Therapeutic compounds and methods

Patent metadata

Field	Value
Publication number	US-9598441-B2
Application number	US-201214239881-A
Country	US
Kind code	B2
Filing date	Aug 30, 2012
Priority date	Aug 30, 2011
Publication date	Mar 21, 2017
Grant date	Mar 21, 2017

Abstract

The invention provides compounds of formula I: and salts thereof. The invention also provides pharmaceutical compositions comprising a compound of formula I, processes for preparing compounds of formula I, intermediates useful for preparing compounds of formula I and therapeutic methods for treating cancer using compounds of formula I.

First claim

What is claimed is:

1. A compound of formula I:

wherein:
R 1 is (C 1 -C 6 )alkylaryl, wherein any (C 1 -C 6 )alkylaryl of R 1 is optionally substituted with one or more groups selected from (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 7 )carbocycle, halogen, —CN, —OR a1 , —NR q1 R r1 , —NR n1 COR p1 , NO 2 , —C(O)R n1 and —C(O)OR n1 or R 1 is

wherein each R 1a and R 1b is independently selected from H, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 7 )carbocycle, halogen, —CN, —OR n1 , —NR q1 R r1 , —NR n1 COR p1 , NO 2 , —C(O)R n1 and —C(O)OR n1 ;
R 2a and R 2b are each H, or R 2a and R 2b together are oxo (═O);
R 3 is —(C 1 -C 6 )alkylaryl or —(C 1 -C 6 )alkylheteroaryl, wherein any —(C 1 -C 6 )alkylaryl or —(C 1 -C 6 )alkylheteroaryl of R 3 is optionally substituted with one or more groups selected from Z 1 , (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl and (C 2 -C 6 )alkynyl;
R 4a is H, (C 1 -C 8 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 7 )carbocycle, halogen, —CN, —OR n3 , —NR q3 R r3 , —NR n3 COR p3 , NO 2 , —C(O)R n3 or —C(O)OR n3 ;
R 4b is H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 3 -C 7 )carbocycle, halogen, —CN, —OR n3 , —NR q3 R r3 , —NR n3 COR p3 , NO 2 , —C(O)R n3 or —C(O)OR n3 ;
R 4c is H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 3 -C 7 )carbocycle, halogen, —CN, —OR n3 , —NR q3 R r3 , —NR n3 COR p3 , NO 2 , —C(O)R n3 or —C(O)OR n3 ;
R 4d is H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 3 -C 7 )carbocycle, halogen, —CN, —OR n3 , —NR q3 R r3 , —NR n3 COR p3 , NO 2 , —C(O)R n3 or —C(O)OR n3 ;
each Z 1 is independently selected from (C 3 -C 7 )carbocycle, halogen, —CN, —OR n2 , —NR q2 R r2 , —NR n2 COR p2 , NO 2 , —C(O)R n2 and —C(O)OR n2 ;
each R n1 is independently selected from H, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl and (C 3 -C 7 )carbocycle;
each R p1 is independently selected from (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl and (C 3 -C 7 )carbocycle;
R q1 and R n1 are each independently selected from H, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl and (C 3 -C 7 )carbocycle, or R q1 and R n1 together with the nitrogen to which they are attached form a heterocycle;
each R n2 is independently selected from H, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl and (C 3 -C 7 )carbocycle;
each R p2 is independently selected from (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl and (C 3 -C 7 )carbocycle;
R q2 and R r2 are each independently selected from H, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl and (C 3 -C 7 )carbocycle, or R q2 and R r2 together with the nitrogen to which they are attached form a heterocycle;
each R q3 is independently selected from H, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl and (C 3 -C 7 )carbocycle;
each R p3 is independently selected from (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl and (C 3 -C 7 )carbocycle; and
R q3 and R r3 are each independently selected from H, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl and (C 3 -C 7 )carbocycle, or R q3 and R r3 together with the nitrogen to which they are attached form a heterocycle;
or a pharmaceutically acceptable salt thereof;
provided:
R 3 is not 2-chlorophenylmethyl, 2-fluorophenylmethyl, 2,6-dichlorophenylmethyl, 4-chlorophenylmethyl, or 4-fluorophenylmethyl when R 1 is phenyl, R 4a is H, R 4b is H, R 4c is H, R 4d is H and R 2a and R 2b together are oxo (═O);
R 3 is not 2-phenylethyl when R 1 is phenyl, R 4a is H, R 4b is H, R 4c is Br, R 4d is H and R 2a and R 2b together are oxo (═O); and provided that:
when R 3 is benzyl the benzyl is substituted with one or more groups selected from Z 1 , (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl and (C 7 -C 6 )alkynyl; and
when R 3 is substituted naphthylmethyl-, the substituted naphthylmethyl- is substituted with one or more groups selected from Z 1 , (C 7 -C 6 )alkenyl and (C 2 -C 6 )alkynyl and at least one of R 1a or R 1b is selected from (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 7 )carbocycle, halogen, —CN, —OR n1 , —NR q1 R r1 , —NR n1 COR p1 , NO 2 , —C(O)R n1 and —C(O)OR n1 ; and the remaining R 1a or R 1b is selected from H, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 2 )carbocycle, halogen, —CN, —OR n1 , —NR q1 R r1 , —NR n COR p1 , NO 2 , —C(O)R n1 and —C(O)OR n1 ; or
when R 3 is unsubstituted naphthylmethyl at least one of R 1a or R 1b is independently selected from (C 7 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 7 )carbocycle, halogen, —CN, —OR n1 , —NR q1 R r1 , —NR n1 COR p1 , NO 2 , —C(O)R n1 and —C(O)OR n1 and the remaining R 1a or R 1b is selected from H, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 7 -C 6 )alkynyl, (C 3 -C 7 )carbocycle, halogen, —CN, —OR n1 , —NR q1 R r1 , —NR n1 COR p1 , NO 2 , —C(O)R n1 and —C(O)OR n1 .

2. The compound of claim 1 wherein R 2a and R 2b together are oxo (═O).

3. The compound of claim 1 wherein R 3 is —(C 1 -C 6 )alkylaryl, wherein —(C 1 -C 6 )alkylaryl is optionally substituted with one or more groups selected from Z 1 , (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl and (C 2 -C 6 )alkynyl.

4. The compound of claim 1 wherein each Z 1 is independently selected from (C 3 -C 7 )carbocycle, Br, I, —CN, —OR n2 , —O(C 3 -C 7 )carbocycle, —NR q2 R r2 , —NR n2 COR p2 , NO 2 , —C(O)R n2 and —C(O)OR n2 .

5. The compound of claim 1 wherein R 1 is:

wherein each R 1a and R 1b is independently selected from H, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 7 -C 6 )alkynyl, (C 3 -C 7 )carbocycle, halogen, —CN, —OR n1 , —NR q1 R r1 , —NR n1 COR p1 , NO 2 , —C(O)R n1 and —C(O)OR n1 .

6. The compound of claim 1 selected from:

and pharmaceutically acceptable salts thereof.

7. A pharmaceutical composition comprising a compound of formula I as described in claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

8. A method for treating breast cancer, pancreatic cancer or a mesothelioma in a mammal comprising administering to the mammal an effective amount of a compound of formula I as described in claim 1 , or a pharmaceutically acceptable salt thereof.

9. A method for treating breast cancer, pancreatic cancer or a mesothelioma in a mammal comprising administering to the mammal an effective amount of a compound of formula I:

wherein:
R 1 is aryl or —(C 1 -C 6 )alkylaryl, wherein any aryl or —(C 1 -C 6 )alkylaryl of R 1 is optionally substituted with one or more groups selected from (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 7 )carbocycle, halogen, —CN, —OR n1 , —NR q1 R r1 , —NR n1 COR p1 , NO 2 , —C(O)R n1 and —C(O)OR n1 ;
R 2a and R 2b are each H, or R 2a and R 2b together are oxo(═O);
R 3 is (C 1 -C 6 )alkyl, —(C 1 -C 6 )alkylaryl or —(C 1 -C 6 )alkylheteroaryl, wherein any (C 1 -C 6 )alkyl of R 3 is optionally substituted with one or more Z 1 groups and wherein any —(C 1 -C 6 )alkylaryl or —(C 1 -C 6 )alkylheteroaryl of R 3 is optionally substituted with o

Assignees

• Rishi Arun K
• Larsen Scott D
• Univ Wayne State
• Univ Michigan
• Dept Of Veteran Affairs

Inventors

• Rishi Arun K
• Larsen Scott D

Classifications

• C07D513/20

  Spiro-condensed systems · CPC title

• C07D513/10 Primary

  Spiro-condensed systems · CPC title

• A61K31/433

  Thidiazoles · CPC title