Granted Patent B2

US 10,947,237 · App. 15/557,007 · Granted Mar 16, 2021

Inventors: Ashoke Bhattacharjee (Cheshire, CT); Erin M. Duffy (Deep River, CT); Zoltan F. Kanyo (North Haven, CT); Somenath Chowdhury (New Haven, CT); Vinay Thakur (New Haven, CT); Wan Lau (New Haven, CT)

Assignee: BIOVERSYS AG

C07D487/04C07D471/04

Abstract

Claims (151)

1. A compound of Formula (A):

or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer

wherein:

is a single or a double bond;

X is —NHC(NH)NH 2 , —CH 2 NH 2 , —CH 2 NHC(NH)NH 2 , —CH 2 NHCH 2 C(O)CH 3 , —CH 2 NHC(NH)(C 1 -C 4 )alkyl, —CH 2 NHC(NH)(C 3 -C 7 )cycloalkyl, —CH 2 NHC(NH)heteroaryl, heteroaryl, —CH 2 heteroaryl, —NHCH 2 heteroaryl, —CH 2 NHheteroaryl, —CH(OH)heteroaryl, —CH 2 heterocycloalkyl, —NHCH 2 heterocycloalkyl, or —CH 2 NHheterocycloalkyl, wherein the (C 1 -C 4 )alkyl, cycloalkyl, heterocycloalkyl and heteroaryl are optionally substituted with one or more R 7 ;

Z is O, CH 2 , NR 11 , or S(O) p ;

W is N(R 5 ) or C(R 5 )(R 5′ );

R 1 is H, (C 1 -C 4 )alkyl, (C 2 -C 4 )alkenyl, (C 2 -C 4 )alkynyl, (C 1 -C 3 )alkoxy, (C 1 -C 3 )haloalkyl, —O(C 1 -C 3 )haloalkyl, heterocycloalkyl, halogen, —NO 2 , wherein the (C 1 -C 4 )alkyl, (C 2 -C 4 )alkenyl, and heterocycloalkyl are optionally substituted with one or more R 12 ; or

R 1 and R 2 together with the carbon atoms to which they are attached form a (C 3 -C 7 )cycloalkyl or heterocycloalkyl;

R 2 is —F, —Cl, —CF 3 , —SCF 3 , or —OCF 3 ;

R 3 is H or —NO 2 ;

R 4 is H, (C 1 -C 3 )alkyl, (C 2 -C 3 )alkenyl, halogen, or —NO 2 ;

R 5 is H or —CH 3 ;

R 5′ is H; or

R 6 is H, (C 1 -C 3 )alkyl, (C 2 -C 3 )alkenyl, (C 1 -C 3 )haloalkyl, CH 2 NHC(NH)NH 2 , —CH 2 NHC(NH)(C 1 -C 3 )alkyl, —(CH 2 ) n OH, —CH 2 S(O) p NH 2 , —CH 2 NH(C 1 -C 3 )alkyl, —CH 2 C(O)NH 2 , —(CH 2 ) n NH 2 , —CH 2 heterocycloalkyl, —CH 2 NHheterocycloalkyl, —(CH 2 ) n heteroaryl, or —CH 2 NHheteroaryl, wherein the heteroaryl and heterocycloalkyl is optionally substituted with one or more R 8 ; or

R 5 and R 6 together with the carbon atoms to which they are attached and the Z atom connecting said two carbon atoms, form a (C 5 -C 6 )cycloalkyl or a 5- to 6-membered heterocycloalkyl ring containing 1-3 heteroatoms optionally substituted with one or more R 9 ; or

when W is N(R 5 ), R 6 and W together with the Z atom connecting W and the carbon atom to which R 6 is attached, form a 5- to 6-membered heterocycloalkyl ring containing 1-3 heteroatoms optionally substituted with one or more R 9 ;

at least one of R 5 and R 6 is not H;

each R 7 is independently (C 1 -C 3 )alkyl, halogen, oxo, —OH, or —NH 2 ;

each R 8 is independently (C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy, halogen, oxo, —NH 2 , or —NHR 10 ;

each R 9 is independently (C 1 -C 3 )alkyl, (C 2 -C 4 )alkenyl, —NH 2 , —NHC(NH)NH 2 , —NHC(NH)(C 1 -C 3 )alkyl,_CH 2 heteroaryl, —NHheterocycloalkyl, or —NHheteroaryl, wherein the (C 1 -C 3 )alkyl is optionally substituted with one or more substituents independently selected from —NHC(NH)NH 2 , —OH and —NH 2 ;

each R 10 is independently —CH 2 aryl optionally substituted with (C 1 -C 3 )alkoxy or halogen;

R 11 is H, —NHC(NH)NH 2 , —C(O)H, —C(O)(C 1 -C 4 )alkyl, —C(O)O(C 1 -C 4 )alkyl, (C 1 -C 4 )alkyl, (C 3 -C 6 )cycloalkyl, or heterocycloalkyl, wherein the (C 1 -C 4 )alkyl is optionally substituted with one or more substituents independently selected from —OH, (C 1 -C 3 )alkoxy, —NH 2 , and —NHC(NH)NH 2 ;

each R 12 is independently selected from (C 1 -C 3 )alkoxy, (C 1 -C 3 )haloalkyl, (C 1 -C 3 ) hydroxyalkyl, halogen, —OH, —NH 2 , —NH(C 1 -C 4 )alkyl, —N((C 1 -C 4 )alkyl) 2 , and oxo;

R 13 is —CH 3 , —CH═CH 2 , —CF 3 , —CH 2 F, or —CH 2 OH;

R 13′ is H or —CH 3 ;

n is 1 or 2;

each p is independently 0, 1, or 2; and

provided that when Z is NH, X is —CH 2 NHC(NH)NH 2 or —CH 2 NH 2 , R 1 is H or F, R 3 is H, R 5 is methyl, and R 6 is H, then R 4 is (C 1 -C 3 )alkyl, (C 2 -C 3 )alkenyl, F, I, or —NO 2 ;

provided that when Z is NH, W is not CH(CH 3 ), and X is not CH 2 NHC(NH)NH 2 , and R 2 is not Cl, and R 13 is not CH 3 , and R 6 , R 1 , R 3 , R 4 , and R 13′ are not H.

2. The compound of claim 1 , wherein when Z is NH, X is —NHC(NH)NH 2 , —CH 2 NHC(NH)NH 2 , —CH 2 NHC(NH)(C 1 -C 3 alkyl) or —CH 2 NH 2 , and R 5 is H or CH 3 , then R 6 is not CH 3 , —CH═CH 2 , —(CH 2 ) n NH 2 , —(CH 2 ) n OH or a group of Formula:

and

when Z is NH, X is —NHC(NH)NH 2 , —CH 2 NHC(NH)CH 3 , —CH 2 NHC(NH)NH 2 , —CH 2 NH 2 or a group of Formula:

then R 5 and R 6 do not from a ring of Formula:

and

when Z is O, X is —CH 2 NHC(NH)NH 2 , and R 5 is H, then R 6 is not a group of Formula:

3. The compound of claim 1 , wherein:

Z is O, CH 2 , or NH;

R 1 is H or —NO 2 ;

R 2 is —Cl or —OCF 3 ;

R 4 is H or —NO 2 ;

R 11 is H;

R 13 is —CH 3 ; and

R 13′ is H.

4. The compound of claim 1 , wherein:

R 6 is H, (C 1 -C 3 )alkyl, (C 2 -C 3 )alkenyl, (C 1 -C 3 )haloalkyl, —CH 2 NHC(NH)NH 2 , —CH 2 NHC(NH)CH 3 , —(CH 2 ) n OH, —CH 2 S(O) 2 NH 2 , —CH 2 NHCH 2 CH 3 , —CH 2 C(O)NH 2 , —(CH 2 ) n NH 2 , —CH 2 heterocycloalkyl, —CH 2 NH 2 heterocycloalkyl, —(CH 2 ) n heteroaryl, or —CH 2 NH 2 heteroaryl, wherein the heteroaryl and heterocycloalkyl is optionally substituted with one or more R 8 .

5. The compound of claim 1 , wherein:

R 6 is H, (C 1 -C 3 )alkyl, (C 2 -C 3 )alkenyl, (C 1 -C 3 )haloalkyl, —CH 2 NHC(NH)NH 2 , —(CH 2 ) n OH, —CH 2 S(O) p NH 2 , —CH 2 NH(C 1 -C 3 )alkyl, —CH 2 C(O)NH 2 , —(CH 2 ) n NH 2 , —CH 2 heterocycloalkyl, —CH 2 NH 2 heterocycloalkyl, —(CH 2 ) n heteroaryl, or —CH 2 NH 2 heteroaryl, wherein the heteroaryl and heterocycloalkyl is optionally substituted with one or more R 8 ; and

provided that when Z is NH, X is —CH 2 NHC(NH)NH 2 or —CH 2 NH 2 , R 1 is H, R 3 is H, R 4 is H, then R 6 is not H, —CH 3 , —CH 2 OH, —CH 2 NH 2 NH 2 , or —CH═CH 2 .

6. The compound of claim 1 , wherein:

R 6 is (C 1 -C 3 )alkyl, (C 2 -C 3 )alkenyl, (C 1 -C 3 )haloalkyl, —CH 2 NHC(NH)NH 2 , CH 2 NHC(NH)CH 3 , —CH 2 CH 2 OH, —CH 2 OH, —CH 2 S(O) 2 NH 2 , CH 2 NHCH 2 CH 3 , —CH 2 C(O)NH 2 , —CH 2 CH 2 NH 2 , —CH 2 NH 2 , or a group of Formulae:

wherein any one of the Formulae is optionally substituted with one or more R 8 .

7. The compound of claim 1 , wherein:

R 6 is (C 1 -C 3 )alkyl, (C 2 -C 3 )alkenyl, (C 1 -C 3 )haloalkyl, —CH 2 NHC(NH)NH 2 , —(CH 2 ) n OH, —CH 2 S(O) p NH 2 , —CH 2 NH(C 1 -C 3 )alkyl, —CH 2 C(O)NH 2 , —(CH 2 ) n NH 2 ,

wherein the heteroaryl and heterocycloalkyl are optionally substituted with one or more R 8 ; and

provided that when Z is NH, X is —CH 2 NHC(NH)NH 2 or —CH 2 NH 2 , R 1 is H, R 3 is H, R 4 is H, then R 6 is not (C 1 -C 3 )alkyl or (C 2 -C 3 )alkenyl.

8. The compound of claim 1 , wherein:

R 6 is

and

provided that when Z is NH, X is —CH 2 NHC(NH)NH 2 or —CH 2 NH 2 , R 1 is H, R 3 is H, R 4 is H, then R 6 is not (C 1 -C 3 )alkyl or (C 2 -C 3 )alkenyl.

9. The compound of claim 1 , wherein:

X is —CH 2 NHCH 2 C(O)CH 3 , —CH 2 NHC(NH)(C 1 -C 4 )alkyl, —CH 2 NHC(NH)(C 3 -C 7 )cycloalkyl, —CH 2 NHC(NH)heteroaryl, heteroaryl, —NHCH 2 heteroaryl, —CH 2 NHheteroaryl, —CH(OH)heteroaryl, —CH 2 heterocycloalkyl, —NHCH 2 heterocycloalkyl, or —CH 2 NHheterocycloalkyl, wherein the (C 1 -C 4 )alkyl, cycloalkyl, heterocycloalkyl and heteroaryl are optionally substituted with one or more R 7 ;

R 1 is H;

R 3 is H;

R 4 is H;

R 5 and R 6 together with the carbon atoms to which they are attached and the Z atom connecting said two carbon atoms, form a (C 5 -C 6 )cycloalkyl or a 5- to 6-membered heterocycloalkyl ring containing 1-3 heteroatoms optionally substituted with one or more R 9 ;

provided that when Z is NH, R 1 is H, R 2 is H, R 3 is H and R 4 is H, then X is not —CH 2 NHC(NH)CH 3 .

10. The compound of claim 1 , wherein:

X is —CH 2 NHCH 2 C(O)CH 3 , —CH 2 NHC(NH)(C 1 -C 4 )alkyl, —CH 2 NHC(NH)(C 3 -C 7 )cycloalkyl, —CH 2 NHC(NH)heteroaryl, or —CH(OH)heteroaryl, wherein the (C 1 -C 4 )alkyl, cycloalkyl, and heteroaryl are optionally substituted with one or more R 7 ;

R 1 is H;

R 3 is H;

R 4 is H;

R 5 and R 6 together with the carbon atoms to which they are attached and the Z atom connecting said two carbon atoms, form a (C 5 -C 6 )cycloalkyl or a 5- to 6-membered heterocycloalkyl ring containing 1-3 heteroatoms optionally substituted with one or more R 9 ; and

provided that when Z is NH, R 1 is H, R 2 is H, R 3 is H and R 4 is H, then X is not —CH 2 NHC(NH)CH 3 .

11. The compound of claim 1 , wherein:

X is —CH 2 NHCH 2 C(O)CH 3 , —CH 2 NHC(NH)(C 1 -C 4 )alkyl, —CH 2 NHC(NH)(C 1 -C 4 )haloalkyl, —CH 2 NHC(NH)(C 3 -C 7 )cycloalkyl, or a group selected from:

wherein the (C 1 -C 4 )alkyl, cycloalkyl, and any one of the above structures are optionally substituted with one or more R 7 .

12. The compound of claim 1 , wherein

when Z is NH and X is —NHC(NH)NH 2 , —CH 2 NHC(NH)NH 2 , or —CH 2 NH 2 ,

then R 5 and R 6 do not from a ring of Formula:

13. The compound of claim 11 , wherein the compound is not:

14. The compound of claim 1 , wherein

when Z is NH and X is any one of the following Formulae:

then R 5 and R 6 do not from a ring of Formula:

15. The compound of claim 1 , wherein:

R 5 and R 6 form a ring of Formula:

16. The compound of claim 1 , wherein:

X is

wherein each heterocycloalkyl and heteroaryl in the above structures is optionally substituted with one or more R 7 ;

R 1 is H;

R 3 is H;

R 4 is H;

R 5 and R 6 together with the carbon atoms to which they are attached and the Z atom connecting said two carbon atoms, form a (C 5 -C 6 )cycloalkyl or a 5- to 6-membered heterocycloalkyl ring containing 1-3 heteroatoms optionally substituted with one or more R 9 ; and

provided that when Z is NH, R 1 is H, R 2 is H, R 3 is H and R 4 is H, then X is not —CH 2 NHC(NH)CH 3 .

17. The compound of claim 1 , wherein

Z is O;

W is CH 2 ; and

R 6 is (C 1 -C 3 )alkyl, (C 2 -C 3 )alkenyl, (C 1 -C 3 )haloalkyl, —(CH 2 ) n OH, —CH 2 NHC(NH)NH 2 , CH 2 NH 2 , CH 2 NHheteroaryl, or —CH 2 NHC(═NH) (C 1 -C 3 )alkyl.

18. The compound of claim 1 , wherein

Z is O;

W is CH 2 ; and

R 6 is CH 3 , —CH═CH 2 , CH 2 F, —CH 2 NHC(NH)NH 2 , —CH 2 NHC(═NH)CH 3 , —CH 2 OH, or —CH 2 NH 2 .

19. The compound of claim 17 , wherein

when X is —CH 2 NHC(NH)NH 2 , then R 6 is not a group of Formula:

20. The compound of claim 1 , wherein:

Z is O;

R 6 is H, (C 1 -C 3 )alkyl, (C 2 -C 3 )alkenyl, (C 1 -C 3 )haloalkyl, —CH 2 NHC(NH)NH 2 , —(CH 2 ) n OH, —CH 2 S(O) p NH 2 , —CH 2 NH(C 1 -C 3 )alkyl, —CH 2 C(O)NH 2 , —(CH 2 ) n NH 2 , —CH 2 heterocycloalkyl, —CH 2 NH 2 heterocycloalkyl, —(CH 2 ) n heteroaryl, or —CH 2 NH 2 heteroaryl, wherein the heteroaryl and heterocycloalkyl is optionally substituted with one or more R 8 ; and

at least one of R 5 and R 6 is not H.

21. The compound of claim 1 , wherein:

Z is CH 2 ;

R 6 is H, (C 1 -C 3 )alkyl, (C 2 -C 3 )alkenyl, (C 1 -C 3 )haloalkyl, —CH 2 NHC(NH)NH 2 , —(CH 2 ) n OH, —CH 2 S(O) p NH 2 , —CH 2 NH(C 1 -C 3 )alkyl, —CH 2 C(O)NH 2 , —(CH 2 ) n NH 2 , —CH 2 heterocycloalkyl, —CH 2 NH 2 heterocycloalkyl, (CH 2 ) n heteroaryl, or —CH 2 NH 2 heteroaryl, wherein the heteroaryl and heterocycloalkyl is optionally substituted with one or more R 8 ; and

at least one of R 5 and R 6 is not H.

22. The compound of claim 1 , wherein:

Z is NH;

R 6 is H, (C 1 -C 3 )alkyl, (C 2 -C 3 )alkenyl, (C 1 -C 3 )haloalkyl, —CH 2 NHC(NH)NH 2 , —(CH 2 ) n OH, —CH 2 S(O) p NH 2 , —CH 2 NH(C 1 -C 3 )alkyl, —CH 2 C(O)NH 2 , —(CH 2 ) n NH 2 , —CH 2 heterocycloalkyl, —CH 2 NH 2 heterocycloalkyl, —(CH 2 ) n heteroaryl, or —CH 2 NH 2 heteroaryl, wherein the heteroaryl and heterocycloalkyl is optionally substituted with one or more R 8 ;

at least one of R 5 and R 6 is not H; and

provided that when X is —CH 2 NHC(NH)NH 2 or —CH 2 NH 2 , R 1 is H, R 3 is H, R 4 is H, then R 6 is not H, (C 1 -C 3 )alkyl or (C 2 -C 3 )alkenyl.

23. The compound of claim 1 , wherein:

X is —CH 2 NH 2 or —CH 2 NHC(NH)NH 2 ;

Z is NH;

R 1 is H or —NO 2 ;

R 2 is —Cl or —OCF 3 ;

R 3 is H or —NO 2 ;

R 4 is —NO 2 ;

R 5 is H or —CH 3 ;

and R 6 is H.

24. The compound of claim 1 , wherein X is —NHC(NH)NH 2 , —CH 2 NH 2 , or —CH 2 NHC(NH)NH 2 .

25. The compound of claim 1 , wherein X is —CH 2 NHCH 2 C(O)CH 3 , —CH 2 NHC(NH)(C 1 -C 4 )alkyl, —CH 2 NHC(NH)(C 3 -C 7 )cycloalkyl, or —CH 2 NHC(NH)heteroaryl, wherein the (C 1 -C 4 )alkyl, cycloalkyl, and heteroaryl optionally substituted with one or more R 7 .

26. The compound of claim 1 , wherein X is —CH(OH)heteroaryl optionally substituted with one or more R 7 .

27. The compound of claim 1 , wherein X is

wherein each is optionally substituted with one or more R 7 .

28. The compound of claim 1 , wherein R 2 is —Cl.

29. The compound of claim 1 , wherein R 1 is H, R 3 is H and R 4 is H.

30. The compound of claim 1 , wherein Z is NH.

31. The compound of claim 1 , wherein Z is O.

32. The compound of claim 1 , wherein Z is CH 2 .

33. The compound of claim 1 , wherein R 5 is H.

34. The compound of claim 1 , wherein W is NR 5 .

35. The compound of claim 1 , wherein W is CHR 5 .

36. The compound of claim 1 , wherein R 6 is (C 1 -C 3 )alkyl, (C 2 -C 3 )alkenyl, or (C 1 -C 3 )haloalkyl.

37. The compound of claim 1 , wherein R 6 is (C 1 -C 3 )alkyl, (C 2 -C 3 )alkenyl, or (C 1 -C 3 )haloalkyl and X is —CH 2 NHCH 2 C(O)CH 3 , —CH 2 NHC(NH)(C 1 -C 4 )alkyl, —CH 2 NHC(NH)(C 3 -C 7 )cycloalkyl, or —CH 2 NHC(NH)heteroaryl, or —CH(OH)heteroaryl, wherein the (C 1 -C 4 )alkyl, cycloalkyl and heteroaryl is optionally substituted with one or more R 7 .

38. The compound of claim 1 , wherein R 6 is —CH 2 NHC(NH)NH 2 , —(CH 2 ) n OH, —CH 2 S(O) p NH 2 , —CH 2 NH(C 1 -C 3 )alkyl, —CH 2 C(O)NH 2 , or —(CH 2 ) n NH 2 .

39. The compound of claim 1 , wherein R 6 is

wherein each heteroaryl and heterocycloalkyl is optionally substituted with one or more R 8 .

40. The compound of claim 1 , wherein R 6 is

41. The compound of claim 1 having any one of the following Formulae:

42. The compound of claim 1 , wherein the compound of Formula A is selected from any one of compounds 1, 3-76, 78, 81-89, 91, 92, 96, 97, 106, 107, 109-111, 119, 120, 127, 128, 132-135, 137, 138, 143, 150, 151, and 153:

43. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer.

44. A method of treating a microbial infection comprising administering to a subject in need thereof an effective amount of a compound of claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer.

45. A method of reducing the risk of a microbial infection comprising administering to a subject in need thereof an effective amount of a compound of claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer.

46. A method of delaying the onset of a microbial infection comprising administering to a subject in need thereof an effective amount of a compound of claim 1 , or a tautomer thereof, or a pharmaceutically acceptable salt of said compound or tautomer.

Assignments (10)