Pyrazole compounds
Pharmaceutical compositions and compounds are provided. The compounds of the invention demonstrate anti-proliferative activity, and may promote apoptosis in cells lacking normal regulation of cell cycle and death. In one embodiment of the invention, pharmaceutical compositions of the compounds in combination with a physiologically acceptable carrier are provided. The pharmaceutical compositions are useful in the treatment of hyperproliferative disorders, which disorders include tumor growth, lymphoproliferative diseases, angiogenesis. The compounds of the invention are substituted pyrazoles and pyrazolines.
1. A pharmaceutical composition comprising a pharmaceutically acceptable carrier, diluent or excipient and a compound of formula (Ia):
wherein
n is 0 to 5;
R 3 and R 4 are each independently —N(R 7 ) 2 or —N(R 7 )C(O)R 6 ;
R 5 is aryl optionally substituted with one or more substituents selected from the group consisting of alkyl, halo, nitro, cyano, haloalkyl, haloalkoxy, aryl, heterocyclyl, heterocyclylalkyl, —OR 6 , —R 8 —OR 6 , —R 8 —[O—R 8 ] m —OR 6 (where m is 1 to 4), —S(O) 2 OH, —S(O) t R 7 (where t is 0 to 2), —S(O) t —R 8 —OR 6 , —S(O) t —N(R 6 ) 2 , —R 8 —P(O)(OR 9 ) 2 , —C(O)OR 6 , —R 8 —C(O)OR 6 , —C(O)N(R 6 ) 2 , —N(R 7 ) 2 , —R 8 —N(R 7 ) 2 , and —N(R 9 )C(O)R 6 ;
or R 5 is heterocyclyl optionally substituted with one or more substituents selected from the group consisting of alkyl, halo, nitro, cyano, haloalkyl, haloalkoxy, aryl, heterocyclyl, heterocyclylalkyl, —OR 6 , —R 8 —OR 6 , —R 8 —[O—R 8 ] m —OR 6 (where m is 1 to 4), —S(O) 2 OH, —S(O) t R 7 (where t is 0 to 2), —S(O) t —R 8 —OR 6 , —S(O) t —N(R 6 ) 2 , —R 8 —P(O)(OR 9 ) 2 , —C(O)OR 6 , —R 8 —C(O)OR 6 , —C(O)N(R 6 ) 2 , —N(R 7 ) 2 , —R 8 —N(R 7 ) 2 , and —N(R 9 )C(O)R 6 ;
each R 6 is independently hydrogen, alkyl, aryl, aralkyl, hetereocyclyl or heterocyclylalkyl;
each R 7 is independently hydrogen, alkyl, haloalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, or —R 8 —OR 9 ;
each R 8 is a straight or branched alkylene chain; and
each R 9 is hydrogen or alkyl;
as a single stereoisomer, a mixture of stereoisomers, a solvate or a polymorph; or a pharmaceutically acceptable salt thereof.
2. The pharmaceutical composition of claim 1 comprising a pharmaceutically acceptable carrier, diluent or excipient and a compound of formula (Ia)
wherein:
n is 0 to 5;
R 3 and R 4 are each independently —N(R 7 ) 2 or —N(R 7 )C(O)R 6 ;
R 5 is aryl optionally substituted with one or more substituents selected from the group consisting of alkyl, halo, nitro, cyano, haloalkyl, haloalkoxy, aryl, heterocyclyl, heterocyclylalkyl, —OR 6 , —R 8 —OR 6 , —R 8 —[O—R 8 ] m —OR 6 (where m is 1 to 4), —S(O) 2 OH, —S(O) t R 7 (where t is 0 to 2), —S(O) t —R 8 —OR 6 , —S(O) t —N(R 6 ) 2 , —R 8 —P(O)(OR 9 ) 2 , —C(O)OR 6 , —R 8 —C(O)OR 6 , —C(O)N(R 6 ) 2 , —N(R 7 ) 2 , —R 8 —N(R 7 ) 2 , and —N(R 9 )C(O)R 6 ;
each R 6 is independently hydrogen, alkyl, aryl, aralkyl, hetereocyclyl or heterocyclylalkyl;
each R 7 is independently hydrogen, alkyl, haloalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, or —R 8 —OR 9 ;
each R 8 is a straight or branched alkylene chain; and
each R 9 is hydrogen or alkyl.
3. The pharmaceutical composition of claim 2 comprising a pharmaceutically acceptable carrier, diluent or excipient and a compound of formula (Ia) wherein:
n is 0;
R 3 and R 4 are each —N(R 7 ) 2 ;
R 5 is aryl optionally substituted with one or more substituents selected from the group consisting of alkyl, halo, nitro, cyano, haloalkyl, haloalkoxy, aryl, heterocyclyl, heterocyclylalkyl, —OR 6 , —R 8 —OR 6 , —R 8 —[O—R 8 ] m —OR 6 (where m is 1 to 4), —S(O) 2 OH, —S(O) t R 7 (where t is 0 to 2), —S(O) t —R 8 —OR 6 , —S(O) t —N(R 6 ) 2 , —R 8 —P(O)(OR 9 ) 2 , —C(O)OR 6 , —R 8 —C(O)OR 6 , —C(O)N(R 6 ) 2 , —N(R 7 ) 2 , —R 8 —N(R 7 ) 2 , and —N(R 9 )C(O)R 6 ;
each R 6 is independently hydrogen, alkyl, aryl, aralkyl, hetereocyclyl or heterocyclylalkyl;
each R 7 is independently hydrogen, alkyl, haloalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, or —R 8 —OR 9 ;
each R 8 is a straight or branched alkylene chain; and
each R 9 is hydrogen or alkyl.
4. The pharmaceutical composition of claim 3 comprising a pharmaceutically acceptable carrier, diluent or excipient and a compound of formula (Ia) wherein:
n is 0;
R 3 and R 4 are each —N(R 7 ) 2 ;
R 5 is aryl optionally substituted with one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, haloalkoxy, aryl, and aralkyl;
each R 7 is independently hydrogen, alkyl, haloalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, or —R 8 —OR 9 ;
each R 8 is a straight or branched alkylene chain; and
each R 9 is hydrogen or alkyl.
5. The pharmaceutical composition of claim 4 comprising a pharmaceutically acceptable carrier, diluent or excipient and a compound of formula (Ia) wherein:
n is 0;
R 3 and R 4 are each —N(R 7 ) 2 ;
R 5 is aryl optionally substituted with one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, haloalkoxy, aryl and aralkyl;
and each R 7 is independently hydrogen or alkyl.
6. The pharmaceutical composition of claim 5 comprising a pharmaceutically acceptable carrier, diluent or excipient and a compound of formula (Ia) wherein:
n is 0:
R 3 and R 4 are each —N(R 7 ) 2 ;
R 5 is phenyl optionally substituted with one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, haloalkoxy, aryl, and aralkyl optionally substituted by —N(R 7 ) 2 ;
and each R 7 is hydrogen or alkyl.
7. The pharmaceutical composition of claim 6 comprising a pharmaceutically acceptable carrier, diluent or excipient and a compound selected from the group consisting of the following:
4-(2,3,4,5,6-pentafluorophenylhydrazono)-4H-pyrazole-3,5-diamine;
4-[(3,5-difluorophenyl)hydrazono]-4H-pyrazole-3,5-diamine;
4-[(2,3,4-trifluorophenyl)hydrazono]-4H-pyrazole-3,5-diamine;
4-[(3-trifluoromethoxyphenyl)hydrazono]-4H-pyrazole-3,5-diamine;
4-[(4-chloro-3-trifluoromethylphenyl)hydrazono]-4H-pyrazole-3,5-diamine;
4-[(4-benzylphenyl)hydrazono]-4H-pyrazole-3,5-diamine;
4-(4-(phenyl)phenylhydrazono)-4H-pyrazole-3,5-diamine;
4-{[4-(4-methylaminobenzyl)phenyl]hydrazono}-4H-pyrazole-3,5-diamine;
4-[(2,3-difluoro-4-trifluoromethylphenyl)hydrazono]-4H-pyrazole-3,5-diamine;
4-[(3-fluoro-5-trifluoromethylphenyl)hydrazono]-4H-pyrazole-3,5-diamine; and
N-ethyl-4-(phenylhydrazono)-4H-pyrazole-3,5-diamine.
8. The pharmaceutical composition of claim 5 comprising a pharmaceutically acceptable carrier, diluent or excipient and a compound of formula (Ia) wherein:
n is 0:
R 3 and R 4 are each —NH 2 ; and
R 5 is naphthyl optionally substituted with one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, and haloalkoxy.
9. The pharmaceutical composition of claim 8 comprising a pharmaceutically acceptable carrier, diluent or excipient and a compound selected from the group consisting of the following:
4-(naphthalen-2-ylhydrazono)-4H-pyrazole-3,5-diamine; and
4-[(4-bromonaphthalen-1-yl)hydrazono]-4H-pyrazole-3,5-diamine.
10. The pharmaceutical composition of claim 3 comprising a pharmaceutically acceptable carrier, diluent or excipient and a compound of formula (Ia) wherein:
n is 0;
R 3 and R 4 are each —N(R 7 ) 2 ;
R 5 is aryl optionally substituted with one or more substituents selected from the group consisting of halo, haloalkyl, haloalkoxy, —OR 6 , —R 8 —OR 6 , and —R 8 —[O—R 8 ] m —OR 6 (where m is 1 to 4);
each R 6 is independently hydrogen, alkyl aryl, or aralkyl;
each R 7 is independently hydrogen, alkyl, aryl, or aralkyl; and
each R 8 is a straight or branched alkylene chain.
11. The pharmaceutical composition of claim 10 comprising a pharmaceutically acceptable carrier, diluent or excipient and a compound of formula (Ia) wherein:
n is 0;
R 3 and R 4 are each —NH 2 ; and
R 5 is phenyl optionally substituted with one or more substituents selected from the group consisting of halo, haloalkyl, haloalkoxy, —OR 6 , —R 8 —OR 6 , and —R 8 —[O—R 8 ] m —OR 6 (where m is 1 to 4);
each R 6 is independently hydrogen, alkyl, aryl, or aralkyl; and
each R 8 is a straight or branched alkylene chain.
12. The pharmaceutical composition of claim 11 comprising a pharmaceutically acceptable carrier, diluent or excipient and a compound selected from the group consisting of the following:
{2-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]phenyl}methanol;
{3-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]phenyl}methanol; and
4-({3-[2-(2-methoxyethoxy)ethoxymethyl]phenyl}hydrazono)-4H-pyrazole-3,5-diamine.
13. The pharmaceutical composition of claim 3 comprising a pharmaceutically acceptable carrier, diluent or excipient and a compound of formula (Ia) wherein:
n is 0;
R 3 and R 4 are each —N(R 7 ) 2 ;
R 5 is aryl optionally substituted with one or more substituents selected from the group consisting of alkyl, nitro, —OR 6 , —R 8 —OR 6 , —C(O)OR 6 , —C(O)N(R 6 ) 2 , —N(R 7 ) 2 , —R 8 —N(R 7 ) 2 , and —N(R 9 )C(O)R 6 ;
each R 6 is independently hydrogen, alkyl, aryl, aralkyl, hetereocyclyl or heterocyclylalkyl;
each R 7 is independently hydrogen, alkyl, haloalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, or —R 8 —OR 9 ;
each R 8 is a straight or branched alkylene chain; and
each R 9 is hydrogen or alkyl.
14. The pharmaceutical composition of claim 13 comprising a pharmaceutically acceptable carrier, diluent or excipient and a compound of formula (Ia) wherein:
n is 0;
R 3 and R 4 are each —NH 2 ;
R 5 is phenyl optionally substituted with one or more substituents selected from the group consisting of alkyl, nitro, —OR 6 , —R 8 —OR 6 , —C(O)OR 6 , —C(O)N(R 6 ) 2 , —N(R 7 ) 2 , —R 8 —N(R 7 ) 2 , and —N(R 9 )C(O)R 6 ;
each R 6 is independently hydrogen, alkyl, aryl, or aralkyl;
each R 7 is independently hydrogen, alkyl, haloalkyl, aryl, aralkyl, —R 8 —OR 9 , or heterocyclyl optionally substituted by —C(O)N(R 9 ) 2 ;
each R 8 is a straight or branched alkylene chain; and
each R 9 is hydrogen or alkyl.
15. The pharmaceutical composition of claim 14 comprising a pharmaceutically acceptable carrier, diluent or excipient and a compound selected from the group consisting of the following:
5-{4-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]benzylamino}-[2,1,3]-thiadiazole-4-carboxylic acid amide;
4-[(3-nitrophenyl)hydrazono]-4H-pyrazole-3,5-diamine;
4-[(4-methoxy-3-nitrophenyl)hydrazono]-4H-pyrazole-3,5-diamine;
4-[(4-nitro-3-trifluoromethylphenyl)hydrazono]-4H-pyrazole-3,5-diamine;
4-[(4-phenylaminophenyl)hydrazono]-4H-pyrazole-3,5-diamine;
4-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]-2-diethylaminomethylphenol;
4-[(2-methyl-5-nitrophenyl)hydrazono]-4H-pyrazole-3,5-diamine;
{3-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]-5-nitrophenyl}methanol;
4-[(3-diethylaminomethylphenyl)hydrazono]-4H-pyrazole-3,5-diamine; and
4-[(3-dimethylaminomethylphenyl)hydrazono]-4H-pyrazole-3,5-diamine.
16. The pharmaceutical composition of claim 3 comprising a pharmaceutically acceptable carrier, diluent or excipient and a compound of formula (Ia) wherein:
n is 0;
R 3 and R 4 are each —NH 2 ;
R 5 is phenyl optionally substituted with one or more substituents selected from the group consisting of —S(O) 2 OH, —S(O) t R 7 (where t is 0 to 2), —S(O) t —R 8 —OR 6 , —S(O) t —N(R 6 ) 2 , and —R 8 —P(O)(OR 9 ) 2 ,
each R 6 is independently hydrogen, alkyl, aryl, aralkyl, hetereocyclyl or heterocyclylalkyl;
each R 7 is independently hydrogen, alkyl, haloalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, or —R 8 —OR 9 ;
each R 8 is a straight or branched alkylene chain; and
each R 9 is hydrogen or alkyl.
17. The pharmaceutical composition of claim 16 comprising a pharmaceutically acceptable carrier, diluent or excipient and a compound selected from the group consisting of the following:
4-[M-(3,5-diaminopyrazol-4-ylidene)hydrazino]-N-(2,6-dimethylpyrimidin-4-yl)benzenesulfonamide;
4-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]benzenesulfonamide;
4-[(3-methylsulfanylphenyl)hydrazono]-4H-pyrazole-3,5-diamine;
4-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]-N-(pyrimidin-2-yl)benzenesulfonamide;
1-{3-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]phenyl}ethanethione;
{4-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]benzyl}phosphonic acid diethyl ester;
3-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]benzenesulfonamide;
4-[(4-trifluoromethanesulfonylphenyl)hydrazono]-4H-pyrazole-3,5-diamine;
4-[(4-methanesulfonylphenyl)hydrazono]-4H-pyrazole-3,5-diamine;
N-butyl-3-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]benzenesulfonamide;
4-[(3-methanesulfonylphenyl)hydrazono]-4H-pyrazole-3,5-diamine;
4-{[4-(morpholine-4-sulfonyl)phenyl]hydrazono}-4H-pyrazole-3,5-diamine;
4-{[4-(pyrrolidine-1-sulfonyl)phenyl]hydrazono}-4H-pyrazole-3,5-diamine;
4-[(3-trifluoromethanesulfonylphenyl)hydrazono]-4H-pyrazole-3,5-diamine;
2-{3-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]benzenesulfonyl}ethanol;
4-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]-N-methylbenzenesulfonamide;
3-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]-N-methylbenzenesulfonamide;
4-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]-N-ethylbenzenesulfonamide;
3-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]-N-ethylbenzenesulfonamide; and
3-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]-N-(2-hydroxyethyl)benzenesulfonamide.
18. The pharmaceutical composition of claim 3 comprising a pharmaceutically acceptable carrier, diluent or excipient and a compound of formula (Ia) wherein:
n is 0;
R 3 and R 4 are each —NH 2 ;
R 5 is phenyl optionally substituted with one or more substituents selected from the group consisting of alkyl, nitro, halo, haloalkyl, heterocyclyl, heterocyclylalkyl (optionally substituted by alkyl), and —OR 6 ; and
R 6 is hydrogen or alkyl.
19. The pharmaceutical composition of claim 18 comprising a pharmaceutically acceptable carrier, diluent or excipient and a compound of formula (Ia) wherein:
n is 0;
R 3 and R 4 are each —NH 2 ;
R 5 is phenyl optionally substituted with one or more substituents selected from the group consisting of alkyl, nitro, halo, haloalkyl, morpholinyl, piperidinyl, morpholinylmethyl, morpholinylethyl, pyrrolidinylmethyl, piperidinylmethyl, piperazinylmethyl (optionally substituted by alkyl), and —OR 6 ; and
R 6 is hydrogen or alkyl.
20. The pharmaceutical composition of claim 19 comprising a pharmaceutically acceptable carrier, diluent or excipient and a compound selected from the group consisting of the following:
4-[(4-morpholin-4-ylphenyl)hydrazono]-4H-pyrazole-3,5-diamine;
4-[(3-chloro-4-(morpholin-4-yl)phenyl)hydrazono]-4H-pyrazole-3,5-diamine;
4-[(4-(piperidin-1yl)phenyl)hydrazono]-4H-pyrazole-3,5-diamine;
4-[(3-(morpholin-4-ylmethyl)phenyl)hydrazono]-4H-pyrazole-3,5-diamine;
4-[(3-(piperidin-1-ylmethyl)phenyl)hydrazono]-4H-pyrazole-3,5-diamine;
4-[(4-methyl-3-(morpholin-4-yl)phenyl)hydrazono]-4H-pyrazole-3,5-diamine;
4-[(4-methoxy-3-(morpholin-4-yl)methylphenyl)hydrazono]-4H-pyrazole-3,5-diamine;
4-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]-2-(morpholin-4-yl)methylphenol;
4-[(2-methyl-4-(morpholin-4-yl)phenyl)hydrazono]-4H-pyrazole-3,5-diamine;
4-[(4-fluoro-2-(morpholin-4-ylmethyl)phenyl)hydrazono]-4H-pyrazole-3,5-diamine;
4-[(3-(morpholin-4-ylmethyl)-5-trifluoromethylphenyl)hydrazono]-4H-pyrazole-3,5-diamine;
4-[(3-fluoro-4-(morpholin-4-ylmethyl)phenyl)hydrazono]-4H-pyrazole-3,5-diamine;
4-[(4-(morpholin-4-ylmethyl)phenyl)hydrazono]-4H-pyrazole-3,5-diamine;
4-{[4-((4-methylpiperazin-1-yl)methyl)phenyl]hydrazono}-4H-pyrazole-3,5-diamine;
4-{[3-((4-methylpiperazin-1-yl)methyl)phenyl]hydrazono}-4H-pyrazole-3,5-diamine;
4-[(3-morpholin-4-ylmethyl)-5-nitrophenyl)hydrazono]-4H-pyrazole-3,5-diamine;
4-{[4-(2-(morpholin-4-yl)ethyl)phenyl]hydrazono}-4H-pyrazole-3,5-diamine;
4-[(3-(pyrrolidin-1-ylmethyl)phenyl)hydrazono]-4H-pyrazole-3,5-diamine; and
4-[(4-(piperidin-1-ylmethyl)phenyl)hydrazono]-4H-pyrazole-3,5-diamine.
21. The pharmaceutical composition of claim 1 comprising a pharmaceutically acceptable carrier, diluent or excipient and a compound of formula (Ia) wherein:
n is 0 to 5;
R 3 and R 4 are each independently —N(R 7 ) 2 or —N(R 7 )C(O)R 6 ;
R 5 is heterocyclyl optionally substituted with one or more substituents selected from the group consisting of alkyl, halo, nitro, cyano, haloalkyl, haloalkoxy, aryl, heterocyclyl, heterocyclylalkyl, —OR 6 , —R 8 —OR 6 , —R 8 —[O—R 8 ] m —OR 6 (where m is 1 to 4), —S(O) 2 OH, —S(O) t R 7 (where t is 0 to 2), —S(O) t —R 8 —OR 6 , —S(O) t —N(R 6 ) 2 , —R 8 —P(O)(OR 9 ) 2 , —C(O)OR 6 , —R 8 —C(O)OR 6 , —C(O)N(R 6 ) 2 , —N(R 7 ) 2 , —R 8 —N(R 7 ) 2 , and —N(R 9 )C(O)R 6 ;
each R 6 is independently hydrogen, alkyl, aryl, aralkyl, hetereocyclyl or heterocyclylalkyl;
each R 7 is independently hydrogen, alkyl, haloalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, or —R 8 —OR 9 ;
each R 8 is a straight or branched alkylene chain; and
each R 9 is hydrogen or alkyl.
22. The pharmaceutical composition of claim 21 comprising a pharmaceutically acceptable carrier, diluent or excipient and a compound of formula (Ia) wherein:
n is 0;
R 3 and R 4 are each independently —N(R 7 ) 2 ;
R 5 is heterocyclyl optionally substituted with one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, heterocyclyl, heterocyclylalkyl, —OR 6 , and —N(R 7 ) 2 ;
R 6 is alkyl, aryl, aralkyl, hetereocyclyl or heterocyclylalkyl;
each R 7 is independently hydrogen, alkyl, haloalkyl, aryl, aralkyl, or —R 8 —OR 9 ;
each R 8 is a straight or branched alkylene chain; and
each R 9 is hydrogen or alkyl.
23. The pharmaceutical composition of claim 22 comprising a pharmaceutically acceptable carrier, diluent or excipient and a compound of formula (Ia) wherein:
n is 0;
R 3 and R 4 are each independently —N(R 7 ) 2 ;
R 5 is heterocyclyl optionally substituted with one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, —OR 6 , —N(R 7 ) 2 , morpholinyl, piperidinyl, and piperazinyl (optionally substituted by alkyl);
R 6 is hydrogen, alkyl, aryl, or aralkyl;
each R 7 is independently hydrogen, alkyl, haloalkyl, aryl, aralkyl, or —R 8 —OR 9 ;
each R 8 is a straight or branched alkylene chain; and
each R 9 is hydrogen or alkyl.
24. The pharmaceutical composition of claim 23 comprising a pharmaceutically acceptable carrier, diluent or excipient and a compound of formula (Ia) selected from the group consisting of the following:
4-[(4H-[1,2,4]-triazol-3-yl)hydrazono]-4H-pyrazole-3,5-diamine;
4-[(1H-pyrazol-3-yl)hydrazono]-4H-pyrazole-3,5-diamine;
4-(pyridin-4-ylhydrazono)-4H-pyrazole-3,5-diamine;
4-[(6-methoxypyridin-3-yl)hydrazono]-4H-pyrazole-3,5-diamine;
4-[(1H-indazol-5-yl)hydrazono]-4H-pyrazole-3,5-diamine;
4-(quinolin-6-ylhydrazono)-4H-pyrazole-3,5-diamine;
4-[(6-chloropyridin-3-yl)hydrazono]-4H-pyrazole-3,5-diamine;
4-(isoquinolin-5-ylhydrazono)-4H-pyrazole-3,5-diamine;
4-(quinolin-3-ylhydrazono)-4H-pyrazole-3,5-diamine;
4-(benzo[1,2,5]thiadiazol-4-ylhydrazono)-4H-pyrazole-3,5-diamine;
4-(quinolin-8-ylhydrazono)-4H-pyrazole-3,5-diamine;
4-(quinolin-5-ylhydrazono)-4H-pyrazole-3,5-diamine;
4-[(2H-benzotriazol-5-yl)hydrazono]-4H-pyrazole-3,5-diamine;
4-[(2-methyl-2H-benzotriazol-5-yl)hydrazono]-4H-pyrazole-3,5-diamine;
4-(benzo[2,1,3]thiadiazol-5-ylhydrazono)-4H-pyrazole-3,5-diamine;
7-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]-4-trifluoromethylchroman-2-one;
4-(quinazolin-6-ylhydrazono)-4H-pyrazole-3,5-diamine;
4-[(1-methyl-1H-benzotriazol-5-yl)hydrazono]-4H-pyrazole-3,5-diamine;
4-[(3-methyl-3H-benzotriazol-5-yl)hydrazono]-4H-pyrazole-3,5-diamine;
4-[(2,2-difluorobenzo[1,3]dioxol-5-yl)hydrazono]-4H-pyrazole-3,5-diamine;
4-[(2,2,3,3-tetrafluoro-2,3-dihydrobenzo[1,4]dioxin-6-yl)hydrazono]-4H-pyrazole-3,5-diamine;
4-[(1,1-dioxo-1H-benzo[b]thiophen-6-yl)hydrazono]-4H-pyrazole-3,5-diamine;
4-(phthalazin-5-ylhydrazono)-4H-pyrazole-3,5-diamine;
4-[(6-(piperidin-1-yl)pyridin-3-yl)hydrazono]-4H-pyrazole-3,5-diamine;
4-[(6-(morpholin-4-yl)pyridin-3-yl)hydrazono]-4H-pyrazole-3,5-diamine;
4-{[6-(4-methylpiperazin-1-yl)pyridin-3-yl]hydrazono}-4H-pyrazole-3,5-diamine;
2-[{5-[N′-(3,5-diaminopyrazol-4-ylidene)hydrazino]pyridin-2-yl}(2-hydroxyethyl)amino]ethanol;
4-[(2,6-dimethoxypyridin-3-yl)hydrazono]-4H-pyrazole-3,5-diamine;
4-[(2,6-dichloropyridin-3-yl)hydrazono]-4H-pyrazole-3,5-diamine;
4-[(6-fluoropyridin-3-yl)hydrazono]-4H-pyrazole-3,5-diamine; and
4-[(4-methylpyridin-3-yl)hydrazono]-4H-pyrazole-3,5-diamine.
25. A pharmaceutical composition comprising a pharmaceutically acceptable carrier, diluent or excipient and a compound of formula (Ib):
wherein:
n is 0 to 5;
R 1 is hydrogen, alkyl, aryl, aralkyl or —C(O)R 6 ;
R 3 and R 4 are each independently —N(R 7 ) 2 or —N(R 7 )C(O)R 6 ;
R 5 is aryl optionally substituted with one or more substituents selected from the group consisting of alkyl, halo, nitro, cyano, haloalkyl, haloalkoxy, aryl, heterocyclyl, heterocyclylalkyl, —OR 6 , —R 8 —OR 6 , —R 8 —[O—R 8 ] m —OR 6 (where m is 1 to 4), —S(O) 2 OH, —S(O) t R 7 (where t is 0 to 2), —S(O) t —R 8 —OR 8 , —S(O) t —N(R 6 ) 2 , —R 8 —P(O)(OR 9 ) 2 , —C(O)OR 6 , —R 8 —C(O)OR 6 , —C(O)N(R 6 ) 2 , —N(R 7 ) 2 , —R 8 —N(R 7 ) 2 , and —N(R 9 )C(O)R 6 ;
or R 5 is heterocyclyl optionally substituted with one or more substituents selected from the group consisting of alkyl, halo, nitro, cyano, haloalkyl, haloalkoxy, aryl, heterocyclyl, heterocyclylalkyl, —OR 6 , —R 8 —OR 6 , —R 8 —[O—R 8 ] m —OR 6 (where m is 1 to 4), —S(O) 2 OH, —S(O) t R 7 (where t is 0 to 2), —S(O) t —R 8 —OR 6 , —S(O) t —N(R 6 ) 2 , —R 8 —P(O)(OR 9 ) 2 , —C(O)OR 6 , —R 8 —C(O)OR 6 , —C(O)N(R 6 ) 2 , —N(R 7 ) 2 , —R 8 —N(R 7 ) 2 , and —N(R 9 )C(O)R 6 ;
each R 6 is independently hydrogen, alkyl, aryl, aralkyl, hetereocyclyl or heterocyclylalkyl;
each R 7 is independently hydrogen, alkyl, haloalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, or —R 8 —OR 9 ;
each R 8 is a straight or branched alkylene chain; and
each R 9 is hydrogen or alkyl,
as a single stereoisomer, a mixture of stereoisomers, a solvate or a polymorph; or a pharmaceutically acceptable salt thereof.
26. The pharmaceutical composition of claim 25 comprising a pharmaceutically acceptable carrier, diluent or excipient and a compound of formula (Ib) wherein:
n is 0;
R 1 is hydrogen, alkyl, aryl, aralkyl or —C(O)R 6 ;
R 3 and R 4 are each independently —N(R 7 ) 2 ;
R 5 is phenyl optionally substituted with one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, haloalkoxy, or aryl;
or R 5 is pyridinyl or isoquinolinyl;
R 6 is alkyl, aryl, or aralkyl; and
each R 7 is independently hydrogen or alkyl.
27. The pharmaceutical composition of claim 26 comprising a pharmaceutically acceptable carrier, diluent or excipient and a compound of formula (Ib) selected from group consisting of the following:
1-benzyl-4-phenylazo-1H-pyrazole-3,5-diamine;
1-{2-[3,5-diamino-4-(pyridin-3-ylazo)pyrazol-1-yl]-2-oxoethyl}pyrrolidine-2-carboxylic acid methyl ester; and
4-(isoquinolin-5-ylazo)-1-methyl-1H-pyrazole-3,5-diamine.
28. A pharmaceutical composition comprising a pharmaceutically acceptable carrier, diluent or excipient and a compound of formula (Ia):
wherein:
n is 0;
R 3 and R 4 are each —NH 2 ; and
R 5 is phenyl substituted at the 4-position by fluoro and at the 3-position by trifluoromethyl, namely, 4-[(4-fluoro-3-trifluoromethylphenyl)hydrazono]-4H-pyrazole-3,5-diamine,
as a single stereoisomer, a mixture of stereoisomers, a solvate or a polymorph; or a pharmaceutically acceptable salt thereof.
29. A compound of formula (Ia):
wherein:
n is 0;
R 3 and R 4 are each —NH 2 ; and
R 5 is phenyl substituted at the 4-position by fluoro and at the 3-position by trifluoromethyl, namely, 4-[(4-fluoro-3-trifluoromethylphenyl)hydrazono]-4H-pyrazole-3,5-diamine,
as a single stereoisomer, a mixture of stereoisomers, a solvate or a polymorph; or a pharmaceutically acceptable salt thereof.