Substituted Nicotinamide Compounds

1 . A compound represented by the following structural Formula:

wherein

X 1 is selected from CH or N;

X 2 is selected from CH, N or N-oxide;

is a 5 or 6-membered aryl or heteroaryl;

R 1 , R 2 , R 5 and R 6 are independently selected from

1) hydrogen, or

2) C 1 -C 6 alkyl;

wherein R 1 and R 2 can be combined to form the moiety (CH 2 ) n , where n is 2 or 3; or

wherein R 1 and R 5 can be combined to form the moiety (CH 2 ) n , where n is 1, 2 or 3;

R 3 is selected from

1) C 1 -C 6 alkyl, or

2) (CR 10 2 ) a R 9 ;

wherein R 3 and R 5 , or R 3 and R 6 , can be combined to form the moiety (CH 2 ) n ,

where n is 1, 2 or 3;

R 4 is selected from

1) hydrogen,

2) C 1 -C 6 alkyl,

3) C(O)OR 7 ,

4) S(O) 2 R 7 ,

5) C(O)NR 10 R 7 , or

6) C(O)R 7 ;

wherein R 3 and R 4 can be combined to form the moiety to (CH 2 ) n , where n is 3 or 4;

R 7 is independently selected from

1) H,

2) C 1 -C 6 alkyl, or

3) (CR 10 2 ) a R 9 ;

R 8 is independently selected from

1) unsubstituted or substituted aryl,

2) unsubstituted or substituted heteroaryl,

3) halo,

4) CN,

5) amide,

6) carboxyl,

7) C 1 -C 7 alkyl,

8) C 1 -C 7 alkoxy,

9) C 1 -C 7 haloalkyl,

10) C 1 -C 7 haloalkyloxy,

11) C 1 -C 7 hydroxyalkyl,

12) C 1 -C 7 alkenyl,

13) C 1 -C 7 alkynyl,

14) C 1 -C 7 alkyl-C(═O)O—,

15) C 1 -C 7 alkyl-C(═O)—,

16) hydroxyalkoxy,

17) —NHSO 2 ,

18) —SO 2 NH,

19) C 1 -C 7 alkyl-NHSO 2 —,

20) C 1 -C 7 alkyl-SO 2 NH—,

21) C 1 -C 7 alkylsulfonyl,

22) C 1 -C 7 alkylamino,

23) di(C 1 -C 7 )alkylamino, or

24) L 1 -R 12 ,

R 9 is aryl, which may be optionally substituted with unsubstituted or substituted C 1 -C 6 alkyl, halo or OR 10 ;

R 10 is independently selected from

1) hydrogen, or

2) unsubstituted or substituted C 1 -C 6 alkyl;

R 11 is independently selected from

1) NH 2 ,

2) OR 10 , or

3) SH;

L 1 is selected from

1) a bond,

2) C 1 -C 4 alkylene,

3) C 1 -C 4 alkynyl,

4) C 1 -C 4 alkenyl,

5) —O—,

6) —S—,

7) —NH—,

8) —C(═O)NH—,

9) —NHC(═O)—,

10) —NHC(═O)NH—,

11) —SO 2 NH—,

12) —NHSO 2 —,

13) —SO 2 —,

14) —C(═O)— or

15) —C(═O)O—;

R 12 is selected from:

1) substituted or unsubstituted heteroaryl,

2) substituted or unsubstituted heterocyclyl,

3) substituted or unsubstituted aryl, or

4) substituted or unsubstituted C 3 -C 8 cycloalkyl;

a is independently selected from 0, 1, or 2;

p is selected from 0, 1, 2, 3 or 4;

or a stereoisomer or a pharmaceutically acceptable salt thereof.

2 . The compound of Formula I, according to claim 1 , wherein

X 1 is selected from CH or N;

X 2 is selected from CH or N;

is selected from:

1) phenyl, or

2) pyrazolyl;

R 8 is independently selected from

1) unsubstituted or substituted aryl,

2) unsubstituted or substituted heteroaryl,

3) halo,

4) C 1 -C 7 alkyl,

5) C 1 -C 7 alkoxy,

6) C 1 -C 7 haloalkyl,

7) C 1 -C 7 haloalkyloxy,

8) C 1 -C 7 hydroxyalkyl, or

9) hydroxyalkoxy;

R 12 is selected from:

1) substituted or unsubstituted heteroaryl, or

2) substituted or unsubstituted aryl;

or a stereoisomer or a pharmaceutically acceptable salt thereof.

3 . The compound according to claim 1 , of Formula IA wherein

X 1 is selected from CH or N;

X 2 is selected from CH or N;

R 8 is independently selected from

1) unsubstituted or substituted aryl,

2) unsubstituted or substituted heteroaryl,

3) halo,

4) C 1 -C 7 alkyl,

5) C 1 -C 7 alkoxy,

6) C 1 -C 7 haloalkyl,

7) C 1 -C 7 haloalkyloxy,

8) C 1 -C 7 hydroxyalkyl, or

9) hydroxyalkoxy;

or a stereoisomer or a pharmaceutically acceptable salt thereof.

4 . The compound according to claim 1 , of Formula IB wherein

X 1 is selected from CH or N;

X 2 is selected from CH or N;

R is H or halo;

R 8 is independently selected from

1) unsubstituted or substituted aryl,

2) unsubstituted or substituted heteroaryl,

3) halo,

4) C 1 -C 7 alkyl,

5) C 1 -C 7 alkoxy,

6) C 1 -C 7 haloalkyl,

7) C 1 -C 7 haloalkyloxy,

8) C 1 -C 7 hydroxyalkyl, or

9) hydroxyalkoxy;

or a stereoisomer or a pharmaceutically acceptable salt thereof.

5 . The compound according to claim 1 , represented by Formula II

wherein

R 2 and R 6 are independently selected from

1) hydrogen, or

2) C 1 -C 6 alkyl;

R 3 is selected from

1) C 1 -C 6 alkyl, or

2) (CR 10 2 ) a R 9 ;

R 4 is selected from

1) hydrogen,

2) C 1 -C 6 alkyl,

3) C(O)OR 7 ,

4) S(O) 2 R 7 ,

5) C(O)NR 10 R 7 , or

6) C(O)R 7 ;

n is selected from 1, 2 or 3;

or a stereoisomer or a pharmaceutically acceptable salt thereof.

6 . The compound of Formula II, according to claim 5 , wherein

is selected from:

1) phenyl, or

2) pyrazolyl;

or a stereoisomer or a pharmaceutically acceptable salt thereof.

7 . A compound selected from

benzyl-(2S)-4-(5-{[(2-aminophenyl)amino]carbonyl}pyridin-2-yl)-2-methylpiperazine-1-carboxylate;

benzyl-(2R)-4-(5-{[(2-aminophenyl)amino]carbonyl}pyridin-2-yl)-2-methylpiperazine-1-carboxylate;

N-(2-aminophenyl)-6-[(3S)-3-methylpiperazin-1-yl]nicotinamide;

N-(2-aminophenyl)-6-(trans-2,5-dimethylpiperazin-1-yl)nicotinamide;

benzyl 4-(5-{[(2-aminophenyl)amino]carbonyl}pyridin-2-yl)-trans-2,5-dimethylpiperazine-1-carboxylate;

N-(2-aminophenyl)-6-[(3S)-3-isopropylpiperazin-1-yl]nicotinamide;

benzyl-(2S)-4-(5-{[(2-aminophenyl)amino]carbonyl}pyridin-2-yl)-2-isopropylpiperazine-1-carboxylate;

(2S)-4-(5-{[(2-aminophenyl)amino]carbonyl}pyridin-2-yl)-2-methylpiperazine-1-carboxylate;

N-(2-aminophenyl)-6-[(3S)-3-benzylpiperazin-1-yl]nicotinamide;

tert-butyl-(2S)-4-(5-{[(2-aminophenyl)amino]carbonyl}pyridin-2-yl)-2-benzylpiperazine-1-carboxylate;

N-(2-aminophenyl)-6-(cis-3,5-dimethylpiperazin-1-yl)nicotinamide;

benzyl 5-(5-{[(2-aminophenyl)amino]carbonyl}pyridin-2-yl)-2,5-diazabicyclo[4.2.0]octane-2-carboxylate;

benzyl 4-(5-{[(2-aminophenyl)amino]carbonyl}pyridin-2-yl)-2,2-dimethylpiperazine-1-carboxylate;

N-(2-aminophenyl)-6-[3,3-dimethyl-4-(3-phenylpropanoyl)piperazin-1-yl]nicotinamide;

N-(2-aminophenyl)-6-[3,3-dimethyl-4-(phenylacetyl)piperazin-1-yl]nicotinamide;

N-(2-aminophenyl)-6-(4-benzoyl-3,3-dimethylpiperazin-1-yl)nicotinamide;

N-(2-aminophenyl)-6-[3,3-dimethyl-4-(phenylsulfonyl)piperazin-1-yl]nicotinamide;

N-(2-aminophenyl)-6-(3,3-dimethylpiperazin-1-yl)nicotinamide hydrochloride;

N-(2-aminophenyl)-6-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)nicotinamide;

N-(2-aminophenyl)-6-(octahydro-2H-pyrido[1,2-a]pyrazin-2-yl)nicotinamide;

benzyl-(2S)-4-(5-{[(2-aminophenyl)amino]carbonyl}-1-oxidopyridin-2-yl)-2-methylpiperazine-1-carboxylate;

(2S)-4-(5-{[(2-aminophenyl)amino]carbonyl}pyridin-2-yl)-2-methyl-N-phenylpiperazine-1-carboxamide;

(2S)-4-(5-{[(2-aminophenyl)amino]carbonyl}pyridin-2-yl)-N-benzyl-2-methylpiperazine-1-carboxamide;

(2S)-4-(5-{[(2-aminophenyl)amino]carbonyl}pyridin-2-yl)-2-methyl-N-[(1S)-1-phenylethyl]piperazine-1-carboxamide;

(2S)-4-(5-{[(2-aminophenyl)amino]carbonyl}pyridin-2-yl)-2-methyl-N-[(1R)-1-phenylethyl]piperazine-1-carboxamide;

(2S)-4-(5-{[(2-aminophenyl)amino]carbonyl}pyridin-2-yl)-N-(4-methoxybenzyl)-2-methylpiperazine-1-carboxamide;

(2S)-4-(5-{[(2-aminophenyl)amino]carbonyl}pyridin-2-yl)-2-methyl-N-[(2-phenylethyl]piperazine-1-carboxamide;

N-(2-aminophenyl)-6-[(1R,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]nicotinamide;

tert-butyl-(1S,4S)-5-(5-{[(2-aminophenyl)amino]carbonyl}pyridin-2-yl)-2,5-diazabicyclo [2.2.1]heptane-2-carboxylate;

benzyl-(1S,4S)-5-(5-{[(2-aminophenyl)amino]carbonyl}pyridin-2-yl)-2,5-diazabicyclo [2.2.1]heptane-2-carboxylate;

N-(2-aminophenyl)-6-[(1S,4S)-5-(3-phenylpropanoyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]nicotinamide;

N-(2-aminophenyl)-6-[(1S,4S)-5-benzyl-2,5-diazabicyclo[2.2.1]hept-2-yl]nicotinamide;

N-(2-aminophenyl)-6-[(1S,4S)-5-(4-chlorophenyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]nicotinamide;

N-(2-aminophenyl)-6-[(1S,4S)-5-(4-fluorophenyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]nicotinamide;

N-(2-aminophenyl)-6-(2,5-diazabicyclo[2.2.2]oct-2-yl)nicotinamide;

tert-butyl-5-(5-{[(2-aminophenyl)amino]carbonyl}pyridin-2-yl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylate;

benzyl-5-(5-{[(2-aminophenyl)amino]carbonyl}pyridin-2-yl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylate;

pyridin-3-ylmethyl-5-(5-{[(2-aminophenyl)amino]carbonyl}pyridin-2-yl)-2,5-diazabicyclo [2.2.2]octane-2-carboxylate;

tert-butyl 3-(5-{[(2-aminophenyl)amino]carbonyl}pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate;

benzyl 3-(5-{[(2-aminophenyl)amino]carbonyl}pyridin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate;

benzyl-(2S)-4-(5-{[(2-aminophenyl)amino]carbonyl}pyrimidin-2-yl)-2-methylpiperazine-1-carboxylate;

benzyl-(1S,4S)-5-(5-{[(2-aminophenyl)amino]carbonyl}pyrimidin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate;

benzyl-(2S)-4-(4-{[(2-aminophenyl amino]carbonyl}phenyl)-2-methylpiperazine-1-carboxylate;

benzyl-(2R)-4-(4-{[(2-aminophenyl amino]carbonyl}phenyl)-2-methylpiperazine-1-carboxylate;

benzyl-(1S,4S)-5-(4-{[(2-aminophenyl)amino]carbonyl}phenyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate;

benzyl-(2S)-4-(5-{[(4-aminobiphenyl-3-yl)amino]carbonyl}pyridin-2-yl)-2-methylpiperazine-1-carboxylate;

benzyl-(2S)-4-(5-{[(4-amino-1-phenyl-1H-pyrazol-3-yl)amino]carbonyl}pyridin-2-yl)-2-methylpiperazine-1-carboxylate;

or a stereoisomer or a pharmaceutically acceptable salt thereof.

8 . A compound selected from

benzyl 5-(5-{[(2-aminophenyl)amino]carbonyl}pyridin-2-yl)-2,5-diazabicyclo[4.2.0]octane-2-carboxylate trifluoroacetate;

N-(2-aminophenyl)-6-(2,5-diazabicyclo[2.2.2]oct-2-yl)nicotinamide hydrochloride;

benzyl-5-(5-{[(2-aminophenyl)amino]carbonyl}pyridin-2-yl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylate bis-trifluoroacetate;

pyridin-3-ylmethyl-5-(5-{[(2-aminophenyl)amino]carbonyl}pyridin-2-yl)-2,5-diazabicyclo [2.2.2]octane-2-carboxylate trifluoroacetate;

benzyl-(2S)-4-(5-{[(2-aminophenyl)amino]carbonyl}pyrimidin-2-yl)-2-methylpiperazine-1-carboxylate trifluoroacetate; or

benzyl-(2R)-4-(4-{[(2-aminophenyl amino]carbonyl}phenyl)-2-methylpiperazine-1-carboxylate trifluoroacetate.

9 . A pharmaceutical composition comprising a pharmaceutically effective amount of the compound according to claim 1 , and a pharmaceutically acceptable carrier.

10 . A method for the treatment or prevention of cancer in a mammal comprising the step of administering to a mammal a therapeutically effective amount of the compound of claim 1 .