EP1389618B1

Pyrazolo 1,5-a pyridines and medicines containing the same

Abstract

This record has no abstract on file.

EP1389618B1, drawing sheet 1 — Sheet 1 of 68

Term

Term ended

Expired 25 April 2022, 4.4 years ago.

Parties

Owner: Eisai R&D Management Co., Ltd.
Applicants: EISAI R&D MAN CO LTD
Inventors: HIBI, Shigeki, Tsukuba-shi, Ibaraki 305-0051, Japan
KIKUCHI, Koichi, Tsuchiura-shi, Ibaraki 300-0013, Japan
HOSHINO, Yorihisa, Tsukuba-shi, Ibaraki 305-0045, Japan
SOEJIMA, Motohiro, Tsukuba-shi, Ibaraki 305-0005, Japan
and 7 more inventorsShow fewer
YOSHIUCHI, Tatsuya, Moriya-shi, Ibaraki 302-0115, Japan
SHIN, Kogyoku, Tsukuba-shi, Ibaraki 305-0061, Japan
ONO, Mutsuko, Ushiku-shi, Ibaraki 300-1222, Japan
TAKAHASHI, Yoshinori, Tsukuba-shi, Ibaraki 305-0061, Japan
SHIBATA, Hisashi, Ushiku-shi, Ibaraki 300-1232, Japan
INO, Mitsuhiro, Ushiku-shi, Ibaraki 300-1234, Japan
HIRAKAWA, Tetsuya, Tsukuba-shi, Ibaraki 305-0051, Japan

Examination

Agent: HOFFMANN EITLE
Filing to grant: 9.1 years

Reach

Cites: 7 earlier patents⁠
Family: 48 members in 21 offices⁠US6HU4JP4KR4EP3NO3AT2BR2+13

Classification

CPC: C07D471/04A61K31/437C07F5/025C07F7/2208A61P1/00A61P1/04+58 more
IPC: C07D471 04C07F7 22A61K31 437A61K31 444A61P3 04A61P3 10+13 more

37 claims: 2 independent, 35 dependent

1
A compound represented by the general formula:[wherein R 1 represents hydrogen, halogen, nitro, cyano or the formula -G 1 -R 1a (wherein G 1 represents a single bond, methylene, oxygen, sulfur, sulfinyl, sulfonyl, - C(O)-, -C(O)O-, -OC(O)-, -NR 1b -, -C(O)-NR 1b -, -S(O) 2 -NR 1b -, -NR 1b -C(O)- or -NR 1b -S(O) 2 -;and R 1a and R 1b each independently represent hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-8 cycloalkyl or C 5-8 cycloalkenyl);R 2 , R 3 and R 4 each independently represent hydrogen, halogen, cyano, nitro, hydroxyl, C 6-14 aryl, a 5- to 14-membered heteroaryl group or the formula -G 2 -R 2a (wherein G 2 represents a single bond, C 1-6 alkylene, oxygen, sulfur, sulfinyl, sulfonyl, -C(O)-, -C(O)O-, - OC(O)-, -NR 2b -, -C(O)-NR 2b -, -S(O) 2 -NR 2b -, -NR 2b -C(O)- or -NR 2b -S(O) 2 -;R 2a and R 2b each independently represent hydrogen, C 1-6 alkyl optionally substituted with 1-3 halogen, C 2-10 alkenyl, C 2-10 alkynyl, C 3-8 cycloalkyl or C 5-8 cycloalkenyl);R 2 and R 3 or R 3 and R 4 may bond together to form a 5- to 7-membered ring optionally containing 1 to 4 hetero atoms in the ring and optionally containing carbonyl in the ring;R 5 and R 6 each independently represent the formula -X 5 -X 6 -X 7 (wherein X 5 represents a single bond or -CO-;X 6 represents a single bond, -NR 3a -, oxygen, sulfur, sulfinyl, sulfonyl, C 1-10 alkylene, C 2-10 alkenylene or C 2-10 alkynylene;and X 7 and R 3a each independently represent hydrogen, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-8 cycloalkyl, C 5-8 cycloalkenyl, C 6-14 aryl, a 5- to 14-membered heteroaryl group, a 4- to 14-membered heterocyclic group, a 9- to 11-membered benzene fused ring group, an 8- to 11-membered heteroaryl fused ring group or a bicyclic 7- to 12-membered hydrocarbon ring group);R 5 and R 6 may bond together to form a 5- to 10-membered ring optionally containing 1 to 4 hetero atoms in the ring and optionally containing carbonyl in the ring;R 6 and R 2 may bond together to form a 6- to 7-membered ring optionally containing 1 or 2 hetero atoms in the ring and optionally containing carbonyl in the ring;and Ar represents C 6-14 aryl, a 5- to 14-membered heteroaryl group, a 9- to 11-membered benzene fused ring group or an 8- to 11-membered heteroaryl fused ring group;with the proviso that R 1a , R 1b , R 3a , X 6 , X 7 and Ar may each independently have 1 to 4 groups selected from Substituent Group A below;The group consisting of methylenedioxy, ethylenedioxy and the formula -V 1 -V 2 -V 3 (wherein V 1 represents a single bond, C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, oxygen, sulfur, carbonyl, -CO-O-, -O-CO- or -NR 3b -;V 2 represents a single bond or C 1-6 alkylene;and V 3 and R 3b each independently represent C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 5-8 cycloalkenyl, C 6-14 aryl, a 5- to 14-membered heteroaryl group, a 4- to 14-membered heterocyclic group, hydrogen, halogen, hydroxyl, cyano, C 1-6 alkoxy or the formula -N(R 3c )R 3d (wherein R 3c and R 3d each independently represent hydrogen or C 1-6 alkyl))], a salt thereof or a hydrate of the foregoing.
7
A compound according to any one of claims 1 to 6, a salt of the compound or a hydrate of the foregoing, wherein R 2 , R 3 and R 4 each independently represent hydrogen, halogen, cyano, nitro, hydroxyl, or the formula -G 20 -R 20 (wherein G 20 represents a single bond, oxygen, sulfur, sulfinyl or sulfonyl, and R 20 represents C 1-6 alkyl optionally substituted with 1 to 3 halogen, C 2-10 alkenyl, C 2-10 alkynyl or C 3-8 cycloalkyl).
8
A compound according to any one of claims 1 to 6, a salt of the compound or a hydrate of the foregoing, wherein R 2 , R 3 and R 4 are hydrogen.
9
A compound according to any one of claims 1 to 8, a salt of the compound or a hydrate of the foregoing, wherein Ar is phenyl, 1,3-benzodioxolyl, naphthyl, pyridyl, pyrazyl, pyrimidyl, pyridazyl, thienyl, furanyl, imidazolyl, thiazolyl, quinolinyl, isoquinolinyl, indolinyl, benzofuranyl, benzothienyl, oxazolyl or isoxazolyl, and Ar may have 1 to 4 groups selected from Substituent Group B below;The group consisting of halogen, cyano, hydroxyl, methylenedioxy, ethylenedioxy, the formula -V 4 -V 5 (wherein V 4 represents a single bond, oxygen, or sulfur, and V 5 represents C 1-6 alkyl or C 3-8 cycloalkyl) and the formula -N(R 5a )R 5b (wherein R 5a and R 5b each independently represent hydrogen or C 1-6 alkyl).
12
A compound according to any one of claims 1 to 8, a salt of the compound or a hydrate of the foregoing, wherein Ar is the formula:(wherein R 40 and R 41 each independently represent methoxy, ethoxy, ethyl, methyl, dimethylamino or halogen, R 42 represents hydrogen, methoxy, methyl, dimethylamino or halogen, and Z 1 and Z 2 each independently represent methine or nitrogen).
14
A compound according to any one of claims 1 to 13, a salt of the compound or a hydrate of the foregoing, wherein X 5 is a single bond, and X 6 is a single bond, C 1-6 alkylene optionally having 1 to 3 groups selected from Substituent Group A, Z 2-6 alkenylene optionally having 1 to 3 groups selected from Substituent Group A or C 2-6 alkynylene optionally having 1 to 3 groups selected from Substituent Group A.
15
A compound according to any one of claims 1 to 13, a salt of the compound or a hydrate of the foregoing, wherein X 5 is a single bond, and X 6 is a single bond or C 1-6 alkylene optionally having 1 to 3 groups selected from Substituent Group C below;The group consisting of halogen, hydroxyl, C 1-6 alkoxy, nitrile, C 3-8 cycloalkyl, and C 1-6 alkyl.
16
A compound according to any one of claims 1 to 13, a salt of the compound or a hydrate of the foregoing, wherein X 5 is a single bond, and X 6 is a single bond, 1,2-ethylene or methylene.
17
A compound according to any one of claims 1 to 16, a salt of the compound or a hydrate of the foregoing, wherein X 7 is C 1-10 alkyl optionally having 1 to 3 groups selected from Substituent Group A, C 2-10 alkenyl optionally having 1 to 3 groups selected from Substituent Group A, C 2-10 alkynyl optionally having 1 to 3 groups selected from Substituent Group A, C 3-8 cycloalkyl optionally having 1 to 3 groups selected from Substituent Group A, Z 5-3 cycloalkenyl optionally having 1 to 3 groups selected from Substituent Group A, C 6-14 aryl optionally having 1 to 3 groups selected from Substituent Group A, a 5- to 14-membered heteroaryl group optionally having 1 to 3 groups selected from Substituent Group A, a 4- to 14-membered heterocyclic group optionally having 1 to 3 groups selected from Substituent Group A or a bicyclic 7- to 12-membered hydrocarbon ring group optionally having 1 to 3 groups selected from Substituent Group A.
18
A compound according to any one of claims 1 to 16, a salt of the compound or a hydrate of the foregoing, wherein X 7 is C 1 - 10 alkyl optionally having 1 to 3 groups selected from Substituent Group A, C 3-8 cycloalkyl optionally having 1 to 3 groups selected from Substituent Group A, a 5- to 6-membered heteroaryl group optionally having 1 to 3 groups selected from Substituent Group A or a 4- to 7-membered heterocyclic group optionally having 1 to 3 groups selected from Substituent Group A.
19
A compound according to any one of claims 1 to 16, a salt of the compound or a hydrate of the foregoing, wherein X 7 is C 1-10 alkyl optionally having 1 to 3 groups selected from Substituent Group D below, C 3-8 cycloalkyl optionally having 1 to 3 groups selected from Substituent Group D below, a 5- to 6-membered heteroaryl group optionally having 1 to 3 groups selected from Substituent Group D below or a 4- to 7-membered heterocyclic group optionally having 1 to 3 groups selected from Substituent Group D below;The group consisting of halogen, hydroxyl, C 1-6 alkoxy, nitrile, C 3-8 cycloalkyl, dimethylamino and C 1-6 alkyl.
20
A compound according to any one of claims 1 to 16, a salt of the compound or a hydrate of the foregoing, wherein X 7 is hydrogen, C 1-10 alkyl optionally having 1 or 2 groups selected from Substituent Group E below, C 3-8 cycloalkyl optionally having 1 or 2 groups selected from Substituent Group E below, tetrahydrofuranyl optionally having 1 or 2 groups selected from Substituent Group E below, tetrahydrothiophenyl optionally having 1 or 2 groups selected from Substituent Group E below, dihydropyranyl optionally having 1 or 2 groups selected from Substituent Group E below, tetrahydropyranyl optionally having 1 or 2 groups selected from Substituent Group E below, dioxolanyl optionally having 1 or 2 groups selected from Substituent Group E below, pyrrolidin-2-onyl optionally having 1 or 2 groups selected from Substituent Group E below, dihydrofuran-2-onyl optionally having 1 or 2 groups selected from Substituent Group E below, furanyl optionally having 1 or 2 groups selected from Substituent Group E below, thienyl optionally having 1 or 2 groups selected from Substituent Group E below, pyrrolidinyl optionally having 1 or 2 groups selected from Substituent Group E below, piperidyl optionally having 1 or 2 groups selected from Substituent Group E below, oxazolyl optionally having 1 or 2 groups selected from Substituent Group E below, isoxazolyl optionally having 1 or 2 groups selected from Substituent Group E below, thiazolyl optionally having 1 or 2 groups selected from Substituent Group E below, pyrrolyl optionally having 1 or 2 groups selected from Substituent Group E below, pyrazolyl optionally having 1 or 2 groups selected from Substituent Group E below, morpholinyl optionally having 1 or 2 groups selected from Substituent Group E below, dioxanyl optionally having 1 or 2 groups selected from Substituent Group E below or pyridyl optionally having 1 or 2 groups selected from Substituent Group E below;The group consisting of hydroxyl, methyl, ethyl, methoxy, dimethylamino, cyano, chlorine and fluorine.
22
A compound according to any one of claims 1 to 16, a salt of the compound or a hydrate of the foregoing, wherein X 7 is hydrogen, C 1-10 alkyl, C 3-8 cycloalkyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydropyranyl, tetrahydropyranyl, dioxolanyl, pyrrolidin-2-onyl, dihydrofuran-2-onyl, furanyl, thienyl, pyrrolidinyl, piperidyl, oxazolyl, isoxazolyl, thiazolyl, pyrrolyl, pyrazolyl, morpholinyl, dioxanyl or pyridyl.
23
A compound according to any one of claims 1 to 16, a salt of the compound or a hydrate of the foregoing, wherein X 7 is hydrogen, C 1-10 alkyl, C 3-8 cycloalkyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, dioxolanyl, furanyl, thienyl, oxazolyl, dioxanyl, pyridyl, piperidyl or thiazolyl.
24
A compound represented by the general formula:[wherein R 7a represents hydrogen, nitro, -NO or -NHR 7d (wherein R 7d represents hydrogen, t-butoxycarbonyl or benzyloxycarbonyl);R 7c represents methylene, oxygen or sulfur;and R 7b represents hydrogen, halogen, the formula: (wherein R 8a and R 8b each independently represent hydrogen or C 1-6 alkyl, or R 3a and R 8b may bond together to form 1,2-ethylene, 1,3-propylene or 2,3-dimethylbutan-2,3-diyl), the formula: (wherein R 8c , R 8d and R 8e each independently represent C 1-6 alkyl) or the formula: (wherein R 40 and R 41 each independently represent methoxy, ethoxy, ethyl, dimethylamino, methyl or halogen, R 42 represents hydrogen, methoxy, methyl or halogen, and Z 1 and Z 2 each independently represent methine or nitrogen), with the proviso that compounds satisfying the following conditions (1), (2) or (3) are not included in the above definitions: (1) R 7c is oxygen, R 7b is hydrogen and R 7a is hydrogen, nitro, -NO or -NH 2 , (2) R 7c is sulfur, R 7b is hydrogen and R 7a is nitro or -NH 2 , or (3) R 7c is methylene, R 7b is hydrogen and R 7a is -NO], a salt thereof or a hydrate of the foregoing.

Independent claims15

1,534 paragraphs, as filed

Technical Field

0001The present invention relates to novel compounds having Corticotropin-Releasing Factor receptor antagonistic activity, salts thereof and hydrates of the foregoigng, to process for producing the same and to the use of the same as medicine.

Background Art

0002Corticotropin-Releasing Factor (hereinafter abbreviated as "CRF") is a neuropeptide consisting of 41 amino acids which was first isolated from ovine hypothalamus [<nplcit id="ncit0001" npl-type="s"><text>Science, 213, 1394 (1981</text></nplcit>)], after which its presence was also confirmed in rats [<nplcit id="ncit0002" npl-type="s"><text>Proc. Natl. Acad. Sci. USA, 80, 4851 (1983</text></nplcit>)] and in humans [<nplcit id="ncit0003" npl-type="s"><text>EMBO J. 5, 775 (1983</text></nplcit>)]. CRF is most abundant in the pituitary gland and hypothalamus, and is also widely distributed throughout the cerebral cortex, cerebellum and other areas of the brain. Its presence has also been confirmed in peripheral tissue such as the placenta, adrenal gland, lung, liver, pancrea and digestive tract [<nplcit id="ncit0004" npl-type="s"><text>J. Clin. Endocrinol. Metab., 65, 176 (1987</text></nplcit>), <nplcit id="ncit0005" npl-type="s"><text>J. Clin. Endocrinol. Metab., 67, 768 (1988</text></nplcit>), <nplcit id="ncit0006" npl-type="s"><text>Regul. Pept., 18, 173 (1987</text></nplcit>), <nplcit id="ncit0007" npl-type="s"><text>Peptides, 5 (Suppl. 1), 71 (1984</text></nplcit>)]. Two subtype CRF receptor has been described, CRF1 and CRF2, and the CRF1 receptor is reported to be widely distributed in the cerebral cortex, cerebellum, olfactory bulb, pituitary gland, amygdaloid nucleus and elsewhere. Recently, 2 subtypes of the CRF2 receptor have been confirmed, CRF2α and CRF2β, of which it has been discovered that CRF2α receptors are abundantly distributed in the hypothalamus, septal nuleus and choroid plexus, while CRF2β receptors are primarily distributed in peripheral tissue such as the skeletal muscle, or in the cerebral blood vessels of the central nervous system [<nplcit id="ncit0008" npl-type="s"><text>J. Neuroscience, 15(10)6340 (1995</text></nplcit>); <nplcit id="ncit0009" npl-type="s"><text>Endocrinology, 137, 72 (1996</text></nplcit>); <nplcit id="ncit0010" npl-type="s"><text>BBA, 1352, 129 (1997</text></nplcit>)]. The fact that each of these receptors has a different distribution profile suggests that their roles are also different. CRF is produced and secreted in the hypothalamus and promotes stress-induced release of adrenocorticotropic hormone (ACTH) [<nplcit id="ncit0011" npl-type="s"><text>Recent Prog. Horm. Res., 39, 245 (1983</text></nplcit>)]. In addition to its endocrine role, CRF also functions as a neurotransmitter or neuromodulator in the brain, integrating electrophysiological, autonomic and behavioral changes in response to stress [<nplcit id="ncit0012" npl-type="s"><text>Brain Res. Rev., 15, 71 (1990</text></nplcit>); <nplcit id="ncit0013" npl-type="s"><text>Pharmacol. Rev., 43, 425 (1991</text></nplcit>)].

0003CRF has been implicated in a variety of disease to date, as indicated by the following publications.

0004It was reported that elevated concentrations of CRF in the cerebrospinal fluid of patients with major depression compared with healthy controls [<nplcit id="ncit0014" npl-type="s"><text>Am. J. Psychiatry, 144(7), 873 (1987</text></nplcit>)]; CRF-mRNA levels in the hypothalamus of depressive patients are higher than that of healthy individuals [<nplcit id="ncit0015" npl-type="s"><text>Am. J. Psychiatry, 152, 1372 (1995</text></nplcit>)]; CRF receptors in cerebral cortex are reduced in suicide victims [<nplcit id="ncit0016" npl-type="s"><text>Arch. Gen. Psychiatry, 45, 577 (1988</text></nplcit>)]; plasma ACTH increase is diminished with administration of CRF to depressive patients [<nplcit id="ncit0017" npl-type="s"><text>N. Engl. J. Med., 314, 1329 (1986</text></nplcit>)]; CRF levels in the cerebrospinal fluid of some anxiety patients with obsessive-compulsive disorder, posttraumatic stress disorder or Tourette's syndrome are higher than in that of healthy individuals [<nplcit id="ncit0018" npl-type="s"><text>Arch. Gen. Psychiatry, 51, 794 (1994</text></nplcit>); <nplcit id="ncit0019" npl-type="s"><text>Am. J. Psychiatry, 154, 624 (1997</text></nplcit>); <nplcit id="ncit0020" npl-type="s"><text>Biol. Psychiatry, 39, 776 (1996</text></nplcit>)]; plasma ACTH increase is diminished with administration of CRF to panic disorder patients [<nplcit id="ncit0021" npl-type="s"><text>Am. J. Psychiatry, 143, 896 (1986</text></nplcit>)]; anxiety behavior has been observed in experimental animals by central administration of CRF [<nplcit id="ncit0022" npl-type="s"><text>Brain Res., 574, 70 (1992</text></nplcit>); <nplcit id="ncit0023" npl-type="s"><text>J. Neurosci., 10(1), 176 (1992</text></nplcit>)]. In addition, anxiety behavior is observed more frequently in CRF overexpressing mice than in normal mice [<nplcit id="ncit0024" npl-type="s"><text>J. Neurosci., 14(5), 2579 (1994</text></nplcit>)], and CRF levels in the locus coeruleus are reduced by administration of anxiolytics [<nplcit id="ncit0025" npl-type="s"><text>J. Pharmaco. Exp. Ther., 258, 349 (1991</text></nplcit>)]. Also, the peptide CRF antagonist α-helical CRF(9-41) exhibits an anxiolytic effect in animal models [<nplcit id="ncit0026" npl-type="s"><text>Brain Res., 509, 80 (1990</text></nplcit>); <nplcit id="ncit0027" npl-type="s"><text>Regulatory Peptides, 18, 37 (1987</text></nplcit>); <nplcit id="ncit0028" npl-type="s"><text>J. Neurosci., 14(5), 2579 (1994</text></nplcit>)]; abnormal behavior withdrawal from alcohol or addictive drugs such as cocaine are inhibited by the peptide CRF antagonist α-helical CRF(9-41) [<nplcit id="ncit0029" npl-type="s"><text>Psychopharmacology, 103, 227 (1991</text></nplcit>)]; CRF inhibits sexual behavior in rats [<nplcit id="ncit0030" npl-type="s"><text>Nature, 305, 232 (1983</text></nplcit>)]; CRF reduces sleep in rats and is thus implicated the involvement in sleep disorder [<nplcit id="ncit0031" npl-type="s"><text>Pharmacol. Biochem. Behav., 26, 699 (1987</text></nplcit>)]; the peptide CRF antagonist α-helical CRF(9-41) suppresses brain damage or electroencephalogram disturbances due to brain ischemia or NMDA receptor activation [<nplcit id="ncit0032" npl-type="s"><text>Brain Res., 545, 339 (1991</text></nplcit>), <nplcit id="ncit0033" npl-type="s"><text>Brain Res., 656, 405 (1994</text></nplcit>)]; CRF elicits electroencephalogram and induces convulsions [<nplcit id="ncit0034" npl-type="s"><text>Brain Res., 278, 332 (1983</text></nplcit>)]; cerebrospinal CRF levels are elevated in schizophrenic patients compared with healthy individuals [<nplcit id="ncit0035" npl-type="s"><text>Am. J. Psychiatry, 144(7), 873 (1987</text></nplcit>)]; CRF contents in cerebral cortex is reduced in Alzheimer's patients, Parkinson's patients and progressive supranuclear palsy patients [<nplcit id="ncit0036" npl-type="s"><text>Neurology, 37, 905 (1987</text></nplcit>)]; and CRF is reduced in the ganglia in Huntington's disease [<nplcit id="ncit0037" npl-type="s"><text>Brain Res., 437, 355 (1987</text></nplcit>), <nplcit id="ncit0038" npl-type="s"><text>Neurology, 37, 905 (1987</text></nplcit>)]. In addition, CRF administration has been found to enhance learning and memory in rats [<nplcit id="ncit0039" npl-type="s"><text>Nature, 378, 284 (1995</text></nplcit>); <nplcit id="ncit0040" npl-type="s"><text>Neuroendocrinology, 57, 1071 (1993</text></nplcit>)], and CRF levels of cerebrospinal fluid are reduced in amyotrophic lateral sclerosis patients. Oversecretion of ACTH and adrenocorticosteroids are exhibited in CRF overexpressing mice, these mice display abnormalities similar to Cushing's syndrome, including muscular atrophy, alopecia and infertility [<nplcit id="ncit0041" npl-type="s"><text>Endocrinology, 130(6), 3378 (1992</text></nplcit>)]; cerebrospinal CRF levels are elevated in anorexia nervosa patients compared with healthy individuals, and plasma ACTH increase is low with administration of CRF to anorexia nervosa patients [<nplcit id="ncit0042" npl-type="s"><text>J. Clin. Endocrinol. Metab., 62, 319 (1986</text></nplcit>)]; and CRF suppress food consumption in experimental animals [<nplcit id="ncit0043" npl-type="s"><text>Neuropharmacology, 22(3A), 337 (1983</text></nplcit>)]. Moreover, the peptide CRF antagonist α-helical CRF(9-41) reverses stress-induced reduction in food intake in animal models [<nplcit id="ncit0044" npl-type="s"><text>Brain Res. Bull., 17(3), 285 (1986</text></nplcit>)]; CRF has suppressed body weight gain in genetically obese animals [<nplcit id="ncit0045" npl-type="s"><text>Physiol. Behav., 45, 565 (1989</text></nplcit>)]; a link has been suggested between low CRF levels and obesity syndrome [<nplcit id="ncit0046" npl-type="s"><text>Endocrinology, 130, 1931 (1992</text></nplcit>)]; the anorexic action and body weight-reducing effects of serotonin reuptake inhibitors has been possibly linked to CRF release [<nplcit id="ncit0047" npl-type="s"><text>Pharmacol. Rev., 43, 425 (1991</text></nplcit>)]; and CRF acts centrally or peripherally to inhibit gastric contraction and reduce gastric emptying [<nplcit id="ncit0048" npl-type="s"><text>Regulatory Peptides, 21, 173 (1988</text></nplcit>); <nplcit id="ncit0049" npl-type="s"><text>Am. J. Physiol., 253, G241 (1987</text></nplcit>)]. Furthermore, abdominal surgery-induced reduced gastric function is reversed by the peptide CRF antagonist α-helical CRF(9-41) [<nplcit id="ncit0050" npl-type="s"><text>Am. J. Physiol., 262, G616 (1992</text></nplcit>)]; and CRF promotes secretion of bicarbonate ion in the stomach, thereby lowering gastric acid secretion and suppressing cold restraint stress ulcers [<nplcit id="ncit0051" npl-type="s"><text>Am. J. Physiol., 258, G152 (1990</text></nplcit>)]. Also, administration of CRF increases ulcers in non-restraint stress animals [<nplcit id="ncit0052" npl-type="s"><text>Life Sci., 45, 907 (1989</text></nplcit>)], and CRF suppresses small intestinal transit and promotes large intestinal transit, and defecation is induced. In addition, the peptide CRF antagonist α-helical CRF(9-41) has a inhibiting effect against restraint stress-induced gastric acid secretion reduced gastric emptying, and small intestinal transit and accelerated large intestinal transit [<nplcit id="ncit0053" npl-type="s"><text>Gastroenterology, 95, 1510 (1988</text></nplcit>)]; psychological stress in healthy individuals increases anxiety or sensations of gas and abdominal pain during colonic distension and CRF lowers the discomfort threshold [<nplcit id="ncit0054" npl-type="s"><text>Gastroenterol., 109, 1772 (1995</text></nplcit>); <nplcit id="ncit0055" npl-type="s"><text>Neurogastroenterol. Mot., 8, 9 (1996</text></nplcit>)]; irritable bowel syndrome patients experience excessive acceleration of colonic motility with CRF administration compared to healthy individuals [<nplcit id="ncit0056" npl-type="s"><text>Gut, 42, 845 (1998</text></nplcit>)]; administration of CRF increases blood pressure, heart rate and body temperature, while the peptide CRF antagonist α-helical CRF(9-41) suppresses stress-induced increases in blood pressure, heart rate and body temperature [<nplcit id="ncit0057" npl-type="s"><text>J. Physiol., 460, 221 (1993</text></nplcit>)]; CRF production is increased locally in inflammation sites in experimental animals and in the synovial fluid of rheumatic arthritis patients [<nplcit id="ncit0058" npl-type="s"><text>Science, 254, 421 (1991</text></nplcit>); <nplcit id="ncit0059" npl-type="s"><text>J. Clin. Invest., 90, 2555 (1992</text></nplcit>); <nplcit id="ncit0060" npl-type="s"><text>J. Immunol., 151, 1587 (1993</text></nplcit>)]; CRF provokes degranulation of mast cells and promotes vascular permeability [<nplcit id="ncit0061" npl-type="s"><text>Endocrinology, 139(1), 403 (1998</text></nplcit>); <nplcit id="ncit0062" npl-type="s"><text>J. Pharmacol. Exp. Ther., 288(3), 1349 (1999</text></nplcit>)]; CRF is detected in autoimmune thyroiditis patients [<nplcit id="ncit0063" npl-type="s"><text>Am. J. Pathol., 145, 1159 (1994</text></nplcit>)]; administration of CRF to experimental autoimmune encephalomyelitis rats has notably suppressed progression of symptoms such as paralysis [<nplcit id="ncit0064" npl-type="s"><text>J. Immumol., 158, 5751 (1997</text></nplcit>)]; and urocortin (a CRF analogue) has increased growth hormone secretion in a pituitary adenoma culture system from an acromegalia patient [<nplcit id="ncit0065" npl-type="s"><text>Endocri. J, 44, 627 (1997</text></nplcit>)]. Furthermore, CRF simulates secretion of cytokines such as interleukin-1 and interleukin-2 by leukocytes [<nplcit id="ncit0066" npl-type="s"><text>J. Neuroimmunol., 23, 256 (1989</text></nplcit>); <nplcit id="ncit0067" npl-type="s"><text>Neurosci. Lett., 120, 151 (1990</text></nplcit>)]; and CRF administration and stress both suppress T lymphocyte proliferation and natural killer cell activity. The peptide CRF antagonist α-helical CRF(9-41) improves the reduced function of these immune cells caused by CRF administration or stress [<nplcit id="ncit0068" npl-type="s"><text>Endocrinology, 128(3), 1329 (1991</text></nplcit>)], and ventilation is notably increased by administration of CRF [<nplcit id="ncit0069" npl-type="s"><text>Eur. J. Pharmacol., 182, 405 (1990</text></nplcit>)]. Finally, aggravated breathing and insomnia have been observed as a result of CRF administration to elderly patients under chronic artificial respiration [<nplcit id="ncit0070" npl-type="s"><text>Acta Endocrinol. Copenh., 127, 200 (1992</text></nplcit>)].

0005The research cited above suggests that CRF antagonists may be expected to exhibit excellent effects for treatment or prevention of depression and depressive symptoms such as major depression, single-episode depression, recurrent depression, depression-induced child abuse and postpartum depression, mania, anxiety, generalized anxiety disorder, panic disorder, phobias, obsessive-compulsive disorder, posttraumatic stress disorder, Tourette's syndrome, autism, affective disorder, dysthymia, bipolar disorder, cyclothymic personality, schizophrenia, Alzheimer's disease, senile dementia of Alzheimer's type, neurodegenerative disease such as Parkinson's disease and Huntington's disease, multi-infarct dementia, senile dementia, anorexia nervosa, increased appetite and other eating disorders, obesity, diabetes, alcohol dependence, pharmacophilia for drugs such as cocaine, heroin or benzodiazepines, drug or alcohol withdrawal symptoms, sleep disorder, insomnia, migraine, stress-induced headache, muscle contraction induced headache, ischemic neuronal damage, excitotoxic neuronal damage, stroke, progressive supranuclear palsy, amyotrophic lateral sclerosis, multiple sclerosis, muscular spasm, chronic fatigue syndrome, psychosocial dwarfism, epilepsy, head trauma, spinal cord injury, cheirospasm, spasmodic torticollis, cervicobrachial syndrome, primary glaucoma, Meniere's syndrome, autonomic imbalance, alopecia, neuroses such as cardiac neurosis, gastric neurosis and bladder neurosis, peptic ulcer, irritable bowel syndrome, ulcerative colitis, Crohn's disease, diarrhea, constipation, postoperative ileus, stress-associated gastrointestinal disorders and nervous vomiting, hypertension, cardiovascular disorders such as angina pectoris nervosa, tachycardia, congestive heart failure, hyperventilation syndrome, bronchial asthma, apneusis, sudden infant death syndrome, inflammatory disorders (for example, rheumatic arthritis, osteoarthritis, lumbago, etc.), pain, allergosis (for example, atopic dermatitis, eczema, hives, psoriasis, etc.), impotence, menopausal disorder, fertilization disorder, infertility, cancer, HIV infection-related immune dysfunction, stress-induced immune dysfunction, hemorrhagic stress, Cushing's syndrome, thyroid function disorder, encephalomyelitis, acromegaly, incontinence, osteoporosis, and the like. As examples of CRF antagonists there have been reported peptide CRF receptor antagonists with modifications or deletions of portions of the amino acid sequence of human or other mammalian CRF, and such antagonists have shown ACTH release-inhibiting effects or anxiolytic effects [<nplcit id="ncit0071" npl-type="s"><text>Science, 224, 889(1984</text></nplcit>), <nplcit id="ncit0072" npl-type="s"><text>J. Pharmacol. Exp. Ther., 269, 564 (1994</text></nplcit>), <nplcit id="ncit0073" npl-type="s"><text>Brain Research Reviews, 15, 71 (1990</text></nplcit>)]. However, peptide derivatives have low utility value as drugs from the standpoint of pharmacokinetics including their chemical stability in the body, oral absorption, bioavailability and migration into the brain.

0006On the other hand, the following non-peptide CRF antagonists have also been reported. <ol id="ol0001" compact="compact"><li>[1] Compounds represented by the formula: <chemistry id="chem0001" num="0001"><img file="EP1389618B1_D0001.tif" /></chemistry> [wherein R1 represents NR4R5, etc.; R2 represents C1-6 alkyl, etc.; R3 represents C1-6 alkyl, etc.; R4 represents C1-6 alkyl, etc.; R5 represents C1-8 alkyl, etc.; and Ar represents phenyl, etc.], stereoisomers thereof or pharmacologically acceptable acid addition salts of the foregoing (<patcit id="pcit0001" dnum="WO9729109A"><text>WO97/29109</text></patcit>);</li><li>[2] Compounds represented by the formula: <chemistry id="chem0002" num="0002"><img file="EP1389618B1_D0002.tif" /></chemistry> [wherein the dotted lines represent single bonds or double bonds; A represents CR7, etc.; B represents NR1R2, etc.; J and K are the same or different and represent nitrogen, etc.; D and E are the same or different and represent nitrogen, etc.; G represents nitrogen, etc.; R1 represents C1-C6 alkyl, etc.; R2 represents C1-C12 alkyl, etc.; and R7 represents hydrogen, etc.] or pharmacologically acceptable salts thereof (<patcit id="pcit0002" dnum="WO9808847A"><text>WO98/08847</text></patcit>);</li><li>[3] The anilinopyrimidine compounds described in <patcit id="pcit0003" dnum="WO9510506A"><text>WO95/10506</text></patcit>, the pyrazolopyridine compounds described in <patcit id="pcit0004" dnum="WO9534563A"><text>WO95/34563</text></patcit>, the pyrazole compounds described in <patcit id="pcit0005" dnum="WO9413661A"><text>WO94/13661</text></patcit>, the pyrazole compounds and pyrazolopyrimidine compounds described in <patcit id="pcit0006" dnum="WO9413643A"><text>WO94/13643</text></patcit>, the aminopyrazole compounds described in <patcit id="pcit0007" dnum="WO9418644A"><text>WO94/18644</text></patcit> the pyrazolopyrimidine compounds described in <patcit id="pcit0008" dnum="WO9413677A"><text>WO94/13677</text></patcit>, the pyrrolopyrimidine compounds described in <patcit id="pcit0009" dnum="WO9413676A"><text>WO94/13676</text></patcit>, the thiazole compounds described in <patcit id="pcit0010" dnum="EP659747A"><text>EP-659747</text></patcit> and <patcit id="pcit0011" dnum="EP611766A"><text>EP-611766</text></patcit>, the anilinopyrimidine compounds described in <nplcit id="ncit0074" npl-type="s"><text>J. Med. Chem., 39, 4358(1996</text></nplcit>), the anilinotriazine compounds described in <nplcit id="ncit0075" npl-type="s"><text>ibid. 39, 4354(1996</text></nplcit>) and the thienopyrimidine compounds described in <patcit id="pcit0012" dnum="WO9729110A"><text>WO97/29110</text></patcit>; and</li><li>[4] As pyrazolo[1,5-a]pyridine compounds, the compounds described, for example, in <patcit id="pcit0013" dnum="EP433854A"><text>EP4.33854</text></patcit>, <patcit id="pcit0014" dnum="EP433853A"><text>EP433853</text></patcit> or <patcit id="pcit0015" dnum="US5445943A"><text>US5445943</text></patcit>.</li></ol>

Disclosure of the Invention

0007As mentioned above, it is ardently desired to provide CRF receptor antagonists which are useful as drugs, but clinically effective agents that exhibit excellent CRF receptor antagonism and satisfy the requirements of pharmacological activity, dosage and safety as medicines have not yet been discovered. It is therefore an object of the present invention to investigate and discover such excellent CRF receptor antagonists.

0008As a result of much diligent examination and research in light of the circumstances described above, the present inventors have discovered novel pyrazolo[1,5-a]pyridine compounds exhibiting excellent CRF receptor antagonism.

0009The invention provides: <ol id="ol0002" compact="compact"><li><1> a compound represented by the general formula: <chemistry id="chem0003" num="0003"><img file="EP1389618B1_D0003.tif" /></chemistry> [wherein R1 represents hydrogen, halogen, nitro, cyano or the formula -G1-R1a (wherein G1 represents a single bond, methylene, oxygen, sulfur, sulfinyl, sulfonyl, - C(O)-, -C(O)O-, -OC(O)-, -NR1b-, -C(O)-NR1b-, -S(O)2-NR1b-, -NR1b-C(O)- or -NR1b-S(O)2-; and R1a and R1b each independently represent hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-8 cycloalkyl or C5-8 cycloalkenyl); R2, R3 and R4 each independently represent hydrogen, halogen, cyano, nitro, hydroxyl, C6-14 aryl, a 5- to 14-membered heteroaryl group or the formula -G2-R2a (wherein G2 represents a single bond, C1-6 alkylene, oxygen, sulfur, sulfinyl, sulfonyl, -C(O)-, -C(O)O-, - OC(O)-, -NR2b-, -C(O)-NR2b-, -S(O)2-NR2b-, -NR2b-C(O)- or -NR2b-S(O)2-; R2a and R2b each independently represent hydrogen, C1-6 alkyl optionally substituted with 1-3 halogen, C2-10 alkenyl, C2-10 alkynyl, C3-8 cycloalkyl or C5-8 cycloalkenyl); R2 and R3 or R3 and R4 may bond together to form a 5- to 7-membered ring optionally containing 1 to 4 hetero atoms in the ring and optionally containing carbonyl in the ring; R5 and R6 each independently represent the formula -X5-X6-X1 (wherein X5 represents a single bond or -CO-; X6 represents a single bond, -NR3a-, oxygen, sulfur, sulfinyl, sulfonyl, C1-10 alkylene, C2-10 alkenylene or C2-10 alkynylene; and X7 and R3a each independently represent hydrogen, C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-8 cycloalkyl, C5-8 cycloalkenyl, C6-14 aryl, a 5- to 14-membered heteroaryl group, a 4- to 14-membered heterocyclic group, a 9- to 11-membered benzene fused ring group, an 8- to 11-membered heteroaryl fused ring group or a bicyclic 7- to 12-membered hydrocarbon ring group); R5 and R6 may bond together to form a 5- to 10-membered ring optionally containing 1 to 4 hetero atoms in the ring and optionally containing carbonyl in the ring; R6 and R2 may bond together to form a 6- to 7-membered ring optionally containing 1 or 2 hetero atoms in the ring and optionally containing carbonyl in the ring; and Ar represents C6-14 aryl, a 5- to 14-membered heteroaryl group, a 9- to 11-membered benzene fused ring group or an 8- to 11-membered heteroaryl fused ring group; with the proviso that R1a, R1b, R3a, X6, X7 and Ar may each independently have 1 to 4 groups selected from Substituent Group A below; <Substituent Group A> The group consisting of methylenedioxy, ethylenedioxy and the formula -V1-V2-V3 (wherein V1 represents a single bond, C1-6 alkylene, C2-6 alkenylene, C2-6 alkynylene, oxygen, sulfur, carbonyl, -CO-O-, -O-CO- or -NR3b-; V2 represents a single bond or C1-6 alkylene; and V3 and R3b each independently represent C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C5-8 cycloalkenyl, C6-14 aryl, a 5- to 14-membered heteroaryl group, a 4- to 14-membered heterocyclic group, hydrogen, halogen, hydroxyl, cyano, C1-6 alkoxy or the formula -N(R3c)R3d (wherein R3c and R3d each independently represent hydrogen or C1-6 alkyl))], a salt thereof or a hydrate of the foregoing.</li><li><2> a compound according to <1>, a salt of the compound or a hydrate of the foregoing, wherein R1 is the formula -G10-R10 (wherein G10 represents a single bond, methylene, oxygen, sulfur, sulfinyl or sulfonyl and R10 represents C1-6 alkyl optionally substituted with 1 to 3 halogen, C2-6 alkenyl, C2-6 alkynyl or C3-8 cycloalkyl);</li><li><3> a compound according to <2>, a salt of the compound or a hydrate of the foregoing, wherein R10 is methyl, ethyl, n-propyl, iso-propyl, trifluoromethyl, difluoromethyl, monofluoromethyl, cyclopropyl or cyclobutyl;</li><li><4> a compound according to <1>, a salt of the compound or a hydrate of the foregoing, wherein R1 is methoxy;</li><li><5> a compound according to <1>, a salt of the compound or a hydrate of the foregoing, wherein R1 is ethyl;</li><li><6> a compound according to <1>, a salt of the compound or a hydrate of the foregoing, wherein R1 is methylthio;</li><li><7> a compound according to any one of <1> to <6>, a salt of the compound or a hydrate of the foregoing, wherein R2, R3 and R4 each independently represent hydrogen, halogen, cyano, nitro, hydroxyl, or the formula -G20-R20 (wherein G20 represents a single bond, oxygen, sulfur, sulfinyl or sulfonyl, and R20 represents C1-6 alkyl optionally substituted with 1 to 3 halogen, C2-10 alkenyl, C2-10 alkynyl or C3-8 cycloalkyl);</li><li><8> a compound according to any one of <1> to <6>, a salt of the compound or a hydrate of the foregoing, wherein R2, R3 and R4 are hydrogen;</li><li><9> a compound according to any one of <1> to <8>, a salt of the compound or a hydrate of the foregoing, wherein Ar is phenyl, 1,3-benzodioxolyl, naphthyl, pyridyl, pyrazyl, pyrimidyl, pyridazyl, thienyl, furanyl, imidazolyl, thiazolyl, quinolinyl, isoquinolinyl, indolinyl, benzofuranyl, benzothienyl, oxazolyl or isoxazolyl, and Ar may have 1 to 4 groups selected from Substituent Group B below; <Substituent Group B> The group consisting of halogen, cyano, hydroxyl, methylenedioxy, ethylenedioxy, the formula -V4-V5 (wherein V4 represents a single bond, oxygen, or sulfur, and V5 represents C1-6 alkyl or C3-8 cycloalkyl) and the formula -N(R5a)R5b (wherein R5a and R5b each independently represent hydrogen or C1-6 alkyl);</li><li><10> A compound according to any one of <1> to <9>, a salt of the compound or a hydrate of the foregoing, wherein Ar is phenyl or pyridyl, and Ar may optionally have 1 to 3 groups selected from Substituent Group B in <9>;</li><li><11> a compound according to <9> or <10>, a salt of the compound or a hydrate of the foregoing, wherein Substituent Group B is the group consisting of halogen, cyano, C1-6 alkyl, C3-8 cycloalkyl, dimethylamino and C1-6 alkoxy;</li><li><12> a compound according to any one of <1> to <8>, a salt of the compound or a hydrate of the foregoing, wherein Ar is the formula: <chemistry id="chem0004" num="0004"><img file="EP1389618B1_D0004.tif" /></chemistry> (wherein R40 and R41 each independently represent methoxy, ethoxy, ethyl, methyl, dimethylamino or halogen, R42 represents hydrogen, methoxy, methyl, dimethylamino or halogen, and Z1 and Z2 each independently represent methine or nitrogen);</li><li><13> a compound according to <12>, a salt of the compound or a hydrate of the foregoing, wherein Z1 and Z2 are methine;</li><li><14> a compound according to any one of <1> to <13>, a salt of the compound or a hydrate of the foregoing, wherein X5 is a single bond, and X6 is a single bond, C1-6 alkylene optionally having 1 to 3 groups selected from Substituent Group A, C2-6 alkenylene optionally having 1 to 3 groups selected from Substituent Group A or C2-6 alkynylene optionally having 1 to 3 groups selected from Substituent Group A.</li><li><15> a compound according to any one of <1> to <13>, a salt of the compound or a hydrate of the foregoing, wherein X5 is a single bond, and X6 is a single bond or C1-6 alkylene optionally having 1 to 3 groups selected from Substituent Group C below; <Substituent Group C> The group consisting of halogen, hydroxyl, C1-6 alkoxy, nitrile, C3-8 cycloalkyl, and C1-6 alkyl;</li><li><16> a compound according to any one of <1> to <13>, a salt of the compound or a hydrate of the foregoing, wherein X5 is a single bond, and X6 is a single bond, 1,2-ethylene or methylene;</li><li><17> a compound according to any one of <1> to <16>, a salt of the compound or a hydrate of the foregoing, wherein X7 is C1-10 alkyl optionally having 1 to 3 groups selected from Substituent Group A, C2-10 alkenyl optionally having 1 to 3 groups selected from Substituent Group A, C2-10 alkynyl optionally having 1 to 3 groups selected from Substituent Group A, C3-8 cycloalkyl optionally having 1 to 3 groups selected from Substituent Group A, C5-8 cycloalkenyl optionally having 1 to 3 groups selected from Substituent Group A, C6-14 aryl optionally having 1 to 3 groups selected from Substituent Group A, a 5- to 14-membered heteroaryl group optionally having 1 to 3 groups selected from Substituent Group A, a 4- to 14-membered heterocyclic group optionally having 1 to 3 groups selected from Substituent Group A or a bicyclic 7- to 12-membered hydrocarbon ring group optionally having 1 to 3 groups selected from Substituent Group A;</li><li><18> a compound according to any one of <1> to <16>, a salt of the compound or a hydrate of the foregoing, wherein X7 is C1-10 alkyl optionally having 1 to 3 groups selected from Substituent Group A, C3-8 cycloalkyl optionally having 1 to 3 groups selected from Substituent Group A, a 5- to 6-membered heteroaryl group optionally having 1 to 3 groups selected from Substituent Group A or a 4- to 7-membered heterocyclic group optionally having 1 to 3 groups selected from Substituent Group A;</li><li><19> a compound according to any one of <1> to <16>, a salt of the compound or a hydrate of the foregoing, wherein X7 is C1-10 alkyl optionally having 1 to 3 groups selected from Substituent Group D below, C3-8 cycloalkyl optionally having 1 to 3 groups selected from Substituent Group D below, a 5- to 6-membered heteroaryl group optionally having 1 to 3 groups selected from Substituent Group D below or a 4- to 7-membered heterocyclic group optionally having 1 to 3 groups selected from Substituent Group D below; <Substituent Group D> The group consisting of halogen, hydroxyl, C1-6 alkoxy, nitrile, C3-8 cycloalkyl, dimethylamino and C1-6 alkyl;</li><li><20> a compound according to any one of <1> to <16>, a salt of the compound or a hydrate of the foregoing, wherein X7 is hydrogen, C1-10 alkyl optionally having 1 or 2 groups selected from Substituent Group E below, C3-8 cycloalkyl optionally having 1 or 2 groups selected from Substituent Group E below, tetrahydrofuranyl optionally having 1 or 2 groups selected from Substituent Group E below, tetrahydrothiophenyl optionally having 1 or 2 groups selected from Substituent Group E below, dihydropyranyl optionally having 1 or 2 groups selected from Substituent Group E below, tetrahydropyranyl optionally having 1 or 2 groups selected from Substituent Group E below, dioxolanyl optionally having 1 or 2 groups selected from Substituent Group E below, pyrrolidin-2-onyl optionally having 1 or 2 groups selected from Substituent Group E below, dihydrofuran-2-onyl optionally having 1 or 2 groups selected from Substituent Group E below, furanyl optionally having 1 or 2 groups selected from Substituent Group E below, thienyl optionally having 1 or 2 groups selected from Substituent Group E below, pyrrolidinyl optionally having 1 or 2 groups selected from Substituent Group E below, piperidyl optionally having 1 or 2 groups selected from Substituent Group E below, oxazolyl optionally having 1 or 2 groups selected from Substituent Group E below, isoxazolyl optionally having 1 or 2 groups selected from Substituent Group E below, thiazolyl optionally having 1 or 2 groups selected from Substituent Group E below, pyrrolyl optionally having 1 or 2 groups selected from Substituent Group E below, pyrazolyl optionally having 1 or 2 groups selected from Substituent Group E below, morpholinyl optionally having 1 or 2 groups selected from Substituent Group E below, dioxanyl optionally having 1 or 2 groups selected from Substituent Group E below or pyridyl optionally having 1 or 2 groups selected from Substituent Group E below; <Substituent Group E> The group consisting of hydroxyl, methyl, ethyl, methoxy, dimethylamino, cyano, chlorine and fluorine;</li><li><21> a compound according to <20>, a salt of the compound or a hydrate of the foregoing, wherein Substituent Group E is the group consisting of methyl, methoxy, dimethylamino, chlorine and fluorine;</li><li><22> a compound according to any one of <1> to <16>, a salt of the compound or a hydrate of the foregoing, wherein X7 is hydrogen, C1-10 alkyl, C3-8 cycloalkyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydropyranyl, tetrahydropyranyl, dioxolanyl, pyrrolidin-2-onyl, dihydrofuran-2-onyl, furanyl, thienyl, pyrrolidinyl, piperidyl, oxazolyl, isoxazolyl, thiazolyl, pyrrolyl, pyrazolyl, morpholinyl, dioxanyl or pyridyl;</li><li><23> a compound according to any one of <1> to <16>, a salt of the compound or a hydrate of the foregoing, wherein X7 is hydrogen, C1-10 alkyl, C3-8 cycloalkyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, dioxolanyl, furanyl, thienyl, oxazolyl, dioxanyl, pyridyl, piperidyl or thiazolyl;</li><li><24> a compound represented by the general formula: <chemistry id="chem0005" num="0005"><img file="EP1389618B1_D0005.tif" /></chemistry> [wherein R7a represents hydrogen, nitro, -NO or -NHR7d (wherein R7d represents hydrogen, t-butoxycarbonyl or benzyloxycarbonyl); R7c represents methylene, oxygen or sulfur; and R7b represents hydrogen, halogen, the formula: <chemistry id="chem0006" num="0006"><img file="EP1389618B1_D0006.tif" /></chemistry> (wherein R8a and R8b each independently represent hydrogen or C1-6 alkyl, or R8a and R8b may bond together to form 1,2-ethylene, 1,3-propylene or 2,3-dimethylbutan-2,3-diyl), the formula: <chemistry id="chem0007" num="0007"><img file="EP1389618B1_D0007.tif" /></chemistry> (wherein R8c, R8d and R8e each independently represent C1-6 alkyl) or the formula: <chemistry id="chem0008" num="0008"><img file="EP1389618B1_D0008.tif" /></chemistry> (wherein R40 and R41 each independently represent methoxy, ethoxy, ethyl, dimethylamino, methyl or halogen, R42 represents hydrogen, methoxy, methyl or halogen, and Z1 and Z2 each independently represent methine or nitrogen), with the proviso that compounds satisfying the following conditions (1), (2) or (3) are not included in the above definitions: <ol id="ol0003" compact="compact"><li>(1) R7c, is oxygen, R7b is hydrogen and R7a is hydrogen, nitro, -NO or -NH2, (2) R7c is sulfur, R7b is hydrogen and R7a is nitro or -NH2, or (3) R7c is methylene, R7b is hydrogen and R7a is -NO], a salt thereof or a hydrate of the foregoing;</li></ol></li><li><25> a compound according to <24>, a salt of the compound or a hydrate of the foregoing, wherein R7a and R7b are hydrogen;</li><li><26> a compound according to <24>, a salt of the compound or a hydrate of the foregoing, wherein R7b is not hydrogen;</li><li><27> a compound represented by the general formula: <chemistry id="chem0009" num="0009"><img file="EP1389618B1_D0009.tif" /></chemistry> [wherein R5 and R6 have the same definitions as R5 and R6 in <1>, respectively; R7c represents methylene, oxygen or sulfur; and R7e represents halogen, the formula: <chemistry id="chem0010" num="0010"><img file="EP1389618B1_D0010.tif" /></chemistry> (wherein R8a and R8b each independently represent hydrogen or C1-6 alkyl, or R8a and R8b may bond together to form 1,2-ethylene, 1,3-propylene or 2,3-dimethylbutan-2,3-diyl), or the formula: <chemistry id="chem0011" num="0011"><img file="EP1389618B1_D0011.tif" /></chemistry> (wherein R8c, R8d and R8e each independently represent C1-6 alkyl)], a salt thereof or a hydrate of the foregoing;</li><li><28> a Corticotropin-Releasing Factor (CRF) receptor antagonist comprising a compound according to <1>;</li><li><29> a Corticotropin-Releasing Factor (CRF)-1 receptor or Corticotropin-Releasing Factor (CRF)-2 receptor antagonist comprising a compound according to <1>;</li><li><30> a therapeutic or prophylactic agent for a disease associated with Corticotropin-Releasing Factor (CRF), comprising a compound according to <1>;</li><li><31> a therapeutic or prophylactic agent for depression, depressive symptom, mania, anxiety, generalized anxiety disorder, panic disorder, phobias, obsessive-compulsive disorder, posttraumatic stress disorder, Tourette's syndrome, autism, affective disorder, dysthymia, bipolar disorder, cyclothymic personality or schizophrenia, comprising a compound according to <1>;</li><li><32> a therapeutic or prophylactic agent for a depressive symptom which is major depression, single-episode depression, recurrent depression, depression-induced child abuse or postpartum depression, comprising a compound according to <1>;</li><li><33> a therapeutic or prophylactic agent for peptic ulcer, irritable bowel syndrome, ulcerative colitis, Crohn's disease, diarrhea, constipation, postoperative ileus, stress-associated gastrointestinal disorders or nervous vomiting, comprising a compound according to <1>;</li><li><34> a therapeutic or prophylactic agent for Alzheimer's disease, senile dementia of Alzheimer's type, neurodegenerative disease, multi-infarct dementia, senile dementia, anorexia nervosa, eating disorder, obesity, diabetes, alcohol dependence, pharmacophilia, drug withdrawal symptoms, alcohol withdrawal symptoms, sleep disorder, insomnia, migraine, stress-induced headache, muscle contraction induced headache, ischemic neuronal damage, excitotoxic neuronal damage, stroke, progressive supranuclear palsy, amyotrophic lateral sclerosis, multiple sclerosis, muscular spasm, chronic fatigue syndrome, psychosocial dwarfism, epilepsy, head trauma, spinal cord injury, cheirospasm, spasmodic torticollis, cervicobrachial syndrome, primary glaucoma, Meniere's syndrome, autonomic imbalance, alopecia, neurosis, hypertension, cardiovascular disorder, tachycardia, congestive heart failure, hyperventilation syndrome, bronchial asthma, apneusis, sudden infant death syndrome, inflammatory disorder, pain, allergosis, impotence, menopausal disorder, fertilization disorder, infertility, cancer, HIV infection-induced immune dysfunction, stress-induced immune dysfunction, hemorrhagic stress, Cushing's syndrome, thyroid function disorder, encephalomyelitis, acromegaly, incontinence or osteoporosis, comprising a compound according to <1>;</li><li><35> the use of a compound according to <1> or a salt thereof for the manufacture of a Corticotropin-Releasing Factor (CRF) receptor antagonist;</li><li><36> the use of a compound according to <1> or a salt thereof for the manufacture of a Corticotropin-Releasing Factor (CRF)-1 receptor antagonist or Corticotropin-Releasing Factor (CRF) -2 receptor antagonist;</li><li><37> the use of a compound according to <1> or a salt thereof for the manufacture of a therapeutic or prophylactic agent for depression, depressive symptom, mania, anxiety, generalized anxiety disorder, panic disorder, phobia, obsessive-compulsive disorder, posttraumatic stress disorder, Tourette's syndrome, autism, affective disorder, dysthymia, bipolar disorder, cyclothymic personality, schizophrenia, peptic ulcer, irritable bowel syndrome, ulcerative colitis, Crohn's disease, diarrhea, constipation, postoperative ileus, stress-associated gastrointestinal disorders or nervous vomiting.</li></ol>

Best Mode for Carrying Out the Invention

0010The present invention will now be explained in greater detail.

0011Several of the structural formulas given for compounds throughout the present specification will represent a specific isomer for convenience, but the invention is not limited to such specific isomers and encompasses all isomers and isomer mixtures, including geometric isomers, asymmetric carbon-derived optical isomers, stereoisomers and tautomers, implied by the structures of the compounds, of which any isomer or mixture thereof may be used. The compounds of the invention therefore may include those having asymmetric carbons in their molecules and existing as optically active forms or racemic forms, and all such compounds are encompassed by the invention without restrictions. There are also no restrictions on any crystalline polymorphism of the compounds, and any crystal forms may be used alone or in mixtures, while the compounds of the invention also include anhydrides and hydrates. Metabolites of the compounds of the present invention, produced by degradation in the body, are also encompassed by the claims of the invention.

0012The symbols and terms used throughout the present specification will now be defined, with a more detailed description of the invention.

0013The term "CRF receptor antagonist" as used throughout the present specification refers to a substance capable of inactivating CRF receptors. Such substances also include those capable of attenuating or inhibiting the physiological activity of CRF.

0014As diseases included among "diseases associated with CRF" or "diseases associated with CRF receptors" according to the present specification there may be mentioned depression and depressive symptoms (major depression, single-episode depression, recurrent depression, depression-induced child abuse, postpartum depression, etc.), mania, anxiety, generalized anxiety disorder, panic disorder, phobias, obsessive-compulsive disorder, posttraumatic stress disorder, Tourette's syndrome, autism, affective disorder, dysthymia, bipolar disorder, cyclothymic personality, schizophrenia, peptic ulcer, irritable bowel syndrome, ulcerative colitis, Crohn's disease, diarrhea, constipation, postoperative ileus, stress-associated gastrointestinal disorders, nervous vomiting, Alzheimer's disease, senile dementia of Alzheimer's type, neurodegenerative disease, multi-infarct dementia, senile dementia, anorexia nervosa, eating disorder, obesity, diabetes, alcohol dependence, pharmacophilia, drug withdrawal symptoms, alcohol withdrawal symptoms, sleep disorder, insomnia, migraine, stress-induced headache, muscle contraction induced headache, ischemic neuronal damage, excitotoxic neuronal damage, stroke, progressive supranuclear palsy, amyotrophic lateral sclerosis, multiple sclerosis, muscular spasm, chronic fatigue syndrome, psychosocial dwarfism, epilepsy, head trauma, spinal cord injury, cheirospasm, spasmodic torticollis, cervicobrachial syndrome, primary glaucoma, Meniere's syndrome, autonomic imbalance, alopecia, neurosis, hypertension, cardiovascular disorder, tachycardia, congestive heart failure, hyperventilation syndrome, bronchial asthma, apneusis, sudden infant death syndrome, inflammatory disorder, pain, allergosis, impotence, menopausal disorder, fertilization disorder, infertility, cancer, HIV infection-related immune dysfunction, stress-induced immune dysfunction, hemorrhagic stress, Cushing's syndrome, thyroid function disorder, encephalomyelitis, acromegaly, incontinence, osteoporosis, and the like. The compounds of the invention are effective for treatment or prevention of the aforementioned diseases.

0015The term "neurodegenerative disease" as used throughout the present specification refers to either acute degenerative disease or chronic degenerative disease, and specifically it includes, for example, neuropathies such as subarachnoid hemorrhage, acute stage cerebrovascular disorder, etc. and Alzheimer's disease, Parkinson's disease, Huntington's chorea, amyotrophic lateral sclerosis, spinocerebellar degeneration, etc. The term "eating disorder" as used throughout the present specification refers to increased appetite, cibophobia and the like. The term "cardiovascular disorder" as used throughout the present specification refers to angina pectoris nervosa and the like. The term "inflammatory disorder" as used throughout the present specification refers to, for example, rheumatic arthritis, osteoarthritis, lumbago and the like, and the term "allergosis" refers to, for example, atopic dermatitis, eczema, hives, psoriasis and the like.

0016Throughout the present specification, "n-" signifies "normal", "sec-" signifies "secondary" and "tert-" and "t-" both signify "tertiary".

0017Halogen as used throughout the present specification refers to fluorine, chlorine, bromine, iodine and the like, with fluorine, chlorine or bromine being preferred.

0018The terms "C1-6 alkyl" and "C1-10 alkyl" used throughout the present specification refer respectively to a linear or branched alkyl group of 1 to 6 carbons and a linear or branched alkyl group of 1 to 10 carbons, and are preferably methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-ethylpropyl, n-hexyl, 1-methyl-2-ethylpropyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1-propylpropyl, 1-methylbutyl, 2-methylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, or the like, more preferably methyl, ethyl, n-propyl, iso-propyl or tert-butyl, and even more preferably methyl, ethyl or iso-propyl.

0019The terms "C2-6 alkenyl" and "C2-10 alkenyl" used throughout the present specification refer respectively to a linear or branched alkenyl group of 2 to 6 carbons and a linear or branched alkenyl group of 2 to 10 carbons, and preferred examples of such groups include vinyl, allyl, 1-propenyl, 2-propenyl, isopropenyl, 2-methyl-1-propenyl, 3-methyl-1-propenyl, 2-methyl-2-propenyl, 3-methyl-2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 1-hexenyl, 1,3-hexanedienyl and 1,6-hexanedienyl.

0020The terms "C2-6 alkynyl" and "C2-10 alkynyl" used throughout the present specification refer respectively to an alkynyl group of 2 to 6 carbons and an alkynyl group of 2 to 10 carbons, and preferred examples of such groups include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 3-methyl-1-propynyl, 1-ethynyl-2propynyl, 2-methyl-3-propynyl, 1-pentynyl, 1-hexynyl, 1,3-hexanediynyl and 1,6-hexanediynyl.

0021The term "C1-6 alkylene" used throughout the present specification refers to a divalent group derived by removing another hydrogen from any desired position of the aforementioned "C1-6 alkyl", and as specific examples there may be mentioned methylene, ethylene, methylethylene, propylene, ethylethylene, 1,1-dimethylethylene, 1,2-dimethylethylene, trimethylene, 1-methyltrimethylene, 1-ethyltrimethylene, 2-methyltrimethylene, 1,1-dimethyltrimethylene, tetramethylene, pentamethylene and hexamethylene, preferably methylene and 1,2-ethylene, and more preferably methylene.

0022The term "C2-6 alkenylene" used through the present specification refers to a divalent group derived by removing another hydrogen from the aforementioned "C2-6 alkenyl", and as specific examples there may be mentioned vinylene, propenylene, butenylene, pentenylene and hexenylene, preferably vinylene, propenylene, butenylene, pentenylene, even more preferably vinylene, propenylene and butenylene, and even more preferably 1,2-vinylene and 1,3-propenylene.

0023The term "C2-6 alkynylene" used throughout the present specification refers to a monovalent group derived by removing another hydrogen from the aforementioned "C2-6 alkynylene", and as specific examples there may be mentioned ethynylene, propynylene, butynylene, pentynylene and hexynylene, preferably ethynylene, propynylene, butynylene and pentynylene, more preferably ethynylene, propynylene and butynylene, even more preferably ethynylene and propynylene, and most preferably ethynylene.

0024The term "C3-8 cycloalkyl" used throughout the present specification refers to a cyclic aliphatic hydrocarbon group of 3 to 8 carbons, and as examples there may be mentioned cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl, preferably cyclopropyl, cyclobutyl and cyclopentyl, and more preferably cyclopropyl.

0025The term "C5-8 cycloalkenyl" used throughout the present specification refers to a cycloalkenyl group composed of 5 to 8 carbons, and as examples there may be mentioned cyclopenten-3-yl, cyclohexen-1-yl and cyclohexen-3-yl.

0026The terms "C1-6 alkoxy" and "C1-10 alkoxy" used throughout the present specification refer respectively to an oxy group bonded with the aforementioned "C1-6 alkyl" and an oxy group bonded with the aforementioned "C1-10 alkyl", and as examples there may be mentioned methoxy, ethoxy, n-propoxy, iso-propoxy, sec-propoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy, iso-pentyloxy, sec-pentyloxy, n-hexoxy, iso-hexoxy, 1,1-dimethylpropyloxy, 1,2-dimethylpropoxy, 2,2-dimethylpropyloxy, 2-ethylpropoxy, 1-methyl-2-ethylpropoxy, 1-ethyl-2-methylpropoxy, 1,1,2-trimethylpropoxy, 1,1,2-trimethylpropoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 2,2-dimethylbutoxy, 2,3-dimethylbutyloxy, 1,3-dimethylbutyloxy, 2-ethylbutoxy, 1,3-dimethylbutoxy, 2-methylpentoxy, 3-methylpentoxy and hexyloxy, preferably methoxy, ethoxy, n-propoxy, iso-propoxy, sec-propoxy, n-butoxy, iso-butoxy, sec-butoxy and tert-butoxy, and more preferably methoxy.

0027The terms "C1-6 alkylthio" and "C1-10 alkylthio" used throughout the present specification refer respectively to a thio group bonded with the aforementioned "C1-6 alkyl" and a thio group bonded with the aforementioned "C1-10 alkyl", and as examples there may be mentioned methylthio, ethylthio, n-propylthio, iso-propylthio, n-butylthio, iso-butylthio, sec-butylthio, tert-butylthio, n-pentylthio, 1,1-dimethylpropylthio, 1,2-dimethylpropylthio, 2,2-dimethylpropylthio, 1-ethylpropylthio, 2-ethylpropylthio, n-hexyl, 1-methyl-2-ethylpropylthio, 1-ethyl-2-methylpropylthio, 1,1,2-trimethylpropylthio, 1-propylpropylthio, 1-methylbutylthio, 2-methylbutylthio, 1,1-dimethylbutylthio, 1,2-dimethylbutylthio, 2,2-dimethylbutylthio, 1,3-dimethylbutylthio, 2,3-dimethylbutylthio, 2-ethylbutylthio, 2-methylpentylthio and 3-methylpentylthio.

0028The term "C1-6 alkylsulfinyl" used throughout the present specification refers to a sulfinyl group bonded with the aforementioned "C1-6 alkyl", and as examples there may be mentioned methylsulfinyl, ethylsulfinyl, n-propylsulfinyl and iso-propylsulfinyl.

0029The term "C1-6 alkylsulfonyl" used throughout the present specification refers to a sulfonyl group bonded with the aforementioned "C1-6 alkyl", and as examples there may be mentioned methylsulfonyl, ethylsulfonyl, n-propylsulfonyl and iso-propylsulfonyl.

0030The term "C6-14 aryl" used throughout the present specification refers to an aromatic hydrocarbon ring group of 6 to 14 carbons, which may be a monocyclic, bicyclic or tricyclic fused ring. As preferred examples of such groups there may be mentioned phenyl, indenyl, 1-naphthyl, 2-naphthyl, azulenyl, heptalenyl, biphenyl, indacenyl, acenaphthyl, fluorenyl, phenalenyl, phenanthrenyl, anthracenyl, cyclopentacyclooctenyl and benzocyclooctenyl, preferably phenyl, 1-naphthyl or 2-naphthyl, and more preferably phenyl.

0031The term "5- to 14-membered heteroaryl group" used throughout the present specification refers to a 5- to 14-membered aromatic heterocycle group, which is monocyclic, bicyclic or tricyclic group containing at least one hetero atom selected from N, O and S,. As specific examples of such groups there may be mentioned nitrogen-containing heteroaryl groups such as pyrrolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, tetrazolyl, benzotriazolyl, pyrazolyl, imidazolyl, benzimidazolyl, indolyl, isoindolyl, indolidinyl, purinyl, indazolyl, quinolyl, isoquinolyl, quinolidyl, phthalazyl, naphthylidinyl, quinoxalyl, quinazolinyl, cinnolinyl, pteridinyl, imidazotriazinyl, pyrazinopyridazinyl, acridinyl, phenanthridinyl, carbazolyl, carbazolinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, imidazopyridinyl, imidazopyrimidinyl, pyrazolopyridinyl, and pyrazolopyridinyl; sulfur-containing heteroaryl groups such as thienyl and benzothienyl; oxygen-containing heteroaryl groups such as furyl, pyranyl, cyclopentapyranyl, benzofuryl and isobenzofuryl; and heteroaryl groups containing two or more different hetero atoms, such as thiazolyl, isothiazolyl, benzothiazolyl, benzothiadiazolyl, phenothiazinyl, isoxazolyl, furazanyl, phenoxazinyl, oxazolyl, isoxazoyl, benzoxazolyl, oxadiazolyl, pyrazoloxazolyl, imidazothiazolyl, thienofuranyl, furopyrrolyl, pyridoxazinyl and benzo[1,2,5]thiadiazolyl.

0032The "5- to 14-membered heteroaryl group" is preferably pyrrolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, indolyl, thienyl, benzothienyl, furyl, benzofuranyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl or oxadiazolyl, and more preferably pyridyl, thienyl, furyl, thiazolyl or oxazolyl.

0033The term "5- to 6-membered heteroaryl group" used throughout the present specification refers to a 5- to 6-membered heteroaryl group among the aforementioned 5-to 14-membered heteroaryl group, and as specific examples there may be mentioned pyrrolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl and oxadiazolyl, and more preferably pyridyl, thienyl, furyl, thiazolyl or oxazolyl.

0034The term "9- to 11-membered benzene fused ring group" used throughout the present specification refers to a bicyclic group comprising a non-aromatic ring fused with a benzene ring, and having 9 to 11 atoms composing the ring of the ring group. The "9- to 11-membered benzene fused ring" of a "9- to 11-membered benzene fused ring group" is a ring represented by the following formula: <chemistry id="chem0012" num="0012"><img file="EP1389618B1_D0012.tif" /></chemistry> (wherein Y1, Y2, Y3, Y4 and Y5 represent carbonyl, oxygen, sulfur, methylene or the formula -NR31- (wherein R31 represents hydrogen or C1-6 alkyl), and such a "9- to 11-membered benzene fused ring" is preferably a ring represented by the formula: <chemistry id="chem0013" num="0013"><img file="EP1389618B1_D0013.tif" /></chemistry><chemistry id="chem0014" num="0014"><img file="EP1389618B1_D0014.tif" /></chemistry> (wherein Y1, Y2, Y3 and Y4 have the same definitions as above), more preferably a ring represented by the formulas: <chemistry id="chem0015" num="0015"><img file="EP1389618B1_D0015.tif" /></chemistry><chemistry id="chem0016" num="0016"><img file="EP1389618B1_D0016.tif" /></chemistry><chemistry id="chem0017" num="0017"><img file="EP1389618B1_D0017.tif" /></chemistry> and even more preferably a ring represented by the formula: <chemistry id="chem0018" num="0018"><img file="EP1389618B1_D0018.tif" /></chemistry>

0035The term "9- to 11-membered benzene fused ring group" refers to a monovalent group derived by removing a hydrogen atom from any desired position of the "9- to 11-membered benzene fused ring".

0036The term "8- to 11-membered heteroaryl fused ring group" used throughout the present specification refers to a bicyclic group comprising a non-aromatic ring fused with "5- to 6-membered aromatic heterocycle" such as pyridine, thiophene or furan, and having 8 to 11 atoms composing the ring of the ring group.

0037The term "monocyclic 4- to 8-membered non-aromatic heterocyclic group" used throughout the present specification refers to: <ol id="ol0004" compact="compact"><li>[1] a monocyclic non-aromatic cyclic group,</li><li>[2] having 4 to 8 atoms in the ring of the cyclic group,</li><li>[3] containing 1 or 2 hetero atoms among the atoms of the ring of the cyclic group,</li><li>[4] optionally including 1 or 2 double bonds in the ring, and</li><li>[5] optionally including 1 to 3 carbonyl in the ring.</li></ol>

0038As specific examples of the "monocyclic 4- to 8-membered non-aromatic heterocycle" of a "monocyclic 4-to 8-membered non-aromatic heterocyclic group" there may be mentioned pyrrolidine, piperidine, azepane, pyridone, pyrazinone, tetrahydrofuran, tetrahydrothiophene, tetrahydropyran, morpholine, thiomorpholine, piperazine, thiazolidine, dioxane, imidazoline, thiazoline, azetidine, oxetane, thietane, dioxolane, piperidin-4-one, piperidin-3-one, piperidin-2-one, pyrrolidin-2-one, tetrahydrofuran-2-one and 3,4-dihydro-2H-pyran.

0039A "monocyclic 4- to 8-membered non-aromatic heterocyclic group" is a monovalent group derived by removing a hydrogen atom from any desired position of a "monocyclic 4- to 8-membered non-aromatic heterocycle".

0040The term "bicyclic 7- to 12-membered hydrocarbon ring" used throughout the present specification refers to a bicyclic hydrocarbon ring having 7 to 12 carbon atoms in the ring.

0041Specifically, it refers to <ol id="ol0005" compact="compact"><li>[1] a hydrocarbon ring represented by the formula: <chemistry id="chem0019" num="0019"><img file="EP1389618B1_D0019.tif" /></chemistry> (wherein M1a, M2a and M3a each independently represent the formula -(CH2)m1- (wherein m1 is an integer of 0-2), with the proviso that M1a, M2a and M3a are not all - (CH2)0-),</li><li>[2] a hydrocarbon ring represented by the formula: <chemistry id="chem0020" num="0020"><img file="EP1389618B1_D0020.tif" /></chemistry> (wherein M6a represents the formula -(CH2)m3- (wherein m3 is an integer of 0-3)), or</li><li>[3] a hydrocarbon ring represented by the formula: <chemistry id="chem0021" num="0021"><img file="EP1389618B1_D0021.tif" /></chemistry> (wherein M4a and M5a each independently represent the formula -(CH2)m2- (wherein m2 is an integer of 0-3)).</li></ol> As specific examples of the "bicyclic 7- to 12-membered hydrocarbon ring" there may be mentioned bicyclo[3.1.0]hexane, bicyclo[4.1.0]heptane, spiro[2.4]heptane, spiro[2.5]octane, bicyclo[4.4.0]decane(decahydro-naphthalene), octahydro-indene(bicyclo[4.3.0]nonane), bicyclo[3.3.1]nonane, bicyclo[3.2.1]octane, spiro[4.5]decane, spiro[3.5]nonane,norbornane, adamantane, bicyclo[1.1.0]butane, spiro[2.2]pentane, bicyclo[2.1.0]pentane, bicyclo[3.1.0]hexane, bicyclo[4.1.0]heptane, nortricyclane, quadricyclane, bicyclo[3.3.0]octane, bicyclo[2.2.2]octane, perhydroquinacene, bicyclo[3.3.3]undecane and perhydroanthracene.

0042The "bicyclic 7- to 12-membered hydrocarbon cycle" is preferably bicyclo[4.4.0]decane(decahydronaphthalene), octahydro-indene(bicyclo[4.3.0]nonane), bicyclo[3.3.1]nonane, bicyclo[3.2.1]octane, spiro[5.4]decane or spiro[3.5]nonane, and more preferably bicyclo[4.4.0]decane(decahydro-naphthalene) or octahydro-indene(bicyclo[4.3.0]nonane).

0043The term "bicyclic 7- to 12-membered hydrocarbon ring group" used throughout the present specification refers to a monovalent group derived by removing a hydrogen atom from any desired position of the aforementioned "bicyclic 7- to 12-membered hydrocarbon cycle".

0044The term "bicyclic 7- to 12-membered non-aromatic heterocyclic group" used throughout the present specification refers to <ol id="ol0006" compact="compact"><li>[1] a bicyclic non-aromatic cyclic group,</li><li>[2] having 7 to 12 atoms in the ring of the cyclic group,</li><li>[3] containing 1 to 3 hetero atoms among the atoms of the ring of the cyclic group,</li><li>[4] optionally including 1 to 3 double bonds in the ring, and</li><li>[5] optionally including 1 to 3 carbonyl in the ring.</li></ol>

0045That is, a "bicyclic 7- to 12-membered non-aromatic heterocyclic group" is a monovalent derived from the aforementioned "bicyclic 7- to 12-membered hydrocarbon cycle" by [1] replacing any 1 to 3 methine or methylene in the ring with oxygen, sulfur, nitrogen or -NH-, and then [2] removing a hydrogen atom at any desired position of the ring.

0046The term "4- to 14-membered heterocyclic group" used throughout the present specification has 4 to 14 members and refers to <ol id="ol0007" compact="compact"><li>[1] a monocyclic, bicyclic or tricyclic heterocyclic group,</li><li>[2] having 4 to 14 atoms in the ring of the cyclic group,</li><li>[3] containing 1 to 3 hetero atoms among the atoms of the ring of the cyclic group,</li><li>[4] optionally including 1 to 3 double bonds in the ring, and</li><li>[5] optionally including 1 to 3 carbonyl in the ring.</li></ol>

0047Specifically, for example, it refers the aforementioned "monocyclic 4- to 8-membered non-aromatic heterocyclic group" or "bicyclic 7- to 12-membered non-aromatic heterocyclic group".

0048The "4- to 14-membered heterocyclic group" is preferably a "4- to 7-membered heterocyclic group" as defined below, and more preferably there may be mentioned tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, dioxoranyl, pyrrolidin-2-onyl, dihydrofuran-2-onyl and piperidinyl.

0049The term "4- to 7-membered heterocyclic group" used throughout the present specification refers to 4-to 7-membered heterocyclic groups among the groups referred by "4- to 14-membered heterocyclic group" as defined above. Specifically, it refers to a monovalent group derived by removing a hydrogen atom from any desired position of a ring represented by, for example, the formula: <chemistry id="chem0022" num="0022"><img file="EP1389618B1_D0022.tif" /></chemistry> (wherein X10 represents sulfur, oxygen or -NX12 (wherein X12 represents hydrogen or C1-6 alkyl), X11 represents methylene, sulfur, oxygen or • -NX13 (wherein X13 represents hydrogen or C1-6 alkyl), and s represents an integer of 1-3), and preferably there may be mentioned tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, dioxoranyl, pyrrolidin-2-onyl, dihydrofuran-2-onyl and piperidinyl. The term "tetrahydrofuranyl" used throughout the present specification refers to a monovalent group derived by removing a hydrogen atom from any desired position of a tetrahydrofuran ring, and specifically there may be mentioned tetrahydrofuran-2-yl and tetrahydrofuran-3-yl.

0050The term "tetrahydrothiophenyl" used throughout the present specification refers to a monovalent group derived by removing a hydrogen atom from any desired position of a tetrahydrothiophene ring, and specifically there may be mentioned tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl.

0051The term "tetrahydropyranyl" used throughout the present specification refers to a monovalent group derived by removing a hydrogen atom from any desired position of a tetrahydropyran ring, and specifically there may be mentioned tetrahydropyran-2-yl, tetrahydropyran-3-yl and tetrahydropyran-4-yl.

0052The term "dioxolanyl" used throughout the present specification refers to a monovalent group derived by removing a hydrogen atom from any desired position of a dioxolane ring, and specifically there may be mentioned dioxolan-2-yl and dioxolan-4-yl.

0053The term "pyrrolidin-2-onyl" used throughout the present specification refers to a monovalent group derived by removing a hydrogen atom from any desired position of a pyrrolidin-2-one ring, and specifically there may be mentioned pyrrolidin-2-on-1-yl, pyrrolidin-2-on-3-yl, pyrrolidin-2-on-4-yl and pyrrolidin-2-on-5-yl.

0054The term "furanyl" used throughout the present specification refers to a monovalent group derived by removing a hydrogen atom from any desired position of a furan ring, and specifically there may be mentioned 2-furanyl and 3-furanyl.

0055The term "thienyl" used throughout the present specification refers to a monovalent group derived by removing a hydrogen atom from any desired position of a thiophene ring, and specifically there may be mentioned 2-thienyl and 3-thienyl.

0056The term "pyrrolidinyl" used throughout the present specification refers to a monovalent group derived by removing a hydrogen atom from any desired position of a pyrrolidine ring, and specifically there may be mentioned 1-pyrrolidinyl, 2-pyrrolidinyl and 3-pyrrolidinyl.

0057The term "piperidyl" used throughout the present specification refers to a monovalent group derived by removing a hydrogen atom from any desired position of a piperidine ring, and specifically there may be mentioned 1-pyrrolidinyl, 2-pyrrolidinyl and 3-pyrrolidinyl.

0058The term "oxazolyl" used throughout the present specification refers to a monovalent group derived by removing a hydrogen atom from any desired position of an oxazole ring, and specifically there may be mentioned 2-oxazolyl, 4-oxazolyl and 5-oxazolyl.

0059The term "isoxazolyl" used throughout the present specification refers to a monovalent group derived by removing a hydrogen atom from any desired position of an isoxazole ring, and specifically there may be mentioned 3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl.

0060The term "thiazolyl" used throughout the present specification refers to a monovalent group derived by removing a hydrogen atom from any desired position of a thiazole ring, and specifically there may be mentioned 2-thiazolyl, 4-thiazolyl and 5-thiazolyl.

0061The term "pyrrolyl" used throughout the present specification refers to a monovalent group derived by removing a hydrogen atom from any desired position of a pyrrole ring, and specifically there may be mentioned 1-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl.

0062The term "pyrazolyl" used throughout the present specification refers to a monovalent group derived by removing a hydrogen atom from any desired position of a pyrazole ring, and specifically there may be mentioned 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl and 5-pyrazolyl.

0063The term "morpholinyl" used throughout the present specification refers to a monovalent group derived by removing a hydrogen atom from any desired position of a morpholine ring, and specifically there may be mentioned 4-morpholinyl, 2-morpholinyl and 3-morpholinyl.

0064The term "pyridyl" used throughout the present specification refers to a monovalent group derived by removing a hydrogen atom from any desired position of a pyridine ring, and specifically there may be mentioned 2-pyridyl, 3-pyridyl and 4-pyridyl.

0065The term "dioxanyl" used throughout the present specification refers to a monovalent group derived by removing a hydrogen atom from any desired position of a 1,3-dioxane ring or 1,4-dioxane ring, and specifically there may be mentioned 1,3-dioxan-2-yl, 1,3-dioxan-4-yl, 1,3-dioxan-5-yl and 1,4-dioxan-2-yl.

0066The term "dihydropyranyl" used throughout the present specification refers to a monovalent group derived by removing a hydrogen atom from any desired position of a 3,4-dihydro-2H-pyran ring or 3,6-dihydro-2H-pyran ring, and specifically there may be mentioned 3,4-dihydro-2H-pyran-2-yl, 3,4-dihydro-2H-pyran-3-yl, 3,4-dihydro-2H-pyran-4-yl, 3,4-dihydro-2H-pyran-5-yl, 3,4-dihydro-2H-pyran-6-yl, 3,6-dihydro-2H-pyran-2-yl, 3,6-dihydro-2H-pyran-3-yl, 3,6-dihydro-2H-pyran-4-yl, 3,6-dihydro-2H-pyran-5-yl and 3,6-dihydro-2H-pyran-6-yl.

0067The term "dihydrofuran-2-onyl" used throughout the present specification refers to a monovalent group derived by removing a hydrogen atom from any desired position of a dihydrofuran-2-one ring, and specifically there may be mentioned dihydrofuran-2-on-3-yl, dihydrofuran-2-on-4-yl and dihydrofuran-2-on-5-yl.

0068A compound of general formula (I) above wherein "R2 and R3 or R3 and R4 may bond together to form a 5- to 7-membered ring optionally containing 1 to 4 hetero atoms in the ring and optionally containing carbonyl in the ring" is a compound in which the pyrazolo[1,5-a]pyridine in general formula (I) is fused with M1 at the bonding positions of R2 and R3, as represented by the formula: <chemistry id="chem0023" num="0023"><img file="EP1389618B1_D0023.tif" /></chemistry> (wherein R1, R4, R5, R6 and Ar have the same definitions as above, ring M1 is a 5- to 7-membered ring optionally having 1 to 4 hetero atoms and optionally having carbonyl in the ring, and ring M1 also optionally has a substituent selected from Substituent Group A above), or a compound in which the pyrazolo[1,5-a]pyridine in general formula (I) is fused with M1 at the bonding positions of R4 and R3, as represented by the formula: <chemistry id="chem0024" num="0024"><img file="EP1389618B1_D0024.tif" /></chemistry> (wherein R1, R2, R5, R6 and Ar have the same definitions as above, ring M1 is a 5- to 7-membered ring optionally having 1 to 4 hetero atoms and optionally having a carbonyl group in the ring, and ring M1 also optionally has a substituent selected from Substituent Group A above).

0069As rings for "ring M1" there may be mentioned as preferable pyridine optionally having a substituent selected from Substituent Group A, benzene optionally having a substituent selected from Substituent Group A, thiophene optionally having a substituent selected from Substituent Group A, cyclohexane optionally having a substituent selected from Substituent Group A, pyridine optionally having a substituent selected from Substituent Group A and piperidin-2-one optionally having a substituent selected from Substituent Group A.

0070A compound of general formula (I) above wherein "R5 and R6 may bond together to form a 5- to 10-membered ring optionally containing 1 to 4 hetero atoms in the ring and optionally containing carbonyl in the ring" is a compound wherein R5 and R6 in formula (I) bond together to form ring M2, as represented by the formula: <chemistry id="chem0025" num="0025"><img file="EP1389618B1_D0025.tif" /></chemistry> (wherein R1, R2, R3, R4 and Ar have the same definitions as above, ring M2 is a 5- to 10-membered ring optionally having 1 to 4 hetero atoms and optionally having carbonyl in the ring, and ring M2 also optionally has a substituent selected from Substituent Group A above.

0071As rings for "ring M2" there may be mentioned as preferable "5- to 14-membered heteroaryl group" optionally having a substituent selected from Substituent Group A, "4- to 14-membered heterocyclic group" optionally having a substituent selected from Substituent Group A, "9- to 11-membered benzene fused ring group" optionally having a substituent selected from Substituent Group A, and "8- to 11-membered heteroaryl fused ring group" optionally having a substituent selected from Substituent Group A.

0072A compound of general formula (I) above wherein "R6 and R2 may bond together to form a 6- to 7-membered ring optionally containing 1 or 2 hetero atoms in the ring and optionally containing carbonyl in the ring" is a compound wherein R6 and R2 bond together as M3 to form a ring, as represented by the formula: <chemistry id="chem0026" num="0026"><img file="EP1389618B1_D0026.tif" /></chemistry> (wherein R1, R3, R4, R5 and Ar have the same definitions as above, and M3 represents optionally substituted 1,2-ethylene, optionally substituted 1,3-propylene, optionally substituted 1,2-vinylene or optionally substituted amide.

0073The term "salt" used throughout the present specification is not particularly restricted so long as it is a salt formed with a compound of the present invention and is pharmacologically acceptable, and as preferred salts there may be mentioned hydrogen halide acid salt (for example, hydrofluoride, hydrochloride, hydrobromide and hydroiodide), inorganic acid salt (for example, sulfate, nitrate, perchlorate, phosphate, carbonate and bicarbonate), organic carboxylate (for example, acetate, trifluoroacetate, oxalate, maleate, tartarate, fumarate and citrate), organic sulfonate (for example, methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate and camphorsulfonate), amino acid salt (for example, aspartate and glutamate), quaternary amine salt, alkali metal salt (for example, sodium salt and potassium salt) or alkaline earth metal salt (for example, magnesium salt and calcium salt), and more preferred as "pharmacologically acceptable salt" are hydrochloride, oxalate, trifluoroacetate and the like.

0074Representative production schemes for compounds represented by formula (I) above according to the invention will now be presented. In the following production schemes, R1, R2, R3,R4, R5, R6, R8a, R8b, R8c, R8d and Ar have the same respective definitions given above, X represents halogen (for example, fluorine, chlorine, bromine or iodine), and XBS represents boron substituted with OR8a and OR8b or tin substituted with R8c, R8d and R8e, Y represents NRy, O, S(O)n, and A represents NO or NO2. A group represented by ProtN is an amino protecting group, and a group represented by ProtO is a hydroxyl protecting group. AX represents Ar or X [where Ar and X have the same respective definitions as given above], an Ar ring has the same definition for Ar given above, a Het ring represents an optionally substituted 5- to 14-membered heteroaryl or 9- to 11-membered benzene fused ring group, and R1c and R1d each represent optionally substituted C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl or the like. Rca represents optionally substituted C1-6 alkyl or the like, and Lev represents a leaving group such as halogen or trifluoromethanesulfonyl. Rar and Rhet each represent cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, C2-6 alkenyloxy, C2-6 alkynyloxy, or the like. Rrr represents cyano, C1-6 alkoxy, optionally substituted aryl or optionally substituted 5- to 14-membered heteroaryl, and RX1 represents C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, halogenated C1-6 alkyl, benzyl, a substituent serving as a protective group for a Y atom such as Boc, or the like. Ry and R60 each represent a substituent selected from Substituent Group A, n represents an integer of 0-2 and m represents an integer of 0-6. The term "room temperature" used below refers to a range of 0-40°C. <chemistry id="chem0027" num="0027"><img file="EP1389618B1_D0027.tif" /></chemistry>Step A: A halogenated compound (1) may be reacted in the presence of a catalyst such as a palladium catalyst or copper (I) iodide, in the presence of an acetylene derivative and a base and in an inert solvent at 0-250°C, to obtain an acetylene derivative (2). The solvent used will differ depending on the starting material, reagent, etc. and is not particularly restricted so long as it does not inhibit the reaction and dissolves the starting material to some extent, but preferably there may be mentioned benzene, toluene, xylene, anisole, N,N-dimethylformamide, 1,2-dimethoxyethane, tetrahydrofuran, dioxane, n-butanol, ethanol, methanol, 1-methyl-2-pyrrolidinone, water or mixtures thereof. The base used will differ depending on the starting material, solvent, etc. and is not particularly restricted so long as it does not inhibit the reaction, and as preferred bases there may be mentioned potassium carbonate, sodium carbonate, cesium fluoride, potassium fluoride, sodium hydrogencarbonate, triethylamine and diethylamine. These bases may also be used as solvents. When a palladium or nickel metal complex is used, its use will also differ depending on the starting material, solvent, etc. and is not particularly restricted so long as it does not inhibit the reaction, but Pd(PPh3)4, Pd(OAc)2/PPh3, PdCl2, PdCl2(dppf), Ni(dpp)2Cl2 and the like are preferred. Step B: The acetylene compound (2) may be treated with an N-amination agent (for example, hydroxylamine-O-sulfonic acid or O-mesitylenesulfonylhydroxylamine) in a solvent (for example, ethyl acetate, tetrahydrofuran, diethyl ether, dichloromethane, 1,2-dimethoxyethane, water, or the like) at a temperature of between -50°C and room temperature to obtain an N-aminopyridinium salt, and this may be reacted in the presence of a base at a temperature of between 0°C and 250°C to obtain a closed ring compound (3). The solvent used will differ depending on the starting material, reagent, etc. and is not particularly restricted so long as it does not inhibit the reaction and dissolves the starting material to some extent, but preferably there may be mentioned benzene, toluene, xylene, anisole, N,N-dimethylformamide, 1,2-dimethoxyethane, tetrahydrofuran, dioxane, n-butanol, ethanol, methanol and 1-methyl-2-pyrrolidinone. The base used will differ depending on the starting material, solvent, etc. and is not particularly restricted so long as it does not inhibit the reaction, but as preferred bases there may be mentioned potassium carbonate, sodium carbonate, cesium fluoride, potassium fluoride, sodium hydrogencarbonate, triethylamine, sodium methoxide, sodium ethoxide, sodium tert-butoxide and potassium tert-butoxide. <chemistry id="chem0028" num="0028"><img file="EP1389618B1_D0028.tif" /></chemistry>Step A: The pyrazolo[1,5-a]pyridine derivative (3) obtained in Production Scheme 1 may be treated with an alkyllithium reagent (for example, n-butyllithium, sec-butyllithium or tert-butyllithium) in an inert solvent at a temperature of between -78°C and room temperature and then reacted with a halogenating agent to obtain a 7-halogenated compound (4). The halogenating agent used will differ depending on the starting material, solvent, etc. and is not particularly restricted so long as it does not inhibit the reaction, but preferably there may be mentioned bromine, iodine, N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, hexachloroethane, 1,2-dibromoethane, 1,2-dibromo-1,1,2,2-tetrachloroethane and 1,2-diiodoethane. The solvent used will differ depending on the starting material, reagents, etc. and is not particularly restricted so long as it does not inhibit the reaction and dissolves the starting material to some extent, but preferably there may be mentioned hexane, pentane, tetrahydrofuran and diethyl ether. Step B: The halogenated compound (4) may be reacted with a heteroaryl-boric acid or aryl-boric acid compound or an aryl-metal compound (for example, a heteroaryl-tin compound or aryl-tin compound) and a palladium or nickel complex, at a temperature of between 0°C and 250°C, to obtain an aryl- or heteroaryl-substituted derivative (5). The solvent used will differ depending on the starting material, reagents, etc. and is not particularly restricted so long as it does not inhibit the reaction and dissolves the starting material to some extent, but preferably there may be mentioned benzene, toluene, xylene, mesitylene, anisole, N,N-dimethylformamide, 1,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxane, n-butanol, ethanol, methanol, 1-methyl-2-pyrrolidinone, water and mixtures thereof. The base used will differ depending on the starting material, solvent, etc. and is not particularly restricted so long as it does not inhibit the reaction, but as preferred bases there may be mentioned potassium carbonate, sodium carbonate, barium hydroxide, cesium fluoride, potassium fluoride, sodium hydrogencarbonate and triethylamine. When a palladium or nickel complex is used, its use will also differ depending on the starting material, solvent, etc. and is not particularly restricted so long as it does not inhibit the reaction, but Pd(PPh3)4, Pd(OAc)2/PPh3, PdCl2, PdCl2(dppf), Ni(dpp)2Cl2 and the like are preferred. Step C: The pyrazolo[1,5-a]pyridine derivative (5) may be reacted with a nitrating agent either in a solvent or without a solvent, to obtain a 3-nitro-pyrazolo[1,5-a]pyridine derivative (6). The solvent, if used, will differ depending on the starting material, reagent, etc. and is not particularly restricted so long as it does not inhibit the reaction and dissolves the starting material to some extent, but preferably there may be mentioned acetic anhydride, acetic acid, sulfuric acid, trifluoroacetic anhydride, trifluoroacetic acid, acetonitrile, 1,2-dimethoxyethane and tetrahydrofuran. The nitrating agent used will differ depending on the starting material, solvent, etc. and is not particularly restricted so long as it does not inhibit the reaction, but preferably there may be mentioned copper nitrate trihydrate, nitric acid, fuming nitric acid, sodium nitrate, BF4NO2, NH4+NO3-, and the like. The reaction temperature will normally be from -50°C to 200°C.

0075Alternatively, the pyrazolo[1,5-a]pyridine derivative (5) may be reacted with a nitrosating agent to obtain a 3-nitroso-pyrazolo[1,5-a]pyridine derivative (6). This reaction may also be conducted either without a solvent or with a solvent, in which case the solvent will differ depending on the starting material, reagent, etc. and is not particularly restricted so long as it does not inhibit the reaction and dissolves the starting material to some extent, but preferably there may be mentioned solvents such as acetic anhydride, acetic acid, hydrochloric acid, sulfuric acid, trifluoroacetic anhydride, trifluoroacetic acid, acetonitrile, 1,2-dimethoxyethane and the like, or their mixtures with water or ethanol. The nitrosating agent used will differ depending on the starting material, solvent, etc. and is not particularly restricted so long as it does not inhibit the reaction, but preferably there may be mentioned sodium nitrite, BF4NO and the like. The reaction temperature will normally be from -20°C to 200°C. Step D: The nitro derivative or nitroso derivative (6) may be reacted with a metal (powder) either in the presence or in the absence of an acid and either in a solvent or without a solvent, to obtain a 3-aminopyrazolo[1,5-a]pyridine derivative (7). The reaction temperature will normally be from -10°C to 150°C. The acid, if used, will differ depending on the starting material, solvent, etc. and is not particularly restricted so long as it does not inhibit the reaction, but preferably there may be mentioned acetic acid, hydrochloric acid, sulfuric acid and the like. The solvent, if used, will differ depending on the starting material, reagent, etc. and is not particularly restricted so long as it does not inhibit the reaction and dissolves the starting material to some extent, but preferably there may be mentioned methanol, ethanol, n-butanol, water and the like, either alone or mixture thereof. The metal (powder) used may be Zn, Fe, SnCl2, NiCl2 or the like.

0076As an alternative method, the nitro or nitroso derivative (6) may be subjected to hydrogenation reaction under a hydrogen atmosphere to obtain a 3-amino-pyrazolo[1,5-a]pyridine derivative (7). The hydrogen pressure will normally be from 1 to 100 atmospheres, and the reaction temperature from 0-200°C. The reaction may be conducted either without a solvent or with a solvent, in which case the solvent will differ depending on the starting material, reagent, etc. and is not particularly restricted so long as it does not inhibit the reaction and dissolves the starting material to some extent, but preferably there may be mentioned methanol, ethanol, propanol, butanol, tetrahydrofuran, 1,4-dioxane, ethyl acetate, acetone, N,N-dimethylformamide and the like. The reaction may be conducted either in the presence or in the absence of an acid, and using a metal catalyst. The acid and metal catalyst used will differ depending on the starting material, solvent, etc. and is not particularly restricted so long as it does not inhibit the reaction, but as preferred acids there may be mentioned acetic acid and hydrochloric acid, while as preferred metal catalysts there may be mentioned Pd-C, PtO2, Pt-C, Raney-Ni and the like. Also, ammonium formate or the like may be heated in a solvent such as methanol to generate hydrogen in the system during the reaction to obtain a 3-aminopyrazolo[1,5-a]pyridine derivative (7). Step E: The 3-aminopyrazolo[1,5-a]pyridine derivative (7) may be reacted with a carbonyl derivative (for example, diethylketone) or an aldehyde derivative (for example, propionaldehyde) in the presence of a reducing agent to obtain a pyrazolo[1,5-a]pyridine derivative represented by formula (I) or (I'). Compound (I) or compound (I') may be obtained depending on the number of moles of the carbonyl derivative. The reaction may be conducted in the presence or in the absence of an acid, with or without a solvent, and in the presence or in the absence of an inorganic salt. The solvent, if used, will differ depending on the starting material, reagent, etc. and is not particularly restricted so long as it does not inhibit the reaction and dissolves the starting materials to some extent, but preferably there may be mentioned tetrahydrofuran, diethyl ether, 1,2-dichloroethane, dichloromethane, chloroform, acetonitrile, water and the like, which may be used alone or as mixed solvents. The acid, inorganic salt and reducing agent used will differ depending on the starting material, solvent, etc. and are not particularly restricted so long as they do not inhibit the reaction, but preferably there may be mentioned acetic acid, sulfuric acid and the like as acids, sodium sulfate and the like as inorganic salts, and sodium triacetoxyborohydride, sodium borohydride, sodium cyanoborohydride and the like as reducing agents. The reaction temperature will normally be from -10°C to 150°C. <chemistry id="chem0029" num="0029"><img file="EP1389618B1_D0029.tif" /></chemistry>Step A: The pyrazolo[1,5-a]pyridine derivative (4) may be subjected to nitration reaction or nitrosation reaction in the same manner as Step C of Production Scheme 2 above, to obtain compound (8). Step B: The halogenated compound (8) may be subjected to cross-coupling reaction in the same manner as Step B of Production Scheme 2 above, to obtain an aryl- or heteroaryl-substituted derivative (6). <chemistry id="chem0030" num="0030"><img file="EP1389618B1_D0030.tif" /></chemistry>Step A: The 3-amino-pyrazolo[1,5-a]pyridine derivative (7) may be may be subjected to reaction with an amino-protecting reagent (for example, di-tert-butyl dicarbonate) to obtain a 3-aminopyrazolo[1,5-a]pyridine derivative (9) having the 3-position amino group protected with a carbamate group (for example, t-butoxycarbonyl). The reaction may be conducted with or without a solvent, and in the presence or in the absence of a base. The solvent, if used, will differ depending on the starting material, reagent, etc. and is not particularly restricted so long as it does not inhibit the reaction and dissolves the starting materials to some extent, but preferably there may be mentioned tetrahydrofuran, diethyl ether, 1,4-dioxane, dichloromethane, 1,2-dichloroethane, chloroform, N,N-dimethylformamide, and the like. The base, if used, will differ depending on the starting material, solvent, etc. and is not particularly restricted so long as it does not inhibit the reaction, but preferably there may be mentioned triethylamine, sodium hydride, potassium carbonate, sodium carbonate, cesium carbonate, sodium hydrogencarbonate, 4-(dimethylamino)pyridine, sodium bis(trimethylsilyl)amide, and the like. The reaction temperature will normally be from -70°C to 150°C. As preferred examples of protecting groups ("ProtN" in this scheme) there may be mentioned, in addition to Boc, also 9-fluorenylmethoxycarbonyl (Fmoc), 2,2,2-trichloroethoxycarbonyl (Troc), and the like, in which case the amino group is protected using a reagent and reaction suitable for that protecting group. Step B: The 3-aminopyrazolo[1,5-a]pyridine derivative (9) may be reacted with an alkylating agent (for example, an optionally substituted alkyl halide), to obtain a pyrazolo[1,5-a]pyridine derivative (10). The reaction may be conducted with or without a solvent, and in the presence or in the absence of a base. The solvent, if used, will differ depending on the starting material, reagent, etc. and is not particularly restricted so long as it does not inhibit the reaction and dissolves the starting materials to some extent, but preferably there may be mentioned tetrahydrofuran, diethyl ether, N,N-dimethylformamide, dimethylsulfoxide, and the like. The base, if used, will differ depending on the starting material, solvent, etc. and is not particularly restricted so long as it does not inhibit the reaction, but preferably there may be mentioned sodium hydride, potassium hydride, potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, and the like. The reaction temperature will normally be from -70°C to 200°C. Step C: The amino group-protected 3-amino-pyrazolo[1,5-a]pyridine derivative (10) may be subjected to deprotecting reaction to obtain a 3-monoalkylaminopyrazolo[1,5-a]pyridine derivative (I'). The reaction may be conducted either in the presence or in the absence of a deprotecting reagent. If used, the deprotecting reagent will differ depending on the starting material, solvent, etc. and is not particularly restricted so long as it does not inhibit the reaction, but preferably there may be mentioned hydrochloric acid, sulfuric acid, trifluoroacetic acid, methanesulfonic acid, iodotrimethylsilane, aluminum (III) chloride, trimethylsilyl triflate, and the like. When a group other than Boc (such as Fmoc, Troc or the like) is used as the protecting group, the deprotection is carried out using reagents and reaction suitable for that protecting group. The reaction may be conducted with or without a solvent, and if it is carried out with a solvent, the solvent is preferably ethyl acetate, tetrahydrofuran, diethyl ether, 1,4-dioxane, acetonitrile, dichloromethane, chloroform, nitromethane, phenol, anisole, thiophenol or the like. The solvent will depend on the starting material, reagent, etc. and is not particularly restricted so long as it does not inhibit the reaction and dissolves the starting materials to some extent. The reaction temperature will normally be from -70°C to 200°C. Step D: The pyrazolo[1,5-a]pyridine derivative (I') may be reacted with a carbonyl derivative (for example, diethylketone), an aldehyde derivative (for example, propionaldehyde) or a carbonyl-equivalent compound (for example, ((1-ethoxycyclopropyl)oxy)trimethylsilane), in the presence of a reducing agent, to obtain a pyrazolo[1,5-a]pyridine derivative (I). The reaction temperature will normally be from -10°C to 150°C. The reaction may be conducted in the presence or in the absence of an acid, with or without a solvent, and in the presence or in the absence of an inorganic salt. The solvent, if used, will differ depending on the starting material, reagent, etc. and is not particularly restricted so long as it does not inhibit the reaction and dissolves the starting materials to some extent, but preferably there may be mentioned tetrahydrofuran, diethyl ether, 1,2-dichloroethane, dichloromethane, chloroform, acetonitrile, ethanol, methanol, water and the like, which may be used alone or as mixed solvents. The acid, inorganic salt and reducing agent used will differ depending on the starting material, solvent, etc. and are not particularly restricted so long as they do not inhibit the reaction, but preferably there may be mentioned acetic acid, sulfuric acid and the like as acids, sodium sulfate and the like as inorganic salts, and sodium triacetoxyborohydride, sodium borohydride, sodium cyanoborohydride and the like as reducing agents.

0077Alternatively, the pyrazolo[1,5-a]pyridine derivative (I') may be reacted with an acylating agent either in the presence or in the absence of a base, and with or without a solvent, to obtain a pyrazolo[1,5-a]pyridine derivative (I). The reaction temperature will normally be from -20°C to 150°C. The solvent, if used, will differ depending on the starting material, reagent, etc. and is not particularly restricted so long as it does not inhibit the reaction and dissolves the starting materials to some extent, but preferably there may be mentioned tetrahydrofuran, diethyl ether, 1,2-dichloroethane, dichloromethane, acetonitrile, ethanol, methanol, water and the like, which may be used alone or as mixed solvents. The base, if used, will differ depending on the starting material, solvent, etc. and is not particularly restricted so long as it does not inhibit the reaction, but preferably there may be mentioned triethylamine, N,N-diisopropylethylamine, 4-(dimethylamino)pyridine, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, and the like. <chemistry id="chem0031" num="0031"><img file="EP1389618B1_D0031.tif" /></chemistry>Step A: The nitro derivative or nitroso derivative (8) may be reacted with a metal (powder) to obtain a 3-aminopyrazolo[1,5-a]pyridine derivative (11). The reaction temperature will normally be from -10°C to 150°C. The reaction may be conducted either in the presence or in the absence of an acid, and with or without a solvent. The acid, if used, will differ depending on the starting material, solvent, etc. and is not particularly restricted so long as it does not inhibit the reaction, but preferably there may be mentioned acetic acid, hydrochloric acid, sulfuric acid, and the like. The solvent, if used, will differ depending on the starting material, reagents, etc. and is not particularly restricted so long as it does not inhibit the reaction and dissolves the starting materials to some extent, but preferably there may be mentioned methanol, ethanol, n-butanol, tetrahydrofuran, water and the like, which may be used alone or as mixed solvents. The metal (powder) used may be zinc, iron, SnCl2, NiCl2, or the like. Step B: The 3-aminopyrazolo[1,5-a]pyridine derivative (11) may be subjected to reaction in the same manner as Step A of Production Scheme 4 above, and the amino group thereof protected, to obtain compound (12). Step C: The halogenated compound (12) may be subjected to cross-coupling reaction using a palladium catalyst in the same manner as Step B of Production Scheme 2 above, to obtain compound (9). <chemistry id="chem0032" num="0032"><img file="EP1389618B1_D0032.tif" /></chemistry>Step A: A carboxylic acid derivative (13) and an azidating agent (for example, diphenylphosphoryl azide (DPPA)) may be reacted with or without a solvent and in the presence or in the absence of a base at a temperature from -70°C to 250°C to produce an acid azide derivative, and the acid azide derivative heated to 0-250°C for rearrangement reaction, such as Curtius rearrangement reaction, to produce isocyanate in the system, and then subjected to reaction with t-butanol or the like, to obtain a 3-aminopyrazolo[1,5-a]pyridine derivative ((9) or (12)) protected with a carbamate group such as t-butoxycarbonyl(Boc). The solvent, if used, will differ depending on the starting material, reagents, etc. and is not particularly restricted so long as it does not inhibit the reaction and dissolves the starting material to some extent, but preferably there may be mentioned benzene, toluene, xylene, diphenylether, t-butanol, tetrahydrofuran, dioxane, acetonitrile, N,N-dimethylformamide and the like, which may be used alone or as mixed solvents. The base, if used, will differ depending on the starting material, solvent, etc. and is not particularly restricted so long as it does not inhibit the reaction, but preferably there may be mentioned triethylamine, diisopropylethylamine, 4-(dimethylamino)pyridine, pyridine, and the like. As an alternative method for synthesis of the acid azide derivative, the carboxylic acid derivative (9) may be converted to an acid chloride or mixed acid anhydride and subjected to reaction with an azidating agent (for example, sodium azide, trimethylsilyl azide, etc.) to obtain the acid azide derivative. As yet alternative methods, the target compound ((9) or (12)) may also be obtained by Hofmann rearrangement or Schmidt rearrangement reaction. <chemistry id="chem0033" num="0033"><img file="EP1389618B1_D0033.tif" /></chemistry>Step A: Compound (12) may be alkylated in the same manner as Step B of Production Scheme 4 to obtain Compound (13). Step B: Compound (13) may be deprotected of the protecting group in the same manner as Step C of Production Scheme 4 to obtain Compound (14). Step C: Compound (14) may be alkylated or acylated in the same manner as Step D of Production Scheme 4 to obtain Compound (15). Step C: Compound (11) may be alkylated in the same manner as Step E of Production Scheme 2 to obtain Compound (15). Step E: Compound (15) may be cross-coupled using a palladium complex or the like in the same manner as Step B of Production Scheme 2 to obtain Compound (I). <chemistry id="chem0034" num="0034"><img file="EP1389618B1_D0034.tif" /></chemistry>Step A: Compound (19) was produced according to the method disclosed in Heterocycles, 1977, 6, 379. Specifically, Compound (17) may be reacted with Compound (18), to obtain Compound (19). Step B: Compound (20) may be obtained by reduction of Compound (19) according to Step D of Production Scheme 2. Step C: Compound (21) having the 3-position amino group protected may be obtained from Compound (20) according to Step A of Production Scheme 4. Step D: A halogenated compound (12') may be obtained from the 3-position amino group-protected Compound (21) by introducing a halogen at the 7-position according to Step A of Production Scheme 2. <chemistry id="chem0035" num="0035"><img file="EP1389618B1_D0035.tif" /></chemistry>Step A: Compound (Is) may be oxidized using an oxidizing agent such as m-chloroperbenzoic acid or the like, either with or without a solvent, to obtain a sulfoxide (Is1). The reaction temperature will normally be from - 70°C to 150°C. The solvent, if used, will differ depending on the starting material, reagent, etc. and is not particularly restricted so long as it does not inhibit the reaction and dissolves the starting material to some extent, but preferably there may be mentioned acetone, acetic acid, trifluoroacetic acid, dichloromethane, chloroform, benzene, nitromethane, methanol, ethanol, water, and the like, which may be used alone or as mixed solvents. As oxidizing agents to be used there may be mentioned m-chloroperbenzoic acid, trifluoroperacetic acid, bis(trimethylsilyl)peroxy acid, sodium periodate, dinitrogen tetroxide, nitric acid/sulfuric acid mixture, chromic acid, and the like. Step B: The sulfoxide (Is1) may be oxidized using an oxidizing agent such as m-chloroperbenzoic acid or the like, either with or without a solvent, to obtain a sulfone (Is2). The reaction temperature will normally be from -70°C to 150°C. The solvent, if used, will differ depending on the starting material, reagent, etc. and is not particularly restricted so long as it does not inhibit the reaction and dissolves the starting material to some extent, but preferably there may be mentioned acetone, acetic acid, trifluoroacetic acid, dichloromethane, chloroform, benzene, methanol, ethanol, water, and the like, which may be used alone or as mixed solvents. As oxidizing agents to be used there may be mentioned m-chloroperbenzoic acid, chromic acid, osmium tetroxide, potassium permanganate, and the like. <chemistry id="chem0036" num="0036"><img file="EP1389618B1_D0036.tif" /></chemistry>Step A: A 2-pyridylacetic acid ester (22) and hydroxylamine-O-sulfonic acid (23) may be reacted in the presence or in the absence of a base, and with a solvent, to obtain a 2-hydroxypyrazolo[1,5-a]pyridine derivative (24). The reaction temperature will normally be from 0°C to 100°C. The solvent used will differ depending on the starting materials, reagent, etc. and is not particularly restricted so long as it does not inhibit the reaction and dissolves the starting materials to some extent, but preferably there may be mentioned acetone, acetic acid, methanol, ethanol, water, and the like, which may be used alone or as mixed solvents. Step B: A 2-hydroxypyrazolo[1,5-a]pyridine derivative (24) may be reacted with an alkylating agent either with or without a solvent, and in the presence or in the absence of a base, to obtain Compound (25). The reaction temperature will normally be from 0°C to 100°C. The solvent, if used, will differ depending on the starting material, reagent, etc. and is not particularly restricted so long as it does not inhibit the reaction and dissolves the starting material to some extent, but preferably there may be mentioned acetone, methanol, ethanol, water, and the like, which may be used alone or as mixed solvents. As alkylating agents there may be mentioned dimethylsulfuric acid, alkyl halides, diazomethane, trimethylsilyldiazomethane, or the like. The base, if used, will differ depending on the starting material, solvent, etc. and is not particularly restricted so long as it does not inhibit the reaction, but preferably there may be mentioned calcium carbonate, sodium carbonate, sodium hydrogencarbonate, triethylamine, and the like. Step C: Compound (25) may be used to obtain Compound (26) in the same manner as Step A of Production Scheme 2. Step D: Compound (26) may be used to obtain Compound (8') in the same manner as Step C of Production Scheme 2. <chemistry id="chem0037" num="0037"><img file="EP1389618B1_D0037.tif" /></chemistry>Step A: A step of converting the leaving group Lev substituting at the 7-position or N atom at the 3-position of a pyrazolo[1,5-a]pyridine derivative represented by formula (Ia1) or formula (Ih1), to a desired substituent Rar or Rrr. The following reactions may be employed. <ol id="ol0008" compact="compact"><li>[1] A pyrazolo[1,5-a]pyridine derivative represented by formula (Ia1) or formula (Ih1) may be heated and reacted with a metal cyanide compound such as copper (I) cyanide, zinc cyanide or potassium cyanide, either with or without a solvent and in the presence or in the absence of a catalyst, to obtain a pyrazolo[1,5-a]pyridine derivative represented by formula (Ia2) or formula (Ih2) The reaction temperature will normally be from 40°C to 250°C. The solvent, if used, will differ depending on the starting material, reagent, etc. and is not particularly restricted so long as it does not inhibit the reaction and dissolves the starting material to some extent, but preferably there may be mentioned N,N-dimethylformamide, 1-methyl-2-pyrrolidinone, 1,3-dimethyl-2-imidazolidinone, tetrahydrofuran, 1,4-dioxane, pyridine, quinoline, and the like, which may be used alone or as mixed solvents. The catalyst, if used, will differ depending on the starting material, solvent, etc. and is not particularly restricted so long as it does not inhibit the reaction, but preferably there may be mentioned crown ethers such as 18-crown-6.</li><li>[2] A pyrazolo[1,5-a]pyridine derivative represented by formula (Ia1) or formula (Ih1) may be reacted with an organic boric acid derivative, an organic tin derivative or a metal cyanide compound such as copper (I) cyanide, zinc cyanide or potassium cyanide, in the presence of a palladium or nickel complex, either with or without a solvent and in the presence or in the absence of a base, to obtain a pyrazolo[1,5-a]pyridine derivative represented by formula (Ia2) or formula (Ih2). The reaction temperature will normally be from 0°C to 150°C. The solvent, if used, will differ depending on the starting material, reagent, etc. and is not particularly restricted so long as it does not inhibit the reaction and dissolves the starting material to some extent, but preferably there may be mentioned N,N-dimethylformamide, 1-methyl-2-pyrrolidinone, 1,3-dimethyl-2-imidazolidinone, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene, xylene, ethanol, water, and the like, which may be used alone or as mixed solvents. As examples of palladium or nickel complexes to be used there may be mentioned Pd(PPh3)4, Pd(OAc)2/PPh3, Pd2(dba)3, PdCl2, PdCl2(dppf), Ni(dpp)2Cl2, and the like. The base, if used, will differ depending on the starting material, solvent, etc. and is not particularly restricted so long as it does not inhibit the reaction, but preferably there may be mentioned potassium carbonate, sodium carbonate, cesium fluoride, potassium fluoride, sodium hydrogencarbonate, barium hydroxide, triethylamine, and the like.</li></ol><chemistry id="chem0038" num="0038"><img file="EP1389618B1_D0038.tif" /></chemistry>Step A: A step of removing Rx1 from a compound represented by formula (Ia3) having YRx1, wherein Rx1 is considered to be a protecting group, under conditions for its deprotection. For example, when YRx1 is a C1-6 alkoxy group, it may be reacted with a deprotecting reagent such as boron tribromide, either with or without a solvent, to obtain a compound represented by formula (Ia4). The reaction may be conducted either in the presence or in the absence of a deprotecting agent. The deprotecting agent, if used, will differ depending on the starting material, reagent, etc., and preferably there may be mentioned boron tribromide, iodotrimethylsilane, boron trifluoride diethyl etherate, hydrochloric acid, and the like. The solvent used will differ depending on the starting material, reagent, etc. and is not particularly restricted so long as it does not inhibit the reaction and dissolves the starting material to some extent, but preferably there may be mentioned chloroform, dichloromethane, acetonitrile, ethyl acetate, methanol, ethanol, water, and the like, which may be used alone or as mixed solvents.

0078This step also includes deprotection of Rx1 considered as a protecting group when Y is NRy or S(O)n. Step B: For example, a compound represented by formula (Ia4) having a phenolic hydroxyl group may be reacted with an alkylating agent (for example, an optionally substituted alkyl halide), either in the presence or in the absence of a base, and with or without a solvent, to obtain a compound represented by formula (Ia5) having Ry introduced therein. The reaction is conducted either with or without a solvent, and in the presence or in the absence of a base. The solvent, if used, will differ depending on the starting material, reagent, etc. and is not particularly restricted so long as it does not inhibit the reaction and dissolves the starting material to some extent, but preferably there may be mentioned tetrahydrofuran, diethyl ether, N,N-dimethylformamide, dimethylsulfoxide, acetone, ethanol, methanol, water, and the like. The base, if used, will differ depending on the starting material, solvent, etc. and is not particularly restricted so long as it does not inhibit the reaction, but preferably there may be mentioned sodium hydride, potassium hydride, potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide, sodium hydroxide, and the like. The reaction temperature will normally be from -70°C to 200°C.

0079As an alternative method, an optionally substituted alcohol derivative may be used for Mitsunobu reaction in the presence of a diazo compound such as diethyl azodicarboxylate and an organic phosphorus compound such as triphenylphosphine, with or without a solvent, at a reaction temperature of from - 70°C to 100°C, to obtain a compound represented by formula (Ia5) having Ry introduced therein. The solvent, if used, will differ depending on the starting material, reagent, etc. and is not particularly restricted so long as it does not inhibit the reaction and dissolves the starting material to some extent, but preferably there may be mentioned tetrahydrofuran, diethyl ether, and the like.

0080The step may also include introduction of substituents by suitable substituent-introduction methods when Y is NRy or S(O)n. <chemistry id="chem0039" num="0039"><img file="EP1389618B1_D0039.tif" /></chemistry>Step A: Compound (Io) having a hydroxyl group protected with a benzoate group or the like, on substituent R60 on N atom at the 3-position may be subjected to deprotecting reaction to obtain Compound (1o1) having a hydroxyl group on the substituent R60 on N atom at the 3-position. The reaction may be conducted either in the presence or in the absence of a deprotecting agent. The deprotecting agent, if used, will differ depending on the starting material, solvent, etc. and is not particularly restricted so long as it does not inhibit the reaction, but preferably there may be mentioned sodium hydroxide, potassium hydroxide, sodium hydrogencarbonate, potassium carbonate, sodium carbonate, and the like. The reaction may also be conducted without or with a solvent, in which case the solvent is not particularly restricted so long as it does not inhibit the reaction and dissolves the starting material to some extent, but preferably there may be mentioned methanol, ethanol, n-butanol, water, and the like. The reaction temperature will normally be from 0°C to 200°C. When a group other than a benzoate group (for example, methoxymethyl, benzyl, acetyl, etc.) is used as the protecting group, deprotection is carried out by reaction using a reagent suited for that protecting group. <chemistry id="chem0040" num="0040"><img file="EP1389618B1_D0040.tif" /></chemistry>Step A: Compound (12) or (15) may be reacted with a boric acid ester derivative such as triethoxyborane or a halogenated organic tin compound such as trimethyltin chloride, either with or without a solvent, after using an organic lithium reagent such as n-butyllithium to convert the halogen atom to an anion, to obtain an organic boric acid derivative or organic tin derivative represented by formula (27) or (28). The reaction temperature will normally be from -100°C to room temperature. The solvent used will differ depending on the starting material, reagent, etc. and is not particularly restricted so long as it does not inhibit the reaction and dissolves the starting material to some extent, but preferably there may be mentioned tetrahydrofuran, diethyl ether, n-hexane, n-pentane, and mixtures thereof. The organic lithium reagent used will differ depending on the starting material or solvent, but preferably there may be mentioned n-butyllithium, sec-butyllithium, tert-butyllithium, and the like. The boric acid ester used will also differ depending on the starting material, solvent, etc., but preferably there may be mentioned trimethoxyborane, triethoxyborane, triisopropyloxyborane, and the like. The organic tin compound used will likewise differ depending on the starting material, solvent, etc., but preferably there may be mentioned trimethyltin chloride, tributyltin chloride, tributyltin bromide, and the like. Instead of using an organic lithium reagent, the organic boric acid derivative or organic tin derivative represented by formula (27) or (28) may be obtained by the reaction of a Grignard reagent, which is converted from the halide by using metallic magnesium, and a boric acid ester, diborane compound or a halogenated organic tin reagent, either with or without a solvent.

0081As an alternative method, Compound (12) or (15) may be subjected to coupling reaction with a diborane such as bis(pinacolato)diborane or an organic tin compound such as hexamethylditin (IV), in the presence of a Pd catalyst such as tetrakis(triphenylphosphine)palladium (0) complex, in the presence or in the absence of a base and with or without a solvent, to obtain an organic boric acid derivative or organic tin derivative represented by formula (27) or (28). The reaction temperature will normally be from 0°C to 200°C. The solvent used will differ depending on the starting material, reagent, etc. and is not particularly restricted so long as it does not inhibit the reaction and dissolves the starting material to some extent, but preferably there may be mentioned dioxane, toluene, 1,2-dimethoxyethane, and mixtures thereof. Step B: Compound (27) or (28) may be subjected to coupling reaction in the same manner as Step B of Production Scheme 2 above, to obtain Compound (9) or (I). <chemistry id="chem0041" num="0041"><img file="EP1389618B1_D0041.tif" /></chemistry>Step A: A pyrazolo[1,5-a]pyridine derivative (I') may be reacted with an aryl halide (for example, bromobenzene) or a heteroaryl halide (for example, 2-bromopyridine), in the presence or in the absence of an organic phosphorus compound such as tri-t-butylphosphine, and in the presence of a Pd catalyst such as Pd2(dba)3, to obtain a pyrazolo[1,5-a]pyridine derivative (I) wherein R6 is an aryl or heteroaryl group. The reaction temperature will normally be from 0°C to 250°C. The reaction may be conducted in the presence or in the absence of a base, and with or without a solvent. The solvent, if used, will differ depending on the starting material, reagent, etc. and is not particularly restricted so long as it does not inhibit the reaction and dissolves the starting material to some extent, but preferably there may be mentioned toluene, xylene, mesitylene, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, 1,4-dioxane, water, and the like, which may be used alone or as mixed solvents. The base, if used, will differ depending on the starting material, solvent, etc. and is not particularly restricted so long as it does not inhibit the reaction, but preferably there may be mentioned sodium t-butoxide, potassium t-butoxide, sodium carbonate, potassium carbonate, barium carbonate, cesium carbonate, and the like. As organic phosphorus compounds to be used there may be mentioned tri-t-butylphosphine, 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, di-t-butyl-o-biphenylphosphine, and the like. As Pd catalysts to be used there may be mentioned dichlorobis(tri-o-tolylphosphine)palladium complex, tetrakis(triphenylphosphine)palladium complex, Pd2(dba)3, Pd2(dba)3CHCl3, Pd(OAc)2, PdCl2(PPh3)2, and the like.

0082Representative production schemes for compound (I) according to the present invention have been described above, but the starting compounds and reagents used for production of the compounds of the invention may also form salts or hydrates which will differ depending on the starting materials and solvent used, and these are not particularly restricted so long as the reaction is not inhibited. The solvents used will also differ depending on the starting materials and reagents, and they are not particularly restricted so long as they do not inhibit the reaction and dissolve the starting materials to some extent. When compound (I) of the present invention is obtained as a free compound, a common method may be used to convert it to a salt which compound (I) can form. The different isomers (for example, geometric isomers, and optical isomers, rotational isomers, stereoisomers and tautomers based on asymmetric carbons) obtained for compound (I) according to the invention may be purified and isolated using common separation means such as recrystallization, diastereomer salt methods, enzymatic separation methods and chromatography methods (for example, thin-layer chromatography, column chromatography, gas chromatography, etc.).

0083The compounds of the present invention represented by the formula (I) and their salts exhibit excellent antagonism against CRF receptors and particularly CRF1 receptor, as well as low toxicity and high safety, and are therefore highly useful as drugs. The compounds of the invention and their salts may therefore be used to obtain Corticotropin-Releasing Factor (CRF) receptor antagonists and Corticotropin-Releasing Factor (CRF)-1 receptor or Corticotropin-Releasing Factor (CRF)-1 receptor antagonists.

0084The compounds of the present invention and their salts may be used to obtain pharmaceutical compositions (formulations) as (i) therapeutic or prophylactic agents for diseases associated with Corticotropin-Releasing Factor (CRF), (ii) therapeutic or prophylactic agents for depression, depressive symptom, mania, anxiety, generalized anxiety disorder, panic disorder, phobias, obsessive-compulsive disorder, posttraumatic stress disorder, Tourrete's syndrome, autism, affective disorder, dysthymia, bipolar disorder, cyclothymic personality and schizophrenia, (iii) therapeutic or prophylactic agents for depressive symptoms such as major depression, single-episode depression, recurrent depression, depression-induced child abuse or postpartum depression, (iv) therapeutic or prophylactic agents for peptic ulcer, irritable bowel syndrome, ulcerative colitis, Crohn's disease, diarrhea, constipation, postoperative ileus, stress-associated gastrointestinal disorders and nervous vomiting, and (v) therapeutic or prophylactic agents for Alzheimer's disease, senile dementia of Alzheimer's type, neurodegenerative disease, multi-infarct dementia, senile dementia, anorexia nervosa, eating disorder, obesity, diabetes, alcohol dependence, pharmacophilia, drug withdrawal symptoms, alcohol withdrawal symptoms, sleep diorder, insomnia, migraine, stress-induced headache, muscle contraction induced headache, ischemic neuronal damage, excitotoxic neuronal damage, stroke, progressive supranuclear palsy, amyotrophic lateral sclerosis, multiple sclerosis, muscular spasm, chronic fatigue syndrome, psychosocial dwarfism, epilepsy, head trauma, spinal cord injury, cheirospasm, spasmodic torticollis, cervicobrachial syndrome, primary glaucoma, Meniere's syndrome, autonomic imbalance, alopecia, neurosis, hypertension, cardiovascular disorder, tachycardia, congestive heart failure, hyperventilation syndrome, bronchial asthma, apneusis, sudden infant death syndrome, inflammatory disorder, pain, allergosis, impotence, menopausal disorder, fertilization disorder, infertility, cancer, HIV infection-related immune dysfunction, stress-induced immune dysfunction, hemorrhagic stress, Cushing's syndrome, thyroid function disorder, encephalomyelitis, acromegaly, incontinence and osteoporosis.

0085Treatment or prevention of a disease associated with Corticotropin-Releasing Factor (CRF) receptors is also possible by single or multiple administration of a therapeutically effective dose of a compound of the invention or salt thereof to a patient with the disease associated with CRF receptors.

0086Compounds represented by formula (I) according to the present invention and salts thereof or hydrates of the foregoing may be used directly or in admixture with publicly known pharmaceutically acceptable carriers, and formulated by common methods. As preferred dosage forms there may be mentioned tablets, powders, fine particles, granules, coated tablets, capsules, syrups, lozenges, inhalants, suppositories, injections, ointments, eye salves, eye drops, nasal drops, ear drops, paps, lotions and the like. For the formulation there may be employed any commonly used excipients, binders, disintegrators, lubricants, coloring agents, corrective coatings, and if necessary, stabilizers, emulsifiers, absorbefacients, surfactants, pH adjustors, preservatives, antioxidants, or the like, in combination with various components that are ordinarily used as starting materials for pharmaceutical formulations.

0087As such components there may be mentioned animal and vegetable oils such as soybean oil, beef tallow and synthetic glycerides; hydrocarbons such as liquid paraffin, squalane and solid paraffin; ester oils such as octyldodecyl myristate and isopropyl myristate; higher alcohols such as cetostearyl alcohol and behenyl alcohol; silicone resins; silicone oils; surfactants such as polyoxyethylene fatty acid esters, sorbitan fatty acid esters, glycerin fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene hydrogenated castor oil and polyoxyethylene-polyoxypropylene block copolymer; water-soluble polymers such as hydroxyethylcellulose, polyacrylic acid, carboxyvinyl polymer, polyethylene glycol, polyvinylpyrrolidone and methylcellulose; lower alcohols such as ethanol and isopropanol; polyhydric alcohols such as glycerin, propylene glycol, dipropylene glycol and sorbitol; sugars such as glucose and sucrose; inorganic powders such as silicic anhydride, magnesium aluminum silicate and aluminum silicate; purified water, and the like. Examples of excipients which may be used include lactose, corn starch, white soft sugar, glucose, mannitol, sorbit, crystalline cellulose and silicon dioxide; examples of binders which may be used include polyvinyl alcohol, polyvinyl ether, methylcellulose, ethylcellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropylcellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone, polypropylene glycol/polyoxyethylene block polymer and meglumine, calcium citrate, dextrin pectin and carboxymethylcellulose calcium; examples of disintegrators which may be used include starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium hydrogencarbonate, calcium citrate, dextrin, pectin and carboxymethylcellulose calcium; examples of lubricants which may be used include magnesium stearate, talc, polyethylene glycol, silica and hydrogenated vegetable oils; examples of coloring agents which may be used include any of those approved for addition to drugs; examples of corrective coatings which may be used include cocoa powder, menthol, aromatic powders, mentha oil, borneol and powdered cinnamon; and examples of antioxidants which may be used include those approved for addition to drugs, such as ascorbic acid and alpha-tocopherol.

0088An oral formulation may be prepared by combining a compound of the present invention or salt thereof with an excipient, if necessary adding a binder, disintegrator, lubricant, coloring agent, corrective coating or the like, and forming a powder, fine particles, granules, tablets, coated tablets, capsules, etc. by a common method.

0089The tablets or granules may, of course, also be coated with a sugar coating, gelatin coating or other type of suitable coating if necessary.

0090In the case of a liquid formulation such as syrup, injection, eye drops or the like, a common method may be used for formulation with a pH adjustor, solubilizer, isotonizing agent or the like, as well as a solubilizing aid, stabilizer, buffering agent, suspending agent, antioxidant, etc. if necessary. In the case of a liquid formulation, it may also be lyophilized, and an injection may be administered intravenously, subcutaneously or intramuscularly. As preferred examples of suspending agents there may be mentioned methyl cellulose, polysorbate 80, hydroxyethyl cellulose, gum arabic, tragacanth powder, sodium carboxymethylcellulose, polyoxyethylene sorbitan monolaurate and the like; as preferred examples of solubilizing aids there may be mentioned polyoxyethylene hydrogenated castor oil, polysorbate 80, nicotinamide, polyoxyethylene sorbitan monolaurate and the like; as preferred examples of stabilizing agents there may be mentioned sodium sulfite, sodium metasulfite, ether and the like; and as preferred examples of preservatives there may be mentioned methyl paraoxybenzoate, ethyl paraoxybenzoate, sorbic acid, phenol, cresol, chlorocresol, and the like.

0091There are no particular restrictions on the method of preparing an external agent, and any common method may be employed. The base materials used may be any raw materials commonly employed in drugs, quasi drugs, cosmetics and the like, and as examples there may be mentioned raw materials such as animal and vegetable oils, mineral oils, ester oils, waxes, higher alcohols, fatty acids, silicone oils, surfactants, phospholipids, alcohols, polyhydric alcohols, water-soluble polymers, clay minerals, purified water and the like, with addition of pH adjustors, antioxidants, chelating agents, antiseptics and fungicides, coloring agents, aromas and the like if necessary. Also, if necessary, there may also be included differentiation-inducing components, or other components such as circulation promoters, microbicides, antiphlogistic agents, cell activators, vitamins, amino acids, humectants, keratolytic agents and the like.

0092Drug formulations comprising the compounds of the present invention and salts thereof or hydrates of the foregoing as effective ingredients are useful for disease treatment or prevention in mammals (for example, humans, mice, rats, guinea pigs, rabbits, dogs, horses, monkeys, etc.), and especially for disease treatment or prevention in humans.

0093Although the dosage of a drug according to the present invention will differ depending on the patient's severity of symptoms, age, gender, body weight, the dosage form, type of salt, drug sensitivity and specific type of disease, etc., it will generally be from about 30 µg to 10 g, preferably from 100 µg to 500 mg, more preferably from 100 µg to 100 mg per day for adult humans in the case of oral administration or about 1-3000 µg/kg and preferably about 3-1000 µg/kg in the case of injection, administered once or divided over several times a day.

[EXAMPLES]

0094The following production examples, examples and test examples serve only for the purpose of illustration and are not intended to be restrictive on the compounds of the invention in any way. It will be apparent to those skilled in the art that various modifications may be added beyond these examples and within the scope of the claims of the invention in the present specification in order to maximize the effect of the invention, and such modifications are also encompassed within the claims.

Production Example 1

2-(1-Butynyl)pyridine

0095After dissolving 2-bromopyridine (50 g) in diethylamine (500 mL) and adding dichlorobis(triphenylphosphine)palladium (II) (2.2 g) and copper iodide (0.3 g), the mixture was stirred at room temperature for 4 hours while introducing 1-butyne (100 g) as a gas. After bubbling in nitrogen, extraction was performed with ethyl acetate. The insoluble portion was filtered out with celite, and then the organic layer was washed with water and brine. After drying over anhydrous magnesium sulfate and filtration, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and the title compound (35 g) was obtained from the n-hexane:ethyl acetate (5:1) fraction as a brown oil.

00961H NMR (400MHz, CDCl3) δ 1.26 (t, J = 7.6 Hz, 3H), 2.45 (q, J = 7.6 Hz, 2H), 7.16-7.20 (m, 1H), 7.35-7.38 (m, 1H), 7.59-7.63 (m, 1H), 8.53-8.54 (m, 1H).

Production Example 2

2-Ethylpyrazolo[1,5-a]pyridine

0097After dissolving 2-(1-butynyl)pyridine (12.8 g) in dichloromethane (60 mL), a solution of O-mesitylenesulfonylhydroxyamine (Reference document: Synthesis, 1997, 1) (20 g) in dichloromethane (132 mL) was added dropwise while cooling on ice, and the mixture was stirred for 30 minutes. Diethyl ether (2 L) was added to the reaction mixture to precipitate crystals, which were collected by filtration and dried under reduced pressure to obtain N-amino-2-(1-butynyl)pyridinium mesitylenesulfonate (12.6 g) as colorless crystals.

0098A 6.1 g portion of the obtained N-amino-2-(1-butynyl)pyridinium mesitylenesulfonate was dissolved in tetrahydrofuran (600 mL), potassium tert-butoxide (3.55 g) was added at room temperature, and the mixture was vigorously stirred for 30 minutes. After adding ice water to the reaction mixture, extraction was performed with ethyl acetate. The aqueous layer was again extracted with ethyl acetate, the insoluble portion was filtered with a celite filter, and the organic layers were combined and washed with brine. After drying over anhydrous magnesium sulfate and filtration, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and the title compound (0.63 g) was obtained from the n-hexane:ethyl acetate (10:1) fraction as a light yellow oil.

00991H NMR (400MHz, CDCl3) δ 1.36 (t, J = 7.6 Hz, 3H), 2.86 (q, J = 7.6 Hz, 2H), 6,30 (s, 1H), 6.65 (ddd, J = 1.6, 6.8, 6.8 Hz, 1H), 7.04 (ddd, J = 1.2, 6.8, 8.8 Hz, 1H), 7.41 (ddd, J = 1.2, 1.2, 8.8 Hz, 1H), 8.37 (ddd, J = 1.2, 1.2, 6.8 Hz, 1H).

Production Example 3

7-Bromo-2-ethylpyrazolo[1,5-a]pyridine

0100After dissolving 2-ethylpyrazolo[1,5-a]pyridine (80 mg) in tetrahydrofuran (1 mL), an n-butyllithiumhexane solution (1.6 M; 0.58 mL) was added dropwise at -78°C under a nitrogen stream, and the mixture was stirred for 30 minutes. A solution of 1,2-dibromo-1,1,2,2-tetrachloroethane (196 mg) in tetrahydrofuran (0.5 mL) was added to the reaction mixture, and stirring was continued for 30 minutes. The temperature was increased to room temperature, water was added, extraction was performed with ethyl acetate and the organic layer was washed with water and brine. After drying over anhydrous magnesium sulfate and filtration, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography and the title compound (90 mg) was obtained from the n-hexane:ethyl acetate (20:1) fraction as a light brown oil.

01011H NMR (400MHz, CDCl3) δ 1.36 (t, J = 7.6 Hz, 3H), 2.93 (q, J = 7.6 Hz, 2H), 6,49 (s, 1H), 6.94 (dd, J = 7.2, 8.4 Hz, 1H), 6.99 (dd, J = 1.6, 7.2 Hz, 1H), 7.44 (dd, J = 1.6, 8.4 Hz, 1H).

Production Example 4

7-(2,4-Dichlorophenyl)-2-ethylpyrazolo[1,5-a]pyridine

0102After dissolving 7-bromo-2-ethylpyrazolo[1,5-a]pyridine (300 mg) in ethanol (2 mL) and toluene (4 mL), 2,4-dichlorophenylboric acid (508 mg), tetrakis(triphenylphosphine)palladium (0) complex (154 mg) and 2M aqueous sodium carbonate (1.33 mL) were added and the mixture was heated and stirred at 80°C for 3 hours under a nitrogen stream. Water was added to the reaction mixture, extraction was performed with ethyl acetate and the organic layer was washed with brine. After drying over anhydrous magnesium sulfate and filtration, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and the title compound (380 mg) was obtained from the n-hexane:ethyl acetate (100:1) fraction as a light yellow oil.

01031H NMR (400MHz, CDCl3) δ 1.30 (t, J = 7.6 Hz, 3H), 2.82 (q, J = 7.6 Hz, 2H), 6,42 (s, 1H), 6.64 (dd, J = 1.6, 6.8 Hz, 1H), 7.12 (dd, J = 6.8, 8.8 Hz, 1H), 7.38 (dd, J = 2.0, 8.4 Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H), 7.51 (dd, J = 1.6, 8.8 Hz, 1H), 7.55 (d, J = 2.0 Hz, 1H).

Production Example 5

7-(2,4-Dichlorophenyl)-2-ethyl-3-nitropyrazolo[1,5-a]pyridine

0104After dissolving 7-(2,4-dichlorophenyl)-2-ethylpyrazolo[1,5-a]pyridine (280 mg) in acetonitrile (20 mL), nitronium tetrafluoroborate (255 mg) was added 4 times at 30 minute intervals while stirring on ice. The reaction mixture was added to ice water, extraction was performed with ethyl acetate and the extract was washed with water and brine. After drying over anhydrous magnesium sulfate and filtration, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and the title compound (115 mg) was obtained from the n-hexane:ethyl acetate (20:1) fraction as yellow crystals.

01051H NMR (400MHz, CDCl3) δ 1.30 (t, J = 7.6 Hz, 3H), 3.15 (q, J = 7.6 Hz, 2H), 7.07 (dd, J = 1.6, 7.2 Hz, 1H), 7.43 (d, J = 1.2 Hz, 1H), 7.60 (t, J = 1.2 Hz, 1H), 7.70 (dd, J = 7.2, 8.8 Hz, 1H), 8.44 (dd, J = 1. 6, 8.8 Hz, 1H).

Production Example 6

7-Bromo-2-ethyl-3-nitropyrazolo[1,5-a]pyridine

0106After dissolving 7-bromo-2-ethylpyrazolo[1,5-a]pyridine (1.1 g) in acetonitrile (20 mL), nitronium tetrafluoroborate (1.3 g) was added while stirring on ice, and stirring was continued for 30 minutes. The reaction mixture was added to ice water, extraction was performed with ethyl acetate and the extract was washed with water and brine. After drying over anhydrous magnesium sulfate and filtration, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and the title compound (670 mg) was obtained from the n-hexane:ethyl acetate (10:1) fraction as yellow crystals.

01071H NMR (400MHz, CDCl3) δ 1.42 (t, J = 7.6 Hz, 3H), 3.27 (q, J = 7.6 Hz, 2H), 7.39 (dd, J = 1.2, 7.6 Hz, 1H), 7.50 (dd, J = 7.6, 8.8 Hz, 1H), 8.38 (dd, J = 1.2, 8.8 Hz, 1H).

Production Example 7

7-(2-Chloro-4-methoxyphenyl)-2-ethyl-3-nitropyrazolo[1,5-a]pyridine

0108After dissolving 7-bromo-2-ethyl-3-nitropyrazolo[1,5-a]pyridine (100 mg) in 1,2-dimethoxyethane (6 mL) and water (1 mL), 2-chloro-4-methoxyphenylboric acid (138 mg), tetrakis(triphenylphosphine)palladium (0) complex (86 mg) and barium hydroxide octahydrate (233 mg) were added and the mixture was heated and stirred at 80°C for 3 hours under a nitrogen stream. Water was added to the reaction mixture, extraction was performed with ethyl acetate and the extract was washed with saturated aqueous sodium hydrogencarbonate and brine, in that order. After drying over anhydrous magnesium sulfate and filtration, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and the title compound (90 mg) was obtained from the n-hexane:ethyl acetate (30:1) fraction as yellow crystals.

01091H NMR (400MHz, CDCl3) δ 1.30 (t, J = 7.6 Hz, 3H), 3.15 (q, J = 7.6 Hz, 2H), 3.90 (s, 3H), 6.96 (dd, J = 2.4, 8.4 Hz, 1H), 7.07 (dd, J = 1.6, 7.2 Hz, 1H), 7.10 (d, J = 2.4 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.68 (dd, J = 7.2, 8.8 Hz, 1H), 8.40 (dd, J = 1.6, 8.8 Hz, 1H).

Production Example 8

2-Ethyl-4-methoxypyrazolo[1,5-a]pyridine

0110After adding dichlorobis(triphenylphosphine)palladium (II) (671 mg) and copper iodide (91 mg) to a solution of 2-bromo-3-methoxypyridine (18.0 g) in diethylamine (250 mL), 1-butyne (15.5 g) was bubbled through at room temperature, and the mixture was stirred for 20 hours. Upon completion of the reaction, the solvent was distilled off under reduced pressure. Water was added to the obtained residue, extraction was performed with ethyl acetate, the extract was washed with brine and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (500 g), and 2-(1-butynyl)-4-methoxypyridine (10.0 g) was obtained from the n-hexane:ethyl acetate (2:1) fraction as a brown oil.

0111To a solution of the obtained 2-(1-butynyl)-4-methoxypyridine (10.0 g) in dichloromethane (100 mL) there was added dropwise a solution of O-mesitylenesulfonylhydroxyamine (16.0 g) in dichloromethane (100 mL) at 0°C, and the mixture was stirred for 1 hour. Diethyl ether (250 mL) was added to the reaction mixture, and the precipitated solid was suction filtered and dried to obtain N-amino-2-(1-butynyl)-4-methoxypyridinium mesitylenesulfonate as a white salt (20.7 g).

0112Potassium tert-butoxide (11.1 g) was added to a solution of N-amino-2-(1-butynyl)-4-methoxypyridinium mesitylenesulfonate (20.7 g) in tetrahydrofuran (300 mL) and N,N-dimethylformamide (15 mL), and the mixture was stirred at room temperature for 1 hour. Water was added while cooling on ice, extraction was performed with ethyl acetate, the extract was washed with brine and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (200 g), and the title compound (6.44 g) was obtained from the n-hexane:ethyl acetate (3:1) fraction as a yellow oil.

01131H NMR (400MHz, CDCl3) δ 1.35 (t, J = 7.6 Hz, 3H), 2.84 (q, J = 7.6 Hz, 2H), 3.93 (s, 3H), 6.32 (d, J = 7.7 Hz, 1H), 6.42 (s, 1H), 6.57 (t, J = 7.5 Hz, 1H), 8.03 (dd, J = 0.7, 7.0 Hz, 1H).

Production Example 9

7-Bromo-2-ethyl-4-methoxypyrazolo[1,5-a]pyridine

0114n-Butyllithium (1.31 mL) was slowly added dropwise to a solution of 2-ethyl-4-methoxypyrazolo[1,5-a]pyridine (303 mg) in tetrahydrofuran (15 mL) at -78°C. After stirring the mixture at -78°C for 1 hour, 1,2-dibromoethane (0.18 mL) was added and stirring was continued for 1 hour. Saturated aqueous ammonium chloride was added, extraction was performed with ethyl acetate, the extract was washed with brine and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (20 g), and the title compound (282 mg) was obtained from the n-hexane:ethyl acetate (5:1) fraction as a colorless oil.

01151H NMR (400MHz, CDCl3) δ 1.35 (t, J = 7.7 Hz, 3H), 2.91 (q, J = 7.7 Hz, 2H), 3.93 (s, 3H), 6.28 (d, J = 8.1 Hz, 1H), 6.61 (s, 1H), 6.85 (d, J = 8.1 Hz, 1H).

Production Example 10

7-Bromo-2-ethyl-4-methoxy-3-nitropyrazolo[1,5-a]pyridine

0116After adding nitronium tetrafluoroborate (176 mg) to a solution of 7-bromo-2-ethyl-4-methoxypyrazolo[1,5-a]pyridine (282 mg) in acetonitrile (20 mL) at 0°C, the mixture was stirred for 20 minutes. Upon completion of the reaction, water was added, extraction was performed with ethyl acetate, the extract was washed with saturated aqueous sodium hydrogencarbonate and brine and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (20 g), and the title compound (159 mg) was obtained from the n-hexane:ethyl acetate (3:1) fraction as yellow crystals.

01171H NMR (400MHz, CDCl3) δ 1.39 (t, J = 7.5 Hz, 3H), 3.13 (q, J = 7.5 Hz, 2H), 3.99 (s, 3H), 6.72 (d, J = 8.4 Hz, 1H), 7.19 (d, J = 8.3 Hz, 1H).

Production Example 11

2-Ethyl-4-methoxy-7-(2-methoxy-4,6-dimethylphenyl)-3-nitropyrazolo[1,5-a]pyridine

0118After adding 4,6-dimethyl-2-methoxyphenylboric acid (191 mg), barium hydroxide octahydrate (334 mg) and tetrakis(triphenylphosphine)palladium (0) complex (123 mg) to a solution of 7-bromo-2-ethyl-4-methoxy-3-nitropyrazolo[1,5-a]pyridine (159 mg) in a mixture of ethyleneglycol diethyl ether (15 mL) and water (7.5 mL), the mixture was heated at 80°C for 30 minutes. Water was added, extraction was performed with ethyl acetate, the extract was washed with saturated aqueous sodium hydrogencarbonate and brine and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (20 g), and the title compound (185 mg) was obtained from the n-hexane:ethyl acetate (5:1) fraction as yellow crystals.

01191H NMR (400MHz, CDCl3) δ 1.24 (t, J = 7.5 Hz, 3H), 1.98 (s, 3H), 2.40 (s, 3H), 2.99 (q, J = 7.5 Hz, 2H), 3.66 (s, 3H), 4.03 (s, 3H), 6.68 (s, 1H), 6.78 (s, 1H), 6.81 (d, J = 8.1 Hz, 1H), 6.90 (d, J = 8.1 Hz, 1H).

Production Example 12

tert-Butyl N-[2-methylthiopyrazolo[1,5-a]pyridin-3-yl]carbamate

01202-Methylthio-3-nitropyrazolo[1,5-a]pyridine (Reference document: <nplcit id="ncit0076" npl-type="s"><text>Heterocycles, 1977, 6, 379</text></nplcit>) (400 mg) was suspended in ethanol (20 mL), and then water (10 mL), acetic acid (2 mL) and zinc powder (800 mg) were added and the mixture was heated and stirred at 80°C for 30 minutes. The reaction mixture was filtered, water was added to the filtrate, extraction was performed with ethyl acetate and the extract was washed with saturated aqueous sodium hydrogencarbonate and brine. After drying over anhydrous magnesium sulfate and filtration, the solvent was concentrated under reduced pressure to obtain 2-methylthiopyrazolo[1,5-a]pyridin-3-yl]amine as a crude product. This was then dissolved in dichloromethane (5 mL), triethylamine (0.4 mL) was added, di-tert-butyl dicarbonate (625 mg) was further added while cooling on ice, and the mixture was stirred overnight at room temperature. After adding water to the reaction mixture, extraction was performed twice with ethyl acetate and the organic layer was washed with water and brine. After drying over anhydrous magnesium sulfate and filtration, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and the title compound (230 mg) was obtained from the n-hexane:ethyl acetate (5:1) fraction as a yellow oil.

01211H NMR (400MHz, CDCl3) δ 1.53 (br s, 9H), 2.60 (s, 3H), 6.00-6.15 (m, 1H), 6.69 (t, J = 6.8 Hz, 1H), 7.11 (t, J = 8.0 Hz, 1H), 7.40-7.50 (m, 1H), 8.83 (d, J = 6.8 Hz, 1H).

Production Example 13

tert-Butyl N-[7-iodo-2-methylthiopyrazolo[1,5-a]pyridin-3-yl]carbamate

0122After dissolving tert-butyl N-[2-methylthiopyrazolo[1,5-a]pyridin-3-yl]carbamate (21.6 g) in tetrahydrofuran (1 L), a solution of n-butyllithium in hexane (1.6 M; 130 mL) was added dropwise at -78°C under a nitrogen stream, and the mixture was stirred for 30 minutes. A solution of 1,2-diiodoethane (24 g) in tetrahydrofuran (50 mL) was added to the reaction mixture, and stirring was continued for 1 hour. Saturated aqueous ammonium chloride was added to the reaction mixture, the temperature was raised to room temperature, extraction was performed with ethyl acetate and the extract was washed with water and brine. After drying over anhydrous magnesium sulfate and filtration, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and the title compound was obtained from the n-hexane:ethyl acetate (5:1) fraction as yellow crystals.

01231H NMR (400MHz, CDCl3) δ 1.52 (s, 9H), 2.64 (s, 3H), 6.02-6.10 (m, 1H), 6.81 (dd, J = 7.2, 8.8 Hz, 1H), 7.22 (dd, J = 1.2, 7.2 Hz, 1H), 7.42-7.50 (m, 1H).

Production Example 14

7-Bromo-2-methoxypyrazolo[1,5-a]pyridine

0124A solution of 2-methoxypyrazolo[1,5-a]pyridine (7.15 g) [CAS No.59942-88-0] in tetrahydrofuran (140 mL) was cooled to -78°C under a nitrogen stream, and then a solution of n-butyllithium in hexane (1.6 M; 46 mL) was added dropwise and the mixture was stirred for 30 minutes. A solution of 1,2-dibromo-1,1,2,2-tetrachloroethane (18.9 g) in tetrahydrofuran (30 mL) was added dropwise at -78°C, and stirring was continued for 1 hour. After increasing the temperature of the reaction mixture to room temperature and adding water, extraction was performed with ethyl acetate and the extract was washed with brine. After drying the obtained organic layer over anhydrous magnesium sulfate and filtering it, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and the title compound (7.1 g) was obtained from the n-hexane:ethyl acetate (50:1) fraction as a yellow oil.

01251H NMR (400MHz, CDCl3) δ 4.03 (s, 3H), 6.02 (s, 1H), 6.91-6.97 (m, 2H), 7.31 (dd, J = 2.4, 7.6 Hz, 1H).

Production Example 15

2-Methoxy-7-(2-methoxy-4,6-dimethylphenyl)-3-nitrosopyrazolo[1,5-a]pyridine

0126After dissolving 7-bromo-2-methoxypyrazolo[1,5-a]pyridine (400 mg) in acetic acid (4 mL), an aqueous solution (2 mL) containing sodium nitrite (134 mg) was added and the mixture was stirred at room temperature for 30 minutes. The precipitated crystals were collected by filtration and washed with water. After dissolving the obtained crude 7-bromo-2-methoxy-3-nitrosopyrazolo[1,5-a]pyridine, without further purification, in 1,2-dimethoxyethane (40 mL) and water (20 mL), 4,6-dimethyl-2-methoxyphenylboric acid (475 mg), tetrakis(triphenylphosphine)palladium (0) complex (203 mg) and barium hydroxide octahydrate (829 mg) were added and the mixture was heated and stirred at 80°C for 1 hour. Water was added to the reaction mixture, extraction was performed with ethyl acetate, the organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered, and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography, and the title compound (200 mg) was obtained from the n-hexane:ethyl acetate (5:1) fraction as a brown oil.

01271H NMR (400MHz, CDCl3) δ 2.05 (s, 3H), 2.43 (s, 3H), 3.70 (s, 3H), 4.20 (s, 3H), 6.70 (s, 1H), 6.79 (s, 1H), 6.08 (dd, J = 1.6, 7.2 Hz, 1H), 7.80 (dd, J = 7.2, 8.4 Hz, 1H), 8.30 (dd, J = 1.6, 8.4 Hz, 1H).

Production Example 16

7-Bromo-2-methoxypyrazolo[1,5-a]pyridine-3-amine

0128After dissolving 7-bromo-2-methoxypyrazolo[1,5-a]pyridine (1 g) in acetic acid (10 mL), an aqueous solution (5 mL) containing sodium nitrite (334 mg) was added and the mixture was stirred at room temperature for 20 minutes. After adding ethanol (60 mL) and water (30 mL) to the reaction mixture, zinc powder (1 g) was added and the mixture was heated and stirred at 60°C for 30 minutes. The insoluble residue was filtered out, water was added, and extraction was performed with ethyl acetate. After washing the organic layer with brine, drying it over anhydrous magnesium sulfate and filtering it, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and the title compound (750 mg) was obtained from the n-hexane:ethyl acetate (3:1) fraction as brown crystals.

01291H NMR (400MHz, CDCl3) δ 4.13 (s, 3H), 6.78 (dd, J = 1.6, 6.8 Hz, 1H), 6.81 (dd, J = 6.8, 8.4 Hz, 1H), 7.24 (dd, J = 1.6, 8.4 Hz, 1H).

Production Example 17

tert-Butyl N-(7-bromo-2-methoxypyrazolo[1,5-a]pyridin-3-yl)carbamate

0130After dissolving 7-bromo-2-methoxypyrazolo[1,5-a]pyridine-3-amine (810 mg) in dichloromethane (20 mL), triethylamine (0.7 mL) was added, di-tert-butyl dicarbonate (923 µL) was further added while cooling on ice, and the mixture was stirred overnight at room temperature. After adding water to the reaction mixture, extraction was performed with ethyl acetate and the organic layer was washed with brine. After drying over anhydrous magnesium sulfate and filtration, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and the title compound (1.05 g) was obtained from the n-hexane:ethyl acetate (10:1) fraction as yellow crystals.

01311H NMR (400MHz, CDCl3) δ 1.49 (s, 9H), 4.12 (s, 3H), 6.89 (dd, J = 1.2, 7.6 Hz, 1H), 6.94 (dd, J = 7.6, 8.8 Hz, 1H), 7.30-7.39 (m, 1H).

Production Example 18

3-[(tert-Butoxycarbonyl)amino]-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-7-ylboric acid

0132After dissolving tert-butyl N-(7-iodo-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl)carbamate (200 mg) in tetrahydrofuran (2 mL), the mixture was cooled to -78°C and n-butyllithium (1.6 M; 0.66 mL) was added dropwise. The mixture was stirred for 1 hour at the same temperature, triethoxyborane (109 µL) was added and the temperature was increased to room temperature. Saturated aqueous ammonium chloride was added to the obtained reaction mixture, and extraction was performed with ethyl acetate. The obtained organic layer was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (106 mg) as grayish white crystals.

01331H NMR (400MHz, CDCl3) δ 1.53 (br s, 9H), 2.59 (s, 3H), 6.05 (br s, 1H), 6.66 (ddd, J = 1.6, 1.6, 6.8 Hz, 1H), 7.04-7.12 (m, 1H), 7.44 (br s, 2H), 8.27 (ddd, J = 1.6, 1.6, 7.2 Hz, 1H).

Example 1

tert-Butyl

N-[7-(2,4-dichlorophenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]carbamate

0134After dissolving [7-(2,4-dichlorophenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]amine (60 mg) and triethylamine (0.041 mL) in dichloromethane, di-tert-butyl dicarbonate (71 mg) was added while cooling on ice, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, extraction was performed with ethyl acetate and the organic layer was washed with water and brine. After drying over anhydrous magnesium sulfate and filtration, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and the title compound (59 mg) was obtained from the n-hexane:ethyl acetate (10:1) fraction as a light yellow oil.

01351H NMR (400MHz, CDCl3) δ 1.26 (t, J = 7.6 Hz, 3H), 1.68 (s, 9H), 2.79 (q, J = 7.6 Hz, 2H), 6.70 (dd, J = 1.6, 6.8 Hz, 1H), 7.20 (dd, J = 6.8, 8.8 Hz, 1H), 7.39 (dd, J = 2.0, 8.4 Hz, 1H), 7.44-7.50 (m, 2H), 7.56 (d, J = 2.0 Hz, 1H).

Example 2

N-[7-(2,4-Dichlorophenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]-N,N-dipropylamine

01367-(2,4-Dichlorophenyl)-2-ethyl-3-nitropyrazolo[1,5-a]pyridine (110 mg) was suspended in ethanol (6 mL), and then water (3 mL), acetic acid (1 mL) and zinc powder (220 mg) were added and the mixture was heated and stirred at 60°C for 1 hour. The reaction mixture was filtered, water was added to the filtrate, extraction was performed with ethyl acetate and the extract was washed with saturated aqueous sodium hydrogencarbonate and brine. After drying over anhydrous magnesium sulfate and filtration; the solvent was concentrated under reduced pressure to obtain [7-(2,4-dichlorophenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]amine (90 mg) as crude crystals. These were dissolved in tetrahydrofuran (1 mL), and after adding propionaldehyde (0.059 mL) and 3 M aqueous sulfuric acid (0.294 mL), sodium borohydride (22.2 mg) was added in five portions while vigorously stirring on ice, and stirring was continued for 30 minutes. Water was added to the reaction mixture, extraction was performed with diethyl ether and the extract was washed with saturated sodium hydrogencarbonate and brine. After drying over anhydrous magnesium sulfate and filtration, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and the title compound (59 mg) was obtained from the n-hexane:ethyl acetate (100:1) fraction as a yellow oil.

01371H NMR (400MHz, CDCl3) δ 0.88 (t, J = 7.6 Hz, 6H), 1.23 (t, J = 7.6 Hz, 3H), 1.34-1.44 (m, 4H), 2.75 (q, J = 7.6 Hz, 2H), 3.02 (t, J = 7.2 Hz, 4H), 6.57 (dd, J = 1.2, 6.8 Hz, 1H), 7.01 (dd, J = 6.8, 8.8 Hz, 1H), 6.57 (dd, J = 2.0, 8.0 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.51 (dd, J = 1.2, 8.8 Hz, 1H), 7.54 (d, J = 2.0 Hz, 1H).

Example 3

N-[7-(2-Chloro-4-methoxyphenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]-N,N-dipropylamine

01387-(2-Chloro-4-methoxyphenyl)-2-ethyl-3-nitropyrazolo[1,5-a]pyridine (5 mg) was suspended in ethanol (2 mL), and then water (1 mL), acetic acid (0.5 mL) and zinc powder (10 mg) were added and the mixture was heated and stirred at 80°C for 30 minutes. The reaction mixture was filtered, water was added to the filtrate, extraction was performed with ethyl acetate and the extract was washed with saturated aqueous sodium hydrogencarbonate and brine. After drying over anhydrous magnesium sulfate and filtration, the solvent was concentrated under reduced pressure to obtain [7-(2-chloro-4-methoxyphenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]amine as crude crystals. These were dissolved in tetrahydrofuran (1 mL) without further purification, and after adding propionaldehyde (0.015 mL) and 3 M aqueous sulfuric acid (0.071 mL), sodium borohydride (5.4 mg) was added in five portions while vigorously stirring on ice, and stirring was continued for 30 minutes. Water was added to the reaction mixture, extraction was performed with diethyl ether and the extract was washed with saturated sodium hydrogencarbonate and brine. After drying over anhydrous magnesium sulfate and filtration, the solvent was concentrated under reduced pressure and the residue was purified by preparative TLC [n-hexane:ethyl acetate (5:1), Rf=0.5] to obtain the title compound (6 mg) as a light yellow oil.

01391H NMR (400MHz, CDCl3) δ 0.88 (t, J = 7.6 Hz, 6H), 1.23 (t, J = 7.6 Hz, 3H), 1.34-1.44 (m, 4H), 2.76 (q, J = 7.6 Hz, 2H), 3.02 (t, J = 7.6 Hz, 4H), 3.87 (s, 3H), 6.56 (dd, J = 1.6, 6.4 Hz, 1H), 6.92 (dd, J = 2.8, 8.6 Hz, 1H), 6.99 (dd, J = 6.4, 8.6 Hz, 1H), 7.06 (d, J = 2.8 Hz, 1H), 7.32 (d, J = 8.6 Hz, 1H), 7.45 (dd, J = 1.6, 8.6 Hz, 1H).

0140The compounds of Examples 4 to 22 were synthesized according to the production methods of Examples 1, 2 and 3.

Example 4

N-[2-Ethyl-7-(2-methoxy-4,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N,N-dipropylamine

(Light yellow crystals)

01411H NMR (400MHz, CDCl3) δ 0.87 (t, J = 7.6 Hz, 6H), 1.19 (t, J = 7.6 Hz, 3H), 1.34-1.44 (m, 4H), 1.98 (s, 3H), 2.39 (s, 3H), 2.74 (q, J = 7.6 Hz, 2H), 3.02 (t, J = 7.6 Hz, 4H), 3.68 (s, 3H), 6.49 (dd, J = 1.2, 6.8 Hz, 1H), 6.68 (s, 1H), 6.76 (s, 1H), 6.99 (dd, J = 6.8, 8.8 Hz, 1H), 6.99 (dd, J = 1.2, 8.8 Hz, 1H).

Example 5

N-[7-(2,6-Dimethoxy-4-methylphenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]-N,N-dipropylamine

(Light yellow oil)

01421H NMR (400MHz, CDCl3) δ 0.87 (t, J = 7.6 Hz, 6H), 1.21 (t, J = 7.6 Hz, 3H), 1.34-1.44 (m, 4H), 2.43 (s, 3H), 2.74 (q, J = 7.6 Hz, 2H), 3.01 (t, J = 7.6 Hz, 4H), 3.70 (s, 6H), 6.51 (s, 2H), 6.57 (dd, J = 1.2, 6.8 Hz, 1H), 6.99 (dd, J = 6.8, 8.8 Hz, 1H), 6.99 (dd, J = 1.2, 8.8 Hz, 1H).

Example 6

N-[7-(2,4-Dimethoxyphenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]-N,N-dipropylamine

(Light yellow oil)

01431H NMR (400MHz, CDCl3) δ 0.87 (t, J = 7.6 Hz, 6H), 1.24 (t, J = 7.6 Hz, 3H), 1.34-1.44 (m, 4H), 2.75 (q, J = 7.6 Hz, 2H), 3.01 (t, J = 7.6 Hz, 4H), 3.75 (s, 3H), 3.87 (s, 3H), 6.58-6.62 (m, 3H), 6.98 (dd, J = 6.8, 9.2 Hz, 1H), 7.42 (dd, J = 1.6, 8.8 Hz, 1H), 7.49 (d, J = 9.2 Hz, 1H).

Example 7

N-[2-Ethyl-7-(4-methoxy-2-methylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N,N-dipropylamine

(Light yellow oil)

01441H NMR (400MHz, CDCl3) δ 0.88 (t, J = 7.6 Hz, 6H), 1.23 (t, J = 7.6 Hz, 3H), 1.34-1.44 (m, 4H), 2.10 (s, 3H), 2.75 (q, J = 7.6 Hz, 2H), 3.01 (t, J = 7.6 Hz, 4H), 3.86 (s, 3H), 6.49 (dd, J = 1.6, 6.8 Hz, 1H), 6.82 (dd, J = 2.8, 8.4 Hz, 1H), 6.86 (d, J = 2.8 Hz, 1H), 6.99 (dd, J = 6.8, 8.8 Hz, 1H), 7.32 (d, J = 8.4 4 Hz, 1H), 7.45 (dd, J = 1.6, 8.8 Hz, 1H).

Example 8

N,N-Dicyclopropylmethyl-N-[2-ethyl-7-(2-methoxy-4,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]amine

(Colorless crystals)

01451H NMR (400MHz, CDCl3) δ -0.02-0.04 (m, 4H), 0.30-0.36 (m, 4H), 0.80-0.90 (m, 2H), 1.22 (t, J = 7.6 Hz, 4H), 1.97 (s, 3H), 2.39 (s, 3H), 2.72-2.84 (m, 2H), 2.99 (d, J = 6.4 Hz, 2H), 3.68 (s, 3H), 6.48 (dd, J = 1.2, 6.8 Hz, 1H), 6.69 (s, 1H), 6.77 (s, 1H), 6.99 (dd, J = 6.8, 8.8 Hz, 1H), 7.46 (dd, J = 1.2, 8.8 Hz, 1H).

Example 9

N,N-Dicyclopropylmethyl-N-[2-ethyl-7-(4-methoxy-2-methylphenyl)pyrazolo[1,5-a]pyridin-3-yl]amine

(Yellow oil)

01461H NMR (400MHz, CDCl3) δ -0.02-0.06 (m, 4H), 0.30-0.38 (m, 4H), 0.78-0.90 (m, 2H), 1.26 (t, J = 7.5 Hz, 3H), 2.08 (s, 3H), 2.81 (q, J = 7.5 Hz, 2H), 3.00 (d, J = 6.6 Hz, 4H), 3.86 (s, 3H), 6,49 (dd, J = 1.4, 6.7 Hz, 1H), 6.80-6.90 (m, 2H), 6.99 (dd, J = 6.8, 9.0 Hz, 1H), 7.34 (d, J = 8.2 Hz, 1H), 7.48 (dd, J = 1.4, 8.9 Hz, 1H).

0147MS(ESI) m/z 390 MH+

Example 10

N-[7-(4-Chloro-2-methoxyphenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]-N,N-dicyclopropylmethylamine

(Yellow oil)

01481H NMR (400MHz, CDCl3) δ -0.02-0.06 (m, 4H), 0.30-0.37 (m, 4H), 0.76-0.88 (m, 2H), 1.25 (t, J = 7.5 Hz, 3H), 2.79 (q, J = 7.5 Hz, 2H), 2.98 (d, J = 6.6 Hz, 4H), 3.75 (s, 3H), 6,57 (dd, J = 1.3, 6.8 Hz, 1H), 6.97 (dd, J = 6.8, 8.8 Hz, 1H), 7.01 (d, J = 2.0 Hz, 1H), 7.05 (dd, J = 2.0, 8.1 Hz, 1H), 7.46 (d, J = 1.6 Hz, 1H), 7.48 (d, J = 1.3 Hz, 1H).

0149MS(ESI) m/z 410 MH+

Example 11

N,N-Dicyclopropylmethyl-N-[2-ethyl-7-(4-methoxy-2,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]amine

(Yellow crystals)

01501H NMR (400MHz, CDCl3) δ -0.02-0.06 (m, 4H), 0.30-0.40 (m, 4H), 0.81-0.94 (m, 2H), 1.24 (t, J = 7.5 Hz, 3H), 2.04 (s, 6H), 2.81 (q, J = 7.5 Hz, 2H), 3.03 (d, J = 6.6 Hz, 4H), 3.87 (s, 3H), 6,45 (dd, J = 1.5, 6.8 Hz, 1H), 6.73 (s, 2H), 7.02 (dd, J = 6.8, 8.8 Hz, 1H), 7.49 (dd, J = 1.4, 8.9 Hz, 1H).

0151MS(ESI) m/z 404 MH+

Example 12

N,N-Dicyclopropylmethyl-N-[7-(2,6-dimethoxy-4-methylphenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]amine

(Yellow oil)

01521H NMR (400MHz, CDCl3) δ 0.00-0.04 (m, 4H), 0.30-0.36 (m, 4H), 0.80-0.90 (m, 2H), 1.23 (t, J = 7.6 Hz, 3H), 2.43 (s, 3H), 2.78 (q, J = 7.6 Hz, 2H), 2.98 (d, J = 6.8 Hz, 4H), 3.69 (s, 6H), 6.51 (s, 2H), 6.56 (dd, J = 1.6, 6.8 Hz, 1H), 6.98 (dd, J = 6.8, 8.8 Hz, 1H), 7.44 (dd, J = 1.6, 8.8 Hz, 1H).

Example 13

N,N-Dicyclopropylmethyl-N-[7-(2,4-dimethoxy-6-methylphenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]amine

(Colorless crystals)

01531H NMR (400MHz, CDCl3) δ -0.02- -0.03 (m, 2H), 0.29-0.35 (m, 2H), 0.80-0.90 (m, 1H), 1.23 (t, J = 7.6 Hz, 3H), 2.00 (s, 3H), 2.74-2.84 (m, 2H), 2.99 (d, J = 6.4 Hz, 2H), 3.67 (s, 3H), 3.86 (s, 3H), 6.44 (d, J = 2.0 Hz, 1H), 6.47-6.50 (m, 2H), 6.98 (dd, J = 6.8, 8.8 Hz, 1H), 7.45 (dd, J = 1.6, 8.8 Hz, 1H).

Example 14

N,N-Dicyclopropylmethyl-N-[2-ethyl-7-(2,4,6-trimethoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]amine

(Light yellow crystals)

01541H NMR (400MHz, CDCl3) δ 0.00-0.04 (m, 4H), 0.30-0.36 (m, 4H), 0.80-0.90 (m, 2H), 1.23 (t, J = 7.6 Hz, 3H), 2.79 (q, J = 7.6 Hz, 2H), 2.99 (d, J = 6.8 Hz, 4H), 3.69 (s, 6H), 3.88 (s, 3H), 6.25 (s, 2H), 6.55 (dd, J = 1.6, 6.8 Hz, 1H), 6.98 (dd, J = 6.8, 8.8 Hz, 1H), 7.43 (dd, J = 1.6, 8.8 Hz, 1H).

Example 15

N,N-Dicyclopropylmethyl-N-[7-(2,4-dimethoxyphenyl)-2-

ethylpyrazolo[1,5-

]pyridin-3-yl]amine

(Yellow oil)

01551H NMR (400MHz, CDCl3) δ 0.00-0.05 (m, 4H), 0.32-0.38 (m, 4H), 0.80-0.90 (m, 2H), 1.26 (t, J = 7.6 Hz, 3H), 2.80 (q, J = 7.6 Hz, 2H), 2.98 (d, J = 6.8 Hz, 4H), 3.74 (s, 3H), 3.87 (s, 3H), 6.57-6.63 (m, 3H), 6.97 (dd, J = 6.8, 8.8 Hz, 1H), 7.44 (dd, J = 1.6, 8.8 Hz, 1H), 7.48 (dd, J = 1.2, 7.6 Hz, 1H).

Example 16

N,N-Dicyclopropylmethyl-N-[2-ethyl-7-(2-methoxy-4-methylphenyl)pyrazolo[1,5-a]pyridin-3-yl]amine

(Yellow oil)

01561H NMR (400MHz, CDCl3) δ 0.00-0.05 (m, 4H), 0.32-0.38 (m, 4H), 0.80-0.90 (m, 2H), 1.26 (t, J = 7.6 Hz, 3H), 2.43 (s, 3H), 2.80 (q, J = 7.6 Hz, 2H), 2.99 (d, J = 6.8 Hz, 4H), 3.75 (s, 3H), 6.59 (dd, J = 0.8, 6.8 Hz, 1H), 6.86 (s, 1H), 6.89 (br d, J = 7.6 Hz, 1H), 6.98 (dd, J = 6.8, 8.8 Hz, 1H), 7.41 (d, J = 7.6 Hz, 1H), 7.45 (dd, J = 0.8, 8.8 Hz, 1H).

Example 17

N,N-Dicyclopropylmethyl-N-[2-ethyl-7-(2-methoxy-4-trifluoromethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]amine

(Yellow oil)

01571H NMR (400MHz, CDCl3) δ 0.01-0.06 (m, 4H), 0.32-0.37 (m, 4H), 0.78-0.80 (m, 2H), 1.26 (t, J = 7.6 Hz, 3H), 2.80 (q, J = 7.6 Hz, 2H), 2.99 (d, J = 6.8 Hz, 4H), 3.81 (s, 3H), 6.61 (dd, J = 1.2, 6.8 Hz, 1H), 7.00 (dd, J = 6.8, 8.8 Hz, 1H), 7.24 (br s, 1H), 7.34 (br d J = 7.6 Hz, 1H), 7.51 (dd, J = 1.2, 8.8 Hz, 1H), 7.65 (d, J = 7.6 Hz, 1H).

Example 18

N-[7-(4-Chloro-2,6-dimethoxyphenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]-N,N-dicyclopropylmethylamine

(Yellow oil)

01581H NMR (400MHz, CDCl3) δ -0.02-0.06 (m, 4H), 0.30-0.38 (m, 4H), 0.78-0.91 (m, 2H), 1.23 (t, J = 7.5 Hz, 3H), 2.79 (q, J = 7.5 Hz, 2H), 2.99 (d, J = 6.6 Hz, 4H), 3.70 (s, 6H), 6,54 (dd, J = 1.5, 6.8 Hz, 1H), 6.69 (s, 2H), 6.98 (dd, J = 6.8, 8.8 Hz, 1H), 7.46 (dd, J = 1.5, 8.8 Hz, 1H).

0159MS(ESI) m/z 440 MH+

Example 19

N-[7-(2-Chloro-4-methoxyphenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]-N,N-dicyclopropylmethylamine

(Yellow oil)

01601H NMR (400MHz, CDCl3) δ -0.02-0.06 (m, 4H), 0.30-0.38 (m, 4H), 0.77-0.90 (m, 2H), 1.26 (t, J = 7.5 Hz, 3H), 2.80 (q, J = 7.5 Hz, 2H), 2.99 (d, J = 6.6 Hz, 4H), 3.86 (s, 3H), 6,55 (dd, J = 1.3, 6.8 Hz, 1H), 6.92 (dd, J = 2.6, 8.6 Hz, 1H), 6.99 (dd, J = 6.8, 9.0 Hz, 1H), 7.06 (d, J = 2.4 Hz, 1H), 7.47(d, J = 8.4 Hz, 1H), 7.49 (dd, J = 1.3, 8.8 Hz, 1H).

0161MS(ESI) m/z 410 MH+

Example 20

N,N-Dicyclopropylmethyl-N-[7-(2,4-dichloro-6-methoxyphenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]amine

(White crystals)

01621H NMR (400MHz, CDCl3) δ -0.02-0.06 (m, 4H), 0.30-0.40 (m, 4H), 0.79-0.92 (m, 2H), 1.24 (t, J = 7.5 Hz, 3H), 2.80 (dq, J = 2.2, 7.5 Hz, 2H), 3.00 (d, J = 6.8 Hz, 4H), 3.72 (s, 3H), 6,55 (dd, J = 1.5, 6.8 Hz, 1H), 6.94 (d, J = 1.8 Hz, 1H), 7.01 (dd, J = 6.8, 8.8 Hz, 1H), 7.17 (d, J = 1.8 Hz, 1H), 7.52 (dd, J = 1.4, 8.9 Hz, 1H).

0163MS(ESI) m/z 444 MH+

Example 21

N,N-Dicyclopropylmethyl-N-[2-ethyl-7-(4-methoxy-2-trifluoromethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]amine

(Yellow oil)

01641H NMR (400MHz, CDCl3) δ -0.03-0.03 (m, 4H), 0.30-0.36 (m, 4H), 0.78-0.86 (m, 2H), 1.21 (t, J = 7.6 Hz, 3H), 2.70-2.82(m, 2H, 2.98 (d, J = 6.4 Hz, 4H), 3.91 (s, 3H), 6.49 (d, J = 6.0 Hz, 1H), 6.98 (dd, J = 6.8, 8.8 Hz, 1H), 7.16 (dd, J = 2.8, 8.8 Hz, 1H), 7.26-7.32 (m, 1H), 7.45-7.51 (m, 2H).

Example 22

N-[7-(2-Chloro-6-methoxy-4-methylphenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]-N,N-dicyclopropylmethylamine

(Light yellow crystals)

01651H NMR (400MHz, CDCl3) δ 0.00-0.04 (m, 4H), 0.32-0.36 (m, 4H), 0.80-0.92 (m, 2H), 1.23 (t, J = 8.0 Hz, 3H), 2.42 (s, 3H), 2.76-2.84 (m, 2H), 3.00 (d, J = 6.4 Hz, 4H), 3.70 (s, 3H), 6.55 (dd, J = 1.6, 6.8 Hz, 1H), 6.76 (br s, 1H), 6.98 (br s, 1H), 7.01 (dd, J = 6.8, 8.8 Hz, 1H), 7.50 (dd, J = 1.6, 8.8 Hz, 1H).

Example 23

N-[7-(2,4-Dichlorophenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]-N-(3-hexyl)amine

0166After dissolving [7-(2,4-dichlorophenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]amine (30 mg) in acetic acid (1 mL), 3-hexanone (0.024 mL) and sodium sulfate (139 mg) were added and the mixture was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (41.5 mg) was then added, and stirring was continued for 2 hours. Water was added to the reaction mixture, extraction was performed with ethyl acetate and the extract was washed with saturated aqueous sodium hydrogencarbonate and brine. After drying the obtained organic layer over anhydrous magnesium sulfate and filtering it, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and the title compound (21 mg) was obtained from the n-hexane:ethyl acetate (30:1) fraction as a yellow oil.

01671H NMR (400MHz, CDCl3) δ 0.86-0.93 (m, 3H), 0.97 (t, J = 7.6 Hz, 3H), 1.22-1.30 (m, 5H), 1.40-1.54 (m, 4H), 2.72-2.80 (m, 2H), 2.94-3.02 (m, 1H), 6.54-6.60 (m, 1H), 6.98-7.06 (m, 1H), 7.25-7.27 (m, 1H), 7.36 (dd, J = 2.0, 8.4 Hz, 1H), 7.48 (d, J = 8.4 Hz, 1H); 7.54 (d, J = 2.0 Hz, 1H).

Example 24

N-[7-(2,4-Dichlorophenyl)-2-ethylpyrazolo[1,5-

a]pyridin-3-yl]-N-(2-methoxyethyl)amine

0168After dissolving tert-butyl N-[7-(2,4-dichlorophenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]carbamate (57 mg) in N,N-dimethylformamide (2 mL), sodium hydride (60%, 7.3 mg) was added while cooling on ice, and then 2-bromoethyl methyl ether (0.015 mL) was added and the mixture was stirred for 1 hour. Water was added to the reaction mixture, extraction was performed with ethyl acetate and the extract was washed with brine. The obtained organic layer was dried over anhydrous magnesium sulfate and filtered, and then the solvent was concentrated under reduced pressure to obtain a crude product. This was dissolved in ethyl acetate (1 mL) without purification, a 4 N hydrochloric acid/ethyl acetate solution (2 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was neutralized with 5 N aqueous sodium hydroxide while cooling on ice, and then extraction was performed with ethyl acetate and the organic layer was washed with water and brine. After drying over anhydrous magnesium sulfate and filtration, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and the title compound (46 mg) was obtained from the n-hexane:ethyl acetate (5:1) fraction as a yellow oil.

01691H NMR (400MHz, CDCl3) δ 1.26 (t, J = 7.6 Hz, 3H), 2.77 (q, J = 7.6 Hz, 2H), 3.25 (t, J = 4.8 Hz, 2H), 3.41 (s, 3H), 3.50 (t, J = 4.8 Hz, 2H), 6.57 (dd, J = 1.6, 6.8 Hz, 1H), 7.03 (dd, J = 6.8, 8.8 Hz, 1H), 7.37 (dd, J = 2.0, 8.4 Hz, 1H), 7.47 (d, J = 8.4 Hz, 1H), 7.50-7.53 (m, 1H), 7.54 (d, J = 2.0 Hz, 1H).

Example 25

N-[7-(2,4-Dichlorophenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]-N-(2-methoxyethyl)-N-propylamine

0170N-[7-(2,4-Dichlorophenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]-N-(2-methoxyethyl)amine (14 mg) was dissolved in tetrahydrofuran (1 mL), and after adding propionaldehyde (0.016 mL) and 3 M aqueous sulfuric acid (0.77 mL), sodium borohydride (5.8 mg) was added in five portions while vigorously stirring on ice, and stirring was continued for 30 minutes. Water was added to the reaction mixture, extraction was performed with diethyl ether and the extract was washed with saturated aqueous sodium hydrogencarbonate and brine. After drying over anhydrous magnesium sulfate and filtration, the solvent was concentrated under reduced pressure and the residue was purified by preparative TLC [n-hexane:ethyl acetate (5:1), Rf=0.5] to obtain the title compound (9.5 mg) as a light yellow oil.

01711H NMR (400MHz, CDCl3) δ 0.87 (t, J = 7.6 Hz, 3H), 1.23 (t, J = 7.6 Hz, 3H), 1.34-1.44 (m, 2H), 2.75 (q, J = 7.6 Hz, 2H), 3.08 (dd, J = 6.4, 7.2 Hz, 2H), 3.28 (t, J = 6.0 Hz, 2H), 3.29 (s, 3H), 3.35 (t, J = 6.0 Hz, 2H), 6.59 (dd, J = 1.6, 6.8 Hz, 1H), 7.03 (dd, J = 6.8, 8.8 Hz, 1H), 7.37 (dd, J = 2.0, 8.4 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.52 (dd, J = 1.6, 8.8 Hz, 1H), 7.54(d, J = 2.0 Hz, 1H).

0172The compounds of Examples 26 to 39 were synthesized according to the production method of Example 25.

Example 26

N-Cyclopropylmethyl-N-[7-(2,4-dichlorophenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]-N-(2-methoxyethyl)amine

(Light yellow oil)

01731H NMR (400MHz, CDCl3) δ 0.01-0.03 (m, 2H), 0.34-0.38 (m, 2H), 0.80-0.90 (m, 1H), 1.25 (t, J = 7.6 Hz, 3H), 2.77 (q, J = 7.6 Hz, 2H), 2.98 (d, J = 6.4 Hz, 2H), 3.29 (s, 3H), 3.37 (br s, 4H), 6.58 (dd, J = 1.6, 6.8 Hz, 1H), 7.03 (dd, J = 6.8, 9.2 Hz, 1H), 7.38 (dd, J = 2.0, 8.4 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.53 (dd, J = 1.6, 9.2 Hz, 1H), 7.55 (d, J = 2.0 Hz, 1H).

Example 27

N-[7-(2,4-Dichlorophenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]-N-isobutyl-N-(2-methoxyethyl)amine

(Light yellow oil)

01741H NMR (400MHz, CDCl3) δ 0.91 (d, J = 6.8 Hz, 6H), 1.24 (t, J = 7.6 Hz, 3H), 1.52-1.62 (m, 1H), 2.76 (q, J = 7.6 Hz, 2H), 2.92 (d, J = 7.2 Hz, 2H), 3.23 (t, J = 6.0 Hz, 2H), 3.29 (s, 3H), 3.37 (t, J = 6.0 Hz, 2H), 6.57-6.60 (m, 1H), 7.04(dd, J = 6.8, 8.8 Hz, 1H), 7.37 (dd, J = 2.0, 8.4 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.52-7.55 (m, 1H), 7.54 (d, J = 2.0 Hz, 1H).

Example 28

N-[2-Ethyl-7-(2-methoxy-4,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-isobutyl-N-(2-methoxyethyl)amine

(Light yellow oil)

01751H NMR (400MHz, CDCl3) δ 0.85-0.95 (m, 6H), 1.16-1.26 (m, 3H), 1.52-1.62 (m, 1H), 1.97 (s, 3H), 2.39 (s, 3H), 2.70-2.80 (m, 2H), 2.87-2.95 (m, 2H), 3.20-3.40 (m, 4H), 3.68 (s, 3H), 6.47-6.54 (m, 1H), 6.69 (s, 1H), 6.77 (s, 1H), 6.98-7.06 (m, 1H), 7.42-7.50 (m, 1H).

Example 29

N-[2-Ethyl-7-(2-methoxy-4,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-isobutyl-N-(2-methoxyethyl)amine

(Light yellow oil)

0176MS(ESI) m/z 396 MH+

Example 30

N-[2-Ethyl-7-(2-methoxy-4,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(3-fluoropropyl)-N-propylamine

(Light yellow oil)

01771H NMR (400MHz, CDCl3) δ 0.88 (t, J = 7.6 Hz, 3H), 1.20 (t, J = 7.6 Hz, 3H), 1.38-1.46 (m, 2H), 1.68-1.82 (m, 2H), 1.98 (s, 3H), 2.39 (s, 3H), 2.73 (q, J = 7.6 Hz, 2H), 3.00-3.05 (m, 2H), 3.22 (t, J = 6.8 Hz, 2H), 3.68 (s, 3H), 4.52 (td, J = 6.0, 47.6 Hz, 2H), 6.52 (dd, J = 1.6, 6.8 Hz, 1H), 6.69 (s, 1H). 6.77 (s, 1H), 7.02 (dd, J = 6.8, 8.8 Hz, 1H), 7.42 (dd, J = 1.6, 8.8 Hz, 1H).

Example 31

N-[2-Ethyl-7-(2-methoxy-4,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-propyl-N-tetrahydro-2-furanylmethylamine

(Light yellow oil)

0178MS (ESI) m/z 422 MH+

Example 32

N-Cyclopropylmethyl-N-[2-ethyl-7-(2-methoxy-4,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-propylamine

(Light yellow oil)

0179MS(ESI) m/z 392 MH+

Example 33

N-Cyclopropylmethyl-N-[2-ethyl-7-(2-methoxy-4,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(2-methoxyethyl)amine

(Light yellow oil)

0180MS(ESI) m/z 408 MH+

Example 34

N-Cyclopropylmethyl-N-[2-ethyl-7-(2-methoxy-4,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(3-fluoropropyl)amine

(Light yellow oil)

01811H NMR (400MHz, CDCl3) δ -0.02-0.02 (m, 2H), 0.32-0.38 (m, 2H), 0.80-0.90 (m, 2H), 1.20 (t, J = 7.6 Hz, 3H), 1.70-1.82 (m, 2H), 1.97 (s, 3H), 2.39 (s, 3H), 2.74 (q, J = 7.6 Hz, 2H), 2.92 (d, J = 6.8 Hz, 2H), 3.30 (t, J = 6.8 Hz, 2H), 3.68 (s, 3H), 4.55 (td, J = 6.0, 47.2 Hz, 2H), 6.51 (dd, J = 1.2, 6.8 Hz, 1H), 6.69 (s, 1H). 6.77 (s, 1H), 7.02 (dd, J = 6.8, 8.8 Hz, 1H), 7.44 (dd, J = 1.2, 8.8 Hz, 1H).

Example 35

N-Cyclopropylmethyl-N-[2-ethyl-7-(2-methoxy-4,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2-furanylmethylamine

(Light yellow oil)

0182MS(ESI) m/z 434 MH+

Example 36

N-Cyclopropylmethyl-N-[2-ethyl-7-(2-methoxy-4,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-3-furanylmethylamine

(Yellow oil)

01831H NMR (400MHz, CDCl3) δ -0.02-0.03 (m, 2H), 0.33-0.40 (m, 2H), 0.80-0.90 (m, 1H), 1.21 (t, J = 7.2 Hz, 3H), 1.60-1.70 (m, 1H), 1.88-1.98 (m, 1H), 1.99 (s, 3H), 2.23-2.32 (m, 1H), 2.40 (s, 3H), 2.76 (q, J = 7.2 Hz, 2H), 2.92 (d, J = 6.4 Hz, 2H), 3.06-3.13 (m, 1H), 3.21-3.28 (m, 1H), 3.60-3.65 (m, 1H), 3.66-3.72 (m, 4H), 3.73-3.86 (m, 2H), 6.52 (br d, J = 6.8 Hz, 1H), 6.70 (s, 1H), 6.78 (s, 1H), 7.03 (dd, J = 6.8, 8.8 Hz, 1H), 7.45 (br d, J = 8.8 Hz, 1H).

Example 37

N-Cyclopropylmethyl-N-[7-(2,6-dimethoxy-4-methylphenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-3-furanylmethylamine

(Yellow oil)

01841H NMR (400MHz, CDCl3) δ -0.02-0.04 (m, 2H), 0.34-0.40 (m, 2H), 0.80-0.90 (m, 1H), 1.21 (t, J = 7.2 Hz, 3H), 1.55-1.67 (m, 1H), 1.86-1.96 (m, 1H), 2.43 (s, 3H), 2.74 (q, J = 7.2 Hz, 2H), 2.90 (d, J = 6.8 Hz, 2H), 3.04-3.11 (m, 1H), 3.20-3.26 (m, 1H), 3.58-3.84 (m, 7H), 6.51 (s, 2H), 6.57-6.60 (m, 1H), 6.98-7.04 (m, 1H), 7.40-7.44 (m, 1H).

Example 38

N-Cyclopropylmethyl-N-[7-(2,6-dimethoxy-4-methylphenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2-furanylmethylamine

(Light yellow oil)

01851H NMR (400MHz, CDCl3) δ -0.01-0.04 (m, 2H), 0.32-0.38 (m, 2H), 0.80-0.90 (m, 1H), 1.22 (t, J = 7.6 Hz, 3H), 1.62-1.70 (m, 1H), 1.75-1.95 (m, 3H), 2.43 (s, 3H), 2.77 (q, J = 7.6 Hz, 2H), 2.96 (d, J = 6.8 Hz, 2H), 3.03-3.10 (m, 1H), 3.40-3.46 (m, 1H), 3.64-3.72 (m, 4H), 3.80-3.90 (m, 2H), 6.51 (s, 2H), 6.57 (dd, J = 1.2, 6.8 Hz, 1H), 7.00 (dd, J = 6.8, 8.8 Hz, 1H), 7.46 (dd, J = 1.2, 8.8 Hz, 1H).

Example 39

N-Cyclopropyl-N-[7-(2,6-dimethoxy-4-methylphenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]-N-(1,3-dioxolan-2-ylmethyl)amine

(Yellow oil)

01861H NMR (400MHz, CDCl3) δ -0.02-0.04 (m, 2H), 0.32-0.38 (m, 2H), 0.80-0.90 (m, 1H), 1.22 (t, J = 7.6 Hz, 3H), 2.41 (s, 3H), 2.77 (q, J = 7.6 Hz, 2H), 3.01 (d, J = 7.2 Hz, 2H), 3.35 (d, J = 4.4 Hz, 2H), 3.68 (s, 6H), 3.78-3.84 (m, 2H), 3.94-3.98 (m, 2H), 4.90 (t, J = 4.4 Hz, 1H), 6.49 (s, 2H), 6.56 (dd, J = 1.2, 6.8 Hz, 1H), 7.00 (dd, J = 6.8, 8.8 Hz, 1H), 7.44 (dd, J = 1.2, 8.8 Hz, 1H).

Example 40

N-Cyclopropylmethyl-N-[7-(2,4-dimethoxy-6-methylphenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-3-furanylmethylamine

0187After dissolving N-(7-bromo-2-ethylpyrazolo[1,5-a]pyridin-3-yl)-N-cyclopropylmethyl-N-tetrahydro-3-furanylmethylamine (150 mg) in 1,2-dimethoxyethane (20 mL) and water (10 mL), 2,4-dimethoxy-6-methylphenylboric acid (155 mg), tetrakis(triphenylphosphine)palladium (0) complex (92 mg) and barium hydroxide octahydrate (250 mg) were added and the mixture was heated and stirred at 80°C for 1 hour. Water was added to the reaction mixture, extraction was performed with ethyl acetate, the organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered, and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography, and the title compound (88 mg) was obtained from the n-hexane:ethyl acetate (6:1) fraction as a yellow oil.

01881H NMR (400MHz, CDCl3) δ -0.02-0.04 (m, 2H), 0.32-0.41 (m, 2H), 0.80-0.92 (m, 1H), 1.23 (t, J = 7.5 Hz, 3H), 1.58-1.70 (m, 1H), 1.87-2.00 (m, 1H), 2.02 (s, 3H), 2.22-2.34 (m, 1H), 2.76 (dq, J = 1.8, 7.5 Hz, 2H), 2.92 (dd, J = 1.7, 6.8 Hz, 2H), 3.06-3.14 (m, 1H), 3.20-3.29 (m, 1H), 3.60-3.65 (m, 1H), 3.66-3.88 (m, 3H), 3.68 (s, 3H), 3.87 (s, 3H), 6.45 (d, J = 2.4 Hz, 1H), 6.49 (d, J = 2.2 Hz, 1H), 6.52 (dd, J = 0.9, 6.8 Hz, 1H), 7.03 (dd, J = 6.8, 8.8 Hz, 1H), 7.42-7.48 (m, 1H).

0189The compounds of Examples 41 to 46 were synthesized according to the production method of Example 40.

Example 41

N-Cyclopropylmethyl-N-[2-ethyl-7-(4-methoxy-2,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-3-furanylmethylamine

(Yellow crystals)

01901H NMR (400MHz, CDCl3) δ -0.03-0.06 (m, 2H), 0.33-0.42 (m, 2H), 0.80-0.92 (m, 1H), 1.23 (t, J = 7.5 Hz, 3H), 1.60-1.73 (m, 1H), 1.90-2.02 (m, 1H), 2.04 (s, 6H), 2.24-2.38 (m, 1H), 2.78 (q, J = 7.5 Hz, 2H), 2.94 (d, J = 6.8 Hz, 2H), 3.13 (dd, J = 8.6, 12.0 Hz, 1H), 3.27 (dd, J = 6.6, 12.0 Hz, 1H), 3.64 (dd, J = 5.5, 8.6 Hz, 1H), 3.68-3.90 (m, 3H), 3.87 (s, 3H), 6.48 (dd, J = 1.3, 6.6 Hz, 1H), 6.74 (s, 2H), 7.05 (dd, J = 6.6, 8.8 Hz, 1H), 7.48 (dd, J = 1.3, 8.8 Hz, 1H).

Example 42

N-[7-(9-Chloro-2-methoxyphenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]-N-cyclopropylmethyl-N-tetrahydro-3-furanylmethylamine

(Light brown oil)

01911H NMR (400MHz, CDCl3) δ -0.02-0.06 (m, 2H), 0.34-0.42 (m, 2H), 0.78-0.90 (m, 1H), 1.25 (t, J = 7.5 Hz, 3H), 1.58-1.69 (m, 1H), 1.85-1.96 (m, 1H), 2.18-2.32 (m, 1H), 2.76 (q, J = 7.5 Hz, 2H), 2.90 (d, J = 6.8 Hz, 2H), 3.08 (dd, J = 8.6, 12.0 Hz, 1H), 3.23 (dd, J = 6.8, 12.0 Hz, 1H), 3.58-3.86 (m, 4H), 3.76 (s, 3H), 6.61 (dd, J = 1.3, 6.8 Hz, 1H), 6.98-7.04 (m, 2H), 7.06 (dd, J = 1.9, 8.1 Hz, 1H), 7.45 (dd, J = 1.3, 8.9 Hz, 1H), 7.46 (d, J = 8.1 Hz, 1H).

Example 43

N-Cyclopropylmethyl-N-[2-ethyl-7-(2-[2-(fluoromethoxy)-4,6-dimethylbenzyl]oxy-4,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-3-furanylmethylamine

(Yellow oil)

01921H NMR (400MHz, CDCl3) δ -0.08-0.02 (m, 2H), 0.28-0.36 (m, 2H), 0.72-0.85 (m, 1H), 1.17 (t, J = 7.5 Hz, 3H), 1.56-1.70 (m, 1H), 1.84-1.96 (m, 1H), 1.88 (s, 3H), 1.96 (s, 3H), 2.23 (s, 3H), 2.16-2.26 (m, 1H), 2.40 (s, 3H), 2.64-2.78 (m, 2H), 2.80-2.94 (m, 2H), 3.02-3.10 (m, 1H), 3.14-3.25 (m, 1H), 3.56-3.86 (m, 4H), 4.87 (d, J = 11.0 Hz, 1H), 5.03 (d, J = 11.0 Hz, 1H), 5.38 (s, 1H), 5.52 (s, 1H), 6.42 (dd, J = 1.4, 6.9 Hz, 1H), 6.60 (s, 1H), 6.70 (s, 1H), 6.78 (s, 1H), 6.91 (s, 1H), 6.90-6.97 (m, 1H), 7.37 (dd, J = 1.3, 8.8 Hz, 1H).

Example 44

N-[7-(2-Chloro-6-methoxy-4-methylphenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]-N-cyclopropylmethyl-N-tetrahydro-3-furanylmethylamine

(Yellow oil)

01931H NMR (400MHz, CDCl3) δ -0.02-0.06 (m, 2H), 0.32-0.42 (m, 2H), 0.78-0.92 (m, 1H), 1.22 (t, J = 7.6 Hz, 3H), 1.58-1.70 (m, 1H), 1.86-1.98 (m, 1H), 2.22-2.34 (m, 1H), 2.42 (s, 3H), 2.70-2.82 (m, 2H), 2.91 (dd, J = 1.6, 6.8 Hz, 2H), 3.04-3.14 (m, 1H), 3.24 (dd, J = 6.7, 12.0 Hz, 1H), 3.59-3.87 (m, 4H), 3.70 (s, 3H), 6.58 (dd, J = 1.3, 6.8 Hz, 1H), 6. 75 (s, 1H), 6. 98 (s, 1H), 7.04 (dd, J = 6.8, 8.9 Hz, 1H), 7.44-7.51 (m, 1H).

Example 45

N-Cyclopropylmethyl-N-2-ethyl-7-[2-(fluoromethoxy)-4,6-dimethylphenyl]pyrazolo[1,5-a]pyridin-3-yl-N-tetrahydro-3-furanylmethylamine

(Yellow oil)

01941H NMR (400MHz, CDCl3) δ -0.03-0.08 (m, 2H), 0.33-0.44 (m, 2H), 0.80-0.94 (m, 1H), 1.23 (t, J = 7.6 Hz, 3H), 1.60-1.74 (m, 1H), 1.89-2.01 (m, 1H), 2.08 (s, 3H), 2.22-2.36 (m, 1H), 2.43 (s, 3H), 2.72-2.83 (m, 2H), 2.93 (d, J = 6.8 Hz, 2H), 3.08- 3.16 (m, 1H), 3.22-3.31 (m, 1H), 3.58-3.92 (m, 4H), 5.32 (d, J = 2.6 Hz, 0.5H), 5.45 (d, J = 2.7 Hz, 0.5H), 5.54 (d, J = 2.7 Hz, 0.5H), 5.68 (d, J = 2.7 Hz, 0.5H), 6.56 (dd, J = 1.3, 6.8 Hz, 1H), 6.97 (s, 1H), 7.01 (s, 1H), 7.07 (dd, J = 6.8, 8.8 Hz, 1H), 7.49 (dd, J = 1.3, 8.8 Hz, 1H).

Example 46

N-[7-(2,6-Dimethoxy-4-methylphenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]-N-propyl-N-tetrahydro-3-furanylmethylamine

(Yellow oil)

01951H NMR (400MHz, CDCl3) δ 0.88 (t, J = 7.3 Hz, 3H), 1.21 (t, J = 7.5 Hz, 3H), 1.34-1.46 (m, 2H), 1.54-1.68 (m, 1H), 1.85-1.96 (m, 1H), 2.18-2.32 (m, 1H), 2.43 (s, 3H), 2.73 (q, J = 7.5 Hz, 2H), 2.94-3.05 (m, 3H), 3.14 (dd, J = 6.6, 12.0 Hz, 1H), 3.58 (dd, J = 5.5, 8.4 Hz, 1H), 3.62-3.85 (m, 3H), 3.69 (s, 6H), 6.51 (s, 2H), 6.59 (dd, J = 1.5, 6.8 Hz, 1H), 7.01 (dd, J = 6.8, 8.8 Hz, 1H), 7.40 (dd, J = 1.3, 8.8 Hz, 1H).

0196MS(ESI) m/z 438 MH+

Example 47

N-Cyclopropylmethyl-N-[2-ethyl-7-(2-methoxy-4,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylmethylamine

0197After dissolving N-cyclopropylmethyl-N-[2-ethyl-7-(2-methoxy-4,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]amine (255 mg) in tetrahydrofuran (2 mL), tetrahydro-2H-4-pyrancarbaldehyde (173 mg) [CAS No.50675-18-8] and sodium triacetoxyborohydride (241 mg) were added, and the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, extraction was performed with ethyl acetate, and the extract was washed with brine. After drying over anhydrous magnesium sulfate and filtration, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and the title compound (134 mg) was obtained from the n-hexane:ethyl acetate (5:1) fraction as a yellow oil.

01981H NMR (400MHz, CDCl3) δ -0.04-0.00 (m, 2H), 0.31-0.35 (m, 2H), 0.76-0.88 (m, 1H), 1.20 (t, J = 7.6 Hz, 3H), 1.24-1.34 (m, 2H), 1.54-1.65 (m, 1H), 1.72-1.80 (m, 2H), 1.98 (s, 3H), 2.39 (s, 3H), 2.74 (dq, J = 1.6, 7.6 Hz, 2H), 2.88 (d, J = 6.8 Hz, 2H), 3.04 (d, J = 6.8 Hz, 2H), 3.31 (dt, J = 2.0, 11.6 Hz, 2H), 3.68 (s, 3H), 3.92-3.98 (m, 2H), 6.51 (dd, J = 1.6, 6.8 Hz, 1H), 6.69 (s, 1H), 6.77 (s, 1H), 7.01 (dd, J = 6.8, 8.8 Hz, 1H), 7.44(dd, J = 1.6, 8.8 Hz, 1H).

0199The compounds of Examples 48 to 61 were synthesized according to the production method of Example 47.

Example 48

N-Cyclopropylmethyl-N-[2-ethyl-7-(4-methoxy-2,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylamine

(White crystals)

02001H NMR (400MHz, CDCl3) δ -0.02-0.05 (m, 2H), 0.34-0.42 (m, 2H), 0.78-0.90 (m, 1H), 1.31 (t, J = 7.5 Hz, 3H), 1.56-1.70 (m, 2H), 1.88-1.98 (m, 2H), 2.12 (s, 6H), 2.86 (q, J = 7.5 Hz, 2H), 3.10 (d, J = 6.8 Hz, 2H), 3.33-3.44 (m, 1H), 3.50 (dt, J = 2.0, 12.0 Hz, 2H), 3.95 (s, 3H), 4.04-4.12 (m, 2H), 6,56 (dd, J = 1.4, 6.7 Hz, 1H), 6.82 (s, 2H), 7.13 (dd, J = 6.8, 8.8 Hz, 1H), 7.53 (dd, J = 1.4, 8.8 Hz, 1H).

0201MS(ESI) m/z 434 MH+

Example 49

N-[7-(4-Chloro-2,6-dimethoxyphenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]-N-cyclopropylmethyl-N-tetrahydro-2H-4-pyranylamine

(Yellow oil)

02021H NMR (400MHz, CDCl3) δ -0.02-0.06 (m, 2H), 0.30-0.40 (m, 2H), 0.75-0.88 (m, 1H), 1.29 (t, J = 7.5 Hz, 3H), 1.51-1.64 (m, 2H), 1.83-1.92 (m, 2H), 2.83 (q, J = 7.5 Hz, 2H), 3.05 (d, J = 6.6 Hz, 2H), 3.26-3.38 (m, 1H), 3.44 (dt, J = 2.0, 12.0 Hz, 2H), 3.77 (s, 6H), 3.98-4.06 (m, 2H), 6,64 (dd, J = 1.4, 6.9 Hz, 1H), 6.76 (s, 2H), 7.08 (dd, J = 6.9, 8.8 Hz, 1H), 7.48 (dd, J = 1.4, 8.8 Hz, 1H).

0203MS(ESI) m/z 470 MH+

Example 50

N-[2-Ethyl-7-(4-methoxy-2,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-propyl-N-tetrahydro-2H-4-pyranylamine

(White crystals)

02041H NMR (400MHz, CDCl3) δ 0.85 (t, J = 7.4 Hz, 3H), 1.19 (t, J = 7.5 Hz, 3H), 1.25-1.38 (m, 2H), 1.46-1.60 (m, 2H), 1.74-1.83 (m, 2H), 2.01 (s, 6H), 2.72 (q, J = 7.4 Hz, 2H), 3.08 (t, J = 7.2 Hz, 2H), 3.11-3.22 (m, 1H), 3.37 (dt, J = 2.0, 12.0 Hz, 2H), 3.84 (s, 3H), 3.92-4.00 (m, 2H), 6,45 (dd, J = 1.4, 6.6 Hz, 1H), 6.70 (s, 2H), 7.02 (dd, J = 6.8, 8.8 Hz, 1H), 7.41 (dd, J = 1.4, 8.9 Hz, 1H).

0205MS(ESI) m/z 422 MH+

Example 51

N-[7-(4-Chloro-2,6-dimethoxyphenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]-N-propyl-N-tetrahydro-2H-4-pyranylamine

(Yellow crystals)

02061H NMR (400MHz, CDCl3) δ 0.84 (t, J = 7.3 Hz, 3H), 1.20 (t, J = 7.5 Hz, 3H), 1.23-1.37 (m, 2H), 1.46-1.60 (m, 2H), 1.74-1.84 (m, 2H), 2.73 (q, J = 7.5 Hz, 2H), 3.07 (t, J = 7.3 Hz, 2H), 3.10-3.21 (m, 1H), 3.36 (dt, J = 1.8, 12.0 Hz, 2H), 3.70 (s, 6H), 3.90-3.99 (m, 2H), 6,57 (dd, J = 1.4, 6.9 Hz, 1H), 6.69 (s, 2H), 7.01 (dd, J = 6.9, 8.9 Hz, 1H), 7.40 (dd, J = 1.4, 8.9 Hz, 1H).

0207MS(ESI) m/z 458 MH+

Example 52

N-Cyclopropylmethyl-N-[2-ethyl-7-(2-methoxy-4,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylamine

(Yellow oil)

02081H NMR (400MHz, CDCl3) δ -0.10- -0.04 (m, 2H), 0.24-0.32 (m, 2H), 0.70-0.80 (m, 1H), 1.21 (t, J = 7.6 Hz, 3H), 1.46-1.60 (m, 2H), 1.76-1.84 (m, 2H), 1.97 (s, 3H), 2.40 (s, 3H), 2.70-2.80 (m, 2H), 2.98 (d, J = 6.4 Hz, 2H), 3.22-3.30 (m, 1H), 3.34-3.42 (m, 2H), 3.68 (s, 3H), 3.92-3.99 (m, 2H), 6.51 (dd, J = 1.2, 6.8 Hz, 1H), 6.69 (s, 1H), 6.77 (s, 1H), 7.02 (dd, J = 6.8, 9.2 Hz, 1H), 7.40 (dd, J = 1.2, 9.2 Hz, 1H).

Example 53

N-[2-Ethyl-7-(2-methoxy-4,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(3-fluoropropyl)-N-tetrahydro-2H-4-pyranylamine

(Yellow oil)

02091H NMR (400MHz, CDCl3) δ 1.19 (t, J = 7.2 Hz, 3H), 1.48-1.60 (m, 2H), 1.60-1.74 (m, 2H), 1.76-1.84 (m, 2H), 1.97 (s, 3H), 2.40 (s, 3H), 2.68-2.76 (m, 2H), 3.12-3.20 (m, 1H), 3.29 (t, J = 6.4 Hz, 2H), 3.36 (dt, J = 1.6, 11.6 Hz, 2H), 3.69 (s, 3H), 3.94-4.00 (m, 2H), 4.51 (td, J = 5.6, 47.6 Hz, 2H), 6.54 (dd, J = 1.2, 6.8 Hz, 1H), 6.69 (s, 1H), 6.77 (s, 1H), 7.05 (dd, J = 6.8, 8.8 Hz, 1H), 7.39 (dd, J = 1.2, 8.8 Hz, 1H).

Example 54

[2-Ethyl-7-(2-methoxy-4,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(2-methoxyethyl)-N-tetrahydro-2H-4-pyranylamine

(Yellow oil)

02101H NMR (400MHz, CDCl3) δ 1.20 (t, J = 7.6 Hz, 3H), 1.47-1.58 (m, 2H), 1.77-1.84 (m, 2H), 1.98 (s, 3H), 2.40 (s, 3H), 2.68-2.76 (m, 2H), 3.16-3.25 (m, 1H), 3.26 (s, 3H), 3.27-3.40 (m, 6H), 3.69 (s, 3H), 3.92-3.99 (m, 2H), 6.53 (dd, J = 1.2, 6.8 Hz, 1H), 6.70 (s, 1H), 6.77 (s, 1H), 7.05 (dd, J = 6.8, 8.8 Hz, 1H), 7.40 (dd, J = 1.2, 8.8 Hz, 1H).

Example 55

N-Cyclopropylmethyl-N-[7-(2,6-dimethoxy-4-methylphenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylamine

(Yellow oil)

02111H NMR (400MHz, CDCl3) δ -0.06- -0.01 (m, 2H), 0.26-0.32 (m, 2H), 0.70-0.80 (m, 1H), 1.22 (t, J = 7.6 Hz, 3H), 1.46-1.62 (m, 2H), 1.76-1.84 (m, 2H), 2.43 (s, 3H), 2.75 (q, J = 7.6 Hz, 2H), 2.97 (d, J = 6.8 Hz, 2H), 3.22-3.30 (m, 1H), 3.32-3.40 (m, 2H), 3.69 (s, 6H), 3.92-3.98 (m, 2H), 6.51 (s, 2H), 6.58 (dd, J = 1.6, 6.8 Hz, 1H), 7.01 (dd, J = 6.8, 8.8 Hz, 1H), 7.39 (dd, J = 1.6, 8.8 Hz, 1H).

Example 56

N-[7-(2,6-Dimethoxy-4-methylphenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]-N-(3-fluoropropyl)-N-tetrahydro-2H-4-pyranylamine

(Yellow oil)

02121H NMR (400MHz, CDCl3) δ 1.20 (t, J = 7.2 Hz, 3H), 1.49-1.60 (m, 2H), 1.61-1.74 (m, 2H), 1.77-1.84 (m, 2H), 2.43 (s, 3H), 2.72 (q, J = 7.2 Hz, 2H), 3.12-3.20 (m, 1H), 3.28 (t, J = 6.8 Hz, 2H), 3.36 (dt, J = 2.0, 12.4 Hz, 2H), 3.70 (s, 6H), 3.93-3.99 (m, 2H), 4.50 (td, J = 6.0, 47.2 Hz, 2H), 6.51 (s, 2H), 6.62 (dd, J = 1.2, 6.8 Hz, 1H), 7.04 (dd, J = 6.8, 8.8 Hz, 1H), 7.38 (dd, J = 1.2, 8.8 Hz, 1H).

Example 57

N-[7-(2,6-Dimethoxy-4-methylphenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]-N-(2-methoxyethyl)-N-tetrahydro-2H-4-pyranylamine

(Yellow oil)

02131H NMR (400MHz, CDCl3) δ 1.21 (t, J = 7.6 Hz, 3H), 1.47-1.59 (m, 2H), 1.77-1.84 (m, 2H), 2.43 (s, 3H), 2.72 (q, J = 7.6 Hz, 2H), 3.15-3.24 (m, 1H), 3.26 (s, 3H), 3.27-3.40 (m, 6H), 3.70 (s, 3H), 3.92-3.98 (m, 2H), 6.51 (s, 2H), 6.61 (dd, J = 1.6, 6.8 Hz, 1H), 7.04 (dd, J = 6.8, 8.8 Hz, 1H), 7.38 (dd, J = 1.6, 8.8 Hz, 1H).

Example 58

N-Cyclopropylmethyl-N-[7-(2,4-dimethoxy-6-methylphenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylamine

(Yellow oil)

02141H NMR (400MHz, CDCl3) δ -0.10- -0.01 (m, 2H), 0.23-0.32 (m, 2H), 0.70-0.80 (m, 1H), 1.22 (t, J = 7.6 Hz, 3H), 1.46-1.58 (m, 2H), 1.77-1.85 (m, 2H), 2.00 (s, 3H), 2.68-2.82 (m, 2H), 2.98 (d, J = 7.6 Hz, 2H), 3.22-3.31 (m, 1H), 3.38 (dt, J = 2.0, 12.0 Hz, 2H), 3.68 (s, 3H), 3.86 (s, 3H), 3.73-4.00 (m, 2H), 6.44 (d, J = 2.0 Hz, 1H), 6.48 (d, J = 2.0 Hz, 1H), 6.51 (dd, J = 1.2, 6.8 Hz, 1H), 7.01 (dd, J = 6.8, 8.8 Hz, 1H), 7.40 (dd, J = 1.2, 8.8 Hz, 1H).

Example 59

N-[7-(2,4-Dimethoxy-6-methylphenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]-N-(3-fluoropropyl)-N-tetrahydro-2H-4-pyranylamine

(Yellow oil)

02151H NMR (400MHz, CDCl3) δ 1.20 (t, J = 7.6 Hz, 3H), 1.48-1.60 (m, 2H), 1.60-1.74 (m, 2H), 1.76-1.84 (m, 2H), 2.00 (s, 3H), 2.72 (q, J = 7.6 Hz, 2H), 3.12-3.20 (m, 1H), 3.29 (t, J = 6.8 Hz, 2H), 3.36 (dt, J = 2.0, 12.0 Hz, 2H), 3.68 (s, 3H), 3.86 (s, 3H), 3.93-4.00 (m, 2H), 4.51 (td, J = 6.0, 47.2 Hz, 2H), 6.44 (d, J = 2.0 Hz, 1H), 6.48 (d, J = 2.0 Hz, 1H), 6.54 (dd, J = 1.6, 6.8 Hz, 1H), 7.04 (dd, J = 6.8, 8.8 Hz, 1H), 7.38 (dd, J = 1.6, 8.8 Hz, 1H).

Example 60

N-Cyclopropylmethyl-N-[2-ethyl-7-(2-methoxy-4,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-3-pyranylamine

(Yellow oil)

02161H NMR (400MHz, CDCl3) δ -0.02-0.06 (m, 2H), 0.32-0.42 (m, 2H), 0.78-0.88 (m, 1H), 1.30 (t, J = 7.6 Hz, 3H), 1.30-1.44 (m, 1H), 1.66-1.76 (m, 2H), 2.06 (s, 3H), 2.06-2.18 (m, 1H), 2.49 (s, 3H), 2.83(q, J = 7.6 Hz, 2H), 3.06 (d, J = 6.8 Hz, 2H), 3.18-3.38 (m, 3H), 3.77 (s, 3H), 3.86-3.96 (m, 1H), 4.12-4.20 (m, 1H), 6.61 (dd, J = 1.2, 6.8 Hz, 1H), 6.78 (s, 1H), 6.86 (s, 1H), 7.12 (dd, J = 6.8, 8.8 Hz, 1H), 7.48 (dd, J = 1.2, 8.8 Hz, 1H).

Example 61

N-Cyclopropylmethyl-N-[7-(2,6-dimethoxy-4-methylphenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylmethylamine

(Yellow oil)

02171H NMR (400MHz, CDCl3) δ -0.01-0.03 (m, 2H), 0.34-0.40 (m, 2H), 0.80-0.90 (m, 1H), 1.23 (t, J = 7.6 Hz, 3H), 1.20-1.34 (m, 2H), 1.56-1.62 (m, 1H), 1.74-1.80 (m, 2H), 2.45 (s, 3H), 2.77 (q, J = 7.6 Hz, 2H), 2.89 (d, J = 6.4 Hz, 2H), 3.06 (d, J = 6.8 Hz, 2H), 3.32 (dt, J = 2.0, 11.6 Hz, 2H), 3.71 (s, 6H), 3.92-3.98 (m, 2H), 6.53 (s, 2H), 6.60 (dd, J = 1.2, 6.8 Hz, 1H), 7.01 (dd, J = 6.8, 8.8 Hz, 1H), 7.45 (dd, J = 1.2, 8.8 Hz, 1H).

Example 62

N,N-Dicyclopropylmethyl-N-[2-ethyl-4-methoxy-7-(2-methoxy-4,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]amine

02182-Ethyl-4-methoxy-7-(2-methoxy-4,6-dimethylphenyl)-3-nitropyrazolo[1,5-a]pyridine (185 mg) was dissolved in a mixture of ethanol (7 mL) and water (7.5 mL), and then acetic acid (0.3 mL) and zinc powder (185 mg) were added and the reaction mixture was heated at 60°C for 20 minutes. The reaction mixture was filtered with celite, and the obtained filtrate was concentrated under reduced pressure. Water was added, extraction was performed with ethyl acetate, the extract was washed with saturated aqueous sodium hydrogencarbonate and brine and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 2-ethyl-4-methoxy-7-(2-methoxy-4,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-amine as a crude product.

0219To a solution of the obtained crude 2-ethyl-4-methoxy-7-(2-methoxy-4,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-amine in tetrahydrofuran (10 mL) there were added cyclopropanecarboxyaldehyde (0.20 mL) and 3 M sulfuric acid (0.87 mL), and then sodium borohydride (79 mg) was slowly added at 0°C and the mixture was stirred at room temperature for 30 minutes. A 5 N aqueous sodium hydroxide solution was added while cooling on ice to make the reaction mixture basic, and then extraction was performed with ethyl acetate, the extract was washed with saturated aqueous sodium hydrogencarbonate and brine and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (20 g), and the title compound (185 mg) was obtained from the n-hexane:ethyl acetate (6:1) fraction as white crystals.

02201H NMR (400MHz, CDCl3) δ -0.32-0.46 (m, 8H), 0.70-0.88 (m, 2H), 1.20 (t, J = 7.5 Hz, 3H), 1.97 (s, 3H), 2.38 (s, 3H), 2.74-2.97 (m, 6H), 3.67 (s, 3H), 3.93 (s, 3H), 6,34 (d, J = 7.7 Hz, 1H), 6.38 (d, J = 7.7 Hz, 1H), 6.68 (s, 1H), 6.75 (s, 1H).

0221MS(ESI) m/z 434 MH+

Example 63

N-[2-Ethyl-4-methoxy-7-(2-methoxy-4,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(1-ethylpropyl)amine

0222To a solution of 2-ethyl-4-methoxy-7-(2-methoxy-4,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-amine (100 mg) in acetic acid (10 mL) there was added 3-pentanone (0.04 mL), and then sodium triacetoxyborohydride (85.0 mg) was slowly added at room temperature and the mixture was stirred for 3 hours. A 5 N aqueous sodium hydroxide solution was added while cooling on ice, and then extraction was performed with ethyl acetate, the organic layer was washed with saturated aqueous sodium hydrogencarbonate and brine and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (10 g), and the title compound (69 mg) was obtained from the n-hexane:ethyl acetate (5:1) fraction as yellow crystals.

02231H NMR (400MHz, CDCl3) δ 0.94 (t, J = 7.5 Hz, 3H), 0.96 (t, J = 7.5 Hz, 3H), 1.21 (t, J = 7.5 Hz, 3H), 1.42-1.55 (m, 4H), 1.98 (s, 3H), 2.38 (s, 3H), 2.70 (q, J = 7.5 Hz, 2H), 2.87-2.96 (m, 1H), 3.67 (s, 3H), 3.92 (s, 3H), 6,20 (d, J = 7.7 Hz, 1H), 6.28 (d, J = 7.5 Hz, 1H), 6.67 (s, 1H), 6.74 (s, 1H).

0224MS(ESI) m/z 396 MH+

Example 64

tert-Butyl N-[7-(2,4-dichlorophenyl)-2-methylthiopyrazolo[1,5-a]pyridin-3-yl]carbamate

0225After dissolving tert-butyl N-[2-methylthiopyrazolo[1,5-a]pyridin-3-yl]carbamate (220 mg) in tetrahydrofuran (3 mL), a solution of n-butyllithium in hexane (1.6 M; 1.51 mL) was added dropwise at -78°C under a nitrogen stream, and the mixture was stirred for 30 minutes. A solution of 1,2-dibromo-1,1,2,2-tetrachloroethane (384 mg) in tetrahydrofuran (2 mL) was added to the reaction mixture, and stirring was continued for 30 minutes. Saturated aqueous ammonium chloride was added to the reaction mixture, the temperature was raised to room temperature, extraction was performed with ethyl acetate and the extract was washed with water and brine. After drying over anhydrous magnesium sulfate and filtration, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and tert-butyl N-[7-bromo-2-methylthiopyrazolo[1,5-a]pyridin-3-yl]carbamate was obtained from the n-hexane:ethyl acetate (10:1) fraction as yellow crystals. After dissolving this in 1,2-dimethoxyethane (6 mL) and water (1 mL), 2,4-dichlorophenylboric acid (191 mg), tetrakis(triphenylphosphine)palladium (0) complex (116 mg) and barium hydroxide octahydrate (315 mg) were added and the mixture was heated and stirred at 80°C for 4 hours under a nitrogen stream. Water was added to the reaction mixture, extraction was performed with ethyl acetate and the extract was washed with brine. After drying over anhydrous magnesium sulfate and filtration, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and the title compound (160 mg) was obtained from the n-hexane:ethyl acetate (20:1) fraction as a yellow oil.

02261H NMR (400MHz, CDCl3) δ 1.58 (s, 9H), 2.46 (s, 3H), 6.67 (m, 1H), 7.16 (dd, J = 6.8, 8.8 Hz, 1H), 7.36 (dd, J = 2.0, 8.4 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.54 (d, J = 2.0 Hz, 1H).

Example 65

tert-Butyl N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]carbamate

0227After dissolving tert-butyl N-[7-iodo-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]carbamate (2.0 g) in 1,2-dimethoxyethane (60 mL) and water (30 mL), 4,6-dimethyl-2-methoxyphenylboric acid (1.33 g), tetrakis(triphenylphosphine)palladium (0) complex (865 mg) and barium hydroxide octahydrate (2.34 g) were added and the mixture was heated and stirred at 80°C for 3 hours. Water was added to the reaction mixture, extraction was performed with ethyl acetate and the extract was washed with brine. After drying over anhydrous magnesium sulfate and filtration, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and the title compound (2.1 g) was obtained from the n-hexane:ethyl acetate (20:1) fraction as yellow amorphous.

02281H NMR (400MHz, CDCl3) δ 1.54 (br s, 9H), 1.98 (s, 3H), 2.39 (s, 3H), 2.42 (s, 3H), 3.64 (s, 3H), 6.02-6.12 (m, 1H), 6.58 (dd, J = 1.6, 6.8 Hz, 1H), 7.13 (dd, J = 6.8, 9.2 Hz, 1H), 7.42-7.48 (m, 1H).

Example 66

N-Cyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine

0229After dissolving tert-butyl N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]carbamate (400 mg) in N,N-dimethylformamide (5 mL), sodium hydride (60%, 58 mg) was added while cooling on ice, and then (bromomethyl)cyclopropane (111 µL) was added and the mixture was stirred for 1 hour at 40°C. Water was added to the reaction mixture, extraction was performed with ethyl acetate and the extract was washed with brine. After drying the obtained organic layer over anhydrous magnesium sulfate and filtering it, the solvent was concentrated under reduced pressure to obtain crude tert-butyl N-cyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]carbamate. This was dissolved in ethyl acetate (10 mL) without purification, a 4 N hydrochloric acid/ethyl acetate solution (20 mL) was added, and the mixture was stirred at 40°C for 1 hour. The reaction mixture was neutralized with 5 N aqueous sodium hydroxide while cooling on ice, and then extraction was performed with ethyl acetate and the organic layer was washed with brine. After drying over anhydrous magnesium sulfate and filtration, the solvent was distilled off under reduced pressure to obtain the title compound (368 mg) as a yellow oil.

02301H NMR (400MHz, CDCl3) δ 0.18-0.23 (m, 2H), 1.50-0.55 (m, 1H), 1.1.04-1.13 (m, 1H), 1.98 (s, 3H), 2.38 (s, 3H), 2.39 (s, 3H), 2.99 (d, J = 6.8 Hz, 2H), 3.66 (s, 3H), 6.51 (dd, J = 1.2, 6.8 Hz, 1H), 6.66 (br s, 1H), 6.74 (br s, 1H), 7.00 (dd, J = 6.8, 8.8 Hz, 1H), 7.42 (dd, J = 1.6, 8.8 Hz, 1H).

Example 67

N-[7-(2-Methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N,N-dipropylamine

0231tert-Butyl N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]carbamate (50 mg) was dissolved in a 4 N hydrochloric acid/ethyl acetate solution (2 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was neutralized with 5 N aqueous sodium hydroxide and extracted with ethyl acetate, and the organic layer was concentrated to obtain 7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridine-3-amine. This was dissolved in tetrahydrofuran (1 mL), and after adding propionaldehyde (0.078 mL) and 3 M aqueous sulfuric acid (0.363 mL), sodium borohydride (27 mg) was added in five portions at a time while vigorously stirring on ice, and stirring was continued for 30 minutes. After adding saturated aqueous sodium hydrogencarbonate to neutralize the reaction mixture, extraction was performed with ethyl acetate and the organic layer was concentrated. The residue was purified by silica gel column chromatography, and the title compound (20.6 mg) was obtained from the n-hexane:ethyl acetate (7:1) fraction as a light yellow oil.

02321H NMR (400MHz, CDCl3) δ 0.88 (t, J = 7.6 Hz, 6H), 1.34-1.44 (m, 4H), 1.99 (s, 3H), 2.40 (s, 3H), 2.43 (s, 3H), 3.01-3.06 (m, 4H), 3.63 (s, 3H), 6.49 (dd, J = 1.2, 6.8 Hz, 1H), 6.67 (s, 1H). 6.75 (s, 1H), 7.03 (dd, J = 6.8, 8.8 Hz, 1H), 7.39 (dd, J = 1.2, 8.8 Hz, 1H).

0233The compounds of Examples 68 to 101 were synthesized according to the production method of Example 67.

Example 68

N-[7-(2,6-Dimethoxy-4-methylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N,N-dipropylamine

(Light yellow oil)

02341H NMR (400MHz, CDCl3) δ 0.84-0.92 (m, 6H), 1.34-1.44 (m, 4H), 2.40-2.48 (m, 6H), 3.00-3.10 (m, 4H), 3.70 (s, 6H), 6.49 (s, 2H), 6.56-6.60 (m, 1H), 6.99-7.05 (m, 1H), 7.35-7.42 (m, 1H).

Example 69

N-[7-(2,6-Dimethoxy-3-pyridyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N,N-dipropylamine

(Light yellow oil)

02351H NMR (400MHz, CDCl3) δ 0.88 (t, J = 6.8 Hz, 6H), 1.33-1.42 (m, 4H), 2.50 (s, 3H), 2.95-3.06 (m, 4H), 3.93 (s, 3H), 3.99 (s, 3H), 6.42 (d, J = 8.4 Hz, 1H), 6.67-6.74 (m, 1H), 6.98-7.06 (m, 1H), 7.34-7.42 (m, 1H), 7.98 (d, J = 8.4 Hz, 1H).

Example 70

N-[7-(6-Methoxy-2-methyl-3-pyridyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N,N-dipropylamine

(Light yellow oil)

02361H NMR (400MHz, CDCl3) δ 0.88 (t, J = 7.2 Hz, 6H), 1.32-1.42 (m, 4H), 2.30 (s, 3H), 2.47 (s, 3H), 3.00-3.06 (m, 4H), 4.00 (s, 3H), 6.48 (d, J = 6.8 Hz, 1H), 6.66 (d, J = 8.4 Hz, 1H), 7.03 (dd, J = 6.8, 8.4 Hz, 1H), 7.42 (d, J = 8.4 Hz, 1H), 7.61 (d, J =8.4 Hz, 1H).

Example 71

N3,N3-Dipropyl-7-[6-(dimethylamino)-4-methyl-3-pyridyl]-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-amine

(Light yellow oil)

02371H NMR (400MHz, CDCl3) δ 0.82 (t, J = 7.6 Hz, 6H), 1.19-1.70 (m, 4H), 2.06 (s, 3H), 2.42 (s, 3H), 2.90-3.00 (m, 4H), 3.13 (s, 6H), 6.40-6.47 (m, 2H), 6.92-7.02 (m, 1H), 7.30-7.40 (m, 1H), 8.08 (s, 1H).

0238MS(ESI) m/z 398 MH+

Example 72

N,N-Dicyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine

(Light yellow oil)

02391H NMR (400MHz, CDCl3) δ 0.00-0.04 (m, 4H), 0.28-0.34 (m, 4H), 0.80-0.90 (m, 2H), 1.99 (s, 3H), 2.40 (s, 3H), 2.44 (s, 3H), 2.97-3.04 (m, 4H), 3.68 (s, 3H), 6.49 (dd, J = 1.2, 6.8 Hz, 1H), 6.67 (s, 1H). 6.76 (s, 1H), 7.03 (dd, J = 6.8, 8.8 Hz, 1H), 7.46 (dd, J = 1.2, 8.8 Hz, 1H).

Example 73

N,N-Diisobutyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine

(Light yellow oil)

0240MS(ESI) m/z 426 MH+

Example 74

N-[7-(2,4-Dimethoxy-6-methylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N,N-dipropylamine

(Light yellow oil)

02411H NMR (400MHz, CDCl3) δ 0.88 (t, J = 7.2 Hz, 6H), 1.35-1.44 (m, 4H), 2.02 (s, 3H), 2.43 (s, 3H), 3.03 (t, J = 7.6 Hz, 4H), 3.67 (s, 3H), 3.86 (s, 3H), 6.42 (br s, 1H), 6.46 (br s, 1H), 6.47-6.51 (m, 1H), 7.00-7.05 (m, 1H), 7.37-7.40 (m, 1H).

Example 75

N-[7-(2-Methoxy-4-methylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N,N-dipropylamine

(Light yellow oil)

02421H NMR (400MHz, CDCl3) δ 0.88 (t, J = 7.6 Hz, 6H), 1.35-1.44 (m, 4H), 2.44 (s, 3H), 2.47 (s, 3H), 3.03 (t, J = 7.6 Hz, 4H), 3.77 (s, 3H), 6.61 (dd, J = 1.2, 6.8 Hz, 1H), 6.84 (s, 1H), 7.02 (dd, J = 6.8, 8.8 Hz, 1H), 7.37-7.40 (m, 1H), 7.43 (d, J = 7.6 Hz, 1H).

Example 76

N,N-Dicyclopropylmethyl-N-[7-(2,6-dimethoxy-4-methylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine

(Colorless oil)

02431H NMR (400MHz, CDCl3) δ -0.01-0.05 (m, 4H), 0.28-0.34 (m, 4H), 0.80-0.92 (m, 2H), 2.43 (m, 3H), 2.46 (s, 3H), 3.00 (d, J = 6.4 Hz, 2H), 3.69 (s. 6H), 6.49 (s, 2H), 6.57 (dd, J = 1.6, 6.8 Hz, 1H), 7.02 (dd, J = 6.8, 8.8 Hz, 1H), 7.44 (dd, J = 1.6, 8.8 Hz, 1H).

Example 77

N-[7-(4-Chloro-2-methoxyphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N,N-dicyclopropylmethylamine

(Light yellow oil)

02441H NMR (400MHz, CDCl3) δ 0.02-0.06 (m, 4H), 0.30-0.34 (m, 4H), 0.80-0.90 (m, 2H), 2.48 (s, 3H), 2.99 (d, J = 6.4 Hz, 4H), 3.76 (s, 3H), 6.59 (dd, J = 1.6, 6.8 Hz, 1H), 7.00-7.03 (m,21H), 7.06 (dd, J = 2.0, 8.0 Hz, 1H), 7.46-7.50 (m, 2H).

Example 78

N-[7-(2-Chloro-4-methoxyphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N,N-dicyclopropylmethylamine

(Light yellow oil)

02451H NMR (400MHz, CDCl3) δ 0.01-0.06 (m, 4H), 0.28-0.35 (m, 4H), 0.80-0.90 (m, 2H), 2.49 (s, 3H), 2.99 (d, J = 6.4 Hz, 4H), 3.88 (s, 3H), 6.55-6.58 (m, 1H), 6.90-6.94 (m, 1H), 7.01-7.07 (m, 2H), 7.45-7.53 (m, 2H).

Example 79

N,N-Dicyclopropylmethyl-N-[7-(4-methoxy-2-methylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine

(Light yellow oil)

02461H NMR (400MHz, CDCl3) δ 0.00-0.04 (m, 4H), 0.28-0.34 (m, 4H), 0.78-0.88 (m, 2H), 2.10 (s, 3H), 2.48 (s, 3H), 2.99 (d, J = 6.8 Hz, 4H), 3.87 (s, 3H), 6.47-6.51 (m, 1H), 6.81-6.86 (m, 1H), 7.03 (dd, J = 6.8, 8.8 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.45-7.49 (m, 1H).

Example 80

N-[7-(4-Methoxy-2,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N,N-dipropylamine

(Light yellow crystals)

02471H NMR (400MHz, CDCl3) δ 0.89 (t, J = 7.3 Hz, 6H), 1.30-1.46 (m, 4H), 2.01 (s, 6H), 2.41 (s, 3H), 3.03 (t, J = 7.1 Hz, 4H), 3.84 (s, 3H), 6,43 (br d, J = 6.4 Hz, 1H), 6.69 (s, 2H), 6.98-7.07 (m, 1H), 7.40 (br d, J = 9.3 Hz, 1H).

0248MS(ESI) m/z 398 MH+

Example 81

N,N-Dicyclopropylmethyl-N-[7-(4-methoxy-2,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine

(Light yellow crystals)

02491H NMR (400MHz, CDCl3) δ -0.06-0.10 (m, 4H), 0.22-0.36 (m, 4H), 0.80-0.94 (m, 2H), 2.01 (s, 6H), 2.44 (s, 3H), 3.01 (d, J = 6.4 Hz, 4H), 3.85 (s, 3H), 6,44 (br d, J = 6.4 Hz, 1H), 6.70 (s, 2H), 7.00-7.09 (m, 1H), 7.47 (br d, J= 8.6 Hz, 1H).

0250MS(ESI) m/z 422 MH+

Example 82

N,N-Dicyclopropylmethyl-N-[7-[4-methoxy-2-(trifluoromethyl)phenyl]-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine

(Yellow oil)

02511H NMR (400MHz, CDCl3) δ 0.00-0.04 (m, 4H), 0.27-0.32 (m, 4H), 0.80-0.90 (m, 2H), 2.42 (s, 3H), 2.95-3.05 (m, 4H), 3.93 (s, 3H), 6.50 (dd, J = 1.6, 6.8 Hz, 1H), 7.02 (dd, J = 6.8, 8.8 Hz, 1H), 7.15 (dd, J = 2.4, 8.4 Hz, 1H), 7.29 (d, J = 2.4 Hz, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.49 (dd, J = 1.6, 8.8 Hz, 1H).

Example 83

N-[7-[2-Chloro-4-(trifluoromethoxy)phenyl]-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N,N-dicyclopropylmethylamine

(Yellow oil)

02521H NMR (400MHz, CDCl3) δ 0.00-0.04 (m, 4H), 0.28-0.34 (m, 4H), 0.80-0.90 (m, 2H), 2.48 (s, 3H), 3.00 (d, J = 6.4 Hz, 4H), 6.58 (dd, J = 1.6, 6.8 Hz, 1H), 7.05 (dd, J = 6.8, 8.8 Hz, 1H), 7.23-7.27 (m, 1H), 7.40-7.42 (m, 1H), 7.54 (dd, J = 1.6, 8.8 Hz, 1H), 7.59 (dd, J = 8.4 Hz, 1H).

Example 84

N,N-Dicyclopropylmethyl-N-[7-(4-methyl-1,3-benzodioxol-5-yl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine

(Yellow crystals)

02531H NMR (400MHz, CDCl3) δ 0.00-0.04 (m, 4H), 0.28-0.33 (m, 4H), 0.80-0.90 (m, 2H), 1.95 (s, 3H), 2.50 (s, 3H), 3.00 (d, J = 6.8 Hz, 4H), 6.04 (s, 2H), 6.50 (dd, J = 1.2, 6.8 Hz, 1H), 6.76 (d, J = 8.4 Hz, 1H), 6.93 (d, J = 8.4 Hz, 1H), 7.48 (dd, J = 1.2, 8.8 Hz, 1H).

Example 85

N-[7-(2,4-Dimethoxyphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N,N-dipropylamine

(Yellow oil)

02541H NMR (400MHz, CDCl3) δ 0.88 (t, J = 7.3 Hz, 6H), 1.30-1.45 (m, 4H), 2.48 (s, 3H), 3.02 (t, J = 7.3 Hz, 4H), 3.76 (s, 3H), 3.88 (s, 3H), 6.56-6.64 (m, 3H), 7.01 (dd, J = 6.9, 8.9 Hz, 1H), 7.37 (dd, J = 1.4, 8.8 Hz, 1H), 7.49 (d, J = 8.9 Hz, 1H).

Example 86

N,N-Dicyclopropylmethyl-N-[7-(2,4-dimethoxyphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine

(Yellow oil)

02551H NMR (400MHz, CDCl3) δ -0.02-0.08 (m, 4H), 0.25-0.34 (m, 4H), 0.75-0.88 (m, 2H), 2.47 (s, 3H), 2.97 (d, J = 6.8 Hz, 4H), 3.72 (s, 3H), 3.86 (s, 3H), 6.54-6.60 (m, 3H), 6,99 (dd, J = 6.8, 8.8 Hz, 1H), 7.41 (dd, J = 1.4, 8.8 Hz, 1H), 7.47 (dd, J = 0.8, 8.0 Hz, 1H).

Example 87

N-[7-(4-Chloro-2,6-dimethoxyphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N,N-dipropylamine

(Yellow crystals)

02561H NMR (400MHz, CDCl3) δ 0.88 (t, J = 7.3 Hz, 6H), 1.33-1.45 (m, 4H), 2.43 (s, 3H), 3.02 (t, J = 7.3 Hz, 4H), 3.70 (s, 6H), 6,54 (dd, J = 1.4, 6.9 Hz, 1H), 6.67 (s, 2H), 7.02 (dd, J = 6.9, 8.9 Hz, 1H), 7.40 (dd, J = 1.5, 8.8 Hz, 1H).

0257MS(ESI) m/z 434 MH+

Example 88

N-[7-(4-Chloro-2,6-dimethoxyphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N,N-dicyclopropylmethylamine

(Yellow crystals)

02581H NMR (400MHz, CDCl3) δ -0.02-0.06 (m, 4H), 0.26-0.34 (m, 4H), 0.77-0.91 (m, 2H), 2.45 (s, 3H), 2.99 (d, J = 6.6 Hz, 4H), 3.69 (s, 6H), 6,54 (dd, J = 1.5, 6.8 Hz, 1H), 6.66 (s, 2H), 7.02 (dd, J = 6.8, 8.8 Hz, 1H), 7.45 (dd, J = 1.4, 8.9 Hz, 1H).

0259MS(ESI) m/z 458 MH+

Example 89

N-[7-(2-Chloro-6-methoxy-4-methylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N,N-dipropylamine

(Yellow crystals)

02601H NMR (400MHz, CDCl3) δ 0.88 (t, J = 7.4 Hz, 6H), 1.33-1.45 (m, 4H), 2.41 (s, 3H), 2.43 (s, 3H), 3.03 (t, J = 7.4 Hz, 4H), 3.70 (s, 3H), 6,55 (dd, J = 1.3, 6.8 Hz, 1H), 6.72 (s, 1H), 6.95 (s, 1H), 7.04 (dd, J = 6.9, 8.9 Hz, 1H), 7.43 (dd, J = 1.4, 8.9 Hz, 1H).

0261MS(ESI) m/z 418 MH+

Example 90

N-[7-(2-Chloro-6-methoxy-4-methylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N,N-dicyclopropylmethylamine

(Yellow crystals)

02621H NMR (400MHz, CDCl3) δ -0.02-0.08 (m, 4H), 0.26-0.36 (m, 4H), 0.78-0.92 (m, 2H), 2.41 (s, 3H), 2.45 (s, 3H), 3.00 (d, J = 6.6 Hz, 4H), 3.69 (s, 3H), 6,55 (dd, J = 1.5, 6.8 Hz, 1H), 6.73 (s, 1H), 6.96 (s, 1H), 7.04 (dd, J = 6.8, 9.0 Hz, 1H), 7.49 (dd, J = 1.4, 8.9 Hz, 1H).

0263MS(ESI) m/z 442 MH+

Example 91

N,N-Dicyclopropylmethyl-N-[2-(methylsulfanyl)-7-(2,4,6-trimethoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]amine

(Light yellow crystals)

02641H NMR (400MHz, CDCl3) δ 0.00-0.06 (m, 4H), 0.28-0.34 (m, 4H), 0.80-0.90 (m, 2H), 2.46 (s, 3H), 2.99 (d, J = 6.4 Hz, 4H), 3.69 (s, 6H), 3.89 (s, 3H), 6.23 (s, 2H), 6.56 (dd, J = 1.2, 6.8 Hz, 1H), 7.02 (dd, J = 6.8, 8.8 Hz, 1H), 7.43 (dd, J = 1.2, 8.8 Hz, 1H).

Example 92

N,N-Dicyclopropylmethyl-N-[7-(2,4-dimethoxy-6-methylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine

(Yellow oil)

02651H NMR (400MHz, CDCl3) δ -0.01-0.04 (m, 4H), 0.28-0.34 (m, 4H), 0.80-0.92 (m, 2H), 2.02 (m, 3H), 2.45 (s, 3H), 2.96-3.04 (m, 4H), 3.67 (s, 3H), 3.87 (s. 6H), 6.42 (d, J = 2.0 Hz, 2H), 6.47 (d, J = 2.0 Hz, 2H), 6.49 (dd, J = 1.6, 6.8 Hz, 1H), 7.03 (dd, J = 6.8, 8.8 Hz, 1H), 7.46 (dd, J = 1.6, 8.8 Hz, 1H).

Example 93

N3,N3-Dicyclopropylmethyl-7-[6-(dimethylamino)-2-methyl-3-pyridyl]-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-amine

(Yellow oil)

02661H NMR (400MHz, CDCl3) δ 0.00-0.40 (m, 4H), 0.29-0.33 (m, 4H), 0.80-0.90 (m, 2H), 2.23 (s, 3H), 2.51 (s, 3H), 2.99 (d, J = 6.8 Hz, 4H), 3.15 (s, 6H), 6.42-6.48 (m, 2H), 7.00-7.04 (m, 1H), 7.44 (dd, J = 1.6, 8.8 Hz, 1H), 7.52 (d, J = 8.8 Hz, 1H).

Example 94

N3,N3-Dicyclopropylmethyl-7-[6-(dimethylamino)-2,4-dimethyl-3-pyridyl]-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-amine

(Yellow oil)

02671H NMR (400MHz, CDCl3) δ -0.01-0.02 (m, 4H), 0.26-0.32 (m, 4H), 0.80-0.90 (m, 2H), 1.95 (s, 3H), 2.15 (s, 3H), 2.45 (s, 3H), 3.00 (d, J = 6.8 Hz, 4H), 3.13 (s, 6H), 6.30 (s, 1H), 6.43 (dd, J = 1.6, 6.8 Hz, 1H), 7.01 (dd, J = 6.8, 8.8 Hz, 1H), 7.46 (dd, J = 1.6, 8.8 Hz, 1H).

Example 95

N3,N3-Dicyclopropylmethyl-7-[6-(dimethylamino)-3-pyridyl]-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-amine

(Yellow oil)

02681H NMR (400MHz, CDCl3) δ 0.00-0.70 (m, 4H), 0.29-0.34 (m, 4H), 0.80-0.85 (m, 2H), 2.61 (s, 3H), 2.95 (d, J = 6.8 Hz, 4H), 3.17 (s, 6H), 6.60-6.64 (m, 2H), 7.01-7.05 (m, 1H), 7.39-7.42 (m, 1H), 8.28-8.31 (m, 1H), 8.71-8.72 (m, 1H).

Example 96

N,N-Dicyclopropylmethyl-N-[7-(4-methoxy-6-methyl-3-pyridyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine

(Yellow oil)

02691H NMR (400MHz, CDCl3) δ -0.04-0.08 (m, 4H), 0.26-0.37 (m, 4H), 0.74-0.93 (m, 2H), 2.46 (s, 3H), 2.79 (s, 3H), 2.97 (d, J = 6.8 Hz, 4H), 3.88 (s, 3H), 6,60 (dd, J = 1.3, 6.8 Hz, 1H), 6.90 (s, 1H), 7.02 (dd, J = 6.8, 8.9 Hz, 1H), 7.53 (dd, J = 1.4, 8.9 Hz, 1H), 8.80 (s, 1H).

Example 97

N,N-Dicyclopropylmethyl-N-[7-(4,6-dimethyl-3-pyridyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine

(Brown oil)

02701H NMR (400MHz, CDCl3) δ -0.04-0.08 (m, 4H), 0.24-0.36 (m, 4H), 0.76-0.98 (m, 2H), 2.11 (s, 3H), 2.46 (s, 3H), 2.60 (s, 3H), 2.98 (d, J = 6.8 Hz, 4H), 6,52 (dd, J = 1.3, 6.8 Hz, 1H), 7.05 (dd, J = 6.8, 8.8 Hz, 1H), 7.12 (s, 1H), 7.52 (dd, J = 1.5, 8.9 Hz, 1H), 8.46 (s, 1H).

Example 98

N3,N3-Dicyclopropylmethyl-7-[6-(dimethylamino)-4-methyl-3-pyridyl]-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-amine

(Light yellow oil)

02711H NMR (400MHz, CDCl3) δ -0.02-0.08 (m, 4H), 0.26-0.36 (m, 4H), 0.78-0.90 (m, 2H), 2.09 (s, 3H), 2.50 (s, 3H), 2.99 (d, J = 6.5 Hz, 4H), 3.15 (s, 6H), 6.45 (s, 1H), 6,50 (dd, J = 1.6, 6.8 Hz, 1H), 7.03 (dd, J = 6.8, 8.8 Hz, 1H), 7.47 (dd, J = 1.6, 8.9 Hz, 1H), 8.15 (s, 1H).

Example 99

N-[7-(2-Methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N,N-ditetrahydro-3-furanylmethylamine

(Yellow oil)

02721H NMR (400MHz, CDCl3) δ 1.55-1.66 (m, 2H), 1.89-1.98 (m, 2H), 1.98-2.01 (m, 3H), 2.18-2.28 (m, 2H), 2.40 (s, 3H), 2.43 (s, 3H), 2.96-3.03 (m, 2H), 3.11-3.19 (m, 2H), 3.56-3.61 (m, 2H), 3.64-3.70 (m, 5H), 3.74-3.84 (m, 4H), 6.53 (d, J = 1.6, 6.8 Hz., 1H), 6.67 (s, 1H), 6.76 (s, 1H), 7.08 (dd, J = 6.8, 8.8 Hz, 1H), 7.31 (dd, J = 1.6, 8.8 Hz, 1H).

Example 100

N,N-Di(3-furylmethyl)-N-[7-(4-methoxy-2,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine

(Yellow oil)

02731H NMR (400MHz, CDCl3) δ 1.97 (s, 6H), 2.42 (s, 3H), 3.84 (s, 3H), 4.12 (s, 4H), 6.28-6.33 (m, 2H), 6.39 (dd, J = 1.3, 8.1 Hz, 1H), 6.68 (s, 2H), 6.95 (dd, J = 6.8, 8.9 Hz, 1H), 7.13 (dd, J = 1.4, 8.9 Hz, 1H), 7.20-7.25 (m, 2H), 7.26-7.32 (m, 2H).

Example 101

N-[7-(4-Bromo-2-methoxyphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N,N-dicyclopropylmethylamine

(Yellow oil)

02741H NMR (400MHz, CDCl3) δ 0.00-0.08 (m, 4H), 0.28-0.46 (m, 4H), 0.78-0.89 (m, 2H), 2.48 (s, 3H), 2.95-3.03 (m, 4H), 3.76 (s, 3H), 6.59 (dd, J = 1.3, 6.8 Hz, 1H), 7.02 (dd, J = 6.8, 8.8 Hz, 1H), 7.16 (s, 1H), 7.21 (d, J = 8.0 Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.48 (dd, J = 1.3, 8.8 Hz, 1H).

Example 102

N-[7-(2,4-Dichlorophenyl)-2-methylthiopyrazolo[1,5-a]pyridin-3-yl]-N-propylamine

0275After dissolving tert-butyl N-[7-(2,4-dichlorophenyl)-2-methylthiopyrazolo[1,5-a]pyridin-3-yl]carbamate (150 mg) in N,N-dimethylformamide (3 mL), sodium hydride (60%, 21 mg) was added while cooling on ice, and then 1-iodopropane (0.041 mL) was added and the mixture was stirred for 30 minutes. Water was added to the reaction mixture, extraction was performed with ethyl acetate and the extract was washed with brine. The obtained organic layer was dried over anhydrous magnesium sulfate and filtered, and then the solvent was distilled off under reduced pressure to obtain a crude product. This was dissolved in ethyl acetate (1 mL) without purification, a 4 N hydrochloric acid/ethyl acetate solution (4 mL) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was neutralized with 5 N aqueous sodium hydroxide while cooling on ice, and then extraction was performed with ethyl acetate and the organic layer was washed with water and brine. After drying over anhydrous magnesium sulfate and filtration, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and the title compound (60 mg) was obtained from the n-hexane:ethyl acetate (20:1) fraction as a yellow oil.

02761H NMR (400MHz, CDCl3) δ 0.99 (t, J = 7.6 Hz, 3H), 1.63-1.72 (m, 2H), 2.45 (s, 3H), 3.20 (t, J = 7.6 Hz, 2H), 6.62 (br d, J = 6.4 Hz, 1H), 7.06 (dd, J = 6.4, 8.4 Hz, 1H), 7.36 (dd, J = 2.0, 8.4 Hz, 1H), 7.44(d, J = 8.4 Hz, 1H), 7.53 (d, J = 2.0 Hz, 1H), 7.63-7.69 (m, 1H).

Example 103

N-[7-(2,4-Dichlorophenyl)-2-methylthiopyrazolo[1,5-a]pyridin-3-yl]-N,N-dipropylamine

0277N-[7-(2,4-dichlorophenyl)-2-methylthiopyrazolo[1,5-a]pyridin-3-yl]-N-propylamine (59 mg) was dissolved in tetrahydrofuran (1 mL), and after adding propionaldehyde (0.035 mL) and 3 M aqueous sulfuric acid (0.16 mL), sodium borohydride (12 mg) was added in five portions while vigorously stirring on ice, and stirring was continued for 30 minutes. Water was added to the reaction mixture, extraction was performed with diethyl ether and the extract was washed with saturated aqueous sodium hydrogencarbonate and brine. After drying over anhydrous magnesium sulfate and filtration, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and the title compound (49 mg) was obtained from the n-hexane:ethyl acetate (100:1) fraction as a yellow oil.

02781H NMR (400MHz, CDCl3) δ 0.88 (t, J = 7.6 Hz, 6H), 1.33-1.44 (m, 4H), 2.46 (s, 3H), 3.02 (t, J = 7.6 Hz, 2H), 6.56 (br d, J = 6.4 Hz, 1H), 7.03 (dd, J = 6.4, 8.4 Hz, 1H), 7.36 (dd, J = 2.0, 8.4 Hz, 1H), 7.45 (d, J = 8.4 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.54 (d, J = 2.0 Hz, 1H).

0279The compounds of Examples 104 to 158 were synthesized according to the production method of Examples 102 and 103.

Example 104

N-Isobutyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-propylamine

(Light yellow oil)

02801H NMR (400MHz, CDCl3) δ 0.85-0.95 (m, 9H), 1.35-1.45 (m, 2H), 1.50-1.60 (m, 1H), 1.99 (s, 3H), 2.40 (s, 3H), 2.42 (s, 3H), 2.86 (d, J = 6.8 Hz, 2H), 2.98 (t, J = 6.8 Hz, 2H), 3.68 (s, 3H), 6.47-6.51(m, 1H), 6.67 (s, 1H), 6.75 (s, 1H), 7.00-7.06 (m, 1H), 7.38-7.43 (m, 1H).

Example 105

N-Cyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-propylamine

(Yellow oil)

02811H NMR (400MHz, CDCl3) δ -0.03-0.01 (m, 2H), 0.27-0.32 (m, 2H), 0.80-0.90 (m, 1H), 0.90 (t, J = 7.6 Hz, 3H), 1.35-1.45 (m, 2H), 1.99 (s, 3H), 2.40 (s, 3H), 2.43 (s, 3H), 2.93 (d, J = 6.8 Hz, 2H), 3.10-3.15 (m, 2H), 3.68 (s, 3H), 6.49 (dd, J = 1.2, 6.8 Hz, 1H), 6.67 (s, 1H). 6.75 (s, 1H), 7.03 (dd, J = 6.8, 8.8 Hz, 1H), 7.43 (dd, J = 1.2, 8.8 Hz, 1H).

Example 106

N-[7-(2-Methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(2-methoxyethyl)-N-propylamine

(Light yellow oil)

02821H NMR (400MHz, CDCl3) δ 0.88 (t, J = 7.2 Hz, 3H), 1.30-1.44 (m, 2H), 1.99 (s, 3H), 2.40 (s, 3H), 2.43 (s, 3H), 3.06-3.12 (m, 2H), 3.28, (s, 3H), 3.28-3.32 (m, 2H), 3.35-3.40 (m, 2H), 3.68 (s, 3H), 6.51 (dd, J = 1.2, 6.8 Hz, 1H), 6.67 (s, 1H). 6.75 (s, 1H), 7.05 (dd, J = 6.8, 8.8 Hz, 1H), 7.41 (dd, J = 1.6, 8.8 Hz, 1H).

Example 107

N-Cyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(2-methoxyethyl)amine

(Light yellow oil)

02831H NMR (400MHz, CDCl3) δ -0.02-0.02 (m, 2H), 0.28-0.32 (m, 2H), 0.82-0.92 (m, 2H), 1.99 (s, 3H), 2.40 (s, 3H), 2.44 (s, 3H), 2.98 (d, J = 6.8 Hz, 2H), 3.29 (s, 3H), 3.36-3.42 (m, 4H), 3.68 (s, 3H), 6.51 (dd, J = 1.2, 6.8 Hz, 1H), 6.67 (s, 1H). 6.76 (s, 1H), 7.05 (dd, J = 6.8, 8.8 Hz, 1H), 7.44 (dd, J = 1.2, 8.8 Hz, 1H).

Example 108

N-Isobutyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(2-methoxyethyl)amine

(Light yellow oil)

0284MS(ESI) m/z 428 MH+

Example 109

N-(3-Fluoropropyl)-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-propylamine

(Light yellow oil)

02851H NMR (400MHz, CDCl3) δ 0.89 (t, J = 7.2 Hz, 3H), 1.36-1.45 (m, 2H), 1.68-1.82 (m, 2H), 1.99 (s, 3H), 2.40 (s, 3H), 2.43 (s, 3H), 3.01-3.06 (m, 2H), 3.23 (t, J = 6.8 Hz, 2H), 3.68 (s, 3H), 4.56 (td, J = 6.0, 47.6 Hz, 2H), 6.51 (dd, J = 1.6, 6.8 Hz, 1H), 6.67 (s, 1H). 6.75 (s, 1H), 7.06 (dd, J = 6.8, 8.8 Hz, 1H), 7.37 (dd, J = 1.6, 8.8 Hz, 1H).

Example 110

N-Cyclopropylmethyl-N-(3-fluoropropyl)-N-[7-(2-methoxy-9,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine

(Light yellow oil)

02861H NMR (400MHz, CDCl3) δ -0.02-0.02 (m, 2H), 0.28-0.36 (m, 2H), 0.80-0.92 (m, 1H), 1.70-1.84 (m, 2H), 1.99 (s, 3H), 2.40 (s, 3H), 2.43 (s, 3H), 2.93 (d, J = 6.8 Hz, 2H), 3.31 (t, J = 7.6 Hz, 2H), 3.68 (s, 3H), 4.57 (td, J = 6.0, 47.2 Hz, 2H), 6.50 (dd, J = 1.6, 6.8 Hz, 1H), 6.67 (s, 1H), 6.76 (s, 1H), 7.05 (dd, J = 6.8, 8.8 Hz, 1H), 7.40 (dd, J = 1.6, 8.8 Hz, 1H).

Example 111

N-(3-Fluoropropyl)-N-isobutyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine

(Light yellow oil)

0287MS(ESI) m/z 430 MH+

Example 112

N-Cyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2-furanylmethylamine

(Light yellow oil)

0288MS(ESI) m/z 452 MH+

Example 113

N-Isobutyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2-furanylmethylamine

(Light yellow oil)

0289MS(ESI) m/z 454 MH+

Example 114

N-[7-(2-Methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(2-morpholinoethyl)-N-propylamine

(Light yellow oil)

0290MS(ESI) m/z 469 MH+

Example 115

N1-[7-(2-Methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N2,N2-dimethyl-N1-propyl-1,2-ethanediamine

(Light yellow oil)

0291MS(ESI) m/z 427 MH+

Example 116

N-[7-(2-Methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-propyl-N-(2-tetrahydro-1H-1-pyrrolylethyl)amine

(Light yellow oil)

0292MS(ESI) m/z 453 MH+

Example 117

N-[7-(2-Methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-propyl-N-(2-pyridylmethyl)amine

(Light yellow oil)

0293MS(ESI) m/z 447 MH+

Example 118

N-Cyclopropylmethyl-N-[7-(4-methoxy-2,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-propylamine

(Yellow oil)

02941H NMR (400MHz, CDCl3) δ -0.04-0.05 (m, 2H), 0.26-0.37 (m, 2H), 0.82-0.98 (m, 1H), 0.96 (t, J = 7.3 Hz, 3H), 1.38-1.52 (m, 2H), 2.06 (s, 6H), 2.47 (s, 3H), 2.98 (d, J = 6.8 Hz, 2H), 3.12-3.20 (m, 2H), 3.90 (s, 3H), 6.44-6.50 (m, 1H), 6.74 (s, 2H), 7.03-7.12 (m, 1H), 7.44-7.52 (m, 1H).

0295MS(ESI) m/z 410 MH+

Example 119

N-Isobutyl-N-[7-(4-methoxy-2,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-propylamine

(Yellow crystals)

02961H NMR (400MHz, CDCl3) δ 0.89 (t, J = 7.4 Hz, 3H), 0.93 (d, J = 6.6 Hz, 6H), 1.33-1.45 (m, 2H), 1.52-1.64 (m, 1H), 2.01 (s, 6H), 2.41 (s, 3H), 2.87 (d, J = 7.1 Hz, 2H), 2.98 (t, J = 7.4 Hz, 2H), 3.84 (s, 3H), 6.42 (dd, J = 1.3, 6.8 Hz, 1H), 6.69 (s, 2H), 7.03 (dd, J = 6.8, 8.8 Hz, 1H), 7.42 (dd, J = 1.3, 8.8 Hz, 1H).

0297MS(ESI) m/z 412 MH+

Example 120

N-Cyclopropylmethyl-N-isobutyl-N-[7-(4-methoxy-2,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine

(Yellow crystals)

02981H NMR (400MHz, CDCl3) δ -0.02-0.05 (m, 2H), 0.32-0.39 (m, 2H), 0.87-0.99 (m, 1H), 1.01 (d, J = 6.6 Hz, 6H), 1.60-1.74 (m, 1H), 2.10 (s, 6H), 2.49 (s, 3H), 2.96 (d, J = 6.8 Hz, 2H), 3.02 (d, J = 7.1 Hz, 2H), 3.93 (s, 3H), 6.50 (dd, J = 1.5, 6.8 Hz, 1H), 6.77 (s, 2H), 7.11 (dd, J = 6.8, 9.0 Hz, 1H), 7.54 (dd, J = 1.4, 8.8 Hz, 1H).

0299MS(ESI) m/z 424 MH+

Example 121

N-Cyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-[(3-methyl-3-oxetanyl)methyl]amine

(Light yellow oil)

03001H NMR (400MHz, CDCl3) δ -0.04-0.04 (m, 2H), 0.30-0.40 (m, 2H), 0.76-0.86 (m, 1H), 0.87 (s, 3H), 1.97 (s, 1.5H), 1.98 (s, 1.5H), 2.40 (s, 3H), 2.45 (s, 3H), 2.86-3.01 (m, 2H), 3.20-3.25 (m, 1H), 3.52-3.74 (m, 8H), 6.55 (dd, J = 1.2, 6.8 Hz, 1H), 6.67 (s, 1H), 6.76 (s, 1H), 7.11 (dd, J = 6.8, 8.8 Hz, 1H), 7.44-7.48 (m, 1H).

Example 122

N-Cyclopropylmethyl-N-[7-(2,6-dimethoxy-4-methylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2-furanylmethylamine

(Yellow oil)

03011H NMR (400MHz, CDCl3) δ -0.02-0.02 (m, 2H), 0.29-0.34 (m, 2H), 0.80-0.90 (m, 1H), 1.62-1.72 (m, 1H), 1.75-1.85 (m, 2H), 1.86-1.96 (m, 1H), 2.43 (m, 3H), 2.44 (s, 3H), 2.96 (d, J = 6.8 Hz, 2H), 3.05-3.11 (m, 1H), 3.40-3.45 (m, 1H), 3.65-3.72 (m, 4H), 3.80-3.90 (m, 2H), 6.49 (s, 2H), 6.57 (dd, J = 1.6, 6.8 Hz, 1H), 7.04 (dd, J = 6.8, 8.8 Hz, 1H), 7.44 (dd, J = 1.6, 8.8 Hz, 1H).

Example 123

N-Cyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-3-furanylmethylamine

(Yellow oil)

03021H NMR (400MHz, CDCl3) δ -0.04-0.02 (m, 2H), 0.28-0.34 (m, 2H), 0.80-0.88 (m, 1H), 1.60-1.70 (m, 1H), 1.88-1.98 (m, 1H), 1.98 (s, 1.5H), 1.99 (s, 1.5H), 2.20-2.30 (m, 1H), 2.40 (s, 3H), 2.43 (s, 3H), 2.88-2.92 (m, 2H), 3.04-3.10 (m, 1H), 3.20-3.26 (m, 1H), 3.60-3.64 (m, 1H), 3.65-3.70 (m, 4H), 3.74-3.84 (m, 2H), 6.50 (dd, J = 1.2, 6.8 Hz, 1H), 6.67 (s, 1H), 6.75 (s, 1H), 7.05 (dd, J = 6.8, 8.8 Hz, 1H), 7.39-7.41 (m, 1H).

Example 124

N-Ethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-3-furanylmethylamine

(Light yellow oil)

03031H NMR (400MHz, CDCl3) δ 0.97 (t, J = 7.2 Hz, 3H), 1.55-1.66 (m, 1H), 1.87-1.97 (m, 1H), 1.98 (s, 1.5H), 1.99 (s, 1.5H), 2.20-2.28 (m, 1H), 2.40 (s, 3H), 2.43 (s, 3H), 3.02 (dd, J = 8.4, 12.0 Hz, 1H), 3.10 (q, J = 7.2 Hz, 2H), 3.19 (dd, J = 6.4, 12.0 Hz, 1H), 3.57 (dd, J = 5.6, 8.4 Hz, 1H), 3.63-3.71 (m, 4H), 3.72-3.84 (m, 2H), 6.51 (dd, J = 1.2, 6.8 Hz, 1H), 6.67 (s, 1H), 6.75 (s, 1H), 7.05 (dd, J = 6.8, 9.2 Hz, 1H), 7.35 (dd, J = 1.6, 9.2 Hz, 1H).

Example 125

N-Cyclopropylmethyl-N-[7-(2,6-dimethoxy-4-methylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-3-furanylmethylamine

(Light yellow oil)

03041H NMR (400MHz, CDCl3) δ 0.00-0.05 (m, 2H), 0.30-0.38 (m, 2H), 0.80-0.90 (m, 1H), 1.55-1.70 (m, 1H), 1.86-1.96 (m, 1H), 2.22-2.30 (m, 1H), 2.44 (s, 3H), 2.45 (s, 3H), 2.90 (d, J = 6.4 Hz, 2H), 3.04-3.10 (m, 1H), 3.21-3.26 (m, 1H), 3.60-3.68 (m, 2H), 3.70 (s, 6H), 3.73-3.84 (m, 2H), 6.49 (s, 2H), 6.57-6.60 (m, 1H), 7.02-7.07 (m, 1H), 7.36-7.40 (m, 1H).

Example 126

1-(2-(Cyclopropylmethyl)[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]aminoethyl)-2-pyrrolidinone

(Light yellow oil)

03051H NMR (400MHz, CDCl3) δ -0.07-0.03 (m, 2H), 0.27-0.47 (m, 2H), 0.78-0.88 (m, 1H), 1.86-1.96 (m, 2H), 1.99 (s, 3H), 2.28-2:36 (m, 2H), 2.40 (s, 3H), 2.43 (s, 3H), 2.88-2.98 (m, 2H), 3.32-3.43 (m, 6H), 3.68 (s, 3H), 6.51 (dd, J = 1.3, 6.8 Hz, 1H), 6.67 (s, 1H), 6.76 (s, 1H), 7.05 (dd, J = 6.8, 8.8 Hz, 1H), 7.39 (dd, J = 1.3, 8.8 Hz, 1H).

Example 127

N-[7-(2,6-Dimethoxy-4-methylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-propyl-N-tetrahydro-3-furanylmethylamine

(White crystals)

03061H NMR (400MHz, CDCl3) δ 0.89 (t, J = 7.3 Hz, 3H), 1.39 (ddq, J = 7.3, 7.3, 7.3 Hz, 2H), 1.57-1.67 (m, 1H), 1.87-1.97 (m, 1H), 2.18-2.31 (m, 1H), 2.44 (s, 3H), 2.44 (s, 3H), 2.97-3.04 (m, 1H), 3.01 (dd, J = 7.3, 7.3 Hz, 2H), 3.12-3.20 (m, 1H), 3.55-3.84 (m, 4H), 3.70 (s, 6H), 6.49 (s, 2H), 6.58 (dd, J = 1.3, 6.8 Hz, 1H), 7.05 (dd, J = 6.8, 8.8 Hz, 1H), 7.35 (dd, J = 1.3, 8.8 Hz, 1H).

Example 128

N-[7-(4-Methoxy-2,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-propyl-N-tetrahydro-3-furanylmethylamine

(Yellow oil)

03071H NMR (400MHz, CDCl3) δ 0.90 (t, J = 7.3 Hz, 3H), 1.32-1.45 (m, 2H), 1.56-1.68 (m, 1H), 1.87-2.00 (m, 1H), 2.01 (s, 6H), 2.15-2.30 (m, 1H), 2.42 (s, 3H), 2.96-3.06 (m, 3H), 3.17 (dd, J = 6.6, 12.0 Hz, 1H), 3.59 (dd, J = 5.7, 8.4 Hz, 1H), 3.62-3.71 (m, 1H), 3.72-3.84 (m, 2H), 3.85 (s, 3H), 6.45 (dd, J = 1.4, 6.8 Hz, 1H), 6.69 (s, 2H), 7.05 (dd, J = 6.8, 8.8 Hz, 1H), 7.36 (dd, J = 1.3, 8.9 Hz, 1H).

Example 129

N-Cyclopropylmethyl-N-[7-(4-methoxy-2,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-3-furanylmethylamine

(Yellow oil)

03081H NMR (400MHz, CDCl3) 5 -0.03-0.05 (m, 2H), 0.30-0.38 (m, 2H), 0.82-0.94 (m, 1H), 1.62-1.75 (m, 1H), 1.92-2.04 (m, 1H), 2.05 (s, 3H), 2.06 (s, 3H), 2.24-2.37 (m, 1H), 2.46 (s, 3H), 2.95 (d, J = 6.8 Hz, 2H), 3.12 (dd, J = 8.7, 12.0 Hz, 1H), 3.29 (dd, J = 6.6, 12.0 Hz, 1H), 3.66 (dd, J = 5.7, 8.6 Hz, 1H), 3.71 (dd, J = 7.4, 8.4 Hz, 1H), 3.81 (dd, J = 7.2, 8.8 Hz, 1H), 3.84-3.90 (m, 1H), 3.89 (s, 3H), 6.49 (dd, J = 1.5, 6.8 Hz, 1H), 6.74 (s, 2H), 7.09 (dd, J = 6.8, 8.8 Hz, 1H), 7.44 (dd, J = 1.5, 8.8 Hz, 1H).

Example 130

N-[7-(4-Methoxy-2,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-propyl-N-tetrahydro-2-furanylmethylamine

(Yellow oil)

03091H NMR (400MHz, CDCl3) δ 0.89 (t, J = 7.4 Hz, 3H), 1.32-1.46 (m, 2H), 1.58-1.70 (m, 1H), 1.74-1.99 (m, 3H), 2.00 (s, 3H), 2.01 (s, 3H), 2.41 (s, 3H), 3.01 (dd, J = 6.8, 12.0 Hz, 1H), 3.09 (t, J = 7.5 Hz, 2H), 3.33 (dd, J = 5.6, 12.0 Hz, 1H), 3.64-3.74 (m, 1H), 3.77-3.90 (m, 2H), 3.85 (s, 3H), 6.44 (dd, J = 1.5, 6.8 Hz, 1H), 6.69 (s, 2H), 7.05 (dd, J = 6.8, 8.8 Hz, 1H), 7.43 (dd, J = 1.4, 8.8 Hz, 1H).

Example 131

N-Cyclopropylmethyl-N-[7-(4-methoxy-2,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2-furanylmethylamine

(Yellow oil)

03101H NMR (400MHz, CDCl3) δ -0.02-0.05 (m, 2H), 0.28-0.38 (m, 2H), 0.80-0.97 (m, 1H), 1.67-1.78 (m, 1H), 1.79-2.06 (m, 3H), 2.05 (s, 3H), 2.06 (s, 3H), 2.46 (s, 3H), 3.02 (d, J = 6.8 Hz, 2H), 3.14 (dd, J = 7.0, 13.0 Hz, 1H), 3.47 (dd, J = 5.5, 13.0 Hz, 1H), 3.70-3.80 (m, 1H), 3.82-3.98 (m, 2H), 3.89 (s, 3H), 6.48 (dd, J = 1.5, 6.8 Hz, 1H), 6.74 (s, 2H), 7.09 (dd, J = 6.8, 8.8 Hz, 1H), 7.51 (dd, J = 1.4, 8.8 Hz, 1H).

Example 132

N-[7-(4-Chloro-2,6-dimethoxyphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-propyl-N-tetrahydro-2-furanylmethylamine

(Yellow crystals)

03111H NMR (400MHz, CDCl3) δ 0.88 (t, J = 7.1 Hz, 3H), 1.30-1.46 (m, 2H), 1.54-1.70 (m, 1H), 1.72-2.00 (m, 3H), 2.43 (s, 3H), 2.95-3.12 (m, 3H), 3.25-3.38 (m, 1H), 3.62-3.76 (m, 1H), 3.70 (s, 6H), 3.77-3.90 (m, 2H), 6.55 (dd, J = 1.4, 6.8 Hz, 1H), 6.67 (s, 2H), 7.04 (dd, J = 6.8, 8.9 Hz, 1H), 7.43 (dd, J = 1.4, 8.9 Hz, 1H).

Example 133

N-[7-(4-Chloro-2,6-dimethoxyphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopropylmethyl-N-tetrahydro-2-furanylmethylamine

(Yellow oil)

03121H NMR (400MHz, CDCl3) δ -0.02-0.05 (m, 2H), 0.28-0.36 (m, 2H), 0.77-0.92 (m, 1H), 1.62-1.72 (m, 1H), 1.73-1.99 (m, 3H), 2.44 (s, 3H), 2.96 (t, J = 7.2 Hz, 2H), 3.00-3.12 (m, 1H), 3.35-3.46 (m, 1H), 3.62-3.76 (m, 1H), 3.70 (s, 6H), 3.77-3.92 (m, 2H), 6.55 (dd, J = 1.3, 6.8 Hz, 1H), 6.67 (s, 2H), 7.04(dd, J = 6.9, 8.8 Hz, 1H), 7.46 (dd, J = 1.3, 8.8 Hz, 1H).

Example 134

N-(3-Furylmethyl)-N-[7-(4-methoxy-2,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-propylamine

(Light yellow oil)

03131H NMR (400MHz, CDCl3) δ 0.88 (t, J = 7.3 Hz, 3H), 1.34-1.46 (m, 2H), 1.99 (s, 6H), 2.42 (s, 3H), 3.07 (t, J = 7.4 Hz, 2H), 3.84 (s, 3H), 4.09 (s, 2H), 6.32 (d, J = 1.1 Hz, 1H), 6.41 (dd, J = 1.3, 6.8 Hz, 1H), 6.68 (s, 2H), 7.00 (dd, J = 6.8, 8.9 Hz, 1H), 7.23 (s, 1H), 7.25-7.30 (m, 2H).

Example 135

N-Cyclopropylmethyl-N-(3-furylmethyl)-N-[7-(4-methoxy-2,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine

(Yellow oil)

03141H NMR (400MHz, CDCl3) δ -0.02-0.08 (m, 2H), 0.30-0.40 (m, 2H), 0.82-0.96 (m, 1H), 2.04 (s, 6H), 2.48 (s, 3H), 3.00 (d, J = 6.6 Hz, 2H), 3.89 (s, 3H), 4.24 (s, 2H), 6.42 (s, 1H), 6.47 (dd, J = 1.3, 6.8 Hz, 1H), 6.74 (s, 2H), 7.06 (dd, J = 6.8, 8.9 Hz, 1H), 7.30-7.36 (m, 2H), 7.41 (dd, J = 1.3, 8.9 Hz, 1H).

Example 136

N-(3-Furylmethyl)-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-propylamine

(Yellow oil)

03151H NMR (400MHz, CDCl3) δ 0.87 (t, J = 7.4 Hz, 3H), 1.33-1.46 (m, 2H), 1.97 (s, 3H), 2.39 (s, 3H), 2.43 (s, 3H), 3.06 (t, J = 7.3 Hz, 2H), 3.67 (s, 3H), 4.09 (s, 2H), 6.32-6.38 (m, 1H), 6.48 (dd, J = 1.3, 6.8 Hz, 1H), 6.66 (s, 1H), 6.75 (s, 1H), 7.00 (dd, J = 6.8, 8.8 Hz, 1H), 7.20-7.32 (m, 3H).

Example 137

N-Cyclopropylmethyl-N-(3-furylmethyl)-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine

(Yellow oil)

03161H NMR (400MHz, CDCl3) δ -0.03-0.06 (m, 2H), 0.28-0.38 (m, 2H), 0.80-0.93 (m, 1H), 2.00 (s, 3H), 2.42 (s, 3H), 2.46 (s, 3H), 2.97 (dd, J = 2.1, 6.7 Hz, 2H), 3.69 (s, 3H), 4.22 (s, 2H), 6.38-6.42 (m, 1H), 6.51 (dd, J = 1.5, 6.8 Hz, 1H), 6.69 (s, 1H), 6.78 (s, 1H), 7.05 (dd, J = 6.8, 8.8 Hz, 1H), 7.26-7.34 (m, 2H), 7.39 (dd, J = 1.5, 8.8 Hz, 1H).

Example 138 ∼

N-[7-(2,6-Dimethoxy-4-methylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-propyl-N-tetrahydro-2-furanylmethylamine

(White crystals)

03171H NMR (400MHz, CDCl3) δ 0.87 (t, J = 7.3 Hz, 3H), 1.40 (ddq, J = 7.3, 7.3, 7.3 Hz, 2H), 1.58-1.68 (m, 1H), 1.72-1.98 (m, 3H), 2.44 (s, 3H), 2.44 (s, 3H), 2.96-3.04 (m, 1H), 3.07 (dd, J = 7.3, 7.3 Hz, 2H), 3.31-3.38 (m, 1H), 3.63-3.73 (m, 1H), 3.69 (s, 6H), 3.78-3.89 (m, 2H), 6.49 (s, 2H), 6.57 (dd, J = 1.3, 6.8 Hz, 1H), 7.04 (dd, J = 6.8, 8.8 Hz, 1H), 7.41 (dd, J = 1.3, 8.8 Hz, 1H).

Example 139

3-(Cyclopropylmethyl)[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]aminotetrahydro-2-furanone

(White crystals)

03181H NMR (400MHz, CDCl3) δ -0.03-0.08 (m, 2H), 0.23-0.34 (m, 2H), 0.80-0.92 (m, 1H), 1.98 (s, 3H), 2.21-2.47 (m, 2H), 2.40 (s, 3H), 2.43 (s, 3H), 3.15-3.23 (m, 1H), 3.25-3.33 (m, 1H), 3.67 (s, 3H), 4.08-4.21 (m, 3H), 6.54 (dd, J = 1.3, 6.8 Hz, 1H), 6.67 (s, 1H), 6.76 (s, 1H), 7.10 (dd, J = 6.8, 8.8 Hz, 1H), 7.65 (dd, J = 1.3, 8.8 Hz, 1H).

Example 140

N-Cyclopropylmethyl-N-[7-(2,4-dimethoxy-6-methylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-3-furanylmethylamine

(Yellow oil)

03191H NMR (400MHz, CDCl3) δ -0.02-0.01 (m, 2H), 0.30-0.35 (m, 2H), 0.80-0.90 (m, 1H), 1.60-1.70 (m, 1H), 1.88-1.98 (m, 2H), 2.01 (s, 1.5H), 2.02 (s, 1.5H), 2.20-2.30 (m, 1H), 2.43 (s, 3H), 2.88-2.92 (m, 2H), 3.04-3.10 (m, 1H), 3.20-3.27 (m, 1H), 3.60-3.65 (m, 1H), 3.65-3.70 (m, 4H), 3.74-3.85 (m, 2H), 3.84 (s. 3H), 6.42 (d, J = 2.0 Hz, 1H), 6.46 (d, J = 2.0 Hz, 1H), 6.50 (dd, J = 1.2, 6.8 Hz., 1H), 7.05 (dd, J = 6.8, 8.8 Hz, 1H), 7.37-7.40 (m, 1H).

Example 141

N-[7-(2,4-Dimethoxy-6-methylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-propyl-N-tetrahydro-3-furanylmethylamine

(Yellow oil)

03201H NMR (400MHz, CDCl3) δ 0.89 (t, J = 7.6 Hz, 3H), 1.34-1.44 (m, 2H), 1.58-1.66 (m, 1H), 1.88-1.96 (m, 1H), 2.01 (s, 1.5H), 2.02 (s, 1.5H), 2.20-2.30 (m, 1H), 2.43 (s, 3H), 2.97-3.04 (m, 3H), 3.14-3.20 (m, 2H), 3.56-3.60 (m, 1H), 3.63-3.70 (m, 4H), 3.74-3.83 (m, 2H), 3.87 (s, 3H), 6.42 (d, J = 2.0 Hz, 1H), 6.46 (d, J = 2.0 Hz, 1H), 6.50 (dd, J = 1.2, 6.8 Hz, 1H), 7.05 (dd, J = 6.8, 8.8 Hz, 1H), 7.35 (dd, J = 1.2, 8.8 Hz, 1H).

Example 142

N-Cyclopropylmethyl-N-[7-(2,4-dimethoxy-6-methylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2-furanylamine

(Light yellow crystals)

03211H NMR (400MHz, CDCl3) δ -0.06-0.00 (m, 2H), 0.26-0.35 (m, 2H), 0.82-0.90 (m, 1H), 1.57-1.72 (m, 1H), 1.74-1.88 (m, 2H), 1.90-1.99 (m, 1H), 2.01 (s, 1.5H), 2.02 (s, 1.5H), 2.44 (s, 3H), 2.97 (d, J = 6.8 Hz, 2H), 3.05-3.12 (m, 1H), 3.38-3.45 (m, 1H), 3.66 (s, 1.5H), 3.67 (s, 1.5H), 3.67-3.72 (m, 2H), 3.80-3.92 (m, 5H), 6.42 (d, J = 2.0 Hz, 1H), 6.46 (d, J = 2.0 Hz, 1H), 6.48-6.52 (m, 1H), 7.04 (dd, J = 6.8, 8.8 Hz, 1H), 7.42-7.47 (m, 1H).

Example 143

N-[7-(2,4-Dimethoxy-6-methylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-propyl-N-tetrahydro-2-furanylamine

(Light yellow crystals)

03221H NMR (400MHz, CDCl3) δ 0.88 (t, J = 7.6 Hz, 3H), 1.35-1.44 (m, 2H), 1.58-1.68 (m, 1H), 1.76-1.87 (m, 2H), 1.88-1.99 (m, 1H), 2.01 (s, 1.5H), 2.02 (s, 1.5H), 2.43 (s, 3H), 2.98-3.04 (m, 1H), 3.05-3.10 (m, 2H), 3.30-3.36 (m, 1H), 3.66 (s, 3H), 3.66-3.72 (m, 1H), 3.80-3.86 (m, 2H), 3.87 (s, 3H), 6.42 (d, J = 2.0 Hz, 1H), 6.46 (d, J = 2.0 Hz, 1H), 6.50 (dd, J = 1.6, 6.8 Hz, 1H), 7.04 (dd, J = 6.8, 8.8 Hz, 1H), 7.40-7.44 (m, 1H).

Example 144

N-Cyclopropylmethyl-N-[7-(2,6-dimethoxy-4-methylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(3-furylmethyl)-amine

(Yellow oil)

03231H NMR (400MHz, CDCl3) δ -0.02-0.04 (m, 2H), 0.30-0.37 (m, 2H), 0.80-0.92 (m, 1H), 2.44 (s, 3H), 2.46 (s, 3H), 2.95 (d, J = 6.8 Hz, 2H), 3.69 (s, 6H), 4.21 (s, 2H), 6.38-6.42 (m, 1H), 6.49 (s, 2H), 6.57 (dd, J = 1.3, 6.8 Hz, 1H), 7.02 (dd, J = 6.8, 8.8 Hz, 1H), 7.28-7.32 (m, 2H), 7.37 (dd, J = 1.5, 8.8 Hz, 1H).

Example 145

N-[7-(2-Methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-propyl-N-tetrahydro-3-furanylmethylamine

(Yellow oil)

03241H NMR (400MHz, CDCl3) δ 0.89 (t, J = 7.2 Hz, 3H), 1.34-1.43 (m, 2H), 1.55-1.66 (m, 1H), 1.88-1.98 (m, 1H), 1.99 (s, 1.5H), 2.00 (s, 1.5H), 2.20-2.30 (m, 1H), 2.40 (s, 3H), 2.42 (s, 3H), 2.96-3.05 (m, 3H), 3.14-3.20 (m, 1H), 3.58 (dd, J = 5.6, 8.4 Hz, 1H), 3.63-3.70 (m, 1H), 3.68 (s, 3H), 3.74-3.84 (m, 2H), 6.51 (dd, J = 1.6, 6.8 Hz, 1H), 6.67 (s, 1H), 6.75 (s, 1H), 7.05 (dd, J = 6.8, 8.8 Hz, 1H), 7.35 (dd, J = 1.6, 6.8 Hz, 1H).

Example 146

N-Cyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(2-tetrahydro-2-furanylethyl)amine

(Yellow oil)

03251H NMR (400MHz, CDCl3) δ -0.03-0.00 (m, 2H), 0.26-0.32 (m, 2H), 0.80-0.90 (m, 1H), 1.38-1.50 (m, 1H), 1.50-1.60 (m, 1H), 1.64-1.76 (m, 1H), 1.80-1.90 (m, 1H), 1.91-1.98 (m, 1H), 1.98 (s, 1.5H), 1.99 (s, 1.5H), 2.40 (s, 3H), 2.43 (s, 3H), 2.93 (d, J = 6.8 Hz, 2H), 3.20-3.34 (m, 2H), 3.66-3.73 (m, 1H), 3.68 (s, 3H), 3.80-3.86 (m, 1H), 3.88-3.96 (m, 1H), 6.49 (dd, J = 1.6, 6.8 Hz, 1H), 6.67 (s, 1H), 6.75 (s, 1H), 7.03 (dd, J = 6.8, 8.8 Hz, 1H), 7.42 (dd, J = 1.6, 8.8 Hz, 1H).

Example 147

N-Cyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(3-pyridylmethyl)amine

(Yellow oil)

03261H NMR (400MHz, CDCl3) δ -0.04-0.01 (m, 2H), 0.28-0.35 (m, 2H), 0.80-0.89 (m, 1H), 1.94 (s, 3H), 2.39 (s, 3H), 2.44 (s, 3H), 2.87-2.97 (m, 2H), 3.65 (s, 3H), 4.36 (s, 2H), 6.48 (dd, J = 1.3, 6.8 Hz, 1H), 6.66 (s, 1H), 6.74 (s, 1H), 7.03 (dd, J = 6.8, 8.8 Hz, 1H), 7.17 (dd, J = 4.8, 8.0 Hz, 1H), 7.38 (dd, J = 1.3, 8.8 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 8.42 (d, J = 4.8 Hz, 1H), 8.61 (s, 1H).

Example 148

N-Cyclopropylmethyl-N-[7-(2,6-dimethoxy-4-methylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(2-furylmethyl)amine

(Yellow oil)

03271H NMR (400MHz, CDCl3) δ -0.04-0.06 (m, 2H), 0.28-0.36 (m, 2H), 0.80-0.93 (m, 1H), 2.42 (s, 3H), 2.45 (s, 3H), 3.00 (d, J = 6.8 Hz, 2H), 3.68 (s, 6H), 4.31 (s, 2H), 6.08-6.12 (m, 1H), 6.24 (dd, J = 1.8, 3.1 Hz, 1H), 6.48 (s, 2H), 6.55 (dd, J = 1.4, 6.8 Hz, 1H), 6.99 (dd, J = 6.8, 8.9 Hz, 1H), 7.24 (dd, J = 1.3, 8.8 Hz, 1H), 7.32 (dd, J = 0.7, 1.8 Hz, 1H).

Example 149

N-Cyclopropylmethyl-N-[7-(2,6-dimethoxy-4-methylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-[(5-methyl-2-furyl)methyl]amine

(Yellow oil)

03281H NMR (400MHz, CDCl3) δ -0.02-0.06 (m, 2H), 0.28-0.36 (m, 2H), 0.80-0.93 (m, 1H), 2.22 (s, 3H), 2.42 (s, 3H), 2.45 (s, 3H), 3.00 (d, J = 6.8 Hz, 2H), 3.68 (s, 6H), 4.25 (s, 2H), 5.78-5.82 (m, 1H), 5.97 (d, J = 3.1 Hz, 1H), 6.48 (s, 2H), 6.55 (dd, J = 1.4, 6.9 Hz, 1H), 6.98 (dd, J = 6.8, 8.9 Hz, 1H), 7.25 (dd, J = 1.4, 8.9 Hz, 1H).

Example 150

N-Cyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(1H-3-pyrrolylmethyl)amine

(Yellow oil)

03291H NMR (400MHz, CDCl3) δ -0.06- -0.03 (m, 2H), 0.28-0.34 (m, 2H), 0.78-0.88 (m, 1H), 1.97 (s, 3H), 2.39 (s, 3H), 2.44 (s, 3H), 2.88 (d, J = 6.4 Hz, 2H), 3.66 (s, 3H), 4.34 (s, 2H), 6.07-6.10 (m, 1H), 6.09 (dd, J = 2.4, 5.6 Hz, 1H), 6.50 (dd, J = 1.6, 6.8 Hz, 1H), 6.66 (s, 1H), 6.70-6.72 (m, 1H), 6.74 (s, 1H), 7.04 (dd, J = 6.8, 8.8 Hz, 1H), 7.35 (dd, J = 1.6, 8.8 Hz, 1H), 8.70-8.80 (m, 1H).

Example 151

N-Cyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(1H-4-pyrazolylmethyl)amine

(Yellow oil)

03301H NMR (400MHz, CDCl3) δ 0.00-0.02 (m, 2H), 0.33-0.39 (m, 2H), 0.82-0.92 (m, 1H), 1.98 (s, 3H), 2.41 (s, 3H), 2.47 (s, 3H), 2.95 (d, J = 6.8 Hz, 2H), 3.67 (s, 3H), 4.49 (s, 2H), 6.14 (d, J = 1.6 Hz, 1H), 6.53 (dd, J = 1.2, 6.8 Hz, 1H), 6.68 (s, 1H), 6.70 (s, 1H), 7.08 (dd, J = 6.8, 8.8 Hz, 1H), 7.39 (dd, J = 1.2, 8.8 Hz, 1H), 7.48 (d, J = 1.2 Hz, 1H).

Example 152

N-Cyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(4-pyridylmethyl)amine

(Yellow oil)

03311H NMR (400MHz, CDCl3) δ -0.06- -0.02 (m, 2H), 0.29-0.36 (m, 2H), 0.81-0.90 (m, 1H), 1.95 (s, 3H), 2.39 (s, 3H), 2.44 (s, 3H), 2.83-2.95 (m, 2H), 3.65 (s, 3H), 4.37 (s, 2H), 6.49 (dd, J = 1.3, 6.8 Hz, 1H), 6.65 (s, 1H), 6.73 (s, 1H), 7.05 (dd, J = 6.8, 8.8 Hz, 1H), 7.39 (d, J = 6.0 Hz, 2H), 7.43 (dd, J = 1.3, 8.8 Hz, 1H), 8.47 (d, J = 6.0 Hz, 2H).

Example 153

N-Cyclopropylmethyl-N-(2,2-difluoroethyl)-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine

(Yellow oil)

03321H NMR (400MHz, CDCl3) δ -0.02-0.04 (m, 2H), 0.28-0.38 (m, 2H), 0.78-0.90 (m, 1H), 1.97 (s, 3H), 2.38 (s, 3H), 2.42 (s, 3H), 2.99 (dd, J = 1.6, 6.8 Hz, 2H), 3.49 (dd, J = 4.4, 9.6 Hz, 2H), 3.66 (s, 3H), 5.76 (tt, J = 4.6, 56.4 Hz, 1H), 6.52 (dd, J = 1.6, 7.2 Hz, 1H), 6.65 (s, 1H), 6.74 (s, 1H), 7.08 (dd, J = 6.8, 8.8 Hz, 1H), 7.41 (dd, J = 1.6, 8.8 Hz, 1H).

Example 154

N-(2,2-Difluoroethyl)-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-3-furanylmethylamine

(Yellow oil)

03331H NMR (400MHz, CDCl3) δ 1.58-1.66 (m, 1H), 1.90-1.98 (m, 1H), 1.99 (s, 3H), 2.18-2.26 (m, 1H), 2.40 (s, 3H), 2.44 (s, 3H), 3.06-3.14 (m, 1H), 3.22-3.28 (m, 1H), 3.36-3.46 (m, 2H), 3.56-3.62 (m, 1H), 3.64-3.72 (m, 1H), 3.68 (s, 3H), 3.72-3.84 (m, 2H), 5.74 (tt, J = 4.4, 56.4 Hz, 1H), 6.56 (dd, J = 1.6, 6.8 Hz, 1H), 6.67 (s, 1H), 6.76 (s, 1H), 7.12 (dd, J = 6.8, 8.8 Hz, 1H), 7.36 (dd, J = 1.2, 8.8 Hz, 1H).

Example 155

N-Cyclopropylmethyl-N-[7-[2-(fluoromethoxy)-4,6-dimethylphenyl]-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-3-furanylmethylamine

(Light yellow oil)

03341H NMR (400MHz, CDCl3) δ -0.06-0.01 (m, 2H), 0.28-0.35 (m, 2H), 0.78-0.88 (m, 1H), 1.59-1.70 (m, 1H), 1.88-1.98 (m, 1H), 2.04 (s, 3H), 2.20-2.30 (m, 1H), 2.40 (s, 3H), 2.41 (s, 3H), 2.84-2.94 (m, 2H), 3.02-3.10 (m, 1H), 3.20-3.27 (m, 1H), 3.58-3.70 (m, 2H), 3.72-3.85 (m, 2H), 5.40 (dd, J = 2.4, 75 Hz, 1H), 5.53 (dd, J = 2.4, 75 Hz, 1H), 6.50 (dd, J = 1.3, 6.8 Hz, 1H), 6.91 (s, 1H), 6.94 (s, 1H), 7.05 (dd, J = 6.8, 8.8 Hz, 1H), 7.40 (dd, J = 1.3, 8.8 Hz, 1H).

Example 156

N-Cyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-[(1-methyl-1H-2-imidazolyl)methyl]amine

(Light yellow amorphous)

03351H NMR (400MHz, CDCl3) δ -0.08-0.02 (m, 2H), 0.23-0.33 (m, 2H), 0.75-0.85 (m, 1H), 1.98 (s, 3H), 2.40 (s, 3H), 2.43 (s, 3H), 2.85-2.91 (m, 2H), 3.65 (s, 3H), 3.66 (s, 3H), 4.43 (s, 2H), 6.49 (dd, J = 1.3, 6.8 Hz, 1H), 6.66 (s, 1H), 6.74 (s, 1H), 6.79 (d, J = 1.2 Hz, 1H), 6.91 (d, J = 1.2 Hz, 1H), 7.02 (dd, J = 6.8, 8.8 Hz, 1H), 7.26 (dd, J = 1.3, 8.8 Hz, 1H).

Example 157

N3-Cyclopropylmethyl-N3-[6-(dimethylamino)-3-pyridyl]methyl-7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-amine

(Light yellow amorphous)

03361H NMR (400MHz, CDCl3) δ -0.12- -0.02 (m, 2H), 0.22-0.32 (m, 2H), 0.75-0.86 (m, 1H), 1.95 (s, 3H), 2.39 (s, 3H), 2.43 (s, 3H), 2.80-2.92 (m, 2H), 3.04 (s, 6H), 3.65 (s, 3H), 4.19 (s, 2H), 6.44 (d, J = 8.0 Hz, 1H), 6.47 (dd, J = 1.3, 6.8 Hz, 1H), 6.65 (s, 1H), 6.73 (s, 1H), 7.00 (dd, J = 6.8, 8.8 Hz, 1H), 7.40 (dd, J = 1.3, 8.8 Hz, 1H), 7.53 (dd, J = 2.4, 8.0 Hz, 1H), 8.11 (d, J = 2.4 Hz, 1H).

Example 158

2-[7-(2-Methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amino-1-methylethyl benzoate

(Yellow oil)

03371H NMR (400MHz, CDCl3) δ 1.41-1.49 (m, 3H), 1.96 (s, 3H), 2.35 (s, 3H), 2.39 (s, 3H), 3.35-3.49 (m, 2H), 3.66 (s, 3H), 5.25-5.36 (m, 1H), 6.52 (dd, J = 6.8 Hz, 1H), 6.66 (s, 1H), 6.75 (s, 1H), 7.01 (dd, J = 6.8, 8.8 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.46 (dd, J = 8.0, 8.0 Hz, 1H), 7.46 (d, J = 8.8 Hz, 1H), 7.57 (dd, J = 8.0, 8.0 Hz, 1H), 8.07 (d, J = 8.0 Hz, 2H).

Example 159

N-Cyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylmethylamine

0338After dissolving N-cyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine (100 mg) in tetrahydrofuran (2 mL), tetrahydro-2H-4-pyrancarbaldehyde (78 mg) [CAS No.50675-18-8] and sodium triacetoxyborohydride (87 mg) were added, and the mixture was stirred for 1 hour. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, extraction was performed with ethyl acetate, and the extract was washed with brine. After drying over anhydrous magnesium sulfate and filtration, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and the title compound (70 mg) was obtained from the n-hexane:ethyl acetate (7:1) fraction as a yellow oil.

03391H NMR (400MHz, CDCl3) δ -0.05-0.00 (m, 2H), 0.27-0.35 (m, 2H), 0.80-0.90 (m, 1H), 1.22-1.33 (m, 2H), 1.50-1.62 (m, 1H), 1.75-1.82 (m, 2H), 2.00 (s, 3H), 2.40 (s, 3H), 2.43 (s, 3H), 2.88 (d, J = 6.4 Hz, 2H), 3.05 (d, J = 7.2 Hz, 2H), 3.28-3.35 (m, 2H), 3.69 (s, 3H), 3.90-3.96 (m, 2H), 6.50 (dd, J = 1.2, 6.8 Hz, 1H), 6.68 (s, 1H), 6.76 (s, 1H), 7.04 (dd, J = 6.8, 8.8 Hz, 1H), 7.40 (dd, J = 1.2, 8.8 Hz, 1H).

0340The compounds of Examples 160 to 198 were synthesized according to the production method of Example 159.

Example 160

N-[7-(4-Chloro-2,6-dimethoxyphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopropylmethyl-N-tetrahydro-2H-4-pyranylamine

(Yellow oil)

03411H NMR (400MHz, CDCl3) δ -0.02-0.06 (m, 2H), 0.26-0.36 (m, 2H), 0.72-0.88 (m, 1H), 1.50-1.65 (m, 2H), 1.84-1.94 (m, 2H), 2.49 (s, 3H), 3.04 (d, J = 6.6 Hz, 2H), 3.30-3.39 (m, 1H), 3.44 (dt, J = 1.5, 12.0 Hz, 2H), 3.75 (s, 6H), 3.96-4.04 (m, 2H), 6,61 (br d, J = 6.8 Hz, 1H), 6.73 (s, 2H), 7.10 (dd, J = 6.9, 8.9 Hz, 1H), 7.45 (br d, J = 8.8 Hz, 1H).

0342MS(ESI) m/z 488 MH+

Example 161

N-Cyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylamine

(Light yellow amorphous)

03431H NMR (400MHz, CDCl3) δ -0.08- -0.04 (m, 2H), 0.22-0.26 (m, 2H), 0.70-0.80 (m, 1H), 1.46-1.60 (m, 2H), 1.80-1.86 (m, 2H), 1.99 (s, 3H), 2.40 (s, 3H), 2.43 (s, 3H), 2.99 (d, J = 6.4 Hz, 2H), 3.26-3.34 (m, 1H), 3.35-3.43 (m, 2H), 3.68 (s, 3H), 3.92-3.98 (m, 2H), 6.50 (dd, J = 1.2, 6.8 Hz, 1H), 6.67 (s, 1H), 6.75 (s, 1H), 7.05 (dd, J = 6.8, 8.8 Hz, 1H), 7.38 (dd, J = 1.2, 8.8 Hz, 1H).

Example 162

N-[7-(2-Methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-propyl-N-tetrahydro-2H-4-pyranylamine

(Light yellow crystals)

03441H NMR (400MHz, CDCl3) δ 0.87 (t, J = 7.2 Hz, 3H), 1.26-1.36 (m, 2H), 1.50-1.60 (m, 2H), 1.80-1.86 (m, 2H), 2.40 (s, 3H), 2.42 (s, 3H), 3.09 (t, J = 6.4 Hz, 2H), 3.16-3.24 (m, 1H), 3.38 (t, J = 11.6 Hz, 2H), 3.69 (s, 3H), 3.92-3.98 (m, 2H), 6.49-6.52 (m, 1H), 6.67 (s, 1H), 6.75 (s, 1H), 7.02-7.08 (m, 1H), 7.34-7.38 (m, 1H).

Example 163

N-(3-Fluoropropyl)-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylamine

(Light yellow crystals)

03451H NMR (400MHz, CDCl3) δ 1.50-1.73 (m, 4H), 1.80-1.86 (m, 2H), 1.99 (s, 3H), 3.14-3.23 (m, 1H), 3.30 (t, J = 6.8 Hz, 2H), 3.37 (dt, J = 2.0, 12.0 Hz, 2H), 3.69 (s, 3H), 3.92-4.00 (m, 2H), 4.55 (td, J = 5.6, 47.6 Hz, 2H), 6.53 (dd, J = 1.2, 6.8 Hz, 1H), 6.67 (s, 1H), 6.75 (s, 1H), 7.07 (dd, J = 6.8, 8.8 Hz, 1H), 7.33 (dd, J = 1.2, 8.8 Hz, 1H).

Example 164

N-Cyclopropylmethyl-N-[7-(2,6-dimethoxy-4-methylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylamine

(Light yellow amorphous)

03461H NMR (400MHz, CDCl3) δ -0.04-0.00 (m, 2H), 0.24-0.30 (m, 2H), 0.70-0.80 (m, 1H), 1.48-1.62 (m, 2H), 1.80-1.86 (m, 2H), 2.44 (s, 3H), 2.45 (s, 3H), 2.99 (d, J = 6.8 Hz, 2H), 3.25-3.40 (m, 2H), 3.69 (s, 6H), 3.90-3.98 (m, 2H), 6.49 (s, 2H), 6.58 (dd, J = 1.2, 6.8 Hz, 1H), 7.04 (dd, J = 6.8, 8.8 Hz, 1H), 7.37 (dd, J = 1.2, 8.8 Hz, 1H).

Example 165

N-[7-(2,6-Dimethoxy-4-methylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-propyl-N-tetrahydro-2H-4-pyranylamine

(Light yellow crystals)

03471H NMR (400MHz, CDCl3) δ 0.86 (t, J = 7.2 Hz, 3H), 1.28-1.36 (m, 2H), 1.49-1.60 (m, 2H), 1.80-1.86 (m, 2H), 2.43 (s, 6H), 3.09 (t, J = 7.2 Hz, 2H), 3.15-3.24 (m, 1H), 3.33-3.40 (m, 2H), 3.70 (s, 6H), 3.92-3.98 (m, 2H), 6.49 (s, 2H), 6.57-6.60 (m, 1H), 7.02-7.06 (m, 1H), 7.32-7.36 (m, 1H).

Example 166

N-[7-(2,6-Dimethoxy-4-methylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(3-fluoropropyl)-N-tetrahydro-2H-4-pyranylamine

(Light yellow crystals)

03481H NMR (400MHz, CDCl3) δ 1.50-1.73 (m, 4H), 1.80-1.86 (m, 2H), 2.42 (s, 1.5H), 2.43 (s, 1.5H), 2.44 (s, 3H), 3.14-3.23 (m, 1H), 3.29 (t, J = 6.4 Hz, 2H), 3.37 (t, J = 12.0 Hz, 2H), 3.70 (s, 6H), 3.92-3.99 (m, 2H), 4.54 (td, J = 5.6, 47.6 Hz, 2H), 6.49 (s, 2H), 6.58-6.62 (m, 1H), 7.04-7.08 (m, 1H), 7.29-7.33 (m, 1H).

Example 167

N-[7-(4-Methoxy-2,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-propyl-N-tetrahydro-2H-4-pyranylamine

(Yellow oil)

03491H NMR (400MHz, CDCl3) δ 0.87 (t, J = 7.3 Hz, 3H), 1.24-1.37 (m, 2H), 1.46-1.60 (m, 2H), 1.78-1.86 (m, 2H), 2.01 (s, 6H), 2.40 (s, 3H), 3.09 (t, J = 7.2 Hz, 2H), 3.15-3.25 (m, 1H), 3.38 (dt, J = 2.0, 12.0 Hz, 2H), 3.85 (s, 3H), 3.92-3.99 (m, 2H), 6,44 (dd, J = 1.5, 6.8 Hz, 1H), 6.69 (s, 2H), 7.05 (dd, J = 6.8, 9.0 Hz, 1H), 7.37 (dd, J = 1.4, 8.9 Hz, 1H).

0350MS(ESI) m/z 440 MH+

Example 168

N-Cyclopropylmethyl-N-[7-(4-methoxy-2,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylamine

(Yellow crystals)

03511H NMR (400MHz, CDCl3) δ -0.02-0.06 (m, 2H), 0.28-0.37 (m, 2H), 0.78-0.90 (m, 1H), 1.55-1.68 (m, 2H), 1.89-1.98 (m, 2H), 2.11 (s, 6H), 2.51 (s, 3H), 3.09 (d, J = 6.6 Hz, 2H), 3.35-3.45 (m, 1H), 3.49 (dt, J = 2.0, 12.0 Hz, 2H), 3.95 (s, 3H), 4.02-4.09 (m, 2H), 6,54 (dd, J = 1.4, 6.6 Hz, 1H), 6.79 (s, 2H), 7.15 (dd, J = 6.7, 8.9 Hz, 1H), 7.49 (dd, J = 1.4, 8.9 Hz, 1H).

0352MS(ESI) m/z 452 MH+

Example 169

N-(3-Fluoropropyl)-N-[7-(4-methoxy-2,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylamine

(Light brown oil)

03531H NMR (400MHz, CDCl3) δ 1.48-1.65 (m, 2H), 1.66-1.74 (m, 2H), 1.78-1.87 (m, 2H), 2.01 (s, 6H), 2.40 (s, 3H), 3.14-3.24 (m, 1H), 3.29 (t, J = 6.6 Hz, 2H), 3.37 (dt, J = 2.0, 12.0 Hz, 2H), 3.85 (s, 3H), 3.92-4.00 (m, 2H), 4.49 (t, J = 5.8 Hz, 1H), 4.61 (t, J = 5.8 Hz, 1H), 6,46 (dd, J = 1.5, 6.8 Hz, 1H), 6.69 (s, 2H), 7.07 (dd, J = 6.8, 8.8 Hz, 1H), 7.34 (dd, J = 1.4, 8.8 Hz, 1H). MS(ESI) m/z 458 MH+

Example 170

N-[7-(4-Chloro-2,6-dimethoxyphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(3-fluoropropyl)-N-tetrahydro-2H-4-pyranylamine

(Yellow crystals)

03541H NMR (400MHz, CDCl3) δ 1.48-1.65 (m, 2H), 1.66-1.74 (m, 2H), 1.78-1.87 (m, 2H), 2.42 (s, 3H), 3.16-3.23 (m, 1H), 3.28 (t, J = 6.6 Hz, 2H), 3.36 (dt, J = 1.8, 12.0 Hz, 2H), 3.70 (s, 6H), 3.90-4.00 (m, 2H), 4.48 (t, J = 5.8 Hz, 1H), 4.60 (t, J = 5.8 Hz, 1H), 6,57 (dd, J = 1.4, 6.9 Hz, 1H), 6.67 (s, 2H), 7.06 (dd, J = 6.8, 8.8 Hz, 1H), 7.33 (dd, J = 1.4, 8.8 Hz, 1H).

Example 171

N-[7-(4-Chloro-2,6-dimethoxyphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-propyl-N-tetrahydro-2H-4-pyranylamine

(Yellow crystals)

03551H NMR (400MHz, CDCl3) δ 0.86 (t, J = 7.4 Hz, 3H), 1.25-1.38 (m, 2H), 1.47-1.60 (m, 2H), 1.78-1.87 (m, 2H), 2.42 (s, 3H), 3.08 (t, J = 7.3 Hz, 2H), 3.14-3.24 (m, 1H), 3.37 (dt, J = 2.0, 12.0 Hz, 2H), 3.70 (s, 6H), 3.91-3.99 (m, 2H), 6,55 (dd, J = 1.4, 6.9 Hz, 1H), 6.67 (s, 2H), 7.04 (dd, J = 6.8, 8.8 Hz, 1H), 7.36 (dd, J = 1.4, 8.8 Hz, 1H).

0356MS(ESI) m/z 476 MH+

Example 172

N-[7-(2-Chloro-6-methoxy-4-methylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopropylmethyl-N-tetrahydro-2H-4-pyranylamine

(Light green crystals)

03571H NMR (400MHz, CDCl3) δ -0.05-0.00 (m, 2H), 0.20-0.26 (m, 2H), 0.70-0.90 (m, 1H), 1.50-1.62 (m, 2H), 1.80-1.88 (m, 2H), 2.42 (s, 3H), 2.43 (s, 3H), 2.99 (d, J = 6.8 Hz, 2H), 3.25-3.44 (m, 3H), 3.70 (s, 3H), 3.90-3.95 (m, 2H), 6.56 (dd, J = 1.6, 7.2 Hz, 1H), 6.73 (s, 1H), 6.96 (d, J = 0.8 Hz, 1H), 7.06 (dd, J = 7.2, 9.2 Hz, 1H), 7.42 (dd, J = 1.6, 8.8 Hz, 1H).

Example 173

N-[7-(2-Chloro-6-methoxy-4-methylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-propyl-N-tetrahydro-2H-4-pyranylamine

(Light yellow crystals)

03581H NMR (400MHz, CDCl3) δ 0.86 (t, J = 7.2 Hz, 3H), 1.25-1.36 (m, 2H), 1.50-1.70 (m, 2H), 1.78-1.88 (m, 2H), 2.41 (s, 3H), 2.42 (s, 3H), 3.09 (t, J = 7.6 Hz, 2H), 3.15-3.22 (m, 1H), 3.34-3.40 (m, 2H), 3.70 (s, 3H), 3.93-3.96 (m, 2H), 6.56 (dd, J = 1.2, 6.8 Hz, 1H), 6.73 (s, 1H), 6.96 (br s, 1H), 7.06 (dd, J = 7.2, 9.2 Hz, 1H), 7.39 (dd, J = 1.6, 8.8 Hz, 1H).

Example 174

N-Cyclopropylmethyl-N-[7-(4-methoxy-2,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(1-methyl-4-piperidyl)amine

(Yellow crystals)

03591H NMR (400MHz, CDCl3) δ -0.02-0.06 (m, 2H), 0.27-0.36 (m, 2H), 0.78-0.92 (m, 1H), 1.56-1.68 (m, 2H), 1.83-1.93 (m, 1H), 1.98-2.10 (m, 3H), 2.11 (s, 6H), 2.33 (s, 3H), 2.51 (s, 3H), 2.88-2.97 (m, 2H), 3.10 (d, J = 6.6 Hz, 2H), 3.12-3.22 (m, 1H), 3.95 (s, 3H), 6,53 (dd, J = 1.4, 6.7 Hz, 1H), 6.79 (s, 2H), 7.13 (dd, J = 6.8, 8.8 Hz, 1H), 7.49 (dd, J = 1.4, 8.8 Hz, 1H).

0360MS (ESI) m/z 465 MH+

Example 175

1-(4-(Cyclopropylmethyl)[7-(4-methoxy-2,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]aminopiperidino)-1-ethanone

(Light yellow oil)

03611H NMR (400MHz, CDCl3) δ -0.02-0.06 (m, 2H), 0.28-0.38 (m, 2H), 0.78-0.90 (m, 1H), 1.43-1.56 (m, 2H), 1.97-2.08 (m, 2H), 2.11 (s, 3H), 2.13 (s, 3H), 2.15 (s, 3H), 2.52 (s, 3H), 2.86 (dt, J = 2.8, 14.0 Hz, 1H), 3.09 (d, J = 6.6 Hz, 2H), 3.19 (dt, J = 2.8, 14.0 Hz, 1H), 3.38-3.50 (m, 1H), 3.82-3.92 (m, 1H), 3.95 (s, 3H), 4.48-4.58 (m, 1H), 6,56 (dd, J = 1.5, 6.8 Hz, 1H), 6.80 (s, 2H), 7.16 (dd, J = 6.8, 8.8 Hz, 1H), 7.47 (dd, J = 1.5, 8.8 Hz, 1H).

0362MS(ESI) m/z 493 MH+

Example 176

N-Cyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2-thiophenylamine

(Light yellow oil)

03631H NMR (400MHz, CDCl3) δ -0.04-0.06 (m,2H), 0.26-0.36 (m, 2H), 0.78-0.88 (m, 1H), 1.85-1.95 (m, 1H), 2.03 (s, 1.5H), 2.04 (s, 1.5H), 2.15-2.25 (m, 1H), 2.46 (s, 3H), 2.49 (s, 3H), 2.76-2.84 (m, 1H), 2.85-2.92 (m, 2H), 2.93-3.01 (m, 1H), 3.02-3.08 (m, 2H), 3.74 (s, 3H), 4.01-4.12 (m, 1H), 6,57 (dd, J = 1.4, 6.8 Hz, 1H), 6.73 (s, 1H), 6.81 (s, 1H), 7.12 (dd, J = 6.8, 8.8 Hz, 1H), 7.46 (dd, J = 1.4, 8.8 Hz, 1H).

Example 177

N-Cyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1;5-a]pyridin-3-yl]-N-tetrahydro-2H-3-pyranylamine

(Yellow solid)

03641H NMR (400MHz, CDCl3) δ -0.02-0.04 (m, 2H), 0.26-0.36 (m, 2H), 0.78-0.88 (m, 1H), 1.32-1.44 (m, 1H), 1.62-1.78 (m, 2H), 2.06 (s, 3H), 2.04-2.18 (m, 1H), 2.48 (s, 3H), 2.50 (s, 3H), 2.98-3.10 (m, 2H), 3.20-3.38 (m, 3H), 3.76 (s, 3H), 3.82-3.92 (m, 1H), 4.12-4.22 (m, 1H), 6.60 (dd, J = 1.6, 7.2 Hz, 1H), 6.75 (s, 1H), 6.83 (s, 1H), 7.15 (dd, J = 7.2, 8.8 Hz, 1H), 7.45 (dd, J = 1.6, 8.8 Hz, 1H).

0365MS (ESI)m/z 452 MH+

Example 178

N-(3-Furylmethyl)-N-[7-(4-methoxy-2,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylamine

(Yellow oil)

03661H NMR (400MHz, CDCl3) δ 1.50-1.66 (m, 2H), 1.84-1.94 (m, 2H), 1.97 (s, 6H), 2.40 (s, 3H), 3.24-3.34 (m, 1H), 3.39 (t, J = 12.0 Hz, 2H), 3.84 (s, 3H), 3.92-4.02 (m, 2H), 4.20 (s, 2H), 6.28 (s, 1H), 6.42 (d, J = 6.6 Hz, 1H), 6.68 (s, 2H), 7.03 (dd, J = 6.8, 8.7 Hz, 1H); 7.17-7.30 (m, 3H).

Example 179

N-(3-Furylmethyl)-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylamine

(Yellow amorphous)

03671H NMR (400MHz, CDCl3) δ 1.50-1.66 (m, 2H), 1.82-1.94 (m, 2H), 1.95 (s, 3H), 2.39 (s, 3H), 2.41 (s, 3H), 3.22-3.33 (m, 1H), 3.38 (br t, J = 12.0 Hz, 2H), 3.66 (s, 3H), 3.90-4.02 (m, 2H), 4.20 (s, 2H), 6.28-6.33 (m, 1H), 6.49 (dd, J = 1.3, 6.8 Hz, 1H), 6.66 (s, 1H), 6.74 (s, 1H), 7.03 (dd, J = 6.8, 8.9 Hz, 1H), 7.18-7.30 (m, 3H).

Example 180

N-[7-(2,6-Dimethoxy-4-methylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2-furanylmethyl-N-tetrahydro-2H-4-pyranylamine

(White crystals)

03681H NMR (400MHz, CDCl3) δ 1.47-1.66 (m, 4H), 1.73-1.94 (m, 4H), 2.43 (s, 3H), 2.44 (s, 3H), 2.97-3.05 (m, 1H), 3.15-3.25 (m, 1H), 3.30-3.47 (m, 3H), 3.62-3.85 (m, 3H), 3.70 (s, 6H), 3.90-3.99 (m, 2H), 6.49 (s, 2H), 6.59 (dd, J = 1.3, 6.8 Hz, 1H), 7.05 (dd, J = 6.8, 8.8 Hz, 1H), 7.35 (dd, J = 1.3, 8.8 Hz, 1H).

Example 181

N-Cyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-3-furanylamine

(White solid)

03691H NMR (400MHz, CDCl3) δ -0.15- -0.03 (m, 2H), 0.18-0.31 (m, 2H), 0.70-0.81 (m, 1H), 1.78-2.05 (m, 2H), 1.98 (s, 3H), 2.40 (s, 3H), 2.44 (s, 3H), 2.80-2.98 (m, 2H), 3.55-3.67 (m, 1H), 3.68 (s, 3H), 3.75-3.95 (m, 3H), 4.08-4.18 (m, 1H), 6.52 (d, J = 6.8 Hz, 1H), 6.68 (s, 1H), 6.76 (s, 1H), 7.07 (dd, J = 6.8, 8.8 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H).

Example 182

N-[7-(2-Methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-3-furanyl-N-tetrahydro-3-furanylmethylamine

(White solid)

03701H NMR (400MHz, CDCl3) δ 1.54-1.68 (m, 1H), 1.76-2.18 (m, 4H), 1.98 (s, 3H), 2.40 (s, 3H), 2.44 (s, 3H), 2.98-3.24 (m, 2H), 3.49-4.07 (m, 9H), 3.68 (s, 3H), 6.54 (d, J = 6.8 Hz, 1H), 6.67 (s, 1H), 6.76 (s, 1H), 7.09 (dd, J = 6.8, 8.8 Hz, 1H), 7.34 (d, J = 8.8 Hz, 1H).

Example 183

N-Cyclopropylmethyl-N-[7-(2,6-dimethoxy-4-methylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-3-pyranylamine

(Yellow oil)

03711H NMR (400MHz, CDCl3) δ -0.02-0.04 (m, 2H), 0.28-0.34 (m, 2H), 0.74-0.84 (m, 1H), 1.28-1.38 (m, 1H), 1.60-1.70 (m, 2H), 2.04-2.12 (m, 1H), 2.48 (s, 3H), 2.49 (s, 3H), 2.98-3.06 (m, 2H), 3.20-3.34 (m, 3H), 3.74 (s, 6H), 3.80-3.86 (m, 1H), 4.10-4.18 (m, 1H), 6.54 (s, 2H), 6.64 (dd, J = 1.2, 6.8 Hz, 1H), 7.10 (dd, J = 6.8, 8.8 Hz, 1H), 7.40 (dd, J = 1.2, 8.8 Hz, 1H).

Example 184

N-Cyclopropylmethyl-N-[7-(2,4-dimethoxy-6-methylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-3-pyranylamine

(Yellow oil)

03721H NMR (400MHz, CDCl3) δ -0.02-0.04 (m, 2H), 0.28-0.34 (m, 2H), 0.76-0.86 (m, 1H), 1.30-1.42 (m, 1H), 1.60-1.74 (m, 2H), 2.06-2.16 (m, 1H), 2.50 (s, 3H), 3.00-3.10 (m, 2H), 3.20-3.38 (m, 3H), 3.74 (s, 3H), 3.84-3.90 (m, 1H), 3.94 (s, 3H), 4.12-4.20 (m, 1H), 6.50 (s, 1H), 6.53 (s, 1H), 6.58 (dd, J = 1.2, 7.2 Hz, 1H), 7.12 (dd, J = 7.2, 8.8 Hz, 1H), 7.43 (dd, J = 1.2, 8.8 Hz, 1H).

Example 185

N-Cyclopropylmethyl-N-[7-(2,4-dimethoxy-6-methylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylamine

(Yellow oil)

03731H NMR (400MHz, CDCl3) δ -0.02-0.04 (m, 2H), 0.26-0.34 (m, 2H), 0.78-0.88 (m, 1H), 1.52-1.68 (m, 2H), 1.86-1.96 (m, 2H), 2.09 (s, 3H), 2.51 (s, 3H), 3.02-3.10 (m, 2H), 3.32-3.40 (m, 1H), 3.40-3.50 (m, 2H), 3.75 (s, 3H), 3.94 (s, 3H), 3.98-4.08 (m, 2H), 6.49 (s, 1H), 6.54 (s, 1H), 6.58 (dd, J = 1.2, 6.8 Hz, 1H), 7.12 (dd, J = 6.8, 8.8 Hz, 1H), 7.46 (dd, J = 1.2, 8.8 Hz, 1H).

Example 186

N-Cyclopropylmethyl-N-[7-(4-methoxy-2,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-3-pyranylamine

(Yellow oil)

03741H NMR (400MHz, CDCl3) δ -0.02-0.04 (m, 2H), 0.28-0.36 (m, 2H), 0.78-0.88 (m, 1H), 1.32-1.44 (m, 1H), 1.66-1.78 (m, 2H), 2.10 (s, 6H), 2.10-2.18 (m, 1H), 2.50 (s, 3H), 3.02-3.12 (m, 2H), 3.24-3.40 (m, 3H), 3.84-3.94 (m, 1H), 3.94 (s, 3H), 4.14-4.20 (m, 1H), 6.50 (dd, J = 1.2, 6.8 Hz, 1H), 6.78 (s, 2H), 7.15 (dd, J = 6.8, 8.8 Hz, 1H), 7.48 (dd, J = 1.2, 8.8 Hz, 1H).

Example 187

N-Cyclopropylmethyl-N-[7-(2,6-dimethoxy-4-methylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylmethylamine

(Yellow oil)

03751H NMR (400MHz, CDCl3) δ -0.02-0.00 (m, 2H), 0.32-0.38 (m, 2H), 0.82-0.92 (m, 1H), 1.24-1.35 (m, 2H), 1.55-1.60 (m, 1H), 1.87-1.95 (m, 2H), 2.46 (s, 6H), 2.90 (d, J = 6.8 Hz, 2H), 3.06 (d, J = 7.2 Hz, 2H), 3.32 (dt, J = 2.0, 12.0 Hz, 2H), 3.72 (s, 6H), 3.92-3.98 (m, 2H), 6.52 (s, 2H), 6.60 (dd, J = 1.6, 6.8 Hz, 1H), 7.05 (dd, J = 6.8, 8.8 Hz, 1H), 7.41 (dd, J = 1.6, 8.8 Hz, 1H).

Example 188

N-[7-(2-Methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-3-furanylmethyl-N-tetrahydro-2H-4-pyranylamine

(White amorphous)

03761H NMR (400MHz, CDCl3) δ 1.48-1.65 (m, 2H), 1.74-1.95 (m, 4H), 1.99 (s, 3H), 2.09-2.19 (m, 1H), 2.40 (s, 3H), 2.42 (s, 3H), 3.01-3.25 (m, 3H), 3.31-3.41 (m, 2H), 3.54-3.84 (m, 4H), 3.69 (s, 3H), 3.91-4.00 (m, 2H), 6.52 (dd, J = 1.3, 6.8 Hz, 1H), 6.67 (s, 1H), 6.76 (s, 1H), 7.07 (dd, J = 6.8, 8.8 Hz, 1H), 7.31 (dd, J = 1.3, 8.8 Hz, 1H).

Example 189

N-Cyclopropylmethyl-N-(3,4-dihydro-2H-2-pyranylmethyl)-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine

(Yellow oil)

03771H NMR (400MHz, CDCl3) δ -0.05-0.00 (m, 2H), 0.28-0.34 (m, 2H), 0.83-0.92 (m, 1H), 1.58-1.70 (m, 1H), 1.90-2.04 (m, 2H), 1.99 (s, 1.5H), 2.01 (s, 1.5H), 2.04-2.13 (m, 1H), 2.40 (s, 3H), 2.42 (s, 3H), 2.97 (d, J = 6.8 Hz, 2H), 3.17-3.23 (m, 1H), 3.46-3.52 (m, 1H), 3.69 (s, 1.5H), 3.70 (s, 1.5H), 3.77-3.83 (m, 1H), 4.60-4.65 (m, 1H), 6.33 (br d, J = 6.4 Hz, 1H), 6.50-6.53 (m, 1H), 6.65 (br s, 1H), 6.74 (br s, 1H), 7.03-7.08 (m, 1H), 7.43-7.47 (m, 1H).

Example 190

N-Cyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-[(2-methoxy-3-pyridyl)methyl]amine

(Yellow oil)

03781H NMR (400MHz, CDCl3) δ -0.08-0.02 (m, 2H), 0.27-0.37 (m, 2H), 0.82-0.93 (m, 1H), 1.96 (s, 3H), 2.39 (s, 3H), 2.43 (s, 3H), 2.88-3.00 (m, 2H), 3.66 (s, 3H), 3.92 (s, 3H), 4.34 (s, 2H), 6.48 (dd, J = 1.3, 6.8 Hz, 1H), 6.66 (s, 1H), 6.74 (s, 1H), 6.82 (dd, J = 4.8, 7.2 Hz, 1H), 7.02 (dd, J = 6.8, 8.8 Hz, 1H), 7.41 (dd, J = 1.3, 8.8 Hz, 1H), 7.86 (dd, J = 2.0, 7.2 Hz, 1H), 7.99 (dd, J = 2.0, 4.8 Hz, 1H).

Example 191

N-[7-(2,6-Dimethoxy-4-methylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranyl-N-tetrahydro-2H-4-pyranylmethylamine

(White amorphous)

03791H NMR (400MHz, CDCl3) δ 1.16-1.28 (m, 2H), 1.39-1.65 (m, 3H), 1.71-1.86 (m, 4H), 2.43 (s, 3H), 2.44 (s, 3H), 2.98-3.15 (m, 3H), 3.22-3.40 (m, 4H), 3.71 (s, 6H), 3.86-3.99 (m, 4H), 6.50 (s, 2H), 6.60 (d, J = 6.8 Hz, 1H), 7.05 (dd, J = 6.8, 8.8 Hz, 1H), 7.31 (d, J = 8.8 Hz, 1H).

Example 192

N-(2,2-Difluoroethyl)-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylamine

(White solid)

03801H NMR (400MHz, CDCl3) δ 1.44-1.58 (m, 2H), 1.80-1.86 (m, 2H), 1.99 (s, 3H), 2.40 (s, 3H), 2.43 (s, 3H), 3.18-3.28 (m, 1H), 3.32-3.42 (m, 2H), 3.44-3.54 (m, 2H), 3.68 (s, 3H), 3.92-3.98 (m, 2H), 5.67(tt, J = 4.4, 56.4 Hz, 1H), 6.56 (dd, J = 1.6, 6.8 Hz, 1H), 6.67 (s, 1H), 6.76 (s, 1H), 7.12 (dd, J = 6.8, 8.8 Hz, 1H), 7.35 (dd, J = 1.6, 8.8 Hz, 1H).

Example 193

N-(2,2-Difluoroethyl)-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylmethylamine

(Brown oil)

03811H NMR (400MHz, CDCl3) δ 1.20-1.32 (m, 2H), 1.50-1.62 (m, 1H), 1.76-1.82 (m, 2H), 2.00 (s, 3H), 2.41 (s, 3H), 2.45 (s, 3H), 3.06 (d, J = 7.2, 2H), 3.28-3.48 (m, 4H), 3.69 (s, 3H), 3.92-3.98 (m, 2H), 5.74(tt, J = 4.4, 56.4 Hz, 1H), 6.56 (dd, J = 1.6, 6.8 Hz, 1H), 6.67 (s, 1H), 6.76 (s, 1H), 7.11 (dd, J = 6.8, 8.8 Hz, 1H), 7.36 (dd, J = 1.2, 8.8 Hz, 1H).

Example 194

N-Butyl-N-[7-(2,6-dimethoxy-4-methylphenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylmethylamine

(Yellow oil)

03821H NMR (400MHz, CDCl3) δ 0.85 (t, J = 7.2 Hz, 3H), 1.19-1.40 (m, 6H), 1.48-1.60 (m, 1H), 1.74-1.80 (m, 2H), 2.43 (s, 6H), 2.95 (d, J = 6.8 Hz, 2H), 3.01 (t, J = 6.8 Hz, 2H), 3.30 (dt, J = 2.0, 11.6 Hz, 2H), 3.70 (s, 3H), 3.88-3.95 (m, 2H), 6.48 (s, 2H), 6.57 (dd, J = 1.6, 7.2 Hz, 1H), 7.02 (dd, J = 7.2, 8.8 Hz, 1H), 7.33 (dd, J = 1.6, 8.8 Hz, 1H).

Example 195

N-Cyclobutylmethyl-N-[7-(2,6-dimethoxy-4-methylphenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylmethylamine

(Yellow oil)

03831H NMR (400MHz, CDCl3) δ 1.18-1.29 (m, 2H), 1.48-1.63 (m, 3H), 1.70-1.80 (m, 4H), 1.81-1.90 (m, 2H), 2.30-2.40 (m, 1H), 2.43 (s, 3H), 2.44 (s, 3H), 2.93 (d, J = 6.8 Hz, 2H), 3.04 (d, J = 7.0 Hz, 2H), 3.30 (dt, J = 2.0, 12.0 Hz, 2H), 3.69 (s, 6H), 3.89-3.94 (m, 2H), 6.48 (s, 2H), 6.57 (dd, J = 1.6, 6.8 Hz, 1H), 7.02 (dd, J = 6.8, 8.8 Hz, 1H), 7.31 (dd, J = 1.6, 8.8 Hz, 1H).

Example 196

N-Cyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-3-pyranylmethylamine

(Yellow oil)

03841H NMR (400MHz, CDCl3) δ -0.02-0.06 (m, 2H), 0.28-0.42 (m, 2H), 0.82-0.92 (m, 1H), 1.22-1.32 (m, 1H), 1.52-1.66 (m, 2H), 1.72-1.80 (m, 1H), 1.86-1.94 (m, 1H), 2.04 (br s, 3H), 2.45 (br s, 3H), 2.47 (br s, 3H), 2.86-2.94 (m, 2H), 2.96-3.04 (m, 1H), 3.14-3.22 (m, 1H), 3.24-3.30 (m, 1H), 3.40-3.46 (m, 1H), 3.72 (br s, 3H), 3.84-3.90 (m, 1H), 4.12-4.18 (m, 1H), 6.54 (dd, J = 1.6, 6.8 Hz, 1H), 6.71 (s, 1H), 6.79 (s, 1H), 7.07 (dd, J = 6.8, 8.8 Hz, 1H), 7.44 (dd, J = 1.6, 8.8 Hz, 1H).

0385MS(ESI) m/z 466 MH+

Example 197

N-Cyclopropylmethyl-N-[7-(2,6-dimethoxy-4-methylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-3-pyranylmethylamine

(Yellow oil)

03861H NMR (400MHz, CDCl3) δ -0.02-0.04 (m, 2H), 0.30-0.36 (m, 2H), 0.80-0.90 (m, 1H), 1.18-1.28 (m, 1H), 1.52-1.60 (m, 2H), 1.66-1.76 (m, 1H), 1.82-1.90 (m, 1H), 2.45 (s, 6H), 2.84-2.92 (m, 2H), 2.94-2.98 (m, 1H), 3.10-3.18 (m, 1H), 3.18-3.26 (m, 1H), 3.36-3.44 (m, 1H), 3.70 (s, 6H), 3.80-3.86 (m, 1H), 4.08-4.12 (m, 1H), 6.49 (s, 2H), 6.57 (dd, J = 1.6, 8.8 Hz, 1H), 7.03 (dd, J = 6.8, 8.8 Hz, 1H), 7.39 (dd, J = 1.6, 8.8 Hz, 1H).

Example 198

N-Cyclopropylmethyl-N-(5,6-dihydro-2H-3-pyranylmethyl)-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine

(Yellow oil)

03871H NMR (400MHz, CDCl3) δ -0.02-0.04 (m, 2H), 0.28-0.38 (m, 2H), 0.80-0.88 (m, 1H), 2.01 (s, 3H), 2.06-2.14 (m, 2H), 2.44 (s, 3H), 2.47 (s, 3H), 2.84-2.96 (m, 2H), 3.71 (s, 3H), 3.71-3.76 (m, 4H), 4.30-4.34 (m, 2H), 5.75 (br s, 1H), 6.53 (dd, J = 1.6, 6.8 Hz, 1H), 6.70 (s, 1H), 6.78 (s, 1H), 7.07 (dd, J = 6.8, 8.8 Hz, 1H), 7.44 (dd, J = 1.6, 8.8 Hz, 1H).

0388MS (ESI)m/z 464 MH+

Example 199

N-[7-(2-Methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(2-oxetanylmethyl)amine

0389After dissolving tert-butyl N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]carbamate (100 mg) in N,N-dimethylformamide (2 mL), sodium hydride (60%, 15 mg) was added while cooling on ice, the mixture was stirred for 30 minutes, 2-oxetanylmethyl 4-methyl-1-benzenesulfonate (70 mg) was added and the mixture was stirred for 1 hour at 40°C. 2-Oxetanylmethyl 4-methyl-1-benzenesulfonate (23 mg) [CAS No.115845-51-7] and sodium hydride (60%, 5 mg) were again added, and the mixture was stirred for 1 hour. Water was added to the reaction mixture, extraction was performed with ethyl acetate and the extract was washed with brine. After drying the obtained organic layer over anhydrous magnesium sulfate and filtering it, the solvent was concentrated under reduced pressure to obtain crude tert-butyl N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(2-oxetanylmethyl)carbamate. This was dissolved in ethyl acetate (2 mL) without purification, a 4 N hydrochloric acid/ethyl acetate solution (1 mL) was added, and the mixture was stirred' at room temperature for 1 hour. The reaction mixture was neutralized with 5 N aqueous sodium hydroxide while cooling on ice, and then extraction was performed with ethyl acetate and the organic layer was washed with brine. After drying the obtained organic layer over anhydrous magnesium sulfate and filtering it, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and the title compound (8 mg) was obtained from the n-hexane:ethyl acetate (3:1) fraction as a yellow oil.

03901H NMR (400MHz, CDCl3) δ 1.94-2.04 (m, 1H), 2.00 (s, 3H), 2.24-2.34 (m, 1H), 2.40 (s, 3H), 2.44 (s, 3H), 3.24-3.35 (m, 2H), 3.49-3.62 (m, 2H), 4.46-4.54 (m, 1H), 6.48-6.54 (m, 1H), 6.67 (s, 1H), 6.75 (s, 1H), 7.00-7.06 (m, 1H), 7.44-7.50 (m, 1H).

0391MS(ESI) m/z 383 MH+

Example 200

N-Cyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(2-oxetanylmethyl)amine

0392After dissolving N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(2-oxetanylmethyl)amine (8 mg) in N,N-dimethylformamide (2 mL), sodium hydride (60%, 1.6 mg) was added while cooling on ice, and then cyclopropylmethyl bromide (3.8 µL) was added and the mixture was stirred at room temperature for 12 hours. Water was added to the reaction mixture, extraction was performed with ethyl acetate and the extract was washed with brine. After drying over anhydrous magnesium sulfate and filtration, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and the title compound (1.8 mg) was obtained from the n-hexane:ethyl acetate (10:1) fraction as a yellow oil.

03931H NMR (400MHz, CDCl3) δ 0.22-0.26 (m, 2H), 0.54-0.60 (m, 2H), 1.06-1.16 (m, 1H), 1.99 (s, 1.5H), 2.00 (s, 1.5H), 2.00-2.08 (m, 1H), 2.16-2.26 (m, 1H), 2.39 (s, 3H), 2.43 (br s, 3H), 3.28-3.40 (m, 4H), 3.44-3.50 (m, 1H), 3.56-3.64 (m, 1H), 3.67 (s, 3H), 4.20-4.26 (m, 1H), 6.45-6.52 (m, 1H), 6.66 (s, 1H), 6.75 (s, 1H), 6.97-7.04 (m, 1H), 7.50-7.56 (m, 1H).

0394The compound of Example 201 was synthesized according to the production method of Examples 199 and 200.

Example 201

N-Cyclopropylmethyl-N-(1,3-dioxolan-2-ylmethyl)-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine

(Yellow oil)

03951H NMR (400MHz, CDCl3) δ -0.02-0.04 (m, 2H), 0.24-0.36 (m, 2H), 0.82-0.94 (m, 1H), 2.00 (s, 3H), 2.41 (s, 3H), 2.45 (s, 3H), 3.00-3.08 (m, 2H), 3.39 (d, J = 4.0 Hz, 2H), 3.68 (s, 3H), 3.80-3.90 (m, 2H), 3.92-4.00 (m, 2H), 5.00 (t, J = 4.0 Hz, 1H), 6.51 (dd, J = 1.2, 6.8 Hz, 1H), 6.67 (s, 1H), 6.75 (s, 1H), 7.06 (dd, J = 6.8, 8.8 Hz, 1H), 7.47 (dd, J = 1.6, 8.8 Hz, 1H).

0396MS(ESI) m/z 454 MH+

Example 202

1-(Cyclopropylmethyl)[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amino-2-propanol

(Yellow oil)

0397Cyclopropanecarboxyaldehyde (0.047 mL) and 3 M sulfuric acid (0.21 mL) were added to a solution of 2-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amino-1-methylethyl benzoate (100 mg) in tetrahydrofuran (0.7 mL) while cooling on ice, and then sodium borohydride (16 mg) was slowly added thereto at the same temperature. The mixture was stirred for 30 minutes at room temperature, and then 5 N aqueous sodium hydroxide (0.3 mL) was added while cooling on ice to make the reaction mixture basic. Methanol (2.1 mL) was added to the reaction mixture, and after heating to reflux for 1 hour, it was returned to room temperature, extraction was performed with ethyl acetate, and the extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane = 1:5) to obtain the title compound (80 mg) as a yellow oil.

03981H NMR (400MHz, CDCl3) δ -0.03-0.07 (m, 2H), 0.32-0.45 (m, 2H), 0.83-0.92 (m, 1H), 1.08-1.14 (m, 3H), 1.98 (s, 3H), 2.40 (s, 3H), 2.44 (s, 3H), 2.69-2.78 (m, 1H), 2.83-2.91 (m, 1H), 2.96-3.04 (m, 1H), 3.42-3.50 (m, 1H), 3.56-3.68 (m, 1H), 3.68 (s, 3H), 6.54 (dd, J = 1.3, 6.8 Hz, 1H), 6.67 (s, 1H), 6.76 (s, 1H), 7.09 (dd, J = 6.8, 8.8 Hz, 1H), 7.39 (dd, J = 1.3, 8.8 Hz, 1H)

Example 203

1-(Cyclopropylmethyl)[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amino-3-fluoro-2-propanol

(Brownish oil)

0399p-Toluenesulfonic acid hydrate (40 mg) and epifluorohydrin (0.15 mL) [CAS No.503-09-3] were added to a solution of N-cyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine (50 mg) in 1,2-dimethoxyethane (0.40 mL), and the mixture was heated to reflux for 3 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate:n-hexane = 1:5) to obtain the title compound (24 mg) as a brownish oil.

04001H NMR (400MHz, CDCl3) δ -0.03-0.09 (m, 2H), 0.34-0.46 (m, 2H), 0.84-0.94 (m, 1H), 1.99 (s, 3H), 2.40 (s, 3H), 2.44 (s, 3H), 2.87-2.94 (m, 1H), 2.97-3.04 (m, 1H), 3.06-3.14 (m, 1H), 3.48-3.55 (m, 1H), 3.68 (s, 3H), 3.68-3.79 (m, 2H), 4.30-4.57 (m, 2H), 6.55 (dd, J = 1.3, 6.8 Hz, 1H), 6.68 (s, 1H), 6.76 (s, 1H), 7.11 (dd, J = 6.8, 8.8 Hz, 1H), 7.39 (dd, J = 1.3, 8.8 Hz, 1H).

0401The compounds of Examples 204 to 206 were synthesized according to the production methods of Examples 202 and 203.

Example 204

1-(Cyclopropylmethyl)[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amino-3-methoxy-2-propanol

(Yellow oil)

04021H NMR (400MHz, CDCl3) δ -0.05-0.07 (m, 2H), 0.32-0.44 (m, 2H), 0.84-0.93 (m, 1H), 1.98 (s, 3H), 2.40 (s, 3H), 2.43 (s, 3H), 2.86-2.93 (m, 1H), 2.96-3.06 (m, 2H), 3.35 (s, 3H), 3.36-3.51 (m, 3H), 3.67 (s, 3H), 6.54 (dd, J = 1.3, 6.8 Hz, 1H), 6.67 (s, 1H), 6.76 (s, 1H), 7.08 (dd, J = 6.8, 8.8 Hz, 1H), 7.40 (dd, J = 1.3, 8.8 Hz, 1H).

Example 205

(2S)-1-(Cyclopropylmethyl)[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amino-3-methoxypropan-2-ol

(Yellow oil)

04031H NMR (400MHz, CDCl3) δ -0.05-0.07 (m, 2H), 0.32-0.44 (m, 2H), 0.84-0.93 (m, 1H), 1.98 (s, 3H), 2.40 (s, 3H), 2.43 (s, 3H), 2.86-2.93 (m, 1H), 2.96-3.06 (m, 2H), 3.35 (s, 3H), 3.36-3.51 (m, 3H), 3.67 (s, 3H), 6.54 (dd, J = 1.3, 6.8 Hz, 1H), 6.67 (s, 1H), 6.76 (s, 1H), 7.08 (dd, J = 6.8, 8.8 Hz, 1H), 7.40 (dd, J = 1.3, 8.8 Hz, 1H).

Example 206

4-(Cyclopropylmethyl)[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amino-2-butanol

(Light yellow oil)

04041H NMR (400MHz, CDCl3) δ -0.01-0.11 (m, 2H), 0.27-0.39 (m, 2H), 0.72-0.83 (m, 1H), 1.17-1.21 (m, 3H), 1.47-1.68 (m, 2H), 1.99 (s, 3H), 2.41 (s, 3H), 2.45 (s, 3H), 2.88-3.02 (m, 2H), 3.18-3.28 (m, 1H), 3.61-3.75 (m, 1H), 3.68 (s, 3H), 4.02-4.12 (m, 1H), 6.54 (d, J = 6.8 Hz, 1H), 6.68 (s, 1H), 6.76 (s, 1H), 7.09 (dd, J = 6.8, 8.8 Hz, 1H), 7.50 (d, J = 8.8 Hz, 1H).

Example 207

4-[3-[Di(cyclopropylmethyl)amino]-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-7-yl]-3-methoxybenzonitrile

0405After dissolving N-[7-(4-bromo-2-methoxyphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N,N-dicyclopropylmethylamine (60 mg) in N,N-dimethylformamide (0.26 mL), zinc cyanide (31 mg) and tetrakis (triphenylphosphine) palladium (0) complex (23 mg) were added, the mixture was heated and stirred at 95°C for 12 hours and then cooled to room temperature, and ethyl acetate was added. After filtering out the precipitated insoluble portion, extraction was performed with ethyl acetate. The obtained organic layer was washed with water and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:n-hexane = 1:8) to obtain the title compound (32 mg) as a yellow oil.

04061H NMR (400MHz, CDCl3) δ 0.00-0.07 (m, 4H), 0.28-0.35 (m, 4H), 0.78-0.87 (m, 2H), 2.46 (s, 3H), 2.95-3.02 (m, 4H), 3.80 (s, 3H), 6.62 (dd, J = 1.3, 6.8 Hz, 1H), 7.04 (dd, J = 6.8, 8.8 Hz, 1H), 7.25 (d, J = 1.1 Hz, 1H), 7.38 (dd, J = 1.1, 7.7 Hz, 1H), 7.52 (dd, J = 1.3, 8.8 Hz, 1H), 7.67 (d, J = 7.7 Hz, 1H).

0407The compounds of Examples 208 to 210 were synthesized according to the production method of Example 207.

Example 208

4-[3-[(Cyclopropylmethyl)(tetrahydro-3-furanylmethyl)amino]-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-7-yl]-3-methoxybenzonitrile

(Yellow amorphous)

04081H NMR (400MHz, CDCl3) δ -0.03-0.08 (m, 2H), 0.30-0.41 (m, 2H), 0.78-0.88 (m, 1H), 1.60-1.70 (m, 1H), 1.87-1.98 (m, 1H), 2.16-2.29 (m, 1H), 2.45 (s, 3H), 2.84-2.94 (m, 2H), 3.02-3.10 (m, 1H), 3.20-3.28 (m, 1H), 3.59-3.87 (m, 4H), 3.81 (s, 3H), 6.64 (dd, J = 1.9, 6.8 Hz, 1H), 7.07 (dd, J = 6.8, 8.8 Hz, 1H), 7.26 (d, J = 1.1 Hz, 1H), 7.38 (dd, J = 1.1, 7.8 Hz, 1H), 7.45 (dd, J = 1.9, 8.8 Hz, 1H), 7.66 (d, J = 7.8 Hz, 1H).

Example 209

4-[3-[Di(cyclopropylmethyl)amino]-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-7-yl]-3-methoxy-5-methylbenzonitrile

(Light yellow crystals)

04091H NMR (400MHz, CDCl3) δ -0.03-0.08 (m, 4H), 0.25-0.37 (m, 4H), 0.78-0.91 (m, 2H), 2.06 (s, 3H), 2.41 (s, 3H), 2.94-3.06 (m, 4H), 3.72 (s, 3H), 6.48 (d, J = 6.8 Hz, 1H), 7.06 (dd, J = 6.8, 8.8 Hz, 1H), 7.09 (s, 1H), 7.25 (s, 1H), 7.52 (d, J = 8.8 Hz, 1H).

Example 210

4-[3-[(Cyclopropylmethyl)(tetrahydro-3-furanylmethyl)amino]-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-7-yl]-3-methoxy-5-methylbenzonitrile

(Light yellow crystals)

04101H NMR (400MHz, CDCl3) δ -0.06-0.03 (m, 2H), 0.27-0.36 (m, 2H), 0.78-0.88 (m, 1H), 1.58-1.70 (m, 1H), 1.88-1.98 (m, 1H), 2.06 (s, 3H), 2.19-2.32 (m, 1H), 2.40 (s, 3H), 2.84-2.96 (m, 2H), 3.02-3.10 (m, 1H), 3.21-3.29 (m, 1H), 3.58-3.86 (m, 4H), 3.72 (s, 3H), 6.49 (dd, J = 1.3, 6.8 Hz, 1H), 7.07 (dd, J = 6.8, 8.8 Hz, 1H), 7.09 (s, 1H), 7.25 (s, 1H), 7.44 (dd, J = 1.3, 8.8 Hz, 1H).

Example 211

5-((Cyclopropylmethyl)[7-(2,6-dimethoxy-4-methylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]aminomethyl)-2-furonitrile

0411Zinc cyanide (31 mg) and tetrakis(triphenylphosphine)palladium (0) complex (52 mg) were added to a solution of N-[(5-bromo-2-furyl)methyl]-N-cyclopropylmethyl-N-[7-(2,6-dimethoxy-4-methylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine (122 mg) in a mixture of N,N-dimethylformamide (3 mL) and N-methyl-2-pyrrolidinone (3 mL), and the mixture was heated at 155°C for 4 hours. The reaction mixture was cooled to room temperature, water was added, extraction was performed with ethyl acetate, the extract was washed with saturated aqueous sodium hydrogencarbonate and brine and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and the title compound (23 mg) was obtained from the n-hexane:ethyl acetate (1:4) fraction as a yellow oil.

04121H NMR (400MHz, CDCl3) δ 0.01-0.08 (m, 2H), 0.33-0.40 (m, 2H), 0.80-0.93 (m, 1H), 2.43 (s, 3H), 2.45 (s, 3H), 3.00 (d, J = 6.8 Hz, 2H), 3.68 (s, 6H), 4.37 (s, 2H), 6.27 (d, J = 3.7 Hz, 1H), 6.48 (s, 2H), 6.59 (dd, J = 1.5, 7.0 Hz, 1H), 6.95 (d, J = 3.5 Hz, 1H), 7.05 (dd, J = 7.0, 8.8 Hz, 1H), 7.29 (dd, J = 1.4, 8.9 Hz, 1H).

Example 212

N,N-Dicyclopropylmethyl-N-[7-[2-methoxy-6-methyl-4-(1,3-thiazol-2-yl)phenyl]-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine

0413After dissolving N-[7-(4-bromo-2-methoxy-6-methylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N,N-dicyclopropylmethylamine (45 mg) in toluene (0.60 mL), tributylstannylthiazole (52 mg) and tetrakis (triphenylphosphine)palladium (0) complex (9 mg) were added, the mixture was heated and stirred at 120°C for 2 hours and then cooled to room temperature, and ethyl acetate was added. After filtering out the precipitated insoluble portion, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:n-hexane = 1:5) to obtain the title compound (30 mg) as white crystals.

04141H NMR (400MHz, CDCl3) δ -0.03-0.08 (m, 4H), 0.25-0.38 (m, 4H), 0.80-0.92 (m, 2H), 2.10 (s, 3H), 2.43 (s, 3H), 2.95-3.07 (m, 4H), 3.79 (s, 3H), 6.53 (d, J = 6.8 Hz, 1H), 7.06 (dd, J = 6.8, 8.8 Hz, 1H), 7.38 (d, J = 3.2 Hz, 1H), 7.48 (d, J = 8.8 Hz, 1H), 7.49 (s, 1H), 7.52 (s, 1H), 7.91 (d, J = 3.2 Hz, 1H).

0415The compound of Example 213 was synthesized according to the production method of Example 212.

Example 213

N,N-Dicyclopropylmethyl-N-[7-[2-methoxy-6-methyl-4-(3-pyridyl)phenyl]-2-(methylsulfanyl)pyrazolo(1,5-a]pyridin-3-yl]amine

(Light yellow solid)

04161H NMR (400MHz, CDCl3) δ -0.02-0.08 (m, 4H), 0.28-0.38 (m, 4H), 0.81-0.92 (m, 2H), 2.11 (s, 3H), 2.45 (s, 3H), 2.96-3.08 (m, 4H), 3.77 (s, 3H), 6.55 (d, J = 6.8 Hz, 1H), 7.04 (s, 1H), 7.07 (dd, J = 6.8, 8.8 Hz, 1H), 7.15 (s, 1H), 7.40 (dd, J = 4.8, 8.0 Hz, 1H), 7.50 (d, J = 8.8 Hz, 1H), 7.95 (d, J = 8.0 Hz, 1H), 8.63 (d, J = 4.8 Hz, 1H), 8.92 (s, 1H).

Example 214

3-((Cyclopropylmethyl)[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]aminomethyl)-2-pyridinol

(White crystals)

0417After dissolving N-cyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-[(2-methoxy-3-pyridyl)methyl]amine (63 mg) in ethanol (1 mL), a 4 N hydrochloric acid/ethyl acetate solution (1 mL) was added at room temperature and the mixture was heated to reflux for 3 hours. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture for neutralization while cooling on ice, and extraction was performed with ethyl acetate. The obtained organic layer was washed with water and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate) to obtain the title compound (49 mg) as white crystals.

04181H NMR (400MHz, CDCl3) δ -0.05-0.06 (m, 2H), 0.27-0.38 (m, 2H), 0.84-0.97 (m, 1H), 1.97 (s, 3H), 2.40 (s, 3H), 2.44 (s, 3H), 2.91-3.03 (m, 2H), 3.66 (s, 3H), 4.36 (s, 2H), 6.27 (dd, J = 6.4, 6.4 Hz, 1H), 6.50 (d, J = 6.8 Hz, 1H), 6.68 (s, 1H), 6.76 (s, 1H), 7.05 (dd, J = 6.8, 8.8 Hz, 1H), 7.23 (d, J = 6.4 Hz, 1H), 7.52 (d, J = 8.8 Hz, 1H), 7.85 (d, J = 6.4 Hz, 1H).

0419The compound of Example 215 was synthesized according to the production method of Example 214.

Example 215

3-((Cyclopropylmethyl)[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]aminomethyl)-2-pyrazinol

(Light yellow crystals)

04201H NMR (400MHz, CDCl3) δ 0.00-0.09 (m, 2H), 0.30-0.49 (m, 2H), 0.78-0.91 (m, 1H), 1.97 (s, 3H), 2.40 (s, 3H), 2.47 (s, 3H), 2.94-3.03 (m, 2H), 3.66 (s, 3H), 4.69 (s, 2H), 6.57 (dd, J = 1.3, 6.8 Hz, 1H), 6.66 (s, 1H), 6.74 (s, 1H), 7.14 (dd, J = 6.8, 8.8 Hz, 1H), 7.55 (dd, J = 1.3, 8.8 Hz, 1H), 7.83 (br s, 2H).

Example 216

2-[3-[Di(cyclopropylmethyl)amino]-2-(methylsulfanyl)pyrazolo [1,5-a]pyridin-7-yl]-3,5-dimethylphenol

0421A 1 M boron tribromide/dichloromethane solution (0.42 mL) was added to a solution of N,N-dicyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine (35 mg) in dichloromethane (10 mL) at room temperature under a nitrogen atmosphere, and the mixture was stirred for 10 minutes. The reaction mixture was added to ice water, extraction was performed with ethyl acetate, and the organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and the title compound (17 mg) was obtained from the n-hexane:ethyl acetate (6:1) fraction as white crystals.

04221H NMR (400MHz, CDCl3) δ -0.02-0.02 (m, 4H), 0.24-0.30 (m, 4H), 0.74-0.82 (m, 2H), 2.23 (s, 3H), 2.32 (s, 3H), 2.50 (s, 3H), 2.88-3.00 (m, 4H), 6.64 (d, J = 6.8 Hz, 1H), 6.76 (s, 1H), 7.09 (dd, J = 6.8, 8.0 Hz, 1H), 7.48 (d, J = 8.8 Hz, 1H), 7.65 (s, 1H).

0423MS(ESI)m/z 408 MH+

Example 217

N,N-Dicyclopropylmethyl-N-[7-(2-ethoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine

0424After adding ethanol (2 µL), triphenylphosphine (15 mg) and diethyl azodicarboxylate (9 µL) to a solution of 2-[3-[di(cyclopropylmethyl)amino]-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-7-yl]-3,5-dimethylphenol (15 mg) in tetrahydrofuran (0.45 mL) under a nitrogen atmosphere, the mixture was stirred at room temperature overnight. The reaction mixture was added to water, extraction was performed with ethyl acetate, and the organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and the title compound (3.7 mg) was obtained from the n-hexane:ethyl acetate (9:1) fraction as a yellow oil.

04251H NMR (400MHz, CDCl3) δ -0.02-0.04 (m, 4H), 0.26-0.32 (m, 4H), 0.80-0.92 (m, 2H), 1.06 (t, J = 6.8 Hz, 3H), 2.04 (s, 3H), 2.39 (s, 3H), 2.45 (s, 3H), 3.02 (d, J = 6.4 Hz, 4H), 3.84-4.04 (m, 2H), 6.51 (dd, J = 0.8, 8.4 Hz, 1H), 6.67 (s, 1H), 6.76 (s, 1H), 7.04 (dd, J = 6.8, 8.8 Hz, 1H), 7.47 (dd, J = 0.8, 8.8 Hz, 1H).

0426The compounds of Examples 218 to 223 were synthesized according to the production method of Example 217.

Example 218

N,N-Dicyclopropylmethyl-N-[7-[2-(2-fluoroethoxy)-4,6-dimethylphenyl]-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine

(Yellow oil)

04271H NMR (400MHz, CDCl3) δ -0.02-0.04 (m, 4H), 0.26-0.34 (m, 4H), 0.82-0.92 (m, 2H), 2.04 (s, 3H), 2.40 (s, 3H), 2.44 (s, 3H), 3.02 (d, J = 6.4 Hz, 4H), 3.94-4.50 (m, 4H), 6.53 (dd, J = 0.8, 7.2 Hz, 1H), 6.70 (s, 1H), 6.82 (s, 1H), 7.05 (dd, J = 7.2, 8.8 Hz, 1H), 7.47 (d, J = 8.8 Hz, 1H).

Example 219

N-[7-[2-(Cyclopropylmethoxy)-4,6-dimethylphenyl]-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N,N-dicyclopropylmethylamine

(Yellow oil)

04281H NMR (400MHz, CDCl3) δ -0.02-0.08 (m, 6H), 0.28-0.38 (m, 6H), 0.86-0.96 (m, 3H), 2.07 (s, 3H), 2.42 (s, 3H), 2.48 (s, 3H), 3.05 (d, J = 6.8 Hz, 4H), 3.71 (dd, J = 6.4, 10.0 Hz, 1H), 3.81 (dd, J = 6.4, 10.0 Hz, 1H), 6.55 (dd, J = 1.6, 6.8 Hz, 1H), 6.71 (s, 1H), 6.80 (s, 1H), 7.08 (dd, J = 6.8, 8.8 Hz, 1H), 7.51 (dd, J = 1.6, 8.8 Hz, 1H).

Example 220

N,N-Dicyclopropylmethyl-N-[7-[2-(2-methoxyethoxy)-4,6-dimethylphenyl]-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine

(Yellow oil)

04291H NMR (400MHz, CDCl3) δ -0.02-0.04 (m, 4H), 0.26-0.34 (m, 4H), 0.78-0.88 (m, 2H), 2.02 (s, 3H), 2.38 (s, 3H), 2.44 (s, 3H), 3.00 (d, J = 7.2 Hz, 4H), 3.11 (s, 3H), 3.28-3.36 (m, 1H), 3.38-3.44 (m, 1H), 3.90-3.96 (m, 1H), 3.44-4.10 (m, 1H), 6.50 (dd, J = 1.2, 7.2 Hz, 1H), 6.69 (s, 1H), 6.77 (s, 1H), 7.02 (dd, J = 6.8, 8.8 Hz, 1H), 7.45 (dd, J = 1.2, 8.8 Hz, 1H).

0430MS(ESI) m/z 466 MH+

Example 221

N,N-Dicyclopropylmethyl-N-[7-(2-isopropoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine

(Yellow oil)

04311H NMR (400MHz, CDCl3) δ -0.02-0.02 (m, 4H), 0.26-0.34 (m, 4H), 0.82-0.92 (m, 2H), 0.96 (d, J = 6.4 Hz, 3H), 1.15 (d, J = 6.0 Hz, 3H), 2.04 (s, 3H), 2.41 (s, 3H), 2.46 (s, 3H), 2.98-3.08 (m, 4H), 4.24-4.36 (m, 1H), 6.51 (d, J = 6.8 Hz, 1H), 6.71 (s, 1H), 6.77 (s, 1H), 7.05 (dd, J = 7.2, 8.8 Hz, 1H), 7.47 (dd, J = 1.2, 8.8 Hz, 1H).

0432MS(ESI) m/z 450 MH+

Example 222

2-[3-[Di(cyclopropylmethyl)amino]-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-7-yl]-3,5-dimethylphenoxymethylcyanide

(Yellow oil)

04331H NMR (400MHz, CDCl3) δ -0.02-0.04 (m, 4H), 0.26-0.34 (m, 4H), 0.80-0.92 (m, 2H), 2.02 (s, 3H), 2.43 (s, 3H), 2.44 (s, 3H), 3.01 (d, J = 6.4 Hz, 4H), 4.57 (dd, J = 16.0, 25.6 Hz, 2H), 6.50 (dd, J = 1.6, 6.8 Hz, 1H), 6.81 (s, 1H), 6.92 (s, 1H), 7.06 (dd, J = 6.8, 8.8 Hz, 1H), 7.50 (dd, J = 1.6, 8.8 Hz, 1H).

0434MS(ESI) m/z 447 MH+

Example 223

N,N-Dicyclopropylmethyl-N-[7-[2,4-dimethyl-6-(2-tetrahydro-1H-1-pyrrolylethoxy)phenyl]-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine

(Yellow oil)

04351H NMR (400MHz, CDCl3) δ -0.02-0.04 (m, 4H), 0.24-0.34 (m, 4H), 0.78-0.88 (m, 2H), 1.56-1.64 (m, 4H), 2.01 (s, 3H), 2.20-2.32 (m, 4H), 2.37 (s, 3H), 2.42 (s, 3H), 2.42-2.58 (m, 2H), 2.94-3.04 (m, 4H), 3.92-4.06 (m, 2H), 6.47 (dd, J = 1.6, 7.2 Hz, 1H), 6.64 (s, 1H), 6.74 (s, 1H), 7.00 (dd, J = 7.2, 9.2 Hz, 1H), 7.44 (dd, J = 1.6, 8.8 Hz, 1H).

0436MS(ESI) m/z 505 MH+

Example 224

N-Cyclopropyl-N-cyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine

0437After dissolving N-cyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine (100 mg) in methanol (10 mL), ((1-ethoxycyclopropyl)oxy)trimethylsilane (60 µL), acetic acid (298 µL) and sodium cyanoborohydride (171 mg) were added and the mixture was heated to reflux for 6 hours. After cooling the reaction mixture to room temperature, saturated aqueous sodium hydrogencarbonate was added, extraction was performed with ethyl acetate, and the organic layer was washed with brine. After drying the obtained organic layer over anhydrous magnesium sulfate and filtering it, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and the title compound (74 mg) was obtained from the n-hexane:ethyl acetate (10:1) fraction as a yellow oil.

04381H NMR (400MHz, CDCl3) δ -0.01-0.04 (m, 2H), 0.26-0.36 (m, 2H), 0.46-0.52 (m, 4H), 0.80-0.90 (m, 1H), 2.00 (s, 3H), 2.41 (s, 3H), 2.43 (s, 3H), 2.88-2.94 (m, 1H), 2.98-3.06 (m, 2H), 3.69 (s, 3H), 6.50 (dd, J = 1.6, 6.8 Hz, 1H), 6.68 (s, 1H), 6.76 (s, 1H), 7.02 (dd, J = 6.8, 8.8 Hz, 1H), 7.42 (dd, J = 1.6, 8.8 Hz, 1H).

0439The compound of Example 225 was synthesized according to the production method of Example 224.

Example 225

N-Cyclopropyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2-furanylmethylamine

(Light yellow oil)

04401H NMR (400MHz, CDCl3) δ 0.42-0.57 (m, 4H), 1.55-1.64 (m, 1H), 1.75-1.95 (m, 3H), 2.00 (s, 3H), 2.40 (s, 3H), 2.42 (s, 3H), 2.86-2.92 (m, 1H), 3.06-3.13 (m, 1H), 3.42-3.48 (m, 1H), 3.64-3.71 (m, 4H), 3.79-3.88 (m, 2H), 6.50 (dd, J = 1.6, 6.8 Hz, 1H), 6.67 (s, 1H), 6.75 (s, 1H), 7.04 (dd, J = 6.8, 8.8 Hz, 1H), 7.40 (dd, J = 1.6, 8.8 Hz, 1H).

Example 226

N3-Cyclopropylmethyl-N3-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]nicotinamide

0441Triethylamine (0.038 mL) and chloronicotinic acid hydrochloride (20 mg) were added to a solution of N-cyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine (33 mg) in dichloromethane (0.8 mL) while cooling on ice, and the mixture was stirred at the same temperature for 1 hour. Saturated aqueous sodium hydrogencarbonate was added while cooling on ice, extraction was performed with ethyl acetate, and the extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:n-hexane = 3:2) to obtain the title compound (36 mg) as white crystals.

04421H NMR (400MHz, CDCl3) δ 0.08-0.33 (m, 2H), 0.37-0.54 (m, 2H), 1.03-1.17 (m, 1H), 2.02 (s, 3H), 2.31 (s, 3H), 2.38 (s, 3H), 3.52-3.62 (m, 1H), 3.67 (s, 3H), 3.87-3.97 (m, 1H), 6.57 (dd, J = 1.3, 6.8 Hz, 1H), 6.65 (s, 1H), 6.69 (s, 1H), 6.95 (dd, J = 4.8, 8.0 Hz, 1H), 7.17 (dd, J = 6.8, 8.8 Hz, 1H), 7.27 (dd, J = 1.3, 8.8 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 8.31 (d, J = 4.8 Hz, 1H), 8.56 (s, 1H).

0443The compound of Example 227 was synthesized according to the production method of Example 226.

Example 227

N1-[7-(2-Methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N1-(3-pyridylmethyl)-1-cyclopropanecarboxyamide

(White amorphous substance)

04441H NMR (400MHz, CDCl3) δ 0.61-0.71 (m, 2H), 1.01-1.11 (m, 2H), 1.45-1.52 (m, 1H), 1.91 (s, 3H), 2.39 (s, 3H), 2.40 (s, 3H), 3.67 (s, 3H), 4.57 (d, J = 14.0 Hz, 1H), 5.25 (d, J = 14.0 Hz, 1H), 6.58 (d, J = 6.8 Hz, 1H), 6.66 (s, 1H), 6.75 (s, 1H), 6.77 (d, J = 8.8 Hz, 1H), 7.04 (dd, J = 6.8, 8.8 Hz, 1H), 7.11 (dd, J = 4.8, 8.0 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 8.30 (s, 1H), 8.41 (d, J = 4.8 Hz, 1H).

Example 228

N,N-Dicyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfinyl)pyrazolo[1,5-a]pyridin-3-yl]amine

0445m-Chloroperbenzoic acid (234 mg) was added to a solution of N,N-dicyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine (200 mg) in dichloromethane (10 mL) at 0°C, and the mixture was stirred for 2 hours. Water was added to the reaction mixture, extraction was performed with ethyl acetate, the extract was washed with saturated aqueous sodium hydrogencarbonate and brine and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (20 g), and the title compound (162 mg) was obtained from the n-hexane:ethyl acetate (1:1) fraction as a light yellow oil.

04461H NMR (400MHz, CDCl3) δ -0.02-0.08 (m, 4H), 0.28-0.38 (m, 4H), 0.80-0.94 (m, 2H), 1.94 (s, 1.5 H), 2.00 (s, 1.5H), 2.39 (s, 3H), 2.96 (s, 1.5H), 2.97 (s, 1.5H), 3.04-3.16 (m, 4H), 3.64 (s, 1.5H), 3.66 (s, 1.5H), 6.66 (s, 0.5H), 6.67 (s, 0.5H), 6,72 (dd, J = 2.6, 6.9 Hz, 0.5H), 6,73 (dd, J = 2.6, 6.9 Hz, 0.5H), 6.74 (s, 0.5H), 6.76 (s, 0.5H), 7.15 (dd, J = 6.8, 8.9 Hz, 0.5H), 7.16 (dd, J = 6.8, 8.9 Hz, 0.5H), 7.60-7.68 (m, 1H).

Example 229

N,N-Dicyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfonyl)pyrazolo[1,5-a]pyridin-3-yl]amine

0447m-Chloroperbenzoic acid (91 mg) was added to a solution of N,N-dicyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfinyl)pyrazolo[1,5-a]pyridin-3-yl]amine (162 mg) in dichloromethane (10 mL) at 0°C, and the mixture was stirred for 4 hours. Water was added to the reaction mixture, extraction was performed with ethyl acetate, the extract was washed with saturated aqueous sodium hydrogencarbonate and brine and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (10 g), and the title compound (9 mg) was obtained from the n-hexane:ethyl acetate (1:2) fraction as a yellow oil.

04481H NMR (400MHz, CDCl3) δ -0.02-0.08 (m, 4H), 0.24-0.34 (m, 4H), 0.79-0.92 (m, 2H), 1.96 (s, 3H), 2.38 (s, 3H), 3.08 (dd, J = 3.7, 6.8 Hz, 4H), 3.21 (s, 3H), 3.64 (s, 3H), 6.66 (s, 1H), 6.75 (s, 1H), 6.78 (dd, J = 1.4, 6.9 Hz, 1H), 7.19 (dd, J = 6.9, 8.9 Hz, 1H), 7.72 (dd, J = 1.4, 8.9 Hz, 1H).

Example 230

N,N-Dicyclopropylmethyl-N-[2-methoxy-7-(2-methoxy-4,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]amine

04492-Methoxy-7-(2-methoxy-4,6-dimethylphenyl)-3-nitrosopyrazolo[1,5-a]pyridine (200 mg) was suspended in ethanol (10 mL), and then water (5 mL), acetic acid (0.5 mL) and zinc powder (200 mg) were added and the mixture was heated and stirred at 60°C for 1 hour. The reaction mixture was filtered, water was added to the filtrate, extraction was performed with ethyl acetate and the organic layer was washed with saturated aqueous sodium hydrogencarbonate and brine. The obtained organic layer was dried over anhydrous magnesium sulfate and filtered, and then the solvent was concentrated under reduced pressure to obtain 2-methoxy-7-(2-methoxy-4,6-dimethylphenyl)pyrazolo[1,5-a]pyridine-3-amine as a crude product. This was dissolved in tetrahydrofuran (5 mL) without purification, and after adding cyclopropanecarboxyaldehyde (0.166 mL) and 3 M aqueous sulfuric acid (0.739 mL), sodium borohydride (56 mg) was added in five portions while vigorously stirring on ice, and stirring was continued for 1 hour. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, extraction was performed with ethyl acetate, and the extract was washed with brine. After drying over anhydrous magnesium sulfate and filtration, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and the title compound (240 mg) was obtained from the n-hexane:ethyl acetate (30:1) fraction as a yellow oil.

04501H NMR (400MHz, CDCl3) δ -0.02-0.04 (m, 4H), 0.26-0.34 (m, 4H), 0.80-0.90 (m, 2H), 2.00 (m, 3H), 2.41 (s, 3H), 2.87-2.98 (m, 4H), 3.70 (s, 3H), 3.86 (s, 3H), 6.44 (dd, J = 1.6, 6.8 Hz, 1H), 6.69 (s, 1H), 6.77 (s, 1H), 7.02 (dd, J = 6.8, 8.8 Hz, 1H), 7.39 (dd, J = 1.6, 8.8 Hz, 1H).

0451The compounds of Examples 231 to 236 were synthesized according to the production method of Example 230.

Example 231

N-[2-Methoxy-7-(2-methoxy-4,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N,N-ditetrahydro-2H-4-pyranylamine

(Light brown powder)

04521H NMR (400MHz, CDCl3) δ 1.42-1.56 (m, 4H), 1.72-1.80 (m, 4H), 1.99 (s, 3H), 3.33-3.43 (m, 6H), 3.70 (s, 3H), 3.83 (s, 3H), 3.90-3.96 (m, 4H), 6.43 (dd, J = 1.6, 6.8 Hz, 1H), 6.68 (s, 1H), 6.76 (s, 1H), 7.04 (dd, J = 6.8, 8.8 Hz, 1H), 7.26 (dd, J = 1.6, 8.8 Hz, 1H).

Example 232

N,N-Dicyclopropylmethyl-N-[7-(2,6-dimethoxy-4-methylphenyl)-2-methoxypyrazolo[1,5-a]pyridin-3-yl]amine

(White crystals)

04531H NMR (400MHz, CDCl3) δ -0.03-0.05 (m, 4H), 0.27-0.34 (m, 4H), 0.78-0.91 (m, 2H), 2.44 (s, 3H), 2.87-2.96 (m, 4H), 3.71 (s, 6H), 3.87 (s, 3H), 6.47 (dd, J = 1.3, 6.8 Hz, 1H), 6.50 (s, 2H), 7.01 (dd, J = 6.8, 8.8 Hz, 1H), 7.37 (dd, J = 1.3, 8.8 Hz, 1H).

Example 233

N,N-Dicyclopropylmethyl-N-[7-(2,4-dimethoxy-6-methylphenyl)-2-methoxypyrazolo[1,5-a]pyridin-3-yl]amine

(Yellow oil)

04541H NMR (400MHz, CDCl3) δ -0.05-0.05 (m, 4H), 0.23-0.33 (m, 4H), 0.79-0.91 (m, 2H), 2.02 (s, 3H), 2.85-2.99 (m, 4H), 3.68 (s, 3H), 3.86 (s, 3H), 3.87 (s, 3H), 6.40 (dd, J = 1.5, 6.8 Hz, 1H), 6.43 (d, J = 2.2 Hz, 1H), 6.47 (d, J = 2.2 Hz, 1H), 7.01 (dd, J = 6.8, 8.8 Hz, 1H), 7.38 (dd, J = 1.5, 8.8 Hz, 1H).

Example 234

N-[7-(2-Chloro-6-methoxy-4-methylphenyl)-2-methoxypyrazolo[1,5-a]pyridin-3-yl]-N,N-dicyclopropylmethylamine

(White crystals)

04551H NMR (400MHz, CDCl3) δ -0.04-0.06 (m, 4H), 0.24-0.35 (m, 4H), 0.79-0.90 (m, 2H), 2.42 (s, 3H), 2.86-2.99 (m, 4H), 3.71(s, 3H), 3.87 (s, 3H), 6.46 (dd, J = 1.3, 6.8 Hz, 1H), 6.74 (s, 1H), 6.97 (s, 1H), 7.03 (dd, J = 6.8, 8.8 Hz, 1H), 7.42 (dd, J = 1.3, 8.8 Hz, 1H).

Example 235

N,N-Dicyclopropylmethyl-N-[2-methoxy-7-(4-methoxy-2,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]amine

(Light yellow crystals)

04561H NMR (400MHz, CDCl3) δ -0.05-0.02 (m, 4H), 0.25-0.31 (m, 4H), 0.79-0.90 (m, 2H), 2.03 (s, 6H), 2.86-2.98 (m, 4H), 3.85 (s, 3H), 3.85 (s, 3H), 6.33 (dd, J = 1.5, 6.8 Hz, 1H), 6.70 (s, 2H), 7.01 (dd, J = 6.8, 8.8 Hz, 1H), 7.39 (dd, J = 1.5, 8.8 Hz, 1H).

Example 236

N-[7-(2-Chloro-4-methoxyphenyl)-2-methoxypyrazolo[1,5-a]pyridin-3-yl]-N,N-dicyclopropylmethylamine

(Yellow oil)

04571H NMR (400MHz, CDCl3) δ -0.02-0.05 (m, 4H), 0.27-0.33 (m, 4H), 0.78-0.89 (m, 2H), 2.86-2.97 (m, 4H), 3.88(s, 3H), 3.90 (s, 3H), 6.47 (dd, J = 1.5, 6.8 Hz, 1H), 6.92 (dd, J = 2.6, 8.6 Hz, 1H), 7.01 (dd, J = 6.8, 8.8 Hz, 1H), 7.06 (d, J = 2.6 Hz, 1H), 7.43 (dd, J = 1.5, 8.8 Hz, 1H), 7.45 (d, J = 8.6 Hz, 1H).

Example 237

tert-Butyl N-[7-(2,4-dimethoxy-6-methylphenyl)-2-methoxypyrazolo[1,5-a]pyridin-3-yl]carbamate

0458After dissolving tert-butyl N-(7-bromo-2-methoxypyrazolo[1,5-a]pyridin-3-yl)carbamate (300 mg) in 1,2-dimethoxyethane (10 mL) and water (5 mL), 6-methyl-2,4-dimethoxyphenylboric acid (258 mg), tetrakis (triphenylphosphine) palladium (0) complex (203 mg) and barium hydroxide octahydrate (415 mg) were added and the mixture was heated and stirred at 80°C for 3 hours. Water was added to the reaction mixture, extraction was performed with ethyl acetate and the extract was washed with brine. After drying the obtained organic layer over anhydrous magnesium sulfate and filtering it, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and the title compound (230 mg) was obtained from the n-hexane:ethyl acetate (5:1) fraction as a brown oil.

04591H NMR (400MHz, CDCl3) δ 1.53 (s, 9H), 2.02 (s, 3H), 3.66 (s, 3H), 3.87 (s, 3H), 3.90 (s, 3H), 6.42 (d, J = 2.0 Hz, 1H), 6.47 (d, J = 2.0 Hz, 1H), 6.49 (dd, J = 1.2, 6.8 Hz, 1H), 6.94 (dd, J = 6.8, 8.8 Hz, 1H), 7.26-7.33 (m, 1H).

Example 238

N-Cyclopropylmethyl-N-[7-(2,4-dimethoxy-6-methylphenyl)-2-methoxypyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2-furanylmethylamine

0460After dissolving tert-butyl N-[7-(2,4-dimethoxy-6-methylphenyl)-2-methoxypyrazolo[1,5-a]pyridin-3-yl]carbamate (50 mg) in N,N-dimethylformamide (2 mL), sodium hydride (60%, 15 mg) was added while cooling on ice, and then 2-tetrahydrofuranylmethyl chloride (16 µL) was added and the mixture was stirred for 3 hours at 60°C under a nitrogen stream. Water was added to the reaction mixture, extraction was performed with ethyl acetate and the extract was washed with brine. After drying over anhydrous magnesium sulfate and filtration, the solvent was concentrated under reduced pressure to obtain tert-butyl N-[7-(2,4-dimethoxy-6-methylphenyl)-2-methoxypyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2-furanylmethylcarbamate. The crude product was dissolved in ethyl acetate (2 mL) without purification, a 4 N hydrochloric acid/ethyl acetate solution (4 mL) was added, and the mixture was stirred at 40°C for 1 hour. The reaction mixture was neutralized with 5 N aqueous sodium hydroxide while cooling on ice, and then extraction was performed with ethyl acetate and the organic layer was washed with water and brine. The obtained organic layer was dried over anhydrous magnesium sulfate and filtered, and the solvent was concentrated under reduced pressure to obtain N-[7-(2,9-dimethoxy-6-methylphenyl)-2-methoxypyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2-furanylmethylamine as a crude product. This was dissolved in tetrahydrofuran (2 mL) without purification, and after adding cyclopropanecarboxyaldehyde (27 µL) and 3 M aqueous sulfuric acid (0.121 mL), sodium borohydride (9 mg) was added in five portions while vigorously stirring on ice, and stirring was continued for 30 minutes. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, extraction was performed with ethyl acetate, the solvent was concentrated, the residue was purified by silica gel column chromatography, and the title compound (31 mg) was obtained from the n-hexane:ethyl acetate (5:1) fraction as a yellow oil.

04611H NMR (400MHz, CDCl3) δ -0.06-0.01 (m, 2H), 0.25-0.32 (m, 2H), 0.80-0.90 (m, 1H), 1.52-1.70 (m, 1H), 1.74-1.95 (m, 3H), 2.01 (s, 1.5H), 2.03 (s, 1.5H), 2.80-3.06 (m, 3H), 3.26-3.35 (m, 1H), 3.65-3.72 (m, 4H), 3.80-3.90 (m, 8H), 6.38-6.42 (m, 1H), 6.44 (s, 1H), 6.47 (s, 1H), 6.99-7.05 (m, 1H), 7.34-7.40 (m, 1H).

0462The compounds of Examples 239 to 255 below were synthesized according to the production methods of Examples 237 and 238.

Example 239

N-Cyclopropylmethyl-N-[2-methoxy-7-(2-methoxy-4,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-3-furanylmethylamine

(Light yellow oil)

04631H NMR (400MHz, CDCl3) δ -0.08-0.04 (m, 2H), 0.22-0.36 (m, 2H), 0.78-0.88 (m, 1H), 1.60-1.70 (m, 1H), 1.85-1.97 (m, 1H), 2.00 (s, 3H), 2.21-2.31 (m, 1H), 2.41 (s, 3H), 2.75-2.89 (m, 2H), 2.92-3.03 (m, 1H), 3.09-3.19 (m, 1H), 3.54-3.82 (m, 4H), 3.70 (s, 3H), 3.85 (s, 3H), 6.41 (dd, J = 1.5, 6.8 Hz, 1H), 6.59 (s, 1H), 6.76 (s, 1H), 7.03 (dd, J = 6.8, 8.8 Hz, 1H), 7.31 (dd, J = 1.5, 8.8 Hz, 1H).

Example 240

N-[7-(2-Chloro-6-methoxy-4-methylphenyl)-2-methoxypyrazolo[1,5-a]pyridin-3-yl]-N-cyclopropylmethyl-N-tetrahydro-3-furanylmethylamine

(Yellow oil)

04641H NMR (400MHz, CDCl3) δ -0.06-0.03 (m, 2H), 0.26-0.35 (m, 2H), 0.78-0.87 (m, 1H), 1.57-1.68 (m, 1H), 1.85-1.97 (m, 1H), 2.20-2.31 (m, 1H), 2.42 (s, 3H), 2.78-2.88 (m, 2H), 2.93-3.03 (m, 1H), 3.10-3.19 (m, 1H), 3.56-3.84 (m, 4H), 3.71 (s, 3H), 3.86 (s, 3H), 6.47 (d, J = 6.8 Hz, 1H), 6.74 (s, 1H), 6.97 (s, 1H), 7.04 (dd, J = 6.8, 8.8 Hz, 1H), 7.34 (d, J = 8.8 Hz, 1H).

Example 241

N-[7-(2-Chloro-4-methoxyphenyl)-2-methoxypyrazolo[1,5-a]pyridin-3-yl]-N-cyclopropylmethyl-N-tetrahydro-3-furanylmethylamine

(Yellow oil)

04651H NMR (400MHz, CDCl3) δ -0.02-0.08 (m, 2H), 0.28-0.38 (m, 2H), 0.75-0.87 (m, 1H), 1.58-1.69 (m, 1H), 1.84-1.95 (m, 1H), 2.16-2.29 (m, 1H), 2.78-2.86 (m, 2H), 2.93-3.01 (m, 1H), 3.09-3.18 (m, 1H), 3.57-3.85 (m, 4H), 3.88 (s, 3H), 3.89 (s, 3H), 6.48 (dd, J = 1.3, 6.8 Hz, 1H), 6.92 (dd, J = 2.4, 8.8 Hz, 1H), 7.03 (dd, J = 6.8, 8.8 Hz, 1H), 7.06 (d, J = 2.4 Hz, 1H), 7.34 (dd, J = 1.3, 8.8 Hz, 1H), 7.45 (d, J = 8.8 Hz, 1H).

Example 242

N-[7-(2-Chloro-4-methoxyphenyl)-2-methoxypyrazolo[1,5-a]pyridin-3-yl]-N-cyclopropylmethyl-N-tetrahydro-2-furanylmethylamine

(Yellow oil)

04661H NMR (400MHz, CDCl3) δ -0.03-0.04 (m, 2H), 0.27-0.34 (m, 2H), 0.78-0.88 (m, 1H), 1.49-1.68 (m, 2H), 1.71-1.95 (m, 2H), 2.82-2.95 (m, 2H), 2.98-3.05 (m, 1H), 3.27-3.35 (m, 1H), 3.53-3.72 (m, 1H), 3.78-3.88 (m, 2H), 3.88 (s, 3H), 3.90 (s, 3H), 6.48 (dd, J = 1.3, 6.8 Hz, 1H), 6.91 (dd, J = 2.4, 8.4 Hz, 1H), 7.03 (dd, J = 6.8, 8.8 Hz, 1H), 7.06 (d, J = 2.4 Hz, 1H), 7.42 (dd, J = 1.3, 8.8 Hz, 1H), 7.44 4 (d, J = 8.4 Hz, 1H).

Example 243

N-Cyclopropylmethyl-N-[7-(2,4-dimethoxy-6-methylphenyl)-2-methoxypyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-3-furanylmethylamine

(Light yellow oil)

04671H NMR (400MHz, CDCl3) δ -0.06-0.02 (m, 2H), 0.25-0.35 (m, 2H), 0.77-0.86 (m, 1H), 1.55-1.70 (m, 1H), 1.86-1.96 (m, 1H), 2.02 (s, 1.5H), 2.03 (s, 1.5H), 2.22-2.30 (m, 1H), 2.76-2.88 (m, 2H), 2.93-3.02 (m, 1H), 3.10-3.18 (m, 1H), 3.55-3.62 (m, 1H), 3.63-3.68 (m, 1H), 3.68 (s, 1.5H), 3.69 (s, 1.5H), 3.73-3.85 (m, 2H), 3.86 (s, 3H), 3.87 (s, 3H), 6.41 (dd, J = 1.2, 6.8 Hz, 1H), 6.43 (d, J = 2.0 Hz, 1H), 6.47 (d, J = 2.0 Hz, 1H), 7.02 (dd, J = 6.8, 8.8 Hz, 1H), 7.28-7.32 (m, 1H).

Example 244

N-Cyclopropylmethyl-N-[7-(2,6-dimethoxy-4-methylphenyl)-2-methoxypyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-3-furanylmethylamine

(Yellow amorphous)

04681H NMR (400MHz, CDCl3) δ -0.02-0.04 (m, 2H), 0.28-0.36 (m, 2H), 0.78-0.90 (m, 1H), 1.58-1.70 (m, 1H), 1.85-1.96 (m, 1H), 2.20-2.33 (m, 1H), 2.44 (s, 3H), 2.83 (d, J = 6.8 Hz, 2H), 2.98 (dd, J = 8.5, 12.0 Hz, 1H), 3.14 (dd, J = 6.7, 12.0 Hz, 1H), 3.59 (dd, J = 5.9, 8.5 Hz, 1H), 3.62-3.86 (m, 3H), 3.72 (s, 6H), 3.87 (s, 3H), 6.49 (dd, J = 1.5, 6.7 Hz, 1H), 6.51 (s, 2H), 7.03 (dd, J = 6.8, 8.8 Hz, 1H), 7.30 (dd, J = 1.5, 8.8 Hz, 1H).

Example 245

N-Cyclopropylmethyl-N-[7-(2,6-dimethoxy-4-methylphenyl)-2-methoxypyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2-furanylmethylamine

(Yellow crystals)

04691H NMR (400MHz, CDCl3) δ -0.02-0.04 (m, 2H), 0.28-0.36 (m, 2H), 0.80-0.93 (m, 1H), 1.60-1.72 (m, 1H), 1.73-1.96 (m, 3H), 2.45 (s, 3H), 2.83-2.96 (m, 2H), 3.02 (dd, J = 7.0, 12.0 Hz, 1H), 3.33 (dd, J = 5.7, 12.0 Hz, 1H), 3.64-3.76 (m, 1H), 3.72 (s, 6H), 3.80-3.92 (m, 2H), 3.87 (s, 3H), 6.49 (dd, J = 1.3, 6.8 Hz, 1H), 6.51 (s, 2H), 7.03 (dd, J = 6.8, 8.9 Hz, 1H), 7.37 (dd, J = 1.5, 8.8 Hz, 1H).

Example 246

N-Cyclopropylmethyl-N-[2-methoxy-7-(2-methoxy-4,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2-furanylmethylamine

(Yellow oil)

04701H NMR (400MHz, CDCl3) δ -0.08-0.03 (m, 2H), 0.22-0.33 (m, 2H), 0.80-0.92 (m, 1H), 1.56-1.70 (m, 1H), 1.73-1.96 (m, 3H), 1.99 (s, 3H), 2.40 (s, 3H), 2.80-3.06 (m, 3H), 3.25-3.37 (m, 1H), 3.63-3.72 (m, 1H), 3.69 (s, 3H), 3.79-3.91 (m, 2H), 3.85 (s, 3H), 6.40 (dd, J = 1.3, 6.8 Hz, 1H), 6.68 (s, 1H), 6.76 (s, 1H), 7.02 (dd, J = 6.8, 8.8 Hz, 1H), 7.37 (dd, J = 1.3, 8.8 Hz, 1H).

Example 247

N-Cyclopropylmethyl-N-[7-(2,6-dimethoxy-4-methylphenyl)-2-methoxypyrazolo[1,5-a]pyridin-3-yl]-N-(3-furylmethyl)amine

(Yellow crystals)

04711H NMR (400MHz, CDCl3) δ -0.02-0.04 (m, 2H), 0.28-0.36 (m, 2H), 0.80-0.92 (m, 1H), 2.45 (s, 3H), 2.87 (d, J = 6.6 Hz, 2H), 3.71 (s, 6H), 3.88 (s, 3H), 4.11 (s, 2H), 6.34-6.38 (m, 1H), 6.48 (dd, J = 1.5, 6.9 Hz, 1H), 6.50 (s, 2H), 7.00 (dd, J = 6.8, 8.8 Hz, 1H), 7.22-7.32 (m, 3H).

Example 248

N-Cyclopropylmethyl-N-[7-(2,6-dimethoxy-4-methylphenyl)-2-methoxypyrazolo[1,5-a]pyridin-3-yl]-N-(2-furylmethyl)amine

(Yellow oil)

04721H NMR (400MHz, CDCl3) δ -0.02-0.06 (m, 2H), 0.28-0.37 (m, 2H), 0.80-0.94 (m, 1H), 2.43 (s, 3H), 2.93 (d, J = 6.6 Hz, 2H), 3.70 (s, 6H), 3.86 (s, 3H), 4.24 (s, 2H), 6.07 (d, J = 3.1 Hz, 1H), 6.22 (dd, J = 1.8, 3.1 Hz, 1H), 6.46 (dd, J = 1.3, 6.8 Hz, 1H), 6.49 (s, 2H), 6.98 (dd, J = 6.8, 8.8 Hz, 1H), 7.21 (dd, J = 1.5, 8.8 Hz, 1H), 7.24-7.34 (m, 1H).

Example 249

N-[7-(2-Chloro-6-methoxy-4-methylphenyl)-2-methoxypyrazolo[1,5-a]pyridin-3-yl]-N-cyclopropylmethyl-N-tetrahydro-2-furanylmethylamine

(Yellow oil)

04731H NMR (400MHz, CDCl3) δ -0.02-0.04 (m, 2H), 0.28-0.36 (m, 2H), 0.82-0.92 (m, 1H), 1.60-1.72 (m, 2H), 1.78-1.98 (m, 2H), 2.45 (s, 3H), 2.84-2.98 (m, 2H), 3.02-3.08 (m, 1H), 3.30-3.38 (m, 1H), 3.68-3.74 (m, 1H), 3.74 (s, 3H), 3.82-3.92 (m, 2H), 3.88 (s, 3H), 6.49 (d, J = 7.2 Hz, 1H), 6.77 (s, 1H), 6.99 (s, 1H), 7.06 (dd, J = 6.8, 8.8 Hz, 1H), 7.43 (dd, J = 1.6, 9.2 Hz, 1H).

0474MS (ESI) m/z 456 MH+

Example 250

N-[2-Methoxy-7-(2-methoxy-4,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-propyl-N-tetrahydro-3-furanylmethylamine

(Yellow oil)

04751H NMR (400MHz, CDCl3) δ 0.89 (t, J = 7.6 Hz, 3H), 1.32-1.42 (m, 2H), 1.56-1.66 (m, 1H), 1.86-1.96 (m, 1H), 1.99 (s, 1.5H), 2.00 (s, 1.5H), 2.18-2.28 (m, 1H), 2.41 (s, 3H), 2.88-2.96 (m, 3H), 3.05-3.12 (m, 1H), 3.53-3.58 (m, 1H), 3.63-3.69 (m, 1H), 3.70 (s, 3H), 3.72-3.83 (m, 2H), 3.85 (s, 3H), 6.41 (dd, J = 1.6, 6.8 Hz, 1H), 6.68 (s, 1H), 6.76 (s, 1H), 7.03 (dd, J = 6.8, 8.8 Hz, 1H), 7.25-7.28 (m, 1H).

Example 251

N-[2-Methoxy-7-(2-methoxy-4,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-propyl-N-tetrahydro-2-furanylmethylamine

(Yellow oil)

04761H NMR (400MHz, CDCl3) δ 0.87 (t, J = 7.6 Hz, 3H), 1.35-1.44 (m, 2H), 1.58-1.66 (m, 1H), 1.74-1.96 (m, 3H), 1.99 (s, 1.5H), 2.00 (s, 1.5H), 2.41 (s, 3H), 2.94 (dd, J = 6.8, 12.4 Hz, 1H), 2.99 (t, J = 7.6 Hz, 1H), 3.25 (ddd, J = 4.0, 5.6, 12.4 Hz, 1H), 3.64-3.70 (m, 1H), 3.70 (s, 3H), 3.80-3.85 (m, 2H), 3.85 (s, 3H), 6.40 (dd, J = 1.2, 6.8 Hz, 1H), 6.68 (s, 1H), 6.76 (s, 1H), 7.03 (dd, J = 6.8, 8.8 Hz, 1H), 7.34 (td, J = 1.8, 6.8 Hz, 1H).

Example 252

N-Cyclopropylmethyl-N-[2-methoxy-7-(4-methoxy-2,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-3-furanylmethylamine

(Yellow oil)

04771H NMR (400MHz, CDCl3) δ -0.10-0.00 (m, 2H), 0.22-0.32 (m, 2H), 0.76-0.86 (m, 1H), 1.58-1.69 (m, 1H), 1.86-1.97 (m, 1H), 2.02 (s, 3H), 2.03 (s, 3H), 2.20-2.31 (m, 1H), 2.79-2.86 (m, 2H), 2.93-3.02 (m, 1H), 3.10-3.19 (m, 1H), 3.55-3.61 (m, 1H), 3.63-3.71 (m, 1H), 3.72-3.85 (m, 2H), 3.84 (s, 3H), 3.85 (s, 3H), 6.34 (dd, J = 1.3, 6.8 Hz, 1H), 6.70 (s, 2H), 7.02 (dd, J = 6.8, 8.8 Hz, 1H), 7.32 (dd, J = 1.3, 8.8 Hz, 1H).

Example 253

N-Cyclopropylmethyl-N-7-[2-(fluoromethoxy)-4,6-dimethylphenyl]-2-methoxypyrazolo[1,5-a]pyridin-3-yl-N-tetrahydro-3-furanylmethylamine

(Yellow oil)

04781H NMR (400MHz, CDCl3) δ -0.04-0.06 (m, 2H), 0.24-0.36 (m, 2H), 0.78-0.90 (m, 1H), 1.60-1.72 (m, 1H), 1.90-1.98 (m, 1H), 2.08 (br s, 3H), 2.22-2.32 (m, 1H), 2.45 (s, 3H), 2.80-2.90 (m, 2H), 2.96-3.04 (m, 1H), 3.14-3.20 (m, 1H), 3.58-3.86 (m, 4H), 3.86 (s, 3H), 5.38-5.66 (m, 2H), 6.45 (dd, J = 1.2, 6.8 Hz, 1H), 6.96 (s, 1H), 6.99 (s, 1H), 7.06 (dd, J = 6.8, 8.8 Hz, 1H), 7.35 (dd, J = 1.2, 8.8 Hz, 1H).

Example 254

N-Cyclopropyl-N-[7-(2,6-dimethoxy-4-methylphenyl)-2-methoxypyrazolo[1,5-a]pyridin-3-yl]-N-(1,3-dioxolan-2-ylmethyl)amine

(Yellow oil)

04791H NMR (400MHz, CDCl3) δ -0.02-0.04 (m, 2H), 0.28-0.32 (m, 2H), 0.82-0.92 (m, 1H), 2.44 (s, 3H), 2.94 (d, J = 6.8 Hz, 2H), 3.30 (d, J = 4.4 Hz, 2H), 3.70 (s, 6H), 3.82-3.86 (m, 2H), 3.87 (s, 3H), 3.92-3.98 (m, 2H), 4.91 (t, J = 4.4 Hz, 1H), 6.48 (dd, J = 1.6, 6.8 Hz, 1H), 6.49 (s, 2H), 7.02 (dd, J = 6.8, 8.8 Hz, 1H), 7.38 (dd, J = 1.6, 8.8 Hz, 1H).

0480MS(ESI) m/z 454 MH+

Example 255

N-Cyclopropyl-N-[7-(2,6-dimethoxy-4-methylphenyl)-2-methoxypyrazolo[1,5-a]pyridin-3-yl]-N-[2-(1,3-dioxolan-2-yl)ethyl]amine

(Yellow oil)

04811H NMR (400MHz, CDCl3) δ -0.02-0.04 (m, 2H), 0.28-0.34 (m, 2H), 0.82-0.92 (m, 1H), 1.74-1.82 (m, 2H), 2.44 (s, 3H), 2.87 (d, J = 6.8 Hz, 2H), 3.22 (t, J = 7.2 Hz, 2H), 3.71 (s, 6H), 3.82-3.90 (m, 2H), 3.86 (s, 3H), 3.92-4.00 (m, 2H), 4.97 (t, J = 4.4 Hz, 1H), 6.47 (dd, J = 1.6, 6.8 Hz, 1H), 6.49 (s, 2H), 7.00 (dd, J = 6.8, 8.8 Hz, 1H), 7.31 (dd, J = 1.6, 8.8 Hz, 1H).

0482MS(ESI) m/z 468 MH+

Example 256

N-Cyclopropylmethyl-N-[2-methoxy-7-(2-methoxy-4,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylmethylamine

0483After dissolving N-cyclopropylmethyl-N-[2-methoxy-7-(2-methoxy-4,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]amine (134 mg) in tetrahydrofuran (10 mL), tetrahydro-2H-4-pyrancarbaldehyde (131 mg) and sodium triacetoxyborohydride (243 mg) were added, and the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium hydrogencarbonate was added to the obtained reaction mixture, extraction was performed with ethyl acetate, and the extract was washed with brine. After drying over anhydrous magnesium sulfate and filtration, the solvent was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and the title compound (120 mg) was obtained from the n-hexane:ethyl acetate (4:1) fraction as a yellow amorphous.

04841H NMR (400MHz, CDCl3) δ -0.03-0.12 (m, 2H), 0.30-0.44 (m, 2H), 0.84-0.97 (m, 1H), 1.30-1.44 (m, 2H), 1.58-1.74 (m, 1H), 1.78-1.90 (m, 2H), 2.08 (s, 3H), 2.49 (s, 3H), 2.82-2.96 (m, 2H), 2.97-3.10 (m, 2H), 3.38 (dt, J = 2.0, 12.0 Hz, 2H), 3.79 (s, 3H), 3.93 (s, 3H), 3.96-4.06 (m, 2H), 6.49 (dd, J = 1.3, 6.8 Hz, 1H), 6.77 (s, 1H). 6.85 (s, 1H), 7.10 (dd, J = 6.8, 8.8 Hz, 1H), 7.39 (dd, J = 1.3, 8.8 Hz, 1H).

0485The compounds of Examples 257 to 266 below were synthesized according to the production method of Example 256.

Example 257

N-Cyclopropylmethyl-N-[2-methoxy-7-(2-methoxy-4,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylamine

(Yellow oil)

04861H NMR (400MHz, CDCl3) δ -0.10- -0.01 (m, 2H), 0.20-0.28 (m, 2H), 0.70-0.80 (m, 1H), 1.44-1.56 (m, 2H), 1.78-1.85 (m, 2H), 2.00 (s, 3H), 2.41 (s. 3H), 2.87-2.99 (m, 2H), 3.14-3.34 (m, 2H), 3.34-3.42 (m, 2H), 3.70 (s, 3H), 3.84 (s, 3H), 3.92-3.98 (m, 2H), 6.41 (dd, J = 1.6, 6.8 Hz, 1H), 6.69 (s, 1H), 6.76 (s, 1H), 7.03 (dd, J = 6.8, 8.8 Hz, 1H), 7.32 (dd, J = 1.6, 8.8 Hz, 1H).

Example 258

N-[7-(2-Chloro-4-methoxyphenyl)-2-methoxypyrazolo[1,5-a]pyridin-3-yl]-N-cyclopropylmethyl-N-tetrahydro-2H-4-pyranylamine

(Yellow oil)

04871H NMR (400MHz, CDCl3) δ -0.05-0.04 (m, 2H), 0.21-0.30 (m, 2H), 0.68-0.78 (m, 1H), 1.41-1.55 (m, 2H), 1.75-1.85 (m, 2H), 2.89-2.96 (m, 2H), 3.12-3.22 (m, 1H), 3.32-3.42 (m, 2H), 3.88 (s, 3H), 3.89 (s, 3H), 3.88-3.98 (m, 2H), 6.49 (dd, J = 1.3, 6.8 Hz, 1H), 6.92 (dd, J = 2.4, 8.8 Hz, 1H), 7.03 (dd, J = 6.8, 8.8 Hz, 1H), 7.06 (d, J = 2.4 Hz, 1H), 7.36 (dd, J = 1.3, 8.8 Hz, 1H), 7.45 (d, J = 8.8 Hz, 1H).

Example 259

N-Cyclopropylmethyl-N-[7-(2,4-dimethoxy-6-methylphenyl)-2-methoxypyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylamine

(Yellow oil)

04881H NMR (400MHz, CDCl3) δ -0.06- -0.02 (m, 2H), 0.20-0.28 (m, 2H), 0.70-0.80 (m, 1H), 1.44-1.55 (m, 2H), 1.78-1.86 (m, 2H), 2.02 (s, 3H), 2.88-3.00 (m, 2H), 3.14-3.24 (m, 1H), 3.34-3.42 (m, 2H), 3.69 (s, 3H), 3.85 (s, 3H), 3.87 (s, 3H), 3.92-3.98 (m, 2H), 6.41 (dd, J = 1.6, 6.8 Hz, 1H), 6.44 (d, J = 2.0 Hz, 1H), 6.47 (d, J = 2.0 Hz, 1H), 7.03 (dd, J = 6.8, 8.8 Hz, 1H), 7.31 (dd, J = 1.6, 8.8 Hz, 1H).

Example 260

N-Cyclopropylmethyl-N-[7-(2,6-dimethoxy-4-methylphenyl)-2-methoxypyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylamine

(Yellow crystals)

04891H NMR (400MHz, CDCl3) δ -0.03-0.06 (m, 2H), 0.24-0.33 (m, 2H), 0.72-0.85 (m, 1H), 1.46-1.60 (m, 2H), 1.80-1.90 (m, 2H), 2.47 (s, 3H), 2.97 (d, J = 6.6 Hz, 2H), 3.16-3.28 (m, 1H), 3.41 (dt, J = 1.8, 12.0 Hz, 2H), 3.74 (s, 6H), 3.89 (s, 3H), 3.93-4.03 (m, 2H), 6.52 (dd, J = 1.5, 7.0 Hz, 1H), 6.54 (s, 2H), 7.06 (dd, J = 6.8, 8.8 Hz, 1H), 7.34 (dd, J = 1.3, 8.9 Hz, 1H).

Example 261

N-Cyclopropylmethyl-N-[2-methoxy-7-(2-methoxy-4,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-3-pyranylamine

(Yellow oil)

04901H NMR (400MHz, CDCl3) δ -0.02-0.06 (m, 2H), 0.26-0.38 (m, 2H), 0.78-0.88 (m, 1H), 1.32-1.44 (m, 1H), 1.62-1.76 (m, 2H), 2.09 (s, 3H), 2.09-2.16 (m, 1H), 2.50 (s, 3H), 2.94-3.08 (m, 2H), 3.20-3.30 (m, 3H), 3.79 (s, 3H), 3.84-3.92 (m, 1H), 3.94 (s, 3H), 4.12-4.22 (m, 1H), 6.51 (dd, J = 1.2, 6.8 Hz, 1H), 6.78 (s, 1H), 6.85 (s, 1H), 7.13 (dd, J = 6.8, 8.8 Hz, 1H), 7.39 (dd, J = 1.6, 9.2 Hz, 1H).

Example 262

N-Cyclopropylmethyl-N-[7-(2,6-dimethoxy-4-methylphenyl)-2-methoxypyrazolo[1,5-a]pyridin-3-ly]-N-tetrahydro-2H-4-pyranylmethylamine

(Yellow crystals)

04911H NMR (400MHz, CDCl3) δ -0.04-0.08 (m, 2H), 0.28-0.40 (m, 2H), 0.80-0.94 (m, 1H), 1.20-1.38 (m, 2H), 1.52-1.70 (m, 1H), 1.74-1.84 (m, 2H), 2.47 (s, 3H), 2.84 (d, J = 6.6 Hz, 2H), 2.97 (d, J = 6.9 Hz, 2H), 3.33 (dt, J = 2.0, 12.0 Hz, 2H), 3.75 (s, 6H), 3.89 (s, 3H), 3.90-4.00 (m, 2H), 6.52 (dd, J = 1.4, 6.9 Hz, 1H), 6.54 (s, 2H), 7.04 (dd, J = 6.8, 8.8 Hz, 1H), 7.33 (dd, J = 1.4, 8.8 Hz, 1H).

Example 263

N-[7-(2-Chloro-6-methoxy-4-methylphenyl)-2-methoxypyrazolo[1,5-a]pyridin-3-yl]-N-cyclopropylmethyl-N-tetrahydro-2H-4-pyranylamine

(Yellow solid)

04921H NMR (400MHz, CDCl3) δ -0.02-0.02 (m, 2H), 0.28-0.32 (m, 2H), 0.74-0.84 (m, 1H), 1.50-1.64 (m, 2H), 1.84-1.92 (m, 2H), 2.47 (s, 3H), 2.99 (br d, J = 6.4 Hz, 2H), 3.20-3.30 (m, 1H), 3.40-3.48 (m, 2H), 3.77 (s, 3H), 3.90 (s, 3H), 3.96-4.04 (m, 2H), 6.53 (dd, J = 1.6, 8.8 Hz, 1H), 6.79 (s, 1H), 7.02 (s, 1H), 7.09 (dd, J = 6.8, 8.8 Hz, 1H), 7.41 (dd, J = 1.2, 8.8 Hz, 1H). MS(ESI) m/z 456 MH+

Example 264

N-Cyclopropylmethyl-N-[2-methoxy-7-(4-methoxy-2,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylamine

(Yellow oil)

04931H NMR (400MHz, CDCl3) δ -0.10- -0.05 (m, 2H), 0.17-0.24 (m, 2H), 0.67-0.78 (m, 1H), 1.42-1.55 (m, 2H), 1.77-1.87 (m, 2H), 2.02 (s, 6H), 2.90-2.96 (m, 2H), 3.13-3.23 (m, 1H), 3.33-3.43 (m, 2H), 3.83 (s, 3H), 3.85 (s, 3H), 3.90-3.99 (m, 2H), 6.35 (dd, J = 1.3, 6.8 Hz, 1H), 6.70 (s, 2H), 7.02 (dd, J = 6.8, 8.8 Hz, 1H), 7.32 (dd, J = 1.3, 8.8 Hz, 1H).

Example 265

N-[2-Methoxy-7-(2-methoxy-4,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranyl-N-tetrahydro-2H-4-pyranylmethylamine

(White amorphous)

04941H NMR (400MHz, CDCl3) δ 1.16-1.29 (m, 2H), 1.39-1.59 (m, 3H), 1.64-1.84 (m, 4H), 1.99 (s, 3H), 2.41 (s, 3H), 2.90-3.04 (m, 3H), 3.20-3.40 (m, 4H), 3.70 (s, 3H), 3.83 (s, 3H), 3.86-3.97 (m, 4H), 6.41 (dd, J = 1.3, 6.8 Hz, 1H), 6.68 (s, 1H), 6.75 (s, 1H), 7.02 (dd, J = 6.8, 8.8 Hz, 1H), 7.21 (dd, J = 1.3, 8.8 Hz, 1H).

Example 266

N-Cyclopropylmethyl-N-[7-(2,6-dimethoxy-4-methylphenyl)-2-methoxypyrazolo[1,5-a]pyridin-3-yl]-N-(1,3-oxazol-2-ylmethyl)amine

(Yellow oil)

04951H NMR (400MHz, CDCl3) δ -0.02-0.10 (m, 2H), 0.28-0.38 (m, 2H), 0.82-0.96 (m, 1H), 2.43 (s, 3H), 2.97 (d, J = 6.6 Hz, 2H), 3.69 (s, 6H), 3.84 (s, 3H), 4.38 (s, 2H), 6.44-6.53 (m, 1H), 6.49 (s, 2H), 7.00 (s, 1H), 7.01 (dd, J = 6.7, 8.8 Hz, 1H), 7.27 (dd, J = 1.5, 8.8 Hz, 1H), 7.55 (s, 1H).

0496MS(ESI) m/z 449 MH+

Example 267

N-[7-(2-Methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(2-pyridyl)amine

0497After dissolving [7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine (40 mg) in toluene (1 mL), 2-bromopyridine (0.013 mL), sodium t-butoxide (25 mg) and dichlorobis(tri-o-tolylphosphine)palladium complex (3 mg) were added and the mixture was heated and stirred at 120°C for 5 hours. The mixture was cooled to room temperature, water was added, and extraction was performed with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography, and the title compound (12 mg) was obtained from the ethyl acetate:n-hexane (1:2) fraction as white crystals.

04981H NMR (400MHz, CDCl3) δ 2.05 (s, 3H), 2.35 (s, 3H), 2.40 (s, 3H), 3.70 (s, 3H), 6.61 (dd, J = 1.3, 6.8 Hz, 1H), 6.68 (s, 1H), 6.76 (s, 1H), 6.89 (ddd, J = 0.8, 4.8, 7.2 Hz, 1H), 6.97 (dd, J = 0.8, 8.4 Hz, 1H), 7.06 (dd, J = 6.8, 8.8 Hz, 1H), 7.14 (dd, J = 1.3, 8.8 Hz, 1H), 7.54 (ddd, J = 0.8, 7.2, 8.4 Hz, 1H), 8.31 (dd, J = 0.8, 4.8 Hz, 1H).

Example 268

N-Cyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(2-pyridyl)amine

0499The title compound (4 mg) was obtained as light yellow crystals in the same manner as Example 267 using N-cyclopropylmethyl-N-[2-ethyl-7-(2-methoxy-4,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]amine (50 mg), with Pd2(dba)3CHCl3 as the catalyst, and also using 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl and sodium t-butoxide.

05001H NMR (400MHz, CDCl3) δ 0.05-0.17 (m, 2H), 0.29-0.41 (m, 2H), 1.09-1.20 (m, 1H), 2.04 (s, 3H), 2.40 (s, 3H), 2.42 (s, 3H), 3.72 (s, 3H), 6.18 (d, J = 8.4 Hz, 1H), 6.58 (dd, J = 4.8, 7.2 Hz, 1H), 6.62 (dd, J = 0.8, 6.8 Hz, 1H), 6.71 (s, 1H), 6.79 (s, 1H), 7.12 (dd, J = 6.8, 8.8 Hz, 1H), 7.23 (dd, J = 0.8, 8.8 Hz, 1H), 7.29 (dd, J = 7.2, 8.4 Hz, 1H), 8.22 (d, J = 4.8 Hz, 1H).

0501The compounds of Examples 269 and 270 were synthesized according to the production methods of Examples 267 and 268.

Example 269

N-[7-(2,6-Dimethoxy-4-methylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-propyl-N-(2-pyridyl)amine

(Light yellow crystals)

05021H NMR (400MHz, CDCl3) δ 0.90-0.96 (m, 3H), 1.60-1.75 (m, 2H), 2.41 (s, 3H), 2.45 (s, 3H), 3.74 (s, 6H), 6.14 (d, J = 8.8 Hz, 1H), 6.52 (s, 2H), 6.55 (dd, J = 4.8, 7.2 Hz, 1H), 6.69 (dd, J = 1.3, 6.8 Hz, 1H), 7.11 (dd, J = 6.8, 8.8 Hz, 1H), 7.15 (dd, J = 1.3, 8.8 Hz, 1H), 7.25 (dd, J = 7.2, 8.8 Hz, 1H), 8.21 (d, J = 4.8 Hz, 1H).

Example 270

N-Cyclopropylmethyl-N-[7-(2,6-dimethoxy-4-methylphenyl)-2-methoxypyrazolo[1,5-a]pyridin-3-yl]-N-(2-pyridyl)amine

(Light yellow crystals)

05031H NMR (400MHz, CDCl3) δ 0.09-0.17 (m, 2H), 0.32-0.40 (m, 2H), 1.09-1.21 (m, 1H), 2.45 (s, 3H), 3.74 (s, 6H), 3.87 (s, 6H), 6.28 (d, J = 8.4 Hz, 1H), 6.52 (s, 2H), 6.53 (dd, J = 5.0, 7.2 Hz, 1H), 6.61 (dd, J = 1.3, 6.8 Hz, 1H), 7.08 (dd, J = 6.8, 8.8 Hz, 1H), 7.12 (dd, J = 1.3, 8.8 Hz, 1H), 7.27 (dd, J = 7.2, 8.4 Hz, 1H), 8.18 (d, J = 5.0 Hz, 1H).

Example 271

3-(2,5-Diethyl-1H-1-pyrrolyl)-7-(2,6-dimethoxy-4-methylphenyl)-2-ethylpyrazolo[1,5-a]pyridine

0504After dissolving 7-(2,6-dimethoxy-4-methylphenyl)-2-ethyl-3-nitropyrazolo[1,5-a]pyridine (600 mg) in a mixture of ethanol (30 mL) and water (30 mL), acetic acid (3 mL) and zinc powder (600 mg) were added and the mixture was stirred at 60°C for 2 hours. The ethanol of the obtained reaction mixture was distilled off under reduced pressure, and then saturated aqueous sodium hydrogencarbonate and ethyl acetate were added to the residue and extraction was performed with ethyl acetate. The obtained organic layers were combined, washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 7-(2,6-dimethoxy-4-methylphenyl)-2-ethylpyrazolo[1,5-a]pyridine-3-amine (500 mg) as a crude product.

0505The obtained crude 7-(2,6-dimethoxy-4-methylphenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-amine (160 mg) was dissolved in toluene (50 mL), and then 3,6-octanedione (1 g) and acetic acid (15 mL) were added and the mixture was heated to reflux for 4 hours. The toluene of the obtained reaction mixture was distilled off under reduced pressure, and then saturated aqueous sodium hydrogencarbonate was added to the residue and extraction was performed with ethyl acetate. The extracted organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography, and the title compound (19 mg) was obtained from the n-hexane:ethyl acetate (10:1) fraction as white crystals.

05061H NMR (400MHz, CDCl3) δ 1.07 (t, J = 7.6 Hz, 3H), 1.08 (t, J = 7.6 Hz, 6H), 2.25 (q, J = 7.6 Hz, 2H), 2.26 (q, J = 7.6 Hz, 2H), 2.45 (s, 3H), 2.55 (q, J = 8.0 Hz, 2H), 3.73 (s, 6H), 5.99 (s, 2H), 6.54 (s, 2H), 6.73 (dd. J = 2.0, 6.4 Hz, 1H), 7.10-7.15 (m, 2H).

0507The compounds of Examples 272 to 276 were synthesized according to the production method of Example 25.

Example 272

N3-Cyclopropylmethyl-N3-tetrahydro-3-furanylmethyl-7-[6-(dimethylamino)-4-methyl-3-pyridyl]-2-ethylpyrazolo[1,5-a]pyridin-3-amine

(Yellow oil)

05081H NMR (400MHz, CDCl3) δ -0.05-0.05 (m, 2H), 0.35-0.42 (m, 2H), 0.80-0.90 (m, 1H), 1.25 (t, J = 7.6 Hz, 3H), 1.55-1.70 (m, 1H), 1.85-1.95 (m, 1H), 2.07 (s, 3H), 2.20-2.30 (m, 1H), 2.77 (q, J = 7.6 Hz, 2H), 2.90 (d, J = 6.8 Hz, 2H), 3.06-3.11 (m, 1H), 3.14 (s, 6H), 3.17-3.25 (m, 2H), 3.60-3.84 (m, 4H), 6.46 (s, 1H), 6.53 (dd, J = 1.6, 6.8 Hz, 1H), 7.02 (dd, J = 6.8, 8.8 Hz, 1H), 7.45 (dd, J = 1.6, 9.2 Hz, 1H), 8.16 (s, 1H).

Example 273

N3-Cyclopropylmethyl-N3-tetrahydro-3-furanylmethyl-7-[6-(dimethylamino)-2,4-dimethyl-3-pyridyl]-2-ethylpyrazolo[1,5-a]pyridin-3-amine

(Yellow oil)

05091H NMR (400MHz, CDCl3) δ -0.05-0.00 (m, 2H), 0.30-0.40 (m, 2H), 0.75-0.90 (m, 1H), 1.21 (t, J = 7.2 Hz, 3H), 1.60-1.70 (m, 1H), 1.85-1.97 (m, 4H), 2.14 (s, 3H), 2.22-2.32 (m, 1H), 2.75 (q, J = 7.6 Hz, 2H), 2.91 (d, J = 6.4 Hz, 2H), 3.05-3.15 (m, 7H), 3.20-3.28 (m, 1H), 3.59-3.88 (m, 4H), 6.31 (s, 2H), 6.46 (dd, J = 1.6, 6.8 Hz, 1H), 7.00 (dd. J = 6.8, 9.2 Hz, 1H), 7.43 (dd, J = 1.2, 8.8 Hz, 1H).

Example 274

N-Cyclopropylmethyl-N-(1,3-dioxolan-2-ylmethyl)-N-[2-ethyl-7-(4-methoxy-2,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]amine

(Yellow oil)

05101H NMR (400MHz, CDCl3) δ -0.04-0.04 (m, 2H), 0.34-0.38 (m, 2H), 0.84-0.96 (m, 1H), 1.25 (t, J = 7.6 Hz, 3H), 2.05 (s, 6H), 2.81 (q, J = 7.6 Hz, 2H), 3.07 (d, J = 6.8 Hz, 2H), 3.41 (d, J = 4.4 Hz, 2H), 3.86-3.90 (m, 2H), 3.87 (s, 3H), 3.98-4.04 (m, 2H), 6.47 (dd, J = 1.2, 6.8 Hz, 1H), 6.73 (s, 2H), 7.05 (dd, J = 6.8, 8.8 Hz, 1H), 7.51 (dd, J = 1.2, 8.8 Hz, 1H).

Example 275

N3-Cyclopropylmethyl-N3-(1,3-dioxolan-2-ylmethyl)-7-[6-(dimethylamino)-4-methyl-3-pyridyl]-2-ethylpyrazolo[1,5-a]pyridin-3-amine

(Yellow oil)

05111H NMR (400MHz, CDCl3) δ -0.02-0.04 (m, 2H), 0.32-0.38 (m, 2H), 0.80-0.92 (m, 1H), 1.28 (t, J = 7.6 Hz, 3H), 2.08 (s, 3H), 2.81 (q, J = 7.6 Hz, 2H), 3.03 (d, J = 6.8 Hz, 2H), 3.15 (s, 6H), 3.36 (d, J = 4.4 Hz, 2H), 3.80-3.88 (m, 2H), 3.92-4.00 (m, 2H), 4.91 (t, J = 4.4 Hz, 1H), 6.46 (s, 1H), 6.53 (dd, J = 1.6, 6.8 Hz, 1H), 7.02 (dd, J = 6.8, 8.8 Hz, 1H), 7.49 (dd, J = 1.6, 8.8 Hz, 1H), 8.16 (s, 1H).

Example 276

N3-Cyclopropylmethyl-N3-(1,3-dioxolan-2-ylmethyl)-7-[6-(dimethylamino)-2,4-dimethyl-3-pyridyl]-2-ethylpyrazolo[1,5-a]pyridin-3-amine

(Yellow oil)

05121H NMR (400MHz, CDCl3) δ -0.02-0.04 (m, 2H), 0.32-0.38 (m, 2H), 0.82-0.92 (m, 1H), 1.26 (t, J = 7.6 Hz, 3H), 1.99 (s, 3H), 2.18 (s, 3H), 2.81 (q, J = 7.6 Hz, 2H), 3.07 (d, J = 6.8 Hz, 2H), 3.16 (s, 6H), 3.04 (d, J = 4.4 Hz, 2H), 3.82-3.90 (m, 2H), 3.96-4.02 (m, 2H), 4.96 (t, J = 4.4 Hz, 1H), 6.34 (s, 1H), 6.48 (dd, J = 1.2, 6.8 Hz, 1H), 7.03 (dd, J = 6.8, 8.8 Hz, 1H), 7.50 (dd, J = 1.2, 8.8 Hz, 1H).

0513The compounds of Examples 277 to 286 were synthesized according to the production method of Example 47.

Example 277

N-[7-(2,6-Dimethoxy-4-methylphenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]-N-propyl-N-tetrahydro-2H-4-pyranylmethylamine

(Yellow oil)

05141H NMR (400MHz, CDCl3) δ 0.87 (t, J = 7.3 Hz, 3H), 1.20 (t, J = 7.6 Hz, 3H), 1.22-1.32 (m, 2H), 1.39 (ddq, J = 7.3, 7.3, 7.3 Hz, 2H), 1.51-1.63 (m, 1H), 1.70-1.78 (m, 2H), 2.43 (s, 3H), 2.74 (q, J = 7.6 Hz, 2H), 2.93-2.98 (m, 2H), 2.97 (dd, J = 7.3, 7.3 Hz, 2H), 3.26-3.35 (m, 2H), 3.70 (s, 6H), 3.90-3.97 (m, 2H), 6.51 (s, 2H), 6.59 (dd, J = 1.3, 6.8 Hz, 1H), 7.00 (dd, J = 6.8, 8.8 Hz, 1H), 7.41 (dd, J = 1.3, 8.8 Hz, 1H).

Example 278

N-Butyl-N-[7-(2,6-dimethoxy-4-methylphenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylmethylamine

(Yellow oil)

05151H NMR (400MHz, CDCl3) δ 0.86 (t, J = 7.1 Hz, 3H), 1.20 (t, J = 7.6 Hz, 3H), 1.16-1.42 (m, 6H), 1.49-1.63 (m, 1H), 1.66-1.80 (m, 2H), 2.43 (s, 3H), 2.73 (q, J = 7.6 Hz, 2H), 2.95 (d, J = 7.0 Hz, 2H), 3.00 (t, J = 7.1 Hz, 2H), 3.30 (dt, J = 2.0, 12.0 Hz, 2H), 3.70 (s, 6H), 3.88-4.00 (m, 2H), 6.51 (s, 2H), 6.59 (dd, J = 1.4, 6.9 Hz, 1H), 7.00 (dd, J = 6.8, 8.8 Hz, 1H), 7.41 (dd, J = 1.4, 8.8 Hz, 1H).

0516MS(ESI) m/z 466 MH+

Example 279

N-Cyclobutylmethyl-N-[7-(2,6-dimethoxy-4-methylphenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylmethylamine

(Yellow oil)

05171H NMR (400MHz, CDCl3) δ 1.21 (t, J = 7.6 Hz, 3H), 1.17-1.32 (m, 2H), 1.50-1.66 (m, 3H), 1.67-1.94 (m, 6H), 2.25-2.40 (m, 1H), 2.43 (s, 3H), 2.72 (q, J = 7.5 Hz, 2H), 2.93 (d, J = 7.0 Hz, 2H), 3.04 (d, J = 7.1 Hz, 2H), 3.31 (dt, J = 1.9, 12.0 Hz, 2H), 3.69 (s, 6H), 3.88-4.00 (m, 2H), 6.51 (s, 2H), 6.59 (dd, J = 1.3, 6.8 Hz, 1H), 7.00 (dd, J = 7.0, 8.8 Hz, 1H), 7.39 (dd, J = 1.5, 8.8 Hz, 1H).

0518MS(ESI) m/z 478 MH+

Example 280

N-Butyl-N-[2-ethyl-7-(2,4,6-trimethoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylmethylamine

(Light yellow crystals)

05191H NMR (400MHz, CDCl3) δ 0.85 (t, J = 6.8 Hz, 3H), 1.21 (t, J = 7.6 Hz, 3H), 1.22-1.40 (m, 6H), 1.50-1.60 (m, 1H), 1.70-1.77 (m, 2H), 2.73 (q, J = 7.6 Hz, 2H), 2.95 (d, J = 6.8 Hz, 2H), 3.00 (t, J = 6.8 Hz, 2H), 3.26-3.34 (m, 2H), 3.70 (s, 6H), 3.88 (s, 3H), 3.90-3.96 (m, 2H), 6.24 (s, 2H), 6.58 (dd, J = 1.6, 6.8 Hz, 1H), 6.99 (dd, J = 6.8, 8.8 Hz, 1H), 7.39 (dd, J = 1.6, 8.8 Hz, 1H).

Example 281

N-Cyclobutylmethyl-N-[2-ethyl-7-(2,4,6-trimethoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylmethylamine

(Light yellow crystals)

05201H NMR (400MHz, CDCl3) δ 1.21 (t, J = 7.6 Hz, 3H), 1.23-1.30 (m, 2H), 1.52-1.62 (m, 3H), 1.71-1.82 (m, 4H), 1.82-1.92 (m, 2H), 2.27-2.36 (m, 1H), 2.72 (q, J = 7.6 Hz, 2H), 2.93 (d, J = 6.8 Hz, 2H), 3.03 (d, J = 7.2 Hz, 2H), 3.26-3.34 (m, 2H), 3.69 (s, 6H), 3.88 (s, 3H), 3.90-3.96 (m, 2H), 6.24 (s, 2H), 6.57 (dd, J = 1.2, 6.8 Hz, 1H), 6.99 (dd, J = 6.8, 8.8 Hz, 1H), 7.37 (dd, J = 1.2, 8.8 Hz, 1H).

Example 282

N-Cyclopropylmethyl-N-[2-ethyl-7-(2,4,6-trimethoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylmethylamine

(Light yellow crystals)

05211H NMR (400MHz, CDCl3) δ -0.02-0.03 (m, 2H), 0.34-0.40 (m, 2H), 0.80-0.90 (m, 1H), 1.23 (t, J = 7.6 Hz, 3H), 1.23-1.34 (m, 2H), 1.54-1.64 (m, 1H), 1.73-1.80 (m, 2H), 2.78 (q, J = 7.6 Hz, 2H), 2.89 (d, J = 6.8 Hz, 2H), 3.05 (d, J = 6.8 Hz, 2H), 3.27-3.36 (m, 2H), 3.71 (s, 6H), 3.89 (s, 3H), 3.92-3.97 (m, 2H), 6.26 (s, 2H), 6.59 (dd, J = 1.6, 6.8 Hz, 1H), 7.00 (dd, J = 6.8, 8.8 Hz, 1H), 7.43 (dd, J = 1.6, 8.8 Hz, 1H).

Example 283

N-[7-(2,6-Dimethoxy-4-methylphenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]-N,N-ditetrahydro-2H-4-pyranylmethylamine

(Yellow amorphous)

05221H NMR (400MHz, CDCl3) δ 1.21 (t, J = 7.6 Hz, 3H), 1.20-1.31 (m, 4H), 1.52-1.60 (m, 2H), 1.70-1.78 (m, 4H), 2.44 (s, 3H), 2.74 (q, J = 7.6 Hz, 2H), 2.93 (d, J = 6.8 Hz, 4H), 3.26-3.34 (m, 4H), 3.71 (s, 6H), 3.90-3.96 (m, 4H), 6.52 (s, 2H), 6.62 (dd, J = 1.6, 6.8 Hz, 1H), 7.02 (dd, J = 6.8, 8.8 Hz, 1H), 7.41 (dd, J = 1.6, 8.8 Hz, 1H).

Example 284

N3-Cyclopropylmethyl-N3-tetrahydro-2H-4-pyranylmethyl-7-[6-(dimethylamino)-4-methyl-3-pyridyl]-2-ethylpyrazolo[1,5-a]pyridin-3-amine

(Yellow oil)

05231H NMR (400MHz, CDCl3) δ -0.02-0.04 (m, 2H), 0.33-0.41 (m, 2H), 0.78-0.91 (m, 1H), 1.28 (t, J = 7.5 Hz, 3H), 1.23-1.36 (m, 2H), 1.54-1.67 (m, 1H), 1.72-1.82 (m, 2H), 2.10 (s, 3H), 2.80 (q, J = 7.5 Hz, 2H), 2.90 (d, J = 6.8 Hz, 2H), 3.07 (d, J = 7.1 Hz, 2H), 3.17 (s, 6H), 3.33 (dt, J = 2.0, 12.0 Hz, 2H), 3.92-4.00 (m, 2H), 6.48 (s, 1H), 6.55 (dd, J = 1.5, 6.8 Hz, 1H), 7.03 (dd, J = 6.8, 8.8 Hz, 1H), 7.48 (dd, J = 1.4, 8.8 Hz, 1H), 8.19 (s, 1H).

Example 285

N3-Cyclopropylmethyl-N3-tetrahydro-2H-4-pyranylmethyl-7-[6-(dimethylamino)-2,4-dimethyl-3-pyridyl]-2-ethylpyrazolo[1,5-a]pyridin-3-amine

(Yellow oil)

05241H NMR (400MHz, CDCl3) δ -0.08- -0.02 (m, 2H), 0.29-0.35 (m, 2H), 0.76-0.87 (m, 1H), 1.21 (t, J = 7.6 Hz, 3H), 1.22-1.34 (m, 2H), 1.54-1.66 (m, 1H), 1.72-1.81 (m, 2H), 1.96 (s, 3H), 2.15 (s, 3H), 2.75 (q, J = 7.6 Hz, 2H), 2.84-2.90 (m, 2H), 3.02-3.07 (m, 2H), 3.12 (s, 6H), 3.27-3.36 (m, 2H), 3.90-3.98 (m, 2H), 6.30 (s, 1H), 6.44 (dd, J = 1.3, 6.8 Hz, 1H), 6.98 (dd, J = 6.8, 8.8 Hz, 1H), 7.43 (dd, J = 1.3, 8.8 Hz, 1H).

Example 286

N-Cyclopropylmethyl-N-[7-(2,4-dimethoxy-6-methylphenyl)-2-ethylpyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylmethylamine

(Yellow oil)

05251H NMR (400MHz, CDCl3) δ -0.05-0.00 (m, 2H), 0.31-0.36 (m, 2H), 0.77-0.87 (m, 1H), 1.21 (t, J = 7.6 Hz, 3H), 1.22-1.32 (m, 2H), 1.56-1.64 (m, 1H), 1.72-1.80 (m, 2H), 2.00 (s, 3H), 2.72-2.79 (m, 2H), 2.87 (d, J = 6.4 Hz, 2H), 3.04 (d, J = 6.8 Hz, 2H), 3.27-3.35 (m, 2H), 3.67 (s, 3H), 3.85 (s, 3H), 3.90-3.96 (m, 2H), 6.43 (d, J = 2.0 Hz, 1H), 6.47 (d, J = 2.0 Hz, 1H), 6.49 (dd, J = 1.2, 6.8 Hz, 1H), 6.99 (dd, J = 6.8, 8.8 Hz, 1H), 7.43 (dd, J = 1.2, 8.8 Hz, 1H).

0526The compounds of Examples 287 to 292 were synthesized according to the production methods of Examples 102 and 103.

Example 287

N-Cyclopropylmethyl-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-[(3-methyl-5-isoxazolyl)methyl]amine

(Light yellow oil)

05271H NMR (400MHz, CDCl3) δ -0.01-0.06 (m, 2H), 0.31-0.38 (m, 2H), 0.82-0.92 (m, 1H), 1.96 (s, 3H), 2.22 (s, 3H), 2.39 (s, 3H), 2.44 (s, 3H), 2.97-3.03 (m, 2H), 3.66 (s, 3H), 4.43 (s, 2H), 5.95 (s, 1H), 6.49 (dd, J = 1.3, 6.8 Hz, 1H), 6.65 (s, 1H), 6.73 (s, 1H), 7.03 (dd, J = 6.8, 8.8 Hz, 1H), 7.32 (dd, J = 1.3, 8.8 Hz, 1H).

Example 288

N3-Cyclopropylmethyl-N3-[6-(dimethylamino)-2-pyridyl]methyl-7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-amine

(Yellow oil)

05281H NMR (400MHz, CDCl3) δ -0.05-0.02 (m, 2H), 0.25-0.32 (m, 2H), 0.84-0.93 (m, 1H), 1.97 (s, 3H), 2.39 (s, 3H), 2.45 (s, 3H), 2.94-3.00 (m, 2H), 3.04 (s, 6H), 3.66 (s, 3H), 4.37 (s, 2H), 6.34 (d, J = 8.2 Hz, 1H), 6.47 (dd, J = 1.3, 6.8 Hz, 1H), 6.66 (s, 1H), 6.74 (s, 1H), 6.99 (d, J = 7.3 Hz, 1H), 7.01 (dd, J = 6.8, 8.8 Hz, 1H), 7.42 (dd, J = 7.3, 8.2 Hz, 1H), 7.47 (dd, J = 1.3, 8.8 Hz, 1H).

Example 289

N-Cyclopropylmethyl-N-(5-isoxazolylmethyl)-N-[7-(2-methoxy-4,6-dimethylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]amine

(Light yellow oil)

05291H NMR (400MHz, CDCl3) δ -0.02-0.08 (m, 2H), 0.31-0.41 (m, 2H), 0.83-0.93 (m, 1H), 1.96 (s, 3H), 2.40 (s, 3H), 2.44 (s, 3H), 2.98-3.08 (m, 2H), 3.66 (s, 3H), 4.52 (s, 2H), 6.14 (d, J = 1.2 Hz, 1H), 6.51 (dd, J = 1.3, 6.8 Hz, 1H), 6.66 (s, 1H), 6.75 (s, 1H), 7.04 (dd, J = 6.8, 8.8 Hz, 1H), 7.31 (dd, J = 1.3, 8.8 Hz, 1H), 8.10 (d, J = 1.2 Hz, 1H).

Example 290

N-[7-(2,6-Dimethoxy-4-methylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(1,3-dioxolan-2-ylmethyl)-N-propylamine

(Light yellow crystals)

05301H NMR (400MHz, CDCl3) δ 0.87 (t, J = 7.2 Hz, 3H), 1.40 (tq, J = 7.2, 7.2 Hz, 2H), 2.44 (s, 3H), 2.44 (s, 3H), 3.14 (t, J = 7.2 Hz, 2H), 3.29 (d, J = 4.4 Hz, 2H), 3.81 (s, 6H), 3.82-3.88 (m, 2H), 3.92-4.00 (m, 2H), 4.92 (t, J = 4.4 Hz, 1H), 6.48 (s, 2H), 6.57 (dd, J = 1.6, 6.8 Hz, 1H), 7.04 (dd, J = 6.8, 8.8 Hz, 1H), 7.42 (d, J = 8.8 Hz, 1H).

Example 291

N-Cyclopropylmethyl-N-[7-(2,6-dimethoxy-4-methylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(1,3-dioxolan-2-ylmethyl)amine

(Light yellow oil)

05311H NMR (400MHz, CDCl3) δ -0.04-0.06 (m, 2H), 0.28-0.34 (m, 2H), 0.82-0.92 (m, 1H), 2.42 (s, 3H), 2.44 (s, 3H), 3.02 (d, J = 6.4 Hz, 2H), 3.36 (d, J = 4.4 Hz, 2H), 3.67 (s, 6H), 3.78-3.84 (m, 2H), 3.90-3.98 (m, 2H), 4.92 (t, J = 4.4 Hz, 1H), 6.47 (s, 2H), 6.56 (dd, J = 1.2, 6.8 Hz, 1H), 7.02 (dd, J = 7.2, 8.8 Hz, 1H), 7.43 (dd, J = 1.2, 8.8 Hz, 1H).

Example 292

N-[7-(2,6-Dimethoxy-4-methylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(1,3-dioxolan-2-ylmethyl)-N-tetrahydro-3-furanylmethylamine

(Yellow oil)

05321H NMR (400MHz, CDCl3) δ 1.56-1.66 (m, 1H), 1.86-1.96 (m, 1H), 2.20-2.32 (m, 1H), 2.44 (s, 3H), 2.44 (s, 3H), 3.08-3.16 (m, 1H), 3.22-3.32 (m, 3H), 3.56-3.68 (m, 2H), 3.69 (s, 6H), 3.72-3.84 (m, 2H), 3.84-3.88 (m, 2H), 3.94-3.98 (m, 2H), 4.93 (t, J = 4.4 Hz, 1H), 6.48 (s, 2H), 6.59 (dd, J = 1.2, 6.8 Hz, 1H), 7.06 (dd, J = 7.2, 8.8 Hz, 1H), 7.39 (dd, J = 1.6, 8.8 Hz, 1H).

0533The compounds of Examples 293 and 294 were synthesized according to the production method of Example 159.

Example 293

N-[7-(2,6-Dimethoxy-4-methylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N-(1,3-dioxolan-2-ylmethyl)-N-tetrahydro-2H-4-pyranylmethylamine

(Yellow oil)

05341H NMR (400MHz, CDCl3) δ 1.22-1.32 (m, 2H), 1.50-1.60 (m, 1H), 1.76-1.84 (m, 2H), 2.44 (s, 3H), 2.44 (s, 3H), 3.09 (d, J = 6.8 Hz, 2H), 3.25 (d, J = 4.4 Hz, 2H), 3.24-3.36 (m, 2H), 3.70 (s, 6H), 3.82-3.88 (m, 2H), 3.90-3.98 (m, 4H), 4.92 (t, J = 4.4 Hz, 1H), 6.49 (s, 2H), 6.59 (dd, J = 1.2, 6.8 Hz, 1H), 7.05 (dd, J = 6.8, 8.8 Hz, 1H), 7.40 (d, J = 8.8 Hz, 1H).

Example 294

N-[7-(2,6-Dimethoxy-4-methylphenyl)-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]-N,N-ditetrahydro-2H-4-pyranylmethylamine

(Light yellow amorphous)

05351H NMR (400MHz, CDCl3) δ 1.21-1.32 (m, 4H), 1.48-1.61 (m, 2H), 1.74-1.83 (m, 4H), 2.43 (s, 3H), 2.44 (s, 3H), 2.89-2.95 (m, 4H), 3.26-3.35 (m, 4H), 3.70 (s, 6H), 3.89-3.96 (m, 4H), 6.48 (s, 2H), 6.59 (dd, J = 1.3, 6.8 Hz, 1H), 7.04 (dd, J = 6.8, 8.8 Hz, 1H), 7.31 (dd, J = 1.3, 8.8 Hz, 1H).

0536The compounds of Examples 295 to 298 were synthesized according to the production methods of Examples 237 and 238.

Example 295

N-[7-(2,6-Dimethoxy-4-methylphenyl)-2-methoxypyrazolo[1,5-a]pyridin-3-yl]-N-(1,3-dioxolan-2-ylmethyl)-N-tetrahydro-3-furanylmethylamine

(Yellow oil)

05371H NMR (400MHz, CDCl3) δ 1.54-1.66 (m, 1H), 1.86-1.96 (m, 1H), 2.18-2.32 (m, 1H), 2.44 (s, 3H), 2.98-3.06 (m, 1H), 3.14-3.24 (m, 3H), 3.52-3.68 (m, 2H), 3.71 (s, 6H), 3.72-3.84 (m, 2H), 3.86 (s, 3H), 3.90-3.98 (m, 2H), 4.91 (t, J = 4.4 Hz, 1H), 6.48 (dd, J = 1.2, 6.8 Hz, 1H), 6.49 (s, 2H), 7.04 (dd, J = 6.8, 8.8 Hz, 1H), 7.30 (dd, J = 1.2, 8.8 Hz, 1H).

Example 296

N3-Cyclopropylmethyl-N3-tetrahydro-3-furanylmethyl-7-[6-(dimethylamino)-2,4-dimethyl-3-pyridyl]-2-methoxypyrazolo[1,5-a]pyridin-3-amine

(Yellow oil)

05381H NMR (400MHz, CDCl3) δ -0.09-0.01 (m, 2H), 0.23-0.33 (m, 2H), 0.75-0.86 (m, 1H), 1.58-1.69 (m, 1H), 1.86-1.96 (m, 1H), 1.97 (s, 3H), 2.15 (s, 3H), 2.20-2.30 (m, 1H), 2.79-2.85 (m, 2H), 2.94-3.01 (m, 1H), 3.10-3.18 (m, 1H), 3.13 (s, 6H), 3.55-3.61 (m, 1H), 3.63-3.70 (m, 1H), 3.71-3.83 (m, 2H), 3.84 (s, 3H), 6.29 (s, 1H), 6.34 (dd, J = 1.3, 6.8 Hz, 1H), 6.99 (dd, J = 6.8, 8.8 Hz, 1H), 7.29 (dd, J = 1.3, 8.8 Hz, 1H).

Example 297

N3-Cyclopropylmethyl-N3-tetrahydro-3-furanylmethyl-7-[6-(dimethylamino)-4-methyl-3-pyridyl]-2-methoxypyrazolo[1,5-a]pyridin-3-amine

(Yellow oil)

05391H NMR (400MHz, CDCl3) δ -0.06-0.05 (m, 2H), 0.25-0.36 (m, 2H), 0.75-0.87 (m, 1H), 1.57-1.68 (m, 1H), 1.84-1.96 (m, 1H), 2.11 (s, 3H), 2.15-2.29 (m, 1H), 2.78-2.85 (m, 2H), 2.92-3.01 (m, 1H), 3.08-3.17 (m, 1H), 3.15 (s, 6H), 3.56-3.69 (m, 2H), 3.70-3.83 (m, 2H), 3.89 (s, 3H), 6.41 (dd, J = 1.3, 6.8 Hz, 1H), 6.44 (s, 1H), 7.01 (dd, J = 6.8, 8.8 Hz, 1H), 7.31 (dd, J = 1.3, 8.8 Hz, 1H), 8.13 (s, 1H).

Example 298

N-Cyclopropylmethyl-N-(1,3-dioxolan-2-ylmethyl)-N-[2-methoxy-7-(4-methoxy-2,6-dimethylphenyl)pyrazolo[1,5-a]pyridin-3-yl]amine

(Yellow oil)

05401H NMR (400MHz, CDCl3) δ -0.04-0.06 (m, 2H), 0.24-0.34 (m, 2H), 0.84-0.96 (m, 1H), 2.07 (s, 6H), 2.99 (d, J = 6.8 Hz, 2H), 3.35 (d, J = 4.4 Hz, 2H), 3.84-3.92 (m, 2H), 3.89 (s, 6H), 3.94-4.04 (m, 2H), 4.98 (t, J = 4.4 Hz, 1H), 6.39 (d, J = 6.8 Hz, 1H), 6.74 (s, 2H), 7.07 (dd, J = 6.8, 8.8 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H).

0541The compounds of Examples 299 to 312 were synthesized according to the production method of Example 256.

Example 299

N-Butyl-N-[7-(2,6-dimethoxy-4-methylphenyl)-2-methoxypyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylmethylamine

(Yellow oil)

05421H NMR (400MHz, CDCl3) δ 0.83-0.89 (m, 3H), 1.18-1.38 (m, 6H), 1.55-1.60 (m, 1H), 1.68-1.77 (m, 2H), 2.44 (s, 3H), 2.86 (d, J = 6.8 Hz, 2H), 2.90-2.95 (m, 2H), 3.25-3.32 (m, 2H), 3.71 (s, 6H), 3.85 (s, 3H), 3.88-3.96 (m, 2H), 6.46-6.49 (m, 1H), 6.49 (s, 2H), 7.00 (dd, J = 6.4, 8.8 Hz, 1H), 7.22-7.24 (m, 1H).

Example 300

N-Cyclobutylmethyl-N-[7-(2,6-dimethoxy-4-methylphenyl)-2-methoxypyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylmethylamine

(Light yellow crystals)

05431H NMR (400MHz, CDCl3) δ 1.18-1.30 (m, 2H), 1.50-1.62 (m, 3H), 1.70-1.90 (m, 6H), 2.28-2.36 (m, 1H), 2.43 (s, 3H), 2.84 (d, J = 7.2 Hz, 2H), 2.95 (d, J = 7.2 Hz, 2H), 3.25-3.33 (m, 2H), 3.70 (s, 6H), 3.85 (s, 3H), 3.88-3.94 (m, 2H), 6.47 (dd, J = 1.2, 6.8 Hz, 1H), 6.49 (s, 2H), 7.00 (dd, J = 6.8, 8.8 Hz, 1H), 7.22 (dd, J = 1.2, 8.8 Hz, 1H).

Example 301

N-[7-(2,6-Dimethoxy-4-methylphenyl)-2-methoxypyrazolo[1,5-a]pyridin-3-yl]-N-(1,3-dioxolan-2-ylmethyl)-N-tetrahydro-2H-4-pyranylmethylamine

(Yellow oil)

05441H NMR (400MHz, CDCl3) δ 1.20-1.32 (m, 2H), 1.50-1.62 (m, 1H), 1.74-1.82 (m, 2H), 2.44 (s, 3H), 2.99 (d, J = 7.2 Hz, 2H), 3.18 (d, J = 4.4 Hz, 2H), 3.24-3.32 (m, 2H), 3.72 (s, 6H), 3.80-3.86 (m, 2H), 3.87 (s, 3H), 3.90-3.98 (m, 4H), 4.89 (t, J = 4.4 Hz, 1H), 6.49 (dd, J = 1.6, 6.8 Hz, 1H), 6.50 (s, 2H), 7.03 (dd, J = 6.8, 8.8 Hz, 1H), 7.30 (dd, J = 1.6, 8.8 Hz, 1H).

Example 302

N-Butyl-N-[7-(2,6-dimethoxy-4-methylphenyl)-2-methoxypyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylamine

(White crystals)

05451H NMR (400MHz, CDCl3) δ 0.79-0.87 (m, 3H), 1.23-1.36 (m, 4H), 1.45-1.54 (m, 2H), 1.77-1.86 (m, 2H), 2.44 (s, 3H), 3.01-3.13 (m, 3H), 3.32-3.41 (m, 2H), 3.72 (s, 6H), 3.86 (s, 3H), 3.90-3.98 (m, 2H), 6.49 (dd, J = 1.3, 6.8 Hz, 1H), 6.50 (s, 2H), 7.02 (dd, J = 6.8, 8.8 Hz, 1H), 7.25 (dd, J = 1.3, 8.8 Hz, 1H).

Example 303

N-Cyclobutylmethyl-N-[7-(2,6-dimethoxy-4-methylphenyl)-2-methoxypyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylamine

(White amorphous)

05461H NMR (400MHz, CDCl3) δ 1.43-1.85 (m, 6H), 2.19-2.29 (m, 1H), 2.44 (s, 3H), 3.00-3.10 (m, 3H), 3.31-3.40 (m, 2H), 3.71 (s, 6H), 3.85 (s, 3H), 3.90-3.98 (m, 2H), 6.48 (dd, J = 1.3, 6.8 Hz, 1H), 6.50 (s, 2H), 7.02 (dd, J = 6.8, 8.8 Hz, 1H), 7.24 (dd, J = 1.3, 8.8 Hz, 1H).

Example 304

N-[7-(2-Chloro-4-methoxyphenyl)-2-methoxypyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-3-furanylmethyl-N-tetrahydro-2H-4-pyranylamine

(Light yellow amorphous)

05471H NMR (400MHz, CDCl3) δ 1.41-1.65 (m, 3H), 1.74-1.91 (m, 3H), 2.08-2.17 (m, 1H), 2.93-3.08 (m, 2H), 3.11-3.18 (m, 1H), 3.30-3.40 (m, 2H), 3.54-3.72 (m, 3H), 3.75-3.83 (m, 1H), 3.87 (s, 3H), 3.88 (s, 3H), 3.90-3.97 (m, 2H), 6.50 (dd, J = 1.3, 6.8 Hz, 1H), 6.91 (dd, J = 2.4, 8.4 Hz, 1H), 7.04 (dd, J = 6.8, 8.8 Hz, 1H), 7.06 (d, J = 2.4 Hz, 1H), 7.25 (dd, J = 1.3, 8.8 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H).

Example 305

N-[7-(2-Chloro-4-methoxyphenyl)-2-methox pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranyl-N-tetrahydro-2H-4-pyranylmethylamine

(Light yellow amorphous)

05481H NMR (400MHz, CDCl3) δ 1.17-1.30 (m, 2H), 1.36-1.54 (m, 3H), 1.65-1.74 (m, 2H), 1.75-1.83 (m, 2H), 2.91-3.05 (m, 3H), 3.20-3.29 (m, 2H), 3.30-3.39 (m, 2H), 3.88 (s, 3H), 3.88 (s, 3H), 3.85-3.97 (m, 4H), 6.50 (dd, J = 1.3, 6.8 Hz, 1H), 6.91 (dd, J = 2.4, 8.4 Hz, 1H), 7.02 (dd, J = 6.8, 8.8 Hz, 1H), 7.06 (d, J = 2.4 Hz, 1H), 7.25 (dd, J = 1.3, 8.8 Hz, 1H), 7.45 (d, J = 8.4 Hz, 1H).

Example 306

N-Butyl-N-[2-methoxy-7-(2,4,6-trimethoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylmethylamine

(Yellow oil)

05491H NMR (400MHz, CDCl3) δ 0.85 (t, J = 6.8 Hz, 3H), 1.19-1.36 (m, 6H), 1.49-1.55 (m, 1H), 1.70-1.77 (m, 2H), 2.87 (d, J = 7.2 Hz, 2H), 2.93 (t, J = 7.2 Hz, 2H), 3.25-3.32 (m, 2H), 3.71 (s, 6H), 3.86 (s, 3H), 3.89 (s, 3H), 3.89-3.94 (m, 2H), 6.24 (s, 2H), 6.48 (dd, J = 1.6, 6.8 Hz, 1H), 7.00 (dd, J = 6.8, 8.8 Hz, 1H), 7.23 (dd, J = 1.6, 8.8 Hz, 1H).

Example 307

N-Cyclobutylmethyl-N-[2-methoxy-7-(2,4,6-trimethoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylmethylamine

(Yellow oil)

05501H NMR (400MHz, CDCl3) δ 1.20-1.30 (m, 2H), 1.49-1.60 (m, 3H), 1.70-1.86 (m, 6H), 2.28-2.35 (m, 1H), 2.83 (d, J = 7.2 Hz, 2H), 2.95 (d, J = 7.2 Hz, 2H), 3.25-3.32 (m, 2H), 3.70 (s, 6H), 3.86 (s, 3H), 3.88 (s, 3H), 3.88-3.94 (m, 2H), 6.23 (s, 2H), 6.47 (dd, J = 1.6, 6.8 Hz, 1H), 7.00 (dd, J = 6.8, 8.8 Hz, 1H), 7.21 (dd, J = 1.6, 8.8 Hz, 1H).

Example 308

N-Cyclopropylmethyl-N-[2-methoxy-7-(2,4,6-trimethoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylmethylamine

(Yellow oil)

05511H NMR (400MHz, CDCl3) δ -0.02-0.02 (m, 2H), 0.28-0.34 (m, 2H), 0.80-0.90 (m, 1H), 1.18-1.32 (m, 2H), 1.50-1.60 (m, 1H), 1.72-1.77 (m, 2H), 2.80 (d, J = 6.4 Hz, 2H), 2.94 (d, J = 7.2 Hz, 2H), 3.25-3.32 (m, 2H), 3.71 (s, 6H), 3.86 (s, 3H), 3.88 (s, 3H), 3.88-3.94 (m, 2H), 6.24 (s, 2H), 6.47 (dd, J = 1.6, 6.8 Hz, 1H), 6.99 (dd, J = 6.8, 8.8 Hz, 1H), 7.28 (dd, J = 1.6, 8.8 Hz, 1H).

Example 309

N3-Cyclopropylmethyl-N3-tetrahydro-2H-4-pyranylmethyl-7-[6-(dimethylamino)-2,4-dimethyl-3-pyridyl]-2-methoxypyrazolo[1,5-a]pyridin-3-amine

(Yellow oil)

05521H NMR (400MHz, CDCl3) δ -0.02-0.04 (m, 2H), 0.30-0.38 (m, 2H), 0.82-0.96 (m, 1H), 1.28-1.43 (m, 2H), 1.57-1.72 (m, 1H), 1.79-1.89 (m, 2H), 2.05 (s, 3H), 2.24 (s, 3H), 2.87 (d, J = 6.6 Hz, 2H), 3.03 (d, J = 7.1 Hz, 2H), 3.21 (s, 6H), 3.38 (dt, J = 2.0, 12.0 Hz, 2H), 3.93 (s, 3H), 3.96-4.05 (m, 2H), 6.38 (s, 1H), 6.42 (dd, J = 1.5, 6.8 Hz, 1H), 7.07 (dd, J = 6.8, 8.8 Hz, 1H), 7.38 (dd, J = 1.4, 8.8 Hz, 1H).

Example 310

N3-Cyclopropylmethyl-N3-tetrahydro-2H-4-pyranylmethyl-7-[6-(dimethylamino)-4-methyl-3-pyridyl]-2-methoxypyrazolo[1,5-a]pyridin-3-amine

(Yellow oil)

05531H NMR (400MHz, CDCl3) δ -0.03-0.08 (m, 2H), 0.29-0.38 (m, 2H), 0.78-0.94 (m, 1H), 1.24-1.38 (m, 2H), 1.50-1.66 (m, 1H), 1.73-1.84 (m, 2H), 2.15 (s, 3H), 2.84 (d, J = 6.8 Hz, 2H), 2.98 (d, J = 7.1 Hz, 2H), 3.19 (s, 6H), 3.33 (dt, J = 1.6, 12.0 Hz, 2H), 3.93 (s, 3H), 3.90-4.00 (m, 2H), 6.45 (dd, J = 0.6, 6.8 Hz, 1H), 6.49 (s, 1H), 7.05 (dd, J = 6.8, 7.3 Hz, 1H), 7.36 (dd, J = 0.7, 8.8 Hz, 1H), 8.19 (s, 1H).

Example 311

N-[7-(2-Chloro-4-methoxyphenyl)-2-methoxypyrazolo[1,5-a]pyridin-3-yl]-N,N-ditetrahydro-2H-4-pyranylmethylamine

(Yellow oil)

05541H NMR (400MHz, CDCl3) δ 1.18-1.31 (m, 4H), 1.46-1.58 (m, 2H), 1.70-1.80 (m, 4H), 2.81-2.88 (m, 4H), 3.24-3.34 (m, 4H), 3.88 (s, 3H), 3.89 (s, 3H), 3.89-3.96 (m, 4H), 6.50 (dd, J = 1.3, 6.8 Hz, 1H), 6.91 (dd, J = 2.4, 8.4 Hz, 1H), 7.02 (dd, J = 6.8, 8.8 Hz, 1H), 7.06 (d, J = 2.4 Hz, 1H), 7.25 (dd, J = 1.3, 8.8 Hz, 1H), 7.46 (d, J = 8.4 Hz, 1H).

Example 312

N-Cyclopropylmethyl-N-[7-(2,4-dimethoxy-6-methylphenyl)-2-methoxypyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylmethylamine

(Yellow oil)

05551H NMR (400MHz, CDCl3) δ -0.05-0.00 (m, 2H), 0.23-0.34 (m, 2H), 0.76-0.86 (m, 1H), 1.22-1.33 (m, 2H), 1.50-1.60 (m, 1H), 1.68-1.80 (m, 2H), 2.02 (s, 3H), 2.74-2.86(m, 2H), 2.89-3.00 (m, 2H), 3.29 (dt, J = 2.0, 11.6 Hz, 2H), 3.69 (s, 3H), 3.85 (s, 3H), 3.86 (s, 3H), 3.88-3.94 (m, 2H), 6.39 (dd, J = 1.2, 6.8 Hz, 1H), 6.42 (d, J = 2.0 Hz, 1H), 6.46 (d, J = 2.0 Hz, 1H), 7.00 (dd, J = 6.8, 9.2 Hz, 1H), 7.29 (dd, J = 1.2, 9.2 Hz, 1H).

0556The compounds of Examples 313 to 314 were synthesized according to the production method of Example 40.

Example 313

N-Cyclopropylmethyl-N-[2-ethyl-7-(4-ethyl-2,6-dimethoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-3-furanylmethylamine

(Yellow oil)

05571H NMR (400MHz, CDCl3) δ -0.04-0.02 (m, 2H), 0.32-0.40 (m, 2H), 0.78-0.88 (m, 1H), 1.12-1.36 (m, 6H), 1.56-1.64 (m, 1H), 1.82-1.92 (m, 1H), 2.18-2.30 (m, 1H), 2.66-2.78 (m, 4H), 2.84-2.92 (m, 2H), 3.02-3.10 (m, 1H), 3.18-3.24 (m, 1H), 3.76-3.82 (m, 4H), 3.69 (s, 6H), 6.51 (s, 2H), 6.57 (dd, J = 1.2, 6.8 Hz, 1H), 6.99 (dd, J = 6.8, 8.8 Hz, 1H), 7.40 (dd, J = 1.2, 8.8 Hz, 1H).

Example 314

N-Cyclopropylmethyl-N-[2-ethyl-7-(4-ethyl-2,6-dimethoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2H-4-pyranylmethylamine

(Yellow oil)

05581H NMR (400MHz, CDCl3) δ -0.02-0.04 (m, 2H), 0.34-0.40 (m, 2H), 0.80-0.88 (m, 1H), 1.22-1.36 (m, 2H), 1.24 (t, J = 7.6 Hz, 3H), 1.35 (t, J = 7.6 Hz, 3H), 1.54-1.66 (m, 1H), 1.74-1.82 (m, 2H), 2.74 (q, J = 7.6 Hz, 2H), 2.79 (q, J = 7.6 Hz, 2H), 2.90 (d, J = 6.8 Hz, 2H), 3.60 (d, J = 7.2 Hz, 2H), 3.30-3.38 (m, 2H), 3.73 (s, 6H), 3.92-3.98 (m, 2H), 6.55 (s, 2H), 6.61 (dd, J = 1.6, 6.8 Hz, 1H), 7.01 (dd, J = 6.8, 8.8 Hz, 1H), 7.44 (dd, J = 1.2, 8.8 Hz, 1H).

0559In the Examples and Production Examples throughout the present specification, aldehyde compounds, halogenated compounds and sulfonates such as dihydro-2H-pyran-3(4H)one [CAS NO.23462-75-1], (R)-3-tetrahydropyrancarboxyaldehyde [CAS NO.143810-10-0], (S)-3-tetrahydropyrancarboxyaldehyde [CAS NO.141822-85-7], (±)-3-tetrahydropyrancarboxyaldehyde [CAS NO.77342-93-9], 3-formyl-5,6-dihydro-2H-pyran [CAS NO.13417-49-7], 2-oxazolecarboxyaldehyde [CAS NO.65373-52-6], 6-dimethylamino-2-pyridinecarboxyaldehyde [CAS NO.208110-83-2], 6-dimethylamino-3-pyridinecarboxyaldehyde [CAS NO.149805-92-5], 3-methyl-5-isoxazolemethanol methanesulfonate [CAS NO.96603-41-7], 3-(phenylmethoxy)-1-butanol 4-methylbenzenesulfonate [CAS NO.96556-29-5], [(2-bromo-1-methylethoxy)methyl]-benzene [CAS NO.135364-12-4], 5-(bromomethyl)isoxazole [CAS NO.69735-35-9] and the like may be used as starting materials.

[Test Examples]

0560Compounds of the present invention were evaluated in regard to Corticotropin-Releasing Factor Receptor (CRFR) binding affinity and inhibiton of CAMP production. The test methods and results were as follows.

Test Example 1

(1) Preparation of CRFR-expressing cells

0561Membrane fraction of the cell highly expressing human CRFR1 was used as the experimental material for a CRFR binding experiment. The CRFR expressing cells were prepared in the following manner. The full-length CRFR1 gene was obtained from a human brain cDNA library (QuickClone™, Clontech) by PCR. The obtained DNA fragments were inserted into cloning vectors and the base sequences were determined. cDNA having the correct base sequence was then relinked to an expression vector (pcDNA3.1™, Invitrogen). The CRFR1 expression vector was introduced into HEK293 cells, and the resistant cells which grew in cell medium containing G418 (1 mg/ml) were cloned by limiting dilution. From these cloned cells, the clones with high binding affinity between the membrane fraction and sauvagine per unit of protein in the binding experiment described below were selected out and used for the final experiment.

(2) Preparation of membrane fraction

0562The cloned cells obtained in (1) were collected and disrupted with an ultrasonic generator in sonicate buffer (D-PBS(-) 10 mM MgCl2, 2 mM EGTA). The suspension obtained from ultrasonic disruption was centrifuged (46,000 x g, 10 minutes), and the precipitate was resuspended in sonicate buffer and the same procedure was repeated. The final precipitate was then suspended in binding buffer (D-PBS(-) 10 mM MgCl2, 2mM EGTA, 1.5% BSA, 0.15 mM bacitracin, 1 x protease inhibitor cocktail (COMPLETE™, Boehringer)), and used as the membrane fraction after adjusting the protein concentration to 1.6 mg/ml.

(3) Binding experiment

0563The sauvagine binding experiment was conducted following the protocol of SPA™ (Amersham Pharmacia), using a 96-well plate. The experiment was conducted according to the SPA beads instruction manual. After allowing 40 mg of the membrane fraction protein, 0.5 mg of SPA beads and 50 pM of 125I-sauvagine (Amersham Pharmacia) to stand at room temperature for 2 hours in the presence of the test compound, the mixture was centrifuged (1000 x g, 5 minutes) and the radioactivity of each well was measured with a TopCount™ (Packard).

(4) Calculation of binding affinity

0564The radioactivity for non-radioactive sauvagine added in a 1000-fold excess was subtracted from each value as the non-specific binding, and the radioactivity of a sample without addition of the test substance (control) was defined as 100%, with each value represented as a percentage (% of control). A graph was drawn with the concentration of the test substance plotted on the horizontal axis and the percentage (% of control) plotted on the vertical axis, and the concentration which resulted in a 50% value for the percentage (% of control) was determined from the graph to calculate the IC50 value.

Test Example 2

(1) Test procedure

0565The AtT-20 cells were of a mouse pituitary gland tumor-derived cell line which is known to respond to Corticotropin-Releasing Factor (CRF), leading to activation of the intracellular adenylate cyclase system, production of cyclic AMP (CAMP), and release of adenocorticotropic hormone (ACTH) (<nplcit id="ncit0077" npl-type="s"><text>Biochem. Biophys. Res. Com. 106, 1364-1371, 1982</text></nplcit>). For the experiment, the cells (1 x 105) were suspended in D-MEM medium (0.1% FBS) and seeded in a 96-well plate, phosphodiesterase inhibitor (IBMX, Calbiochem) was added to a final concentration of 1 mM, and were cultured at 37°C for 30 minutes. A dilution of the test compound was added, culturing was continued for 30 minutes at 37°C, and CRF (30 nM) was added and culturing was continued for 30 minutes at 37°C. The cells were collected by centrifugation (500 x g, 5 minutes) and lysed with lysis buffer (0.2% dodecyltrimethylammmonium bromide), and the intracellular CAMP production was quantified by the HTRF method. A CAMP kit HTRF (CIS Diagnostics Co., Ltd.) was used for the CAMP quantification.

(2) Calculation of cAMP production inhibition

0566The obtained data were processed in the following manner. The CAMP production of cells to which 30 nM CRF had been added was defined as 100% (control), and the value for each specimen was represented as a percentage (% of control). A graph was drawn with the concentration of the test substance plotted on the horizontal axis and the percentage (% of control) plotted on the vertical axis, and the concentration which resulted in a 50% value for the percentage (% of control) was determined from the graph to calculate the IC50 value.

0567In Test Example 1, the compound of the invention exhibited excellent binding affinity for CRFR, with an IC50 value of 5-5000 nM. In Test Example 2, the compound of the invention exhibited excellent inhibition against CRF-dependent CAMP production. Some of the results are shown below in Table 1. <tables id="tabl0001" num="0001"><table frame="all"><title>Table 1</title><tgroup cols="3"><colspec colnum="1" colname="col1" colwidth="47mm" /><colspec colnum="2" colname="col2" colwidth="59mm" /><colspec colnum="3" colname="col3" colwidth="55mm" /><thead><row><entry valign="top">Compound No. (Example No.)</entry><entry valign="top">CRF1 receptor binding affinity IC50 (nM)</entry><entry valign="top">Adenylate cyclase activity IC50 (nM)</entry></row></thead><tbody><row><entry>Example 3</entry><entry>50</entry><entry>130</entry></row><row><entry>Example 6</entry><entry>160</entry><entry>200</entry></row><row><entry>Example 25</entry><entry>210</entry><entry>550</entry></row><row><entry>Example 27</entry><entry>55</entry><entry>300</entry></row><row><entry>Example 103</entry><entry>90</entry><entry>400</entry></row><row><entry>Example 108</entry><entry>50</entry><entry>20</entry></row></tbody></tgroup></table></tables>

Industrial Applicability

0568As explained above, the present invention provides novel pyrazolo[1,5-a]pyridine compounds having CRF receptor antagonistic activity, their salts and novel pharmaceutical compositions comprising them. The compounds of the invention or their salts exhibit excellent antagonism against CRF receptors and particularly against CRF1 receptor, while having low toxicity and high safety, and are therefore highly useful as drugs. The compounds of the invention and pharmaceutical compositions comprising them are useful for treatment or prevention of diseases associated with CRF and/or CRF receptors, and particularly they are useful as therapeutic or prophylactic agents for depression and depressive symptoms (major depression, single-episode depression, recurrent depression, depression-induced child abuse, postpartum depression, etc.), mania, anxiety, generalized anxiety disorder, panic disorder, phobias, obsessive-compulsive disorder, posttraumatic stress disorder, Tourette's syndrome, autism, affective disorder, dysthymia, bipolar disorder, cyclothymic personality, schizophrenia, peptic ulcer, irritable bowel syndrome, ulcerative colitis, Crohn's disease, diarrhea, constipation, postoperative ileus, stress-associated gastrointestinal disorders, nervous vomiting, and the like.

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Document	Relation	Office
WO03078435A	Cites	World Intellectual Property Organization (WIPO)
WO0135917A1	Cites	World Intellectual Property Organization (WIPO)
WO9729109A1	Cites	World Intellectual Property Organization (WIPO)
WO9808847A1	Cites	World Intellectual Property Organization (WIPO)
US4990516A	Cites	United States of America
US5338743A	Cites	United States of America
US5457200A	Cites	United States of America

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2001133207	Japan	–	2001-04-27
2001133207	Japan	A	2001-04-27
0204173	Japan	W	2002-04-25

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CA2443802A1	Canada	A1	2002-11-07
WO02088121A1	World Intellectual Property Organization (WIPO)	A1	2002-11-07
NO20034788D0	Norway	D0	2003-10-24
NO20034788L	Norway	L	2003-12-29
KR20040008163A	Republic of Korea	A	2004-01-28
MXPA03009738A	Mexico	A	2004-01-29
MXPA03009738A	Mexico	A	2004-01-29
EP1389618A1	European Patent Office (EPO)	A1	2004-02-18
CZ20032937A3	Czechia	A3	2004-03-17
IL158624A0	Israel	A0	2004-05-12
CN1505630A	China	A	2004-06-16
US2004122039A1	United States of America	A1	2004-06-24
BR0209252A	Brazil	A	2004-07-20
BR0209252A	Brazil	A	2004-07-20
JPWO2002088121A1	Japan	A1	2004-08-19
HU0401292A2	Hungary	A2	2004-12-28
HUP0401292A2	Hungary	A2	2004-12-28
NZ529333A	New Zealand	A	2005-01-28
PL367067A1	Poland	A1	2005-02-21
ZA200308860B	South Africa	B	2005-04-26
RU2003134371A	Russian Federation	A	2005-06-27
EP1389618A4	European Patent Office (EPO)	A4	2005-07-20
US7091215B2	United States of America	B2	2006-08-15
US2006217348A1	United States of America	A1	2006-09-28
CN1290846C	China	C	2006-12-20
AU2002251546B2	Australia	B2	2007-01-18
RU2308457C2	Russian Federation	C2	2007-10-20
US7285666B2	United States of America	B2	2007-10-23
US2007249663A1	United States of America	A1	2007-10-25
TWI292760B	Taiwan Province of China	B	2008-01-21
KR20080031501A	Republic of Korea	A	2008-04-08
KR100876622B1	Republic of Korea	B1	2008-12-31
JP4206273B2	Japan	B2	2009-01-07
KR100881647B1	Republic of Korea	B1	2009-02-04
NO326783B1	Norway	B1	2009-02-16
JP2009051843A	Japan	A	2009-03-12
US7625925B2	United States of America	B2	2009-12-01
CZ301491B6	Czechia	B6	2010-03-24
CA2443802C	Canada	C	2010-04-13
HU0401292A3	Hungary	A3	2011-01-28
HUP0401292A3	Hungary	A3	2011-01-28
IL158624A	Israel	A	2011-04-28
EP1389618B1This record	European Patent Office (EPO)	B1	2011-06-15
AT512962T	Austria	T	2011-07-15
ATE512962T1	Austria	T1	2011-07-15
ES2366082T3	Spain	T3	2011-10-17
JP4977668B2	Japan	B2	2012-07-18
PL214231B1	Poland	B1	2013-07-31

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Pyrazolo 1,5-a pyridines and medicines containing the same

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