IP Library Granted Patent US 9,598,404
Granted Patent B2
US 9,598,404 · App. 14/992,396 · Granted Mar 21, 2017

Deoxycytidine kinase inhibitors

Inventors: Caius G. Radu (Los Angeles, CA); Zheng Li (Oakland, CA); Raymond M. Gipson (Los Angeles, CA); Jue Wang (Los Angeles, CA); Nagichettiar Satyamurthy (Los Angeles, CA); Arnon Lavie (Chicago, IL); Jennifer M. Murphy (Los Angeles, CA); David A. Nathanson (Los Angeles, CA); Michael E. Jung (Los Angeles, CA)
Assignees: THE REGENTS OF THE UNIVERSITY OF CALIFORNIA; THE BOARD OF TRUSTEES OF THE UNIVERSITY OF ILLINOIS
C07D417/12A61K31/426A61K31/44A61K31/506A61K31/513C07B59/002C07D405/12C07D409/12C07D413/12C07B2200/05
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Quick Facts
Patent No.
US 9,598,404
App. No.
14/992,396
Granted
Mar 21, 2017
Kind
B2
Abstract

Provided herein are compounds that bind to dCK and methods for treating cancer.

Claims (32)

1. A compound having the formula:

wherein:

Y is C(R 8 ) or N;

Z is C(R 9 ) or N;

X is CH 2 , O, N(R 10 ), S, S(O) or S(O) 2 ;

R 1 is hydrogen, halogen, —N 3 , —CF 3 , —CCl 3 , —CBr 3 , —CI 3 , —CN, —COR 1A , —OR 1A , —NR 1A R 1B , —C(O)OR 1A , —C(O)NR 1A R 1B , —NO 2 , —SR 1A , —S(O) n1 R 1A , —S(O) n1 OR 1A , —S(O) n1 NR 1A R 1B , —NHNR 1A R 1B , —ONR 1A R 1B , —NHC(O)NHNR 1A R 1B , 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 4 is hydrogen, halogen, —N 3 , —CF 3 , —CCl 3 , —CBr 3 , —CI 3 , —CN, —COR 4A , —OR 4A , —NR 4A R 4B , —C(O)OR 4A , —C(O)NR 4A R 4B , —NO 2 , —SR 4A , S(O) n4 R 4A , —S(O) n4 OR 4A , —S(O) n4 NR 4A R 4B , —NHNR 4A R 4B , —ONR 4A R 4B , —NHC(O)NHNR 4A R 4B , 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 hydrogen, halogen, —N 3 , —CF 3 , —CCl 3 , —CBr 3 , —CI 3 , —CN, —COR 5A , —OR 5A , —NR 5A R 5B , —C(O)OR 5A , —C(O)NR 5A R 5B , —NO 2 , —SR 5A , —S(O) n5 R 5A , —S(O) n5 OR 5A , —S(O) n5 NR 5A R 5B , —NHNR 5A R 5B , —ONR 5A R 5B , —NHC(O)NHNR 5A R 5B , 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, wherein R 5 and R 6 are optionally combined to form a substituted or unsubstituted cycloalkyl;

R 6 is unsubstituted C 1 -C 6 alkyl;

R 8 is hydrogen, halogen, —N 3 , —CF 3 , —CCl 3 , —CBr 3 , —CI 3 , —CN, —COR 8A , —OR 8A , —NR 8A R 8B , —C(O)OR 8A , —C(O)NR 8A R 8B , —NO 2 , —SR 8A , —S(O) n8 R 8A , —S(O) n8 OR 8A , —S(O) n8 NR 8A R 8B , —NHNR 8A R 8B , —ONR 8A R 8B , —NHC(O)NHNR 8A R 8B , 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 9 is hydrogen, halogen, —N 3 , —CF 3 , —CCl 3 , —CBr 3 , —CI 3 , —CN, —COR 9A , —OR 9A , —NR 9A R 9B , —C(O)OR 9A , —C(O)NR 9A R 9B , —NO 2 , —SR 9A , —S(O) n9 R 9A , —S(O) n9 OR 9A , —S(O) n9 NR 9A R 9B , —NHNR 9A R 8B , —ONR 9A R 9B , —NHC(O)NHNR 9A R 9B , 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 10 is H, —CH 3 , —C 2 H 5 , —C 3 H 7 , —CH 2 C 6 H 5 ;

R 1A , R 1B , R 4A , R 4B , R 5A , R 5B , R 8A , R 8B , R 9A , and, R 9B are independently hydrogen, oxo, halogen, —CF 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —S(O) 2 Cl, —S(O) 3 H, —S(O) 4 H, —S(O) 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC(O)NHNH 2 , —NHC(O)NH 2 , —NHS(O) 2 H, —NHC(O)H, —NHC(O)—OH, —NHOH, —OCF 3 , —OCHF 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; and

n1, n4, n5, n8, and n9 are independently 1, 2, or 3.

2. The compound of claim 1 , wherein is hydrogen.

3. The compound of claim 2 , wherein R 5 and R 6 are each unsubstituted C 1 -C 6 alkyl.

4. The compound of claim 3 , wherein R 1 is hydrogen, halogen, —OR 1A , 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.

5. The compound of claim 4 , wherein R 1 is —OR 1A , and R 1A is substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.

6. The compound of claim 5 , wherein R 1A is —CH 3 , —C 2 H 5 , —C 3 H 7 , —CD 3 , —CD 2 CD 3 , —(CH 2 ) 2 OH, —(CH 2 ) 3 OH, —CH 2 CH(OH)CH 3 , —(CH 2 ) 2 CH(OH)CH 3 , —CH 2 C(CH 3 ) 2 OH, —(CH 2 ) 2 C(CH 3 ) 2 OH, —(CH 2 ) 2 F, —(CH 2 ) 3 F, —CH 2 CH(F)CH 3 , —(CH 2 ) 2 CH(F)CH 3 , —(CH 2 ) 2 (CH 3 ) 2 F, —(CH 2 ) 2 Cl, —(CH 2 ) 3 Cl, —CH 2 CH(Cl)CH 3 , —(CH 2 ) 2 CH(Cl)CH 3 , —CH 2 C(CH 3 ) 2 Cl, —(CH 2 ) 2 C(CH 3 ) 2 Cl, —(CH 2 ) 2 NHSO 2 CH 3 , —(CH 2 ) 3 NHSO 2 CH 3 , —(CH 2 ) 2 N(CH 2 CH 2 OH)SO 2 CH 3 , —(CH 2 ) 3 N(CH 2 CH 2 OH)SO 2 CH 3 , —(CH 2 ) 2 N(CH 2 CH 2 F)SO 2 CH 3 , or —(CH 2 ) 2 N(CH 2 CH 2 Cl)SO 2 CH 3 .

7. The compound of claim 6 , wherein Y is C(R 8 ).

8. The compound of claim 7 , wherein R 8 is hydrogen, halogen, —OR 8A , 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.

9. The compound of claim 8 , wherein R 8 is —OR 8A , and R 8A is hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.

10. The compound of claim 9 , wherein R 8A is —CH 3 , —C 2 H 5 , —CD 3 , —CD 2 CD 3 , —(CH 2 ) 2 OH, —(CH 2 CH 2 ) 3 OH, —CH 2 C(CH 3 ) 2 OH, —(CH 2 ) 2 C(CH 3 ) 2 OH, —(CH 2 ) 2 F, —(CH 2 ) 3 F, —CH 2 C(CH 3 ) 2 F, or —(CH 2 ) 2 C(CH 3 ) 2 F.

11. The compound of claim 10 , wherein Z is CH.

12. The compound of claim 11 , wherein Xis S.

13. The compound of claim 1 having the formula:

14. The compound of claim 13 , wherein R iA is substituted or unsubstituted heterocycloalkyl.

15. The compound of claim 1 having the structure:

16. The compound of claim 1 having the structure:

17. The compound of claim 1 having the structure:

18. A pharmaceutical formulation, comprising the compound of claim 1 and a pharmaceutically acceptable excipient.

19. A method of treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of the compound of claim 1 , wherein said cancer is a hematological malignancy.

Assignments (3)
CONFIRMATORY LICENSE Recorded Jun 27, 2016
From: UNIVERSITY OF CALIFORNIA LOS ANGELES
To: NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT
Reel/Frame 039166/0758 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Feb 25, 2016
From: RADU, CAIUS G.; LI, ZHENG; GIPSON, RAYMOND M.; SATYAMURTHY, NAGICHETTIAR; MURPHY, JENNIFER M.; NATHANSON, DAVID A.; JUNG, MICHAEL E.; WANG, JUE
To: THE REGENTS OF THE UNIVERSITY OF CALIFORNIA
Reel/Frame 037832/0768 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Feb 25, 2016
From: LAVIE, ARNON
To: THE BOARD OF TRUSTEES OF THE UNIVERSITY OF ILLINOIS
Reel/Frame 037927/0215 →
Continuity (3)
Continuation PCTUS2014050931 · Aug 13, 2014
Provisional Application 61865468 · Aug 13, 2013
Related Publication 20160237076A1 · Aug 18, 2016