WO2016021742A1 - Heterocyclic compounds as ep4 receptor antagonists - Google Patents

Heterocyclic compounds as ep4 receptor antagonists 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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French (fr)
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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/en

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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

The present invention provides a compound represented by the formula (1) : wherein each symbol is as defined in the specification or a salt thereof has 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, inflammatory breast cancer etc.) and the like.

Description

DESCRIPTION
HETEROCYCLIC COMPOUNDS AS EP4 RECEPTOR ANTAGONISTS Technical Field
[0001]
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.
[0002]
(Background of the Invention)
Prostaglandin E2 (PGE2) 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.
[0003]
Emerging biology has revealed important roles of EP4 receptors in immune system (non-patent documents 2 and 3) . For example, 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-Ιβ expression with LPS via EP4 receptors in macrophages. Thl, Thl7 and macrophage cells play key roles in the development of
autoimmune/inflammatory diseases. Thus, 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 .
[0004]
Non-steroidal anti-inflammatory drugs (NSAIDs) and COX-2 inhibitors are clinically proven to relieve inflammation and pain by inhibiting the synthesis of arachidonic acid pathway metabolites including PGE2. However, their use is associated with adverse effects due to pleiotropic function of
arachidonic acid pathway metabolites and imbalance in their levels. An imbalance between TXA2 and PGI2, for example, has been implicated in the vasospasm, hyperaggregability and thromboembolism that are associated with many cardiovascular diseases (non-patent document 6) . As EP4 selective antagonists specifically block PGE2 function through only EP4 receptor, leaving functions through other receptors intact, it is
expected that they will not exhibit the adverse effects
similar to that of NSAIDs and COX-2 inhibitors (non-patent document 7). Further, compared to other targeted therapies (e.g. JAK, TNFa, IL-6) for RA, EP4 antagonist has been shown to improve both joint damage and inflammatory pain in animal models. Thus, this mechanism has potential to "complete
symptom management" for RA in clinic (non-patent document 8).
[0005]
In addition to autoimmune diseases, endometriosis, aortic aneurysm (e.g. abdominal aortic aneurysm, thoracic aortic aneurysm, thoracoabdominal aortic aneurysm etc.) and
ankylosing spondylitis are other indications for EP4
antagonist. Endometriosis (EM) 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
abundantly expressed in human endometriosis tissues (ectopic and eutopic endometrium) during the proliferative phase of the menstrual cycle (non-patent document 12) . In human
immortalized endometriotic epithelial and stromal cells
selective inhibition of EP4 induced apoptosis (non-patent document 12), inhibited proliferation (non-patent document 13), inhibited migration and invasion (non-patent document 14) and inhibited adhesion (non-patent document 15). These studies suggest that inhibition of EP4 signaling is a potential
therapeutic option for women with EM (non-patent document 15) .
[0006]
Abdominal aortic aneurysm (AAA) is a common, progressive, and life-threatening degenerative vascular disease (non-patent documents 16 and 17). It is an inflammatory disorder
characterized by localized connective tissue degeneration and smooth muscle cell apoptosis, leading to aortic dilatation and rupture (non-patent documents 18-20) . After rupture occurs, the probability of mortality is greater than 60% (non-patent document 21) . No pharmacotherapy has been found to be
effective at decreasing the growth rate or rupture rate of
AAAs except. In aneurysm walls, 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
macrophages in the lesion (non-patent documents 23 and 24). 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) .
[0007]
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. Ankylosing
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. Since 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.
[0008]
Examples of the compound having a structure similar to the compound described in the present specification include the following compounds.
[0009]
(1) Patent document 1 describes a compound represented by the formula:
[0010]
Figure imgf000006_0001
[0011]
wherein
Z is a direct bond, 0, S, SO, S02, N (R ) , CO, CH (OR ) , CON (R11), N (R11) CO, S02N (R11), N (R11) S02, OC(R )2, SC(Rn)2 or N(Rn)C(R )2;
R11 is hydrogen or Ci_6 alkyl;
Q1 is aryl, heteroaryl, etc;
R1 is halogen, trifluoromethyl, etc;
m is 0, 1 or 2;
R2 is hydrogen;
R3 is hydrogen or Ci_6 alkyl;
L is a direct bond or -[C(R22)2]n- [n is 1 or 2] , and each R22 independently is hydrogen or Ci_4 alkyl;
Q2 is
[0012]
Figure imgf000006_0002
[0013]
G1 and G5 are each hydrogen;
G2 and G4 are each hydrogen, halogen, hydroxy, amino, carboxy, etc.; and
G3 is hydrogen, halogen, hydroxy, amino, carboxy, etc.,
as an erbB2 receptor inhibitor.
[0014]
(2) Patent document 2 describes a compound represented by the formula:
[0015]
Figure imgf000007_0001
[0016]
wherein
Z is a direct bond, 0, S, N(R2) wherein R2 is hydrogen or Ci_6 alkyl;
Q1 is C3-7 cycloalkyl, heterocyclyl, etc.;
R1 is hydrogen or Ci_6 alkyl;
Q2 is
[0017]
Figure imgf000007_0002
[0018]
G1, G2, G3, G4 and G5 are each hydrogen, halogen, hydroxy, amino, carboxy, etc . ;
X2 is a direct bond, 0, S, SO, S02, CH(OR6), CON(R6), etc.;
R6 is hydrogen or Ci-6 alkyl; and
Q3 is aryl or heteroaryl,
as an erbB2 receptor inhibitor.
[0019]
(3) Patent document 3 describes a compound represented by the formula:
[0020]
Figure imgf000008_0001
[0021]
wherein
Cycl1 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) ;
Cyc21 is a 5-membered mono-cyclic heterocyclic ring optionally having substituent (s) ;
Cyc41 is a 5- to 10-membered mono-cyclic or bi-cyclic
carbocyclic ring optionally having substituent ( s ) , or a 5- to 10-membered mono-cyclic or bi-cyclic heterocyclic ring
optionally having substituent (s) ;
X1 is -CH2-, -CO- or -S02-;
Z1 is bond, -N(R51)-CO-, -CO-N(R51)-, -N (R51) - or -0-;
R51 is H, Ci-4 alkyl optionally having substituent ( s ) , or R51 and the substituent of Cyc41 is taken together to form a Ci_4 alkylene optionally having substituent (s) or a C2-4 alkenylene optionally having substituent (s) ;
R10 is H or a substituent;
R110 is a substituent; and
p is 0-8,
as an agent for the prophylaxis or treatment of metabolic disease (diabetes), cerebrovascular disease (stroke) etc.
[0022]
(4) Patent document 4 describes a compound represented by the formula:
[0023]
Figure imgf000009_0001
[0024]
wherein
A is an optionally substituted hydrocarbon group or an
optionally substituted heterocyclic group;
m is 0, 1 or 2;
X is a bond, 0, S, CH2, 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,
as a proton pump inhibitor.
(5) Non-Patent Document 32 describes the following compound:
[0025]
Figure imgf000010_0001
[0026]
(6) Non-Patent Document 33 describes the following compounds :
[0027]
Figure imgf000010_0002
Document List
Patent Document
[0028]
[Patent Document 1] WO 2003/040109
[Patent Document 2] WO 2003/040108
[Patent Document 3] WO 2010/080864
[Patent Document 4] WO 2006/011670
Non-Patent Document
[0029]
[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 3] J. Allergy Clin. Immunol., 2013.
131 (2) : p. 532-40 el-2
[Non-Patent Document 4] Immunity, 2010. 33(2): p. 279-88
[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
5 [Non-Patent Document 11] N. Engl. J. Med., 2008. 359(11): p.
1136-42
[Non-Patent Document 12] Mol. Endocrinol., 2009. 23(8): p.
1291-305
[Non-Patent Document 13] Fertil Steril, 2010. 93(8): p. 2498-
10 506
[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.
1167-72
[Non-Patent Document 18] J. Clin. Invest., 1998. 102(11): p.
1900-10
20 [Non-Patent Document 19] J. Clin. Invest., 2002. 110(5): p.
625-32
[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
25 [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
30 [Non-Patent Document 26] Scand. J. Rheumatol., 2008. 37: p.
120-126
[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
[Non-Patent Document 33] Am. Chem. Soc. Med. Chem. Lett., 2010, Vol.1, pages 54-58
Summary of the Invention
Problems to be Solved by the Invention
[0030]
The present invention aims to provide 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 (e.g. abdominal aortic aneurysm, thoracic aortic aneurysm, thoracoabdominal aortic aneurysm etc.), endometriosis, ankylosing spondylitis,
inflammatory breast cancer etc.) and the like.
Means of Solving the Problems
[0031]
The present inventors have conducted intensive studies, and have found that a compound represented by the below- mentioned formula (1) unexpectedly has an EP4 receptor
antagonistic action, and therefore, is useful as ah agent for the prophylaxis or treatment of EP4 receptor associated
diseases (e.g., rheumatoid arthritis, aortic aneurysm (e.g.
abdominal aortic aneurysm, thoracic aortic aneurysm,
thoracoabdominal aortic aneurysm etc.), endometriosis,
ankylosing spondylitis, inflammatory breast cancer etc.) and the like, and completed the present invention based on these findings .
Accordingly, the present invention provides the following.
[1] A compound represented by the formula (I) :
Figure imgf000013_0001
[0033]
wherein
Ring A is an optionally further substituted pyridine or an optionally further substituted pyridazine,
G1 is N or CR4,
R4 is a hydrogen atom or a substituent,
Ring B is an optionally substituted 6-membered aromatic ring, R1 and R2 are each independently a hydrogen atom or an
optionally substituted Ci-e alkyl group, or R1 and R2 are joined together to form a cycloalkane or a heterocycle, each of which is optionally substituted,
R3 is a hydrogen atom or a substituent,
Ring C is an optionally further substituted ring,
R5 is a substituent,
Ring D is an optionally substituted ring, and
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 (I).
[2] The compound or salt of the above-mentioned [1], wherein Ring A is pyridine optionally further having one substituent, on the carbon atom adjacent to G1, selected from
(1) a halogen atom,
(2) an optionally halogenated Ci-6 alkyl group, and
(3) a C3-10 cycloalkyl group,
G1 is CR4,
R4 is a hydrogen atom,
Ring B is a 6-membered aromatic ring optionally having 1 to 3 substituents selected from
(1) a halogen atom,
(2) an optionally halogenated Ci-6 alkyl group,
(3) an optionally halogenated Ci_6 alkoxy group, and
(4) a C3-10 cycloalkyl group,
R1 and R2 are each independently a hydrogen atom or a Ci-6 alkyl group, or R1 and R2 are joined together to form a cycloalkane, R3 is a hydrogen atom,
Ring C is a C6-i4 aromatic hydrocarbon ring or a 5- or 6- membered monocyclic aromatic heterocycle, each optionally having 1 to 3 substituents, in addition to R5, selected from
(1) a halogen atom, and
(2) an optionally halogenated Ci-6 alkyl group,
R5 is
(1) a carboxy group,
(2) a Ci-6 alkoxy-carbonyl group,
(3) a cyano group,
(4) a Ci-6 alkyl group optionally having 1 to 3 substituents selected from
(a) a halogen atom,
(b) a hydroxy group, and
' (c) a carboxy group,
(5) a carbamoyl group optionally having 1 or 2 substituents selected from
(a) a Ci-6 alkyl group,
(b) a Ci-6 alkoxy group,
(c) a C7-16 aralkyloxy group, and
(d) a Ci-6 alkylsulfonyl group, or
(6) a sulfamoyl group,
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
(1) a halogen atom,
(2) a cyano group,
(3) an optionally halogenated Ci-6 alkyl group, and (4) an optionally halogenated Ci_6 alkoxy group, and W is -0- or -0-CH2- (wherein the left bond is bonded to Ring B, and the right bond is bonded to Ring D) .
[3] 4- [ (IS) -1- [ [8- (3-Fluorophenoxy) -1- isoquinolyl] amino] ethyl] benzoic acid or a salt thereof.
[4] 4- [ (IS) -1- [ [5-Chloro-8- ( 4-fluorophenoxy) -2 , 7-naphthyridin- 1-yl] amino] ethyl] benzoic acid or a salt thereof.
[5] 4- [ (IS) -1- [ [8- (3-Fluorophenoxy) -2 , 7-naphthyridin-l- yl] amino] ethyl] benzoic acid or a salt thereof.
[6] A medicament comprising the compound or salt of the above- mentioned [1] .
[7] The medicament of the above-mentioned [6], which is an EP4 receptor antagonist.
[8] The medicament of the above-mentioned [6], which is an agent for the prophylaxis or treatment of EP4 receptor
associated diseases.
[9] 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.
[10] The compound or salt the above-mentioned [1] for use in the prophylaxis or treatment of EP4 receptor associated
diseases .
[11] The compound or salt the above-mentioned [10] , wherein the EP4 receptor associated diseases is selected from
rheumatoid arthritis, aortic aneurysm, endometriosis,
ankylosing spondylitis and inflammatory breast cancer.
[12] 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.
[13] 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.
[14] The method of the above-mentioned [13], wherein the EP4 receptor associated diseases is selected from rheumatoid arthritis, aortic aneurysm, endometriosis, ankylosing
spondylitis and inflammatory breast cancer.
[15] Use of the compound or salt of the above-mentioned [1] for the production of an agent for the prophylaxis or
treatment of EP4 receptor associated diseases.
[16] Use of the above-mentioned [15], wherein the EP4 receptor associated diseases is selected from rheumatoid arthritis, aortic aneurysm, endometriosis, ankylosing spondylitis and inflammatory breast cancer.
Effect of the Invention
[0034]
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.,
rheumatoid arthritis, aortic aneurysm, endometriosis,
ankylosing spondylitis, inflammatory breast cancer etc.) and the like.
[0035]
[Detailed Description of the Invention]
The definition of each substituent used in the present specification is described in detail in the following. Unless otherwise specified, each substituent has the following definition.
In the present specification, examples of the "halogen atom" include fluorine, chlorine, bromine and iodine.
In the present specification, 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 .
In the present specification, examples of the "optionally halogenated Ci-6 alkyl group" include a Ci_6 alkyl group
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,
pentafluoroethyl, propyl, 2 , 2-difluoropropyl, 3,3,3- trifluoropropyl, isopropyl, butyl, 4 , 4 , 4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5, 5, 5-trifluoropentyl, hexyl and 6, 6, 6-trifluorohexyl .
In the present specification, examples of the "C2_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.
In the present specification, examples of the "C2-6 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 .
In the present specification, examples of the "C3-10
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.
In the present specification, 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 .
In the present specification, examples of the "C3-10
cycloalkenyl group" include cyclopropenyl, cyclobutenyl,
cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl .
In the present specification, examples of the "C6-1 aryl group" include phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2- anthryl and 9-anthryl.
In the present specification, examples of the "C7-i6
aralkyl group" include benzyl, phenethyl, naphthylmethyl and phenylpropyl .
[0036]
In the present specification, examples of the "Ci-6 alkoxy group" include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy.
In the present specification, examples of the "optionally halogenated Ci_6 alkoxy group" include a Ci_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.
In the present specification, examples of the "C3-i0
cycloalkyloxy group" include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy and
cyclooctyloxy .
In the present specification, examples of the "Ci_6
alkylthio group" include methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, pentylthio and hexylthio.
In the present specification, 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.
Specific examples thereof include methylthio,
difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4 , 4 , -trifluorobutylthio, pentylthio and hexylthio.
In the present specification, 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.
In the present specification, 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.
In the present specification, examples of the "Ci-6 alkoxy-carbonyl group" include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,
isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl and hexyloxycarbonyl .
In the present specification, examples of the "C6-i aryl- carbonyl group" include benzoyl, 1-naphthoyl and 2-naphthoyl.
In the present specification, examples of the "C7-i6
aralkyl-carbonyl group" include phenylacetyl and
phenylpropionyl .
In the present specification, examples of the "5- to 14- membered aromatic heterocyclylcarbonyl group" include
nicotinoyl, isonicotinoyl, thenoyl and furoyl.
In the present specification, examples of the "3- to 14- membered non-aromatic heterocyclylcarbonyl group" include morpholinylcarbonyl, piperidinylcarbonyl and
pyrrolidinylcarbonyl .
In the present specification, examples of the "mono- or di-Ci-6 alkyl-carbamoyl group" include methylcarbamoyl,
ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl and N- ethyl-N-methylcarbamoyl .
In the present specification, examples of the "mono- or di-C7-i6 aralkyl-carbamoyl group" include benzylcarbamoyl and phenethylcarbamoyl .
In the present specification, examples of the "Ci-6 alkylsulfonyl group" include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl , butylsulfonyl, see- butylsulfonyl and tert-butylsulfonyl .
In the present specification, 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,
isopropylsulfonyl, butylsulfonyl, 4,4, 4-trifluorobutylsulfonyl, pentylsulfonyl and hexylsulfonyl .
In the present specification, examples of the "C6-14
arylsulfonyl group" include phenylsulfonyl , 1-naphthylsulfonyl and 2-naphthylsulfonyl .
[0037]
In the present specification, examples of the
"substituent" 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
substituted hydroxy group, an optionally substituted sulfanyl (SH) group and an optionally substituted silyl group.
In the present specification, examples of the
"hydrocarbon group" (including "hydrocarbon group" of
"optionally substituted hydrocarbon group") include a Ci_6 alkyl group, a C2-6 alkenyl group, a C2_6 alkynyl group, a C3-10
cycloalkyl group, a C3-10 cycloalkenyl group, a C6-i4 aryl group and a C7_i6 aralkyl group.
[0038]
In the present specification, examples of the "optionally substituted hydrocarbon group" include a hydrocarbon group optionally having substituent ( s ) selected from the following substituent group A.
[substituent group A]
(1) a halogen atom,
(2) a nitro group,
(3) a cyano group,
(4) an oxo group,
(5) a hydroxy group,
(6) an optionally halogenated Ci-6 alkoxy group,
(7) a C6-14 aryloxy group (e.g., phenoxy, naphthoxy) , (8) a C7-16 aralkyloxy group (e.g., benzyloxy) ,
(9) a 5- to 1 -membered aromatic heterocyclyloxy group (e.g., pyridyloxy) ,
(10) a 3- to 14-membered non-aromatic heterocyclyloxy group (e.g., morpholinyloxy, piperidinyloxy) ,
(11) a Ci-6 alkyl-carbonyloxy group (e.g., acetoxy,
propanoyloxy) ,
(12) a Ce-14 aryl-carbonyloxy group (e.g., benzoyloxy, 1- naphthoyloxy, 2-naphthoyloxy) ,
(13) a Ci-6 alkoxy-carbonyloxy group (e.g., methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy) , (14) a mono- or di-Ci-6 alkyl-carbamoyloxy group (e.g.,
methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy, diethylcarbamoyloxy) ,
(15) a C3-i4 aryl-carbamoyloxy group (e.g., phenylcarbamoyloxy, naphthylcarbamoyloxy) ,
(16) a 5- to 14-membered aromatic heterocyclylcarbonyloxy group (e.g., nicotinoyloxy) ,
(17) a 3- to 14-membered non-aromatic heterocyclylcarbonyloxy group (e.g., morpholinylcarbonyloxy, piperidinylcarbonyloxy) ,
(18) an optionally halogenated Ci-6 alkylsulfonyloxy group (e.g., methylsulfonyloxy, trifluoromethylsulfonyloxy) ,
(19) a C6-i4 arylsulfonyloxy group optionally substituted by a Ci-6 alkyl group (e.g., phenylsulfonyloxy, toluehesulfonyloxy) , (20) an optionally halogenated Ci-6 al.kylthio group,
(21) a 5- to 14-membered aromatic heterocyclic group,
(22) a 3- to 14-membered non-aromatic heterocyclic group,
(23) a formyl group,
(24) a carboxy group,
(25) an optionally halogenated Ci_6 alkyl-carbonyl group,
(26) a C6-i4 aryl-carbonyl group,
(27) a 5- to 14-membered aromatic heterocyclylcarbonyl group,
(28) a 3- to 14-membered non-aromatic heterocyclylcarbonyl group,
(29) a Ci-6 alkoxy-carbonyl group, (30) a Ce-14 aryloxy-carbonyl group (e.g., phenyloxycarbonyl, 1- naphthyloxycarbonyl, 2-naphthyloxycarbonyl) ,
(31) a Cv-16 aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl, phenethyloxycarbonyl) ,
(32) a carbamoyl group,
(33) a thiocarbamoyl group,
(34) a mono- or di-Ci_6 alkyl-carbamoyl group,
(35) a C6-i4 aryl-carbamoyl group (e.g., phenylcarbamoyl) ,
(36) a 5- to 14-membered aromatic heterocyclylcarbamoyl group (e.g., pyridylcarbamoyl, thienylcarbamoyl) ,
(37) a 3- to 14-membered non-aromatic heterocyclylcarbamoyl group (e.g., morpholinylcarbamoyl, piperidinylcarbamoyl) ,
(38) an optionally halogenated Ci_6 alkylsulfonyl group,
(39) a C6-i4 arylsulfonyl group,
(40) a 5- to 14-membered aromatic heterocyclylsulfonyl group (e.g., pyridylsulfonyl, thienylsulfonyl) ,
(41) an optionally halogenated Ci_6 alkylsulfinyl group,
(42) a C6-i4 arylsulfinyl group (e.g., phenylsulfinyl, 1- naphthylsulfinyl, 2-naphthylsulfinyl ) ,
(43) a 5- to 14-membered aromatic heterocyclylsulfinyl group (e.g., pyridylsulfinyl, thienylsulfinyl) ,
(44) an amino group,
(45) a mono- or di-Ci-6 alkylamino group (e.g., methylamino, ethylamino, propylamino, isopropylamino, butylamino,
dimethylamino, diethylamino, dipropylamino, dibutylamino, N- ethyl-N-methylamino) ,
(46) a mono- or di-C6-i arylamino group (e.g., phenylamino) ,
(47) a 5- to 14-membered aromatic heterocyclylamino group (e.g., pyridylamino) ,
(48) a C7-i6 aralkylamino group (e.g., benzylamino) ,
(49) a formylamino group,
(50) a Ci-6 alkyl-carbonylamino group (e.g., acetylamino, propanoylamino, butanoylamino) ,
(51) a (Ci-6 alkyl) (Ci-6 alkyl-carbonyl) amino group (e.g., N- acetyl-N-methylamino) , (52) a Ce-14 aryl-carbonylamino group (e.g., phenylcarbonylamino, naphthylcarbonylamino) ,
(53) a Ci-6 alkoxy-carbonylamino group (e.g.,
methoxycarbonylamino, ethoxycarbonylamino,
propoxycarbonylamino, butoxycarbonylamino, tert- butoxycarbonylamino) ,
(54) a C7-16 aralkyloxy-carbonylamino group (e.g.,
benzyloxycarbonylamino) ,
(55) a Ci-6 alkylsulfonylamino group (e.g., methylsulfonylamino, ethylsulfonylamino) ,
(56) a C6-i4 arylsulfonylamino group optionally substituted by a Ci-6 alkyl group (e.g., phenylsulfonylamino,
toluenesulfonylamino) ,
(57) an optionally halogenated Ci_6 alkyl group,
(58) a C2-6 alkenyl group,
(59) a C2-6 alkynyl group,
(60) a C3-10 cycloalkyl group,
(61) a C3-10 cycloalkenyl group and
(62) a C6-i4 aryl group.
[0039]
The number of the above-mentioned substituents in the "optionally substituted hydrocarbon group" is, for example, 1 to 5, preferably 1 to 3. When the number of the substituents is two or more, the respective substituents may be the same or different.
In the present specification, examples of the
"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.
[0040]
In the present specification, examples of the "aromatic heterocyclic group" (including "5- to 14-membered 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.
Preferable examples of the "aromatic heterocyclic group" 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; and
8- to 14-membered fused polycyclic (preferably bi or
tricyclic) aromatic heterocyclic groups such as
benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl , benzothiazolyl, benzisothiazolyl,
benzotriazolyl, imidazopyridinyl, thienopyridinyl,
furopyridinyl, pyrrolopyridinyl, pyrazolopyridinyl ,
oxazolopyridinyl, thiazolopyridinyl , imidazopyrazinyl ,
imidazopyrimidinyl, thienopyrimidinyl, furopyrimidinyl,
pyrrolopyrimidinyl, pyrazolopyrimidinyl, oxazolopyrimidinyl , thiazolopyrimidinyl, pyrazolotriazinyl, naphtho [2, 3-b] thienyl, phenoxathiinyl, indolyl, isoindolyl, lH-indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl,
quinoxalinyl, quinazolinyl , cinnolinyl, carbazolyl, β- carbolinyl, phenanthridinyl, acridinyl, phenazinyl,
phenothiazinyl, phenoxazinyl and the like.
[0041]
In the present specification, examples of the "non- aromatic heterocyclic group" (including "3- to 14-membered non-aromatic heterocyclic group") 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.
Preferable examples of the "non-aromatic heterocyclic group" include 3- to 8-membered monocyclic non-aromatic heterocyclic groups such as aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrothienyl,
tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl , pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl,
tetrahydroisothiazolyl, tetrahydrooxazolyl ,
tetrahydroisooxazolyl, piperidinyl, piperazinyl,
tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl , tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl, tetrahydropyranyl, tetrahydrothiopyranyl , morpholinyl, thiomorpholinyl, azepanyl, diazepanyl, azepinyl, oxepanyl, azocanyl, diazocanyl and the like; and
9- to 14-membered fused polycyclic (preferably bi or
tricyclic) non-aromatic heterocyclic groups such as
dihydrobenzofuranyl, dihydrobenzimidazolyl,
dihydrobenzoxazolyl, dihydrobenzothiazolyl ,
dihydrobenzisothiazolyl, dihydronaphtho [2, 3-b] thienyl, tetrahydroisoquinolyl, tetrahydroquinolyl, 4H-quinolizinyl, indolinyl, isoindolinyl, tetrahydrothieno [2, 3-c] pyridinyl, tetrahydrobenzazepinyl, tetrahydroquinoxalinyl,
tetrahydrophenanthridinyl, hexahydrophenothiazinyl,
hexahydrophenoxazinyl, tetrahydrophthalazinyl,
tetrahydronaphthyridinyl, tetrahydroquinazolinyl ,
tetrahydrocinnolinyl, tetrahydrocarbazolyl, tetrahydro-β- carbolinyl, tetrahydroacrydinyl, tetrahydrophenazinyl, tetrahydrothioxanthenyl, octahydroisoquinolyl and the like.
[0042]
In the present specification, preferable examples of the "7- to 10-membered bridged heterocyclic group" include
quinuclidinyl and 7-azabicyclo [2.2.1 ] heptanyl .
In the present specification, examples of the "nitrogen- containing heterocyclic group" include a "heterocyclic group" containing at least one nitrogen atom as a ring-constituting atom.
In the present specification, examples of the "optionally substituted heterocyclic group" include a heterocyclic group optionally having substituent (s ) selected from the
aforementioned substituent group A.
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.
[0043]
In the present specification, 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 C2-6 alkenyl group, a C3-10 cycloalkyl group, a C3-10 cycloalkenyl group, a C6-14 aryl group, a C7-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
optionally halogenated Ci-6 alkoxy group, a hydroxy group, a nitro group, a cyano group, an amino group and a carbamoyl group".
Examples of the "acyl group" also include a hydrocarbon- sulfonyl group, a heterocyclylsulfonyl group, a hydrocarbon- sulfinyl group and a heterocyclylsulfinyl group.
Here, the hydrocarbon-sulfonyl group means a hydrocarbon group-bonded sulfonyl group, the heterocyclylsulfonyl group means a heterocyclic group-bonded sulfonyl group, the
hydrocarbon-sulfinyl group means a hydrocarbon group-bonded sulfinyl group and the heterocyclylsulfinyl group means a heterocyclic group-bonded sulfinyl group.
Preferable examples of the "acyl group" include a formyl group, a carboxy group, a Ci-6 alkyl-carbonyl group, a C2-6 alkenyl-carbonyl group (e.g., crotonoyl) , a C3_i0 cycloalkyl- carbonyl group (e.g., cyclobutanecarbonyl,
cyclopentanecarbonyl, cyclohexanecarbonyl,
cycloheptanecarbonyl) , a C3_io cycloalkenyl-carbonyl group (e.g., 2-cyclohexenecarbonyl) , a C6-i4 aryl-carbonyl group, a C7-i5 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,
naphthyloxycarbonyl) , a C7-i6 aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl, phenethyloxycarbonyl) , 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-C3_io cycloalkyl-carbamoyl group (e.g., cyclopropylcarbamoyl ) , a mono- or di-C-6-i aryl-carbamoyl group (e.g., phenylcarbamoyl) , a mono- or di-C7-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- methylthiocarbamoyl) , a mono- or di-C2-6 alkenyl-thiocarbamoyl group (e.g., diallylthiocarbamoyl) , a mono- or di-C3_io
cycloalkyl-thiocarbamoyl group (e.g., cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl) , a mono- or di-C6-i4 aryl-thiocarbamoyl group (e.g., phenylthiocarbamoyl) , a mono- or di-C7-i6 aralkyl- thiocarbamoyl group (e.g., benzylthiocarbamoyl ,
phenethylthiocarbamoyl) , a 5- to 14-membered aromatic
heterocyclylthiocarbamoyl group (e.g., pyridylthiocarbamoyl) , a sulfino group, a Ci-6 alkylsulfinyl group (e.g.,
methylsulfinyl, ethylsulfinyl ) , a sulfo group, a Ci_6
alkylsulfonyl group, a C6-i4 arylsulfonyl group, a phosphono group and a mono- or di-Ci-6 alkylphosphono group (e.g.,
dimethylphosphono, diethylphosphono, diisopropylphosphono, dibutylphosphono) .
[0044]
In the present specification, examples of the "optionally substituted amino group" include an amino group optionally having Ml or 2 substituents selected from a Ci-6 alkyl group, a C2-6 alkenyl group, a C3-10 cycloalkyl group, a C6_i4 aryl group, a C7_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-C7-i6 aralkyl-carbamoyl group, a Ci_6 alkylsulfonyl group and a C6-i4 arylsulfonyl group, each of which optionally has 1 to 3 substituents selected from
substituent group A".
Preferable examples of the optionally substituted amino group include an amino group, a mono- or di- (optionally
halogenated Ci_6 alkyl) amino group (e.g., methylamino,
trifluoromethylamino, dimethylamino, ethylamino, diethylamino, propylamino, dibutylamino) , a mono- or di-C2-6 alkenylamino group (e.g., diallylamino) , a mono- or di-C3-io cycloalkylamino group (e.g., cyclopropylamino, cyclohexylamino) , a mono- or di-C6-14 arylamino group (e.g., phenylamino) , a mono- or di-C7_i6 aralkylamino group (e.g., benzylamino, dibenzylamino) , a mono- or di- (optionally halogenated Ci_6. alkyl) -carbonylamino group (e.g., acetylamino, propionylamino) , a mono- or di-C6-i4 aryl- carbonylamino group (e.g., benzoylamino) , a mono- or di-C7-i6 aralkyl-carbonylamino group (e.g., benzylcarbonylamino) , a mono- or di-5- to 14^membered aromatic
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-C7_i6 aralkyl-carbamoyl) amino group (e.g.,
benzylcarbamoylamino) , a Ci_6 alkylsulfonylamino group (e.g., methylsulfonylamino, ethylsulfonylamino) , a C6_i4
arylsulfonylamino group (e.g., phenylsulfonylamino) , a (Ci-6 alkyl) (Ci-6 alkyl-carbonyl ) amino group (e.g., N-acetyl-N- methylamino) and a (Ci-6 alkyl) (C6-i4 aryl-carbonyl) amino group
(e.g., N-benzoyl-N-methylamino) .
[0045]
In the present specification, examples of the "optionally substituted carbamoyl group" include a carbamoyl group
optionally having "1 or 2 substituents selected from a Ci_6 alkyl group, a C2-6 alkenyl group, a C3_i0 cycloalkyl group, a C6- 14 aryl group, a C7_i6 aralkyl group, a Ci_6 alkoxy group, a C7_i6 aralkyloxy group, a Ci-6 alkyl-carbonyl group, a C6-i4 aryl- carbonyl group, a C7-i6 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, a mono- or di-Ci-6 alkyl-carbamoyl group and a mono- or di-C7_i6 aralkyl- carbamoyl group, each of which optionally has 1 to 3
substituents selected from substituent group A".
Preferable examples of the optionally substituted
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-C3_i0 cycloalkyl- carbamoyl group (e.g., cyclopropylcarbamoyl,
cyclohexylcarbamoyl ) , a mono- or di-C6-i4 aryl-carbamoyl group (e.g., phenylcarbamoyl) , a mono- or di-C7_i6 aralkyl-carbamoyl group, a mono- or di-Ci-6 alkyl-carbonyl-carbamoyl group (e.g., acetylcarbamoyl, propionylcarbamoyl) , a mono- or di-C3-i4 aryl- carbonyl-carbamoyl group (e.g., benzoylcarbamoyl) and a 5- to 14-membered aromatic heterocyclylcarbamoyl group (e.g.,
pyridylcarbamoyl) .
[0046] In the present specification, 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 C2-6 alkenyl group, a C3-.10 cycloalkyl group, a C6- 14 aryl group, a C_i6 aralkyl group, a Ci-6 alkyl-carbonyl group, a C6-i4 aryl-carbonyl group, a C7_i6 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-C7_i6 aralkyl-carbamoyl group, each of which optionally has 1 to 3 substituents selected from substituent group A".
Preferable examples of the optionally substituted
thiocarbamoyl group include a thiocarbamoyl group, a mono- or di-Ci-6 alkyl-thiocarbamoyl group (e.g., methylthiocarbamoyl , ethylthiocarbamoyl , dimethylthiocarbamoyl,
diethylthiocarbamoyl, N-ethyl-N-methylthiocarbamoyl) , a mono- or di-C2-6 alkenyl-thiocarbamoyl group (e.g.,
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-C7_i6 aralkyl- thiocarbamoyl group (e.g., benzylthiocarbamoyl,
phenethylthiocarbamoyl) , a mono- or di-Ci_6 alkyl-carbonyl- thiocarbamoyl group (e.g., acetylthiocarbamoyl ,
propionylthiocarbamoyl) , a mono- or di-C6-i4 aryl-carbonyl- thiocarbamoyl group (e.g., benzoylthiocarbamoyl) and a 5- to 14-membered aromatic heterocyclylthiocarbamoyl group (e.g., pyridylthiocarbamoyl) .
[0047]
In the present specification, examples of the "optionally substituted sulfamoyl group" include a sulfamoyl group
optionally having "1 or 2 substituents selected from a Ci-s alkyl group, a C2-6 alkenyl group, a C3-10 cycloalkyl group, a C6- 14 aryl group, a C7_i6 aralkyl group, a Ci_6 alkyl-carbonyl group, a C6_i4 aryl-carbonyl group, a C7_i6 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-C7-i6 aralkyl-carbamoyl group, each of which optionally has 1 to 3 substituents selected from substituent group A".
Preferable examples of the optionally substituted
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-C2-6 alkenyl-sulfamoyl group (e.g., diallylsulfamoyl) , a mono- or di-C3_io cycloalkyl- sulfamoyl group (e.g., cyclopropylsulfamoyl,
cyclohexylsulfamoyl) , a mono- or di-C6-i4 aryl-sulfamoyl group (e.g., phenylsulfamoyl) , a mono- or di-C7_i6 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-C6-i4 aryl-carbonyl-sulfamoyl group (e.g., benzoylsulfamoyl) and a 5- to 14-membered
aromatic heterocyclylsulfamoyl group (e.g.., pyridylsulfamoyl) .
[0048]
In the present specification, examples of the "optionally substituted hydroxy group" include a hydroxyl group optionally having "a substituent selected from a Ci-6 alkyl group, a C2-6 alkenyl group, a C3-10 cycloalkyl group, a C6-i4 aryl group, a C7_ 16 aralkyl group, a Ci_6 alkyl-carbonyl group, a Ce-14 aryl- carbonyl group, a C7-i6 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-C7_i6 aralkyl-carbamoyl group, a Ci_6 alkylsulfonyl group and a C6-14 arylsulfonyl group, each of which optionally has 1 to 3 substituents selected from
substituent group A".
Preferable examples of the optionally substituted hydroxy group include a hydroxy group, a Ci_6 alkoxy group, a C2-6
alkenyloxy group (e.g., allyloxy, 2-butenyloxy, 2-pentenyloxy, 3-hexenyloxy) , a C3-10 cycloalkyloxy group (e.g., cyclohexyloxy) , a C6_i4 aryloxy group (e.g., phenoxy, naphthyloxy) , a C7-i6
aralkyloxy group (e.g., benzyloxy, phenethyloxy) , a Ci_6 alkyl- carbonyloxy group (e.g., acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy) , a C6-1 aryl-carbonyloxy group
(e.g., benzoyloxy) , a C7_i6 aralkyl-carbonyloxy group (e.g., benzylcarbonyloxy) , a 5- to 14-membered aromatic
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) , a 5- to 14-membered aromatic
heterocyclyloxy group (e.g., pyridyloxy) , a carbamoyloxy group, a Ci-6 alkyl-carbamoyloxy group (e.g., methylcarbamoyloxy) , a
C7-16 aralkyl-carbamoyloxy group (e.g., benzylcarbamoyloxy) , a Ci-6 alkylsulfonyloxy group (e.g., methylsulfonyloxy,
ethylsulfonyloxy) and a Ce-1 arylsulfonyloxy group (e.g., phenylsulfonyloxy) .
[0049]
In the present specification, examples of the "optionally substituted sulfanyl group" include a sulfanyl group
optionally having "a substituent selected from a Ci_6 alkyl group, a C2-6 alkenyl group, a C3-10 cycloalkyl group, a C6-i4 aryl group, a C7_i6 aralkyl group, a Ci-6 alkyl-carbonyl group, a C6-i4 aryl-carbonyl group and a 5- to 14-membered aromatic heterocyclic group, each of which optionally has 1 to 3
substituents selected from substituent group A" and a
halogenated sulfanyl group.
Preferable examples of the optionally substituted
sulfanyl group include a sulfanyl (-SH) group, a Ci_6 alkylthio group, a C2-6 alkenylthio group (e.g., allylthio,. 2-butenylthio, 2-pentenylthio, 3-hexenylthio) , a C3-10 cycloalkylthio group (e.g., cyclohexylthio) , a C6_i4 arylthio group (e.g., phenylthio, naphthylthio) , a C7-i6 aralkylthio group (e.g., benzylthio, phenethylthio) , a Ci-6 alkyl-carbonylthio group (e.g.,
acetylthio, propionylthio, butyrylthio, isobutyrylthio,
pivaloylthio) , a C6-i4 aryl-carbonylthio group (e.g.,
benzoylthio) , a 5- to 14-membered aromatic heterocyclylthio group (e.g., pyridylthio) and a halogenated thio group (e.g., pentafluorothio) .
[0050]
In the present specification, 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 C2-6 alkenyl group, a C3-10 cycloalkyl group, a C6-i4 aryl group and a C7_i6 aralkyl group, each of which optionally has 1 to 3 substituents selected from substituent group A".
Preferable examples of the optionally substituted silyl group include a tri-Ci_6 alkylsilyl group (e.g., trimethylsilyl, tert-butyl (dimethyl) silyl) .
[0051]
In the present specification, examples of the
"hydrocarbon ring" include a C6-i4 aromatic hydrocarbon ring, C3_ 10 cycloalkane and C3-10 cycloalkene.
In the present specification, examples of the "C6-14
aromatic hydrocarbon ring" include benzene and naphthalene.
In the present specification, examples of the "C3-10
cycloalkane" include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane and cyclooctane.
In the present specification, examples of the "C3-10
cycloalkene" include cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene and cyclooctene.
In the present specification, examples of the
"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.
[0052]
In the present specification, 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. Preferable examples of the "aromatic heterocycle"
include 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; and
8- to 14-membered fused polycyclic (preferably bi or
tricyclic) aromatic heterocycles such as benzothiophene,
benzofurah, benzimidazole, benzoxazole,- benzisoxazole,
benzothiazole, benzisothiazole, benzotriazole, imidazopyridine, thienopyridine, furopyridine, pyrrolopyridine,
pyrazolopyridine, oxazolopyridine, thiazolopyridine,
imidazopyrazine, imidazopyrimidine, thienopyrimidine ,
furopyrimidine, pyrrolopyrimidine, pyrazolopyrimidine,
oxazolopyrimidine, thiazolopyrimidine, pyrazolopyrimidine, pyrazolotriazine, naphtho [2 , 3-b] thiophene, phenoxathiine, indole, isoindole, lH-indazole, purine, isoquinoline,
quinoline, phthalazine, naphthyridine, quinoxaline,
quinazoline, cinnoline, carbazole, β-carboline, phenanthridine, acridine, phenazine, phenothiazine, phenoxathiine and the like.
[0053]
In the present specification, examples of the "non- aromatic heterocycle" 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. Preferable examples of the "non-aromatic heterocycle" 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,
thiazolidine, tetrahydroisothiazole, tetrahydrooxazole,
tetrahydroisoxazole, piperidine, piperazine,
tetrahydropyridine, dihydropyridine, dihydrothiopyran,
tetrahydropyrimidine, tetrahydropyridazine, dihydropyran, tetrahydropyran, tetrahydrothiopyran, morpholine,
thiomorpholine, azepanine, diazepane, azepine, azocane,
diazocane, oxepane and the like; and
9- to 14-membered fused polycyclic (preferably bi or
tricyclic) non-aromatic heterocycles such as dihydrobenzofuran, dihydrobenzimidazole, dihydrobenzoxazole, dihydrobenzothiazole, dihydrobenzisothiazole, dihydronaphtho [2, 3-b] thiophene,
tetrahydroisoquinoline, tetrahydroquinoline, 4H-quinolizine, indoline, isoindoline, tetrahydrothieno [2, 3-c] pyridine,
tetrahydrobenzazepine, tetrahydroquinoxaline,
tetrahydrophenanthridine, hexahydrophenothiazine,
hexahydrophenoxazine, tetrahydrophthalazine,
tetrahydronaphthyridine, tetrahydroquinazoline,
tetrahydrocinnoline, tetrahydrocarbazole, tetrahydro-β- carboline, tetrahydroacridine, tetrahydrophenazine,
tetrahydrothioxanthene, octahydroisoquinoline and the like.
In the present specification, examples of the "nitrogen- containing heterocycle" include a "heterocycle" containing at least one nitrogen atom as a ring-constituting atom.
[0054]
The definition of each symbol in the formula (I) is explained in detail in the following.
[0055]
Ring A is an optionally substituted pyridine or an
optionally substituted pyridazine. [0056]
The "pyridine" of the "optionally further substituted pyridine" for Ring A optionally has one substituent on the carbon atom adjacent to G1, in addition to R4. Examples of the substituent include substituents selected from the
aforementioned substituent group A.
[0057]
The "pyridazine" of the "optionally further substituted pyridazine" for Ring A optionally has one substituent on the carbon atom adjacent to G1. Examples of the substituent include substituents selected from the aforementioned
substituent group A.
[0058]
Ring A is preferably an optionally further substituted pyridine,
[0059]
Ring A is more preferably pyridine optionally further having one halogen atom (e.g., a chlorine atom) on the carbon atom adjacent to G1.
[0060]
In another embodiment, Ring A is more preferably pyridine optionally further having one substituent, on the carbon atom adjacent to G1, 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-g alkyl group (e.g., methyl)), and
(3) a C3-10 cycloalkyl group (e.g., cyclopropyl) .
[0061]
G1 is N or CR4.
G1 is preferably CR4.
[0062]
R4 is a hydrogen atom or a substituent.
R4 is preferably a hydrogen atom.
[0063]
Ring B is an optionally substituted 6-membered aromatic ring.
[0064]
-Examples of the "6-membered aromatic ring" of the
"optionally further substituted 6-membered aromatic ring" for Ring B include a benzene ring and a 6-membered aromatic
heterocycle (e.g., pyridine, pyridazine, pyrimidine, triazine etc. ) .
[0065]
The "6-membered aromatic ring" of the "optionally
substituted 6-membered aromatic ring" for Ring B optionally has 1 to 3 substituents at substitutable position (s). Examples of the substituent 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.
[0066]
Ring B is preferably a 6-membered aromatic ring
(preferably benzene, pyridine) optionally having 1 to 3
halogen atoms (e.g., a chlorine atom).
[0067]
Ring B is more preferably benzene or pyridine, each optionally having 1 to 3 halogen atoms (e.g., a chlorine atom).
[0068]
In another embodiment, Ring B is preferably a 6-membered aromatic ring (preferably benzene, pyridine) optionally having 1 to 3 substituents selected from
(1) a halogen atom (e.g., a chlorine atom, a bromine atom),
(2) an optionally halogenated Ci-e alkyl group (preferably a Ci-6 alkyl group (e.g., methyl)),
(3) an optionally halogenated Ci-6 alkoxy group (preferably a Ci_6 alkoxy group (e.g., methoxy) ) , and
(4) a C3-10 cycloalkyl group (e.g., cyclopropyl) .
[0069]
In this embodiment, Ring B is more preferably benzene or pyridine, each optionally having 1 to 3 substituents 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)),
(3) an optionally halogenated Ci_6 alkoxy group (preferably a Ci-6 alkoxy group (e.g., methoxy) ) , and
(4) a C3-10 cycloalkyl group (e.g., cyclopropyl) .
[0070]
R1 and R2 are each independently a hydrogen atom or an optionally substituted Ci_6 alkyl group, or R1 and R2 are joined together to form a cycloalkane or a heterocycle, each of which is optionally substituted.
[0071]
Examples of the "cycloalkane" for R1 and R2 include a C3-10 cycloalkane.
[0072]
Examples of the "heterocycle" for R1 and R2 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) .
[0073]
Preferably, R1 and R2 are each independently a hydrogen atom or a Ci-6 alkyl group (e.g., methyl, ethyl), or R1 and R2 are joined together to form a cycloalkane (preferably a C3-.10 cycloalkane (e.g., cyclopropane)).
[0074]
More preferably, R1 is a hydrogen atom or a Ci-6 alkyl group (e.g., methyl, ethyl) and R2 is a hydrogen atom, or R1 and R2 are joined together to form a cycloalkane (preferably a C3-10 cycloalkane (e.g., cyclopropane)).
[0075]
R3 is a hydrogen atom or a substituent.
[0076]
R3 is preferably a hydrogen atom.
[0077] . Ring C is an optionally further substituted ring.
[0078]
Examples of the "ring" of the "optionally further
substituted ring" for Ring C include a hydrocarbon ring and a heterocycle (preferably a 06-ι4 aromatic hydrocarbon ring or a 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocycle, more preferably a C6_i4 aromatic hydrocarbon ring (preferably benzene) or a 5- or 6-membered monocyclic aromatic heterocycle (preferably pyridine, thiophene) , particularly preferably benzene, pyridine or thiophene) .
[0079]
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
aforementioned substituent group A. When the number of the substituents is plural, the respective substituents may be the same or different.
[0080]
Ring C is preferably a C6-i4 aromatic hydrocarbon ring
(preferably benzene) further having no substituent other than R5.
[0081]
Ring C is more preferably benzene further having no · substituent other than R5.
[0082]
In another embodiment, Ring C is preferably a C6-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 R5, selected from
(1) a halogen atom (e.g., a fluorine atom, a chlorine atom), and
(2) an optionally halogenated i- alkyl group (preferably a Ci-6 alkyl group (e.g., methyl)). [0083]
In this embodiment, Ring C is more preferably benzene, . pyridine or thiophene, each optionally having 1 to 3
substituents, in addition to R5, selected from
(1) a halogen atom (e.g., a fluorine atom, a chlorine atom), and
(2) an optionally halogenated Ci_6 alkyl group (preferably a Ci-6 alkyl group (e.g., methyl)).
[0084]
R5 is a substituent.
[0085]
R5 is preferably an acyl group.
R5 is more preferably a carboxy group or a Ci-e alkoxy- carbonyl group (e.g., methoxycarbonyl) .
R5 is still more preferably a carboxy group.
[0086]
In another embodiment, R5 is preferably an acyl group (preferably a carboxy group, a Ci_6 alkoxy-carbonyl group) , a cyano group, an optionally substituted hydrocarbon group
(preferably an optionally substituted Ci_6 alkyl group) , an optionally substituted carbamoyl group or an optionally
substituted sulfamoyl group.
[0087]
In this embodiment, R5 is more preferably
(1) a carboxy group,
(2) a Ci-6 alkoxy-carbonyl group,
(3) a cyano group,
(4) a Ci-6 alkyl group (e.g., methyl, ethyl, isopropyl)
optionally having 1 to 3 substituents selected from
(a) a halogen atom (e.g., a fluorine atom),
(b) a hydroxy group, and .
(c) a carboxy group,
(5) a carbamoyl group optionally having 1 or 2 substituents selected from
(a) a Ci-6 alkyl group (e.g., methyl), (b) a Ci-6 alkoxy group (e.g., methoxy, ethoxy) ,
(c) a C7-i6 aralkyloxy group (e.g., benzyloxy) , and
(d) a Ci-6 alkylsulfonyl group (e.g., methylsulfonyl) , or (6) a sulfamoyl group.
[0088]
In this embodiment, R5 is more preferably a carboxy group or a Ci-6 alkoxy-carbonyl group (e.g., methoxycarbonyl) .
In this embodiment, R5 is still more preferably a carboxy group.
[0089]
Ring D is an optionally substituted ring.
[0090]
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 C6-i4 aromatic hydrocarbon ring (preferably benzene) or a 5- or 6-membered monocyclic aromatic heterocycle (preferably pyridine) , particularly preferably benzene or pyridine) .
[0091]
The "ring" of the "optionally substituted ring" for Ring D optionally has 1 to 5 (preferablyl to 3) substituents at substitutable position (s). Examples of the substituent 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.
[0092]
Ring D is preferably a CS-i4 aromatic hydrocarbon ring (preferably benzene) optionally having 1 to 3 substituents selected from
(1) a halogen atom (e.g., a fluorine atom, a chlorine atom),
(2) a cyano group,
(3) an optionally halogenated Ci_6 alkyl group (e.g., methyl, trifluoromethyl) , and (4) an optionally halogenated Ci-6 alkoxy group (e.g., methoxy, trifluoromethoxy) .
[0093]
Ring D is more preferably benzene optionally having 1 to 3 substituents selected from
(1) a halogen atom (e.g., a fluorine atom, a chlorine atom),
(2) a cyano group,
(3) an optionally halogenated Ci-6 alkyl group (e.g., methyl, monofluoromethyl, difluoromethyl, trifluoromethyl ) , and
(4) an optionally halogenated Ci-6 alkoxy group (e.g., methoxy, monofluoromethoxy, difluoromethoxy,
trifluoromethoxy) .
[0094]
In another embodiment, Ring D is preferably a Ce-i4
aromatic hydrocarbon ring (preferably benzene) or a 5- or 6- membered monocyclic aromatic heterocycle (preferably pyridine), each optionally having 1 to 3 substituents selected from
(1) a halogen atom (e.g., a fluorine atom, a chlorine atom),
(2) a cyano group,
(3) an optionally halogenated Ci_6 alkyl group (e.g., methyl, monofluoromethyl, difluoromethyl, trifluoromethyl) , and
(4) an optionally halogenated Ci_6 alkoxy group (e.g., methoxy, monofluoromethoxy, difluoromethoxy,
trifluoromethoxy) .
[0095]
In this embodiment,. Ring D is more preferably benzene or pyridine, each optionally having 1 to 3 substituents selected from
(1) a halogen atom (e.g., a fluorine atom, a chlorine atom), (2) a cyano group,
(3) an optionally halogenated Ci-6 alkyl group (e.g., methyl, monofluoromethyl, difluoromethyl, trifluoromethyl) , and
(4) an optionally halogenated Ci-6 alkoxy group (e.g.,
methoxy, monofluoromethoxy, difluoromethoxy,
trifluoromethoxy) . [0096]
is a bond, or,,a spacer in which the number of atoms in the main chain is 1 to 4.
[0097]
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).
[0098]
Specific examples of the "spacer in which the number of atoms in the main chain is 1 to 4" for include
(1) a bond;
(2) a Ci-4 alkylene group (e.g., -CH2-, -(CH2)2-, -CH2-CH (CH3) -, -CH (CH3) -CH2-, -(CH2)3-, -(CH2)4- etc.) optionally substituted by the aforementioned substituent group A (preferably an oxo group and a hydroxy group) ;
(3) a C2-4 alkenylene group (e.g., -CH=CH-, -CH=CH-CH2-, -CH2- CH=CH- etc.) optionally substituted by the aforementioned substituent group A;
(4) -X- wherein X is 0, NR6 (R6 is a hydrogen atom or a
substituent), S, S (0) , S (0) . or S(0)2;
(5) - (CH2)mi-X- (CH2)m2- wherein X is as defined above, ml and m2 are each independently an integer of 0 to 3, and ml+m2 is an integer of 1 to 3;
(6) -X1.- (CH2) m-X2- wherein X1 and X2 are each independently 0, NR6 (R6 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;
(7) -CO-NR6- or -NR6-C0- wherein R6 is as defined above;
(8) -S(0)2-NR6- or -NR6-S(0)2- wherein R6 is as defined above;
(9) a C3-6 cycloalkylene (e.g., cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene etc.);
(10) 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.); (11) -Xx-Y-X2- wherein X1 and X2 are as defined above, and Y is a divalent non-aromatic heterocyclic group (e.g., 1,2- aziridinediyl, 1, 3-azetidinediyl, 1, 3-pyrrolidinediyl, 1,3- piperidinediyl etc.);
and the like.
[0099]
is preferably -0-.
In another embodiment, W is preferably -0- or -0-CH2-
(wherein the left bond is bonded to Ring B, and the right bond is bonded to Ring D) .
In this embodiment, W is more preferably -0- .
[0100]
Preferable examples of compound (I) include the following compounds .
[0101]
[Compound A-l]
Compound (I) wherein
Ring A is pyridine optionally further having one halogen atom (e.g., a chlorine atom) on the carbon atom adjacent to G1, G1 is CR4,
R4 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) ,
R1 and R2 are each independently a hydrogen atom or a Ci_6 alkyl group (e.g., methyl), or R1 and R2 are joined together to form a cycloalkane (preferably a C3-i0 cycloalkane (e.g.,
cyclopropane) ) ,
R3 is a hydrogen atom,
Ring C is a C6-14 aromatic hydrocarbon ring (preferably benzene) further having no substituent other than R5,
R5 is an acyl group (preferably a carboxy group or a C1-6 alkoxy-carbonyl group (e.g., methoxycarbonyl) ) , Ring D is a C6-i4 aromatic hydrocarbon ring (preferably benzene) optionally having 1 to 3 substituents selected from
(1) a halogen atom (e.g., a fluorine atom, a chlorine atom),
(2) a cyano group,
(3) an optionally halogenated Ci_6 alkyl group (e.g., methyl, monofluoromethyl, difluoromethyl, trifluoromethyl) , and
(4) an optionally halogenated Ci_6 alkoxy group (e.g., methoxy, monofluoromethoxy, difluoromethoxy, trifluoromethoxy) , and
W is -0-.
[0102]
[Compound A-2]
Compound (I) wherein
Ring A is pyridine optionally further having one
substituent, on the carbon atom adjacent to G1, 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
(3) a C3-10 cycloalkyl group (e.g., cyclopropyl) ,
G1 is CR4,
R4 is a hydrogen atom,
Ring B is a 6-membered aromatic ring (preferably benzene, pyridine) optionally having 1 to 3 substituents 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)),
(3) an optionally halogenated Ci_6 alkoxy group (preferably a Ci-6 alkoxy group- (e.g., methoxy)), and
(4) a C3-10 cycloalkyl group (e.g., cyclopropyl),
R1 and R2 are each independently a hydrogen atom or a Ci_6 alkyl group (e.g., methyl, ethyl),, or R1 and R2 are joined together to form a cycloalkane (preferably a C3-10 cycloalkane (e.g., cyclopropane)),
R3 is a hydrogen atom,
Ring C is a C6-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 R5, selected from
(1) a halogen atom (e.g., a fluorine atom, a chlorine atom), and
(2) an optionally halogenated Ci-6 alkyl group (preferably a Ci-6 alkyl group (e.g., methyl)),
R5 is
(1) a carboxy group, ^
(2) a Ci-6 alkoxy-carbonyl group,
(3) a cyano group,
(4) a Ci-6 alkyl group (e.g., methyl, ethyl, isopropyl)
optionally having 1 to 3 substituents selected from
(a) a halogen atom (e.g., a fluorine atom),
(b) a hydroxy group, and
(c) a carboxy group,
(5) a carbamoyl group optionally having 1 or 2 substituents selected from
(a) a Ci-6 alkyl group (e.g., methyl),
(b) a Ci-6 alkoxy group (e.g., methoxy, ethoxy) ,
(c) a C7-16 aralkyloxy group (e.g., benzyloxy) , and
(d) a Ci-6 alkylsulfonyl group (e.g., methylsulfonyl) , or
(6) a sulfamoyl group,
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
substituents selected from
(1) a halogen atom (e.g., a fluorine atom, a chlorine atom),
(2) a cyano group,
(3) an optionally halogenated Ci-6 alkyl group (e.g., methyl, monofluoromethyl, difluoromethyl, trifluoromethyl ) , and
(4) an optionally halogenated Ci-6 alkoxy group (e.g.,
methoxy, monofluoromethoxy, difluoromethoxy,
trifluoromethoxy) , and
W is -0- or -0-CH2- (wherein the left bond is bonded to Ring B, and the right bond is bonded to Ring D) . [0103]
[Compound B-2]
Compound (I) wherein
Ring A is pyridine optionally further having one
substituent, on the carbon atom adjacent to G1, 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
(3) a C3-10 cycloalkyl group (e.g., cyclopropyl) ,
G1 is CR4,
R4 is a hydrogen atom,
Ring B is benzene or pyridine, each optionally having 1 to 3 substituents 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)),
(3) an optionally halogenated Ci-6 alkoxy group (preferably a Ci-6 alkoxy group (e.g., methoxy) ) , and
(4) a C3-10 cycloalkyl group (e.g., cyclopropyl),
R1 is a hydrogen atom or a Ci-6 alkyl group (e.g., methyl, ethyl) ,
R2 is a hydrogen atom, or
R1 and R2 are joined together to form a cycloalkane
(preferably a C3-10 cycloalkane (e.g., cyclopropane)),
R3 is a hydrogen atom,
Ring C is benzene, pyridine or thiophene, each optionally having 1 to 3 substituents, in addition to R5, selected from
(1) a halogen atom (e.g., a fluorine atom, a chlorine atom), and
(2) an optionally halogenated Ci-6 alkyl group (preferably a
Ci-6 alkyl group (e.g., methyl)),
R5 is
(1) a carboxy group,
(2) a Ci-6 alkoxy-carbonyl group,
(3) a cyano group, (4) a Ci-6 alkyl group (e.g., methyl, ethyl, isopropyl)
optionally having 1 to 3 substituents selected from
(a) a halogen atom (e.g., a fluorine atom),
(b) a hydroxy group, and
(c) a carboxy group,
(5) a carbamoyl group optionally having 1 or 2 substituents selected from
(a) a Ci-6 alkyl group (e.g., methyl),
(b) a Ci-6 alkoxy group (e.g., methoxy, ethoxy) ,
(c) a C7-16 aralkyloxy group (e.g., benzyloxy) , and
(d) a Ci-6 alkylsulfonyl group (e.g., methylsulfonyl) , or
(6) a sulfamoyl group,
Ring D is benzene or pyridine, each optionally having 1 to 3 substituents selected from
(1) a halogen atom (e.g., a fluorine atom, a chlorine atom),
(2) a cyano group,
(3) an optionally halogenated Ci-6 alkyl group (e.g., methyl, monofluoromethyl, difluoromethyl, trifluoromethyl) , and
(4) an optionally halogenated Ci_6 alkoxy group (e.g., methoxy, monofluoromethoxy, difluoromethoxy,
trifluoromethoxy) , and
W is -0- or -0-CH2- (wherein the left bond is bonded to Ring B, and the right bond is bonded to Ring D) .
[0104]
[Compound C-2]
Compound (I) wherein
Ring A is pyridine optionally further having one
substituent, on the carbon atom adjacent to G1, 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
(3) a C3-10 cycloalkyl group (e.g., cyclopropyl) ,
G1 is CR4,
R4 is a hydrogen atom,
Ring B is benzene or pyridine, each optionally having 1 to 3 substituents 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)),
(3) an optionally halogenated Ci-6 alkoxy group (preferably a Ci-6 alkoxy group (e . g ., methoxy) ) , and
(4) a C3-10 cycloalkyl group (e.g., cyclopropyl) ,
R1 is a hydrogen atom or a Ci-6 alkyl group (e.g., methyl, ethyl),
R2 is a hydrogen atom, or
R1 and R2 are joined together to form a cycloalkane
(preferably a C3-10 cycloalkane (e.g., cyclopropane)),
R3 is a hydrogen atom,
Ring C is benzene, pyridine or thiophene, each optionally having 1 to 3 substituents, in addition to R5, selected from
(1) a halogen atom (e.g., a fluorine atom, a chlorine atom), and
(2) an optionally halogenated Ci-6 alkyl group (preferably a Ci-6 alkyl group (e.g., methyl)),
R5 is a carboxy group,
Ring D is benzene or pyridine, each optionally having 1 to 3 substituents selected from
(1) a halogen atom (e.g., a fluorine atom, a chlorine atom),
(2) a cyano group,
(3) an optionally halogenated Ci-6 alkyl group (e.g., methyl, monofluoromethyl , difluoromethyl, trifluoromethyl ) , and
(4) an optionally halogenated Ci_6 alkoxy group (e.g.,
methoxy, monofluoromethoxy, difluoromethoxy,
trifluoromethoxy) , and
W is -0-.
[0105]
When compound (I) is in a form of a salt, examples
thereof 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. Preferable examples of 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. Preferable examples of the salt with organic base include salts with trimethylamine, triethylamine, pyridine, picoline, 2 , 6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, Ν,Ν'- 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. 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, benzenesulfonic 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.
Among them, a pharmaceutically acceptable salt is
preferable. For example, when a compound has an acidic
functional group, 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., and when a compound has a basic functional group, 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.
[0106] 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
procedure of organic chemistry. The preparation of such
starting materials is described in conjunction with the
following representative process and within the following examples. Alternatively, necessary starting materials are obtained by a method known per se or a method analogous
thereto .
[0107]
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
compound (I) and the like.
[0108]
When 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) . Preferable examples of 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.
[0109]
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.
[0110]
Unless otherwise specified, each symbol in the general formulas in the schemes is as defined above.
[0111]
Compound (I) is prepared as outlined in Schemes below:
Scheme 1: Synthesis of compound (I)
[0112]
Figure imgf000052_0001
III
[0113]
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 C6-i4 aryloxy group, a sulfanyl group, a Ci_6 alkylthio group, a C6-i4 arylthio group, a Ci-6 alkylsulfinyl group, a C6- arylsulfinyl group, a Ci_6 alkylsulfonyl group, a C6-i4 arylsulfonyl group and a boronic acid group, with an amine of compound (III) (N-arylation reaction) as shown in Scheme 1. Functional groups in compound (II) or (III) may be protected - if necessary, and after the N-arylation reaction, it can be removed by conventional means. Compound (I) having an ester moiety may be further hydrolyzed to obtain the corresponding carboxylic acid, which may be further derivatized.
[0114]
Scheme 2: Synthesis of compound (I) wherein W is not a bond [0115]
Figure imgf000053_0001
[0116]
As shown in Scheme 2, 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.
[0117]
Scheme 3 : Synthesis of compound (I)
[0118]
Figure imgf000053_0002
VI VII
[0119]
As shown in Scheme 3, compound (I) may be prepared by coupling compound (VI) with compound (VII) wherein L is a leaving group.
[0120]
Scheme 4 : Synthesis of compound (I) wherein W is a bond
[0121]
Figure imgf000053_0003
IV VIII I
[0122]
As shown in Scheme 4, compound (I) may be prepared by the coupling compound (IV) wherein L is leaving group, with compound (VIII) .
[0123]
Scheme 5: Synthesis of compound (la), which is compound (I) wherein R5 is - (CR7R8) n (CO) OR6 wherein R7 and R8 are each
independently a hydrogen atom or a Ci-6 alkyl group, R6 is a Ci-6 alkyl group, and n is 0-1
[0124] .
Figure imgf000054_0001
[0125]
As shown in Scheme 5, compound (la) may be prepared by carbonylation of compound (I) wherein R5 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.
[0126]
[0127]
Scheme 6: Synthesis of compound (lb), which is compound (I) wherein R5 is - (CR7R8) n (CO) OH wherein R7 and R8 are each
independently a hydrogen atom or a Ci_6 alkyl group, and n is 0- 1
[0128]
Figure imgf000054_0002
la lb
[0129]
As shown in Scheme 6, compound (lb) may be prepared by ester hydrolysis of compound (la) . [0130]
Scheme 7: Synthesis of compound (Ic), which is compound (I) wherein R5 is - (CR7R8) n (CO) NHS (0) 2R9 wherein R7 and R8 are each independently a hydrogen atom or a Ci-6 alkyl group, R9 is a Ci-6 alkyl group, a C3-i0 cycloalkyl group, a C6-i4 aryl group or a heteroaromatic group, and n is 0-1
[0131]
Figure imgf000055_0001
[0132]
As shown in Scheme 7, compound (Ic) may be prepared by amide coupling of compound (lb) with the corresponding
sulfonamide.
[0133]
Scheme 8: Synthesis of compound (Id), which is compound (I) wherein R5 is 5-tetrazolyl
[0134]
Figure imgf000055_0002
[0135]
As shown in Scheme 8, compound (Id) may be prepared from compound (I) wherein R5 is a cyano group, by conversion of the nitrile group to tetrazole (Tetrazole formation) .
[0136]
Scheme 9: Synthesis of compound (II) wherein Gi is CR4 and L is a leaving group, preferably a chlorine atom
[0137]
Figure imgf000056_0001
Figure imgf000056_0002
[0138]
As shown in Scheme 9, compound (II) may be prepared by coupling compound (IX) with compound (V) to obtain compound (XI) , followed by N-oxidation and subsequent chlorination. Alternatively, compound (XI) may be obtained by coupling compound (X) with compound (VII) .
[0139]
Scheme 10: Synthesis of compound (II) wherein d is CR4, L is a leaving group, preferably a chlorine atom or a bromine atom, and ring B is a nitrogen-containing 6-membered heteroaromatic ring such as pyridine, pyrimidine or pyridazine
[0140]
Figure imgf000056_0003
[0141]
As shown in Scheme 10, 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.
[0142]
Scheme 11: Synthesis of compound (II) wherein L is a leaving group and ring B is a nitrogen-containing 6-membered heteroaromatic ring such as pyridine, pyrimidine or pyridazine 0143]
Figure imgf000057_0001
[0144]
As shown in Scheme 11, 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 .
[0145]
N-Arylation :
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
diazabicyclo [5.4.0] undec-7ene (DBU) ; alkali or alkaline earth metal carbonates such as sodium carbonate and potassium carbonate; alkali metal hydrides such as sodium hydride; and 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.).
Alternatively, the 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. When L is a boronic acid group, the reaction may be carried out in the presence of a suitable catalyst.
[0146]
Coupling Reaction:
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
(CHC13) , carbon tetrachloride (CC14) , ethylene dichloride (EDC) etc.); ethers (e.g., diethyl ether, diisopropyl ether, DME, THF, dioxane etc.); alcohols (e.g., methanol, ethanol etc.); ethyl acetate, acetonitrile, DMF, DMSO, water and mixture thereof. The reaction may be carried out at 0°C to reflux temperature. The reaction may be carried out in presence of a suitable catalyst such as
tetrakis (triphenylphosphine) palladium ( 0 ) ,
5 bis (tricyclohexylphosphine) palladium (0) ,
bis (triphenylphosphine) palladium (II) chloride,
bis (triphenylphosphine) palladium (II) acetate,
trifluoromethanesulfonate palladium ( II ) acetate and
palladium (II) chloride. The reaction may be carried out in
■ io presence of a suitable additive agent (e.g.,
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
25 carried out in presence or absence of a base. 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-
20 diazabicyclo [5, 4.0] undecane, triethylamine and N- methylmorpholine . The reaction may be carried out in presence or absence of a dehydrating agent (e.g., molecular sieves etc . ) .
[0147]
25 Carbonylation Reaction:
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. The suitable catalyst include palladium reagents such as palladium acetate and
30 palladium dibenzylacetone; and nickel catalysts. Preferred
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,
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.
[0148]
Ester Hydrolysis :
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,
diethyl ether, THF, DME, DMF and DMSO or mixtures thereof.
These reactions may be carried out at 0°C to refluxing
temperature.
Alternatively, 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. ) or a 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.
[0149]
Amide Coupling:
Condition-I :
Amide coupling may be carried out using any suitable amide coupling regents such as oxalyl chloride, thionyl
chloride, BOP-C1, DCC, HOBt, HOAt, HATU, EDCI, propylphosphonic anhydride (T3P) , alkyl chloroformate and the like.. 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
pyridines. The amide coupling may be carried- out in the
presence of a solvent such as dichloromethane, dichloroethane, DMF, N, N-dimethylacetamide, THF, acetonitrile or mixture of solvent. The reaction may be carried out at a temperature
10 ranging from -20°C to 150°C, preferably from about 0°C to 100°C.
The reaction may be carried out optionally in presence of a catalytic amount of DMF.
Condition-II :
When R is not H, 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).
[0150] '
20 Tetrazole formation:
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,
25 trialkyltin azide and trimethylsilylazide . This reaction may be carried out in presence or absence of a catalyst such as dialkyltin oxide (alkyl is methyl or butyl) , alkylamino
hydrochloride or hydrobromide, lithium chloride and copper sulphate. The reaction may be carried out in the presence or
30 absence of an acid or a base. Examples of the suitable base
include trimethylamine, triethylamine and N,N-diisopropyl ethyl amine, and examples of the suitable acid include
ammonium chloride, hydrogen chloride, aluminium chloride and zinc bromide. The reaction may be carried out at temperature
35 50°C to 200°C. [0151]
iV-Oxidation :
N-Oxidation may be carried out using a suitable reagent such as H2O2/ACOH, H202/manganese tetrakis (2 , 6- dichlorophenyl) porphyrin, H202/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.
[0152]
Chlorination :
Chlorination may be carried out using a suitable reagent such as POCI3, S0C12, (C0)2C12, N-chloro succinimide and
CBr4/triphenylphosphine. The reaction may be carried out in presence or absence of an additive (e.g., ammonium chloride, DBU, PCI5, 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.
[0153]
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.
When desired, compound (I) can be synthesized by
performing deprotection reaction, acylation reaction,
alkylation reaction, hydrogenation reaction, oxidation
reaction, reduction reaction, reaction of carbon chain
extension, substituent exchange reaction singly or two or more thereof in combination. 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,
distillation, crystallization, recrystallization,
chromatography and the like.
When 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. In addition, when compound (I) is racemic, d-form and 1-form can be isolated according to a conventional optical resolution.
[0154]
In each of the above-mentioned reactions, when the
compound has a functional group such as an amino group, a hydroxy group or a carboxyl group, the reaction can be carried out after a protecting group generally used in peptide
chemistry and the like is introduced into these groups. By removing the protecting group as necessary after the reaction, 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
substituent include a halogen atom (e.g., fluorine, chlorine, bromine, iodine etc.), Ci-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,
phenylhydrazine, sodium N-methyldithiocarbamate,
tetrabutylammonium fluoride, palladium acetate and the like, a reduction method, and the like can be employed.
[0155]
The thus-obtained compound (I), other reaction
intermediate therefor and starting materials thereof 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..
[0156]
A salt of compound (I), can be produced according to a method known per se. For example, 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 an inorganic base.
When compound (I) contains an optical isomer, each
optical isomer and a mixture thereof are encompassed in the scope of the present invention, and these isomers can be
subjected to optical resolution or can be produced
respectively, according to a method known per se, if desired.'
When 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. In addition, when compound (I) is racemic, S-form and R-form can be isolated according to a conventional optical resolution.
When compound (I) contains a stereoisomer, each isomer and a mixture thereof are encompassed in the present invention.
[0157] Compound .(I) may be a prodrug, and the prodrug of
compound (I) refers to a compound which is converted to
compound (I) as a result of a reaction with an enzyme, gastric acid, etc. under physiological conditions in vivo, thus a compound that undergoes enzymatic oxidation, reduction,
hydrolysis etc. to convert to compound (I) and a compound that undergoes hydrolysis and the like by gastric acid, etc. to convert to compound (I) .
[0158]
Examples of the prodrug for compound (I) include
(1) a compound obtained by subjecting an amino group in
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,
tetrahydrofurylation, pyrrolidylmethylation,
pivaloyloxymethylation, tert-butylation, ethoxycarbonylation, tert-butoxycarbonylation, acetylation,
cyclopropylcarbonylation and the like) ;
(2) 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 acetylation, palmitoylation,
propanoylation, pivaloylation, succinylation, fumarylation, alanylation or dimethylaminomethylcarbonylation and the like) ; (3) 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 (I) to ethyl esterification, phenyl esterification, carboxymethyl esterification, dimethylaminomethyl esterification,
pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl
esterification, phthalidyl esterification, (5-methyl-2-oxo- 1, 3-dioxolen-4-yl) methyl esterification,
cyclohexyloxycarbonylethyl esterification or methylamidation and the like) and the like. Any of these compounds can be produced from compound (I) according to a method known per se .
[0159]
A prodrug of compound (I) may also be one which is converted to compound (I) under physiological conditions as 5 described in "IYAKUHIN no KAIHATSU (Development of
Pharmaceuticals)", Vol. 7, Design of Molecules, p. 163-198,
Published by HIROKAWA SHOTEN (1990) .
[0160]
In the present specification, compound (I) and a prodrug 10 thereof are sometimes collectively abbreviated as "the
compound of the present invention".
[0161]
When compound (I) has isomers such as optical isomer, stereoisomer, positional isomer, rotamer and the like, such
15 isomers and a mixture thereof are also encompassed in compound (I) . For example, when 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
20 known per se (e.g., concentration, solvent extraction, column chromatography, recrystallization, etc.).
[0162]
Compound (I) may be a crystal, and a single crystal form and a mixture of crystal forms are both encompassed in
25 compound (I) . 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., 3H, UC, 30 1C, 18F, 35S, 125I etc.) and the like.
Compound (I) also encompasses a deuterium conversion form wherein 1H is converted to 2H(D).
Compound (I) may be a pharmaceutically acceptable cocrystal or a salt thereof. The cocrystal or a salt thereof 35 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.
[0163]
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
prophylaxis or treatment of various diseases mentioned below.
[0164]
As pharmacologically acceptable carriers, various organic or inorganic carrier substances conventionally used as
preparation materials can be used. These are incorporated as excipient, lubricant, binder and disintegrant for solid
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.
[0165]
Preferable examples of the excipient include lactose, sucrose, D-mannitol, 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 .
[0166]
Preferable examples of the lubricant include magnesium stearate, calcium stearate, talc and colloidal silica.
[0167]
Preferable examples of the binder include gelatinated starch, sucrose, gelatin, gum arabic, methylcellulose,
carboxymethylcellulose, sodium carboxymethylcellulose,
crystalline cellulose, sucrose, D-mannitol, trehalose, dextrin, pullulan, hydroxypropylcellulose, hydroxypropylmethylcellulose and polyvinylpyrrolidone.
[0168]
Preferable examples of the disintegrant include lactose, sucrose, starch, carboxymethylcellulose, calcium
carboxymethylcellulose, croscarmellose sodium, sodium
carboxymethyl starch, light anhydrous silicic acid and low- substituted hydroxypropylcellulose.
[0169]
Preferable examples of 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.
[0170]
Preferable examples of the solubilizing agents include polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoa.te, ethanol, trisaminomethane, cholesterol,
triethanolamine, sodium carbonate, sodium citrate, sodium salicylate and sodium acetate.
[0171]
Preferable examples of the suspending agent include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, lauryl aminopropionate, lecithin, benzalkonium
chloride, benzethonium chloride, glycerol monostearate and the like; hydrophilic polymers such as polyvinyl alcohol,
polyvinylpyrrolidone, sodium carboxymethylcellulose,
methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose and the like; polysorbates, and
polyoxyethylene hydrogenated castor oil.
[0172] ,
Preferable examples of the isotonicity agent include sodium chloride, glycerol, D-mannitol, D-sorbitol and glucose. [0173]
Preferable examples of the buffer include buffers such as phosphate, acetate, carbonate, citrate and the like.
Preferable examples of the soothing agent include benzyl alcohol.
[0174]
Preferable examples of the preservative include p- oxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid and sorbic acid.
Preferable examples of the antioxidant include sulfite and ascorbate.
[0175]
Preferable examples of 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., β-carotene, chlorophyll, ferric oxide red) .
[0176]
Preferable examples of the sweetening agent include saccharin sodium, dipotassium glycyrrhizinate, aspartame and stevia .
[0177]
Examples of the dosage form of the pharmaceutical
composition include oral preparations such as tablet
(including sugar-coated tablet, film-coated tablet, sublingual tablet, orally disintegrating tablet) , capsules (including soft capsule, microcapsule) , granule, powder, troche, syrup, emulsion, suspension, films (e.g., orally disintegrable films) and the like; and 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 can be respectively safely administered orally or parenterally (e.g., topically, rectally, intravenously administered) .
[0178]
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.
[0179]
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.
[0180]
While the content of the compound of the present
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% .
[0181]
During production of an oral preparation, coating may be applied as necessary for the purpose of masking of taste, enteric property or durability.
[0182]
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.
[0183]
As the sugar coating base, sucrose is used. Moreover, one or more kinds selected from talc, precipitated calcium carbonate, gelatin, gum arabic, pullulan, carnauba wax and the like may be used in combination. [0184]
Examples of the water-soluble film coating base include cellulose polymers such as hydroxypropyl cellulose,
hydroxypropylmethyl cellulose, hydroxyethyl cellulose, methylhydroxyethyl cellulose etc.; synthetic polymers such as polyvinylacetal diethylaminoacetate, aminoalkyl methacrylate copolymer E [Eudragit E (trade name) ] , polyvinylpyrrolidone etc.; and polysaccharides such as pullulan etc.
[0185]
Examples of the enteric film coating base 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
[Eudragit L-30D55 (trade name) ] , methacrylic acid copolymer S [Eudragit S (trade name)] etc.; and naturally occurring substances such as shellac etc.
[0186]
Examples of the sustained-release film coating base 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.
[0187]
The above-mentioned coating bases may be used after mixing with two or more kinds thereof at appropriate ratios . For coating, for example, a light shielding agent such as titanium oxide, red ferric oxide and the like can be used.
[0188]
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) .
[0189]
Since the compound of the present invention have superior EP4 receptor antagonistic action, they are also useful as safe medicaments based on such action.
For example, 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
prophylaxis or treatment of EP4 receptor associated diseases, specifically, the diseases described in (1) - (7) below.
[0190]
(1) 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
inflammatory response syndrome (SIRS) , postoperative or
posttraumatic inflammation, pneumonia, nephritis, meningitis, cystitis, pharyngolaryngitis, gastric mucosal injury,
meningitis, spondylitis, arthritis, dermatitis, chronic
pneumonia, bronchitis, pulmonary infarction, silicosis,
pulmonary sarcoidosis etc.),
(2) 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
spondylarthritis, polymyositis, dermatomyositis (DM) ,
polyarteritis nodosa (PN) , mixed connective tissue disease
(MCTD) , 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,
dermatitis, radiodermatitis etc.) (especially, psoriasis, rheumatoid arthritis, inflammatory bowel disease, Sjogren's syndrome, Behcet's disease, multiple sclerosis and systemic lupus erythematosus) ,
(3) osteoarticular degenerative disease (e.g., rheumatoid arthritis, osteoporosis, osteoarthritis etc.),
(4) neoplastic diseases [e.g., malignant tumor, angiogenesis glaucoma, infantile hemangioma, multiple myeloma, acute
myeloblastic leukemia, chronic sarcoma, multiple myeloma, chronic myelogenous leukemia, metastasis melanoma, Kaposi's sacroma, vascular proliferation, cachexia, metastasis of the breast cancer, 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. ) , ovarian cancer (e.g., ovarian epithelial carcinoma,
extragonadal germ cell tumor, ovarian germ cell tumor, ovarian low malignant potential tumor etc.), prostate cancer (e.g., hormone-dependent prostate cancer, non-hormone dependent
prostate cancer etc.), 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, hematologic cancer and the like 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, leiomyosarcoma, rhabdomyosarcoma, cancer of unknown primary) ,
(5) cardiovascular disease (e.g., 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) ,
(6) hormone-dependent diseases (sex hormone-dependent cancers (e.g., prostate cancer, uterine cancer, breast cancer,
pituitary tumor) , prostatic hyperplasia, endometriosis, uterine fibroid, precocious puberty, dysmenorrhea, amenorrhea, premenstrual syndrome, polycystic ovary syndrome) ,
(7) acute and chronic pain (e.g., neuropathic pain (e.g., peripheral neuropathy, diabetic neuropathy, post herpetic neuralgia, trigeminal neuralgia, back pain, cancer neuropathy, HIV neuropathy, phantom limb pain, carpal tunnel syndrome, central post-stroke pain, and pain associated with chronic alcoholism, hypothyroidism, uremia, multiple sclerosis, spinal cord injury, Parkinson's disease, epilepsy and vitamin
deficiency), inflammatory pain (e.g., osteoarthritis,
ankylosing spondylitis), visceral pain (e.g., pain associated with gastrointestinal disorders (gastro-esophageal reflux, dyspepsia, irritable bowel syndrome (IBS) , functional
abdominal pain syndrome (FAPS) , inflammatory bowel disease (IBD) , Crohn's disease, ileitis, ulcerative colitis)), pain from central nervous system trauma, strains/sprains, burns, myocardial infarction and acute pancreatitis, postoperative pain, renal colic, posttraumatic pain, back pain, cancer pain (e.g., tumor related pain (e.g., bone pain, headache, facial pain or visceral pain) , pain associated with cancer therapy (e.g., pain associated with postchemotherapy syndrome, chronic postsurgical pain syndrome, post radiation syndrome) ,
chemotherapy, immunotherapy, hormonal therapy or radiotherapy) , pain resulting from musculo-skeletal disorders (e.g., myalgia, fibromyalgia, spondylitis, sero-negative (non-rheumatoid) arthropathies, non-articular rheumatism, dystrophinopathy, glycogenosis, polymyositis and pyomyositis) , heart and
vascular pain (e.g., pain caused by angina, myocardical
infarction, mitral stenosis, pericarditis, Raynaud's
phenomenon, scleroderma and skeletal muscle ischemia) , head pain (e.g., migraine (including migraine with aura and
migraine without aura) , cluster headache, tension-type
headache, mixed headache and headache associated with vascular disorders), orofacial pain (e.g., dental pain, otic pain, burning mouth syndrome and temporomandibular myofascial pain) ) .
[0191]
The medicament of the present invention can be preferably used as an agent for the prophylaxis or treatment of rheumatoid arthritis, thoracic and abdominal aortic aneurysm, endometriosis or ankylosing spondylitis.
[0192]
Here, the above-mentioned "prophylaxis" of a disease means, for example, administration of a medicament containing the compound of the present invention to patients who are expected to have a high risk of the onset due to some factor relating to the disease but have not developed the disease or patients who have developed the disease but do not have a subjective symptom, or administration of a medicament
containing the compound of the present invention to patients who are feared to show recurrence of the disease after treatment of the disease,
and the like.
[0193]
The dose of the compound of the present invention varies depending on the administration subject, route of
administration, target disease, symptoms, etc. For example, when it is administered orally to an adult patient (body weight 60 kg), its dose is about 0.01 to 100 mg/kg body weight per dose, preferably 0.05 to 30 mg/kg body weight per dose, more preferably 0.1 to 10 mg/kg body weight per dose and this amount is desirably administered in 1 to 3 portions daily.
[0194]
The compound of the present invention can also be used together with other medicaments.
Hereinafter, a medicament to be used in combination with the compound of the present invention is referred to as
"concomitant drug", and a combination of the compound of the present invention and concomitant drug is referred to as "the combination agent of the present invention".
For example, when the compound of the present invention is used as a prophylactic or therapeutic agent for EP4
receptor associated disease, it can be used in combination with the following drugs. (1) non-steroidal anti-inflammatory drug (NSAIDs)
(1) Classical NSAIDs
alcofenac, aceclofenac, sulindac, tolmetin, etodolac, fenoprofen, thiaprofenic acid, meclofenamic acid, meloxicam, tenoxicam, lornoxicam, nabumeton, acetaminophen, phenacetin, ethenzamide, sulpyrine, antipyrine, migrenin, aspirin,
mefenamic acid, flufenamic acid, diclofenac sodium, loxoprofen sodium, phenylbutazone, indomethacin, ibuprofen, ketoprofen, naproxen, oxaprozin, flurbiprofen, fenbufen, pranoprofen, floctafenine, piroxicam, epirizole, tiaramide hydrochloride, zaltoprofen, gabexate mesylate, camostat mesylate, ulinastatin, colchicine, probenecid, sulfinpyrazone, benzbromarone,
allopurinol, sodium aurothiomalate, hyaluronate sodium, sodium salicylate, morphine hydrochloride, salicylic acid, atropine, scopolamine, morphine, pethidine, levorphanol, oxymorphone or a salt thereof and the like.
(ii) cyclooxygenase inhibitor (COX-1 selective inhibitor, COX- 2 selective inhibitor etc.)
salicylic acid derivatives (e.g., celecoxib, aspirin), etoricoxib, valdecoxib, diclofenac, indomethacin, loxoprofen and the like.
(iii) nitric oxide-releasing NSAIDs.
(iv) JAK inhibitor
tofacitinib, ruxolitinib and the like.
[0195]
(2) disease-modifying anti-rheumatic drugs (D ARDs)
(i) Gold preparation
auranofin and the like.
(ii) penicillamine
D-penicillamine and the like.
(iii) aminosalicylic acid preparation
sulfasalazine, mesalazine, olsalazine, balsalazide and the like.
(iv) antimalarial drug
chloroquine and the like. (v) pyrimidine synthesis inhibitor
leflunomide and the like.
(vi) prograf
[0196]
(3) anti-cytokine drug
(I) protein drug
(i) TNF inhibitor
etanercept, infliximab, adalimumab, certolizumab pegol, golimumab, PASSTNF-a, soluble TNF-a receptor, TNF-a binding protein, anti-TNF-a antibody and the like.
(ii) interleukin-1 inhibitor
anakinra (interleukin-1 receptor antagonist) , soluble interleukin-1 receptor and the like.
(iii) interleukin-6 inhibitor
tocilizumab (anti-interleukin-6 receptor antibody) , anti- interleukin-6 antibody and the like.
(iv) interleukin-10 drug
interleukin-10 and the like.
(v) interleukin-12/23 inhibitor
ustekinumab, briakinumab (anti-interleukin-12/23
antibody) and the like.
(II) non-protein drug
(i) MAPK inhibitor
BMS-582949 and the like.
(ii) gene modulator
inhibitor of molecule involved in signal transduction, such as NF-K, NF-κΒ, IKK-1, IKK-2, AP-1 and the like, and the like.
(iii) cytokine production inhibitor
iguratimod, tetomilast and the like.
(iv) TNF-a converting enzyme inhibitor
(v) interleukin-ΐβ converting enzyme inhibitor
VX-765 and the like.
(vi) interleukin-6 antagonist
HMPL-004 and the like. (vii) interleukin-8 inhibitor
IL-8 antagonist, CXCR1 & CXCR2 antagonist, reparixin and the like.
(viii) chemokine antagonist
CCR9 antagonist (CCX-282, CCX-025) , MCP-1 antagonist and the like.
(ix) interleukin-2 receptor antagonist
denileukin, diftitox and the like.
(x) therapeutic vaccines
TNF-a vaccine and the like.
(xi) gene therapy drug
gene therapy drugs aiming at promoting the expression of gene having an anti-inflammatory action such as interleukin-4, interleukin-10, soluble interleukin-1 receptor, soluble TNF-a receptor and the like.
(xii) antisense compound
ISIS 104838 and the like.
[0197]
(4) integrin inhibitor
natalizumab, vedolizumab, AJT 300, TRK-170, E-6007 and the like.
(5) immunomodulator (immunosuppressant)
methotrexate, cyclophosphamide, X-68, atiprimod
dihydrochloride, BMS-188667, CKD-461, rimexolone, cyclosporine, tacrolimus, gusperimus, azathiopurine, antilymphocyte serum, freeze-dried sulfonated normal immunoglobulin, erythropoietin, colony stimulating factor, interleukin, interferon and the like.
(6) steroid
dexamethasone, hexestrol, methimazole, betamethasone, triamcinolone, triamcinolone acetonide, fluocinonide,
fluocinolone acetonide, predonisolone, methylpredonisolone, cortisone acetate, hydrocortisone, fluorometholone,
beclomethasone dipropionate, estriol and the like.
(7) angiotensin converting enzyme inhibitor enalapril, captopril, ramipril, lisinopril, cilazapril, perindopril and the like.
[0198]
(8) angiotensin II receptor antagonist
candesartan, candesartan cilexetil, azilsartan,
azilsartan medoxomil, valsartan, irbesartan, olmesartan, eprosartan and the like.
(9) diuretic drug
hydrochlorothiazide, spironolactone, furosemide,
indapamide, bendrofluazide, cyclopenthiazide and the like.
(10) cardiotonic drug
digoxin, dobutamine and the like.
(11) β receptor antagonist
carvedilol, metoprolol, atenolol and the like.
(12) Ca sensitizer
MCC-135 and the like.
(13) Ca channel antagonist
nifedipine, diltiazem, verapamil and the like.
(14) anti-platelet drug, anticoagulator
heparin, aspirin, warfarin and the like.
(15) HMG-CoA reductase inhibitor
atorvastatin, simvastatin and the like.
[0199]
(16) contraceptive
(i) sex hormone or derivatives thereof
gestagen or a derivative thereof (progesterone, 17a- hydroxy progesterone, medroxyprogesterone, medroxyprogesterone acetate, norethisterone, norethisterone enanthate,
norethindrone, norethindrone acetate, norethynodrel,
levonorgestrel , norgestrel, ethynodiol diacetate, desogestrel, norgestimate, gestodene, progestin, etonogestrel, drospirenone, dienogest, trimegestone, nestorone, chlormadinone acetate, mifepristone, nomegestrol acetate, Org-30659, TX-525, EMM- 310525) or a combination agent of a gestagen or a derivative thereof and an estrogen or a derivative thereof (estradiol, estradiol benzoate, estradiol cypionate, estradiol
dipropionate, estradiol enanthate, estradiol hexahydrpbenzoate, estradiol phenylpropionate, estradiol undecanoate, estradiol valerate, estrone, ethinylestradiol, mestranol) and the like. (ii) antiestrogen
ormeloxifene, mifepristone, Org-33628 and the like,
(iii) spermatocide
ushercell and the like.
[0200]
(17) others
(i) T cell inhibitors
(ii) inosine monophosphate dehydrogenase (IMPDH) inhibitor
mycophenolate mofetil and the like.
(iii) adhesion molecule inhibitor
ISIS-2302, selectin inhibitor, ELAM-1, VCAM-1, ICAM-1 and the like.
(iv) thalidomide
(v) cathepsin inhibitor
(vi) matrix metalloprotease (MMPs) inhibitor
V-85546 and the like.
(vii) glucose-6-phosphate dehydrogenase inhibitor
(viii) Dihydroorotate dehydrogenase (DHODH) inhibitor
(ix) phosphodiesterase IV(PDE IV) inhibitor
roflumilast, CG-1088 and the like.
(x) phospholipase A2 inhibitor
(xi) iNOS inhibitor
VAS-203 and the like.
(xii) microtubule stimulating drug
paclitaxel and the like.
(xiii) microtuble inhibitor
reumacon and the like.
(xiv) MHC class II antagonist
(xv) prostacyclin agonist
iloprost and the like.
(xvi) CD4 antagonist zanolimumab and the like.
(xvii) CD23 antagonist
(xviii) LTB4 receptor antagonist
DW-1305 and the like.
(xix) 5-lipoxygenase inhibitor
zileuton and the like.
(xx) cholinesterase inhibitor
galanthamine and the like.
(xxi) tyrosine kinase inhibitor
Tyk2 inhibitor (the compound described in WO 2010/142752) and the like.
(xxii) cathepsin B inhibitor
(xxiii) adenosine deaminase inhibitor
pentostatin and the like.
(xxiv) osteogenesis stimulator
(xxv) dipeptidylpeptidase inhibitor
(xxvi) collagen agonist
(xxvii) capsaicin cream
(xxviii) hyaluronic acid derivative
synvisc (hylan G-F 20), orthovisc and the like.
(xxix) glucosamine sulfate
(xxx) amiprilose
(xxxi) CD-20 inhibitor
rituximab, ibritumomab, tositumomab, ofatumumab and the like.
(xxxii) BAFF inhibitor
belimumab, tabalumab, atacicept, A-623 and the like.
(xxxiii) CD52 inhibitor
alemtuzumab and the like.
(xxxiv) IL-17 inhibitor
secukinumab (AIN-457) , LY-2439821, AMG827 and the like
[0201]
Other concomitant drugs besides the above-mentioned include, for example, antibacterial agent, antifungal agent, antiprotozoal agent, antibiotic, antitussive and expectorant drug, sedative, anesthetic, antiulcer drug, antiarrhythmic agent, hypotensive diuretic drug, anticoagulant, tranquilizer, antipsychotic, antitumor drug, hypolipidemic drug, muscle relaxant, antiepileptic drug, antidepressant, antiallergic drug, cardiac stimulants, therapeutic drug for arrhythmia, vasodilator, vasoconstrictor, therapeutic drug for diabetes, antinarcotic, vitamin, vitamin derivative, antiasthmatic, therapeutic agent for pollakisuria/anischuria, antipruritic drug, therapeutic agent for atopic dermatitis, therapeutic agent for allergic rhinitis, hypertensor, endotoxin-antagonist or -antibody, signal transduction inhibitor, inhibitor of inflammatory mediator activity, antibody to inhibit
inflammatory mediator activity, inhibitor of anti-inflammatory mediator activity, antibody to inhibit anti-inflammatory mediator activity and the like. Specific examples thereof include the following.
[0202]
(1) antibacterial agent
(i) sulfa drug
sulfamethizole, sulfisoxazole, sulfamonomethoxine, sulfamethizole, salazosulfapyridine, silver sulfadiazine and the like.
(ii) quinolone antibacterial agent
nalidixic acid, pipemidic acid trihydrate, enoxacin, norfloxacin, ofloxacin, tosufloxacin tosylate, ciprofloxacin hydrochloride, lomefloxacin hydrochloride, sparfloxacin, fleroxacin and the like.
(iii) antiphthisic
isoniazid, ethambutol (ethambutol hydrochloride) , p- aminosalicylic acid (calcium p-aminosalicylate) , pyrazinamide, ethionamide, protionamide, rifampicin, streptomycin sulfate, kanamycin sulfate, cycloserine and the like.
(iv) antiacidfast bacterium drug
diaphenylsulfone, rifampicin and the like.
(v) antiviral drug idoxuridine, acyclovir, vidarabine, gancyclovir and the like .
[0203]
(vi) anti-HIV agent
zidovudine, didanosine, zalcitabine, indinavir sulfate ethanolate, ritonavir and the like.
(vii) antispirochetele
(viii) antibiotic
tetracycline hydrochloride, ampicillin, piperacillin, gentamicin, dibekacin, kanendomycin, lividomycin, tobramycin, amikacin, fradiomycin, sisomicin, tetracycline,
oxytetracycline, rolitetracycline, doxycycline, ampicillin, piperacillin, ticarcillin, cephalothin, cephapirin,
cephaloridine, cefaclor, cephalexin, cefroxadine, cefadroxil, cefamandole, cefotoam, cefuroxime, cefotiam, cefotiam hexetil, cefuroxime axetil, cefdinir, cefditoren pivoxil, ceftazidime, cefpiramide, cefsulodin, cefmenoxime, cefpodoxime proxetil, cefpirome, cefozopran, cefepime, cefsulodin, cefmenoxime, cefmetazole, cefminox, cefoxitin, cefbuperazone, latamoxef, flomoxef, cefazolin, cefotaxime, cefoperazone, ceftizoxime, moxalactam, thienamycin, sulfazecin, aztreonam or a salt a salt thereof, griseofulvin, lankacidin-group [Journal of
Antibiotics (J. Antibiotics ), 38 , 877-885(1985)], azole compound [2- [ (1R, 2R) -2- (2, 4-difluorophenyl) -2-hydroxy-l- methyl-3- (lH-1, 2, 4-triazol-l-yl) propyl] -4- [4- (2, 2, 3, 3- tetrafluoropropoxy) phenyl] -3 (2H, 4H) -1,2, 4-triazolone,
fluconazole, itraconazole and the like] and the like.
[0204]
(2) antifungal agent
(i) polyethylene antibiotic (e.g., amphotericin B, nystatin, trichomycin)
(ii) griseofulvin, pyrrolnitrin and the like
(iii) cytosine metabolism antagonist (e.g., flucytosine)
(iv) imidazole derivative (e.g., econazole, clotrimazole, miconazole nitrate, bifonazole, croconazole) (v) triazole derivative (e.g., fluconazole, itraconazole)
(vi) thiocarbamic acid derivative (e.g., trinaphthol) and the like .
(3) antiprotozoal agent
metronidazole, tinidazole, diethylcarbamazine citrate, quinine hydrochloride, quinine sulfate and the like.
[0205]
(4) antitussive and expectorant drug
ephedrine hydrochloride, noscapine hydrochloride, codeine phosphate, dihydrocodeine phosphate, isoproterenol
hydrochloride, ephedrine hydrochloride, methylephedrine hydrochloride, noscapine hydrochloride, alloclamide,
chlophedianol, picoperidamine, cloperastine, protokylol, isoproterenol, salbutamol, terbutaline, oxymetebanol , morphine hydrochloride, dextromethorfan hydrobromide, oxycodone
hydrochloride, dimemorphan phosphate, tipepidine hibenzate, pentoxyverine citrate, clofedanol hydrochloride, benzonatate, guaifenesin, bromhexine hydrochloride, ambroxol hydrochloride, acetylcysteine, ethyl cysteine hydrochloride, carbocysteine and the like.
(5) sedative
chlorpromazine hydrochloride, atropine sulfate,
phenobarbital, barbital, amobarbital, pentobarbital,
thiopental sodium, thiamylal sodium, nitrazepam, estazolam, flurazepam, haloxazolam, triazolam, flunitrazepam,
bromovalerylurea, chloral hydrate, triclofos sodium and the like.
[0206]
(6) anesthetic
(6-1) local anesthetic
***e hydrochloride, procaine hydrochloride, lidocaine, dibucaine hydrochloride, tetracaine hydrochloride, mepivacaine hydrochloride, bupivacaine hydrochloride, oxybuprocaine
hydrochloride, ethyl aminobenzoate, oxethazaine and the like. (6-2) general anesthetic (i) inhalation anesthetic (e.g., ether, halothane, nitrous oxide, isoflurane, enflurane) ,
(ii) intravenous anesthetic (e.g., ketamine hydrochloride, droperidol, thiopental sodium, thiamylal sodium,
pentobarbital) and the like.
(7) antiulcer drug
histidine hydrochloride, lansoprazole, metoclopramide, pirenzepine, cimetidine, ranitidine, famotidine, urogastrone, oxethazaine, proglumide, omeprazole, sucralfate, sulpiride, cetraxate, gefarnate, aldioxa, teprenone, prostaglandin and the like.
(8) antiarrhythmic agent
(i) sodium channel blocker (e.g., quinidine, procainamide, disopyramide, ajmaline, lidocaine, mexiletine, phenytoin) , (ii) β-blocker (e.g., propranolol, alprenolol, bufetolol hydrochloride, oxprenolol, atenolol, acebutolol, metoprolol, bisoprolol, pindolol, carteolol, arotinolol hydrochloride) ,
(iii) potassium channel blocker (e.g., amiodarone) ,
(iv) calcium channel blocker (e.g., verapamil, diltiazem) and the like.
[0207]
(9) hypotensive diuretic drug
hexamethonium bromide, clonidine hydrochloride, hydrochlorothiazide, trichlormethiazide, furosemide,
- ethacrynic acid, bumetanide, mefruside, azosemide,
spironolactone, potassium canrenoate, triamterene, amiloride, acetazolamide, D-mannitol, isosorbide, aminophylline and the like.
(10) anticoagulant
heparin sodium, sodium citrate, activated protein C, tissue factor pathway inhibitor, antithrombin III, dalteparin sodium, warfarin potassium, argatroban, gabexate, sodium citrate, ozagrel sodium, ethyl icosapentate, beraprost sodium, alprostadil, ticlopidine hydrochloride, pentoxifylline, dipyridamole, tisokinase, urokinase, streptokinase and the like.
(11) tranquilizer
diazepam, lorazepam, oxazepam, chlordiazepoxide, medazepam, oxazolam, cloxazolam, clotiazepam, bromazepam, etizolam, fludiazepam, hydroxyzine and the like.
(12) antipsychotic
chlorpromazine hydrochloride, prochlorperazine,
trifluoperazine, thioridazine hydrochloride, perphenazine maleate, fluphenazine enanthate, prochlorperazine maleate, levomepromazine maleate, promethazine hydrochloride,
haloperidol, bromperidol, spiperone, reserpine, clocapramine hydrochloride, sulpiride, zotepine and the like.
[0208]
(13) antitumor drug
6-0- (N-chloroacetylcarbamoyl) fumagillol, bleomycin, methotrexate, actinomycin D, mitomycin C, daunorubicin, adriamycin, neocarzinostatin, cytosine arabinoside,
fluorouracil, tetrahydrofuryl-5-fluorouracil, picibanil, lentinan, levamisole, bestatin, azimexon, glycyrrhizin, doxorubicin hydrochloride, aclarubicin hydrochloride,
bleomycin hydrochloride, peplomycin sulfate, vincristine sulfate, vinblastine sulfate, irinotecan hydrochloride, cyclophosphamide, melphalan, busulfan, thiotepa, procarbazine hydrochloride, cisplatin, azathioprine, mercaptopurine, tegafur, carmofur, cytarabine, methyltestosterone,
testosterone propionate, testosterone enanthate, mepitiostane, fosfestrol, chlormadinone acetate, leuprorelin acetate, buserelin acetate and the like.
(14) hypolipidemic drug
clofibrate, ethyl 2-chloro-3- [4- (2-methyl-2- ,
phenylpropoxy) phenyl] propionate [Chemical and Pharmaceutical Bulletin (Chem. Pharm. Bull), 38, 2792-2796 (1990)],
pravastatin, simvastatin, probucol, bezafibrate, clinofibrate, nicomol, cholestyramine, dextran sulfate sodium and the like. (15) muscle relaxant pridinol, tubocurarine , pancuronium, tolperisone
hydrochloride, chlorphenesin carbamate, baclofen,
chlormezanone, mephenesin, chlorzoxazone, eperisone,
tizanidine and the like.
(16) antiepileptic drug
phenytoin, ethosuximide, acetazolamide, chlordiazepoxide, trimethadione, carbamazepine, phenobarbital, primidone, sulthiame, sodium valproate, clonazepam, diazepam, nitrazepam and the like.
[0209]
(17) antidepressant
imipramine, clomipramine, noxiptiline, phenelzine, amitriptyline hydrochloride, nortriptyline hydrochloride, amoxapine, mianserin hydrochloride, maprotiline hydrochloride, sulpiride, fluvoxamine maleate, trazodone hydrochloride and the like.
(18) antiallergic drug
diphenhydramine, chlorpheniramine, tripelennamine, metodilamine, clemizole, diphenylpyraline, methoxyphenamine, sodium cromoglicate, tranilast, repirinast, amlexanox,
ibudilast, ketotifen, terfenadine, mequitazine, azelastine hydrochloride, epinastine, ozagrel hydrochloride, pranlukast hydrate, seratrodast and the like.
(19) cardiac stimulants
trans-7T-oxocamphor, terephyllol, aminophylline,
etilefrine, dopamine, dobutamine, denopamine, aminophylline, vesnarinone, amrinone, pimobendan, ubidecarenone, digitoxin, digoxin, methyldigoxin, lanatoside C, G-strophanthin and the like .
(20) vasodilator
oxyfedrine, diltiazem, tolazoline, hexobendine, bamethan, clonidine, methyldopa, guanabenz and the like.
(21) vasoconstrictor
dopamine, dobutamine denopamine and the like.
(22) hypotensive diuretic hexamethonium bromide, pentolinium, mecamylamine, ecarazine, clonidine, diltiazem, nifedipine and the like.
(23) therapeutic drug for diabetes
tolbutamide, chlorpropamide, acetohexamide, glibenclamide, tolazamide, acarbose, epalrestat, troglitazone, glucagon, glymidine, glipizide, phenformin, buformin, metformin and the like .
[0210]
(24) antinarcotic
levallorphan, nalorphine, naloxone or a salt thereof and the like.
(25) liposoluble vitamins
(i) vitamin A: vitamin Αχ, vitamin A2 and retinol palmitate
(ii) vitamin D: vitamin Di, D2, D3, D4and D5
(iii) vitamin E: -tocopherol, β-tocopherol, γ-tocopherol, δ- tocopherol, dl-a-tocopherol nicotinate
(iv) vitamin K: vitamin Ki, K2, K3and K4
(v) folic acid (vitamin M) and the like.
(26) vitamin derivative
various derivatives of vitamins, for example, vitamin D3 derivatives such as 5, 6-trans-cholecalciferol, 2,5- hydroxycholecalciferol, 1-a-hydroxycholecalciferol and the like, vitamin D2 derivatives such as 5 , 6-trans-ergocalciferol and the like, and the like.
(27) antiasthmatic
isoprenaline hydrochloride, salbutamol sulfate,
procaterol hydrochloride, terbutaline sulfate, trimetoquinol hydrochloride, tulobuterol hydrochloride, orciprenaline
sulfate, fenoterol hydrobromide, ephedrine hydrochloride, ipratropium bromide, oxitropium bromide, flutropium bromide, theophylline, aminophylline, sodium cromoglicate, tranilast, repirinast, amlexanox, ibudilast, ketotifen, terfenadine, mequitazine, azelastine, epinastine, ozagrel hydrochloride, pranlkast hydrate, seratrodast, dexamethasone, prednisolone, hydrocortisone, hydrocortisone sodium succinate, beclometasone dipropionate and the like.
(28) therapeutic agent for pollakisuria/anischuria
flavoxate hydrochloride and the like.
(29) therapeutic agent for atopic dermatitis
sodium cromoglicate and the like.
[0211]
(30) therapeutic agent for allergic rhinitis
sodium cromoglicate, chlorpheniramine maleate,
alimemazine tartrate, clemastine fumarate, homochlorcyclizine hydrochloride, fexofenadine, mequitazine and the like.
(31) hypertensor
dopamine, dobutamine, denopamine, digitoxin, digoxin, methyldigoxin, lanatoside C, G-strophanthin and the like.
(32) others
hydroxycam, diacerein, megestrol acetate, nicergoline, prostaglandins and the like.
[0212]
In another embodiment, when the compound of the present invention is used as an agent for the prophylaxis or treatment of chronic or acute pain, from among EP4 receptor associated disease, it can be used in combination with the following drugs .
(1) opioid analgesic, for example, morphine, heroin,
hydromorphone, oxymorphone, levorphanol, levallorphan, methadone, meperidine, fentanyl, ***e, codeine,
dihydrocodeine, oxycodone, hydrocodone, propoxyphene,
nalmefene, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol, nalbuphine or pentazocine;
(2) non-steroidal antiinflammatory drug (NSAID) , for example, aspirin, diclofenac, diflusinal, etodolac, fenbufen,
fenoprofen, flufenisal, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, nabumetone, naproxen, oxaprozin, phenylbutazone, piroxicam, sulindac, tolmetin or zomepirac; cyclooxygenase-2 (COX-2) inhibitors, for example, celecoxib, rofecoxib, meloxicam, 4- (4-cyclohexyl-2-methyl-l, 3-oxazol-5-yl ) -2- fluorobenzenesulfonamide, L-745, L-337, N- [2- (cyclohexyloxy) - 4-nitrophenyl] methanesulfonamide, N- (2-cyclohexyloxy-4- nitrophenyl) methanesulfonamide or N- (methylsulfonyl) -2- (cyclohexyloxy) -4-nitroaniline; or a pharmaceutically
acceptable salt thereof;
(3) barbiturate sedative, for example, amobarbital,
aprobarbital, butabarbital, butabital, mephobarbital,
metharbital, methohexital, pentobarbital, phenobartital, secobarbital, talbutal, theamylal or thiopental or a
pharmaceutically acceptable salt thereof;
(4) benzodiazepine having a sedative action, for example, chlordiazepoxide, clorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam or triazolam or a pharmaceutically
acceptable salt thereof;
(5) Hi antagonist having a sedative action, for example, diphenhydramine, pyhlamine, promethazine, chlorpheniramine or chlorcyclizine or a pharmaceutically acceptable salt thereof;
(6) sedative, for example, loxoprofen sodium, acetaminophen, acetylsalicylic acid, glutethimide, meprobamate, methaqualone or dichloralphenazone or a pharmaceutically acceptable salt thereof;
(7) skeletal muscle relaxant, for example, baclofen,
cahsoprodol, chlorzoxazone, cyclobenzaphne, methocarbamol or orphrenadine or a pharmaceutically acceptable salt thereof;
(8) NMDA receptor antagonist, for example, dextromethorphan ((+) -3-hydroxy-N-methylmorphinan) or its metabolite
dextrorphan ((+) -3-hydroxy-N-methylmorphinan) , ketamine, memantine, pyrroloquinoline quinone or cis-4- (phosphonomethyl) -2-pipehdinecarboxylic acid or a
pharmaceutically acceptable salt thereof;
(9) -adrenergic, for example, doxazosin, tamsulosin,
clonidine or 4-amino-6, 7-dimethoxy-2- (5-methanesulfonamido- 1,2,3, 4-tetrahydroisoquinol-2-yl) -5- (2-pyhdyl) quinazoline;
(10) tricyclic antidepressant, for example, desipramine, imipramine, clomipramine, doxepin, amythptiline or
nortriptiline;
(11) anticonvulsant, for example, carbamazepine, lamotrigine or valproate;
(12) tachykinin (NK) antagonist (particularly an NK-3, NK-2 or NK-1 antagonist) , for example, 5- [ [ (2R, 3S) -2- [ (1R) -1- [3, 5- bis (thfluoromethyl) phenyl] ethoxy-3- ( 4-fluorophenyl) -4- morpholinyl] methyl] -1, 2-dihydro-3H-l , 2, 4-thazol-3-one,
lanepitant, dapitant or 3- [ [2-methoxy-5- (thfluoromethoxy) phenyl] methylamino] -2-phenyl-piperidine
(2S,3S) ;
(13) muscarinic antagonist, for example, oxybutin, tolterodine, propiverine, tropsium chloride or darifenacin;
(14) COX-2 inhibitor, for example, celecoxib, rofecoxib or valdecoxib;
(15) non-selective COX inhibitor (preferably, having a
protective effect on the gastrointestinal tract) , for example, nitroflurbiprofen;
(16) coal-tar analgesic, particularly paracetamol;
(17) neuroleptic, for example, droperidol;
(18) vanilloid receptor agonist (e.g., resinferatoxin) or antagonist (e.g., capsazepine) ;
(19) β-adrenergic, for example, propranolol;
(20) local anaesthetic, for example, mexiletine tocainide or lidocaine;
(21) corticosteriod, for example, dexamethasone or prednisone;
(22) serotonin receptor agonist or antagonist;
(23) cholinergic (nicotinic) analgesic;
(24) tramadol hydrochloride;
(25) PDEV inhibitor, such as sildenafil, vardenafil or
taladafil;
(26) α-2-δ ligand, for example, gabapentin or pregabalin;
(27) canabinoid; and
(28) antidepressant (e.g., amitriptyline, trazodone,
duloxetine, milnacipran, fluoxetine, paroxetine, sertraline^ citalopram and imipramine) , anticonvulsant (e.g., phenytoin or carbamazepine) , narcotic drug (e.g., methadone, tramadol) , Chinese herbal medicine (e.g., gosha-j inki-gan, shakuyaku- kanzoh-toh) and vitamin.
[0213]
For combined use, the administration time of the compound of the present invention and the concomitant drug is not restricted, and the compound of the present invention or the concomitant drug can be administered to an administration subject simultaneously, or may be administered at different times. The dosage of the concomitant drug may be determined according to the dose clinically used, and can be
appropriately selected depending on an administration subject, administration route, disease, combination and the like.
The administration form of the combined use is not particularly limited, and the compound of the present
invention and a concomitant drug only need to be combined on administration. Examples of such administration mode include the following:
(1) administration of a single preparation obtained by
simultaneously processing the compound of the present
invention and the concomitant drug, (2) simultaneous
administration of two kinds of preparations of the compound of the present invention and the concomitant drug, which have been separately produced, by the same administration route, (3) administration of two kinds of preparations of the
compound of the present invention and the concomitant drug, which have been separately produced, by the same
administration route in a staggered manner, (4) simultaneous administration of two kinds of preparations of the compound of the present invention and the concomitant drug, which have been separately produced, by different administration routes, (5) administration of two kinds of preparations of the
compound of the present invention and the concomitant drug, which have been separately produced, by different administration routes in a staggered manner (e.g., administration in the order of the compound of the present invention and the concomitant drug, or in the reverse order) and the like.
The mixing ratio of the compound of the present invention and a concomitant drug in the combination agent of the present invention can be appropriately selected based on the subject , of administration, administration route, disease and the like.
For example, while the content of the compound of the present invention in the combination agent of the present invention varies depending on the preparation form, it is generally about 0.01 - 100 wt%, preferably about 0.1 - 50 wt%, more preferably about 0.5 - 20 wt%, of the whole preparation.
[0214]
The content of the concomitant drug in the combination agent of the present invention varies depending on the
preparation form, and generally about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, further preferably about 0.5 to 20% by weight, of the entire preparation.
While the content of the additive such as a carrier and the like in the combination agent of the present invention varies depending on the form of a preparation, it is generally about 1 to 99.99% by weight, preferably about 10 to 90% by weight, based on the preparation.
When the compound of the present invention and the concomitant drug are separately prepared, the same content may be adopted.
The dose of the combination agent varies depending on the kind of the compound of the present invention, administration route, symptom, age of patients and the like. For example, for oral administration to patients (body weight about 60 kg) with inflammatory bowel disease (IBD) , about 0.1 mg/kg body weight - about 30 mg/kg body weight, preferably about 1 mg/kg body weight - 20 mg/kg body weight, of compound (I) can be
administered once to several portions per day. The dose of the pharmaceutical composition of the present invention as a sustained-release preparation varies depending on the kind and content of compound (I), dosage form, period of sustained drug release, subject animal of administration (e.g., mammals such as mouse, rat, hamster, guinea" pig, rabbit, cat, dog, bovine, horse, swine, sheep, monkey, human etc.), and administration object. For example, for application by parenteral administration, about 0.1 to about 100 mg of
compound (I) needs to be released from the administered
preparation per 1 week.
[0215]
Any amount of the concomitant drug can be adopted as long as the side effects do not cause a problem. The daily dosage in terms of the concomitant drug varies depending on the
severity, age, sex, body weight, sensitivity difference of the subject, administration period, interval, and nature,
pharmacology, kind of the pharmaceutical preparation, kind of effective ingredient, and the like, and not particularly
restricted, and the amount of a drug is, in the case of oral administration for example, generally about 0.001 to 2000 mg, preferably about 0.01 to 500 mg, further preferably about 0.1 to 100 mg, per 1 kg of a mammal and this is generally
administered once to 4-times, divided in a day.
When the combination agent of the present invention is administered, the compound of the present invention and the concomitant drug can be administered simultaneously, or may be administered in a staggered manner. When administered at a time interval, the interval varies depending on the effective ingredient, dosage form and administration method, and, for example, when the concomitant drug is administered first, a method in which the compound of the present invention is
administered within time range of from 1 minute to 3 days, preferably from 10 minutes to 1 day, more preferably from 15 minutes to 1 hour, after administration of the concomitant drug is an example. When the compound of the present invention is administered first, a method in which the concomitant drug is administered within time range of from 1 minute to 1 day, preferably from 10 minutes to 6 hours, more preferably from 15 minutes to 1 hour after administration of the compound of the present invention is an example.
Examples
[0216]
The present invention is explained in detail in the following by referring to Preparations, Examples, Experimental Examples and Formulation Examples, which are not to be
construed as limitative, and the invention may be changed within the scope of the present invention.
[0217]
In the following Examples, the "room temperature" generally means about 10°C to about 35°C. The ratios indicated for mixed solvents are volume mixing ratios, unless otherwise specified. % means wt%, unless otherwise specified.
[0218]
In silica gel column chromatography, basic silica gel means use of aminopropylsilane-bound silica gel. In HPLC (high performance liquid chromatography) , C18 means use of
octadecyl-bound silica gel. The ratios of elution solvents are volume mixing ratios, unless otherwise specified.
[0219]
1H NMR (proton nuclear magnetic resonance spectrum) was measured by Fourier-transform type NMR. For the analysis, ACD/SpecManager (trade name) and the like were used. Peaks with very mild protons such as a hydroxy group, an amino group and the like are not described.
[0220]
MS (mass spectrum) was measured by LC/MS (liquid
chromatography mass spectrometer) . As ionization method, ESI (Electro Spray Ionization) method or APCI (Atomospheric
Pressure Chemical Ionization) method was used. The data indicates those found. Generally, a molecular ion peak is observed. In the case of a salt, a molecular ion peak or fragment ion peak of free form is generally observed.
[0221]
Preparation 1: l-Chloro-8- [3-
(trifluoromethyl) henoxy] isoquinoline
[0222]
Figure imgf000097_0001
[0223]
Step 1 : 8-Bromoisoquinoline
A mixture of 2-bromobenzaldehyde (50 g, 270 mmol) , aminoacetaldehyde dimethyl acetal (28.4 g, 270 mmol) and toluene (400 mL) was refluxed under argon. Dehydration was carried out using dean stark for 2.0 hours. After removal of calculated amount of water, the reflux was continued for 1.0 hour. The toluene was evaporated under reduced pressure, the residue was dissolved in dichloromethane (600 mL) , and the solution was cooled to 0°C. To the cooled solution was slowly added aluminium chloride (118.9 g, 891.7 mmol) under argon. The reaction mixture was stirred at 45°C for 2.0 hours. After the completion of the reaction was confirmed by TLC, the mixture was cooled to room temperature and slowly poured into an ice water. The mixture was basified with 10% sodium hydroxide solution, and the dichloromethane layer was
separated. The aqueous layer was re-extracted with dichloromethane (2 x 100 mL) . The combined dichloromethane layers were washed with brine, and dried over sodium sulfate. The dichloromethane was evaporated, and the residue was purified by silica gel (100-200 mesh) column chromatography 5 with 8-12%. ethyl acetate in hexane as a mobile phase to give the title compound as an off-white solid (28 g, 49.8%).
MS(ESI)m/z: 208 [M (79Br)+l] ,210 [M (81Br)+l]; XH NMR (400 MHz, DMSO-d5) : δ 7.17 (t, J= 7.8 Hz, 1H) ; 7.91 (d, J= 6.0 Hz, 1H) ; 8.02 (d, J = 8.4 Hz, 1H) ; 8.05 (d, J = 8.8 Hz, 1H) ; 8.65 10 (d, J = 5.2 Hz, 1H) 9.48 (s, IH) .
[0224]
Step 2: 8- [3- (Trifluoromethyl)phenoxy] isoquinoline
A mixture of 8-bromoisoquinoline (1.0 g, 4.8 mmol) , 3- trifluoromethylphenol (1.55 g, 9.6 mmol), cesium carbonate is (3.9 g, 12 mmol) and dimethylsulfoxide (10 mL) was degassed with argon for 30 min, and to the mixture were added copper (I) iodide (0.91 g, 4.8 mmol), copper powder (0.30 g, 4.8 mmol) and 2, 2, 6, 6-tetramethyl-3, 5-heptanedione (0.49 mL, 2.5 mmol). Degassing was continued for additional 20 min. The resulting
20 mixture was heated at 100°C for 4 hours under argon atmosphere.
The reaction mixture was cooled to room temperature, and to the mixture were added water (50 mL) followed by 10% aqueous sodium hydroxide solution' (50 mL) . The mixture was extracted with ethyl acetate (3 x 50 mL) . The combined organic layers
25 were washed with water (25 mL) and brine (50 mL) , and dried over sodium sulfate. The organic layer was concentrated under vacuum, and the residue was purified by combiflash with 8-12% ethyl acetate in hexane as a mobile phase to give the title compound as an off-white solid (0.65 g., 47%). MS(ESI)m/z:
30 290.1 ( +l) . 1H NMR (400 MHz, CDC13) : δ 7.11 (d, J = 7.2 Hz, 1H) ; 7.45 (dd, J= 1.6 & 7.6 Hz, 1H) ; 7 , 56-7.60 (m, 2H) ; 7.66- 7.70 (m, 1H) ; 7.73-7.81 (m, 2H) ; 7.92 (d, J = 5.6 Hz, 1H) ;
8.61 (bs, 1H) 9.51 (bs, 1H) .
[0225]
35 Step 3: 8- [3- (Trifluoromethyl)phenoxy] isoquinoline N-oxide To a solution of 8- [3- (trifluoromethyl) phenoxy] isoquinoline (0.65 g, 2.24 mmol) in dichloromethane (25 mL) was added 3-chloroperbenzoic acid (0.969 g, 3.37 mmol) at 0°C. The mixture was stirred at room temperature overnight (for 18 hours) . After the completion of the reaction was confirmed by TLC, aqueous saturated sodium bicarbonate solution (25 mL) was added thereto, and the stirring was continued for 2.0 hours. The dichloromethane layer was separated, and the aqueous layer was re-extracted with dichloromethane (2 x 25 mL) . The combined organic layers were washed with brine, and dried over sodium sulfate. The organic layer was concentrated under vacuo, and the obtained crude product was used in the next step without further purification. MS(ESI)m/z: 306.1 (M+l) .
[0226]
Step 4: l-Chloro-8- [3- (trifluoromethyl) henoxy] isoquinoline
A mixture of 8- [ 3- (trifluoromethyl ) phenoxy] isoquinoline N-oxide (0.60 g, 1.96 mmol) and phosphorous oxychloride (6 mL) was heated at 100°C for 5 hours. After the completion of the reaction by TLC, the phosphorous oxychloride was evaporated, and the obtained residue was dissolved in ethyl acetate. The ethyl acetate layer was washed with saturated sodium
bicarbonate and water brine, and dried over sodium sulfate. The ethyl acetate layer was concentrated, and the obtained residue was purified on combiflash with 6-8% ethyl acetate in hexane as a mobile phase to give the title compound as an off- white solid (0.5 g, 79%). S(ESI)m/z: 324.1, [M(35C1)+1] 326.1 [M(37C1)+1]; ¾ NMR (400 MHz, DMSO-d5) : δ 7.23 (dd, J = 2.4 & 8.4 Hz, 1H) ; 7.34 (s, 1H) ; 7.41 (d, J = 7.6 Hz, 1H) ; 7.50 (d, J = 7.6, 1H) ; 7.62 (t, J = 8.0 Hz, 1H) ; 7.88 (t, J = 8.0 Hz, 1H) ; 7.98-8.00 (m, 2H) ; 8.36 (d, J = 5.6 Hz, 1H)
[0227]
Preparations 2 to 22 :
The compounds of Preparations 2 to 22 were synthesized in analogous manner to that of preparation 1. [0228]
Table 1
Figure imgf000100_0001
l-Chloro-8- (3, 5- 291.8 (35C1),
17
difluorophenoxy) isoquinoline 293.8 (37C1)
291.8 (35C1),
18 l-Chloro-8- ( 2-fluorophenoxy) isoquinoline
293.8 (37C1)
289.8 (35C1),
19 l-Chloro-8- ( 2-chlorophenoxy) isoquinoline
291.8 (37C1) l-Chloro-8- [4-fluoro-3- 341.8 (35C1),
20
.(trifluoromethyl ) phenoxy] isoquinoline 343.8 (37C1) l-Chloro-8- (3,4- 325.7 (35C1),
21
dichlorophenoxy) isoquinoline 327.7 (37C1) l-Chloro-8- [ (5-chloro-3- 291.0 (35C1),
22
pyridyl) oxy] isoquinoline 293.0 (37C1)
[0229]
Preparation 23: 1 , 5-Dichloro-8- (4-fluorophenoxy) isoquinoline
Figure imgf000101_0001
[0231]
Step 1: 5-Chloro-8- (4-fluorophenoxy) isoquinoline
N-Chlorosuccinimide (0.67 g, 2.0 mmol) was added in portion wise to a solution of 8- ( 4-fluorophenoxy) isoquinoline (0.6 g, 2.5 mmol) in sulfuric acid (3 mL) at 0°C. The reaction mixture was then warmed to room temperature and stirred at for 2 hours. After the completion of the reaction was confirmed by TLC, the reaction mixture was cooled to 0°C and quenched with ice cold water, and the precipitate thus obtained was
collected by filtration and washed with cold n-hexane to give the title compound (0.5 g, 73%). MS.(EI)m/z: 274.1 [M (35C1) +1] , 276.1 [M (37C1 ) +1 ] ; XH NMR DMSO-d5: δ 6.83 (d, J = 8.0 Hz,. 1H) ; 7.35-7.43 (m, 2H) ; 7.53-7.57 (m, 1H) ; 7.75-7.78 (m, 1H) ; 7.96 (d, J= 8.0 Hz, 1H) ; 8.20 (d, J = 6.4 Hz, 1H) ; 8.82 (d, J = 6.0 Hz, 1H) , 9.3 (s, 1H) . [0232]
Step 2: 5-Chloro-8- (4-fluorophenoxy) -isoquinoline N^oxide
To a solution of 5-chloro-8- ( 4-fluorophenoxy) isoquinoline (0.4 g, 1.46 mmol) in dichloromethane (10 mL) was added 3- chloroperbenzoic acid (0.78 g, 2.93 mmol) at 0°C. The mixture was stirred at room temperature overnight (for 18 hours) .
After the completion of the reaction was confirmed by TLC, aqueous saturated sodium bicarbonate solution (15 mL) was added thereto, and the stirring was continued for 2.0 hours. The dichloromethane layer was separated, and the aqueous layer was re-extracted with dichloromethane (2 x 25 mL) . The
combined organic layers were washed with brine, and dried over sodium sulfate. The organic layer was concentrated under vacuo, and the obtained crude product was used in the next reaction without further purification.
[0233]
Step 3: 1 , 5-Dichloro-8- (4-fluorophenoxy) isoquinoline
A mixture of 5-chloro-8- ( 4-fluorophenoxy) -isoquinoline N- oxide and phosphorous oxychloride (10 mL) was heated at 100°C for 16 hours. After the completion of the reaction was
confirmed by TLC, the phosphorous oxychloride was evaporated, and the obtained residue was dissolved in ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, water and brine, and dried over sodium sulfate. The organic layer was concentrated, and the obtained residue was purified on combiflash with 2-6% ethyl acetate in hexane as a mobile phase to give the title compound as an off-white solid (0.435 g, 95% in two steps). MS(ESI)m/z: 308.0 [M (35C1) +1] ,310.0
[M(37C1) +1] .
[0234]
Preparation 24 :
The compound of Preparation 24 was synthesized in
analogous manner to that of preparation 23. .
[0235]
Table 2 Prep. MS(EI)m/z:
IUPAC Name
No. (M+l)
1, 5-Dichloro-8- [3- 357.7 (35C1),
24
(trifluoromethyl) phenoxy] isoquinoline 359.7 (37C1)
[0236]
Preparation 25: 1 , 4-Dichloro-8- (4-f uorophenoxy) isoquinoline
[0237]
Figure imgf000103_0001
[0238]
Step 1: 8- (4-Fluorophenoxy) isoquinolin-l-ol
A mixture of l-chloro-8- ( 4-fluorophenoxy) isoquinoline (0.5 g, 1.82 mmol) and sodium acetate (1.4 g, 18.2 mmol) in acetic acid (15 mL) was heated at 100°C for 4 hours. After the completion of the reaction was confirmed by TLC, the reaction mixture was poured into ice cold water, and the solid thus obtained was collected by filtration, washed with water and n- hexane, and dried to give the title compound as a pale- brownish solid (0.430g, 92%). MS(ESI)m/z: 255.9 (M+l); XH NMR DMS0-dff: δ 6.51 (d, J= 7.2 Hz, IH) ; 6.85-6.91 (m, 3H) ; 7.12- 7.17 (m, 3H) ; 7.44 (d, J = 8.0 Hz, 1H) ; 7.63 (t, J = 8.0 Hz , 1H) ; 11.0 (bs, 1H) .
[0239]
Step 2: 4-Chloro-8- (4-fluorophenoxy) isoquinolin-l-ol
N-Chlorosuccinimide (0.22 g, 1.66 mmol) was added in portion wise to a solution of 8- (4-fluorophenoxy) isoquinolin- l-ol (0.42 g, 1.66 mmol) in N,N-dimethylacetamide (15 mL) at 0°C. The reaction mixture was warmed to room temperature and stirred at 30-35°C for 3 hours. After the completion of the reaction was confirmed by TLC, the reaction mixture was cooled to 0°C and quenched with ice cold water, and the precipitate thus obtained was collected by filtration and washed with cold solution of n-hexane to give the title compound (0.4 g, 83%). MS(ESI)m/z: 289.8 [M (35C1) +1] , 291.8 [M (37C1) +1] ; 1H NMR DMSO-c : δ 6.89-6.93 (m, 2H) ; 7.05 (d, J= 8.4 Hz, 1H) ; 7.14-7.18 (m, 2H) ; 7.48 (d, J = 5.2 Hz, 1H); 7.63 (d, J= 8.4 Hz, 1H) ; 7.81 (t, J = 8.4 Hz, 1H) ; 11.32 (bs, 1H) .
[0240]
Step 3 : 1 , 4-Dichloro-8- (4-fluorophenoxy) isoquinoline
A mixture of 4-chloro-8- ( -fluorophenoxy) isoquinolin-l-ol (0.4 g, 1.38 mmol) and phosphorous oxychloride (8 mL) was refluxed for 16 hours. After the completion of the reaction mixture was confirmed by TLC, the reaction mixture was cooled to room temperature, and concentrated. The residue was diluted with aqueous sodium bicarbonate solution (20 mL) , and the mixture was extracted with ethyl acetate (3 x 15 mL) . The combined organic layers were washed with water and brine, and dried over sodium sulfate. The organic layer was concentrated, and the obtained crude product was purified by silica gel
(100-200 mesh) column chromatography with 2-4% ethyl acetate in hexane as a mobile phase to give the title compound as an off-white solid (0.3 g, 70%). MS(ESI)m/z: 307.8 [M(35C1)+1], 309.7 [M(37C1) +1] ; 1H NMR DMSO-cfe: δ 6.98-7.03 (m, 2H) ; 7.08- 7.28 (m, 3H) ; 7.73 (d, J= 7.6 Hz, 1H) ; 8.02 (dd, J = 1.2, 8.4 Hz, 1H) ; 8.37 (s, 1H) .
[0241]
Preparations 26 and 27:
The compounds of Preparations 26 and 27 were synthesized in analogous manner to that of preparation 25.
[0242]
Table 3
Figure imgf000104_0001
[0243]
Preparation 28: l-Chloro-8- (4-fluorophenoxy) -2 ,7-naphthyridine
[
Figure imgf000105_0001
[0245]
Step 1: 2-Chloro-4-methylpyridine-3-carbonitrile
A mixture of 2-hydroxy-4-methylpyridine-3-carbonitrile (3.0 g, 22.38 mmol; obtained as described in WO 2011/088201), phosphoryl chloride (6.26 mL, 67.16 mmol) and phosphorus pentachloride (1.4 g, 6.71 mmol) was refluxed for 2 hours. The reaction mixture was cooled to room temperature, and then concentrated under vacuo to dryness. The obtained residue was diluted with aqueous sodium bicarbonate solution. The
precipitate thus obtained was collected by filtration and dried to give the title compound as an off-white solid (3.0 g, 88%). MS(ESI)m/z: 153.1 (M+l) ; 1H NMR CDC13: δ 8.43 (d, J = 5.2 Hz, 1H), 7.22 (d, J = 4.8 Hz, 1H) , 2.8 ( s, 3H) .
[0246]
Step 2: 2- (4-Fluorophenoxy) -4-methylpyridine-3-carbonitrile To a mixture of 2-chloro-4-methylpyridine-3-carbonitrile
(1.0 g, 6.57 mmol) and 4-fluorophenol (0.81 g, 7.23 mmol) in N, N-dimethylformamide (10 mL) was added potassium carbonate (1.8 g, 13.15 mmol). The reaction mixture was heated at 80°C for 12 hours, then cooled to room temperature, and poured into ice cold water to obtain precipitate. The precipitate was collected by filtration and dried to give the title compound as a white solid (1.2 g, 80%). MS(ESI)m/z: 228.9 (M+l) ; XH NMR DMSO-de: δ 2.54 (s, 3H) ; 7.24 (d, J = 5.6 Hz, 1H) ; 7.27-7.29 (m, 4H) ; 8.21 (d, J = 5.2 Hz, 1H) .
[0247]
Step 3: 8- (4-Fluorophenoxy) -2 , 7-naphthyridin-l-ol
A mixture of 2- ( 4-fluorophenoxy) -4-methylpyridine-3- carbonitrile (1.2 g, 5.26 mmol) , N, -dimethylformamide
dimethyl acetal (0.7 mL, 5.26 mmol) and DMF (15 mL) was
refluxed for 12 hours. After the disappearance of the starting material was confirmed by TLC, the reaction mixture was cooled to room temperature and concentrated to dryness. To the
residue were added acetic acid (5 mL) and sulfuric acid (5 mL) , and the mixture was heated to 50°C for 2 hours. The reaction mixture was cooled to room temperature, and poured into an ice cold solution of aqueous sodium bicarbonate to obtain
precipitate. The precipitate was collected by filtration, and washed with n-hexane to give the title compound as a white powder (1.2 g 89% yield). MS(ESI)m/z: 256.9 (M+l); XH NMR
DMSO-d^: δ 6.48 (d, J = 6.8 Hz, 1H) , 7.10-7.20 (m, 2H) , 7.21- 7.31 (m, 3H) , 7.43 (t, J= 6.4 Hz, 1H) , 8.07 (d, J = 6.0 Hz, 1H) , 11.5 (bs, 1H) .
[0248]
Step 4 : l-Chloro-8- (4-fluorophenoxy) -2 , 7-naphthyridine
A mixture of 8- ( 4-fluorophenoxy) -2 , 7-naphthyridin-l-ol
(400 mg, 1.56 mmol) and phosphoryl chloride (4 mL, 15.85 mmol) was heated at 130°C for 20 min, cooled to room temperature and concentrated to dryness. The obtained crude product (0.4 g) was used in the next step without any purification.
MS(ESI)m/z: (M+l).274.9 [M( 35C1)+1], 276.8 [M(37C1)+1]; 1H NMR DMSO: δ 7.14-7.25 (m, 4H) , 7.29 (d, J= 5.2 Hz, 1H) , 7.53 (d, J = 5.6 Hz, 1H) , 8.14 (d, J = 6.0 Hz, 1H) , 8.46 (d, J = 6.0 Hz, 1H) .
[0249]
Preparations 29 to 52: The compounds of Preparations 29 to 52 were synthesized in analogous manner to that of preparation 28.
[0250]
Table 4
Figure imgf000107_0001
l-Chloro-8- (2-fluoro-4-methoxy-phenoxy) - 305.1 (35C1),
41
2, 7-naphthyridine 307.1 (37C1) l-Chloro-8- ( -fluoro-2-methoxy-phenoxy) - 305.1 (35C1),
42
2, 7-naphthyridine 307.0 (37C1) l-Chloro-8- [2-chloro-3- 359.0 (35C1),
43 (trifluoromethyl) phenoxy] -2,7- 361.0 (37C1 naphthyridine
l-Chloro-8- ( 4-chloro-2-methoxy-phenoxy) - 321.0 (35C1),
44
2, 7-naphthyridine 323.0 (37C1) l-Chloro-8- [4- (trifluoromethyl) phenoxy] - 325.0 (35C1),
45
2, 7-naphthyridine 327.0 (37C1) l-Chloro-8- ( 4-chlorophenoxy) -2, 7- 291.0 (35C1),
46
naphthyridine 293.0 (37C1) l-Chloro-8- ( 4-fluoro-3-methyl-phenoxy) - 289.1 (35C1),
47
2, 7-naphthyridine 291.1 (37C1) l-Chloro-8- (2-chloro-4-fluoro-phenoxy) - 309.0 (35C1),
48
2, 7-naphthyridine 311.0 (37C1) l-Chloro-8- ( 3-chloro-4-fluoro-phenoxy) - 309.0 (35C1),
49
2 , 7-naphthyridine 311.0 (37C1) l-Chloro-8- [3- (trifluoromethoxy) phenoxy] - 341.0 (35C1),
50
2, 7-naphthyridine 343.0 (37C1) l-Chloro-8- [4- (trifluoromethoxy) phenoxy] - 341.1 (35C1),
51
2 , 7-naphthyridine 343.1 (37C1) l-Chloro-8- [ ( 5-fluoro-3-pyridyl) oxy] -2,7- 276.0 (35C1),
52
naphthyridine 278.1 (37C1)
[0251]
Preparation 53: 4 , 8-Dichloro-l- (4-fluorophenoxy) -2 , 7- naphthyridine
[0252]
Figure imgf000109_0001
[0253]
Step 1 : 5-Chloro-2-hydroxy-4-methylpyridine-3-carbonitrile
To a mixture of 2-hydroxy-4-methylpyridine-3-carbonitrile (2.5 g, 18.6 mmol) in N, N-dimethylacetamide (1 mL) was added N-chlorosuccinimide (2.48 g, 18.65 mmol) in portion wise at 0°C under nitrogen. The reaction mixture was stirred at 30-35°C for 3 hours. The reaction mixture was cooled to room
temperature, and then poured into ice cold water, and the solid was collected by filtration. The solid was washed with n-hexane to give the title compound as an off-white solid (2.0 g, 64%). MS(ESI)m/z: (M+l) 168.9 [M(35C1)+1], 170.9
[M(37C1) +1] ; XH NMR DMSO-d6: δ 2.4 (s, 3H) , 8.02 (s, 1H) , 12.78 (bs, 1H) .
[0254]
Step 2: 2 , 5-Dichloro-4-methylpyridine-3-carbonitrile
A mixture of 5-chloro-2-hydroxy-4-methylpyridine-3- carbonitrile (2.0 g, 11.9 mmol), phosphoryl chloride (3.33 mL, 35.71 mmol) and phosphorus pentachloride (0.74 g, 3.57 mmol) was refluxed for 1 hour. The reaction mixture was cooled to room temperature and then concentrated to dryness. The
obtained residue was diluted with aqueous sodium bicarbonate solution. The precipitate thus obtained was collected by filtration, and dried to give the title compound as an off- white solid (1.8 g, 81%). MS(ESI)m/z: 186.9 [M(35C1)+1], 188.9 [M(37C1)+1] ; XH NMR CDC13: δ 2.8 (s, 3H) , 8.48 (s, 1H) . [0255]
Step 3: 5-Chloro-2- (4-fluorophenoxy) -4-methylpyridine-3- carbonitrile
To a mixture of 2 , 5-dichloro-4-methylpyridine-3- carbonitrile (1.3 g, 6.95 mmol) and 4-fluorophenol (0.85 g, 7.64 mmol) in N, N-dimethylformamide (15 mL) was added
potassium carbonate (1.9 g, 13.9 mmol). The reaction mixture was heated at 80°C for 16 hours, cooled to room temperature, and poured into an ice cold water to obtain precipitate. The precipitate was collected by filtration, and dried to give the title compound as a white solid (1.2 g, 67%). MS(ESI)m/z:
262.8 (M+l); 1H MR CDC13: δ 2.6 (s, 3H) , 7.07-7.15 (m, 4H) , 8.17 (s, 1H)
[0256]
Step 4: 5-Chloro-8- (4-fluorophenoxy) -2 , 7-naphthyridin-l-ol
A mixture of 5-chloro-2- ( 4-fluorophenoxy) -4- methylpyridine-3-carbonitrile (1.2 g, 4.56 mmol) and N,N- dimethylformamide dimethyl acetal (0.6 ml, 4.56 mmol) in DMF (12 mL) was refluxed for 12 hours. After the disappearance of the starting material was confirmed by TLC, the reaction
mixture was cooled to room temperature and concentrated to dryness. To the residue were added acetic acid (6 mL) and sulfuric acid (6 mL) , and the mixture was heated to 50°C for 2 hours. The reaction mixture was cooled to room temperature, and poured into an ice cold solution of aq. sodium bicarbonate to obtain precipitate. The precipitate was collected by
filtration to give the title compound as a white powder (1.0 g, 76%). MS(ESI)m/z: 290.8 [M(35C1)+1], 292.8 [M (37C1 ) +1 ] ; 1H NMR DMSO-d£: δ 6.59 (d, J = 7.2 Hz, 1H) , 7.16-7.21 (m, 2H) , 7.22- 7.30 (m, 2H) , 7.63 (t, J = 6.8 Hz, 1H) , 8.25 (s, 1H) , 11.8 (bs, 1H) .
[0257]
Step 5 : 4 , 8-Dichloro-l- (4-fluorophenoxy) -2 , 7-naphthyridine
A mixture of 5-chloro-8- ( 4-fluorophenoxy) -2 , 7- naphthyridin-l-ol (0.7 g, 2.40 mmol) and phosphoryl chloride (14 mL) was heated at 130°C for 1 hour. The reaction mixture was cooled to room temperature and concentrated to dryness.
The obtained residue was diluted with sodium bicarbonate solution (20 mL) , and the mixture was extracted with ethyl acetate (3 x 15 mL) . The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under vacuo to give a crude product. The crude product was purified by silica gel (100-200 mesh size) column chromatography using 2% ethyl acetate in hexane as mobile phase to give the title compound (0.5 g, 67%). MS(ESI)m/z: 308.7 [M(35C1)+1], 310.8
[M(37C1)+1]; XH NMR CDC13: δ 7.1-7.25 (m, 4H) , 7.92 (d, J = 6 Hz,
1H) , 8.19 (s, 1H), 8.60 (d, J = 6 Hz, 1H) .
[0258]
Preparations 54 and 55:
The compounds of Preparations 54 and.55 were synthesized in analogous manner to that of preparation 53.
[0259]
Table 5
Figure imgf000111_0001
[0260]
Preparation 56: 4-Bromo-8-chloro-l- (3-fluorophenoxy)
naphthyridine
[0261]
Figure imgf000112_0001
[0262]
Step 1: 5-Bromo-2-hydroxy-4-methylpyriciine-3-carbonitrile
To a mixture of 2-hydroxy-4-methylpyridine-3-carbonitrile (2.20 g, 16.40 mmol) in N, N-dimethylacetamide (22.0 mL) was added N-bromosuccinimide (3.21 g, 18.04 mmol) in portion wise at 0°C under nitrogen. The reaction mixture was stirred at 40°C for 2 hours. The reaction mixture was cooled to room temperature, and then poured into ice cold water, and the solid was collected by filtration. The solid was washed with n-hexane to give the title compound as an off-white solid (2.7 g, 77%). MS(ESI)m/z: (M+l) 212.9 [M(79Br)+l], 214.9
[M(81Br) +1] ; XH NMR DMSO-d6: δ 2.42 (s, 3H) , 8.08 (s, 1H) , 12.78 (br s, 1H) .
[0263]
Step 2: 5-Bromo-2-chloro-4-methyl-pyridine-3-carbonitrile
A mixture of 5-bromo-2-hydroxy-4-methylpyridine-3- carbonitrile (2.0 g, 9.38 mmol), phosphoryl chloride (2.62 mL 28.16 mmol) and phosphorus pentachloride (0.58 g, 2.81 mmol) was refluxed for 2 hour. The reaction mixture was cooled to room temperature and then concentrated to dryness. The
obtained residue was diluted with aqueous sodium bicarbonate solution. The precipitate thus obtained was collected by filtration, and dried to give the title compound as an off- Ill white solid (2.0 g, 92%). MS (ESI ) m/z : 230.9 [M(79Br)+l], 232.9 [M(81Br)+l]; lR NMR DMSO-d6: δ 2.59 (s, 3H) , 8.82 ( s , 1H)
[0264]
Step 3: 5-Bromo-2- (3-fluorophenoxy) -4-methyl-pyridine-3- carbonitrile
To a mixture of 5-bromo-2-chloro-4-methyl-pyridine-3- carbonitrile (2.0 g, 8.64 mmol) and 3-fluorophenol (1.18 mL, 12.9 mmol) in N, N-dimethylformamide (20 mL) was added
potassium carbonate (2.38 g, 17.2 mmol). The reaction mixture was heated at 100°C for 16 hours, cooled to room temperature, and poured into an ice cold water, and the mixture was
extracted with ethyl acetate (3 x 25 mL) . The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under vacuo to give a crude product. The crude product was purified by silica gel (100-200 mesh size) column chromatography using 5% ethyl acetate in hexane as mobile phase to give the title compound (2.0 g, 75%). MS(ESI)m/z:
307.0 [M(79Br)+l], 309.0 [M ( 81Br) +1 ] ; XH NMR CDC13: δ 2.63 (s, 3H) , 6.91-7.02 (m, 3H)7.36-7.42 (m, 1H) , 8.32 (s, 1H) .
[0265]
Step 4 : 5-Bromo-8- (3-fluorophenoxy) -2 , 7-naphthyridin-l-ol
A mixture of 5-bromo-2- ( 3-fluorophenoxy) -4-methyl- pyridine-3-carbonitrile (2.4g, 7.81 mmol) and N,N- dimethylformamide dimethyl acetal (3.12 ml, 23.44 mmol) in DMF (15 mL) was refluxed for 12 hours. After the disappearance of the starting material was confirmed by TLC, the reaction
mixture was cooled to room temperature and concentrated to dryness. To the residue were added acetic acid (7.8 mL) and sulfuric acid (7.8 mL) , and the mixture was heated to 50°C for 2 hours. The reaction mixture was cooled to room temperature, and poured into an ice cold solution of aq. sodium bicarbonate, and the mixture was extracted with ethyl acetate (3 x 25 mL) . The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under vacuo to give a crude product. The crude product was as such used for next reaction (2.2 g, 75%). MS(ESI)m/z: 334.9. [ (79Br)+l], 337.0 [M(81Br)+l].
[0266]
Step 5 : 4-Bromo-8-chloro-l- (3-fluorophenoxy) -2 , 7-naphthyridine
A mixture of 5-bromo-8- ( 3-fluorophenoxy) -2 , 7- naphthyridin-l-ol (2.2 g, 6.56 mmol) and phosphoryl chloride (20 mL) was heated at 130°C for 1 hour. The reaction mixture was cooled to room temperature and concentrated to dryness.
The obtained residue was diluted with sodium bicarbonate
solution (20 mL) , and the mixture was extracted with ethyl acetate (3 x 15 mL) . The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under vacuo to give a crude product. The crude product was purified by silica gel (100-200 mesh size) column chromatography using 7% ethyl acetate in hexane as mobile phase to give the title compound (1.5 g, 64%). MS(ESI)m/z: 353.0 [M(79Br)+l], 354.9
[M(81Br)+l] ; ¾ NMR CDC13: δ 6.99-7.06 (m, 3H) . 7.41-7.45 (m, 1H), 7.91 (d, J = 5.6 Hz, 1H) , 8.34 (s, 1H) , 8.60 (d, J= 5.6 Hz, 1H) .
[0267]
Preparation 57: 8-Chloro-l- (3-fluorophenoxy) -4-methoxy-2 , 7- naphthyridine
[0268]
Figure imgf000114_0001
[0269] Step 1: 2- (3-Fluorophenoxy) -5-hydroxy-4-me hyl-pyridine-3- carbonitrile
A mixture of 5-bromo-2- (3-fluorophenoxy) -4-methyl- pyridine-3-carbonitrile (0.63 g, 2.72 mmol, synthesized as described in Step 3 of preparation 56) and 1,4-dioxane (6.5 mL) was degassed with argon for 0.5 hours. To the mixture were added potassium acetate (0.80 g, 8.16 mmol), bispinacoloto diborane (0.83 g, 3.26 mmol) and PdCl2(dppf) DCM complex (0.067 g, 0.08 mmol). The mixture was heated for 2 hours. The
disappearance of the starting material was confirmed by TLC. Then the reaction mixture was cooled to 0°C, treated with hydrogen peroxide (30%) solution (0.92 mL, 8.16 mmol) and stirred for 1 hour. The reaction mixture was diluted with DCM and poured into water. The aqueous layer was extracted with DCM (3 x 15 mL) . The combined organic layers were washed with saturated sodium thiosulphate solution (10 mL) , then brine (20 mL) , dried over sodium sulfate and concentrated under vacuo to give a crude product. The crude product was as such used for next reaction (0.5 g, 89%). MS(ESI)m/z: 245.0 [M+l]
[0270]
Step 2: 2- (3-Fluorophenoxy) -5-methoxy-4-methyl-pyridine-3- carbonitrile
To a mixture of 2- (3-fluorophenoxy) -5-hydroxy-4-methyl- pyridine-3-carbonitrile (0.7 g, 2.86 mmol) in N, - dimethylacetamide (10.0 mL) were added cesium carbonate (2.79 g, 8.59 mmol) and methyl iodide (0.89 mL, 14.34 mmol) at room temperature under nitrogen. The reaction mixture was stirred at 65°C for 18 hours. The reaction mixture was cooled to room temperature, and then poured into ice cold water, and the mixture was extracted with ethyl acetate (3 x 15 mL) . The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under vacuo to give a crude product. The crude product was purified by silica gel (100-200 mesh size) column chromatography using 7% ethyl acetate in
- hexane as mobile phase to give the title compound (0.7 g, 94%). MS (ESI ) m/z : 259.1. [M+l] , ; XH NMR DMSO-d6: δ 2.40 (s, -3H) , 3.92 (s, 3H) , 7.03-716 (m, 3H) , 7.44-7.50 (m, 1H) , 8.09(s, 1H) .
[0271]
Step 3: 8- (3-Fluorophenoxy) -5-methoxy-2 , 7-napht yridin-l-ol
5 A mixture of 2- (3-fluorophenoxy) -5-methoxy-4-methyl- pyridine-3-carbonitrile (0.7 g, 7.81 mmol) and N,N- dimethylformamide dimethyl acetal (1.08 ml, 8.13 mmol) in DMF (7 mL) was refluxed for 12 hours. The disappearance of the starting material was confirmed by TLC, then the reaction
10 mixture was cooled to room temperature and concentrated to
dryness. The obtained residue was diluted with acetic acid (2.7 mL) and sulfuric acid (2.7 mL) , and the mixture was heated to 50°C for 2 hours. The reaction mixture was cooled to room temperature, and poured into an ice cold solution of aq.
15 sodium bicarbonate, and the mixture was extracted with ethyl acetate (3 x 10 mL) . The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under vacuo to give a crude product. The crude product was as such used for next reaction (0.3 g, 38%). MS (ESI ) m/z : 287.0 [M)+l]
20 [0272]
Step 4: 8-Chloro-l- (3-fluorophenoxy) -4-methoxy-2 ,7- naphthyridine
A mixture of 8- ( 3-fluorophenoxy) -5-methoxy-2 , 7- naphthyridin-l-ol (0.3 g, 1.04 mmol) and phosphoryl chloride
25 (1.0 mL) was heated at 100°C for 16 hours. The reaction
mixture was cooled to room temperature and concentrated to dryness. The obtained residue was diluted with sodium
bicarbonate solution (20 mL) , and the mixture was extracted with ethyl acetate (3 x 15 mL) . The combined organic layers
30 were washed with brine, dried over sodium sulfate and
concentrated under vacuo to give a crude product. The crude product was purified by silica gel (100-200 mesh size) column chromatography using 7% ethyl acetate in hexane as mobile phase to give the title compound (0.05 g, 16%). MS(ESI)m/z:
35 305.0 [M+l]. [0273]
Preparation 58: 1 , 4-Dichloro-8- (4-fluorophenoxy) -2 , 7- naphthyridine
[0274]
Figure imgf000117_0001
[0275]
Step 1 : 4-Chloro-8- (4-fluorophenoxy) -2 , 7-naphthyridin-l-ol
To a mixture of 8- ( -fluorophenoxy) -2, 7-naphthyridin-l-ol (Step 3 of Preparation 28, 0.65 g, 2.53 mmol) in N,N- dimethylacetamide (20 mL) was added W-chlorosuccinimide (0.33 g, 2.53 mmol) in portion wise at 0°C under nitrogen. The reaction mixture was stirred at 30-35°C for 1 hour. The reaction mixture was cooled to room temperature, and then poured into ice cold water. The solid was collected by
filtration, and washed with n-hexane to give the title
compound as an off-white solid (0.4 g, 55%). MS(ESI)m/z: 291.1 [M(35C1)+1], 293.1 [M(37C1) +1] ; XH NMR DMSO-d6: δ 7.10-7.30 (m, 4H), 7.35 (d, J= 5.2 Hz, 1H) , 7.78 (d, J = 6.4 Hz, 1H) , 8.26 (d, J= 5.6 Hz, 1H) , 11.9 (bs, 1H) .
[0276]
Step 2 : 1 , 4-Dichloro-8- (4-fluorophenoxy) -2 , 7-naphthyridine
A mixture of ~4-chloro-8- ( 4-fluorophenoxy) -2, 7- naphthyridin-l-ol (0.4 g, 1.38 mmol) and phosphoryl chloride (8 mL) was heated at 130°C for 2 hour. The reaction mixture was cooled to room temperature and concentrated to dryness. The obtained residue was diluted with sodium bicarbonate solution (20 mL) , and the mixture was extracted with ethyl acetate (3 x 15 mL) . The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under vacuo to give a crude product. The crude product was used in next reaction without further purification.
[0277]
Preparations 59 and 60:
The compounds of Preparations 59 and 60 were synthesized in analogous manner to that of preparation 58.
[0278]
Table 6
Figure imgf000118_0002
[0279]
Preparation 61: l-Chloro-8- (4-fluorophenoxy) -2 , 6-naphthyridine
[0280]
Figure imgf000118_0001
[0281]
Step 1: 3-Bromo-4,5-dimethyl-pyridine
To a mixture of 3, 4-dimethylpyridine (5.0 g, 46.6 mmol) in cone sulfuric acid (50.0 mL) was added N-bromosuccinimide (9.31 g, 51.32 mmol) in portion wise at room temperature under nitrogen. The reaction mixture was stirred at 60°C for 18 hours. The reaction mixture was cooled to room temperature, then poured into ice cold water, and basified with 10% NaOH solution. The aqueous layer was extracted with ethyl acetate (3 x 50 mL) . The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under vacuo to give a crude product. The crude product was purified by silica gel (100-200 mesh size) column chromatography using 5% ethyl acetate in hexane as mobile phase to give the title compound (0.8 g, 9.3%). MS(ESI)m/z: 186.0 [M(79Br)+l], 188.0
[M(81Br)+l]; ¾ N R CDC13: δ 2.31 (s, 3H) , 2.36 (s, 3H) , 8.23 (s,
1H) , 8.51 (s, 1H) .
[0282]
Step 2: 3-Bromo-5-methyl-pyridine-4-carbaldehyde oxime
A solution of 3-bromo-4 , 5-dimethyl-pyridine (1.0 g, 5.37 mmol) and butyl nitrite (0.72 g, 6.98 mmol) in N, NT- dimethyIformamide (10.0 mL) was cooled to -78°C. To the
mixture was added a solution of potassium tert-butoxide (1.39 g, 12.36 mmol) in N, N-dimethylformamide (5.0 mL) . The reaction mixture was stirred at -50°C for an hour, and then a mixture of glacial acetic acid (1.5 mL) and water (2.5 mL) was added thereto. The reaction mixture was poured into ice cold water, and the solid was collected by filtration. The solid was washed with water to give the title compound as off-white solid (0.75 g, 64.7%). MS(ESI)m/z: (M+l) 215.0 [M (79Br) +1 ] , 216.9 [M(81Br) +1] .
[0283]
Step 3 : 3-Bromo-5-methyl-pyridine-4-carbonitrile
A mixture of 3-bromo-5-methyl-pyridine-4-carbaldehyde oxime (0.65 g, 3.02 mmol) and acetic anhydride (3.0 mL) was heated at 120°C for 4 hours. The reaction mixture was cooled to room temperature and then concentrated to dryness. The obtained residue was diluted with dichloromethane, and the mixture was washed with water, brine, dried over sodium
sulfate and concentrated under vacuo to give a crude product which was used as such for next reaction. MS(ESI)m/z: 197.0
[M(79Br)+l], 198.9 [M(81Br)+l].
[0284]
Step 4: 3- (4-Fluorophenoxy) -5-methyl-pyridine-4-carbonitrile
A mixture of 3-bromo-5-methyl-pyridine-4-carbonitrile (2.0 g, 10.1 mmol) , 3-fluorophenol (1.85 mL, 20.3 mmol) and cesium carbonate (9.89 g, 30.4 mmol) in dimethylsulfoxide (20 mL) was degassed with argon for 30 min. To the mixture were added copper (I) iodide (1.93 g, 10.1 mmol), copper powder
(0.65 g, 10.1 mmol) and 2 , 2 , 6, 6-tetramethyl-3.5-heptanedione (1.05 mL, 5.0 mmol). The mixture was continued degassing for another 20 min. The resulting mixture was heated at 100°C for 18 hours under argon atmosphere. The mixture was cooled to room temperature and diluted with water (100 mL) followed by 10% aqueous sodium hydroxide solution (50 mL) . The aqueous layer was extracted with ethyl acetate (3 x 100 mL) . The combined organic layers were washed with water (50 mL) and brine (100 mL) , dried over sodium sulfate and concentrated under vacuo to give a crude product. The crude product was purified by combiflash with 8-12% ethyl acetate in hexane as a mobile phase to give the title compound as off white solid
(0.80 g, 35%). MS(ESI)m/z: 229.1; 1R N R DMSO-d6 2.52 (s, 3H) , 7.02-7.05 (m, 1H) , 7.09-7.19 (m, 1H) , 7.47- 7.53 (m 1H) , 8.30 (s, 1H) , 8.56, (s, 1H) .
[0285]
Step 5: 8- (4-Fluorophenoxy) -2 , 6-naphthyridin-l-ol
A mixture of 3- ( 4-fluorophenoxy) -5-methyl-pyridine-4- carbonitrile (0.5 g, 2.19 mmol) and N, -dimethylformamide dimethyl acetal (0.88 mL, 6.57 mmol) in DMF (6 mL) was
refluxed for 24 hours. After confirming the disappearance of the starting material by TLC, the reaction mixture was cooled to room temperature and concentrated to dryness. To the
residue were added ethanol (3 mL) and 50% aq. hydrobromic acid (3 mL) , and the mixture was heated to 80°C for 18 hours. The reaction mixture was cooled to room temperature, and
concentrated, and the mixture was poured into an ice cold solution of aq. sodium bicarbonate. The aqueous layer was extracted with ethyl acetate (3 x 15 mL) . The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under vacuo to give a crude product. The crude product was as such used for next reaction (0.5 g) .
MS (ESI)m/z: 257.1. [M+l] .
[0286]
Step 6 : l-Chloro-8- (4-fluorophenoxy) -2 , 6-naphthyridine
A mixture of 8- ( 4-fluorophenoxy) -2 , 6-naphthyridin-l-ol
(0.5 g, 1.95 mmol) and phosphoryl chloride (5 mL) was heated at 130°C for ' 3 hour. The reaction mixture was cooled to room temperature and concentrated to dryness. The obtained residue was diluted with sodium bicarbonate solution (10 mL) , and the mixture was extracted with ethyl acetate (3 x 15 mL) . The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under vacuo to give a crude product. The crude product was purified by silica gel (100-200 mesh size) column chromatography using 7% ethyl acetate in hexane as mobile phase to give the title compound (0.105 g, 20%). MS(ESI)m/z: 275.0 [M(35C1)+1], 277.0 [M(37C1)+1]; ¾ NMR CDCI3 : δ 6.70-6.90 (m, 3H) , 7.27-7.36 (m, 1H) , 7.77 (d, J =
5.6Hz, 1H) , 8.43 (br s, 1H) , 8.52 (d, J = 5.6 Hz, 1H) , 9.17 (bs, 1H) .
[0287]
Preparations 62-76
The compounds of Preparations 62-76 were either obtained from commercial source or prepared as per literature method.
[0288]
Table 7
Figure imgf000122_0001
[0289]
Preparation 77: (IS) -1- ( -Vinylphenyl) ethanamine
[0290]
Figure imgf000123_0001
[0291]
Step 1: Ethyl 4- [ (IS) -1- (tert- butoxycarbonylamino) ethyl]benzoate
To a mixture of ethyl 4- [ (IS) -1-aminoethyl] benzoate (5.0 g, 25.90 mmol) in DCM (50 mL) were added triethylamine (10.8 mL, 77.72 mmol) and BOC anhydride (6.77 g, 31.08 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction completion was confirmed by TLC, then diluted with water (50 mL) and extracted with dichloromethane (2 x 100 mL) . The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under vacuo to give a crude product. The crude product was purified by silica gel column chromatography using 5-10% ethyl acetate in hexane to give the title compound (5.0 g, 60%).
[0292]
Step 2: tert-Butyl N- [ (IS) -1- [4- (hydroxymethyl)phenyl] ethyl] carbamate
To a solution of ethyl 4- [ ( IS ) -1- (tert- butoxycarbonylamino) ethyl] benzoate (5.0 g, 17 mmol) in THF (50 mL) was added lithium aluminium hydride (34 mL, 34 mmol) (1.0 M slution in THF) at 0°C under nitrogen. The reaction mixture was stirred at room temperature for 1 hour, and the product formation was confirmed by TLC. The mixture was quenched by aq. sodium sulfate solution, and the solid obtained was filtered, and the filtrate was concentrated to dryness to give the title compound (3.3 g, 77%). MS(EI)m/z: 196.2 (M-56 + 1); lE NMR (400 MHz, , CDC13) : δ 1.42 (s, 12H) , 4.68 (s, 2H) , 4.78 (br s, 2H) , 7.28-7.35 (m, 4H) . [0293]
Step 3: tert-Butyl N- [ (IS) -1- (4-formylphenyl) ethyl] carbamate
To a solution of tert-butyl N- [ (IS) -1- [4- (hydroxymethyl) phenyl] ethyl] carbamate (3.3 g, 13.1 mmol) in DCM (60 mL) was added manganese oxide (14 g, 157.7 mmol), and the reaction mixture was stirred at room temperature for 1.5 hours. The product formation was confirmed by TLC. The mixture was filtered through celite pad, then the filtrate was concentrated under vacuo to give the title compound (3.0 g, 92%). MS(EI)m/z: 194.2 (M-56 + 1); 1R NMR (400 MHz, , CDC13) : δ 1.33 (s, 12H) , 4.84 (br s, 1H) , 7.32 (d, J = 4.8 Hz, 1H) , 7.47 (d, J = 8.0 Hz, 2H) , 7.85 (d, J = 8.4 Hz, 2H) , 9.99 (s, 1H) .
[0294]
Step 4: tert-Butyl N- [ (IS) -1- (4-vinylphenyl) ethyl] carbamate
To a solution of tert-butyl N- [ (IS) -1- (4- formylphenyl) ethyl] carbamate (3.0 g, 12.04 mmol) in 1,4- dioxane (30 mL) were added potassium carbonate (3.3 g, 24.00 mmol) and methyltriphenylphosphonium bromide (5.16 g, 14.45 mmol) . The resulting mixture was heated at 110°C for 16 hours under argon atmosphere. The reaction was cooled to room temperature, then diluted with water (50 mL) and extracted with ethyl acetate (3 x 50 mL) . The combined organic layers were washed with water (25 mL) , brine (50 mL) , dried over sodium sulfate and concentrated under vacuo to give a crude product. The crude product was purified by combiflash column chromatography using 10-20% ethyl acetate in hexane as a mobile phase to give the title compound. (2.5 g, 84%)
MS(ESI)m/z: 192.1 (M-56 + 1); lH NMR (400 MHz, CDC13) : δ 1.42 (s, 12H) , 4.77 (br s, 2H) , 5.22 (d, J = 7.6 Hz, 1H) , 5.73 (d, J = 18.0 Hz, 1H) , 6.66-6.73 (m, 1H) , 7.24 (s, 1H) , 7.26 (s, 1H) , 7.37 (d, J = 8.4 Hz, 2H) .
[0295]
Step 5 : (IS) -1- (4-Vinylphenyl) ethanamine
To a solution of tert-butyl N- [ (IS) -1- (4- vinylphenyl) ethyl] carbamate (2.5 g, 10.12 mmol) in DCM (25 mL) was added TFA (5 mL) , and the reaction mixture was heated at 70°C for 4 hours. The product formation was confirmed by TLC. The mixture was diluted with DCM followed by aq. NaHC03
solution (50 mL) and extracted with dichloromethane (2 x 100 mL) . The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under vacuo to give the title compound (1.28 g, 86%). 1H NMR (400 MHz , , DMSO-d6) : δ 1.48 (d, J = 6.8 Hz, 3H) , 4.41 (br s, 1H) , 5.30 (d, J = 11.6 Hz, 1H) , 5.88 (d, J = 18.0 Hz, 1H) ; 6.71-6.78 (m, 1H) , 7.45 (d, J = 8.0 Hz, 2H) ; 7.54 (d, J = 8.0 Hz, 2H) ; 8.26 (bs, 2H) .
[0296]
Example Al: Methyl 4- [ (IS) -1- [ [8- [3- (trifluoromethyl)phenoxy] - 1-isoquinolyl] amino] ethyl]benzoate
[0297]
Figure imgf000125_0001
[0298]
A mixture of l-chloro-8- [3- (trifluoromethhyl) phenoxy] isoquinoline (0.1 g, 0.31 mmol;
Preparation 1) and methyl 4- [ (IS) -1-aminoethyl] benzoate (0.083 g, 0.46 mmol, Preparation 63) was heated at 140°C for 2.0 hours. The residue was purified by combiflash with 6-8% ethyl acetate in hexane as a mobile phase to give the title compound as an off white solid (0.11 g, 76%). MS(ESI) m/z: 467.2 (M+l) ; 1H NMR CDC13: δ 1.43 (d, J= 6.8 Hz, 3H) ; 3.81 (s, 3H) ; 5.30-5.35 (m, 1H) ; 6.96 (d, J= 5.6 Hz, 1H) ; 7.03 (dd, J= 1.8 & 7.0 Hz, 1H),7.33 (d, J= 8.4 Hz, 3H) ; 7.46 (d, J= 6.8 Hz, 1H) ; 7.54- 7.65 (m, 4H) ; 7.67 (t, J= 7.6, 1H) ; 7.77-8.00 (m, 3H) .
[0299]
Example A2 : Ethyl 4- [1- [ [8- (4-fluorophenoxy) -2 , 7-naphthyridin- 1-yl] amino] cyclopropyl]benzoate
0300]
Figure imgf000126_0001
The Example A2 was performed in analogous manner to that of Example Al using l-chloro-8- ( 4-fluorophenoxy) -2 , 7- naphthyridine (0.2 g, 0.73 mmol, Preparation 28) and ethyl 4-
( 1-aminocyclopropyl ) benzoate (0.18 g, 0.88 mmol; Preparation 66) to give the title compound (0.04 g, 12%). MS(ESI) m/z: 444.1 (M+l); XH NMR DMSO-d&: δ 1.36 (t, J = 7.2 Hz, 3H) ; 1.45- 1.55 (m, 4H) ; 4.34 (q, j = 7.2 Hz, 2H) ; 6.80 (d, J = 5.6 Hz, 1H ); 7.11 (d, J= 5.6 Hz, 1H) ; 7.15-7.26 (m, 4H) ; 7.29 (d, J = 8.8 Hz, 2H), 7.92-7.96 (m, 3H) , 8.12 (d, J = 5.6 Hz, 2H) .
[0301]
Example A3: Ethyl 4- [[ [8- (3-fluorophenoxy) -1- isoquinolyl] amino]methyl]benzoate
Figure imgf000126_0002
The Example A3 was performed in analogous manner to that of Example Al using l-chloro-8- ( 3-fluorophenoxy) isoquinoline (0.15 g, 0.54 mmol, Preparation 3) and ethyl 4- (aminomethyl) benzoate (0.27 g, 1.6 mmol; Preparation 67) to give the title compound (0.07 g,. 30%). MS(ESI) m/z: 417.2 (M+l); XH NMR DMSO-d6: δ 1.29 (t, J = 7.2 Hz, 3H) ; 4.28 (q, J = 7.2 Hz, 2H) ; 4.78 (d, J= 6.0 Hz, 2H) ; 6.85 (d, J = 7.2 Hz, 1H) ; 6.94 (t, J= 5.2 Hz, 2H) ; 7.10 (d, J= 9.2 Hz, 2H) ; 7.35 (d, J= 7.6 Hz, 2H) ; 7.47-7.54 (m, 3H) ; 7.80 (s, 1H) ; 7.82 (d, J = 4.0 Hz, 2 H) ; 7.96 (s, 1H)
[0302] Example A4: Methyl 4- [ (IS) -1- [ [8- (4-fluorophenoxy) -2 , 7- naphthyridin-l-yl] amino] ethyl]benzoate
0303]
Figure imgf000127_0001
[0304]
The Example A4 was performed in a similar manner to that of Example Al using l-chloro-8- (4-fluorophenoxy) -2, 7- naphthyridine (0.2 g, 0.73 mmol; Preparation 28) and methyl 4- [ (IS) -1-aminoethyl] benzoate (0.19 g, 1.09 mmol, Preparation 63) to give the title compound (0.2 g 66%). MS(ESI) m/z:
417.2 (M+l); 1U NMR DMSO-d6: δ 1.62 (d, J = 6.8 Hz, 3H) ; 3.89 (s, 3H) , 5.54-5.57 (m, 1H) ; 6.74 (d, J = 6.0 Hz, 1H) ; 7.08 (d, J = 6.0 Hz, 1H) ; 7.15-7.24 (m, 4H) ; 7.48 (d, J = 8.0 Hz, 2H) ; 7.79 (d, J= 6.8 Hz, 1H) ; 7.93 (d, J= 5.2 Hz, 1H) ; 7.98 (d, J = 8.8 Hz, 2H) ; 8.05 (d, J= 5.2 Hz, 1H) .
[0305]
The compounds of Examples A5 to A84 and A86 were synthesized in a similar manner to that of Example Al .
[0306]
Table 8
Figure imgf000127_0002
Figure imgf000128_0001
yl] amino] ethyl] enzoate
Figure imgf000129_0001
Figure imgf000130_0001
Figure imgf000131_0001
Figure imgf000132_0001
nzoate
Figure imgf000133_0001
ate
Figure imgf000134_0001
Figure imgf000135_0001
Figure imgf000136_0001
Figure imgf000137_0001
Methyl 4-[l-[ [8-(3- fluorophenoxy) -2, 7-
A78 432.2 naphthyridin-1- yl] amino] propyl ] benzoate
Methyl 6- [1- [ [8- (3- fluorophenoxy) -2, 7-
A79 naphthyridin-1- • 419.2 yl] amino] ethyl] pyridine-3-
Figure imgf000138_0001
carboxylate
Methyl 4- [ (IS) -1- [ [8- [ (5- fluoro-3-pyridyl) oxy] -2,7-
A80 419.2 naphthyridin-1- yl] amino] ethyl] benzoate
Methyl 4-[l-[ [8- (3- fluorophenoxy) -2, 7-
A81 naphthyridin-1- 432.2 yl] amino] ethyl] -3-methyl- benzoate
Methyl 3-chloro-4- [ (IS) -1- [ [8- (3-fluorophenoxy) -2, 7-
A82 452.1 naphthyridin-1- yl] amino] ethyl] enzoate
Methyl 5- [1- [ [8- (3- fluorophenoxy) -2,7-
A83 naphthyridin-1- 424.2
Figure imgf000138_0002
yl] amino] ethyl] thiophene-
2-carboxylate
Methyl 2-fluoro-4- [ 1- [ [ 8- ( 3-fluorophenoxy) -2,7-
A84 naphthyridin-1- 436.2 yl] amino] ethyl] benzoate 8- (3-Fluorophenoxy) - [ (lS)-l-(4-
A86 386.1
vinylphenyl) ethyl] -2
naphthyridin-1-amine
NA: not available
[0307]
Example Bl : Methyl 4- [ (IS) -1- [ [5-cyclopropyl-8- (3- fluorophenoxy) -2 , 7-naphthyridin-1-yl] amino] ethyl]benzoate
0308]
Figure imgf000139_0001
[0309]
A mixture of methyl 4- [ (IS) -1- [ [5-bromo-8- (3- fluorophenoxy) -2 , 7-naphthyridin-l-yl] amino] ethyl] benzoate (0.2 g, 0.4 mmol, Preparation A51) , cyclopropyl boronic acid (0.103 g, 1.20 mmol), potassium phosphate (0.299 g, 1.41 mmol), water (0.2 mL) and toluene (4 mL) was degassed with argon for 30 min. To the mixture were added palladium acetate (0.009 g, 0.04 mmol) and tricyclohexylphosphine (0.022 g, 0.08 mmol), and the mixture was degassed for another 20 min. The resulting mixture was heated at 100 °C for 18 hours under argon atmosphere. The reaction was cooled to room temperature and filtered through celite pad. The filtrate was concentrated under vacuum, and the residue was purified by combiflash with 8-12% ethyl
acetate in hexane as a mobile phase to give the title compound (0.167 g, 91.75,%). MS(EI)m/z: 458.2 (M+l); XH NMR CDC13: δ 0.61-0.64 (m, 2H) , 0.96-1.01 (m, 2H) , 1.61 (d, J= 6.8Hz, 3H) , 1.91-1.95 (m, 1H) , 5.54-5.58 (m, 1H) , 6.98-7.01 (m, 3H) , 7.20 (d, J= 6.0 Hz, 1H) , 7.40-7.48 (m, 3H) , 7.77 (d, J= 6.8Hz, 1H) , 7.80 (s, 1H) , 7.98 (d, J= 8.0 Hz, 2H) , 8.14 (d, J = 6.0 Hz, 1H) .
[0310]
The compounds of Examples B2 to B4 were synthesized in a similar manner to that of Example Bl.
[0311]
Table 9
Figure imgf000140_0002
[0312]
Example CI: Methyl 4- [ (IS) -1- [ [8- [ (3-fluorophenyl)methoxy] - 2 , 7-naphthyridin-l-yl] amino] ethyl]benzoate
[0313]
Figure imgf000140_0001
[0314]
Step 1 : 4- [ (IS) -1- [ (8-Methoxy-2 , 7-naphthyridin-l- yl) amino] ethyl]benzoic acid A mixture of methyl 4- [ (IS) -1- [ [8- [3- (trifluoromethyl) phenoxy] -2, 7-naphthyridin-l- yl] amino] ethyl] benzoate (5.5 g, 2.40 mmol, Preparation A48) and lithium hydroxide monohydrate (4.8 g, 118 mol) in mixture of THF:MeOH:H20 (2:3:1, 110 mL) was strirred at room temprature for 3 days. The product formation was confirmed by TLC, then the reaction mixture was concentrated to dryness, then to the mixture was added water (20 mL) , and the mixture was acidified by 2N HC1 (pH = 2-3), and extracted with ethyl acetate (3 x 30 mL) . The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under vacuo to give the ttle compound (3.5 g, 92%). MS (ESI) m/z: 324.1 (M+l)
[0315]
Step 2 : Methyl 4- [ (IS) -1- [ (8-methoxy-2 , 7-naphthyridin-1- yl) amino] ethyl]benzoate
To a solution of 4- [ (IS) -1- [ ( 8-methoxy-2 , 7-naphthyridin- 1-yl) amino] ethyl] benzoic acid (3.5 g, 10.83 mmol) in DMF (35 mL) were added potassium carbonate (3.0 g, 21.67 mmol) and methyl iodide (1.0 mL, 16.25 mmol). The resulting mixture was strirred at room temprature for 1 hour under argon atmosphere. The product formation was confirmed by TLC, then the reaction mixture was diluted with water (350 mL) and extracted with ethyl acetate (3 x 50 mL) . The combined organic layers were washed with water (100 mL) , brine (100 mL) , dried over sodium sulfate and evaporated under vacuum to give the title compound (3.5 g, 96%). MS (ESI) m/z: 338.1 (M+l); ¾ NMR (400 MHz, DMSO- d6) : δ 1.58 (d, J = 6.8 Hz, 3H) ; 3.82 (s, 3H) , 4.13 (s, 3H) , 5.40-5.44 (m, 1H) , 6.79 (d, J = 6.0 Hz, 1H) ; 7.16 (d, J = 6.0 Hz, 1H) , 7.55 (d, J= 8.4 Hz, 2H) ; 7.90-7.95 (m, 4H) , 8.07 (d, J = 5.2 Hz, 1H) .
[0316]
Step 3 : Methyl 4- [ (IS) -1- [ (8-hydroxy-2 , 7-naphthyridin-1- yl) amino] ethyl]benzoate
To a solution of methyl 4- [ (IS) -1- [ (8-methoxy-2, 7- naphthyridin-l-yl) amino] ethyl] benzoate (3.5 g, 10.38 mmol) in acetonitrile (35 mL) were added sodium iodide (1.55 g, 10.38 mmol) and chlorotrimethylsilane (1.32 mL, 10.38 mmol) . The resulting mixture was strirred at room temprature for 1 hour under argon atmosphere. The product formation was confirmed by TLC, then the reaction mixture was diluted with aqueous sodium bicarbonate (100 mL) and extracted with ethyl acetate (3 x 50 mL) . The combined organic layers were washed with water (100 mL) , brine (100 mL) , dried over sodium sulfate and evaporated under vacuum to give a crude product. The crude product was purified by combiflash column chromatography using 50-55% ethyl acetate in hexane as a mobile phase to give the title compound (2.5 g, 75%). MS (ESI) m/z: 324.1 (M+l) ; 1E NMR (400 MHz, DMSO-d6) : δ 1.49 (d, J = 7.2 Hz, 3H) ; 3.80 (s, 3H) , 5.32- 5.35 (m, 1H) , 6.34-6.36 (m, 1H) ; 6.54 (d, J = 5.2 Hz, 1H) , 7.27-7.30 (m, 1H) ; 7.48 (d, J = 8.4 Hz, 2H) , 7.89 (d, J = 8.0 Hz, 2H) , 7.92 (d, J = 5.6 Hz, 1H) , 9.82 (d, J = 7.6 Hz, 1H) , 11.51 (d, J = 5.2 Hz, 1H) .
[0317]
Step 4: Methyl 4- [ (IS) -1- [ [8- [ (3-fluorophenyl)methoxy] -2 , 7- naphthyridin-l-yl] amino] ethyl]benzoate
To a solution of methyl 4- [ (IS) -1- [ (8-hydroxy-2, 7- naphthyridin-l-yl) amino] ethyl] benzoate (0.25 g, 0.77 mmol) in tolune (10 mL) were added silver carbonate (0.42 g, 1.55 mmol). and 3-fluorobenzyl bromide (0.11 mL, 0.93 mmol). The resulting mixture was stirred and heated at 120°C for 16 hours, and the product formation was confirmed by TLC. The reaction mixture was cooled to room temperature, then filtetred on celite pad and washed with ethyl acetate (20 mL) . The organic layer was concentrated under vacuum, and the residue was purified by combiflash column chromatography using 10-15% ethyl acetate in hexane as a mobile phase to give the title compound (0.18 g, 54%). MS(ESI) m/z: 432.2 (M+l); XH NMR (400 MHz, CDC13): δ 1.41 (d, J= 6.4 Hz, 3H) ; 3.89 (s, 3H) , 5.39-5.44 (m, 1H) , 5.53 (s, 2H) , 6.63 (d, J = 5.6 Hz, 1H) ; 6.68 (d, J = 5.6 Hz, 1H) , 6.84-6.88 (m, 1H) , 7.03 (d, J = 6.0 Hz, 1H) ; 7.06-7.11 (m, 1H) , 7.20-7.23 (m, 1H) , 7.26-7.29 (m, 2H) , 7.34-7.37 (m, 1H) , 7.88-7.90 (m, 3H) , 7.96-8.03 (m, 1H) .
[0318]
The compounds of Examples C2 and C3 were synthesized in a similar manner to that of Example
[0319]
Table. 10
Figure imgf000143_0002
[0320]
Example Dl: 4- [ (IS) -1- [ [8- [3- (Trifluoromethyl)phenoxy] -1- isoquinolyl] amino] ethyl]benzoic acid
[0321]
Figure imgf000143_0001
[0322]
To a solution of methyl 4- [ (IS) -1- [ [8- [3- (trifluoromethyl) henoxy] -1-isoquinolyl] amino] ethyl] benzoate (110 mg, 0.23 mmol, Example Al) in mixture of solvent
THF:methanol :H20 (3:2:2, 7 mL) was added lithium hydroxide (49 mg, 1.13 mmol). The reaction mixture was stirred at room temperature overnight, and the product formation was confirmed by TLC. The mixture was concentrated in vacuum and neutralized with IN HC1. The solid thus obtained was collected by
filtration under vacuum and dried to give the title compound. MS(EI)m/z: 453.1 (M+l) ; lH NMR (400 MHz, DMSO-di) : δ 1.44 (d, J = 7.2Hz, 3H) ; 5.32-5.35 (m, 1H) ; 6.98-6.99 (d, J = 5.2Hz, 1H) ; 7.04 (dd, J = 1.6 & 7.2Hz, 1H) ; 7.30-7.36 (m, 3H) ; 7.57-7.70 (m, 6H) ; 7.76-7.80 (m, 3H) ; 12.80 (bs, 1H) .
Example D2 : 4- [1- [ [8- (4-Fluorophenoxy) -2 , 7-naphthyridin-l- yl] amino] cyclopropyl]benzoic acid
[0323]
Figure imgf000144_0001
[0324]
The Example D2 was performed in a similar manner to that of Example Dl using the compound mentioned in Example A2 (0.04 g, 0.09 mmol) to give the title compound (0.014 g, 36%).
MS(EI) m/z: 416.1 (M+ ) ; 1H NMR DMSO: δ 1.42-1.47 (m, 4H) ; 6.93
(d, J= 6.0 Hz, 1H) ; 7.29-7.33 (m, 5H) ; 7.38-7.42 (m, 2H) ;
7.80 (d, J = 8.4' Hz, 2H) ; 7.96 (d, J = 5.6 Hz, 1H) ; 8.04 (d, J = 5.6 Hz, 1H) ; 8.27 (s, 1H) ; 12.70 (bs, 1H) .
Example D3 : 4- [ [ [8- (3-Fluorophenoxy) -1- isoquinolyl] amino]methyl] benzoic acid
[0325]
Figure imgf000144_0002
[0326]
The Example D3 was performed in a similar manner to that of Example Dl using the compound mentioned in Example A3 (0.07 g, 0.017 mmol) to give the title compound (0.033 g, 51%).
MS (EI) m/z: 389.1 (M+l) ; XH NMR DMSO: δ 4.80 (d, J= 6.0 Hz, 2H) ; 6.86 (dd, J = 1.2 & 7.6Hz, 1H) ; 6.93 (d, J= 6.0 Hz, 2H) ; 7.10 (dd, J = 9.2 & 1.2 Hz, 2H) ; 7.31 (d, J= 8.4 Hz, 2H) ;
7.47-7.56 (m, 3H) ; 7.79 (d,. J = 8.4 Hz, 2H) ; 7.82 (d, J= 6.0 Hz, 1H) ; 7.94 (t, J= 5.6 Hz, 1H) ; 12.8 (bs, 1H) .
[0327]
Example D4 : 4- [ (IS) -1- [ [8- (4-Fluorophenoxy) -2 , 7-naphthyridin- 1-yl] amino] ethyl]benzoic acid
0328]
Figure imgf000145_0001
[0329]
To a solution of methyl 4- [ (IS) -1- [ [8- (4-fluorophenoxy) - 2 , 7-naphthyridin-l-yl] amino] ethyl] benzoate (0.2 g, 0.47 mmol, Example A4 ) in 8 mL of combined solvent THF:H20 (3:1) was added potassium hydroxide (0.053 g, 0.95 mmol). The reaction mixture was stirred at 80°C for 18 hours, and the product formation was confirmed by TLC. The mixture was concentrated in vacuum and neutralized with IN HC1. The solid thus obtained was collected by filtration under vacuum and dried to give the title
compound as a white solid (0.12 g, 62%). MS(EI)m/z: 404 (M+l); XH NMR DMSO: δ 1.55 (d, J= 7.2Hz, 3H) ; 5.46-5.47 (m, 1H) ; 6.88 (d, J= 5.6 Hz, 1H) ; 7.28 (d, J = 5.6 Hz, 1H) ; 7.30-7.34 (m, 2H) ; 7.40-7.43 (m, 2H) ; 7.55 (d, J= 8.0 Hz, 2H) ; 7.83.-7.88 (m, 3H) ; 7.96 (d, J = 5.6 Hz, 1H) ; 8.02 (d, J = 5.6 Hz, 1H) ; 12.85 (bs, 1H)
[0330]
The compounds of Examples D5-D92 were synthesized in a similar manner to that of Example Dl or D4.
[0331] Table 11
Figure imgf000146_0001
Figure imgf000147_0001
Figure imgf000148_0001
Figure imgf000149_0001
Figure imgf000150_0001
Figure imgf000151_0001
Figure imgf000152_0001
Figure imgf000153_0001
(m, 4H) , 7.07 (d, J = 7.2 Hz,
1H), 7.32-7.37 (m, 3H) , 7.47- 7.57 (m, 2H) , 7.65 (d, J = 6.8
Hz, 1H) , 7.76-7.80 (m, 3H) ,
12.80 (bs, 1H) .
4-[(lS)-l-[[8-(3- Methoxyphenoxy) -1- isoquinolyl] amino] ethyl] benzoi
c acid
¾ NMR OMSO-d6: δ 1.44 (d, J =
6.8 Hz, 3H) , 3.75 (s, 3H) ,
5.32-5.36 (m, 1H),' 6.61 (dd, J
D27 415.4
= 1.8, 7. Hz, 1H) , 6.76 (t, J
= 2.2 Hz, 1H) , 6.83 (dd, J =
2.4, 8.4 Hz, 1H) , 6.92 (d, J =
6.0 Hz, 1H) , 6.95 (d, J = 7.6
Hz, 1H), 7.32-7.38 (m, 3H) ,
7.50-7.60 (m, 3H) ,■ 7.76-7.79
(m, 3H) , 12.80 (bs, 1H) .
4- [1- [ [8- (3-Methylphenoxy) -1- isoquinolyl] amino] cyclopropyl]
benzoic acid
XH NMR DMSO-c¾: δ 1.20-1.26 (m,
2H) , 1.37-1.45 (m, 2H) , 2.32
(s, 3H) , 6.83 (d, J = 8.0 Hz,
1H) , 6.97 (d, J = 6.0 Hz, 2H) ,
D28 411.2
7.03 (s, 1H) , 7.07 (d, J = 7.6
0k ° Hz, 1H) , 7.20 (d, J = 8.0 Hz,
2H) , 7.35 (t, J = 8.0 Hz, 1H) ,
7.48-7.56 (m, 2H) , 7.75 (d, J
= 8.4 Hz, 2H) , 7.79 (d, J =
6.0 Hz, 1H) , 8.04 (s, 1H) ,
12.75 (bs, 1H) .
Figure imgf000155_0001
Figure imgf000156_0001
Figure imgf000157_0001
J = 8.4 Hz, 2H) , 12.80 (bs,
1H) .
4-[ (lS)-l-[[8-(2,4- Difluorophenoxy) -1- isoquinolyl] amino] ethyl] benzoi
c acid
λϋ NMR DMSO-ds:■ δ 1.44 (d, J =
6.8 Hz, 3H) , 5.32-5.35 (m,
D37 421.2
1H) , 6.90 (dd, J = 1.8, 8.2 .
°
F Hz, 2H) , 6.96 (d, <J = 6.0 Hz,
1H), 7.09-7.15 (m, 2H) , 7.31- 7.35 (m, 3H) , 7.59-7.62 (m,
2H), 7.78-7.80 (m, 3H) , 12.80
(bs, 1H) .
4-[ (lS)-l-[ [4-Chloro-8-[3- (trifluoromethyl) phenoxy] -1- isoquinolyl] amino] ethyl]benzoi
c acid
XH NMR DMSO-d6: δ 1.45 (d, J =
6.8 Hz, 3H) , 5.30 (q, J = 7.2
D38 487.1
Hz, 1H) , 7.15 (dd, J = 6.4 &
3.6 Hz, 1H) , 7.33 (d, J = 8.4
Hz, 2H) , 7.39 (d, J= 8.0 Hz,
1H), 7.62-7.71 (m, 4H) , 7.76- 7.81 (m, 4H) , 7.93 (s, 1H) ,
12.82 (bs, 1H) .
4- [ (IS) -1- [ [4-Chloro-8- (3- fluorophenoxy) -1- isoquinolyl] amino] ethyl] benzoi
c acid
D39 XH NMR DMSO-d6: δ 1.45 (d, J = 437.1
0s ■ 6.8 Hz, 3H) , 5.31 (q, J = 6.8
Hz, 1H) , 6.97 (dd, J = 8.4 &
2.0 Hz, 1H) , 7.09-7.17 (m,
3H) , 7.34 (d, J = 8.4 Hz, 2H) ,
Figure imgf000159_0001
1H) , 6.92-6.95 (m, 2H) , 7.38
(d, <J = 8.0 Hz, 2H) , 7.42- 7.62 (m, 5H) , 7.69 (dd, J =
5.6 & 3.2 Hz, 1H) , 7.78-7.80
(m, 3H) , 12.80 (bs, 1H) .
4-[ (lS)-l-[ [8-(3,4- Dichlorophenoxy) -1- isoquinolyl] amino] ethyl] benzoi
c acid
XH NMR .DMSO-d^: δ 1.45 (d, J =
6.8 Hz, 3H) , 5.32-5.35 (m,
1H) , 6.95 (d, J = 6.0 Hz, 1H) ,
D43 7.03 (dd, J = 1.6 & 7.2 Hz,
1H) , 7.08 (dd, J = 8.8 & 2.4
Figure imgf000160_0001
Hz, 1H) , 7.33 (d, J = 8.4 Hz,
2H) , 7.39 (d, J= 7.6 Hz, 1H) ,
7.52 (d, J = 2.8 Hz, 1H) ,
7.53-7.62 (m, 2H) , 7.69 (d, J
= 8.8 Hz, 1H) , 7.79 (d, J =
8.0 Hz, 3H) , 12.80 (bs, 1H) .
4- [ (IS) -1- [ [5-Chloro-8- [3- (trifluoromethyl) phenoxy] -1- isoquinolyl] amino] ethyl] benzoi
c acid
1H NMR DMSO-c : δ 1.44 (d, J =
6.8 Hz, 3H) , 5.35 (q, J = 6.8
487.1
D44 Hz, 1H) , 7.00 (d, J = 8.8 Hz,
1H) , 7.11 (d, J = 6.4 Hz, 1H) ,
7.30 (d, J = 8.4 Hz, 2H) , 7.40
(d, J = 9.2 Hz, 1H), 7.62-7.70
(m, 4H) , 7.75-7.80 (m, 3H) ,
7.96 (d, J = 5.6 Hz, 1H) ,
12.75 (bs, 1H) .
Figure imgf000161_0001
Figure imgf000162_0001
Figure imgf000163_0001
Figure imgf000164_0001
7.49-7.55 (m, 1H) , 7.73 (d,J =
6.8 Hz, 1H) , 7.97 (d, J = 5.2
Hz, 1H) , 8.05 (d, J = 5.6 Hz,
1H) , 12.23 (br. s, 1H) ) .
4-[ (lS)-l-[ [8-(3- Fluorophenoxy) -2, 6- naphthyridin-1- yl] amino] ethyl] benzoic acid
XH NMR (400 MHz, DMSO-di) : δ
1.45 (d, J = 6.8 Hz, 3H) ,
5.31-5.35 (m, 1H) , 6.99 (dd, J
D55 = 1.6, 8.0, 1.6 Hz, 1H) , 7.10- 404.0
0L, ° 7.20 (m, 3H) , 7.33 (d, J = 8.4
Hz, 2H) , 7.39 (d, J = 6.8 Hz,
1H) , 7.48-7.53 (m, 1H) , 7.79
(d, J = 8.4 Hz, 2H) , 8.00 (d,
J = 5.6 Hz, 1H) , 8.16 (s, 1H) ,
8.98 (s, 1H) , 12.80 (br s,
1H) .
4-[ (lS)-l-[ [8-(3- Chlorophenoxy) -2,7- naphthyridin-1- yl] amino] ethyl] benzoic acid
lti NMR DMSO-d6: δ 1.56 (d, J =
6.8 Hz, 3H) , 5.44-5.47 (m,
1H) , 6.89 (d, J = 6.0 Hz, 1H) ,
D56 H 7.30 (d, J = 5.6 Hz, 1H) , 420.1
7.35-7.41 (m, 2H) , 7.52 (d, J
= 8.0 Hz, 1H) , 7.55.-7.58 (m,
3H) , 7.79 (d, J = 6.8 Hz, 1H) ,
7.87 (d, J = 8.0 Hz, 2H) , 7.98
(d, J = 5.2 Hz, 1H) , 8.02 (d,
J = 5.2 Hz, 1H) , 12.85 (bs,
1H) .
D57 4-[ (lS)-l-[ [8-(3,5- 422.1
Figure imgf000166_0001
Figure imgf000167_0001
4- [ (IS) -1- [ [8- [2-Fluoro-3- (trifluoromethyl) phenoxy] -2, 7- naphthyridin-1- yl] amino] ethyl] benzoic acid
XH NMR DMSO-d6: δ 1.59 (d, J =
6.8 Hz, 3H) , 5.52-5.56 (m,
062 1H) , 6.92 (d, J = 5.6 Hz, 1H) , 472.0
7.35 (d, J = 6.0 Hz, 1H) ,
F
7.54-7.59 (m, 3H) , 7.75-7.78
(m, 1H) , 7.83-7.89 (m, 3H) ,
7.94-7.98 (m, 2H) , 8.05 (d, J
= 5.6 Hz, 1H) , 12.80 (br s,
1H) .
4-[ (lS)-l-[ [8- [4-Fluoro-3- (trifluoromethyl) phenoxy] -2,7- naphthyridin-1- yl] amino] ethyl] benzoic acid
XH NMR DMSO-d6: δ 1.57 (d, J =
7.2 Hz, 3H) , 5.45-5.49 (m,
1H) , 6.90 (d, J = 6.0 Hz, 1H) ,
D63 7.31 (d, J = 6.0 Hz, 1H) , 7.58 472.0
(d, J = 8.0 Hz, 2H) , 7.63-7.68
Figure imgf000168_0001
(m, 1H) , 7.78-7.81 (m, 2H) ,
7.88 (d, J = 8.4 Hz, 2H) , 7.91
(dd, J = 5.6 & 2.4 Hz, 1H) ,
7.97 (d, J = 5.6 Hz, 1H) , 8.02
(d, J = 5.2 Hz, 1H) , 12.80
(bs, 1H) .
4- [ (IS) -1- [ [8- [4-Fluoro-2- (trifluoromethyl) phenoxy] -2, 7- naphthyridin-1-
D64 yl] amino] ethyl] benzoic acid 472.0
1R NMR DMSO-d6: δ 1.52 (d, J =
Figure imgf000168_0002
7.2 Hz, 3H) , 5.45-5.49 (m,
1H), 6.92 (d, J = 5.2 Hz, 1H) ,
Figure imgf000169_0001
7.88 (d, J = 8 Hz, 2H) , 7.99
(d, J = 6 Hz, 1H) , 8.02 (d, J
= 5.2 Hz, 1H), 12.85 (bs, 1H) .
4- [ (IS) -1- [ [8- (2-Fluoro-4- methoxy-phenoxy) -2, 7- naphthyridin-1- yl] amino] ethyl] benzoic acid
1H NMR (400 MHz, DMSO-d6) : δ
1.57 (d, J = 6.8 Hz, 3H) , 3.81
(s, 3H) , 5.47-5.51 (m, 1H) ,
D67 6.87-6.90 (m, 2H) , 7.07 (dd, J 434.0
= 12.4, 2.8 Hz, 1H) , 7.30 (d,
Figure imgf000170_0001
J = 5.6 Hz, 1H) , 7.48 (t, J =
8.8 Hz, 1H) , 7.55 (d, J = 8
Hz, 2H) , 7.83-7.89 (m, 3H) ,
7.96 (d, J = 5.2 Hz 1H) , 8.03
(d, J = 5.6 Hz, 1H) , 12.85
(bs, 1H) .
4- [ (IS) -1- [ [8- (4-Fluoro-2- methoxy-phenoxy) -2, 7- naphthyridin-1- yl] amino] ethyl] benzoic acid
XH NMR (400 MHz, DMSO-d6) : δ
1.55 (d, J = 7.2 Hz, 3H) , 3.75
(s, 3H) , 5.48-5.51 (m, 1H) ,
D68 6.85-6.90 (m, 2H) , 7.15 (dd, J 434.0
= 10.8, 3.2 Hz, 1H) , 7.25 (d,
F J = 5.2 Hz, 1H) , 7.44- 7.48
(m, 1H) , 7.54 (d, J = 8 Hz,
2H) , 7.89 (d, J = 8.4 Hz, 2H) ,
7.95 (d, J = 6 Hz, 2H) , 8.01
(d, J = 5.2 Hz, 1H) , 12.85
(bs, 1H) .
Figure imgf000171_0001
Figure imgf000172_0001
Figure imgf000173_0001
1H) , 6.92 (d, J = 5.6 Hz, 1H) ,
7.32-7.35 (m, 2H) , 7.44 (dd, J
= 8.0 & 2.0 Hz, 1H) , 7.51 (br
s, 1H) , 7.57 (d, J = 8.0 Hz,
2H) , 7.60-7.65 (m, 1H) , 7.87
(d, J= 8.0 Hz, 2H) , 7.99-8.02
(m, 2H) , 12.80 (b s, 1H) .
4-[ (lS)-l-[ [8-[4-
(Trifluoromethoxy) phenoxy] -
2, 7-naphthyridin-l- yl] amino] ethyl] benzoic acid
1H NMR DMSO-d6: δ 1.58 (d, J=
6.4 Hz, 3H) , 5.45-5.48 (m,
D77 470.1
1H) , 6.92 (d, J = 6.0 Hz, 1H) ,
7.33 (d, J = 5.6 Hz, 1H) , 7.52
F
(s, 4H) , 7.57 (d, J = 8.0 Hz,
2H) , 7.88 (d, J = 8.8 Hz, 2H) ,
7.99-8.02 (m, 2H) , 12.82 (bs,
1H).
4- [1- [ [8- (3-Fluorophenoxy) - 2, 7-naphthyridin-l- yl] amino] propyl] benzoic acid
XH NMR DMSO-d6: 5.0.90 (t, J =
6.8 Hz, 3H) , 1.90 (d, J = 6.8
Hz, 2H) ,5.25-5.29 (m, 1H) ,
6.88 (d, J = 6 Hz, 1H) , 7.19
D78 (td, J = 8.4, 2.8 Hz, 1H) , 418.0
7.24 (dd, J = 8.2 & 2.2 Hz,
1H), 7.30 (d, J = 5.2 Hz, 1H) ,
7.38 (dt, J = 10.4 & 2.0 Hz,
1H), 7.52-7.58 (m, 3H) , 7.84-
7.89 (m, 3H) , 7.98 (d, J = 3.6
Hz, 1H) , 8.00 (d, J = 3.6 Hz,
1H) , 12.70 (bs, 1H) .
Figure imgf000175_0001
Figure imgf000176_0001
Figure imgf000177_0001
Figure imgf000178_0001
Figure imgf000179_0001
Figure imgf000180_0001
[0332]
Example El: 4- [ (IS) -1- [ [8- (3-Fluorophenoxy) -2 , 7-naphthyridin- 1-yl] amino] ethyl]benzamide
Figure imgf000180_0002
[0334]
To a solution of 4- [ (IS) -1- [ [8- (3-fluorophenoxy) -2, 7- naphthyridin-l-yl] amino] ethyl] benzoic acid (0.5 g, 1.24 mmol, Example D45) in THF (10 ml) were added triethylamine (0.25 g, 2.48 mmol) and ethyl chloroformate (0.13 ml, 1.364 mmol) at 0 °C under argon atmosphere. After 15 min stirring at 0°C, 7N ammonia solution (10 ml) in dioxane was added thereto, and the mixture was stirred for 1 hr. The reaction mixture was concentrated under vacuum, and the obtained residue was purified by silica gel (100-200) column chromatography with 35% ethyl acetate : hexane to give title compound as white solid (430 mg,86%). MS(ESI)m/z: 403.1 (M+l) ; XH NMR (400 MHz, DMSO- d6) : δ 1.55 (d, J = 6.8 Hz, 3H) , 5.41-5.47 (m, 1H) , 6.89 (d, J = 5.6 Hz, 1H), 7.15-7.39 (m, 5H) , 7.48-7.56 (m, 3H) , 7.77-7.82 (m, 3H) , 7.89 (bs, 1H) , 7.98 (d, J = 6.0 Hz, 1H) , 8.02 (d, J = 5.6 Hz, 1H) .
[0335]
The compounds of Examples E2-E5 were synthesized in a similar manner to that of Example El.
[0336]
Table 12
Figure imgf000181_0001
Figure imgf000182_0001
Hz, 1H) , 7.34-7.40 (m,
4H), 7.41-7.45 (m, 2H) ,
7.50-7.56 (m, 3H) , 7.67
(d, J = 8.4 Hz, 2H) , 7.77
(d, J = 6.8 Hz, 1H) , 7.98
(d, J = 5.6 Hz, 1H) , 8.02
(d, J = 5.2 Hz, 1H) ,
11.65 (bs, 1H) .
[0337]
Example Fl: 4- [ (IS) -1- [ [8- (3-Fl orophenoxy) -2 , 7-naphthyridin- 1-yl] amino] ethyl] -N-methylsulfonyl-benzamide
0338]
Figure imgf000183_0001
[0339]
To a mixture of 4- [ (IS) -1- [ [8- (3-fluorophenoxy) -2, 7- naphthyridin-l-yl] amino] ethyl] benzoic acid (0.25 g, 0.62 mmol, Example D45) , triethylamine (0.3 ml, 1.861 mmol),
methanesulfonamide (0.176 g, 1.861 mmol) and 4-N,N- dimethylaminopyridine (0.015 g, 0.124 mmol) in acetonitrile (10 ml) was added 2-methyl-6-nitrobenzoic anhydride (0.256 g, 0.74 mmol) at 0°C under argon atmosphere. After 15 min
stirring at 0°C, the mixture was allowed to stirred at room temperature for 3 hr. Water was added thereto, and the mixture was extracted with ethyl acetate (3 x 20 mL) . The combined organic layers were washed with water (20 mL) , brine (20 mL) and dried over sodium sulfate. The organic layer was
concentrated under vacuum, and the residue was purified by silica gel (100-200) column chromatography with 20-30% ethyl acetate in hexane as a mobile phase to give the title compound as light yellow solid (0.025 g, 8.5%). MS(ESI)m/z: 481.2 (M+l); XH NMR (400 MHz, DMSO-d ) : δ 1.56 (d, J= 6.8 Hz, 3H) , 2.90 (s, 3H) , 5.41-5.47 (m, 1H) , 6.80 (bs, 2H) , 6.89 (d, J = 5.6 Hz, 1H) , 7.15-7.24 (m, 2H) , 7.31 (d, 1H) , 7.34-7.39 (m, ■1H) , 7.48-7.58 (m, 3H) , 7.79 (d, J=6.4 Hz, 1H) , 7.88 (d, J = 8.4 Hz, 2H) , 7.98 (d, J = 5.6 Hz, 1H) , 8.01 (d, J = 5.6 Hz, 1H) .
[0340]
Example Gl : 4- [1- [ [8- (3-Fluorophenoxy) -2 , 7-naphthyridin-l- yl] amino] ethyl]benzenesulfonamide
[0341]
Figure imgf000184_0001
[0342]
The Example Gl was performed in analogous manner to that of Example Al using l-chloro-8- ( 3-fluorophenoxy) -2 , 7- naphthyridine (0.1 g, 0.37 mmol, Preparation 28) and 4-(l- aminoethyl) enzenesulfonamide (0.087 g, 0.44 mmol; Preparation 76) to give the title compound (0.021 g, 13%). MS (ESI) m/z: 439.0 (M+l); XH NMR DMSO-d6: δ 1.56 (d, J = 6.8 Hz, 3H) , 5.41- 5.42 (m, 1H) , 6.89 (d, J = 6 Hz, 1H) , 7.17-7.27 (m, 4 H) , 7.31(d, J = 6 Hz, 1H) , 7.38 (dt, J = 10.4, 2.1 Hz, 1H) , 7.51- 7.57 (m, 1H) , 7.62 (d, J= 8 Hz, 2H),7.75 (d, J = 8.4 Hz, 2H) , 7.79 (d, J = 2.8 Hz, 1H) , 7.99 (d, J = 6 Hz, 1H) , 8.01 (d, J = 6 Hz, 1H)
[0343]
Example HI : 4- [ (IS) -1- [ [8- (3-Fluorophenoxy) -2 , 7-naphthyridin- 1-yl] amino] ethyl]benzonitrile
[0344]
Figure imgf000184_0002
[0345]
solution of 4- [ (IS) -1- [ [8- (3-fluorophenoxy) naphthyridin-l-yl] amino] ethyl] benzamide (0.4 g^ift 0.995 mmol, Example El) in pyridine (10 ml) were added immidazole (0.135 g, 1.99 mmol) and phosphorus oxychloride (0.61 g, 3.98 mmol) at - 20°C under argon atmosphere. The mixture was stirred for 1 hrs at -20°C. Water was added thereto, and the mixture was
extracted with ethyl acetate (3 x 20 mL) . The combined organic layers were washed with water (20 mL) , brine (20 mL) and dried over sodium sulfate. The organic layer was concentrated under vacuum, and the residue was purified by silica gel (100-200) column chromatography with 20-30% ethyl acetate in hexane as a mobile phase to give the title compound as light yellow solid (0.33 g, 86%) . MS(ESI)m/z: 385.1 (M+l) ; XH NMR (400 MHz,
CDC13) : δ 1.60 (d, J = 6.8 Hz, 3H) , 5.47-5.52 (m, 1H) , 6.76 (d, J = 5.6 Hz, 1H) , 7.00-7.06 (m, 3H) , 7.11 (d, J = 5.2 Hz, 1H) , 7.41-7.49 (m, 1H) , 7.51 (d, J = 8.4 Hz, 2H) , 7.60 (d, j = 8.8 Hz, 2H) , 7.68 (d, J = 6.4 Hz, 1H) , 7.96 (d, J = 5.6 Hz, 1H) , 8.02 (d, J = 5.6 Hz, 1H) .
[0346]
Example II: 2 , 2 , 2-Trifluoro-1- [4- [ (IS) -1- [ [8- (3- fluorophenoxy) -2 , 7-naphthyridin-l- yl] amino] ethyl]phenyl] ethanol
[0347]
Figure imgf000185_0001
[0348]
Step 1: [4- [ (IS) -1- [ [8- (3-Fluorophenoxy) -2 , 7-naphthyridin-l- yl] amino] ethy ]phenyl]methanol
To a solution of methyl 4- [ (IS) -1- [ [8- (3-fluorophenoxy) - 2, 7-naphthyridin-l-yl] amino] ethyl ] benzoate (1.0 g, 2.39 mmol, Example A45) in THF (10 ml) was added lithium aluminium
hydride (2.4 ml, 2.39 mmol) (1.0 M slution in THF) at 0°C under nitrogen. The reaction mixture was stirred at room temperature for 1 hour and the product formation was confirmed by TLC. The mixture was quenched by aq. sodium sulfate solution, and the obtained solid was removed by filtration, and the filtrate was concentrated to dryness to give the title compound (0.8 g, 86%). MS(EI)m/z: 390.1 (M+l) ; 1H NMR (400 MHz, , CDC13) : δ 1.61 (d, J = 7.2 Hz, 3H), 4.66 (d, J = 4.4 Hz, 2H) , 5.51-5.55 (m, 1H) , 6.73 (d, J = 5.6 Hz, 1H) , 6.98-7.05 (m, 3H) , 7.09 (d, J = 6.0 Hz, 1H) , 7.32 (d, J = 8.4 Hz, 2H) , 7.41 (d, J = 8.0 Hz, 2H) , 7.73 (d, J = 6.8 Hz, 1H) , 7.94 (d, J= 6.0 Hz, 1H) , 8.09 (d, J = 6.0 Hz, 1H) .
[0349]
Step 2 : 4- [ (IS) -1- [ [8- (3-Fluorophenoxy) -2 , 7-naphthyridin-l- yl] amino] ethyl]benzaldehyde
To a solution of [4- [ (IS) -1- [ [8- (3-fluorophenoxy) -2, 7- naphthyridin-l-yl] amino] ethyl] phenyl] methanol (0.6 g, 1.54 mmol) in DCM (20 ml) was added Desmartine periodinane (0.98 g, 2.31 mmol) at 0°C under nitrogen. The reaction mixture was stirred at room temperature for 1 hour and the product
formation was confirmed by TLC. Then water (25 mL) was added thereto, and the mixture was extracted with dichloromethane (2 x 25 mL) . The combined organic layers were washed with brine and dried over sodium sulfate. The organic layer was
concentrated under vacuo to give the title compound (0.5 g., 84%) as a crude product, which was used in the next step
without further purification. MS(EI)m/z: 388.2 (M+l); XH NMR (400 MHz, , CDCI3) : δ 1.63 (d, J = 6.8 Hz, 3H) , 5.53-5.57 (m, 1H) , 6.76 (d, J= 5.6 Hz, 1H) , 7.02-7.07 (m, 3H) , 7.11 (d, J = 5.2 Hz, 1H) , 7.42-7.46 (m, 1H) , 7.58 (d, J = 8.4 Hz, 2H) , 7.73 (d, J = 6.4 Hz, 1H) , 7.84 (d, J = 7.6 Hz, 2H) , 7.97 (d, J =
5.2 Hz, 1H) , 8.05 (d, J = 5.6 Hz, 1H) , 9.98 (s, 1H) .
[0350]
Step 3: 2,2,2-Trifluoro-l-[4-[(lS)-l-[[8-(3-fluorophenoxy)- 2 , 7-naphthyridin-l-yl] amino] ethyl]phenyl] ethanol
To a solution of 4- [ (IS) -1- [ [8- (3-fluorophenoxy) -2, 7- naphthyridin-l-yl] amino] ethyl] benzaldehyde (0.1 g, 1.54 mmol) in DMF (5 ml) were added dropwise potassium carbonate (0.1 g, 0.77 mmol) and trifluoromethyltrimethylsilane (2.0 M solution in THF) (1.3 mL, 2.58 mmol) at 0°C under nitrogen. The
reaction mixture was stirred at room temperature for 1 hour and the product formation was confirmed by TLC. Then water (25 mL) was added thereto, and the mixture was extracted with ethyl acetate (2 x 15 mL) . The combined organic layers were washed with brine and dried over sodium sulfate. The organic layer was concentrated under vacuo, and the obtained crude material was purified by combiflash column chromatography using 5-10% ethyl acetate in hexane as a mobile phase to give the title compound (0.04 g, 34%). MS(EI)m/z: 458.3 (M+l) XH
NMR DMSO-d6: δ 1.25 (d, J = 6.8 Hz, 3H) , 5.09 (bs, 1H) , 5.55 (d, J = 6.8 Hz, 1H) , 6.01 (d, J = 7.6 Hz, 1H) , 6.08 (d, J = 12. A Hz, 1H) , 6.36-6.38 (m, 1H) , 6.53 (d, J = 7.2 Hz, 1H) , 6.73 (t, J = 5.2 Hz, 1H) , 6.88-6.94 (m, 1H) , 7.37 (t, J = 6.8 Hz, 1H) , 7.43 (d, J = 7.6 Hz, 2H) , 7.52 (d, J = 5.2 Hz, 1H) , 7.80 (d, J = 7.6 Hz, 2H) , 8.62 (d, J= 5.6 Hz, 1H) , 11.20 (d, J = 4.8 Hz, 1H) .
[0351],
Example 12: 1 , 1,1 ,3,3, 3-Hexafluoro-2- [4- [ (IS) -1- [ [8- (3- fluorophenoxy) -2 , 7-naphthyridin-l- yl] amino] ethyl]phenyl]propan-2-ol
[0352]
Figure imgf000187_0001
[0353]
Step 1: 2,2,2-Trifluoro-l- [4- [ (IS) -l-[ [8- (3-fluorophenoxy)
2 , 7-naphthyridin-l-yl] amino] ethyl]phenyl] ethanone
To a solution of 2, 2, 2-trifluoro-1- [4- [ (IS) -1- [ [8- (3 fluorophenoxy) -2, 7-naphthyridin-l- yl] amino] ethyl] phenyl] ethanol (0.3 g, 0.65 mmol, Example II) in DCM (15 mL) was added Desmartine periodinane (0.42 g, 0.98 mmol) at 0°C under nitrogen. The reaction mixture was stirred at room temperature for 1 hour and the product formation was confirmed by TLC. Then water (25 mL) was added thereto, and the mixture was extracted with dichloromethane (2 x 25 mL) .
The combined organic layers were washed with brine and dried over sodium sulfate. The organic layer was concentrated under vacuo, and the obtained crude material was purified by
combiflash column chromatography using 5-10% ethyl acetate in hexane as a mobile phase to give the title compound (0.1 g, 33%). MS(EI)m/z: 456.2 (M+l) XH NMR DMSO-d6: δ 1.28 (d, J =
6.8 Hz, -3H), 5.65-5.67 (m, 1H) , 6.03 (d, J = 8.0 Hz, 1H) , 6.11 (d, J= 13.2 Hz, 1H), 6.39-6.42 (m, 1H) , 6.54-6.56 (m, 1H) ,
6.90-6.95 (m, 1H) , 7.38-7.43 (m, 1H) , 7.55 (d, J = 5.2 Hz, 1H) , 8.03 (d, J = 8.1 Hz, 2H), 8.11 (d, J = 8.0 Hz, 2H) , 8.63 (d J = 5.2 Hz, 1H) , 11.20 (d, J = 4.8 Hz, 1H) .
[0354]
Step 2: 1,1,1,3,3, 3-Hexafluoro-2- [4- [ (IS) -1- [ [8- (3- fluorophenoxy) -2 , 7-naphthyridin-l- yl] amino] ethyl]phenyl]propan-2-ol
To a solution of 2, 2, 2-trifluoro-1- [4- [ (IS) -1- [ [8- (3- fluorophenoxy) -2, 7-naphthyridin-l- yl] amino] ethyl] phenyl] ethanone (0.1 g, 0.22 mmol) in DMF (10 mL) were added dropwise potassium carbonate (0.09 g, 0.66 mmol) and trifluoromethyltrimethylsilane (2.0 M solution in THF) (1.1 mL, 2.19 mmol) at 0°C under nitrogen. The reaction mixture was stirred at room temperature for 16 hour and the product formation was confirmed by TLC. Then water (25 mL) was added thereto, and the mixture was extracted with ethyl
acetate (2 x 15 mL) . The combined organic layers were washed with brine and dried over sodium sulfate. The organic layer was concentrated under vacuo and the obtained crude material was purified by LCMS purification method using ACN: formic acid and water as a mobile phase to give the title compound (0.011 g, 10%). MS(EI)m/z: 526.2 (M+l) ¾ NMR DMSO-d6: δ 1.27 (d, J= 6.4 Hz, 3H) , 5.63 (d, J = 6.8 Hz, 1H) , 6.01 (d, J = 7.6 Hz, 1H) , 6.04 (d, J = 8.4 Hz, 1H) , 6.09 (d, J = 12.0 Hz, 1H) ,
6.37-6.41 (m, 1H) , 6.53 (d, J = 6.8 Hz, 1H) , 6.90-6.96 (m, 1H) , 7.37 (t, J= 6.0 Hz, 1H) , 7.51 (d, J= 5.6 Hz, 1H) , 7.62 (d, J = 8.4 Hz, 2H) , 7.91 (d, J = 8.4 Hz, 2H) , 8.61 (d, J = 6.0 Hz, 1H) , 11.20 (bs, 1H) .
[0355]
Example Jl : 1- [4- [ (IS) -1- [ [8- (3-Fluorophenoxy) -2 , 7- naph hyridin-l-yl] amino] ethyl]phenyl] ethane-1 , 2-diol
[0356]
Figure imgf000189_0001
[0357]
To a mixture of 8- ( 3-fluorophenoxy) -N- [ (IS) -1- (4- vinylphenyl) ethyl] -2, 7-naphthyridin-l-amine (0.11 g, 0.28 mmol, Example A86) in acetone : hexane (10:1) (11 mL) were added
dropwise N-methylmorpholine N-oxide (0.15 g, 1.26 mmol) and osmium tetroxide (0.2 mL) (1.0 g, in 10 mL) , and the mixture was stirred at room temperature for 1 hour and the product formation was confirmed by TLC. To the reaction mixture was added water (10 mL) , and the mixture was extracted with ethyl acetate (3 x 10 mL) . The combined organic layers were washed with water (25 mL) , brine (20 mL) and dried over sodium
sulfate. The organic layer was concentrated under vacuum, and the residue was purified by combiflash column chromatography using 25-30% ethyl acetate in hexane as a mobile phase to give the title compound (0.03 g., 27%). MS(ESI)m/z: 420.1 (M+l); ¾ NMR DMSO-d6: δ 1.52 (d, J= 6.8 Hz, 3H) , 3.85 (t, J = 6.8 Hz, 2H) , 5.47-5.49 (m, 1H) , 4.65 (t, J = 5.6 Hz, 1H) , 5.13 (t, J = 4.4 Hz,. 1H) , 5.39-5.43 (m, 1H) , 6.88 (d, J = 5.6 Hz, 1H) ,
7.15-7.21 (m, 2H) , 7.26 (d, J = 8.0 Hz, 2H) , 7.30 (d, J = 5.2 Hz, 1H), 7.33 (bs, 1H) , 7.37 (d, J = 8.0 Hz, 2H) , 7.49-7.54 (m, 1H) , 7.74 (d, J = 7.2 Hz, 1H) , 7.97 (d, J = 5.2 Hz, 1H) , 8.06 (d, J = 5.2 Hz, 1H) .
[0358]
The following compounds as shown in Table 13 can also be prepared according to Schemes 1-11 or in the same manner as in the above-mentioned Examples.
[0359]
Table 13
Structure IUPAC NAME
4- [1- [ [3-fluoro-8- ( 3-fluorophenoxy) -1- isoquinolyl] amino] cyclopropyl] benzoic acid
4- [ (IS) -1- [ [3-cyano-8- ( 3-fluorophenoxy) -1- isoquinolyl] amino] ethyl] benzoic acid
4- [ (IS) -1- [ [3-chloro-8- ( 3-fluorophenoxy) -1- isoquinolyl] amino] ethyl] benzoic acid
4- [ (IS) -1- [ [3-bromo-8- (3-fluorophenoxy) -1- isoquinolyl] amino] ethyl ] benzoic acid
4- [ (IS) -1- [ [8- (3-fluorophenoxy) -3-methyl-l- isoquinolyl] amino] ethyl] benzoic acid
Figure imgf000190_0001
4- [ (IS) -1- [ [8- (3-fluorophenoxy) -3-methoxy-l- isoquinolyl] amino] ethyl] benzoic acid cX 0
Figure imgf000191_0001
4- [ (IS) -1- [ [3-bromo-8- ( 3-fluorophenoxy) -2,7- naphthyridin-l-yl] amino] ethyl] enzoic acid
Figure imgf000192_0001
4- [ (IS) -1- [ [8- (3-fluorophenoxy) -3-methyl-2, 7- naphthyridin-l-yl] amino] ethyl] benzoic acid
4- [ (IS) -1- [ [8- (3-fluorophenoxy) -3-methoxy- 2, 7-naphthyridin-l-yl ] amino] ethyl] benzoic acid
4- [ (IS) -1- [ [3-methoxy-8- [3-
(trifluoromethyl) phenoxy] -2, 7-naphthyridin-l- yl] amino] ethyl] benzoic acid
4- [ (IS) -1- [ [3-cyclopropyl-8- (3- fluorophenoxy) -2, 7-naphthyridin-l- yl] amino] ethyl] benzoic acid
4- [1- [ [8- (3-fluorophenoxy) -3-methyl-2 , 7- naphthyridin-l-yl] amino] cyclopropyl] benzoic acid
4- [ (IS) -1- [ [4-fluoro-8- [3-
(trifluoromethyl) phenoxy] -2, 7-naphthyridin-l- yl ] amino] ethyl ] benzoic acid
4- [1- [ [5-cyano-8- ( 3-fluorophenoxy) -2, 7- naphthyridin-l-yl] amino] cyclopropyl] benzoic acid
Figure imgf000193_0001
Figure imgf000194_0001
methylpropanoic acid
2- [4- [1- [ [8- (4-fluorophenoxy) -1- isoquinolyl] amino] cyclopropyl] phenyl] -2- methylpropanoic acid
Figure imgf000195_0001
1- [4- [ (IS) -1- [ [8- (4-fluorophenoxy) -1- isoquinolyl] amino] ethyl] phenyl] cyclopropaneca rboxylic acid
1- [4- [1- [ [8- (4-fluorophenoxy) -1- isoquinolyl] amino] cyclopropyl] phenyl] cyclopro panecarboxylic acid
5- [ (IS) -1- [ [8- [3- (trifluoromethoxy) phenoxy] - 1-isoquinolyl] amino] ethyl ] pyridine-2- carboxylic acid
Figure imgf000195_0002
6- [1- [ [8- (3-fluorophenoxy) -1- isoquinolyl] amino] cyclopropyl] pyridine-3- carboxylic acid
4- [1- [ [8- [3- (trifluoromethoxy) phenoxy] -1- isoquinolyl] amino] cyclopropyl] bicyclo [2.2.2] o ctane-l-carboxylic acid
Figure imgf000195_0003
2-isopropyl-4- [1- [ [8- (4-methoxyphenoxy) -1- isoquinolyl] amino] cyclopropyl] benzoic acid
4- [ (IS) -1- [ [8- [ (4-chlorophenoxy) methyl] -1- isoquinolyl] amino] ethyl] benzoic acid
4- [1- [ [8- [ (4-chlorophenyl)methyl] -1- isoquinolyl] amino] cyclopropyl] benzoic acid
4- [ (IS) -1- [ [8- [ (3-cyanophenyl)methoxy] -1- isoquinolyl] amino] ethyl] benzoic acid
Figure imgf000197_0001
4- [ (IS) -1- [ [8- [3- (3-methylphenoxy) azetidin-1- yl] -2, 7-naphthyridin-l-yl] amino] ethyl] benzoic acid
4- [ (IS) -1- [ [8- [1- (3-fluorophenyl) azetidin-3- yl] oxy-l-isoquinolyl] amino] ethyl ] benzoic acid
4-[l-[[8-(3- (isoxazol-3-yl) phenoxy) -1- isoquinolyl] amino] cyclopropyl] benzoic acid
Figure imgf000198_0001
Figure imgf000199_0001
Figure imgf000200_0001
Figure imgf000201_0001
[0360]
Formulation Example 1 (production of capsule)
1) compound of Example 1 30 mg 2) fine powder cellulose 10 mg
3) lactose 19 mg
4) magnesium stearate 1 mg
Total 60 mg
1), 2), 3) and 4) are mixed and filled in a gelatin capsule.
[0361]
Formulation Example 2 (production of tablet)
1) compound of Example 1 30 g
2) lactose 50 g 3) cornstarch 15 g
4) calcium carboxymethylcellulose 44- g
5) magnesium stearate 1 g
1000 tablets total 140 g
The total amount of 1), 2) and 3) and 4) (30 g) is kneaded with water, vacuum dried, and sieved. The sieved powder is mixed with 4) (14 g) and 5) (1 g), and the mixture is punched by a tableting machine, whereby 1000 tablets
containing 30 mg of the compound of Example 1 per tablet are obtained.
[0362]
Experimental Example 1
Membrane preparation:
The full-length coding sequences for human EP1
(NM_000955), human EP2 (ΝΜ_00095β) , human EP3 (NM_198717) and human EP4 (NM_000958) were cloned into pcDNA3.1(+) vector
(Life Technologies, CA, USA) . In order to prepare
overexpressed EP 1-4 membrane in Freestyle293 cells (Life
Technologies, CA, USA), the pcDNA3.1(+) vector encoding a cDNA of the relevant gene was transiently transfected into
FreeStyle293 cells using 293Fectin (Life Technologies, CA,
USA) according to the manufacturer instruction manual. After .2 days, cultured cells were centrifuged (1,000 * g, 10 min, 4°C) and pellets homogenized by a probe sonicator (Sonics vibracell, Sonics and Materials Inc., USA; 31% Amp, 5sec pulse, lmin interval, 4 cycles) in ice-cold 50 mM Tris-HCl buffer (pH 7.5 at 25°C) containing 0.5 mM EDTA, 250 mM Sucrose and 10 mM MgCl2. Cell homogenates were centrifuged (890 χ g, 10 min, 4°C) , and the supernatant was recovered. Total membrane fractions were isolated by ultracentrifugation (140, 000 χ g, 60 min, 4°C) .
Pellets were re-suspended in the same buffer, and stored at - 80°C until use. The protein concentration in homogenate was determined with the BCA Protein Assay Kit (Pierce
Biotechnology, Inc., IL, USA) according to the manufacturer protocol.
[0363]
Primary in vitro binding assay:
The binding affinity of the compounds was evaluated using a competitive radioligand binding assay which measured the specific binding of [3H] PGE2 to the human EP4 receptor.
Briefly, varying concentrations of NCEs were incubated with cell membrane fractions generated HEK293F cells transiently transfected with human EP4 receptor as described above. Each reaction consisted of 10 pg membrane protein and NCE in 50 mM Tris.Hcl, pH-6.0 by NaOH, 10 mM MgCl2 and 0.5 mM EDTA assay buffer. Radioligand, [3H] PGE2 (American Radiochemicals Inc. Specific Activity 180 Ci/mmol) , at a final of 1 nM was added to each reaction where the final assay volume was 200 μ] and concentration of DMSO was adjusted to 1%. Appropriate controls included total binding in the assay (vehicle control) and control for non-specific binding. Non-specific binding was evaluated by incubating the hEP4 protein with 10 μΜ unlabeled PGE2 under the same assay conditions as NCEs. The reaction was incubated at room temperature for 2 hours and terminated by harvesting the reaction contents to a PEI coated GF/C filter plate ( PerkinElmer) . The plate was washed four times with cold 50mM Tris-HCl, pH-7.5 wash buffer and dried at 50°C for 2 hours or at 37°C overnight. [3H] PGE2 bound to the protein was quantified by the addition of 25 pL of Microscint PS
(PerkinElmer) and plate was read on MicroBeta2 liquid
Scintillation and luminescence counter (PerkinElmer) . Data was analyzed using GraphPad Prism 5 (GraphPad Software Inc., San Diego, CA) where non-specific binding was normalized to 0% specific binding of [3JPGE2 and vehicle control (DMSO) was normalized to 100% specific binding of [3]PGE2. Binding affinity of NCEs, Ki, was generated using One site - Fit Ki equation in GraphPad Prism 5.
[0364]
Functional Assay :
The functional assay for hEP4 activation and inhibition was carried out via the quantitative determination of agonist, PGE2, induced cAMP response using HTRF in a competitive immunoassay (Cisbio dynamic 2 kit) . NCEs at varying
concentrations were evaluated for inhibition of PGE2 induced increase in cAMP. Briefly, C6 glioma cells overexpressing hEP4 (Takeda) were cultured in DMEM (low glucose, pyruvate) , 10% FBS (Gibco) and PenStep. The cells were harvested on the day of the assay, washed with HBSS + 10 mM HEPES (pH 7.4) + 0.1% BSA buffer and pre-incubated with varying concentrations of NCE. Each reaction contained 7000 cells and NCEs in HBSS + 10 mM HEPES + 0.1% BSA assay buffer along with PDE inhibitors
IBMX and Ro 20-1724 (final concentration of each inhibitor 200 mM) . Following 15 min pre-incubation, the cells were treated with EC80 concentration of agonist PGE2 for 30 min to induce cAMP. Final volume of the assay was 6 L and DMSO
concentration was maintained at 1%. The reaction was
terminated with the addition of cAMP labeled with the dye d2 in lysis buffer according to manufacturers' protocol. This was followed by the addition Of the anti-cAMP antibody labeled with Cryptate according to the manufacturers' protocol. The reaction was incubated at room temperature in dark for 45 min and the plate was evaluated for fluorescence at 665 nm (FRET) and 620 nm (cryptate emission) on a Flexstation III microplate reader (Molecular Devices, Sunnyvale, CA) Ex max: 313 nm; Eml : 620 nm ; Em2 : 665 nm. Data was analyzed using GraphPad Prism 5 (GraphPad Software Inc., San Diego, CA) where cells treated with agonist (EC8o) was normalized to 0% inhibition of hEP4 and cells treated with buffer (no agonist) was normalized to 100% inhibition of hEP4. IC50 of NCEs was generated using nonlinear regression - Log ( inhibitor) vs. response equation in GraphPad Prism 5.
[0365]
Table 14: Potency of compound in hEP4 radioligand binding assay and cell based assay (cAMP) at 1 μΜ
% Inhibition at 1 uM*
Compound hEP4 radioligand hEP4 cell based
binding assay assay (cAMP)
Example Dl 99 94
Example D2 67 NA
Example D3 79 NA
Example D4 92 78 Example D5 93 85
Example D6 52 62
Example D7 17 49
Example D8 94 88
Example D9 99 93
Example D10 100 95
Example Dll 86 NA
Example D12 97 65
Example D13 98 84
Example D14 100 101
Example D15 91 l44
Example D16 80 NA
Example D17 83 NA
Example D18 31 NA
Example D19 94 NA
Example D20 92 NA
Example D21 54 NA
Example D22 39 NA
Example D23 97 NA
Example D26 95 101
Example D27 98 110
Example D28 92 NA
Example D29 36 NA
Example D30 93 60
Example D31 87 83
Example D32 100 NA
Example D33 103 95
Example D34 104 92
Example D35 101 . 86
Example D36 98 76
Example D37 99 86
Example D38 NA 103
Example D39 NA 86
Example D40 97 94 Example D41 96 93
Example D42 100 103
Example D 3 96 84
Example D44 77 89
Example D45 99 94
Example D46 83 93
Example D47 NA 83
Example D48 93 102
Example D49 83 89
Example D50 97 106
Example D51 98 99
Example D52 91 97
Example D53 100 98
Example D54 83 60
Example D55 90 55
Example D56 94 91
Example D57 95 91
Example D58 95 92
Example D59 92 86
Example D60 96 89
Example D61 94 91
Example D62 98 90
Example D63 96 82
Example D64 90 at 3 μΜ 83
- Example D65 97 86
Example D66 50 at 3 μΜ 8
Example D67 91 46
Example D68 91 57
Example D69 92 93
Example D70 91 at 3 μΜ 25
Example D71 94 at 3 μΜ 42
Example D72 93 70
Example D73 96 92
Example D74 95 97 Example D75 96 93
Example D76 97 98
Example D77 87 7.8
Example D78 80 NA
Example D79 77 90
Example D80 72 81
Example D81 83 NA
Example D82 92 51
Example D83 82 NA
Example D84 97 81
Example D86 67 79
Example D87 99 100
Example D88 98 96
Example D89 95 68
Example D90 91 at 3 μ 80
Example D91 81 at 3 μΜ 23
Example D92 93 at 3 μΜ 77
Example El 68 NA
Example E2 66 NA
Example E3 57 NA
Example E4 67 NA
Example E5 72 NA
Example Fl 60 NA
Example Gl 33 NA
Example HI 73 NA
Example 11 No inhibition NA
Example 12 7 NA
Example Jl 48 NA
NA: not available
Industrial Applicability
[0366]
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., rheumatoid arthritis, aortic aneurysm (e.g. abdominal aortic aneurysm, thoracic aortic aneurysm, thoracoabdominal aortic aneurysm etc.), endometriosis, ankylosing spondylitis, inflammatory breast cancer etc.) and the like.
[0367]
This application is based on patent application No. 2249/DEL/2014 filed on August 7, 2014 in India, the contents of which are encompassed in full herein.

Claims

CLAIMS compound represented by the formula
Figure imgf000209_0001
wherein
Ring A is an optionally further substituted pyridine or an optionally further substituted pyridazine,
G1 is N or CR4,
R4 is a hydrogen atom or a substituent,
Ring B is an optionally substituted 6-membered aromatic ring,
R1 and R2 are each independently a hydrogen atom or an
optionally substituted Ci_6 alkyl group, or R1 and R2 are joined together to form a cycloalkane or a heterocycle, each of which is optionally substituted,
R3 is a hydrogen atom or a substituent,
Ring C is an optionally further substituted ring,
R5 is a substituent,
Ring D is an optionally substituted ring, and
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.
2. The compound or salt according to claim 1, wherein
Ring A is pyridine optionally further having one substituent, on the carbon atom adjacent to G1, selected from
(1) a halogen atom,
(2) an optionally halogenated Ci_6 alkyl group, and
(3) a C3-10 cycloalkyl group,
G1 is CR4,
R4 is a hydrogen atom, Ring B is a β-membered aromatic ring optionally having 1 to 3 substituents selected from
(1) a halogen atom,
(2) an optionally halogenated Ci_6 alkyl group,
(3) an optionally halogenated Ci-6 alkoxy group, and
(4) a C3-10 cycloalkyl group,
R1 and R2 are each independently a hydrogen atom or a Ci_6 alkyl group, or R1 and R2 are joined together to form a cycloalkane, R3 is a hydrogen atom,
Ring C is a C6-i4 aromatic hydrocarbon ring or a 5- or 6- membered monocyclic aromatic heterocycle, each optionally having 1 to 3 substituents, in addition to R5, selected from
(1) a halogen atom, and
(2) an optionally halogenated Ci-6 alkyl group,
R5 is
(1) a carboxy group,
(2) a Ci-6 alkoxy-carbonyl group,
(3) a cyano group,
(4) a Ci-6 alkyl group optionally having 1 to 3 substituents selected from
(a) a halogen atom,
(b) a hydroxy group, and
(c) a carboxy group,
(5) a carbamoyl group optionally having 1 or 2 substituents selected from
(a) a Ci-6 alkyl group,
(b) a Ci-6 alkoxy group,
(c) a C7-16 aralkyloxy group, and
(d) a Ci-6 alkylsulfonyl group, or
(6) a sulfamoyl group,
Ring D is a Ce-i4 aromatic hydrocarbon ring or a 5- or 6- membered monocyclic aromatic heterocycle, each optionally having 1 to 3 substituents selected from
(1) a halogen atom,
(2) a cyano group, (3) an optionally halogenated Ci-6 alkyl group, and
(4) an optionally halogenated Ci-6 alkoxy group, and
W is -0- or -0-CH2- (wherein the left bond is bonded to Ring B, and the right bond is bonded to Ring D) .
3. 4- [ (IS) -1- [ [8- (3-Fluorophenoxy) -1- isoquinolyl] amino] ethyl] benzoic acid or a salt thereof.
4. 4- [ (IS) -1- [ [5-Chloro-8- ( 4-fluorophenoxy) -2, 7-naphthyridin- 1-yl] amino] ethyl] benzoic acid or a salt thereof.
5. 4- [ (IS) -1- [ [8- (3-Fluorophenoxy) -2 , 7-naphthyridin-l- yl] amino] ethyl] benzoic acid or a salt thereof.
6. A medicament comprising the compound or salt of claim 1.
7. The medicament of claim 6, which is an EP4 receptor
antagonist .
8. The medicament of claim 6, which is an agent for the prophylaxis or treatment of EP4 receptor associated diseases.
9. The medicament of claim 6, which is an agent for the prophylaxis or treatment of rheumatoid arthritis, aortic aneurysm, endometriosis, ankylosing spondylitis or
inflammatory breast cancer.
10. The compound or salt of claim 1 for use in the prophylaxis or treatment of EP4 receptor associated diseases.
11. The compound or salt of claim 10, wherein the EP4 receptor associated diseases is selected from rheumatoid arthritis, aortic aneurysm, endometriosis, ankylosing spondylitis and inflammatory breast cancer.
12. A method of inhibiting EP4 in a mammal, which comprises administering an effective amount of the compound or salt of claim 1 to the mammal.
13. 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 claim 1 to the mammal .
14. The method of claim 13, wherein the EP4 receptor
associated diseases is selected from rheumatoid arthritis, aortic aneurysm, endometriosis, ankylosing spondylitis and inflammatory breast cancer.
15. Use of the compound or salt of claim 1 for the production of an agent for the prophylaxis or treatment of EP4 receptor associated diseases.
16. Use of claim 15, wherein the EP4 receptor associated diseases is selected from rheumatoid arthritis, aortic
aneurysm, endometriosis, ankylosing spondylitis and
inflammatory breast cancer.
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