O) 1-2R 16、或-N(R 16a)C(＝O)NR 17R 17a； 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, 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, C 1-6 alkane Amino, C 1-6 alkoxy, halo C 1-6 alkoxy, -S (= O) 0-2 R 14 , -C (= O) R 15 , -OS (= O) 1-2 R 14a , -OC (= O) R 15a , -N (R 16a ) C (= O) R 16 , -OC (= O) NR 17 R 17a , -NR 17 R 17a , -N (R 16a ) S (= O) 1-2 R 16 or -N (R 16a ) C (= O) NR 17 R 17a ;
    各R 14、R 14a、R 15、R 15a、和R 16分别独立地为H、C 1-4烷基、C 2-4烯基、C 2-4炔基、卤代C 1-4烷基、氰基取代的C 1-4烷基、C 6-10芳基、C 6-10芳基C 1-4烷基、C 1-9杂芳基、C 1-9杂芳基C 1-4烷基、C 3-8环烷基、C 3-8环烷基C 1-4烷基、C 3-7杂环基、或C 3-7杂环基C 1-4烷基；和 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 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
    各R 16a、R 17、和R 17a和分别独立地为H、C 1-4烷基、C 2-4烯基、C 2-4炔基、氰基取代的C 1-4烷基、或卤代C 1-4烷基。 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.
  18. 根据权利要求1-4和7任一项所述的化合物，其中，The compound according to any one of claims 1-4 and 7, wherein:
    各R 5、R 6、R 7、R 8、R 9和R 10分别独立地为H、-CN、-NO 2、-OH、-NH 2、F、Cl、Br、I、甲基、乙基、丙基、丁基、甲氧基、乙氧基、丙氧基、-CH 2CN、-CH 2OH、-CH 2CH 2CN、-CH 2CH 2OH、-CF 3、-CH 2CF 3、-OCF 3、或-OCH 2CF 3。 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 .
  19. 根据权利要求1所述的化合物，其为具有以下结构之一的化合物：The compound according to claim 1, which is a compound having one of the following structures:
    Figure PCTCN2019099219-appb-100011
    Figure PCTCN2019099219-appb-100011
    Figure PCTCN2019099219-appb-100012
    Figure PCTCN2019099219-appb-100012
    Figure PCTCN2019099219-appb-100013
    Figure PCTCN2019099219-appb-100013
    Figure PCTCN2019099219-appb-100014
    Figure PCTCN2019099219-appb-100014
    Figure PCTCN2019099219-appb-100015
    Figure PCTCN2019099219-appb-100015
    Figure PCTCN2019099219-appb-100016
    Figure PCTCN2019099219-appb-100016
    Figure PCTCN2019099219-appb-100017
    Figure PCTCN2019099219-appb-100017
    Figure PCTCN2019099219-appb-100018
    Figure PCTCN2019099219-appb-100018
    Figure PCTCN2019099219-appb-100019
    Figure PCTCN2019099219-appb-100019
    或其药学上可接受的盐、水合物、溶剂化物、立体异构体、互变异构体、氮氧化物、代谢物、前药、或混合物。Or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, tautomer, nitrogen oxide, metabolite, prodrug, or mixture thereof.
  20. 药物组合物，所述药物组合物包含权利要求1-19中任一项所述的化合物，以及药学上可以接受的辅料、稀释剂或载体。A pharmaceutical composition comprising a compound according to any one of claims 1 to 19, and a pharmaceutically acceptable excipient, diluent, or carrier.
  21. 根据权利要求20所述的药物组合物，其进一步包含附加治疗剂。The pharmaceutical composition according to claim 20, further comprising an additional therapeutic agent.
  22. 使用根据权利要求1-19任一项所述的化合物或权利要求20-21任一项所述的药物组合物在制备用于预防或治疗哺乳动物由FXR介导的疾病的药物中的用途。Use of a compound according to any one of claims 1-19 or a pharmaceutical composition according to any one of claims 20-21 in the manufacture of a medicament for the prevention or treatment of a disease mediated by FXR in a mammal.
  23. 根据权利要求22所述的用途，其中，所述FXR介导的疾病包括非酒精性脂肪性肝病，非酒精性脂肪肝炎，慢性肝内或肝外胆汁淤积病症，由慢性胆汁淤积病症或者急性肝内胆汁淤积病症导致的肝纤维化，慢性乙型肝炎，胆囊结石，肝癌，结肠癌，或者肠道炎性疾病。The use according to claim 22, wherein the FXR-mediated diseases include non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, chronic intrahepatic or extrahepatic cholestasis disorders, chronic cholestasis disorders or acute liver disease Liver fibrosis due to internal cholestasis, chronic hepatitis B, gallbladder stones, liver cancer, colon cancer, or inflammatory bowel disease.
PCT/CN2019/099219 2018-08-08 2019-08-05 Spiro bridged ring compound, pharmaceutical composition thereof and use thereof WO2020029908A1 (en)

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