SMALL MOLECULE INHIBITORS OF BCL-2- ASSOCIATED DEATH PROMOTER (BAD) PHOSPHORYLATION

• US 20200131139A1
• Filed: 04/18/2018
• Published: 04/30/2020
• Est. Priority Date: 04/19/2017
• Status: Active Grant

• Current Assignee: Bangalore University, National University of Singapore, University of Mysore
• Original Assignee: Bangalore University, National University of Singapore, University of Mysore
• Inventors: Lobie, Peter Edward, Pandey, Vijay Kumar, Kanchugarakoppal Subbegowda, Ranpappa, Salundi, Bassappa, Chakrabhavi Dhananjaya, Mohan, Rangappa, Shobith, Venkatachalaiah, Srinivasa
• Granted Patent: US 11,292,773 B2
• Time in Patent Office: Days
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 213/53 Nitrogen atoms
• CPC Class Codes: C07D 241/04 having no double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 295/096 with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
• CPC Class Codes: C07D 295/155 with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
• CPC Class Codes: C07D 295/192 from aromatic carboxylic acids
• CPC Class Codes: C07D 307/52 Radicals substituted by nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 333/20 by nitrogen atoms nitro, nitroso radicals C07D333/12
• CPC Class Codes: C07D 405/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 409/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 413/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 471/06 Peri-condensed systems

Abstract

The invention relates to compounds of general formula (I): wherein R¹, n, R^2a, R^2b, 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.

Claims

1. A compound of general formula (I):

3. A compound according to claim 1 wherein n is 1 or 2 and at least one R¹ group is OH.

7. A compound according to claim 1, wherein R^2a and R^2b together with the nitrogen atom to which they are attached form a 6-membered heterocyclic ring optionally substituted with one or more substituents R⁶.

8. A compound according to claim 7 wherein R^2a and R^2b together with the nitrogen atom to which they are attached form a piperazine ring substituted by a single R⁶ substituent at the piperazine 4-position such that the compound of general formula (I) is a compound of general formula (IB):

9. A compound according to claim 1,

wherein R⁶ is phenyl, heteroaryl, —

O-phenyl, —

O-heteroaryl, benzyl, —

CH(phenyl)₂, —

CH₂—

heteroaryl and —

CH(heteroaryl)₂, where the heteroaryl group is selected from pyridinyl, indolyl, isoindolyl, benzoxazolyl and benzisoxazolyl, and wherein any of the above R⁶ groups may be substituted as defined in claim 1.

10. A compound according to claim 1, wherein R³ is phenyl optionally substituted with one or more substituents R⁷ such that the compound of general formula I) is a compound of general formula (IC):

22. A compound according to claim 10 wherein z is 0, 1 or 2 R⁷ not present (i.e. z is 0), or R⁷ is halo, —

C_1-4 alkyl, benzyl, —

O(C_1-4 alkyl) benzyloxy, —

C_1-4 haloalkyl, —

O(C_1-4 haloalkyl) or —

C(O)NR⁸R⁹, where R⁸ and R⁹ together with the nitrogen atom to which they are attached form a piperidinyl ring or wherein R⁸ is H and R⁹ is C_3-7 cycloalkyl.

23. A compound according to claim 1 which is a compound of general formula (ID):

24. A compound according to claim 1 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);

(4-((2-hydroxyphenyl)(4-(4-Methoxyphenyl)piperazinyl)methyl)phenyl)(piperidin-1-yl)methanone (Compound

     4);

3-((5-chloro-2-hydroxyphenyl)(4-(4-methoxyphenyl)piperazin-1-yl)methyl)-N-cyclopentylbenzamide (Compound

     5);

2-((4-(benzyloxy)-3-fluorophenyl)(4-(4-methoxyphenyl)piperazin-1-yl)methyl)-4-chlorophenol (Compound

     6);

2-((4-(benzyloxy)-3-fluorophenyl)(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)methyl)phenol (Compound

     7);

2-((4-(2,3-dichlorophenyl)piperazin-1-yl)(o-tolyl)methyl)phenol (Compound

     8);

N-cyclopentyl-3-((4-(2,3-dichlorophenyl)piperazin-1-yl)(2-hydroxyphenyl)methyl) benzamide (Compound 9, NPB);

2-((4-(benzyloxy)-3-fluorophenyl)(4-(2,3-dichlorophenyl)piperazin-1-yl)methyl)phenol (Compound

     10);

2-((4-((4-chlorophenyl)(phenyl)methyl)piperazin-1-yl)(phenyl)methyl)phenol (Compound

     11);

2-((4-((4-chlorophenyl)(phenyl)methyl)piperazin-1-yl)(p-tolyl)methyl)phenol (Compound

     12);

2-((4-chlorophenyl)(4-((4-chlorophenyl)(phenyl)methyl)piperazin-1-yl)methyl)phenol (Compound

     13);

2-((4-((4-chlorophenyl)(phenyl)methyl)piperazin-1-yl)(4-ethylphenyl)methyl)phenol (Compound

     14);

(4-((4-((4-chlorophenyl)(phenyl)methyl)piperazin-1-yl)(2-hydroxyphenyl)methyl)phenyl) (piperidin-1-yl)methanone (Compound

     15);

N-cyclopentyl-3-((4-(2,3-dichlorophenyl)piperazin-1-yl)(4-hydroxy-[1,1′

-biphenyl]-3-yl)methyl)benzamide (Compound

     16);

N-cyclopentyl-3-((4-(2,3-dichlorophenyl)piperazin-1-yl)(4-hydroxy-2′

-methyl-[1,1′

-biphenyl]-3-yl)methyl)benzamide (Compound

     17);

N-cyclopentyl-3-((4-(2,3-dichlorophenyl)piperazin-1-yl)(4-hydroxy-3′

-methyl-[1,1′

-biphenyl]-3-yl)methyl)benzamide (Compound

     18);

N-cyclopentyl-3-((4-(2,3-dichlorophenyl)piperazin-1-yl)(4-hydroxy-4′

-methyl-[1,1′

-biphenyl]-3-yl)methyl)benzamide (Compound

     19);

3-((2′

-chloro-4-hydroxy-[1,1′

-biphenyl]-3-yl)(4-(2,3-dichlorophenyl)piperazin-1-yl)methyl)-N-cyclopentylbenzamide (Compound

     20);

3-((3′

-chloro-4-hydroxy-[1,1′

-biphenyl]-3-yl)(4-(2,3-dichlorophenyl)piperazin-1-yl)methyl)-N-cyclopentylbenzamide (Compound

     21);

3-((4′

-chloro-4-hydroxy-[1,1′

-biphenyl]-3-yl)(4-(2,3-dichlorophenyl)piperazin-1-yl)methyl)-N-cyclopentylbenzamide (Compound

     22);

N-cyclopentyl-3-((4-(2,3-dichlorophenyl)piperazin-1-yl)(4′

-ethyl-4-hydroxy-[1,1′

-biphenyl]-3-yl)methyl)benzamide (Compound

     23);

N-cyclopentyl-3-((4-(2,3-dichlorophenyl)piperazin-1-yl)(4-hydroxy-4′

-(piperidine-1-carbonyl)-[1,1′

-biphenyl]-3-yl)methyl)benzamide (Compound

     24);

N-cyclopentyl-3-((4-(2,3-dichlorophenyl)piperazin-1-yl)(4-hydroxy-4′

-methoxy-[1,1′

-biphenyl]-3-yl)methyl)benzamide (Compound

     25);

N-cyclopentyl-3-((4-(2,3-dichlorophenyl)piperazin-1-yl)(2′

-ethyl-4-hydroxy-[1,1′

-biphenyl]-3-yl)methyl)benzamide (Compound

     26);

N-cyclopentyl-3-((4-(2,3-dichlorophenyl)piperazin-1-yl)(2′

-fluoro-4-hydroxy-[1,1′

-biphenyl]-3-yl)methyl)benzamide (Compound

     27);

N-cyclopentyl-3-((4-(2,3-dichlorophenyl)piperazin-1-yl)(3′

-fluoro-4-hydroxy-[1,1′

-biphenyl]-3-yl)methyl)benzamide (Compound

     28);

N-cyclopentyl-3-((4-(2,3-dichlorophenyl)piperazin-1-yl)(4′

-fluoro-4-hydroxy-[1,1′

-biphenyl]-3-yl)methyl)benzamide (Compound

     29);

N-cyclopentyl-3-((4-(2,3-dichlorophenyl)piperazin-1-yl)(4-hydroxy-3′

-nitro-[1,1′

-biphenyl]-3-yl)methyl)benzamide (Compound

     30);

N-cyclopentyl-3-((4-(2,3-dichlorophenyl)piperazin-1-yl)(4-hydroxy-3′

-sulfamoyl-[1,1′

-biphenyl]-3-yl)methyl)benzamide (Compound

     31);

N-cyclopentyl-3-((4-(2,3-dichlorophenyl)piperazin-1-yl)(4-hydroxy-2′

-(trifluoromethyl)-[1,1′

-biphenyl]-3-yl)methyl)benzamide (Compound

     32);

N-cyclopentyl-3-((4-(2,3-dichlorophenyl)piperazin-1-yl)(4-hydroxy-3′

-(trifluoromethyl)-[1,1′

-biphenyl]-3-yl)methyl)benzamide (Compound

     33);

N-cyclopentyl-3-((4-(2,3-dichlorophenyl)piperazin-1-yl)(4-hydroxy-4′

-(trifluoromethyl)-[1,1′

-biphenyl]-3-yl)methyl)benzamide (Compound

     34);

3-((2′

-cyano-4-hydroxy-[1,1′

-biphenyl]-3-yl)(4-(2,3-dichlorophenyl)piperazin-1-yl)methyl)-N-cyclopentylbenzamide (Compound

     35);

3-((3′

-cyano-4-hydroxy-[, 1′

-biphenyl]-3-yl)(4-(2,3-dichlorophenyl)piperazin-1-yl)methyl)-N-cyclopentylbenzamide (Compound

     36)

3-((4′

-cyano-4-hydroxy-[, 1′

-biphenyl]-3-yl)(4-(2,3-dichlorophenyl)piperazin-1-yl)methyl)-N-cyclopentylbenzamide (Compound

     37);

3-((2′

-chloro-4-hydroxy-4′

-(trifluoromethyl)-[, 1′

-biphenyl]-3-yl)(4-(2,3-dichlorophenyl) piperazin-1-yl)methyl)-N-cyclopentylbenzamide (Compound

     38);

N-cyclopentyl-3-((2′

,4′

-dichloro-4-hydroxy-[, 1′

-biphenyl]-3-yl)(4-(2,3-dichlorophenyl) piperazin-1-yl)methyl)benzamide (Compound

     39);

3-((4′

-chloro-2′

,4-dihydroxy-[, 1′

-biphenyl]-3-yl)(4-(2,3-dichlorophenyl)piperazin-1-yl)methyl)-N-cyclopentylbenzamide (Compound

     40);

3-((4-(4-chlorophenyl)piperazin-1-yl)(2-hydroxyphenyl)methyl)-N-cyclopentylbenzamide (Compound 41, NCK1)

2-((4-chlorophenyl)(4-(2,3-dichlorophenyl)piperazin-1-yl)methyl)phenol (Compound 42, NCK2)

2-((4-(2,3-dichlorophenyl)piperazin-1-yl)(3-methoxyphenyl)methyl)phenol (Compound 43, NCK3)

1-(5-((4-(2,3-dichlorophenyl)piperazin-1-yl)(2-hydroxyphenyl)methyl)thiophen-2-yl)ethanone (Compound 44, NCK4)

2-((4-(2,3-dichlorophenyl)piperazin-1-yl)(naphthalen-1-yl)methyl)phenol (Compound 45, NCK5)

5-((4-(2,3-dichlorophenyl)piperazin-1-yl)(2-hydroxyphenyl)methyl)furan-2-carbaldehyde (Compound 46, NCK6)

2-((4-(5,6-dichlorocyclohexa-1,5-dien-1-yl)piperazin-1-yl)(2-fluoro-3-methylpyridin-4-yl)methyl)phenol (Compound 47, NCK7)

2-((4-(2,3-dichlorophenyl)piperazin-1-yl)(4-(trifluoromethyl)phenyl)methyl)phenol (Compound 48, NCK8)

2-((6-chloro-5-methylpyridin-3-yl)(4-(2,3-dichlorophenyl)piperazin-1-yl)methyl)phenol (Compound 49, NCK9)

2-((4-(2,3-dichlorophenyl)piperazin-1-yl)(pyridin-3-yl)methyl)phenol (Compound 50, NCK10)

1-(5-((4-(4-chlorophenyl)piperazin-1-yl)(2-hydroxyphenyl)methyl)thiophen-2-yl)ethanone (Compound 51, NCK14)

3-((4-(4-chlorophenyl)piperazin-1-yl)(4-(diethylamino)-2-hydroxyphenyl)methyl)-N-cyclopentylbenzamide (Compound 52, NCK16)

N-cyclopentyl-3-((4-(2,3-dichlorophenyl)piperazin-1-yl)(4-(diethylamino)-2-hydroxyphenyl)methyl)benzamide (Compound 53, NCK18)

N-cyclopentyl-3-((4-(2,3-dichlorophenyl)piperazin-1-yl)(2-hydroxy-4,6-dimethoxyphenyl)methyl)benzamide (Compound 54, NCK19)

2-((4-chlorophenyl)(4-(4-chlorophenyl)piperazin-1-yl)methyl)phenol (Compound 55, NCK20)

2-((4-(4-chlorophenyl)piperazin-1-yl)(6-methylpyridin-3-yl)methyl)phenol (Compound 56, NCK21)

2-(o-tolyl(4-(p-tolyl)piperazin-1-yl)methyl)phenol (Compound 57, SG1)

2-((4-(p-tolyl)piperazin-1-yl)(4-(trifluoromethyl)phenyl)methyl)phenol (Compound 58, SG2) N-cyclopentyl-4-((2-hydroxyphenyl)(4-(p-tolyl)piperazin-1-yl)methyl)benzamide (Compound 59, SG3)

2-((4-chlorophenyl)(4-(p-tolyl)piperazin-1-yl)methyl)phenol (Compound 60, SG4)

2-((3-methoxyphenyl)(4-(p-tolyl)piperazin-1-yl)methyl)phenol (Compound 61, SG5)

5-((2-hydroxyphenyl)(4-(p-tolyl)piperazin-1-yl)methyl)furan-2-carbaldehyde (Compound 62, SG6)

2-((6-methylpyridin-3-yl)(4-(p-tolyl)piperazin-1-yl)methyl)phenol (Compound 63, SG7);

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

25. A process for the preparation of a compound according to claim 1 which comprises reacting an aldehyde of general formula (II):

26. A process for the preparation of a compound according to claim 1 which comprises reacting a compound of general formula (I) in which R¹ is halo with a compound of general formula (V):

27. A method for the treatment of cancer, the method comprising administering to a patient in need of such treatment an effective amount of a compound according to claim 1.

28. The method according to claim 27, wherein the cancer is a cancer in which there is BAD phosphorylation.

29. The method according to claim 28, wherein the cancer is breast cancer, endometrial cancer, ovarian cancer, liver cancer, colon cancer, prostate cancer or pancreatic cancer.

30. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable excipient.

31. A pharmaceutical composition according to claim 29 which is formulated for intraperitoneal administration, hepatoportal administration, intravenous administration, intra articular administration, pancreatic duodenal artery administration, intramuscular administration, or any combination thereof.

2. A compound of general formula general formula (IA):

4. A compound according to claim 2 wherein m is other than 0 and R¹ is halo or an aryl or heteroaryl group optionally substituted as defined in claim 2.

5. A compound according to claim 4 wherein R¹ is an aryl or heteroaryl group optionally substituted with halo, OH, cyano, nitro, —

SO₂NH₂, —

C(O)NR⁴R⁵, —

C_1-4 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 R⁴ and R⁵ together with the nitrogen atom to which they are attached form a piperidine or pyrrolidine ring.

6. A compound according to claim 5 wherein R¹ is an aryl or heteroaryl group optionally substituted with chloro, fluoro, methyl, ethyl, trifluoromethyl, benzyl, methoxy, ethoxy, benzyloxy, trifluoromethoxy and piperidine-1-carbonyl.

11-21. -21. (canceled)