WO2018059314A1 - Dérivés d'azabicycle, leur procédé de préparation et leur utilisation - Google Patents

Dérivés d'azabicycle, leur procédé de préparation et leur utilisation Download PDF

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WO2018059314A1
WO2018059314A1 PCT/CN2017/102883 CN2017102883W WO2018059314A1 WO 2018059314 A1 WO2018059314 A1 WO 2018059314A1 CN 2017102883 W CN2017102883 W CN 2017102883W WO 2018059314 A1 WO2018059314 A1 WO 2018059314A1
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alkyl
group
compound
cyclopropyl
cycloalkyl
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PCT/CN2017/102883
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English (en)
Chinese (zh)
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刘钢
于华
杨定菊
何婷
宋宏梅
曾宏
胡晓
刘瑞红
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 CN201780005121.7A priority Critical patent/CN108430998B/zh
Publication of WO2018059314A1 publication Critical patent/WO2018059314A1/fr

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    • 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
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—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
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention generally relates to compounds for the treatment of diseases or conditions mediated by farnesoid X receptor (FXR), and more particularly to FXR agonist compounds, as well as stereoisomers, tautomers thereof, and more 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 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 and activates FXR, which controls the expression of multiple genes through heterodimeric complexes with retinoid X receptors (RXR), including bile acids, cholesterol, and triacids in the liver and circulation.
  • RXR retinoid X receptors
  • Gene expression for glycerol, lipoprotein homeostasis (Kalaany, NY; Mangelsdorf, DJLXRS and FXR: the yin and yang of cholesterol and fat metabolism.
  • FXR also appears to be involved in paracrine and endocrine signaling by up-regulating 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 the steady state of bile acids (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 metabolic benefits (Mudaliar, S.; Henry, RR; Sanyal, AJet al., Efficacy and safety of the farnesoid X receptor agonist obeticholic acid in patients with type 2diabetes 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 3trial in two decades–an international study of the FXR agonist obeticholic acid in PBC patients. J. Hepatol., 2014, 60, S525–S526).
  • WO2016097933 discloses a method of treating an FXR agonist or a partial agonist of the formula (I) for the treatment of a condition mediated by FXR, which is incorporated herein by reference in its entirety:
  • FXR agonist compounds having good pharmacodynamic or pharmacokinetic properties for the treatment of diseases or conditions mediated by FXR.
  • the present invention generally relates to FXR agonist compounds of the general formula (I) or stereoisomers, tautomers, polymorphs, solvents thereof Compounds (eg, hydrates), pharmaceutically acceptable salts, esters, metabolites, N-oxides, and chemically protected forms and prodrugs thereof:
  • R 1 is selected from the group consisting of hydrogen, halogen, hydroxy, amino, C 1-6 alkyl, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkyl-O-, -C ( O) NR 6 (CHR 3 ) q CO 2 R 4 , -C(O)NR 6 (CHR 3 ) q SO 3 R 5 , -ER 4 , -E-OR 4 , -E-CN, -E-NR 4 R 5 , C 3-10 cycloalkyl-O-, -OC 1-6 alkyl-OR 4 , -OC 3-10 heterocycloalkyl, -EC(O)OR 4 , -EC(O)R 4 , -EC(O)NR 4 R 5 , -EC(O)NR 4 SO 2 R 4 , -E-NR 4 C(O)R 4 , -E-SO x -R 4 , -E-SO 3 H, -E
  • R 3 , R 5 and R 6 are each independently selected from the group consisting of hydrogen, C 1-6 alkyl, halo C 1-6 alkyl and C 3-6 cycloalkyl;
  • Each R 4 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, halo C 1-6 alkyl, C 3-8 cycloalkyl, -C 1-6 alkyl-C 3-8 cycloalkyl, C a 3-8 heterocycloalkyl group, a -C 1-6 alkyl-C 3-8 heterocycloalkyl group, a 5- or 6-membered heteroaryl group, and an aryl group, wherein the alkyl group, cycloalkyl group, heterocycloalkyl group , aryl and heteroaryl are unsubstituted or selected from the group consisting of halogen, CN, OH, oxo, C(O)OH, C 1-3 alkyl, halo C 1-3 alkyl, SO 3 H, 1 , 2 , 3 or 4 substituents of C 1-3 alkyl-O-, halo C 1-3 alkyl-O- and -SO 2 -C 1-3 alkyl;
  • x 0, 1 or 2;
  • q 1, 2, 3, 4, 5 or 6;
  • B is selected from a C 6-14 aryl group and a 5 to 14 membered monocyclic or bicyclic heteroaryl group comprising 1, 2, 3, 4 or 5 heteroatoms independently selected from N, O and S, said aryl group Or a heteroaryl group is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, hydroxy, CN, amino, C 1-6 alkyl, C 1-6 alkyl- O-, C 1-6 alkyl-OC 1-6 alkyl-O-, halo C 1-6 alkyl, halo C 1-6 alkyl-O-, hydroxy C 1-6 alkyl, CN -C 1-6 alkyl, C 3-6 cycloalkyl and C 1-6 alkyl-S(O) m -;
  • N-linked B group is not directly adjacent to the -(CH 2 ) p -O- group;
  • each R 2 is independently selected from the group consisting of hydrogen, halogen, hydroxy, oxo, CN, C 1-6 alkyl, C 1 6 alkyl-O-, halo C 1-6 An alkyl group, a hydroxy C 1-6 alkyl group or a C 3-6 cycloalkyl group;
  • n 0, 1 or 2;
  • n 1, 2, 3 or 4;
  • p 0, 1, 2 or 3;
  • Each Ra is independently selected from a C 1-6 alkyl group, a C 3-8 cycloalkyl group, a C 1-6 alkyl-O- group, a halogenated C 1-6 alkyl group, a halogenated C 3-8 cycloalkyl group, and Halogenated C 1-6 alkyl-O-;
  • Rb and Rc are independently selected from the group consisting of hydrogen, halogen, hydroxy, CN, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkyl-O-, halo C 1-6 alkyl- O-, C 3-8 cycloalkyl and halogenated C 3-8 cycloalkyl;
  • Rd is selected from a C 3-10 cycloalkyl or C 5-14 bridged ring system, a fused ring system or a spiro ring system, optionally substituted by 1, 2 or 3 Re;
  • Re is independently selected from the group consisting of hydrogen, halogen, hydroxy, CN, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkyl-O-, halo C 1-6 alkyl-O- a C 3-8 cycloalkyl group, a halogenated C 3-8 cycloalkyl group, and a C 6-10 monocyclic or bicyclic aryl group;
  • W is selected from N, N-O and CRb, and Rb is as defined above.
  • the present invention relates to a FXR agonist compound of the formula (I) or a stereoisomer, tautomer, polymorph, solvate (e.g. hydrate), pharmaceutically acceptable salt, ester thereof , metabolites, N-oxides and their chemically protected forms and prodrugs:
  • R 1 is selected from the group consisting of hydrogen, halogen, hydroxy, amino, C 1-6 alkyl, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkyl-O-, -C ( O) NR 6 (CHR 3 ) q CO 2 R 4 , -C(O)NR 6 (CHR 3 ) q SO 3 R 5 , -ER 4 , -E-OR 4 , -E-CN, -E-NR 4 R 5 , C 3-10 cycloalkyl-O-, -OC 1-6 alkyl-OR 4 , -OC 3-10 heterocycloalkyl, -EC(O)OR 4 , -EC(O)R 4 , -EC(O)NR 4 R 5 , -EC(O)NR 4 SO 2 R 4 , -E-NR 4 C(O)R 4 , -E-SO x -R 4 , -E-SO 3 H, -E
  • R 3 , R 5 and R 6 are each independently selected from the group consisting of hydrogen, C 1-6 alkyl, halo C 1-6 alkyl and C 3-6 cycloalkyl;
  • Each R 4 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, halo C 1-6 alkyl, C 3-8 cycloalkyl, -C 1-6 alkyl-C 3-8 cycloalkyl, C a 3-8 heterocycloalkyl group, a -C 1-6 alkyl-C 3-8 heterocycloalkyl group, a 5- or 6-membered heteroaryl group, and an aryl group, wherein the alkyl group, cycloalkyl group, heterocycloalkyl group , aryl and heteroaryl are unsubstituted or selected from the group consisting of halogen, CN, OH, oxo, C(O)OH, C 1-3 alkyl, halo C 1-3 alkyl, SO 3 H, 1 , 2 , 3 or 4 substituents of C 1-3 alkyl-O-, halo C 1-3 alkyl-O- and -SO 2 -C 1-3 alkyl;
  • x 0, 1 or 2;
  • q 1, 2, 3, 4, 5 or 6;
  • B is selected from a C 6-14 aryl group and a 5 to 14 membered monocyclic or bicyclic heteroaryl group comprising 1, 2, 3, 4 or 5 heteroatoms independently selected from N, O and S, said aryl group Or a heteroaryl group is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, hydroxy, CN, amino, C 1-6 alkyl, C 1-6 alkyl- O-, C 1-6 alkyl-OC 1-6 alkyl-O-, halo C 1-6 alkyl, halo C 1-6 alkyl-O-, hydroxy C 1-6 alkyl, CN -C 1-6 alkyl, C 3-6 cycloalkyl and C 1-6 alkyl-S(O) m -;
  • N-linked B group is not directly adjacent to the -(CH 2 ) p -O- group;
  • each R 2 is independently selected from the group consisting of hydrogen, halogen, hydroxy, CN, C 1-6 alkyl, C 1-6 alkyl-O-, halo C 1-6 alkyl, Hydroxy C 1-6 alkyl or C 3-6 cycloalkyl;
  • n 0, 1 or 2;
  • n 1, 2, 3 or 4;
  • p 0, 1, 2 or 3;
  • Each Ra is independently selected from a C 1-6 alkyl group, a C 3-8 cycloalkyl group, a C 1-6 alkyl-O- group, a halogenated C 1-6 alkyl group, a halogenated C 3-8 cycloalkyl group, and Halogenated C 1-6 alkyl-O-;
  • Rb and Rc are independently selected from the group consisting of hydrogen, halogen, hydroxy, CN, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkyl-O-, halo C 1-6 alkyl- O-, C 3-8 cycloalkyl and halogenated C 3-8 cycloalkyl;
  • Rd is selected from a C 3-10 cycloalkyl or C 5-14 bridged ring system, a fused ring system or a spiro ring system, optionally substituted by 1, 2 or 3 Re;
  • Re is independently selected from the group consisting of hydrogen, halogen, hydroxy, CN, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkyl-O-, halo C 1-6 alkyl-O- a C 3-8 cycloalkyl group, a halogenated C 3-8 cycloalkyl group, and a C 6-10 monocyclic or bicyclic aryl group;
  • W is selected from N, N-O and CRb, and Rb is as defined above.
  • the "5 to 14 membered aza fused ring system” refers to a 5 to 14 membered fused bicyclic carbocyclic group that shares two mutually bonded carbon atoms, with the exception of a shared carbon atom. At least one (e.g., 1, 2 or 3) ring carbon atoms are replaced by nitrogen atoms.
  • the compound of formula (I) does not include: 2- ⁇ 5- ⁇ [5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4 -yl]methoxy ⁇ hexahydro-1H-isoindole-2(3H)-yl ⁇ benzo[d]thiazole-6-carboxylic acid; 2- ⁇ 5- ⁇ [5-cyclopropyl-3-( 2,6-dichlorophenyl)isoxazol-4-yl]methoxy ⁇ hexahydrocyclopenta[c]pyrrole-2(1H)-yl ⁇ benzo[d]thiazole-6-carboxylic acid ;2- ⁇ 5- ⁇ [5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl]methoxy ⁇ hexahydrocyclopenta[c]pyrrole- 2(1H)-yl ⁇ benzo[d]oxazo
  • compositions comprising a compound of formula (I) 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 encompasses 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 the pharmaceutical composition.
  • kits for preventing or treating a disease or condition mediated by FXR comprising:
  • a) a first container comprising at least one compound of the formula (I) as the first therapeutic agent or the pharmaceutical composition as the 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 invention further encompasses the compounds of formula (I) or the pharmaceutical compositions for use in preventing or treating a disease or condition mediated by FXR.
  • the invention further encompasses the use of a compound of formula (I) or a pharmaceutical composition for the manufacture of a medicament for the prevention or treatment of a disease or condition mediated by FXR.
  • the invention also includes a process for the preparation of a compound of the formula (I).
  • 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.
  • the compounds of the invention also show better drug safety.
  • 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.
  • the 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-
  • carbocyclyl and “carbocyclic” are used interchangeably herein to refer to any ring system wherein all ring atoms are carbon and contain from 3 to 14 ring carbon atoms, More suitably it contains from 3 to 12 carbon atoms, more suitably from 3 to 10 carbon atoms, and more suitably from 3 to 8 carbon atoms.
  • a carbocyclyl group can be saturated or partially unsaturated, but does not include a non-aromatic ring in which an aromatic ring is fused to an aromatic ring. Examples of carbocyclic groups include monocyclic ring systems, bicyclic ring systems, and tricyclic ring systems, particularly monocyclic ring systems and bicyclic ring systems.
  • Carbocyclyl groups include bridged ring systems (such as bicyclo [2.2.1] heptyl), fused ring systems (such as bicyclo [3.1.0] hexyl) or spiro ring systems (such as spiro[2.3] hexyl).
  • cycloalkyl refers to having from 3 to 12 carbon atoms (C 3-12 ), especially from 3 to 10 carbon atoms (C 3-10 ) or from 3 to 8 carbon atoms ( C 3-8 ) a saturated carbon ring in the form of a single ring.
  • the 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.
  • fused ring system means a fused bicyclic or polycyclic form of a carbocyclic group having 5 to 14 ring carbon atoms (C 5-14 ), wherein two carbon rings are fused. Share two carbon atoms that are bonded to each other.
  • the fused ring system is a fused bicyclic carbocyclic group that shares two carbon atoms bonded to each other.
  • Such fused ring systems may have, for example, 5 to 10 ring carbon atoms (C 5-10 ), especially 7 to 10 ring carbon atoms (C 7-10 ).
  • the two carbon rings of the C 7-10 fused ring system can be arranged into a 4-membered ring and a 5-membered ring (bicyclo[4,5] system), two 5-membered rings (bicyclo[5,5] system), 5 Yuan and 6-membered rings (bicyclo[5,6] systems), or two 6-membered rings (bicyclo[6,6] systems).
  • Examples of such fused ring systems include, but are not limited to, bicyclo [3.1.0] hexyl, bicyclo [3.2.0] heptyl, bicyclo [4.3.0] fluorenyl or bicyclo [4.4.0] fluorenyl.
  • the fused ring system can be optionally substituted with one or more (e.g., 1, 2, 3 or 4) suitable substituents.
  • aza fused ring system refers to a fused ring system as described above, wherein in one type of embodiment, at least one (eg, 1, 2 or 3) ring carbons other than a shared carbon atom.
  • the atom is replaced by a nitrogen atom; in another class of embodiments, at least one (eg, 1 or 2) of the shared carbon atoms is replaced by a nitrogen atom, and optionally, at least one other than the shared carbon atom (eg, 1 , 2 or 3) ring carbon atoms are replaced by nitrogen atoms.
  • the aza-fused ring system may have from 5 to 14 ring members, especially from 5 to 10 ring members, for example 6, 7, 8, or 9 ring members.
  • nitrogen heterofused ring systems include, but are not limited to, octahydrocyclopenta[c]pyrrole, octahydro-1H-indole, octahydro-1H-cyclopenta[c]pyridine, 3-aza [3.2.0] Heptane and octahydropyrrolo[1,2-a]pyrazine.
  • the aza fused ring system optionally additionally contains 1, 2 or 3 heteroatoms independently selected from N, O and S.
  • the aza-heavy ring system can be attached to the remainder of the molecule via a heteroatom (e.g., N) or a carbon atom.
  • the aza fused ring system 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.
  • 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 having, for example, 3 to 10 (suitably 3-8, more suitably 3-6) ring atoms, wherein At least one ring atom is a hetero atom selected from N, O and S and the remaining ring atoms are saturated (ie heterocycloalkyl) or partially unsaturated (ie having one or more double bonds in the ring and/or Or a triple bond) carbocyclic group.
  • a “3-10 membered heterocyclyl” is a ring carbon atom having 2-9 (eg, 2, 3, 4, 5, 6, 7, 8, or 9) and independently selected from N, O, and S.
  • heterocyclic groups include, but are not limited to, oxiranyl, aziridine, azetidinyl, oxetanyl, tetrahydrofuranyl, dioxolyl ( Dioxolinyl), pyrrolidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, Piperazinyl or trithianyl.
  • the 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, benzo[d]thiazolyl, benzo[d]isothiazolyl, 1H-benzene And [d] imidazolyl, imidazo[1,2-a]pyridyl, thiazolo[4,5-b]pyridyl, isothiazolo[4,5-c]pyridinyl, quinolyl, 1H- Mercapto, 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,
  • Heteroaryl can be optionally one One or more (eg, 1, 2, 3 or 4) substituents are substituted.
  • the substituent may be bonded to the C ring atom of the heteroaryl group or, if applicable, to the N ring atom of the heteroaryl group.
  • 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.
  • substituted means that one or more (eg, 1, 2, 3 or 4) hydrogens on the designated atom are replaced by the indicated group, provided that the specified atom is not exceeded in the current situation.
  • the lower normal valence and the substitution form a substantially stable compound.
  • optionally substituted means that the group may be unsubstituted or may be substituted with a specified group or group of atoms. If a group is described as “optionally substituted with”, the group may be substituted with (1) unsubstituted or (2) with a designated group.
  • 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 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 of the compound rotating the plane polarized light, where (-) or 1 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. Particular stereoisomers may also be referred to as enantiomers, and mixtures of such isomers are often referred to as enantiomeric mixtures.
  • 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.
  • the compounds of the invention may be prepared in racemic form, or a single enantiomer may be prepared by enantioselective synthesis or by resolution.
  • 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.
  • pharmaceutically acceptable salt refers to a pharmaceutically acceptable organic or inorganic salt of a compound of the invention.
  • exemplary salts include, but are not limited to, sulfates, citrates, isonicotinic acid salts, salicylates, acid citrates, tartrates, oleates, citrates, pantoates, hydrogen tartrate, Ascorbate, gentisate, gluconate, glucuronate, saccharide).
  • 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 invention may exist in the form of solvates (e.g., hydrates) wherein the compounds of the invention comprise a polar solvent which is a structural element of the crystal lattice of the compound, especially such as water, methanol or ethanol.
  • a polar solvent which is a structural element of the crystal lattice of the compound, especially 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, delipidization, 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 metabolic product thereof.
  • N-oxides 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.
  • the synthesis of N-oxides for the preparation of heterocyclic and tertiary amines is well known to those skilled in the art and includes the use of peroxyacids such as peroxyacetic acid and m-chloroperoxybenzoic acid (MCPBA), hydrogen peroxide, alkyl groups.
  • MCPBA m-chloroperoxybenzoic acid
  • Hydrogen peroxide such as t-butyl hydroperoxide, sodium perborate and dioxirane such as dimethyl dioxirane 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.
  • 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 whose position is isotopic.
  • 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 present invention provides a compound of the formula (I) or a stereoisomer, tautomer, polymorph, solvate thereof (e.g., hydrate), pharmaceutically acceptable salt, ester, metabolite, N-oxidation And the form and prodrug of its chemical protection.
  • the compound of the formula (I) has the following structure:
  • R 1 is selected from the group consisting of hydrogen, halogen, hydroxy, amino, C 1-6 alkyl, halo C 1-6 alkyl, hydroxy C 1-6 alkyl, C 1-6 alkyl-O-, -C ( O) NR 6 (CHR 3 ) q CO 2 R 4 , -C(O)NR 6 (CHR 3 ) q SO 3 R 5 , -ER 4 , -E-OR 4 , -E-CN, -E-NR 4 R 5 , C 3-10 cycloalkyl-O-, -OC 1-6 alkyl-OR 4 , -OC 3-10 heterocycloalkyl, -EC(O)OR 4 , -EC(O)R 4 , -EC(O)NR 4 R 5 , -EC(O)NR 4 SO 2 R 4 , -E-NR 4 C(O)R 4 , -E-SO x -R 4 , -E-SO 3 H, -E
  • R 3 , R 5 and R 6 are each independently selected from the group consisting of hydrogen, C 1-6 alkyl, halo C 1-6 alkyl and C 3-6 cycloalkyl;
  • Each R 4 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, halo C 1-6 alkyl, C 3-8 cycloalkyl, -C 1-6 alkyl-C 3-8 cycloalkyl, C a 3-8 heterocycloalkyl group, a -C 1-6 alkyl-C 3-8 heterocycloalkyl group, a 5- or 6-membered heteroaryl group, and an aryl group, wherein the alkyl group, cycloalkyl group, heterocycloalkyl group , aryl and heteroaryl are unsubstituted or selected from the group consisting of halogen, CN, OH, oxo, C(O)OH, C 1-3 alkyl, halo C 1-3 alkyl, SO 3 H, 1 , 2 , 3 or 4 substituents of C 1-3 alkyl-O-, halo C 1-3 alkyl-O- and -SO 2 -C 1-3 alkyl;
  • x 0, 1 or 2;
  • q 1, 2, 3, 4, 5 or 6;
  • B is selected from a C 6-14 aryl group and a 5 to 14 membered monocyclic or bicyclic heteroaryl group comprising 1, 2, 3, 4 or 5 heteroatoms independently selected from N, O and S, said aryl group Or a heteroaryl group is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, hydroxy, CN, amino, C 1-6 alkyl, C 1-6 alkyl- O-, C 1-6 alkyl-OC 1-6 alkyl-O-, halo C 1-6 alkyl, halo C 1-6 alkyl-O-, hydroxy C 1-6 alkyl, CN -C 1-6 alkyl, C 3-6 cycloalkyl and C 1-6 alkyl-S(O) m -;
  • N-linked B group is not directly adjacent to the -(CH 2 ) p -O- group;
  • each R 2 is independently selected from the group consisting of hydrogen, halogen, hydroxy, oxo, CN, C 1-6 alkyl, C 1-6 alkyl-O-, halo C 1-6 An alkyl group, a hydroxy C 1-6 alkyl group or a C 3-6 cycloalkyl group;
  • n 0, 1 or 2;
  • n 1, 2, 3 or 4;
  • p 0, 1, 2 or 3;
  • Each Ra is independently selected from C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 alkyl-O-, halo C 1-6 alkyl; halo C 3-8 cycloalkyl and Halogenated C 1-6 alkyl-O-;
  • Rb and Rc are independently selected from the group consisting of hydrogen, halogen, hydroxy, CN, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkyl-O-, halo C 1-6 alkyl- O-, C 3-8 cycloalkyl and halogenated C 3-8 cycloalkyl;
  • Rd is selected from a C 3-10 cycloalkyl or C 5-14 bridged ring system, a fused ring system or a spiro ring system, optionally substituted by 1, 2 or 3 Re;
  • Re is independently selected from the group consisting of hydrogen, halogen, hydroxy, CN, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkyl-O-, halo C 1-6 alkyl-O- a C 3-8 cycloalkyl group, a halogenated C 3-8 cycloalkyl group, and a C 6-10 monocyclic or bicyclic aryl group;
  • W is selected from N, N-O and CRb, and Rb is as defined above.
  • each R 2 is independently selected from the group consisting of hydrogen, halogen, hydroxy, CN, C 1-6 alkyl, C 1-6 alkyl-O-, halo C 1-6 alkyl, hydroxy C 1-6 alkyl or C 3-6 cycloalkyl.
  • the "5 to 14 membered aza fused ring system” refers to a 5 to 14 membered fused bicyclic carbocyclic group that shares two mutually bonded carbon atoms, wherein in addition to the shared carbon atom At least one (e.g., 1, 2, or 3) ring carbon atoms other than the nitrogen atom are replaced by a nitrogen atom.
  • the "5 to 14 membered aza fused ring system” refers to a 5 to 14 membered fused bicyclic carbocyclic group that shares two mutually bonded carbon atoms, wherein the shared carbon atom At least one (e.g., 1 or 2) is replaced by a nitrogen atom, and optionally, at least one (e.g., 1, 2, or 3) ring carbon atoms other than the common carbon atom are replaced by a nitrogen atom.
  • the compound of formula (I) does not include: 2- ⁇ 5- ⁇ [5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole-4 -yl]methoxy ⁇ hexahydro-1H-isoindole-2(3H)-yl ⁇ benzo[d]thiazole-6-carboxylic acid; 2- ⁇ 5- ⁇ [5-cyclopropyl-3-( 2,6-dichlorophenyl)isoxazol-4-yl]methoxy ⁇ hexahydrocyclopenta[c]pyrrole-2(1H)-yl ⁇ benzo[d]thiazole-6-carboxylic acid ;2- ⁇ 5- ⁇ [5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl]methoxy ⁇ hexahydrocyclopenta[c]pyrrole- 2(1H)-yl ⁇ benzo[d]oxazo
  • It is selected from a 5- to 10-membered saturated aza fused ring system which is bonded to B through a ring nitrogen atom; optionally, the 5 to 10 membered saturated aza fused ring system additionally contains 1 O atom or N atom.
  • h 0, 1, 2 or 3.
  • each R 2 is independently selected from the group consisting of hydrogen, halogen, hydroxy, oxo, C 1-6 alkyl, C 1-6 alkyl-O-, halo C 1-6 alkane Base; and n is 1 or 2.
  • each R 2 is independently selected from the group consisting of hydrogen, F, Cl, hydroxy, oxo, C 1-3 alkyl, C 1-3 alkyl-O-, halo C 1-3 alkyl In particular, it is selected from the group consisting of hydrogen, hydroxyl and oxo.
  • p is 0, 1 or 2, in particular 0 or 1.
  • the parts together form a structure selected from the following:
  • the parts together may also form a structure selected from the following:
  • Part of the structure selected from the following:
  • R 1 is selected from the group consisting of hydrogen, halogen, hydroxy, amino, C 1-4 alkyl, halo C 1-4 alkyl, hydroxy C 1-4 alkyl, C 1- 4- alkyl-O-, -C(O)NR 6 (CHR 3 ) q CO 2 R 4 , -C(O)NR 6 (CHR 3 ) q SO 3 R 5 , -ER 4 , -E-OR 4 , -E-CN, -E-NR 4 R 5 , C 3-6 cycloalkyl-O-, -OC 1-4 alkyl-OR 4 , C 3-6 heterocycloalkyl-O-, -EC (O)OR 4 , -EC(O)R 4 , -EC(O)NR 4 R 5 , -EC(O)NR 4 SO 2 R 4 , -E-NR 4 C(O)R 4 , -E -SO x -R 4, -
  • R 1 is selected from the group consisting of hydrogen, halogen, hydroxy, C 1-3 alkyl, halo C 1-3 alkyl, hydroxy C 1-3 alkyl, C 1 -3 alkyl-O -, -C(O)NR 6 (CHR 3 ) q CO 2 R 4 , -C(O)NR 6 (CHR 3 ) q SO 3 R 5 , -E-OR 4 , -E-NR 4 R 5 , -OC 1-4 alkyl-OR 4 , -EC(O)OR 4 , -EC(O)NR 4 R 5 , -EC(O)NR 4 SO 2 R 4 , pyrrolyl, pyrazolyl, triazole , tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, imidazolyl, pyridyl
  • R 1 is selected from -C(O)NR 6 (CHR 3 ) q CO 2 R 4 , -C(O)NR 6 (CHR 3 ) q SO 3 R 5 , -EC(O)OR 4 and - EC(O)NR 4 R 5 .
  • E is a bond, a C 1-4 alkyl group or a C 3-5 cycloalkyl group. In a class of embodiments, E is a bond or an unsubstituted C 1-2 alkyl group, preferably a bond.
  • each R 4 is independently selected from hydrogen, C 1-4 alkyl, halo C 1-4 alkyl, C 3-6 cycloalkyl, -C 1-4 alkyl -C 3-6 cycloalkyl, C 3-6 heterocycloalkyl (for example, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl or tetrahydrothiopyranyl), -C 1-3 alkyl-C 3-6 heterocycloalkyl, 5- or 6-membered heteroaryl and phenyl.
  • each R 4 is independently selected from the group consisting of hydrogen and C 1-3 alkyl.
  • R 3 , R 5 and R 6 are each independently selected from the group consisting of hydrogen, C 1-3 alkyl, halo C 1-3 alkyl and cyclopropyl. In a class of embodiments, R 3 , R 5 and R 6 are each independently hydrogen. In a class of embodiments of the invention, q is 1, 2 or 3, preferably 1.
  • R 1 is selected from the group consisting of C(O)OH, CH 2 C(O)OH, C(O)NHCH 2 C(O)OH, C(O)NH 2 , C(O)NHCH 2 S(O) 2 OH, C(O)NH(CH 2 ) 2 S(O) 2 OH, C(O)NH(CH 2 ) 3 S(O) 2 OH and More preferably, R 1 is selected from the group consisting of C(O)OH, CH 2 C(O)OH, C(O)NHCH 2 C(O)OH, and C(O)NH 2 .
  • B is selected from C 6-10 monocyclic or bicyclic aryl groups and 5 to 10 members comprising 1, 2, 3 or 4 heteroatoms independently selected from N, O and S. Monocyclic or bicyclic heteroaryl.
  • the aryl or heteroaryl group is selected from the group consisting of phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, thienyl, oxazolyl, furyl, pyrrolyl, pyrazolyl, Triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, imidazolyl, triazinyl, oxadiazolyl, thiadiazolyl, benzothiazolyl, benzisothiazolyl, imidazopyridyl, Quinolinyl, fluorenyl, pyrroloazinyl, benzofuranyl, benzothienyl, oxazolyl, benzoxazolyl, benzisoxazolyl, quinazolinyl, pyrrolopyridinyl , pyrazolopyrimidinyl, imi
  • the aryl or heteroaryl is selected from the group consisting of phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, oxazolyl, benzo[d]thiazolyl, benzo[d Isothiazolyl, 1H-benzo[d]imidazolyl, imidazo[1,2-a]pyridyl, thiazolo[4,5-b]pyridyl, isothiazolo[4,5-c]pyridine , quinolyl, 1H-indenyl, pyrrolo[1,2-b]pyridazinyl, benzofuranyl, benzo[b]thienyl, 1H-carbazolyl, benzo[d] Azyl, benzo[d]isoxazolyl, quinazolinyl, 1H-pyrrolo[3,2-c]pyridyl, pyrazolo[
  • C 3-6 cycloalkyl e.g. cyclopropyl
  • halo C 1-6 alkyl (E.g. C 1-3 alkyl), C 1-6 alkyl -O- (C 1-4 alkyl e.g. -O-), halo-C 1-6 alkyl group (e.g., halo C 1-3 alkyl And C 3-6 cycloalkyl (for example cyclopropyl).
  • the substituent may be bonded to the C ring atom of the heteroaryl group or, if applicable, to the N ring atom of the heteroaryl group.
  • B is a 5 or 6 membered monocyclic heteroaryl or a 9 or 10 membered bicyclic heteroaryl
  • B is a group represented by one of the following structural formulae:
  • Y 1 is CH or N;
  • Y 2 is CH or N; preferably, Y 1 is CH and Y 2 is CH; or Y 1 is N and Y 2 is CH; or Y 1 is CH and Y 2 is N;
  • Y 6 is CH or N
  • Y 7 is S, O or NR g
  • R g is H or C 1-6 alkyl, preferably H
  • Y 2 and Y 13 are both CH; or, either Y 12 and Y 13 are CH, the other is N; Y 14 is CH or N; Y 15 is CH or N; Y 16 is S , O or NR h , Rh is H or C 1-6 alkyl (eg C 1-3 alkyl);
  • B is pyridyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, benzo[d]thiazolyl, benzo[d]isothiazolyl, 1H-benzo[d]imidazolyl, Imidazo[1,2-a]pyridinyl, thiazolo[4,5-b]pyridinyl, isothiazolo[4,5-c]pyridinyl, quinolinyl, 1H-indenyl, benzofuran , 1H-carbazolyl, benzo[d]oxazolyl, benzo[d]isoxazolyl, 1H-pyrrolo[3,2-c]pyridyl, imidazo[1,2-b] Pyridazinyl, 1H-[1,2,3]triazolo[4,5-b]pyridinyl or [1,2,4]triazolo[1,5-a]pyridinyl, pyrazoly
  • B is pyridyl, thiazolyl, benzo[d]thiazolyl, benzo[d]oxazolyl, 1H-carbazolyl, benzo[d]isothiazolyl, quinolyl;
  • B is unsubstituted or substituted with 1, 2 or 3 substituents independently selected from the group consisting of halogen, hydroxy, C 1-6 alkyl (eg, C 1-3 alkyl), C 1- 6 alkyl-O- (eg C 1-4 alkyl-O-), halogenated C 1-6 alkyl (eg halogenated C 1-3 alkyl), hydroxy C 1-6 alkyl (eg hydroxyl C) 1-3 alkyl) and C 3-6 cycloalkyl (for example cyclopropyl), preferably halogen, C 1-6 alkyl (eg C 1-3 alkyl), C 1-6 alkyl-O- ( For example, C 1-4 alkyl-O-), halogenated C 1-6 alkyl (eg, halogenated C 1-3 alkyl), and C 3-6 cycloalkyl (eg, cyclopropyl), and the substitution
  • the group may be attached to a C ring atom or, if applicable,
  • each Ra is independently selected from C 1-4 alkyl, C 3-6 cycloalkyl, C 1-4 alkyl-O-, halo C 1-4 alkyl, Halogenated C 3-6 cycloalkyl and halo C 1-4 alkyl-O-.
  • each Ra is independently selected from C 1-4 alkyl, halo C 1-4 alkyl (eg, F or Cl substituted C 1-4 alkyl) and C 3-6 cycloalkyl, such as methyl.
  • Z is And Rb and Rc are independently selected from the group consisting of hydrogen, halogen, hydroxy, CN, C 1-3 alkyl, halo C 1-3 alkyl, C 1-3 alkyl-O-, halo C 1-3 alkyl -O-, C 3-6 cycloalkyl and halogenated C 3-6 cycloalkyl.
  • Rb and Rc are independently selected from the group consisting of hydrogen, halogen, C1-3 alkyl, halo C1-3 alkyl, C1-3 alkyl-O-, halo C1-3 Alkyl-O-, such as hydrogen, F, Cl, Br, I, methyl, ethyl, n-propyl or isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, Chloromethyl, fluoroethyl, fluoropropyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, cyclopropyl or halocyclopropyl.
  • W is N; in yet another class of embodiments, W is CRb, and wherein Rb is as defined above, preferably hydrogen.
  • Z is Rd.
  • Rd is selected from a C3-6 cycloalkyl group or a C5-11 saturated bridged ring system, a saturated fused ring system, or a saturated spiro ring system, optionally substituted with 1, 2, or 3 Re.
  • Rd is selected from bicyclo[3.1.0]hexyl, spiro[2.3]hexyl, bicyclo[3.1.1]heptyl, spiro[2.5, optionally substituted with 1, 2 or 3 Re.
  • Re is independently selected from the group consisting of hydrogen, halogen, hydroxy, CN, C 1-3 alkyl, halo C 1-3 alkyl, C 1-3 alkyl-O-, halo C 1-3 Alkyl-O-, C 3-6 cycloalkyl, halogenated C 3-6 cycloalkyl, and phenyl.
  • Re is independently selected from the group consisting of hydrogen, C1-3 alkyl, C3-6 cycloalkyl (such as cyclopropyl), and phenyl.
  • D is selected from:
  • D is further selected from:
  • the halogen is selected from the group consisting of F, Cl, Br and I, preferably F or Cl.
  • the compound of formula (I) of the invention is selected from the group consisting of:
  • the compound of the formula (I) of the invention is selected from the following compounds or any combination thereof:
  • 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.
  • tautomer or “tautomeric form” refers to a structural isomer that differs in energy that can be converted 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.
  • a pharmaceutical composition comprising at least one of the compounds of the formula (I), stereoisomers, tautomers, polymorphs, solvates thereof of the invention as described above (for example, a hydrate, a pharmaceutically acceptable salt, an ester, a metabolite, an N-oxide, a chemically protected form or prodrug 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, especially for injections.
  • 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, especially for injections.
  • 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'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), stereoisomers, tautomers, polymorphs, solvates (e.g., 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), stereoisomers, tautomers, polymorphs, solvates thereof (eg, hydrates) of the invention, 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 a foot Sufficient, and in other cases, larger doses may still be employed without causing any deleterious side effects, provided that the larger dose is first divided into several smaller doses for administration 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, particularly preferably from 1 to 50 mg, for example 1.5. Mg, 2 mg, 4 mg, 10 mg, 25 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), stereoisomers, tautomers, polymorphs, solvates e.g., hydrates
  • pharmaceutically acceptable salts esters
  • esters metabolite, N-oxide, its chemically protected form or prodrug
  • the combination therapies of the invention comprise the administration of at least one compound of the general formula (I), stereoisomers, tautomers, polymorphs, solvates thereof (e.g. hydrates), 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.
  • metabolites of the compounds of formula (I) described herein are also within the scope of the invention. Such products may be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, delipidization, enzymatic hydrolysis, and the like of the administered compound. Accordingly, the invention includes metabolites of the compounds of formula (I), including those prepared by contacting a compound of the invention with a mammal for a time sufficient to produce its metabolites.
  • 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.
  • kits 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, a solvate (such as a hydrate), as a first therapeutic agent, A pharmaceutically acceptable salt, ester, metabolite, N-oxide, or chemically protected form or prodrug thereof, or a pharmaceutical composition of the invention as a first pharmaceutical composition.
  • the kit may also include a label or package insert on or associated with the container.
  • the term "package insert” refers to instructions generally included in commercial packages of therapeutic products that include indications, usage, dosage, administration, contraindications, and/or warnings associated with the use of the therapeutic product. information.
  • 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 pharmaceutical composition comprising the other therapeutic agent of the 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 present.
  • 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.
  • a further object of the invention is to provide a process for the preparation of a compound of the formula (I) according to the invention, which process comprises the steps of:
  • X is a halogen (e.g., F, Cl, Br, or I);
  • PG is a protecting group, and in one embodiment, PG is R"-OC(O)-, wherein R" is selected from C1-6 alkyl (particularly C 1-4 alkyl) and benzyl, which are optionally independently selected from one or more of halogen (eg F, Cl, Br or I) and nitro (eg 1, 2, 3 or 4)
  • the PG may be selected from the group consisting of trichloroethoxycarbonyl, dichloroethoxycarbonyl, monochloroethoxycarbonyl, tert-butoxycarbonyl (Boc), benzyloxycarbonyl and 3,5-di Nitrobenzyloxycarbonyl, preferably Boc;
  • Y is halogen (for example F, Cl, Br or I), sulfonyl (for example trifluoromethanesulfonyl or p-tolu
  • the reaction is preferably carried out in a suitable organic solvent.
  • the organic solvent may be selected from the group consisting of tetrahydrofuran, ethers (e.g., diethyl ether, ethylene glycol monomethyl ether, etc.), N-methylpyrrolidone, dimethylformamide, dimethylacetamide, dioxane, dimethyl Sulfone and any combination thereof, preferably tetrahydrofuran.
  • the reaction is preferably carried out in the presence of a suitable alkali metal alkoxide and a catalyst.
  • the catalyst may be a catalyst system comprising a crown ether, which may be selected from the group consisting of sodium t-butoxide, potassium t-butoxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, and the crown ether is optional. From 15-crown-5 and 18-crown-6.
  • 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 - Crown ether-5 combination or uncle A combination of potassium butoxide and 18-crown-6.
  • 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 1-3 h, for example 2 or 2.5 h.
  • the reaction for removing the protective group PG 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 protecting group PG is R"-OC(O)- (e.g., Boc) as defined above
  • the compound IN-3 is an ester, and the reaction is preferably carried out by acid hydrolysis of the ester in the presence of an acid.
  • the acid may be a solution of a mineral acid in an organic solvent, such as a hydrogen chloride solution in dioxane; or a suitable organic acid such as a carboxylic acid or a halogenated acid including, but not limited to, formic acid, fluoroacetic acid , difluoroacetic 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 1-3 h, for example 2 h.
  • compound IN-4 is subjected to a substitution reaction with compound IN-5 to give compound IN-6.
  • 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 such as an organic amine such as triethylamine, N,N-diisopropylethylamine, or N-methylmorpholine or pyridine, preferably N,N-diisopropyl B. amine.
  • the substitution reaction is preferably carried out at a suitable temperature.
  • the temperature may be, for example, 100 to 140 ° C, preferably 120 ° C or 130 ° C.
  • the substitution reaction is preferably carried out for a suitable period of time, for example 2 to 24 hours, 2 to 18 hours or 2 to 12 hours, in particular 2 to 6 hours, for example 3, 4 or 5 hours.
  • compound IN-4 is coupled with compound IN-5 to give compound IN-6.
  • 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, triphenylphosphine palladium, 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 RuPhos, XPhos, SPhos and CPhos, preferably RuPhos.
  • 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 in a suitable protective atmosphere (e.g. N 2 environment) under performed.
  • the coupling reaction is carried out at a suitable temperature, which may be, for example, 70-100 ° C, preferably 80 ° C.
  • the coupling reaction is carried out for a suitable period of time, for example 1-3 h, for example 2 h.
  • the reaction for removing the protecting group is preferably carried out in a suitable organic solvent.
  • the organic solvent may be selected from the group consisting of tetrahydrofuran, ethers (such as diethyl ether, ethylene glycol monomethyl ether, etc.), N-methylpyrrolidone, dimethylformamide, dimethylacetamide, dioxane, dichloromethane, and Any combination thereof is preferably tetrahydrofuran.
  • the compound IN-6 is an ester, and the reaction is preferably carried out by an alcoholysis reaction of the ester in the presence of an alcohol and a basic catalyst.
  • the alcohol may be, for example, methanol or ethanol.
  • the basic catalyst 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, for example, from room temperature to 80 ° C, such as from 40 to 60 ° C.
  • the reaction is preferably carried out for a suitable period of time, for example 2 to 5 h, for example 3 or 4 h.
  • 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 invention relates to the intermediate compound IN-6:
  • R 1 ' represents a group having a removable protecting group and which can provide R 1 by removing the protecting group; and R 1 , B, ring R 2 , n, p and D are as defined above.
  • R 1 ' represents R "' - OC (O) -E-, R"'- OC (O) - (CHR 3) q NR 6 C (O) - , or R "' - OS (O) 2 (CHR 3 ) q NR 6 C(O)-, wherein R"' is selected from C 1-6 alkyl (especially C 1-4 alkyl) and benzyl, optionally independently Substituted from one or more (eg 1, 2, 3 or 4) substituents selected from halogen (eg F, Cl, Br or I) and nitro, preferably selected from methyl, ethyl, propyl, iso a propyl group, a butyl group, an isobutyl group and a t-butyl group, more preferably a methyl group; and wherein E, R 3 , R 6 , q, B, ring R 2, n, p and D are as defined above.
  • compound IN-6 is selected from the group consisting of:
  • compound IN-6 is selected from the following compounds or any combination thereof:
  • 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 by thin layer chromatography using an aluminum plate (20 x 20 cm) manufactured by Merck using GF 254 (0.4 to 0.5 nm).
  • reaction was monitored by thin layer chromatography (TLC) or LCMS using the developing solvent system: dichloromethane and methanol system, n-hexane and ethyl acetate system, petroleum ether and ethyl acetate system, solvent volume ratio according to compound
  • TLC thin layer chromatography
  • LCMS LCMS using the developing solvent system: dichloromethane and methanol system, n-hexane and ethyl acetate system, petroleum ether and ethyl acetate system, solvent volume ratio according to compound
  • the polarity is adjusted differently or adjusted by adding triethylamine or the like.
  • 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.
  • the compound obtained in the first step (68 mg, 2.57 mmol) was dissolved in dry THF (10 mL), then t-BuOK (0.58 g, 5.14 mmol), 18-crown-6 (1.36 g, 5.14 mmol) and 4- (Chloromethyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole (771 mg, 2.57 mmol) was stirred at room temperature for 2 hr. Water and ethyl acetate were added to the mixture, and the mixture was evaporated.
  • the third step 5-cyclopropyl-3-(2,6-dichlorophenyl)-4-((((3aR,5r,6aS)-octahydrocyclopenta[c]pyrrole-5-) Preparation of oxy)methyl)isoxazole
  • the fourth step 2-((3aR,5r,6aS)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) Preparation of Methyl Hydrocyclopenta[c]pyrrole-2(1H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylate
  • the compound obtained in the third step (135 mg, 0.35 mmol) was dissolved in DMA (4 mL), and 2-bromo-4-fluorobenzo[d]thiazole-6-carboxylic acid methyl ester (100 mg, 0.35 mmol) and DIPEA (0.45 g) , 3.5 mmol), stirred at 100 ° C - 110 ° C for 4 hours. After cooling, water and ethyl acetate were added to the mixture, and the mixture was evaporated.
  • Step 5 2-((3aR,5r,6aS)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) Preparation of Hydrocyclopenta[c]pyrrole-2(1H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid
  • the compound obtained in the first step (0.68 mg, 2.57 mmol) was dissolved in dry THF (10 mL), and then t-BuOK (0.58 g, 5.14 mmol), 18-crown-6 (1.36 g, 5.14 mmol) and 4 -(Chloromethyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole (771 mg, 2.57 mmol) was stirred at room temperature for 2 hr. Water and ethyl acetate were added to the mixture, and the mixture was evaporated.
  • the fourth step 2-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) Preparation of Methyl Hydrocyclopenta[c]pyrrole-2(1H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylate
  • the compound obtained in the third step (135 mg, 0.35 mmol) was dissolved in DMA (4 mL), and 2-bromo-4-fluorobenzo[d]thiazole-6-carboxylic acid methyl ester (100 mg, 0.35 mmol) and DIPEA (0.45 g) , 3.5 mmol), stirred at 100 ° C - 120 ° C for 4 hours. After cooling, water and ethyl acetate were added to the mixture, and the mixture was evaporated.
  • Step 5 2-((3aR,5s,6aS)-5-((5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) Preparation of Hydrocyclopenta[c]pyrrole-2(1H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid
  • Second step 6-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) Preparation of hydrogencyclopenta[c]pyrrole-2(1H)-yl)nicotinic acid
  • Methyl 4-amino-3-hydroxybenzoate (1.0 g, 5.98 mmol) was dissolved in tetrahydrofuran (50 mL). After the reaction mixture was diluted with dilute hydrochloric acid to dryness, EtOAc (EtOAc).
  • the third step 2-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) Preparation of Methyl Hydrocyclopenta[c]pyrrole-2(1H)-yl)benzo[d]oxazole-6-carboxylate
  • the fourth step 2-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) Preparation of Hydrocyclopenta[c]pyrrole-2(1H)-yl)benzo[d]oxazole-6-carboxylic acid
  • the third step 2-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) Preparation of Methyl Hydrocyclopenta[c]pyrrole-2(1H)-yl)-4-methoxybenzo[d]thiazole-6-carboxylate
  • the fourth step 2-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) Preparation of Hydrocyclopenta[c]pyrrole-2(1H)-yl)-4-methoxybenzo[d]thiazole-6-carboxylic acid
  • the compound obtained in the first step (0.79 g, 4.18 mmol) was dissolved in DMF (10 mL). Water and ethyl acetate were added to the mixture, and the mixture was evaporated.
  • the benzotriazole compound (0.25g, 2.07mmol) dissolved in dry DCM (10mL), was added dropwise at 0 °C SOCl 2 (92.6mg, 2.07mmol ). After stirring at room temperature for 30 min, the compound obtained in the fourth step (0.45 g, 1.59 m mol) was further added until TLC showed that the starting material was completely reacted. Water and ethyl acetate were added to the mixture, and the mixture was evaporated.
  • Step 6 (3aR, 5s, 6aS)-5-((5-cyclopropyl-3-(2-trifluoromethylphenyl)isoxazol-4-yl)methoxy)hexahydrocyclopentane
  • Step 7 5-cyclopropyl-3-(2-trifluoromethylphenyl)-4-((((3aR,5s,6aS)-octahydrocyclopenta[c]pyrrole-5-) Preparation of oxy)methyl)isoxazole
  • Step 8 2-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2-trifluoromethylphenyl)isoxazol-4-yl)methoxy) Preparation of Methyl Hydrocyclopenta[c]pyrrole-2(1H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylate
  • Step 9 2-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2-trifluoromethylphenyl)isoxazol-4-yl)methoxy) Preparation of Hydrocyclopenta[c]pyrrole-2(1H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid
  • the title compound was synthesized in the same manner as in the second step of Example 8.
  • the compound obtained in the first step of this Example (2.1 g, 0.011 mol) was used in place of 2-trifluoromethylbenzaldehyde oxime to give the title compound ( 2.2 g, yield: 90.5%).
  • the third step preparation of methyl 5-cyclopropyl-3-(2-difluoromethoxyphenyl)isoxazole-4-carboxylate
  • the fourth step preparation of (5-cyclopropyl-3-(2-difluoromethoxyphenyl)isoxazol-4-yl)methanol
  • Step 6 (3aR, 5s, 6aS)-5-((5-cyclopropyl-3-(2-difluoromethoxyphenyl)isoxazol-4-yl)methoxy)hexahydrocyclohexane
  • Step 7 5-cyclopropyl-3-(2-difluoromethoxyphenyl)-4-((((3aR,5s,6aS)-octahydrocyclopenta[c]pyrrole-5) Preparation of -yl)oxy)methyl)isoxazole
  • Step 8 2-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2-difluoromethoxyphenyl)isoxazol-4-yl)methoxy) Preparation of methyl hexahydrocyclopenta[c]pyrrole-2(1H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylate
  • Step 9 2-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2-difluoromethoxyphenyl)isoxazol-4-yl)methoxy) Preparation of Hexahydrocyclopenta[c]pyrrole-2(1H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid
  • the first step preparation of 2,6-difluorobenzaldehyde oxime
  • the title compound was synthesized in the same manner as in the second step of Example 8.
  • the compound obtained in the first step of this Example (3.0 g, 0.019 mol) was used in place of 2-trifluoromethylbenzaldehyde oxime to give the title compound ( 3.2 g, yield: 88.9%).
  • the third step preparation of methyl 5-cyclopropyl-3-(2,6-difluorophenyl)isoxazole-4-carboxylate
  • Step 5 Preparation of 4-(chloromethyl)-5-cyclopropyl-3-(2,6-difluorophenyl)isoxazole
  • Step 6 (3aR, 5s, 6aS)-5-((5-cyclopropyl-3-(2,6-difluorophenyl)isoxazol-4-yl)methoxy)hexahydrocyclopentane
  • Step 7 5-cyclopropyl-3-(2,6-difluorophenyl)-4-((((3aR,5s,6aS)-octahydrocyclopenta[c]pyrrole-5-) Preparation of oxy)methyl)isoxazole
  • Step 8 2-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2,6-difluorophenyl)isoxazol-4-yl)methoxy) Preparation of Methyl Hydrocyclopenta[c]pyrrole-2(1H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylate
  • the ninth step 2-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2,6-difluorophenyl)isoxazol-4-yl)methoxy) Preparation of Hydrocyclopenta[c]pyrrole-2(1H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid
  • Example 14 2-((3aS,5R,7aR)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) Hydrogen-1H-isoindole-2(3H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid (Compound 15-A) and 2-((3aR,5S,7aS)-5-( (5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)hexahydro-1H-isoindole-2(3H)-yl)-4- Preparation of fluorobenzo[d]thiazole-6-carboxylic acid (Compound 15-B)
  • Second step 5-cyclopropyl-3-(2,6-dichlorophenyl)-4-((((3aS,5R,7aR)-octahydro-1H-isoindole-5-yl)oxy) Methyl)isoxazole (Compound 15-3A) and 5-cyclopropyl-3-(2,6-dichlorophenyl)-4-((((3aR,5S,7aS)-octahydro- Preparation of 1H-isoindole-5-yl)oxy)methyl)isoxazole (Compound 15-3B)
  • the product from the first step (125 mg, 0.25 mmol) was dissolved in DCM (4 mL). Stir at room temperature for 2 hours until TLC showed the starting material was completely. The mixture was concentrated to give the desired product of this step. The obtained product was used in the next reaction without purification.
  • the third step 2-((3aS,5R,7aR)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) Methyl-1H-isoindole-2(3H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylate (Compound 15-4A) and 2-((3aR,5S,7aS)-5 -((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)hexahydro-1H-isoindole-2(3H)-yl)- Preparation of methyl 4-fluorobenzo[d]thiazole-6-carboxylate (Compound 15-4B)
  • the fourth step 2-((3aS,5R,7aR)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) Hydrogen-1H-isoindole-2(3H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid (Compound 15-A) and 2-((3aR,5S,7aS)-5-( (5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)hexahydro-1H-isoindole-2(3H)-yl)-4- Preparation of fluorobenzo[d]thiazole-6-carboxylic acid (Compound 15-B)
  • Second step 2-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) Preparation of Hydrocyclopenta[c]pyrrole-2(1H)-yl)benzo[d]thiazole-6-carboxylic acid
  • Second step 2-((3aR,5S,6aS)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) Preparation of Hydrocyclopenta[c]pyrrole-2(1H)-yl)-4-fluorobenzo[d]thiazole-6-carboxamido)acetic acid
  • Second step 6-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)methoxy
  • the title compound was synthesized in the same manner as in the first step of the procedure.
  • the title compound was obtained by substituting 6-chloro-nicotinic acid methyl ester (51 mg, 0.2 mmol) with methyl 6-chloro-5-fluoronicotinate. 80 mg, yield: 81%).
  • the title compound was synthesized by the procedure of the first step of Example 18, using 6-chloro-nicotinic acid methyl ester (69 mg, 0.32 mmol) in place of methyl 6-chloro-5-fluoronicotinate to give the title compound (90 mg, Yield: 53%).
  • Second step 6-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)methoxy
  • Example 21 2-((3aR,5s,6aS)-5-(((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) Preparation of methyl)hexahydrocyclopenta[c]pyrrole-2(1H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid (Compound 37)
  • the compound obtained in the first step (140 mg, 0.20 mmol) was evaporated. The mixture was concentrated to give the title compound.
  • the third step 2-((3aR,5s,6aS)-5-(((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) Preparation of methyl)hexahydrocyclopenta[c]pyrrole-2(1H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid methyl ester
  • the compound obtained in the second step (111 mg, 0.28 mmol) was dissolved in DMA (4 mL), and 2-bromo-4-fluorobenzo[d]thiazole-6-carboxylic acid methyl ester (80.9 mg, 0.28 mmol) and DIPEA (0.36) g, 2.8 mmol), stirred at 100 ° C - 120 ° C for 4 hours. After cooling, water and ethyl acetate were added to the mixture, and the mixture was evaporated.
  • Example 22 2-((1R,5S)-6-((5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)-3- Azabicyclo[3.2.0]heptan-3-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid (Compound 38A) and 2-((1S,5R)-6-((5-cyclo) Propyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)-3-azabicyclo[3.2.0]heptan-3-yl)-4-fluorobenzene And [d] Preparation of thiazole-6-carboxylic acid (Compound 38B)
  • Second step 4-(((1R,5S)-3-azabicyclo[3.2.0]heptan-6-yl)oxy)methyl)-5-cyclopropyl-3-(2, 6-Dichlorophenyl)isoxazole trifluoroacetate (compound 38-3A) and 4-((((1S,5R)-3-azabicyclo[3.2.0]heptan-6-yl)) Preparation of oxy)methyl)-5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazole trifluoroacetate (compound 38-3B)
  • the product obtained in the first step (110 mg, 0.20 mmol) was dissolved in DCM (4mL) Stir at room temperature for 2 hours until TLC showed the starting material was completely. The mixture was concentrated to give the desired product of this step. The obtained compound was used in the next reaction without purification.
  • the third step 2-((1R,5S)-6-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)-3- Azabicyclo[3.2.0]heptan-3-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid methyl ester (compound 38-4A) and 2-((1S,5R)-6-( (5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)-3-azabicyclo[3.2.0]heptan-3-yl)- Preparation of methyl 4-fluorobenzo[d]thiazole-6-carboxylate (Compound 38-4B)
  • Step 4 2-((1R,5S)-6-((5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)-3- Azabicyclo[3.2.0]heptan-3-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid (Compound 38A) and 2-((1S,5R)-6-((5-cyclo) Propyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)-3-azabicyclo[3.2.0]heptan-3-yl)-4-fluorobenzene And [d] Preparation of thiazole-6-carboxylic acid (Compound 38B)
  • Example 23 2-((3aS,4R,6aR)-4-((5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)6 Hydrocyclopenta[c]pyrrole-2(1H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid (Compound 39A) and 2-((3aR,4S,6aS)-4- ((5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-yl Preparation of 4-fluorobenzo[d]thiazole-6-carboxylic acid (Compound 39B)
  • Second step 5-cyclopropyl-3-(2,6-dichlorophenyl)-4-((((3aS,4R,6aR)-octahydrocyclopentadiene[c]pyrrol-4-yl) Oxy)methyl)isoxazole trifluoroacetate (compound 39-3A) and 5-cyclopropyl-3-(2,6-dichlorophenyl)-4-((((3aR,4S) Of 6aS)-octahydrocyclopentadienyl[c]pyrrol-4-yl)oxy)methyl)isoxazole trifluoroacetate (Compound 39-3B)
  • the product obtained in the first step (200 mg, 0.42 mmol) was dissolved in DCM (4mL) Stir at room temperature for 2 hours until TLC showed the starting material was completely. The mixture was concentrated to give the desired product of this step. The obtained compound was used in the next reaction without purification.
  • the fourth step 2-((3aS,4R,6aR)-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) Hydrocyclopenta[c]pyrrole-2(1H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid (Compound 39A) and 2-((3aR,4S,6aS)-4- ((5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-yl Preparation of 4-fluorobenzo[d]thiazole-6-carboxylic acid (Compound 39B)
  • Example 24 2-((3aR,5S,7aS)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)hexa Hydrogen-1H-isoindole-2(3H)-yl)-4-methoxybenzo[d]thiazole-6-carboxylic acid (Compound 40A) and 2-((3aS,5R,7aR)-5-( (5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)hexahydro-1H-isoindole-2(3H)-yl)-4- Preparation of methoxybenzo[d]thiazole-6-carboxylic acid (Compound 40B)
  • Second step 2-((3aR,5S,7aS)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) Hydrogen-1H-isoindole-2(3H)-yl)-4-methoxybenzo[d]thiazole-6-carboxylic acid (Compound 40A) and 2-((3aS,5R,7aR)-5-( (5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)hexahydro-2H-isoindole-2(3H)-yl)-4- Preparation of methoxybenzo[d]thiazole-6-carboxylic acid (Compound 40B)
  • Example 25 2-((3aR,5S,7aS)-5-((5-cyclopropyl-3-(2,6-difluorophenyl)isoxazol-4-yl)methoxy)6 Hydrogen-1H-isoindole-2(3H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid (Compound 41A) and 2-((3aS,5R,7aR)-5-((5) -cyclopropyl-3-(2,6-difluorophenyl)isoxazol-4-yl)methoxy)hexahydro-1H-isoindole-2(3H)-yl)-4-fluorobenzene And [d] Preparation of thiazole-6-carboxylic acid (Compound 41B)
  • Example 26 6-((3aR,5S,7aS)-5-((5-cyclopropyl-3-(2-(difluoromethoxy)phenyl)isoxazol-4-yl)methoxy Hexyl)hexahydro-1H-isoindole-2(3H)-yl)-5-fluoronicotinic acid (compound 42A) and 6-((3aS,5R,7aR)-5-((5-cyclopropyl-) 3-(2-(Difluoromethoxy)phenyl)isoxazol-4-yl)methoxy)hexahydro-1H-isoindole-2(3H)-yl)-5-fluoronicotinic acid Preparation of Compound 42B)
  • the third step 6-((3aR,5S,7aS)-5-((5-cyclopropyl-3-(2-(difluoromethoxy)phenyl)isoxazol-4-yl)methoxy Methyl hexahydro-1H-isoindole-2(3H)-yl)-5-fluoronicotinate (compound 42-4A) and 6-((3aS,5R,7aR)-5-((5- Cyclopropyl-3-(2-(difluoromethoxy)phenyl)isoxazol-4-yl)methoxy)hexahydro-1H-isoindole-2(3H)-yl)-5- Preparation of methyl fluoronicotinate (compound 42-4B)
  • Example 27 2-((7R,8aS)-7-((5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy))hexahydro Pyrrolo[1,2-a]pyrazine-2(1H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid (Compound 43A) and 2-((7S,8aR)-7-( (5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy))hexahydropyrrolo[1,2-a]pyrazine-2(1H) Of 4-fluorobenzo[d]thiazole-6-carboxylic acid (Compound 43B)
  • the product of the first step (130mg, 0.536mmol) was dissolved in dry tetrahydrofuran (20mL), under N 2 protection cooled to about 0 °C, potassium tert-butoxide (120mg, 1.073mmol) and 18-crown-6 (284 mg, 1.073 mmol).
  • Step 5 2-((7R,8aS)-7-((5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy))hexahydro Pyrrolo[1,2-a]pyrazine-2(1H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid (Compound 43A) and 2-((7S,8aR)-7-( (5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy))hexahydropyrrolo[1,2-a]pyrazine-2(1H) Of 4-fluorobenzo[d]thiazole-6-carboxylic acid (Compound 43B)
  • the product of the fourth step (150 mg, 0.243 mmol) was dissolved in methanol (5 mL). The mixture was stirred at 40 ° C overnight. The reaction was shown to be complete by LC-MS. Aqueous hydrochloric acid (2N) was added until the solution became acidic, and the mixture was concentrated directly. The desired product of this step was obtained by preparative HPLC (Compound 43 as a mixture of compound 43-A and 43-B; 59 mg, yield: 40.2% ).
  • Example 28 2-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2-(difluoromethyl)phenyl)isoxazol-4-yl)methoxy) Preparation of hexahydrocyclopenta[c]pyrrole-2(1H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid (Compound 44)
  • the 2-difluoromethyl-benzaldehyde (2g, 0.013mol) was dissolved in ethanol (30mL) and water (10mL), was added NaOH (0.92g, 0.026mol) and NH 2 OH.HCl (1.2g, 0.015mol) , The mixture was heated to reflux and stirred overnight. The reaction mixture was concentrated and filtered, and then filtered, and the title compound was obtained from the title compound (2.2 g, yield: 100.0%).
  • the compound obtained in the first step (2 g, 11.7 mmol) was dissolved in DMF (20 mL). Water and ethyl acetate were added to the mixture, and the EA layer was evaporated.
  • the compound obtained in the third step (1 g, 3.4 mmol) was dissolved in dry THF (20mL), and LiAlH 4 (0.26 g, 6.8 mol) was added. The mixture was stirred at 0 ° C until TLC showed the starting material was completely. To the mixture was added sodium sulfate decahydrate to terminate the reaction, which was filtered, dried, and evaporated.
  • Step 5 Preparation of 4-(chloromethyl)-5-cyclopropyl-3-(2-(difluoromethyl)phenyl)isoxazole
  • the benzotriazole (0.75g, 6.56mmol) was dissolved in dry DCM (20mL), was added dropwise SOCl 2 (0.78g, 6.56mmol) at 0 °C. After stirring at room temperature for 30 min, the compound obtained in the fourth step (0.9 g, 3.28 m mol) was added until TLC showed that the starting material was completely reacted. Water and ethyl acetate were added to the mixture, and the mixture was evaporated.
  • Step 6 (3aR, 5s, 6aS)-5-((5-cyclopropyl-3-(2-(difluoromethyl)phenyl)isoxazol-4-yl)methoxy)hexahydro
  • Step 7 5-cyclopropyl-3-(2-(difluoromethyl)phenyl)-4-((((3aR,5s,6aS)-octahydrocyclopenta[c]pyrrole- Preparation of 5-yl)oxy)methyl)isoxazole trifluoroacetate
  • Step 8 2-((3aR,5s,6aS)-5-((5-Cyclopropyl-3-(2-(difluoromethyl)phenyl)isoxazol-4-yl)methoxy) Preparation of methyl hexahydrocyclopenta[c]pyrrole-2(1H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylate
  • Step 9 2-((3aR,5s,6aS)-5-((5-Cyclopropyl-3-(2-(difluoromethyl)phenyl)isoxazol-4-yl)methoxy) Preparation of hexahydrocyclopenta[c]pyrrole-2(1H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid
  • Second step 7-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) Preparation of Hydrocyclopenta[c]pyrrole-2(1H)-yl)imidazo[1,2-a]pyridine-3-carboxylic acid
  • Second step 2-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) Preparation of Hydrocyclopenta[c]pyrrole-2(1H)-yl)-4-methylbenzo[d]thiazole-6-carboxylic acid
  • Example 31 2-((3aR,5S,7aS)-5-((5-cyclopropyl-3-(2-(difluoromethoxy)phenyl)isoxazol-4-yl)methoxy hexahydro-1H-isoindole-2(3H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid (Compound 48A) and 2-((3aS,5R,7aR)-5- ((5-Cyclopropyl-3-(2-(difluoromethoxy)phenyl)isoxazol-4-yl)methoxy)hexahydro-1H-isoindole-2(3H)-yl Preparation of 4-fluorobenzo[d]thiazole-6-carboxylic acid (Compound 48B)
  • Second step 5-cyclopropyl-3-(2-(difluoromethoxy)phenyl)-4-((((3aR,5S,7aS)-octahydro-1H-isoindole-5-) Ethyl)oxy)methyl)isoxazole trifluoroacetate (compound 48-3A) and 5-cyclopropyl-3-(2-(difluoromethoxy)phenyl)-4-((Preparation of (3aS,5R,7aR)-octahydro-1H-isoindol-5-yl)oxy)methyl)isoxazole trifluoroacetate (Compound 48-3B)
  • the third step 2-((3aR,5S,7aS)-5-((5-cyclopropyl-3-(2-(difluoromethoxy)phenyl)isoxazol-4-yl)methoxy Methyl hexahydro-1H-isoindole-2(3H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylate (compound 48-4A) and 2-((3aS,5R,7aR) -5-((5-Cyclopropyl-3-(2-(difluoromethoxy)phenyl)isoxazol-4-yl)methoxy)hexahydro-1H-isoindole-2 ( Preparation of 3H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid methyl ester (Compound 48-4B)
  • Second step 2-((3aR,5S,6aS)-5-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)methoxy Of hexahydrocyclopenta[c]pyrrole-2(1H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid
  • Example 36 2-((3aR,5S,6aS)-5-((5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazole-4-yl)methoxy Of hexahydrocyclopenta[c]pyrrole-2(1H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid (Compound 27)
  • the second step preparation of 3,5-dichloro-N-hydroxyisonicotinyl chloride
  • the title compound was synthesized in the same manner as in the second step of Example 8.
  • the compound obtained in the first step of this Example (2.0 g, 0.010 mol) was used in place of 2-trifluoromethylbenzaldehyde oxime to give the title compound ( 1.2 g, yield: 50.3%).
  • the third step preparation of methyl 5-cyclopropyl-3-(2,4-dichloropyridin-3-yl)isoxazole-4-carboxylate
  • Step 5 Preparation of 4-(chloromethyl)-5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazole
  • Step 6 (3aR, 5S, 6aS)-5-((5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)methoxy)
  • Step 7 5-Cyclopropyl-3-(3,5-dichloropyridin-4-yl)-4-((((3aR,5S,6aS)-octahydrocyclopenta[c]pyrrole) Preparation of 5-(5-yl)oxy)methyl)isoxazole
  • Step 8 2-((3aR,5s,6aS)-5-((5-Cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)methoxy Of hexahydrocyclopenta[c]pyrrole-2(1H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid methyl ester
  • Step 9 2-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(3,5-dichloropyridin-4-yl)isoxazol-4-yl)methoxy Of hexahydrocyclopenta[c]pyrrole-2(1H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid
  • Second step 6-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2-(difluoromethoxy)phenyl)isoxazol-4-yl)methoxy Of hexahydrocyclopenta[c]pyrrole-2(1H)-yl)-5-fluoronicotinic acid
  • Example 38 6-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)methoxy Of hexahydrocyclopenta[c]pyrrole-2(1H)-yl)-5-fluoronicotinic acid (Compound 50)
  • Second step 6-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)methoxy Of hexahydrocyclopenta[c]pyrrole-2(1H)-yl)-5-fluoronicotinic acid
  • Second step 6-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2-(difluoromethoxy)phenyl)isoxazol-4-yl)methoxy Of hexahydrocyclopenta[c]pyrrole-2(1H)-yl)nicotinic acid
  • Example 40 6-((3aR,5s,6aS)-5-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)methoxy Of hexahydrocyclopenta[c]pyrrole-2(1H)-yl)nicotinic acid (compound 52)
  • the title compound was synthesized in the same manner as in the first step of Example 2, using 5-cyclopropyl-4-((((3aR,5s,6aS)-octahydrocyclopenta[c]pyrrole-5). -yl)oxy)methyl)-3-(2-(trifluoromethoxy)phenyl)isoxazole (74 mg, 0.18 mmol) in place of 5-cyclopropyl-3-(2,6-dichloro Phenyl)-4-((((3aR,5s,6aS)-octahydrocyclopenta[c]pyrrole-5-yl)oxy)methyl)isoxazole, the title compound (27mg , yield: 27.8%).
  • Second step 6-((3aR,5r,6aS)-5-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)methoxy Of hexahydrocyclopenta[c]pyrrole-2(1H)-yl)nicotinic acid
  • Example 41 2-((3aR,5S,7aS)-5-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)methoxy Hexahydro-1H-isoindole-2(3H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid (Compound 53A) and 2-((3aS,5R,7aR)-5- ((5-Cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)methoxy)hexahydro-1H-isoindole-2(3H)-yl Preparation of 4-fluorobenzo[d]thiazole-6-carboxylic acid (Compound 53B)
  • the synthesis of the target product of this step was carried out in a similar manner to the first step of Example 31, using the compound 4-(chloromethyl)-5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl) Oxazole (74 mg, 0.18 mmol) was substituted for the compound 4-(chloromethyl)-5-cyclopropyl-3-(2-(difluoromethoxy)phenyl)isoxazole to obtain the target product of this step ( 118 mg, yield: 56.1%).
  • the synthesis of the target product of this step was carried out in a similar manner to the second step of Example 31, and the product of the first step of Example 31 (118 mg, 0.18 mmol) was used in place of the product of the first step of Example 31 to obtain the target product of this step.
  • the obtained product was used in the next reaction without purification.
  • the third step 2-((3aR,5S,7aS)-5-((5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)methoxy Methyl hexahydro-1H-isoindole-2(3H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylate (compound 53-4A) and 2-((3aS,5R,7aR) -5-((5-Cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazol-4-yl)methoxy)hexahydro-1H-isoindole-2 ( Preparation of 3H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid methyl ester (Compound 53-4B)
  • the synthesis of the target product of this step was carried out in the same manner as in the third step of Example 31, and the product of the second step of Example 31 was replaced with the product of the second step of the present example (97 mg, 0.23 mmol) to obtain the target product of this step ( 125 mg, yield: 87%).
  • the synthesis of the target product of this step was carried out in the same manner as in the fourth step of Example 31, and the product of the third step of Example 31 was replaced by the product of the third step of the present example (125 mg, 0.20 mmol) to obtain the target product of this step ( Compound 53, which is a mixture of Compounds 53A and 53B; 100 mg, yield: 80%).
  • Example 42 6-((3aR,5S,7aS)-5-((5-cyclopropyl-3-(2-(difluoromethoxy)phenyl)isoxazol-4-yl)methoxy Hexyl-1H-isoindolin-2(3H)-yl)nicotinic acid (54A) and 6-((3aS,5R,7aR)-5-((5-cyclopropyl-3-(2-) Preparation of (difluoromethoxy)phenyl)isoxazol-4-yl)methoxy)hexahydro-1H-isoindole-2(3H)-yl)nicotinic acid (54B)
  • Second step 6-((3aR,5S,7aS)-5-((5-cyclopropyl-3-(2-(difluoromethoxy)phenyl)isoxazol-4-yl)methoxy Hexyl-1H-isoindolin-2(3H)-yl)nicotinic acid (compound 54A) and 6-((3aS,5R,7aR)-5-((5-cyclopropyl-3-(2) -(Difluoromethoxy)phenyl)isoxazol-4-yl)methoxy)hexahydro-1H-isoindole-2(3H)-yl)nicotinic acid (Compound 54B)
  • Example 44 2-((3aR,5S,7aS)-5-((5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)methoxy) hexahydro-1H-isoindole-2(3H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid (56A) and 2-((3aS,5R,7aR)-5-(( 5-cyclopropyl-3-(2-(trifluoromethyl)phenyl)isoxazol-4-yl)methoxy)hexahydro-1H-isoindole-2(3H)-yl)-4 -Preparation of fluorobenzo[d]thiazole-6-carboxylic acid (56B)
  • the synthesis of the target product of this step was carried out in the same manner as in the first step of Example 31, using the compound 4-(chloromethyl)-5-cyclopropyl-3-(2-(trifluoromethyl)phenyl).
  • the azole (320 mg, 1.1 mmol) was substituted for the compound 4-(chloromethyl)-5-cyclopropyl-3-(2-(difluoromethoxy)phenyl)isoxazole to give the desired product (322 mg). , yield: 58.2%).
  • Second step 5-cyclopropyl-4-((((3aR,5S,7aS)-octahydro-1H-isoindol-5-yl)oxy)methyl)-3-(2-(three) Fluoromethyl)phenyl)isoxazole trifluoroacetate (compound 56-3A) and 5-cyclopropyl-4-((((3aS,5R,7aR)-octahydro-1H-isoindole- Preparation of 5-yl)oxy)methyl)-3-(2-(trifluoromethyl)phenyl)isoxazole trifluoroacetate (Compound 56-3B)
  • the synthesis of the target product of this step was carried out in the same manner as in the third step of Example 31, and the product of the second step of Example 31 was replaced by the product of the second step of the present example (160 mg, 0.39 mmol) to obtain the target product of this step ( 190 mg, yield: 79.5%).
  • the synthesis of the target product of this step was carried out in the same manner as in the fourth step of Example 31, and the product of the third step of the present example (190 mg, 0.31 mmol) was used instead of the product of the third step of Example 31 to obtain the target product of this step ( Compound 56, which is a mixture of Compounds 56A and 56B; 150 mg, yield: 80%).
  • Example 45 2-((3aR,4r,6aR)-4-((5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) A Hexahydrocyclopenta[c]pyrrole-2(1H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid (Compound 57A) and 2-((3aS,4s,6aS) 4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)methyl)hexahydrocyclopenta[c]pyrrole- Preparation of 2(1H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid (Compound 57B)
  • the title compound of this step was synthesized in a similar manner to the third step of Example 2, and the product of the first step of this example (234 mg, 0.46 mmol) was used in place of the compound (3aR, 5S, 6aS)-5-((5-ring) Propyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester The target product of this step. The obtained product was used in the next reaction without purification.
  • the third step 2-((3aR, 4r, 6aR)-4-(((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) Methyl)hexahydrocyclopenta[c]pyrrole-2(1H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid methyl ester (compound 57-4A) and 2-((3aS) ,4s,6aS)-4-(((5-cyclopropyl-3-) (2,6-dichlorophenyl)isoxazol-4-yl)methoxy)methyl)hexahydrocyclopenta[c]pyrrole-2(1H)-yl)-4-fluorobenzo Preparation of [d]methyl thiazole-6-carboxylate (Compound 57-4B)
  • Step 4 2-((3aR,4r,6aR)-4-((5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) A Hexahydrocyclopenta[c]pyrrole-2(1H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid (Compound 57-A) and 2-((3aS,4s, 6aS)-4-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy)methyl)hexahydrocyclopenta[c] Preparation of pyrrole-2(1H)-yl)-4-fluorobenzo[d]thiazole-6-carboxylic acid (Compound 57-B)
  • the third step preparation of 2-amino-5-bromo-3-fluorophenol
  • the fourth step preparation of 6-bromo-4-fluorobenzo[d]oxazole-2-thiol
  • the fourth step the obtained compound was dissolved in SOCl 2 (5mL), was added 3 drops of DMF, was heated at reflux for 20min, the reaction solution was evaporated to dryness, the residue was purified by preparative silica gel plate to afford the title compound (359mg, 75.8%).
  • Step 6 6-Bromo-2-((3aR,5S,6aS)-5-((5-cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)) Preparation of oxy)hexahydrocyclopenta[c]pyrrole-2(1H)-yl)-4-fluorobenzo[d]oxazole
  • Step 7 2-((3aR,5S,6aS)-5-((5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) Preparation of Hydrocyclopenta[c]pyrrole-2(1H)-yl)-4-fluorobenzo[d]oxazole-6-carbonitrile
  • Step 8 2-((3aR,5S,6aS)-5-((5-Cyclopropyl-3-(2,6-dichlorophenyl)isoxazol-4-yl)methoxy) Preparation of Hydrocyclopenta[c]pyrrole-2(1H)-yl)-4-fluorobenzo[d]oxazole-6-carboxylic acid
  • the compound obtained in the seventh step (513 mg, 0.93 mmol) was dissolved in EtOH (8 mL), 40% aqueous EtOAc (3 mL). The organic phase was purified by silica gel chromatography eluting
  • y is the FRET binding signal
  • max and min are the maximum and minimum values of the fitted curve
  • x is the logarithmic concentration of the compound
  • Hillslope is the slope of the curve.
  • Max represents the maximum activation effect of the compound of the present invention
  • Max' represents the maximum activation effect of CDCA, both of which are calculated by the formula shown above.
  • Integrated Table 2 and EC 50 values and relative potency activation data in Table 3 show that the compounds of the present invention have a good effect on FXR.
  • Compound 2, Compound 5, Compound 7, Compound 8, Compound 9, Compound 10, Compound 11, Compound 12, Compound 14, Compound 15, Compound 23, Compound 27, Compound 28, Compound 40 and Compound 53 showed strong The activation of FXR.
  • 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 shows the compound compound 2, compound 7, compound 8, compound 9, compound 12, compound 15-t(1), compound 15-t(2), compound 16, compound 22, compound 23, Compound 27, Compound 28, Compound 40, Compound 48, Compound 48-t(2), Compound 53 have an EC 50 value between 0.008 ⁇ M and 1.15 ⁇ M and an Emax value greater than 250% in an in vitro cell assay, indicating the above-described invention.
  • the compounds have good FXR activating activity in in vitro cellular assays.
  • mice Male C57BL/6 mice were fed a high-fat diet (feed formula: base diet + 10% sucrose + 10% lard + 5% cholesterol) for 1 month, and were randomly grouped according to animal body weight.
  • the treatment group was intragastrically administered with 10 mg/kg of the compound of the present invention, administered once a day for 14 days, and continued to be fed with a high-fat diet while administering.
  • the control group was given the same volume of physiological saline.
  • the TC reduction rate of the administration group was 100%* (control group TC-treatment group TC)/control group TC.
  • Table 5 shows that oral administration of 10 mg/kg of the compound of the present invention, Compound 2, Compound 23, Compound 48, Compound 48-t(2), for 14 consecutive days, can significantly reduce total cholesterol in hyperlipidemic mice. Level, the degree of reduction is between 20% and 60%. It is shown that the compounds of the present invention have good pharmacological effects in in vivo tests.
  • the compounds of the present invention and the positive compounds were administered to male SD rats by intravenous (IV) and gavage (PO), respectively, to examine the pharmacokinetic characteristics.
  • IV and PO were 1 mg/kg and 2 mg/kg, respectively, and the vehicle system was 5% DMSO: 5% Solutol: 90% normal saline.
  • IV and PO administration blood was collected at different time points, and the blood was anticoagulated with sodium heparin. After centrifugation, plasma samples were obtained and stored at -80 °C. Plasma samples were processed by precipitation protein and analyzed by LC-MS/MS.
  • Table 6-1 shows that the AUC last of the compound of the present invention and the compound 15 administered by IV at a dose of 1 mg/kg in the body were 552 h*ng/ml and 435 h*ng/ml, respectively, corresponding C Max was 1297 ng/ml and 1111 ng/ml, respectively, indicating that Compound 10 and Compound 15 of the present invention have excellent drug exposure in rats by IV administration.
  • Table 6-2 shows that the AUC last of the present compounds 10 and 15 administered by PO at a dose of 2 mg/kg in rats were 309 h*ng/ml and 209 h*ng/ml, respectively, and their bioavailability. The degrees were 28% and 24%, respectively, indicating that the compound 10 and the compound 15 of the present invention have excellent drug exposure and bioavailability in rats by PO administration.
  • 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.

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Abstract

L'invention concerne des dérivés d'azabicycle, leur procédé de préparation et leur utilisation. En particulier, l'invention concerne un composé agoniste de FXR et un stéréomère, un tautomérid, une substance polymorphe, un solvate (tel qu'un hydrate), un sel pharmaceutiquement acceptable, un ester, un métabolite, un N-oxyde de celui-ci et une forme chimiquement protégée et un promédicament de celui-ci. L'invention concerne également un procédé de préparation du composé, une composition pharmaceutique comprenant le composé, une boîte de médicament, et l'utilisation de celui-ci dans le traitement de maladies ou d'états à médiation par FXR.
PCT/CN2017/102883 2016-09-28 2017-09-22 Dérivés d'azabicycle, leur procédé de préparation et leur utilisation WO2018059314A1 (fr)

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