WO2016088903A1

WO2016088903A1 - Heterocyclic compounds

Info

Publication number: WO2016088903A1
Application number: PCT/JP2015/084734
Authority: WO
Inventors: Anil M. DESHPANDE; Dinesh Barawkar; Santosh Patil; Digambar BANKAR
Original assignee: Takeda Pharmaceutical Company Limited
Priority date: 2014-12-05
Filing date: 2015-12-04
Publication date: 2016-06-09

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 etc.) and the like.

Description

DESCRIPTION

HETEROCYCLIC COMPOUNDS

Technical Field

[0001]

The present invention relates to a novel heterocyclic compound having an EP4 receptor antagonistic action, and is useful as an agent -for the prophylaxis or treatment of EP4 receptor associated diseases (e.g., rheumatoid arthritis, aortic aneurysm, endometriosis, ankylosing spondylitis etc.) and the like.

.[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-coupled 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 (ηόη-patent documents 30 and 31), a safe and chronically-treatable EP4 antagonist may be an alternative symptom-relieving pharmacotherapy 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]

[0011]

wherein

A is hydrogen, C₁-C₆-alkyl, C₂-C₆-alkenyl_/ C₂-C₆-alkynyl, benzyl or C₃-C₇-cycloalkyl;

B is hydrogen, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, benzyl or C₃-C₇-cycloaikyl;

R₁ is hydrogen, C₁-C₆-alkyl, C₂-C₆-alkenyl or C₃-C₇-cycloalkyl; R₂ is hydrogen, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₃-C₇-cycloalkyl, C₁-C₆-alkylcarbonyl, C₁-C₆-alkoxycarbonyl, aitiinocarbonyl or hydrazinocarbonyl;

or,. R₁ and R₂, together with the .carbon atom to which they are attached, form a C₃-C₇-cycloalkyl ring;

n is 0 or 1;

X is a bond or a C₁-C₆-alkylene; and

R3 is a 5- or 6-membered heteroaromatic ring which contains 1-4 heteroatoms, carbocyclic aromatic ring which may be

substituted, etc,

as an inhibitor of platelet aggregation, and is useful as. an- - agent for the prophylaxis or treatment ,of cardiocirculatory diseases.

Document List

Patent Document

[0012]

[Patent Document.1] EP 344634 Al

Non-Patent Document

[0013]

[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. 292-310

[Non-Patent Document 9] BMJ, 2001. 323(7304): p. 93-5

[Non-Patent Document 10] J. Pharm. Pharm. Sci., 2013. 16(5): 821-47

[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- 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., 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

[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

[Non-Patent Document 22] Circulation, 1999. 100(1): p. 48-54 [Non-Patent Document 23] PLoS One, 2012. 7(5): p. e36724

[Non-Patent Document 24] J. Vase. Surg., 2003. 38 (2): p. 354-9 [Non-Patent ·. Document 25] Am. J. Pathol., 2012. 181(1): p. 313- 21

[Non-Patent Document 26] Scand. J. Rheumatol., 2008. 37: p.

120-126

[Non-Patent Document 27] Arthritis Rheum., 1997. 40: p. 1823- 1828

[Non-Patent Document 28] Ann. Rheum. Dis., 2000. 59: p. 883- 886

[Non-Patent Document 29] Nature Genetics., 2011. 43: p.. 761- 767

[Non-Patent Document 30] Eur. J. Pharmacol., 2008, 580: p.

116-121

[Non-Patent Document 31] Bioorg. Med. Chem. Lett., 2010. 15: p. 3760-3

Summary of the Invention

Problems to be Solved by the Invention

[0014]

The present invention aims to provide a novel

heterocyclic compound having an EP4 receptor antagonistic action, and useful as an agent for the prophylaxis or

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 etc.) and the like.

Means of Solving the Problems

[0015]

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 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 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) :

[0016]

[0017]

wherein

Ring A is an optionally further substituted 5- or 6-membered ring,

G¹ is N, C or CR⁴,

G² is N, C or CR⁵,

R⁴ is a hydrogen atom or a substituent,

R⁵ is a hydrogen atom or a. substituent,

Ring B is an optionally further substituted 5-membered non- aromatic heterocycle containing 1 to 3 nitrogen atoms,

Ring E is an optionally substituted C_3-6 cycloalkane or an optionally substituted heterocycle-,

R¹ and R² are each independently a hydrogen atom or an

optionally substituted C_{1- 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,

Ring D is an optionally further 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 ) ) ·

[0018]

[2] The compound or salt according to the above-mentioned [1] , wherein

the partial structure:

[0'019]

[0020]

is

[0021]

[0022]

Ring A is benzene optionally further substituted by 1 to 3 halogen atoms,

Ring E is a C_3-6 cycloalkane or a 3- to 14-membered non-aromatic heterocycle,

R¹ and R² are each independently a hydrogen atom or a C_{1- 6}alkyl group, or R¹ and R² are joined together to form a C_3-6

cycloalkane, _

R³ is a hydrogen atom;

Ring C is a C_6-14 aromatic hydrocarbon ring or a 5- to 14- membered aromatic heterocycle, each of which is optionally further substituted by 1 to 3 substituents selected from a carboxy group and a G_{1- 6}alkoxy-carbonyl group,

Ring D is a C_6-14. aromatic hydrocarbon ring or a 5- to 14- membered aromatic heterocycle, each of which is optionally further substituted by 1 to 3 substituents selected from

(1) a halogen atom,

(2) a cyano group,

(3) an optionally . halogenated C_{1- 6}alkyl group, and

(4) an optionally halogenated C_{1- 6}alkoxy group, and

W is -CH₂-, -CH(CH₃)-, -SO₂-, -CH₂CH₂O- or -OCH₂CH₂- . ^'.

[0023]

[3] 4- [ (IS) -1- [. [1 ` - [ ( 4-chlorophenyl) methyl] spiro [cyclopropane- 1, 3 '-indoline] -7 '-carbonyl] amino] ethyl] benzoic acid or a salt thereof.

[4], 4-[l-[[l'-[[4- (trifluoromethyl) phenyl] methyl] spiro [cyclopropane-1, 3'- indoline] -7 '-carbonyl] amino] cyclopropyl] benzoic acid or a salt thereof.

[5] 4-.[l- [ [1 ` - [ (3, 4-difluorophenyl) methyl] spiro [cyclopropane- 1,3 '-indoline] -7 '-carbonyl] amino] cyclopropyl] benzoic acid or a salt thereof.

[0024]

[6] A medicament comprising the compound or salt according to the above-mentioned [1] .^'

[7] The medicament according to the above-mentioned [6] which is an^'EP4 receptor antagonist.

[8] The medicament according to the above-mentioned [6] which is an agent for the prophylaxis or treatment of EP4 receptor associated diseases.

[9] The medicament according to 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.

[0025]

[10] The compound or salt according to the above-mentioned [1] for use in the prophylaxis or treatment of EP4 receptor associated diseases.

[11] The compound or salt according to the above-mentioned [1] for use in the prophylaxis or treatment of rheumatoid

arthritis, aortic aneurysm, endometriosis, ankylosing

spondylitis or inflammatory breast cancer.

[0026]

[12] A method of inhibiting EP4 receptor in a mammal, which comprises administering an effective amount of the compound or salt according to' the above-mentioned [1] to the mammal.

[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 according to the above-mentioned [1] to the mammal.

[14] A method for the prophylaxis or treatment of rheumatoid arthritis, aortic aneurysm, endometriosis, ankylosing

spondylitis or inflammatory breast cancer, which comprises administering an effective amount of the compound or salt according to the above-mentioned [1] to the mammal.

[0027]

[15] Use of the compound or salt according to the above- mentioned [1] for the production of an agent for the

prophylaxis or treatment of EP4 receptor associated diseases.

[16] Use of the compound or. salt according to the above- mentioned [1] for the production of an agent for the

prophylaxis or treatment of rheumatoid arthritis, aortic aneurysm, endometriosis, ankylosing spondylitis or

inflammatory breast cancer.

Effect of the Invention

[0028]

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 etc.) and the like.

[0029] [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 "C_{1- 6}alkyl group" include methyl, ethyl, propyl, .isopropyl, butyl,

isobutyl, sec-butyl, tert-butyl, pentyl, isropent.yl, neopentyl,

1-ethylpropyl, hexyl, isohexyl, 1, 1-dimethylbutyl, 2,2- dimethylbutyl, 3, 3-dimethylbutyl and 2-ethylbutyl.

In the present specification, examples of. the "optionally halogenated C_{1- 6}alkyl group" include a C_{1- 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 "C_{2- 6} alkenyl group" include ethenyl, 1-propenyl, 2-propenyl, 2- methyl-l-propenyl, 1-butenyl, 2-butenyl, 3-butehyl, ^"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 "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 .

In the present specification, examples of the "C_3-10 cycloalkyl group" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl_/ bicyclo[3.2. l]octyl and adamantyl.

In the present specification_/ examples of the. "optionally halogenated C_3-10 cycloalkyl group" include a C_3-10 cycloalkyl group optionally having 1 to 7, preferably 1 to 5, halogen atoms. Specific examples thereof include cyclopropyl, 2,2- difluorocyclopropyl, 2, 3-difluorocyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl .

In the present specification, examples of the "C_3-10 cycloalkenyl group" include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl .

In the present specification, examples of the "C_6-14 aryl group" include phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2- anthryl and 9-anthryl.

In the present specification, examples of the "C_7-16 aralkyl group" include benzyl, phenethyl, naphthylmethyl and phenylpropyl .

[0030]

In the present specification, examples of the "C_{1- 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 C₁- ₆alkoxy group" include a C₁- ₆alkoxy 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 "C_3-10 cycloalkyloxy group" include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy and

cyclooctyloxy.

In the present specification, examples of the "C₁- ₆ alkylthiio group" include methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, pentylthio and hexylthio.

In the present specification, examples of the "optionally halogenated C_{1- 6}alkylthio group" include a C_{1- 6}alkylthio group, optionally having 1 to 7, preferably 1 to 5/ halogen atoms .

Specific examples thereof include methylthio,

difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4, 4, 4-trifluorobutylthio, pentylthio and hexylthio.

In the present specification, examples of the "C₁- ₆alkyl- carbonyl group" include acetyl, propanoyl, butanoyl, 2- methylpropa.noyl, pentanoyl, 3-methylbutanoyl, 2-methylbutanoyl, 2 , 2-dimethylpropanoyI., hexanoyl and heptanoyl .

In the present specification, examples of the "optionally halogenated C_{1- 6}alkyl-carbonyl group" include a C_{1- 6}alkyl- carbonyl group optionally having 1 to 7, preferably 1 to 5, halogen atoms. Specific examples thereof include acetyl, chloroacetyl, trifluoroacetyl, trichloroacetyl, propanoyl, butanoyl, pentanoyl and hexanoyl.

In the present specification, examples of the "C_{1- 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 "C_6-14 aryl- carbonyl group" include- benzoyl, 1-naphthoyl and 2-naphthoyl.

In the present specification, examples of the "C_7-16 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-C₁- ₆alkyl-carbamoyl group" include methylcarbamoyl,

ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl and N- . ethyl-N-methylcarbamoyl .

In the present specification, examples of the "mono- or di-C_7-16 aralkyl-carbamoyl group" include benzylcarbamoyl and phenethylcarbamoyl .

In the present specification, examples of the "C_{1- 6} alkylsulfonyl group" include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, sec- butylsulfonyl and tert-butylsulfonyl .

^' In the present specification, examples of the "optionally halogenated C_{1- 6}alkylsulfonyl group" include a C_{1- 6}

alkylsulfonyl group optionally having 1 to 7, preferably 1 to 5, halogen atoms. Specific examples thereof, include

methylsulfonyl, difluoromethylsulfonyl,

trifluoromethylsulfonyl, ethylsulfonyl, propylsulfonyl,

isopropylsulfonyl, . butylsulfonyl, 4,4, 4-trifluorobutylsulfonyl, pentylsulfonyl and hexylsulfonyl.

In the present specification, examples of the "C_6-14 arylsulfonyl group" include phenylsulfonyl, 1-naphthylsulfonyl and 2-naphthylsulfonyl.

[0031] ^·

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 C₁- ₆alkyl group, a C_{2- 6}alkenyl group,, a C_{2- 6}alkynyl group, a C_3-10 cycloalkyl group, a C_3-10 cycloalkenyl group, a C_6-14 aryl group and a C_7-16 aralkyl group.

[0032]

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 C₁- ₆alkoxy group,

(7) a C_6-14 aryloxy group (e.g., phenoxy, naphthoxy) ,

(8) a C_7-16 aralkyloxy group (e.g., benzyloxy) ,

(9) a 5- to 14-membered aromatic heterocyclyloxy group (e.g., pyridyloxy) ,

(10) a 3- to 14-membered non-aromatic heterocyclyloxy group (e.g., morpholinyloxy, piperidinyloxy) ,

(11) a C₁- ₆alkyl-carbonyloxy group (e.g., acetoxy,

propanoyloxy) ,

(12) a C₆-₁₄ aryl-carbonyloxy group (e.g., benzoyloxy, 1- naphthoyloxy, 2-naphthoyloxy) ,

(13) a C₁- ₆alkoxy-carbonyloxy group (e.g., methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy) ,

(14) a mono- or di-C₁- ₆alkyl-carbamoyloxy group (e.g.,

methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy, diethylcarbamoyloxy) ,

(15) a C_6-14 aryl-carbamoyloxy group (e.g., phenylcarbamoyloxy, naphthyicarbamoyloxy) ,

(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 C₁- ₆alkylsulfonyloxy group (e.g. methylsulfonyloxy, trifluoromethylsulfonyloxy) ,

(19) a C_6-14 arylsulfonyloxy group optionally substituted by a C_{1- 6}alkyl group (e.g., phenylsulfonyloxy, toluenesulfonyloxy) ,

(20) an optionally halogenated C₁-₆ alkylthio 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 C₁- ₆alkyl-carbonyl group,

(26) a C_6-14 aryl-carbonyl group,

(27) a 5- to 14-membered aromatic heterocyclylcarbonyl group,

(28) a 3- to 14-membered non-aromatic heterocyclylcarbonyl group,

(29) a C₁- ₆alkoxy-carbonyl group,

(30) a C_6-14 aryloxy-carbonyl group (e.g., phenyloxycarbonyl, 1- naphthyloxycarbonyl, 2-naphthyloxycarbonyl) ,

(31) a C_7-16 aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl, phenethyloxycarbonyl) ,

(32) a carbamoyl group,

(33) a thiocarbamoyl group,

(34) a mono-. or di-C₁- ₆alkyl-carbamoyl group,

(35) a C_6-14 aryl-carbamoyl group (e.g., phenylcarbamoyl) ,

(36) a 5- to 14-membered aromatic heterocyclylcarbamoyl group (e.g., pyridylcarbamoyl, thienylcarbamoyl) ,

(37) a 3- to 1.4-membered non-aromatic heterocyclylcarbamoyl group (e.g., morpholinylcarbamoyl, piperidinylcarbamoyl) ,

(38) an optionally halogenated C₁- ₆alkylsulfonyl group,

(39) a C_6-14 arylsulfonyl group,

(40) a 5- to 14-membered aromatic heterocyclylsulfonyl group (e.g., pyridylsulfonyl, thienylsulfonyl) , .

(41) an optionally halogenated C₁- ₆alkylsulfinyl group,

(42) a C_6-14 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-C₁- ₆alkylamino group (e.g., methylamino, ethylamino, propylamino, isopropylamino,. butylamino,

dimethylamino, diethylamino, dipropylamino, dibutylamino, N- ethyl-N-methylamino) ,

(46) a mono- or di-C_6-14 arylamino group (e.g., phenylamino) ,

(47) a 5- to 14-membered aromatic heterocyclylamino group

(e.g., pyridylamino) ,

(48) a C_7-16 aralkylamino group (e.g., benzylamino) ,

(49) a formylamino group,^'

(.50) a C₁- ₆alkyl-carbonylamino^' group (e.g., acetylamino, propanoylamino, butanoylamino) ,

(51) a (C₁- ₆alkyl) (C₁- ₆alkyl-carbonyl) amino group (e.g., N- acetyl-N-methylamino) ,

(52) a C_6-14 aryl-carbonylamino group (e.g., phenylcarbonylamino, naphthylcarbonylamino) ,

(53) a C₁- ₆alkoxy-carbonylamino group (e.g.,

methoxycarbonylamino, ethoxycarbonylamino,

propoxycarbonylamino, butoxycarbonylamino, tert- butoxycarbonylamino) ,

(54) a C_7-16 aralkyloxy-carbonylamino group (e.g.,

benzylo^'xycarbonylamino) ,

(55) a C_{1- 6}alkylsulfonylamino group (e.g., methylsulfonylamino, ethylsulfonylamino) ,

(56) a C_6-14 arylsulfonylamino group optionally substituted by a C₁- ₆alkyl group (e.g., phenylsulfonylamino,

toluenesulfonylamino) ,

(57) an optionally halogenated C₁- ₆alkyl group,

(58) a C_{2- 6}alkenyl group,

(59) a C_{2- 6}alkynyl group,

(60) a C_3-10 cycloalkyl group,

(61) a C_3-10 cycloalkenyl group and

(62) a C_6-14 aryl group. [0033]

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.

[0034]

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, 4-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, thiazolopyrimidiriyl, 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.

[0035]

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, thiazolidiriyl,

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, dihydrobenzisothia.zolyl, 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, tetrahydrophenaziriyl,

tetrahydrothioxanthenyl, octahydroisoquinolyl and the like.

[0036]

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.

[0037]

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 C₁- ₆alkyl group, a C_{2- 6} alkenyl group, a C_3-10 cycloalkyl group, a C_3-10 cycloalkenyl group, a C_6-14 aryl group, a C_7-16 aralkyl group, a 5- to 14- membered aromatic heterocyclic group and a 3- to 14-membered non-aromatic heterocyclic group, each of which optionally has 1 to 3 substituents selected from a halogen atom, an

optionally halogenated C_{1- 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 C_{1- 6} ^,alkyl-carbonyl group, a C_{2- 6} alkenyl-carbonyl group (e.g., crotonoyl) , a C_3-10 cycloalkyl- carbonyl group (e.g., cyclobutanecarbonyl,

cyclopentanecarbonyl, cyclohexanecarbonyl,

cycloheptanecarbonyl) , a C_3-10 cycloalkenyl-carbonyl group, (e.g., 2-cyclohexenecarbonyl) , ^'a C_6-14 aryl-carbonyl group, a C_7-16 aralkyl-carbonyl group, a 5- to 14-membered aromatic

heterocyclylcarbonyl group, a 3- to 14-membered non-aromatic heterocyclylcarbonyl group, a C_{1- 6}alkoxy-carbonyl group, a C_6-14 aryloxy-carbonyl group (e.g.., phenyloxycarbonyl,

naphthyloxycarbonyl) , a C_7-16 aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl, phenethyloxycarbonyl) , a carbamoyl group, a mono- or di-C_{1- 6}alkyl-carbamoyl group, a mono- or di-C_{2- 6} alkenyl-carbamoyl group (e.g., diallylcarbamoyl) , a mono- or di-C_3-10 cycloalkyl-carbamoyl group (e.g., cyclopropylcarbamoyl) , a mono- or di-C_6-14 aryl-carbamoyl group (e.g., phenylcarbamoyl) , a mono- or di-C_7-16 aralkyl-carbamoyl group, a 5- to 14-membered aromatic heterocyclylcarbamoyl group (e.g., pyridylcarbamoyl) , a thiocarbamoyl group, a mono- or di-C₁- ₆alkyl-thiocarbamoyl group (e.g., methylthiocarbamoyl, N-ethyl-N- methylthiocarbamoyl) , a mono- or di-C_{2- 6}alkenyl-thiocarbamoyl group (e.g., diallylthiocarbamoyl) , a mono- or di-C_3-10

cycloalkyl-thiocarbamoyl group (e.g., cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl) , a mono- or di-C_6-14 aryl-thiocarbamoyl group (e.g., phenylthiocarbamoyl) , a mono- or di-C_7-16 aralkyl- thiocarbamoyl group (e.g., benzylthiocarbamoyl,

phenethylthiocarbamoyl) , a 5- to 14-membered aromatic

heterocyclylthiocarbamoyl group (e.g., pyridylthiocarbamoyl) , . a sulfino group, a C₁- ₆alkylsulfinyl group (e.g.,

methylsulfinyl, . ethylsulfinyl) , a sulfo group, a C₁- ₆

alkylsulfonyl group, a C_6-14 arylsulfonyl group, a phosphono group and a mono- or di-C₁- ₆alkylphosphono group (e.g.,

dimethylphosphono, diethylphosphono, diisopropylphosphono, dibutylphosphono) .

[0038]

In the present specification, examples of the "optionally substituted amino group" include an amino group optionally having "1 or 2 substituents selected from a C₁- ₆alkyl group, a C_{2- 6}alkenyl group, a C_3-10 cycloalkyl group, a C_6-14 aryl group, a C_7-16 aralkyl group, a C_{1- 6}alkyl-carbonyl group, a C_6-14 aryl- carbonyl group, a C_7-16 aralkyl-carbonyl group, a 5- to 14- membered aromatic heterocyclylcarbonyl group, a 3- to 14- membered non-aromatic heterocyclylcarbonyl group, a C₁- ₆alkoxy- carbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-C₁- ₆alkyl-carbamoyl group, a mono- or di-C_7-16 aralkyl-carbamoyl group, a C_{1- 6} alkylsulfonyl group and a C_6-14 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 C₁- ₆alkyl) amino group (e.g., methylamino,

trifluoromethylamino, dimethylamino, ethylamino, diethylamino, propylamino, dibutylamino) , a mono- or di-C_{2- 6}alkenylamino group (e.g., diallylamino) , a mono- or di-C_3-10 cycloalkylamino group (e.g., cyclopropylamino/ cyclohexylamino) , a mono- or di-C_6-14 arylamino group (e.g., phenylamino) , a mono- or di-C_7-16 aralkylamino group (e.g., benzylamino, dibenzylamino) , a mono- or di- (optionally halogenated C_{1- 6}alkyl) -carbonylamino group (e.g., acetylamino, propionylamino) , a mono- or di-C_6-14 aryl- carbonylamino group (e.g., benzoylamino) , a mono- or di-C_7-16 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-C_{1- 6}alkoxy- carbonylamino group (e.g., tert-butoxycarbonylamino) , a. 5- to 14-membered aromatic heterocyclylamino group (e.g.,

pyridylamino) , a carbamoylamino group, a (mono- or di-C_{1- 6} alkyl-carbamoyl) amino group (e.g., methylcarbamoylamino) , a (mono- or di-C_7-16 aralkyl-carbamoyl) amino group (e.g.,

benzylcarbamoylamino) , a C_{1- 6}alkylsulfonylamino group (e.g., methylsulfonylamino, ethylsulfonylamino) , a C_6-14

arylsulfonylamino^' group (e.g., phenylsulfonylamino) , a (C_{1- 6} alkyl) (C₁- ₆alkyl-carbonyl) amino group (e.g., N-acetyl-N- methylamino) and a (C₁- ₆alkyl) (C_6-14 aryl-carbonyl) amino group (e.g., N-benzoyl-N-methylamino) .

[0039]

In the present specification, examples of the "optionally substituted carbamoyl group" include a carbamoyl group

optionally having "1 or 2 substituents selected from a C_{1- 6} alkyl . group, a C_{2- 6}alkenyl group, a C_3-10 cycloalkyl group, a C₆- 14 aryl group, a C_7-16 aralkyl group, a C₁- ₆alkyl-carbonyl group, a C_6-14 aryl-carbonyl group, a C_7-16 aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclylcarbonyl group, a 3- to 14-membered non-aromatic heterocyclylcarbonyl group, a C₁- ₆ alkoxy-carbonyl group, a 5- to 14-membered aromatic

heterocyclic group, a carbamoyl group, a mono- or di-C_{1- 6}alkyl- carbamoyl group and a mono- or di-C_7-16 aralkyl-carbamoyl group, each of which optionally has 1 to 3 substituents selected from substituent group A".

Preferable examples of the optionally substituted

carbamoyl group include a carbamoyl group, a mono- or di-C₁- ₆ alkyl-carbamoyl group, a mono- or di-C_{2- 6}alkenyl-carbamoyl group (e.g., diallylcarbamoyl) , a mono- or di-C3_-10 cycloalkyl- carbamoyl group (e.g., cyclopropylcarbamoyl,

cyclohexylcarbamoyl) , a mono- or di-C_6-14 aryl-carbamoyl group (e.g., phenylcarbamoyl) , a mono- or di-C_7-16 aralkyl-carbamoyl group, a mono- or di-C₁- ₆alkyl-carbonyl-carbamoyl group -(e.g., acetylcarbamoyl, propionylcarbamoyl) , a mono- or di-C_6-14 aryl- carbonyl-carbamoyl group (e.g., benzoylcarbamoyl) and a 5- to 14-membered aromatic heterocyclylcarbamoyl group (e.g., pyridylcarbamoyl ) .

[0040] .

In the present specification, examples of the "optionally substituted thiocarbamoyl group" include a thiocarbamoyl group optionally having "1 or 2 substituents selected from a C_{1- 6} alkyl group, a C_{2- 6}alkenyl group, a C3-.10 cycloalkyl group, a ϋβ- i4 aryl group, a C_7-16 aralkyl group, a C₁- ₆alkyl-carbonyl group, a C_6-14 aryl-carbonyl group, a C_7-16 aralkyl-carbonyl group, a 5- to 14-membered aromatic heterocyclylcarbonyl group, a 3- to 14-membered non-aromatic heterocyclylcarbonyl group, a C₁- ₆ alkoxy-carbonyl group, a 5- to 14-membered aromatic

Preferable examples of the optionally substituted

thiocarbamoyl group include a thiocarbamoyl group, a mono- or di-C₁- ₆alkyl-thiocarbamoyl group (e.g., methylthiocarbamoyl, ethylthiocarbamoyl, dimethylthiocarbamoyl,

diethylthiocarbamoyl, N-ethyl-N-methylthiocarbamoyl). , a mono- or di-C_{2- 6}alkenyl-thiocarbamoyl group (e.g.,

diallylthiocarbamoyl) , a mono- or di-C_3-10 cyc^'loalkyl- thiocarbamoyl group (e.g., cyclopropylthiocarbamoy1, cyclohexylthiocarbamoyl) , a mono- or di-C_6-14 aryl-thiocarbamoyl group (e.g., phenylthiocarbamoyl) , a mono- or di-C_7-16 aralkyl- thiocarbamoyl group (e.g., benzylthiocarbamoyl,

phenethylthiocarbamoyl) , a mono- or di-C₁- ₆alkyl-carbonyl- thiocarbamoyl group (e.g., acetylthiocarbamoyl,

propionylthiocarbamoyl) , a mono- or di-C_6-14 aryl-carbonyl- thiocarbamoyl group (e.g., benzoylthiocarbamoyl) and a 5- to 14-membered aromatic heterocyclylthiocarbamoyl group (e.g., pyridylthiocarbamoyl) .

[0041}

In the present specification, examples of the "optionally substituted, sulfamoyl group" include a sulfamoyl group

optionally having "1 or 2 substituents selected from a C₁- ₆ alkyl group, a C_{2- 6}alkenyl group, a C_3-10 cycloalkyl group, a C₆- 14 aryl group, a C_7-16 aralkyl group, a. C₁- ₆alkyl-carbonyl group, a C₆-₁₄ aryl-carbonyl group, a C_7-16 aralkyl-carbonyl group, a 5- to 14-membered aromatic heter.ecyclylcarbonyl group, a 3- to 14-membered non-aromatic heterocyclylcarbonyl group, a C_{1- 6} alkoxy-carbonyl group, a 5- to 14-membered aromatic

Preferable examples of the optionally substituted

sulfamoyl group include a sulfamoyl group, a mono- or di-C₁- 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-C_3-10 cycloalkyl- sulfamoyl group (e.g., cyclopropylsulfamoyl,

cyclohexylsulfamoyl) , a mono- or di-C_6-14 aryl-sulfamoyl group (e.g., phenylsulfamoyl) , a mono- or di-C_7-16 aralkyl-sulfamoyl group (e.g., benzylsulfamoyl, phenethylsulfamoyl) , a mono- or di-C₁- ₆alkyl-carbonyl-sulfamoyl group (e.g., acetylsulfamoyl, propionylsulfamoyl) , a mono- or di-C_6-14 aryl-carbonyl-sulfamoyl group (e.g., benzoylsulfamoyl) and a 5- to 14-membered

aromatic heterocyclylsulfamoyl group (e.g., pyridylsulfamoyl) .

[0042]

In the present specification, examples of the "optionally substituted hydroxy group" include a hydroxyl group optionally having "a substituent selected from a C_{1- 6}alkyl group, a C_{2- 6} alkenyl group, a C₃_LO cycloalkyl group, a C_6-14 aryl group, a C₇_ 16 aralkyl group, a C₁- ₆alkyl-carbonyl group, a C_6-14 aryl- carbonyl group, a C_7-16 aralkyl-carbonyl group, a 5- to 14- membered aromatic heterocyclylcarbonyl group, a 3- to 14- membered non-aromatic heterocyclylcarbonyl group, a C₁- ₆alkoxy- carbonyl group, a 5- to 14-membered aromatic heterocyclic group, a carbamoyl group, a mono- or di-C₁- ₆alkyl-carbamoyl group, a mono- or di-C_7-16 aralkyl-carbamoyl group, a C₁- ₆ alkylsulfonyl group and a C_6-14 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 C₁- ₆alkoxy group, a C_{2- 6} alkenyloxy group (e.g., allyloxy, 2-butenyloxy, 2-pentenyloxy, 3-hexenyloxy) , a C_3-10 cycloalkyloxy group (e.g., cyclohexyloxy) , a C_6-14 aryloxy group (e.g., phenoxy, naphthyloxy) , a C_7-16 aralkyloxy group (e.g., benzyloxy, phienethyloxy) , a C₁- ₆alkyl- carbonyloxy group (e.g., acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy) , a C_6-14 aryl-carbonyloxy group

(e.g., benzoyloxy) , a C_7-16 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- C₁- ₆alkoxy-carbonyloxy group (e.g., tert-butoxycarbonyloxy) , a 5- to 14-membered aromatic

heterocyclyloxy group (e.g., pyridyloxy) , a carbamoyloxy group, a C₁- ₆alkyl-carbamoyloxy group (e.g., methylcarbamoyloxy) , a C_7-16 aralkyl-carbamoyloxy group (e.g., benzylcarbamoyloxy) , a C₁- ₆alkylsulfonyloxy group (e.g., methylsulfonyloxy, ethylsulfonyloxy) and a. C_6-14 arylsulfonyloxy group (e.g., phenylsulfonyloxy).

[0043]

In. the present specification, examples of the "optionally substituted sulfanyl group" include a sulfanyl group

optionally having "a substituent selected from a C₁- ₆alkyl group, a C_{2- 6}alkenyl group, a C_3-10 cycloalkyl group, a C_6-14.

aryl group, a C_7-16 aralkyl group, a C₁- ₆alkyl-carbonyl group, a C_6-14 aryl-carbonyl group and a 5- to 14-membered aromatic heterocyclic group, each of which optionally has 1 to 3

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 C₁- ₆alkylthio . group, a C_{2- 6}alkenylthio group (e.g., allylthio, 2-butenylthio, 2-pentenylthio, 3-hexenylthio) , a C_3-10 cycloaikylthio group (e.g., cyclohexylthio) , a C₆-₁₄ arylthio group (e.g., phenylthio, naphthylthio) , .a C_7-16 aralkylthio group (e.g., benzylthio, phenethylthio) , a C₁- ₆alkyl-carbonylthio group (e.g.,

acetylthio, propionylthio, butyrylthio, isobutyrylthio,

pivaloylthio) , a C_6-14 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) .

[0044]

In the present specification, examples of the "optionally substituted silyl group" include a silyl group optionally having ^ΛΛ1 to 3 substituents selected from a C₁- ₆alkyl group, a C_{2- 6}alkenyl group, a C_3-10 cycloalkyl group, a C₆-₁₄ aryl group and a C_7-16 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-C_{1- 6}alkylsilyl group (e.g., trimethylsilyl, tert-butyl (dimethyl) silyl) . [0045]

In the present specification, examples of the

"hydrocarbon ring" include a C_6-14 aromatic hydrocarbon ring, C₃- 10 cycloalkane and C_3-10 cycloalkene.

In the present specification, examples of the "C_6-14 aromatic hydrocarbon ring" include benzene and naphthalene.

In the present specification, examples of the "C_3-10 cycloalkane" include cyclopropane, cyclobutane, cyclopentane, cyclohexane, . cycloheptane and cyclooctane.

In the present specification, examples of the "C_3-10 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.

[0046] ^"

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, benzofuran, benzimidazole, benzoxazole, benzisoxazole,

benzothiazole, benzisothiazole, benzotriazole, imidazopyridine, thienopyridine, furopyridine, pyrrolopyridine, pyrazolopyridine, oxazolopyridine, thiazolopyridine, imidazopyrazine, imidazopyrimidine, thienopyrimi^'dine,

furopyrimidine, pyrrolopyrimidine, pyrazolopyrimidine,

oxazolopyrimidine, thiazolopyrimidine, pyrazolopyrimidine, pyrazolotriazine, naphtho [2, 3-b] thiophene, phehoxathiine, indole, isoindole, lH-indazole, purine, isoquinoline,

quinoline, phthalazine, naphthyridine, quinoxaline,

quinazoline, cinnoline, carbazole, β-carboline, phenanthridine> acridine, phenazine, phenothiazine, phenoxathiine and the like.

[0047]

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

9-¹ 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.

[0048]

The definition of each symbol in the formula (I)^' is explained in detail in the following.

[0049]

Ring A is an optionally further substituted 5- or 6- membered ring.

[0050]

The "5- or 6-membered ring" of the "optionally further substituted 5- or 6-membered ring" for Ring A include benzene, a C_{5- 6}cycloalkane, a 5- or 6-membered aromatic heterocycle and a 5- or 6-membered non-aromatic heterocycle.

In the present specification, examples of the "C_{5- 6} cycloalkane" include cyclopentane and cyclohexane.

In the present specification, examples of the ^Λ'5- or 6- membered aromatic heterocycle" include a 5- or 6-membered one from among the "aromatic heterocycle".

In the present specification, examples of the "5- or 6- membered non-aromatic heterocycle" include a 5- or 6-membered one from among the "non-aromatic heterocycle".

[0051]

The "5- or 6-membered ring" of the "optionally further substituted 5- or 6-membered ring" for Ring A optionally has 1 to^' 5 substituents (preferably 1 to 3) at substitutable

position(s), in addition to -CO-N (R³) -C (R¹) (R²) -Ring C.

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.

[0052]

Ring A is preferably an optionally further substituted benzene .

Ring A is more preferably benzene optionally further substituted by 1 to 3 halogen atoms (e.g., a fluorine atom, a chlorine atom) .

[0053]

In another embodiment, Ring A is preferably an optionally further substituted 5- or 6-membered aromatic ring (preferably an optionally further substituted 6-membered aromatic ring (preferably benzene, pyridine, particularly preferably

benzene) ) .

[0054]

In this embodiment, Ring A is more preferably a 5- or 6- membered aromatic ring (preferably a 6-membered aromatic ring (preferably benzene, pyridine, particularly preferably

benzene) ) optionally .further substituted by 1 to 3 halogen atoms (e.g., a fluorine atom, a chlorine atom).

[0055]

In this embodiment, Ring A is still more preferably benzene or pyridine, each of which is optionally further substituted by 1 to 3 halogen atoms (e.g., a fluorine atom, a chlorine atom) .

[0056]

In this embodiment, Ring A is particularly^' preferably benzene optionally further substituted by 1 to 3 halogen atoms (e.g., a fluorine atom, a chlorine atom).

[0057]

G¹ is N, C or CR⁴ wherein R⁴ is a hydrogen atom or a substituent .

G¹ is preferably C.

G² is N, C or CR⁵, wherein R⁵ is a hydrogen atom or a substituent . G² is preferably C.

[0058]

Ring B is an optionally further substituted 5-membered . non-aromatic heterocycle containing 1 to 3 nitrogen atoms.

[0059]

Examples of the "5-membered non-aromatic heterocycle containing 1 to 3 nitrogen atoms" of the "optionally further substituted 5-membered non-aromatic heterocycle containing 1 to 3 nitrogen atoms" for Ring B include pyrroline, pyrrolidine, imidazoline, imidazolidine, pyrazolone, pyrazolidine,

triazoline, triazolidine and the like.

[0Ό60]

The "5-membered non-aromatic heterocycle containing 1 to 3 nitrogen atoms" of the "optionally .further substituted 5- membered non-aromatic heterocycle containing 1 to 3 nitrogen atoms" for Ring B optionally has 1 or 2 substituents on the carbon atom between the spiro carbon atom and the nitrogen atom bonded to W, in addition to -W-Ring D. 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.

[0061]

Ring B is preferably an optionally further substituted pyrroline.

Ring B is more preferably pyrroline.

[0062]

The partial structure:

[0063]

[0064]

is preferably

[0065]

[0066]

which is optionally further substituted, more preferably

[0067]

[0068]

Ring E is an optionally substituted C_3-6 cycloalkane or an optionally substituted heterocycle.

In the present specification, examples of the "C_{3- 6} cycloalkane" include cyclopropane, cyclobutane, cyclopentane and cyclohexane.

[0069]

The "C₃- ₆cycloalkane" of the "optionally substituted C₃-₆ cycloalkane" and the "heterocycle" of the "optionally

substituted heterocycle" for Ring E optionally have 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. [0070] · . .

Ring E is preferably an optionally substituted C_3-6 ^' cycloalkane (e.g., cyclopropane).

Ring E is. more preferably a C_3-6 cycloalkane (e.g., cyclopropane) .

[0071]

In another embodiment, Ring E is preferably an optionally substituted C_3-6 cycloalkane (e.g., cyclopropane, cyclopentane) or an optionally substituted 3- to 14-membered (preferably 4- to 10-membered) non-aromatic heterocycle (preferably an

optionally substituted 3- to 8-membered monocyclic non- aromatic heterocycle (e.g., tetrahydropyran) ) .

[0072]

In this embodiment, Ring E is more preferably a C_3-6 cycloalkane (e.g., cyclopropane, cyclopentane) or a 3- to 14- membered (preferably 4- to 10-membered) non-aromatic

heterocycle (preferably a 3- to 8-membered monocyclic non- aromatic heterocycle (e.g., tetrahydropyran)).

[0073]

R¹ and R² are each independently a hydrogen atom or an optionally substituted C_{1- 6}alkyl group, or R¹ and R² are joined together to form a cycloalkane or a heterocycle, each of which is optionally substituted.

[0074]

Examples of the "cycloalkane" formed by R¹ and R² include a C3-.10 cycloalkane (preferably a C₃- ₆cycloalkane) .

[0075]

Examples of the "heterocycle" formed by 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) .

[0076]

The "cycloalkane" and "heterocycle" formed by R¹ and R² optionally have 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.

[0077]

Preferably, R¹ and R² are each independently a hydrogen atom or a C_{1- 6}alkyl group (e.g., methyl, ethyl), or R¹ and R² are joined together to form an optionally substituted

cycloalkane (preferably an optionally substituted C_3-10

cycloalkane, more preferably an optionally substituted C_3-6 cycloalkane (e.g., cyclopropane)).

[0078]

More preferably, R¹ and R² are each independently a hydrogen atom or a C_{1- 6}alkyl group (e.g., methyl, ethyl), or R¹ and R² are joined together to form a cycloalkane (preferably a C_3-10 cycloalkane, more preferably a C₃- ₆cycloalkane (e.g., cyclopropane) ) .

[0079]

Still more preferably, R¹ is a- C_{1- 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 C_3-10 cycloalkane, more preferably a C_3-6 cycloalkane (e.g.,

cyclopropane) ) .

[0080]

R³ is a hydrogen atom or a . substituent .

[008_.1·]

R³ is preferably a hydrogen atom.

[0082]

Ring C is an optionally further substituted ring.

[0083]

Examples of the "ring" of the "optionally further

substituted ring" for Ring C include. a hydrocarbon ring and a heterocycle (preferably a C_6-14 aromatic hydrocarbon ring or a 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocycle, more preferably a C_6-14 aromatic hydrocarbon ring or a 5- or 6-membered monocyclic aromatic heterocycle, particularly preferably benzene or pyridine) .

[0084]

The "ring" of the "optionally^' further substituted ring" for Ring C optionally has 1 to 5 (preferablyl to 3)

substituents at substitutable position (s), in addition to - C (R¹) (R²) -N (R³) -CO-Ring A. 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.

[0085]

Ring C is preferably an optionally further substituted C_6-14 aromatic hydrocarbon ring (preferably benzene) .

[0086]

Ring C is more preferably a C_6-14 aromatic hydrocarbon ring (preferably benzene) optionally further substituted by 1 to 3 (preferably one) substituents selected from a carboxy group (including a carboxylato group) and a C_{1- 6}alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl) [preferably, optionally further substituted by 1 to 3 (preferably one) carboxy groups (including a carboxylato group) ] .

[0087]

Ring C is still more preferably benzene optionally further substituted by 1 to 3 (preferably one) substituents selected from a carboxy group (including a carboxylato group) and a C₁- ₆alkoxy-carbonyl group (e.g., methoxycarbonyl,

ethoxycarbonyl) [preferably optionally further substituted by 1 to 3 (preferably one) carboxy groups (including a

carboxylato group) ] .

[0088]

In another embodiment, Ring C is preferably an optionally further substituted C_6-14 aromatic -hydrocarbon ring (preferably benzene) or an optionally further substituted 5- to. 14- membered (preferably 5- to 10-membered) aromatic heterocycle (preferably an optionally further substituted 5- or 6-membered monocyclic aromatic heterocycle (preferably pyridine) ) . [0089]

In this embodiment, Ring C is more preferably a Cg_-14 aromatic hydrocarbon ring (preferably benzene) or a 5- to 14- membered (preferably 5- to 10-membered) aromatic heterocycle (preferably a 5- or 6-membered monocyclic aromatic heterocycle (preferably pyridine) ) , each of which is optionally further substituted by 1 to 3 (preferably one) substituents selected from a carboxy group (including a carboxylato group) and a C_{1- 6} alkoxy-carbonyl group (e.g., methoxycarbonyl , ethoxycarbonyl) [preferably optionally further substituted by 1 to 3

(preferably one) carboxy groups (including a carboxylato .

group) ] .

[0090]

In this embodiment, Ring C is still more preferably benzene or pyridine, each of which is optionally further substituted by 1 to 3 (preferably, one) substituents selected from a carboxy group (including a carboxylato group) and a C₁- ₆ alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl) [preferably optionally further substituted by 1 to 3

(preferably one) carboxy groups (including a carboxylato group) ] .

[0091]

Ring D is an optionally further substituted ring.

[0092]

Examples of the "ring" .of the "optionally further

substituted ring" for Ring D include a hydrocarbon ring and a heterocycle (preferably a C₆-₁₄ aromatic hydrocarbon ring

(preferably benzene) or a 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocycle (preferably a 5- or 6- membered monocyclic aromatic heterocycle (preferably .

pyridine) ) ) .

[0093]

The "ring" of the "optionally further substituted ring" for Ring D optionally has 1 to 5 (preferablyl to 3)

substituents at substitutable position (s), in addition to -W- Ring B. 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.

[0094]

Ring D is preferably an optionally further substituted C_6-14 aromatic hydrocarbon ring (preferably benzene) or an optionally further substituted 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocycle (preferably an

optionally further substituted 5- or 6-membered monocyclic aromatic heterocycle (preferably pyridine) ) .

[0095]

Ring D is more preferably a C_6-14 aromatic hydrocarbon ring (preferably benzene) or a 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocycle (preferably a 5- or 6- membered monocyclic aromatic heterocycle (preferably

pyridine) ) , each of which is optionally further- substituted by 1 to 3 substituents . selected from

(1) a halogen atom (e.g., a fluorine atom, a chlorine atom), (2) a cyano group,

(3) an optionally halogenated C_{1- 6}alkyl group (e.g., methyl, isopropyl, trifluoromethyl) , and

(4) an. optionally halogenated C₁- ₆alkoxy group (e.g., trifluoromethoxy) .

[0096]

Ring D is still more preferably benzene or pyridine, each of which is optionally further substituted by.l to 3

substituents selected from

(1) a halogen atom (e.g., a fluorine atom, a chlorine atom), (2) a cyano group,

(4) an optionally halogenated C₁- ₆alkoxy group (e.g.,

trifluoromethoxy) .

[0097] In another embodiment, Ring D is more preferably a C_6-14 aromatic hydrocarbon ring (preferably benzene) or a 5- to .14- membered (preferably 5- to 10-membered) aromatic heterocycle (preferably a 5- or 6-membered monocyclic aromatic heterocycle (preferably pyridine) ) , each of which is optionally further substituted by 1 to 3 substituents selected from

(1) a halogen atom (e.g., a fluorine atom, a chlorine atom),

(2) a cyano group,

(4) an optionally halogenated C_{1- 6}alkoxy group (e.g.,

methoxy, trifluoromethoxy) .

[0098]

In this embodiment, Ring D is still more preferably benzene or pyridine, each of which is optionally further

substituted by 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 C₁- ₆alkyl group (e.g., methyl, isopropyl, trifluoromethyl) , and

(4) an optionally halogenated C_{1- 6}alkoxy group (e.g.,

methoxy, trifluoromethoxy) .

[0099]

W is a bond, or a spacer in which the number of atoms in the main chain is 1 to 4.

[0100]

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) .

[0101]

Specific examples of the "spacer in which the number of atoms in the main chain is 1 to 4" for W include

(1) a bond;

(2) a Ci-4 alkylene group (e.g., -CH₂-, -(CH₂)2-_/ -CH(CH₃)-, - CH₂-CH(CH₃>-, -CH(CH₃)-CH₂-, -(CH₂)₃-, -(CH₂)₄- etc.) optionally substituted by the aforementioned substituent group A

(preferably a halogen atom (e.g., a fluorine atom, a chlorine atom) , 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(O), or S(O)₂;

(5) - (CH₂)_m1-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) -X`- (CH₂)m-X²- wherein X¹ and X² are each independently 0, C(O), NR⁶ (R⁶ is a hydrogen atom or a substituent), S, S (O) or S(0)2, and m is an integer of 1 to 2;

(7) -C0-NR⁶- or -NR⁶-C0- wherein R⁶ is as defined above;

(8) -S(O)₂-NR⁶- or -NR⁶-S (O)₂- wherein R⁶ is as defined above;

(9) a C₃-.₆cycloalkylene (e.g.., cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene etc.);

(10) a divalent non-aromatic heterocyclic group (e.g., 1,2- aziridiriediyl, 1, 3-azetidinediyl, 1, 3-pyrrolidinediyl, 1,3- piperidinediyl, 1, 4-piperidinediyl, 1, 4-morpholinediyl etc.);

(11) -X¹-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.

[0102]

W is preferably

(1) a C_1-4 alkylene group (e.g., -CH₂-) ,

(2) -SO₂-,

(3) -(CH₂)_m1-0- wherein ml is an integer of 0 to 3 (e.g., - CH₂CH₂O-) , or

(4) -0-(CH₂)in2- wherein m2 is an integer of 0 to 3 (e.g., - OCH₂CH₂-) .

W is more preferably -CH₂-, -S0₂-_/ -CH₂CH₂0- or -OCH₂CH₂-.

[0103]

In another embodiment, W is preferably

(1) a Ci-4 alkylene group (e.g., -CH₂-, -CH(CH₃)-),

(2) -SO₂-,

(3) -(CH₂)_m1-0- wherein ml is an integer^' of 0 to 3 (e.g., - CH₂CH₂O-) , or

(4) -0-(CH₂)ni2- wherein m2 is an integer of 0 to 3 (e.g., - OCH₂CH₂-).^'

In this embodiment, W is more preferably -CH₂-, -CH(CH3)-, -SO₂-, -CH₂CH₂O- or -OCH₂CH₂-.

[0104]

Preferable examples of compound (I) include the following compounds.

[0105]

[Compound A-l]

Compound (I) wherein

the partial structure:

[0106]

[0107]

is

[0108]

[0109]

Ring A is benzene optionally further substituted by 1 to 3 halogen atoms (e.g., a fluorine atom, a chlorine atom);

Ring E is a C_3-6 cycloalkane (e.g., cyclopropane);

R¹ and R² are each ^' independently a hydrogen atom or a C_{1- 6} alkyl group (e.g., methyl, ethyl) [preferably R¹ is a C_{1- 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 C_3-10 cycloalkane, more preferably a C_3-6 cycloalkane (e.g., cyclopropane) ) ;

R³ is a hydrogen atom;

Ring C is a C₆-₁₄ aromatic hydrocarbon ring (preferably benzene) optionally further substituted by 1 to 3 (preferably one) substituents selected from a carboxy group (including a carboxylato group) and a C₁- ₆alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl ) [preferably optionally

further substituted by 1 to 3 (preferably one) carboxy groups (including a carboxylato group) ] ;

Ring D is a C_6-14 aromatic hydrocarbon ring (preferably benzene) or a 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocycle (preferably a 5- or 6-membered monocyclic aromatic heterocycle (preferably pyridine) ) , each of which is optionally further substituted by 1 to 3 ^' substituents selected from

(1) a halogen atom (e.g., a fluorine atom, a chlorine atom),

(2) a cyano group,

(3) an optionally halogenated C_{1- 6}alkyl group (e.g., methyl, isopropyl, trifluoromethyl) , and (4) an optionally halogenated C_{1- 6}alkoxy group (e.g., trifluoromethoxy) ; and

W is -CH₂-, -SO₂-, -CH₂CH₂O- or -OCH₂CH₂-.

[0110]

[Compound A-2]

Compound (I) wherein

the partial structure:

[0111]

[0112]

is

[0113]

[0114]

Ring A is a 5- or 6-membered aromatic ring (preferably 6-membered aromatic ring (preferably benzene, pyridine, particularly preferably benzene) ) optionally further

substituted by 1 to 3 halogen atoms (e.g., a fluorine atom, a chlorine atom) ;

Ring E is a C₃- ₆cycloalkane (e.g., cyclopropane, cyclopentane) or a 3- to 14-membered (preferably 4-' to 10- membered) non-aromatic heterocycle (preferably a 3- to 8- membered monocyclic non-aromatic heterocycle (e.g.,

tetrahydropyran) ) ; R¹ and R² are. each independently a hydrogen, atom or a C_{1- 6} alkyl group (e.g.., methyl, ethyl) [preferably R¹ is a C_{1- 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 C_3-10 cycloalkane, more preferably a C_3-6 cycloalkane (e.g., cyclopropane) ) ;

R³ is a hydrogen atom;

Ring C is a C_6-14 aromatic hydrocarbon ring (preferably benzene) or a 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocycle (preferably a 5- or 6-membered monocyclic aromatic heterocycle (preferably pyridine) ) , each, of which is optionally further substituted by 1 to 3 (preferably one) substituents selected from a carboxy group (including a

carboxylato group) and a C₁- ₆alkoxy-carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl) [preferably optionally

Ring D is a C_6-14 aromatic hydrocarbon ring (preferably benzene) or a 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocycle (preferably a 5- or 6-membered monocyclic aromatic heterocycle (preferably pyridine) ) , each of which is optionally further substituted by 1 to 3 substituents selected from . ^'

(1) a halogen atom (e.g., a fluorine atom, a chlorine atom),

(2) a cyano group,

(3) an optionally halogenated C_{1- 6}alkyl group (e.g., methyl, isopropyl, trifluoromethyl) , . and

(4) an optionally halogenated C_{1- 6}alkoxy group (e.g.,

methoxy, trifluoromethoxy) ; and

W is -CH₂-, -CH(CH₃)-, -SO₂-, -CH₂CH₂O- or -OCH₂CH₂-.

[0115]

[Compound A-3]

Compound (I) wherein

the partial structure:

[0116]

[0119]

Ring. A is benzene optionally further substituted by 1 to 3 halogen atoms (e.g., a fluorine atom, a chlorine atom);

Ring E is a C₃- ₆cycloalkane (e.g., cyclopropane,

cyclopentane) or a 3- to 14-membered (preferably 4- to 10- membered) non-aromatic heterocycle (preferably a 3- to 8- membered monocyclic non-aromatic heterocycle (e.g.,

tetrahydropyran) ) ;

R¹ and R² are each independently a hydrogen atom or a C₁- ₆ alkyl group (e.g., methyl, ethyl) [preferably R¹ is a C₁- ₆alkyl group (e.g., methyl._/ ethyl) and R² is a hydrogen atom], or R¹ and R² are joined together to form a C_3-6 cycloalkane (e.g., cyclopropane) ;

R³ is a hydrogen atom;

Ring C is a C_6-14 aromatic hydrocarbon ring (preferably benzene) or a 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocycle (preferably a 5- or 6-membered monocyclic aromatic heterocycle (preferably pyridine) ) , each of which is optionally further substituted by 1 to 3 (preferably one) substituents selected from a carboxy group (including a

Ring D is a C_6-14 aromatic hydrocarbon ring (preferably benzene^") or a 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocycle (preferably a 5- or 6-membered monocyclic aromatic heterocycle (preferably pyridine) ) , each of which is optionally further substituted by 1 to 3 substituents selected from

(1) a halogen atom (e.g., a fluorine atom, a chlorine atom),

(2) a cyano group,

(3) an optionally halogenated C₁- ₆alkyl group (e.g., methyl., isopropyl, trifluoromethyl) , and

(4) an optionally halogenated C₁- ₆alkoxy group (e.g.,

methoxy, trifluoromethoxy) ; and

W is -CH₂-, -CH(CH₃)-, -S0₂-, -CH₂CH₂0- or -OCH₂CH₂-.

[0120]

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, p.icoline, 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, benzenesulfohic acid, p- toluenesulfonic acid and the like. Preferable examples of the salt with basic amino acid include salts with arginine,. lysine, ornithine and the like. Preferable examples of the salt with acidic amino acid include salts with aspartic acid, glutamic acid and the like.

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.

[0121]

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.

[0122] 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.

[0123]

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 berizylcarbamate group, a benzyl group, a methyl group, an ethyl group, a tert-butyl and the like-.

[0124]

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.

.[0125]

Unless otherwise specified, each symbol in the general formulas in the schemes is as defined above.

[0126]

Compound (I) is prepared as outlined in Schemes below: Scheme 1: Synthesis of compound (I)

[0127]

[0128]

As 'shown in Scheme 1, compound (I) may be prepared by reacting compound (II) with compound (III) wherein W is a spacer in which the number of atoms in the main chain is 1 to 4, and X is a leaving group such as a halogen atom, a C₁- ₆ alkylsulfonyl group or a C_6-14 arylsulfonyl group, or X/WX may ^" be a formyl group (reductive alkylation) , or X may be a hydroxy group (cross coupling reaction),, or WX may be a halogen atom or a triflate (Ullman or Buchwald coupling) or a boronic acid or a boronate ester (Chan-Evans-Lam coupling) . The functional group in compound (II) or (III) may be

protected if necessary, and after the iV-alkylation- reaction or iV-arylation reaction,, it can be removed by a conventional means. Compound (I) having an ester moiety may be further hydrolyzed to obtain the corresponding carboxylic acid or its salt, which may be further derivatized. Compound (III) may be a commercially available product, or can also be prepared according to a. method known per se or a method analogous ^' thereto.

[0129]

Scheme 2: Synthesis of compound (I) wherein W is C(O) or S(O)₂

[0130]

[0131] As shown in Scheme 2, compound (I) may be prepared by coupling compound (II) With compound (III) wherein X is - C(O)OH or -S(O)₂0H, or a reactive derivative thereof such as an acid halide (e.g., an acid chloride, an acid bromide)^: or a mixed anhydride (e.g., a mixed anhydride with a chloroformate) . The functional group in compound (II) or. (Ill) may be

protected if necessary, and after the amide/sulfonamide

coupling reaction, it can be removed by a conventional means. Compound (I) having an ester moiety^'may be further hydrolyzed to obtain the corresponding carboxylic acid, or its salt, which may be further derivatized.

[0132]

Scheme_.3: Synthesis of compound (I)

[0133]

[0134]

As shown in Scheme 3, compound (I) may be prepared by coupling compound (IV) with compound (V) (amide coupling

reaction) . The functional group in compound (IV) or (V) may be protected if necessary, and after the amide coupling reaction, it can be removed by a conventional means. ^' Compound (I) having an ester moiety may be further hydrolyzed to obtain the

corresponding carboxylic acid, which may be further

derivatized. Compound (V) may be a commercially available product, or can also be prepared according to a method known per se or a method analogous thereto.

[0135]

Scheme 4: Synthesis of compound (lb) wherein Ring C is further substituted by a group of the formula: - (CR⁶R⁷) _nC (O) OR⁵ wherein R⁶ and.R⁷ are each independently a hydrogen atom or a C_{1- 6}alkyl group, or R⁶ and R⁷ are joined together to form a C_3-6

cycloalkane, R⁵ is a C_{1- 6}alkyl group, and n is 0-1

[0136]

[0137]

As shown in Scheme 4, compound (lb) may be prepared by carbonylation of compound (la) wherein R⁴ is a halogen atom, preferably a bromine atom. The functional group in compound (la) may be protected if necessary, and after the

carbonylation, it can be removed by a conventional means.

Compound (la) may be. prepared according to the method Schemes 1 to 3 wherein Ring C is substituted by R⁴. Compound (lb) may also be prepared according to the method Schemes 1 to 3 wherein Ring C is substituted by a group of the formula: - (CR⁶R⁷)_nC(O)OR⁵.

[0138]

Scheme 5: Synthesis of compound (Ic) wherein Ring C is further substituted by a group of the formula: -(CR⁶R⁷)_nC(O)OH wherein each symbols is as defined in above

[0139]

[0140]

As shown in Scheme 5, compound (Ic) may be prepared by ester hydrolysis of compound (lb) .

[0141]

Scheme 6: Synthesis of compound (Id) wherein Ring C is further substituted by 5-tetrazolyl^'

[0142]

[0143]

. As shown in Scheme 6, compound CId) may be prepared from compound (la) wherein R⁴ is a cyano group, by conversion of the cyano group to 5-tetrazolyl (tetrazole formation) .

[0144]

Scheme 7: Synthesis of compound (II)

[0145]

[0146]

As shown in Scheme 7, compound (II) may be prepared by amide coupling of compound (VI) wherein R is a hydrogen atom or a lower alkyl group, and PG is an amino-protecting group such as tert-butoxycarbonyl with compound (V) to obtain compound (VII) , followed by deprotection.

[0147]

Scheme 8: Synthesis of compound (IV)

[0148]

[0149]

As shown in Scheme 8, compound (IV) may be prepared by deprotection of compound (VI) wherein R is a lower alkyl group such as methyl, ethyl, and PG is an amino-protecting group such as tert-butoxycarbonyl to obtain compound (VIII) ,

followed by N-alkylation and subsequent hydrolysis.

[0150]

N-Alkylation:

Alkyl compounds haying a suitable leaving group such as a halogen atom, a C_{1- 6}alkylsulfonyl group and a C_6-14 arylsulfonyl group may be reacted with an amine. The reaction may be carried out in the absence or presence of a base, in an

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 examples of the polar solvent inert to the reaction include acetonitrile, alcohols (e.g., methanol, ethanol, propanol, n- butanol etc.), chlorinated solvents (e.g., chloroform,

dichloromethane, 1, 2-dichloroethane etc.), ethers (e.g., tetrahydrofuran (THF) , dioxane, dimethoxyethane (DME) etc.), amides (e.g., N,N-dimethylformamide (DMF) , N,N- dimethylacetamide (DMA), iV-methylpyrrolidine (NMP) etc..) and non-polar solvents (e.g., toluene etc.), along with a phase transfer catalyst. Additionally, the iV-alkylation may be carried out in presence of an ionic liquid such as l-butyl-3- methylimidazolium tetrafluorophos^'phate [Bmim(PF4)], l-butyl-3- methylimidazolium hexafluorophosphate [Bmim(PF6) ] and tetrabutylammonium chloride [TBAC] . The ionic liquid may be used as a reaction solvent, or it may be used as an additive when the N-alkylation is conducted in the above-mentioned solvent. In addition, microwave irradiation may be employed to enhance the rate of the iV-alkylation.

Alternatively, the N-alkylation may be carried out by cross coupling of an appropriate amine and alcohol under

Mitsunobu reaction condition using a phosphine (e.g.,

triarylphosphine, tricycloalkylphosphine etc.) and a dialkyl azodicarboxylate (e.g., diethyl azodicarboxylate (DEAD), .

diisopropyl . azodicarboxylate (DIAD) etc.). The cross coupling is carried out in an appropriate solvent such as THF and dioxane at 0 to 40°C to reflux temperature.

Alternatively, the N-alkylation may be carried out by using reductive amination (reductive alkylation) using an appropriate amine, aldehyde and reducing agent (e.g., sodium cyanoborohydride (NaBH3CN) , sodium triacetoxyborohydride

(NaBH(0C0CH3) 3) etc.). The preferred solvent^'s for this

reaction are chlorinated solvents such as dichloromethane, 1, 2-dichloroethane etc.

[0151]

N-Axylation:

Aryl compounds having a suitable leaving- group such as a halogen atom, a triflate, a boronic acid and a boronate ester may be reacted with an amine using an appropriate catalyst.

The N-arylation reaction may be carried out according to

methods known from the literature such as copper mediated

Ullman coupling, Buchwalds palladium catalyzed cross coupling and Chan-Evans-Lam modified Ullman coupling.

The reaction may be carried out in presence of a suitable catalyst such as copper (I) or copper (II) salts (e.g. copper chloride, copper acetate, copper triflate) , palladium, rhodium, iron etc. The reaction may be carried out in presence of a suitable ligand such as diamines (e.g. ethylene diamine, Ν,Ν'- dimethylamine, cis-cyclohexane-1, 2-diamine, trans-cyclohexane- 1, 2-diamine) ^: mono and diketones, diesters, ketone-esters. The reaction may be carried out in presence of base as an additive such as cesium carbonate, potassium carbonate, potassium

phosphate, potassium hydroxide, triethylamine, pyridine, dimethylaminopyridine . Preferred solvent for the reaction may be toluene, dichloromethane, dichloroethane, DMF, N,N- dimethylacetamide, dioxane, THF, acetonitrile, methanol, butanol, iso-butanol, t-butanol and water. The reaction may be carried out at a temperature ranging from room temperature to 150°C, preferably 40°C to 100°C.

[0152]

Amide Coupling:

Condition-I :

Amide coupling may be carried out using any suitable amide coupling regent (e.g., oxalyl chloride, thionyl chloride, BOP-C1, DCC, HOBt, HOAt, HATU, EDCI, propylphosphonic

anhydride (T3P) , alkyl chloroformate etc.). Preferred base is selected from organic non-nucleophillic bases (e.g.,

triethylamine, di-isopropylethylamine, pyridine, N- methylpy^'rrolidine, iV,N-dimethylaminopyridine, DBU etc.), sodium hydride, sodium hydroxide, other hindered amines and pyridines. The amide coupling may be carried out in the

presence of a solvent such as dichloromethane, dichloroethane, DMF, Ν,Ν-dimethylacetamide, THF, acetonitrile and a mixture thereof. The amide coupling may be carried out at a

temperature ranging from -20°C to 150°C, preferably from about 0°C to ^'100°C. The amide coupling may be carried put optionally in presence of a catalytic amount of N,N-dimethylformamide

(DMF) .

[0153]

Condition-II :

When an ester is used instead of a carboxylic acid as a raw material compound, the amide coupling may be carried out by heating an ester and an amine either in the absence of a solvent or in presence of a high boiling solvent such as toluene, xylene and DMSO. The amide coupling may be carried out in presence of a trialkyl aluminium (Chem. Commun., 2008, 1100-1102) .

[0154]

Sulfonamide Coupling:

Sulfonamide may be prepared by reacting an appropriate amine with an appropriate sulfonyl halide in the presence of a base such as organic non-nucleophillic bases (e.g.,

triethylamine, di-isopropylethylamine, AT-methylpyrrolidine, iV,N-dimethylaminopyridine,. DBU etc.), other hindered amines . and pyridines. The sulfonamide coupling may be carried out in the presence of a solvent such as dichloromethane,

dichloroethane, THF, 1,4-dioxane, acetonitrile, N,N- dimethylformamide (DMF) and a mixture thereof.

[0155]

Caxbonylation 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. Suitable examples of the catalyst include palladium reagents such as palladium acetate and palladium dibenzylacetone; and nickel catalysts. Preferred base is selected from iV,iV-diisopropylethylamine, N- methylmorpholine, triethylamine etc. If required, the

carbonylation reaction may be carried out in the presence or absence of an additive such as 1,1'- bis (diphenylphosphino) ferrocene, triphenylphosphine and 1,3- bis- (diphenylphosphine) propane. The carbonylation 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 ^'80°C.

[0156]

Ester Hydrolysis: Ester hydrolysis may be carried out under a general saponification condition employing an inorganic base such as alkali and alkaline earth^' metal hydroxides, carbonates and bicarbonates (e.g., lithium hydroxide, sodium hydride, sodium carbonate, potassium carbonate, cesium carbonate etc.) in the presence of a solvent such as water, methanol, ethanol,

diethyl ether, THF, DME, DMF and DMSO and mixtures thereof.

The ester hydrolysis may be carried out at 0°C to refluxing temperature.

Alternatively, the ester hydrolysis may be carried out under an acidic condition, for example, in presence of a

hydrogen halide (e.g., hydrochloric acid, hydrobromic acid etc.), a sulfonic acid (e.g., p-toluenesulfonic acid,

benzenesulfonic acid, pyridium p-toluenesulfonate etc.) or a carboxylic acid (e.g., acetic acid, trifluoroacetic acid etc.). Suitable examples of the solvent includes acetonitrile,

toluene, 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. ) ; hexamethylphophoramide and DMSO. The ester hydrolysis may be carried out at temperature in the range from -20°C to 100°C, preferably from 20°C to 35°C.

[0157]

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 examples of the tetrazole forming reagent includes sodium azide, lithium azide, trialkyltin azide and

trimethylsilylazide. The tetrazole formation may be carried out in presence or absence of a catalyst such as dialkyltin oxide (alkyl is methyl or butyl) , alkylamine hydrochloride or hydrobromide, lithium chloride and copper sulphate . The

tetrazole formation may be carried out in the presence or absence of an acid or a base. Suitable examples of the base include trimethylamine, triethylamine and N,N- diisopropylethylamine, and suitable examples of the acid include ammonium chloride, hydrogen chloride, aluminium

chloride and zinc bromide. The tetrazole formation may be carried out at temperature 50°C to 200°C.

[0158]

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.

[0159]

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, C₁- ₆ alkyl-carbonyl (e.g., acetyl, propionyl etc.), phenylcarbonyl, C₁- ₆alkoxy-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.), C₁- ₆alkyl-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.

[0160]

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.

[0161]

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 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.

[0162]

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) .

[0163]

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, eth^'oxycarbonylation, 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 acetylatian, 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 (Γ) to ethyl esterification, phenyl esterification, carboxymethyl esterification, dimethylaminometnyl 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.

[0164]

A prodrug of compound (I) may also be one which is converted to compound (I) under physiological conditions as described in "IYAKUHIN no KAIHATSU (Development of .

Pharmaceuticals)", Vol. 7, Design of Molecules, p. 163-198,. Published by HIROKAWA SHOTEN (1990) .

[0165]

- In the present specification, compound (I) and a prodrug thereof are sometimes collectively abbreviated as "the

compound of the present invention".

[0166]

When compound (I) has isomers such as optical isomer, stereoisomer, positional isomer, rotamer and the like, such isomers and a mixture thereof are also encompassed in compound (I) . 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 known per se (e.g., concentration, solvent extraction, column chromatography, recrystallization, etc.).

[0167]

Compound (I) may be a crystal, and a single crystal form and a mixture of crystal forms are both encompassed in

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, ¹¹C,

¹⁴C, 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 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.

[0168]

.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 belo.w.

[0169]

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.

[0170]

Preferable examples of the excipient include lactose, sucrose, D-marinitol, D-sorbitol, starch, gelatinated starch, dextrin, crystalline cellulose, low-substituted

hydroxypropylcellulose, sodium carboxymethylcellulose, gum arabic, pullulan, light anhydrous silicic acid, synthesis aluminum silicate and magnesium alumino metasilicate .

[0171]

Preferable examples of the lubricant include magnesium stearate, calcium stearate, talc and colloidal silica.

[0172]

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.

[0173]

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 .

[0174]

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.

[0175]

Preferable examples of the solubilizing agents include polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate,, sodium citrate, soclium salicylate and sodium acetate.

[0176]

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.

[0177]

Preferable examples of the isotonicity agent include sodium chloride, glycerol, D-mannitol, D-sorbitol and glucose.

[0178]

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.

[0179]

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.

[0180]

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) . [0181]

Preferable examples of the sweetening agent include saccharin sodium, dipotassium glycyrrhizinate, aspartame and stevia.

[0182]

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) .

[0183]

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.

[0184]

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.

[0185]

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%.

[0186]

During production of an oral preparation, coating may be applied as necessary for the purpose of masking of taste, enteric property or durability.

[0187]

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.

[0188]

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.

[0189]

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

[0190]

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.

[0191] 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.

[0192]

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.

'[0193]

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) .

[0194]

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.

[0195]

(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 di^'sease, 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) ) .

[0196]

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.

[0197]

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.

[0198]

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.

[0199]

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)

(i) 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, fenbufeh, 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,

.[0200]

(2) disease-modifying anti-rheumatic drugs (DMARDs)

(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

[0201]

(3) anti-cytokine drug

(I) protein drug

(i) TNF inhibitor

etanercept, infliximab, adalimumab, certolizumab pegol, golimumab, PASSTNF-α, 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, CXCRl & 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.

[0202]

(4) integrin inhibitor

natalizumab, vedolizumab, AJM300, TRK-170, E-6007 and the like..

(5) immunomodulator (immunosuppressant)

methotrexate, cyclophosphamide, MX-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.

[0203]

(8) angiotensin II receptor antagonist

candesartan, candesartan eilexetil, 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.

[0204]

(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 hexahydrobenzoate, 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.

[0205]

(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 compounds 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

[0206]

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.

[0207]

(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.

[0208]

(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, liyidomycin, 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-l,2,4-triazol-l-yl)propyl]-4-[4-(2,2,3,3- tetrafluoropropoxy) phenyl] -3 (2H, 4Ή) -1, 2, 4-triazolone,

fluconazole, itraconazole and the like] and the like.

[0209]

(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.

[0210]

(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.

[0211] ^■

(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. [0212]

(9) hypotensive diuretic drug

hexanethonium bromide, clonidine hydrochloride,

hydrochlorothiazide, trichlormethiazide, furosemide,

ethacryhic 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.

[0213]

(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.

[0214]

(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, ibu^'dilast, ketotifen, terfenadine, mequitazine, azelastine hydrochloride, epinastine, ozagrel hydrochloride_/ pranlukast hydrate, seratrodast. and the like.

(19) cardiac stimulants

trans-7i-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, guanabehz and the like.

(21) vasoconstrictor

dopamine, dobutamine denopamine and the like.

(22) hypotensive diuretic

hexanethonium 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 .

[0215]

(24) antinarcotic

levallorphan, nalorphine, naloxone or a salt thereof and the like.

(25) liposoluble vitamins

(i) vitamin A: vitamin Ai, vitamin A2 and retinol palmitate

(ii) vitamin D: vitamin Di, D2, D3, D4 and D5

(iii) vitamin E: a-tocopherol, β-tocopherol, γ-tocopherol, δ- tocopherol, dl-a-tocopherol nicotinate

(iv) vitamin K: vitamin Ki, ¾, K3 and 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.

[0216]

(30) therapeutic agent for allergic rhinitis

sodium cromoglicate, chlorpheniramine maleate,

alimemazine tartrate, clemastine fumarate, homochl^'orcyclizine 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.

[0217J

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, pxaprozin,. phenylbutazone, piroxicam, sulindac, tolmetin or zomepirac; cyclooxygenase-2 (COX-2) inhibitors, for example, celecoxib, rofecoxib, meloxicam, 4- ( 4-cycl.ohexyl-2-methyl-1, 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 it^'s metabolite

dextrorphan ((+) -3-hydroxy-N-methylmorphinan) , ketamine, memantine, pyrroloquinoline quinone or cis-4- (phosphonomethyl) -2-piperidinecarboxylic acid or a

pharmaceutically acceptable salt thereof;

(9) a-adrenergic, for example, doxazosin, tamsulosin,

clonidine or 4-amino-6, 7-dimethoxy-2- (5-methanesulfonamido- 1,2,3, 4-tetrahydroisoquinol-2-yl) -5- (2-pridyl) 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 (trifluoromethyl) phenyl] ethoxy-3- (4-fluorophenyl) -4- morpholinyl] methyl] -1, 2-dihydro-3H-l, 2, 4-triazol-3-one,

lanepitant, dapitant or 3- [ [2-methoxy-5- (trifluoromethoxy) 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-jinki-gan, shakuyaku- kanzoh-toh). and vitamin.

[0218]

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.

[0219]

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.

[0220]

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 nig, 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 l 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 h, more preferably from 15 minutes to 1 hour after administration of the compound of the present invention is an example.

Examples

[0221]

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.

[0222]

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.

[0223]

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.

[0224]

XH NMR (protone 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.

[0225]

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.

[0226]

Preparation 1 : Methyl 4- [ (IS) -1- (spiro [cyclopropane-1 , 3 ` - indoline] -7 ` -carbonylamino) ethyl]benzoate [0227]

[0228]

Step 1: Spiro [cyclopropane-1 , 3' -indoline] -2 ' -one

■ .An oven dried round bottom flask equipped with dropping funnel capped with rubber septum and nitrogen inlet and set in a removable dry ice-acetone bath was purged with nitrogen, and charged with an indolin-2-one (30.0 g, 225.3 mmol) ,

diisopropylamine (66.3 mL, 470.3 mmol) and dry THF (400 mL) . The content of flask was cooled to -20°C. The starting

material was partially dissolved in THF at room temperature, re-precipitated as reaction mixture, and cooled down. A solution of n-BuLi as a 2.5 M solution in hexanes (360.5 mL, 901.2 mmol) was slowly transferred to dropping funnel via cannula, and then slowly added to the reaction mixture. The rate of addition was adjusted to keep the temperature of reaction mixture at -20 to -30°C. When the addition was complete_y the dry ice bath was removed and replaced with regular ice bath, and the temperature was maintained at 0°C for 1 h. To the resulting reaction mixture was carefully added a solution of 1, 2-dibromoethane (58.24 mL, 675.9 mmol) in THF (60 mL) . The resulting reaction mixture was then stirred 18 h at RT. The reaction mixture was then quenched with brine (40 mL) , con.HCl (60 mL) and water (180 mL) . The resulted mixture (pH 2-3) upon standing separated into two layers. The Organic layer was removed, and the aqueous layer was extracted with ethyl acetate (200 mL) . The combined organic layer was then washed successively with sat. aq. sodium bicarbonate solution, water and brine, dried over sodium sulfate and evaporated under reduced pressure to obtain a solid. The solid thus obtained was washed with heptane: water (1:1) to give the title compound as a solid (35 g, 97.6%).

MS(ESI)m/z: 160.1 [M+l] ; ¹HNMR (400 MHz, DMSO-d₆) : δ 1.50-1.55 (m, 2H), 1.44-1.48 (m, 2H)-, 6.88-6.97 (m, 3H) , 7.14 (t, J = 8.4 Hz, 1H) , 10.6 (s, 1H) .

[0229]

Step 2: Spiro [cyclopropane-1,3' -indoline]

To mixture of spiro [cyclopropane-1, 3 ` -indoline] -2 ' -one (35.0 g,. 219.87 mmol) in THF (750 niL) was slowly added lithium aluminium hydride (2M solution in THF) (219.9 mL, 439.7 mmol) at 0°C. The resulting mixture was allowed to be warmed to room temperature and then heated to reflux for 18 hour under argon atmosphere. Upon completion as monitored by TLC, the reaction mixture was cooled to room temperature, quenched with ice, basified with aqueous ammonia, and extracted with ethyl

acetate (2 x 750· mL) . The combined organic layers were washed successively with water (100 mL) and brine (100 mL) , dried over sodium, sulfate and concentrated under vacuum to obtain a crude oily product (32 g, 100%) . The product was subjected to next reaction without further purification.

MS(ESI)m/z: 146.1 [M+l] ; ¹HNMR (400 MHz, DMSO-d₆) : δ 0.88 (s, 4H) , 3.43 (s, 2H), 5.54 (s, 1H) , 6.44-6.55 (m, 3H) , 6.85 (t, J = 7.6 Hz, 1H) .

[0230]

Step 3: tert-Butyl spiro [cyclopropane-1, 3 '-indoline] -1'- carboxylate

To a solution of spiro [cyclopropane-1, 3 ` -indoline] (32 g, 220.4 mmol) in dichloromethane (500 mL) were added di-tert- butyl dicarbonate (52.8 g, 242.42 mmol^") and triethylamine

(92.15 mL, 660.1 mmol) at 0^eC. The mixture was stirred at room temperature for 18 h. After the completion of the reaction as confirmed by TLC, the reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by flash column chromatography using silica gel and hexanes. The pure' column fractions were combined and concentrated to give the title compound as a white solid (37 g, 68.5%).

MS(ESI)m/z: 190.1 [M-tBu]+l]; ^lHNMR (400 MHz, DMSO-d₆) : δ 0.98- 1.00 (m, 2H), 1.07-1.97 (m, 2H) , 1.50 (s, 9H) , 3.90 (s, 2H}., 6.74 (d, J = 7.6 Hz, 1H) , 6.89 (t, J = 7.6 Hz, 1H) , 7.10(t, J = 7.6 Hz, 1H), 7.60 (bs, 1H)

[0231]

Step 4: l'-te-rt-Butoxycarbonylspiro [cyclopropane-1,3'- indoline] -7 ` -carboxylic acid

A mixture of tert-butyl spiro [cyclopropane-1, 3 ` -indoline]-l'-carboxylate (37 g, 150.8 mmol) and TMEDA (29.8 mL,

199.1 mmol) in diethyl ether (750 mL) was cooled to -78°C and maintained under argon. 1.3 M sec-butyl lithium cyclohexane solution (139.23 mL, 181 mmol) was added in a dropwise manner to the resultant reaction mixture. The reaction mixture was stirred for 1 h at -78°C. Carbon dioxide generated by passing dry ice vapors through cone, sulfuric acid solution was

bubbled in the reaction mixture for 30 min, and the bath was removed. After 10 min of stirring, the reaction mixture was quenched with 1 N HC1 (pH 2-3) , warmed to RT and extracted with ethyl acetate (4 x 500 mL) . The combined organic layers were washed successively with water (100 mL) and brine (100 mL) , dried over sodium sulfate and concentrated under vacuum. The residue thus obtained was triturated with 200 ml of

diethyl ether :hexane (1:1) to give the title compound as an off-white solid (24.5 g, 56.15%).

MS(ESI)m/z: 234.1 [ [M-t-Bu] +1] ; ¹HNMR (400 MHz, DMSO-d₆) : δ 1.00-1.03 (m, 2H), 1.11-1.13 (m, 2H) , 1.44 (s, 9H) , 3.98- (s, 2H), 6.89 (d, J= 7.6 Hz, 1H) , 7.00 (d, J= 7.6 Hz, 1H) , 7.35 (d, J= 7.6 Hz, 1H) , 12.6 (bs, 1H)

[0232]

Step 5: tert-Butyl 7 ' - [ [ (IS) -1- (4- methoxycarbonylphenyl) ethyl] carbamoyl] spiro [cyclopropane-1 , 3 ' - indoline] -1 ` -carboxylate

To a mixture of 1 ` -tert-butoxycarbonylspiro [cyclopropane- 1, 3' -indoline] -7 ` -carboxylic acid (6.5 g, 22.5 irimol) , methyl 4-[ (IS) -1-aminoethyl] benzoate (6.37 g, 33.7 mmol) and HATU (10.2 g, 26.9 mmol) in acetonitrile (100 mL) was added DIPEA (11.73 mL, 67.39 mmol) at 0°C, and the resulting reaction

5 mixture was stirred for 18 h at RT. The reaction mixture was concentrated, the residue was quenched with water (100 mL) , and the mixture was extracted with ethyl acetate (3 x 150 mL) . The combined organic layers were washed successively with water (100 mL) and brine (100 mL) , dried over sodium sulfateo and concentrated under vacuum. The crude mixture thus obtained was purified by flash column chromatography using silica gel and 20-25% ethyl acetate in hexane. The pure column fractions were combined and concentrated to give the title compound as an off-white solid (9 g, 89%).

5 MS(ESI)m/z: 451.2 [ [M+l] ; ¹HNMR (400 MHz, DMSO-d₆) : δ 1.0 (s, 2H) , 1.23 (s, 2H), 1.42 (s, 9H) , 1.43 (d, J= 6.8 Hz, 3H) , 3.84 (s, 3H), 3.99^' (s, 3H) , 5.07-5.11 (m, 1H) , 6.83 (t, J = 7.6 Hz, 1H) , 7.00 (t, J = 7.2 Hz, 1H) , 7.17 (d, J= 7.6 Hz, 2H), 7.55 (d, J= 8.0 Hz, 2H). , 7.9 (d, J= 8.0 Hz, 2H) , 8.430 (d, J = 7.6 Hz, 1H)

[0233]

Step 6: Methyl 4- [ (IS) -1- (spiro [cyclcpropane-1 ,3 ' -indoline] - 7 ` -carbonylamino) ethyl]benzoate

To a mixture of tert-butyl 7 ` - [ [ (IS) -1- (4- methoxycarbonylphenyl) ethyl] carbamoyl] spiro [cyclopropane-1, 3 ` - indoline] -1 ` -carboxylate (9 g, 117 mmol) in DCM (90 mL) was added TFA (40 mL) at 0°C. The resulting reaction mixture was stirred at RT for 1 h. Upon completion, the reaction mixture was concentrated under vacuum. The residue thus obtained was dissolved in ethyl acetate, and the solution was washed^' successively with saturated aq. sodium bicarbonate solution, water and brine, dried over sodium sulfate and concentrated under reduced pressure to give the title compound as a brown solid (6.5 g, 93%) .

MS(ESI)m/z: 351.1 [M+l]; ¹HNMR (400 MHz, DMSO-d₆) : δ 0.92 (d, J = 6.4 Hz, 4H), 1.48 (d, J = 7.2 Hz, 3H) , 3.55 (s, 2H) , 3.84 (s 3H) , 5.16-5.20 (m, 1H) , 6.46 (d, J= 8 Hz, 1H) , 6.61-6.65 (m, 2H), 7.49-7.52 (m, 3H) , 7.91 (d, J= 8.0 Hz, 1H) , 8.51 (d, J = 7.2 Hz, 1H)

[0234]

The compounds of Preparations 2 to 11 were synthesized in the analogous manner to that of Preparation 1. Various amines used in Step 5 for amide coupling were commercially available or synthesized following literature methods.

[0235] Table 1

[0236]

Preparation 12 : Methyl 4- [1- (spiro [indoline-3, 4 ' - tetrahydropyran].-7 carbonylamino) cyclopropyl]benzoate

.[0237]

[0238]

Step 1: 4- (2-Fluorophenyl) tetrahydropyran-4-carbonitrile To a solution of 2- (2-fluorophenyl) acetonitrile (10.0 g, 74.07 mmol) in DMSO (300 mL) was added sodium hydride (6.8 g, 170.37 mmol) at 0°C portion wise. After 30 minutes, 1-chloro- 2- (2-chloroethoxy) ethane (6.2 mL, 62.9 mmol) was added thereto in dropwise manner, and the reaction mixture was heated at 75°C under nitrogen for 3 hours. The product formation was

confirmed by TLC, then the reaction mixture was poured into ice cold water (3000 mL) and extracted with, ethyl acetate (3^'x 100 mL) . The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under vacuo. The residue thus obtained was purified by column chromatography using 5-8% ethyl acetate in hexane as a mobile phase to give the title compound (8.5 g, 56%) .

MS(EI)m/z: 20-.₆1 (M + 1); ¹H NMR (400 MHz, CDC1₃) : δ 2.16-2.19 (m, 2H), 2.23-2.30 (m, 2H) , 3.91-3.97 (m, 2H) , 4.08 (dd, J = 3.6 & 11.6 Hz, 2H), 7.11-7.17^" (m, 1H) , 7.16-7.22 (m, 1H) ,

7.34-7.37 (m, 1H) , 7.42-7.47 (m, 1H) .

[0239]

Step 2: Spixo[indoline-3,4 ' -tetrahydropyran]

To a solution of 4- (2-fluorophenyl) tetrahydropyran-4- carbonitrile (8.5 g, 41.46 mmol). in 1, 2-dimethoxyethane (150 mL) was added LAH (2.0 M solution, 32 mL, 64.26 mmol) in a dropwise manner at 0°C under nitrogen atmosphere. The reaction mixture was kept on stirring for 3 hours and allowed to come to room temperature. Afterwards, the reaction mixture was heated to reflux temperature and kept on stirring for 26 hours. The product formation was confirmed by TLC, then the reaction mixture was cooled to 0°C and added aqueous saturated- solution of sodium sulphate in dropwise manner. The formed suspension was filtered, the residue was washed with ethyl acetate, and the filtrate was evaporated under vacuo. The residue thus obtained was purified by combiflash column chromatography using 15-20% ethyl acetate in hexane as mobile phase to give the title compound (4.0 g, 51%).

MS(EI)m/z: 190.1 (M + 1); ¹H NMR (400 MHz, , CDC1₃) : δ 1.66 (dd, J = 2.0 & 13.6 Hz, 2H), 1.94-2.02 (m, 2H) , 3.53-3.59 (m, 4H) , 3.94-3.99 (m, 2H) , 6.65 (d, J = 7.6 Hz, 1H) , 6.74-6.77 (m, 1H) , 7.03-7.07 (m, 1H) , 7.09 (d, J= 7.6 Hz, 1H) .

[0240]

Step 3: tert-Butyl spiro [indoline-3 , 4 '—tetrahydropyran] -1- carboxylate

To a solution of spiro [indoline-3, 4` -tetrahydropyran] (4.0 g, 21.16 mmol) in DCM (40 mL) was added triethylamine

(8.8 mL, 63.49 itimol) at 0°C followed by ditert-butyl carbonate (5.0 g, 23.28 mmol).^" The reaction mixture was stirred at room temperature for 5 hours, and the product formation was

confirmed by TLC. The organic solvent was evaporated under vacuo, and the obtained residue was purified by combiflash column chromatography using hexane as mobile phase to give the title compound (3.0 g, 50%).

MS(EI)m/z: 234.1 (M + 1-56) ¹H NMR (400 MHz, , CDC1₃) : δ 1.49- 1.52- (m, 11H), 1.82-1.89 (m, 2H) , 3.42-3.48 (m, 2H) , 3.82-3.87 (m, 4H), 6.95-6.99 (m, 1H) , 7.15-7.19 (m, 1H) , 7.26 (d, J = 7.6 Hz, 1H), 7.58-7.62 (bs, 1H) .

[0241]

Step 4: l-tert-Butoxycarbonylspiro[indoline-3,4'- tetrahydropyran] -7-carboxylic acid

A mixture of tert-butyl spiro [indoline-3, 4 ' - tetrahydropyran] -1-carboxylate (0.5 g, 1.73 mmol) and TMEDA (0.52 mL, 3.46 mmol) in THF (10 mL) was cooled to -78°C and maintained under argon atmosphere. To the above mixture was added sec-butyl lithium in cyclohexane (1.3 M, 2.7 mL, 3.46 mmol) in a dropwise manner. The reaction mixture was stirred for 1.5 h at -78°C. The carbon dioxide generated by passing dry ice vapors through cone, sulfuric acid solution was

bubbled in the reaction mixture for 3 minutes. The reaction mixture was allowed to stir for 10 minutes then quenched with 1 N HC1 (pH 2-3) and warmed to room temperature. The reaction mixture was extracted with ethyl acetate (4 x 20 mL) , and the combined organic layers were washed with water (20 mL) and brine (20 mL) , dried over sodium sulfate and concentrated under vacuum. The residue thus obtained was triturated with diethyl etherrhexane (1:1, 20 mL) to give the title compound (0.35 g, 61%) .

MS(ESI)m/z: 234.1 [M +1]; ¹H NMR (400 MHz, DMSO-d₆) : δ 1.26- 1.40 (m, 11H), 1.80-1.90- (m, 2H) , 3.42.-3.50 (m, 2H) , 3.80-3.88 (m, 2H), 4.00 (s, 2H) , 7.09-7.13 (m, 1H) , 7.41-7.47 (m, 2H) , 12.60 (bs, 1H) .

[0242]

Step 5: tert-Butyl 7- [ [1- (4- methoxycarbonylphenyl) cyclopropyl] carbamoyl] spiro [indoline- 3,4' -tetrahydropyran] -1-carboxylate

To a mixture of 1-tert-butoxycarbonylspiro [indoline-3, 4` - tetrahydropyran] -7-carboxylic acid (0.3 g, 0.9 mmol) , methyl 4- (l-aminocyclopropyl)benzoate . (0.3 g, 1.35 mmol) and HATU

(0.51 g, 1.35 mmol) in acetonitrile (10 mL) at 0°C was added DIPEA (0.46 mL, 2.70 mmol). The resulting reaction mixture was stirred for 2 hours at room temperature. The product formation was confirmed by TLC, then the reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (3 x 20 mL) . The combined organic layers were washed with water (20 mL) and brine (20 mL) , dried over sodium sulfate and

concentrated under vacuo. The crude mixture thus obtained was purified by combiflash column chromatography to give the title compound (0.4 g, 88%).

MS(ESI)m/z: 407.2 [[M-t-Bu]+l]

[0243]

Step 6 : Methyl 4- [1- (spiro [indoline-3 , 4` -tetrahydropyran] -7 carbonylamino) cyclopropyl]benzoate

To a solution of the crude tert-butyl 7-[[l-(4- methoxycarbonylphenyl) cyclopropyl] carbamoyl] spiro [indoline- 3, 4` -tetrahydropyran] -1-carboxylate (0.4 g, 0.79 mmol) in DCM (10 mL) was added TFA (2 mL) at 0°C. The resulting reaction mixture was stirred at room temperature for 2 hours. The reaction completion was confirmed by TLC, then the reaction mixture was concentrated under vaccum. The residue thus obtained was dissolved in. ethyl acetate (3 x 15 mL)' , and the solution was washed with saturated aq. sodium bicarbonate solution, water and brine, dried over sodium sulfate and concentrated under vacuo. The crude mixture thus obtained was purified by. combiflash column chromatography to give the title compound (0.3 g, 94%).

MS(ESI)m/z: 407.2 [M+l]; ¹H NMR (400 MHz, DMSO-d₆) : δ 1.30-1.33 (m, 4H), 1.48 (d, J = 13.2 Hz, 2H) , 1.74-1.81 (m, 2H) , 3.39- 3.45 (m, 2H) , 3.51 (s, 3H) , 3.78-3.80. (m, 4H) ,. 6.49-6.53 (m, 1H), 6.63 (s, 1H), 7.12 (d, J = 6.8 Hz, 1H) , 7.26 (d, J= 8.4 Hz, 1H), 7.54 .(d, J= 8.4 Hz, 1H) , 7.83 (d, J = 8.8 Hz, 1H) , 8.90 (s, 1H).

[0244]

Preparation 13: Methyl 4- [1- (spiro[l,2-dihydropyrrolo[3,2- c]pyridine-3 , 1 ' -cyclopropane] -7- carbonylamino) cyclopropyl]benzoate

[0245]

[0246]

Step 1: 1- (4-Chloro-3-pyridyl) cyclopropanecarbonitrile

To a solution of 2- (2-chlorophenyl) acetonitrile (5.0 g, 32.76 mmol) in THF (100 mL) was added sodium hydride powder

(3.6 g, 65.53 mmol) in a portion at 0°C. To the above

suspension was added 1, 2-dibromoethane (5.01 mL, 49.15 mmol) in a dropwise manner over a period of 30 minutes. The reaction mixture was allowed to stir at room temperature under nitrogen atmosphere for 1.5 hours. The product formation was confirmed by TLC, then the reaction mixture was poured into ice cold water (500 itiL) and extracted with ethyl acetate (3 x 100 mL) . The combined organic layers were washed with brine, and dried over sodium sulfate, and the solvent was evaporated under vacuo. The residue thus obtained was purified by column chromatography using 5-8% ethyl acetate in hexane as a mobile phase- to give the title compound (4.2 g, 72%)

MS(EI)m/z: 179.0 (M + 1); ¹HNMR (400 MHz, DMSO-d₆) : δ 1.52-1.55 (m, 2H), 1.77-1.80 (m, 2H) , 7.67 (d, J = 5.6 Hz, 1H) , 8.56 (d, J = 5.2 Hz, 1H) , 8.70. (s, 1H) .

[0247]

Step 2: Spiro [1, 2-dihydropyrrolo[3, 2-c]pyridine-3,1'- cyclopropane]

To a solution of 1- (4-chloro-3- pyridyl) cyclopropanecarbonitrile (4.2 g, 23.51 mmol) in 1,2- dimethoxyethane (150 mL) was added LAH (2.5 M solution, 23.51 mL, 58.78 mmol) in a dropwise manner at 0°C under nitrogen atmosphere. After addition, the reaction mixture was kept on stirring for 3 hours and allowed to come to room temperature. Next, the reaction mixture was heated to reflux temperature for 3 hours. The product formation was confirmed by TLC, then the reaction mixture was cooled to 0°C and added ^' aqueous saturated solution of sodium sulphate in a dropwise manner. The formed suspension was filtered, the residue was washed with ethyl acetate, and the filtrate was evaporated under vacuo. The residue thus obtained was purified by combiflash using 15-20% ethyl acetate in hexane as mobile phase to give the title compound (3.4 g, 99%) .

MS(EI)m/z: 147.1 (M + 1); ¹H NMR (400 MHz, , DMSO-d₆) : δ 0.80- 0.93(m, 2H), 1.29-1.50 (m, 2H) , 4.82 (s, 2H) , 7.83 (s, 1H) , 8.65 (d, J = 5.6 Hz, 1H) , 8.92 (d, J= 6.8 Hz, 1H) , 12.0-13.5 (bs, 1H) .

[0248]

Step 3 : tert-Butyl spiro [2H-pyrrolo [3 , 2-c]pyridine-3 , 1 ' - cyclopropane] -1-carboxylate

To a solution of spiro [1, 2-dihydropyrrolo [3, 2-c] pyridine- 3,1 '-cyclopropane] (3.4 g, 23.26 irimol) in THF (40 mL) were added triethylamine (6.47 mL, 46.51 mmol) at 0°C, followed by diter,t.-butyl carbonate (7.6 g., 34.88 mmol), and the mixture was stirred at room temperature for 4 hours. The product formation was confirmed by TLC, then the reaction mixture was evaporated under vacuo. The residue thus obtained was purified by combiflash using hexane as mobile phase to give the title compound (5.0 g, 87%).

MS (EI) m/z: 247.1 (M + 1)

[0249]

Step 4: l-tert-Butoxycarbonylspiro[2H-pyrrolo[3,2-c]pyridine- 3,1* -cyclopropane] -7-carboxylic acid

A mixture of tert-butyl spiro [2H-pyrrolo [3, 2-c]pyridine- 3, 1 ` -cyclopropane] -1-carboxylate (5.0 q, 20.30 mmol) and TMEDA (7.61 mL, 50.75 mmol) in THF (10 mL) was cooled to -78°C and maintained under argon atmosphere. To the above mixture was added sec-Butyl lithium in cyclohexane (1.3 M, 39.04 mL, 50.75 mmol) in a dropwise manner. The resultant reaction mixture was stirred for 1.5 h at -78°C. The carbon dioxide generated by passing dry ice vapors through cone, sulfuric acid solution was bubbled in the reaction mixture for 3 minutes. The

reaction mixture was allowed to stir for 10 minutes then quenched with 1 N HC1 (pH 2-3) and warmed to room temperature. The reaction mixture was extracted with ethyl acetate (4 x 20 mL) , and the combined organic layers were washed with water (20 mL) and brine (20 mL) , dried over sodium sulfate and concentrated under vacuum. The residue thus obtained was triturated with diethyl ether: hexane (1:1, 20 mL) to give the title compound (5.0 g, 85%).

MS(ESI)m/z: 291.1 [M + 1]; ¹H NMR (400 MHz, DMSO-d₆) : δ 0.91- 1.09 (m, 2H), 1.10-1.16 (m, 2H) , 1.42 (s, 9H) , 3.88 (s, 2H) , 8.22 (s, 1H), 8.32 (s, 1H) , 12.60 (bs, 1H) .

[0250]

Step 5: text-Butyl 7- [ [1- (4- methoxycazbonylphenyl) cyclopropyl] carbamoyl] spiro [2H- pyrrolo [3,2-c]pyridine-3, 1 ` -cyclopropane] -l-carboxylate

To a mixture of 1-tert-butoxycarbonylspiro [2H- pyrrolo [3, 2-c] pyridine-3, 1 ` -cyclopropane] -7-carboxylic acid

(0.3 g, 1.03 mmol), methyl 4- (1-aminocyclopropyl) benzoate

(0.28 g, 1.24 mmol) and HATU (0.589 g, 1.55 mmol) in DMF (10 itiL) at 0°C was added DIPEA (0.36 mL, 2.06 mmol), and the

resulting reaction mixture was stirred for^' 2 hour at room temperature. The reaction mixture was quenched with water (20 mL) and extracted with ethyl acetate (3 x 20 mL) . The combined organic layers, were washed with water (20 mL) and brine (20 mL) , dried over sodium sulfate and concentrated under vacuo. The crude mixture thus obtained was carried further for the next reaction..

MS(ESI)m/z: 464.1 [ [M + 1]

[0251]

Step 6: Methyl 4- [1- (spiro[l, 2-dihydropyrrolo[3,2-c]pyridine- 3,1' -cyclopropane] -7-carbony1ami.no) cyclopropyl]benzoate

To a solution of the crude tert-butyl .7- [ [1- (4- methoxycarbonylphenyl) cyclopropyl] carbamoyl] spiro [2H- pyrrolo [3, 2-c] pyridine-3,1' -cyclopropane] -l-carboxylate (0.4 g, 0.89 mmol) in DCM (10 mL) was added TFA (2 mL) at 0°C. The resulting reaction mixture was stirred at room temperature for 2 hours. Upon completion, the reaction mixture was

concentrated under vacuum. The residue thus obtained was dissolved in ethyl acetate (3 x 15 mL) , and the solution was washed with saturated aq. sodium bicarbonate solution, water and brine, dried over sodium sulfate and concentrated under vacuo. The crude mixture thus obtained was purified by

combiflash column chromatography to give the title compound (0.3 g, 96%) .

MS(ESI)m/z: 364.2 [M+l]

[0252]

Example Al: Methyl 4- [ (IS) -1- [ [l` - [ (4- chlorophenyl)methyl] spiro [cyclopropane-1 , 3 ' -indoline] -7` - carbony1] amino]ethyl]benzoate [0253]

[0254]

To a stirred^' solution of methyl 4-[(lS)-l- (spiro [cyclopropane-1, 3 ` -indoline] -7 ' - .

carbonylamino) ethyl]benzoate obtained in Preparation 1 (200 mg, 0.57 mmol) in acetonitrile (3 mL) were added DIPEA (184.66 mg, 1.43 mmol) and 4-chlorobenzyl bromide (152.2 mg, 0.74), and the reaction mixture was heated at 80°C for -4 hours. Upon completion as monitored by TLC, the reaction mixture was

quenched with water and extracted with ethyl acetate (100 mL x 2) . The combined organic layers were washed successively with sodium bicarbonate, water and brine, dried over sodium sulfate and concentrated to obtain a crude product. The crude product^' was purified by flash column chromatography using silica gel and 20-25% ethyl acetate in hexane. The pure column fractions were combined and concentrated to give the title compound as an off-white solid (0.17 g, 63%) .

1H NMR (400 MHz, DMSO-d₆) : δ 0.91 (s, 4H) , 1.29 (d, J= 6.8 Hz, 3H), 3.26-3.3-3 (m, 2H) , 4.28 (dd, J = 15.2, 49.2 Hz, 2H) ,

4.99-5.03 (m, 1H) , 6.50-66 (m, 2H) , 6.97 (d, J = 1.2, 6.8 Hz, 1H), 7.16 (d, J= 8 Hz, 2H) , 7.23-7.34 (m, 4 H) , 7.69 (d, J= 8 Hz, 2H), 8.75 (d, J= 8.4 Hz, 1H)

[0255]

Example A2 : Methyl 4- [ (IS) -1- [ [1 ` - [ (3-ehlorpphenyl)methyl] -5 ' - fluoro-spixo [cyclopropane-1 , 3 ' -indoline] -7 ' - caxbonyl] amino] ethyl]benzoate

[0256]

[0257]

The title compound was obtained as an off-white solid (100 mg, 57.5%) using the similar way to that of Example Al using the compound obtained in Preparation 5 (130 mg, 0.36 mmol) and 3-chlorobenzyl bromide (89.38 mg, 0.43 mmol).

MS(ESI)m/z:493.2 (M+l) .

[0258]

Example A3: Methyl 4- [ (IS) -1- [ [1 ' - (4- fiuorophenyl) sulfonylspiro [cyclopropane-1 , 3 ` -indoline] -7 ` - caxbonyl] amino] ethyl]benzoate

[0259]

[0260]

To a stirred solution of methyl 4-[(lS)-l-

(spiro [cyclopropane-1, 3 ` -indoline] -7 ` - carbonylamino) ethyl] benzoate obtained in Preparation 1^" (100 mg, 0.28 mmol) and triethylamine (34.63 mg, 0.34 mmol) in

dichloromethane (2 mL) was added 4-fluorobenzenesulfonyl

chloride (65.97 mg, 0.31 mmol) at 0°C, and the reaction mixture was stirred for 2 h at rt. Upon completion as monitored by TLC, the reaction mixture was quenched with water and extracted with ethyl acetate (3 mL x 2) . The combined organic layers were washed successively with water and .brine, dried over sodium^, sulfate and concentrated to obtain a crude product. The crude product was purified by flash column chromatography using silica gel and.40-60% ethyl acetate in hexane. The pure column fractions were combined and concentrated to give the title compound as an off-white solid (0.11 g, 76%).

MS(ESI)m/z: 509 [[M+l]; ¹H NMR (400 MHz, DMSO-d₆) : δ 0.35-0.60 (m, 4H)., 1.49 (d, J= 7.6 Hz, 3H) , 3.85 (s, 3H), 3.93-4.00 (m. 2H), 5.17-5.21 (m, 1H) , 6.77 (d, J= 8 Hz, 1H) , 7.24 (t, J = 7.6 Hz, 1H), 7.32-7.38 (m, 3H) , 7.44-7.47 (m, 2H) , 7.59 (d, J = 8.4 Hz, 2H), 7.93 (d, J— 8.4 Hz, 2H) , 8.49 (d, J= 8.4 Hz, 1H) .

[0261]

The compounds of Examples A4 to A77 were synthesized in the analogous manner to that of Examples Al to. A3.

[0262]

Table 2

[0263]

Example 1: Potassium 4- [ (IS) -1- [ [1 ' - [ (4- chlorophenyl)methyl] spiro [cyclopropane-1 , 3 ' -indoline] -7 ` - caxbonyl] amino] ethyl]benzoate

[0264]

To a stirred solution of methyl 4- [ (IS) -1- [ [1 ` - [ (4- chlorophenyl) methyl] spiro [cyclopropane-1, 3 ` -indoline] -7 ` - carbonyl] amino] ethyl] benzoate (4.1 g, 8.6 mmol) obtained in Example Al in ethanol (40 mL) was added 2 M potassium

hydroxide solution in water (4.75 mL, 10.4 mmol). The reaction mixture was then heated at 80°C for 3 h. Upon completion as monitored by LC-MS, the reaction mixture was cooled to- RT, and the solvent was evaporated under reduced pressure to obtain an off-white solid. The moisture was removed using azeotropic distillation with toluene, and the resultant solid was

triturated with diethyl ether (100 mL) , filtered and dried to give the title compound as an off-white solid (4.1 g, 95%).

MS(ESI)m/z: 460.8; ¹H NMR (400 mHz, DMSO-d₆) : δ 0.91 (s, 4H) , 1.29 (d, J= 6.8 Hz, 3H) , 3.26-3.33 (m, 2H) , 4.28 (dd, J =

15.2, 49.2 Hz, 2H) , 4.99-5.03 (m, 1H) , 6.50-6.60 (m, 2H) , 6.97 (d, J = 1.2, 6.8 Hz, 1H)^', 7.16 (d, J = 8 Hz, 2H) , 7.23-7.34 (m, 4H),-7.69 (d, J = 8 Hz, 2H) , 8.75 (d, J= 8.4 Hz, 1H)

[0266]

.Example 2: 4- [ (IS) -1- [ [1 ` - [ (3-Chlorophenyl)methyl] -5 ` -fluoro- spiro [cyclopropane-1 , 3 ` -indoline] -7 ` - carbonyl] amino] ethyl]benzoic acid

[0267]

[0268]

To a stirred solution of methyl 4- [ (IS) -1- [ [1 ' - [ (3- chlorophenyl ) methyl ] -5 ` -fluoro-spiro [cyclopropane-1, 3 * - indoline] -7 ' -carbonyl] amino] ethyl] benzoate (0.1 g,.0.2 mmol) obtained in Example A2 in ethanol (1 mL) was added 2 M

potassium hydroxide solution in water (0.1 mL, 0.22 mmol). The reaction mixture was then heated at 80°C for 3 h. Upon

completion as monitored by LC-MS, the reaction mixture was cooled to RT, arid the solvent was evaporated under reduced pressure to obtain .an off-white solid. The moisture was removed using azeotropic distillation with toluene, and the resultant solid was triturated with diethyl ether (10 mL) , filtered and dried to give the title compound as an off white- solid (0.034 g, 34%) .

MS(ESI)m/z: 479.2 (M + 1); ¹H NMR .(400 mHz, DMSO-d₆) : δ 0.98- 1.23 (m, 4H) , 1.32 (d, .J = 6.9 Hz, 3H) , 3.26-3.37 (m, 2H) , 4.17 (dd, J= 15.2 & 8.8 Hz, 2H) , 5.01-5.04 (m, 1H) , 6.63 (dd, J= 2.4 & 8.4 Hz, 1H) , 6.80_, (dd,- J= 2.4 & 10.0 Hz, 1H) , 7.10- 7.16 (m, 4H), 7.40 (d, J= 8.4 Hz, 2H) , 7.79 (d, J = 8.4 Hz, 2H), 8.99 (d, J= 8.0 Hz, 1H) , 12.8 (bs, 1H)..

[0269]

Example 3: Potassium 4- [ (IS) -1- [ [1 · - (4- fluorophenyl) sulfonylspiro [cyclopropane-1 , 3 ` -indoline] -7 ` - carbonyl] amino] ethyl]benzoate

[0270]

To a stirred solution of methyl 4- [ (IS) -1- [ [1* - (4- fluorophenyl) sulfonylspiro [cyclopropane-1, 3 ` -indoline] -7 ` - carbonyl] amino] ethyl] benzoate (0.1 g, 0.2 mmol) obtained in Example A3 in ethanol (1 mL) was added 2 M potassium hydroxide solution in water (0.1 mL, 0.22 mmol). The reaction mixture was then heated at 80°C for 2 h. Upon completion as monitored by LC-MS, the reaction mixture was cooled to RT, and the solvent was evaporated under reduced pressure to .obtain an off-white solid. The moisture was removed using azeotropic distillation with toluene, and the resultant . solid was

triturated with diethyl ether (10 mL) , filtered and dried to give the title compound as an off-white solid (0.017 g, 17%) . MS(ESI)m/z: 495.2; ¹H NMR (400 MHz, DMSO-d₆: δ 0.30-0.40 (m, IH), 0.50-0.59 (m, 2H) , 0.60-0.67 (m, IH) , 1.48 (d, J = 1.2 Hz, 2H), 3.99 (dd, J= 12.8 & 36.8 Hz, 2H) , 5.10-5.15 (m, IH) , 6.75 (d, J= 6.6 Hz, IH) , 7.18-7.49 (m, 8H) , 7.76 (d, J= 8.4 Hz, 2H), 8.32 (d, J= 8 Hz, 2H)

. [0272]

The compounds of Examples 4 to 77 were synthesized in the analogous manner to that of Examples 1 to 3.

-[0273]

Table 3

[0274]

Formulation Example 1 (production of capsule)

1) compound of Example 1

2) fine powder cellulose

3) lactose

4) magnesium stearate

1) , 2), 3) and 4) are mixed and filled in a gelatin capsule.

[0275] ^'

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.

[0276]

Experimental Example 1

Membrane preparation:

The full-length coding sequences for human EP1.

(NM_000955), human EP2 (NM_000956) , 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 ^χ g, 10 min, 4°C) and pellets homogenized by a probe sonicator (Sonics vibracell, Sonics and Materials Inc., USA; 31% Amp, 5sec pulse, Imin 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.

[0277]

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 ]iL 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 uM unlabeled PGE2 under the same assay conditions as NCEs.. The reaction was incubated at room temperature for 2 h 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 h or at 37°C overnight. [3H] PGE2 bound to the protein was

quantified by the addition of 25 μΐ 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 [3]PGE2 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.

[0278]

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 ]iL 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 (EC₈ ^"o) was normalized to 0% inhibition of hEP4 and cells treated with buffer (no agonist) was normalized to 100% inhibition of hEP4. IC₅o of NCEs was generated using non- linear regression - Log (inhibitor) vs. response equation in GraphPad Prism 5.

[0279]

Table 4: Potency of compound in hEP4 radioligand binding assay at 300 nM and cell based assay (cAMP) at 1 μΜ

* NA = Not Available; NI = No Inhibition

Industrial Applicability

[0280]

[0281]

This application is based on patent application No.

3555/DEL/2014 filed on December 5, 2014 in India, the contents of which are encompassed in full herein.

Claims

1. A compound represented by the formula (I)

wherein

Ring A is an optionally further substituted 5- or 6-membered ring,

G¹ is N, C or CR⁴,

G² is N, C or CR⁵,

R⁴ is a hydrogen atom or a substituent,

R⁵ is a hydrogen atom or a substituent,

Ring E is an optionally substituted C_3-6 cycloalkane or an optionally substituted heterocycle,

R¹ and R² are each independently a hydrogen atom or an

R³ is a hydrogen atom or a substituent,

Ring C is an optionally further substituted ring,

Ring D is an optionally further 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

the partial structure:

Ring A is benzene optionally further substituted by 1 to 3 halogen atoms,

Ring E is a C_3-6 cycloalkane or a 3- to 14-membered non-aromatic heterocycle,

R¹ and R² are each independently a hydrogen atom or a C₁- ₆alkyl group, or R¹ and R² are joined together to form a C_3-6

cycloalkane,

R³ is a hydrogen atom;

Ring C is a C_6-14 aromatic hydrocarbon ring or a 5- to 14- membered aromatic heterocycle, each of which is optionally further substituted by 1 to 3 substituents selected from a carboxy group and a C₁- ₆alkoxy-carbonyl group,

Ring D is a C_6-14 aromatic hydrocarbon ring or a 5- to 14- membered aromatic heterocycle, each of which is optionally further substituted by 1 to 3 substituents selected from

(1) a halogen atom,

(2) a cyano group,.

(3) an optionally halogenated C₁- ₆alkyl group, and

(4) an optionally halogenated C₁- ₆alkoxy group, and

W is -CH₂-, -CH(CH₃)-, -SO₂-, -CH₂CH₂O- or -OCH₂CH₂-.

3. 4-[ (lS)-l-[ [1 ` -[ (4-chlorophenyl) methyl] spiro [cyclopropane- 1, 3 '-indoline] -7 '-carbonyl] amino] ethyl] benzoic acid or a salt thereof. 4.

4-[l-[[l'-[[4-

(trifluoromethyl) phenyl] methyl] spiro [cyclopropane-1, 3'- indoline] -7 '-carbonyl] amino] cyclbpropyl] benzoic acid or a salt thereof.

5. 4- [1- [ [1 ` - [ (3 , 4-difluorophenyl) methyl] spiro [cyclopropane-

I, 3 '-indoline] -7 '-carbonyl] amino] cyclopropyl] benzoic acid or a salt thereof.

6. A medicament comprising the compound or salt according to claim 1.

7. The medicamen£ according to claim 6 which is an EP4 receptor antagonist.

8. The medicament according to claim 6 which is an agent for the prophylaxis or treatment of EP4 receptor associated diseases.

9. The medicament according to 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 according to claim 1 for use in the prophylaxis or treatment of EP4 receptor associated diseases.

11. The compound or salt according to claim 1 for use in the prophylaxis or treatment of rheumatoid arthritis, aortic aneurysm, endometriosis, ankylosing spondylitis or

inflammatory breast cancer.

12. A method of inhibiting ^' EP4 receptor in a mammal, which comprises administering an effective amount of the compound or salt according to 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 according to claim 1 to the mammal.

14. A method for the prophylaxis or treatment of rheumatoid arthritis, aortic aneurysm, endometriosis, ankylosing

spondylitis or inflammatory breast cancer, which comprises administering an effective amount of the compound or salt according to claim 1 to the mammal.

15. Use of the compound or salt according to claim 1 for the production of an agent for the prophylaxis or treatment of EP4 receptor associated diseases.

16. Use of the compound or salt according to claim 1 for the production of an agent for the prophylaxis or treatment of rheumatoid arthritis, aortic aneurysm, endometriosis,

ankylosing spondylitis or inflammatory breast cancer.