WO2016088903A1 - Composés hétérocycliques - Google Patents

Composés hétérocycliques Download PDF

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Publication number
WO2016088903A1
WO2016088903A1 PCT/JP2015/084734 JP2015084734W WO2016088903A1 WO 2016088903 A1 WO2016088903 A1 WO 2016088903A1 JP 2015084734 W JP2015084734 W JP 2015084734W WO 2016088903 A1 WO2016088903 A1 WO 2016088903A1
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group
compound
ring
membered
optionally
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PCT/JP2015/084734
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English (en)
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Anil M. DESHPANDE
Dinesh Barawkar
Santosh Patil
Digambar BANKAR
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Takeda Pharmaceutical Company Limited
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Publication of WO2016088903A1 publication Critical patent/WO2016088903A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to a novel heterocyclic compound having an EP4 receptor antagonistic action, and is useful as an agent -for the prophylaxis or treatment of EP4 receptor associated diseases (e.g., rheumatoid arthritis, aortic aneurysm, endometriosis, ankylosing spondylitis etc.) and the like.
  • EP4 receptor associated diseases e.g., rheumatoid arthritis, aortic aneurysm, endometriosis, ankylosing spondylitis etc.
  • PGE2 Prostaglandin E2
  • COX cyclooxygenases
  • EP4 receptor activation stimulates dendritic cells and promotes IL-23 production synergistically -with CD40 and Toll-like receptor signaling.
  • PGE2 then enhances the expansion of-Thl7 cells with IL-23.
  • EP4 receptor activation promotes the differentiation of Thl from naive T cells synergistically with _ IL-12.
  • PGE2 synergistically induces IL-6 and IL- ⁇ expression with LPS via EP4 receptors in macrophages.
  • Thl, .Thl7 and macrophage cells play key roles in the development of
  • a selective EP4 receptor antagonist is expected to inhibit IL-23 & IL-6
  • Thl & Thl7 function reduces inflammatory pain and offers an attractive therapeutic approach for rheumatoid arthritis (RA) , inflammatory bowel diseases and other autoimmune/ inflammatory diseases.
  • Non-steroidal anti-inflammatory drugs and COX-2 inhibitors are clinically proven to relieve ' inflammation and pain by inhibiting the synthesis of arachidonic acid pathway metabolites including PGE2.
  • NSAIDs non-steroidal anti-inflammatory drugs
  • COX-2 inhibitors are clinically proven to relieve ' inflammation and pain by inhibiting the synthesis of arachidonic acid pathway metabolites including PGE2.
  • their use is associated with adverse effects due to pleiotropic function of
  • aortic aneurysm e.g. abdominal aortic aneurysm, thoracic aortic aneurysm,, thoracoabdominal aortic aneurysm etc.
  • endometriosis e.g. abdominal aortic aneurysm, thoracic aortic aneurysm,, thoracoabdominal aortic aneurysm etc.
  • Endometriosis is a chronic, estrogen- dependent inflammatory disease and defined as the presence of functional endometrial tissue at ectopic sites. It is a common disease that 10-20% of women of reproductive . age are affected. The most common symptom is a dysmenorrhea. Chronic pelvic pain, dyspareunia, dyschezia (pain on defecation), loin pain, lower abdominal pain or back pain> pain on micturition, pain on exercise are also part of the symptoms of EM (non-patent document 9) . Current treatments include surgical intervention, pharmacotherapies using- NSAIDs, COX-2 inhibitors and hormonal therapies, or- a combination of both. NSAIDs or COX-2
  • inhibitors are effective in relieving pelvic pain, but can cause severe side effects including gastrointestinal injury, nephropathy, and increase cardiovascular risk (non-patent document 10) .
  • Hormonal therapy controls disease conditions, but has side effect such as pseudomenopause and decreased bone density due to suppression of estrogen production (non-patent document 11) .
  • Development of a safer, but equally efficacious treatment is highly demanded.
  • EP4 receptor proteins were
  • Non-patent document 12 selective inhibition of EP4 induced apoptosis
  • non-patent document 13 inhibited proliferation
  • non-patent document 14 inhibited migration and invasion
  • adhesion inhibited adhesion
  • Abdominal aortic aneurysm is a common, progressive, and life-threatening degenerative vascular disease (non-patent documents 16 and 17) . It is an inflammatory disorder
  • non-patent documents 18-20 characterized by localized connective tissue degeneration and smooth muscle cell apoptosis, leading to aortic dilatation and rupture. After rupture occurs, the probability of mortality is greater, than 60% (non-patent document 21). No pharmacotherapy has been found to be
  • AAAs except.
  • COX-2 is widely expressed in macrophages and smooth muscle cells, along with locally synthetized PGE2 ' (non-patent document 22).
  • EP4 expression is increased in the aneurysm areas. of human AAA tissues, both in human aortic aneurysm smooth muscle cell as well as in
  • EP4 receptor antagonist or global gene deletion of the EP4 receptor significantly decreased MMP-2 activation and IL-6 production in human AAA tissues and the rate of AAA formation in preclinical mouse models (non-patent document 23 and 25).
  • Ankylosing spondylitis is the prototypic
  • spondyloarthropathy one of a group of conditions which also includes psoriatic arthritis, reactive arthritis and arthritis complicating inflammatory bowel disease.
  • spondylitis is highly heritable (non-patent documents 26 and 27) and familial (non-patent document 28) . Men are affected 2- 3 times more frequently than women. The disease is known to be strongly associated with HLA-B27. Since association between EP4 receptor gene (PTGER4) and ankylosing spondylitis has been also demonstrated (non-patent document 29) , EP4 receptor is likely to be involved in disease pathogenesis. There is no cure for ankylosing spondylitis as yet, but the -patient? s back pain and stiffness usually show good symptomatic response to NSAIDs.
  • PTGER4 receptor gene PTGER4 receptor gene
  • EP4 antagonists are known to possess analgesic activity at least in animal models ( ⁇ -patent documents 30 and 31), a safe and chronically-treatable EP4 antagonist may be an alternative symptom-relieving pharmacotherapy for ankylosing spondylitis.
  • Examples of the compound having a structure similar to the compound described in the present specification include the following compounds.
  • Patent document 1 describes a compound represented by the formula:
  • A is hydrogen, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl / C 2 -C 6 -alkynyl, benzyl or C 3 -C 7 -cycloalkyl;
  • B is hydrogen, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, benzyl or C 3 -C 7 -cycloaikyl;
  • R 1 is hydrogen, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl or C 3 -C 7 -cycloalkyl
  • R 2 is hydrogen, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 3 -C 7 -cycloalkyl, C 1 -C 6 -alkylcarbonyl, C 1 -C 6 -alkoxycarbonyl, aitiinocarbonyl or hydrazinocarbonyl;
  • R 1 and R 2 together with the .carbon atom to which they are attached, form a C 3 -C 7 -cycloalkyl ring;
  • n 0 or 1
  • X is a bond or a C 1 -C 6 -alkylene
  • R3 is a 5- or 6-membered heteroaromatic ring which contains 1-4 heteroatoms, carbocyclic aromatic ring which may be
  • Non-Patent Document 1 Pharmacol. Rev., 2011. 63(3): p. 471-
  • Non-Patent Document 5 Immunity, 2010. 33(2): p. 150-2
  • Non-Patent Document 6 Thromb. Res., 2013. 132(1): .p. 56-62
  • Non-Patent Document 7 Postepy Hig. Med. Dosw., (Online),. 2012. 66: p. 287-94
  • Non-Patent Document 8 Br . J. Pharmacol., 2010. 160(2): p. 292-310
  • Non-Patent Document 9 BMJ, 2001. 323(7304): p. 93-5
  • Non-Patent Document 12 Mol. Endocrinol., 2009. 23(8): p. 1291-305 '
  • Non-Patent Document 15 Biol. Reprod, 2013. 88(3): p-. 77
  • Non-Patent Document 16 Arterioscler . Thromb. Vase. Biol., 1996. 16 ( 8) : p. 963-70
  • Non-Patent Document 17 N. Engl. J. Med., 1993. 328(16): p.
  • Non-Patent Document 18 J. Clin. Invest., 1998. 102(11): p. 1900-10
  • Non-Patent Document 20 J. Immunol., 2004. 172(4): p. 2607-12 .
  • Non-Patent Document 21 World J. Surg., 2008. 32(6): p. 976- 86
  • Non-Patent Document 22 Circulation, 1999. 100(1): p. 48-54
  • Non-Patent Document 23 PLoS One, 2012. 7(5): p. e36724
  • Non-Patent Document 24 J. Vase. Surg., 2003. 38 (2): p. 354-9
  • Non-Patent ⁇ . Document 25 Am. J. Pathol., 2012. 181(1): p. 313- 21
  • Non-Patent Document 26 Scand. J. Rheumatol., 2008. 37: p.
  • Non-Patent Document 27 Arthritis Rheum., 1997. 40: p. 1823- 1828
  • Non-Patent Document 28 Ann. Rheum. Dis., 2000. 59: p. 883- 886
  • Non-Patent Document 29 Nature Genetics., 2011. 43: p.. 761- 767
  • Non-Patent Document 30 Eur. J. Pharmacol., 2008, 580: p.
  • Non-Patent Document 31 Bioorg. Med. Chem. Lett., 2010. 15: p. 3760-3
  • the present invention aims to provide a novel
  • heterocyclic compound having an EP4 receptor antagonistic action and useful as an agent for the prophylaxis or
  • aortic aneurysm e.g. abdominal aortic aneurysm, thoracic aortic aneurysm, thoracoabdominal aortic aneurysm etc.
  • endometriosis ankylosing spondylitis etc.
  • aortic aneurysm e.g. abdominal aortic aneurysm, thoracic aortic aneurysm, thoracoabdominal aortic aneurysm etc.
  • endometriosis e.g., endometriosis
  • the present invention provides the following.
  • Ring A is an optionally further substituted 5- or 6-membered ring
  • G 1 is N, C or CR 4 ,
  • G 2 is N, C or CR 5 ,
  • R 4 is a hydrogen atom or a substituent
  • R 5 is a hydrogen atom or a. substituent
  • Ring B is an optionally further substituted 5-membered non- aromatic heterocycle containing 1 to 3 nitrogen atoms
  • Ring E is an optionally substituted C 3-6 cycloalkane or an optionally substituted heterocycle-,
  • R 1 and R 2 are each independently a hydrogen atom or an
  • R 1 and R 2 are joined together to form a cycloalkane or a heterocycle, each of which is optionally substituted,
  • R 3 is a hydrogen atom or a substituent
  • Ring C is an optionally further substituted ring
  • Ring D is an optionally further substituted ring
  • W is a bond, or a spacer in which the number of atoms in the . main chain is 1 to 4, or a salt thereof (hereinafter to be referred to as compound
  • Ring A is benzene optionally further substituted by 1 to 3 halogen atoms,
  • Ring E is a C 3-6 cycloalkane or a 3- to 14-membered non-aromatic heterocycle
  • R 1 and R 2 are each independently a hydrogen atom or a C 1- 6 alkyl group, or R 1 and R 2 are joined together to form a C 3-6
  • R 3 is a hydrogen atom
  • Ring C is a C 6-14 aromatic hydrocarbon ring or a 5- to 14- membered aromatic heterocycle, each of which is optionally further substituted by 1 to 3 substituents selected from a carboxy group and a G 1- 6 alkoxy-carbonyl group,
  • Ring D is a C 6-14 . aromatic hydrocarbon ring or a 5- to 14- membered aromatic heterocycle, each of which is optionally further substituted by 1 to 3 substituents selected from
  • W is -CH 2 -, -CH(CH 3 )-, -SO 2 -, -CH 2 CH 2 O- or -OCH 2 CH 2 - . ' .
  • a medicament comprising the compound or salt according to the above-mentioned [1] . '
  • a method of inhibiting EP4 receptor in a mammal which comprises administering an effective amount of the compound or salt according to' the above-mentioned [1] to the mammal.
  • a method for the. prophylaxis or treatment of EP4 receptor associated diseases in a mammal which comprises administering an effective amount of the compound or salt according to the above-mentioned [1] to the mammal.
  • spondylitis or inflammatory breast cancer which comprises administering an effective amount of the compound or salt according to the above-mentioned [1] to the mammal.
  • Compound (I) has a superior EP4 receptor antagonistic action, which is useful as an agent for the prophylaxis or treatment of EP4 receptor associated diseases (e.g.,
  • each substituent used in the present specification is described. in detail in the following. Unless otherwise specified, each substituent ' has the following
  • halogen atom examples include fluorine, chlorine, bromine and iodine.
  • examples of the "C 1- 6 alkyl group” include methyl, ethyl, propyl, .isopropyl, butyl,
  • examples of. the "optionally halogenated C 1- 6 alkyl group” include a C 1- 6 alkyl group
  • examples of the "C 2- 6 alkenyl group” include ethenyl, 1-propenyl, 2-propenyl, 2- methyl-l-propenyl, 1-butenyl, 2-butenyl, 3-butehyl, " 3-methyl-
  • examples of the "C 2- 6 alkynyl group” include ethynyl, 1-propynyl, 2-propynyl, 1- butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3- pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4- hexynyl, 5-hexynyl and 4-methyl-2-pentynyl .
  • examples of the "C 3-10 cycloalkyl group” include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl / bicyclo[3.2. l]octyl and adamantyl.
  • optionally halogenated C 3-10 cycloalkyl group include a C 3-10 cycloalkyl group optionally having 1 to 7, preferably 1 to 5, halogen atoms. Specific examples thereof include cyclopropyl, 2,2- difluorocyclopropyl, 2, 3-difluorocyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl .
  • examples of the "C 3-10 cycloalkenyl group” include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl .
  • examples of the "C 6-14 aryl group” include phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2- anthryl and 9-anthryl.
  • examples of the "C 7-16 aralkyl group” include benzyl, phenethyl, naphthylmethyl and phenylpropyl .
  • examples of the "C 1- 6 alkoxy group” include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy.
  • 'examples of the "optionally halogenated C 1 - 6 alkoxy group” include a C 1 - 6 alkoxy group optionally having 1 to 7, preferably 1 to 5, halogen atoms. Specific examples thereof include methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2, 2, 2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4, 4, 4-trifluorobutoxy, isobutoxy, sec- butoxy, pentyloxy and hexyloxy.
  • examples of the "C 3-10 cycloalkyloxy group” include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy and
  • examples of the "C 1 - 6 alkylthiio group” include methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, pentylthio and hexylthio.
  • examples of the "optionally halogenated C 1- 6 alkylthio group” include a C 1- 6 alkylthio group, optionally having 1 to 7, preferably 1 to 5/ halogen atoms .
  • difluoromethylthio trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4, 4, 4-trifluorobutylthio, pentylthio and hexylthio.
  • examples of the "C 1 - 6 alkyl- carbonyl group” include acetyl, propanoyl, butanoyl, 2- methylpropa.noyl, pentanoyl, 3-methylbutanoyl, 2-methylbutanoyl, 2 , 2-dimethylpropanoyI., hexanoyl and heptanoyl .
  • examples of the "optionally halogenated C 1- 6 alkyl-carbonyl group” include a C 1- 6 alkyl- carbonyl group optionally having 1 to 7, preferably 1 to 5, halogen atoms. Specific examples thereof include acetyl, chloroacetyl, trifluoroacetyl, trichloroacetyl, propanoyl, butanoyl, pentanoyl and hexanoyl.
  • examples of the "C 1- 6 alkoxy-carbonyl group” include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,
  • examples of the "C 6-14 aryl- carbonyl group” include- benzoyl, 1-naphthoyl and 2-naphthoyl.
  • examples of the "C 7-16 aralkyl-carbonyl group” include phenylacetyl and
  • examples of the "5- to 14- membered aromatic heterocyclylcarbonyl group” include
  • examples of the "3- to 14- membered non-aromatic heterocyclylcarbonyl group” include morpholinylcarbonyl, piperidinylcarbonyl and
  • examples of the "mono- or di-C 1 - 6 alkyl-carbamoyl group" include methylcarbamoyl
  • examples of the "mono- or di-C 7-16 aralkyl-carbamoyl group” include benzylcarbamoyl and phenethylcarbamoyl .
  • examples of the "C 1- 6 alkylsulfonyl group” include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, sec- butylsulfonyl and tert-butylsulfonyl .
  • examples of the "optionally halogenated C 1- 6 alkylsulfonyl group” include a C 1- 6
  • alkylsulfonyl group optionally having 1 to 7, preferably 1 to 5, halogen atoms. Specific examples thereof, include
  • examples of the "C 6-14 arylsulfonyl group” include phenylsulfonyl, 1-naphthylsulfonyl and 2-naphthylsulfonyl.
  • substituted include a halogen atom, a cyano group, a nitro group, an optionally substituted hydrocarbon group, an
  • optionally substituted heterocyclic group an acyl group, an optionally substituted amino group, an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group, an optionally substituted sulfamoyl group, an optionally
  • hydrocarbon group (including “hydrocarbon group” of
  • “optionally substituted hydrocarbon group” include a C 1 - 6 alkyl group, a C 2- 6 alkenyl group,, a C 2- 6 alkynyl group, a C 3-10 cycloalkyl group, a C 3-10 cycloalkenyl group, a C 6-14 aryl group and a C 7-16 aralkyl group.
  • examples of the "optionally substituted hydrocarbon group” include a hydrocarbon group optionally having substituent (s) selected from the following substituent group A.
  • a C 6-14 aryloxy group e.g., phenoxy, naphthoxy
  • a C 1 - 6 alkyl-carbonyloxy group e.g., acetoxy
  • a C 6 - 14 aryl-carbonyloxy group e.g., benzoyloxy, 1- naphthoyloxy, 2-naphthoyloxy
  • a C 6 - 14 aryl-carbonyloxy group e.g., benzoyloxy, 1- naphthoyloxy, 2-naphthoyloxy
  • a C 1 - 6 alkoxy-carbonyloxy group e.g., methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy
  • a C 1 - 6 alkoxy-carbonyloxy group e.g., methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy
  • a C 6-14 aryl-carbamoyloxy group e.g., phenylcarbamoyloxy, naphthyicarbamoyloxy
  • a 5- to 14-membered aromatic heterocyclylcarbonyloxy group e.g., nicotinoyloxy
  • a 3- to 14-membered non-aromatic heterocyclylcarbonyloxy group e.g., morpholinylcarbonyloxy, piperidinylcarbonyloxy
  • an optionally halogenated C 1 - 6 alkylsulfonyloxy group e.g. methylsulfonyloxy, trifluoromethylsulfonyloxy
  • a C 6-14 aryloxy-carbonyl group e.g., phenyloxycarbonyl, 1- naphthyloxycarbonyl, 2-naphthyloxycarbonyl
  • a C 7-16 aralkyloxy-carbonyl group e.g., benzyloxycarbonyl, phenethyloxycarbonyl
  • a C 6-14 aryl-carbamoyl group e.g., phenylcarbamoyl
  • a 5- to 14-membered aromatic heterocyclylcarbamoyl group e.g., pyridylcarbamoyl, thienylcarbamoyl
  • a 5- to 14-membered aromatic heterocyclylsulfonyl group e.g., pyridylsulfonyl, thienylsulfonyl
  • a 5- to 14-membered aromatic heterocyclylsulfonyl group e.g., pyridylsulfonyl, thienylsulfonyl
  • a C 6-14 arylsulfinyl group e.g., phenylsulfinyl, 1- naphthylsulfinyl, 2-naphthylsulfinyl
  • a 5- to 14-membered aromatic heterocyclylsulfinyl group e.g., pyridylsulfinyl, thienylsulfinyl
  • a mono- or di-C 1 - 6 alkylamino group e.g., methylamino, ethylamino, propylamino, isopropylamino,. butylamino,
  • a C 1 - 6 alkyl-carbonylamino ' group e.g., acetylamino, propanoylamino, butanoylamino
  • a C 6-14 aryl-carbonylamino group e.g., phenylcarbonylamino, naphthylcarbonylamino
  • a C 1- 6 alkylsulfonylamino group e.g., methylsulfonylamino, ethylsulfonylamino
  • a C 6-14 arylsulfonylamino group optionally substituted by a C 1 - 6 alkyl group e.g., phenylsulfonylamino
  • the number of. the above-mentioned substituents in the "optionally substituted hydrocarbon group” is, for example, 1 to 5, preferably 1 to 3.
  • the respective substituents may be the same or different.
  • heterocyclic group (including “heterocyclic group” of
  • optionally substituted heterocyclic group include (i) an aromatic heterocyclic group, (ii) a non-aromatic heterocyclic group and (iii) a 7- to 10-membered bridged heterocyclic group, each containing, as a ring-constituting atom besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.
  • examples of the "aromatic heterocyclic group” include a 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocyclic group containing, as a ring-constituting atom besides carbon atom, 1 to 4 hetero . atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.
  • aromatic heterocyclic group examples include 5- or 6-membered monocyclic aromatic heterocyclic groups such as thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl,
  • pyrazinyl pyrimidinyl, pyridazinyl, 1, 2, 4-oxadiazolyl, 1,3,4- oxadiazolyl, 1, 2, 4-thiadiazolyl, 1, 3, 4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl and the like;
  • benzothiophenyl benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl,
  • quinoxalinyl quinazolinyl, cinnolinyl, carbazolyl, ⁇ - carbolinyl, phenanthridinyl, acridinyl, phenazinyl,
  • non- aromatic heterocyclic group examples include a 3- to 14-membered (preferably 4- to 10-membered) non-aromatic heterocyclic group ' containing, as a ring-constituting atom besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.
  • non-aromatic heterocyclic group examples include 3- to 8-membered monocyclic non-aromatic
  • heterocyclic groups such as aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrothienyl,
  • examples of the "nitrogen- containing heterocyclic group” include a “heterocyclic group” containing at least one nitrogen atom as a ring-constituting atom.
  • examples of the "optionally substituted heterocyclic group” include a heterocyclic group optionally having substituent (s) selected from the
  • substituted heterocyclic group is, for example, 1 to 3.
  • the respective substituents may be the same or different.
  • acyl group examples include a formyl group, a carboxy group, a carbamoyl group, a thiocarbamoyl group, a sulfino group, a sulfo group, a
  • sulfamoyl group and a phosphono group each optionally having "1 or 2 substituents selected from a C 1 - 6 alkyl group, a C 2- 6 alkenyl group, a C 3-10 cycloalkyl group, a C 3-10 cycloalkenyl group, a C 6-14 aryl group, a C 7-16 aralkyl group, a 5- to 14- membered aromatic heterocyclic group and a 3- to 14-membered non-aromatic heterocyclic group, each of which optionally has 1 to 3 substituents selected from a halogen atom, an
  • acyl group also include a hydrocarbon- sulfonyl group, a heterocyclylsulfonyl group, a hydrocarbon- sulfinyl group and a heterocyclylsulfinyl group.
  • the hydrocarbon-sulfonyl group means a hydrocarbon group-bonded sulfonyl group
  • the heterocyclylsulfonyl group means a heterocyclic group-bonded sulfonyl group
  • hydrocarbon-sulfinyl group means a hydrocarbon group-bonded sulfinyl group and the heterocyclylsulfinyl group means a heterocyclic group-bonded sulfinyl group.
  • acyl group examples include a formyl group, a carboxy group, a C 1- 6 , alkyl-carbonyl group, a C 2- 6 alkenyl-carbonyl group (e.g., crotonoyl) , a C 3-10 cycloalkyl- carbonyl group (e.g., cyclobutanecarbonyl,
  • cycloheptanecarbonyl a C 3-10 cycloalkenyl-carbonyl group, (e.g., 2-cyclohexenecarbonyl) , ' a C 6-14 aryl-carbonyl group, a C 7-16 aralkyl-carbonyl group, a 5- to 14-membered aromatic
  • heterocyclylcarbonyl group a 3- to 14-membered non-aromatic heterocyclylcarbonyl group, a C 1- 6 alkoxy-carbonyl group, a C 6-14 aryloxy-carbonyl group (e.g.., phenyloxycarbonyl,
  • a C 7-16 aralkyloxy-carbonyl group e.g., benzyloxycarbonyl, phenethyloxycarbonyl
  • a carbamoyl group a mono- or di-C 1- 6 alkyl-carbamoyl group, a mono- or di-C 2- 6 alkenyl-carbamoyl group (e.g., diallylcarbamoyl) , a mono- or di-C 3-10 cycloalkyl-carbamoyl group (e.g., cyclopropylcarbamoyl) , a mono- or di-C 6-14 aryl-carbamoyl group (e.g., phenylcarbamoyl) , a mono- or di-C 7-16 aralkyl-carbamoyl group, a 5- to 14-membered aromatic heterocyclylcarbamoyl group, a C 7-16 aralkyl
  • cycloalkyl-thiocarbamoyl group e.g., cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl
  • a mono- or di-C 6-14 aryl-thiocarbamoyl group e.g., phenylthiocarbamoyl
  • a mono- or di-C 7-16 aralkyl- thiocarbamoyl group e.g., benzylthiocarbamoyl
  • heterocyclylthiocarbamoyl group e.g., pyridylthiocarbamoyl
  • a sulfino group a C 1 - 6 alkylsulfinyl group (e.g.,
  • alkylsulfonyl group a C 6-14 arylsulfonyl group, a phosphono group and a mono- or di-C 1 - 6 alkylphosphono group (e.g.,
  • examples of the "optionally substituted amino group” include an amino group optionally having "1 or 2 substituents selected from a C 1 - 6 alkyl group, a C 2- 6 alkenyl group, a C 3-10 cycloalkyl group, a C 6-14 aryl group, a C 7-16 aralkyl group, a C 1- 6 alkyl-carbonyl group, a C 6-14 aryl- carbonyl group, a C 7-16 aralkyl-carbonyl group, a 5- to 14- membered aromatic heterocyclylcarbonyl group, a 3- to 14- membered non-aromatic heterocyclylcarbonyl group, a C 1 - 6 alkoxy- carbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-C 1 - 6 alkyl-carbamoyl group, a mono- or di-C 7-16 aralkyl
  • optionally substituted amino group examples include an amino group, a mono- or di- (optionally
  • halogenated C 1 - 6 alkyl amino group e.g., methylamino
  • heterocyclylcarbonylamino group e.g., nicotinoylamino, isonicotinoylamino
  • a mono- or di-3- to- 14-membered non- aromatic heterocyclylcarbonylamino group e.g.,
  • piperidinylcarbonylamino a mono- or di-C 1- 6 alkoxy- carbonylamino group (e.g., tert-butoxycarbonylamino) , a. 5- to 14-membered aromatic heterocyclylamino group (e.g.,
  • pyridylamino a carbamoylamino group, a (mono- or di-C 1- 6 alkyl-carbamoyl) amino group (e.g., methylcarbamoylamino) , a (mono- or di-C 7-16 aralkyl-carbamoyl) amino group (e.g.,
  • benzylcarbamoylamino a C 1- 6 alkylsulfonylamino group (e.g., methylsulfonylamino, ethylsulfonylamino) , a C 6-14
  • arylsulfonylamino ' group e.g., phenylsulfonylamino
  • a (C 1- 6 alkyl) (C 1 - 6 alkyl-carbonyl) amino group e.g., N-acetyl-N- methylamino
  • a (C 1 - 6 alkyl) (C 6-14 aryl-carbonyl) amino group e.g., N-benzoyl-N-methylamino
  • examples of the "optionally substituted carbamoyl group” include a carbamoyl group
  • heterocyclic group a carbamoyl group, a mono- or di-C 1- 6 alkyl- carbamoyl group and a mono- or di-C 7-16 aralkyl-carbamoyl group, each of which optionally has 1 to 3 substituents selected from substituent group A".
  • carbamoyl group include a carbamoyl group, a mono- or di-C 1 - 6 alkyl-carbamoyl group, a mono- or di-C 2- 6 alkenyl-carbamoyl group (e.g., diallylcarbamoyl) , a mono- or di-C3 -10 cycloalkyl- carbamoyl group (e.g., cyclopropylcarbamoyl,
  • cyclohexylcarbamoyl a mono- or di-C 6-14 aryl-carbamoyl group (e.g., phenylcarbamoyl) , a mono- or di-C 7-16 aralkyl-carbamoyl group, a mono- or di-C 1 - 6 alkyl-carbonyl-carbamoyl group -(e.g., acetylcarbamoyl, propionylcarbamoyl) , a mono- or di-C 6-14 aryl- carbonyl-carbamoyl group (e.g., benzoylcarbamoyl) and a 5- to 14-membered aromatic heterocyclylcarbamoyl group (e.g., pyridylcarbamoyl ) .
  • a mono- or di-C 6-14 aryl-carbamoyl group e.g., phen
  • examples of the "optionally substituted thiocarbamoyl group” include a thiocarbamoyl group optionally having "1 or 2 substituents selected from a C 1- 6 alkyl group, a C 2- 6 alkenyl group, a C3-.10 cycloalkyl group, a ⁇ - i4 aryl group, a C 7-16 aralkyl group, a C 1 - 6 alkyl-carbonyl group, a C 6-14 aryl-carbonyl group, a C 7-16 aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclylcarbonyl group, a 3- to 14-membered non-aromatic heterocyclylcarbonyl group, a C 1 - 6 alkoxy-carbonyl group, a 5- to 14-membered aromatic
  • heterocyclic group a carbamoyl group, a mono- or di-C 1- 6 alkyl- carbamoyl group and a mono- or di-C 7-16 aralkyl-carbamoyl group, each of which optionally has 1 to 3 substituents selected from substituent group A".
  • thiocarbamoyl group include a thiocarbamoyl group, a mono- or di-C 1 - 6 alkyl-thiocarbamoyl group (e.g., methylthiocarbamoyl, ethylthiocarbamoyl, dimethylthiocarbamoyl,
  • diethylthiocarbamoyl N-ethyl-N-methylthiocarbamoyl
  • a mono- or di-C 2- 6 alkenyl-thiocarbamoyl group e.g.,
  • diallylthiocarbamoyl a mono- or di-C 3-10 cyc ' loalkyl- thiocarbamoyl group (e.g., cyclopropylthiocarbamoy1, cyclohexylthiocarbamoyl) , a mono- or di-C 6-14 aryl-thiocarbamoyl group (e.g., phenylthiocarbamoyl) , a mono- or di-C 7-16 aralkyl- thiocarbamoyl group (e.g., benzylthiocarbamoyl,
  • phenethylthiocarbamoyl phenethylthiocarbamoyl
  • a mono- or di-C 1 - 6 alkyl-carbonyl- thiocarbamoyl group e.g., acetylthiocarbamoyl
  • propionylthiocarbamoyl a mono- or di-C 6-14 aryl-carbonyl- thiocarbamoyl group (e.g., benzoylthiocarbamoyl) and a 5- to 14-membered aromatic heterocyclylthiocarbamoyl group (e.g., pyridylthiocarbamoyl) .
  • a mono- or di-C 6-14 aryl-carbonyl- thiocarbamoyl group e.g., benzoylthiocarbamoyl
  • a 5- to 14-membered aromatic heterocyclylthiocarbamoyl group e.g., pyridylthiocarbamoyl
  • examples of the "optionally substituted, sulfamoyl group” include a sulfamoyl group
  • heterocyclic group a carbamoyl group, a mono- or di-C 1- 6 alkyl- carbamoyl group and a mono- or di-C 7-16 aralkyl-carbamoyl group, each of which optionally has 1 to 3 substituents selected from substituent group A".
  • sulfamoyl group include a sulfamoyl group, a mono- or di-C 1 - 6 alkyl-sulfamoyl group (e.g., methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl, diethylsulfamoyl, N-ethyl-N-.
  • methylsulfamoyl methylsulfamoyl
  • a mono- or di-C 2- 6 alkenyl-sulfamoyl group e.g., diallylsulfamoyl
  • a mono- or di-C 3-10 cycloalkyl- sulfamoyl group e.g., cyclopropylsulfamoyl
  • cyclohexylsulfamoyl a mono- or di-C 6-14 aryl-sulfamoyl group (e.g., phenylsulfamoyl) , a mono- or di-C 7-16 aralkyl-sulfamoyl group (e.g., benzylsulfamoyl, phenethylsulfamoyl) , a mono- or di-C 1 - 6 alkyl-carbonyl-sulfamoyl group (e.g., acetylsulfamoyl, propionylsulfamoyl) , a mono- or di-C 6-14 aryl-carbonyl-sulfamoyl group (e.g., benzoylsulfamoyl) and a 5- to 14-membered
  • aromatic heterocyclylsulfamoyl group e.g., pyridylsulfamoyl
  • examples of the "optionally substituted hydroxy group” include a hydroxyl group optionally having "a substituent selected from a C 1- 6 alkyl group, a C 2- 6 alkenyl group, a C 3 _LO cycloalkyl group, a C 6-14 aryl group, a C 7 _ 16 aralkyl group, a C 1 - 6 alkyl-carbonyl group, a C 6-14 aryl- carbonyl group, a C 7-16 aralkyl-carbonyl group, a 5- to 14- membered aromatic heterocyclylcarbonyl group, a 3- to 14- membered non-aromatic heterocyclylcarbonyl group, a C 1 - 6 alkoxy- carbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-C 1 - 6 alkyl-carbamoyl group, a mono- or di-C 7-16
  • the optionally substituted hydroxy group include a hydroxy group, a C 1 - 6 alkoxy group, a C 2- 6 alkenyloxy group (e.g., allyloxy, 2-butenyloxy, 2-pentenyloxy, 3-hexenyloxy) , a C 3-10 cycloalkyloxy group (e.g., cyclohexyloxy) , a C 6-14 aryloxy group (e.g., phenoxy, naphthyloxy) , a C 7-16 aralkyloxy group (e.g., benzyloxy, phienethyloxy) , a C 1 - 6 alkyl- carbonyloxy group (e.g., acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy) , a C 6-14 aryl-carbonyloxy group
  • heterocyclylcarbonyloxy group e.g., nicotinoyloxy
  • a 3- to 14-membered non-aromatic heterocyclylcarbonyloxy group e.g., piperidinylcarbonyloxy
  • a- C 1 - 6 alkoxy-carbonyloxy group e.g., tert-butoxycarbonyloxy
  • heterocyclyloxy group e.g., pyridyloxy
  • a carbamoyloxy group e.g., a C 1 - 6 alkyl-carbamoyloxy group (e.g., methylcarbamoyloxy) , a C 7-16 aralkyl-carbamoyloxy group (e.g., benzylcarbamoyloxy) , a C 1 - 6 alkylsulfonyloxy group (e.g., methylsulfonyloxy, ethylsulfonyloxy) and a.
  • C 6-14 arylsulfonyloxy group e.g., phenylsulfonyloxy.
  • examples of the "optionally substituted sulfanyl group” include a sulfanyl group
  • aryl group a C 7-16 aralkyl group, a C 1 - 6 alkyl-carbonyl group, a C 6-14 aryl-carbonyl group and a 5- to 14-membered aromatic heterocyclic group, each of which optionally has 1 to 3
  • sulfanyl group include a sulfanyl (-SH) group, a C 1 - 6 alkylthio . group, a C 2- 6 alkenylthio group (e.g., allylthio, 2-butenylthio, 2-pentenylthio, 3-hexenylthio) , a C 3-10 cycloaikylthio group (e.g., cyclohexylthio) , a C 6 - 14 arylthio group (e.g., phenylthio, naphthylthio) , .a C 7-16 aralkylthio group (e.g., benzylthio, phenethylthio) , a C 1 - 6 alkyl-carbonylthio group (e.g.,
  • benzoylthio) a.5- to 14-membered aromatic heterocyclylthio group (e.g., pyridylthio) and a halogenated thio group (e.g., pentafluorothio) .
  • examples of the "optionally substituted silyl group” include a silyl group optionally having ⁇ 1 to 3 substituents selected from a C 1 - 6 alkyl group, a C 2- 6 alkenyl group, a C 3-10 cycloalkyl group, a C 6 - 14 aryl group and a C 7-16 aralkyl group, each of which optionally has 1 to 3 substituents selected from substituent. group A".
  • the optionally substituted silyl group include a tri-C 1- 6 alkylsilyl group (e.g., trimethylsilyl, tert-butyl (dimethyl) silyl) .
  • a tri-C 1- 6 alkylsilyl group e.g., trimethylsilyl, tert-butyl (dimethyl) silyl
  • hydrocarbon ring include a C 6-14 aromatic hydrocarbon ring, C 3 - 10 cycloalkane and C 3-10 cycloalkene.
  • examples of the "C 6-14 aromatic hydrocarbon ring” include benzene and naphthalene.
  • examples of the "C 3-10 cycloalkane” include cyclopropane, cyclobutane, cyclopentane, cyclohexane, . cycloheptane and cyclooctane.
  • examples of the "C 3-10 cycloalkene” include cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene and cyclooctene.
  • heterocycle include an aromatic heterocycle and a non- aromatic heterocycle, each containing, as a ring-constituting atom besides carbon atom, " 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.
  • examples of the "aromatic . heterocycle” include a 5- to 14-membered (preferably 5- to 10- membered) aromatic heterocycle containing, as a ring- constituting atom besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom,, a sulfur atom and an oxygen atom.
  • aromatic heterocycle a 5- to 14-membered (preferably 5- to 10- membered) aromatic heterocycle containing, as a ring- constituting atom besides carbon atom, 1 to 4 hetero atoms selected from a nitrogen atom,, a sulfur atom and an oxygen atom.
  • 5- or 6-membered monocyclic aromatic heterocycles such as thiophene, furan, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, pyridine, pyrazine,
  • pyrimidine pyridazine, 1, 2, 4-oxadiazole, 1, 3, 4-oxadiazole, 1, 2, 4-thiadiazole, 1, 3, 4-thiadiazole, triazole, tetrazole, triazine and the like;
  • aromatic heterocycles such as benzothiophene, benzofuran, benzimidazole, benzoxazole, benzisoxazole,
  • benzothiazole benzisothiazole, benzotriazole, imidazopyridine, thienopyridine, furopyridine, pyrrolopyridine, pyrazolopyridine, oxazolopyridine, thiazolopyridine, imidazopyrazine, imidazopyrimidine, thienopyrimi ' dine,
  • oxazolopyrimidine thiazolopyrimidine, pyrazolopyrimidine, pyrazolotriazine, naphtho [2, 3-b] thiophene, phehoxathiine, indole, isoindole, lH-indazole, purine, isoquinoline,
  • non- aromatic heterocycle examples include a 3- to 14-membered (preferably 4- to 10-membered) non-aromatic heterocycle containing, as a ring-constituting atom besides carbon atom* 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.
  • non-aromatic heterocycle containing, as a ring-constituting atom besides carbon atom* 1 to 4 hetero atoms selected from a nitrogen atom, a sulfur atom and an oxygen atom.
  • heterocycle include 3- to 8-membered monocyclic non-aromatic heterocycles such as aziridine, oxirane, thiirane, azetidine, oxetane, thietane, tetrahydrothiophene, tetrahydrofuran,
  • tricyclic non-aromatic heterocycles such as dihydrobenzofuran, dihydrobenzimidazole, dihydrobenzoxazole, dihydrobenzothiazole, dihydrobenzisothiazole, dihydronaphtho [2, 3-b] thiophene,
  • examples of the "nitrogen- containing heterocycle” include a “heterocycle” containing at least one nitrogen atom as a ring-constituting atom.
  • Ring A is an optionally further substituted 5- or 6- membered ring.
  • the "5- or 6-membered ring" of the "optionally further substituted 5- or 6-membered ring" for Ring A include benzene, a C 5- 6 cycloalkane, a 5- or 6-membered aromatic heterocycle and a 5- or 6-membered non-aromatic heterocycle.
  • examples of the "C 5- 6 cycloalkane” include cyclopentane and cyclohexane.
  • examples of the ⁇ '5- or 6- membered aromatic heterocycle include a 5- or 6-membered one from among the "aromatic heterocycle”.
  • examples of the "5- or 6- membered non-aromatic heterocycle” include a 5- or 6-membered one from among the “non-aromatic heterocycle”.
  • the "5- or 6-membered ring" of the “optionally further substituted 5- or 6-membered ring" for Ring A optionally has 1 to ' 5 substituents (preferably 1 to 3) at substitutable
  • substituents examples include substituents selected from the aforementioned substituent group A.
  • the respective substituents may be the same or different.
  • Ring A is preferably an optionally further substituted benzene .
  • Ring A is more preferably benzene optionally further substituted by 1 to 3 halogen atoms (e.g., a fluorine atom, a chlorine atom) .
  • halogen atoms e.g., a fluorine atom, a chlorine atom
  • Ring A is preferably an optionally further substituted 5- or 6-membered aromatic ring (preferably an optionally further substituted 6-membered aromatic ring (preferably benzene, pyridine, particularly preferably
  • Ring A is more preferably a 5- or 6- membered aromatic ring (preferably a 6-membered aromatic ring (preferably benzene, pyridine, particularly preferably
  • benzene optionally .further substituted by 1 to 3 halogen atoms (e.g., a fluorine atom, a chlorine atom).
  • halogen atoms e.g., a fluorine atom, a chlorine atom
  • Ring A is still more preferably benzene or pyridine, each of which is optionally further substituted by 1 to 3 halogen atoms (e.g., a fluorine atom, a chlorine atom) .
  • halogen atoms e.g., a fluorine atom, a chlorine atom
  • Ring A is particularly ' preferably benzene optionally further substituted by 1 to 3 halogen atoms (e.g., a fluorine atom, a chlorine atom).
  • halogen atoms e.g., a fluorine atom, a chlorine atom
  • G 1 is N, C or CR 4 wherein R 4 is a hydrogen atom or a substituent .
  • G 1 is preferably C.
  • G 2 is N, C or CR 5 , wherein R 5 is a hydrogen atom or a substituent .
  • G 2 is preferably C.
  • Ring B is an optionally further substituted 5-membered . non-aromatic heterocycle containing 1 to 3 nitrogen atoms.
  • Examples of the "5-membered non-aromatic heterocycle containing 1 to 3 nitrogen atoms" of the “optionally further substituted 5-membered non-aromatic heterocycle containing 1 to 3 nitrogen atoms" for Ring B include pyrroline, pyrrolidine, imidazoline, imidazolidine, pyrazolone, pyrazolidine,
  • the "5-membered non-aromatic heterocycle containing 1 to 3 nitrogen atoms" of the "optionally .further substituted 5- membered non-aromatic heterocycle containing 1 to 3 nitrogen atoms" for Ring B optionally has 1 or 2 substituents on the carbon atom between the spiro carbon atom and the nitrogen atom bonded to W, in addition to -W-Ring D.
  • substituents include substituents selected from the
  • Ring B is preferably an optionally further substituted pyrroline.
  • Ring B is more preferably pyrroline.
  • Ring E is an optionally substituted C 3-6 cycloalkane or an optionally substituted heterocycle.
  • examples of the "C 3- 6 cycloalkane” include cyclopropane, cyclobutane, cyclopentane and cyclohexane.
  • substituted heterocycle for Ring E optionally have 1 to 5 (preferably 1 to 3) substituents at substitutable position (s).
  • substituents include substituents selected from the aforementioned substituent group A. When the number of the substituents is plural, the respective substituents may be the same or different. [0070] ⁇ . .
  • Ring E is preferably an optionally substituted C 3-6 ' cycloalkane (e.g., cyclopropane).
  • Ring E is. more preferably a C 3-6 cycloalkane (e.g., cyclopropane) .
  • Ring E is preferably an optionally substituted C 3-6 cycloalkane (e.g., cyclopropane, cyclopentane) or an optionally substituted 3- to 14-membered (preferably 4- to 10-membered) non-aromatic heterocycle (preferably an
  • Ring E is more preferably a C 3-6 cycloalkane (e.g., cyclopropane, cyclopentane) or a 3- to 14- membered (preferably 4- to 10-membered) non-aromatic
  • heterocycle preferably a 3- to 8-membered monocyclic non- aromatic heterocycle (e.g., tetrahydropyran)).
  • R 1 and R 2 are each independently a hydrogen atom or an optionally substituted C 1- 6 alkyl group, or R 1 and R 2 are joined together to form a cycloalkane or a heterocycle, each of which is optionally substituted.
  • Examples of the "cycloalkane” formed by R 1 and R 2 include a C3-.10 cycloalkane (preferably a C 3 - 6 cycloalkane) .
  • heterocycle examples include a non-aromatic heterocycle (preferably a 3- to 8-membered monocyclic non-aromatic heterocycle, more preferably a 3- to 8-membered monocyclic saturated heterocycle) .
  • the "cycloalkane” and “heterocycle” formed by R 1 and R 2 optionally have 1 to 5 (preferably 1 to 3) substituents at substitutable position (s).
  • substituents include substituents selected from the aforementioned substituent group A. When the number of the substituents is plural, the respective substituents may be the same or different.
  • R 1 and R 2 are each independently a hydrogen atom or a C 1- 6 alkyl group (e.g., methyl, ethyl), or R 1 and R 2 are joined together to form an optionally substituted
  • cycloalkane more preferably an optionally substituted C 3-6 cycloalkane (e.g., cyclopropane)).
  • R 1 and R 2 are each independently a hydrogen atom or a C 1- 6 alkyl group (e.g., methyl, ethyl), or R 1 and R 2 are joined together to form a cycloalkane (preferably a C 3-10 cycloalkane, more preferably a C 3 - 6 cycloalkane (e.g., cyclopropane) ) .
  • a cycloalkane preferably a C 3-10 cycloalkane, more preferably a C 3 - 6 cycloalkane (e.g., cyclopropane)
  • R 1 is a- C 1- 6 alkyl group (e.g., methyl, ethyl) and R 2 is a hydrogen atom, or R 1 and R 2 are joined together to form a cycloalkane (preferably a C 3-10 cycloalkane, more preferably a C 3-6 cycloalkane (e.g.,
  • R 3 is a hydrogen atom or a . substituent .
  • R 3 is preferably a hydrogen atom.
  • Ring C is an optionally further substituted ring.
  • substituted ring" for Ring C include. a hydrocarbon ring and a heterocycle (preferably a C 6-14 aromatic hydrocarbon ring or a 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocycle, more preferably a C 6-14 aromatic hydrocarbon ring or a 5- or 6-membered monocyclic aromatic heterocycle, particularly preferably benzene or pyridine) .
  • a hydrocarbon ring and a heterocycle preferably a C 6-14 aromatic hydrocarbon ring or a 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocycle, more preferably a C 6-14 aromatic hydrocarbon ring or a 5- or 6-membered monocyclic aromatic heterocycle, particularly preferably benzene or pyridine
  • the "ring” of the "optionally ' further substituted ring” for Ring C optionally has 1 to 5 (preferablyl to 3)
  • substituents at substitutable position (s), in addition to - C (R 1 ) (R 2 ) -N (R 3 ) -CO-Ring A examples include substituents selected from the aforementioned substituent group A. When the number of the substituents is plural, ' the respective substituents may be the same or different.
  • Ring C is preferably an optionally further substituted C 6-14 aromatic hydrocarbon ring (preferably benzene) .
  • Ring C is more preferably a C 6-14 aromatic hydrocarbon ring (preferably benzene) optionally further substituted by 1 to 3 (preferably one) substituents selected from a carboxy group (including a carboxylato group) and a C 1- 6 alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl) [preferably, optionally further substituted by 1 to 3 (preferably one) carboxy groups (including a carboxylato group) ] .
  • a C 6-14 aromatic hydrocarbon ring preferably benzene
  • 1 to 3 preferably one
  • Ring C is still more preferably benzene optionally further substituted by 1 to 3 (preferably one) substituents selected from a carboxy group (including a carboxylato group) and a C 1 - 6 alkoxy-carbonyl group (e.g., methoxycarbonyl,
  • ethoxycarbonyl [preferably optionally further substituted by 1 to 3 (preferably one) carboxy groups (including a
  • Ring C is preferably an optionally further substituted C 6-14 aromatic -hydrocarbon ring (preferably benzene) or an optionally further substituted 5- to. 14- membered (preferably 5- to 10-membered) aromatic heterocycle (preferably an optionally further substituted 5- or 6-membered monocyclic aromatic heterocycle (preferably pyridine) ) .
  • Ring C is more preferably a Cg -14 aromatic hydrocarbon ring (preferably benzene) or a 5- to 14- membered (preferably 5- to 10-membered) aromatic heterocycle (preferably a 5- or 6-membered monocyclic aromatic heterocycle (preferably pyridine) ) , each of which is optionally further substituted by 1 to 3 (preferably one) substituents selected from a carboxy group (including a carboxylato group) and a C 1- 6 alkoxy-carbonyl group (e.g., methoxycarbonyl , ethoxycarbonyl) [preferably optionally further substituted by 1 to 3
  • a carboxy group including a carboxylato group
  • a C 1- 6 alkoxy-carbonyl group e.g., methoxycarbonyl , ethoxycarbonyl
  • Ring C is still more preferably benzene or pyridine, each of which is optionally further substituted by 1 to 3 (preferably, one) substituents selected from a carboxy group (including a carboxylato group) and a C 1 - 6 alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl) [preferably optionally further substituted by 1 to 3
  • Ring D is an optionally further substituted ring.
  • substituted ring" for Ring D include a hydrocarbon ring and a heterocycle (preferably a C 6 - 14 aromatic hydrocarbon ring
  • benzene or a 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocycle (preferably a 5- or 6- membered monocyclic aromatic heterocycle (preferably .
  • Ring D optionally has 1 to 5 (preferablyl to 3)
  • substituents at substitutable position (s), in addition to -W- Ring B examples include substituents selected from the aforementioned substituent group A. When the number of the substituents is plural, the respective
  • Ring D is preferably an optionally further substituted C 6-14 aromatic hydrocarbon ring (preferably benzene) or an optionally further substituted 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocycle (preferably an
  • Ring D is more preferably a C 6-14 aromatic hydrocarbon ring (preferably benzene) or a 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocycle (preferably a 5- or 6- membered monocyclic aromatic heterocycle (preferably
  • a halogen atom e.g., a fluorine atom, a chlorine atom
  • a cyano group e.g., a fluorine atom, a chlorine atom
  • an optionally halogenated C 1- 6 alkyl group e.g., methyl, isopropyl, trifluoromethyl
  • Ring D is still more preferably benzene or pyridine, each of which is optionally further substituted by.l to 3
  • a halogen atom e.g., a fluorine atom, a chlorine atom
  • a cyano group e.g., a fluorine atom, a chlorine atom
  • an optionally halogenated C 1- 6 alkyl group e.g., methyl, isopropyl, trifluoromethyl
  • Ring D is more preferably a C 6-14 aromatic hydrocarbon ring (preferably benzene) or a 5- to .14- membered (preferably 5- to 10-membered) aromatic heterocycle (preferably a 5- or 6-membered monocyclic aromatic heterocycle (preferably pyridine) ) , each of which is optionally further substituted by 1 to 3 substituents selected from
  • a halogen atom e.g., a fluorine atom, a chlorine atom
  • an optionally halogenated C 1- 6 alkyl group e.g., methyl, isopropyl, trifluoromethyl
  • Ring D is still more preferably benzene or pyridine, each of which is optionally further
  • a halogen atom e.g., a. fluorine atom, a chlorine atom
  • an optionally halogenated C 1 - 6 alkyl group e.g., methyl, isopropyl, trifluoromethyl
  • W is a bond, or a spacer in which the number of atoms in the main chain is 1 to 4.
  • Examples of the "spacer in which the number of atoms in the main chain is 1 to 4" for W include spacers wherein the main chain consists of 1 to 4 atoms selected from a carbon atom, a nitrogen atom, a sulfur atom (optionally oxidized) and an oxygen atom, each of which optionally has substituent (s) selected from the aforementioned substituent group A at
  • Ci-4 alkylene group e.g., -CH 2 -, -(CH 2 )2- / -CH(CH 3 )-, - CH 2 -CH(CH 3 >-, -CH(CH 3 )-CH 2 -, -(CH 2 ) 3 -, -(CH 2 ) 4 - etc.
  • a Ci-4 alkylene group e.g., -CH 2 -, -(CH 2 )2- / -CH(CH 3 )-, - CH 2 -CH(CH 3 >-, -CH(CH 3 )-CH 2 -, -(CH 2 ) 3 -, -(CH 2 ) 4 - etc.
  • halogen atom e.g., a fluorine atom, a chlorine atom
  • oxo group e.g., an oxo group and a hydroxy group
  • X 1 and X 2 are each independently 0, C(O), NR 6 (R 6 is a hydrogen atom or a substituent), S, S (O) or S(0)2, and m is an integer of 1 to 2;
  • a C 3 -. 6 cycloalkylene e.g., cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene etc.
  • a divalent non-aromatic heterocyclic group e.g., 1,2- aziridiriediyl, 1, 3-azetidinediyl, 1, 3-pyrrolidinediyl, 1,3- piperidinediyl, 1, 4-piperidinediyl, 1, 4-morpholinediyl etc.
  • a divalent non-aromatic heterocyclic group e.g., 1,2- aziridiriediyl, 1, 3-azetidinediyl, 1, 3-pyrrolidinediyl, 1,3- piperidinediyl, 1, 4-piperidinediyl, 1, 4-morpholinediyl etc.
  • W is preferably
  • m2 is an integer of 0 to 3 (e.g., - OCH 2 CH 2 -) .
  • W is more preferably -CH 2 -, -S0 2 - / -CH 2 CH 2 0- or -OCH 2 CH 2 -.
  • W is preferably
  • Ci-4 alkylene group e.g., -CH 2 -, -CH(CH 3 )-
  • W is more preferably -CH 2 -, -CH(CH3)-, -SO 2 -, -CH 2 CH 2 O- or -OCH 2 CH 2 -.
  • compound (I) include the following compounds.
  • Ring A is benzene optionally further substituted by 1 to 3 halogen atoms (e.g., a fluorine atom, a chlorine atom);
  • Ring E is a C 3-6 cycloalkane (e.g., cyclopropane);
  • R 1 and R 2 are each ' independently a hydrogen atom or a C 1- 6 alkyl group (e.g., methyl, ethyl) [preferably R 1 is a C 1- 6 alkyl group (e.g., methyl, ethyl) and R 2 is a hydrogen atom], or R 1 and R 2 are joined together to form a cycloalkane (preferably a C 3-10 cycloalkane, more preferably a C 3-6 cycloalkane (e.g., cyclopropane) ) ;
  • a cycloalkane preferably a C 3-10 cycloalkane, more preferably a C 3-6 cycloalkane (e.g., cyclopropane)
  • R 3 is a hydrogen atom
  • Ring C is a C 6 - 14 aromatic hydrocarbon ring (preferably benzene) optionally further substituted by 1 to 3 (preferably one) substituents selected from a carboxy group (including a carboxylato group) and a C 1 - 6 alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl ) [preferably optionally
  • Ring D is a C 6-14 aromatic hydrocarbon ring (preferably benzene) or a 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocycle (preferably a 5- or 6-membered monocyclic aromatic heterocycle (preferably pyridine) ) , each of which is optionally further substituted by 1 to 3 ' substituents selected from
  • a halogen atom e.g., a fluorine atom, a chlorine atom
  • an optionally halogenated C 1- 6 alkyl group e.g., methyl, isopropyl, trifluoromethyl
  • an optionally halogenated C 1- 6 alkoxy group e.g., trifluoromethoxy
  • W is -CH 2 -, -SO 2 -, -CH 2 CH 2 O- or -OCH 2 CH 2 -.
  • Ring A is a 5- or 6-membered aromatic ring (preferably 6-membered aromatic ring (preferably benzene, pyridine, particularly preferably benzene) ) optionally further
  • halogen atoms e.g., a fluorine atom, a chlorine atom
  • Ring E is a C 3 - 6 cycloalkane (e.g., cyclopropane, cyclopentane) or a 3- to 14-membered (preferably 4-' to 10- membered) non-aromatic heterocycle (preferably a 3- to 8- membered monocyclic non-aromatic heterocycle (e.g.,
  • R 1 and R 2 are. each independently a hydrogen, atom or a C 1- 6 alkyl group (e.g.., methyl, ethyl) [preferably R 1 is a C 1- 6 alkyl group (e.g., methyl, ethyl) and R 2 is a hydrogen atom], or R 1 and R 2 are joined together to form a cycloalkane (preferably a C 3-10 cycloalkane, more preferably a C 3-6 cycloalkane (e.g., cyclopropane) ) ;
  • a cycloalkane preferably a C 3-10 cycloalkane, more preferably a C 3-6 cycloalkane (e.g., cyclopropane)
  • R 3 is a hydrogen atom
  • Ring C is a C 6-14 aromatic hydrocarbon ring (preferably benzene) or a 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocycle (preferably a 5- or 6-membered monocyclic aromatic heterocycle (preferably pyridine) ) , each, of which is optionally further substituted by 1 to 3 (preferably one) substituents selected from a carboxy group (including a
  • Ring D is a C 6-14 aromatic hydrocarbon ring (preferably benzene) or a 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocycle (preferably a 5- or 6-membered monocyclic aromatic heterocycle (preferably pyridine) ) , each of which is optionally further substituted by 1 to 3 substituents selected from . '
  • a halogen atom e.g., a fluorine atom, a chlorine atom
  • an optionally halogenated C 1- 6 alkyl group e.g., methyl, isopropyl, trifluoromethyl
  • W is -CH 2 -, -CH(CH 3 )-, -SO 2 -, -CH 2 CH 2 O- or -OCH 2 CH 2 -.
  • Ring. A is benzene optionally further substituted by 1 to 3 halogen atoms (e.g., a fluorine atom, a chlorine atom);
  • Ring E is a C 3 - 6 cycloalkane (e.g., cyclopropane,
  • cyclopentane or a 3- to 14-membered (preferably 4- to 10- membered) non-aromatic heterocycle (preferably a 3- to 8- membered monocyclic non-aromatic heterocycle (e.g.,
  • R 1 and R 2 are each independently a hydrogen atom or a C 1 - 6 alkyl group (e.g., methyl, ethyl) [preferably R 1 is a C 1 - 6 alkyl group (e.g., methyl. / ethyl) and R 2 is a hydrogen atom], or R 1 and R 2 are joined together to form a C 3-6 cycloalkane (e.g., cyclopropane) ;
  • R 3 is a hydrogen atom
  • Ring C is a C 6-14 aromatic hydrocarbon ring (preferably benzene) or a 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocycle (preferably a 5- or 6-membered monocyclic aromatic heterocycle (preferably pyridine) ) , each of which is optionally further substituted by 1 to 3 (preferably one) substituents selected from a carboxy group (including a
  • Ring D is a C 6-14 aromatic hydrocarbon ring (preferably benzene " ) or a 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocycle (preferably a 5- or 6-membered monocyclic aromatic heterocycle (preferably pyridine) ) , each of which is optionally further substituted by 1 to 3 substituents selected from
  • a halogen atom e.g., a fluorine atom, a chlorine atom
  • an optionally halogenated C 1 - 6 alkyl group e.g., methyl., isopropyl, trifluoromethyl
  • W is -CH 2 -, -CH(CH 3 )-, -S0 2 -, -CH 2 CH 2 0- or -OCH 2 CH 2 -.
  • metal salts such as metal salts, an ammonium salt,, salts with organic base, salts with inorganic acid, salts with organic acid, salts with basic or acidic amino acid, and the like.
  • the metal salt include alkali metal salts such as sodium salt, potassium salt and the .like;
  • alkaline earth metal salts such as calcium salt, magnesium salt, barium salt and the like; an aluminum salt, and the like.
  • the salt with organic base include salts with trimethylamine, triethylamine, pyridine, p.icoline, 2, 6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, ⁇ , ⁇ '- dibenzylethylenediamine and the like.
  • salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
  • Preferable examples of the salt with ' organic acid include salts with, formic acid-, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfohic acid, p- toluenesulfonic acid and the like.
  • Preferable examples of the salt with basic amino acid include salts with arginine,. lysine, ornithine and the like.
  • Preferable examples of the salt with acidic amino acid include salts with aspartic acid, glutamic acid and the like.
  • examples thereof include inorganic salts such as alkali metal salts (e.g., sodium salt, potassium salt etc.), alkaline earth metal salts (e.g., calcium salt,
  • magnesium salt etc. and the like, ammonium salt etc.
  • examples thereof include salts with inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like, and salts with organic acid such as acetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid,
  • maleic acid citric acid, succinic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like.
  • Compound (I) may be prepared by any process known to be applicable to the preparation of chemically-related compounds. Such processes are provided as one embodiment of the invention, and are illustrated by the following representative process.
  • the starting material and/or the production intermediate for the compound (I) may form a salt. While the salt is not particularly limited as long as the reaction can be performed, examples thereof include those similar to the salts of
  • the starting material has an amino group, a carboxyl group, a hydroxy group or a heterocyclic group
  • these groups may be protected by a protecting group generally used in peptide chemistry and the like. By removing the protecting group as necessary after the reaction, the objective compound can be obtained.
  • The. protection and deprotection can be performed according to a method known per se, for example, the method described in "Protective Groups in Organic Synthesis, 3rd Ed", John Wiley and Sons, Inc. (1999) (Theodora W. Greene, Peter G. M. Wuts) .
  • the protecting group include a tert-butylcarbamate group, a berizylcarbamate group, a benzyl group, a methyl group, an ethyl group, a tert-butyl and the like-.
  • the compound obtained in each step can be used directly as the reaction mixture or as a crude product for the next reaction. It can also be isolated from a reaction mixture by a conventional method, and can be easily purified by a
  • compound (I) may be prepared by reacting compound (II) with compound (III) wherein W is a spacer in which the number of atoms in the main chain is 1 to 4, and X is a leaving group such as a halogen atom, a C 1 - 6 alkylsulfonyl group or a C 6-14 arylsulfonyl group, or X/WX may " be a formyl group (reductive alkylation) , or X may be a hydroxy group (cross coupling reaction),, or WX may be a halogen atom or a triflate (Ullman or Buchwald coupling) or a boronic acid or a boronate ester (Chan-Evans-Lam coupling) .
  • the functional group in compound (II) or (III) may be
  • Compound (I) having an ester moiety may be further hydrolyzed to obtain the corresponding carboxylic acid or its salt, which may be further derivatized.
  • Compound (III) may be a commercially available product, or can also be prepared according to a. method known per se or a method analogous ' thereto.
  • compound (I) may be prepared by coupling compound (II) With compound (III) wherein X is - C(O)OH or -S(O) 2 0H, or a reactive derivative thereof such as an acid halide (e.g., an acid chloride, an acid bromide) : or a mixed anhydride (e.g., a mixed anhydride with a chloroformate) .
  • an acid halide e.g., an acid chloride, an acid bromide
  • a mixed anhydride e.g., a mixed anhydride with a chloroformate
  • compound (I) may be prepared by coupling compound (IV) with compound (V) (amide coupling
  • Compound (V) may be a commercially available product, or can also be prepared according to a method known per se or a method analogous thereto.
  • R 5 is a C 1- 6 alkyl group
  • n is 0-1
  • compound (lb) may be prepared by carbonylation of compound (la) wherein R 4 is a halogen atom, preferably a bromine atom.
  • R 4 is a halogen atom, preferably a bromine atom.
  • the functional group in compound (la) may be protected if necessary, and after the
  • Compound (la) may be. prepared according to the method Schemes 1 to 3 wherein Ring C is substituted by R 4 .
  • Compound (lb) may also be prepared according to the method Schemes 1 to 3 wherein Ring C is substituted by a group of the formula: - (CR 6 R 7 ) n C(O)OR 5 .
  • compound (Ic) may be prepared by ester hydrolysis of compound (lb) .
  • compound CId) may be prepared from compound (la) wherein R 4 is a cyano group, by conversion of the cyano group to 5-tetrazolyl (tetrazole formation) .
  • compound (II) may be prepared by amide coupling of compound (VI) wherein R is a hydrogen atom or a lower alkyl group, and PG is an amino-protecting group such as tert-butoxycarbonyl with compound (V) to obtain compound (VII) , followed by deprotection.
  • compound (IV) may be prepared by deprotection of compound (VI) wherein R is a lower alkyl group such as methyl, ethyl, and PG is an amino-protecting group such as tert-butoxycarbonyl to obtain compound (VIII) ,
  • Alkyl compounds haying a suitable leaving group such as a halogen atom, a C 1- 6 alkylsulfonyl group and a C 6-14 arylsulfonyl group may be reacted with an amine.
  • the reaction may be carried out in the absence or presence of a base, in an
  • Preferred base is selected from organic non-nucleophilic bases such as triethylamine, di-isopropylethylamine (Hunig's base), pyridine, 2, 6-lutidine, collidine, 4- dimethylaminopyrimidine, N-methylpyrrolidine and
  • DBU diazabicyclo[5.4.0]undec-7ene
  • alkali or alkaline earth metal carbonates such as sodium carbonate and potassium
  • polar solvent inert to the reaction include acetonitrile, alcohols (e.g., methanol, ethanol, propanol, n- butanol etc.), chlorinated solvents (e.g., chloroform,
  • dichloromethane 1, 2-dichloroethane etc.
  • ethers e.g., tetrahydrofuran (THF) , dioxane, dimethoxyethane (DME) etc.
  • amides e.g., N,N-dimethylformamide (DMF) , N,N- dimethylacetamide (DMA), iV-methylpyrrolidine (NMP) etc..
  • non-polar solvents e.g., toluene etc.
  • the iV-alkylation may be carried out in presence of an ionic liquid such as l-butyl-3- methylimidazolium tetrafluorophos ' phate [Bmim(PF4)], l-butyl-3- methylimidazolium hexafluorophosphate [Bmim(PF6) ] and tetrabutylammonium chloride [TBAC] .
  • the ionic liquid may be used as a reaction solvent, or it may be used as an additive when the N-alkylation is conducted in the above-mentioned solvent.
  • microwave irradiation may be employed to enhance the rate of the iV-alkylation.
  • N-alkylation may be carried out by cross coupling of an appropriate amine and alcohol under
  • a dialkyl azodicarboxylate e.g., diethyl azodicarboxylate (DEAD), .
  • the cross coupling is carried out in an appropriate solvent such as THF and dioxane at 0 to 40°C to reflux temperature.
  • the N-alkylation may be carried out by using reductive amination (reductive alkylation) using an appropriate amine, aldehyde and reducing agent (e.g., sodium cyanoborohydride (NaBH3CN) , sodium triacetoxyborohydride
  • reductive alkylation using an appropriate amine, aldehyde and reducing agent (e.g., sodium cyanoborohydride (NaBH3CN) , sodium triacetoxyborohydride
  • chlorinated solvents such as dichloromethane, 1, 2-dichloroethane etc.
  • Aryl compounds having a suitable leaving- group such as a halogen atom, a triflate, a boronic acid and a boronate ester may be reacted with an amine using an appropriate catalyst.
  • the N-arylation reaction may be carried out according to
  • the reaction may be carried out in presence of a suitable catalyst such as copper (I) or copper (II) salts (e.g. copper chloride, copper acetate, copper triflate) , palladium, rhodium, iron etc.
  • a suitable catalyst such as copper (I) or copper (II) salts (e.g. copper chloride, copper acetate, copper triflate) , palladium, rhodium, iron etc.
  • the reaction may be carried out in presence of a suitable ligand such as diamines (e.g. ethylene diamine, ⁇ , ⁇ '- dimethylamine, cis-cyclohexane-1, 2-diamine, trans-cyclohexane- 1, 2-diamine) : mono and diketones, diesters, ketone-esters.
  • base as an additive such as cesium carbonate, potassium carbonate, potassium
  • Preferred solvent for the reaction may be toluene, dichloromethane, dichloroethane, DMF, N,N- dimethylacetamide, dioxane, THF, acetonitrile, methanol, butanol, iso-butanol, t-butanol and water.
  • the reaction may be carried out at a temperature ranging from room temperature to 150°C, preferably 40°C to 100°C.
  • Amide coupling may be carried out using any suitable amide coupling regent (e.g., oxalyl chloride, thionyl chloride, BOP-C1, DCC, HOBt, HOAt, HATU, EDCI, propylphosphonic
  • suitable amide coupling regent e.g., oxalyl chloride, thionyl chloride, BOP-C1, DCC, HOBt, HOAt, HATU, EDCI, propylphosphonic
  • Preferred base is selected from organic non-nucleophillic bases (e.g.,
  • amide coupling may be carried out at a
  • the amide coupling may be carried put optionally in presence of a catalytic amount of N,N-dimethylformamide
  • the amide coupling may be carried out by heating an ester and an amine either in the absence of a solvent or in presence of a high boiling solvent such as toluene, xylene and DMSO.
  • the amide coupling may be carried out in presence of a trialkyl aluminium (Chem. Commun., 2008, 1100-1102) .
  • Sulfonamide may be prepared by reacting an appropriate amine with an appropriate sulfonyl halide in the presence of a base such as organic non-nucleophillic bases (e.g.,
  • the sulfonamide coupling may be carried out in the presence of a solvent such as dichloromethane,
  • the carbonylation reaction may be carried out by reacting an aryl halide with carbon, monoxide in presence of a catalyst and/or a base in an inert solvent.
  • a catalyst include palladium reagents such as palladium acetate and palladium dibenzylacetone; and nickel catalysts.
  • Preferred base is selected from iV,iV-diisopropylethylamine, N- methylmorpholine, triethylamine etc. If required, the
  • carbonylation reaction may be carried out in the presence or absence of an additive such as 1,1'- bis (diphenylphosphino) ferrocene, triphenylphosphine and 1,3- bis- (diphenylphosphine) propane.
  • an additive such as 1,1'- bis (diphenylphosphino) ferrocene, triphenylphosphine and 1,3- bis- (diphenylphosphine) propane.
  • the carbonylation may be carried out in a suitable solvent such as acetone,
  • reaction temperature varies depending on the kind of the solvent and reagent used for the reaction, it is generally -20°C to 150°C, preferably 50°C to ' 80°C.
  • Ester hydrolysis may be carried out under a general saponification condition employing an inorganic base such as alkali and alkaline earth ' metal hydroxides, carbonates and bicarbonates (e.g., lithium hydroxide, sodium hydride, sodium carbonate, potassium carbonate, cesium carbonate etc.) in the presence of a solvent such as water, methanol, ethanol,
  • an inorganic base such as alkali and alkaline earth ' metal hydroxides, carbonates and bicarbonates (e.g., lithium hydroxide, sodium hydride, sodium carbonate, potassium carbonate, cesium carbonate etc.) in the presence of a solvent such as water, methanol, ethanol,
  • the ester hydrolysis may be carried out at 0°C to refluxing temperature.
  • ester hydrolysis may be carried out under an acidic condition, for example, in presence of a
  • hydrogen halide e.g., hydrochloric acid, hydrobromic acid etc.
  • a sulfonic acid e.g., p-toluenesulfonic acid
  • benzenesulfonic acid pyridium p-toluenesulfonate etc.
  • carboxylic acid e.g., acetic acid, trifluoroacetic acid etc.
  • Suitable examples of the solvent includes acetonitrile,
  • ester hydrolysis may be carried out at temperature in the range from -20°C to 100°C, preferably from 20°C to 35°C.
  • Aryl tetrazole (5H-substituted tetrazole) may be prepared by converting a cyano group into a tetrazole group in an inert solvent such as acetone, DMF, DMSO, NMP and water.
  • Suitable examples of the tetrazole forming reagent includes sodium azide, lithium azide, trialkyltin azide and
  • the tetrazole formation may be carried out in presence or absence of a catalyst such as dialkyltin oxide (alkyl is methyl or butyl) , alkylamine hydrochloride or hydrobromide, lithium chloride and copper sulphate .
  • a catalyst such as dialkyltin oxide (alkyl is methyl or butyl) , alkylamine hydrochloride or hydrobromide, lithium chloride and copper sulphate .
  • tetrazole formation may be carried out in the presence or absence of an acid or a base.
  • Suitable examples of the base include trimethylamine, triethylamine and N,N- diisopropylethylamine, and suitable examples of the acid include ammonium chloride, hydrogen chloride, aluminium
  • the tetrazole formation may be carried out at temperature 50°C to 200°C.
  • Compound (I) contains a stereoisomer depending to the kind of a substituent> and each stereoisomer and a mixture thereof are encompassed in the present invention.
  • Compound (I) may be a hydrate or a non-hydrate.
  • compound (I) can be synthesized by
  • the objective product When the objective product is obtained as a free form by the above-mentioned reaction, it can be converted to a salt according to a conventional method, or when the objective product is obtained as a salt, it can be converted to a free form or other salt according to a conventional method.
  • the thus-obtained compound (I) can also be isolated and purified from a reaction mixture according to a known method such as phase transfer, concentration, solvent extraction,
  • compound (I) contains a configurational isomer, a diastereomer, a conformer and the like, each can be isolated according to the above-mentioned separation and purification methods, if desired.
  • compound (I) is racemic, d-form and 1-form can be isolated according to a conventional optical resolution.
  • the reaction can be. carried out after a protecting group generally used in peptide
  • the objective compound can be obtained.
  • Examples. of the protecting group include formyl, C 1 - 6 alkyl-carbonyl (e.g., acetyl, propionyl etc.), phenylcarbonyl, C 1 - 6 alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl etc.), phenyloxycarbonyl, C7 -10 . aralkyloxy-carbonyl (e.g., benzyloxycarbonyl etc.), trityl, phthaloyl and the like, each of which is optionally substituted. Examples
  • substituents include a halogen atom (e.g., fluorine, chlorine, bromine, iodine etc.), C 1 - 6 alkyl-carbonyl (e.g., acetyl, propionyl, valeryl etc.), nitro and the like.
  • the number of substituents is, for example, 1 to 3.
  • the removal method of the protecting group can be carried out according to a method known per se, and for example, a method using acid, base, ultraviolet rays, hydrazine,
  • tetrabutylammonium fluoride palladium acetate and the like, a reduction method, and the like can be employed.
  • reaction mixture can be isolated and purified from a reaction mixture according to. a method known per se, for example, extraction, concentration, neutralization, filtration, distillation, recrystallization, column chromatography, thin layer chromatography, preparative high performance liquid chromatography (preparative HPLC) , moderate-pressure preparative liquid chromatography (moderate- pressure preparative LC) and the. like.
  • a method known per se for example, extraction, concentration, neutralization, filtration, distillation, recrystallization, column chromatography, thin layer chromatography, preparative high performance liquid chromatography (preparative HPLC) , moderate-pressure preparative liquid chromatography (moderate- pressure preparative LC) and the. like.
  • a salt of compound (I) can be produced according to a method known per se.
  • compound (I) when compound (I) is a basic compound, it can be produced by adding an inorganic acid or organic acid, or when compound (I) is an acidic compound, by adding an organic base or inorganic base.
  • optical isomer and a mixture thereof are encompassed in the scope of the present invention, and these isomers can be
  • compound (I) contains a configurational isomer, a diastereomer, a conformer and the like, each can be isolated according to the above-mentioned separation and purification methods, if desired.
  • compound (I) is racemic, S-form and R-form can be isolated according to a conventional optical resolution.
  • Compound (I) may be a prodrug, ⁇ and the prodrug of
  • compound (I) refers to a compound which is converted to
  • Examples of the prodrug for compound (I) include
  • compound (I) to acylation, alkylation or phosphorylation e.g., a compound obtained by subjecting an amino group in compound (I) to eicosanoylation, alanylation, pentylaminocarbonylation, (5-methyl-2-oxo-l, 3-dioxolen-4-yl)methoxycarbonylation,
  • a compound obtained by subjecting a hydroxy group in compound (I) to acylation, alkylation, phosphorylation or boration e.g., a compound obtained by subjecting a hydroxy group in ' compound (I) to acetylatian, palmitoylation,
  • a compound obtained by subjecting' a carboxyl group in. compound (I) to esterification or amidation e.g., a compound obtained by subjecting a carboxyl group in compound ( ⁇ ) to ethyl esterification, phenyl esterification, carboxymethyl esterification, dimethylaminometnyl esterification,
  • a prodrug of compound (I) may also be one which is converted to compound (I) under physiological conditions as described in "IYAKUHIN no KAIHATSU (Development of .
  • compound (I) has isomers such as optical isomer, stereoisomer, positional isomer, rotamer and the like, such isomers and a mixture thereof are also encompassed in compound (I) .
  • compound (I) has optical isomers
  • an optical isomer resolved from this compound is also encompassed in compound (I) .
  • These isomers can be obtained as a single product according to synthesis methods or separation methods known per se (e.g., concentration, solvent extraction, column chromatography, recrystallization, etc.).
  • Compound (I) may be a crystal, and a single crystal form and a mixture of crystal forms are both encompassed in
  • the crystal can be produced by crystallizing according to a crystallization method known per se.
  • Compound (I) may be a hydrate, a non-hydrate, a solvate or a non-solvate.
  • Compound (I) may be labeled with an isotope (e.g., 3 H, 11 C,
  • Compound (I) also encompasses a . deuterium conversion form wherein 1 H is converted to 2 H(D).
  • Compound (I) may be a pharmaceutically acceptable
  • cocrystal or a salt thereof means a crystalline substance constituted with two or more special solids at room temperature, each having different ' physical properties (e.g., structure, melting point, melting heat, hygroscopicity, solubility and stability etc.).
  • the cocrystal or a salt thereof can be produced according to a cocrystallization a method known per se.
  • Compound (I) may also be used as a PET tracer.
  • the compound of the present invention has low toxicity, and can be used as it is or in the form of a pharmaceutical composition by mixing with a pharmacologically acceptable carrier etc. to mammals (e.g., human, mouse, rat, rabbit, dog, cat, bovine, horse, swine, monkey) as an agent for the
  • preparation materials can be used. These are incorporated as excipient, lubricant, binder and disintegrant for solid
  • solubilizing agent preparations, or solvent, solubilizing agent, suspending agent, isotonicity agent, buffer and soothing agent for liquid
  • preparations and the like, and preparation additives such as preservative, antioxidant, colorant, sweetening agent and the like can be added as necessary.
  • excipient examples include lactose, sucrose, D-marinitol, D-sorbitol, starch, gelatinated starch, dextrin, crystalline cellulose, low-substituted
  • hydroxypropylcellulose sodium carboxymethylcellulose, gum arabic, pullulan, light anhydrous silicic acid, synthesis aluminum silicate and magnesium alumino metasilicate .
  • lubricant examples include magnesium stearate, calcium stearate, talc and colloidal silica.
  • binder examples include gelatinated starch, sucrose, gelatin, gum arabic, methylcellulose,
  • crystalline cellulose sucrose, D-mannitol, trehalose, dextrin, pullulan, hydroxypropylcellulose, hydroxypropylmethylcellulose and polyvinylpyrrolidone.
  • disintegrant examples include lactose, sucrose, starch, carboxymethylcellulose, calcium
  • carboxymethyl starch light anhydrous silicic acid and low- substituted hydroxypropylcellulose .
  • the solvent include water for injection, physiological brine, Ringer's solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil and cottonseed oil.
  • solubilizing agents include polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate,, sodium citrate, soclium salicylate and sodium acetate.
  • suspending agent examples include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, lauryl aminopropionate, lecithin, benzalkonium
  • hydrophilic polymers such as polyvinyl alcohol,
  • methylcellulose hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and the like; polysorbates, and
  • isotonicity agent examples include sodium chloride, glycerol, D-mannitol, D-sorbitol and glucose.
  • buffers such as phosphate, acetate, carbonate, citrate and the like.
  • the soothing agent include benzyl alcohol.
  • Preferable examples of the preservative include p- .
  • oxybenzoates chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid and sorbic acid.
  • antioxidant examples include sulfite and ascorbate.
  • the colorant include aqueous water-soluble food tar colors (e.g., food colors such as Food Color Red Nos. 2 and 3, Food Color Yellow Nos. 4 and 5, Food Color Blue Nos. 1 and 2 and the like), water insoluble lake dyes (e.g., aluminum salt of the above-mentioned water-soluble food tar color) and . natural dyes (e.g., ⁇ -carotene, chlorophyll, ferric oxide red) .
  • aqueous water-soluble food tar colors e.g., food colors such as Food Color Red Nos. 2 and 3, Food Color Yellow Nos. 4 and 5, Food Color Blue Nos. 1 and 2 and the like
  • water insoluble lake dyes e.g., aluminum salt of the above-mentioned water-soluble food tar color
  • natural dyes e.g., ⁇ -carotene, chlorophyll, ferric oxide red
  • sweetening agent examples include saccharin sodium, dipotassium glycyrrhizinate, aspartame and stevia.
  • Examples of the dosage form of the pharmaceutical composition include oral preparations such as tablet
  • capsules including soft capsule, microcapsule
  • parenteral agents such as injection (e.g., subcutaneous injection, . intravenous injection, intramuscular injection, intraperitoneal injection, drip infusion) , external preparations (e.g., dermal preparation, ointment), suppository (e.g., rectal suppository, vaginal suppository), pellet, nasal preparation, pulmonary preparation (inhalant), eye drop and the like.
  • These preparations may be a release control preparation (e.g., sustained-release microcapsule) such as an immediate- release preparation, a sustained-release preparation and the like.
  • a release control preparation e.g., sustained-release microcapsule
  • immediate- release preparation e.g., immediate-release preparation, a sustained-release preparation and the like.
  • the pharmaceutical composition can be produced according to a method. conventionally used in the field of pharmaceutical formulation, for example, the method described in the Japanese Pharmacopoeia, and the like.
  • the invention in the pharmaceutical composition varies depending on the dosage form, dose of the compound of the present invention and the like, it is for example, about 0.1 to 100 wt%.
  • coating may be applied as necessary for the purpose of masking of taste, enteric property or durability.
  • Examples' of the coating base to be used for coating include sugar coating base, water-soluble film coating base, enteric film coating base and sustained-release film coating base.
  • sucrose is used as the sugar coating base.
  • one or more kinds selected from talc, precipitated calcium carbonate, gelatin, gum arabic, pullulan, carnauba wax and the like may be used in combination.
  • water-soluble film coating base examples include cellulose polymers such as hydroxypropyl cellulose,
  • enteric film coating base examples include cellulose polymers such as hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate, carboxymethylethyl cellulose, cellulose acetate phthalate etc.; acrylic polymers such as methacrylic acid copolymer L [Eudragit L (trade name) ] , methacrylic acid copolymer LD
  • sustained-release film coating base examples include cellulose polymers such as ethyl cellulose etc. ; and acrylic polymers such as aminoalkyl methacrylate copolymer RS [Eudragit RS (trade name) ] , ethyl acrylate-methyl methacrylate copolymer suspension [Eudragit NE (trade name) ] etc.
  • the above-mentioned coating bases may be used after mixing with two or more kinds thereof at appropriate ratios .
  • a light shielding agent such as titanium oxide, red ferric oxide and the like can be used.
  • the compound of the present invention shows low toxicity (e.g., acute toxicity, chronic toxicity, genetic toxicity, reproductive toxicity, cardiotoxicity, carcinogenicity) and a few side effects. Therefore, it can be used as an agent for the prophylaxis or treatment or a diagnostic of various diseases in a mammal (e.g., human, bovine, horse, dog, cat, monkey, mouse, rat) .
  • a mammal e.g., human, bovine, horse, dog, cat, monkey, mouse, rat
  • EP4 receptor antagonistic action they are also useful as safe medicaments based on such action.
  • the medicament of the present invention containing the compound of the present invention can be used for a mammal (e.g., mouse, rat, hamster, rabbit, cat, dog, bovine, sheep, monkey, human etc.) as an agent for the mammal (e.g., mouse, rat, hamster, rabbit, cat, dog, bovine, sheep, monkey, human etc.) as an agent for the mammal (e.g., mouse, rat, hamster, rabbit, cat, dog, bovine, sheep, monkey, human etc.) as an agent for the mammal (e.g., mouse, rat, hamster, rabbit, cat, dog, bovine, sheep, monkey, human etc.) as an agent for the mammal (e.g., mouse, rat, hamster, rabbit, cat, dog, bovine, sheep, monkey, human etc.) as an agent for the mammal (e.g., mouse, rat, hamster, rabbit, cat, dog, bovine, sheep, monkey, human etc.
  • inflammatory diseases e.g., acute pancreatitis, chronic pancreatitis, asthma, adult respiratory distress syndrome, chronic obstructive ' pulmonary disease (COPD) , inflammatory bone disease, inflammatory pulmonary disease, inflammatory bowel disease, celiac disease, hepatitis, systemic
  • SIRS inflammatory response syndrome
  • autoimmune diseases e.g., psoriasis, rheumatoid arthritis, inflammatory bowel disease (e . g. , . Crohn' s disease, ulcerative colitis. etc. ) , Sjogren's syndrome, Behcet's disease, multiple sclerosis, systemic lupus erythematosus, ankylopoietic
  • PN polyarteritis nodosa
  • MCTD MCTD
  • scleroderma scleroderma, profundus lupus erythematosus, chronic thyroiditis
  • Graves' disease autoimmune gastritis, type I and type II diabetes, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, chronic active hepatitis, myasthenia gravis, graft versus host disease, Addison's disease, abnormal immunoresponse, arthritis,
  • rheumatoid arthritis inflammatory bowel disease, Sjogren's syndrome, Behcet's disease, multiple sclerosis and systemic lupus erythematosus
  • osteoarticular degenerative disease e.g., rheumatoid arthritis, osteoporosis, osteoarthritis etc.
  • neoplastic diseases e.g., malignant tumor, angiogenesis glaucoma, infantile hemangioma, multiple myeloma, acute
  • cancer e.g., colorectal cancer (e.g., familial colorectal cancer, hereditary nonpolyposis colorectal cancer, gastrointestinal stromal tumor etc.), lung cancer (e.g., non- small cell lung cancer, small cell lung cancer, malignant, mesothelioma etc.), mesothelioma, pancreatic cancer (e.g., pancreatic duct cancer etc.), gastric cancer (e.g., mucinous adenocarcinoma, adenosquamous carcinoma etc.), papillary adenocarcinoma, breast cancer (e.g., invasive ductal carcinoma, ductal carcinoma in situ, inflammatory breast cancer etc.),
  • colorectal cancer e.g., familial colorectal cancer, hereditary nonpolyposis colorectal cancer, gastrointestinal stromal tumor etc.
  • lung cancer e.g., non- small cell lung cancer, small cell lung cancer, malignant,
  • prostate cancer e.g., hormone-dependent prostate cancer, non-hormone dependent
  • liver cancer e.g., primary liver
  • cancer extrahepatic bile duct cancer etc.
  • thyroid cancer e.g., medullary thyroid carcinoma etc.
  • kidney cancer e.g., renal cell carcinoma, transitional cell carcinoma in kidney and urinary duct etc.
  • uterine cancer brain tumor (e.g., pineal astrocytoma, pilocytic astrocytoma, diffuse astrocytoma, anaplastic astrocytoma etc.), melanoma, sarcoma, urinary
  • bladder cancer including multiple myeloma, hypophyseal adenoma, glioma, acoustic
  • neurinoma retinoblastoma, pharyngeal cancer, laryngeal cancer, cancer of the tongue, thymoma, esophagus cancer, duodenal cancer, colorectal cancer, rectal cancer, hepatoma, pancreatic endocrine tumor, bile duct cancer, gallbladder cancer,, penile cancer, urinary duct cancer, testis- tumor, vulvar cancer, cervix cancer, endometrial cancer, uterus sarcoma, cholionic disease, vaginal cancer, skin cancer, fungoid mycosis, basal cell tumor, soft tissue sarcoma, malignant lymphoma, Hodgkin's disease, myelodysplastic syndrome, acute lymphocytic leukemia, chronic lymphocytic leukemia, adult T cell leukemia, chronic bone marrow proliferative disease, pancreatic endocrine tumor, fibrous histiocytoma, lei
  • cardiovascular disease e.g., heart disease (e.g., cardiac hypertrophy, acute, heart failure and chronic .heart failure including congestive, cardiomyopathy, angina pectoris-,
  • heart disease e.g., cardiac hypertrophy, acute, heart failure and chronic .heart failure including congestive, cardiomyopathy, angina pectoris-,
  • myocarditis arrhythmia, tachycardia, myocardial infarction) , myocardial ischemia, venous insufficiency, heart failure after myocardial infarction, hypertension, cor pulmonale,
  • arteriosclerosis including atherosclerosis (e.g., aortic aneurysm (e.g., abdominal aortic aneurysm, thoracic aortic aneurysm, thoracoabdominal aortic aneurysm) , coronary
  • Atherosclerosis cerebral atherosclerosis, peripheral arterial disease, arteriosclerosis obliterans, chronic arterial occlusion
  • intervention e.g., percutaneous transluminal coronary angioplasty, stent placement, coronary angioscopy, intravascular ultrasound, thrombolysis therapy
  • vascular hypertrophy or vascular occluson and organ dysfunction after heart transplant vascular reocclusion and restenosis after bypass surgery

Abstract

La présente invention concerne un composé représenté par la formule (1) : dans laquelle chaque symbole est tel que défini dans la description, ou un sel de celui-ci qui a une action antagoniste vis-à-vis du récepteur EP4, et qui est utile comme agent pour la prophylaxie ou le traitement de maladies associées au récepteur EP4 (par exemple, la polyarthrite rhumatoïde, l'anévrisme de l'aorte, l'endométriose, la spondylarthrite ankylosante, le cancer du sein inflammatoire etc.) et similaires.
PCT/JP2015/084734 2014-12-05 2015-12-04 Composés hétérocycliques WO2016088903A1 (fr)

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JP2018087189A (ja) * 2016-07-07 2018-06-07 小野薬品工業株式会社 医薬用途
US10745397B2 (en) 2015-07-23 2020-08-18 Takeda Pharmaceutical Company Limited 1-Substituted 1,2,3,4-tetrahydro-1,7-naphthyridin-8-amine derivatives and their use as EP4 receptor antagonists
US10941148B2 (en) 2015-10-16 2021-03-09 Eisai R&D Management Co., Ltd. EP4 antagonists
EP3632898A4 (fr) * 2017-05-22 2021-04-14 ONO Pharmaceutical Co., Ltd. Antagoniste d'ep4
WO2022102731A1 (fr) 2020-11-13 2022-05-19 小野薬品工業株式会社 Traitement du cancer par utilisation combinée d'un antagoniste d'ep4 et d'un inhibiteur de point de contrôle immunitaire

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WO2005021508A1 (fr) * 2003-09-03 2005-03-10 Pfizer Inc. Composes de phenyle ou de pyridyle amide utiles comme antagonistes de la prostaglandine e2
US7491748B2 (en) * 2001-08-09 2009-02-17 Ono Pharmaceutical Co., Ltd. Carboxylic acid derivative compounds and drugs comprising these compounds as the active ingredient

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US7491748B2 (en) * 2001-08-09 2009-02-17 Ono Pharmaceutical Co., Ltd. Carboxylic acid derivative compounds and drugs comprising these compounds as the active ingredient
WO2005021508A1 (fr) * 2003-09-03 2005-03-10 Pfizer Inc. Composes de phenyle ou de pyridyle amide utiles comme antagonistes de la prostaglandine e2

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10745397B2 (en) 2015-07-23 2020-08-18 Takeda Pharmaceutical Company Limited 1-Substituted 1,2,3,4-tetrahydro-1,7-naphthyridin-8-amine derivatives and their use as EP4 receptor antagonists
US10941148B2 (en) 2015-10-16 2021-03-09 Eisai R&D Management Co., Ltd. EP4 antagonists
US11434246B2 (en) 2015-10-16 2022-09-06 Eisai R&D Management Co., Ltd. EP4 antagonists
JP2018087189A (ja) * 2016-07-07 2018-06-07 小野薬品工業株式会社 医薬用途
EP3632898A4 (fr) * 2017-05-22 2021-04-14 ONO Pharmaceutical Co., Ltd. Antagoniste d'ep4
US11479550B2 (en) 2017-05-22 2022-10-25 Ono Pharmaceutical Co., Ltd. EP4 antagonist
WO2022102731A1 (fr) 2020-11-13 2022-05-19 小野薬品工業株式会社 Traitement du cancer par utilisation combinée d'un antagoniste d'ep4 et d'un inhibiteur de point de contrôle immunitaire

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