IP Library › Granted Patent US 8,088,760

Granted Patent B2

US 8,088,760 · App. 12/355,692 · Granted Jan 3, 2012

Benzoxazole carboxamide inhibitors of poly(ADP-ribose)polymerase (PARP)

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Quick Facts

Patent No.: US 8,088,760
App. No.: 12/355,692
Granted: Jan 3, 2012
Kind: B2

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Abstract

A compound having the structure set forth in Formula (I) or Formula (II): wherein the variables Y, R 1 , R 2 , R 3 , and R 4 are as defined herein. Provided herein are inhibitors of poly(ADP-ribose)polymerase activity. Also described herein are pharmaceutical compositions that include at least one compound described herein and the use of a compound or pharmaceutical composition described herein to treat diseases, disorders and conditions that are ameliorated by the inhibition of PARP activity.

Claims (273)

1. A compound of Formula (I) or Formula (II):

wherein:

Y is selected from the group consisting of

a) an aryl group optionally substituted with 1, 2, or 3 R 5 ; wherein each R 5 is selected independently from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, cyano, haloalkoxy, haloalkyl, halogen, hydroxyl, hydroxyalkyl, nitro, oxo, heteroaryl, heteroarylalkyl, heteroarylalkoxy, heteroaryloxy, heteroarylthio, heteroarylalkylthio, heterocycle, heterocycloalkoxy, heterocycloalkylthio, heterocyclooxy, heterocyclothio, NR A R B , (NR A R B )alkyl, (NR A R B )carbonyl, (NR A R B )carbonylalkyl, and (NR A R B )sulfonyl, wherein when Y is phenyl, the phenyl is substituted with at least one substituent selected independently from the group consisting of alkoxyalkyl, heteroaryl, heteroarylalkoxy, heteroaryloxy, heteroarylthio, heteroarylalkylthio, heterocycle, heterocycloalkoxy, heterocycloalkylthio, heterocyclooxy, heterocyclothio, and (NR A R B )alkyl;

b) a heteroaryl group optionally substituted with 1, 2, or 3 R 5 ; wherein each R 5 is as previously defined;

c) a L-T group where L is selected from the group consisting of alkenylene, alkylene, alkynylene, cycloalkylene and spiroheterocycle and T is selected from the group consisting of heteroaryl, heteroarylalkoxy, heteroaryloxy, heteroarylthio, heteroarylalkylthio, heterocycle, heterocycloalkoxy, heterocycloalkylthio, heterocyclooxy, heterocyclothio, and NR A R B ;

d) a non-aromatic 4, 5, 6, 7, 8, 9, 10, 11, or 12-membered monocyclic or bicyclic heterocycle ring having 1 or 2 nitrogen atoms and, optionally, one sulfur or oxygen atom, wherein the heterocycle is optionally substituted with 1, 2, or 3 R 6 ; wherein each R 6 is selected independently from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, cyano, haloalkoxy, haloalkyl, halogen, hydroxyl, hydroxyalkyl, nitro, oxo, heteroaryl, heteroarylalkyl, heteroarylalkoxy, heteroaryloxy, heteroarylthio, heteroarylalkylthio, heterocycle, heterocycloalkoxy, heterocycloalkylthio, heterocyclooxy, heterocyclothio, NR A R B , (NR A R B )alkyl, (NR A R B )carbonyl, (NR A R B )carbonylalkyl, and (NR A R B )sulfonyl and wherein when the heterocycle is bicyclic, the optional substituent(s) are attached to either one or both of the cyclic rings;

R 1 , R 2 , and R 3 , are each independently selected from the group consisting of hydrogen, halogen, alkenyl, alkoxy, alkoxycarbonyl, alkyl, cycloalkyl, alkynyl, cyano, haloalkoxy, haloalkyl, hydroxyl, hydroxyalkyl, nitro, NR C R D , and (NR C R D )carbonyl;

each R A , R B , R C , and R D is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, and alkylcarbonyl;

R 4 , is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkoxyalkyl, haloalkyl, hydroxyalkyl, and (NR A R B )alkyl; or

stereoisomers, and salts thereof.

2. The compound of claim 1 , wherein:

R C , and R D are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, and alkylcarbonyl;

R 4 , is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkoxyalkyl, haloalkyl, hydroxyalkyl, and (NR A R B )alkyl;

Y is selected from the group consisting of:

b) a heteroaryl group optionally substituted with 1, 2, or 3 R 5 ; wherein each R 5 is as previously defined;

d) a non-aromatic 4, 5, 6, 7, 8, 9, 10, 11, or 12-membered monocyclic or bicyclic heterocycle ring having 1 or 2 nitrogen atoms and, optionally, one sulfur or oxygen atom; selected from the group consisting of

wherein

n is 0, 1, 2 or 3;

m is 0, 1, 2 or 3;

p is 0, 1, 2 or 3;

each R 6 is selected independently from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, cyano, haloalkoxy, haloalkyl, halogen, hydroxyl, hydroxyalkyl, nitro, oxo, heteroaryl, heteroarylalkoxy, heteroaryloxy, heteroarylthio, heteroarylalkylthio, heterocycle, heterocycloalkoxy, heterocycloalkylthio, heterocyclooxy, heterocyclothio, NR A R B , (NR A R B )alkyl, (NR A R B )carbonyl, (NR A R B )carbonylalkyl, and (NR A R B )sulfonyl;

R 7 is selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, hydroxyalkyl, oxo, heteroaryl, heterocycle, heterocycloalkyl, (NR A R B )alkyl, (NR A R B )carbonyl, (NR A R B )carbonylalkyl, and (NR A R B )sulfonyl;

R 8 is selected from the group consisting of hydrogen, alkyl, alkynyl, alkenyl, alkoxyalkyl, cycloalkyl, haloalkyl, and hydroxyl-C 2 -C 6 alkyl; and

R A , and R B are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, and alkylcarbonyl.

3. The compound of claim 1 , wherein:

R 1 , R 2 , R 3 , and R 4 are hydrogen;

Y is selected from the group consisting of

a) an aryl group optionally substituted with 1, 2, or 3 substituents R 5 ; wherein each R 5 is selected independently from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, cyano, haloalkoxy, haloalkyl, halogen, hydroxyl, hydroxyalkyl, nitro, oxo, heteroaryl, heteroarylalkyl, heteroarylalkoxy, heteroaryloxy, heteroarylthio, heteroarylalkylthio, heterocycle, heterocycloalkoxy, heterocycloalkylthio, heterocyclooxy, heterocyclothio, NR A R B , (NR A R B )alkyl, (NR A R B )carbonyl, (NR A R B )carbonylalkyl, and (NR A R B )sulfonyl, wherein when Y is phenyl, the phenyl is substituted with at least one substituent selected independently from the group consisting of alkoxyalkyl, heteroaryl, heteroarylalkoxy, heteroaryloxy, heteroarylthio, heteroarylalkylthio, heterocycle, heterocycloalkoxy, heterocycloalkylthio, heterocyclooxy, heterocyclothio, and (NR A R B )alkyl;

b) a heteroaryl group optionally substituted with 1, 2, or 3 R 5 ; wherein each R 5 is as previously defined;

wherein

n is 0, 1, 2 or 3;

m is 0, 1, 2 or 3;

p is 0, 1, 2 or 3;

R 8 is selected from the group consisting of hydrogen, alkyl, alkynyl, alkenyl, alkoxyalkyl, cycloalkyl, haloalkyl, hydroxyl-C 2 -C 6 alkyl; and

R A , and R B are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, and alkylcarbonyl.

4. The compound of claim 3 , wherein:

n is 0;

R 7 is hydrogen; and

R 8 is hydrogen.

5. The compound of claim 3 , wherein:

n is 0;

R 7 is hydrogen; and

R 8 is methyl.

6. The compound of claim 2 , wherein Y is selected from the group consisting of

R 1 , R 2 , R 3 , and R 4 are hydrogen;

n is 0; and

R 7 is selected from the group consisting of hydrogen, alkoxyalkyl, alkyl, aryl, arylalkyl, cycloalkyl, haloalkyl, (NR A R B )alkyl, and (NR A R B )sulfonyl; and

R A , and R B are each independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl.

7. The compound of claim 2 , wherein Y is selected from the group consisting of

R 1 , R 2 , R 3 , and R 4 are hydrogen;

n is 0;

R 7 is selected from the group consisting of hydrogen, alkoxyalkyl, alkyl, aryl, arylalkyl, cycloalkyl, haloalkyl, (NR A R B )alkyl, and (NR A R B )sulfonyl; and

R A , and R B are each independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl.

8. The compound of claim 2 , wherein Y is selected from the group consisting of

R 1 , R 2 , R 3 , and R 4 are hydrogen;

n is 0;

R 7 is selected from the group consisting of hydrogen, alkoxyalkyl, alkyl, aryl, arylalkyl, cycloalkyl, haloalkyl, (NR A R B )alkyl, and (NR A R B )sulfonyl; and

R A , and R B are each independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl.

9. The compound of claim 2 , wherein Y is selected from the group consisting of

R 1 , R 2 , R 3 , and R 4 are hydrogen;

m is 0, 1, 2, or 3;

n is 0;

R 7 is selected from the group consisting of hydrogen, alkoxyalkyl, alkyl, aryl, arylalkyl, cycloalkyl, haloalkyl, (NR A R B )alkyl, and (NR A R B )sulfonyl; and

R A , and R B are each independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl.

10. The compound of claim 2 , wherein Y is selected from the group consisting of

R 1 , R 2 , R 3 , and R 4 are hydrogen;

m is 0, 1, 2, or 3;

n is 0;

R 7 is selected from the group consisting of hydrogen, alkoxyalkyl, alkyl, aryl, arylalkyl, cycloalkyl, haloalkyl, (NR A R B )alkyl, and (NR A R B )sulfonyl; and

R A , and R B are each independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl.

11. The compound of claim 3 , wherein Y is

R 1 , R 2 , R 3 , and R 4 are hydrogen;

n is 0;

p is 0, 1, 2, or 3;

R 7 is selected from the group consisting of hydrogen, alkoxyalkyl, alkyl, aryl, arylalkyl, cycloalkyl, haloalkyl, (NR A R B )alkyl, and (NR A R B )sulfonyl; and

R A , and R B are each independently selected from the group consisting of hydrogen, alkyl and cycloalkyl.

12. The compound of claim 3 , wherein Y is selected from the group consisting of

R 1 , R 2 , R 3 , and R 4 are hydrogen; and

n is 0.

13. The compound of claim 3 , wherein Y is selected from the group consisting of

R 1 , R 2 , R 3 , and R 4 are hydrogen;

n is 0;

R 7 is selected from the group consisting of hydrogen, alkoxyalkyl, alkyl, aryl, arylalkyl, cycloalkyl, haloalkyl, (NR A R B )alkyl, and (NR A R B )sulfonyl;

R 8 is methyl or hydrogen; and

R A , and R B are each independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl.

14. The compound of claim 3 , wherein Y is selected from the group consisting of

R 1 , R 2 , R 3 , and R 4 are hydrogen;

n is 0;

R 7 is selected from the group consisting of hydrogen, alkoxyalkyl, alkyl, aryl, arylalkyl, cycloalkyl, haloalkyl, (NR A R B )alkyl, and (NR A R B )sulfonyl;

R 8 is methyl or hydrogen; and

R A , and R B are each independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl.

15. The compound of claim 2 , wherein Y is phenyl substituted with (NR A R B )alkyl.

16. The compound of claim 2 , wherein Y is phenyl substituted with substituted or unsubstituted heterocycle.

17. The compound of claim 2 , wherein Y is the heteroaryl group optionally substituted with 1, 2, or 3 R 5 .

18. The compound of claim 17 , wherein the heteroaryl group is a pyridinyl group.

19. The compound of claim 2 , wherein Y is the L-T group.

20. A compound selected from the group consisting of:

2-(4-((Methylamino)methyl)phenyl)benzo[d]oxazole-4-carboxamide;

2-(2-Methylpyrrolidin-2-yl)benzo[d]oxazole-4-carboxamide;

2-(4-((Methylamino)methyl)phenyl)benzo[d]oxazole-7-carboxamide;

2-(2-Methylpyrrolidin-2-yl)benzo[d]oxazole-7-carboxamide;

2-(Pyrrolidin-2-yl)benzo[d]oxazole-4-carboxamide;

2-(Pyrrolidin-2-yl)benzo[d]oxazole-7-carboxamide;

2-(7-Azabicyclo[2.2.1]heptan-1-yl)benzo[d]oxazole-4-carboxamide;

2-(7-Azabicyclo[2.2.1]heptan-1-yl)benzo[d]oxazole-7-carboxamide;

2-(2-Methyl-7-azabicyclo[2.2.1]heptan-1-yl)benzo[d]oxazole-4-carboxamide;

2-(2-Methyl-7-azabicyclo[2.2.1]heptan-1-yl)benzo[d]oxazole-7-carboxamide;

2-(2-Azabicyclo[2.1.1]hexan-1-yl)benzo[d]oxazole-4-carboxamide;

2-(2-Azabicyclo[2.1.1]hexan-1-yl)benzo[d]oxazole-7-carboxamide;

2-(6-Azabicyclo[3.2.1]octan-5-yl)benzo[d]oxazole-4-carboxamide;

2-(6-Azabicyclo[3.2.1]octan-5-yl)benzo[d]oxazole-7-carboxamide;

2-((1S,5R)-6-Azabicyclo[3.2.1]octan-5-yl)benzo[d]oxazole-4-carboxamide;

2-((1S,5R)-6-Azabicyclo[3.2.1]octan-5-yl)benzo[d]oxazole-7-carboxamide;

2-((1R,5S)-6-Azabicyclo[3.2.1]octan-5-yl)benzo[d]oxazole-4-carboxamide;

2-((1R,5S)-6-Azabicyclo[3.2.1]octan-5-yl)benzo[d]oxazole-7-carboxamide;

2-(2-Benzyl-2-azabicyclo[2.2.2]octan-1-yl)benzo[d]oxazole-4-carboxamide;

2-(2-Benzyl-2-azabicyclo[2.2.2]octan-1-yl)benzo[d]oxazole-7-carboxamide;

2-(2-Azabicyclo[2.2.2]octan-1-yl)benzo[d]oxazole-4-carboxamide;

2-(2-Azabicyclo[2.2.2]octan-1-yl)benzo[d]oxazole-7-carboxamide;

2-(4-Azaspiro[2.4]heptan-5-yl)benzo[d]oxazole-4-carboxamide;

2-(4-Azaspiro[2.4]heptan-5-yl)benzo[d]oxazole-7-carboxamide;

2-((1R,4S)-2-Methyl-2-azabicyclo[2.2.1]heptan-1-yl)benzo[d]oxazole-4-carboxamide;

2-((1R,4S)-2-Methyl-2-azabicyclo[2.2.1]heptan-1-yl)benzo[d]oxazole-7-carboxamide;

2-((1R,4S)-2-Ethyl-2-azabicyclo[2.2.1]heptan-1-yl)benzo[d]oxazole-4-carboxamide;

2-((1R,4S)-2-Ethyl-2-azabicyclo[2.2.1]heptan-1-yl)benzo[d]oxazole-7-carboxamide;

2-((1R,4S)-2-Cyclopropyl-2-azabicyclo[2.2.1]heptan-1-yl)benzo[d]oxazole-4-carboxamide;

2-((1R,4S)-2-Cyclopropyl-2-azabicyclo[2.2.1]heptan-1-yl)benzo[d]oxazole-7-carboxamide;

2-(2-Azabicyclo[2.2.1]heptan-1-yl)benzo[d]oxazole-4-carboxamide;

2-(2-Azabicyclo[2.2.1]heptan-1-yl)benzo[d]oxazole-7-carboxamide;

2-(7-Azabicyclo[2.2.1]heptan-1-yl)-5-chlorobenzo[d]oxazole-4-carboxamide;

2-(7-Azabicyclo[2.2.1]heptan-1-yl)-5-chlorobenzo[d]oxazole-7-carboxamide;

2-(2-Azabicyclo[2.2.1]heptan-1-yl)-5-chlorobenzo[d]oxazole-4-carboxamide;

2-(2-Azabicyclo[2.2.1]heptan-1-yl)-5-chlorobenzo[d]oxazole-7-carboxamide;

2-(1-Azabicyclo[2.2.1]heptan-4-yl)benzo[d]oxazole-4-carboxamide;

2-(1-Azabicyclo[2.2.1]heptan-4-yl)benzo[d]oxazole-7-carboxamide;

2-(Quinuclidin-4-yl)benzo[d]oxazole-4-carboxamide;

2-(Quinuclidin-4-yl)benzo[d]oxazole-7-carboxamide;

2-(1-Azabicyclo[3.3.1]nonan-5-yl)benzo[d]oxazole-4-carboxamide;

2-(1-Azabicyclo[3.3.1]nonan-5-yl)benzo[d]oxazole-7-carboxamide;

2-(Octahydro-1H-quinolizin-2-yl)benzo[d]oxazole-4-carboxamide;

2-(Octahydro-1H-quinolizin-2-yl)benzo[d]oxazole-7-carboxamide;

2-(Octahydro-1H-quinolizin-1-yl)benzo[d]oxazole-4-carboxamide;

2-(Octahydro-1H-quinolizin-1-yl)benzo[d]oxazole-7-carboxamide;

2-(Octahydro-1H-quinolizin-4-yl)benzo[d]oxazole-4-carboxamide;

2-(Octahydro-1H-quinolizin-4-yl)benzo[d]oxazole-7-carboxamide;

2-(Octahydro-1H-quinolizin-3-yl)benzo[d]oxazole-4-carboxamide;

2-(Octahydro-1H-quinolizin-3-yl)benzo[d]oxazole-7-carboxamide;

2-(Octahydrocyclopenta[c]pyrrol-1-yl)benzo[d]oxazole-4-carboxamide;

2-(Octahydrocyclopenta[c]pyrrol-1-yl)benzo[d]oxazole-7-carboxamide;

2-(2-Azabicyclo[2.2.1]heptan-4-yl)benzo[d]oxazole-4-carboxamide;

2-(2-Azabicyclo[2.2.1]heptan-4-yl)benzo[d]oxazole-7-carboxamide;

2-(2-Oxa-5-Azabicyclo[2.2.1]heptan-4-yl)benzo[d]oxazole-4-carboxamide;

2-(2-Oxa-5-Azabicyclo[2.2.1]heptan-4-yl)benzo[d]oxazole-7-carboxamide;

2-(2-Azabicyclo[2.2.2]octan-4-yl)benzo[d]oxazole-4-carboxamide;

2-(2-Azabicyclo[2.2.2]octan-4-yl)benzo[d]oxazole-7-carboxamide;

2-(3-Azabicyclo[3.2.0]heptan-1-yl)benzo[d]oxazole-4-carboxamide;

2-(3-Azabicyclo[3.2.0]heptan-1-yl)benzo[d]oxazole-7-carboxamide;

2-(2-Azabicyclo[3.2.0]heptan-1-yl)benzo[d]oxazole-4-carboxamide;

2-(2-Azabicyclo[3.2.0]heptan-1-yl)benzo[d]oxazole-7-carboxamide;

2-(2-Azabicyclo[3.2.0]heptan-4-yl)benzo[d]oxazole-4-carboxamide;

2-(2-Azabicyclo[3.2.0]heptan-4-yl)benzo[d]oxazole-7-carboxamide;

2-(2-Azabicyclo[3.2.0]heptan-3-yl)benzo[d]oxazole-4-carboxamide;

2-(2-Azabicyclo[3.2.0]heptan-3-yl)benzo[d]oxazole-7-carboxamide;

2-(5-Azaspiro[2.4]heptan-6-yl)benzo[d]oxazole-4-carboxamide;

2-(5-Azaspiro[2.4]heptan-6-yl)benzo[d]oxazole-7-carboxamide;

2-(4-Azaspiro[2.4]heptan-6-yl)benzo[d]oxazole-4-carboxamide;

2-(4-Azaspiro[2.4]heptan-6-yl)benzo[d]oxazole-7-carboxamide;

2-(6-Azaspiro[3.4]octan-7-yl)benzo[d]oxazole-4-carboxamide;

2-(6-Azaspiro[3.4]octan-7-yl)benzo[d]oxazole-7-carboxamide;

2-(5-Azaspiro[3.4]octan-6-yl)benzo[d]oxazole-4-carboxamide;

2-(5-Azaspiro[3.4]octan-6-yl)benzo[d]oxazole-7-carboxamide;

2-(5-Azaspiro[3.4]octan-7-yl)benzo[d]oxazole-4-carboxamide;

2-(5-Azaspiro[3.4]octan-7-yl)benzo[d]oxazole-7-carboxamide;

2-(6-Azaspiro[2.5]octan-5-yl)benzo[d]oxazole-4-carboxamide;

2-(6-Azaspiro[2.5]octan-5-yl)benzo[d]oxazole-7-carboxamide;

2-(4-Azaspiro[2.5]octan-5-yl)benzo[d]oxazole-4-carboxamide;

2-(4-Azaspiro[2.5]octan-5-yl)benzo[d]oxazole-7-carboxamide;

2-(5-Azaspiro[2.5]octan-7-yl)benzo[d]oxazole-4-carboxamide;

2-(5-Azaspiro[2.5]octan-7-yl)benzo[d]oxazole-7-carboxamide;

2-(4-Oxa-7-azaspiro[2.5]octan-5-yl)benzo[d]oxazole-4-carboxamide;

2-(4-Oxa-7-azaspiro[2.5]octan-5-yl)benzo[d]oxazole-7-carboxamide;

2-(4-Azaspiro[2.5]octan-7-yl)benzo[d]oxazole-4-carboxamide;

2-(4-Azaspiro[2.5]octan-7-yl)benzo[d]oxazole-7-carboxamide;

2-(5-Azaspiro[3.5]nonan-6-yl)benzo[d]oxazole-4-carboxamide;

2-(5-Azaspiro[3.5]nonan-6-yl)benzo[d]oxazole-7-carboxamide;

2-(6-Azaspiro[3.5]nonan-8-yl)benzo[d]oxazole-4-carboxamide;

2-(6-Azaspiro[3.5]nonan-8-yl)benzo[d]oxazole-7-carboxamide;

2-(7-Azaspiro[3.5]nonan-6-yl)benzo[d]oxazole-4-carboxamide;

2-(7-Azaspiro[3.5]nonan-6-yl)benzo[d]oxazole-7-carboxamide;

2-(5-Azaspiro[3.5]nonan-8-yl)benzo[d]oxazole-4-carboxamide;

2-(5-Azaspiro[3.5]nonan-8-yl)benzo[d]oxazole-7-carboxamide;

2-(8-Oxa-5-azaspiro[3.5]nonan-6-yl)benzo[d]oxazole-4-carboxamide;

2-(8-Oxa-5-azaspiro[3.5]nonan-6-yl)benzo[d]oxazole-7-carboxamide;

2-(5-Oxa-5-azaspiro[3.5]nonan-6-yl)benzo[d]oxazole-4-carboxamide;

2-(5-Oxa-5-azaspiro[3.5]nonan-6-yl)benzo[d]oxazole-7-carboxamide;

2-(2,3,4,6,7,9a-Hexahydro-1H-quinolizin-2-yl)benzo[d]oxazole-4-carboxamide;

2-(2,3,4,6,7,9a-Hexahydro-1H-quinolizin-2-yl)benzo[d]oxazole-7-carboxamide;

2-(Decahydropyrido[1,2-a]azepin-4-yl)benzo[d]oxazole-4-carboxamide;

2-(Decahydropyrido[1,2-a]azepin-4-yl)benzo[d]oxazole-7-carboxamide;

2-(2-fluoro-4-(pyridine-2-yl)phenyl)benzo[d]oxazole-7-carboxamide;

2-(2-fluoro-4-(piperidin-2-yl)phenyl)benzo[d]oxazole-7-carboxamide;

2-(2-fluoro-4-(1-propylpiperidin-2-yl)phenyl)benzo[d]oxazole-7-carboxamide;

2-(2-fluoro-4-(pyrrolidin-2-yl)phenyl)benzo[d]oxazole-7-carboxamide;

2-(4-((methylamino)methyl)phenyl)benzo[d]oxazole-4-carboxamide;

2-(pyridin-4-yl)benzo[d]oxazole-4-carboxamide;

2-(pyridin-3-yl)benzo[d]oxazole-4-carboxamide;

2-(4-((methylamino)methyl)phenyl)benzo[d]oxazole-7-carboxamide;

5-fluoro-2-(4-((methylamino)methyl)phenyl)benzo[d]oxazole-7-carboxamide;

2-(4-((dimethylamino)methyl)phenyl)benzo[d]oxazole-7-carboxamide;

2-(4-(piperazin-1-ylmethyl)phenyl)benzo[d]oxazole-7-carboxamide;

2-(3-((methylamino)methyl)phenyl)benzo[d]oxazole-7-carboxamide;

2-(3-((dimethylamino)methyl)phenyl)benzo[d]oxazole-7-carboxamide;

2-(3-(pyrrolidin-1-ylmethyl)phenyl)benzo[d]oxazole-7-carboxamide;

2-(3-(piperazin-1-ylmethyl)phenyl)benzo[d]oxazole-7-carboxamide;

2-(3-((2-(dimethylamino)ethylamino)methyl)phenyl)benzo[d]oxazole-7-carboxamide;

2-(pyridin-4-yl)benzo[d]oxazole-7-carboxamide;

2-(pyridin-3-yl)benzo[d]oxazole-7-carboxamide;

2-(1H-indol-2-yl)benzo[d]oxazole-7-carboxamide;

2-(4-methoxyphenylbenzo[d]oxazole-4-carboxamide;

2-(4-methoxyphenylbenzo[d]oxazole-7-carboxamide;

2-(4-((dimethylamino)methyl)phenyl)benzo[d]oxazole-4-carboxamide;

2-(4-((dimethylamino)methyl)phenyl)-5-fluorobenzo[d]oxazole-7-carboxamide;

2-(4-((methoxyamino)methyl)phenyl)benzo[d]oxazole-7-carboxamide;

2-(4-((methoxy(methyl)amino)methyl)phenyl)benzo[d]oxazole-7-carboxamide;

5-fluoro-2-(4-((methoxyamino)methyl)phenyl)benzo[d]oxazole-7-carboxamide;

5-fluoro-2-(4-((methoxy(methyl)amino)methyl)phenyl)benzo[d]oxazole-7-carboxamide;

2-(pyrrolidin-2-yl)benzo[d]oxazole-7-carboxamide;

2-(piperidin-4-yl)benzo[d]oxazole-7-carboxamide;

2-(azetidin-3-yl)benzo[d]oxazole-7-carboxamide;

2-(piperidin-3-yl)benzo[d]oxazole-7-carboxamide;

2-(2-methylpyrrolidin-2-yl)benzo[d]oxazole-7-carboxamide;

2-(4-(pyridin-2-yl)phenyl)benzo[d]oxazole-7-carboxamide;

2-(4-(piperidin-2-yl)phenyl)benzo[d]oxazole-7-carboxamide;

2-(4-(pyridin-3-yl)phenyl)benzo[d]oxazole-7-carboxamide;

2-(4-(piperidin-3-yl)phenyl)benzo[d]oxazole-7-carboxamide;

2-(4-(pyridin-4-yl)phenyl)benzo[d]oxazole-7-carboxamide;

2-(4-(piperidin-4-yl)phenyl)benzo[d]oxazole-7-carboxamide;

2-(3-(pyridin-2-yl)phenyl)benzo[d]oxazole-7-carboxamide;

2-(3-(piperidin-2-yl)phenyl)benzo[d]oxazole-7-carboxamide;

2-(3-(pyridin-3-yl)phenyl)benzo[d]oxazole-7-carboxamide;

2-(3-(piperidin-3-yl)phenyl)benzo[d]oxazole-7-carboxamide;

2-(3-(pyridin-4-yl)phenyl)benzo[d]oxazole-7-carboxamide;

2-(3-(piperidin-4-yl)phenyl)benzo[d]oxazole-7-carboxamide;

2-((1-(2-dimethylamino)acetyl)piperidin-3-yl)benzo[d]oxazole-7-carboxamide;

2-(3-(4-isobutyrylpiperazine-1-carbonyl)phenyl)benzo[d]oxazole-7-carboxamide;

2-(3-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)benzo[d]oxazole-7-carboxamide;

2-(4-(Piperidin-3-yl)phenyl)benzo[d]oxazole-7-carboxamide;

2-(1-azabicyclo[3.2.1]octan-5-yl)benzo[d]oxazole-7-carboxamide;

2-(4-(2-(methylamino)ethyl)phenyl)benzo[d]oxazole-7-carboxamide;

2-(4-(2-(dimethylamino)ethyl)phenyl)benzo[d]oxazole-7-carboxamide;

2-(1-propylpiperidin-3-yl)benzo[d]oxazole-7-carboxamide;

2-(1-propylpiperidin-4-yl)benzo[d]oxazole-7-carboxamide;

2-(2-fluoro-4-(pyridin-4-yl)phenyl)benzo[d]oxazole-7-carboxamide;

2-(2-fluoro-4-(piperidin-4-yl)phenyl)benzo[d]oxazole-7-carboxamide;

2-(2-fluoro-4-(1-propylpiperidin-4-yl)phenyl)benzo[d]oxazole-7-carboxamide;

2-(1-pentylpiperidin-4-yl)benzo[d]oxazol-7-carboxamide;

2-(1-butylpiperidin-4-yl)benzo[d]oxazol-7-carboxamide;

2-(4-(1-propylpiperidin-3-yl)phenyl)benzo[d]oxazole-7-carboxamide;

2-(4-(1-propylpiperidin-4-yl)phenyl)benzo[d]oxazole-7-carboxamide; and

2-(4-(1-(2-(dimethylamino)acetyl)piperidin-4-yl)phenyl)benzo[d]oxazole-7-carboxamide.

21. A pharmaceutical composition comprising a compound, pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable prodrug thereof of claim 1 and a pharmaceutically acceptable carrier, excipient, binder or diluent.

22. A method of inhibiting poly(ADP-ribose)polymerase (PARP) in a subject in need of PARP inhibition comprising administering to the subject a therapeutically acceptable amount of a compound of claim 1 .

23. A method of treating a disease ameliorated by the inhibition of PARP comprising administering to a subject in need of treatment a therapeutically-effective amount of a compound of claim 1 .

24. The method of claim 23 , wherein the disease is selected from the group consisting of: vascular disease; septic shock; ischaemic injury; reperfusion injury; neurotoxicity; haemorraghic shock; inflammatory diseases; multiple sclerosis; secondary effects of diabetes; and acute treatment of cytoxicity following cardiovascular surgery.

25. A method of treating a cancer deficient in Homologous Recombination (HR) dependent DNA double strand break (DSB) repair pathway, comprising administering to a subject in need of treatment a therapeutically-effective amount of a compound of claim 1 .

Assignments (2)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 3, 2011

From: LEAD THERAPEUTICS, INC.

To: BIOMARIN PHARMACEUTICAL INC.

Reel/Frame 025765/0990 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Feb 24, 2009

From: CHU, DANIEL; WANG, BING

To: LEAD THERAPEUTICS, INC.

Reel/Frame 022302/0347 →