Small molecule inhibitors of USP1 deubiquitinating enzyme activity

1. A method for treating a subject having a breast cancer or an ovarian cancer, comprising:

administering to a subject having breast cancer or ovarian cancer in need of such treatment a small molecule inhibitor of ubiquitin specific protease 1 (USP1) according to Formula I:

wherein

X is O or S;

n is 0, 1, 2, 3, or 4;

each occurrence of R 1 is independently hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; —OR A ; —C(═O)R A ; —C(═O)N(R A ) 2 ; —CO 2 R A ; —CN; —SCN; —SR A ; —SOR A ; —SO 2 R A ; —NO 2 ; —N 3 ; —N(R A ) 2 ; —NHC(═O)R A ; —NR A C(═O)N(R A ) 2 ; —OC(═O)OR A ; —OC(═O)R A ; —OC(═O)N(R A ) 2 ; —NR A C(═O)OR A ; or —C(R A ) 3 ; wherein each occurrence of R A is independently a hydrogen, a protecting group, an aliphatic moiety, a heteroaliphatic moiety, an acyl moiety; an aryl moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety;

R 2 is hydrogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic, substituted or unsubstituted, heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; —OR B ; —C(═O)R B ; —C(═O)N(R B ) 2 ; —SOR B ; —NHC(═O)R B ; —NR B C(═O)N(R B ) 2 ; or —C(R B ) 3 ;

wherein each occurrence of R B is independently a hydrogen, a protecting group, an aliphatic moiety, a heteroaliphatic moiety, an acyl moiety; an aryl moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety; and

wherein when R 2 is substituted aliphatic, each substituent is independently selected from an aryl moiety, a heteroaryl moiety, an arylalkyl moiety, a heteroarylalkyl moiety, an alkoxy moiety, an aryloxy moiety, a heteroalkoxy moiety, a heteroaryloxy moiety, an alkylthio moiety, an arylthio moiety, a heteroalkylthio moiety, a heteroarylthio moiety, —F, —Cl, —Br, —I, —OH, —NO 2 , —CF 3 , —CH 2 CF 3 , —CHCl 2 , —CH 2 OH, —CH 2 CH 2 OH, —CH 2 NH 2 , —CH 2 SO 2 CH 3 , —C(O)R x , —CO 2 (R x ), —CON(R x ) 2 , —OC(O)R x , —OCO 2 R x , —OCON(R x ) 2 , —N(R x ) 2 , —S(O) 2 R x , —NR x (CO)R x , wherein each occurrence of R x is independently an aliphatic moiety, a heteroaliphatic moiety, an aryl moiety, a heteroaryl moiety, an arylalkyl moiety, or a heteroalkyl moiety;

or a pharmaceutically acceptable salt thereof,

in an amount effective to treat the breast cancer or the ovarian cancer.

2. The method of claim 1 , wherein the small molecule inhibitor of USP1 according to Formula I is the compound of Formula IV (527):

3. The method of claim 1 , further comprising administering to the subject a DNA cross-linking agent.

4. The method of claim 1 , further comprising administering to the subject a poly (adenosine diphosphate (ADP)-ribose) polymerase (PARP) inhibitor.

5. The method of claim 1 , further comprising administering to the subject a DNA cross-linking agent and a PARP inhibitor.

6. The method of claim 1 , wherein X is O.

7. The method of claim 1 , wherein n is 0.

8. The method of claim 1 , wherein R 2 is substituted or unsubstituted phenyl.

9. The method of claim 8 , wherein R 2 is phenyl substituted with halogen.

10. The method of claim 1 , wherein the subject has breast cancer.

11. The method of claim 1 , wherein the subject has ovarian cancer.

12. A method for treating a subject having a breast cancer or an ovarian cancer, comprising:

administering to a subject having breast cancer or ovarian cancer in need of such treatment a small molecule inhibitor of ubiquitin specific protease 1 (USP1) according to Formula I:

wherein

X is O;

n is 0, 1, 2, 3, or 4;

each occurrence of R 1 is independently hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; —OR A ; —C(═O)R A ; —C(═O)N(R A ) 2 ; —CO 2 R A ; —CN; —SCN; —SR A ; —SOR A ; —SO 2 R A ; —NO 2 ; —N 3 ; —N(R A ) 2 ; —NHC(═O)R A ; —NR A C(═O)N(R A ) 2 ; —OC(═O)OR A ; —OC(═O)R A ; —OC(═O)N(R A ) 2 ; —NR A C(═O)OR A ; or —C(R A ) 3 ; wherein each occurrence of R A is independently a hydrogen, a protecting group, an aliphatic moiety, a heteroaliphatic moiety, an acyl moiety; an aryl moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety;

R 2 is hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; —OR B ; —C(═O)R B ; —C(═O)N(R B ) 2 ; —CO 2 R B ; —CN; —SCN; —SR B ; —SOR B ; —SO 2 R B ; —NO 2 ; —N 3 ; —N(R B ) 2 ; —NHC(═O)R B ; —NR B C(═O)N(R B ) 2 ; —OC(═O)OR B ; —OC(═O)R B ; —OC(═O)N(R B ) 2 ; —NR B C(═O)OR B ; or —C(R B ) 3 ; wherein each occurrence of R B is independently a hydrogen, a protecting group, an aliphatic moiety, a heteroaliphatic moiety, an acyl moiety; an aryl moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety;

or a pharmaceutically acceptable salt thereof,

in an amount effective to treat the breast cancer or the ovarian cancer.