Small molecule inhibitors of BCL-2-associated death promoter (BAD) phosphorylation

Patent metadata

Field	Value
Publication number	US-11292773-B2
Application number	US-201816605630-A
Country	US
Kind code	B2
Filing date	Apr 18, 2018
Priority date	Apr 19, 2017
Publication date	Apr 5, 2022
Grant date	Apr 5, 2022

Abstract

The invention relates to compounds of general formula (I): wherein R1, n, R2a, R2b, and R3 are as defined herein. The compounds are inhibitors of Bcl-2-associated death promoter (BAD) phosphorylation and have anti-apoptotic activity and are useful in the treatment of cancer, particularly breast cancer, endometrial cancer, ovarian cancer, liver cancer, colon cancer, prostate cancer or pancreatic cancer.

First claim

The invention claimed is:

1. A compound of general formula (IB):

wherein:
each R 1 is independently halo, NR 10 R 11 , C 1-6 alkyl, C 1-6 haloalkyl, —O(C 1-6 alkyl), —O(C 1-6 haloalkyl), aryl, heteroaryl, —O-aryl or —O-heteroaryl,
wherein
each R 10 and R 11 is independently selected from H or C 1-6 alkyl;
aryl or heteroaryl groups R 1 are optionally substituted with one or more substituents selected from halo, OH, cyano, nitro, —NR 4 R 5 , —S(O) p NR 4 R 5 , —C(O)NR 4 R 5 , —C 1-6 alkyl, or —O(C 1-6 alkyl), wherein either of the —C 1-6 alkyl, or —O(C 1-6 alkyl) groups are optionally substituted with one or more substituents selected from OH, halo, arylO(C 1-6 alkyl), or O(C 1-6 haloalkyl);
p is 1 or 2;
each R 4 and R 5 is independently selected from H or C 1-4 alkyl or R 4 and R 5 together with a nitrogen atom to which they are attached may form a 3-8-membered heterocyclic ring, optionally containing one or more additional heteroatoms selected from O, N and S;

n is 0, 1, 2, 3, or 4;
R 6 is selected from aryl substituted with one or more substituents selected from halo, C 1-4 alkyl, C 1-4 haloalkyl, —O(C 1-4 alkyl) and —O(C 1-4 haloalkyl); heteroaryl selected from indolyl, isoindolyl, benzoxazolyl and benzisoxazolyl and optionally substituted with one or more substituents selected from halo, C 1-4 alkyl, C 1-4 haloalkyl, —O(C 1-4 alkyl) and —O(C 1-4 haloalkyl); —O-aryl substituted with one or more substituents selected from halo, C 1-4 alkyl, C 1-4 haloalkyl, —O(C 1-4 alkyl) and —O(C 1-4 haloalkyl); —O-heteroaryl selected from indolyl, isoindolyl, benzoxazolyl and benzisoxazolyl and optionally substituted with one or more substituents selected from halo, C 1-4 alkyl, C 1-4 haloalkyl, —O(C 1-4 alkyl) and —O(C 1-4 haloalkyl); and C 1-4 alkyl substituted with two aryl or two heteroaryl groups, wherein at least one of the aryl and heteroaryl groups is substituted with one or more substituents selected from halo, C 1-4 alkyl, C 1-4 haloalkyl, —O(C 1-4 alkyl) and —O(C 1-4 haloalkyl);
R 3 is aryl or heteroaryl any of which is optionally substituted with one or more substituents R 7 selected from halo, —C 1-4 alkyl optionally substituted with aryl, —O(C 1-4 alkyl) optionally substituted with aryl, —C 1-4 haloalkyl, —C(C 1-4 haloalkyl) or —C(O)NR 8 R 9 ;
each R 8 and R 9 is independently selected from H, C 1-4 alkyl or C 3-6 cycloalkyl or R 8 and R 9 together with the nitrogen atom to which they are attached may form a 5- or 6-membered heterocyclic ring, optionally containing one or more additional heteroatoms selected from O, N and S;

or a pharmaceutically acceptable salt, solvate or hydrate thereof or a deuterated or tritiated variant thereof, including all stereoisomers.

2. A compound according to claim 1 , wherein R 3 is phenyl optionally substituted with one or more substituents R 7 such that the compound of general formula (IB) is a compound of general formula (ID):

wherein z is 0 to 5 or a pharmaceutically acceptable salt, solvate or hydrate thereof or a deuterated or tritiated variant thereof, including all stereoisomers.

3. A compound according to claim 1 , wherein n is 0.

4. A compound according to claim 1 , wherein n is other than 0 and R 1 is halo or an aryl or heteroaryl group optionally substituted as defined in claim 1 .

5. A compound according to claim 4 , wherein R 1 is an aryl or heteroaryl group optionally substituted with halo, OH, cyano, nitro, —SO 2 NH 2 , —C(O)NR 4 R 5 , —C 14 alkyl optionally substituted with aryl, —C 1-4 haloalkyl, —O(C 1-4 alkyl) optionally substituted with aryl or —O(C 1-4 haloalkyl), where R 4 and R 5 together with the nitrogen atom to which they are attached form a piperidine or pyrrolidine ring.

6. A compound according to claim 5 , wherein R 1 is an aryl or heteroaryl group optionally substituted with chloro, fluoro, methyl, ethyl, trifluoromethyl, benzyl, methoxy, ethoxy, benzyloxy, trifluoromethoxy or piperidine-1-carbonyl.

7. A compound according to claim 1 , wherein R 3 is heteroaryl optionally substituted with one or more substituents R 7 selected from halo, —C 1-4 alkyl optionally substituted with aryl, —O(C 1-4 alkyl) optionally substituted with aryl, —C 1-4 haloalkyl, —O(C 1-4 haloalkyl) or —C(O)NR 8 R 9 , wherein each R 8 and R 9 is independently selected from H, C 1-4 alkyl or C 3-6 cycloalkyl or R 8 and R 9 together with the nitrogen atom to which they are attached may form a 5- or 6-membered heterocyclic ring, optionally containing one or more additional heteroatoms selected from O, N and S.

8. A compound according to claim 1 wherein each R 1 is independently halo, C 1-6 alkyl, C 1-6 haloalkyl, aryl or heteroaryl, wherein aryl or heteroaryl groups are optionally substituted with one or more substituents selected from halo, OH, cyano, nitro, —S(O) p NR 4 R 5 , —C(O)NR 4 R 5 , —C 1-6 alkyl optionally substituted with aryl, —C 1-6 haloalkyl, —O(C 1-6 alkyl) optionally substituted with aryl or —O(C 1-6 haloalkyl);
p is 0, 1 or 2;
each R 4 and R 5 is independently selected from H or C 1-4 alkyl or R 4 and R 5 together with the nitrogen atom to which they are attached may form a 5- or 6-membered heterocyclic ring, optionally containing one or more additional heteroatoms selected from O, N and S.

9. A compound according to claim 1 , wherein R 6 is phenyl, —O-phenyl, —CH(phenyl) 2 , or —CH(heteroaryl) 2 , where the heteroaryl group is selected from pyridinyl, indolyl, isoindolyl, benzoxazolyl and benzisoxazolyl, and wherein any of the above R 6 groups may be substituted as defined in claim 1 .

10. A compound according to claim 1 , wherein R 6 is

11. A compound according to claim 2 , wherein z is 0, 1 or 2; R 7 is absent or R 7 is halo, —C 1-4 alkyl, benzyl, —O(C 1-4 alkyl), benzyloxy, —C 1-4 haloalkyl, —O 1-4 haloalkyl) or —C(O)NR 8 R 9 , where R 8 and R 9 together with the nitrogen atom to which they are attached form a piperidinyl ring or wherein R 8 is H and R 9 is C 3-6 cycloalkyl.

12. A compound according to claim 2 , wherein z is 1, R 7 is C(O)NR 8 R 9 , R 8 is H, and R 9 is C 3-6 cycloalkyl.

13. A compound of claim 12 selected from the group consisting of:

or a pharmaceutically acceptable salt, solvate or hydrate thereof or a deuterated or tritiated variant thereof, including all stereoisomers.

14. A compound selected from:
2-((2-chlorophenyl)(4-(4-methoxyphenyl)piperazin-1-yl)methyl)phenol (Compound 1);
2-((4-chlorophenyl)(4-(4-methoxyphenyl)piperazin-1-yl)methyl)phenol (Compound 2);
2-((4-(benzyloxy)-3-fluorophenyl)(4-(4-methoxyphenyl)piperazin-1-yl)methyl)phenol (Compound 3);

Assignees

• Nat Univ Singapore
• Univ Of Mysore
• Bangalore Univ

Inventors

• Lobie Peter Edward
• Pandey Vijay Kumar
• Subbegowda Rangappa Kanchugarakoppal
• Salundi Bassappa
• Dhananjaya Mohan Chakrabhavi
• RANGAPPA Shobith
• Venkatachalaiah Srinivasa

Classifications

• C07D471/06

  Peri-condensed systems · CPC title

• C07D413/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D409/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D405/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D333/20

  by nitrogen atoms (nitro, nitroso radicals C07D333/12) · CPC title