Methods and compositions of inhibiting DCN1-UBC12 interaction

Patent metadata

Field	Value
Publication number	US-11116757-B2
Application number	US-201916683076-A
Country	US
Kind code	B2
Filing date	Nov 13, 2019
Priority date	Sep 18, 2015
Publication date	Sep 14, 2021
Grant date	Sep 14, 2021

Abstract

In one aspect, the invention relates to substituted 1-phenyl-3-(piperidin-4-yl)urea analogs, derivatives thereof, and related compounds, which are useful as inhibitors of the DCN1-UBC12 interaction inhibitors of DCN1-mediated cullin-RING ligase activity, methods of making same, pharmaceutical compositions comprising same, methods of treating disorders using the disclosed compounds and compositions, methods of treating disorders associated with a DCN1-UBC12 interaction dysfunction, methods of treating disorders associated with a DCN1-mediated cullin-RING ligase activity dysfunction, methods of male contraception comprising the disclosed compounds and compositions, and kits comprising the disclosed compounds and compositions. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

First claim

What is claimed is:

1. A compound having a structure represented by a formula:

or a pharmaceutically acceptable salt thereof, wherein
each of R 1a , R 1b , and R 1c is independently hydrogen, halogen, —SF 5 , —NO 2 , —CH 3 , —CH 2 F, —CHF 2 , —CF 3 , —OCF 3 , —NHCH 3 , —N(CH 3 ) 2 , —(CH 2 )-phenyl, —(CH 2 )-pyridinyl, —(CH 2 )-pyrimidinyl, —O-phenyl, —O-pyridinyl, or —O-pyrimidinyl, provided that at least one of R 1a , R 1b , and R 1c is not hydrogen; or wherein R 1a and R 1b are optionally covalently bonded and, together with the intermediate atoms, comprise an optionally substituted 3- to 7-membered fused aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalklyl, or heterocycloalkenyl; and wherein R 1c is hydrogen, halogen, —OH, —SCF 3 , —SF 5 , —NO 2 , —CH 3 , —CH 2 F, —CHF 2 , —CF 3 , —OCF 3 , —NHCH 3 , or —N(CH 3 ) 2 ;
R 2 is C3-C6 alkyl, —(C1-C6 alkyl)-CF 3 , —(C1-C6-(C1-C3 alkyl)-cyclopropyl, —(C1-C3 alkyl)-cyclobutyl, —(C1-C3 alkyl)-cyclopentyl, —(C1-C3 alkyl)-cyclohexyl, or —SO 2 —(C1-C6 alkyl); and wherein R 2 is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —SCF 3 , —SF 5 , NO 2 , —CH 3 , —CH 2 F, —CHF 2 , —CF 3 , —OCF 3 , —NHCH 3 , and —N(CH 3 ) 2 ; and
R 3 is Ar 1 or —(C1-C3 alkyl)-Ar 1 ;
wherein Ar 1 is phenyl independently substituted with 0, 1, 2, or 3 groups selected from halogen, —SF 5 , —NO 2 , —CH 3 , —CH 2 F, —CHF 2 , —CF 3 , —OCF 3 , —NHCH 3 , and -N(CH 3 ) 2 , or is pyridinyl having a structure represented by:

wherein each of R 20a , R 20b , R 20c , and R 20d is independently selected from hydrogen, halogen, —SF 5 , —NO 2 , —CH 3 , —CH 2 F, —CHF 2 , —CF 3 , —OCF 3 , —NHCH 3 , —N(CH 3 ) 2 , —NHC(O)CH═CH 2 , and -(CH 2 )NHC(O)CH═CH 2 , provided that at least one of R 20a , R 20b , R 20c , and R 20d is hydrogen.

2. The compound of claim 1 , wherein each of R 1a , R 1b , and R 1c is independently hydrogen, halogen, —SF 5 , —CH 3 , —CF 3 , or —OCF 3 , provided that at least one of R 1a , R 1b , and R 1c is not hydrogen.

3. The compound of claim 1 , wherein R 1c is hydrogen; and wherein each of R 1a and R 1b is independently halogen, —SF 5 , —CH 3 , —CF 3 , or —OCF 3 .

4. The compound of claim 1 , wherein R 1b is hydrogen; and wherein each of R 1a and R 1c is independently halogen, —SF 5 , —CH 3 , —CF 3 , or —OCF 3 .

5. The compound of claim 1 , wherein each of R 1b and R 1c is hydrogen; and wherein R 1a is independently halogen, —SF 5 , —CH 3 , —CF 3 , or —OCF 3 .

6. The compound of claim 1 , wherein R 2 is C3-C6 alkyl, —(CH 2 )-cyclopropyl, —(CH 2 )-cyclobutyl, —(CH 2 )-cyclopentyl, or -(CH 2 )-cyclohexyl.

7. The compound of claim 1 , wherein R 2 is C3-C6 alkyl or —(CH 2 )-cyclopropyl.

8. The compound of claim 1 , wherein R 2 is —(CH 2 )-cyclopropyl.

9. The compound of claim 1 , wherein R 2 is C3-C6 alkyl.

10. The compound of claim 1 , wherein R 2 has a structure represented by a formula:

11. The compound of claim 1 , wherein Ar 1 is phenyl independently substituted with 0, 1, 2, or 3 groups selected from halogen, —SF 5 , —NO 2 , —CH 3 , —CH 2 F, —CHF 2 , —CF 3 , —OCF 3 , —NHCH 3 , and —N(CH 3 ) 2 .

12. The compound of claim 1 , wherein Ar 1 is the pyridinyl group having the structure represented by:

13. A compound having a structure represented by a formula:

14. A contraceptive method comprising the step of administering to a male mammal a prophylactically effective amount of a compound of claim 1 .

15. A method for treating a viral or bacterial infection, the method comprising the step of administering to a mammal suffering from the viral or bacterial infection a therapeutically effective amount of a compound of claim 1 .

16. A contraceptive method comprising the step of administering to a male mammal a prophylactically effective amount of a compound selected from:

or a pharmaceutically acceptable salt thereof.

17. A composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

18. A composition comprising a compound of claim 11 and a pharmaceutically acceptable carrier.

19. A composition comprising a compound of claim 12 and a pharmaceutically acceptable carrier.

20. A compound having a structure represented by a formula:

or a pharmaceutically acceptable salt thereof, wherein
each of R 1a , R 1b , and R 1c is independently hydrogen, halogen, —SF 5 , —NO 2 , —CH 3 , CH 2 F, —CHF 2 , —CF 3 , —OCF 3 , —NHCH 3 , —N(CH 3 ) 2 , —(CH 2 )-phenyl, —(CH 2 )-pyridinyl, —(CH 2 )-pyrimidinyl, —O-phenyl, —O-pyridinyl, or —O-pyrimidinyl, provided that at least one of R 1a , R 1b , and R 1c is not hydrogen; or wherein R 1a and R 1b are optionally covalently bonded and, together with the intermediate atoms, comprise an optionally substituted 3- to 7-membered fused aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocycloalklyl, or heterocycloalkenyl; and wherein R 1c is hydrogen, halogen, —OH, —SCF 3 , —SF 5 , —NO 2 , —CH 3 , —CH 2 F, —CHF 2 , —CF 3 , —OCF 3 , —NHCH 3 , or —N(CH 3 ) 2 ;

R 2 is C3-C6 alkyl, —(C1-C6 alkyl)-CF 3 , —(C1-C6 alkyl)-C≡CH, —(C1-C3 alkyl)-cyclopropyl, —(C1-C3 alkyl)-cyclobutyl, —(C1-C3 alkyl)-cyclopentyl, —(C1-C3 alkyl)-cyclohexyl, —(C1-C3 alkyl)-heteroaryl, or —SO 2 —(C1-C6 alkyl); and wherein R 2 is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —SCF 3 , —SF 5 , NO 2 , —CH 3 , —CH 2 F, —CHF 2 , —CF 3 , —OCF 3 , —NHCH 3 , and —N(CH 3 ) 2 ; and
R 3 is Ar 1 or —(C1-C3 alkyl)-Ar 1 ;
wherein Ar 1 is phenyl independently substituted with 0, 1, 2, or 3 groups selected from halogen, —SF 5 , NO 2 , —CH 3 , —CH 2 F, —CHF 2 , —CF 3 , —OCF 3 , —NHCH 3 , and -N(CH 3 ) 2 .

21. The compound of claim 20 , wherein each of R 1a , R 1b and R 1c is independently hydrogen, halogen, —SF 5 , —CH 3 , —CF 3 , or —OCF 3 , provided that at least one of R 1a , R 1b , and R 1c is not hydrogen.

22. The compound of claim 20 , wherein R 2 is C3-C6 alkyl, —(CH 2 )-cyclopropyl, —(CH 2 )-cyclobutyl, —(CH 2 )-cyclopentyl, or —(CH 2 )-cyclohexyl.

23. The compound of claim 20 , wherein R 2 is C3-C6 alkyl or —(CH 2 )-cyclopropyl.

24. The compound of claim 20 , wherein R 2 has a structure represented by a formula:

25. A composition comprising a co

Assignees

• Memorial Sloan Kettering Cancer Center
• St Jude Childrens Res Hospital

Inventors

• Min Jaeki
• Scott Daniel C
• Bhasin Deepak
• Schulman Brenda A
• Singh Bhuvanesh
• Hammill Jared T
• Guy R Kiplin

Classifications

• A61P31/12

  Antivirals · CPC title

• C07D401/06

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

• C07D409/14

  containing three or more hetero rings · CPC title

• A61P31/04

  Antibacterial agents · CPC title

• C07D401/12

  linked by a chain containing hetero atoms as chain links · CPC title