PCNA inhibitors
Described herein, inter alia, are compositions of PCNA modulators and methods for treating or preventing cancer.
1. A compound having the formula:
wherein
Ring A is substituted or unsubstituted phenyl or substituted or unsubstituted 5 to 6 membered heteroaryl;
Ring B is substituted or unsubstituted 1-naphthyl, or substituted or unsubstituted isoquinolinyl;
R 1 is independently a halogen, —CX 1 3 , —CHX 1 2 , —CH 2 X 1 , —CN, —SO n1 R 10 , —SO v1 NR 7 R 8 , —NHNH 2 , —ONR 7 R 8 , —NHC═(O)NHNH 2 , —NHC═(O)NR 7 R 8 , —N(O) m1 , —NR 7 R 8 , —C(O)R 9 , —C(O)—OR 9 , —C(O)NR 7 R 8 , —OR 10 , —NR 7 SO 2 R 1 , —NR′C═(O)R 9 , —NR′C(O)—OR 9 , —NR 7 OR 9 , —OCX 1 3 , —OCHX 1 2 , —OCH 2 X 1 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or two adjacent R 1 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 2 is independently hydrogen, halogen, —CX 2 3 , —CHX 2 2 , —CH 2 X 2 , —CN, —COOH, —CONH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 3 is independently hydrogen, halogen, —CX 3 3 , —CHX 3 2 , —CH 2 X 3 , —CN, —COOH, —CONH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 7 , R 8 , R 9 , and R 10 are independently hydrogen, halogen, —CX A 3 , —CHX A 2 , —CH 2 X A , —CN, —COOH, —CONH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R 7 and R 8 substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
z1 is independently an integer from 0 to 4;
m1 and v1 are independently 1 or 2;
n1 is independently an integer from 0 to 4; and
X 1 , X 2 , X 3 , and X A are independently —Cl, —Br, —I, or —F.
2. The compound of claim 1 , having the formula:
wherein
R 4 is independently a halogen, —CX 4 3 , —CHX 4 2 , —CH 2 X 4 , —CN, —SO n4 R 14 , —SO v4 NR 11 R 12 , —NHNH 2 , —ONR 11 R 12 , —NHC═(O)NHNH 2 , —NHC═(O)NR 11 R 12 , —N(O) m4 , —NR 11 R 12 , —C(O)R 13 , —C(O)—OR 13 , —C(O)NR 11 R 12 , —OR 14 , —NR 11 SO 2 R 14 , —NR 11 C═(O)R 13 , —NR 11 C(O)—OR 13 , —NR 11 OR 13 , —OCX 4 3 , —OCHX 4 2 , —OCH 2 X 4 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or two adjacent R 4 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 5 is independently a halogen, —CX 5 3 , —CHX 5 2 , —CH 2 X 5 , —CN, —SO n5 R 18 , —SO v5 NR 15 R 16 , —NHNH 2 , —ONR 15 R 16 , —NHC═(O)NHNH 2 , —NHC═(O)NR 15 R 16 , —N(O) m5 , —NR 15 R 16 , —C(O)R 17 , —C(O)—OR 17 , —C(O)NR 15 R 16 , —OR 18 , —NR 15 SO 2 R 18 , —NR 15 C═(O)R 17 , —NR 15 C(O)—OR 17 , —NR 15 OR 17 , —OCX 53 , —OCHX 52 , —OCH 2 X 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or two adjacent R 5 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 11 , R 12 , R 13 , and R 14 are independently hydrogen, halogen, —CX B3 , —CHX B2 , —CH 2 X B , —CN, —COOH, —CONH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R 11 and R 12 substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
R 15 , R 16 , R 17 , and R 18 are independently hydrogen, halogen, —CX C 3 , —CHX C 2 , —CH 2 X C , —CN, —COOH, —CONH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R 15 and R 16 substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
z2 is independently an integer from 0 to 5;
z3 is independently an integer from 0 to 7;
m4, m5, v4 and v5 are independently 1 or 2;
n4 and n5 are independently an integer from 0 to 4; and
X 4 , X 5 , X B , and X C are independently —Cl, —Br, —I, or —F.
3. The compound of claim 1 , wherein R 1 is independently halogen, —OH, —CF 3 , —CHF 2 , —CH 2 F, —OCF 3 , —OCHF 2 , —OCH 2 F, unsubstituted methyl, or unsubstituted methoxy.
4. The compound of claim 2 , wherein R 4 is independently halogen, —CF 3 , —CHF 2 , —CH 2 F, —OCF 3 , —OCHF 2 , —OCH 2 F, —OH, —OR 14 , unsubstituted methyl, or unsubstituted methoxy.
5. The compound of claim 4 , wherein R 14 is hydrogen or unsubstituted C 1 -C 3 alkyl.
6. The compound of claim 2 , wherein R 5 is independently halogen, —CF 3 , —CHF 2 , —CH 2 F, —OCF 3 , —OCHF 2 , —OCH 2 F, —OH, unsubstituted methyl, or unsubstituted methoxy.
7. The compound of claim 1 , wherein R 2 is hydrogen.
8. The compound of claim 1 , wherein R 3 is hydrogen.
9. The compound of claim 1 , wherein Ring A is a substituted or unsubstituted phenyl.
10. The compound of claim 1 , wherein Ring A is a substituted or unsubstituted pyridyl.
11. The compound of claim 1 , wherein Ring B is a substituted or unsubstituted 1-napththyl.
12. The compound of claim 1 , wherein Ring B is a substituted or unsubstituted isoquinolinyl.
13. The compound of claim 2 , having the formula:
14. The compound of claim 1 , having the formula:
15. The compound of claim 1 , wherein Ring B is a substituted or unsubstituted 1-isoquinolinyl, or a substituted or unsubstituted 4-isoquinolinyl.
16. A compound having the formula:
wherein,
W 1 is N or C(R 42 );
W 2 is N or C(R 51 );
W 3 is N or C(R 52 );
R 4.1 , R 42 , and R 4.3 are each independently a hydrogen, halogen, —CX 4 3 , —CHX 4 2 , —CH 2 X 4 , —CN, —SO n4 R 14 , —SO v4 NR 11 R 12 , —NHNH 2 , —ONR 11 R 12 , —NHC═(O)NHNH 2 , —NHC═(O)NR 11 R 12 , —N(O) m4 , —NR 11 R 12 , —C(O)R 13 , —C(O)—OR 13 , —C(O)NR 11 R 12 , —OR 14 , —NR 11 SO 2 R 14 , —NR 11 C═(O)R 13 , —NR 11 C(O)—OR 13 , —NR 11 OR 13 , —OCX 4 3 , —OCHX 4 2 , —OCH 2 X 4 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 5.1 and R 5.2 are each independently a hydrogen, halogen, —CX 5 3 , —CHX 5 2 , —CH 2 X 5 , —CN, —SO n5 R 18 , —SO v5 NR 15 R 16 , —NHNH 2 , —ONR 15 R 16 , —NHC═(O)NHNH 2 , —NHC═(O)NR 15 R 16 , —N(O) m5 , —NR 15 R 16 , —C(O)R 17 , —C(O)—OR 17 , —C(O)NR 15 R 16 , —OR 18 , —NR 15 SO 2 R 18 , —NR 15 C═(O)R 17 , —NR 15 C(O)—OR 17 , —NR 15 OR 17 , —OCX 5 3 , —OCHX 5 2 , —OCH 2 X 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 1.1 , R 1.2 , and R 1.3 are each independently a hydrogen, halogen, —CX 1 3 , —CHX 1 2 , —CH 2 X 1 , —CN, —SO n1 R 10 , —SO v1 NR 7 R 8 , —NHNH 2 , —ONR 7 R 8 , —NHC═(O)NHNH 2 , —NHC═(O)NR 7 R 8 , —N(O) m1 , —NR 7 R 8 , —C(O)R 9 , —C(O)—OR 9 , —C(O)NR 7 R 8 , —OR 10 , —NR 7 SO 2 R 10 , —NRC═(O)R 9 , —NR 7 C(O)—OR 9 , —NR 7 OR 9 , —OCX 1 3 , —OCHX 1 2 , —OCH 2 X 1 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 2 is independently hydrogen, halogen, —CX 2 3 , —CHX 2 2 , —CH 2 X 2 , —CN, —COOH, —CONH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 3 is independently hydrogen, halogen, —CX 3 3 , —CHX 3 2 , —CH 2 X 3 , —CN, —COOH, —CONH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 5 is independently a halogen, —CX 5 3 , —CHX 5 2 , —CH 2 X 5 , —CN, —SO n5 R 18 , —SO v5 NR 15 R 16 , —NHNH 2 , —ONR 15 R 16 , —NHC═(O)NHNH 2 , —NHC═(O)NR 15 R 16 , —N(O) m5 , —NR 15 R 16 , —C(O)R 17 , —C(O)—OR 17 , —C(O)NR 15 R 16 , —OR 18 , —NR 15 SO 2 R 18 , —NR 15 C═(O)R 17 , —NR 15 C(O)—OR 17 , —NR 15 OR 17 , —OCX 5 3 , —OCHX 5 2 , —OCH 2 X 5 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or two adjacent R 5 substituents may optionally be joined to form a substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl
R 7 , R 8 , R 9 , and R 10 are independently hydrogen, halogen, —CX A 3 , —CHX A 2 , —CH 2 X A , —CN, —COOH, —CONH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R 7 and R 8 substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
R 11 , R 12 , R 13 , and R 14 are independently hydrogen, halogen, —CX B 3 , —CHX B 2 , —CH 2 X B , —CN, —COOH, —CONH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R 11 and R 12 substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
R 15 , R 16 , R 17 , and R 18 are independently hydrogen, halogen, —CX C 3 , —CHX C 2 , —CH 2 X C , —CN, —COOH, —CONH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or R 15 and R 16 substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;
z3 is independently an integer from 0 to 5;
m1, m4, m5, v1, v4, and v5 are independently 1 or 2;
n1, n4, and n5 are independently an integer from 0 to 4; and
X′, X 2 , X 3 , X 4 , X 5 , X A , X B , and X C are independently —Cl, —Br, —I, or —F.
17. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
18. The pharmaceutical composition of claim 17 , further comprising an anti-cancer agent.
19. The pharmaceutical composition of claim 18 , wherein the anti-cancer agent is a cisplatin.
20. A method of treating a disease associated with PCNA activity in a patient having said disease, said method comprising administering a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
21. A method of treating cancer in a patient having said cancer, said method comprising administering a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
22. The method of claim 21 , wherein said cancer is leukemia, lung cancer, colon cancer, a central nervous system cancer, brain cancer, neuroblastoma, melanoma, ovarian cancer, renal cancer, prostate cancer, or breast cancer.