WO2019120088A1 - 异噁唑衍生物及其制备方法和用途 - Google Patents

异噁唑衍生物及其制备方法和用途 Download PDF

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WO2019120088A1
WO2019120088A1 PCT/CN2018/119715 CN2018119715W WO2019120088A1 WO 2019120088 A1 WO2019120088 A1 WO 2019120088A1 CN 2018119715 W CN2018119715 W CN 2018119715W WO 2019120088 A1 WO2019120088 A1 WO 2019120088A1
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compound
group
alkyl
pharmaceutically acceptable
cycloalkyl
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PCT/CN2018/119715
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English (en)
French (fr)
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刘金明
蔡家强
吴勇勇
尹伟
王利春
王晶翼
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四川科伦博泰生物医药股份有限公司
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Priority to US16/758,232 priority Critical patent/US11667629B2/en
Priority to EP18892613.3A priority patent/EP3730491B1/en
Priority to CN201880068730.1A priority patent/CN111263759B/zh
Priority to JP2020522863A priority patent/JP7243959B2/ja
Priority to KR1020207010488A priority patent/KR20200102415A/ko
Publication of WO2019120088A1 publication Critical patent/WO2019120088A1/zh

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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
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
    • B65D—CONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
    • B65D85/00—Containers, packaging elements or packages, specially adapted for particular articles or materials
    • B65D85/70—Containers, packaging elements or packages, specially adapted for particular articles or materials for materials not otherwise provided for
    • 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
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof

Definitions

  • the present invention generally relates to compounds for the treatment of diseases or conditions mediated by farnesoid X receptor (FXR), and more particularly to FXR agonist compounds and their stereoisomers, tautomers, polycrystals Forms, solvates (e.g., hydrates), pharmaceutically acceptable salts, esters, metabolites, N-oxides, and chemically protected forms and prodrugs thereof.
  • FXR farnesoid X receptor
  • the invention further relates to a process for the preparation of said compounds, to intermediates, to pharmaceutical compositions and kits comprising said compounds, and to their therapeutic use.
  • the farnesoid X receptor (FXR, NR1H4) is expressed in the liver, the entire gastrointestinal tract, kidney and adrenal glands including the esophagus, stomach, duodenum, small intestine, colon (Kuipers, F. et al, The Farnesoid X Receptor (FXR) as Modulator of Bile Acid Metabolism, Rev. Endocrine Metab. Disorders, 2004, 5: 319-326).
  • FXR is a member of a transcription factor known to be a ligand for ligand activation of nuclear receptors.
  • Bile acids such as chenodeoxycholic acid (CDCA) or its taurine or glycine amide conjugate are endogenous ligands for FXR.
  • Bile acid binds to FXR to activate FXR, and controls the expression of multiple genes through heterodimeric complexes with retinoid X receptor (RXR), including bile acids, cholesterol, and trihydrates in the liver and circulatory system.
  • RXR retinoid X receptor
  • Gene expression for dynamic equilibrium of acid glycerides and lipoproteins (Kalaany, NY; Mangelsdorf, DJ; LXRS and FXR: the yin and yang of cholesterol and fat metabolism, Annu. Rev. Physiol., 2006, 68, 159-191; Calkin , AC; Tontonoz, P.; Transcriptional integration of metabolism by the nuclear sterol-activated receptors LXR and FXR, Nat. Rev. Mol.
  • FXR also appears to be involved in paracrine and endocrine signaling by up-regulation of fibroblast growth factor 15 (rodent) or fibroblast growth factor 19 (monkey, human) (T. Inagaki et al, Fibroblast growth factor 15 functions as an enterohepatic signal to Qualification bile acid homeostasis. Cell Metab., 2005, 2(4), 217-225).
  • Bile acids are amphiphilic molecules that form micelles and emulsifie lipids in the diet. If the bile acid concentration is too high, cytotoxicity is also produced, so there is a physiological mechanism for strictly controlling the concentration of bile acids. FXR plays a key role in controlling bile acids to remain stable in the body (Makishima, M.; Nuclear Receptors as Targets for Drug Development: Regulation of Cholesterol and Bile Acid Metabolism by Nuclear Receptors, J. Pharmacol. Sci., 2005, 97). :177-183).
  • FXR has been shown to regulate complex biological processes beyond metabolism, such as liver regeneration or intestinal barrier integrity. FXR also controls the immune system of the intestines and liver and has certain anti-inflammatory effects (Modica, S.; Gadaleta, RM; Moschetta, A.; Deciphering the nuclear bile acid receptor FXR paradigm, Nucl. Recept. Signal., 2010 , 8, e005).
  • Obeticholic Acid (6-Et CDCA) is a FXR receptor agonist with higher endogenous ligand CDCA activity and has been shown in Phase IIa clinical studies of nonalcoholic fatty liver disease (NAFLD). Significant improvement in insulin sensitivity and other metabolically beneficial effects (Mudaliar, S.; Henry, RR; Sanyal, AJ, et al., Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver Disease, Gastroenterology, 2013, 145, 574-582). Phase IIb studies of oleic acid showed that 72-week treatment was also beneficial for the histopathological improvement of nonalcoholic hepatitis (NASH).
  • NASH nonalcoholic hepatitis
  • liver function impairment is improved (Nevens, F., Andreone, P., Mazzella, G. et al., The first primary biliary cirrhosis (PBC) phase 3 trial in two decades-an international study of the FXR agonist obeticholic acid in PBC patients, J. Hepatol., 2014, 60, S525-S526).
  • the present invention generally relates to compounds of formula (I) or stereoisomers, tautomers, polymorphs, solvates thereof (e.g., hydrates), pharmaceutically acceptable salts, esters, metabolites, N-oxide, its chemically protected form or prodrug,
  • A is selected from the group consisting of thiazolyl, phenylene and pyridylene;
  • B is selected from a C 6-10 aryl group and a 5 to 10 membered heteroaryl group containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S;
  • W is selected from N and CR d , preferably CR d ;
  • R a is selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3 to 14 membered heterocyclic, C 1-6 alkyl- O-, halogenated C 1-6 alkyl, halogenated C 3-8 cycloalkyl and halogenated C 1-6 alkyl-O-;
  • R b , R c and R d are each independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, -NH 2 , nitro, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkane -O-, halogenated C 1-6 alkyl-O-, C 3-8 cycloalkyl, halogenated C 3-8 cycloalkyl, C 3-8 cycloalkyl-O- and halogenated C 3 -8 cycloalkyl-O-;
  • R 1 and R 2 are each independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, -NH 2 , C 1-6 alkyl, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1- 6 alkyl-O-, halo C 1-6 alkyl-O-, C 3-8 cycloalkyl, halogenated C 3-8 cycloalkyl, C 1-6 alkyl-NH- and (C 1 -6 alkyl) 2 -N-;
  • R 3a, R 3b, R 3c and R 3d are each independently selected from hydrogen, halo, cyano, hydroxy, -NH 2, oxo, C 1-6 alkyl, halo C 1- 6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkyl-O-, halogenated C 1-6 alkyl-O-, C 3-8 cycloalkyl and halogenated C 3-8 cycloalkyl; or R 3a , Any two of R 3b , R 3c and R 3d together form a C 1-6 alkylene group, preferably, any two of R 3a , R 3b , R 3c and R 3d together form a C 2-6 alkylene group More preferably, R 3a and R 3b together form a C 2-6 alkylene group;
  • n and n are each independently 0, 1, 2, 3 or 4, preferably 0, 1 or 2;
  • alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of : halogen, hydroxy, oxo, cyano, -NH 2 , nitro, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkyl-O-, halogenated C 1-6 Alkyl-O-, C 3-6 cycloalkyl, halogenated C 3-6 cycloalkyl, C 1-6 alkyl-NH-, (C 1-6 alkyl) 2 -N-, hydroxy C 1 a 6 alkyl group, a cyano-C 1-6 alkyl group, a 3 to 14 membered heterocyclic group, a C 6-14 aryl group and a 5 to 14 membered heteroaryl group.
  • substituents independently selected from the group consisting of :
  • Another aspect of the invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the formula (I) or a stereoisomer, tautomer, polymorph, solvate thereof (e.g., hydrate), pharmaceutically acceptable Acceptable salts, esters, metabolites, N-oxides, chemically protected forms or prodrugs thereof, and one or more pharmaceutically acceptable carriers.
  • the pharmaceutical composition may further comprise one or more additional therapeutic agents suitable for preventing or treating a disease or condition mediated by FXR.
  • the invention also includes a method of preventing or treating a disease or condition mediated by FXR, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the formula (I) or a stereoisomer thereof, Tautomers, polymorphs, solvates (eg, hydrates), pharmaceutically acceptable salts, esters, metabolites, N-oxides, chemically protected forms or prodrugs thereof, or pharmaceutical compositions thereof .
  • a compound of the formula (I) or a stereoisomer thereof Tautomers, polymorphs, solvates (eg, hydrates), pharmaceutically acceptable salts, esters, metabolites, N-oxides, chemically protected forms or prodrugs thereof, or pharmaceutical compositions thereof .
  • kits for preventing or treating a disease or condition mediated by FXR comprising:
  • a first container comprising, as a first therapeutic agent, at least one compound of the formula (I) or a stereoisomer, tautomer, polymorph, solvate thereof (eg hydrated) a pharmaceutically acceptable salt, ester, metabolite, N-oxide, chemically protected form or prodrug thereof or the pharmaceutical composition as a first pharmaceutical composition;
  • a second container optionally present comprising at least one other therapeutic agent as a second therapeutic agent, or a pharmaceutical composition comprising said other therapeutic agent as a second pharmaceutical composition;
  • the present invention also includes the compound of the formula (I) or a stereoisomer, tautomer, polymorph, solvate (e.g., hydrate), pharmaceutically acceptable salt, ester, metabolite thereof.
  • the present invention also includes the compound of the formula (I) or a stereoisomer, tautomer, polymorph, solvate (e.g., hydrate), pharmaceutically acceptable salt, ester, metabolite thereof. , N-oxide, a chemically protected form or prodrug thereof, or the use of the pharmaceutical composition in the manufacture of a medicament for the prevention or treatment of a disease or condition mediated by FXR.
  • the invention also includes methods of preparing the compounds of the invention and corresponding intermediates.
  • the compound of the formula (I) of the present invention has excellent in vivo or in vitro pharmacodynamic or pharmacokinetic properties, exhibits good FXR activating activity and activation, and excellent plasma drug exposure and bioavailability, thus Has good pharmaceutical activity and metabolic advantages in the body.
  • alkyl refers to a saturated straight or branched chain hydrocarbon radical having from 1 to 12 carbon atoms (C 1-12 ), wherein the alkyl group may be optionally one or more (eg, 1 , 2, 3 or 4) substituted substituents.
  • an alkyl group has from 1 to 8 carbon atoms (C 1-8 ), especially from 1 to 6 carbon atoms (C 1-6 ).
  • the alkyl group has from 1 to 4 carbon atoms (C 1-4 ), especially from 1 to 3 carbon atoms (C 1-3 ) or from 1 to 2 carbon atoms (C 1-2 ) .
  • alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), 1-propyl (n-Pr), 2-propyl (i-Pr or isopropyl), 1-butyl ( n-Bu or n-butyl), 2-methyl-1-propyl (i-Bu or isobutyl), 2-butyl (s-Bu or sec-butyl), 2-methyl-2-propene Base (t-Bu or tert-butyl), 1-pentyl (n-pentyl), 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl , 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl (-C(CH 3 ) 2 CH 2 CH 2 CH 3 ), 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-
  • alkenyl refers to a linear or branched monovalent hydrocarbon radical comprising one double bond and having 2 to 6 carbon atoms (“C 2-6 alkenyl”).
  • the alkenyl group is, for example, a vinyl group, a 1-propenyl group, a 2-propenyl group, a 2-butenyl group, a 3-butenyl group, a 2-pentenyl group, a 3-pentenyl group, a 4-pentenyl group, and 2 Hexyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl and 4-methyl-3-pentenyl.
  • the compounds of the invention may exist in pure E (enthafen) form, pure Z (zusammen) form, or any mixture thereof.
  • alkynyl refers to a monovalent hydrocarbon radical containing one or more triple bonds, which preferably has 2, 3, 4, 5 or 6 carbon atoms, such as ethynyl or propynyl.
  • cycloalkyl refers to a (C 3-12), especially from 3 to 10 carbon atoms (C 3- 10), or from 3 to 8 carbon atoms, having from 3 to 12 carbon atoms ( C 3-8 ) a saturated carbon ring in the form of a single ring.
  • a cycloalkyl group has from 3 to 6 carbon atoms ( C3-6 ), such as 3, 4, 5 or 6 carbon atoms.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclodecyl, cycloundecyl, cyclododeyl Alkyl and the like.
  • the cycloalkyl group can be optionally substituted with one or more (e.g., 1, 2, 3 or 4) suitable substituents.
  • aryl as used herein means a C 6-14 aromatic monocyclic or polycyclic (particularly bicyclic) group (C 6-14 aryl), suitably including a C 6-12 aryl group, more Suitably a C 6-10 monocyclic or bicyclic aryl group is included, preferably a C 6 aryl group (ie, phenyl).
  • the aryl group contains at least one aromatic ring (such as one ring or two rings), but may also contain additional rings that are non-aromatic.
  • An example of a typical aryl group containing an aromatic ring is phenyl.
  • An example of a typical aryl group containing two aromatic rings is a naphthyl group.
  • a phenyl group (e.g., indane) fused to a C 5-8 carbocyclic group (suitably, a C 5-6 carbocyclic group) is also an example of an aryl group.
  • the aryl group is optionally substituted with one or more (e.g., 1, 2, 3 or 4) suitable substituents.
  • heterocycle and “heterocyclyl” are used interchangeably herein and refer to have, for example, from 3 to 14 (suitably from 3 to 8, more suitably 3, 4, 5 or 6) a ring atom, wherein at least one of the ring atoms is a hetero atom selected from N, O and S and the remaining ring atoms are saturated (ie heterocycloalkyl) or partially unsaturated (ie one or more within the ring) Double bond and/or triple bond) cyclic group.
  • a "3 to 14 membered heterocyclic group” has 2 to 13 (eg, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13) ring carbon atoms and independently A saturated or partially unsaturated heterocyclic group selected from one or more (e.g., 1, 2, 3 or 4) heteroatoms of N, O and S.
  • saturated heterocyclic groups i.e., heterocycloalkyl groups
  • heterocyclyl can be optionally substituted by one or more (e.g., 1, 2, 3 or 4) suitable substituents.
  • heteroaryl refers to a monocyclic or polycyclic (eg bicyclic or tricyclic) aromatic ring system having from 5 to 14 ring atoms, for example 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13 carbon atoms and independently selected from N, O 1, 1, 2, 4 or 5 of the same or different heteroatoms of S.
  • the heteroaryl group can be benzofused.
  • heteroaryl groups include, but are not limited to, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, thienyl, oxazolyl, furyl, pyrrolyl, pyrazolyl, triazolyl, tetrazole , isoxazolyl, isothiazolyl, imidazolyl, triazinyl, oxadiazolyl, thiadiazolyl, benzothiazolyl, benzisothiazolyl, imidazopyridyl, quinolyl, anthracene , pyrrolopyridazinyl, benzofuranyl, benzothienyl, oxazolyl, benzoxazolyl, benzisoxazolyl, quinazolinyl, pyrrolopyridyl, pyrazolopyrimidinyl , imidazopyridazin,
  • the heteroaryl group is selected from the group consisting of pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, oxazolyl, benzothiazolyl, benzo[d]isothiazolyl, imidazo[1,2 -a]pyridyl, quinolyl, 1H-indenyl, pyrrolo[1,2-b]pyridazinyl, benzofuranyl, benzo[b]thienyl, 1H-carbazolyl, benzo [d]oxazolyl, benzo[d]isoxazolyl, quinazolinyl, 1H-pyrrolo[3,2-c]pyridyl, pyrazolo[1,5-a]pyrimidinyl, imidazole And [1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridinyl and 1H-[1,
  • the heterocyclic group e.g., heterocycloalkyl
  • heteroaryl can be carbon bonded (carbon bonded) or nitrogen bonded (nitrogen linked).
  • a carbon-bonded heterocyclic or heteroaryl group is bonded at the following positions: at the 2, 3, 4, 5 or 6 position of the pyridine, at the 3, 4, 5 or 6 position of the pyridazine, pyrimidine 2, 4, 5 or 6 positions, 2, 3, 5 or 6 positions of pyrazine, 2, 3, 4 or 5 positions of furan, tetrahydrofuran, thiophene, pyrrole or tetrahydropyrrole, 2 of oxazole, imidazole or thiazole , 4 or 5 positions, 3, 4 or 5 positions of isoxazole, pyrazole or isothiazole, 2 or 3 positions of aziridine, 2, 3 or 4 position of azetidine, 2 of quinoline 3, 4, 5, 6, 7 or 8 positions, or 1, 3, 3,
  • nitrogen-bonded heterocyclic or heteroaryl groups are bonded at the following positions: aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, Imidazolidin, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, hydrazine, porphyrin, 1H-carbazole Position 1, position 2 of isoindole or isoindoline, position 4 of morpholine, and position 9 of carbazole or ⁇ -carboline.
  • halo or halogen as used herein includes F, Cl, Br or I.
  • Halo includes, but is not limited to, monosubstituted, disubstituted or trisubstituted, and the halogen atoms used for the substitution may be the same or different.
  • substituted means that one or more (eg, 1, 2, 3 or 4) hydrogens on the designated atom are replaced by the selection of the indicated group, provided that the specified The normal valence of an atom in the present case and the substitution forms a stable compound. Combinations of substituents and/or variables are permissible only if such combinations form stable compounds.
  • chiral refers to molecules that have non-overlapping properties of mirrored pairs, while the term “achiral” refers to molecules that can overlap on their mirror image pairs.
  • stereoisomer refers to a compound having the same chemical composition but differing in the arrangement of atoms or groups in space.
  • Diastereomer refers to a stereoisomer that has two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties such as melting point, boiling point, spectral properties and reactivity. Mixtures of diastereomers can be separated by high resolution analytical methods such as electrophoresis and chromatography.
  • Enantiomer refers to two stereoisomers of a compound that are non-superimposable mirror images of each other.
  • the stereochemical definitions and rules used herein generally follow SP 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 compounds of the invention may contain asymmetric or chiral centers and therefore exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of the invention, including but not limited to their diastereomers, enantiomers and atropisomers, as well as mixtures thereof, such as racemic mixtures, are intended to constitute the invention. a part of.
  • optically active compounds Many organic compounds exist in optically active form, i.e., they have the ability to rotate the plane of plane polarized light.
  • the prefixes D and L, or R and S are used to indicate the absolute configuration of the chiral center of the molecule.
  • the prefixes d and l or (+) and (-) are used to indicate the sign that the compound rotates the plane polarized light, where (-) or l means that the compound is left-handed.
  • Compounds with the prefix (+) or d are dextrorotatory. These stereoisomers are identical for a particular chemical structure, except that they mirror each other.
  • stereoisomers may also be referred to as enantiomers, and mixtures of such isomers are often referred to as enantiomeric mixtures.
  • a 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which can occur without a stereoselective or stereospecific nature of the chemical reaction or process.
  • the terms "racemic mixture” and “racemate” refer to an equimolar mixture of two enantiomers which are not optically active.
  • the stereoisomers of the invention may exist in a predominant form, for example, greater than 50% ee (enantiomeric excess), greater than 80% ee, greater than 90% ee, greater than 95% ee, or greater than 99% Ee.
  • these isomers can be separated by conventional techniques such as preparative chromatography.
  • the compound can be prepared in racemic form, or a single enantiomer can be prepared by enantioselective synthesis or by resolution.
  • diastereoisomers are formed by standard techniques, for example by formation of a salt with an optically active acid such as (-)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaric acid.
  • the compounds can be resolved into fractions and then subjected to fractional crystallization and free base regeneration to separate the compounds into their enantiomeric components.
  • the compound can also be resolved by formation of diastereomeric esters or amides followed by chromatographic purification and removal of the chiral auxiliary. Alternatively, the compound can be resolved using a chiral HPLC column.
  • tautomer or “tautomeric form” refers to structural isomers that differ in energy that can be converted into each other by a low energy barrier.
  • proton tautomers also known as proton transfer tautomers
  • Valence bond tautomers include mutual transformation by recombination of some bonding electrons.
  • the invention encompasses all possible crystalline forms or polymorphs of the compounds of formula (I) which may be a single polymorph or a mixture of more than one polymorph in any ratio.
  • compositions of the invention may exist in free form for treatment or, where appropriate, in the form of their pharmaceutically acceptable derivatives.
  • pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, metabolites, N-oxides, and chemically protected forms and prodrugs, Once the desired individual is administered, the compound of the invention or its metabolite or residue can be provided directly or indirectly.
  • salts refers to a pharmaceutically acceptable organic or inorganic salt of a compound of the invention.
  • exemplary salts include, but are not limited to, sulfates, acetates, chlorides, iodides, nitrates, hydrogen sulfates, acid phosphates, isonicotinic acid salts, salicylates, acid citrates, oils Acid salt, citrate, pantothenate, hydrogen tartrate, ascorbate, gentisate, gluconate, glucuronate, saccharide, formate, benzoate, glutamine Acid salt, and pamoate (i.e., 1,1 '-methylene-bis(2-hydroxy-3-naphthoate)).
  • Pharmaceutically acceptable salts can include inclusion of another molecule such as an acetate ion, a succinate ion, or other counterion.
  • the counter ion can be any organic or inorganic ion that stabilizes the charge on the parent compound.
  • a pharmaceutically acceptable salt may have more than one charged atom in its structure. Where a plurality of charged atoms are part of a pharmaceutically acceptable salt, there may be multiple counterions. Thus, a pharmaceutically acceptable salt can have one or more charged atoms and/or one or more counter ions.
  • the desired pharmaceutically acceptable salt can be prepared by any suitable method available in the art, for example, with a mineral acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, phosphoric acid.
  • a mineral acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, phosphoric acid.
  • an organic acid such as acetic acid, trifluoroacetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranoside acid such as glucose Aldehydic acid or galacturonic acid, ⁇ -hydroxy acid such as citric acid or tartaric acid, amino acid such as aspartic acid or glutamic acid, aromatic acid such as benzoic acid or cinnamic acid, sulfonic acid such as p-toluenesulfonic acid or ethyl sulfonate
  • an organic acid such as acetic acid, trifluoroacetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranoside acid such as glucose Aldehydic acid or galacturonic acid, ⁇
  • the desired pharmaceutically acceptable salt can be prepared by any suitable method, for example, with an inorganic or organic base such as an amine (primary, secondary or tertiary amine), an alkali metal hydroxide or The alkaline acid is treated with an alkaline earth metal hydroxide or the like.
  • suitable salts include, but are not limited to, organic salts derived from amino acids such as glycine and arginine, ammonia, primary, secondary and tertiary amines, and cyclic amines such as piperidine, morpholine and piperazine, and Inorganic salts of sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
  • pharmaceutically acceptable means that the substance or composition must be chemically and/or toxicologically compatible with the other components that make up the formulation and/or the mammals treated therewith.
  • esters as used herein, means an ester derived from a compound of formula (I), including a physiologically hydrolyzable ester which is hydrolyzable under physiological conditions to release the free form of the invention in the form of a free acid or alcohol ( I) Compound.
  • the compounds of the formula (I) according to the invention may also be esters per se.
  • the compounds of the present invention may exist in the form of a solvate (e.g., a hydrate) wherein the compound of the present invention contains a polar solvent as a structural element of the crystal lattice of the compound, particularly such as water, methanol or ethanol.
  • a polar solvent as a structural element of the crystal lattice of the compound, particularly such as water, methanol or ethanol.
  • the amount of polar solvent, particularly water may be present in stoichiometric or non-stoichiometric ratios.
  • a “metabolite” is a product produced by metabolism of a particular compound or salt thereof. Metabolites of the compounds can be identified using conventional techniques known in the art and their activity can be determined using assays such as those described herein. Such products may be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, and the like of the administered compound. Accordingly, the invention includes metabolites of the compounds of the invention, including compounds produced by a process comprising contacting a compound of formula (I) of the invention with a mammal for a period of time sufficient to produce a metabolite thereof.
  • nitrogen-containing heterocycles are capable of forming N-oxides because nitrogen requires the use of a lone pair of electrons to oxidize to oxides; those skilled in the art will recognize that N-oxides can be formed.
  • Nitrogen-containing heterocycle Those skilled in the art will also recognize that tertiary amines are capable of forming N-oxides.
  • N-oxides for the preparation of heterocyclic and tertiary amines
  • peroxyacids such as peracetic acid and m-chloroperoxybenzoic acid (m-CPBA)
  • hydrogen peroxide Alkyl hydroperoxides such as t-butyl hydroperoxide
  • sodium perborate and dioxirane such as dimethyldioxirane oxidize heterocyclic and tertiary amines.
  • any process for preparing a compound of the invention it may be necessary and/or desirable to protect a sensitive group or reactive group on any of the molecules of interest, thereby forming a chemically protected form of the compound of the invention.
  • This can be achieved by conventional protecting groups such as those described in Protective Groups in Organic Chemistry, ed. JFW McOmie, Plenum Press, 1973; and TW Greene & P. GM Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991.
  • Protecting groups which are incorporated herein by reference.
  • the protecting group can be removed at a suitable subsequent stage using methods known in the art.
  • the invention further includes within its scope prodrugs of the compounds of the invention.
  • prodrugs will be functional group derivatives of the compounds which are readily converted in vivo to the desired therapeutically active compound.
  • the term “administering” for use in the methods of treatment of the invention shall include the treatment of various diseases or conditions with a prodrug form of one or more of the claimed compounds, but The prodrug form is converted to the above compound in vivo after administration to the individual.
  • “Design of Prodrug” ed. H. Bundgaard, Elsevier, 1985, a conventional method of selecting and preparing suitable prodrug derivatives is described.
  • any formula or structure shown herein, including compounds of formula (I), is also intended to mean both unlabeled and isotopically labeled forms of the compounds.
  • Isotopically labeled compounds have the structure shown by the formula given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number.
  • isotopes which may be included in the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as, but not limited to, 2 H ( ⁇ , D), 3 H ( ⁇ ), 11 C, 13 C, 14 C, 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I.
  • isotopically-labeled compounds of the invention for example, those containing radioisotopes such as 3 H, 13 C and 14 C are included.
  • isotopically labeled compounds can be used in metabolic studies, reaction kinetic studies, detection or imaging techniques such as positron emission tomography (PET) or single photon emission tomography (SPECT), including drug or substrate tissue distribution. Determination, or for radiotherapy of a patient.
  • the guanidine-labeled or substituted therapeutic compounds of the invention may have improved DMPK (drug metabolism and pharmacokinetic) properties related to distribution, metabolism, and excretion (ADME).
  • substitution with heavier isotopes such as deuterium may provide certain therapeutic advantages due to greater metabolic stability, for example, increased in vivo half-life, or reduced dosage requirements.
  • 18 F-labeled compounds can be used in PET or SPECT studies.
  • the isotopically-labeled compounds of the present invention and prodrugs thereof can generally be prepared by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent by the methods disclosed in the Schemes or Examples and the preparation methods described below.
  • substitution with heavier isotopes, particularly deuterium i.e., 2 H or D
  • hydrazine is considered to be a substituent in the compound of formula (I).
  • concentration of such heavier isotopes, particularly ruthenium, can be defined by isotopic enrichment factors.
  • any atom not specifically designated as a particular isotope is intended to represent any stable isotope of the atom.
  • H hydrogen
  • hydrogen it is understood to mean hydrogen having a natural abundance isotopic composition at that position.
  • any atom clearly indicating ⁇ (D) is intended to mean ⁇ .
  • composition includes a product comprising a therapeutically effective amount of a compound of formula (I) of the present invention, as well as any product produced directly or indirectly from a combination of compounds of formula (I) of the present invention.
  • the invention provides a compound of formula (I) or a stereoisomer, tautomer, polymorph, solvate (eg, hydrate), pharmaceutically acceptable salt, ester thereof , metabolites, N-oxides, their chemically protected forms or prodrugs,
  • A is selected from the group consisting of thiazolyl, phenylene and pyridylene;
  • B is selected from a C 6-10 aryl group and a 5 to 10 membered heteroaryl group containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S;
  • W is selected from N and CR d , preferably CR d ;
  • R a is selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3 to 14 membered heterocyclic, C 1-6 alkyl- O-, halogenated C 1-6 alkyl, halogenated C 3-8 cycloalkyl and halogenated C 1-6 alkyl-O-;
  • R b , R c and R d are each independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, -NH 2 , nitro, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkane -O-, halogenated C 1-6 alkyl-O-, C 3-8 cycloalkyl, halogenated C 3-8 cycloalkyl, C 3-8 cycloalkyl-O- and halogenated C 3 -8 cycloalkyl-O-;
  • R 1 and R 2 are each independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, -NH 2 , C 1-6 alkyl, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1- 6 alkyl-O-, halo C 1-6 alkyl-O-, C 3-8 cycloalkyl, halogenated C 3-8 cycloalkyl, C 1-6 alkyl-NH- and (C 1 -6 alkyl) 2 -N-;
  • R 3a, R 3b, R 3c and R 3d are each independently selected from hydrogen, halo, cyano, hydroxy, -NH 2, oxo, C 1-6 alkyl, halo C 1- 6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkyl-O-, halogenated C 1-6 alkyl-O-, C 3-8 cycloalkyl and halogenated C 3-8 cycloalkyl; or R 3a , Any two of R 3b , R 3c and R 3d together form a C 1-6 alkylene group, preferably, any two of R 3a , R 3b , R 3c and R 3d together form a C 2-6 alkylene group More preferably, R 3a and R 3b together form a C 2-6 alkylene group;
  • n and n are each independently 0, 1, 2, 3 or 4, preferably 0, 1 or 2;
  • alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each optionally substituted by 1, 2 or 3 substituents independently selected from the group consisting of : halogen, hydroxy, oxo, cyano, -NH 2 , nitro, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkyl-O-, halogenated C 1-6 Alkyl-O-, C 3-6 cycloalkyl, halogenated C 3-6 cycloalkyl, C 1-6 alkyl-NH-, (C 1-6 alkyl) 2 -N-, hydroxy C 1 -6 alkyl, cyano-C 1-6 alkyl, 3 to 14 membered heterocyclic, C 6-14 aryl and 5 to 14 membered heteroaryl.
  • substituents independently selected from the group consisting of : halogen, hydroxy, oxo, cyan
  • the invention provides a compound or a stereoisomer, tautomer, polymorph, solvate (eg, hydrate), pharmaceutically acceptable salt, ester, metabolite, N- An oxide, a chemically protected form or prodrug thereof, wherein A is selected from The above group is bonded to the ring nitrogen atom in the formula (I) by one of two positions marked by 1 or 2, and the other group is bonded to the B group.
  • A is selected from The above group is bonded to the ring nitrogen atom in the formula (I) by one of two positions marked by 1 or 2, and the other group is bonded to the B group.
  • the invention provides a compound or a stereoisomer, tautomer, polymorph, solvate (eg, hydrate), pharmaceutically acceptable salt, ester, metabolite, N- An oxide, a chemically protected form or prodrug thereof, wherein B is selected from the group consisting of phenyl and 5- to 6-membered heteroaryl containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S;
  • the heteroaryl group is selected from the group consisting of pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, thienyl, oxazolyl, furyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl , isoxazolyl, isothiazolyl, imidazolyl, triazinyl, oxadiazolyl and thiadiazolyl;
  • B is preferably selected from the group consisting of
  • the invention provides a compound or a stereoisomer, tautomer, polymorph, solvate (eg, hydrate), pharmaceutically acceptable salt, ester, metabolite, N- An oxide, a chemically protected form thereof or a prodrug thereof, wherein in the formula (I) Group is
  • the invention provides a compound or a stereoisomer, tautomer, polymorph, solvate (eg, hydrate), pharmaceutically acceptable salt, ester, metabolite, N- Oxide, its chemically protected form or prodrug, where D is Preferred is
  • the invention provides a compound or a stereoisomer, tautomer, polymorph, solvate (eg, hydrate), pharmaceutically acceptable salt, ester, metabolite, N- An oxide, a chemically protected form thereof or a prodrug, wherein the C 1-6 alkyl group is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl.
  • the invention provides a compound or a stereoisomer, tautomer, polymorph, solvate (eg, hydrate), pharmaceutically acceptable salt, ester, metabolite, N- An oxide, a chemically protected form or prodrug thereof, wherein the halogen is selected from the group consisting of F, Cl, Br and I, preferably F or Cl.
  • the invention provides a compound or a stereoisomer, tautomer, polymorph, solvate (eg, hydrate), pharmaceutically acceptable salt, ester, metabolite, N- oxide, which chemically protected form or prodrug thereof, wherein said halo-C 1- 6 alkyl is selected from CF 3, CHF 2, CH 2 F, CCl 3 , and CH 2 CF 3.
  • Ra is a cyclopropyl group.
  • R b , R c and R d are each independently selected from the group consisting of hydrogen, F, Cl, Br, I, CH 3 , OCH 3 , CF 3 and OCF 3 .
  • R 1 and R 2 are each independently selected from the group consisting of hydrogen, F, Cl, Br, I, CH 3 , CF 3 and CH(CH 3 ) 2 ; preferably, R 1 and R 2 are each independently It is selected from the group consisting of hydrogen, F, Cl, Br, I and CH 3 .
  • the invention provides a compound or a stereoisomer, tautomer, polymorph, solvate (eg, hydrate), pharmaceutically acceptable salt, ester, metabolite, N- An oxide, a chemically protected form thereof or a prodrug, wherein the compound is a compound of the formula (Ia), (Ib), (Ic) or (Id):
  • the invention provides a compound or a stereoisomer, tautomer, polymorph, solvate (eg, hydrate), pharmaceutically acceptable salt, ester, metabolite, N- An oxide, a chemically protected form thereof or a prodrug, wherein the compound is selected from the group consisting of:
  • the compounds of the formula (I) according to the invention may comprise asymmetric centers or chiral centers and may therefore exist in different stereoisomeric forms. All stereoisomeric forms of the compounds of the invention, including but not limited to, their diastereomers, enantiomers and atropisomers, as well as mixtures thereof, such as racemic mixtures, are intended to constitute the present invention. portion.
  • the invention encompasses all diastereomers, including cis-trans (geometric) isomers and conformational isomers.
  • the compound of formula (I) comprises a double bond or a fused ring
  • the cis and trans forms, as well as mixtures thereof, are intended to be encompassed within the scope of the invention.
  • all stereoisomers are considered and included as a compound of the invention if the stereochemistry of any particular chiral atom is not indicated. If stereochemistry is indicated by a solid or dashed line indicating a particular configuration, the stereoisomer is thus indicated and defined.
  • the compounds of the invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and the invention is intended to encompass both solvated and unsolvated forms.
  • the compounds of the invention may also exist in different tautomeric forms, and all such forms are embraced within the scope of the invention.
  • a pharmaceutical composition comprising at least one of the compounds of the formula (I) according to the invention as described above or a stereoisomer, tautomer, polymorph, solvate thereof (eg, hydrate), pharmaceutically acceptable salts, esters, metabolites, N-oxides, chemically protected forms or prodrugs thereof, and one or more pharmaceutically acceptable carriers.
  • the pharmaceutical composition may further comprise one or more additional therapeutic agents, such as other therapeutic agents suitable for preventing or treating a disease or condition mediated by FXR.
  • “Pharmaceutically acceptable carrier” in the context of the present invention means a diluent, adjuvant, excipient or vehicle with which the active ingredient is administered, and which is suitable for contacting humans and/or others within the scope of sound medical judgment. Animal tissue without excessive toxicity, irritation, allergic reactions, or other problems or complications that correspond to a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, 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, etc. Water is an exemplary carrier when the pharmaceutical composition is administered intravenously. It is also possible to use physiological saline and an aqueous solution of glucose and glycerin as a liquid carrier, particularly for injection.
  • Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skimmed milk powder, glycerin, propylene glycol, water, Ethanol and the like.
  • the composition may also contain minor amounts of wetting agents, emulsifying agents or pH buffering agents as needed.
  • Oral formulations may contain standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like. Examples of suitable pharmaceutically acceptable carriers are as described in Remington&apos;s Pharmaceutical Sciences (1990).
  • compositions of the invention may act systemically and/or locally.
  • they may be administered in a suitable route, for example by injection, intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular or transdermal administration; or by oral, buccal, nasal, transmucosal, topical, It is administered in the form of an ophthalmic preparation or by inhalation.
  • compositions of the invention may be administered in a suitable dosage form.
  • the dosage forms include, but are not limited to, tablets, capsules, troches, hard candy, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions. Injectable solutions, elixirs, syrups.
  • Another aspect of the invention provides the therapeutic use of the compounds and pharmaceutical compositions.
  • the invention relates to a method of preventing or treating a disease or condition mediated by FXR, the method comprising administering to a subject in need thereof a therapeutically effective amount of at least one formula of the invention ( Compounds of I) or stereoisomers, tautomers, polymorphs, solvates (such as hydrates), pharmaceutically acceptable salts, esters, metabolites, N-oxides, chemical protection thereof The form or prodrug, or the pharmaceutical composition of the invention.
  • the invention relates to at least one compound of the formula (I) of the invention or a stereoisomer, tautomer, polymorph, solvate thereof (eg hydrate), Pharmaceutically acceptable salts, esters, metabolites, N-oxides, chemically protected forms or prodrugs thereof, or pharmaceutical compositions of the invention are useful in the manufacture of a medicament for the prevention or treatment of a disease or condition mediated by FXR the use of.
  • the FXR mediated disease or condition includes, but is not limited to:
  • Inflammatory bowel disease dyslipidemia, atherosclerosis, diabetes and related diseases; lipid and lipoprotein disorders; clinical complications of type 2 diabetes and type I and type II diabetes, including diabetic nephropathy, diabetic neuropathy Other observed effects of diabetic retinopathy, and clinically significant long-term diabetes; chronic fatty and fibrotic degeneration due to forced lipids, particularly triglyceride accumulation and subsequent activation of the pro-fibrotic pathway Caused diseases and diseases, such as nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH); obesity or metabolic syndrome (dyslipidemia, diabetes, and a combination of abnormally high body mass index);
  • NAFLD nonalcoholic fatty liver disease
  • NASH nonalcoholic steatohepatitis
  • obesity or metabolic syndrome dyslipidemia, diabetes, and a combination of abnormally high body mass index
  • treating means reversing, alleviating, inhibiting the progression of a disease or condition indicated or one or more symptoms of such a disease or condition, or preventing such disease or condition or such One or more symptoms of a disease or condition.
  • “Individual” as used herein includes human or non-human animals.
  • Exemplary human individuals include a human individual (referred to as a patient) or a normal individual having a disease, such as the disease described herein.
  • “Non-human animals” in the present invention include all vertebrates, such as non-mammals (eg, birds, amphibians, reptiles) and mammals, such as non-human primates, domestic animals, and/or domesticated animals (eg, sheep, dogs). , cats, cows, pigs, etc.).
  • terapéuticaally effective amount refers to the amount of a compound that will achieve the therapeutic efficacy described above after administration.
  • the dosage regimen can be adjusted to provide the most desirable response. For example, a single bolus may be administered, several divided doses may be administered over time, or the dose may be proportionally reduced or increased as indicated by the urgent need for treatment. It is noted that the dose value can vary with the type and severity of the condition to be alleviated and can include single or multiple doses. It is to be further understood that for any particular individual, the particular dosage regimen will be adjusted over time according to the individual needs and the professional judgment of the person administering the composition or the composition of the supervised composition.
  • an effective dose will be from about 0.0001 to about 50 mg per kg body weight per day, for example from about 0.01 to about 10 mg/kg/day (single or divided doses). For a 70 kg person, this would add up to about 0.007 mg/day to about 3500 mg/day, such as from about 0.7 mg/day to about 700 mg/day.
  • a dose level that is not higher than the lower limit of the aforementioned range may be sufficient, while in other cases, a larger dose may still be employed without causing any harmful side effects, provided that the larger The dose is divided into several smaller doses to be administered throughout the day.
  • the amount of the compound of the present invention in the pharmaceutical composition may be from about 0.01 mg to about 1000 mg, suitably from 0.1 to 500 mg, preferably from 0.5 to 300 mg, more preferably from 1 to 150 mg and the like.
  • the compounds of formula (I) may be used alone or in combination with one or more other therapeutic agents suitable for the prevention or treatment of a disease or condition mediated by FXR.
  • the compound of formula (I) is combined with, for example, other therapeutic agents having anti-hyperproliferative efficacy in the pharmaceutical composition or as a combination therapy.
  • the additional therapeutic agent can be, for example, a chemotherapeutic agent.
  • the pharmaceutical compositions or other therapeutic agents of the dosing regimen preferably have complementary activities to the compounds of formula (I) such that they do not adversely affect each other. Such compounds are suitably present in combination in amounts effective for the intended purpose.
  • Combination therapies can be administered in a regimen of simultaneous or sequential administration. When administered sequentially, the combination can be administered in two or more administrations.
  • Combination administration includes simultaneous administration using separate pharmaceutical compositions or a single pharmaceutical composition comprising a compound of formula (I) and other therapeutic agents, and sequential administration in any order, wherein preferably two (or all) are present The period of time during which the active agents simultaneously exert their biological activity.
  • Suitable dosages for any of the above concurrently administered agents are those currently used, and may be reduced due to the combined (synergy) action of the newly identified drug with other therapeutic agents or treatments.
  • Combination therapies provide "synergistic effects” and prove to be “synergistic", i.e., the effect achieved when the active ingredients are used together is greater than the sum of the effects produced when the compounds are used separately.
  • the active ingredient (1) is co-formulated in a combined unit dose formulation and administered or delivered simultaneously; (2) when delivered as separate formulations, alternately or in parallel; or (3) by some other regimen, A synergistic effect can be achieved.
  • a synergistic effect can be achieved when the compounds are administered or delivered sequentially, for example, by separate injections in separate syringes, by separate pills or capsules, or by separate infusions.
  • an effective amount of each active ingredient is administered sequentially, i.e., continuously, and in combination therapy, an effective amount of two or more active ingredients are administered together.
  • the compound of formula (I) or a stereoisomer, tautomer, polymorph, solvate (eg hydrate), pharmaceutically acceptable salt, Esters, metabolites, N-oxides, chemically protected forms or prodrugs thereof can be combined with other therapeutic agents such as those described herein, and can also be combined with surgical treatment and radiation therapy.
  • the combination therapies of the invention comprise the administration of at least one compound of formula (I) or a stereoisomer, tautomer, polymorph, solvate thereof (e.g., hydrate), pharmaceutically acceptable Salts, esters, metabolites, N-oxides, chemically protected forms or prodrugs thereof, and the use of at least one other method of treatment.
  • the amount of the compound of formula (I) and other therapeutic agents and the relative timing of administration are selected.
  • the invention includes metabolites of a compound of formula (I), including compounds prepared by contacting a compound of the invention with a mammal for a time sufficient to produce its metabolite.
  • Metabolites are typically prepared by the preparation of a radioisotope (e.g., 14 C or 3 H) labeled compound of the invention at a detectable dose (e.g., greater than about 0.5 mg/kg) to an animal such as a rat, mouse, guinea pig, monkey. Or parenteral administration, metabolizing for a sufficient period of time (usually about 30 seconds to 30 hours), and then separating the transformed product from urine, blood or other biological samples for identification. These products are easy to isolate because they are labeled (others are isolated by the use of antibodies that bind to the remaining epitopes in the metabolite).
  • the metabolite structure is determined by conventional methods, for example by MS, LC/MS or NMR. Analysis of the metabolites was performed in the same manner as conventional drug metabolism studies well known to those skilled in the art. Metabolites, as long as they are not found in vivo, can be used in diagnostic assays to therapeutically administer the compounds of the invention.
  • a "kit” comprising a material for treating the above mentioned diseases or conditions.
  • the kit includes a container comprising a compound of the formula (I), a stereoisomer, a tautomer, a polymorph thereof, a solvate (such as a hydrate) as a first therapeutic agent.
  • the kit may also include a label or package insert on or associated with the container.
  • the term "package insert” refers to instructions typically included in commercial packages of therapeutic products that contain information on the indications, usage, dosage, administration, contraindications, and/or warnings associated with the use of the therapeutic product.
  • Suitable containers include, for example, bottles, vials, syringes, blister packs, and the like.
  • the container can be made of various materials such as glass and plastic.
  • the container may contain a compound of formula (I) or a formulation thereof effective for treating a condition, and may have a sterile inlet (eg, the container may be an intravenous solution bag or have a piercable needle that can be pierced by a hypodermic needle) Cork of the cork).
  • the label or package insert indicates that the composition is used to treat a condition of choice, such as cancer.
  • the label or package insert may indicate that the patient to be treated is a patient label or package insert having a disease or condition such as cirrhosis, hyperproliferative disorder, atherosclerosis, type I diabetes or may also indicate the composition It can be used to treat other conditions.
  • the kit further comprises a second container comprising, as a second therapeutic agent, at least one additional therapeutic agent suitable for preventing or treating a disease or condition mediated by FXR, or as a second A pharmaceutical composition comprising the other therapeutic agent of a pharmaceutical composition.
  • the kit can include instructions for administering the first therapeutic agent or first pharmaceutical composition and the second therapeutic agent or second pharmaceutical composition, if any.
  • the kit may further comprise simultaneous, sequential or sequential to the individual in need thereof Instructions for the first pharmaceutical composition and the second pharmaceutical composition are administered separately.
  • the kit may further comprise a third container comprising a pharmaceutically acceptable buffer such as bacteriostatic water for injection (BWFI), phosphate buffered saline, Ringer's solution and dextrose solution.
  • BWFI bacteriostatic water for injection
  • phosphate buffered saline such as bacteriostatic water for injection (BWFI), phosphate buffered saline, Ringer's solution and dextrose solution.
  • BWFI bacteriostatic water for injection
  • the kit may also include other materials that are desirable for both the commercial and the user, including other buffers, diluents, fillers, injection needles, and syringes.
  • the kit is suitable for delivery of a solid oral form of a compound of formula (I), such as a tablet or capsule.
  • a kit preferably comprises a plurality of unit doses.
  • Such kits can include cards having doses that are positioned for their intended use.
  • An example of such a kit is a "blister pack.”
  • Blister packs are well known in the packaging industry and are widely used to package pharmaceutical unit dosage forms.
  • a memory aid can be provided, for example, in the form of a number, letter or other indicia or calendar insert specifying the date on which the treatment schedule can be administered.
  • the invention provides a method of preparing a compound of formula (I) of the invention, the method comprising the steps of:
  • Hal 1 , Hal 2 and Hal 3 are each independently the same or different halogens, such as F, Cl, Br or I, preferably Cl or Br;
  • PG 1 is an amino protecting group, preferably t-butoxycarbonyl (Boc);
  • PG 2 is a carboxy protecting group, preferably a C 1-6 alkyl group, more preferably a methyl group;
  • Y is a boric acid or borate group, preferably -B(OH) 2 or
  • reaction conditions of each step are as follows:
  • Step A reacting compound IN-1 with compound IN-2 to obtain compound IN-3;
  • the reaction is preferably carried out in a suitable organic solvent.
  • the organic solvent may be selected from a linear or cyclic ether (for example, tetrahydrofuran or diethyl ether, etc.), N-methylpyrrolidone, dimethylformamide, dimethylacetamide, 1,4-dioxane, and Methyl sulfoxide and any combination thereof, preferably tetrahydrofuran or dimethylformamide.
  • the reaction is preferably carried out in the presence of a suitable base such as an alkali metal alkoxide or carbonate and/or a catalyst.
  • the catalyst may be a catalyst system comprising a crown ether, which may be selected from the group consisting of 15-crown-5 and 18-crown-6; the alkali metal carbonate is, for example, potassium carbonate or cesium carbonate;
  • the alkoxide of the alkali metal may be selected from the group consisting of sodium t-butoxide, potassium t-butoxide, sodium methoxide, potassium methoxide, sodium ethoxide, and potassium ethoxide.
  • the alkali metal alkoxide and catalyst are a combination of sodium t-butoxide and/or potassium t-butoxide with 15-crown-5 and/or 18-crown-6, preferably sodium t-butoxide and 15 a combination of crown ether-5 or a combination of potassium t-butoxide and 18-crown-6.
  • the reaction is preferably carried out at a suitable temperature.
  • the temperature is preferably room temperature (20-30 ° C) or 50-100 ° C (for example 50-80 ° C).
  • the reaction is preferably carried out for a suitable period of time, for example 1 to 24 hours, for example 5 to 15 hours.
  • Step B removing the PG 1 group in the compound IN-3 to obtain the compound IN-4;
  • the reaction is preferably carried out in a suitable organic solvent.
  • the organic solvent may be selected from halogenated hydrocarbons (for example, dichloromethane, chloroform, ethyl chloride, dichloroethane, trichloroethane), dimethylformamide, dimethylacetamide, and any combination thereof.
  • dichloromethane is used.
  • the reaction can be carried out under acidic conditions, such as a hydrogen chloride solution in 1,4-dioxane; or a suitable organic acid (such as a carboxylic acid or a halogenated acid including, but not limited to, formic acid, fluoroacetic acid, difluoro
  • a suitable organic acid such as a carboxylic acid or a halogenated acid including, but not limited to, formic acid, fluoroacetic acid, difluoro
  • the reaction is carried out in the presence of acetic acid, trifluoroacetic acid, chloroacetic acid, dichloroacetic acid, trichloroacetic acid, and combinations thereof, preferably trifluoroacetic acid.
  • the reaction is preferably carried out at a suitable temperature.
  • the temperature is preferably room temperature (20-30 ° C).
  • the reaction is preferably carried out for a suitable period of time, for example 1-5 hours or 6-15 hours, for example 2 hours, 4 hours or overnight.
  • Step C-1 reacting compound IN-4 with compound IN-a to give compound IN-5;
  • compound IN-4 is subjected to a substitution reaction with compound IN-a to give compound IN-5.
  • the substitution reaction is preferably carried out in a suitable organic solvent.
  • the organic solvent may be selected from the group consisting of dimethylformamide, dimethylacetamide, tetrahydrofuran, N-methylpyrrolidone, dimethyl sulfoxide, and any combination thereof, preferably dimethylformamide or dimethylacetamide.
  • the substitution reaction is preferably carried out in the presence of a suitable base.
  • the base is an organic base (for example an organic amine such as triethylamine, N,N-diisopropylethylamine, N-methylmorpholine or pyridine, preferably triethylamine or N,N-diiso) Propylethylamine) or an inorganic base (for example an alkali metal salt, preferably potassium carbonate).
  • the substitution reaction is preferably carried out at a suitable temperature.
  • the temperature may be 20-150 ° C, such as 30-140 ° C, preferably 25 ° C, 50 ° C, 100 ° C or 130 ° C, preferably 80 ° C.
  • the substitution reaction is preferably carried out for a suitable period of time, for example 2-24 hours, 2-18 hours or 2-12 hours, for example 5, 8 or 10 hours.
  • compound IN-4 is coupled with compound IN-a to give compound IN-5.
  • the coupling reaction is preferably carried out in the presence of a metal catalyst and a base.
  • the metal catalyst is a palladium metal catalyst such as tris(dibenzylideneacetone)dipalladium, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, triphenyl Palladium phosphide, palladium acetate, preferably tris(dibenzylideneacetone) dipalladium.
  • the base is an inorganic base such as potassium carbonate, cesium carbonate, sodium carbonate, sodium hydrogencarbonate or potassium hydrogencarbonate, preferably cesium carbonate.
  • the coupling reaction is carried out in the presence of an organophosphorus compound derived from biphenyl selected from the group consisting of BINAP, RuPhos and XPhos, preferably BINAP.
  • the coupling reaction is carried out in a suitable organic solvent, which may be selected from the group consisting of benzene, toluene and xylene, for example toluene.
  • the coupling reaction is carried out in a suitable protective atmosphere, such as a nitrogen atmosphere.
  • the coupling reaction is carried out at a suitable temperature, which may be from 70 to 100 ° C, preferably 80 ° C.
  • the coupling reaction is carried out for a suitable period of time, for example 1-3 hours, for example 2 hours.
  • Step D-1 reacting compound IN-5 with compound IN-b to give compound IN-6;
  • the compound IN-5 is subjected to a metal-catalyzed coupling reaction with the compound IN-b to give the compound IN-6.
  • the metal catalyzed coupling reaction is carried out by a conventional method.
  • compound IN-5 and compound IN-b are dissolved in a solvent (for example, water, an organic solvent, or a mixed solvent of an organic solvent and water), and a palladium catalyst and a base are added, optionally under a nitrogen atmosphere, at 50 ° C.
  • the reaction is carried out at a temperature of 120 ° C (preferably 80 ° C or 90 ° C) for 8 to 24 hours (preferably 8 hours or 12 hours).
  • the organic solvent is dimethylformamide, tetrahydrofuran, 1,4-dioxane, toluene or DME.
  • the palladium catalyst is tris(dibenzylideneacetone)dipalladium, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, triphenylphosphine palladium, palladium acetate, preferably [ 1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride or tris(dibenzylideneacetone)dipalladium.
  • the base is preferably an inorganic base such as potassium carbonate, cesium carbonate, sodium carbonate, sodium hydrogencarbonate or potassium hydrogencarbonate or the like.
  • Step E-1 removing the PG 2 group in compound IN-6 to give a compound of formula (I);
  • the reaction is preferably in a suitable organic solvent (the organic solvent may be selected from linear or cyclic ethers (e.g., tetrahydrofuran or diethyl ether, etc.), N-methylpyrrolidone, dimethylformamide, dimethylacetamide, It is carried out in 1,4-dioxane, dimethyl sulfoxide and any combination thereof, preferably tetrahydrofuran.
  • the reaction is preferably carried out in the presence of an alcohol or water and a base.
  • the alcohol can be, for example, methanol or ethanol.
  • the base may be selected from the group consisting of alkali metal hydroxides, which may be selected from the group consisting of lithium hydroxide, sodium hydroxide, and potassium hydroxide.
  • the reaction is preferably carried out at a suitable temperature.
  • the temperature may be from room temperature to 80 ° C, such as 25 ° C or 40-60 ° C.
  • the reaction is preferably carried out for a suitable period of time, for example 2-5 hours or 6-15 hours, for example 2, 3 or 4 hours or overnight.
  • the invention provides a method of preparing a compound of formula (I) of the invention, the method comprising the steps of:
  • reaction conditions of each step are as follows:
  • Step A reacting compound IN-1 with compound IN-2 to obtain compound IN-3;
  • the reaction is preferably carried out in a suitable organic solvent.
  • the organic solvent may be selected from a linear or cyclic ether (for example, tetrahydrofuran or diethyl ether, etc.), N-methylpyrrolidone, dimethylformamide, dimethylacetamide, 1,4-dioxane, and Methyl sulfoxide and any combination thereof, preferably tetrahydrofuran or dimethylformamide.
  • the reaction is preferably carried out in the presence of a suitable base such as an alkali metal alkoxide or carbonate and/or a catalyst.
  • the catalyst may be a catalyst system comprising a crown ether, which may be selected from the group consisting of 15-crown-5 and 18-crown-6; the alkali metal carbonate is, for example, potassium carbonate or cesium carbonate;
  • the alkoxide of the alkali metal may be selected from the group consisting of sodium t-butoxide, potassium t-butoxide, sodium methoxide, potassium methoxide, sodium ethoxide, and potassium ethoxide.
  • the alkali metal alkoxide and catalyst are a combination of sodium t-butoxide and/or potassium t-butoxide with 15-crown-5 and/or 18-crown-6, preferably sodium t-butoxide and 15 a combination of crown ether-5 or a combination of potassium t-butoxide and 18-crown-6.
  • the reaction is preferably carried out at a suitable temperature.
  • the temperature is preferably room temperature (20-30 ° C) or 50-100 ° C (for example 50-80 ° C).
  • the reaction is preferably carried out for a suitable period of time, for example 1 to 24 hours, for example 5 to 15 hours.
  • Step B removing the PG 1 group in the compound IN-3 to obtain the compound IN-4;
  • the reaction is preferably carried out in a suitable organic solvent.
  • the organic solvent may be selected from halogenated hydrocarbons (for example, dichloromethane, chloroform, ethyl chloride, dichloroethane, trichloroethane), dimethylformamide, dimethylacetamide, and any combination thereof.
  • dichloromethane is used.
  • the reaction can be carried out under acidic conditions, such as a hydrogen chloride solution in 1,4-dioxane; or a suitable organic acid (such as a carboxylic acid or a halogenated acid, including but not limited to formic acid, fluoroacetic acid, two This is carried out in the presence of fluoroacetic acid, trifluoroacetic acid, chloroacetic acid, dichloroacetic acid, trichloroacetic acid, and combinations thereof, preferably trifluoroacetic acid.
  • the reaction is preferably carried out at a suitable temperature.
  • the temperature is preferably room temperature (20-30 ° C).
  • the reaction is preferably carried out for a suitable period of time, for example 1-5 hours or 6-15 hours, for example 2 hours, 4 hours or overnight.
  • Step C-2 reacting compound IN-4 with compound IN-c to give compound IN-6;
  • the reaction is preferably carried out in the presence of a metal catalyst and a base.
  • the metal catalyst is a palladium metal catalyst such as tris(dibenzylideneacetone)dipalladium, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, triphenyl Palladium phosphide, palladium acetate, preferably tris(dibenzylideneacetone) dipalladium.
  • the base is an inorganic base such as potassium carbonate, cesium carbonate, sodium carbonate, sodium hydrogencarbonate or potassium hydrogencarbonate, preferably cesium carbonate.
  • the coupling reaction is carried out in the presence of an organophosphorus compound derived from biphenyl selected from the group consisting of BINAP, RuPhos and XPhos, preferably BINAP.
  • the coupling reaction is carried out in a suitable organic solvent, which may be selected from the group consisting of benzene, toluene and xylene, for example toluene.
  • the coupling reaction is carried out in a suitable protective atmosphere, such as a nitrogen atmosphere.
  • the coupling reaction is carried out at a suitable temperature, which may be, for example, from 50 to 100 ° C, preferably 80 ° C.
  • the coupling reaction is carried out for a suitable period of time, for example 1 to 24 hours, for example 5 to 15 hours.
  • Step D-2 removing the PG 2 group in the compound IN-6 to obtain a compound of the formula (I);
  • the reaction is preferably in a suitable organic solvent (the organic solvent may be selected from linear or cyclic ethers (e.g., tetrahydrofuran or diethyl ether, etc.), N-methylpyrrolidone, dimethylformamide, dimethylacetamide, It is carried out in 1,4-dioxane, dimethyl sulfoxide and any combination thereof, preferably tetrahydrofuran.
  • the reaction is preferably carried out in the presence of an alcohol and a base.
  • the alcohol can be, for example, methanol or ethanol.
  • the base may be selected from the group consisting of alkali metal hydroxides, which may be selected from the group consisting of lithium hydroxide, sodium hydroxide, and potassium hydroxide.
  • the reaction is preferably carried out at a suitable temperature.
  • the temperature may be from room temperature to 80 ° C, for example from 40 to 60 ° C.
  • the reaction is preferably carried out for a suitable period of time, for example 2-5 hours, for example 2, 3 or 4 hours.
  • the invention provides a compound of formula (IN-6), or a pharmaceutically acceptable salt thereof,
  • the compound is preferably selected from:
  • suitable means that the choice of a particular compound or condition will depend on the particular synthetic operation being performed and the characteristics of the molecule or molecules to be transformed, but such selection is within the skill of the art. . All of the processes/methods described herein are carried out under conditions sufficient to provide the product shown. Those skilled in the art will appreciate that all reaction conditions (including, for example, reaction solvent, reaction time, reaction temperature, and whether the reaction should be carried out under anhydrous or inert atmosphere, etc.) can be varied to optimize the yield of the desired product, and these Variations are within the abilities of those skilled in the art.
  • the examples provide exemplary methods of preparing compounds of formula (I). Those skilled in the art will appreciate that other synthetic routes can be used to synthesize the compounds of formula (I). While specific materials and reagents are described and discussed in the Examples, other starting materials and reagents can be substituted to provide various derivatives and/or reaction conditions. In addition, many of the example compounds prepared by the methods can be further modified with reference to the present disclosure using conventional chemistry well known to those skilled in the art.
  • the structure of the compound is determined by nuclear magnetic resonance ( 1 H-NMR) or mass spectrometry (MS).
  • the 1 H-NMR shift ( ⁇ ) is given in parts per million (ppm). Chemical shifts are given in units of 10 -6 (ppm).
  • the MS was determined using an Agilent (ESI) mass spectrometer.
  • Thin layer chromatography silica gel plates were prepared using an aluminum plate (20 x 20 cm) manufactured by Merck, and separated by thin layer chromatography using GF 254 (0.4 to 0.5 mm).
  • reaction was monitored by thin layer chromatography (TLC) or LC-MS using a solvent system of dichloromethane and methanol, n-hexane and ethyl acetate or petroleum ether and ethyl acetate.
  • TLC thin layer chromatography
  • LC-MS LC-MS using a solvent system of dichloromethane and methanol, n-hexane and ethyl acetate or petroleum ether and ethyl acetate.
  • Microwave reaction Initiator + 400 W, RT ⁇ 300 ° C microwave reactor.
  • Column chromatography generally uses 200 to 300 mesh silica gel as a carrier.
  • the system of the eluent includes: dichloromethane and methanol systems, n-hexane and ethyl acetate systems, and the volume ratio of the solvent is adjusted depending on the polarity of the compound, and may also be adjusted by adding a small amount of triethylamine.
  • the reaction temperature of the examples is room temperature (20 ° C to 30 ° C) unless otherwise specified.
  • the reagents used in the present invention were purchased from Acros Organics, Aldrich Chemical Company, Shanghai Tebo Chemical Technology Co., Ltd., and the like.
  • N-Boc-4-hydroxypiperidine (1.0 g, 4.95 mmol) was dissolved in dry tetrahydrofuran (20 mL), EtOAc (EtOAc (EtOAc) 1.5 g, 5.61 mmol) and 4-(chloromethyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole (T1-a) (1.0 g, 3.31 mmol). Stir at room temperature overnight until TLC showed the starting material was completely. Water and ethyl acetate were added to the mixture, and the organic layer was evaporated.
  • the third step 4-(((1-(4-bromothiazol-2-yl)piperidin-4-yl)oxy)methyl)-5-cyclopropyl-3-(2,6-dichloro Preparation of phenyl)isoxazole (T1)
  • T2-a 1-(4-Bromophenyl)ethanone (1.0 g, 5 mmol) was dissolved in dry tetrahydrofuran (20 mL), sodium hydride (0.24 g, 6 mmol) was added and stirred for 30 min. (0.65 g, 5.5 mmol). The reaction was stirred at 70 ° C. EtOAc (EtOAc m. Yield: 86%).
  • the compound (T3-1) was synthesized by the method described in Intermediate Preparation Example 2 except that the compound (T2-a) was replaced by 1-(3-bromophenyl)ethanone (T3-a) in the first step. (200 mg, yield: 13%) and compound (T3-2) (230 mg, yield: 15%).
  • T4-a 2-(Trifluoromethoxy)benzaldehyde (T4-a) (150 g, 788.98 mmol) was dissolved in a mixed solvent of ethanol (1000 mL) and water (1000 mL), and hydroxylamine hydrochloride (65.79 g, 946.77) was added under mechanical stirring. A white solid precipitated and a 1M aqueous solution of sodium hydroxide (789 mL, 788.98.
  • reaction was allowed to react at 25 ° C for 2 hours, and 1 M hydrochloric acid (2000 mL) was added to the mixture to adjust the pH of the system to about 5, and the mixture was directly subjected to suction filtration, and dried at 50 ° C overnight to obtain a compound (T4-b) (150 g, Rate: 92%).
  • Step 5 Preparation of 4-(chloromethyl)-5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazole (T4-f)
  • Step 6 (1R, 3r, 5S)-3-((5-Cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)methoxy)- Preparation of 8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (T4-g)
  • Step 7 4-(((1R,3r,5S)-8-azabicyclo[3.2.1]oct-3-yloxy)methyl)-5-cyclopropyl-3-(2-( Preparation of trifluoromethoxy)phenyl)isoxazole (T4-h)
  • Step 8 4-(((1R,3r,5S)-8-(4-Bromothiazol-2-yl)-8-azabicyclo[3.2.1]oct-3-yl)oxy) A Of 5-(4-(trifluoromethoxy)phenyl)isoxazole (T4)
  • the compound (C2-a) was synthesized by the method described in the first step of Example 1 except that (4-(methoxycarbonyl)phenyl)boronic acid was replaced by the compound (3-(methoxycarbonyl)phenyl)boronic acid. (45 mg, yield: 40.5%).
  • Second step 4-(2-(4-(5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)piperidin-1-yl Preparation of thiazol-4-yl)benzoic acid (C2)
  • Example 7 4-(2-((1R,3r,5S)-3-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) Of 8-(azabicyclo[3.2.1]oct-8-yl)thiazol-4-yl)-3-methylbenzoic acid (C37)
  • the compound (T1-a) (1.0 g, 3.33 mmol) was dissolved in DMF (20 mL) at room temperature. After the dissolution was completed, potassium carbonate (0.919 g, 6.66 mmol) and (1R, 3r, 5S) were added with stirring. tert-Butyl 3-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylate (0.756 g, 3.33 mmol) was stirred at EtOAc overnight. A large amount of a white solid was precipitated from the reaction mixture, which was filtered, and the filtrate was washed with water (50 mL) and brine (50 mL). The title compound (1.4 g) of this step.
  • Second step 4-(((1R,3r,5S)-8-azabicyclo[3.2.1]oct-3-yloxy)methyl)-5-cyclopropyl-3-(2,6 -Dichlorophenyl)isoxazole (C37-b) preparation
  • the third step 4-(((1R,3r,5S)-8-(4-bromothiazol-2-yl)-8-azabicyclo[3.2.1]oct-3-yl)oxy) Of 5-(cyclohexyl-3-(2,6-dichlorophenyl)isoxazole (C37-c)
  • Step 5 4-(2-((1R,3r,5S)-3-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) Of 8-(azabicyclo[3.2.1]oct-8-yl)thiazol-4-yl)-3-methylbenzoic acid (C37)
  • Second step 4-(2-((1R,3r,5S)-3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazole-4-yl) Preparation of methoxy)-8-azabicyclo[3.2.1]oct-8-yl)thiazol-4-yl)benzoic acid (C41)
  • Second step 4-(2-((1R,3r,5S)-3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazole-4-yl) Preparation of methoxy)-8-azabicyclo[3.2.1]oct-8-yl)thiazol-4-yl)-3-methylbenzoic acid (C42)
  • Second step 4-(2-((1R,3r,5S)-3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazole-4-yl) Preparation of methoxy)-8-azabicyclo[3.2.1]oct-8-yl]thiazol-4-yl)-3-fluorobenzoic acid (C43)
  • Second step 4-(2-((1R,3r,5S)-3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazole-4-yl) Preparation of methoxy)-8-azabicyclo[3.2.1]oct-8-yl)thiazol-4-yl)-2-fluorobenzoic acid (C44)
  • Example 12 4-(2-((1R,3r,5S)-3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazole-4-yl) Preparation of methoxy)-8-azabicyclo[3.2.1]oct-8-yl]thiazol-4-yl)-3-(trifluoromethyl)benzoic acid (C45)
  • Second step 4-(2-((1R,3r,5S)-3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazole-4-yl) Preparation of methoxy)-8-azabicyclo[3.2.1]oct-8-yl]thiazol-4-yl)-3-(trifluoromethyl)benzoic acid (C45)
  • Example 13 4-(2-((1R,3r,5S)-3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazole-4-yl) Preparation of methoxy)-8-azabicyclo[3.2.1]oct-8-yl)thiazol-4-yl)-2-(trifluoromethyl)benzoic acid (C46)
  • Second step 4-(2-((1R,3r,5S)-3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazole-4-yl) Preparation of methoxy)-8-azabicyclo[3.2.1]oct-8-yl)thiazol-4-yl)-2-(trifluoromethyl)benzoic acid (C46)
  • Second step 4-(2-((1R,3r,5S)-3-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazole-4-yl) Preparation of methoxy)-8-azabicyclo[3.2.1]oct-8-yl)thiazol-4-yl)thiophene-2-carboxylic acid (C47)
  • Emax and Emin are the upper asymptotic and fitting asymptotic estimates of the fitted curve
  • x is the logarithmic concentration of the compound
  • Hillslope is the slope of the curve.
  • Emax represents the maximum activation effect value of the compound tested in the present invention
  • Emax' represents the maximum activation effect value of CDCA, both of which are calculated by the formula shown above.
  • Other compounds of the invention also has good EC 50 values and the relative value of the activation effect, i.e. having a good activating activity of FXR activation and maximum effect.
  • Human embryonic kidney cells HEK293 were cultured in DMEM medium containing 10% FBS.
  • the plasmid was co-transfected to express high expression of FXR and human BSEP luciferase reporter gene.
  • the transfected cells were digested, resuspended, counted, and then seeded in a multiwell plate.
  • Table 4 show that the compounds of the present invention are tested in vitro cell assay, EC 50 values between 0.006 ⁇ M ⁇ 0.091 ⁇ M, Emax values greater than 200%.
  • the compounds of the invention are shown to have good FXR activating activity in in vitro cellular assays.
  • Other compounds of the invention also has good EC 50 values and Emax values, i.e., having good in vitro activity of FXR activation assay.
  • IV and PO intravenous and intragastric
  • the doses of IV and PO were 1 mg/kg and 5 mg/kg, respectively, and the medium of IV was 5% DMSO: 5% Solutol: 90% physiological saline, and the solvent of PO was 0.5% MC.
  • Blood and liver were collected at different time points after IV and PO administration. The blood was anticoagulated with EDTA.K 2 and centrifuged to obtain a plasma sample; the liver was homogenized and stored at -80 °C. Plasma and liver samples were processed by precipitation protein and analyzed by LC-MS/MS.
  • the data in Table 5 shows that the AUC last in the rat was 2409 ⁇ 108 h*ng/mL and the Cmax was 4343 ⁇ 172 ng/mL by the compound C2 of the present invention administered IV at a dose of 1 mg/kg, indicating The compound C2 of the present invention has excellent drug exposure in rats by IV administration.
  • Example 2 of the present invention has excellent plasma drug exposure in rats by IV administration, and has certain drug exposure and significant liver enrichment in rats by PO administration. effect.
  • the compounds of the present invention show good effects in drug safety when applied to drugs for FXR-mediated diseases, and exhibit good drug activity in animal or in vitro pharmacodynamics or pharmacokinetics. Metabolic advantages in the body.
  • test compound 50 ⁇ L was mixed with various liver microsomes (100 ⁇ L), pre-incubated for 5 minutes at 37 ° C, added with NADPH (50 ⁇ L), incubated for 0, 30, 60 minutes, test compound, NADPH and liver microsomes.
  • the incubation concentrations of the enzymes were 1 ⁇ M, 1 mM, and 0.5 mg/mL, respectively.
  • LC-MS/MS mass spectrum was API 5500 and liquid phase was Shimadzu LC-30AD system.
  • the column was Hypersil GOLD C18, 1.9 ⁇ m particle size, 50 ⁇ 2.1 mm; mobile phase A phase was water + 0.1% formic acid, phase B was acetonitrile; flow rate was 0.55 mL/min, and column temperature was 40 °C.
  • the ion source is used as the ESI source positive ion mode, and the scanning mode is multiple reaction monitoring (MRM).
  • the rate constant is obtained by plotting "Ln (drug residue %)" versus "incubation time” to calculate the half-life and liver clearance of the drug, with drug half-life and liver clearance values.
  • the metabolic stability of the drug in liver microsomes was evaluated.

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Abstract

本发明一般涉及异噁唑衍生物及其制备方法和用途。具体地，本发明提供类法尼醇X受体(FXR)激动剂化合物以及其立体异构体、互变异构体、多晶型物、溶剂合物(如水合物)、药学可接受的盐、酯、代谢物、N-氧化物以及其化学保护的形式和前药。本发明还提供所述化合物的制备方法、中间体、包含所述化合物的药物组合物和药盒以及它们用于治疗由FXR介导的疾病或病症的用途。

Description

异噁唑衍生物及其制备方法和用途 发明领域
本发明一般涉及用于治疗由类法尼醇X受体(FXR)介导的疾病或病症的化合物，更具体地涉及FXR激动剂化合物以及其立体异构体、互变异构体、多晶型物、溶剂合物(如水合物)、药学可接受的盐、酯、代谢物、N-氧化物以及其化学保护的形式和前药。本发明还涉及所述化合物的制备方法、中间体、包含所述化合物的药物组合物和药盒以及它们的治疗用途。
发明背景
类法尼醇X受体(FXR，NR1H4)在肝、包括食道、胃、十二指肠、小肠、结肠在内的整个胃肠道、肾和肾上腺中表达(Kuipers，F.等，The Farnesoid X Receptor(FXR)as Modulator of Bile Acid Metabolism，Rev.Endocrine Metab.Disorders，2004，5：319-326)。FXR是已知作为核受体的配体活化的转录因子的一员。胆汁酸如鹅脱氧胆酸(CDCA)或者其牛磺酸或甘氨酸酰胺偶联物是FXR的内源性配体。胆汁酸与FXR结合后激活FXR，通过与视黄醇类X受体(RXR)的异二聚体复合物来控制多种基因的表达，包括在肝脏和循环系统中参与胆汁酸、胆固醇、三酸甘油酯、脂蛋白动态平衡的基因表达(Kalaany，N.Y.；Mangelsdorf，D.J.；LXRS and FXR：the yin and yang of cholesterol and fat metabolism，Annu.Rev.Physiol.，2006，68，159-191；Calkin，A.C.；Tontonoz，P.；Transcriptional integration of metabolism by the nuclear sterol-activated receptors LXR and FXR，Nat.Rev.Mol.Cell Biol.，2012，13，213-224)。FXR似乎还通过上调成纤维细胞生长因子15(啮齿动物)或成纤维细胞生长因子19(猴、人)参与旁分泌和内分泌信号传导(T.Inagaki等，Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis.Cell Metab.，2005，2(4)，217-225)。
胆汁酸是两亲性分子，它们形成胶束并将膳食中的脂质乳化。如果胆汁酸浓度过高也会产生细胞毒性，因此生理上有严格控制胆汁酸浓度的机制。FXR在控制胆汁酸在体内保持稳定状态中起着关键作用(Makishima，M.；Nuclear Receptors as Targets for Drug Development：Regulation of Cholesterol and Bile Acid Metabolism by Nuclear Receptors，J.Pharmacol.Sci.，2005，97：177-183)。
此外，FXR还被证明调节超出代谢的复杂生物流程，如肝再生或肠屏障的完整性。FXR还对肠和肝脏的免疫系统有控制，有一定的抗炎作用(Modica，S.；Gadaleta，R.M.；Moschetta，A.；Deciphering the nuclear bile acid receptor FXR paradigm，Nucl.Recept.Signal.，2010，8，e005)。
奥贝胆酸(Obeticholic Acid，6-Et CDCA)是一种比内源性配体CDCA活性更高的FXR受体激动剂，在非酒精性脂肪性肝病(NAFLD)的IIa期临床研究中显示出对胰岛素敏感性有显著改善以及其他代谢方面的有益作用(Mudaliar，S.；Henry，R.R.；Sanyal，A.J.等，Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2 diabetes and nonalcoholic fatty liver disease，Gastroenterology，2013，145，574-582)。奥贝胆酸的IIb期研究显示72周的治疗对非酒精性肝炎(NASH)的组织病理学的改进也有益。在原发性胆汁性肝硬化(PBC)的III期研究中，患者的肝功能损害得到改善(Nevens，F.，Andreone，P.，Mazzella，G.等，The first primary biliary cirrhosis(PBC)phase 3 trial in two decades-an international study of the FXR agonist obeticholic acid in PBC patients，J.Hepatol.，2014，60，S525-S526)。
WO2012087519中公开了一种FXR的激动剂或部分激动剂用于治疗由FXR介导的病症的方法。然而，现有技术中公开的FXR激动剂化合物在药效动力学或药代动力学性质方面仍存在缺陷。
发明概述
本发明概括地涉及通式(I)的化合物或者其立体异构体、互变异构体、多晶型物、溶剂合物(如水合物)、药学可接受的盐、酯、代谢物、N-氧化物、其化学保护的形式或前药，
Figure PCTCN2018119715-appb-000001
其中：
A选自亚噻唑基、亚苯基和亚吡啶基；
B选自C 6-10芳基以及包含独立地选自N、O和S的1、2、3或4个杂原子的5至10元杂芳基；
D是
Figure PCTCN2018119715-appb-000002
或
Figure PCTCN2018119715-appb-000003
Z是
Figure PCTCN2018119715-appb-000004
W选自N和CR d，优选地是CR d；
R a选自氢、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、3至14元杂环基、C 1-6烷基-O-、卤代C 1-6烷基、卤代C 3-8环烷基和卤代C 1-6烷基-O-；
R b、R c和R d各自独立地选自氢、卤素、羟基、氰基、-NH 2、硝基、C 1-6烷基、卤代C 1-6烷基、C 1-6烷基-O-、卤代C 1-6烷基-O-、C 3-8环烷基、卤代C 3-8环烷基、C 3-8环烷基-O-和卤代C 3-8环烷基-O-；
R 1和R 2各自独立地选自氢、卤素、氰基、羟基、-NH 2、C 1-6烷基、卤代C 1-6烷基、羟基C 1-6烷基、C 1-6烷基-O-、卤代C 1-6烷基-O-、C 3-8环烷基、卤代C 3-8环烷基、C 1-6烷基-NH-和(C 1-6烷基) 2-N-；
R 3a、R 3b、R 3c和R 3d各自独立地选自氢、卤素、氰基、羟基、-NH 2、氧代、C 1-6烷基、卤代C 1- 6烷基、羟基C 1-6烷基、C 1-6烷基-O-、卤代C 1-6烷基-O-、C 3-8环烷基和卤代C 3-8环烷基；或者R 3a、R 3b、R 3c和R 3d中的任意二者共同形成C 1-6亚烷基，优选地，R 3a、R 3b、R 3c和R 3d中的任意二者共同形成C 2-6亚烷基，更优选地，R 3a和R 3b共同形成C 2-6亚烷基；
m和n各自独立地是0、1、2、3或4，优选地是0、1或2；并且
上述烷基、亚烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自任选地被1个、2个或3个独立地选自下列的取代基取代：卤素、羟基、氧代、氰基、-NH 2、硝基、C 1-6烷基、卤代C 1-6烷基、C 1-6烷基-O-、卤代C 1-6烷基-O-、C 3-6环烷基、卤代C 3-6环烷基、C 1-6烷基-NH-、(C 1-6烷基) 2-N-、羟基C 1- 6烷基、氰基-C 1-6烷基、3至14元杂环基、C 6-14芳基和5至14元杂芳基。
本发明的另一方面是药物组合物，其包含所述通式(I)的化合物或者其立体异构体、互变异构体、多晶型物、溶剂合物(如水合物)、药学可接受的盐、酯、代谢物、N-氧化物、其化学保护的形式或前药，以及一种或多种药学可接受的载体。所述药物组合物还可包含适于预防或治疗由FXR介导的疾病或病症的一种或多种其他治疗剂。
本发明还包括预防或治疗由FXR介导的疾病或病症的方法，所述方法包括向有此需要的个体给药治疗有效量的所述通式(I)的化合物或者其立体异构体、互变异构体、多晶型物、溶剂合物(如水合物)、药学可接受的盐、酯、代谢物、N-氧化物、其化学保护的形式或前药或者所述药物组合物。
本发明还包括用于预防或治疗由FXR介导的疾病或病症的药盒，其包括：
a)第一容器，其包含作为第一治疗剂的至少一种所述通式(I)的化合物或者其立体异构体、互变异构体、多晶型物、溶剂合物(如水合物)、药学可接受的盐、酯、代谢物、N-氧化物、其化学保护的形式或前药或者作为第一药物组合物的所述药物组合物；
b)任选存在的第二容器，其包含作为第二治疗剂的至少一种其他治疗剂，或者作为第二药物组合物的包含所述其他治疗剂的药物组合物；和
c)任选存在的包装说明书。
本发明还包括所述通式(I)的化合物或者其立体异构体、互变异构体、多晶型物、溶剂合物(如水合物)、药学可接受的盐、酯、代谢物、N-氧化物、其化学保护的形式或前药或者所述药物组合物，其用于预防或治疗由FXR介导的疾病或病症。
本发明还包括所述通式(I)的化合物或者其立体异构体、互变异构体、多晶型物、溶剂合物(如水合物)、药学可接受的盐、酯、代谢物、N-氧化物、其化学保护的形式或前药或者所述药物组合物在制备用于预防或治疗由FXR介导的疾病或病症的药物中的用途。
本发明还包括制备本发明的化合物的方法和相应中间体。
本发明的通式(I)的化合物具有优良的体内或体外药效动力学或药代动力学性质，显示出良好的FXR激活活性和激活作用以及优良的血浆药物暴露量和生物利用度，因而具有良好的药物活性和体 内代谢优势。
发明详细描述
现详细描述本发明的某些实施方案，其实例在随附结构和分子式中说明。虽然结合列举的实施方案来描述本发明，但是应理解本发明并不限于那些实施方案。相反，本发明意在涵盖可包括在本发明的由权利要求书限定的范围内的所有替代方案、修改和等同。本领域技术人员会认识到，与本文中所述的那些相似或等同的许多方法和材料可用于实施本发明。本发明绝不限于所述的方法和材料。在所引的文献、专利及相似的材料中的一者或多者与本申请(包括但不限于定义的术语、术语用法、所述的技术等)不同或矛盾的情况下，以本申请为准。
定义
除非在下文中另有定义，本文中所用的所有技术术语和科学术语的含义意图与本领域技术人员通常所理解的相同。
术语“包括”、“包含”、“具有”、“含有”或“涉及”及其在本文中的其他变体形式是包含性的或开放式的，且不排除其他未列举的元素或方法步骤。
术语“烷基”用于本文中是指具有1至12个碳原子(C 1-12)的饱和直链或支链烃基，其中所述烷基可任选地被一个或多个(例如1个、2个、3个或4个)适合的取代基取代。在一些实施方案中，烷基具有1至8个碳原子(C 1-8)，特别是1至6个碳原子(C 1-6)。在另一些实施方案中，烷基具有1至4个碳原子(C 1-4)，特别是1至3个碳原子(C 1-3)或者1至2个碳原子(C 1-2)。烷基的实例包括但不限于：甲基(Me)、乙基(Et)、1-丙基(n-Pr)、2-丙基(i-Pr或异丙基)、1-丁基(n-Bu或正丁基)、2-甲基-1-丙基(i-Bu或异丁基)、2-丁基(s-Bu或仲丁基)、2-甲基-2-丙基(t-Bu或叔丁基)、1-戊基(正戊基)、2-戊基、3-戊基、2-甲基-2-丁基、3-甲基-2-丁基、3-甲基-1-丁基、2-甲基-1-丁基、1-己基、2-己基、3-己基、2-甲基-2-戊基(-C(CH 3) 2CH 2CH 2CH 3)、3-甲基-2-戊基、4-甲基-2-戊基、3-甲基-3-戊基、2-甲基-3-戊基、2，3-二甲基-2-丁基、3，3-二甲基-2-丁基、1-庚基、1-辛基等。
如本文中所使用，术语“烯基”意指线性的或支化的单价烃基，其包含一个双键，且具有2-6个碳原子(“C 2-6烯基”)。所述烯基为例如乙烯基、1-丙烯基、2-丙烯基、2-丁烯基、3-丁烯基、2-戊烯基、3-戊烯基、4-戊烯基、2-己烯基、3-己烯基、4-己烯基、5-己烯基、2-甲基-2-丙烯基和4-甲基-3-戊烯基。当本发明的化合物含有亚烯基时，所述化合物可以纯E(异侧(entgegen))形式、纯Z(同侧(zusammen))形式或其任意混合物形式存在。
如本文中所使用，术语“炔基”表示包含一个或多个三键的单价烃基，其优选具有2、3、4、5或6个碳原子，例如乙炔基或丙炔基。
如本文中所用的，术语“环烷基”是指具有3至12个碳原子(C 3-12)、特别是3至10个碳原子(C 3- 10)或3至8个碳原子(C 3-8)的单环形式的饱和碳环。在一些实施方案中，环烷基具有3至6个碳原子(C 3-6)，例如3、4、5或6个碳原子。环烷基的实例包括但不限于：环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基、环癸基、环十一烷基、环十二烷基等。环烷基可任选地被一个或多个(例如1个、2个、3个或4个)适合的取代基取代。
本文所用的术语“芳基”意指C 6-14芳香性单环或多环(特别是双环)基团(C 6-14芳基)，适合地包括C 6-12芳基基团，更适合地包括C 6-10单环或双环芳基基团，优选意指C 6芳基基团(即，苯基)。芳基基团包含至少一个芳香性环(如一个环或两个环)，但也可以包含非芳香性的额外的环。含有一个芳香性环的典型芳基基团的实例是苯基。含有两个芳香性环的典型芳基基团的实例是萘基。与C 5-8碳环基(适合地，C 5-6碳环基)稠合的苯基(如茚满)也是芳基的实例。所述芳基任选地被一个或多个(例如1个、2个、3个或4个)适合的取代基取代。
术语“杂环”和“杂环基”在本文中可互换使用，并且是指具有例如3至14个(适合地具有3至8个，更适合地具有3、4、5或6个)环原子、其中至少一个环原子是选自N、O和S的杂原子且其余环原子是C的饱和(即，杂环烷基)或部分不饱和的(即在环内具有一个或多个双键和/或三键)环状基团。例如，“3至14元杂环基”是具有2至13个(如2、3、4、5、6、7、8、9、10、11、12或13个)环碳原子和独立地选自N、O和S的一个或多个(例如1个、2个、3个或4个)杂原子的饱和或部分不饱和杂环基。饱和杂环基(即，杂环烷基)的实例包括但不限于：环氧乙烷基、氮丙啶基、氮杂环丁基(azetidinyl)、氧杂环丁基(oxetanyl)、四氢呋喃基、吡咯烷基、吡咯烷酮基、咪唑烷基、吡唑烷基、四氢吡喃基、哌啶基、吗啉基、二噻烷基(dithianyl)、硫吗啉基、哌嗪基或三噻烷基(trithianyl)；部分不饱和的杂环基的实例包括但不限于二氧杂环戊烯基(dioxolinyl)和吡咯啉基。杂环基可任选地被一个或多个(例如1个、2个、3个或4个)适合的取代基取代。
本文所使用的术语“杂芳基”指单环或多环(例如双环或三环)芳香性环系统，其具有5至14个环 原子，例如5、6、7、8、9、10、11、12、13或14个环原子，特别地具有1、2、3、4、5、6、7、8、9、10、11、12或13个碳原子和独立地选自N、O和S的1、2、3、4或5个相同或不同的杂原子。杂芳基可以是苯并稠合的。杂芳基的实例包括但不限于：吡啶基、嘧啶基、吡嗪基、哒嗪基、噻唑基、噻吩基、噁唑基、呋喃基、吡咯基、吡唑基、三唑基、四唑基、异噁唑基、异噻唑基、咪唑基、三嗪基、噁二唑基、噻二唑基、苯并噻唑基、苯并异噻唑基、咪唑并吡啶基、喹啉基、吲哚基、吡咯并哒嗪基、苯并呋喃基、苯并噻吩基、吲唑基、苯并噁唑基、苯并异噁唑基、喹唑啉基、吡咯并吡啶基、吡唑并嘧啶基、咪唑并哒嗪基、吡唑并吡啶基、三唑并吡啶基、异喹啉基、四氢异喹啉基、苯并咪唑基、噌啉基、中氮茚基、酞嗪基、异吲哚基、蝶啶基、嘌呤基、呋咱基、苯并呋咱基、喹喔啉基、萘啶基或呋喃并吡啶基。优选地，杂芳基选自：吡啶基、嘧啶基、吡嗪基、哒嗪基、噻唑基、噁唑基、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]噁唑基、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、吡唑并[1，5-a]吡啶基和1H-[1，2，3]三唑并[4，5-b]吡啶基。杂芳基可任选地被一个或多个(例如1个、2个、3个或4个)适合的取代基取代。
在可能的情况下，所述杂环基(如杂环烷基)或杂芳基可以是碳键合的(碳连接的)或氮键合的(氮连接)。作为示例而非限制，碳键合的杂环或杂芳基是在以下位置成键：吡啶的2、3、4、5或6位，哒嗪的3、4、5或6位，嘧啶的2、4、5或6位，吡嗪的2、3、5或6位，呋喃、四氢呋喃、噻吩、吡咯或四氢吡咯的2、3、4或5位，噁唑、咪唑或噻唑的2、4或5位，异噁唑、吡唑或异噻唑的3、4或5位，氮丙啶的2或3位，氮杂环丁烷的2、3或4位，喹啉的2、3、4、5、6、7或8位，或者异喹啉的1、3、4、5、6、7或8位。
作为示例而非限制，氮键合的杂环或杂芳基是在以下位置成键：氮丙啶、氮杂环丁烷、吡咯、吡咯烷、2-吡咯啉、3-吡咯啉、咪唑、咪唑烷、2-咪唑啉、3-咪唑啉、吡唑、吡唑啉、2-吡唑啉、3-吡唑啉、哌啶、哌嗪、吲哚、吲哚啉、1H-吲唑的1位，异吲哚或异吲哚啉的2位，吗啉的4位，以及咔唑或β-咔啉的9位。
本文中使用的术语“卤代”或“卤素”包括F、Cl、Br或I。“卤代”包括但不限于单取代、二取代或三取代，而且，用于取代的卤原子可以相同或不同。
术语“取代的”指所指定的原子上的一个或多个(例如1个、2个、3个或4个)氢被从所指出的基团的选择所代替，条件是未超过所指定的原子在当前情况下的正常原子价并且所述取代形成稳定的化合物。取代基和/或变量的组合仅仅当这种组合形成稳定的化合物时才是允许的。
术语“任选地取代”指(1)未被取代或(2)被特定的基团、原子团或部分取代。
当取代基的键显示为穿过环中连接两个原子的键时，则这样的取代基可键连至该可取代的环中的任一成环原子。
术语“手性”是指具有镜像对的不可重叠性的分子，而术语“非手性”是指可在它们的镜像对上重叠的分子。
术语“立体异构体”是指具有相同的化学组成但原子或基团的空间排列不同的化合物。
“非对映异构体”是指具有两个或多个手性中心并且其分子彼此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，例如熔点、沸点、光谱性质和反应性。非对映异构体的混合物可通过高分辨率的分析方法例如电泳法和色谱法进行分离。
“对映异构体”是指化合物的彼此呈不可重叠的镜像的两种立体异构体。
本文中所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；和Eliel，E.和Wilen，S.，“Stereochemistry of Organic Compounds”，John Wiley&Sons，Inc.，New York，1994。本发明的化合物可包含非对称的或手性的中心，因此以不同的立体异构体形式存在。本发明的化合物的所有立体异构体形式，包括但不限于其非对映异构体、对映异构体和阻转异构体以及它们的混合物例如外消旋混合物，意在构成本发明的一部分。许多有机化合物以旋光形式存在，即，它们具有使平面偏振光的平面旋转的能力。在表述旋光化合物时，前缀D和L，或者R和S，用来表示分子的手性中心的绝对构型。前缀d和l或者(+)和(-)用来指示化合物使平面偏振光旋转的符号，其中(-)或l是指化合物是左旋的。具有前缀(+)或d的化合物是右旋的。对于特定的化学结构，这些立体异构体是相同的，只是它们彼此互为镜像。特定的立体异构体还可称为对映异构体，并且这样的异构体的混合物常称为对映异构体混合物。对映异构体的50∶50混合物称为外消旋混合物或外消旋物，其可在化学反应或过程没有立体选择性或立体专一性的情况下出现。术语“外消旋混合物”和“外消旋物”是指两种对映异构体的等摩尔混合物，不具有旋光性。在一方面，本发明的立体异构体可以占主导的形式存在，例如，大于50％ee(对 映体过量)，大于80％ee，大于90％ee，大于95％ee，或者大于99％ee。
在用于制备本发明的化合物的方法产生立体异构体的混合物的情况中，通过常规技术例如制备色谱可以分离这些异构体。所述化合物可以制备成外消旋的形式，或者，通过对映体选择性合成或者通过拆分可以制备单一的对映异构体。例如，通过标准技术，例如通过与旋光性的酸如(-)-二对甲苯酰基-d-酒石酸和/或(+)-二对甲苯酰基-l-酒石酸形成盐来形成非对映异构体对，然后进行分步结晶和游离碱再生，可以将所述化合物拆分成它们的对映异构体成分。通过形成非对映的酯或酰胺，然后进行色谱纯化和除去手性助剂，也可以拆分所述化合物。或者，使用手性HPLC柱可以拆分所述化合物。
术语“互变异构体”或“互变异构体形式”是指可通过低能垒互相转化的能量不同的结构异构体。例如，质子互变异构体(也称为质子转移互变异构体)包括通过质子迁移互相转化，例如酮-烯醇和亚胺-烯胺异构化。价键互变异构体包括通过一些成键电子的重组互相转化。
本发明涵盖通式(I)的化合物的所有可能的结晶形式或多晶型物，其可为单一多晶型物或多于一种多晶型物的任意比例的混合物。
应当理解，本发明的某些化合物可以游离形式存在用于治疗，或适当时，以其药学可接受的衍生物形式存在。根据在本发明中，药学可接受的衍生物包括但不限于：药学可接受的盐、酯、溶剂合物、代谢物、N-氧化物以及化学保护的形式和前药，在将它们向有此需要的个体给药后，能够直接或间接提供本发明的化合物或者其代谢物或残余物。
因此，当在本文中提及“通式(I)的化合物”、“本发明的化合物”或“本发明的通式(I)的化合物”时，也意在涵盖所述通式(I)的化合物的溶剂合物(如水合物)、药学可接受的盐、酯、代谢物、N-氧化物以及其化学保护的形式和前药。
术语“药学可接受的盐”用于本文中是指本发明的化合物的药学可接受的有机或无机盐。示例性的盐包括但不限于硫酸盐、乙酸盐、氯化物、碘化物、硝酸盐、硫酸氢盐、酸式磷酸盐、异烟酸盐、水杨酸盐、酸式柠檬酸盐、油酸盐、鞣酸盐、泛酸盐、酒石酸氢盐、抗坏血酸盐、龙胆酸盐、葡糖酸盐、葡糖醛酸盐、糖质酸盐、甲酸盐、苯甲酸盐、谷氨酸盐、和扑酸盐(即1，1’-亚甲基-双(2-羟基-3-萘甲酸盐))。药学可接受的盐可包括诸如乙酸根离子、琥珀酸根离子或其他反荷离子的另一种分子的包合。所述反荷离子可以是使母体化合物上的电荷稳定的任何有机或无机离子。此外，药学可接受的盐在其结构中可具有多于一个带电荷的原子。多个带电荷的原子为药学可接受的盐的部分的情况可具有多个反荷离子。因此，药学可接受的盐可具有一个或多个带电荷的原子和/或一个或多个反荷离子。
若本发明的化合物是碱，期望的药学可接受的盐可通过本领域中可利用的任何适合的方法制备，例如，用无机酸例如盐酸、氢溴酸、硫酸、硝酸、甲磺酸、磷酸等或者用有机酸例如乙酸、三氟乙酸、马来酸、琥珀酸、扁桃酸、富马酸、丙二酸、丙酮酸、草酸、乙醇酸、水杨酸、吡喃糖苷基酸例如葡糖醛酸或半乳糖醛酸、α-羟基酸例如柠檬酸或酒石酸、氨基酸例如天冬氨酸或谷氨酸、芳香酸例如苯甲酸或肉桂酸、磺酸例如对甲基苯磺酸或乙磺酸等处理游离的碱。
若本发明的化合物是酸，期望的药学可接受的盐可通过任何适合的方法制备，例如，用无机碱或有机碱例如胺(伯胺、仲胺或叔胺)、碱金属氢氧化物或碱土金属氢氧化物等处理游离的酸。适合的盐的示例性实例包括但不限于，得自氨基酸例如甘氨酸和精氨酸、氨、伯胺、仲胺和叔胺以及环胺例如哌啶、吗啉和哌嗪的有机盐，以及得自钠、钙、钾、镁、锰、铁、铜、锌、铝和锂的无机盐。
术语“药学可接受的”是指物质或组合物必须与构成制剂的其他组分和/或用其治疗的哺乳动物在化学和/或毒理学上相容。
本文所使用的术语“酯”意指衍生自通式(I)化合物的酯，包括生理上可水解的酯，其可在生理条件下水解以释放游离酸或醇形式的本发明的通式(I)化合物。本发明的通式(I)化合物本身也可以是酯。
本发明的化合物可以溶剂合物(如水合物)的形式存在，其中本发明的化合物包含作为所述化合物晶格的结构要素的极性溶剂，特别是例如水、甲醇或乙醇。极性溶剂特别是水的量可以化学计量比或非化学计量比存在。
“代谢物”是特定的化合物或其盐通过体内代谢产生的产物。化合物的代谢物可利用本领域已知的常规技术进行鉴定并且可利用诸如本文中所述的那些试验测定它们的活性。这样的产物可由例如被给药的化合物的氧化、还原、水解、酰胺化、脱酰胺化、酯化、酶解等产生。因此，本发明包括本发明的化合物的代谢物，包括通过包括使本发明的通式(I)的化合物与哺乳动物接触足以产生其代谢物的时间段的方法产生的化合物。
本领域技术人员会理解，由于氮需要可用的孤对电子来氧化成氧化物，因此并非所有的含氮杂环都能够形成N-氧化物；本领域技术人员会识别能够形成N-氧化物的含氮杂环。本领域技术人员还 会认识到叔胺能够形成N-氧化物。用于制备杂环和叔胺的N-氧化物的合成方法是本领域技术人员熟知的，包括用过氧酸如过氧乙酸和间氯过氧苯甲酸(m-CPBA)、过氧化氢、烷基过氧化氢如叔丁基过氧化氢、过硼酸钠和双环氧乙烷(dioxirane)如二甲基双环氧乙烷来氧化杂环和叔胺。这些用于制备N-氧化物的方法已在文献中得到广泛描述和综述，参见例如：T.L.Gilchrist，Comprehensive Organic Synthesis，vol.7，pp 748-750；S.V.Ley，Ed.，Pergamon Press；M.Tisler和B.Stanovnik，Comprehensive Heterocyclic Chemistry，vol.3，pp 18-20。
在制备本发明的化合物的任何过程中，保护在任何有关分子上的敏感基团或反应基团可能是必需的和/或期望的，由此形成本发明的化合物的化学保护的形式。这可以通过常规的保护基实现，例如，在Protective Groups in Organic Chemistry，ed.J.F.W.McOmie，Plenum Press，1973；和T.W.Greene&P.G.M.Wuts，Protective Groups in Organic Synthesis，John Wiley&Sons，1991中所述的那些保护基，这些参考文献通过援引加入本文。使用本领域已知的方法，在适当的后续阶段可以除去保护基。
本发明在其范围内进一步包括本发明的化合物的前药。通常这样的前药会是所述化合物的官能团衍生物，其易于在体内转化成期望的治疗活性化合物。因此，在这些情况中，用于本发明的治疗方法的术语“给药”应包括用所要求保护的化合物中的一种或多种的前药形式来治疗各种疾病或病症，但是在向个体给药后所述前药形式在体内转化成上述化合物。例如，在“Design of Prodrug”，ed.H.Bundgaard，Elsevier，1985中，描述了选择和制备适合的前药衍生物的常规方法。
本文中所示的任何通式或结构，包括通式(I)的化合物在内，还意在表示所述化合物的未标记形式和同位素标记的形式。同位素标记的化合物具有本文给出的分子式所示的结构，除了一个或多个原子被具有选定原子质量或质量数的原子替代。本发明的化合物中可包含的同位素的实例包括氢、碳、氮、氧、磷、氟和氯的同位素，例如，但不限于 2H(氘，D)、 3H(氚)、 11C、 13C、 14C、 15N、 18F、 31P、 32P、 35S、 36Cl和 125I。各种同位素标记的本发明的化合物，例如，其中包含诸如 3H、 13C和 14C的放射性同位素的那些。这样的同位素标记的化合物可用于代谢研究、反应动力学研究、检测或显像技术，例如正电子发射断层摄影术(PET)或单光子发射断层摄影术(SPECT)，包括药物或底物组织分布测定，或者用于患者的放射性治疗。本发明的氘标记的或取代的治疗性化合物可具有改进的有关分布、代谢和排泄(ADME)的DMPK(药物代谢和药物动力学)性质。用较重的同位素例如氘取代可能由于较大的代谢稳定性而提供某些治疗优点，例如，体内半衰期增长，或者剂量要求减小。 18F标记的化合物可用于PET或SPECT研究。本发明的同位素标记的化合物及其前药一般可通过实施路线或实施例中公开的方法和下述制备方法，以易得的同位素标记的试剂替代非同位素标记的试剂进行制备。此外，用较重的同位素特别是氘(即 2H或D)取代可由于较大的代谢稳定性而提供某些治疗优点，例如，体内半衰期增长或者剂量要求减小或者治疗指数改进。应理解，在此情况中氘被视为式(I)的化合物中的取代基。可通过同位素富集系数定义这样的较重的同位素特别是氘的浓度。在本发明的化合物中，未明确指明为特定同位素的任何原子意在表示该原子的任何稳定的同位素。除非另外说明，当明确以“H”或“氢”标明某位置时，应理解为该位置具有其天然丰度同位素组成的氢。因此，在本发明的化合物中，明确标明氘(D)的任何原子意在表示氘。
本文使用的术语“药物组合物”包括包含治疗有效量的本发明的通式(I)的化合物的产品，以及直接地或间接地由本发明的通式(I)化合物的组合产生的任何产品。
化合物
在一些实施方案中，本发明提供通式(I)的化合物或者其立体异构体、互变异构体、多晶型物、溶剂合物(如水合物)、药学可接受的盐、酯、代谢物、N-氧化物、其化学保护的形式或前药，
Figure PCTCN2018119715-appb-000005
其中：
A选自亚噻唑基、亚苯基和亚吡啶基；
B选自C 6-10芳基以及包含独立地选自N、O和S的1、2、3或4个杂原子的5至10元杂芳基；
D是
Figure PCTCN2018119715-appb-000006
或
Figure PCTCN2018119715-appb-000007
Z是
Figure PCTCN2018119715-appb-000008
W选自N和CR d，优选地是CR d；
R a选自氢、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、3至14元杂环基、C 1-6烷基-O-、卤代C 1-6烷基、卤代C 3-8环烷基和卤代C 1-6烷基-O-；
R b、R c和R d各自独立地选自氢、卤素、羟基、氰基、-NH 2、硝基、C 1-6烷基、卤代C 1-6烷基、C 1-6烷基-O-、卤代C 1-6烷基-O-、C 3-8环烷基、卤代C 3-8环烷基、C 3-8环烷基-O-和卤代C 3-8环烷基-O-；
R 1和R 2各自独立地选自氢、卤素、氰基、羟基、-NH 2、C 1-6烷基、卤代C 1-6烷基、羟基C 1-6烷基、C 1-6烷基-O-、卤代C 1-6烷基-O-、C 3-8环烷基、卤代C 3-8环烷基、C 1-6烷基-NH-和(C 1-6烷基) 2-N-；
R 3a、R 3b、R 3c和R 3d各自独立地选自氢、卤素、氰基、羟基、-NH 2、氧代、C 1-6烷基、卤代C 1- 6烷基、羟基C 1-6烷基、C 1-6烷基-O-、卤代C 1-6烷基-O-、C 3-8环烷基和卤代C 3-8环烷基；或者R 3a、R 3b、R 3c和R 3d中的任意二者共同形成C 1-6亚烷基，优选地，R 3a、R 3b、R 3c和R 3d中的任意二者共同形成C 2-6亚烷基，更优选地，R 3a和R 3b共同形成C 2-6亚烷基；
m和n各自独立地是0、1、2、3或4，优选地是0、1或2；并且
上述烷基、亚烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自任选地被1个、2个或3个独立地选自下列的取代基取代：卤素、羟基、氧代、氰基、-NH 2、硝基、C 1-6烷基、卤代C 1-6烷基、C 1-6烷基-O-、卤代C 1-6烷基-O-、C 3-6环烷基、卤代C 3-6环烷基、C 1-6烷基-NH-、(C 1-6烷基) 2-N-、羟基C 1-6烷基、氰基-C 1-6烷基、3至14元杂环基、C 6-14芳基和5至14元杂芳基。
在一些实施方案中，本发明提供化合物或者其立体异构体、互变异构体、多晶型物、溶剂合物(如水合物)、药学可接受的盐、酯、代谢物、N-氧化物、其化学保护的形式或前药，其中A选自
Figure PCTCN2018119715-appb-000009
以上基团通过1或2标记的两个位置之一与通式(I)中的环氮原子连接，并且另一位置与B基团连接。
在一些实施方案中，本发明提供化合物或者其立体异构体、互变异构体、多晶型物、溶剂合物(如水合物)、药学可接受的盐、酯、代谢物、N-氧化物、其化学保护的形式或前药，其中B选自苯基以及包含独立地选自N、O和S的1、2、3或4个杂原子的5至6元杂芳基；特别地，所述杂芳基选自吡啶基、嘧啶基、吡嗪基、哒嗪基、噻唑基、噻吩基、噁唑基、呋喃基、吡咯基、吡唑基、三唑基、四唑基、异噁唑基、异噻唑基、咪唑基、三嗪基、噁二唑基和噻二唑基；B优选自苯基、吡啶基、呋喃基、噻吩基和吡唑基。
在一些实施方案中，本发明提供化合物或者其立体异构体、互变异构体、多晶型物、溶剂合物(如水合物)、药学可接受的盐、酯、代谢物、N-氧化物、其化学保护的形式或前药，其中通式(I)中的
Figure PCTCN2018119715-appb-000010
基团为
Figure PCTCN2018119715-appb-000011
在一些实施方案中，本发明提供化合物或者其立体异构体、互变异构体、多晶型物、溶剂合物(如水合物)、药学可接受的盐、酯、代谢物、N-氧化物、其化学保护的形式或前药，其中D是
Figure PCTCN2018119715-appb-000012
优选是
Figure PCTCN2018119715-appb-000013
在一些实施方案中，本发明提供化合物或者其立体异构体、互变异构体、多晶型物、溶剂合物(如水合物)、药学可接受的盐、酯、代谢物、N-氧化物、其化学保护的形式或前药，其中所述C 1-6烷基选自甲基、乙基、正丙基、异丙基、正丁基、异丁基和叔丁基。
在一些实施方案中，本发明提供化合物或者其立体异构体、互变异构体、多晶型物、溶剂合物(如水合物)、药学可接受的盐、酯、代谢物、N-氧化物、其化学保护的形式或前药，其中所述卤素选自F、Cl、Br和I，优选地是F或Cl。
在一些实施方案中，本发明提供化合物或者其立体异构体、互变异构体、多晶型物、溶剂合物(如水合物)、药学可接受的盐、酯、代谢物、N-氧化物、其化学保护的形式或前药，其中所述卤代C 1- 6烷基选自CF 3、CHF 2、CH 2F、CCl 3和CH 2CF 3。
在优选实施方案中，R a为环丙基。
在优选的实施方案中，R b、R c和R d各自独立地选自氢、F、Cl、Br、I、CH 3、OCH 3、CF 3和OCF 3。
在优选的实施方案中，R 1和R 2各自独立地选自氢、F、Cl、Br、I、CH 3、CF 3和CH(CH 3) 2；优选地，R 1和R 2各自独立地选自氢、F、Cl、Br、I和CH 3。
在一些实施方案中，本发明提供化合物或者其立体异构体、互变异构体、多晶型物、溶剂合物(如水合物)、药学可接受的盐、酯、代谢物、N-氧化物、其化学保护的形式或前药，其中所述化合物是通式(Ia)、(Ib)、(Ic)或(Id)的化合物：
Figure PCTCN2018119715-appb-000014
在一些实施方案中，本发明提供化合物或者其立体异构体、互变异构体、多晶型物、溶剂合物(如水合物)、药学可接受的盐、酯、代谢物、N-氧化物、其化学保护的形式或前药，其中所述化合物选自：
Figure PCTCN2018119715-appb-000015
Figure PCTCN2018119715-appb-000016
Figure PCTCN2018119715-appb-000017
本发明的通式(I)的化合物可包含不对称中心或手性中心，因而可以不同的立体异构体形式存在。本发明化合物的所有立体异构体形式，包括但不限于其非对映异构体、对映异构体和阻转异构体以及它们的混合物例如外消旋混合物，意在构成本发明的一部分。
此外，本发明涵盖所有的非对映异构体，包括顺-反(几何)异构体和构象异构体。例如，若通式(I)的化合物包含双键或稠合环，则顺式和反式形式以及其混合物被涵盖在本发明的范围内。在本文所示的结构中，若未指明任何具体手性原子的立体化学，则所有的立体异构体被视为并被包含为本发明的化合物。若以表示具体构型的楔形实线或虚线指明立体化学，则如此指明和定义该立体异构体。
本发明的化合物可以非溶剂化的形式、以及用药学可接受的溶剂例如水、乙醇等溶剂化的形式存在，并且本发明意在涵盖溶剂化的和非溶剂化的形式。
本发明的化合物还可以不同的互变异构体形式存在，并且所有这样的形式都被涵盖在本发明的范围内。
还应理解，实施方案中的任意两个或更多个实施方案的组合也包括在本发明的范围内。
药物组合物
本发明另一方面提供药物组合物，其包含至少一种如上所述的本发明的通式(I)的化合物或者其 立体异构体、互变异构体、多晶型物、溶剂合物(如水合物)、药学可接受的盐、酯、代谢物、N-氧化物、其化学保护的形式或前药，以及一种或多种药学可接受的载体。在一些实施方案中，所述药物组合物还可包含一种或多种其他治疗剂，例如适于预防或治疗由FXR介导的疾病或病症的其他治疗剂。
本发明中“药学可接受的载体”是指与活性成分一同给药的稀释剂、辅剂、赋形剂或媒介物，并且其在合理的医学判断的范围内适于接触人类和/或其他动物的组织而没有过度的毒性、刺激、过敏反应或与合理的益处/风险比相应的其他问题或并发症。
在本发明的药物组合物中可使用的药学可接受的载体包括但不限于无菌液体，例如水和油，包括那些石油、动物、植物或合成来源的油，例如花生油、大豆油、矿物油、芝麻油等。当所述药物组合物通过静脉内给药时，水是示例性载体。还可以使用生理盐水和葡萄糖及甘油水溶液作为液体载体，特别是用于注射液。适合的药物赋形剂包括淀粉、葡萄糖、乳糖、蔗糖、明胶、麦芽糖、白垩、硅胶、硬脂酸钠、单硬脂酸甘油酯、滑石、氯化钠、脱脂奶粉、甘油、丙二醇、水、乙醇等。所述组合物还可以视需要包含少量的湿润剂、乳化剂或pH缓冲剂。口服制剂可以包含标准载体，如药物级的甘露醇、乳糖、淀粉、硬脂酸镁、糖精钠、纤维素、碳酸镁等。适合的药学可接受的载体的实例如在Remington’s Pharmaceutical Sciences(1990)中所述。
本发明的药物组合物可以系统地作用和/或局部地作用。为此目的，它们可以适合的途径给药，例如通过注射、静脉内、动脉内、皮下、腹膜内、肌内或经皮给药；或通过口服、含服、经鼻、透粘膜、局部、以眼用制剂的形式或通过吸入给药。
对于这些给药途径，可以适合的剂型给药本发明的药物组合物。
所述剂型包括但不限于片剂、胶囊剂、锭剂、硬糖剂、散剂、喷雾剂、乳膏剂、软膏剂、栓剂、凝胶剂、糊剂、洗剂、软膏剂、水性混悬剂、可注射溶液剂、酏剂、糖浆剂。
治疗用途
本发明的另一方面提供所述化合物和药物组合物的治疗用途。
因此，在一些实施方案中，本发明涉及预防或治疗由FXR介导的疾病或病症的方法，所述方法包括向有此需要的个体给药治疗有效量的至少一种本发明的通式(I)的化合物或者其立体异构体、互变异构体、多晶型物、溶剂合物(如水合物)、药学可接受的盐、酯、代谢物、N-氧化物、其化学保护的形式或前药，或者给药本发明的药物组合物。
在另一些实施方案中，本发明涉及至少一种本发明的通式(I)的化合物或者其立体异构体、互变异构体、多晶型物、溶剂合物(如水合物)、药学可接受的盐、酯、代谢物、N-氧化物、其化学保护的形式或前药、或者本发明的药物组合物在制备用于预防或治疗由FXR介导的疾病或病症的药物中的用途。
所述由FXR介导的疾病或病症包括但不限于：
慢性肝内或某些形式的肝外胆汁淤积性病症；肝纤维化；肝的梗阻性或慢性炎性病症；肝硬化；脂肪肝及并发症；与酒精引发的肝硬化或与病毒传染性形式的肝炎相关的胆汁淤积性和纤维变性效果；在部分肝切除术后的肝衰竭或肝缺血；化疗相关的脂肪性肝炎(CASH)；急性肝衰竭；
炎性肠道疾病、血脂异常、动脉粥样硬化、糖尿病和相关疾病；脂质和脂蛋白病症；II型糖尿病以及I型和II型糖尿病的临床并发症，包括糖尿病性肾病、糖尿病性神经病变、糖尿病性视网膜病、及临床上明显的长期糖尿病的其他观察到的效果；由于强迫的脂质、特别是甘油三酯蓄积以及随后的促纤维化途径激活而导致的慢性脂肪性和纤维性变性引起的病症和疾病，例如非酒精性脂肪肝病(NAFLD)或非酒精性脂肪性肝炎(NASH)；肥胖或代谢综合征(血脂障碍、糖尿病和体重指数异常高的合并病症)；
急性心肌梗塞、急性中风或作为慢性梗阻性动脉粥样硬化终点发生的血栓形成；非恶性过度增殖性病症和恶性过度增殖性病症，特别是肝细胞癌、结肠腺瘤和息肉病、结肠腺癌、乳腺癌、胰腺癌、巴特氏食管癌和胃肠道和肝脏的其他形式的肿瘤性疾病。
除非另外说明，本文中所使用的术语“治疗”意指逆转、减轻、抑制所指示的疾病或病症或者这样的疾病或病症的一或多种症状的进展，或预防这样的疾病或病症或者这样的疾病或病症的一或多种症状。
如本文所使用的“个体”包括人或非人动物。示例性人个体包括患有疾病(例如本文所述的疾病)的人个体(称为患者)或正常个体。本发明中“非人动物”包括所有脊椎动物，例如非哺乳动物(例如鸟类、两栖动物、爬行动物)和哺乳动物，例如非人灵长类、家畜和/或驯化动物(例如绵羊、犬、猫、奶牛、猪等)。
如本文中所使用的术语“治疗有效量”指被给药后会实现上述治疗效力的化合物的量。
可调整给药方案以提供最期望的应答。例如，可给药单次推注，可随时间给药数个分剂量，或可如治疗情况的急需所表明而按比例减少或增加剂量。要注意，剂量值可随要减轻的病况的类型及严重性而变化，且可包括单次或多次剂量。要进一步理解，对于任何特定个体，具体的给药方案应根据个体需要及给药组合物或监督组合物的给药的人员的专业判断来随时间调整。
所给药的本发明的化合物的量会取决于所治疗的个体、病症或病况的严重性、给药的速率、化合物的处置及处方医师的判断。一般而言，有效剂量在每日每kg体重约0.0001至约50mg，例如约0.01至约10mg/kg/日(单次或分次给药)。对70kg的人而言，这会合计为约0.007mg/日至约3500mg/日，例如约0.7mg/日至约700mg/日。在一些情况下，不高于前述范围的下限的剂量水平可以是足够的，而在其他情况下，仍可在不引起任何有害副作用的情况下采用较大剂量，条件是首先将所述较大剂量分成数个较小剂量以在一整天中给药。
本发明的化合物在所述药物组合物中的含量或用量可以是约0.01mg至约1000mg，适合地是0.1-500mg，优选0.5-300mg，更优选1-150mg等。
组合治疗
通式(I)的化合物可单独使用，或者与适于预防或治疗由FXR介导的疾病或病症的一种或多种其他治疗剂组合使用。在一些实施方案中，在所述药物组合物或者作为组合治疗的给药方案中，将通式(I)的化合物与例如具有抗过度增殖效力的其他治疗剂组合。所述其他治疗剂可以是例如化疗剂。所述药物组合物或给药方案的其他治疗剂优选地具有与通式(I)的化合物互补的活性，从而它们不会不利地相互影响。这样的化合物适合地以对预期目的有效的量组合存在。
组合治疗可以同时或依次给药的方案施用。当依次施用时，该组合可以在两次或多次给药中施用。组合给药包括使用分开的药物组合物或者包含通式(I)的化合物和其他治疗剂的单一药物组合物同时给药，以及以任意顺序相继地给药，其中优选存在两种(或所有)活性剂同时发挥它们的生物活性的时间段。
上述同时给药的药剂中的任一种的适合的剂量是当前使用的那些，并且由于新鉴定的药物与其他治疗剂或治疗的组合(协同)作用，可以降低。
组合治疗可提供“协同作用”并证明是“协同的”，即，活性成分在一起使用时所达到的效果大于分开使用所述化合物时所产生的效果之和。当所述活性成分：(1)在组合的单位剂量制剂中共同配制并同时给药或者递送时；(2)作为分开的制剂交替或平行地递送时；或者(3)通过一些其他方案时，可达到协同效果。当在交替疗法中递送时，当所述化合物例如通过在分开的注射器中分别注射、通过分开的丸剂或胶囊剂、或通过分开的输注依次给药或递送时，可达到协同效果。通常在交替疗法中，相继地，即连续地，给药有效剂量的各活性成分，而在组合治疗中，一起给药有效剂量的两种或多种活性成分。
在治疗的一个具体的实施方案中，通式(I)的化合物或者其立体异构体、互变异构体、多晶型物、溶剂合物(如水合物)、药学可接受的盐、酯、代谢物、N-氧化物、其化学保护的形式或前药可以与例如本文所述的那些其他治疗剂组合，还可与外科治疗和放疗组合。因此，本发明的组合治疗包括给药至少一种通式(I)的化合物或者其立体异构体、互变异构体、多晶型物、溶剂合物(如水合物)、药学可接受的盐、酯、代谢物、N-氧化物、其化学保护的形式或前药，以及使用至少一种其他治疗方法。为了达到期望的组合治疗效果，选择通式(I)的化合物和其他治疗剂的量以及给药的相对时机。
通式(I)的化合物的代谢物
本文所述的通式(I)的化合物的体内代谢物也在本发明的范围内。这样的产物可由例如被给药的化合物的氧化、还原、水解、酰胺化、脱酰胺化、酯化、酶解等产生。因此，本发明包括通式(I)的化合物的代谢物，包括通过使本发明的化合物与哺乳动物接触足以产生其代谢物的时间的方法制得的化合物。
代谢物通常通过制备本发明的放射性同位素(例如 14C或 3H)标记的化合物，将其以可检测的剂量(例如大于约0.5mg/kg)向动物例如大鼠、小鼠、天竺鼠、猴或人肠胃外给药，代谢足够的时间(通常约30秒至30小时)，然后从尿、血液或其他生物样品分离其转化产物进行鉴定。这些产物易于分离，因为它们是标记的(其他的通过使用能够结合代谢物中存余的表位的抗体进行分离)。代谢物结构以常规方法测定，例如通过MS、LC/MS或NMR分析。通过以与本领域技术人员公知的常规药物代谢研究相同的方式进行代谢物的分析。代谢物，只要未在体内发现它们，可用于诊断测定中，以治疗性给药本发明的化合物。
药盒
在本发明的另一些实施方案中，提供包含用于治疗上述疾病或病症的材料的“药盒”。所述药盒包括容器，所述容器包含作为第一治疗剂的通式(I)的化合物、其立体异构体、互变异构体、多晶型物、溶剂合物(如水合物)、药学可接受的盐、酯、代谢物、N-氧化物、或者其化学保护的形式或前药，或者包含作为第一药物组合物的本发明的药物组合物。在一些实施方案中，所述药盒还可包括在所述容器上或伴随所述容器的标签或包装说明书。术语“包装说明书”是指治疗产品的商业包装中通常包含的说明书，其包含使用该治疗产品相关的适应征、用法、剂量、给药、禁忌和/或警示的信息。适合的容器包括，例如，瓶、小瓶、注射器、泡罩包装等。所述容器可以由各种材料例如玻璃和塑料制成。所述容器可容纳对治疗病症有效的通式(I)的化合物或其制剂，并且可具有无菌入口(例如，所述容器可以是静脉内溶液剂袋或者具有可被皮下注射针刺穿的瓶塞的小瓶)。标签或包装说明书指明所述组合物用于治疗所选的病症例如癌症。此外，标签或包装说明书可指明要治疗的患者是患有诸如肝硬化、过度增殖性病症、动脉粥样硬化、I型糖尿病之类疾病或病症的患者标签或包装说明书还可指明所述组合物可用来治疗其他病症。在另一些实施方案中，所述药盒还包括第二容器，其包含作为第二治疗剂的适于预防或治疗由FXR介导的疾病或病症的至少一种其他治疗剂，或者作为第二药物组合物的包含所述其他治疗剂的药物组合物。因此，在一些实施方案中，所述药盒可包括给药所述第一治疗剂或第一药物组合物和所述第二治疗剂或第二药物组合物(若存在)的说明书。例如，若所述药盒包括含有通式(I)的化合物的第一组合物和包含其他治疗剂的第二药物组合物，则该药盒还可包括向有此需要的个体同时、相继或分开地给药所述第一药物组合物和第二药物组合物的说明书。替代地或者额外的，所述药盒还可包括第三容器，其包含药学可接受的缓冲剂例如抑菌的注射用水(BWFI)、磷酸盐缓冲盐水、林格氏液和葡萄糖溶液。所述药盒还可包括就商业和用户而言令人期望的其他材料，包括其他缓冲剂、稀释剂、填料、注射针和注射器。
在另一些实施方案中，所述药盒适合于递送通式(I)的化合物的固体口服形式例如片剂或胶囊剂。这样的药盒优选地包括多个单位剂量。这样的药盒可包括具有以它们的预期用途定位的剂量的卡片。这样的药盒的一个实例是“泡罩包装”。泡罩包装在包装工业中是公知的并且广泛用于包装药学单位剂量形式。若期望，可以例如指定在治疗时间表中可给药之日的数字、字母或其他标记或者日历插页的形式提供记忆辅助工具。
化合物的制备方法
在一些实施方案中，本发明提供制备本发明的通式(I)的化合物的方法，所述方法包括以下步骤：
Figure PCTCN2018119715-appb-000018
其中：
Hal 1、Hal 2和Hal 3各自独立地为相同或不同的卤素，例如F、Cl、Br或I，优选为Cl或Br；
PG 1为氨基保护基，优选为叔丁氧羰基(Boc)；
PG 2为羧基保护基，优选为C 1-6烷基，更优选为甲基；
Y为硼酸或硼酸酯基团，优选为-B(OH) 2或者
Figure PCTCN2018119715-appb-000019
其余基团如上文所定义；
各步骤的反应条件如下：
步骤A：使化合物IN-1与化合物IN-2反应以得到化合物IN-3；
所述反应优选在适合的有机溶剂中进行。所述有机溶剂可选自直链或环状醚类(例如四氢呋喃或乙醚等)、N-甲基吡咯烷酮、二甲基甲酰胺、二甲基乙酰胺、1，4-二氧六环、二甲基亚砜及其任意组合，优选四氢呋喃或二甲基甲酰胺。所述反应优选在适合的碱(例如碱金属的醇盐或碳酸盐)和/或催化剂的存在下进行。所述催化剂可以是包括冠醚的催化剂系统，所述冠醚可选自15-冠醚-5和18-冠醚-6；所述碱金属的碳酸盐为例如碳酸钾或碳酸铯；所述碱金属的醇盐可选自叔丁醇钠、叔丁醇钾、甲醇钠、甲醇钾、乙醇钠、乙醇钾。优选地，所述碱金属的醇盐和催化剂是叔丁醇钠和/或叔丁醇钾与15-冠醚-5和/或18-冠醚-6的组合，优选叔丁醇钠与15-冠醚-5的组合或叔丁醇钾与18-冠醚-6的组合。所述反应优选在适合的温度下进行。所述温度优选为室温(20-30℃)或50-100℃(例如50-80℃)。所述反应优选进行合适的时间，例如1-24小时，例如5-15小时。
步骤B：移除化合物IN-3中的PG 1基团，以得到化合物IN-4；
所述反应优选在适合的有机溶剂中进行。所述有机溶剂可选自卤代烃类(例如，二氯甲烷、氯仿、氯乙烷、二氯乙烷、三氯乙烷)、二甲基甲酰胺、二甲基乙酰胺及其任意组合，优选二氯甲烷。所述反应可在酸性条件下进行，例如在1，4-二氧六环中的氯化氢溶液；或者合适的有机酸(例如羧酸或卤代酸，包括但不限于甲酸、氟乙酸、二氟乙酸、三氟乙酸、氯乙酸、二氯乙酸、三氯乙酸及其组合，优选三氟乙酸)的存在下进行。所述反应优选在适合的温度下进行。所述温度优选为室温(20-30℃)。所述反应优选进行合适的时间，例如1-5小时或6-15小时，例如2小时、4小时或过夜反应。
步骤C-1：使化合物IN-4与化合物IN-a反应以得到化合物IN-5；
在一些实施方案中，使化合物IN-4与化合物IN-a发生取代反应以得到化合物IN-5。所述取代反应优选在适合的有机溶剂中进行。所述有机溶剂可选自二甲基甲酰胺、二甲基乙酰胺、四氢呋喃、N-甲基吡咯烷酮、二甲基亚砜及其任意组合，优选二甲基甲酰胺或二甲基乙酰胺。所述取代反应优选在适合的碱的存在下进行。优选地，所述碱是有机碱(例如有机胺类如三乙胺、N，N-二异丙基乙胺、N-甲基吗啉或吡啶，优选三乙胺或N，N-二异丙基乙胺)或无机碱(例如碱金属盐，优选碳酸钾)。所述取代反应优选在适合的温度下进行。所述温度可以是20-150℃，例如30-140℃，优选25℃、50℃、100℃或130℃，优选80℃。所述取代反应优选进行合适的时间，例如2-24小时、2-18小时或2-12小时，例如5、8或10小时。
在另一些实施方案中，使化合物IN-4与化合物IN-a发生偶联反应以得到化合物IN-5。所述偶联反应优选在金属催化剂和碱的存在下进行。优选地，所述金属催化剂是钯金属催化剂，例如三(二亚苄基丙酮)二钯、[1，1′-双(二苯基膦基)二茂铁]二氯化钯、三苯基膦钯、醋酸钯，优选三(二亚苄基丙酮)二钯。所述碱是无机碱，例如碳酸钾、碳酸铯、碳酸钠、碳酸氢钠、碳酸氢钾，优选碳酸铯。优选地，所述偶联反应在衍生自联苯的有机磷化合物的存在下进行，所述有机磷化合物选自BINAP、RuPhos和XPhos，优选BINAP。优选地，所述偶联反应在适合的有机溶剂中进行，所述有机溶剂可选自苯、甲苯和二甲苯，例如是甲苯。优选地，所述偶联反应在适合的保护气氛(例如氮气环境)下进行。优选地，所述偶联反应在适合的温度下进行，所述温度可以是70-100℃，优选80℃。优选地，所述偶联反应进行合适的时间，例如1-3小时，例如2小时。
步骤D-1：使化合物IN-5与化合物IN-b反应以得到化合物IN-6；
优选地，使化合物IN-5与化合物IN-b发生金属催化偶联反应得到化合物IN-6。所述金属催化偶联反应采用常规的方法进行。例如：化合物IN-5与化合物IN-b在溶剂(例如水、有机溶剂、或者有机溶剂与水的混合溶剂)中溶解，加入钯催化剂和碱，任选地在氮气保护下，在50℃到120℃的温度(优选80℃或90℃)下反应8到24小时(优选8小时或12小时)。所述有机溶剂为二甲基甲酰胺、四氢呋喃、1，4-二氧六环、甲苯或DME等。所述钯催化剂为三(二亚苄基丙酮)二钯、[1，1′-双(二苯基膦基)二茂铁]二氯化钯、三苯基膦钯、醋酸钯，优选[1，1′-双(二苯基膦基)二茂铁]二氯化钯或三(二亚苄基丙酮)二钯等。所述碱优选是无机碱，例如碳酸钾、碳酸铯、碳酸钠、碳酸氢钠或碳酸氢钾等。
步骤E-1：移除化合物IN-6中的PG 2基团，以得到通式(I)的化合物；
所述反应优选在适合的有机溶剂(所述有机溶剂可选自直链或环状醚类(例如四氢呋喃或乙醚等)、N-甲基吡咯烷酮、二甲基甲酰胺、二甲基乙酰胺、1，4-二氧六环、二甲基亚砜及其任意组合，优选四氢呋喃)中进行。所述反应优选在醇或水以及碱的存在下进行。所述醇可以是例如甲醇或乙醇。所述碱可以选自碱金属氢氧化物，所述碱金属氢氧化物可以选自氢氧化锂、氢氧化钠和氢氧化钾。所述反应优选在适合的温度下进行。所述温度可以是室温至80℃，例如25℃或40-60℃。所述反应优选进行合适的时间，例如2-5小时或6-15小时，例如2、3或4小时或过夜。
在另一些实施方案中，本发明提供制备本发明的通式(I)的化合物的方法，所述方法包括以下步骤：
Figure PCTCN2018119715-appb-000020
其中各基团如上文所定义；
各步骤的反应条件如下：
步骤A：使化合物IN-1与化合物IN-2反应以得到化合物IN-3；
所述反应优选在适合的有机溶剂中进行。所述有机溶剂可选自直链或环状醚类(例如四氢呋喃或乙醚等)、N-甲基吡咯烷酮、二甲基甲酰胺、二甲基乙酰胺、1，4-二氧六环、二甲基亚砜及其任意组合，优选四氢呋喃或二甲基甲酰胺。所述反应优选在适合的碱(例如碱金属的醇盐或碳酸盐)和/或催化剂的存在下进行。所述催化剂可以是包括冠醚的催化剂系统，所述冠醚可选自15-冠醚-5和18-冠醚-6；所述碱金属的碳酸盐为例如碳酸钾或碳酸铯；所述碱金属的醇盐可选自叔丁醇钠、叔丁醇钾、甲醇钠、甲醇钾、乙醇钠、乙醇钾。优选地，所述碱金属的醇盐和催化剂是叔丁醇钠和/或叔丁醇钾与15-冠醚-5和/或18-冠醚-6的组合，优选叔丁醇钠与15-冠醚-5的组合或叔丁醇钾与18-冠醚-6的组合。所述反应优选在适合的温度下进行。所述温度优选为室温(20-30℃)或50-100℃(例如50-80℃)。所述反应优选进行合适的时间，例如1-24小时，例如5-15小时。
步骤B：移除化合物IN-3中的PG 1基团，以得到化合物IN-4；
所述反应优选在适合的有机溶剂中进行。所述有机溶剂可选自卤代烃类(例如，二氯甲烷、氯仿、氯乙烷、二氯乙烷、三氯乙烷)、二甲基甲酰胺、二甲基乙酰胺及其任意组合，优选二氯甲烷。所述反应可在酸性条件下进行，例如在1，4-二氧六环中的氯化氢溶液；或者是合适的有机酸(例如羧酸或卤代酸，包括但不限于甲酸、氟乙酸、二氟乙酸、三氟乙酸、氯乙酸、二氯乙酸、三氯乙酸及其组合，优选三氟乙酸)的存在下进行。所述反应优选在适合的温度下进行。所述温度优选为室温(20-30℃)。所述反应优选进行合适的时间，例如1-5小时或6-15小时，例如2小时、4小时或过夜反应。
步骤C-2：使化合物IN-4与化合物IN-c反应以得到化合物IN-6；
所述反应优选在金属催化剂和碱的存在下进行。优选地，所述金属催化剂是钯金属催化剂，例如三(二亚苄基丙酮)二钯、[1，1′-双(二苯基膦基)二茂铁]二氯化钯、三苯基膦钯、醋酸钯，优选三(二亚苄基丙酮)二钯。所述碱是无机碱，例如碳酸钾、碳酸铯、碳酸钠、碳酸氢钠、碳酸氢钾，优选碳酸铯。优选地，所述偶联反应在衍生自联苯的有机磷化合物的存在下进行，所述有机磷化合物选自BINAP、RuPhos和XPhos，优选BINAP。优选地，所述偶联反应在适合的有机溶剂中进行，所述有机溶剂可选自苯、甲苯和二甲苯，例如是甲苯。任选地，所述偶联反应在适合的保护气氛(例如氮气环境)下进行。优选地，所述偶联反应在适合的温度下进行，所述温度可以是例如50-100℃，优选80℃。优选地，所述偶联反应进行合适的时间，例如1-24小时，例如5-15小时。
步骤D-2：移除化合物IN-6中的PG 2基团，以得到通式(I)的化合物；
所述反应优选在适合的有机溶剂(所述有机溶剂可选自直链或环状醚类(例如四氢呋喃或乙醚等)、N-甲基吡咯烷酮、二甲基甲酰胺、二甲基乙酰胺、1，4-二氧六环、二甲基亚砜及其任意组合，优选四氢呋喃)中进行。所述反应优选在醇和碱的存在下进行。所述醇可以是例如甲醇或乙醇。所述碱可以选自碱金属氢氧化物，所述碱金属氢氧化物可以选自氢氧化锂、氢氧化钠和氢氧化钾。所述反应优选在适合的温度下进行。所述温度可以是室温至80℃，例如40-60℃。所述反应优选进行合适的时间，例如2-5小时，例如2、3或4小时。
在另一些实施方案中，本发明提供通式(IN-6)的化合物或其药学上可接受的盐，
Figure PCTCN2018119715-appb-000021
其中各基团如上述所定义；
所述化合物优选自：
Figure PCTCN2018119715-appb-000022
本文所用的术语“适合的”意指对具体化合物或条件的选择会取决于所要进行的特定合成操作以及所要转化的一个或多个分子的特性，但该选择在本领域技术人员的能力范围内。本文所述的所有工艺/方法的步骤均在足以提供所示产物的条件下进行。本领域技术人员会理解，可以改变所有反应条件(包括例如反应溶剂、反应时间、反应温度以及反应是否应在无水或惰性气氛下进行，等等)以优化期望的产物的收率，且这些变化在本领域技术人员的能力范围内。
实施例提供制备通式(I)的化合物的示例性方法。本领域技术人员会理解，其他合成路线可用来合成通式(I)的化合物。虽然在实施例中描述和讨论了具体的原料和试剂，但是可替换成其他原料和试剂以提供各种衍生物和/或反应条件。此外，还可参考本公开，利用本领域技术人员公知的常规化学对通过所述方法制得的许多实施例化合物进一步进行修饰。
在制备通式(I)的化合物时，可能需要保护中间体的远端官能团(例如羧基或氨基)。对这种保护的需要可随着远端官能团的性质以及制备方法的条件而改变。本领域技术人员容易地确定这样保护的必要性。关于保护基的概述及它们的用途，参见T.W.Greene，Protective Groups in Organic Synthesis，John Wiley&Sons，New York，1991。
实施例
以下结合实施例进一步描述本发明，但提供这些实施例并非意在限制本发明的范围。
化合物的结构是通过核磁共振( 1H-NMR)或质谱(MS)来确定的。 1H-NMR位移(δ)以百万分之一(ppm)的单位给出。化学位移是以10 -6(ppm)作为单位给出。
MS的测定是使用Agilent(ESI)质谱仪。
制备高效液相使用岛津制备高效液相色谱仪。
薄层色谱硅胶板(TLC)使用Merck产的铝板(20×20cm)，薄层色谱法分离纯化采用的是GF 254(0.4～0.5mm)。
反应的监测采用薄层色谱法(TLC)或LC-MS，使用的展开剂体系有：二氯甲烷和甲醇体系、正己烷和乙酸乙酯体系或者石油醚和乙酸乙酯体系。根据化合物的极性不同，需要调节溶剂的体积比，或者需要进一步加入三乙胺等，以实现产物的分离纯化。
微波反应使用
Figure PCTCN2018119715-appb-000023
Initiator+(400W，RT～300℃)微波反应器。
柱色谱法一般使用200～300目硅胶为载体。洗脱剂的体系包括：二氯甲烷和甲醇体系，正己烷和乙酸乙酯体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺进行调节。
除非特别指出，实施例的反应温度为室温(20℃～30℃)。
本发明所使用的试剂购自Acros Organics、Aldrich Chemical Company、上海特伯化学科技有限公司等。
在常规的合成法以及实施例和中间体制备例中，各缩写具有以下含义。
Figure PCTCN2018119715-appb-000024
中间体制备例：
中间体制备例1：4-(((1-(4-溴噻唑-2-基)哌啶-4-基)氧基)甲基)-5-环丙基-3-(2，6-二氯苯基)异噁唑(T1)的制备
Figure PCTCN2018119715-appb-000025
第一步：4-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)哌啶-1-甲酸叔丁酯(T1-b)的制备
将N-Boc-4-羟基哌啶(1.0g，4.95mmol)溶于干燥的四氢呋喃(20mL)，加入叔丁醇钾(0.54g，5.61mmol)搅拌30分钟，加入18-冠醚-6(1.5g，5.61mmol)和4-(氯甲基)-5-环丙基-3-(2，6-二氯苯基)异噁 唑(T1-a)(1.0g，3.31mmol)。在室温下搅拌过夜，直至TLC显示原料反应完全。向混合物加入水和乙酸乙酯，将有机层用水洗，干燥，浓缩，残余物通过硅胶柱色谱法纯化得到本步的标题化合物(1.2g，收率：78％)。
第二步：5-环丙基-3-(2，6-二氯苯基)-4-((哌啶-4-基氧基)甲基)异噁唑(T1-c)的制备
将化合物(T1-b)(1.1g，2.36mmol)溶于二氯甲烷(20mL)，加入三氟乙酸(5mL)。将反应物在室温下搅拌2小时，直至TLC显示原料反应完全，将混合物浓缩，残余物加入冰水中，用饱和碳酸钠调节pH至碱性，用乙酸乙酯萃取，将有机层用水洗，干燥，浓缩得到本步的标题化合物，所得化合物无需纯化直接用于下一步反应。
第三步：4-(((1-(4-溴噻唑-2-基)哌啶-4-基)氧基)甲基)-5-环丙基-3-(2，6-二氯苯基)异噁唑(T1)的制备
将化合物(T1-c)(500mg，1.37mmol)溶于干燥的DMF(10mL)中，加入三乙胺(0.4mL，3mmol)和2，4-二溴噻唑(398mg，1.64mmol)。将混合物在80℃下搅拌过夜，直至TLC显示原料反应完全。向混合物加入水和乙酸乙酯，将有机层用水洗，干燥，浓缩，将残余物通过硅胶柱色谱法纯化得到标题化合物(300mg，收率：42％)。
中间体制备例2：5-(4-溴苯基)-1-甲基-1H-吡唑-3-甲酸甲酯(T2-1)和3-(4-溴苯基)-1-甲基-1H-吡唑-5-甲酸甲酯(T2-2)的制备
Figure PCTCN2018119715-appb-000026
第一步：4-(4-溴苯基)-2，4-二氧代丁酸甲酯(T2-b)的制备
将1-(4-溴苯基)乙酮(T2-a)(1.0g，5mmol)溶于干燥的四氢呋喃(20mL)，加入氢化钠(0.24g，6mmol)搅拌30分钟，加入草酸二甲酯(0.65g，5.5mmol)。将反应物在70℃下搅拌过夜，冷却，向混合物加入水和乙酸乙酯，将有机层用水洗，干燥，浓缩，将残余物通过硅胶柱色谱法纯化得到本步的标题化合物(1.2g，收率：86％)。
第二步：5-(4-溴苯基)-1-甲基-1H-吡唑-3-甲酸甲酯(T2-1)和3-(4-溴苯基)-1-甲基-1H-吡唑-5-甲酸甲酯(T2-2)的制备
将化合物(T2-b)(1.4g，4.93mmol)溶于乙醇(30mL)，加入甲基肼(5mL)。将反应物在80℃搅拌过夜，直至TLC显示原料反应完全。将混合物冷却，然后向其中加入水和乙酸乙酯，将有机层用水洗，干燥，浓缩，将残余物通过硅胶柱色谱法纯化得到化合物(T2-1)(300mg，收率：20％)和化合物(T2-2)(250mg，收率：17％)。
中间体制备例3：5-(3-溴苯基)-1-甲基-1H-吡唑-3-甲酸甲酯(T3-1)和3-(3-溴苯基)-1-甲基-1H-吡唑-5-甲酸甲酯(T3-2)的制备
Figure PCTCN2018119715-appb-000027
除在第一步中以1-(3-溴苯基)乙酮(T3-a)代替化合物(T2-a)之外，以中间体制备例2所述的方法合成化合物(T3-1)(200mg，收率：13％)和化合物(T3-2)(230mg，收率：15％)。
中间体制备例4：4-((((1R，3r，5S)-8-(4-溴噻唑-2-基)-8-氮杂双环[3.2.1]辛-3-基)氧基)甲基)-5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑(T4)的制备
Figure PCTCN2018119715-appb-000028
第一步：(E)-2-(三氟甲氧基)苯甲醛肟(T4-b)的制备
将2-(三氟甲氧基)苯甲醛(T4-a)(150g，788.98mmol)溶于乙醇(1000mL)和水(1000mL)的混合溶剂中，机械搅拌下加入盐酸羟胺(65.79g，946.77mmol)，有白色固体析出，继续加入1M的氢氧化钠水溶液(789mL，788.98mmol)。将反应物在25℃下反应2小时，向混合物加入1M的盐酸(2000mL)调节体系pH为5左右，直接进行抽滤，50℃下烘干过夜，得到化合物(T4-b)(150g，收率：92％)。
第二步：(Z)-N-羟基-2-(三氟甲氧基)亚胺苄基氯(T4-c)的制备
将化合物(T4-b)(150g，731.23mmol)溶于DMF(1000mL)，在0℃机械搅拌下加入N-氯代丁二酰亚胺(117.17g，877.48mmol)，0℃反应1小时。向反应物中加入水(2000mL)，随后用乙酸乙酯(1000mL×3)萃取。将有机层用无水硫酸钠(500g)干燥，过滤浓缩后得到化合物(T4-c)(160g，收率：91％)。
第三步：5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-甲酸甲酯(T4-d)的制备
将3-环丙基-3-氧代丙酸甲酯(189.87g，1.34mol)加入化合物(T4-c)(160g，667.84mmol)中，反应物在-5℃搅拌，滴加三乙胺(500mL)，-5℃反应过夜。将反应液倒入水(20L)中，机械搅拌30分钟，有固体出现，抽滤得到黄色固体，50℃下烘干过夜，得到化合物(T4-d)(120g，收率：55％)。
第四步：(5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲醇(T4-e)的制备
将化合物(T4-d)(120g，366.69mmol)溶于甲苯中，反应物在-10℃搅拌，滴加2M的二异丁基氢化铝(550mL，1.10mol)，室温反应过夜。将反应液倒入加有冰块的甲醇(1000mL)中，机械搅拌下，加入水(3000mL)，进行抽滤，得到黄色固体，滤液用乙酸乙酯(2000mL×3)萃取，无水硫酸钠(500g)干燥，过滤，旋干有机相得到化合物(T4-e)(100g，收率：91％)。
第五步：4-(氯甲基)-5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑(T4-f)的制备
将苯并三氮唑(59.65g，500.74mmol)溶于二氯甲烷中，反应物在-5℃搅拌，滴加二氯亚砜(59.65g，501.39mmol)，室温搅拌半小时后，加入化合物(T4-e)(100g，334.17mmol)的二氯甲烷溶液(500mL)，室温反应6小时。将反应液进行抽滤，滤液旋干得到化合物(T4-f)(106g，收率：94％)。
第六步：(1R，3r，5S)-3-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯(T4-g)的制备
将化合物(T4-f)(74.77g，328.94mmol)溶于四氢呋喃(500mL)中，随后加入18-冠醚-6(118.56g，448.55mmol)。反应物在0℃搅拌，加入叔丁醇钾(50.33g，448.55mmol)，随后移至室温搅拌，加入(1R，3r，5S)-3-羟基-8-氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯(95g，299.03mmol)，室温反应过夜。将反应液旋干，残余物加入乙酸乙酯(1500mL)和水(1500mL)，有机相用饱和食盐水(1500mL)洗两次，有机相浓缩后，经硅胶柱色谱法纯化(洗脱剂：石油醚/乙酸乙酯＝10/1-5/1)得到化合物(T4-g)(85g，收率：56％)。
第七步：4-(((1R，3r，5S)-8-氮杂双环[3.2.1]辛-3-基氧基)甲基)-5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑(T4-h)的制备
将化合物(T4-g)(85g，167.15mmol)溶于二氯甲烷的溶液(500mL)中，随后加入盐酸二氧六环溶液(4M，500mL)。室温反应过夜。将反应液旋干得到化合物(T4-h)(60g，收率：81％)。
第八步：4-((((1R，3r，5S)-8-(4-溴噻唑-2-基)-8-氮杂双环[3.2.1]辛-3-基)氧基)甲基)-5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑(T4)的制备
将化合物(T4-h)(7g，15.73mmol)溶于DMF(50mL)中，随后加入N，N-二异丙基乙胺(10.17g，78.67mmol)和2，4-二溴噻唑(4.59g，18.88mmol)，100℃反应12小时。反应液加水(300mL)，用乙酸乙酯(1000mL)，无水硫酸钠(20g)干燥，过滤，有机相浓缩后，经硅胶柱色谱法纯化(洗脱剂：石油醚/乙酸乙酯＝10/1-6/1)得到化合物(T4)(2.8g，收率：31％)。
实施例1：3-(2-(4-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)哌啶-1-基)噻唑-4-基)苯甲酸(C1)的制备
Figure PCTCN2018119715-appb-000029
第一步：3-(2-(4-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)哌啶-1-基)噻唑-4-基)苯甲酸甲酯(C1-a)的制备
将化合物(T1)(100mg，0.19mmol)和(3-(甲氧基羰基)苯基)硼酸(51mg，0.28mmol)溶于DME(2 mL)中，加入2N的碳酸钠水溶液(0.14mL)和Pd(dppf)Cl 2(13.9mg，0.019mmol)，并在80℃下反应12小时。然后向反应物中加入水，用乙酸乙酯萃取3次，将有机相合并，用饱和食盐水洗，无水硫酸钠干燥，过滤，将浓缩残渣用硅胶柱色谱法纯化得到本步的标题化合物(50mg，收率：45％)。
MS m/z(ESI)：584.1[M+H] +。
1H-NMR(400MHz，DMSO-d 6)δ：7.97-7.92(m，4H)，7.66-7.60(m，2H)，7.55-7.47(m，1H)，7.41(s，1H)，4.33(s，2H)，3.89(s，3H)，3.50-3.39(m，2H)，3.29-3.17(m，2H)，2.39-2.32(m，2H)，1.78-1.69(m，2H)，1.44-1.37(m，1H)，1.25-1.23(m，1H)，1.19-1.05(m，4H)。
第二步：3-(2-(4-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)哌啶-1-基)噻唑-4-基)苯甲酸(C1)的制备
将化合物(C1-a)(20mg，0.034mmol)溶于甲醇(2mL)和四氢呋喃(1mL)，加入氢氧化钠水溶液(2.74mg，0.068mmol)，并在室温下反应2小时。然后去除有机溶剂，将剩余的水相用2N的盐酸调节pH至酸性，然后用乙酸乙酯萃取，浓缩有机相，通过制备薄层色谱法纯化，得到标题化合物(15mg，收率：78.9％)。
MS m/z(ESI)：570.2[M+H] +。
1H-NMR(400MHz，DMSO-d 6)δ：12.91(s，1H)，7.97-7.92(m，4H)，7.66-7.60(m，2H)，7.55-7.47(m，1H)，7.41(s，1H)，4.33(s，2H)，3.50-3.39(m，2H)，3.29-3.17(m，2H)，2.39-2.32(m，2H)，1.78-1.69(m，2H)，1.44-1.37(m，1H)，1.25-1.23(m，1H)，1.19-1.05(m，4H)。
实施例2：4-(2-(4-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)哌啶-1-基)噻唑-4-基)苯甲酸(C2)的制备
Figure PCTCN2018119715-appb-000030
第一步：4-(2-(4-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)哌啶-1-基)噻唑)-4-基)苯甲酸甲酯(C2-a)的制备
除以(4-(甲氧基羰基)苯基)硼酸代替化合物(3-(甲氧基羰基)苯基)硼酸之外，以实施例1第一步所述的方法合成化合物(C2-a)(45mg，收率：40.5％)。
MS m/z(ESI)：584.2[M+H] +。
1H-NMR(400MHz，DMSO-d 6)δ：8.39(s，1H)，8.05-8.06(m，1H)，7.86-7.84(m，1H)，7.62-7.60(m，2H)，7.54-7.48(m，2H)，7.36(s，1H)，4.33(s，2H)，3.89(s，3H)，3.49-3.39(m，3H)，3.25-3.19(m，2H)，2.39-2.32(m，2H)，1.76-1.67(m，2H)，1.45-1.35(m，1H)，1.16-1.08(m，4H)。
第二步：4-(2-(4-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)哌啶-1-基)噻唑-4-基)苯甲酸(C2)的制备
除以化合物(C2-a)代替化合物(C1-a)之外，以实施例1第二步所述的方法合成标题化合物(30mg，收率：68.5％)。
MS m/z(ESI)：570.1[M+H] +。
1H-NMR(400MHz，DMSO-d 6)δ：13.02(s，1H)，8.39(s，1H)，8.05-8.06(m，1H)，7.86-7.84(m，1H)，7.62-7.60(m，2H)，7.54-7.48(m，2H)，7.36(s，1H)，4.33(s，2H)，3.49-3.39(m，3H)，3.25-3.19(m，2H)，2.39-2.32(m，2H)，1.76-1.67(m，2H)，1.45-1.35(m，1H)，1.16-1.08(m，4H)。
实施例3：5-(4-(4-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)哌啶-1-基)苯基)-1-甲基-1H-吡唑-3-甲酸(C3)的制备
Figure PCTCN2018119715-appb-000031
第一步：5-(4-(4-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)哌啶-1-基)苯基)-1-甲基-1H-吡唑-3-甲酸甲酯(C3-a)的制备
将化合物(T2-1)(98.8mg，0.34mmol)和化合物(T1-c)(103mg，0.28mmol)溶于甲苯(2mL)，加入碳酸铯(136.9mg，0.42mmol)、Pd2(dba)3(1.61mg，0.0028mmol)和BINAP(1.74mg，0.0028mmol)，并在80℃下反应过夜。然后向反应物中加入水，用乙酸乙酯萃取3次，将有机相合并用饱和食盐水洗，无水硫酸钠干燥，过滤，浓缩，将残渣用硅胶柱色谱法纯化得到本步的标题化合物(15mg，收率： 9.3％)。
MS m/z(ESI)：581.2[M+H] +。
1H-NMR(400MHz，DMSO-d 6)δ：7.61-7.58(m，4H)，7.53-7.50(s，1H)，6.94(s，1H)，6.88-6.86(m，2H)，4.30(s，2H)，4.06(s，3H)，3.87(s，3H)，3.27-3.23(m，3H)，2.84-2.80(m，2H)，2.34-2.32(m，1H)，1.72-1.68(m，2H)，1.35-1.33(m，2H)，1.16-1.09(m，4H)。
第二步：5-(4-(4-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)哌啶-1-基)苯基)-1-甲基-1H-吡唑-3-甲酸(C3)的制备
将化合物(C3-a)(15mg，0.026mmol)溶于甲醇(1mL)和四氢呋喃(0.5mL)，加入氢氧化钠水溶液(2.07mg，0.52mmol)，并在室温下反应2小时。然后去除有机溶剂，将剩余的水相用2N的盐酸调节pH至酸性，然后用乙酸乙酯萃取，浓缩有机相，通过制备薄层色谱板纯化，得到标题化合物(2mg，收率：13.6％)。
MS m/z(ESI)：567.1[M+H] +。
1H-NMR(400MHz，DMSO-d 6)δ：12.92(s，1H)，7.61-7.58(m，4H)，7.53-7.50(s，1H)，6.94(s，1H)，6.88-6.86(m，2H)，4.30(s，2H)，4.06(s，3H)，3.27-3.23(m，3H)，2.84-2.80(m，2H)，2.34-2.32(m，1H)，1.72-1.68(m，2H)，1.35-1.33(m，2H)，1.16-1.09(m，4H)。
实施例4：3-(4-(4-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)哌啶-1-基)苯基)-1-甲基-1H-吡唑-5-甲酸(C4)的制备
Figure PCTCN2018119715-appb-000032
第一步：3-(4-(4-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)哌啶-1-基)苯基)-1-甲基-1H-吡唑-5-甲酸甲酯(C4-a)的制备
除以化合物(T2-2)代替化合物(T2-1)之外，以实施例3第一步所述的方法合成本步的标题化合物(30mg，收率：15.2％)。
MS m/z(ESI)：581.2[M+H] +。
1H-NMR(400MHz，DMSO-d 6)δ：7.62-7.59(m，4H)，7.54-7.50(s，1H)，6.94(s，1H)，6.88-6.86(m，2H)，4.31(s，2H)，4.11(s，3H)，3.87(s，3H)，3.27-3.23(m，3H)，2.84-2.80(m，2H)，2.34-2.32(m，1H)，1.72-1.68(m，2H)，1.35-1.33(m，2H)，1.16-1.09(m，4H)。
第二步：3-(4-(4-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)哌啶-1-基)苯基)-1-甲基-1H-吡唑-5-甲酸(C4)的制备
除以化合物(C4-a)代替化合物(C3-a)之外，以实施例3第二步所述的方法合成标题化合物(15mg，收率：51％)。
MS m/z(ESI)：567.1[M+H] +。
1H-NMR(400MHz，DMSO-d 6)δ：12.90(s，1H)，7.62-7.59(m，4H)，7.54-7.50(s，1H)，6.94(s，1H)，6.88-6.86(m，2H)，4.31(s，2H)，4.10(s，3H)，3.27-3.23(m，3H)，2.84-2.80(m，2H)，2.34-2.32(m，1H)，1.72-1.68(m，2H)，1.35-1.33(m，2H)，1.16-1.09(m，4H)。
实施例5：3-(3-(4-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)哌啶-1-基)苯基)-1-甲基-1H-吡唑-5-甲酸(C5)的制备
Figure PCTCN2018119715-appb-000033
第一步：3-(3-(4-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)哌啶-1-基)苯基)-1-甲基-1H-吡唑-5-甲酸甲酯(C5-a)的制备
除以化合物(T3-2)代替化合物(T2-1)之外，以实施例3第一步所述的方法合成标题化合物(50mg，收率：25.4％)。
MS m/z(ESI)：581.2[M+H] +。
1H-NMR(400MHz，DMSO-d 6)δ：7.62-7.59(m，2H)，7.53-7.51(s，1H)，7.30-7.26(m，2H)，7.21-7.19(m，2H)，6.87-6.85(m，1H)，4.31(s，2H)，4.11(s，3H)，3.87(s，3H)，3.61-3.58(m，1H)，3.29-3.25(m，2H)，2.86-2.80(m，2H)，2.37-2.31(m，1H)，1.77-1.70(m，3H)，1.16-1.09(m，5H)。
第二步：3-(3-(4-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)哌啶-1-基)苯基)-1-甲基-1H-吡唑-5-甲酸(C5)的制备
除以化合物(C5-a)代替化合物(C3-a)之外，以实施例3第二步所述的方法合成标题化合物(40mg，收率：82.1％)。
MS m/z(ESI)：567.1[M+H] +。
1H-NMR(400MHz，DMSO-d 6)δ：12.90(s，1H)，7.62-7.59(m，2H)，7.53-7.51(s，1H)，7.30-7.26(m，2H)，7.21-7.19(m，2H)，6.87-6.85(m，1H)，4.31(s，2H)，4.11(s，3H)，3.61-3.58(m，1H)，3.29-3.25(m，2H)，2.86-2.80(m，2H)，2.37-2.31(m，1H)，1.77-1.70(m，3H)，1.16-1.09(m，5H)。
实施例6：5-(3-(4-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)哌啶-1-基)苯基)-1-甲基-1H-吡唑-3-甲酸(C6)的制备
Figure PCTCN2018119715-appb-000034
第一步：5-(3-(4-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)哌啶-1-基)苯基)-1-甲基-1H-吡唑-3-甲酸甲酯(C6-a)的制备
除以化合物(T3-1)代替化合物(T2-1)之外，以实施例3第一步所述的方法合成本步的标题化合物(10mg，收率：5.1％)。
MS m/z(ESI)：581.2[M+H] +。
1H-NMR(400MHz，DMSO-d 6)δ：7.63-7.59(m，2H)，7.52-7.51(s，1H)，7.30-7.26(m，2H)，7.21-7.19(m，2H)，6.87-6.85(m，1H)，4.31(s，2H)，4.08(s，3H)，3.89(s，3H)，3.61-3.58(m，1H)，3.29-3.25(m，2H)，2.86-2.80(m，2H)，2.37-2.31(m，1H)，1.77-1.70(m，3H)，1.16-1.09(m，5H)。
第二步：5-(3-(4-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)哌啶-1-基)苯基)-1-甲基-1H-吡唑-3-甲酸(C6)的制备
除以化合物(C6-a)代替化合物(C3-a)之外，以实施例3第二步所述的方法合成标题化合物(5mg，收率：52.1％)。
MS m/z(ESI)：567.1[M+H] +。
1H-NMR(400MHz，DMSO-d 6)δ：12.89(s，1H)，7.63-7.59(m，2H)，7.52-7.51(s，1H)，7.30-7.26(m，2H)，7.21-7.19(m，2H)，6.87-6.85(m，1H)，4.31(s，2H)，4.08(s，3H)，3.61-3.58(m，1H)，3.29-3.25(m，2H)，2.86-2.80(m，2H)，2.37-2.31(m，1H)，1.77-1.70(m，3H)，1.16-1.09(m，5H)。
实施例7：4-(2-((1R，3r，5S)-3-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛-8-基)噻唑-4-基)-3-甲基苯甲酸(C37)的制备
Figure PCTCN2018119715-appb-000035
第一步：(1R，3r，5S)-3-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯(C37-a)的制备
室温下，将化合物(T1-a)(1.0g，3.33mmol)溶于DMF(20mL)中，待溶解完全后，搅拌下加入碳酸钾(0.919g，6.66mmol)和(1R，3r，5S)-3-羟基-8-氮杂双环[3.2.1]辛烷-8-甲酸叔丁酯(0.756g，3.33mmol)，加毕65℃搅拌过夜。反应液有大量白色固体析出，过滤，滤液依次用水(50mL)和饱和食 盐水溶液(50mL)洗涤，有机相用无水硫酸钠干燥，减压蒸除溶剂，将残余物通过硅胶柱色谱法纯化得到本步的标题化合物(1.4g)。
MS m/z(ESI)：494.4[M+H] +。
第二步：4-(((1R，3r，5S)-8-氮杂双环[3.2.1]辛-3-基氧基)甲基)-5-环丙基-3-(2，6-二氯苯基)异噁唑(C37-b)的制备
将化合物(C37-a)(1.4g，2.84mmol)溶于二氯甲烷(20mL)中，加入三氟乙酸(5mL)，30℃下反应4小时。LC-MS监测至原料反应完全，停止反应。反应液加饱和碳酸氢钠水溶液(20mL)淬灭，用二氯甲烷(30mL×3)萃取，有机相用无水硫酸钠干燥，减压蒸除溶剂得粗品，粗品通过硅胶柱色谱法纯化(洗脱剂：石油醚/乙酸乙酯＝4/1)得本步的标题化合物(1.01g)。
MS m/z(ESI)：394.3[M+H] +。
第三步：4-((((1R，3r，5S)-8-(4-溴噻唑-2-基)-8-氮杂双环[3.2.1]辛-3-基)氧基)甲基)-5-环丙基-3-(2，6-二氯苯基)异噁唑(C37-c)的制备
室温下，将化合物(C37-b)(1.01g，2.57mmol)加入到DMF(20mL)，然后加入碳酸钾(710mg，5.14mmol)和2，4-二溴噻唑(625mg，2.57mmol)，25℃下反应过夜直至原料反应完全，反应液加水(20mL)，用乙酸乙酯(20mL×3)萃取，合并有机相水洗，无水硫酸钠干燥，过滤，粗品通过硅胶柱色谱法纯化(洗脱剂：石油醚/乙酸乙酯＝5/1)得本步的标题化合物(830mg)。
MS m/z(ESI)：556.3[M+H] +。
第四步：4-(2-((1R，3r，5S)-3-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛-8-基)噻唑-4-基)-3-甲基苯甲酸甲酯(C37-d)的制备
将化合物(C37-c)(830mg，1.50mmol)加入到DMF(20mL)中，然后加入3-甲基-4-(4，4，5，5-四甲基-1，3，2-二氧杂硼杂环戊烷-2-基)苯甲酸甲酯(414mg，1.50mmol)、碳酸钾(414mg，5.14mmol)和Pd(dppf)Cl 2(163mg，0.2mmol)，90℃下反应12小时，TLC显示反应结束，用乙酸乙酯(30mL×3)萃取，合并有机相水洗，无水硫酸钠干燥，过滤，减压蒸除溶剂，粗品通过硅胶柱色谱法纯化(洗脱剂：石油醚/乙酸乙酯＝5/1)得本步的标题化合物(120mg)。
MS m/z(ESI)：625.6[M+H] +。
第五步：4-(2-((1R，3r，5S)-3-((5-环丙基-3-(2，6-二氯苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛-8-基)噻唑-4-基)-3-甲基苯甲酸(C37)的制备
室温下，将化合物(C37-d)(120mg，0.19mmol)加入到四氢呋喃(10mL)中，然后加入水(2.0mL)和氢氧化锂(14mg，0.51mmol)，室温反应6小时，反应过夜直至原料反应完全，用1N的盐酸调反应液的pH至5-6，加入水(100mL)，然后用乙酸乙酯(30mL×3)萃取，有机相用无水硫酸钠干燥，过滤，减压蒸除溶剂，粗品通过硅胶柱色谱法纯化(洗脱剂：石油醚/乙酸乙酯＝2/1)得标题化合物(20mg)。
MS m/z(ESI)：610.1[M+H] +。
1H-NMR(400MHz，CDCl 3)δ：7.90-7.95(m，2H)，7.70(d，J＝8.0Hz，1H)，7.41-7.36(m，3H)，6.59(s，1H)，5.30(s，2H)，4.26(s，2H)，4.16(s，2H)，3.52-3.50(m，1H)，2.52(s，3H)，2.11-2.00(m，4H)，1.91-1.68(m，6H)，1.25-1.11(m，2H)。
实施例8：4-(2-((1R，3r，5S)-3-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛-8-基)噻唑-4-基)苯甲酸(C41)的制备
Figure PCTCN2018119715-appb-000036
第一步：4-(2-((1R，3r，5S)-3-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛-8-基)噻唑-4-基)苯甲酸甲酯(C41-a)的制备
室温下，将化合物(T4)(1g，1.75mmol)溶于1，4-二氧六环(20mL)中，随后加入4-(4，4，5，5-四甲基-1，3，2-二氧杂硼杂环戊烷-2-基)苯甲酸甲酯(532.50mg，1.93mmol)、[1，1′-双(二苯基膦基)二茂铁]二氯化钯(143.16mg，195.66μmol)和碳酸钾(483.85mg，3.50mmol)，氮气置换2-3遍。80℃反应8小时。反应液用硅藻土抽滤，滤液用乙酸乙酯(100mL×3)洗涤，所得有机相用无水硫酸钠(20g)干燥后过滤浓缩，所得剩余物经硅胶柱色谱法纯化(洗脱剂：石油醚/乙酸乙酯＝10/1-6/1)得到本步的标题化合物(1.12g)。
MS m/z(ESI)：626.1[M+H] +。
第二步：4-(2-((1R，3r，5S)-3-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛-8-基)噻唑-4-基)苯甲酸(C41)的制备
将化合物(C41-a)(390mg，625.31μmol)溶于四氢呋喃(5mL)中，加入氢氧化钠(25.01mg，625.31μmol)的水溶液(2mL)，25℃反应4小时。反应液用1M的稀盐酸调至pH为4，用乙酸乙酯(100mL×3)萃取，有机相用无水硫酸钠干燥，过滤，浓缩，所得剩余物经硅胶柱色谱法纯化(洗脱剂：石油醚/乙酸乙酯＝10/1-6/1)得到标题化合物(150mg)。
MS m/z(ESI)：612.1[M+H] +。
1H-NMR(400MHz，DMSO-d 6)δ：7.96(s，1H)，7.68(dd，J＝18.6，7.7Hz，1H)，7.58(dd，J＝13.9，6.8Hz，1H)，7.45(s，1H)，4.36(s，1H)，4.15(s，1H)，2.36(s，1H)，2.04(d，J＝15.2Hz，1H)，1.82(s，1H)，1.70(d，J＝14.9Hz，1H)，1.39-1.26(m，1H)，1.13(d，J＝22.2Hz，1H)。
实施例9：4-(2-((1R，3r，5S)-3-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛-8-基)噻唑-4-基)-3-甲基苯甲酸(C42)的制备
Figure PCTCN2018119715-appb-000037
第一步：4-(2-((1R，3r，5S)-3-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛-8-基)噻唑-4-基)-3-甲基苯甲酸甲酯(C42-a)的制备
室温下，将化合物(T4)(500mg，876.55mmol)溶于1，4-二氧六环(20mL)中，随后加入3-甲基-4-(4，4，5，5-四甲基-1，3，2-二氧杂硼杂环戊烷-2-基)苯甲酸甲酯(266.25mg，964.20μmol)、[1，1′-双(二苯基膦基)二茂铁]二氯化钯(71.58mg，97.83μmol)和碳酸钾(241.93mg，1.75mmol)，氮气置换2-3遍。80℃反应8小时。反应液用硅藻土抽滤，滤液用乙酸乙酯(100mL×3)洗涤，所得有机相用无水硫酸钠(20g)干燥后浓缩，所得剩余物经硅胶柱色谱法纯化(洗脱剂：石油醚/乙酸乙酯＝10/1-6/1)得到本步的标题化合物(400mg)。
MS m/z(ESI)：640.2[M+H] +。
第二步：4-(2-((1R，3r，5S)-3-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛-8-基)噻唑-4-基)-3-甲基苯甲酸(C42)的制备
将化合物(C42-a)(300mg，468.98μmol)溶于四氢呋喃(5mL)中，加入氢氧化钠(18.76mg，468.98μmol)的水溶液(2mL)，25℃下反应4小时。反应用1M的稀盐酸调至pH为4，用乙酸乙酯(100mL×3)萃取，有机相用无水硫酸钠干燥，过滤，浓缩，所得剩余物经硅胶柱色谱法纯化(洗脱剂：石油醚∶乙酸乙酯＝10∶1-6∶1)得到标题化合物(280mg)。
MS m/z(ESI)：612.1[M+H] +。
1H-NMR(400MHz，DMSO-d 6)δ：7.84(s，1H)，7.80(d，J＝8.1Hz，1H)，7.74-7.68(m，1H)，7.66(d，J＝6.2Hz，1H)，7.58(dd，J＝13.7，6.4Hz，1H)，7.06(s，1H)，4.35(s，1H)，4.11(s，1H)，2.51(d，J＝15.3Hz，4H)，2.41-2.32(m，1H)，2.04(d，J＝14.7Hz，1H)，1.94(s，1H)，1.82(s，2H)，1.69(d，J＝14.6Hz，1H)，1.19-1.14(m，2H)，1.10(m，2H)。
实施例10：4-(2-((1R，3r，5S)-3-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛-8-基]噻唑-4-基)-3-氟苯甲酸(C43)的制备
Figure PCTCN2018119715-appb-000038
第一步：4-(2-((1R，3r，5S)-3-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛-8-基)噻唑-4-基)-3-氟苯甲酸甲酯(C43-a)的制备
室温下，将化合物(T4)(650mg，1.14mmol)溶于1，4-二氧六环(20mL)中，随后加入3-氟-4-(4，4，5，5-四甲基-1，3，2-二氧杂硼杂环戊烷-2-基)苯甲酸甲酯(248.13mg，1.25mmol)、[1，1′-双(二苯基膦基)二茂铁]二氯化钯(93.06mg，127.18μmol)和碳酸钾(314.50mg，2.28mmol)，氮气置换2-3遍。80℃反应8小时。反应液用硅藻土抽滤，滤液用乙酸乙酯(100mL×3)洗涤，所得有机相用无水硫酸钠(20g)干燥 后过滤浓缩，所得剩余物经硅胶柱色谱法纯化(洗脱剂：石油醚/乙酸乙酯＝10/1)得到本步的标题化合物(350mg)。
MS m/z(ESI)：644.1[M+H] +。
第二步：4-(2-((1R，3r，5S)-3-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛-8-基]噻唑-4-基)-3-氟苯甲酸(C43)的制备
将化合物(C43-a)(390mg，625.31μmol)溶于四氢呋喃(5mL)中，加入氢氧化钠(25.01mg，625.31μmol)的水溶液(2mL)，25℃下反应4小时。反应用1M的稀盐酸调至pH为4，用乙酸乙酯(100mL×3)萃取，有机相用无水硫酸钠干燥浓缩，所得剩余物经硅胶柱色谱法纯化(洗脱剂：石油醚/乙酸乙酯＝10/1-6/1)得到标题化合物(1.01g)。
MS m/z(ESI)：620.1[M+H] +。
1H-NMR(400MHz，DMSO-d 6)δ：7.71(t，J＝7.8Hz，1H)，7.66(d，J＝7.4Hz，1H)，7.63-7.54(m，2H)，7.50(d，J＝11.7Hz，1H)，7.33(s，1H)，4.35(s，1H)，4.12(s，1H)，2.39-2.33(m，1H)，2.03(d，J＝14.5Hz，1H)，1.80(s，2H)，1.69(d，J＝14.7Hz，1H)，1.33-1.24(m，1H)，1.16(m，1H)，1.10(m，1H)。
实施例11：4-(2-((1R，3r，5S)-3-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛-8-基)噻唑-4-基)-2-氟苯甲酸(C44)的制备
Figure PCTCN2018119715-appb-000039
第一步：4-(2-((1R，3r，5S)-3-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛-8-基)噻唑-4-基)-2-氟苯甲酸甲酯(C44-a)的制备
室温下，将化合物(T4)(400mg，701.24μmol)溶于1，4-二氧六环(20mL)中，随后加入2-氟-4-(4，4，5，5-四甲基-1，3，2-二氧杂硼杂环戊烷-2-基)苯甲酸甲酯(152.70mg，771.36μmol)、[1，1′-双(二苯基膦基)二茂铁]二氯化钯(57.27mg，78.26μmol)和碳酸钾(193.54mg，1.40mmol)，氮气置换2-3遍。80℃反应8小时。反应液用硅藻土抽滤，滤液用乙酸乙酯(100mL×3)洗涤，所得有机相用无水硫酸钠(20g)干燥后过滤浓缩，所得剩余物经硅胶柱色谱法纯化(洗脱剂：石油醚/乙酸乙酯＝10/1)得到本步的标题化合物(200mg)。
MS m/z(ESI)：630.1[M+H] +。
第二步：4-(2-((1R，3r，5S)-3-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛-8-基)噻唑-4-基)-2-氟苯甲酸(C44)的制备
将化合物(C44-a)(200.00mg，310.73μmol)溶于四氢呋喃(5mL)中，加入氢氧化钠(12.43mg，310.73μmol)的水溶液(2mL)，25℃下反应4小时。反应用1M的稀盐酸调至pH为4，用乙酸乙酯(100mL×3)萃取，有机相用无水硫酸钠干燥浓缩，所得剩余物经硅胶柱色谱法纯化(洗脱剂：石油醚/乙酸乙酯＝10/1-6/1)得到标题化合物(170mg)。
MS m/z(ESI)：620.1[M+H] +。
1H-NMR(400MHz，DMSO-d 6)δ：7.85(d，J＝8.1Hz，1H)，7.72(dd，J＝17.5，10.3Hz，1H)，7.66(d，J＝7.3Hz，1H)，7.58(dd，J＝13.5，6.3Hz，1H)，7.37(d，J＝1.9Hz，1H)，4.36(s，1H)，4.15(s，1H)，2.37(d，J＝4.9Hz，1H)，2.03(d，J＝14.7Hz，1H)，1.82(s，2H)，1.70(d，J＝14.6Hz，1H)，1.33-1.24(m，1H)，1.15(dd，J＝11.0，6.1Hz，1H)，1.10(d，J＝3.0Hz，1H)。
实施例12：4-(2-((1R，3r，5S)-3-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛-8-基]噻唑-4-基)-3-(三氟甲基)苯甲酸(C45)的制备
Figure PCTCN2018119715-appb-000040
第一步：4-(2-((1R，3r，5S)-3-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛-8-基)噻唑-4-基)-3-(三氟甲基)苯甲酸甲酯(C45-a)的制备
室温下，将化合物(T4)(800mg，1.40mmol)溶于1，4-二氧六环(20mL)中，随后加入4-(4，4，5，5-四甲基-1，3，2-二氧杂硼杂环戊烷-2-基)-3-(三氟甲基)苯甲酸甲酯(509.26mg，1.54mmol)、[1，1′-双(二苯基 膦基)二茂铁]二氯化钯(114.53mg，156.53μmol)和碳酸钾(387.08mg，2.80mmol)，氮气置换2-3遍。80℃反应8小时。反应液用硅藻土抽滤，滤液用乙酸乙酯(100mL×3)洗涤，所得有机相用无水硫酸钠(20g)干燥后过滤浓缩，所得剩余物经硅胶柱色谱法纯化(洗脱剂：石油醚/乙酸乙酯＝10/1)得到本步的标题化合物(350mg)。
MS m/z(ESI)：693.1[M+H] +。
第二步：4-(2-((1R，3r，5S)-3-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛-8-基]噻唑-4-基)-3-(三氟甲基)苯甲酸(C45)的制备
将化合物(C45-a)(350.00mg，504.57μmol)溶于四氢呋喃(5mL)中，加入氢氧化钠(20.18mg，504.57μmol)的水溶液(2mL)，25℃下反应4小时。反应用1M的稀盐酸调至pH为4，用乙酸乙酯(100mL×3)萃取，有机相用无水硫酸钠干燥，过滤，浓缩，所得剩余物经硅胶柱色谱法纯化(洗脱剂：石油醚/乙酸乙酯＝10/1-6/1)得到标题化合物(320mg)。
MS m/z(ESI)：680.1[M+H] +。
1H-NMR(400MHz，DMSO-d 6)δ：7.81(d，J＝8.1Hz，1H)，7.70-7.61(m，1H)，7.55(dd，J＝12.1，4.8Hz，1H)，7.03(s，1H)，4.33(s，1H)，4.05(s，1H)，2.33(m)，2.05-1.97(m，1H)，1.79(s，2H)，1.65(d，J＝14.5Hz，1H)，1.25(d，J＝9.3Hz，1H)，1.13(m，1H)，1.08(m，1H)。
实施例13：4-(2-((1R，3r，5S)-3-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛-8-基)噻唑-4-基)-2-(三氟甲基)苯甲酸(C46)的制备
Figure PCTCN2018119715-appb-000041
第一步：4-(2-((1R，3r，5S)-3-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛-8-基)噻唑-4-基)-2-(三氟甲基)苯甲酸甲酯(C46-a)的制备
室温下，将化合物(T4)(0.4g，701.24μmol)溶于1，4-二氧六环(20mL)中，随后加入4-(4，4，5，5-四甲基-1，3，2-二氧杂硼杂环戊烷-2-基)-2-(三氟甲基)苯甲酸甲酯(277.78mg，841.48μmol)、[1，1′-双(二苯基膦基)二茂铁]二氯化钯(57.27mg，70.12μmol)和碳酸钾(193.83mg，1.40mmol)，氮气置换2-3遍。80℃反应8小时。反应液用硅藻土抽滤，滤液用乙酸乙酯(100mL×3)洗涤，所得有机相用无水硫酸钠(20g)干燥后过滤浓缩，所得剩余物经硅胶柱色谱法纯化(洗脱剂：石油醚/乙酸乙酯＝15/1-8/1)得到本步的标题化合物(0.36g)。
MS m/z(ESI)：694.1[M+H] +。
第二步：4-(2-((1R，3r，5S)-3-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛-8-基)噻唑-4-基)-2-(三氟甲基)苯甲酸(C46)的制备
将化合物(C46-a)(360.00mg，518.99μmol)溶于四氢呋喃(5mL)中，加入氢氧化钠(20.71mg，518.99μmol)的水溶液(2mL)，25℃下反应4小时。反应用1M的稀盐酸调至pH为4，用乙酸乙酯(100mL×3)萃取，有机相用无水硫酸钠干燥浓缩，所得剩余物经硅胶柱色谱法纯化(洗脱剂：石油醚/乙酸乙酯＝10/1-6/1)得到标题化合物(45mg)。
MS m/z(ESI)：680.1[M+H] +。
1H-NMR(400MHz，DMSO-d 6)δ：8.21(s，1H)，8.16(d，J＝7.3Hz，1H)，7.83(d，J＝7.2Hz，1H)，7.64(dd，J＝18.9，11.7Hz，1H)，7.57(d，J＝12.8Hz，1H)，4.33(s，1H)，4.12(s，1H)，2.33(s，1H)，2.01(d，J＝12.4Hz，1H)，1.79(s，1H)，1.68(m，1H)，1.19-1.01(m，1H)。
实施例14：4-(2-((1R，3r，5S)-3-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛-8-基)噻唑-4-基)噻吩-2-甲酸(C47)的制备
Figure PCTCN2018119715-appb-000042
第一步：4-(2-((1R，3r，5S)-3-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛-8-基)噻唑-4-基)噻吩-2-甲酸甲酯(C47-a)的制备
室温下，将化合物(T4)(0.5g，876.55μmol)溶于1，4-二氧六环(20mL)中，随后加入4-(4，4，5，5-四甲基-1，3，2-二氧杂硼杂环戊烷-2-基)噻吩-2-甲酸甲酯(282.04mg，1.05mmol)、[1，1′-双(二苯基膦基)二茂铁]二氯化钯(64.43mg，78.89μmol)和碳酸钾(241.93mg，1.75mmol)，氮气置换2-3遍，80℃反应8小时。反应液用硅藻土抽滤，滤液用乙酸乙酯(100mL×3)洗涤，所得有机相用无水硫酸钠(20g)干燥后过滤浓缩，所得剩余物经硅胶柱色谱法纯化(洗脱剂：石油醚/乙酸乙酯＝10/1-6/1)得到本步的标题化合物(0.14g)。
MS m/z(ESI)：632.1[M+H] +。
第二步：4-(2-((1R，3r，5S)-3-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛-8-基)噻唑-4-基)噻吩-2-甲酸(C47)的制备
将化合物(C47-a)(200.00mg，316.61μmol)溶于四氢呋喃(5mL)中，加入氢氧化钠(12.66mg，316.61μmol)的水溶液(2mL)，25℃下反应4小时。反应用1M的稀盐酸调至pH为4，用乙酸乙酯(100mL×3)萃取，有机相用无水硫酸钠干燥，过滤，浓缩，所得剩余物经硅胶柱色谱法纯化(洗脱剂：石油醚/乙酸乙酯＝10/1-6/1)得到本步的标题化合物(0.1g)。
MS m/z(ESI)：618.1[M+H] +。
1H-NMR(400MHz，DMSO-d 6)δ：8.21(s，1H)，8.16(d，J＝7.3Hz，1H)，7.83(d，J＝7.2Hz，1H)，7.64(dd，J＝18.9，11.7Hz，1H)，7.57(d，J＝12.8Hz，1H)，4.33(s，1H)，4.12(s，1H)，2.33(s，1H)，2.01(d，J＝12.4Hz，1H)，1.79(s，1H)，1.68(m，1H)，1.19-1.01(m，1H)。
实施例15：5-(2-((1R，3r，5S)-3-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛-8-基)噻唑-4-基)噻吩-3-甲酸(C48)的制备
Figure PCTCN2018119715-appb-000043
第一步：5-(2-((1R，3r，5S)-3-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛-8-基)噻唑-4-基)噻吩-3-甲酸甲酯(C48-a)的制备
室温下，将化合物(T4)(0.5g，876.55μmol)溶于1，4-二氧六环(20mL)中，随后加入5-(4，4，5，5-四甲基-1，3，2-二氧杂硼杂环戊烷-2-基)噻吩-3-甲酸甲酯(282.04mg，1.05mmol)、[1，1′-双(二苯基膦基)二茂铁]二氯化钯(64.43mg，78.89μmol)和碳酸钾(241.93mg，1.75mmol)，氮气置换2-3遍。80℃反应8小时。反应液用硅藻土抽滤，滤液用乙酸乙酯(100mL×3)洗涤，所得有机相用无水硫酸钠(20g)干燥后过滤浓缩，所得剩余物经硅胶柱色谱法纯化(洗脱剂：石油醚/乙酸乙酯＝10/1-6/1)得到本步的标题化合物(0.2g)。
MS m/z(ESI)：632.1[M+H] +。
第二步：5-(2-((1R，3r，5S)-3-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛-8-基)噻唑-4-基)噻吩-3-甲酸(C48)的制备
将化合物(C48-a)(140.00mg，221.63μmol)溶于四氢呋喃(5mL)中，加入氢氧化钠(8.86mg，221.63μmol)的水溶液(2mL)，25℃下反应4小时。反应用1M的稀盐酸调至pH为4，用乙酸乙酯(100ml×3)萃取，有机相用无水硫酸钠干燥，过滤，浓缩，所得剩余物经硅胶柱色谱法纯化(洗脱剂：石油醚/乙酸乙酯＝10/1-6/1)得到标题化合物(70mg)。
MS m/z(ESI)：618.1[M+H] +。
1H-NMR(400MHz，DMSO-d 6)δ：8.14(s，1H)，7.74-7.68(m，1H)，7.66(d，J＝6.7Hz，1H)，7.58(dd，J＝13.4，6.2Hz，1H)，7.26(s，1H)，4.35(s，1H)，4.09(s，1H)，2.36(s，1H)，2.01(d，J＝15.4Hz，1H)，1.80(s，2H)，1.69(d，J＝14.8Hz，1H)，1.16(d，J＝8.4Hz，1H)，1.10(d，J＝2.8Hz，1H)。
实施例16：5-(2-((1R，3r，5S)-3-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛-8-基)噻唑-4-基)噻吩-2-甲酸(C35)的制备
Figure PCTCN2018119715-appb-000044
第一步：5-(2-((1R，3r，5S)-3-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛-8-基)噻唑-4-基)噻吩-2-甲酸甲酯(C35-a)的制备
室温下，将化合物(T4)(709.12mg，1.24mmol)溶于1，4-二氧六环(20mL)中，随后加入5-(4，4，5，5-四甲基-1，3，2-二氧杂硼杂环戊烷-2-基)噻吩-2-甲酸甲酯(0.4g，1.49mmol)、[1，1′-双(二苯基膦基)二茂铁]二氯化钯(90.87mg，111.28μmol)和碳酸钾(343.11mg，2.48mmol)，氮气置换2-3遍。80℃反应8小时。反应液用硅藻土抽滤，滤液用乙酸乙酯(100mL×3)洗涤，所得有机相用无水硫酸钠(20g)干燥后过滤浓缩，所得剩余物经硅胶柱色谱法纯化(洗脱剂：石油醚/乙酸乙酯＝10/1-6/1)得到本步的标题化合物(0.25g)。
MS m/z(ESI)：632.1[M+H] +。
第二步：5-(2-((1R，3r，5S)-3-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛-8-基)噻唑-4-基)噻吩-2-甲酸(C35)的制备
将化合物(C35-a)(200.00mg，316.61μmol)溶于四氢呋喃(5mL)中，加入氢氧化钠(12.66mg，316.61μmol)的水溶液(2mL)，25℃下反应4小时。反应用1M的稀盐酸调至pH为4，用乙酸乙酯(100mL×3)萃取，有机相用无水硫酸钠干燥，过滤，浓缩，所得剩余物经硅胶柱色谱法纯化(洗脱剂：石油醚/乙酸乙酯＝10/1-6/1)得到本步的标题化合物(25mg)。
MS m/z(ESI)：618.1[M+H] +。
1H-NMR(400MHz，DMSO-d 6)δ：7.65(m，2H)，7.56(m，1H)，7.44(s，1H)，7.31(s，1H)，4.33(s，1H)，4.07(s，1H)，3.52(s，1H)，2.33(s，1H)，1.99(d，J＝14.4Hz，1H)，1.78(s，2H)，1.66(d，J＝14.6Hz，1H)，1.13(m，1H)，1.08(s，1H)。
实施例17：5-(2-((1R，3r，5S)-3-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛-8-基)噻唑-4-基)吡啶甲酸(C50)的制备
Figure PCTCN2018119715-appb-000045
第一步：5-(2-((1R，3r，5S)-3-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛-8-基)噻唑-4-基)吡啶甲酸甲酯(C50-a)的制备
室温下，将化合物(T4)(50mg，87.65μmol溶于1，4-二氧六环(20mL)中，随后加入5-(4，4，5，5-四甲基-1，3，2-二氧杂硼杂环戊烷-2-基)吡啶甲酸甲酯(27.67mg，105.19μmol)、[1，1′-双(二苯基膦基)二茂铁]二氯化钯(7.16mg，8.77μmol)和碳酸钾(12.11mg，87.65μmol)，氮气置换2-3遍。80℃反应8小时。反应液用硅藻土抽滤，滤液用乙酸乙酯(100mL×3)洗涤，所得有机相用无水硫酸钠(20g)干燥后过滤浓缩，所得剩余物经硅胶柱色谱法纯化(洗脱剂：石油醚/乙酸乙酯＝10/1-6/1)得到本步的标题化合物(20mg)。
MS m/z(ESI)：626.1[M+H] +。
第二步：5-(2-((1R，3r，5S)-3-((5-环丙基-3-(2-(三氟甲氧基)苯基)异噁唑-4-基)甲氧基)-8-氮杂双环[3.2.1]辛-8-基)噻唑-4-基)吡啶甲酸(C50)的制备
将化合物(C50-a)(200mg，316.61μmol)溶于四氢呋喃(5mL)中，加入氢氧化钠(12.66mg，316.61μmol)的水溶液(2mL)，25℃下反应4小时。反应用1M的稀盐酸调至pH为4，用乙酸乙酯(100mL×3)萃取，有机相用无水硫酸钠干燥后过滤浓缩，所得剩余物经硅胶柱色谱法纯化(洗脱剂：石油醚/乙酸乙酯＝10/1-6/1)得到标题化合物(25mg)。
MS m/z(ESI)：618.1[M+H] +。
1H-NMR(400MHz，DMSO-d 6)δ：8.88(s，1H)，8.20(dd，J＝8.1，2.1Hz，1H)，7.93(d，J＝8.2Hz，1H)，7.71-7.61(m，1H)，7.55(t，J＝7.5Hz，1H)，7.44(s，1H)，4.32(s，1H)，4.11(s，1H)，3.52(s，1H)，2.33(dd，J＝10.8，5.9Hz，1H)，2.01(d，J＝13.7Hz，1H)，1.79(s，2H)，1.67(d，J＝14.5Hz，1H)，1.13(m，1H)，1.09-1.03(m，1H)。
采用与上述实施例1-17类似的合成方法，制备了如下表1中的化合物：
表1
Figure PCTCN2018119715-appb-000046
Figure PCTCN2018119715-appb-000047
Figure PCTCN2018119715-appb-000048
Figure PCTCN2018119715-appb-000049
Figure PCTCN2018119715-appb-000050
生物学测定
实验例1.胆汁酸受体FXR辅激活因子结合试验
1.试验方法
采用Invitrogen·LanthaScreen TM TR-FRET Famesoid X Receptor Coactivator Assay试剂盒测定化合物对FXR的激活作用。
将受体与不同浓度的待测化合物在室温下孵育后，加入荧光标记的辅激活因子短肽及铽标记的抗体，在室温下反应后检测FRET信号。以无受体蛋白组为空白，使用四参数拟合方程计算待测化合物对FXR的激活活性EC 50及最大激活效应信号值Emax：
y＝Emin+(Emax-Emin)/(1+(x/EC 50)^(-Hillslope))
其中y为FRET结合信号，Emax和Emin分别为拟合曲线的上渐近线估值和下渐近线估值，x 为化合物的对数浓度，Hillslope为曲线斜率。
另外，以鹅去氧胆酸(即CDCA)为阳性对照，通过以下公式计算本发明所测试化合物的相对激活效应：
相对激活效应(％)＝(Emax/Emax’)×100％
其中，Emax代表本发明所测试化合物的最大激活效应值，Emax’代表CDCA的最大激活效应值，二者均通过上文所示的公式计算得到。
2.试验结果
表2.本发明所测试的化合物对FXR的EC 50
化合物编号 EC 50(μM)
CDCA 4.43±0.84
C1 0.178±0.021
C2 0.012±0.004
C3 0.042±0.007
C4 0.010±0.001
C6 0.206±0.018
C35 0.013±0.003
C37 0.015±0.001
C44 0.022±0.005
C45 0.110±0.021
C46 0.002±0.001
C50 0.031±0.008
表2的数据显示，相对于鹅去氧胆酸(CDCA)的值为4.43μM的EC 50，所测试的化合物具有更低的EC 50(0.002-0.206μM)，表明本发明化合物对FXR具有更好的激活活性。
表3.本发明所测试的化合物对FXR的相对激活效应
化合物编号 相对激活效应
CDCA 100％
C2 101％
C4 102％
C35 152％
C37 139％
C44 137％
C45 113％
C46 196％
C50 177％
表3的数据显示，本发明所测试化合物的最大激活效应值与鹅去氧胆酸(CDCA)的最大激活效应值相当或更高，说明本发明化合物对FXR具有很好的最大激活效应。
综合表2和表3的EC 50值和相对激活效应数据显示，本发明的化合物对FXR具有较好的激活作用。
本发明的其他化合物也具有较好的EC 50值以及相对激活效应值，即具有较好的对FXR的激活活性和最大激活效应。
实验例2.荧光素酶报告基因检测试验
1.试验方法
人胚胎肾细胞HEK293培养于含有10％FBS的DMEM培养基中。共转染质粒，使其高表达FXR和人源BSEP荧光素酶报告基因。将转染细胞消化、重悬，计数，然后接种于多孔板中。加入10μL不同浓度待测化合物于多孔板中，使其终浓度分别为64μM、16μM、4μM、1μM、0.25μM、0.0625μM、0.0156μM、0.0039μM、0.000975μM、0.000244μM、0μM，DMSO终浓度为0.5％。待测化合物与细胞孵育18h后，加入Brigh-GloTM检测试剂，用多功能全自动酶标仪检测化学发光单位值(RLU)，以空白孔(不含待测化合物)信号值为100％，计算各待测化合物浓度下的相对信号百分比(％)。用SigmaPlot 10软件采用四参数模型拟合所测试的化合物EC 50和最大激动效应Emax(相对信号百分比)。
2.试验结果
测定结果列于下表4。
表4
化合物编号 EC 50(μM) Emax
C2 0.02±0.01 248％
C4 0.04±0.01 255％
C35 0.091±0.038 378％
C37 0.006±0.002 411％
C41 0.058±0.023 252％
C42 0.033±0.018 320％
C43 0.037±0.019 343％
C44 0.021±0.006 322％
C46 0.014±0.005 301％
C47 0.019±0.007 370％
C48 0.039±0.017 382％
表4的数据显示，本发明所测试的的化合物在体外细胞测定中，EC 50值在0.006μM～0.091μM之间，Emax值大于200％。表明本发明的化合物在体外细胞测定中具有良好的FXR激活活性。
本发明的其他化合物也具有较好的EC 50值和Emax值，即在体外细胞测定中具有较好的FXR激活活性。
实验例3：大鼠药代动力学(PK)和肝组织分布研究
分别通过静脉(IV)和灌胃(PO)给予雄性SD大鼠待测化合物，考察待测化合物的药代动力学和肝组织分布特点。IV和PO的给药剂量分别是1mg/kg和5mg/kg，IV的溶媒为5％DMSO：5％Solutol：90％生理盐水，PO的溶媒为0.5％MC。IV和PO给药后在不同时间点收集血液和肝脏。血液采用EDTA.K 2抗凝，离心后得到血浆样品；将肝脏匀浆，保存于-80℃。血浆和肝脏样品经沉淀蛋白处理后进行LC-MS/MS分析。
应用WinNonlin 6.3软件，采用非房室模型计算药代动力学参数，结果见表5和表6。
表5.IV给药的待测化合物在大鼠体内的药代动力学参数
Figure PCTCN2018119715-appb-000051
表5的数据显示，通过以1mg/kg的剂量IV给药的本发明的化合物C2，在大鼠体内的AUC last为2409±108h*ng/mL，C max为4343±172ng/mL，这表明本发明的化合物C2通过IV给药在大鼠体内具有优良的药物暴露量。
表6.PO给药的待测化合物在大鼠体内的药代动力学参数
Figure PCTCN2018119715-appb-000052
表6的数据显示，通过以5mg/kg的剂量PO给药的本发明的化合物C2，在大鼠血液和肝的AUC last分别为1177±304h*ng/mL和14941±4276h*ng/g，C max分别为252±30ng/mL和3367±830ng/g，表明本发明的化合物C2通过PO给药在大鼠体内具有一定的药物暴露量和明显的肝脏富集作用。
综合表5和表6，本发明的实施例化合物2通过IV给药在大鼠体内具有优良的血浆药物暴露量，通过PO给药在大鼠体内具有一定的药物暴露量和明显的肝脏富集作用。
本发明的其他化合物也具有较好的AUC last值和C max值，在大鼠体内具有较好的药代动力学性质。
本发明化合物在应用于FXR介导的疾病的药物时，在药物安全性方面显示出较好的效果，在动物体内或体外药效动力学或药代动力学方面均显示出良好的药物活性和体内代谢优势。
实验例4：肝微粒体稳定性实验
实验方法：
将待测化合物(50μL)与各种属肝微粒体(100μL)混合，37℃预孵5分钟后，加入NADPH(50μL)，孵育0、30、60分钟，待测化合物、NADPH和肝微粒体酶的孵育浓度分别为1μM、1mM和0.5mg/mL。加入冰乙腈(200μL)终止反应后加入适当体积内标，涡旋、离心取上清，检测。
检测方法：
LC-MS/MS，质谱为API 5500，液相为Shimadzu LC-30AD系统。色谱柱为Hypersil GOLD C18，1.9μm粒径，50×2.1mm；流动相A相为水+0.1％甲酸，B相为乙腈；流速为0.55mL/min，柱温为40℃。采用离子源为ESI源正离子模式，扫描方式为多重反应监测(MRM)。
通过测定不同孵育时间的样品浓度，以“Ln(药物残留量％)”对“孵育时间”作图获得速率常数，从而计算出药物的半衰期与肝清除率，以药物半衰期与肝清除率值来评价药物在肝微粒体中的代谢稳定性。
实验结果：
表7肝微粒体稳定性实验
Figure PCTCN2018119715-appb-000053
结论：从表7的实验数据可以看出，本发明的化合物C46在肝微粒体中具有良好的清除率，并且在人肝微粒体中的清除率为14.9ml/min/kg，清除良好。
除本文中描述的那些实施方案外，根据前述描述，本发明的多种修改对本领域技术人员而言会是显而易见的。这样的修改也意图落入所附权利要求书的范围内。本申请中所引用的各参考文献(包括所有专利、专利申请、期刊文章、书籍及任何其它公开)均以其整体援引加入本文。

Claims (16)

  1. 通式(I)的化合物或者其立体异构体、互变异构体、多晶型物、溶剂合物(如水合物)、药学可接受的盐、酯、代谢物、N-氧化物、其化学保护的形式或前药，
    Figure PCTCN2018119715-appb-100001
    其中：
    A选自亚噻唑基、亚苯基和亚吡啶基；
    B选自C 6-10芳基以及包含独立地选自N、O和S的1、2、3或4个杂原子的5至10元杂芳基；
    D是
    Figure PCTCN2018119715-appb-100002
    Z是
    Figure PCTCN2018119715-appb-100003
    W选自N和CR d，优选地是CR d；
    R a选自氢、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、3至14元杂环基、C 1-6烷基-O-、卤代C 1-6烷基、卤代C 3-8环烷基和卤代C 1-6烷基-O-；
    R b、R c和R d各自独立地选自氢、卤素、羟基、氰基、-NH 2、硝基、C 1-6烷基、卤代C 1-6烷基、C 1-6烷基-O-、卤代C 1-6烷基-O-、C 3-8环烷基、卤代C 3-8环烷基、C 3-8环烷基-O-和卤代C 3-8环烷基-O-；
    R 1和R 2各自独立地选自氢、卤素、氰基、羟基、-NH 2、C 1-6烷基、卤代C 1-6烷基、羟基C 1-6烷基、C 1-6烷基-O-、卤代C 1-6烷基-O-、C 3-8环烷基、卤代C 3-8环烷基、C 1-6烷基-NH-和(C 1-6烷基) 2-N-；
    R 3a、R 3b、R 3c和R 3d各自独立地选自氢、卤素、氰基、羟基、-NH 2、氧代、C 1-6烷基、卤代C 1- 6烷基、羟基C 1-6烷基、C 1-6烷基-O-、卤代C 1-6烷基-O-、C 3-8环烷基和卤代C 3-8环烷基；或者R 3a、R 3b、R 3c和R 3d中的任意二者共同形成C 1-6亚烷基，优选地，R 3a、R 3b、R 3c和R 3d中的任意二者共同形成C 2-6亚烷基，更优选地，R 3a和R 3b共同形成C 2-6亚烷基；
    m和n各自独立地是0、1、2、3或4，优选地是0、1或2；并且
    上述烷基、亚烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基各自任选地被1个、2个或3个独立地选自下列的取代基取代：卤素、羟基、氧代、氰基、-NH 2、硝基、C 1-6烷基、卤代C 1-6烷基、C 1-6烷基-O-、卤代C 1-6烷基-O-、C 3-6环烷基、卤代C 3-6环烷基、C 1-6烷基-NH-、(C 1-6烷基) 2-N-、羟基C 1-6烷基、氰基-C 1-6烷基、3至14元杂环基、C 6-14芳基和5至14元杂芳基。
  2. 权利要求1的化合物或者其立体异构体、互变异构体、多晶型物、溶剂合物(如水合物)、药学可接受的盐、酯、代谢物、N-氧化物、其化学保护的形式或前药，其中A选自
    Figure PCTCN2018119715-appb-100004
    Figure PCTCN2018119715-appb-100005
    以上基团通过1或2标记的两个位置之一与通式(I)中的环氮原子连接，并且另一位置与B基团连接。
  3. 权利要求1或2的化合物或者其立体异构体、互变异构体、多晶型物、溶剂合物(如水合物)、药学可接受的盐、酯、代谢物、N-氧化物、其化学保护的形式或前药，其中B选自苯基以及包含独立地选自N、O和S的1、2、3或4个杂原子的5至6元杂芳基；特别地，所述杂芳基选自吡啶基、嘧啶基、吡嗪基、哒嗪基、噻唑基、噻吩基、噁唑基、呋喃基、吡咯基、吡唑基、三唑基、四唑基、异噁唑基、异噻唑基、咪唑基、三嗪基、噁二唑基和噻二唑基；B优选自苯基、吡啶基、呋喃基、噻吩基和吡唑基。
  4. 权利要求1-3中任一项的化合物或者其立体异构体、互变异构体、多晶型物、溶剂合物(如水合物)、药学可接受的盐、酯、代谢物、N-氧化物、其化学保护的形式或前药，其中通式(I)中的
    Figure PCTCN2018119715-appb-100006
    基团为
    Figure PCTCN2018119715-appb-100007
  5. 权利要求1-4中任一项的化合物或者其立体异构体、互变异构体、多晶型物、溶剂合物(如水合物)、药学可接受的盐、酯、代谢物、N-氧化物、其化学保护的形式或前药，其中D是
    Figure PCTCN2018119715-appb-100008
    优选是
    Figure PCTCN2018119715-appb-100009
  6. 权利要求1-5中任一项的化合物或者其立体异构体、互变异构体、多晶型物、溶剂合物(如水合物)、药学可接受的盐、酯、代谢物、N-氧化物、其化学保护的形式或前药，其中所述C 1-6烷基选自甲基、乙基、正丙基、异丙基、正丁基、异丁基和叔丁基。
  7. 权利要求1-6中任一项的化合物或者其立体异构体、互变异构体、多晶型物、溶剂合物(如水合物)、药学可接受的盐、酯、代谢物、N-氧化物、其化学保护的形式或前药，其中所述卤素选自F、Cl、Br和I，优选地是F或Cl。
  8. 权利要求1-7中任一项的化合物或者其立体异构体、互变异构体、多晶型物、溶剂合物(如水合物)、药学可接受的盐、酯、代谢物、N-氧化物、其化学保护的形式或前药，其中所述卤代C 1-6烷基选自CF 3、CHF 2、CH 2F、CCl 3和CH 2CF 3。
  9. 权利要求1-8中任一项的化合物或者其立体异构体、互变异构体、多晶型物、溶剂合物(如水合物)、药学可接受的盐、酯、代谢物、N-氧化物、其化学保护的形式或前药，其中所述化合物是通式(Ia)、(Ib)、(Ic)或(Id)的化合物：
    Figure PCTCN2018119715-appb-100010
  10. 权利要求1-9中任一项所述的化合物或者其立体异构体、互变异构体、多晶型物、溶剂合物(如水合物)、药学可接受的盐、酯、代谢物、N-氧化物、其化学保护的形式或前药，其中所述化合物选自：
    Figure PCTCN2018119715-appb-100011
    Figure PCTCN2018119715-appb-100012
    Figure PCTCN2018119715-appb-100013
  11. 药物组合物，其包含至少一种权利要求1-10中任一项的化合物或者其立体异构体、互变异构体、多晶型物、溶剂合物(如水合物)、药学可接受的盐、酯、代谢物、N-氧化物、其化学保护的形式或前药，以及一种或多种药学可接受的载体。
  12. 权利要求11的药物组合物，其为选自以下的形式：片剂、胶囊剂、锭剂、硬糖剂、散剂、喷雾剂、乳膏剂、软膏剂、栓剂、凝胶剂、糊剂、洗剂、软膏剂、水性混悬剂、可注射溶液剂、酏剂和糖浆剂。
  13. 药盒，其包括：
    a)第一容器，其包含作为第一治疗剂的至少一种权利要求1-10中任一项的化合物或者其立体异构体、互变异构体、多晶型物、溶剂合物(如水合物)、药学可接受的盐、酯、代谢物、N-氧化物、其化学保护的形式或前药，或作为第一药物组合物的权利要求11或12的药物组合物；
    b)任选存在的第二容器，其包含作为第二治疗剂的至少一种其他治疗剂，或者作为第二药物组合物的包含所述其他治疗剂的药物组合物；和
    c)任选存在的包装说明书。
  14. 权利要求1-10中任一项的化合物或者其立体异构体、互变异构体、多晶型物、溶剂合物(如水合物)、药学可接受的盐、酯、代谢物、N-氧化物、其化学保护的形式或前药、或者权利要求11或12的药物组合物在制备用于预防或治疗由类法尼醇X受体介导的疾病或病症的药物中的用途。
  15. 制备权利要求1-10中任一项的通式(I)的化合物的方法，所述方法包括以下步骤：
    Figure PCTCN2018119715-appb-100014
    其中：
    Hal 1、Hal 2和Hal 3各自独立地为相同或不同的卤素，例如F、Cl、Br或I，优选为Cl或Br；
    PG 1为氨基保护基，优选为叔丁氧羰基(Boc)；
    PG 2为羧基保护基，优选为C 1-6烷基，更优选为甲基；
    Y为硼酸或硼酸酯基团，优选为-B(OH) 2或者
    Figure PCTCN2018119715-appb-100015
    其余基团如权利要求1-10中任一项所定义；
    各步骤的反应条件如下：
    步骤A：使化合物IN-1与化合物IN-2反应以得到化合物IN-3；
    步骤B：移除化合物IN-3中的PG 1基团，以得到化合物IN-4；
    步骤C-1：使化合物IN-4与化合物IN-a反应以得到化合物IN-5；
    步骤D-1：使化合物IN-5与化合物IN-b反应以得到化合物IN-6；以及
    步骤E-1：移除化合物IN-6中的PG 2基团，以得到通式(I)的化合物；
    或者所述方法包括以下步骤：
    Figure PCTCN2018119715-appb-100016
    其中各基团如上述所定义；
    各步骤的反应条件如下：
    步骤A：使化合物IN-1与化合物IN-2反应以得到化合物IN-3；
    步骤B：移除化合物IN-3中的PG 1基团，以得到化合物IN-4；
    步骤C-2：使化合物IN-4与化合物IN-c反应以得到化合物IN-6；以及
    步骤D-2：移除化合物IN-6中的PG 2基团，以得到通式(I)的化合物。
  16. 通式(IN-6)的化合物或其药学上可接受的盐，
    Figure PCTCN2018119715-appb-100017
    其中各基团如权利要求1-10和15中任一项所定义；
    所述化合物优选自：
    Figure PCTCN2018119715-appb-100018
    Figure PCTCN2018119715-appb-100019
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