WO2016021742A1 - Composés hétérocycliques utilisés en tant qu'antagonistes des récepteurs ccr4 - Google Patents

Composés hétérocycliques utilisés en tant qu'antagonistes des récepteurs ccr4 Download PDF

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WO2016021742A1
WO2016021742A1 PCT/JP2015/072884 JP2015072884W WO2016021742A1 WO 2016021742 A1 WO2016021742 A1 WO 2016021742A1 JP 2015072884 W JP2015072884 W JP 2015072884W WO 2016021742 A1 WO2016021742 A1 WO 2016021742A1
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group
compound
optionally
ring
mmol
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PCT/JP2015/072884
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Anil M. DESHPANDE
Dinesh Barawkar
Santosh Patil
Anil PANMAND
Dilip JADHAV
Yogesh Waman
Bheemashankar A. Kulkarni
Takahiko Taniguchi
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Takeda Pharmaceutical Company Limited
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Publication of WO2016021742A1 publication Critical patent/WO2016021742A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
    • C07D217/18—Aralkyl radicals
    • C07D217/20—Aralkyl radicals with oxygen atoms directly attached to the aromatic ring of said aralkyl radical, e.g. papaverine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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 an agent for the prophylaxis or treatment of EP4 receptor associated diseases (e.g., rheumatoid arthritis, aortic aneurysm, endometriosis, ankylosing spondylitis, inflammatory breast cancer etc.) and the like.
  • EP4 receptor associated diseases e.g., rheumatoid arthritis, aortic aneurysm, endometriosis, ankylosing spondylitis, inflammatory breast cancer etc.
  • Prostaglandin E2 is one of the most broadly distributed prostanoids throughout animal species and widely produced within the body by the actions of cyclooxygenases ⁇ (COX) on arachidonic acid. PGE2 is involved in a number of physiological and pathophysiological responses such .as fever, pain, inflammation (non-patent document 1) and elicits its biological functions through four receptor subtypes EP1-4, all G-protein-cpupled receptor.
  • EP4 receptor activation stimulates dendritic cells and promotes IL-23 production synergistically with CD40 and
  • Thl7 cells 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 production and suppression of Thl & Thl7 function (non-patent documents 4 and 5) , reduce inflammatory pain and offers an attractive therapeutic approach for rheumatoid arthritis (RA) , inflammatory bowel diseases and other autoimmune/ inflammatory diseases .
  • RA rheumatoid arthritis
  • 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.
  • aortic aneurysm 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
  • AAA Abdominal aortic aneurysm
  • 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
  • COX-2 is widely expressed in macrophages and smooth muscle cells, along with locally expressed
  • 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 (non-patent documents 30 and 31) ' , a safe and chronically-treatable EP4 antagonist may be an alternative symptom-relieving pharmacothetherapy 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:
  • Z is a direct bond, 0, S, SO, S0 2 , N (R ) , CO, CH (OR ) , CON (R 11 ), N (R 11 ) CO, S0 2 N (R 11 ), N (R 11 ) S0 2 , OC(R ) 2 , SC(R n ) 2 or N(R n )C(R ) 2 ;
  • R 11 is hydrogen or Ci_ 6 alkyl
  • Q 1 is aryl, heteroaryl, etc
  • R 1 is halogen, trifluoromethyl, etc
  • n 0, 1 or 2;
  • R 2 is hydrogen
  • R 3 is hydrogen or Ci_ 6 alkyl
  • L is a direct bond or -[C(R 22 ) 2 ]n- [n is 1 or 2] , and each R 22 independently is hydrogen or Ci_ 4 alkyl;
  • G 2 and G 4 are each hydrogen, halogen, hydroxy, amino, carboxy, etc.;
  • G 3 is hydrogen, halogen, hydroxy, amino, carboxy, etc.
  • Patent document 2 describes a compound represented by the formula:
  • Z is a direct bond, 0, S, N(R 2 ) wherein R 2 is hydrogen or Ci_ 6 alkyl;
  • Q 1 is C3-7 cycloalkyl, heterocyclyl, etc.
  • R 1 is hydrogen or Ci_ 6 alkyl
  • G 1 , G 2 , G 3 , G 4 and G 5 are each hydrogen, halogen, hydroxy, amino, carboxy, etc . ;
  • X 2 is a direct bond, 0, S, SO, S0 2 , CH(OR 6 ), CON(R 6 ), etc.;
  • R 6 is hydrogen or Ci- 6 alkyl
  • Q 3 is aryl or heteroaryl
  • Patent document 3 describes a compound represented by the formula:
  • Cycl 1 is a 5- to 6-membered mono-cyclic carbocyclic ring optionally having substituent ( s ) , or a 5- to 6-membered monocyclic heterocyclic ring optionally having substituent (s) ;
  • Cyc2 1 is a 5-membered mono-cyclic heterocyclic ring optionally having substituent (s) ;
  • Cyc4 1 is a 5- to 10-membered mono-cyclic or bi-cyclic
  • X 1 is -CH 2 -, -CO- or -S0 2 -;
  • R 51 is H, Ci-4 alkyl optionally having substituent ( s ) , or R 51 and the substituent of Cyc4 1 is taken together to form a Ci_ 4 alkylene optionally having substituent (s) or a C 2 - 4 alkenylene optionally having substituent (s) ;
  • R 10 is H or a substituent
  • R 110 is a substituent
  • metabolic disease diabetes
  • cerebrovascular disease stroke
  • Patent document 4 describes a compound represented by the formula:
  • A is an optionally substituted hydrocarbon group or an
  • n 0, 1 or 2;
  • X is a bond, 0, S, CH 2 , etc.
  • Rl is a hydrogen atom, an optionally substituted hydrocarbon group,, an optionally substituted acyl group, an optionally substituted carbamoyl group, or a substituted sulfonyl group;
  • R2 is an optionally substituted hydrocarbon group, or an alkoxycarbonyl group;
  • R3 is a hydrogen atom, an optionally substituted hydrocarbon group, a formyl group, an alkylcarbonyl group, a halogen atom, a cyano group, or R2 and R3 optionally form a ring structure together with the carbon atoms bonded thereto; and
  • R4 and R5 are each a hydrogen atom, a halogen atom, a cyano group, a nitro group, .an optionally substituted hydrocarbon group, an optionally substituted hydrocarbon oxy group, an optionally substituted hydrocarbon thio group, an
  • alkylcarbonyl group carbamoyl group, a mono- or di- alkylcarbamoyl group optionally substituted by hydroxy or benzyloxy, an acyloxy group, a substituted sulfonyl group, a substituted sulfinyl group, an optionally substituted amino group, or a heterocyclyl-carbonyl group,
  • Non-Patent Document 32 describes the following compound:
  • Non-Patent Document 33 describes the following compounds :
  • Patent Document 1 WO 2003/040109
  • Patent Document 3 WO 2010/080864
  • Patent Document 4 WO 2006/011670
  • Non-Patent Document 1 Pharmacol. Rev., 2011. 63(3): p. 471- 538
  • Non-Patent Document 2 Trends Pharmacol. Sci., 2012. 33(6): 304-11
  • 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.
  • Non-Patent Document 9 BMJ, 2001. 323(7304): p. 93-5
  • Non-Patent Document 10 J. Pharm. Pharm. Sci., 2013. 16(5): p. 821-47
  • Non-Patent Document 12 Mol. Endocrinol., 2009. 23(8): p.
  • Non-Patent Document 14 Mol. Cell Endocrinol., 2011. 332(1- 2) : p. 306-13
  • Non-Patent Document 15 Biol. Reprod, 2013. 88(3): p. 77
  • Non-Patent Document 16 Arterioscler . Thromb. Vase. Biol., 15 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.
  • 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 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- 35 886
  • Non-Patent Document 29 Nature Genetics., 2011. 43: p. 761- 767
  • Non-Patent Document 30 Eur J Pharmacol., 2008, 580: p. 116-, 121
  • Non-Patent Document 31 Bioorg Med Chem Lett., 2010. 15: p. 3760-3
  • Non-Patent Document 32 Tetrahedron Letters, vol.52, (2011) , pages 661-664
  • the present invention aims to provide a novel
  • heterocyclic compound having an EP4 receptor antagonistic action is 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
  • diseases e.g., rheumatoid arthritis, aortic aneurysm (e.g.
  • abdominal aortic aneurysm abdominal aortic aneurysm
  • thoracic aortic aneurysm abdominal aortic aneurysm
  • the present invention provides the following.
  • Ring A is an optionally further substituted pyridine or an optionally further substituted pyridazine
  • G 1 is N or CR 4 ,
  • R 4 is a hydrogen atom or a substituent
  • Ring B is an optionally substituted 6-membered aromatic ring
  • R 1 and R 2 are each independently a hydrogen atom or an
  • Ci-e alkyl group or 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
  • R 5 is a substituent
  • Ring D is an optionally substituted ring
  • W is a bond, or a spacer in which the number, of atoms in the main chain is 1 to 4,
  • compound (I) or a salt thereof (hereinafter to be referred to as compound (I).
  • G 1 is CR 4 ,
  • R 4 is a hydrogen atom
  • Ring B is a 6-membered aromatic ring optionally having 1 to 3 substituents selected from
  • R 1 and R 2 are each independently a hydrogen atom or a Ci- 6 alkyl group, or R 1 and R 2 are joined together to form a cycloalkane, R 3 is a hydrogen atom,
  • Ring C is a C 6 -i4 aromatic hydrocarbon ring or a 5- or 6- membered monocyclic aromatic heterocycle, each optionally having 1 to 3 substituents, in addition to R 5 , selected from
  • Ci-6 alkyl group optionally having 1 to 3 substituents selected from
  • Ring D is a C6-14 aromatic hydrocarbon ring or a 5- or 6- membered monocyclic aromatic heterocycle, each optionally having 1 to 3 substituents selected from
  • a medicament comprising the compound or salt of the above- mentioned [1] .
  • the medicament of the above-mentioned [6] which is an agent for the prophylaxis or treatment of rheumatoid arthritis, aortic aneurysm, endometriosis, ankylosing spondylitis or inflammatory breast cancer.
  • a method of inhibiting EP4 in a mammal which comprises administering an effective amount of the compound or salt of 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 of 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.,
  • halogen atom examples include fluorine, chlorine, bromine and iodine.
  • examples of the "Ci- 6 alkyl group” include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, l-ethylpropyl, hexyl, isohexyl, 1, 1-dimethylbutyl, 2,2- dimethylbutyl, 3 , 3-dimethylbutyl and 2-ethylbutyl .
  • examples of the "optionally halogenated Ci-6 alkyl group” include a Ci_ 6 alkyl group
  • halogen atoms optionally having 1 to 7, preferably 1 to 5, halogen atoms.
  • Specific examples thereof include methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2- bromoethyl, 2, 2, 2-trifluoroethyl, tetrafluoroethyl,
  • examples of the "C 2 _ 6 alkenyl group” include ethenyl, 1-propenyl, 2-propenyl, 2- methyl-l-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl- 2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4- methyl-3-pentenyl, 1-hexenyl, 3-hexenyl and 5-hexenyl.
  • 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 .
  • cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo [2.2.1] heptyl, bicyclo [2.2.2] octyl, bicyclo [ 3.2.1] octyl and adamantyl.
  • examples of the "optionally halogenated C3-10 cycloalkyl group” include a C3-10 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 .
  • cycloalkenyl group include cyclopropenyl, cyclobutenyl,
  • cyclopentenyl cyclohexenyl, cycloheptenyl and cyclooctenyl .
  • C6-1 aryl group examples include phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2- anthryl and 9-anthryl.
  • aralkyl group include benzyl, phenethyl, naphthylmethyl and phenylpropyl .
  • examples of the "Ci-6 alkoxy group” include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy.
  • examples of the "optionally halogenated Ci_ 6 alkoxy group” include a Ci_ 6 alkoxy group
  • cycloalkyloxy group include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy and
  • alkylthio group include methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, pentylthio and hexylthio.
  • examples of the "optionally halogenated Ci_ 6 alkylthio group” include a Ci- 6 alkylthio group optionally having 1 to 7, preferably 1 to 5, halogen atoms.
  • difluoromethylthio difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4 , 4 , -trifluorobutylthio, pentylthio and hexylthio.
  • examples of the "Ci-6 alkyl- carbonyl group” include acetyl, propanoyl, butanoyl, 2- methylpropanoyl, pentanoyl, 3-methylbutanoyl, 2-methylbutanoyl, 2, 2-dimethylpropanoyl, hexanoyl and heptanoyl.
  • examples of the "optionally halogenated Ci_ 6 alkyl-carbonyl group” include a Ci_ 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 "Ci- 6 alkoxy-carbonyl group” include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,
  • examples of the "C 6 -i aryl- carbonyl group” include benzoyl, 1-naphthoyl and 2-naphthoyl.
  • 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-Ci-6 alkyl-carbamoyl group” include methylcarbamoyl
  • examples of the "mono- or di-C 7 -i6 aralkyl-carbamoyl group” include benzylcarbamoyl and phenethylcarbamoyl .
  • examples of the "Ci- 6 alkylsulfonyl group” include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl , butylsulfonyl, see- butylsulfonyl and tert-butylsulfonyl .
  • examples of the "optionally halogenated Ci_ 6 alkylsulfonyl group” include a Ci_ 6
  • alkylsulfonyl group optionally having 1 to 7, preferably 1 to 5, halogen atoms. Specific examples thereof include
  • methylsulfonyl difluoromethylsulfonyl , trifluoromethylsulfonyl, ethylsulfonyl, propylsulfonyl,
  • 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 Ci_ 6 alkyl group, a C 2 -6 alkenyl group, a C 2 _ 6 alkynyl group, a C3-10
  • cycloalkyl group a C3-10 cycloalkenyl group, a C 6 -i4 aryl group and a C 7 _i6 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 C6-14 aryloxy group e.g., phenoxy, naphthoxy
  • a C7-16 aralkyloxy group e.g., benzyloxy
  • Ci-6 alkyl-carbonyloxy group e.g., acetoxy
  • a Ce-14 aryl-carbonyloxy group e.g., benzoyloxy, 1- naphthoyloxy, 2-naphthoyloxy
  • a Ce-14 aryl-carbonyloxy group e.g., benzoyloxy, 1- naphthoyloxy, 2-naphthoyloxy
  • Ci-6 alkoxy-carbonyloxy group e.g., methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy
  • a mono- or di-Ci-6 alkyl-carbamoyloxy group e.g.,
  • a C 3 -i4 aryl-carbamoyloxy group e.g., phenylcarbamoyloxy, naphthylcarbamoyloxy
  • a 5- to 14-membered aromatic heterocyclylcarbonyloxy group e.g., nicotinoyloxy
  • a 3- to 14-membered non-aromatic heterocyclylcarbonyloxy group e.g., morpholinylcarbonyloxy, piperidinylcarbonyloxy
  • Ci-6 alkylsulfonyloxy group e.g., methylsulfonyloxy, trifluoromethylsulfonyloxy
  • Ci-6 alkyl group e.g., phenylsulfonyloxy, toluehesulfonyloxy
  • an optionally halogenated Ci- 6 al.kylthio group e.g., phenylsulfonyloxy, toluehesulfonyloxy
  • a Ci-6 alkoxy-carbonyl group (29) a Ci-6 alkoxy-carbonyl group, (30) a Ce-14 aryloxy-carbonyl group (e.g., phenyloxycarbonyl, 1- naphthyloxycarbonyl, 2-naphthyloxycarbonyl) ,
  • a Cv-16 aralkyloxy-carbonyl group e.g., benzyloxycarbonyl, phenethyloxycarbonyl
  • a C 6 -i4 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
  • 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-Ci-6 alkylamino group e.g., methylamino, ethylamino, propylamino, isopropylamino, butylamino,
  • Ci-6 alkyl-carbonylamino group e.g., acetylamino, propanoylamino, butanoylamino
  • a (Ci-6 alkyl) (Ci- 6 alkyl-carbonyl) amino group e.g., N- acetyl-N-methylamino
  • a Ce-14 aryl-carbonylamino group e.g., phenylcarbonylamino, naphthylcarbonylamino
  • Ci-6 alkoxy-carbonylamino group e.g.,
  • Ci-6 alkylsulfonylamino group e.g., methylsulfonylamino, ethylsulfonylamino
  • a C 6 -i4 arylsulfonylamino group optionally substituted by a Ci-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 , -thiadiazolyl, triazolyl, tetrazolyl, triazinyl and the like;
  • benzothiophenyl benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl , benzothiazolyl, benzisothiazolyl,
  • pyrrolopyrimidinyl pyrazolopyrimidinyl, oxazolopyrimidinyl , thiazolopyrimidinyl, pyrazolotriazinyl, naphtho [2, 3-b] thienyl, phenoxathiinyl, indolyl, isoindolyl, lH-indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl,
  • 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,
  • tetrahydropyridinyl dihydropyridinyl, dihydrothiopyranyl , tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl, tetrahydropyranyl, tetrahydrothiopyranyl , morpholinyl, thiomorpholinyl, azepanyl, diazepanyl, azepinyl, oxepanyl, azocanyl, diazocanyl and the like; and
  • dihydrobenzisothiazolyl dihydronaphtho [2, 3-b] thienyl, tetrahydroisoquinolyl, tetrahydroquinolyl, 4H-quinolizinyl, indolinyl, isoindolinyl, tetrahydrothieno [2, 3-c] pyridinyl, tetrahydrobenzazepinyl, tetrahydroquinoxalinyl,
  • 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
  • the number of the substituents in the "optionally substituted heterocyclic group” is, for example, 1 to 3. When the number of the substituents is two or more, the respective substituents may be the same or different.
  • examples of the "acyl group” 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 Ci_ 6 alkyl group, a C 2 -6 alkenyl group, a C3-10 cycloalkyl group, a C3-10 cycloalkenyl group, a C6-14 aryl group, a C 7 -i6 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
  • Ci-6 alkoxy group optionally halogenated Ci-6 alkoxy group, a hydroxy group, a nitro group, a cyano group, an amino group and a carbamoyl group.
  • 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 Ci-6 alkyl-carbonyl group, a C2-6 alkenyl-carbonyl group (e.g., crotonoyl) , a C 3 _i 0 cycloalkyl- carbonyl group (e.g., cyclobutanecarbonyl,
  • cycloheptanecarbonyl a C 3 _io cycloalkenyl-carbonyl group (e.g., 2-cyclohexenecarbonyl) , a C 6 -i4 aryl-carbonyl group, a C 7 -i 5 aralkyl-carbonyl group, a 5- to 14-membered aromatic
  • heterocyclylcarbonyl group a 3- to 14-membered non-aromatic heterocyclylcarbonyl group, a Ci_6 alkoxy-carbonyl group, a C6-1 aryloxy-carbonyl group (e.g., phenyloxycarbonyl,
  • a C 7 -i6 aralkyloxy-carbonyl group e.g., benzyloxycarbonyl, phenethyloxycarbonyl
  • a carbamoyl group a mono- or di-Ci-6 alkyl-carbamoyl group, a mono- or di-C 2 -6
  • alkenyl-carbamoyl group e.g., diallylcarbamoyl
  • a mono- or di-C 3 _io cycloalkyl-carbamoyl group e.g., cyclopropylcarbamoyl
  • a mono- or di-C-6-i aryl-carbamoyl group e.g., phenylcarbamoyl
  • a mono- or di-C 7 -i6 aralkyl-carbamoyl group a 5- to 14-membered aromatic heterocyclylcarbamoyl group (e.g., pyridylcarbamoyl)
  • a thiocarbamoyl group a mono- or di-Ci- 6 alkyl-thiocarbamoyl group (e.g., methylthiocarbamoyl, N-ethyl-N- methylthi
  • cycloalkyl-thiocarbamoyl group e.g., cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl
  • a mono- or di-C 6 -i 4 aryl-thiocarbamoyl group e.g., phenylthiocarbamoyl
  • a mono- or di-C 7 -i 6 aralkyl- thiocarbamoyl group e.g., benzylthiocarbamoyl
  • heterocyclylthiocarbamoyl group e.g., pyridylthiocarbamoyl
  • a sulfino group e.g., a sulfino group
  • a Ci-6 alkylsulfinyl group e.g.,
  • alkylsulfonyl group a C 6 -i4 arylsulfonyl group, a phosphono group and a mono- or di-Ci-6 alkylphosphono group (e.g.,
  • examples of the "optionally substituted amino group” include an amino group optionally having M l or 2 substituents selected from a Ci- 6 alkyl group, a C 2 -6 alkenyl group, a C3-10 cycloalkyl group, a C 6 _i4 aryl group, a C 7 _i6 aralkyl group, a Ci_ 6 alkyl-carbonyl group, a C6-14 aryl- carbonyl group, a C7-16 aralkyl-carbonyl group, a 5- to 14- membered aromatic heterocyclylcarbonyl group, a 3- to 14- membered non-aromatic heterocyclylcarbonyl group, a Ci-6 alkoxy- carbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-Ci_ 6 alkyl-carbamoyl group, a mono- or di-C 7 -i 6
  • optionally substituted amino group examples include an amino group, a mono- or di- (optionally
  • Ci_6 alkyl amino group (e.g., methylamino,
  • alkyl alkyl
  • -carbonylamino group e.g., acetylamino, propionylamino
  • a mono- or di-C6-i4 aryl- carbonylamino group e.g., benzoylamino
  • a mono- or di-C 7 -i 6 aralkyl-carbonylamino group e.g., benzylcarbonylamino
  • 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-Ci-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-Ci_ 6 alkyl-carbamoyl ) amino group (e.g., methylcarbamoylamino) , a (mono- or di-C 7 _i6 aralkyl-carbamoyl) amino group (e.g.,
  • Ci_ 6 alkylsulfonylamino group e.g., methylsulfonylamino, ethylsulfonylamino
  • arylsulfonylamino group e.g., phenylsulfonylamino
  • a (Ci- 6 alkyl) (Ci-6 alkyl-carbonyl ) amino group e.g., N-acetyl-N- methylamino
  • examples of the "optionally substituted carbamoyl group” include a carbamoyl group
  • Ci_ 6 alkyl group optionally having "1 or 2 substituents selected from a Ci_ 6 alkyl group, a C2-6 alkenyl group, a C 3 _i 0 cycloalkyl group, a C 6 - 14 aryl group, a C 7 _i 6 aralkyl group, a Ci_ 6 alkoxy group, a C 7 _i6 aralkyloxy group, a Ci-6 alkyl-carbonyl group, a C 6 -i4 aryl- carbonyl group, a C 7 -i 6 aralkyl-carbonyl group, a 5- to 14- membered aromatic heterocyclylcarbonyl group, a 3- to 14- membered non-aromatic heterocyclylcarbonyl group, a Ci_ 6 alkoxy- carbonyl group, a 5- to 14-membered aromatic heterocyclic group, a Ci_ 6 alkylsulfonyl group, a carbamoyl group
  • carbamoyl group include a carbamoyl group, a mono- or di-Ci-6 alkyl-carbamoyl group, a mono- or di-C2-6 alkenyl-carbamoyl group (e.g., diallylcarbamoyl) , a mono- or di-C 3 _i 0 cycloalkyl- carbamoyl group (e.g., cyclopropylcarbamoyl,
  • cyclohexylcarbamoyl a mono- or di-C 6 -i4 aryl-carbamoyl group (e.g., phenylcarbamoyl) , a mono- or di-C 7 _i 6 aralkyl-carbamoyl group, a mono- or di-Ci-6 alkyl-carbonyl-carbamoyl group (e.g., acetylcarbamoyl, propionylcarbamoyl) , a mono- or di-C 3 -i 4 aryl- carbonyl-carbamoyl group (e.g., benzoylcarbamoyl) and a 5- to 14-membered aromatic heterocyclylcarbamoyl group (e.g.,
  • examples of the "optionally substituted thiocarbamoyl group” include a thiocarbamoyl group optionally having "1 or 2 substituents selected from a Ci_6 alkyl group, a C 2 -6 alkenyl group, a C3-.10 cycloalkyl group, a C6- 14 aryl group, a C_i6 aralkyl group, a Ci- 6 alkyl-carbonyl group, a C 6 -i4 aryl-carbonyl group, a C 7 _i 6 aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclylcarbonyl group, a 3- to 14-membered non-aromatic heterocyclylcarbonyl group, a Ci_6 alkoxy-carbonyl group, a 5- to 14-membered aromatic
  • heterocyclic group a carbamoyl group, a mono- or di-Ci_ 6 alkyl- carbamoyl group and a mono- or di-C 7 _i 6 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-Ci-6 alkyl-thiocarbamoyl group (e.g., methylthiocarbamoyl , ethylthiocarbamoyl , dimethylthiocarbamoyl,
  • diallylthiocarbamoyl a mono- or di-C3_io cycloalkyl- thiocarbamoyl group (e.g., cyclopropylthiocarbamoyl,
  • cyclohexylthiocarbamoyl a mono- or di-C6-i aryl-thiocarbamoyl group (e.g., phenylthiocarbamoyl) , a mono- or di-C 7 _i 6 aralkyl- thiocarbamoyl group (e.g., benzylthiocarbamoyl,
  • phenethylthiocarbamoyl phenethylthiocarbamoyl
  • a mono- or di-Ci_ 6 alkyl-carbonyl- thiocarbamoyl group e.g., acetylthiocarbamoyl
  • propionylthiocarbamoyl a mono- or di-C 6 -i4 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 -i4 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
  • a Ci-s alkyl group optionally having "1 or 2 substituents selected from a Ci-s alkyl group, a C 2 -6 alkenyl group, a C3-10 cycloalkyl group, a C 6 - 14 aryl group, a C 7 _i6 aralkyl group, a Ci_ 6 alkyl-carbonyl group, a C 6 _i4 aryl-carbonyl group, a C 7 _i 6 aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclylcarbonyl group, a 3- to 14-membered non-aromatic heterocyclylcarbonyl group, a Ci-6 alkoxy-carbonyl group, a 5- to 14-membered aromatic
  • heterocyclic group a carbamoyl group, a mono- or di-Ci_ 6 alkyl- carbamoyl group and a mono- or di-C 7 -i 6 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-Ci_ 6 alkyl-sulfamoyl group (e.g., methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl, diethylsulfamoyl, N-ethyl-N- methylsulfamoyl) , a mono- or di-C 2 -6 alkenyl-sulfamoyl group (e.g., diallylsulfamoyl) , a mono- or di-C3_io cycloalkyl- sulfamoyl group (e.g., cyclopropylsulfamoyl,
  • a mono- or di-Ci_ 6 alkyl-sulfamoyl group e.g., methylsulfamoyl, ethyl
  • cyclohexylsulfamoyl a mono- or di-C 6 -i4 aryl-sulfamoyl group (e.g., phenylsulfamoyl) , a mono- or di-C 7 _i 6 aralkyl-sulfamoyl group (e.g., benzylsulfamoyl, phenethylsulfamoyl ) , a mono- or di-Ci-6 alkyl-carbonyl-sulfamoyl group (e.g., acetylsulfamoyl, propionylsulfamoyl) , a mono- or di-C 6 -i 4 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 Ci-6 alkyl group, a C 2 -6 alkenyl group, a C3-10 cycloalkyl group, a C 6 -i4 aryl group, a C 7 _ 16 aralkyl group, a Ci_ 6 alkyl-carbonyl group, a Ce-14 aryl- carbonyl group, a C 7 -i 6 aralkyl-carbonyl group, a 5- to 14- membered aromatic heterocyclylcarbonyl group, a 3- to 14- membered non-aromatic heterocyclylcarbonyl group, a Ci-6 alkoxy- carbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-Ci_ 6 alkyl-carbamoyl group, a mono- or di-C 7 _i 6
  • Preferable examples of the optionally substituted hydroxy group include a hydroxy group, a Ci_ 6 alkoxy group, a C 2 -6
  • alkenyloxy group e.g., allyloxy, 2-butenyloxy, 2-pentenyloxy, 3-hexenyloxy
  • a C3-10 cycloalkyloxy group e.g., cyclohexyloxy
  • a C 6 _i4 aryloxy group e.g., phenoxy, naphthyloxy
  • aralkyloxy group e.g., benzyloxy, phenethyloxy
  • Ci_ 6 alkyl- carbonyloxy group e.g., acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy
  • C6-1 aryl-carbonyloxy group e.g., benzyloxy, phenethyloxy
  • Ci_ 6 alkyl- carbonyloxy group e.g., acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy
  • heterocyclylcarbonyloxy group e.g., nicotinoyloxy
  • a 3- to 14-membered non-aromatic heterocyclylcarbonyloxy group e.g., piperidinylcarbonyloxy
  • a Ci-6 alkoxy-carbonyloxy group e.g., tert-butoxycarbonyloxy
  • heterocyclyloxy group e.g., pyridyloxy
  • carbamoyloxy group e.g., a Ci-6 alkyl-carbamoyloxy group (e.g., methylcarbamoyloxy)
  • Ci-6 alkyl-carbamoyloxy group e.g., methylcarbamoyloxy
  • C7-16 aralkyl-carbamoyloxy group e.g., benzylcarbamoyloxy
  • a Ci-6 alkylsulfonyloxy group e.g., methylsulfonyloxy
  • ethylsulfonyloxy ethylsulfonyloxy
  • a Ce-1 arylsulfonyloxy group e.g., phenylsulfonyloxy
  • examples of the "optionally substituted sulfanyl group” include a sulfanyl group
  • sulfanyl group include a sulfanyl (-SH) group, a Ci_ 6 alkylthio group, a C 2 -6 alkenylthio group (e.g., allylthio, . 2-butenylthio, 2-pentenylthio, 3-hexenylthio) , a C3-10 cycloalkylthio group (e.g., cyclohexylthio) , a C 6 _i4 arylthio group (e.g., phenylthio, naphthylthio) , a C 7 -i 6 aralkylthio group (e.g., benzylthio, phenethylthio) , a Ci- 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 Ci_ 6 alkyl group, a C 2 -6 alkenyl group, a C3-10 cycloalkyl group, a C 6 -i4 aryl group and a C 7 _i 6 aralkyl group, each of which optionally has 1 to 3 substituents selected from substituent group A".
  • the optionally substituted silyl group include a tri-Ci_ 6 alkylsilyl group (e.g., trimethylsilyl, tert-butyl (dimethyl) silyl) .
  • hydrocarbon ring include a C 6 -i 4 aromatic hydrocarbon ring, C 3 _ 10 cycloalkane and C3-10 cycloalkene.
  • aromatic hydrocarbon ring include benzene and naphthalene.
  • cycloalkane include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane and cyclooctane.
  • 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;
  • benzothiazole benzisothiazole, benzotriazole, imidazopyridine, thienopyridine, furopyridine, pyrrolopyridine,
  • imidazopyrazine imidazopyrimidine
  • thienopyrimidine imidazopyrazine
  • oxazolopyrimidine thiazolopyrimidine, pyrazolopyrimidine, pyrazolotriazine, naphtho [2 , 3-b] thiophene, phenoxathiine, indole, isoindole, lH-indazole, purine, isoquinoline,
  • quinazoline quinazoline, cinnoline, carbazole, ⁇ -carboline, phenanthridine, acridine, phenazine, phenothiazine, phenoxathiine and the like.
  • 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 examples include 3- to 8-membered monocyclic non-aromatic heterocycles such as aziridine, oxirane, thiirane, azetidine, oxetane, thietane, tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine, imidazoline, imidazolidine, oxazoline, oxazolidine, pyrazoline, pyrazolidine, thiazoline,
  • 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 substituted pyridine or an
  • the "pyridine” of the “optionally further substituted pyridine” for Ring A optionally has one substituent on the carbon atom adjacent to G 1 , in addition to R 4 .
  • substituents include substituents selected from the
  • the "pyridazine” of the "optionally further substituted pyridazine” for Ring A optionally has one substituent on the carbon atom adjacent to G 1 .
  • substituents include substituents selected from the aforementioned
  • Ring A is preferably an optionally further substituted pyridine
  • Ring A is more preferably pyridine optionally further having one halogen atom (e.g., a chlorine atom) on the carbon atom adjacent to G 1 .
  • halogen atom e.g., a chlorine atom
  • Ring A is more preferably pyridine optionally further having one substituent, on the carbon atom adjacent to G 1 , selected from
  • a halogen atom e.g., a chlorine atom, a bromine atom
  • an optionally halogenated Ci_ 6 alkyl group preferably a
  • Ci-g alkyl group e.g., methyl
  • a C3-10 cycloalkyl group e.g., cyclopropyl
  • G 1 is N or CR 4 .
  • G 1 is preferably CR 4 .
  • R 4 is a hydrogen atom or a substituent.
  • R 4 is preferably a hydrogen atom.
  • Ring B is an optionally substituted 6-membered aromatic ring.
  • Ring B optionally further substituted 6-membered aromatic ring
  • Ring B include a benzene ring and a 6-membered aromatic
  • heterocycle e.g., pyridine, pyridazine, pyrimidine, triazine etc.
  • substituted 6-membered aromatic ring for Ring B optionally has 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.
  • Ring B is preferably a 6-membered aromatic ring
  • halogen atoms e.g., a chlorine atom
  • Ring B is more preferably benzene or pyridine, each optionally having 1 to 3 halogen atoms (e.g., a chlorine atom).
  • Ring B is preferably a 6-membered aromatic ring (preferably benzene, pyridine) optionally having 1 to 3 substituents selected from
  • a halogen atom e.g., a chlorine atom, a bromine atom
  • Ci-e alkyl group preferably a Ci-6 alkyl group (e.g., methyl)
  • Ci- 6 alkoxy group preferably a Ci_6 alkoxy group (e.g., methoxy)
  • Ring B is more preferably benzene or pyridine, each optionally having 1 to 3 substituents selected from
  • a halogen atom e.g., a chlorine atom, a bromine atom
  • Ci_ 6 alkyl group preferably a Ci-6 alkyl group (e.g., methyl)
  • Ci_ 6 alkoxy group preferably a Ci-6 alkoxy group (e.g., methoxy)
  • R 1 and R 2 are each independently a hydrogen atom or an optionally substituted Ci_ 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” for R 1 and R 2 include a C3-10 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
  • R 1 and R 2 are each independently a hydrogen atom or a Ci- 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 (e.g., cyclopropane)).
  • a cycloalkane preferably a C 3 -. 10 cycloalkane (e.g., cyclopropane)).
  • R 1 is a hydrogen atom or a Ci-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 C3-10 cycloalkane (e.g., cyclopropane)).
  • a cycloalkane preferably a C3-10 cycloalkane (e.g., cyclopropane)
  • 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 0 6 - ⁇ 4 aromatic hydrocarbon ring or a 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocycle, more preferably a C 6 _i 4 aromatic hydrocarbon ring (preferably benzene) or a 5- or 6-membered monocyclic aromatic heterocycle (preferably pyridine, thiophene) , particularly preferably benzene, pyridine or thiophene) .
  • a hydrocarbon ring and a heterocycle preferably a 0 6 - ⁇ 4 aromatic hydrocarbon ring or a 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocycle, more preferably a C 6 _i 4 aromatic hydrocarbon ring (preferably benzene) or a 5- or 6-membered monocyclic aromatic heterocycle (preferably pyridine, thiophene) , particularly preferably benzene, pyridine or thiophene)
  • the "ring” of the “optionally further substituted ring” for Ring C optionally has 1 to 5 (preferably 1 to 3)
  • substituents at substitutable position (s). Examples of the substituent include substituents selected from the
  • Ring C is preferably a C 6 -i4 aromatic hydrocarbon ring
  • Ring C is more preferably benzene further having no ⁇ substituent other than R 5 .
  • Ring C is preferably a C 6 -i4
  • aromatic hydrocarbon ring preferably benzene
  • a 5- or 6- membered monocyclic aromatic heterocycle preferably pyridine, thiophene
  • a halogen atom e.g., a fluorine atom, a chlorine atom
  • Ring C is more preferably benzene, . pyridine or thiophene, each optionally having 1 to 3
  • a halogen atom e.g., a fluorine atom, a chlorine atom
  • Ci_ 6 alkyl group preferably a Ci-6 alkyl group (e.g., methyl)
  • R 5 is a substituent
  • R 5 is preferably an acyl group.
  • R 5 is more preferably a carboxy group or a Ci-e alkoxy- carbonyl group (e.g., methoxycarbonyl) .
  • R 5 is still more preferably a carboxy group.
  • R 5 is preferably an acyl group (preferably a carboxy group, a Ci_ 6 alkoxy-carbonyl group) , a cyano group, an optionally substituted hydrocarbon group
  • R 5 is more preferably
  • Ci-6 alkyl group e.g., methyl, ethyl, isopropyl
  • a halogen atom e.g., a fluorine atom
  • Ci-6 alkyl group e.g., methyl
  • Ci-6 alkoxy group e.g., methoxy, ethoxy
  • Ci-6 alkylsulfonyl group e.g., methylsulfonyl
  • (6) a sulfamoyl group e.g., a Ci-6 alkylsulfonyl group (e.g., methylsulfonyl)
  • a sulfamoyl group e.g., a Ci-6 alkylsulfonyl group (e.g., methylsulfonyl)
  • (6) a sulfamoyl group e.g., a sulfamoyl group.
  • R 5 is more preferably a carboxy group or a Ci-6 alkoxy-carbonyl group (e.g., methoxycarbonyl) .
  • R 5 is still more preferably a carboxy group.
  • Ring D is an optionally substituted ring.
  • Examples of the "ring" of the "optionally substituted ring” for Ring D include a hydrocarbon ring and a heterocycle (preferably a C6-14 aromatic hydrocarbon ring or a 5- to 14- membered (preferably 5- to 10-membered) aromatic heterocycle, more preferably a C 6 -i4 aromatic hydrocarbon ring (preferably benzene) or a 5- or 6-membered monocyclic aromatic heterocycle (preferably pyridine) , particularly preferably benzene or pyridine) .
  • a hydrocarbon ring and a heterocycle preferably a C6-14 aromatic hydrocarbon ring or a 5- to 14- membered (preferably 5- to 10-membered) aromatic heterocycle, more preferably a C 6 -i4 aromatic hydrocarbon ring (preferably benzene) or a 5- or 6-membered monocyclic aromatic heterocycle (preferably pyridine) , particularly preferably benzene or pyridine) .
  • the "ring" of the "optionally substituted ring” for Ring D optionally has 1 to 5 (preferablyl 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.
  • Ring D is preferably a C S -i 4 aromatic hydrocarbon ring (preferably benzene) optionally having 1 to 3 substituents selected from
  • a halogen atom e.g., a fluorine atom, a chlorine atom
  • Ci_ 6 alkyl group e.g., methyl, trifluoromethyl
  • Ci-6 alkoxy group e.g., methoxy, trifluoromethoxy
  • Ring D is more preferably benzene optionally having 1 to 3 substituents selected from
  • a halogen atom e.g., a fluorine atom, a chlorine atom
  • Ci- 6 alkyl group e.g., methyl, monofluoromethyl, difluoromethyl, trifluoromethyl
  • Ci-6 alkoxy group e.g., methoxy, monofluoromethoxy, difluoromethoxy,
  • Ring D is preferably a Ce-i 4
  • aromatic hydrocarbon ring preferably benzene
  • 5- or 6- membered monocyclic aromatic heterocycle preferably pyridine
  • a halogen atom e.g., a fluorine atom, a chlorine atom
  • Ci_6 alkyl group e.g., methyl, monofluoromethyl, difluoromethyl, trifluoromethyl
  • Ci_6 alkoxy group e.g., methoxy, monofluoromethoxy, difluoromethoxy,
  • Ring D is more preferably benzene or pyridine, each optionally having 1 to 3 substituents selected from
  • a halogen atom e.g., a fluorine atom, a chlorine atom
  • a cyano group e.g., a fluorine atom, a chlorine atom
  • Ci-6 alkyl group e.g., methyl, monofluoromethyl, difluoromethyl, trifluoromethyl
  • 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 substitutable position(s).
  • Ci-4 alkylene group e.g., -CH 2 -, -(CH 2 ) 2 -, -CH 2 -CH (CH 3 ) -, -CH (CH 3 ) -CH 2 -, -(CH 2 ) 3 -, -(CH 2 ) 4 - etc.
  • substituent group A preferably an oxo group and a hydroxy group
  • X 1 and X 2 are each independently 0, NR 6 (R 6 is a hydrogen atom or a substituent), S, S (0) , S (0) 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- aziridinediyl, 1 , 3-azetidinediyl , 1, 3-pyrrolidinediyl, 1,3- piperidinediyl, 1, 4-piperidinediyl, 1, 4-morpholinediyl etc.
  • W is preferably -0- or -0-CH 2 -
  • W is more preferably -0- .
  • compound (I) include the following compounds .
  • Ring A is pyridine optionally further having one halogen atom (e.g., a chlorine atom) on the carbon atom adjacent to G 1 , G 1 is CR 4 ,
  • R 4 is a hydrogen atom
  • Ring B is a 6-membered aromatic ring (preferably benzene, pyridine) optionally further having 1 to 3 halogen atoms (e.g., a chlorine atom) ,
  • R 1 and R 2 are each independently a hydrogen atom or a Ci_ 6 alkyl group (e.g., methyl), or R 1 and R 2 are joined together to form a cycloalkane (preferably a C 3 -i 0 cycloalkane (e.g.,
  • R 3 is a hydrogen atom
  • Ring C is a C6-14 aromatic hydrocarbon ring (preferably benzene) further having no substituent other than R 5 ,
  • R 5 is an acyl group (preferably a carboxy group or a C1-6 alkoxy-carbonyl group (e.g., methoxycarbonyl) )
  • Ring D is a C 6 -i4 aromatic hydrocarbon ring (preferably benzene) optionally having 1 to 3 substituents selected from
  • a halogen atom e.g., a fluorine atom, a chlorine atom
  • Ci_ 6 alkyl group e.g., methyl, monofluoromethyl, difluoromethyl, trifluoromethyl
  • Ci_ 6 alkoxy group e.g., methoxy, monofluoromethoxy, difluoromethoxy, trifluoromethoxy
  • W is -0-.
  • Ring A is pyridine optionally further having one
  • substituent on the carbon atom adjacent to G 1 , selected from (1) a halogen atom (e.g., a chlorine atom, a bromine atom),
  • Ci- 6 alkyl group preferably a Ci-6 alkyl group (e.g., methyl)
  • G 1 is CR 4 ,
  • R 4 is a hydrogen atom
  • Ring B is a 6-membered aromatic ring (preferably benzene, pyridine) optionally having 1 to 3 substituents selected from
  • a halogen atom e.g., a chlorine atom, a bromine atom
  • Ci_ 6 alkyl group preferably a Ci-6 alkyl group (e.g., methyl)
  • Ci_ 6 alkoxy group preferably a Ci-6 alkoxy group- (e.g., methoxy)
  • R 1 and R 2 are each independently a hydrogen atom or a Ci_ 6 alkyl group (e.g., methyl, ethyl),, or R 1 and R 2 are joined together to form a cycloalkane (preferably a C3-10 cycloalkane (e.g., cyclopropane)),
  • a cycloalkane preferably a C3-10 cycloalkane (e.g., cyclopropane)
  • R 3 is a hydrogen atom
  • Ring C is a C 6 -i4 aromatic hydrocarbon ring (preferably benzene) or a 5- or 6-membered monocyclic aromatic heterocycle (preferably pyridine, thiophene) , each optionally having 1 to 3 substituents, in addition to R 5 , selected from
  • a halogen atom e.g., a fluorine atom, a chlorine atom
  • Ci- 6 alkyl group preferably a Ci-6 alkyl group (e.g., methyl)
  • Ci-6 alkyl group e.g., methyl, ethyl, isopropyl
  • a halogen atom e.g., a fluorine atom
  • Ci-6 alkyl group e.g., methyl
  • Ci-6 alkoxy group e.g., methoxy, ethoxy
  • Ci-6 alkylsulfonyl group e.g., methylsulfonyl
  • Ring D is a e-n aromatic hydrocarbon ring (preferably benzene) or a 5- or 6-membered monocyclic aromatic heterocycle (preferably pyridine) , each optionally having 1 to 3
  • a halogen atom e.g., a fluorine atom, a chlorine atom
  • Ci-6 alkyl group e.g., methyl, monofluoromethyl, difluoromethyl, trifluoromethyl
  • W is -0- or -0-CH 2 - (wherein the left bond is bonded to Ring B, and the right bond is bonded to Ring D) .
  • Ring A is pyridine optionally further having one
  • a halogen atom e.g., a chlorine atom, a bromine atom
  • Ci_ 6 alkyl group preferably a Ci-6 alkyl group (e.g., methyl)
  • G 1 is CR 4 ,
  • R 4 is a hydrogen atom
  • Ring B is benzene or pyridine, each optionally having 1 to 3 substituents selected from
  • a halogen atom e.g., a chlorine atom, a bromine atom
  • an optionally halogenated Ci_ 6 alkyl group preferably a Ci-6 alkyl group (e.g., methyl)
  • Ci- 6 alkoxy group preferably a Ci-6 alkoxy group (e.g., methoxy)
  • R 1 is a hydrogen atom or a Ci-6 alkyl group (e.g., methyl, ethyl) ,
  • R 2 is a hydrogen atom
  • R 1 and R 2 are joined together to form a cycloalkane
  • R 3 is a hydrogen atom
  • Ring C is benzene, pyridine or thiophene, each optionally having 1 to 3 substituents, in addition to R 5 , selected from
  • a halogen atom e.g., a fluorine atom, a chlorine atom
  • Ci-6 alkyl group e.g., methyl
  • a cyano group (3) a cyano group, (4) a Ci-6 alkyl group (e.g., methyl, ethyl, isopropyl)
  • a halogen atom e.g., a fluorine atom
  • Ci-6 alkyl group e.g., methyl
  • Ci-6 alkoxy group e.g., methoxy, ethoxy
  • Ci-6 alkylsulfonyl group e.g., methylsulfonyl
  • Ring D is benzene or pyridine, each optionally having 1 to 3 substituents selected from
  • a halogen atom e.g., a fluorine atom, a chlorine atom
  • Ci-6 alkyl group e.g., methyl, monofluoromethyl, difluoromethyl, trifluoromethyl
  • Ci_ 6 alkoxy group e.g., methoxy, monofluoromethoxy, difluoromethoxy,
  • W is -0- or -0-CH2- (wherein the left bond is bonded to Ring B, and the right bond is bonded to Ring D) .
  • Ring A is pyridine optionally further having one
  • substituent on the carbon atom adjacent to G 1 , selected from (1) a halogen atom (e.g., a chlorine atom, a bromine atom), (2) an optionally halogenated Ci-6 alkyl group (preferably a Ci-6 alkyl group (e.g., methyl)), and
  • G 1 is CR 4 ,
  • R 4 is a hydrogen atom
  • Ring B is benzene or pyridine, each optionally having 1 to 3 substituents selected from
  • a halogen atom e.g., a chlorine atom, a bromine atom
  • Ci_ 6 alkyl group preferably a Ci-6 alkyl group (e.g., methyl)
  • Ci- 6 alkoxy group preferably a Ci-6 alkoxy group (e . g ., methoxy)
  • R 1 is a hydrogen atom or a Ci-6 alkyl group (e.g., methyl, ethyl),
  • R 2 is a hydrogen atom
  • R 1 and R 2 are joined together to form a cycloalkane
  • R 3 is a hydrogen atom
  • Ring C is benzene, pyridine or thiophene, each optionally having 1 to 3 substituents, in addition to R 5 , selected from
  • a halogen atom e.g., a fluorine atom, a chlorine atom
  • Ci- 6 alkyl group preferably a Ci-6 alkyl group (e.g., methyl)
  • R 5 is a carboxy group
  • Ring D is benzene or pyridine, each optionally having 1 to 3 substituents selected from
  • a halogen atom e.g., a fluorine atom, a chlorine atom
  • Ci-6 alkyl group e.g., methyl, monofluoromethyl , difluoromethyl, trifluoromethyl
  • Ci_ 6 alkoxy group e.g.,
  • W is -0-.
  • metal salts examples include 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.
  • metal salt examples 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, picoline, 2 , 6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, ⁇ , ⁇ '- dibenzylethylenediamine and the like.
  • Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
  • the salt with the salt with organic base include salts with trimethylamine, triethylamine, pyridine, picoline, 2 , 6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, ⁇ , ⁇ '- dibenzylethylenediamine and the like.
  • 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, benzenesulfonic acid, p- toluenesulfonic acid and the like.
  • salt with basic amino acid include salts with arginine, lysine, ornithine and the like.
  • 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. Necessary starting materials may be obtained by standard
  • 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
  • the objective compound By removing the protecting group as necessary after the reaction, the objective compound can be obtained.
  • the protection and deprotection can be
  • the protecting group include a tert-butylcarbamate group, a benzylcarbamate 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 separation means such as recrystallization, distillation, chromatography and the like. When the compound in the formula is commercially available, a commercially available product can also be used directly.
  • Compound (I) may be prepared by reacting compound (II) wherein L is a leaving group such as a halogen atom, a Ci- 6 alkoxy group, a C 6 -i4 aryloxy group, a sulfanyl group, a Ci_ 6 alkylthio group, a C 6 -i4 arylthio group, a Ci-6 alkylsulfinyl group, a C 6 - arylsulfinyl group, a Ci_ 6 alkylsulfonyl group, a C 6 -i4 arylsulfonyl group and a boronic acid group, with an amine of compound (III) (N-arylation reaction) as shown in Scheme 1.
  • L is a leaving group such as a halogen atom, a Ci- 6 alkoxy group, a C 6 -i4 aryloxy group, a sulfanyl group, a Ci_ 6 alkylthio group
  • compound (I) may be prepared by coupling compound (IV) wherein L is a leaving group, with compound (V) wherein W is a spacer in which the number of atoms in the main chain is 1 to 4.
  • compound (I) may be prepared by coupling compound (VI) with compound (VII) wherein L is a leaving group.
  • compound (I) may be prepared by the coupling compound (IV) wherein L is leaving group, with compound (VIII) .
  • n 0-1
  • compound (la) may be prepared by carbonylation of compound (I) wherein R 5 is a halogen atom, preferably a bromine atom. Functional groups in compound (I) may be protected if necessary, and after the carbonylation, it can be removed by conventional means.
  • n 0- 1
  • compound (lb) may be prepared by ester hydrolysis of compound (la) .
  • compound (Id) may be prepared from compound (I) wherein R 5 is a cyano group, by conversion of the nitrile group to tetrazole (Tetrazole formation) .
  • compound (II) may be prepared by coupling compound (IX) with compound (V) to obtain compound (XI) , followed by N-oxidation and subsequent chlorination.
  • compound (XI) may be obtained by coupling compound (X) with compound (VII) .
  • compound (II) may be prepared by coupling compound (XII) with compound (V), subjecting the resulting compound (XIII) to cyclization, and subjecting the resulting compound (XIV) to chlorination.
  • compound (II) may be prepared by subjecting compound (XV) to O-protection, subjecting the resulting compound (XVI) to coupling followed by deprotection, and subjecting the resulting compound (XIV) to chlorination .
  • Aromatic compound having a suitable leaving group for example, a halogen atom, a Ci-6 alkoxy group, a C6-1 aryloxy group, a sulfanyl group, a Ci-6 alkylthio group, a Ce-14 arylthio group, a Ci-6 alkylsulfinyl group, a C6-1 arylsulfinyl group, a Ci-6 alkylsulfonyl group, a C6-1 arylsulfonyl group and a boronic acid group, may be reacted with a primary or secondary amine. The reaction may be carried out in the absence or presence of a base, in an appropriate solvent or without solvent.
  • 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 carbonate
  • alkali metal hydrides such as sodium hydride
  • phosphazene bases such as 2-tert-butylimino-2-diethylamino- 1, 3-dimethylperhydro-l, 3, 2-diazaphosphorine (BEMP) .
  • Preferred polar solvent inert to the reaction includes alcohols (e.g., methanol, ethanol, propanol, n-butanol etc.), ethers (e.g., tetrahydrofuran (THF) , dioxane, dimethoxyethane (DME) etc.), and amides (e.g., N, -dimethylformamide (DMF) , N, midlinethylacetamide (DMA), N-methylpyrrolidine (NMP) etc.).
  • alcohols e.g., methanol, ethanol, propanol, n-butanol etc.
  • ethers e.g., tetrahydrofuran (THF) , dioxane, dimethoxyethane (DME) etc.
  • amides e.g., N, -dimethylformamide (DMF) , N, midlinethylacetamide (DMA), N-methylpyr
  • reaction may be carried out in a melt without addition of a solvent.
  • the reaction is carried out at elevated temperatures, preferably from approximately 60°C to reflux temperature.
  • L is a boronic acid group
  • the reaction may be carried out in the presence of a suitable catalyst.
  • the coupling reaction may be carried out in the absence or presence of a base, in an inert solvent or without solvent.
  • Preferred base is selected from an alkali or alkaline earth metal hydroxides, alkoxides, carbonates and hydrides such as sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium carbonate, cesium carbonate, potassium carbonate, BEMP, cesium fluoride (CSF) , sodium hydride and potassium hydride.
  • Preferred inert solvents for the reaction include acetone, benzene, toluene, xylene, nitrobenzene, nitromethane, pyridine, dichloromethane, dichloroethane, THF, DME, DMF, DMA, dioxane, dimethylsulfoxide (DMSO) and NMP.
  • the reaction temperature is generally in the range of 0°C to 200°C.
  • the reaction may be carried out in presence of a metal catalyst such as copper (e.g. cuprous iodide or copper bronze) and palladium.
  • the coupling reaction may be a Suzuki-cross coupling of an aryl halide with an organoboronic acid.
  • Preferred solvents for the reaction may be aromatic hydrocarbons (e.g., benzene, toluene, xylene, nitrobenzene, pyridine etc.); halogenated hydrocarbons (e.g., methylene chloride (DCM) , chloroform
  • reaction may be carried out at 0°C to reflux temperature.
  • reaction may be carried out in presence of a suitable catalyst such as
  • reaction may be carried out in
  • triphenylphosphine tricyclohexylphosphine, tri-tert- butylphosphine, 1, 1' -bis (diphenylphosphino) ferrocene, tri-2- furylphophine, 2- (dicyclohexylphosphino) biphenyl, 2,2'-bis(di- p-tolylphosphino) -1, 1' -binaphthyl etc.).
  • the reaction may be
  • Preferred base is selected from lithium hydroxide, sodium hydroxide,
  • potassium hydroxide barium hydroxide, potassium carbonate, cesium carbonate, sodium ethoxide, potassium tert-butoxide, cesium fluoride, tetrabutylammonium fluoride, pyridine, 1,8-
  • reaction may be carried out in presence or absence of a dehydrating agent (e.g., molecular sieves etc . ) .
  • a dehydrating agent e.g., molecular sieves etc .
  • 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
  • base is selected from N,N-diisopropylethylamine, N- methylmorpholine, triethylamine etc. If required, this
  • reaction may be carried out in the presence or absence of an additive such as 1, 1' -bis (diphenylphosphino) ferrocene,
  • reaction 35 triphenylphosphine and 1, 3-bis- (diphenylphosphine) propane .
  • the reaction may be carried out in a suitable solvent such as acetone, nitromethane, DMF, DMSO, NMP, acetonitrile, DCM, EDC, THF, methanol, ethanol and dioxane. While the 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 8.0°C.
  • Ester hydrolysis may be carried out under general
  • saponification conditions 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,
  • ester hydrolysis may be carried out under 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.
  • the suitable solvent includes alcohols (e.g., methanol, ethanol, propanol, butanol, 2-methoxyethanol, ethylene glycol etc.); ethers (e.g., diethyl ether, THF, dioxane, DME etc.); halogenated solvents (e.g., DCM, EDC, chloroform etc.); hexanmethylphophoramide and DMSO.
  • the reaction may be carried out at temperature in the range from -20°C to 100°C, preferably from 20°C to 35°C.
  • Amide coupling may be carried out using any suitable amide coupling regents such as oxalyl chloride, thionyl
  • Preferred base is selected from organic non- nucleophillic bases such as triethylamine, di-isopropylethyl amine, pyridine, N-methyl pyrrolidine, N,N- 5 dimethylaminopyridine, DBU, other hindered amines and
  • the amide coupling may be carried- out in the
  • reaction may be carried out at a temperature
  • the reaction may be carried out optionally in presence of a catalytic amount of DMF.
  • the amide coupling may be carried out by is heating ester and amine either in the absence of a solvent or in presence of a high boiling solvent such as toluene, xylene and DMSO. Amide coupling may be carried out in presence of a trialkyl aluminium (Chem. Commun., 2008, 1100-1102).
  • 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 tetrazole forming . reagent includes sodium azide, lithium azide,
  • reaction may be carried out in presence or absence of a catalyst such as dialkyltin oxide (alkyl is methyl or butyl) , alkylamino
  • reaction may be carried out in the presence or
  • ammonium chloride hydrogen chloride, aluminium chloride and zinc bromide.
  • the reaction may be carried out at temperature
  • N-Oxidation may be carried out using a suitable reagent such as H2O2/ACOH, H 2 0 2 /manganese tetrakis (2 , 6- dichlorophenyl) porphyrin, H 2 02/methyltrioxorhenium (MTO) , dimethyldioxirane (DMD) , bis (trimethylsilyl) peroxide (BTSP) , Caro's acid, m-chloroperoxybenzoic acid and oxaziridines.
  • the reaction may be carried out in a suitable inert solvent such as acetonitrile, DCM and DCE.
  • the reaction may be carried out at a temperature ranging from -20°C to 100°C, preferably from about 0°C to 100°C.
  • Chlorination may be carried out using a suitable reagent such as POCI 3 , S0C1 2 , (C0) 2 C1 2 , N-chloro succinimide and
  • the reaction may be carried out in presence or absence of an additive (e.g., ammonium chloride, DBU, PCI 5 , triethylamine, diisopropylethyl amine, pyridine, etc.).
  • an additive e.g., ammonium chloride, DBU, PCI 5 , triethylamine, diisopropylethyl amine, pyridine, etc.
  • the reaction may be carried out in a suitable inert solvent such as acetonitrile, toluene, chlorobenzene and DCE.
  • the reaction may be carried out at a temperature ranging from -20°C to reflux temperature, preferably at 0°C to 100°C.
  • the reaction may be carried out in presence or absence of an additive and a solvent.
  • 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
  • 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, Ci_ 6 alkyl-carbonyl (e.g., acetyl, propionyl etc.), phenylcarbonyl , Ci-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 of the protecting group include formyl, Ci_ 6 alkyl-carbonyl (e.g., acetyl, propionyl etc.), phenylcarbonyl , Ci-6 alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl etc.), phenyloxycarbonyl, C7-10 aralkyloxy-carbonyl (e.g.,
  • substituents include a halogen atom (e.g., fluorine, chlorine, bromine, iodine etc.), Ci-6 alkyl-carbonyl (e.g., acetyl,

Abstract

La présente invention concerne un composé représenté par la formule (1): dans laquelle chaque symbole est tel que défini dans le descriptif, ou un sel de celui-ci qui a une action antagoniste vis-à-vis du récepteur EP4, et qui est utile en tant qu'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 analogue.
PCT/JP2015/072884 2014-08-07 2015-08-06 Composés hétérocycliques utilisés en tant qu'antagonistes des récepteurs ccr4 WO2016021742A1 (fr)

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* Cited by examiner, † Cited by third party
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WO2018022992A1 (fr) * 2016-07-29 2018-02-01 Flx Bio, Inc. Modulateurs de récepteurs de chimiokine et leurs utilisations
WO2018210995A1 (fr) 2017-05-18 2018-11-22 Idorsia Pharmaceuticals Ltd Dérivés d'indole n-substitués
CN111163775A (zh) * 2017-10-02 2020-05-15 勃林格殷格翰国际有限公司 作为cdk8/cdk19抑制剂的新型[1,6]萘啶化合物和衍生物
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
US10766858B2 (en) 2016-03-30 2020-09-08 Genentech, Inc. Substituted benzamides and methods of use thereof
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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
US11446298B2 (en) 2017-05-18 2022-09-20 Idorsia Pharmaceuticals Ltd Pyrimidine derivatives
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US11712438B2 (en) 2017-05-18 2023-08-01 Idorsia Pharmaceuticals Ltd Phenyl derivatives as PGE2 receptor modulators
US11839613B2 (en) 2017-05-18 2023-12-12 Idorsia Pharmaceuticals Ltd Pyrimidine derivatives as PGE2 receptor modulators

Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003040108A1 (fr) 2001-11-03 2003-05-15 Astrazeneca Ab Derives quinazoline utilises en tant qu'agents antitumoraux
WO2003040109A2 (fr) 2001-11-03 2003-05-15 Astrazeneca Ab Derives de la quinazoline, agents anti-tumoraux
WO2003066630A2 (fr) * 2002-02-07 2003-08-14 Amgen Inc. Composes et procedes d'utilisation
WO2005021508A1 (fr) * 2003-09-03 2005-03-10 Pfizer Inc. Composes de phenyle ou de pyridyle amide utiles comme antagonistes de la prostaglandine e2
WO2006011670A1 (fr) 2004-07-28 2006-02-02 Takeda Pharmaceutical Company Limited COMPOSÉ DE PYRROLO[2,3-c]PYRIDINE, PROCÉDÉ SERVANT À PRODUIRE CELUI-CI ET UTILISATION DE CELUI-CI
WO2010080864A1 (fr) 2009-01-12 2010-07-15 Array Biopharma Inc. Composés contenant de la pipéridine et leurs utilisations
WO2010142751A1 (fr) 2009-06-10 2010-12-16 Tc Land Expression Méthode de diagnostic/pronostic in vitro et kit d'évaluation du rejet chronique médié par anticorps dans la transplantation rénale
WO2011088201A1 (fr) 2010-01-14 2011-07-21 Glaxo Group Limited Bloqueurs de canaux sodiques sensibles au potentiel
WO2014143609A1 (fr) * 2013-03-11 2014-09-18 Bristol-Myers Squibb Company Isoquinolines servant d'inhibiteurs des canaux ioniques potassiques
WO2014143608A1 (fr) * 2013-03-11 2014-09-18 Bristol-Myers Squibb Company Phthalazines servant d'inhibiteurs des canaux ioniques potassiques

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003040108A1 (fr) 2001-11-03 2003-05-15 Astrazeneca Ab Derives quinazoline utilises en tant qu'agents antitumoraux
WO2003040109A2 (fr) 2001-11-03 2003-05-15 Astrazeneca Ab Derives de la quinazoline, agents anti-tumoraux
WO2003066630A2 (fr) * 2002-02-07 2003-08-14 Amgen Inc. Composes et procedes d'utilisation
WO2005021508A1 (fr) * 2003-09-03 2005-03-10 Pfizer Inc. Composes de phenyle ou de pyridyle amide utiles comme antagonistes de la prostaglandine e2
WO2006011670A1 (fr) 2004-07-28 2006-02-02 Takeda Pharmaceutical Company Limited COMPOSÉ DE PYRROLO[2,3-c]PYRIDINE, PROCÉDÉ SERVANT À PRODUIRE CELUI-CI ET UTILISATION DE CELUI-CI
WO2010080864A1 (fr) 2009-01-12 2010-07-15 Array Biopharma Inc. Composés contenant de la pipéridine et leurs utilisations
WO2010142751A1 (fr) 2009-06-10 2010-12-16 Tc Land Expression Méthode de diagnostic/pronostic in vitro et kit d'évaluation du rejet chronique médié par anticorps dans la transplantation rénale
WO2011088201A1 (fr) 2010-01-14 2011-07-21 Glaxo Group Limited Bloqueurs de canaux sodiques sensibles au potentiel
WO2014143609A1 (fr) * 2013-03-11 2014-09-18 Bristol-Myers Squibb Company Isoquinolines servant d'inhibiteurs des canaux ioniques potassiques
WO2014143608A1 (fr) * 2013-03-11 2014-09-18 Bristol-Myers Squibb Company Phthalazines servant d'inhibiteurs des canaux ioniques potassiques

Non-Patent Citations (36)

* Cited by examiner, † Cited by third party
Title
"Design of Molecules", vol. 7, 1990, HIROKAWA SHOTEN, article "IYAKUHIN no KAIHATSU (Development of Pharmaceuticals", pages: 163 - 198
AM. CHEM. SOC MED CHEM. LETT., vol. 1, 2010, pages 54 - 58
AM. J. PATHOL., vol. 181, no. 1, 2012, pages 313 - 21
ANN. RHEUM. DIS., vol. 59, 2000, pages 883 - 886
ARTERIOSCLER. THROMB. VASE. BIOL., vol. 16, no. 8, 1996, pages 963 - 70
ARTHRITIS RHEUM., vol. 40, 1997, pages 1823 - 1828
BIOL. REPROD, vol. 88, no. 3, 2013, pages 77
BIOORG MED CNEM LETT., vol. 15, 2010, pages 3760 - 3
BMJ, vol. 323, no. 7304, 2001, pages 93 - 5
BR. J. PHARMACOL., vol. 160, no. 2, 2010, pages 292 - 310
CHEMICAL AND PHARMACEUTICAL BULLETIN, vol. 38, 1990, pages 2792 - 2796
CIRCULATION, vol. 100, no. 1, 1999, pages 48 - 54
EUR J PHARMACOL., vol. 580, 2008, pages 116 - 121
FERTIL STERIL, vol. 93, no. 8, 2010, pages 2498 - 506
IMMUNITY, vol. 33, no. 2, 2010, pages 150 - 2
IMMUNITY, vol. 33, no. 2, 2010, pages 279 - 88
J. ALLERGY CLIN. IMMUNOL., vol. 131, no. 2, 2013, pages 532 - 40,E1-2
J. CLIN. INVEST., vol. 102, no. 11, 1998, pages 1900 - 10
J. CLIN. INVEST., vol. 110, no. 5, 2002, pages 625 - 32
J. IMMUNOL., vol. 172, no. 4, 2004, pages 2607 - 12
J. PHARM. PHARM. SCI., vol. 16, no. 5, 2013, pages 821 - 47
J. VASE. SURG, vol. 38, no. 2, 2003, pages 354 - 9
JOURNAL, OF ANTIBIOTICS (J. ANTIBIOTICS, vol. 38, 1985, pages 877 - 885
MOL. CELL ENDOCRINOL., vol. 332, no. 1-2, 2011, pages 306 - 13
MOL. ENDOCRINOL., vol. 23, no. 8, 2009, pages 1291 - 305
N. ENGL. J. MED., vol. 328, no. 16, 1993, pages 1167 - 72
N. ENGL. J. MED., vol. 359, no. 11, 2008, pages 1136 - 42
NATURE GENETICS., vol. 43, 2011, pages 761 - 767
PHARMACOL. REV., vol. 63, no. 3, 2011, pages 471 - 538
PLOS ONE, vol. 7, no. 5, 2012, pages E36724
POSTEPY HIG. MED. DOSW., vol. 66, 2012, pages 287 - 94
SCAND. J. RHEUMATOL., vol. 37, 2008, pages 120 - 126
TETRAHEDRON LETTERS, vol. 52, 2011, pages 661 - 664
THROMB. RES., vol. 132, no. 1, 2013, pages 56 - 62
TRENDS PHARMACOL. SCI., vol. 33, no. 6, 2012, pages 304 - 11
WORLD J. SURG., vol. 32, no. 6, 2008, pages 976 - 86

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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
US11130726B2 (en) 2015-08-27 2021-09-28 Genentech, Inc. Therapeutic compounds and methods of use thereof
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US10899732B2 (en) 2015-11-25 2021-01-26 Genentech, Inc. Substituted benzamides useful as sodium channel blockers
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US10604526B2 (en) 2016-07-29 2020-03-31 Rapt Therapeutics, Inc. Chemokine receptor modulators and uses thereof
TWI817929B (zh) * 2016-07-29 2023-10-11 美商瑞佩特治療公司 趨化介素受體調節劑及其用途
WO2018022992A1 (fr) * 2016-07-29 2018-02-01 Flx Bio, Inc. Modulateurs de récepteurs de chimiokine et leurs utilisations
KR20190041471A (ko) * 2016-07-29 2019-04-22 에프엘엑스 바이오, 인크. 케모카인 수용체 조절제 및 이의 용도
US10179787B2 (en) 2016-07-29 2019-01-15 Flx Bio, Inc. Chemokine receptor modulators and uses thereof
RU2768827C2 (ru) * 2016-07-29 2022-03-24 ФЛЭкс БАЙО, ИНК. Модуляторы хемокинового рецептора и их применение
US10793550B2 (en) 2017-03-24 2020-10-06 Genentech, Inc. 4-piperidin-n-(pyrimidin-4-yl)chroman-7-sulfonamide derivatives as sodium channel inhibitors
US11839613B2 (en) 2017-05-18 2023-12-12 Idorsia Pharmaceuticals Ltd Pyrimidine derivatives as PGE2 receptor modulators
WO2018210995A1 (fr) 2017-05-18 2018-11-22 Idorsia Pharmaceuticals Ltd Dérivés d'indole n-substitués
US11325899B2 (en) 2017-05-18 2022-05-10 Idorsia Pharmaceuticals Ltd Benzofurane and benzothiophene derivatives as PGE2 receptor modulators
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US11028075B2 (en) 2018-02-26 2021-06-08 Genentech, Inc. Therapeutic compounds and methods of use thereof
US10947251B2 (en) 2018-03-30 2021-03-16 Genentech, Inc. Therapeutic compounds and methods of use thereof
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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