HK1139655B

HK1139655B - Pyrrolopyrimidine and pyrrolopyridine derivatives substituted with a cyclic amino group as crf antagonists

Info

Publication number: HK1139655B
Application number: HK10105586.7A
Authority: HK
Inventors: 中里笃郎; 大久保武利; 野泽大; 民田智子; L‧E‧J‧肯尼斯
Original assignee: 大正制药株式会社
Priority date: 2004-06-25
Filing date: 2010-06-07
Publication date: 2014-02-07

Description

Pyrrolopyrimidine and pyrrolopyridine derivatives substituted with a cyclic amino group as CRF receptor antagonists

This application is a divisional application of a patent application entitled "a cyclic amino substituted pyrrolopyrimidine and pyrrolopyridine derivative as CRF receptor antagonist" filed 24/6/2005 under application No. 200580020962.2.

Technical Field

The present invention relates to a therapeutic agent for diseases which are considered to be associated with Corticotropin Releasing Factor (CRF), such as depression, anxiety, alzheimer's disease, parkinson's disease, huntington's chorea, eating disorders, hypertension, gastrointestinal diseases, drug dependence, cerebral infarction, cerebral ischemia, cerebral edema, cerebral trauma, inflammation, immune-related diseases, alopecia, irritable bowel syndrome, sleep disorders, epilepsy, dermatitis, schizophrenia, pain, and the like.

Background

CRF is a hormone comprising 41 amino acids (Science, 213, 1394 1397, 1981; and J. neurosci, 7, 88-100, 1987), and it has been proposed that CRF plays a central role in biological reactions to stress (cell. mol. neurosi., 14, 579-588, 1994; Endocrinol., 132, 723-728, 1994; and neuroendocrinol.61, 445-452, 1995). For CRF, there are two approaches: CRF acts on the peripheral immune system or sympathetic nervous system via the hypothalamic-pituitary-adrenal system, and on the neurotransmitter of CRF in the central nervous system (Corticotropin Releasing Factor: Basic and clinical students of a Neuropeptide, pp.29-52, 1990). Intraventricular administration of CRF to hypophysectomized and normal rats results in anxiety symptoms in both rats (Pharmacol. Rev., 43, 425. sub.473, 1991; and Brain Res. Rev., 15, 71-100, 1990). That is, it is suggested that CRF is involved in the hypothalamic-pituitary-adrenal system and that CRF acts as a neurotransmitter in the central nervous system.

An overview of Owens and Nemeroff in 1991 outlines CRF-related diseases (Pharmacol. Rev., 43, 425-474, 1991). That is, CRF is involved in depression, anxiety, alzheimer's disease, parkinson's disease, huntington's chorea, eating disorder, hypertension, gastrointestinal diseases, drug dependence, inflammation, immune-related diseases, and the like. Recently, it has been reported that CRF is also involved in epilepsy, cerebral infarction, cerebral ischemia, cerebral edema and cerebral trauma (Brain Res.545, 339-. Therefore, antagonists against CRF receptors are useful as therapeutic agents for the above-mentioned diseases.

Opioid analgesics are known for their ability to relieve pain without compromising perception. At least three major opioid receptor types (δ, μ, κ) are involved in the regulation of various opioid effects. In opioid studies, selective agonists of the delta-opioid receptor have shown promising therapeutic potential as analgesics without the adverse side effects associated with morphine and other opioids that are selective for the mu-opioid receptor. There are several indications that excitation of delta-opioid receptors can reduce the pain process (j. pharmacol. exp. ther.307, 1079-1089, 2003).

WO02/002549, WO00/053604 and WO04/058767 disclose pyrrolopyridine and pyrrolopyrimidine derivatives as CRF receptor antagonists. However, the compounds provided by the present invention have not been disclosed.

Disclosure of Invention

It is an object of the present invention to provide CRF receptor antagonists and/or δ -receptor agonists which are effective as therapeutic or prophylactic agents for diseases in which CRF is considered to be involved, such as depression, anxiety, alzheimer's disease, parkinson's disease, huntington's chorea, eating disorders, hypertension, gastrointestinal diseases, drug dependence, cerebral infarction, cerebral ischemia, cerebral edema, cerebral trauma, inflammation, immune-related diseases, alopecia, irritable bowel syndrome, sleep disorders, epilepsy, dermatitis, schizophrenia, pain, and the like.

The present inventors earnestly studied a pyrrolopyrimidine and pyrrolopyridine derivative substituted with a cyclic amino group having a high affinity for CRF receptors and/or δ receptors, thereby completing the present invention.

The following explains the pyrrolopyrimidine and pyrrolopyridine derivatives substituted with a cyclic amino group of the present invention.

A pyrrolopyrimidine or pyrrolopyridine derivative substituted with a cyclic amino group represented by the following formula [1], an independent isomer thereof, a racemic or non-racemic mixture of its isomers or its N-oxide, or a pharmaceutically acceptable salt and hydrate thereof:

(wherein the cyclic amino group is represented by the following formula [ II ]:

wherein the cyclic amino group is a 3-to 8-membered saturated cyclic amine or with C between any two different carbon atoms of the cyclic amine_1-5Alkylene or C_1-4alkylene-O-C_1-4Alkylene bridged 3-to 8-membered saturated cyclic amines independently substituted with- (CR) at the same or different carbon atom of the cyclic amine¹R²)_m-(CHR³)_nA group represented by-X, R⁴And R⁵Substituted;

x is-CO₂R⁹、-CON(R¹⁰)R¹¹、-P(＝O)(R¹²)R¹³or-S (═ O)_kR¹⁴；

Y is N or CR¹⁵；

R¹Is hydrogen, hydroxy, C_1-5Alkyl radical, C_1-5alkoxy-C_1-5Alkyl or hydroxy-C_1-5An alkyl group;

R²is hydrogen or C_1-5An alkyl group;

R³is hydrogen, cyano, C_1-5Alkyl radical, C_1-5alkoxy-C_1-5Alkyl or hydroxy-C_1-5An alkyl group;

m is an integer selected from 0, 1, 2, 3, 4 and 5;

n is 0 or 1;

with the proviso that when X is-CO₂R⁹or-CON (R)¹⁰)R¹¹And when n is 0, m is an integer selected from 1, 2, 3, 4 and 5;

R⁴is hydrogen, hydroxy-C_1-5Alkyl, cyano-C_1-5Alkyl or C_1-5An alkyl group;

R⁵is hydrogen or C_1-5An alkyl group;

R⁶is hydrogen, halogen, C_1-5Alkyl radical, C_3-8Cycloalkyl radical, C_3-8cycloalkyl-C_1-5Alkyl, hydroxy, C_1-5Alkoxy radical, C_3-8Cycloalkoxy or-N (R)¹⁶)R¹⁷；

R⁷And R⁸Are the same or different and are independently hydrogen, halogen, C_1-5Alkyl radical, C_3-8Cycloalkyl radical, C_3-8cycloalkyl-C_1-5Alkyl, hydroxy, C_1-5Alkoxy radical, C_3-8Cycloalkoxy, -N (R)¹⁸)R¹⁹、-CO₂R²⁰Cyano, nitro, C_1-5Alkylthio, trifluoromethyl or trifluoromethoxy; or R⁷And R⁸Together form-CH₂-CH₂-CH₂-CH₂-or-CH ═ CH-;

R⁹is hydrogen, C_1-20Alkyl, aryl, C_3-8Cycloalkyl or-CHR^1aOC(＝O)-A¹-R^1bWherein said C is_1-20Alkyl optionally contains one to four double bonds and/or one to four triple bonds, and/or said C_1-20Alkyl is optionally selected from hydroxy, halogen, cyano, C_1-10Alkoxy radical, C_1-5Alkoxycarbonyl group, C_3-8Cycloalkyl, -C (═ O) N (R)^2a)R^2b、-N(R^3a)R^3bAnd aryl optionally substituted with one or more substituents which may be the same or different and are selected from halogen, C_1-5Alkyl and C_1-5Substituted by a substituent of alkoxy;

R^1ais hydrogen or C_1-5An alkyl group;

A¹is oxygen or a single bond;

R^1bis C_1-5Alkyl radical, C_3-8Cycloalkyl or C_3-8cycloalkyl-C_1-5An alkyl group;

R^2aand R^2bAre the same or different and are independently hydrogen or C_1-3An alkyl group;

R^3aand R^3bAre the same or different and are independently hydrogen or C_1-3An alkyl group; or R^3aAnd R^3bTogether form- (CH)₂)_s-A²-(CH₂)_t-；

A²Is methylene, oxygen, sulfur, NR^4aOr a single bond;

R^4ais hydrogen, C_1-5Alkyl or benzyl;

s and t are the same or different and are independently an integer selected from 1, 2 or 3;

R¹⁰is hydrogen, C_1-5Alkyl radical, C_3-8Cycloalkyl or C_3-8cycloalkyl-C_1-5An alkyl group;

R¹¹is hydrogen, C_1-5Alkyl radical, C_3-8Cycloalkyl radical, C_3-8cycloalkyl-C_1-5Alkyl or-CHR^5a-(CH₂)_u-C(＝O)R^5bOr R¹⁰And R¹¹Together form- (CH)₂)_v-A³-(CH₂)_w-；

R^5aIs hydrogen, C_1-5Alkyl, aryl or heteroaryl, wherein said C_1-5Alkyl is optionally selected from aryl, heteroaryl, hydroxy, hydroxycarbonyl, 4-hydroxyphenyl, C_1-5Alkoxy, amino, guanidino, mercapto, C_1-5Substituted by one substituent of alkylthio or aminocarbonyl, or R¹⁰And R^5aTogether form- (CH)₂)_p-；

p is 3 or 4;

u is 0 or 1;

R^5bis hydroxy, C_1-5Alkoxy, benzyloxy or-N (R)^6a)R^6b；

R^6aAnd R^6bAre the same or different and are independently hydrogen or C_1-3An alkyl group;

v and w are the same or different and are independently an integer selected from 1, 2 or 3;

A³is methylene, oxygen, sulfur or NR^7a；

R^7aIs hydrogen, C_1-5Alkyl or benzyl;

R¹²and R¹³Are the same OR different and are independently-OR²¹or-N (R)²²)R²³；

R¹⁴is-OR²¹or-N (R)²²)R²³；

k is 1 or 2;

R¹⁵is hydrogen, C_1-5Alkyl, halogen, cyano or-CO₂R²⁴；

R¹⁶And R¹⁷Are the same or different and are independently hydrogen, C_1-5Alkyl radical, C_3-8Cycloalkyl or C_3-8cycloalkyl-C_1-5An alkyl group;

R¹⁸and R¹⁹Are the same or different and are independently hydrogen, C_1-5Alkyl radical, C_3-8Cycloalkyl or C_3-8cycloalkyl-C_1-5An alkyl group;

R²⁰is hydrogen or C_1-5An alkyl group;

R²¹is hydrogen, C_1-5Alkyl radical, C_3-8Cycloalkyl or C_3-8cycloalkyl-C_1-5An alkyl group;

R²²and R²³Are the same or different and are independently hydrogen, C_1-5Alkyl radical, C_3-8Cycloalkyl or C_3-8cycloalkyl-C_1-5An alkyl group;

R²⁴is hydrogen or C_1-5An alkyl group;

ar is an aryl or heteroaryl group, unsubstituted or substituted by one or more substituents, which may be the same or different, selected from halogen, C_1-5Alkyl radical, C_3-8Cycloalkyl radical, C_2-5Alkenyl radical, C_2-5Alkynyl, C_1-5Alkoxy radical, C_1-5Alkylthio radical, C_1-5Alkylsulfinyl radical, C_1-5Alkylsulfonyl, cyano, nitro, hydroxy, -CO₂R²⁵、-C(＝O)R²⁶、-CON(R²⁷)R²⁸、-OC(＝O)R²⁹、-NR³⁰CO₂R³¹、-S(O)_rN(R³²)R³³Trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoromethoxy, methylenedioxy, ethylenedioxy and-N (R)³⁴)R³⁵；

R²⁵Is hydrogen, C_1-5Alkyl radical, C_3-8Cycloalkyl or C_3-8cycloalkyl-C_1-5An alkyl group;

R²⁶is hydrogen or C_1-5An alkyl group;

R²⁷and R²⁸Are the same or different and are independently hydrogen, C_1-5Alkyl radical, C_3-8Cycloalkyl or C_3-8cycloalkyl-C_1-5An alkyl group;

R²⁹is hydrogen or C_1-5An alkyl group;

R³⁰is hydrogen or C_1-5An alkyl group;

R³¹is hydrogen or C_1-5An alkyl group;

R³²and R³³Are the same or different and are independently hydrogen, C_1-5Alkyl radical, C_3-8Cycloalkyl or C_3-8cycloalkyl-C_1-5An alkyl group;

r is 1 or 2;

R³⁴and R³⁵Are the same or different and are independently hydrogen, C_1-5Alkyl radical, C_3-8Cycloalkyl or C_3-8cycloalkyl-C_1-5Alkyl groups).

The terms used in the present specification have the following meanings.

The term "3-to 8-membered saturated cyclic amine" refers to aziridine, azetidine, pyrrolidine, piperidine, azepane or azocane.

The term "C_1-5The alkylene group "means a straight or branched alkylene group having 1 to 5 carbon atoms, such as methylene, ethylene, propylene, 1, 3-propylene, 1, 4-butylene, 1, 5-pentylene or the like.

The term "with C between any two different carbon atoms of the cyclic amine_1-5Alkylene or C_1-4alkylene-O-C_1-4Alkylene bridged 3-to 8-membered saturated cyclic amines "include, for example, 8-azabicyclo [3.2.1]Oct-8-yl, 9-azabicyclo [3.3.1]Non-9-yl, 7-azabicyclo [2.2.1]Hept-7-yl, 3-oxa-7-azabicyclo [3.3.1]Non-7-yl and 3-oxa-9-azabicyclo [3.3.1]Non-9-yl.

The term "C_1-20Alkyl "means a straight or branched chain alkyl group having 1 to 20 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, n-butyl, sec-butyl, pentyl, isopentyl, tridecyl, 3, 7, 11, 15-tetramethylhexadecyl, or the like.

The term "C optionally containing one to four double bonds and/or one to four triple bonds_1-20Alkyl "includes, for example, allyl, 3, 7-dimethyl-octa-2, 6-dienyl, but-3-ynyl, dodec-11-ynyl or the like.

The term "C_1-10Alkoxy "means a straight or branched chain alkoxy group having 1 to 10 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy, isopentoxy, decyloxy, 3, 7-dimethyl-octyloxy, or the like.

The term "C_1-5alkoxy-C_1-5Alkyl "means containing C as above_1-5Substituted C with alkoxy as substituent_1-5Alkyl groups such as methoxymethyl, 2-methoxyethyl, 2-ethoxyethyl or the like.

The term "hydroxy-C_1-5Alkyl "refers to a substituted C containing a hydroxyl group_1-5Alkyl radicals, e.g. hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl4-hydroxybutyl, 5-hydroxypentyl or the like.

The term "cyano-C_1-5Alkyl "refers to a substituted C group containing a cyano group_1-5Alkyl groups such as cyanomethyl, 1-cyanoethyl, 2-cyanoethyl, 3-cyanopropyl, 4-cyanobutyl, 5-cyanopentyl or the like.

The term "C_3-8Cycloalkyl "means a cycloalkyl group containing 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or the like.

The term "C_3-8cycloalkyl-C_1-5Alkyl "means containing C as above_3-8Substituted C with cycloalkyl as substituent_1-5Alkyl groups such as cyclopropylmethyl, cyclopropylethyl, cyclopentylethyl or the like.

The term "C_3-8Cycloalkoxy "means a cycloalkoxy group containing 3 to 8 carbon atoms, such as cyclopropoxy, cyclobutoxy, cyclopentoxy, or the like.

The term "halogen" refers to a fluorine, chlorine, bromine or iodine atom.

The term "aryl" refers to a monocyclic or bicyclic group of 6 to 12 ring carbon atoms having at least one aromatic ring, such as phenyl, naphthyl, or the like.

The term "C_1-5Alkoxycarbonyl "means containing the above-mentioned C_1-5A carbonyl group of an alkoxy group such as a methoxycarbonyl group, an ethoxycarbonyl group, a tert-butoxycarbonyl group or the like.

The term "heteroaryl" refers to a monocyclic or bicyclic group of 5 to 12 carbon atoms having at least one aromatic ring containing 1 to 4 atoms in the ring which may be the same or different and selected from nitrogen, oxygen and sulfur, such as pyridyl, pyrimidinyl, imidazolyl, quinolinyl, indolyl, benzofuranyl, quinoxalinyl, benzo [1, 2, 5] thiadiazolyl, benzo [1, 2, 5] oxadiazolyl or the like.

Term(s) for“C_2-5Alkenyl "means a straight or branched chain alkenyl group containing 2 to 5 carbon atoms, such as vinyl, isopropenyl, allyl, or the like.

The term "C_2-5Alkynyl "means a straight or branched chain alkynyl group containing 2 to 5 carbon atoms, such as ethynyl, prop-1-ynyl, prop-2-ynyl or the like.

The term "C_1-5Alkylthio "means a straight or branched chain alkylthio group having 1 to 5 carbon atoms, such as methylthio, ethylthio, propylthio, isopropylthio or the like.

The term "C_1-5Alkylsulfinyl "means a straight or branched alkylsulfinyl group having 1 to 5 carbon atoms, such as methylsulfinyl, ethylsulfinyl or the like.

The term "C_1-5Alkylsulfonyl "means a straight or branched chain alkylsulfonyl group containing 1 to 5 carbon atoms, such as methylsulfonyl, ethylsulfonyl or the like.

The term "aryl or heteroaryl group, which is unsubstituted or substituted by one or more identical or different substituents selected from the group consisting of: halogen, C_1-5Alkyl radical, C_3-8Cycloalkyl radical, C_2-5Alkenyl radical, C_2-5Alkynyl, C_1-5Alkoxy radical, C_1-5Alkylthio radical, C_1-5Alkylsulfinyl radical, C_1-5Alkylsulfonyl, cyano, nitro, hydroxy, -CO₂R²⁵、-C(＝O)R²⁶、-CON(R²⁷)R²⁸、-OC(＝O)R²⁹、-NR³⁰CO₂R³¹、-S(O)_rN(R³²)R³³Trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoromethoxy, methylenedioxy, ethylenedioxy and-N (R)³⁴)R³⁵", includes, for example, 2, 4-dimethylphenyl, 2, 6-dimethylphenyl, 2, 4-dibromophenyl, 2-bromo-4-isopropylphenyl, 2, 4-dichlorophenyl, 2, 6-dichlorophenyl, 2-chloro-4-trifluoromethylphenyl, 4-methoxy-2-methylphenyl2-chloro-4-trifluoromethoxyphenyl group, 4-isopropyl-2-methylthiophenyl group, 2, 4, 6-trimethylphenyl group, 4-bromo-2, 6-dimethylphenyl group, 4-bromo-2, 6-diethylphenyl group, 4-chloro-2, 6-dimethylphenyl group, 2, 4, 6-tribromophenyl group, 2, 4, 5-tribromophenyl group, 2, 4, 6-trichlorophenyl group, 2, 4, 5-trichlorophenyl group, 4-bromo-2, 6-dichlorophenyl group, 6-chloro-2, 4-dibromophenyl group, 2, 4-dibromo-6-fluorophenyl group, 2, 4-dibromo-6-methylphenyl group, 2, 4-dibromo-6-methoxyphenyl group, 2, 4-dibromo-6-methylthiophenyl group, 2, 6-dibromo-4-isopropylphenyl group, 2, 6-dibromo-4-trifluoromethylphenyl group, 2-bromo-4-trifluoromethylphenyl group, 4-bromo-2-chlorophenyl group, 2-bromo-4-chlorophenyl group, 4-bromo-2-methylphenyl group, 4-chloro-2-methylphenyl group, 2, 4-dimethoxyphenyl group, 2, 6-dimethyl-4-methoxyphenyl group, 4-chloro-2, 6-dibromophenyl group, 4-bromo-2, 6-difluorophenyl group, 2, 6-dichloro-4-trifluoromethylphenyl group, 2, 6-dichloro-4-trifluoromethoxyphenyl group, 2, 6-dibromo-4-isopropylphenyl group, 2, 6-dibromo-4-trifluoromethoxyphenyl group, 2-chloro-4, 6-dimethylphenyl group, 2-bromo-4, 6-dimethoxyphenyl group, 2-bromo-4-isopropyl-6-methoxyphenyl group, 2, 4-dimethoxy-6-methylphenyl group, 6-dimethylamino-4-methylpyridin-3-yl group, 2-chloro-6-trifluoromethylpyridin-3-yl group, 2-chloro-6-trifluoromethoxypyridin-3-yl group, 2-chloro-6-methoxypyridin-3-yl group, 6-methoxy-2-trifluoromethylpyridin-3-yl group, 2-chloro-6-difluoromethylpyridin-3-yl group, 6-methoxy-2-methylpyridin-3-yl, 2, 6-dimethoxypyridin-3-yl, 4, 6-dimethyl-2-trifluoromethylpyrimidin-5-yl, 2-dimethylamino-6-methylpyridin-3-yl, 6-dimethylamino-2-methylpyridin-3-yl, 2, 3-dihydrobenzo [1, 4-]Dioxin-5-yl and benzo [1, 3 ]]Dioxol-4-yl, 5, 7-dimethylbenzo [1, 2, 5]]Thiadiazol-4-yl, 5, 7-dimethylbenzo [1, 2, 5]]Oxadiazol-4-yl, 2-isopropoxy-6-trifluoromethylpyridin-3-yl, 2-methoxy-6-methylpyridin-3-yl, 2, 6-dimethylpyridin-3-yl, 2-bromo-6-methoxypyridin-3-yl, 2-chloro-6-dimethylaminopyridin-3-yl, 2, 6-dichloropyridin-3-yl, 2, 4-dimethyl-6-dimethylaminopyridin-3-yl, 2, 4, 6-trimethylpyridin-3-yl, 2, 4, 6-trimethylpyrimidin-5-yl, 4, 6-dimethyl-2-dimethylaminopyridin-5-yl, 2-isopropoxy-6-trifluoromethylpyridin-3-yl, 2-chloro-6-dimethylaminopyridin-3-yl, 2, 6-dichloropyridin, 5-iodo-3-methylpyridin-2-yl, 3-methyl-5-methylaminopyridin-2-yl, 3-diMethylamino-5-methylpyridin-2-yl, 5-methyl-3-methylaminopyridin-2-yl, 3-chloro-5-methylpyridin-2-yl, 3-amino-5-methylpyridin-2-yl, 5-methyl-3-nitropyridin-2-yl, 5-diethylamino-3-methylpyridin-2-yl, 5-fluoro-3-methylpyridin-2-yl, 5-chloro-3-methylpyridin-2-yl, 5-dimethylamino-3-methylpyridin-2-yl, 5-amino-3-methylpyridin-2-yl, methyl-amino-5-methyl-3-, 3-methyl-5-nitropyridin-2-yl, 3-bromo-5-methylpyridin-2-yl, 4-chloro-2, 5-dimethoxyphenyl, 4, 5-dimethyl-2-methoxyphenyl, 5-fluoro-2, 4-dimethylphenyl, 2, 4-dimethoxy-5-methylphenyl, 2-chloro-4-methoxy-5-methylphenyl, 2-chloro-5-fluoro-4-methylphenyl, 2-bromo-4, 5-dimethoxyphenyl, 2-bromo-5-fluoro-4-methoxyphenyl, 2-chloro-4, 5-dimethoxyphenyl, 2, 5-dichloro-4-methoxyphenyl, 2, 4-dichloro-5-fluorophenyl, 2-chloro-5-fluoro-4-methoxyphenyl, 2, 4, 5-trichlorophenyl, 2-chloro-5-fluoro-4-methylphenyl, 5-fluoro-4-methoxy-2-methylphenyl, 4, 5-dimethoxy-2-methylphenyl, 5-chloro-4-methoxy-2-methylphenyl, 2, 4, 5-trimethylphenyl, 6-methoxy-4-methylpyridin-3-yl, 4-methoxy-6-methylpyridin-3-yl, 4, 6-dimethylpyridin-3-yl, p-tolyl, p-methyl-4, 2-chloro-4-isopropylphenyl group, 2-chloro-4-methylphenyl group, 4-amino-2-chlorophenyl group, 2-chloro-4-dimethylcarbamoylphenyl group, 2-chloro-4-methylcarbamoylphenyl group, 4-carbamoyl-2-chlorophenyl group, 2-chloro-4-methylsulfonylphenyl group, 4-carboxy-2-chlorophenyl group, 2-chloro-4-iodophenyl group, 2-bromo-4-methylthiophenyl group, 2-bromo-4-methylsulfinylphenyl group, 2-bromo-4-dimethylaminophenyl group, 2-bromo-4-methylsulfonylphenyl group, 2-bromo-4-cyclopentylphenyl group, 2-chloro-4-cyclopentylphenyl group, 4-amino-2-chlorophenyl group, 2-chloro-4-dimethylcarbamoylphenyl group, 2-chloro-4-iodophenyl, 2-bromo-4-tert-butylphenyl, 2-bromo-4-propylphenyl, 2-bromo-4-methylphenyl, 2-bromo-4-trifluoromethoxyphenyl, 2-bromo-4-methoxyphenyl, 2-bromo-4-ethoxyphenyl, 4-isopropyl-2-methylsulfonylphenyl, 4-cyclopentyl-2-methylthiophenyl, 4-butyl-2-methylthiophenyl, 4-methoxy-2-methylthiophenyl, 2-methylthio-4-propylphenyl, 2-dimethylamino-4-isopropylphenyl, 2-iodo-4-isopropylphenyl, 2-fluoro-4-methylphenyl, 2, 4-difluorophenyl group, 2-chloro-4-methoxyphenyl group, 2-chloro-4-hydroxyphenyl group, 4-cyano-2-methoxyphenyl group, 4-bromo-2-methoxyphenyl group, 2-methoxy-4-methylphenyl group, 4-chloro-2-methoxyphenyl group, 2-hydroxy-4-methylphenyl group, 4-fluoro-2-methoxyphenyl group, 2-hydroxy-4-methylphenyl group, 4-cyano-2-methoxyphenyl group, 2-chloro-4-methylthiophenyl group, 2-methoxy-4-trifluoromethylphenyl group, 4-isopropyl-2-methoxyphenyl group, 2-chloro-4-cyanophenyl group, 2-chloro-4-ethoxycarbonylphenyl group, 2-chloro-4-methylaminophenyl group, 4-cyano-2-trifluoromethylphenyl group, 4-cyano-2-methylphenyl group, 2-methyl-4-trifluoromethoxyphenyl group, 2-hydroxy-4-methoxyphenyl group, 4-fluoro-2-methoxyphenyl group, 4-isopropyl-2-methoxyphenyl group, 2-chloro-4-ethoxycarbonylphenyl group, 2-, 2-cyano-4-trifluoromethylphenyl group, 4-carboxyamino-2-trifluoromethylphenyl group, 4-methoxy-2-trifluoromethylphenyl group, 4-fluoro-2-methylphenyl group, 4-hydroxy-2-methylphenyl group, 4-methoxy-2-methoxycarbonylphenyl group, 2-ethyl-4-methoxyphenyl group, 2-formyl-4-methoxyphenyl group, 4-chloro-2-trifluoromethylphenyl group, 4-dimethylamino-2-trifluoromethylphenyl group, 4-difluoromethoxy-2-methylphenyl group, 2-cyano-4-methoxyphenyl group, 4-hydroxy-2-trifluoromethylphenyl group, 2-cyano-4-methoxyphenyl group, 4-isopropyl-2-trifluoromethylphenyl group, 4-diethylamino-2-methylphenyl group, 4-fluoro-2-trifluoromethylphenyl group, 4-propoxy-2-trifluoromethylphenyl group, 4-dimethylamino-2-methylthiophenyl group, 4-isopropyl-2-isopropylthiophenyl group, 2-ethylthio-4-isopropylphenyl group, 4-methylamino-2-methylthiophenyl group, 2-methylthio-4-propionylphenyl group, 4-acetyl-2-methylthiophenyl group, 4-cyano-2-methylthiophenyl group, 4-methoxy-2-methylthiophenyl group, 4-ethyl-2-methylthiophenyl group, 4-methyl-2-methylthiophenyl group, 4-ethyl-2-methylthiophenyl group, 4-methoxy-2-methyl-2-methylthiophenyl, 4-bromo-2-methylthiophenyl group, 4-isopropyl-2-methylsulfinylphenyl group, 2, 4-dimethylthiophenyl group, 4, 6-dimethyl-2-isopropylphenyl group, 4, 6-dimethyl-2-isopropenylphenyl group, 2-acetyl-4, 6-dimethylphenyl group, 2, 6-dimethyl-4-trifluoromethylphenyl group, 2, 6-dimethyl-4-isopropenylphenyl group, 4-acetyl-2, 6-dimethylphenyl group, 2, 4, 6-triethylphenyl group, 4, 6-dimethyl-2-methylthiophenyl group, 4, 6-dimethyl-2-iodophenyl group, 2-fluoromethoxy-4, 6-dimethylphenyl group, 4, 6-dimethyl-2-isopropoxyphenyl group, 4, 6-dimethyl-2-ethoxyphenyl group, 2, 6-dichloro-4-ethoxyphenyl group, 2-bromo-4, 6-dimethoxyphenyl group, 2-bromo-6-hydroxy-4-methoxyphenyl group, 2, 6-dibromo-4-ethoxyphenyl group, 4-bromo-2-methoxy-6-methylphenyl group, 2, 6-dibromo-4-methoxyphenyl group, 4, 6-dibromo-2-trifluoromethoxyphenyl group, 2,4-dibromo-6-trifluoromethylphenyl group, 4-bromo-2-chloro-6-methylphenyl group, 4-chloro-2, 6-dimethoxyphenyl group, 2, 4-dichloro-6-methoxyphenyl group, 4, 6-dichloro-2-methylthiophenyl group, 4, 6-dichloro-2-trifluoromethylphenyl group, 2, 6-dimethoxy-4-ethylphenyl group, 4, 6-dimethyl-2-methoxyphenyl group, 2, 6-dimethoxy-4-methylphenyl group, 2-chloro-6-methoxy-4-methylphenyl group, 4, 6-dimethyl-2-ethoxyphenyl group, 6-hydroxy-2, 4-dimethylphenyl, 4-cyano-2-methoxy-6-methylphenyl, 6-fluoro-2-methoxy-4-methylphenyl, 4-acetyl-2-methoxy-6-methylphenyl, 2-chloro-4, 6-dimethoxyphenyl, 2, 6-dimethoxy-4-ethoxyphenyl, 2, 4, 6-trimethoxyphenyl, 4, 6-dibromo-2-trifluoromethoxyphenyl, 2-bromo-4-dimethylamino-6-methoxyphenyl, 4-bromo-2-methoxy-6-methylphenyl, 4, 6-dimethoxy-2-propoxyphenyl, 4, 6-dichloro-2-propoxyphenyl group, 2-bromo-6-hydroxy-4-methoxyphenyl group, 2, 4, 6-trifluorophenyl group, 2-bromo-6-fluoro-4-methylphenyl group, 4-difluoromethoxy-2, 6-dimethylphenyl group, 2, 6-dimethyl-4-ethoxyphenyl group, 2, 6-dimethyl-4-isopropoxyphenyl group, 2, 6-dimethyl-4-methylthiophenyl group, 2, 6-dimethyl-4-methylsulfonylphenyl group, 2, 6-dimethyl-4-methylsulfinylphenyl group, 2, 3-dichlorophenyl group, 4-methoxy-2, 3-dimethylphenyl group, 2-bromo-6-hydroxy-4-methoxyphenyl group, 2, 4, 6-trifluorophenyl group, 2, 6-dimethyl-4-isopropoxyphenyl group, 2, 6-dimethyl-, 2-chloro-3-fluoro-4-methoxyphenyl, 2, 3, 4-trichlorophenyl, 4-methoxy-2, 5-dimethylphenyl, 4-cyano-2, 6-dimethylphenyl and 4-fluoro-2, 6-dimethylphenyl.

The "pharmaceutically acceptable salt" in the present invention includes, for example, salts with inorganic acids, such as salts with sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid or the like; salts with organic acids, for example, salts with acetic acid, oxalic acid, lactic acid, tartaric acid, fumaric acid, maleic acid, citric acid, benzenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, benzoic acid, camphorsulfonic acid, ethanesulfonic acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, malic acid, malonic acid, mandelic acid, galactaric acid, naphthalene-2-sulfonic acid, or the like; salts with one or more metal ions, for example, salts with lithium ions, sodium ions, potassium ions, calcium ions, magnesium ions, zinc ions, aluminum ions, or the like; and amines such as ammonia, arginine, lysine, piperazine, choline, diethylamine, 4-phenylcyclohexylamine, 2-aminoethanol, benzathine or the like.

The compounds of the present invention include any isomer, such as diastereomers, enantiomers, geometric isomers and tautomeric forms. In the compound represented by the formula [ I ], if the cyclic amino group contains one or more chiral carbons and/or if there is axial chirality in Ar and the pyrrolopyrimidine (or pyrrolopyridine) ring, several stereoisomers (diastereomers or enantiomers) may exist. The compounds of the present invention include all individual isomers and racemic and non-racemic mixtures of isomers.

Preferred examples of the compound of the present invention are as follows.

That is, preferred are compounds represented by the following formula [ I ], individual isomers thereof, racemic or non-racemic mixtures of isomers thereof or N-oxides thereof, or pharmaceutically acceptable salts and hydrates thereof:

(wherein the cyclic amino group is represented by the following formula [ II ]:

wherein the cyclic amino group is a 3-to 8-membered saturated cyclic amine or with C between any two different carbon atoms of the cyclic amine_1-5Alkylene or C_1-4alkylene-O-C_1-4Alkylene bridged 3-to 8-membered saturated cyclic amines independently substituted with- (CR) at the same or different carbon atom of the cyclic amine¹R²)_m-(CHR³)_n-X、R⁴And R⁵Substituted by the indicated groups;

Y is N or CR¹⁵；

R²is hydrogen or C_1-5An alkyl group;

m is an integer selected from 0, 1, 2, 3, 4 and 5;

n is 0 or 1;

R⁴is hydrogen, hydroxy-C_1-5Alkyl, cyano-C_1-5Alkyl or C_1-5An alkyl group;

R⁵is hydrogen or C_1-5An alkyl group;

R⁹is hydrogen, C_1-10Alkyl radical, C_3-8Cycloalkyl or C_3-8cycloalkyl-C_1-5An alkyl group;

R¹⁰and R¹¹Are the same or different and are independently hydrogen, C_1-5Alkyl radical, C_3-8Cycloalkyl or C_3-8cycloalkyl-C_1-5An alkyl group;

R¹⁴is-OR²¹or-N (R)²²)R²³；

k is 1 or 2;

R¹⁵is hydrogen, C_1-5Alkyl, halogen, cyano or-CO₂R²⁴；

R²⁰is hydrogen or C_1-5An alkyl group;

R²⁴is hydrogen or C_1-5An alkyl group;

ar is an aryl or heteroaryl group, which is unsubstituted or substituted with one or more identical or different substituents selected from the group consisting of: halogen, C_1-5Alkyl radical, C_3-8Cycloalkyl radical, C_2-5Alkenyl radical, C_2-5Alkynyl, C_1-5Alkoxy radical, C_1-5Alkylthio radical, C_1-5Alkylsulfinyl radical, C_1-5Alkylsulfonyl, cyano, nitro, hydroxy, -CO₂R²⁵、-C(＝O)R²⁶、-CON(R²⁷)R²⁸、-OC(＝O)R²⁹、-NR³⁰CO₂R³¹、-S(O)_rN(R³²)R³³Trifluoromethyl, trifluoromethoxy, difluoromethoxy, fluoromethoxy, methylenedioxy, ethylenedioxy and-N (R)³⁴)R³⁵；

R²⁶is hydrogen or C_1-5An alkyl group;

R²⁹is hydrogen or C_1-5An alkyl group;

R³⁰is hydrogen or C_1-5An alkyl group;

R³¹is hydrogen or C_1-5An alkyl group;

R³²and R³³Are the same or different and are independently hydrogen, C_1-5Alkyl radical, C_3-8Cycloalkyl radicalsOr C_3-8cycloalkyl-C_1-5An alkyl group;

r is 1 or 2;

More preferably when Y is N, formula [ I ]]The compounds shown. More preferably represented by the formula [ I]A compound shown in the formula (I): wherein Y is N; m is an integer selected from 1, 2, 3, 4 and 5; n is 0; r¹、R²、R⁴And R⁵Is hydrogen. More preferably represented by the formula [ I]A compound of formula (I) wherein Y is N; the cyclic amino group is a 4-to 7-membered saturated cyclic amine; m is an integer selected from 1, 2 and 3; n is 0; r¹、R²、R⁴And R⁵Is hydrogen; r⁶Is C_1-5An alkyl group; r⁷And R⁸Are the same or different and are independently hydrogen or C_1-5An alkyl group; ar is two or three same or different selected from halogen and C_1-3Alkyl radical, C_1-3Alkoxy radical, C_1-3Alkylthio, trifluoromethyl, trifluoromethoxy and-N (R)³⁴)R³⁵(wherein R is³⁴And R³⁵Are the same or different and are independently hydrogen or C_1-3Alkyl) or a substituent of (a). More preferably represented by the formula [ I]A compound shown in the formula (I): wherein X is-CO₂H、-CONH₂、-P(＝O)(OH)₂or-S (═ O)₂OH; y is N; the cyclic amino group is a 6-membered saturated cyclic amine; m is an integer selected from 1, 2 and 3; n is 0; r¹、R²、R⁴And R⁵Is hydrogen; r⁶Is C_1-3An alkyl group; r⁷And R⁸Are the same or different and are independently hydrogen or C_1-3An alkyl group; ar is two or three same or different selected from chlorine, bromine and C_1-3Alkyl radical, C_1-3Alkoxy radical, C_1-3Phenyl substituted by alkylthio, trifluoromethyl, trifluoromethoxy and dimethylamino substituents. More preferably represented by the formula [ I]A compound shown in the formula (I): wherein X is-CO₂H; y is N; the cyclic amino group is a 6-membered saturated cyclic amine; m isAn integer selected from 1, 2 and 3; n is 0; r¹、R²、R⁴And R⁵Is hydrogen; r⁶Is methyl; r⁷And R⁸The same or different and independently is hydrogen or methyl; ar is two or three same or different selected from chlorine, bromine and C_1-3Alkyl radical, C_1-3Alkoxy radical, C_1-3Alkylthio and phenyl substituted by trifluoromethyl.

It is also preferred that Y is CR¹⁵Hour formula [ I]The compounds shown. More preferably represented by the formula [ I]A compound shown in the formula (I): wherein Y is CR¹⁵(ii) a m is an integer selected from 1, 2, 3, 4 and 5; n is 0; r¹、R²、R⁴And R⁵Is hydrogen; r¹⁵Is hydrogen or halogen. More preferably represented by the formula [ I]A compound shown in the formula (I): wherein Y is CH; the cyclic amino group is a 4-to 7-membered saturated cyclic amine; m is an integer selected from 1, 2 and 3; n is 0; r¹、R²、R⁴And R⁵Is hydrogen; r⁶Is C_1-5An alkyl group; r⁷And R⁸Are the same or different and are independently hydrogen or C_1-5An alkyl group; ar is two or three same or different selected from halogen and C_1-3Alkyl radical, C_1-3Alkoxy radical, C_1-3Alkylthio, trifluoromethyl, trifluoromethoxy and-N (R)³⁴)R³⁵(wherein R is³⁴And R³⁵Are the same or different and are independently hydrogen or C_1-3Alkyl) or a substituent of (a). More preferably represented by the formula [ I]A compound shown in the formula (I): wherein X is-CO₂H、-CONH₂、-P(＝O)(OH)₂or-S (═ O)₂OH; y is CH; the cyclic amino group is a 6-membered saturated cyclic amine; m is an integer selected from 1, 2 and 3; n is 0; r¹、R²、R⁴And R⁵Is hydrogen; r⁶Is C_1-3An alkyl group; r⁷And R⁸Are the same or different and are independently hydrogen or C_1-3An alkyl group; ar is two or three same or different selected from chlorine, bromine and C_1-3Alkyl radical, C_1-3Alkoxy radical, C_1-3Phenyl substituted by alkylthio, trifluoromethyl, trifluoromethoxy and dimethylamino substituents. More preferably, the following formula[I]A compound shown in the formula (I): wherein X is-CO₂H; y is CH; the cyclic amino group is a 6-membered saturated cyclic amine; m is an integer selected from 1, 2 and 3; n is 0; r¹、R²、R⁴And R⁵Is hydrogen; r⁶Is methyl; r⁷And R⁸The same or different and independently is hydrogen or methyl; ar is two or three same or different selected from chlorine, bromine and C_1-3Alkyl radical, C_1-3Alkoxy radical, C_1-3Alkylthio and phenyl substituted by trifluoromethyl.

Preferably, the cyclic amino group is a 6-membered saturated amine.

Preferably X is CO₂H、CONH₂、P(＝O)(OH)₂Or S (═ O)₂And (5) OH. More preferably X is CO₂H。

Preferably Y is N or CH.

Preferably R¹Is hydrogen.

Preferably R²Is hydrogen.

Preferably R³Is hydrogen.

Preferably R⁴Is hydrogen.

Preferably R⁵Is hydrogen.

Preferably R⁶Is C_1-3An alkyl group. More preferred R⁶Is methyl.

Preferably R⁷Is C_1-3An alkyl group. More preferred R⁷Is methyl.

Preferably R⁸Is hydrogen or C_1-3An alkyl group. More preferred R⁸Is hydrogen or methyl.

Preferably, Ar is substituted by two or three of the same or different groups selected from chlorine, bromine, C_1-3Alkyl radical, C_1-3Alkoxy radical, C_1-3Phenyl substituted by alkylthio, trifluoromethyl, trifluoromethoxy and dimethylamino substituents. More preferably Ar is substituted by two or three groups which may be the same or differentSelected from chlorine, bromine and C_1-3Phenyl substituted with a substituent of alkyl.

Particularly preferred compounds of the invention are:

{1- [7- (4-bromo-2, 6-dimethyl-phenyl) -2, 5, 6-trimethyl-7H-pyrrolo [2, 3-d ] pyrimidin-4-yl ] -piperidin-4-yl } -acetic acid

{1- [7- (4-bromo-2, 6-dimethyl-phenyl) -2, 5-dimethyl-7H-pyrrolo [2, 3-d ] pyrimidin-4-yl ] -piperidin-4-yl } -acetic acid

{1- [1- (4-bromo-2, 6-dimethyl-phenyl) -2, 3, 6-trimethyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl ] -piperidin-4-yl } -acetic acid

{1- [1- (4-bromo-2, 6-dimethyl-phenyl) -3, 6-dimethyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl ] -piperidin-4-yl } -acetic acid

{1- [1- (4-chloro-2, 6-dimethyl-phenyl) -2, 3, 6-trimethyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl ] -piperidin-4-yl } -acetic acid

{1- [1- (4-chloro-2, 6-dimethyl-phenyl) -3, 6-dimethyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl ] -piperidin-4-yl } -acetic acid

{1- [1- (2, 6-dibromo-4-isopropyl-phenyl) -2, 3, 6-trimethyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl ] -piperidin-4-yl } -acetic acid

{1- [1- (2, 6-dibromo-4-isopropyl-phenyl) -3, 6-dimethyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl ] -piperidin-4-yl } -acetic acid

{1- [3, 6-dimethyl-1- (2, 4, 6-tribromo-phenyl) -1H-pyrrolo [2, 3-b ] pyridin-4-yl ] -piperidin-4-yl } -acetic acid

{1- [1- (4-bromo-2, 6-dichloro-phenyl) -3, 6-dimethyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl ] -piperidin-4-yl } -acetic acid

{1- [3, 6-dimethyl-1- (2, 4, 6-trichloro-phenyl) -1H-pyrrolo [2, 3-b ] pyridin-4-yl ] -piperidin-4-yl } -acetic acid

{1- [1- (2, 6-dibromo-4-chloro-phenyl) -3, 6-dimethyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl ] -piperidin-4-yl } -acetic acid

{1- [1- (2-bromo-4-isopropyl-phenyl) -3, 6-dimethyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl ] -piperidin-4-yl } -acetic acid

{1- [1- (4-isopropyl-2-methylsulfanyl (sulfanyl) -phenyl) -3, 6-dimethyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl ] -piperidin-4-yl } -acetic acid

{1- [1- (2, 4-dibromo-phenyl) -3, 6-dimethyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl ] piperidin-4-yl } -acetic acid

3- {1- [7- (4-bromo-2, 6-dimethyl-phenyl) -2, 5, 6-trimethyl-7H-pyrrolo [2, 3-d ] pyrimidin-4-yl ] -piperidin-4-yl } -propionic acid

3- {1- [7- (4-bromo-2, 6-dimethyl-phenyl) -2, 5-dimethyl-7H-pyrrolo [2, 3-d ] pyrimidin-4-yl ] -piperidin-4-yl } -propionic acid

3- {1- [1- (4-bromo-2, 6-dimethyl-phenyl) -2, 3, 6-trimethyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl ] -piperidin-4-yl } -propionic acid

3- {1- [1- (4-bromo-2, 6-dimethyl-phenyl) -3, 6-dimethyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl ] -piperidin-4-yl } -propionic acid

3- {1- [1- (4-chloro-2, 6-dimethyl-phenyl) -2, 3, 6-trimethyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl ] -piperidin-4-yl } -propionic acid

3- {1- [1- (4-chloro-2, 6-dimethyl-phenyl) -3, 6-dimethyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl ] -piperidin-4-yl } -propionic acid

3- {1- [1- (2, 6-dibromo-4-isopropyl-phenyl) -2, 3, 6-trimethyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl ] -piperidin-4-yl } -propionic acid

3- {1- [1- (2, 6-dibromo-4-isopropyl-phenyl) -3, 6-dimethyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl ] -piperidin-4-yl } -propionic acid

3- {1- [1- (4-bromo-2, 6-dichloro-phenyl) -3, 6-dimethyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl ] -piperidin-4-yl } -propionic acid

3- {1- [3, 6-dimethyl-1- (2, 4, 6-trichloro-phenyl) -1H-pyrrolo [2, 3-b ] pyridin-4-yl ] -piperidin-4-yl } -propionic acid

3- {1- [1- (2, 6-dibromo-4-chloro-phenyl) -3, 6-dimethyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl ] -piperidin-4-yl } -propionic acid

3- {1- [1- (4-methoxy-2, 6-dimethyl-phenyl) -3, 6-dimethyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl ] -piperidin-4-yl } -propionic acid

3- {1- [1- (2-bromo-4-isopropyl-phenyl) -3, 6-dimethyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl ] -piperidin-4-yl } -propionic acid

3- {1- [1- (4-isopropyl-2-methylsulfanyl-phenyl) -3, 6-dimethyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl ] -piperidin-4-yl } -propionic acid

3- {1- [1- (2, 4-dibromo-phenyl) -3, 6-dimethyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl ] -piperidin-4-yl } -propionic acid

4- {1- [1- (4-bromo-2, 6-dimethyl-phenyl) -2, 3, 6-trimethyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl ] -piperidin-4-yl } -butyric acid

4- {1- [1- (4-bromo-2, 6-dimethyl-phenyl) -3, 6-dimethyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl ] -piperidin-4-yl } -butyric acid

{8- [1- (4-bromo-2, 6-dimethyl-phenyl) -3, 6-dimethyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl ] -8-aza-bicyclo [3.2.1] oct-3-yl } -acetic acid

{1- [1- (4-bromo-2, 6-dimethyl-phenyl) -3, 6-dimethyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl ] -piperidin-3-yl } -acetic acid

2- {1- [1- (4-bromo-2, 6-dimethyl-phenyl) -3, 6-dimethyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl ] -piperidin-4-yl } -acetamide

3- {1- [1- (4-bromo-2, 6-dimethyl-phenyl) -3, 6-dimethyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl ] -piperidin-4-yl } -propionamide

{1- [1- (4-bromo-2, 6-dimethyl-phenyl) -3, 6-dimethyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl ] -piperidin-4-ylmethyl } -phosphonic acid

{1- [1- (4-bromo-2, 6-dimethyl-phenyl) -3, 6-dimethyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl ] -piperidin-4-yl } -methanesulfonic acid

2- {1- [1- (4-bromo-2, 6-dimethyl-phenyl) -3, 6-dimethyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl ] -piperidin-4-yl } -ethanesulfonic acid

2- {1- [1- (4-bromo-2, 6-dimethyl-phenyl) -3, 6-dimethyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl ] -piperidin-4-yl } -ethanesulfonamide

{1- [7- (4-isopropyl-2-methylsulfanyl-phenyl) -2, 5-dimethyl-7H-pyrrolo [2, 3-d ] pyrimidin-4-yl ] -piperidin-4-yl } -acetic acid

4- {1- [7- (4-bromo-2, 6-dimethyl-phenyl) -2, 5, 6-trimethyl-7H-pyrrolo [2, 3-d ] pyrimidin-4-yl ] -piperidin-4-yl } -butyric acid

2- {1- [7- (4-bromo-2, 6-dimethyl-phenyl) -2, 5, 6-trimethyl-7H-pyrrolo [2, 3-d ] pyrimidin-4-yl ] -3, 3-dimethyl-piperidin-4-yl } -acetamide

2, 2-Dimethylpropanoic acid 2- {1- [1- (4-bromo-2, 6-dimethyl-phenyl) -3, 6-dimethyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl ] -piperidin-4-yl } -acetoxymethyl ester

And (S) -ethyl 2- (2- {1- [1- (4-bromo-2, 6-dimethyl-phenyl) -3, 6-dimethyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl ] -piperidin-4-yl } -acetylamino) -3-phenyl-propionate

The formula [1] can be produced by, for example, the methods shown in the following reaction schemes 1 to 4]The compound [ in the following reaction scheme, R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、R⁸M, n, Y and Ar are as defined above; l is¹、L²And L³The same or different and independently is chlorine, bromine, iodine, methylsulfonyloxy, phenylsulfonyloxy, p-toluenesulfonyloxy or trifluoromethylA sulfonyloxy group; x^ais-CN, -CO₂(C_1-5Alkyl), -CON (R)¹⁰)R¹¹or-S (O)₂N(R²²)R²³；X^bIs OR⁹Or N (R)¹⁰)R¹¹；R^aIs C_1-5An alkyl group; d is an integer selected from 1, 2, 3, 4, 5 and 6; e and f are the same or different and are independently an integer selected from 1, 2 and 3]。

Reaction scheme 1

Step 1:

compound (3), a compound of the present invention, can be obtained by reacting compound (1) with compound (2) in an inert solvent or in the absence of any solvent, in the presence or absence of a base. Here, the base includes, for example, amines such as triethylamine, N-diisopropylethylamine, pyridine and the like; inorganic bases such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium hydride and the like; metal alcoholates such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, and the like; metal amides such as sodium amide, lithium diisopropylamide, and the like; and grignard reagents such as methylmagnesium bromide and the like. The inert solvent includes, for example, alcohols such as methanol, ethanol, isopropanol, ethylene glycol and the like; ethers such as diethyl ether, tetrahydrofuran, 1, 4-dioxane, 1, 2-dimethoxyethane, and the like; hydrocarbons such as benzene, toluene, xylene, and the like; esters such as ethyl acetate, ethyl formate and the like; amides such as N, N-dimethylformamide, N-methylpyrrolidone, N-dimethylacetamide and the like; acetonitrile; dimethyl sulfoxide; pyridine; chloroform; dichloromethane; water; and solvent mixtures selected from these inert solvents.

Step 2:

when X is present^aWhen it is a cyano group, the cyano group may be converted into a carboxyl group, C, using an acid or a base in an inert solvent or without any solvent_1-5Alkoxycarbonyl or carbamoyl. Here, the acid includes, for example, organic acids such as formic acid, acetic acid, trifluoroacetic acid, benzenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, benzoic acid, trifluoromethanesulfonic acid and the like; inorganic acids such as sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, polyphosphoric acid, nitric acid, or the like. The base includes, for example, inorganic bases such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide and the like; metal alcoholates, such as sodium methylate, sodium ethylate, potassium tert-butylate and the like. The inert solvent includes, for example, alcohols such as methanol, ethanol, isopropanol, ethylene glycol, t-butanol and the like; ethers such as diethyl ether, tetrahydrofuran, 1, 4-dioxane, 1, 2-dimethoxyethane, and the like; hydrocarbons such as benzene, toluene, xylene, and the like; esters such as ethyl acetate, ethyl formate and the like; amides such as N, N-dimethylformamide, N-methylpyrrolidone, N-dimethylacetamide and the like; acetonitrile; dimethyl sulfoxide; pyridine; chloroform; dichloromethane; water; and solvent mixtures selected from these inert solvents.

Reaction scheme 2

And step 3:

the hydroxyl group in compound (5) which can be prepared by a similar method as described in step 1 can be converted to L using a halogenating agent or a sulfonating agent in an inert solvent or in the absence of any solvent, in the presence or absence of a base². Here, the halogenating agent includes, for example, phosphorus oxychloride, phosphorus oxybromide, phosphorus pentachloride, phosphorus trichloride, phosphorus pentabromide, phosphorus tribromide, thionyl chloride, thionyl bromide, oxalyl chloride, oxalyl bromide, PPh₃-CCl₄、PPh₃-CBr₄And the like. Sulfonating agents include, for example, p-toluenesulfonyl chloride, methanesulfonyl chloride, p-toluenesulphonic anhydride, methanesulfonic anhydride, trifluoromethanesulfonic anhydride, N-phenylbis (trifluoromethanesulfonylimide), and the like. The base includes, for example, amines such as triethylamine, N-diisopropylethylamine, pyridine, N-dimethylaniline, N-diethylaniline and the like; inorganic bases such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium hydride and the like; metal alcoholates such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, and the like; metal amides such as sodium amide, lithium diisopropylamide, and the like; and grignard reagents such as methylmagnesium bromide and the like. The inert solvent includes, for example, alcohols such as methanol, ethanol, isopropanol, ethylene glycol and the like; ethers such as diethyl ether, tetrahydrofuran, 1, 4-dioxane, 1, 2-dimethoxyethane, and the like; hydrocarbons such as benzene, toluene, xylene, and the like; esters such as ethyl acetate, ethyl formate and the like; amides such as N, N-dimethylformamide, N-methylpyrrolidone, N-dimethylacetamide and the like; acetonitrile; dimethyl sulfoxide; pyridine; chloroform; dichloromethane; water; and solvent mixtures selected from these inert solvents.

When L is²When it is not an iodide atom, L may be converted to L using sodium iodide or potassium iodide in an inert solvent before proceeding to the next step²Converted into iodine atoms.

And 4, step 4:

l in the compound (6) can be obtained by reacting the compound (6) with a cyanide compound in an inert solvent in the presence or absence of a phase transfer catalyst or a crown ether²To a cyano group. Herein, cyanide includes, for example, potassium cyanide, sodium cyanide and the like. Phase transfer catalysts include, for example, tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, tetrabutylammonium hydrogen sulfate, tetraethylammonium chloride, tetraethylammonium bromide, tetraethylammonium iodide, benzyltributylammonium chloride, benzyltributylammonium bromideBenzyltributylammonium iodide, benzyltriethylammonium chloride, benzyltriethylammonium bromide, benzyltriethylammonium iodide and the like. Crown ethers include, for example, 15-crown-5, 18-crown-6, and the like. The inert solvent includes, for example, alcohols such as methanol, ethanol, isopropanol, ethylene glycol and the like; ethers such as diethyl ether, tetrahydrofuran, 1, 4-dioxane, 1, 2-dimethoxyethane, and the like; hydrocarbons such as benzene, toluene, xylene, and the like; esters such as ethyl acetate, ethyl formate and the like; amides such as N, N-dimethylformamide, N-methylpyrrolidone, N-dimethylacetamide and the like; acetonitrile; dimethyl sulfoxide; pyridine; chloroform; dichloromethane; water; and solvent mixtures selected from these inert solvents.

And 5:

the cyano group in the compound (7) can be converted into a carboxyl group or a carbamoyl group in the same manner as described in step 2.

Reaction scheme 3

Step 6:

compound (6) can be converted into compound (9) by reacting compound (6) with trialkyl phosphite. Herein, the trialkyl phosphite includes, for example, trimethyl phosphite, triethyl phosphite, triisopropyl phosphite, and the like.

And 7:

the phosphate group in compound (9) can be hydrolyzed using an acid or a base in an inert solvent. Here, the acid includes, for example, organic acids such as formic acid, acetic acid, trifluoroacetic acid, benzenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, benzoic acid, trifluoromethanesulfonic acid and the like; inorganic acids such as sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, polyphosphoric acid, nitric acid, or the like. The base includes, for example, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium hydride, potassium hydride and the like; metal alcoholates, such as sodium methylate, sodium ethylate, potassium tert-butylate and the like. The inert solvent includes, for example, alcohols such as methanol, ethanol, isopropanol, ethylene glycol and the like; ethers such as diethyl ether, tetrahydrofuran, 1, 4-dioxane, 1, 2-dimethoxyethane, and the like; hydrocarbons such as benzene, toluene, xylene, and the like; esters such as ethyl acetate, ethyl formate and the like; amides such as N, N-dimethylformamide, N-methylpyrrolidone, N-dimethylacetamide and the like; acetonitrile; dimethyl sulfoxide; pyridine; water; and solvent mixtures selected from these inert solvents.

And 8:

compound (11) can be obtained by reacting compound (6) with a sulfite in the presence or absence of a phase transfer catalyst or a crown ether in an inert solvent. Herein, the sulfite includes, for example, sodium sulfite, potassium sulfite, and the like. The phase transfer catalyst includes, for example, tetrabutylammonium chloride, tetrabutylammonium bromide, tetrabutylammonium iodide, tetrabutylammonium hydrogen sulfate, tetraethylammonium chloride, tetraethylammonium bromide, tetraethylammonium iodide, benzyltributylammonium chloride, benzyltributylammonium bromide, benzyltributylammonium iodide, benzyltriethylammonium chloride, benzyltriethylammonium bromide, benzyltriethylammonium iodide and the like. Crown ethers include, for example, 15-crown-5, 18-crown-6, and the like. The inert solvent includes, for example, alcohols such as methanol, ethanol, isopropanol, ethylene glycol and the like; ethers such as diethyl ether, tetrahydrofuran, 1, 4-dioxane, 1, 2-dimethoxyethane, and the like; hydrocarbons such as benzene, toluene, xylene, and the like; esters such as ethyl acetate, ethyl formate and the like; amides such as N, N-dimethylformamide, N-methylpyrrolidone, N-dimethylacetamide and the like; acetonitrile; dimethyl sulfoxide; pyridine; water; and solvent mixtures selected from these inert solvents.

Reaction scheme 4

And step 9:

when X is present^bInstead of a hydroxyl group, compound (13), the compound of the present invention, can be synthesized from compound (12) by a conventional method of amidating, esterifying or alkylating a carboxyl group in an inert solvent in the presence or absence of a base. The conventional methods for amidating or esterifying the carboxyl groups are: for example, via the reaction of a mixed acid anhydride obtained by the reaction of compound (12) with a haloformate (e.g., ethyl chloroformate or isobutyl chloroformate) or an acid chloride (e.g., benzoyl chloride or pivaloyl chloride); reaction in the presence of condensing agents (e.g., N' -Dicyclohexylcarbodiimide (DCC), 1- (3-dimethylaminopropyl) -3-and carbodiimide hydrochloride (EDCl), Carbonyldiimidazole (CDI), Diphenylphosphorylazide (DPPA), diethyl cyanophosphate or the like) and optionally additives (e.g., 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide, 4-dimethylaminopyridine or the like); or via an acid halide obtained by reaction of compound (12) with a halogenating agent such as thionyl chloride, oxalyl chloride or the like; the conventional method of alkylating a carboxyl group is to react with an alkylating agent (e.g., an alkyl halide or alkyl sulfonate) in the presence or absence of a reaction-promoting additive (e.g., NaI and KI). When R is⁹When alkoxycarbonyl groups are present, it is possible to use, for example, Protective Group in organic Synthesis (T.W.Greene, P.G.M.Wuts; third edition, 1999, John Wiley&sons, Inc.) converts alkoxycarbonyl groups to carboxyl groups. Bases include, for example, amines, such as triethylamine, N-diisopropylethylamine, pyridine, 1, 8-diazabicyclo [5.4.0]]Undec-7-ene and the like; inorganic bases such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, sodium hydride and the like; metal alcoholates, such as sodium methylate, sodium ethylate, potassium tert-butylate and the like. The acid includes, for exampleOrganic acids such as formic acid, acetic acid, trifluoroacetic acid, benzenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, benzoic acid, trifluoromethanesulfonic acid and the like; inorganic acids such as sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, polyphosphoric acid, nitric acid, or the like. The inert solvent includes, for example, alcohols such as methanol, ethanol, isopropanol, ethylene glycol and the like; ethers such as diethyl ether, tetrahydrofuran, 1, 4-dioxane, 1, 2-dimethoxyethane, and the like; hydrocarbons such as benzene, toluene and the like; amides such as N, N-dimethylformamide, N-methylpyrrolidone, N-dimethylacetamide and the like; acetonitrile; dimethyl sulfoxide; pyridine; chloroform; dichloromethane; water; and solvent mixtures selected from these inert solvents.

Reaction scheme 5

Step 10:

compound (15), a compound of the present invention, can be obtained by reacting compound (6) with compound (14) in an inert solvent in the presence or absence of a base. Bases include amines such as triethylamine, N-diisopropylethylamine, pyridine, 1, 8-diazabicyclo [5.4.0] undec-7-ene, and the like; inorganic bases such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydride and the like; metal alcoholates, such as sodium methylate, sodium ethylate, potassium tert-butylate and the like. The inert solvent includes, for example, alcohols such as methanol, ethanol, isopropanol, ethylene glycol and the like; ethers such as diethyl ether, tetrahydrofuran, 1, 4-dioxane, 1, 2-dimethoxyethane, and the like; hydrocarbons such as benzene, toluene and the like; amides such as N, N-dimethylformamide, N-methylpyrrolidone, N-dimethylacetamide and the like; acetonitrile; dimethyl sulfoxide; pyridine; chloroform; dichloromethane; water; and solvent mixtures selected from these inert solvents.

Reaction scheme 6:

step 11:

compound (18) can be obtained by reacting compound (16) with compound (17) in an inert solvent or in the absence of any solvent, in the presence or absence of a base. The base includes, for example, an amine such as triethylamine, N-diisopropylethylamine or pyridine and the like; inorganic bases such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydroxide, potassium hydroxide, barium hydroxide, sodium hydride and the like; metal alcoholates, such as sodium methylate, sodium ethylate, potassium tert-butylate and the like. The inert solvent includes, for example, alcohols such as methanol, ethanol, isopropanol, ethylene glycol and the like; ethers such as diethyl ether, tetrahydrofuran, 1, 4-dioxane, 1, 2-dimethoxyethane, and the like; hydrocarbons such as benzene, toluene and the like; amides such as N, N-dimethylformamide, N-methylpyrrolidone, N-dimethylacetamide and the like; acetonitrile; dimethyl sulfoxide; pyridine; chloroform; dichloromethane; water; and solvent mixtures selected from these inert solvents.

The compound of the present invention may be prepared in an inert solvent with an inorganic acid (e.g., sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid or the like), with an organic acid (e.g., acetic acid, oxalic acid, lactic acid, tartaric acid, fumaric acid, maleic acid, citric acid, benzenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, benzoic acid, camphorsulfonic acid, ethanesulfonic acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, malic acid, malonic acid, mandelic acid, galactaric acid, naphthalene-2-sulfonic acid or the like), conversion to a salt is carried out with an inorganic base (e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, zinc hydroxide, aluminum hydroxide, or the like) or with an organic base (e.g., ammonia, arginine, lysine, piperazine, choline, diethylamine, 4-phenylcyclohexylamine, 2-aminoethanol, benzathine, or the like). The inert solvent includes, for example, alcohols such as methanol, ethanol, isopropanol, ethylene glycol and the like; ethers such as diethyl ether, tetrahydrofuran, 1, 4-dioxane, 1, 2-dimethoxyethane, and the like; hydrocarbons such as benzene, toluene and the like; esters such as ethyl acetate, ethyl formate and the like; ketones such as ethanone, methyl ethyl ketone, and the like; amides such as N, N-dimethylformamide, N-methylpyrrolidone, N-dimethylacetamide and the like; acetonitrile; dichloromethane; chloroform; dimethyl sulfoxide; pyridine; water; and solvent mixtures selected from these inert solvents.

The compound of the present invention is useful as a therapeutic or prophylactic agent for diseases in which CRF is considered to be involved. For this purpose, the compound of the present invention can be formulated into tablets, pills, capsules, granules, powders, solutions, emulsions, suspensions, injections and the like by conventional preparation techniques by adding conventional fillers, binders, disintegrating agents, pH adjusting agents, solvents and the like.

The compounds of the invention can be administered to adult patients orally or parenterally in a dose of 0.1 to 500 mg/day in one or several portions. The dose can be increased or decreased as appropriate depending on the type of disease and age, weight and symptoms of the patient.

[ embodiments of the invention ]

The present invention is specifically explained with reference to the following examples and test examples, but the present invention is not limited thereto.

Example 1

{1- [1- (4-methoxy-2, 6-dimethyl-phenyl) -3, 6-dimethyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl ] -piperidin-4-yl } -acetic acid (Compound 1-013)

(1) In N₂Under the atmosphereWhile cooling in an ice bath, in 1- (4-methoxy-2, 6-dimethyl-phenyl) -3, 6-dimethyl-1H-pyrrolo [2, 3-b ]]Pyridin-4-ol (1.5 g), triethylamine (1.0 g) in CHCl₃To the mixture in (9 ml), trifluoromethanesulfonic anhydride (1.0 ml) was added, and the mixture was stirred for 30 minutes. Quench the reaction with water and use CHCl₃The mixture is extracted. The organic phase was washed with saturated NaHCO₃Washing with an aqueous solution over anhydrous MgSO₄Dried and filtered. The filtrate was concentrated under reduced pressure to obtain crude trifluoromethanesulfonic acid 1- (4-methoxy-2, 6-dimethylphenyl) -3, 6-dimethyl-1H-pyrrolo [2, 3-b ]]Pyridin-4-yl ester (2.19 g). This material was used in the next step without further purification.

(2) Crude trifluoromethanesulfonic acid 1- (4-methoxy-2, 6-dimethylphenyl) -3, 6-dimethyl-1H-pyrrolo [2, 3-b ]]A mixture of pyridin-4-yl ester (1.1 g), N-diisopropylethylamine (0.65 g) and piperidin-4-ylacetonitrile (1.6 g) was heated at 150 ℃ for 7 hours in a sealed tube. After cooling to room temperature, ethyl acetate and water were poured into the mixture, and separated. The aqueous phase was extracted with ethyl acetate and the organic phase was over MgSO₄Dried and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel: Wako gel C200, eluent: hexane: ethyl acetate 3/1) to give {1- [1- (4-methoxy-2, 6-dimethyl-phenyl) -3, 6-dimethyl-1H-pyrrolo [2, 3-b ] -pale yellow crystals]Pyridin-4-yl]Piperidin-4-yl } -acetonitrile (0.58 g).

(3) Mixing {1- [1- (4-methoxy-2, 6-dimethyl-phenyl) -3, 6-dimethyl-1H-pyrrolo [2, 3-b ]]Pyridin-4-yl]-piperidin-4-yl } -acetonitrile (0.40 g) and concentrated hydrochloric acid (4 ml) were heated at refluxFor 5 hours. After cooling to room temperature, concentrated hydrochloric acid was removed under reduced pressure. Saturated NaHCO was added to the residue₃Aqueous solution and CHCl₃And separating. The aqueous phase was washed with CHCl₃And (4) extracting. The organic phase is treated with 5% KHSO₄Washing with an aqueous solution over MgSO₄Dried and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel: Wako gel C200, eluent: CHCl)₃Methanol 40/1), and the resulting solid was washed with methanol to obtain the title compound (0.21 g).

Example 2

Synthesis of 3- {1- [7- (4-bromo-2, 6-dimethyl-phenyl) -2, 5, 6-trimethyl-7H-pyrrolo [2, 3-d ] pyrimidin-4-yl ] -piperidin-4-yl } -propionamide (Compound 1-040)

(1) Reacting 7- (4-bromo-2, 6-dimethyl-phenyl) -4-chloro-2, 5, 6-trimethyl-7H-pyrrolo [2, 3-d ]]A suspension of pyrimidine (2.0 g), 3- (piperidin-4-yl) propionitrile (1.4 g) and N, N-diisopropylethylamine (1.4 g) in EtOH (4 ml) was heated in a sealed tube at 100 ℃ for 11 hours. After cooling to room temperature, the solvent was removed under reduced pressure. The residue was purified by column chromatography (silica gel: Wako gel C200, eluent: hexane: ethyl acetate: CHCl)₃8/2/1) to obtain white crystals 3- {1- [7- (4-bromo-2, 6-dimethyl-phenyl) -2, 5, 6-trimethyl-7H-pyrrolo [2, 3-d)]Pyrimidin-4-yl]Piperidin-4-yl } -propionitrile (2.0 g).

(2) In 3- {1- [7- (4-bromo-2, 6-dimethyl-phenyl) -2, 5, 6-trimethyl-7H-pyrrolo [2, 3-d ]]Pyrimidin-4-yl]-piperidin-4-yl } -propionitrile (0.40 g) with H₂SO₄(4 ml), and the mixture was cooled to room temperatureStirred for 5 hours. The reaction mixture was poured into ice, and then 4M aqueous NaOH was added to be alkaline. The mixture was extracted with ethyl acetate and the organic phase was taken over Na₂SO₄And (5) drying. The drying agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel: Wako gel C200, eluent: CHCl)₃Methanol 60/1) to obtain an oil. The oily product was crystallized from diethyl ether to obtain the title compound (0.33 g) as white crystals.

Example 3

Synthesis of (2- {1- [1- (4-bromo-2, 6-dimethyl-phenyl) -3, 6-dimethyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl ] -piperidin-4-yl } -ethyl) -phosphonic acid hydrochloride (Compound 1-046)

(1) In 2- {1- [1- (4-bromo-2, 6-dimethyl-phenyl) -3, 6-dimethyl-1H-pyrrolo [2, 3-b ]]Pyridin-4-yl]-piperidin-4-yl } -ethanol (0.93 g), prepared analogously to the method shown in example 1, in CHCl₃To the solution in (10 ml), methanesulfonyl chloride (0.47 g) and pyridine (0.64 g) were added, and the mixture was stirred at room temperature for 3 hours. Adding water to the reaction mixture and adding CHCl to the mixture₃And (4) extracting. The organic phase was washed with water and brine, over Na₂SO₄Dried and filtered. The filtrate was concentrated under reduced pressure to obtain a brown oil. The oily product was crystallized from diisopropyl ether to obtain methanesulfonic acid 2- {1- [1- (4-bromo-2, 6-dimethyl-phenyl) -3, 6-dimethyl-1H-pyrrolo [2, 3-b ]]Pyridin-4-yl]Piperidin-4-yl } -ethyl ester (1.0 g).

(2) Methanesulfonic acid 2- {1- [1- (4-bromo-2, 6-dimethyl-phenyl) -3, 6-dimethyl-1H-pyrrolo [2, 3-b]Pyridin-4-yl]A mixture of piperidin-4-yl } -ethyl ester (0.70 g) and NaI (0.59 g) in acetone (14 ml) was heated at reflux for 3 hours. After cooling to room temperature, water was added and the mixture was extracted with ethyl acetate. The organic phase is washed with water and Na₂SO₄Dried and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel: Wako gel C200, eluent: hexane: ethyl acetate 10/1) to obtain 1- (4-bromo-2, 6-dimethyl-phenyl) -4- [4- (2-iodo-ethyl) -piperidin-1-yl as white crystals]-3, 6-dimethyl-1H-pyrrolo [2, 3-b]Pyridine (0.65 g).

(3) In N₂Under an atmosphere, 1- (4-bromo-2, 6-dimethyl-phenyl) -4- [4- (2-iodo-ethyl) -piperidin-1-yl]-3, 6-dimethyl-1H-pyrrolo [2, 3-b]A mixture of pyridine (0.25 g) and triethyl phosphite (10 ml) was heated at 160 ℃ for 4.5 hours. After the reaction was completed, excess triethyl phosphate was removed under reduced pressure. The residue was purified by column chromatography (silica gel: Wako gel C200, eluent: hexane: ethyl acetate 1/1) to obtain a colorless oil. The oily product was crystallized from diisopropyl ether (10 ml) to give (2- {1- [1- (4-bromo-2, 6-dimethyl-phenyl) -3, 6-dimethyl-1H-pyrrolo [2, 3-b ] as white crystals]Pyridin-4-yl]Piperidin-4-yl } -ethyl) -phosphonic acid diethyl ester (0.16 g).

(4) A mixture of (2- {1- [1- (4-bromo-2, 6-dimethyl-phenyl) -3, 6-dimethyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl ] -piperidin-4-yl } -ethyl) -phosphonic acid diethyl ester (67 mg) and 6M HCl (4 ml) was heated at reflux for 10 hours. 12M HCl (2 mL) was then added and the reaction mixture was heated at reflux for 10 h. The reaction mixture was concentrated under reduced pressure to obtain the title compound (13 mg) as an amorphous substance.

Example 4

Synthesis of 2- {1- [1- (4-bromo-2, 6-dimethyl-phenyl) -3, 6-dimethyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl ] -piperidin-4-yl } -ethanesulfonic acid (Compound 1-048)

1- (4-bromo-2, 6-dimethyl-phenyl) -4- [4- (2-iodo-ethyl) -piperidin-1-yl]-3, 6-dimethyl-1H-pyrrolo [2, 3-b]Pyridine (0.25 g), Na₂SO₃A mixture of (0.28 g), tetrabutylammonium iodide (16 mg), ethanol (5 ml), tetrahydrofuran (5 ml) and water (3 ml) was heated at reflux for 10 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel: Wako gel C200, eluent: ethyl acetate: methanol 5/1) to obtain the title compound (56 mg) as a yellow amorphous substance.

Example 5

Synthesis of ethyl {1- [1- (4-bromo-2, 6-dimethylphenyl) -3, 6-dimethyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl ] -piperidin-4-yl } acetate hydrochloride (Compound 1-050)

In an ice-cooling bath in {1- [1- (4-bromo-2, 6-dimethyl-phenyl) -3, 6-dimethyl-1H-pyrrolo [2, 3-b ]]Pyridin-4-yl]-piperidin-4-yl } -acetic acid (100 mg) in CHCl₃To the solution in (4 ml) were added ethanol (20 mg), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (61 mg) and dimethylaminopyridine (26 mg), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ethyl acetate and water, and separated. Will be provided withThe organic phase was washed with brine, over Na₂SO₄Dried and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel: Wako gel C200, eluent: hexane: ethyl acetate 4/1) to obtain {1- [1- (4-bromo-2, 6-dimethylphenyl) -3, 6-dimethyl-1H-pyrrolo [2, 3-b ] -C]Pyridin-4-yl]-piperidin-4-yl } acetic acid ethyl ester (99 mg). Mixing {1- [1- (4-bromo-2, 6-dimethylphenyl) -3, 6-dimethyl-1H-pyrrolo [2, 3-b ]]Pyridin-4-yl]-piperidin-4-yl } acetic acid ethyl ester was dissolved in ethanol (2 ml) and a solution of 4M HCl in ethyl acetate (60 μ l) was added to the solution while cooling in an ice bath. After stirring at room temperature, the reaction mixture was concentrated under reduced pressure, and the residue was crystallized from diisopropyl ether (1 ml). The crystals were collected by filtration to obtain the title compound (95 mg).

Example 6

Synthesis of {1- [1- (4-bromo-2, 6-dimethyl-phenyl) -3, 6-dimethyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl ] -piperidin-4-yl } -acetic acid 1-cyclohexyloxycarbonyloxy-ethyl ester (Compound 1-071)

A suspension of {1- [1- (4-bromo-2, 6-dimethyl-phenyl) -3, 6-dimethyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl ] -piperidin-4-yl } -acetic acid (300 mg), 1-chloroethylcyclohexylcarbo-ate (293) mg, potassium carbonate (196 mg) and NaI (213 mg) in DMF (3 ml) was heated at 60 ℃ for 3 hours. After cooling to room temperature, water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with hydrochloric acid and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel: Wako gel C200, eluent: hexane: ethyl acetate 4/1) to obtain the title compound (225 mg) as a colorless oil.

Example 7

Synthesis of (S) -2- (2- {1- [1- (4-bromo-2, 6-dimethyl-phenyl) -3, 6-dimethyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl ] -piperidin-4-yl } -acetylamino) -3-phenyl-propionic acid (Compound 1-074)

(1) In an ice-cooling bath in hydrochloric acid {1- [1- (4-bromo-2, 6-dimethyl-phenyl) -3, 6-dimethyl-1H-pyrrolo [2, 3-b ]]Pyridin-4-yl]To a solution of piperidin-4-yl } -acetic acid (300 mg), L-phenylalanine ethyl ester hydrochloride (204 mg), 1-hydroxybenzotriazole (108 mg) and triethylamine (90 mg) in DMF were added 1- (3-dimethylaminopropyl) -3-and carbodiimide hydrochloride (170 mg), and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic phase was washed with saturated NaHCO₃The aqueous solution and brine were washed and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel: Wakogel C200, eluent: hexane: ethyl acetate 1/1) to obtain (S) -2- (2- {1- [1- (4-bromo-2, 6-dimethyl-phenyl) -3, 6-dimethyl-1H-pyrrole [2, 3-b-pyrrole) as a colorless oil]Pyridin-4-yl]Piperidin-4-yl } -acetylamino) -3-phenyl-propionic acid ethyl ester (222 mg).

(2) Mixing (S) -2- (2- {1- [1- (4-bromo-2, 6-dimethyl-phenyl) -3, 6-dimethyl-1H-pyrrole [2, 3-b)]Pyridin-4-yl]A mixture of-piperidin-4-yl } -acetylamino) -3-phenyl-propionic acid ethyl ester (140 mg), 4M NaOH (1 ml) and EtOH (2 ml) was stirred at room temperature for 24 hours. 1M KHSO was added to the reaction mixture₄(10 ml) and the mixture was extracted with ethyl acetate. The organic phase was washed with brine and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel: Wako gel C200, eluent: CHCl)₃MeOH 9/1) to obtain the title compound (35 mg) as an amorphous.

Example 8

Synthesis of 4- {1- [7- (4-bromo-2, 6-dimethyl-phenyl) -2, 5, 6-trimethyl-7H-pyrrolo [2, 3-b ] pyridin-4-yl ] -piperidin-4-yl } -2-cyano-butyric acid ethyl ester (Compound 1-063)

In N₂To a solution of ethyl cyanoacetate (93 mg) in THF (3 ml) was added sodium hydride (33 mg) under an atmosphere and the mixture was stirred for 30 minutes. Methanesulfonic acid 2- {1- [7- (4-bromo-2, 6-dimethyl-phenyl) -2, 5, 6-trimethyl-7H-pyrrole [2, 3-b ] was added]Pyridin-4-yl]Piperidin-4-yl } -ethyl ester (300 mg), and the mixture was heated at reflux for 3 hours. Ethyl cyanoacetate (93 mg) was added to the solution, and the reaction mixture was heated under reflux for 1 hour. Then NaI (7 mg) was added, and the mixture was heated at reflux for 2 hours. After cooling to room temperature, 5% KHSO was added to the reaction mixture₄Aqueous solution and the mixture was extracted with ethyl acetate. The organic phase is passed over MgSO₄Dried and filtered, and the filtrate concentrated under reduced pressure. The residue was purified by column chromatography (silica gel: Wako gel C200, eluent: hexane: ethyl acetate 4/1) to obtain the title compound (57 mg) as a colorless oil.

Example 9

Synthesis of {1- [1- (4-bromo-2, 6-dimethyl-phenyl) -3, 6-dimethyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl ] -piperidin-4-yl } -acetic acid

(1) 1- (4-bromo-2, 6-dimethyl-phenyl) -3, 6-dimethyl-1H-pyrrolo [2, 3-b)]Pyridin-4-yl]-pyridin-4-ylamine (10.0 g), methanesulfonic acid 3-cyanomethyl-5-methanesulfonyloxy-pentyl ester (11.3 g)And a mixture of N, N-diisopropylethylamine (8.25 g) in N-methylpyrrolidinone (10 ml) was heated at 135 ℃ for 4 hours. To the reaction mixture was added methanesulfonic acid 3-cyanomethyl-5-methanesulfonyloxy-pentyl ester (2.60 g) and the mixture was heated at 135 ℃ for 4.5 hours. After cooling to room temperature, the reaction mixture was poured into a mixture of ethyl acetate, hexane and water (10/1/3) and separated. The aqueous phase was extracted with a mixture of ethyl acetate and hexane (10/1). The combined organic phases were washed with brine, over MgSO₄Dried and filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel: Wako gel C200, eluent: hexane: ethyl acetate: CHCl)₃4/1/0.5) to obtain a solid. The solid was crystallized from diisopropyl ether to obtain {1- [1- (4-bromo-2, 6-dimethyl-phenyl) -3, 6-dimethyl-1H-pyrrolo [2, 3-b ] as a solid]Pyridin-4-yl]Piperidin-4-yl } -acetonitrile (8.61 g).

(2) Reacting {1- [1- (4-bromo-2, 6-dimethyl-phenyl) -3, 6-dimethyl-1H-pyrrolo [2, 3-b ]]Pyridin-4-yl]A mixture of-piperidin-4-yl } -acetonitrile (10.0 g) and concentrated hydrochloric acid (100 ml) was heated at reflux for 10 hours. Concentrated hydrochloric acid was evaporated under reduced pressure. NaHCO was added to the residue₃Solution and CHCl₃And phase separation is carried out. The organic phase is treated with H₂O、1M KHSO₄Washed with aqueous solution and brine, over Na₂SO₄Dried and filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel: Wakogel C200, eluent: hexane: ethyl acetate 1/1) to obtain a solid. The solid was recrystallized from EtOH and H was used₂O washes to give the title compound as crystals (6.0 g)

Comparative example 1

Synthesis of methanesulfonic acid 3-cyanomethyl-5-methanesulfonyloxy-pentyl ester

(1) To a solution of dimethyl 3-oxo-glutarate (523 g) in toluene (750 ml) was added cyanoacetic acid (511 g), NH₄OAc (46.3 g) and acetic acid (90.1 g) and heated at reflux for 8 hours while dehydrating with a dean-Stark apparatus. After cooling to room temperature, the reaction mixture was taken up in water and saturated NaHCO₃Aqueous solution and brine. The organic phase is passed over MgSO₄Dried, filtered and concentrated under reduced pressure to give crude 3-cyanomethylene-dimethyl glutarate (403 g) as an oil.¹H NMR(200MHz，CDCl₃)8ppm 3.39(d，J＝0.88Hz， 2H)，3.62(s，2H)，3.72(s，3H)，3.74(s，3H)，5.51(s，1H)。

(2) To a solution of crude 3-cyanomethylene-glutaric acid dimethyl ester (403 g) in methanol (500 ml) was added 5% Pd-C, and the mixture was stirred at room temperature for 4 days. Pd-C was removed by filtration and the filtrate was concentrated under reduced pressure to give crude 3-cyanomethyl-dimethyl glutarate (212 g). The residue was purified by distillation to obtain 3-cyanomethyl-dimethyl glutarate as a yellow oil (bp 130-150 ℃ C., 133 Pa).¹H NMR(200MHz，CDCl₃)δppm 2.46-2.61(m，5H)2.62-2.78(m，4H)3.71(s，6H)。

(3) 3-cyanomethyl-dimethyl glutarate (212 g) was added to LiAlH under a nitrogen atmosphere at-20 deg.C₄(50.0 g) in THF (1.8L). After stirring for 30 minutes, H was slowly added to the reaction mixture₂O (200 ml). Filtering to remove insoluble materials, and concentrating the filtrate under reduced pressure to obtain5-hydroxy-3- (2-hydroxy-ethyl) -valeronitrile (131 g) was obtained.¹HNMR(200MHz，CDCl₃)δppm 1.38-1.91(m，4H)1.98-2.36(m，1H)2.50(d，J＝5.71Hz，2H)3.51-3.90(m，4H)。

(4) 5-hydroxy-3- (2-hydroxy-ethyl) -valeronitrile (100 g) and Et under a nitrogen atmosphere₃A solution of N (170 g) in THF (500 ml) was cooled to-15 ℃ and MsCl (168 g) was added slowly and the reaction mixture was stirred at room temperature for 1.5 h. Adding H to the reaction mixture₂After O (1.2 l), the mixture was stirred at room temperature for 30 minutes. The precipitate was collected by filtration and dried to obtain the title compound (145 g) as light brown crystals.¹HNMR(200MHz，CDCl₃)δppm 1.65-2.09(m，5H)2.68(d，J＝5.75Hz，2H)3.20(s，6H)4.29(t，J＝6.45Hz，4H)。

TABLE 1^*1

^*1: com.no. ═ compound No., ex.no. ═ example No., solvent for crystallization: EtOAc-ethyl acetate, MeOH-methanol, EtOH-ethanol, IPE-diisopropyl ether, Et₂O-diethyl ether, THF-tetrahydrofuran

The analytical data for the amorphous compound are described below.

1-045：

MS(ES，Neg)：504(M-1)^-，506(M+1)^-；NMR(300MHz，DMSO-d6)δ1.33-1.69(4H，m)，1.75-2.13(3H，m)，1.88(6H，s)，2.42(3H，d，J＝1.1Hz)，2.47(3H，s)，2.80-3.25(2H，m)，3.63-3.97(2H，m)，6.77(1H，br s)，7.19(1H，br s)，7.50-7.62(2H，m).

1-046：

MS(ES，Neg)：518(M-1)^-，520(M+1)^-；NMR(300MHz，DMSO-d6)δ1.18-1.98(9H，m)，1.88(6H，s)，2.42(3H，d，J＝0.9Hz)，2.80-3.27(2H，m)，3.65-3.94(2H，m)，6.60-6.85(1H，m)，7.08-7.22(1H，m)，7.19(1H，br s)，7.50-7.62(2H，m).

1-047：

MS(ES，Neg)：504(M-1)^-，506(M+1)^-；NMR(300MHz，DMSO-d6)δ1.30-2.53(2H，m)，1.74-2.15(3H，m)，1.84(6H，s)，2.32(3H，s)，2.43(3H，d，J＝1.1Hz)，2.47(2H，d，J＝6.4Hz)，2.62-2.78(2H，m)，3.36-3.52(2H，m)，6.47(1H，s)，6.94-6.98(1H，m)，7.44(2H，s).

1-048：

MS(ES，Neg)：518(M-1)^-，520(M+1)^-；NMR(300MHz，DMSO-d6)δ1.20-1.87(7H，m)，1.84(6H，s)，2.40-2.60(2H，m)，2.43(3H，d，J＝0.9Hz)，2.49(3H，s)，2.60-2.75(2H，m)，3.41-3.55(2H，m)，6.46(1H，s)，6.94-6.97(1H，m)，7.44(2H，s).

1-063：

MS(ES，Pos)：566(M+1)⁺，568(M+3)⁺；NMR(300MHz，CDCl₃)δ1.28-1.70(6H，m)，135(3H，t，J＝7.1Hz)，1.72-2.12(3H，m)，1.84(6H，s)，1.94(3H，s)，2.37(3H，s)，2.49(3H，s)，2.82-3.00(2H，m)，3.46-3.55(1H，m)，3.90-4.09(2H，m)，4.30(2H，q，J＝7.1Hz)，7.33(2H，s).

1-067

MS(ES，Pos)：566(M+1)⁺，568(M+3)⁺；NMR(300MHz，CDCl₃)δ0.90-1.35(4H，m)，1.45-1.80(10H，m)，1.82-2.05(2H，m)，1.92(6H，s)，2.36(2H，d，J＝7.00Hz)，2.44(3H，s)，2.49(3H，s)，2.70-2.85(2H，m)，3.52-3.61(2H，m)，3.92(2H，d，J＝6.37Hz)，6.43(1H，s)，6.59-6.64(1H，m)，7.29(2H，s).

1-068

MS(ES，Pos)：594(M+1)⁺，596(M+3)⁺；NMR(300MHz，CDCl₃)δ1.50-1.65(4H，m)，1.80-2.00(1H，m)，1.92(6H，s)，2.41(2H，d，J＝7.00Hz)，2.44(3H，s)，2.45-2.49(3H，m)，2.70-2.83(2H，m)，3.50-3.62(2H，m)，5.11(2H，s)，6.42(1H，s)，6.59-6.64(1H，m)，7.25-7.40(6H，m).

1-069

MS(ES，Pos)：555(M+1)⁺，557(M+3)⁺；NMR(300MHz，CDCl₃)δ1.48-1.70(4H，m)，1.78-1.95(3H，m)，1.92(6H，s)，2.25(6H，s)，2.36(2H，d，J＝7.00Hz)，2.44(3H，s)，2.46-2.50(3H，m)，2.70-2.82(2H，m)，3.52-3.62(2H，m)，6.42(1H，s)，6.59-6.63(1H，m)，7.29(2H，s).

1-070

MS(ES，Pos)：606(M+1)⁺，608(M+3)⁺；NMR(200MHz，CDCl₃)δ1.42-1.78(4H，m)，1.60(3H，s)，1.69(3H，s)，1.73(3H，s)，1.80-1.96(1H，m)，1.92(6H，s)，2.01-2.18(4H，m)，2.36(2H，d，J＝6.80Hz)，2.44(3H，s)，2.46-2.51(3H，m)，2.68-2.85(2H，m)，3.49-3.63(2H，m)，4.63(2H，d，J＝7.00Hz)，5.03-5.15(2H，m)，5.30-5.42(2H，m)，6.42(1H，s)，6.58-6.63(1H，m)，7.29(2H，s).

1-071

MS(ES，Pos)：640(M+1)⁺，642(M+3)⁺；NMR(300MHz，CDCl₃)δ1.20-1.62(10H，m)，1.54(3H，d，J＝5.40Hz)，1.70-1.82(2H，m)，1.82-2.04(3H，m)，1.92(6H，s)，2.37-2.42(2H，m)，2.44(3H，s)，2.46-2.50(3H，m)，2.70-2.82(2H，m)，3.49-3.61(2H，m)，4.58-4.70(1H，m)，6.42(1H，s)，6.59-6.63(1H，m)，6.80(1H，q，J＝5.40Hz)，7.29(2H，s).

1-072

MS(ES，Pos)：584(M+1)⁺，586(M+3)⁺；NMR(300MHz，CDCl₃)δ1.23(9H，s)，1.50- 1.65(4H，m)，1.82-1.91(1H，m)，1.92(6H，s)，2.43(2H，d，J＝6.99Hz)，2.45(3H，s)，2.46-2.50(3H，m)，2.71-2.82(2H，m)，3.50-3.61(2H，m)，5.79(2H，s)，6.42(1H，s)，6.59-6.63(1H，m)，7.29(2H，s).

1-073

MS(ES，Pos)：645(M+1)⁺，647(M+3)⁺；NMR(300MHz，CDCl₃)δ1.27(3H，t，J＝7.15Hz)，1.40-1.61(3H，m)，1.70-1.91(2H，m)，1.92(6H，s)，2.17-2.23(2H，m)，2.45(3H，s)，2.46-2.49(3H，m)，2.69-2.81(2H，m)，3.14-3.23(2H，m)，3.48-3.59(2H，m)，4.20(2H，q，J＝7.15Hz)，4.91-4.98(1H，m)，5.89-5.93(1H，m)，6.42(1H，s)，6.59-6.63(1H，m)，7.10-7.18(2H，m)，7.22-7.37(5H，m).

1-075

MS(ES，Pos)：598(M+1)⁺，600(M+3)⁺；NMR(300MHz，CDCl₃)δ1.18-1.43(9H，m)，1.50-1.72(7H，m)，1.83-2.06(2H，m)，1.92(6H，s)，2.35(2H，d，J＝6.99Hz)，2.45(3H，s)，2.47-2.50(3H，m)，2.71-2.84(2H，m)，3.50-3.69(4H，m)，4.10(2H，d，J＝6.68Hz)，6.42(1H，s)，6.60-6.63(1H，m)，7.29(2H，s).

1-076

MS(ES，Pos)：611(M+1)⁺，613(M+3)⁺；NMR(300MHz，CDCl₃)δ0.95-1.05(6H，m)，1.29(3H，t，J＝7.15Hz)，1.48-1.77(6H，m)，1.83-2.18(2H，m)，1.92(6H，s)，2.25(2H，d，J＝6.99Hz)，2.44(3H，s)，2.47-2.50(3H，m)，2.70-2.83(2H，m)，3.49-3.62(2H，m)，4.20(2H，q，J＝7.15Hz)，4.60-4.72(1H，m)，5.85(1H，d，J＝8.24Hz)，6.42(1H，s)，6.59-6.62(1H，m)，7.29(2H，s).

1-077

MS(ES，Pos)：556(M+1)⁺，558(M+3)⁺；NMR(300MHz，CDCl₃)δ1.30(3H，t，J＝7.15Hz)，1.50-1.70(3H，m)，1.85-2.15(2H，m)，1.92(6H，s)，2.40-2.50(2H，m)，2.44(3H，s)，2.47-2.50(3H，m)，2.72-2.84(2H，m)，3.52-3.62(2H，m)，4.24(2H，q，J＝7.15 Hz)，4.64(2H，s)，6.43(1H，s)，6.59-6.63(1H，m)，7.29(2H，s).

1-078

MS(ES，Pos)：643(M+1)⁺，645(M+3)⁺，647(M+5)⁺，649(M+7)⁺；NMR(300MHz，CDCl₃)δ1.45-2.05(9H，m)，2.43-2.46(3H，m)，2.52(3H，s)，2.57(2H，t，J＝7.07Hz)，2.82-3.03(2H，m)，3.47-3.56(1H，m)，4.10-4.25(2H，m)，6.59-6.63(1H，m)，7.82(2H，s).

1-082

MS(ES，Pos)：465(M+1)⁺；NMR(300MHz，CDCl₃)δ1.20-1.80(10H，m)，1.85(3H，s)，2.02(3H，s)，2.2-2.43(5H，m)，2.51(3H，m)，2.92-3.03(2H，m)，3.13(6H，s)，3.91-4.04(2H，m)，6.44-6.48(1H，m)，7.96(1H，s).

^*2: 1HCl salt

^*3: after the compound purified by column chromatography is left to stand, crystals are obtained.

Test example 1[ CRF receptor binding assay ]

Monkey tonsils membranes were used as the recipient preparation.

Use of¹²⁵I-CRF as¹²⁵I-labeling the ligand.

The use was carried out by The following method described in The Journal of Neuroscience, 7, 88(1987)¹²⁵I-binding reaction of labeled ligand.

Preparation of acceptor membrane:

monkey tonsil was placed in a solution containing 10mM MgCl₂And 2mM EDTA in 50mM Tris-HCl buffer (pH 7.0), and centrifuged at 48,000 Xg for 20 minutes, and the precipitate was washed once with Tris-HCl buffer. The washed precipitate was suspended in a suspension containing 10mM MgCl₂2mM EDTA, 0.1% bovine serum albumin and 100 kallikrein units/ml aprotinin in 50mM Tris-HCl buffer (pH 7.0) to obtain a membrane preparation.

CRF receptor binding assay:

the membrane product (0.3 mg protein/ml) was allowed to stand,¹²⁵I-CRF (0.2nM) and test agent were reacted at 25 ℃ for 2 hours. After the reaction is complete, suction is applied by treatment with 0.3% polyethyleneimineThe reaction mixture was filtered, and the glass filter was washed three times with phosphate buffered hydrochloric acid containing 0.01% Triton X-100. After washing, the radioactivity of the filter paper was measured in a gamma particle counting tube.

Bound when the reaction is carried out in the presence of 1. mu.M CRF¹²⁵Amount of I-CRF as¹²⁵Degree of nonspecific binding of I-CRF, and was taken as a total¹²⁵Degree of I-CRF binding and non-specificity¹²⁵The difference between the degree of I-CRF binding was taken as specificity¹²⁵Degree of I-CRF binding. By bringing a concentration (0.2nM)¹²⁵I-CRF was reacted with various concentrations of each test agent under the above conditions to obtain an inhibition curve. Measured from the inhibition curve¹²⁵Test drug concentration (IC) at which I-CRF binding is inhibited by 50%₅₀)。

As a result, it has been found that the compounds include, for example, compounds 1-001, 1-002, 1-003, 1-004, 1-005, 1-006, 1-007, 1-008, 1-009, 1-010, 1-011, 1-012, 1-014, 1-015, 1-016, 1-017, 1-018, 1-019, 1-020, 1-021, 1-022, 1-023, 1-024, 1-025, 1-027, 1-028, 1-029, 1-030, 1-031, 1-032, 1-033, 1-034, 1-035, 1-039, 1-042, 1-045, 1-047, 1-048, 1-049, 1-053, 1-029, 1-032, 1-029, 1-024, 1-056, 1-061, 1-072, 1-073 as typical with an IC of 100nM or less₅₀Compounds of value (v).

Test example 2[ Delta receptor binding assay ]

Murine meninges were used as recipient preparations.

Use of³H-DPDPE([_D-Pen²，_D-Pen⁵]Enkephalin) as³H-labeled ligand.

Use is made by the following method³Binding reaction of H-labeled ligand.

Preparation of acceptor membrane:

rat brain in 10mM MgCl₂And 1mM EDTA in 50mM Tris-HCl buffer (pH 7.4),and centrifuged at 48,000 Xg for 20 minutes, and the precipitate was washed once with Tris-HCl buffer. The washed precipitate was suspended in a suspension containing 10mM MgCl₂And 1mM EDTA in 50mM Tris-HCl buffer (pH 7.4) to obtain a membrane preparation.

Delta opioid (opioid) receptor binding assay:

the membrane preparation (1 mg protein/ml) was allowed to stand,³H-DPDPDPPE (1.5nM) and the test agent were reacted at 25 ℃ for 70 min. After completion of the reaction, the reaction mixture was filtered by drawing through a glass filter (GF/C) treated with 0.3% polyethyleneimine, and the glass filter was filtered with a solution containing 10mM MgCl₂And 1mM EDTA in 50mM Tris-HCl buffer (pH 7.4) three times. After washing, scintillation cocktails were added to the filters and the radioactivity of the filters was measured in a liquid scintillation counter.

Bound by reaction in the presence of 10. mu.M naltrexone (naltrindole)³Amount of H-DPDPDPE as³The degree of nonspecific binding of H-DPDPE was taken and totaled³Degree of H-DPDPDPE binding and non-specificity³The difference between the degrees of binding of H-DPDPPE was taken as specificity³Degree of H-DPDPDPPE binding. By bringing a concentration (1.5nM)³H-DPDPDPE was reacted with each test agent at various concentrations under the above conditions to obtain an inhibition curve. Measured from the inhibition curve³Test drug concentration (IC) at 50% inhibition of H-DPDPDPE binding₅₀)。

As a result, it was found that compounds 1-001, 1-002, 1-003, 1-004, 1-005, 1-006, 1-011, 1-012, 1-016, 1-018, 1-019, 1-020, 1-021, 1-022, 1-025, 1-026, 1-027, 1-032, 1-045, 1-047 and 1-048 can be exemplified as typical compounds having an IC of 500nM or less₅₀Compounds of value (v).

[ Effect of the invention ]

According to the present invention, there is provided a compound having high affinity for CRF receptors and/or δ receptors. These compounds have excellent pharmacokinetic properties including metabolic stability, bioavailability and brain concentration. These compounds are effective against diseases in which CRF is considered to be involved, such as depression, anxiety, alzheimer's disease, parkinson's disease, huntington's chorea, eating disorders, hypertension, gastrointestinal diseases, drug dependence, cerebral infarction, cerebral ischemia, cerebral edema, cerebral trauma, inflammation, immune-related diseases, alopecia, irritable bowel syndrome, sleep disorders, epilepsy, dermatitis, schizophrenia, pain, and the like.

Claims

1. A cyclic amino-substituted pyrrolopyridine derivative represented by the following formula [ I ] or a pharmaceutically acceptable salt thereof:

wherein said cyclic amino group is represented by the following formula [ II ]:

wherein said cyclic amino group is a 6-membered saturated cyclic amine or is substituted with C between any two different carbon atoms of the cyclic amine_1-5Alkylene bridged 6-membered saturated cyclic amines independently- (CR) at the same or different carbon atoms of the cyclic amine¹R²)_m-(CHR³)_nA group represented by-X, R⁴And R⁵Substituted;

x is-CO₂H、-CONH₂、-P(＝O)(OH)₂or-S (═ O)₂R¹⁴；

Y is CH;

R¹is hydrogen;

R²is hydrogen;

m is an integer selected from 1, 2 and 3;

n is 0;

R⁴is hydrogen;

R⁵is hydrogen;

R⁶is C_1-5An alkyl group;

R⁷is C_1-5An alkyl group;

R⁸is hydrogen or C_1-5An alkyl group;

R¹⁴is-OH or-NH₂；

Ar is phenyl substituted with one or more identical or different substituents selected from the group consisting of: halogen, C_1-5Alkyl radical, C_1-5Alkoxy, and C_1-5An alkylthio group.

2. The compound of formula [ I ] according to claim 1]The cyclic amino substituted pyrrolopyridine derivative or a pharmaceutically acceptable salt thereof, wherein the cyclic amino is a 6-membered saturated cyclic amine, R⁶Is methyl, R⁷Is methyl, R⁸Is hydrogen or methyl, Ar is phenyl substituted with one or more identical or different substituents selected from the group consisting of: -CH₃、-OCH₃、-SCH₃-Cl and-Br.

3. The compound of formula [ I ] according to claim 1]A cyclic amino substituted pyrrolopyridine derivative represented by the formula (I), or a pharmaceutically acceptable salt thereof, wherein X is as defined in claim 1; y is CH; the cyclic amino group is a 6-membered saturated cyclic amine; m is an integer selected from 1, 2 and 3; n is 0; r¹、R²、R⁴And R⁵Is hydrogen; r⁶Is C_1-5An alkyl group; r⁷Is C_1-5An alkyl group; r⁸Is hydrogen or C_1-5An alkyl group; ar is phenyl substituted with two or three substituents, which may be the same or different, selected from the group consisting of: halogen, C_1-3Alkyl radical, C_1-3Alkoxy, and C_1-3An alkylthio group.

4. The compound of formula [ I ] according to claim 1]The cyclic amino substituted pyrrolopyridine derivative or the pharmaceutically acceptable salt thereof is shown, wherein X is-CO₂H、-CONH₂、-P(＝O)(OH)₂or-S (═ O)₂OH; y is CH; the cyclic amino group is a 6-membered saturated cyclic amine; m is an integer selected from 1, 2 and 3; n is 0; r¹、R²、R⁴And R⁵Is hydrogen; r⁶Is C_1-3An alkyl group; r⁷Is C_1-3An alkyl group; r⁸Is hydrogen or C_1-3An alkyl group; ar is two or three same or different selected from chlorine, bromine and C_1-3Alkyl radical, C_1-3Alkoxy, and C_1-3Phenyl substituted by the substituent of alkylthio.

5. The compound of formula [ I ] according to claim 1]The cyclic amino substituted pyrrolopyridine derivative or the pharmaceutically acceptable salt thereof is shown, wherein X is-CO₂H; y is CH; the cyclic amino group is a 6-membered saturated cyclic amine; m is an integer selected from 1, 2 and 3; n is 0; r¹、R²、R⁴And R⁵Is hydrogen; r⁶Is methyl; r⁷Is methyl; r⁸Is hydrogen or methyl; ar is two or three same or different selected from chlorine, bromine and C_1-3Alkyl radical, C_1-3Alkoxy, and C_1-3Substitutents of alkylthio radicalsA substituted phenyl group.

6. The compound of the formula [1] according to claim 1, which is selected from

{1- [1- (4-bromo-2, 6-dimethyl-phenyl) -2, 3, 6-trimethyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl ] -piperidin-4-yl } -acetic acid,

{1- [1- (4-bromo-2, 6-dimethyl-phenyl) -3, 6-dimethyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl ] -piperidin-4-yl } -acetic acid,

{1- [1- (4-chloro-2, 6-dimethyl-phenyl) -2, 3, 6-trimethyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl ] -piperidin-4-yl } -acetic acid,

{1- [1- (4-chloro-2, 6-dimethyl-phenyl) -3, 6-dimethyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl ] -piperidin-4-yl } -acetic acid,

{1- [1- (2, 6-dibromo-4-isopropyl-phenyl) -2, 3, 6-trimethyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl ] -piperidin-4-yl } -acetic acid,

{1- [1- (2, 6-dibromo-4-isopropyl-phenyl) -3, 6-dimethyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl ] -piperidin-4-yl } -acetic acid,

{1- [3, 6-dimethyl-1- (2, 4, 6-tribromo-phenyl) -1H-pyrrolo [2, 3-b ] pyridin-4-yl ] -piperidin-4-yl } -acetic acid,

{1- [1- (4-bromo-2, 6-dichloro-phenyl) -3, 6-dimethyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl ] -piperidin-4-yl } -acetic acid,

{1- [3, 6-dimethyl-1- (2, 4, 6-trichloro-phenyl) -1H-pyrrolo [2, 3-b ] pyridin-4-yl ] -piperidin-4-yl } -acetic acid,

{1- [1- (2, 6-dibromo-4-chloro-phenyl) -3, 6-dimethyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl ] -piperidin-4-yl } -acetic acid,

{1- [1- (2-bromo-4-isopropyl-phenyl) -3, 6-dimethyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl ] -piperidin-4-yl } -acetic acid,

{1- [1- (4-isopropyl-2-methylsulfanyl-phenyl) -3, 6-dimethyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl ] -piperidin-4-yl } -acetic acid,

{1- [1- (2, 4-dibromo-phenyl) -3, 6-dimethyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl ] piperidin-4-yl } -acetic acid,

3- {1- [1- (4-bromo-2, 6-dimethyl-phenyl) -2, 3, 6-trimethyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl ] -piperidin-4-yl } -propionic acid,

3- {1- [1- (4-bromo-2, 6-dimethyl-phenyl) -3, 6-dimethyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl ] -piperidin-4-yl } -propionic acid,

3- {1- [1- (4-chloro-2, 6-dimethyl-phenyl) -2, 3, 6-trimethyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl ] -piperidin-4-yl } -propionic acid,

3- {1- [1- (4-chloro-2, 6-dimethyl-phenyl) -3, 6-dimethyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl ] -piperidin-4-yl } -propionic acid,

3- {1- [1- (2, 6-dibromo-4-isopropyl-phenyl) -2, 3, 6-trimethyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl ] -piperidin-4-yl } -propionic acid,

3- {1- [1- (2, 6-dibromo-4-isopropyl-phenyl) -3, 6-dimethyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl ] -piperidin-4-yl } -propionic acid,

3- {1- [1- (4-bromo-2, 6-dichloro-phenyl) -3, 6-dimethyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl ] -piperidin-4-yl } -propionic acid,

3- {1- [3, 6-dimethyl-1- (2, 4, 6-trichloro-phenyl) -1H-pyrrolo [2, 3-b ] pyridin-4-yl ] -piperidin-4-yl } -propionic acid,

3- {1- [1- (2, 6-dibromo-4-chloro-phenyl) -3, 6-dimethyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl ] -piperidin-4-yl } -propionic acid,

3- {1- [1- (4-methoxy-2, 6-dimethyl-phenyl) -3, 6-dimethyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl ] -piperidin-4-yl } -propionic acid,

3- {1- [1- (2-bromo-4-isopropyl-phenyl) -3, 6-dimethyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl ] -piperidin-4-yl } -propionic acid,

3- {1- [1- (4-isopropyl-2-methylsulfanyl-phenyl) -3, 6-dimethyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl ] -piperidin-4-yl } -propionic acid,

3- {1- [1- (2, 4-dibromo-phenyl) -3, 6-dimethyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl ] -piperidin-4-yl } -propionic acid,

4- {1- [1- (4-bromo-2, 6-dimethyl-phenyl) -2, 3, 6-trimethyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl ] -piperidin-4-yl } -butyric acid,

4- {1- [1- (4-bromo-2, 6-dimethyl-phenyl) -3, 6-dimethyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl ] -piperidin-4-yl } -butyric acid,

{8- [1- (4-bromo-2, 6-dimethyl-phenyl) -3, 6-dimethyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl ] -8-aza-bicyclo [3.2.1] oct-3-yl } -acetic acid,

{1- [1- (4-bromo-2, 6-dimethyl-phenyl) -3, 6-dimethyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl ] -piperidin-3-yl } -acetic acid,

2- {1- [1- (4-bromo-2, 6-dimethyl-phenyl) -3, 6-dimethyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl ] -piperidin-4-yl } -acetamide,

3- {1- [1- (4-bromo-2, 6-dimethyl-phenyl) -3, 6-dimethyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl ] -piperidin-4-yl } -propionamide,

{1- [1- (4-bromo-2, 6-dimethyl-phenyl) -3, 6-dimethyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl ] -piperidin-4-ylmethyl } -phosphonic acid,

{1- [1- (4-bromo-2, 6-dimethyl-phenyl) -3, 6-dimethyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl ] -piperidin-4-yl } -methanesulfonic acid,

2- {1- [1- (4-bromo-2, 6-dimethyl-phenyl) -3, 6-dimethyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl ] -piperidin-4-yl } -ethanesulfonic acid,

2- {1- [1- (4-bromo-2, 6-dimethyl-phenyl) -3, 6-dimethyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl ] -piperidin-4-yl } -ethanesulfonamide,

And (S) -ethyl 2- (2- {1- [1- (4-bromo-2, 6-dimethyl-phenyl) -3, 6-dimethyl-1H-pyrrolo [2, 3-b ] pyridin-4-yl ] -piperidin-4-yl } -acetylamino) -3-phenyl-propionate.

7. An antagonist for CRF receptors, comprising the cyclic amino-substituted pyrrolopyridine derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6 as an active ingredient.

8. Use of a cyclic amino substituted pyrrolopyridine derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1-6, in the manufacture of a CRF receptor antagonist.