US2008161374A1PendingUtilityA1
Pyrazole compounds and uses related thereto
Est. expiryMar 23, 2024(expired)· nominal 20-yr term from priority
A61P 43/00A61P 3/10A61P 3/04C07D 401/06A61P 3/00C07D 413/10C07D 231/12C07D 401/14C07D 405/04C07D 401/08C07D 401/04C07D 401/10C07D 403/10
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Claims
Abstract
Substituted pyrazoles are provided that are useful for the treatment of, for example, diabetes, obesity and metabolic syndrome.
Claims
exact text as granted — not AI-modified1 . A pyrazole compound represented by the following formula:
wherein
R 1 is hydrogen, —CO—O-alkyl, —COOH, an alkyl group, an alkoxy group or a cycloalkyl group,
wherein the alkyl group, the alkoxy group and the cycloalkyl group are optionally substituted by 1 to 5 substituents each independently selected from a halogen atom, a haloalkyl group, —OH, —NH 2 , an alkoxy group, a cycloalkyl group, an alkenyl group, —COOH, —CO—O-alkyl, —CO—N(R 10 )(R 11 ), —N(R 10 )—CO—R 11 , an aryl group and a heteroaryl group,
wherein each R 10 and R 11 is independently a hydrogen atom or an alkyl group, and the aryl group and the heteroaryl group are optionally substituted by 1 to 3 substituents each independently selected from a halogen atom, a haloalkyl group, an alkyl group, —(CH 2 ) h —OH, —N(R 12 )(R 13 ), —CN, —NO 2 , an alkoxy group, a cycloalkyl group, an alkenyl group, —CO—R 14 , an aryl group and a heteroaryl group,
wherein the subscript h is an integer of from 0 to 3, R 12 and R 13 in each instance are independently a hydrogen atom, an alkyl group or —CO-alkyl, and each R 14 is independently —OH, an alkoxy group, an alkyl group or —N(R 15 )(R 16 ),
wherein R 15 and R 16 are each independently a hydrogen atom or an alkyl group;
R 2 , R 3 , R 4 and R 5 are each independently a hydrogen atom, an alkyl group, an alkoxy group, a cycloalkyl group or R 2 and R 3 in combination and R 4 and R 5 in combination with the carbon atoms to which they are attached, optionally form a ring represented by
wherein the Y 1 ring is a cycloalkane or a heterocycloalkane,
wherein the cycloalkane and the heterocycloalkane groups are optionally substituted by 1 to 3 substituents each independently selected from a halogen atom, a haloalkyl group, an alkyl group, —(CH 2 ) h —OH, —N(R 12 )(R 13 ), —CN, —NO 2 , an alkoxy group, a cycloalkyl group, an alkenyl group, —CO—R 14 , an aryl group and a heteroaryl group,
wherein the alkyl group, the alkoxy group and the cycloalkyl group are optionally substituted by 1 to 5 substituents each independently selected from a halogen atom, a haloalkyl group, —OH, —NH 2 , an alkoxy group, a cycloalkyl group, an alkenyl group, —COOH, —CO—O-alkyl, —CO—N(R 10 )(R 11 ), an aryl group and a heteroaryl group,
wherein the aryl group and the heteroaryl group are optionally substituted by 1 to 3 substituents each independently selected from a halogen atom, a haloalkyl group, an alkyl group, —(CH 2 ) h —OH, —N(R 12 )(R 13 ), —CN, —NO 2 , an alkoxy group, a cycloalkyl group, an alkenyl group, —CO—R 14 , an aryl group and a heteroaryl group;
the subscript n is an integer of from 1 to 3;
Ar 1 is an aryl group or a heteroaryl group;
R 6 and R 7 are each independently a hydrogen atom, a halogen atom, a haloalkyl group, an alkyl group, —(CH 2 ) j —OH, —N(R 12 )(R 13 ), —CN, —NO 2 , an alkoxy group, a cycloalkyl group, an alkenyl group, —CO—R 14 , an aryl group or heteroaryl group
wherein j is 0-3, and the aryl group and the heteroaryl group are optionally substituted by 1 to 3 substituents each independently selected from a halogen atom, a haloalkyl group,
an alkyl group, —(CH 2 ) h —OH, —N(R 12 )(R 13 ), —CN, —NO 2 , an alkoxy group, a cycloalkyl group, an alkenyl group, —CO—R 14 , an aryl group and a heteroaryl group;
the subscript m is an integer of from 0 to 3;
R 8 and R 9 are each independently a hydrogen atom, a halogen atom, —OH, —NO 2 , —CN, an alkyl group, an alkoxy group, —CO—R 17 , —SO 2 —R 17 , —CO—N(R 18 )(R 19 ), —N(R 20 )(R 21 ) or in combination form —O-alkylene-O—,
wherein the alkyl group and the alkoxy group are optionally substituted by 1 to 5 substituents each independently selected from a halogen atom, a haloalkyl group, —OH, —NH 2 , an alkcoxy group, a cycloalkyl group, an alkenyl group, —COOH, —CO—O-alkyl, —CO—N(R 10 )(R 11 ), —N(R 10 )—CO—R 11 , an aryl group and a heteroaryl group,
wherein the aryl group and the heteroaryl group are optionally substituted by 1 to 3 substituents each independently selected from a halogen atom, a haloalkyl group, an alkyl group, —(CH 2 ) h —OH, —N(R 12 )(R 13 ), —CN, —NO 2 , an alkoxy group, a cycloalkyl group, an alkenyl group, —CO—R 14 , an aryl group and a heteroaryl group,
R 17 is —OH, an alkoxy group, an alkyl group, —NH 2 , —NH-alkyl or —N(-alkyl) 2 ,
wherein the alkoxy group and alkyl groups are optionally substituted by substituents each independently selected from —OH, —SO 2 —R 22 and —(CH 2 ) t —CO—R 23 ,
wherein t is 0-3, R 22 is an alkyl group or —NH 2 , and R 23 is an alkyl group, —NH-alkyl, —N(-alkyl) 2 , or —NH 2 ,
wherein the alkyl groups are optionally substituted by substituents each independently selected from —OH, an alkoxy group or —(CH 2 ) u —N(R 24 )(R 25 )
wherein u is 0-3, and R 24 and R 25 are each independently a hydrogen atom, an alkyl group or —CO-alkyl
R 18 and R 19 are each independently a hydrogen atom, an alkyl group or —(CH 2 ) p —R 26 ,
wherein p is 0-3 and R 26 is —OH, a haloalkyl group, an alkoxy group, —CO—NH 2 or —N(R 24 )(R 25 ),
R 20 and R 21 are each independently a hydrogen atom, an alkyl group —CO—R 23 or in combination with the nitrogen atom to which each is attached form
wherein the alkyl group is optionally substituted by substituents each independently selected from —OH, —SO 2 —R 22 and —(CH 2 ) t —CO—R 23 , X 1 is —CO—, —CH 2 — or CH 2 CH 2 , X 2 is —O—, (CH 2 ) q , —N(R 29 )— or a spiro cyclic ring represented by
wherein q is 0-2, R 29 is a hydrogen atom, —CO—R 30 , —SO 2 —R 30 or —CH 2 ) r —Ar 3
wherein R 30 is an alkyl group, an alkoxy group, —NH-alkyl or —N(-alkyl) 2 , r is 0-3, and Ar 3 is an aryl group or heteroaryl group,
wherein the aryl group and heteroaryl group are optionally substituted by 1 to 3 substituents each independently selected from a halogen atom, a haloalkyl group, an alkyl group, —(CH 2 ) h —OH, —N(R 12 )(R 13 ), —CN, —NO 2 , an alkoxy group, a cycloalkyl group, an alkenyl group, —CO—R 14 , an aryl group and a heteroaryl group, and
the Y 2 ring is spiro cycloalkyl or spiro heterocycloalkyl ring, and
R 27 and R 28 are each independently a hydrogen atom, a halogen atom, a haloalkyl group, an alkyl group, —(CH 2 ) h —OH, —N(R 12 )(R 13 ), —CN, —NO 2 , an alkoxy group, a cycloalkyl group, an alkenyl group, —CO—R 14 , an aryl group or a heteroaryl group;
Ar 2 is an aryl group, a heteroaryl group or a ring having the formula
wherein V 1 is CH or N, X 3 is —CH 2 ) v —,
wherein v is 0-2, and
W 1 is —C(R 31 )(R 32 )—, —CO— or —N(R 33 )—,
wherein R 31 and R 32 are each independently a hydrogen atom, an alkyl group, an alkoxy group, a haloalkyl group, —(CH 2 ) w —OH, —CO—R 34 , -L 1 -Ar 4 or —N(R 35 )(R 36 ),
wherein w is 0-3, R 34 is —OH, an alkoxy group, an alkyl group or —N(R 37 )(R 38 ),
wherein R 37 and R 38 are each independently a hydrogen atom, an alkyl group, —(CH 2 ) x —OH or an alkoxy group,
wherein x is 0-3,
L 1 is —(CH 2 ) y —, —O— or —CO—,
wherein y is 0-3,
Ar 4 is an aryl group or a heteroaryl group,
wherein the aryl group and the heteroaryl group are optionally substituted by 1 to 3 substituents each independently selected from a halogen atom, a haloalkyl group, an alkyl group, —(CH 2 ) h —OH, —N(R 12 )(R 13 ), —CN, —NO 2 , an alkoxy group, a cycloalkyl group, an alkenyl group, —CO—R 14 , an aryl group and a heteroaryl group, and
R 35 and R 36 are each independently a hydrogen atom, an alkyl group, —CO-alkyl, —CO—O-alkyl or -L 1 -Ar 4 , and
R 33 is a hydrogen atom, —CO—R 28 , —SO 2 —R or —(CH 2 ) k —Ar 3 ,
wherein k is 0-3,
and the pyrazole ring labeled A, is selected from
a prodrug thereof or a pharmaceutically acceptable salt thereof.
2 . The pyrazole compound of claim 1 , wherein m is 0.
3 . The pyrazole compound of claim 2 , where R 2 and R 3 are in combination with the carbon atom to which each is attached to form a ring represented by
wherein the Y 1 ring is a C 3-8 cycloalkane group, and the wavy lines indicate the point of attachment to the remainder of the molecule.
4 . The pyrazole compound of claim 3 , wherein Y 1 is a cyclopropane group.
5 . The pyrazole compound of claim 4 , wherein Ar 1 is a phenyl group.
6 . The pyrazole compound of claim 5 , where R 6 and R 7 are each independently a fluorine, a chlorine, or a hydrogen.
7 . The pyrazole compound of claim 4 , wherein Ar 1 is a thienyl, pyrrolyl, or pyridyl group.
8 . The pyrazole compound of claim 4 , wherein Ar 2 is a phenyl group.
9 . The pyrazole compound of claim 8 , wherein R 8 and R 9 are each independently a chlorine or a hydrogen atom.
10 . The pyrazole compound of claim 4 , wherein Ar 2 is a heteroaryl group selected from the group consisting of thienyl, pyrrolyl, oxazolyl, iosoxazolyl, thiazolyl, imidazolyl, pyrazolyl, and pyridyl.
11 . A pyrazole compound represented by the following formula:
wherein
R 1 is hydrogen, —CO—O-alkyl, —COOH, an alkyl group, an alkoxy group or a cycloalkyl group,
wherein the alkyl group, the alkoxy group and the cycloalkyl group are optionally substituted by 1 to 5 substituents each independently selected from a halogen atom, a haloalkyl group, —OH, —NH 2 , an alkoxy group, a cycloalkyl group, an alkenyl group, —COOH, —CO—O-alkyl, —CO—N(R 10 )(R 11 ), —N(R 10 )—CO—R 11 , an aryl group and a heteroaryl group,
wherein each R 10 and R 11 is independently a hydrogen atom or an alkyl group, and the aryl group and the heteroaryl group are optionally substituted by 1 to 3 substituents each independently selected from a halogen atom, a haloalkyl group, an alkyl group, —(CH 2 ) h —OH, —N(R 12 )(R 13 ), —CN, —NO 2 , an alkoxy group, a cycloalkyl group, an alkenyl group, —CO—R 14 , an aryl group and a heteroaryl group,
wherein the subscript h is an integer of from 0 to 3, R 12 and R 13 in each instance are independently a hydrogen atom, an alkyl group or —CO-alkyl, and each R 14 is independently —OH, an alkoxy group, an alkyl group or —N(R 15 )(R 16 ),
wherein R 15 and R 16 are each independently a hydrogen atom or an alkyl group;
R 2 , R 3 , R 4 and R 5 are each independently a hydrogen atom, an alkyl group, an alkoxy group, a cycloalkyl group or R 4 and R 5 in combination with the carbon atoms to which they are attached, optionally form a ring represented by
wherein the Y 1 ring is a cycloalkane or a heterocycloalkane,
wherein the cycloalkane and the heterocycloalkane groups are optionally substituted by 1 to 3 substituents each independently selected from a halogen atom, a haloalkyl group, an alkyl group, —(CH 2 ) h —OH, —N(R 12 )(R 13 ), —CN, —NO 2 , an alkoxy group, a cycloalkyl group, an alkenyl group, —CO—R 14 , an aryl group and a heteroaryl group,
wherein the alkyl group, the alkoxy group and the cycloalkyl group are optionally substituted by 1 to 5 substituents each independently selected from a halogen atom, a haloalkyl group, —OH, —NH 2 , an alkoxy group, a cycloalkyl group, an alkenyl group, —COOH, —CO—O-alkyl, —CO—N(R 10 )(R 11 ), an aryl group and a heteroaryl group,
wherein the aryl group and the heteroaryl group are optionally substituted by 1 to 3 substituents each independently selected from a halogen atom, a haloalkyl group, an alkyl group, —(CH 2 ) h —OH, —N(R 12 )(R 13 ), —CN, —NO 2 , an alkoxy group, a cycloalkyl group, an alkenyl group, —CO—R 14 , an aryl group and a heteroaryl group;
the subscript n is an integer of 0-3;
Ar 1 is an aryl group or a heteroaryl group;
R 6 and R 7 are each independently a hydrogen atom, a halogen atom, a haloalkyl group, an alkyl group, —(CH 2 ) j —OH, —N(R 12 )(R 13 ), —CN, —NO 2 , an alkoxy group, a cycloalkyl group, an alkenyl group, —CO—R 14 , an aryl group or heteroaryl group
wherein j is 0-3, and the aryl group and the heteroaryl group are optionally substituted by 1 to 3 substituents each independently selected from a halogen atom, a haloalkyl group, an alkyl group, —(CH 2 ) h —OH, —N(R 12 )(R 13 ), —CN, —NO 2 , an alkoxy group, a cycloalkyl group, an alkenyl group, —CO—R 14 , an aryl group and a heteroaryl group;
the subscript m is an integer of from 1-3,
R 8 and R 9 are each independently a hydrogen atom, a halogen atom, —OH, —NO 2 , —CN, an alkyl group, an alkoxy group, —CO—R 17 , —SO 2 —R 17 , —CO—N(R 18 )(R 19 ), —N(R 20 )(R 21 ) or in combination form —O-alkylene-O—,
wherein the alkyl group and the alkoxy group are optionally substituted by 1 to 5 substituents each independently selected from a halogen atom, a haloalkyl group, —OH, —NH 2 , an alkoxy group, a cycloalkyl group, an alkenyl group, —COOH, —CO—O-alkyl, —CO—N(R 10 )(R 11 ), —N(R 10 )—CO—R 11 , an aryl group and a heteroaryl group,
wherein the aryl group and the heteroaryl group are optionally substituted by 1 to 3 substituents each independently selected from a halogen atom, a haloalkyl group, an alkyl group, —(CH 2 ) h —OH, —N(R 12 )(R 13 ), —CN, —NO 2 , an alkoxy group, a cycloalkyl group, an alkenyl group, —CO—R 14 , an aryl group and a heteroaryl group,
R 17 is —OH, an alkoxy group, an alkyl group, —NH 2 , —NH-alkyl or —N(-alkyl) 2 ,
wherein the alkoxy group and alkyl groups are optionally substituted by substituents each independently selected from —OH, —SO 2 —R 22 and —(CH 2 ) t —CO—R 23 ,
wherein t is 0-3, R 22 is an alkyl group or —NH 2 , and R 23 is an alkyl group, —NH-alkyl, —N(-alkyl) 2 , or —NH 2 ,
wherein the alkyl groups are optionally substituted by substituents each independently selected from —OH, an alkoxy group or —(CH 2 ) u —N(R 24 )(R 25 )
wherein u is 0-3, and R 24 and R 25 are each independently a hydrogen atom, an alkyl group or —CO-alkyl
R 18 and R 19 are each independently a hydrogen atom, an alkyl group or —(CH 2 ) p —R 26 ,
wherein p is 0-3 and R 26 is —OH, a haloalkyl group, an alkoxy group, —CO—NH 2 or —N(R 24 )(R 25 ),
R 20 and R 21 are each independently a hydrogen atom, an alkyl group —CO—R 23 or in combination with the nitrogen atom to which each is attached form
wherein the alkyl group is optionally substituted by substituents each independently selected from —OH, —SO 2 —R 22 and —(CH 2 ) t —CO—R 23 , X 1 is —CO—, —CH 2 — or —CH 2 —CH 2 —, X 2 is —O—, —(CH 2 ) q —, —N(R 29 )— or a spiro cyclic ring represented by
wherein q is 0-2, R 29 is a hydrogen atom, —CO—R 30 , —SO 2 —R 30 or —(CH 2 ) r —Ar 3
wherein R 30 is an alkyl group, an alkoxy group, —NH-alkyl or —N(-alkyl) 2 , r is 0-3, and Ar 3 is an aryl group or heteroaryl group,
wherein the aryl group and heteroaryl group are optionally substituted by 1 to 3 substituents each independently selected from a halogen atom, a haloalkyl group, an alkyl group, —(CH 2 ) h —OH, —N(R 12 )(R 13 ), —CN, —NO 2 , an alkoxy group, a cycloalkyl group, an alkenyl group, —CO—R 14 , an aryl group and a heteroaryl group, and
the Y 2 ring is spiro cycloalkyl or spiro heterocycloalkyl ring, and
R 27 and R 28 are each independently a hydrogen atom, a halogen atom, a haloalkyl group, an alkyl group, —(CH 2 ) h —OH, —N(R 12 )(R 13 ), —CN, —NO 2 , an alkoxy group, a cycloalkyl group, an alkenyl group, —CO—R 14 , an aryl group or a heteroaryl group;
Ar 2 is an aryl group, a heteroaryl group, or a ring having the formula
wherein V 1 is CH or N, X 3 is —(CH 2 ) v —,
wherein v is 0-2, and
W 1 is —C(R 31 )(R 32 ), —CO— or —N(R 33 )—,
wherein R 31 and R 32 are each independently a hydrogen atom, an alkyl group, an alkoxy group, a haloalkyl group, —(CH 2 ) w —OH, —CO—R 34 , -L 1 -Ar 4 or —N(R 35 )(R 36 ),
wherein w is 0-3, R 34 is —OH, an alkoxy group, an alkyl group or —N(R 37 )(R 38 ),
wherein R 37 and R 38 are each independently a hydrogen atom, an alkyl group, —(CH 2 ) x —OH or an alkoxy group,
wherein x is 0-3,
L 1 is —(CH 2 ) y —, —O— or —CO—,
wherein y is 0-3,
Ar 4 is an aryl group or a heteroaryl group,
wherein the aryl group and the heteroaryl group are optionally substituted by 1 to 3 substituents each independently selected from a halogen atom, a haloalkyl group, an alkyl group, —(CH 2 ) h —OH, —N(R 12 )(R 13 ), —CN, —NO 2 , an alkoxy group, a cycloalkyl group, an alkenyl group, —CO—R 14 , an aryl group and a heteroaryl group, and
R 35 and R 36 are each independently a hydrogen atom, an alkyl group, —CO-alkyl, —CO—O-alkyl or -L 1 -Ar 4 , and
R 33 is a hydrogen atom, —CO—R 28 , —SO 2 —R 28 or —(CH 2 ) k —Ar 3 ,
wherein k is 0-3,
and the pyrazole ring labeled A, is selected from
a prodrug thereof or a pharmaceutically acceptable salt thereof.
12 . The pyrazole compound of claim 11 , wherein n is 0.
13 . The pyrazole compound of claim 12 , where R 2 and R 3 are in combination with the carbon atom to which each is attached to form a ring represented by
wherein the Y 1 ring is a C 3-8 cycloalkane group, and the wavy lines indicate the point of attachment to the remainder of the molecule.
14 . The pyrazole compound of claim 13 , wherein R 2 and R 3 are in combination with the carbon atom to which each is attached to form a cyclopropane group.
15 . The pyrazole compound of claim 14 , wherein Ar 1 is a phenyl group.
16 . The pyrazole compound of claim 15 , where R 6 and R 7 are each independently a fluorine, a chlorine, or a hydrogen.
17 . The pyrazole compound of claim 14 , wherein Ar 1 is a thienyl, pyrrolyl, or pyridyl group.
18 . The pyrazole compound of claim 14 , wherein Ar 2 is a phenyl group.
19 . The pyrazole compound of claim 18 , wherein R 8 and R 9 are each independently a chlorine or a hydrogen atom.
20 . The pyrazole compound of claim 14 , wherein Ar 2 is a heteroaryl group selected from the group consisting of thienyl, pyrrolyl, oxazolyl, iosoxazolyl, thiazolyl, imidazolyl, pyrazolyl, and pyridyl.
21 . A pyrazole compound represented by the following formula:
wherein
R 1 is hydrogen, —CO—O-alkyl, —COOH, an alkyl group, an alkoxy group or a cycloalkyl group,
wherein the alkyl group, the alkoxy group and the cycloalkyl group are optionally substituted by 1 to 5 substituents each independently selected from a halogen atom, a haloalkyl group, —OH, —NH 2 , an alkoxy group, a cycloalkyl group, an alkenyl group, —COOH, —CO—O-alkyl, —CO—N(R 10 )(R 11 ), —N(R 10 )—CO—R 11 , an aryl group and a heteroaryl group,
wherein each R 10 and R 11 is independently a hydrogen atom or an alkyl group, and the aryl group and the heteroaryl group are optionally substituted by 1 to 3 substituents each independently selected from a halogen atom, a haloalkyl group, an alkyl group, —(CH 2 ) h —OH, —N(R 12 )(R 13 ), —CN, —NO 2 , an alkoxy group, a cycloalkyl group, an alkenyl group, —CO—R 14 , an aryl group and a heteroaryl group,
wherein the subscript h is an integer of from 0 to 3, R 12 and R 13 in each instance are independently a hydrogen atom, an alkyl group or —CO-alkyl, and each R 14 is independently —OH, an alkoxy group, an alkyl group or —N(R 15 )(R 16 ),
wherein R 15 and R 16 are each independently a hydrogen atom or an alkyl group;
R 2 , R 3 , R 4 and R 5 are each independently a hydrogen atom, an alkyl group, an alkoxy group, a cycloalkyl group or R 4 and R 5 in combination with the carbon atoms to which they are attached, optionally form a ring represented by
wherein the Y 1 ring is a cycloalkane or a heterocycloalkane,
wherein the cycloalkane and the heterocycloalkane groups are optionally substituted by 1 to 3 substituents each independently selected from a halogen atom, a haloalkyl group, an alkyl group, —(CH 2 ) h —OH, —N(R 12 )(R 13 ), —CN, —NO 2 , an alkoxy group, a cycloalkyl group, an alkenyl group, —CO—R 14 , an aryl group and a heteroaryl group,
wherein the alkyl group, the alkoxy group and the cycloalkyl group are optionally substituted by 1 to 5 substituents each independently selected from a halogen atom, a haloalkyl group, —OH, —NH 2 , an alkoxy group, a cycloalkyl group, an alkenyl group, —COOH, —CO—O-alkyl, —CO—N(R 10 )(R 11 ), an aryl group and a heteroaryl group,
wherein the aryl group and the heteroaryl group are optionally substituted by 1 to 3 substituents each independently selected from a halogen atom, a haloalkyl group, an alkyl group, —(CH 2 ) h —OH, —N(R 12 )(R 13 ), —CN, —NO 2 , an alkoxy group, a cycloalkyl group, an alkenyl group, —CO—R 14 , an aryl group and a heteroaryl group;
the subscript n is an integer of 0-3;
Ar 1 is a heteroaryl group;
R 6 and R 7 are each independently a hydrogen atom, a halogen atom, a haloalkyl group, an alkyl group, —(CH 2 ) j —OH, —N(R 12 )(R 13 ), —CN, —NO 2 , an alkoxy group, a cycloalkyl group, an alkenyl group, —CO—R 14 , an aryl group or heteroaryl group
wherein j is 0-3, and the aryl group and the heteroaryl group are optionally substituted by 1 to 3 substituents each independently selected from a halogen atom, a haloalkyl group, an alkyl group, —(CH 2 ) h —OH, —N(R 12 )(R 13 ), —CN, —NO 2 , an alkoxy group, a cycloalkyl group, an alkenyl group, —CO—R 14 , an aryl group and a heteroaryl group;
the subscript m is an integer of from 0-3,
R 8 and R 9 are each independently a hydrogen atom, a halogen atom, —OH, —NO 2 , —CN, an alkyl group, an alkoxy group, —CO—R 17 , —SO 2 —R 17 , —CO—N(R 18 )(R 19 ), —N(R 20 )(R 21 ) or in combination form —O-alkylene-O—,
wherein the alkyl group and the alkoxy group are optionally substituted by 1 to 5 substituents each independently selected from a halogen atom, a haloalkyl group, —OH, —NH 2 , an alkoxy group, a cycloalkyl group, an alkenyl group, —COOH, —CO—O-alkyl, —CO—N(R 10 )(R 11 ), —N(R 10 )—CO—R 11 , an aryl group and a heteroaryl group,
wherein the aryl group and the heteroaryl group are optionally substituted by 1 to 3 substituents each independently selected from a halogen atom, a haloalkyl group, an alkyl group, —(CH 2 ) h —OH, —N(R 12 )(R 13 ), —CN, —NO 2 , an alkoxy group, a cycloalkyl group, an alkenyl group, —CO—R 14 , an aryl group and a heteroaryl group,
R 17 is —OH, an alkoxy group, an alkyl group, —NH 2 , —NH-alkyl or -N(-alkyl) 2 ,
wherein the alkoxy group and alkyl groups are optionally substituted by substituents each independently selected from —OH, —SO 2 —R 22 and —(CH 2 ) t —CO—R 23 ,
wherein t is 0-3, R 22 is an alkyl group or —NH 2 , and R 23 is an alkyl group, —NH-alkyl, —N(-alkyl) 2 , or —NH 2 ,
wherein the alkyl groups are optionally substituted by substituents each independently selected from —OH, an alkoxy group or —(CH 2 ) u —N(R 24 )(R 25 )
wherein u is 0-3, and R 24 and R 25 are each independently a hydrogen atom, an alkyl group or —CO-alkyl
R 18 and R 19 are each independently a hydrogen atom, an alkyl group or —(CH 2 ) p —R 26 ,
wherein p is 0-3 and R 26 is —OH, a haloalkyl group, an alkoxy group, —CO—NH 2 or —N(R 24 )(R 25 ),
R 20 and R 21 are each independently a hydrogen atom, an alkyl group —CO—R or in combination with the nitrogen atom to which each is attached form
wherein the alkyl group is optionally substituted by substituents each independently selected from —OH, —SO 2 —R 22 and —(CH 2 ) t —CO—R 23 , X 1 is —CO—, —CH 2 — or —CH 2 —CH 2 —, X 2 is —O—, —(CH 2 ) q —, —N(R 29 )— or a spiro cyclic ring represented by
wherein q is 0-2, R 29 is a hydrogen atom, —CO—R 30 , —SO 2 —R 30 or —(CH 2 ) r —Ar 3
wherein R 30 is an alkyl group, an alkoxy group, —NH-alkyl or —N(-alkyl) 2 , r is 0-3, and Ar 3 is an aryl group or heteroaryl group,
wherein the aryl group and heteroaryl group are optionally substituted by 1 to 3 substituents each independently selected from a halogen atom, a haloalkyl group, an alkyl group, —(CH 2 ) h —OH, —N(R 12 )(R 13 ), —CN, —NO 2 , an alkoxy group, a cycloalkyl group, an alkenyl group, —CO—R 14 , an aryl group and a heteroaryl group, and
the Y 2 ring is spiro cycloalkyl or spiro heterocycloalkyl ring, and
R 27 and R 28 are each independently a hydrogen atom, a halogen atom, a haloalkyl group, an alkyl group, —(CH 2 ) h —OH, —N(R 12 )(R 13 ), —CN, —NO 2 , an alkoxy group, a cycloalkyl group, an alkenyl group, —CO—R 14 , an aryl group or a heteroaryl group;
Ar 2 is an aryl group, a heteroaryl group, or a ring having the formula
wherein V 1 is CH or N, X 3 is —(CH 2 ) v —,
wherein v is 0-2, and
W 1 is —C(R 31 )(R 32 )—, —CO— or —N(R 33 )—,
wherein R 31 and R 32 are each independently a hydrogen atom, an alkyl group, an alkoxy group, a haloalkyl group, —(CH 2 ) w —OH, —CO—R 34 , -L 1 -Ar 4 or —N(R 35 )(R 36 ),
wherein w is 0-3, R 34 is —OH, an alkoxy group, an alkyl group or —N(R 37 )(R 38 ),
wherein R 37 and R 38 are each independently a hydrogen atom, an alkyl group, —(CH 2 ) x —OH or an alkoxy group,
wherein x is 0-3,
L 1 is —(CH 2 ) y —, —O— or —CO—,
wherein y is 0-3,
Ar 4 is an aryl group or a heteroaryl group,
wherein the aryl group and the heteroaryl group are optionally substituted by 1 to 3 substituents each independently selected from a halogen atom, a haloalkyl group, an alkyl group, —(CH 2 ) h —OH, —N(R 12 )(R 13 ), —CN, —NO 2 , an alkoxy group, a cycloalkyl group, an alkenyl group, —CO—R 14 , an aryl group and a heteroaryl group, and
R 35 and R 36 are each independently a hydrogen atom, an alkyl group, —CO-alkyl, —CO—O-alkyl or -L 1 -Ar 4 , and
R 33 is a hydrogen atom, —CO—R 28 , —SO 2 —R 28 or —(CH 2 ) k —Ar 3 ,
wherein k is 0-3,
and the pyrazole ring labeled A, is selected from
a prodrug thereof or a pharmaceutically acceptable salt thereof.
22 . The pyrazole compound of claim 21 , wherein m is 0 and n is 0.
23 . The pyrazole compound of claim 22 , where R 2 and R 3 are in combination with the carbon atom to which each is attached to form a ring represented by
wherein the Y 1 ring is a C 3-8 cycloalkane group, and the wavy lines indicate the point of attachment to the remainder of the molecule.
24 . The pyrazole compound of claim 23 , wherein Y 1 is a cyclopropane group.
25 . The pyrazole compound of claim 24 , wherein R 1 is hydrogen, CO—O-alkyl, —COOH, an alkyl group, an alkoxy group or a cycloalkyl group.
26 . The pyrazole compound of claim 25 , wherein Ar 2 is a phenyl group.
27 . The pyrazole compound of claim 26 , wherein R 8 and R 9 are each independently a chlorine or a hydrogen atom.
28 . The pyrazole compound of claim 25 , wherein Ar 2 is a heteroaryl group selected from the group consisting of thienyl, pyrrolyl, oxazolyl, iosoxazolyl, thiazolyl, imidazolyl, pyrazolyl, and pyridyl.
29 . The pyrazole compound of claim 24 , wherein Ar 1 is a thienyl, pyrrolyl, or pyridyl group.
30 . A pyrazole compound represented by the following formula:
wherein
R 1 is hydrogen, —CO—O-alkyl, —COOH, an alkyl group, an alkoxy group or a cycloalkyl group,
wherein the alkyl group, the alkoxy group and the cycloalkyl group are optionally substituted by 1 to 5 substituents each independently selected from a halogen atom, a haloalkyl group, —OH, —NH 2 , an alkoxy group, a cycloalkyl group, an alkenyl group, —COOH, —CO—O-alkyl, —CO—N(R 10 )(R 11 ), —N(R 10 )—CO—R 11 , an aryl group and a heteroaryl group,
wherein each R 10 and R 11 is independently a hydrogen atom or an alkyl group, and the aryl group and the heteroaryl group are optionally substituted by 1 to 3 substituents each independently selected from a halogen atom, a haloalkyl group, an alkyl group, —(CH 2 ) h —OH, —N(R 12 )(R 13 ), —CN, —NO 2 , an alkoxy group, a cycloalkyl group, an alkenyl group, —CO—R 14 , an aryl group and a heteroaryl group,
wherein the subscript h is an integer of from 0 to 3, R 12 and R 13 in each instance are independently a hydrogen atom, an alkyl group or —CO-alkyl, and each R 14 is independently —OH, an alkoxy group, an alkyl group or —N(R 15 )(R 16 ),
wherein R 15 and R 16 are each independently a hydrogen atom or an alkyl group;
R 2 , R 3 , R 4 and R 5 are each independently a hydrogen atom, an alkyl group, an alkoxy group, a cycloalkyl group or R 4 and R 5 in combination with the carbon atoms to which they are attached, optionally form a ring represented by
wherein the Y 1 ring is a cycloalkane or a heterocycloalkane,
wherein the cycloalkane and the heterocycloalkane groups are optionally substituted by 1 to 3 substituents each independently selected from a halogen atom, a haloalkyl group, an alkyl group, —(CH 2 ) h —OH, —N(R 12 )(R 13 ), —CN, —NO 2 , an alkoxy group, a cycloalkyl group, an alkenyl group, —CO—R 14 , an aryl group and a heteroaryl group,
wherein the alkyl group, the alkoxy group and the cycloalkyl group are optionally substituted by 1 to 5 substituents each independently selected from a halogen atom, a haloalkyl group, —OH, —NH 2 , an alkoxy group, a cycloalkyl group, an alkenyl group, —COOH, —CO—O-alkyl, —CO—N(R 10 )(R 11 ), an aryl group and a heteroaryl group,
wherein the aryl group and the heteroaryl group are optionally substituted by 1 to 3 substituents each independently selected from a halogen atom, a haloalkyl group, an alkyl group, —(CH 2 ) h —OH, —N(R 12 )(R 13 ), —CN, —NO 2 , an alkoxy group, a cycloalkyl group, an alkenyl group, —CO—R 14, an aryl group and a heteroaryl group;
the subscript n is an integer of 0-3;
Ar 1 is an aryl group or a heteroaryl group;
R 6 and R 7 are each independently a hydrogen atom, a halogen atom, a haloalkyl group, an alkyl group, —(CH 2 ) j —OH, —N(R 12 )(R 13 ), —CN, —NO 2 , an alkoxy group, a cycloalkyl group, an alkenyl group, —CO—R 14 , an aryl group or heteroaryl group
wherein j is 0-3, and the aryl group and the heteroaryl group are optionally substituted by 1 to 3 substituents each independently selected from a halogen atom, a haloalkyl group, an alkyl group, —(CH 2 ) h —OH, —N(R 12 )(R 13 ), —CN, —NO 2 , an alkoxy group, a cycloalkyl group, an alkenyl group, —CO—R 14 , an aryl group and a heteroaryl group;
the subscript m is an integer of from 0-3,
R 8 and R 9 are each independently a hydrogen atom, a halogen atom, —OH, —NO 2 , —CN, an alkyl group, an alkoxy group, —CO—R 17 , —SO 2 —R 17 , —CO—N(R 18 )(R 19 ), —N(R 2 )(R 21 ) or in combination form —O-alkylene-O—,
wherein the alkyl group and the alkoxy group are optionally substituted by 1 to 5 substituents each independently selected from a halogen atom, a haloalkyl group, —OH, —NH 2 , an alkoxy group, a cycloalkyl group, an alkenyl group, —COOH, —CO—O-alkyl, —CO—N(R 10 )(R 11 ), —N(R 10 )—CO—R 11 , an aryl group and a heteroaryl group,
wherein the aryl group and the heteroaryl group are optionally substituted by 1 to 3 substituents each independently selected from a halogen atom, a haloalkyl group, an alkyl group, —(CH 2 ) h —OH, —N(R 12 )(R 13 ), —CN, —NO 2 , an alkoxy group, a cycloalkyl group, an alkenyl group, —CO—R 14 , an aryl group and a heteroaryl group,
R 17 is —OH, an alkoxy group, an alkyl group, —NH 2 , —NH-alkyl or —N(-alkyl) 2 ,
wherein the alkoxy group and alkyl groups are optionally substituted by substituents each independently selected from —OH, —SO 2 —R 22 and —(CH 2 ) t —CO—R 23 ,
wherein t is 0-3, R 22 is an alkyl group or —NH 2 , and R 23 is an alkyl group, —NH-alkyl, —N(-alkyl) 2 , or —NH 2 ,
wherein the alkyl groups are optionally substituted by substituents each independently selected from —OH, an alkoxy group or —(CH 2 ) u —N(R 24 )(R 25 )
wherein u is 0-3, and R 24 and R 25 are each independently a hydrogen atom, an alkyl group or —CO-alkyl
R 18 and R 19 are each independently a hydrogen atom, an alkyl group or —(CH 2 ) p —R 26 ,
wherein p is 0-3 and R 26 is —OH, a haloalkyl group, an alkoxy group, —CO—NH 2 or —N(R 24 )(R 25 ),
R 20 and R 21 are each independently a hydrogen atom, an alkyl group —CO—R 23 or in combination with the nitrogen atom to which each is attached form
wherein the alkyl group is optionally substituted by substituents each independently selected from —OH, —SO 2 —R 22 and —(CH 2 ) t —CO—R 23 , X 1 is —CO—, —CH 2 — or —CH 2 —CH 2 —, X 2 is —O—, —(CH 2 ) q —, —N(R 29 )— or a spiro cyclic ring represented by
wherein q is 0-2, R 29 is a hydrogen atom, —CO—R 30 , —SO 2 —R 30 or —(CH 2 ) r —Ar 3
wherein R 30 is an alkyl group, an alkoxy group, —NH-alkyl or —N(-alkyl) 2 , r is 0-3, and Ar 3 is an aryl group or heteroaryl group,
wherein the aryl group and heteroaryl group are optionally substituted by 1 to 3 substituents each independently selected from a halogen atom, a haloalkyl group, an alkyl group, —(CH 2 ) h —OH, —N(R 12 )(R 13 ), —CN, —NO 2 , an alkoxy group, a cycloalkyl group, an alkenyl group, —CO—R 14 , an aryl group and a heteroaryl group, and
the Y 2 ring is spiro cycloalkyl or spiro heterocycloalkyl ring, and
R 27 and R 28 are each independently a hydrogen atom, a halogen atom, a haloalkyl group, an alkyl group, —(CH 2 ) h —OH, —N(R 12 )(R 13 ), —CN, —NO 2 , an alkoxy group, a cycloalkyl group, an alkenyl group, —CO—R 14 , an aryl group or a heteroaryl group;
Ar 2 is an aryl group, a heteroaryl group selected from the group consisting of thienyl, pyrrolyl, oxazolyl, isooxazolyl, thiazolyl, imidazolyl, and pyrazolyl, or a ring having the formula
wherein V 1 is CH or N, X 3 is —CH 2 ) v —,
wherein v is 0-2, and
W 1 is —C(R 31 )(R 32 )—, —CO— or —N(R 33 )—,
wherein R 31 and R 32 are each independently a hydrogen atom, an alkyl group, an alkoxy group, a haloalkyl group, —(CH 2 ) w —OH, —CO—R 34 , -L 1 -Ar 4 or —N(R 35 )(R 36 ),
wherein w is 0-3, R 34 is —OH, an alkoxy group, an alkyl group or —N(R 37 )(R 38 ),
wherein R 37 and R 38 are each independently a hydrogen atom, an alkyl group, —(CH 2 ) x —OH or an alkoxy group,
wherein x is 0-3,
L 1 is —(CH 2 ) y —, —O— or —CO—,
wherein y is 0-3,
Ar 4 is an aryl group or a heteroaryl group,
wherein the aryl group and the heteroaryl group are optionally substituted by 1 to 3 substituents each independently selected from a halogen atom, a haloalkyl group, an alkyl group, —(CH 2 ) h —OH, —N(R 12 )(R 13 ), —CN, —NO 2 , an alkoxy group, a cycloalkyl group, an alkenyl group, —CO—R 14 , an aryl group and a heteroaryl group, and
R 35 and R 36 are each independently a hydrogen atom, an alkyl group, —CO-alkyl, —CO—O-alkyl or -L 1 -Ar 4 , and
R 33 is a hydrogen atom, —CO—R , —SO 2 —R or —(CH 2 ) k —Ar 3 ,
wherein k is 0-3,
and the pyrazole ring labeled A, is selected from
a prodrug thereof or a pharmaceutically acceptable salt thereof.
31 . The pyrazole compound of claim 30 , wherein m is 0 and n is 0.
32 . The pyrazole compound of claim 31 , where R 2 and R 3 are in combination with the carbon atom to which each is attached to form a ring represented by
wherein the Y 1 ring is a C 3-8 cycloalkane group, and the wavy lines indicate the point of attachment to the remainder of the molecule.
33 . The pyrazole compound of claim 32 , wherein Y 1 is a cyclopropane group.
34 . The pyrazole compound of claim 33 , wherein R 1 is hydrogen, CO—O-alkyl, —COOH, an alkyl group, an alkoxy group or a cycloalkyl group.
35 . The pyrazole compound of claim 34 , wherein Ar 1 is a phenyl group.
36 . The pyrazole compound of claim 35 , where R 6 and R 7 are each independently a fluorine, a chlorine, or a hydrogen.
37 . The pyrazole compound of claim 34 , wherein Ar 2 is a phenyl group.
38 . The pyrazole compound of claim 37 , wherein R 8 and R 9 are each independently a chlorine or a hydrogen atom.
39 . A pyrazole compound represented by the following formula:
wherein
R 1 is a hydrogen,
R 2 and R 3 are in combination with the carbon atom to which each is attached to form a ring represented by
wherein the Y 1 ring is a C 3-8 cycloalkane or a hetercycloalkane group, and the wavy lines indicate the point of attachment to the remainder of the molecule;
wherein the cycloalkane and the heterocycloalkane groups are optionally substituted by 1 to 3 substituents each independently selected from a halogen atom, a haloalkyl group, an alkyl group, —(CH 2 ) h —OH, —N(R 12 )(R 13 ), —CN, —NO 2 , an alkoxy group, a cycloalkyl group, an alkenyl group, —CO—R 14 , an aryl group and a heteroaryl group,
wherein the alkyl group, the alkoxy group and the cycloalkyl group are optionally substituted by 1 to 5 substituents each independently selected from a halogen atom, a haloalkyl group, —OH, —NH 2 , an alkoxy group, a cycloalkyl group, an alkenyl group, —COOH, —CO—O-alkyl, —CO—N(R 10 )(R 11 ), an aryl group and a heteroaryl group,
wherein the aryl group and the heteroaryl group are optionally substituted by 1 to 3 substituents each independently selected from a halogen atom, a haloalkyl group, an alkyl group, —(CH 2 ) h —OH, —N(R 12 )(R 13 ), —CN, —NO 2 , an alkoxy group, a cycloalkyl group, an alkenyl group, —CO—R 14 , an aryl group and a heteroaryl group;
R 4 and R 5 are each independently a hydrogen atom, an alkyl group, an alkoxy group, a cycloalkyl group or R 4 and R 5 in combination with the carbon atoms to which they are attached, optionally form a ring represented by
wherein the Y 1 ring is a cycloalkane or a heterocycloalkane,
wherein the cycloalkane and the heterocycloalkane groups are optionally substituted by 1 to 3 substituents each independently selected from a halogen atom, a haloalkyl group, an alkyl group, —(CH 2 ) h —OH, —N(R 12 )(R 13 ), —CN, —NO 2 , an alkoxy group, a cycloalkyl group, an alkenyl group, —CO—R 14 , an aryl group and a heteroaryl group,
wherein the alkyl group, the alkoxy group and the cycloalkyl group are optionally substituted by 1 to 5 substituents each independently selected from a halogen atom, a haloalkyl group, —OH, —NH 2 , an alkoxy group, a cycloalkyl group, an alkenyl group, —COOH, —CO—O-alkyl, —CO—N(R 10 )(R 11 ), an aryl group and a heteroaryl group,
wherein the aryl group and the heteroaryl group are optionally substituted by 1 to 3 substituents each independently selected from a halogen atom, a haloalkyl group, an alkyl group, —(CH 2 ) h —OH, —N(R 12 )(R 13 ), —CN, —NO 2 , an alkoxy group, a cycloalkyl group, an alkenyl group, —CO—R 14 , an aryl group and a heteroaryl group;
the subscript n is 0;
Ar 1 is an aryl group;
R 6 and R 7 are each independently a hydrogen atom, a halogen atom, a haloalkyl group, an alkyl group, —(CH 2 ) j —OH, —N(R 12 )(R 13 ), —CN, —NO 2 , an alkoxy group, a cycloalkyl group, an alkenyl group, —CO—R 14 , an aryl group or heteroaryl group
wherein j is 0-3, and the aryl group and the heteroaryl group are optionally substituted by 1 to 3 substituents each independently selected from a halogen atom, a haloalkyl group, an alkyl group, —(CH 2 ) h —OH, —N(R 12 )(R 13 ), —CN, —NO 2 , an alkoxy group, a cycloalkyl group, an alkenyl group, —CO—R 14 , an aryl group and a heteroaryl group;
the subscript m is 0;
R 8 and R 9 are each independently a hydrogen atom, a halogen atom, —OH, —NO 2 , —CN, an alkyl group, an alkoxy group, —CO—R 17 , —SO 2 —R 17 , —CO—N(R 18 )(R 19 ), —N(R 20 )(R 21 ) or in combination form —O-alkylene-O—,
wherein the alkyl group and the alkoxy group are optionally substituted by 1 to 5 substituents each independently selected from a halogen atom, a haloalkyl group, —OH, —NH 2 , an alkoxy group, a cycloalkyl group, an alkenyl group, —COOH, —CO—O-alkyl, —CO—N(R 10 )(R 11 ), —N(R 10 )—CO—R 11 , an aryl group and a heteroaryl group,
wherein the aryl group and the heteroaryl group are optionally substituted by 1 to 3 substituents each independently selected from a halogen atom, a haloalkyl group, an alkyl group, —(CH 2 ) h —OH, —N(R 12 )(R 13 ), —CN, —NO 2 , an alkoxy group, a cycloalkyl group, an alkenyl group, —CO—R 14 , an aryl group and a heteroaryl group,
R 17 is —OH, an alkoxy group, an alkyl group, —NH 2 , —NH-alkyl or —N(-alkyl) 2 ,
wherein the alkoxy group and alkyl groups are optionally substituted by substituents each independently selected from —OH, —SO 2 —R 22 and —(CH 2 ) t —CO—R 23 ,
wherein t is 0-3, R 22 is an alkyl group or —NH 2 , and R 23 is an alkyl group, —NH-alkyl, —N(-alkyl) 2 , or —NH 2 ,
wherein the alkyl groups are optionally substituted by substituents each independently selected from —OH, an alkoxy group or —(CH 2 ) u —N(R 24 )(R 25 )
wherein u is 0-3, and R 24 and R 25 are each independently a hydrogen atom, an alkyl group or —CO-alkyl
R 18 and R 19 are each independently a hydrogen atom, an alkyl group or —(CH 2 ) p —R 26 .
wherein p is 0-3 and R 26 is —OH, a haloalkyl group, an alkoxy group, —CO—NH 2 or —N(R 24 )(R 25 ),
R 20 and R 21 are each independently a hydrogen atom, an alkyl group —CO—R 23 or in combination with the nitrogen atom to which each is attached form
wherein the alkyl group is optionally substituted by substituents each independently selected from —OH, —SO 2 —R 22 and —(CH 2 ) t —CO—R 23 , X 1 is —CO—, —CH 2 — or —CH 2 —CH 2 —, X 2 is —O—, —(CH 2 ) q —, —N(R 29 )— or a spiro cyclic ring represented by
wherein q is 0-2, R 29 is a hydrogen atom, —CO—R 30 , —SO 2 —R 30 or —(CH 2 ) r —Ar 3
wherein R 30 is an alkyl group, an alkoxy group, —NH-alkyl or —N(-alkyl) 2 , r is 0-3, and Ar 3 is an aryl group or heteroaryl group,
wherein the aryl group and heteroaryl group are optionally substituted by 1 to 3 substituents each independently selected from a halogen atom, a haloalkyl group, an alkyl group, —(CH 2 ) h —OH, —N(R 12 )(R 13 ), —CN, —NO 2 , an alkoxy group, a cycloalkyl group, an alkenyl group, CO—R 14 , an aryl group and a heteroaryl group, and
the Y 2 ring is spiro cycloalkyl or spiro heterocycloalkyl ring, and
R 27 and R 28 are each independently a hydrogen atom, a halogen atom, a haloalkyl group, an alkyl group, —(CH 2 ) h —OH, —N(R 12 )(R 13 ), —CN, —NO 2 , an alkoxy group, a cycloalkyl group, an alkenyl group, —CO—R 14 , an aryl group or a heteroaryl group;
Ar 2 is a pyridyl group,
and the pyrazole ring labeled A, is selected from
a prodrug thereof or a pharmaceutically acceptable salt thereof.
40 . The pyrazole compound of claim 39 , wherein Y 1 is a cyclopropane group.
41 . The pyrazole compound of claim 40 , wherein Ar 1 is a phenyl group.
42 . The pyrazole compound of claim 41 , where R 6 and R 7 are each independently a hydrogen, a fluorine, or a chlorine.
43 . A compound selected from the group consisting of
44 . A pharmaceutical composition comprising the pyrazole compound of claim 1 , 11 , 21 , 30 , 39 , or 43 , a prodrug thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
45 . A method for the treatment or prophylaxis of a 11-β-hydroxysteroid dehydrogenase type 1 (HSD1) enzyme-mediated disorder, comprising administering to a subject in need thereof an effective amount of a pyrazole compound, a prodrug thereof or a pharmaceutically acceptable salt thereof, wherein the pyrazole compound represented by the following formula:
wherein
R 1 is a hydrogen, —CO—O-alkyl, —COOH, a hydroxylalkyl group, an alkyl group, an alkoxy group or a cycloalkyl group,
wherein the alkyl group, the alkoxy group and the cycloalkyl group are optionally substituted by 1 to 5 substituents each independently selected from a halogen atom, a haloalkyl group, —OH, —NH 2 , an alkoxy group, a cycloalkyl group, an alkenyl group, —COOH, —CO—O-alkyl, —CO—N(R 10 )(R 11 ), —N(R 10 )—CO—R 11 , an aryl group and a heteroaryl group,
wherein each R 10 and R 11 is independently a hydrogen atom or an alkyl group, and the aryl group and the heteroaryl group are optionally substituted by 1 to 3 substituents each independently selected from a halogen atom, a haloalkyl group, an alkyl group, —(CH 2 ) h —OH, —N(R 12 )(R 13 ), —CN, —NO 2 , an alkoxy group, a cycloalkyl group, an alkenyl group, —CO—R 14 , an aryl group and a heteroaryl group,
wherein the subscript h is an integer of from 0 to 3, R 12 and R 13 in each instance are independently a hydrogen atom, an alkyl group or —CO-alkyl, and each R 14 is independently —OH, an alkoxy group, an alkyl group or —N(R 15 )(R 16 ),
wherein R 15 and R 16 are each independently a hydrogen atom or an alkyl group;
R 2 , R 3 , R 4 and R 5 are each independently a hydrogen atom, an alkyl group, an alkoxy group, a cycloalkyl group or R 2 and R 3 in combination and R 4 and R 5 in combination with the carbon atoms to which they are attached, optionally form a ring represented by
wherein the Y 1 ring is a cycloalkane or a heterocycloalkane,
wherein the cycloalkane and the heterocycloalkane groups are optionally substituted by 1 to 3 substituents each independently selected from a halogen atom, a haloalkyl group, an alkyl group, —(CH 2 ) h —OH, —N(R 12 )(R 13 ), —CN, —NO 2 , an alkoxy group, a cycloalkyl group, an alkenyl group, —CO—R 14 , an aryl group and a heteroaryl group,
wherein the alkyl group, the alkoxy group and the cycloalkyl group are optionally substituted by 1 to 5 substituents each independently selected from a halogen atom, a haloalkyl group, —OH, —NH 2 , an alkoxy group, a cycloalkyl group, an alkenyl group, —COOH, —CO—O-alkyl, —CO—N(R 10 )(R 11 ), an aryl group and a heteroaryl group,
wherein the aryl group and the heteroaryl group are optionally substituted by 1 to 3 substituents each independently selected from a halogen atom, a haloalkyl group, an alkyl group, —(CH 2 ) h —OH, —N(R 12 )(R 13 ), —CN, —NO 2 , an alkoxy group, a cycloalkyl group, an alkenyl group, —CO—R 14 , an aryl group and a heteroaryl group;
the subscript n is an integer of from 0 to 3;
Ar 1 is an aryl group or a heteroaryl group;
R 6 and R 7 are each independently a hydrogen atom, a halogen atom, a haloalkyl group, an alkyl group, —(CH 2 ) j —OH, —N(R 12 )(R 13 ), —CN, —NO 2 , an alkoxy group, a cycloalkyl group, an alkenyl group, —CO—R 14 , an aryl group or heteroaryl group
wherein j is 0-3, and the aryl group and the heteroaryl group are optionally substituted by 1 to 3 substituents each independently selected from a halogen atom, a haloalkyl group, an alkyl group, —(CH 2 ) h —OH, —N(R 12 )(R 13 ), —CN, —NO 2 , an alkoxy group, a cycloalkyl group, an alkenyl group, —CO—R 14 , an aryl group and a heteroaryl group;
the subscript m is an integer of from 0 to 3;
R 8 and R 9 are each independently a hydrogen atom, a halogen atom, —OH, —NO 2 , —CN, an alkyl group, an alkoxy group, —CO—R 17 , —SO 2 —R 17 , —CO—N(R 18 )(R 19 ), —N(R 20 )(R 21 ) or in combination form —O-alkylene-O—,
wherein the alkyl group and the alkoxy group are optionally substituted by 1 to 5 substituents each independently selected from a halogen atom, a haloalkyl group, —OH, —NH 2 , an alkoxy group, a cycloalkyl group, an alkenyl group, —COOH, —CO—O-alkyl, —CO—N(R 10 )(R 11 ), —N(R 10 )—CO—R 11 , an aryl group and a heteroaryl group,
wherein the aryl group and the heteroaryl group are optionally substituted by 1 to 3 substituents each independently selected from a halogen atom, a haloalkyl group, an alkyl group, —(CH 2 ) h —OH, —N(R 12 )(R 13 ), —CN, —NO 2 , an alkoxy group, a cycloalkyl group, an alkenyl group, —CO—R 14 , an aryl group and a heteroaryl group,
R 17 is —OH, an alkoxy group, an alkyl group, —NH 2 , —NH-alkyl or —N(-alkyl) 2 ,
wherein the alkoxy group and alkyl groups are optionally substituted by substituents each independently selected from —OH, —SO 2 —R 22 and —(CH 2 ) t —CO—R 23 ,
wherein t is 0-3, R 22 is an alkyl group or —NH 2 , and R 23 is an alkyl group, —NH-alkyl, —N(-alkyl) 2 , or —NH 2 ,
wherein the alkyl groups are optionally substituted by substituents each independently selected from —OH, an alkoxy group or —(CH 2 ) u —N(R 24 )(R 25 )
wherein u is 0-3, and R 24 and R 25 are each independently a hydrogen atom, an alkyl group or —CO-alkyl
R 18 and R 19 are each independently a hydrogen atom, an alkyl group or —(CH 2 ) p —R 26 ,
wherein p is 0-3 and R 26 is —OH, a haloalkyl group, an alkoxy group, —CO—NH 2 or —N(R 24 )(R 25 ),
R 20 and R 21 are each independently a hydrogen atom, an alkyl group —CO—R 23 or in combination with the nitrogen atom to which each is attached form
wherein the alkyl group is optionally substituted by substituents each independently selected from —OH, —SO 2 —R 22 and —(CH 2 ) t —CO—R 23 , X 1 is —CO—, —CH 2 — or —CH 2 —CH 2 —, X 2 is —O—, —(CH 2 ) q —, —N(R 29 )— or a spiro cyclic ring represented by
wherein q is 0-2, R 29 is a hydrogen atom, —CO—R 30 , —SO 2 —R 30 or —(CH 2 ) r —Ar 3
wherein R 30 is an alkyl group, an alkoxy group, —NH-alkyl or —N(-alkyl) 2 , r is 0-3, and Ar 3 is an aryl group or heteroaryl group,
wherein the aryl group and heteroaryl group are optionally substituted by 1 to 3 substituents each independently selected from a halogen atom, a haloalkyl group, an alkyl group, —(CH 2 ) h —OH, —N(R 12 )(R 13 ), —CN, —NO 2 , an alkoxy group, a cycloalkyl group, an alkenyl group, —CO—R 14 , an aryl group and a heteroaryl group, and
the Y 2 ring is spiro cycloalkyl or spiro heterocycloalkyl ring, and
R 27 and R 28 are each independently a hydrogen atom, a halogen atom, a haloalkyl group, an alkyl group, —(CH 2 ) h —OH, —N(R 12 )(R 13 ), —CN, —NO 2 , an alkoxy group, a cycloalkyl group, an alkenyl group, —CO—R 14 , an aryl group or a heteroaryl group;
Ar 2 is an aryl group, a heteroaryl group or a ring having the formula
wherein V 1 is CH or N, X 3 is —CH 2 ) v —,
wherein v is 0-2, and
W 1 is —C(R 31 )(R 32 )—, —CO— or —N(R 33 )—,
wherein R 31 and R 32 are each independently a hydrogen atom, an alkyl group, an alkoxy group, a haloalkyl group, —(CH 2 ) w —OH, —CO—R 34 , -L 1 -Ar 1 or —N(R 35 )(R 36 ),
wherein w is 0-3, R 34 is —OH, an alkoxy group, an alkyl group or —N(R 37 )(R 38 ),
wherein R 37 and R 38 are each independently a hydrogen atom, an alkyl group, —(CH 2 ) x —OH or an alkoxy group,
wherein x is 0-3,
L 1 is —(CH 2 ) y —, —O— or —CO—,
wherein y is 0-3,
Ar 4 is an aryl group or a heteroaryl group,
wherein the aryl group and the heteroaryl group are optionally substituted by 1 to 3 substituents each independently selected from a halogen atom, a haloalkyl group, an alkyl group, —(CH 2 ) h —OH, —N(R 12 )(R 13 ), —CN, —NO 2 , an alkoxy group, a cycloalkyl group, an alkenyl group, —CO—R 14 , an aryl group and a heteroaryl group, and
R 35 and R 36 are each independently a hydrogen atom, an alkyl group, —CO-alkyl, —CO—O-alkyl or -L 1 -Ar 4 , and
R 33 is a hydrogen atom, —CO—R 28 , —SO 2 —R 28 or —(CH 2 ) k —Ar 3 ,
wherein k is 0-3,
and the pyrazole ring labeled A, is selected from
46 . The method according to claim 45 , wherein m is 0 and n is 0.
47 . The method according to claim 46 , wherein R 2 and R 3 are in combination with the carbon atom to which each is attached to form a ring represented by
wherein the Y 1 ring is a C 3-8 cycloalkane group, and the wavy lines indicate the point of attachment to the remainder of the molecule.
48 . The method according to claim 47 , wherein Y 1 is a cyclopropane group.
49 . The method according to claim 48 , wherein Ar 1 is an phenyl group.
50 . The method according to claim 49 , wherein R 6 and R 7 are each independently a fluorine atom, a chlorine atom, or a hydrogen atom.
51 . The pyrazole compound of claim 48 , wherein Ar 2 is a phenyl group.
52 . The pyrazole compound of claim 51 , wherein R 8 and R 9 are each independently a chlorine or a hydrogen atom.
53 . The pyrazole compound of claim 48 , wherein Ar 1 is a thienyl, pyrrolyl, or pyridyl group.
54 . The pyrazole compound of claim 48 , wherein Ar 2 is a heteroaryl group selected from the group consisting of thienyl, pyrrolyl, oxazolyl, iosoxazolyl, thiazolyl, imidazolyl, pyrazolyl, and pyridyl.
55 . The method according to claim 45 , wherein the disorder is selected from a group consisting of diabetes, obesity, and metabolic syndrome.
56 . The method according to claim 55 , wherein the disorder is diabetes.
57 . The method according to claim 55 , wherein the disorder is obesity.
58 . The method according to claim 55 , wherein the disorder is metabolic syndrome.
59 . The method of claim 55 , wherein a different therapeutic drug of diabetes is used in combination.
60 . The method of claim 59 , wherein the different therapeutic drug of diabetes is one or more pharmaceutical agents selected from the group consisting of an insulin preparation, a sulfonylurea, an insulin secretagogue, a sulfonamide, a biguanide, an a-glucosidase inhibitor, a PTP1B inhibitor and an insulin sensitizer.
61 . The method of claim 60 , wherein the different therapeutic drug of diabetes is one or more pharmaceutical agents selected from the group consisting of insulin, glibenclamide, tolbutamide, glyclopyramide, acetohexamide, glimepiride, tolazamide, gliclazide, nateglinide, glybuzole, metformin hydrochloride, buformine hydrochloride, voglibose, acarbose and pioglitazone hydrochloride.
62 . The method of claim 55 , wherein a different therapeutic drug of obesity is used in combination.
63 . The method of claim 62 , wherein the different therapeutic drug of obesity is Mazindol.Join the waitlist — get patent alerts
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