IP Library › Granted Patent US 11,021,471

Granted Patent B2

US 11,021,471 · App. 16/612,308 · Granted Jun 1, 2021

Antibacterial compounds

Inventors: Min Teng (San Diego, CA); Baskar Nammalwar (San Diego, CA); Konstantin Taganov (San Diego, CA); Xiaoming Li (San Diego, CA); David T. Puerta (San Diego, CA)

Assignee: FORGE THERAPEUTICS, INC.

C07D405/14 A61P31/04 C07D309/40 C07D405/06 C07D405/12 C07D407/04 C07D413/10 C07D471/04 C07D487/04 C07D493/04

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Quick Facts

Patent No.: US 11,021,471
App. No.: 16/612,308
Granted: Jun 1, 2021
Kind: B2

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Abstract

Provided herein are heterocyclic derivative compounds and pharmaceutical compositions comprising said compounds that are useful for inhibiting the growth of gram-negative bacteria. Furthermore, the subject compounds and compositions are useful for the treatment of bacterial infection, such as urinary tract infection and the like.

Claims (103)

1. A compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (I):

wherein,

n is 0, 1, or 2;

m is 0, 1, or 2;

A 1 is OH or SH;

A 2 is O or S;

L is *—CR 1 R 2 —CR 3 R 4 —; *—N(R 5 )—CR 3 R 4 —; *—CR 1 R 2 —N(R 5 )—; *—O—CR 3 R 4 —; *—CR 1 R 2 —O—; *—S—CR 3 R 4 —; *—CR 1 R 2 —S—; *—N(R 5 )—C(O)—; *—C(O)—N(R 5 )—; *—N(R 5 )—S(O) 2 —; *—S(O) 2 —N(R 5 )—, or

wherein the * denotes a bond to the 4H-pyran-4-one ring or 4H-pyran-4-thione ring;

R 1 , R 3 , and R 5 are each independently H, unsubstituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclalkyl, —COR 11 , —CON(R 11 ) 2 , optionally substituted (C 0 -C 4 alkylene)-CN, optionally substituted (C 0 -C 4 alkylene)-OR 11 , optionally substituted (C 0 -C 4 alkylene)-N(R 11 ) 2 , optionally substituted (C 0 -C 4 alkylene)N(R 12 )—COR 11 , optionally substituted (C 0 -C 4 alkylene)N(R 12 )—CO 2 R 11 , optionally substituted (C 0 -C 4 alkylene)N(R 12 )—CON(R 11 ) 2 , optionally substituted (C 0 -C 4 alkylene)-SO 2 N(R 11 ) 2 , optionally substituted (C 0 -C 4 alkylene)-SO 2 R 11 , optionally substituted (C 0 -C 4 alkylene)N(R 12 )—SO 2 N(R 11 ) 2 , optionally substituted (C 0 -C 4 alkylene)N(R 12 )—SO 2 R 11 , optionally substituted (C 0 -C 4 alkylene)-O—SO 2 N(R 11 ) 2 , optionally substituted (C 1 -C 4 alkylene)-N(R 12 )—SO 2 R 11 , optionally substituted (C 1 -C 4 alkylene)-SO 2 R 11 , or optionally substituted (C 0 -C 4 alkylene)N(R 11 )—PO (optionally substituted C 1 -C 4 alkyl) 2 ;

R 2 and R 4 are each independently H or optionally substituted C 1 -C 3 alkyl;

R 6 is H;

X is halogen or optionally substituted C 1 -C 3 alkyl;

Y is halogen or optionally substituted C 1 -C 3 alkyl;

W is a bond, —C≡C—, or —C≡C—C≡C—;

Z is H, -L2-G, optionally substituted (C 1 -C 4 alkylene)-OCON(R 13 ) 2 , optionally substituted (C 1 -C 4 alkylene)-N(R 14 )CON(R 13 ) 2 , or optionally substituted (C 1 -C 4 alkylene)-SO 2 N(R 13 ) 2 ;

L2 is a bond, optionally substituted C 1 -C 4 alkylene, —C(O)—, or —SO 2 —;

G is optionally substituted heterocyclyl, optionally substituted heteroaryl, —N(R 13 ) 2 , —OR 13 , or —CN;

each R 11 is independently selected from H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; or two R 11 groups together with the nitrogen to which they are attached join to form an optionally substituted N-heterocyclyl;

each R 12 is independently H or optionally substituted alkyl;

each R 13 is independently H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; or two R 13 groups together with the nitrogen to which they are attached join to form an optionally substituted N-heterocyclyl; and

each R 14 is independently H or optionally substituted alkyl;

provided that if R 1 is H, then R 3 or R 5 is not H; or if R 3 is H, then R 1 or R 5 is not H; and if W is a bond, then R 1 is not propyl, —CH 2 CH 2 OH, —CH 2 CH(OH)CH 2 OH;

wherein:

R 1 is unsubstituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclalkyl, —COR 11 , —CON(R 11 ) 2 , optionally substituted (C 1 -C 4 alkylene)-CN, optionally substituted (C 1 -C 4 alkylene)-OR 11 , optionally substituted (C 1 -C 4 alkylene)-N(R 11 ) 2 , optionally substituted (C 1 -C 4 alkylene)N(R 12 )—COR 11 , optionally substituted (C 1 -C 4 alkylene)N(R 12 )—CO 2 R 11 , optionally substituted (C 1 -C 4 alkylene)N(R 12 )—CON(R 11 ) 2 , optionally substituted (C 1 -C 4 alkylene)N(R 12 )—SO 2 N(R 11 ) 2 , optionally substituted (C 1 -C 4 alkylene)-O—SO 2 N(R 11 ) 2 , optionally substituted (C 1 -C 4 alkylene)-N(R 12 )—SO 2 R 11 , optionally substituted (C 1 -C 4 alkylene)-SO 2 R 11 , or optionally substituted (C 1 -C 4 alkylene)N(R 11 )—PO (optionally substituted C 1 -C 4 alkyl) 2 ; or

R 3 is unsubstituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclalkyl, —COR 11 , —CON(R 11 ) 2 , optionally substituted (C 1 -C 4 alkylene)-CN, optionally substituted (C 1 -C 4 alkylene)-OR 11 , optionally substituted (C 1 -C 4 alkylene)-N(R 11 ) 2 , optionally substituted (C 1 -C 4 alkylene)N(R 12 )—COR 11 , optionally substituted (C 1 -C 4 alkylene)N(R 12 )—CO 2 R 11 , optionally substituted (C 1 -C 4 alkylene)N(R 12 )—CON(R 11 ) 2 , optionally substituted (C 1 -C 4 alkylene)N(R 12 )—SO 2 N(R 11 ) 2 , optionally substituted (C 1 -C 4 alkylene)-O—SO 2 N(R 11 ) 2 , optionally substituted (C 1 -C 4 alkylene)-N(R 12 )—SO 2 R 11 , optionally substituted (C 1 -C 4 alkylene)-SO 2 R 11 , or optionally substituted (C 1 -C 4 alkylene)N(R 11 )—PO (optionally substituted C 1 -C 4 alkyl) 2 .

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

R 1 is H, unsubstituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclalkyl, —CON(R 11 ) 2 , optionally substituted (C 1 -C 4 alkylene)-CN, optionally substituted (C 1 -C 4 alkylene)-OR 11 , optionally substituted (C 1 -C 4 alkylene)-N(R 11 ) 2 , optionally substituted (C 1 -C 4 alkylene)N(R 12 )—COR 11 , optionally substituted (C 1 -C 4 alkylene)N(R 12 )—CO 2 R 11 , optionally substituted (C 1 -C 4 alkylene)N(R 12 )—CON(R 11 ) 2 , optionally substituted (C 1 -C 4 alkylene)N(R 12 )—SO 2 N(R 11 ) 2 , optionally substituted (C 1 -C 4 alkylene)-O—SO 2 N(R 11 ) 2 , optionally substituted (C 1 -C 4 alkylene)-N(R 12 )—SO 2 R 11 , optionally substituted (C 1 -C 4 alkylene)-SO 2 R 11 , or optionally substituted (C 1 -C 4 alkylene)N(R 11 )—PO (optionally substituted C 1 -C 4 alkyl) 2 ; and

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

R 3 is H, unsubstituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclalkyl, —COR 11 , —CON(R 11 ) 2 , optionally substituted (C 1 -C 4 alkylene)-CN, optionally substituted (C 1 -C 4 alkylene)-OR 11 , optionally substituted (C 1 -C 4 alkylene)-N(R 11 ) 2 , optionally substituted (C 1 -C 4 alkylene)N(R 12 )—COR 11 , optionally substituted (C 1 -C 4 alkylene)N(R 12 )—CO 2 R 11 , optionally substituted (C 1 -C 4 alkylene)N(R 12 )—CON(R 11 ) 2 , optionally substituted (C 1 -C 4 alkylene)N(R 12 )—SO 2 N(R 11 ) 2 , optionally substituted (C 1 -C 4 alkylene)-O—SO 2 N(R 11 ) 2 , optionally substituted (C 1 -C 4 alkylene)-N(R 12 )—SO 2 R 11 , optionally substituted (C 1 -C 4 alkylene)-SO 2 R 11 , or optionally substituted (C 1 -C 4 alkylene)N(R 11 )—PO (optionally substituted C 1 -C 4 alkyl) 2 .

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 and R 4 are each independently H or optionally substituted C 1 -C 3 alkyl; and R 5 is H or unsubstituted alkyl.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein n is 0; and m is 0.

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Z is -L2-G, optionally substituted (C 1 -C 4 alkylene)-OCON(R 13 ) 2 , optionally substituted (C 1 -C 4 alkylene)-N(R 14 )CON(R 13 ) 2 , or optionally substituted (C 1 -C 4 alkylene)-SO 2 N(R 13 ) 2 .

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L is selected from *—CR 1 R 2 —CR 3 R 4 —; *—CR 1 R 2 —N(R 5 )—; or *—C(O)—N(R 5 )—.

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A 1 is OH; and A 2 is O.

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

3-hydroxy-2-(1-(methylsulfonyl)-2-(44(4-(morpholinomethyl)phenyl)ethynyl)phenyl)ethyl)-4H-pyran-4-one;

3-hydroxy-4-oxo-N-(4-(phenylbuta-1,3-diyn-1-yl)phenyl)-4H-pyran-2-carboxamide;

N-(3-([1,1′-biphenyl]-4-yl)-2-(3-hydroxy-4-oxo-4H-pyran-2-yl)propyl)methanesulfonamide;

2-(1-([1,1′-biphenyl]-4-yl)-3-(methylsulfonyl)propan-2-yl)-3-hydroxy-4H-pyran-4-one;

2-(1-([1,1′-biphenyl]-4-yl)-3-hydroxypropan-2-yl)-3-hydroxy-4H-pyran-4-one;

2-(1-([1,1′-biphenyl]-4-yl)-3-aminopropan-2-yl)-3-hydroxy-4H-pyran-4-one; and

2-(([1,1′-biphenyl]-4-yl(2-hydroxyethyl)amino)methyl)-3-hydroxy-4H-pyran-4-one.

10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, having the structure of Formula (Ia), Formula (Ib), or Formula (Ic):

11. The compound of claim 1 , wherein the compound, or a pharmaceutically acceptable salt thereof, has the structure of formula (Id):

12. A compound, or a pharmaceutically acceptable salt thereof, having the structure of Formula (II):

wherein,

n is 0, 1, or 2;

m is 0, 1, or 2;

A 1 is OH;

A 2 is O;

L is a bond, *—CR 1 R 2 —CR 3 R 4 —; *—N(R 5 )—CR 3 R 4 —; *—CR 1 R 2 —N(R 5 )—; *—O—CR 3 R 4 —; *—CR 1 R 2 —O—; *—S—CR 3 R 4 —; *—CR 1 R 2 —S—; *—N(R 5 )—C(O)—; *—C(O)—N(R 5 )—; *—N(R 5 )—S(O) 2 —; *—S(O) 2 —N(R 5 )—, or

wherein the * denotes a bond to the 4H-pyran-4-one ring;

R 1 and R 3 are each independently H, unsubstituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroaralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclalkyl, —CON(R 11 ) 2 , optionally substituted (C 0 -C 4 alkylene)-CN, optionally substituted (C 0 -C 4 alkylene)-OR 11 , optionally substituted (C 0 -C 4 alkylene)-N(R 11 ) 2 , optionally substituted (C 0 -C 4 alkylene)N(R 12 )—COR 11 , optionally substituted (C 0 -C 4 alkylene)N(R 12 )—CO 2 R 11 , optionally substituted (C 0 -C 4 alkylene)N(R 12 )—CON(R 11 ) 2 , optionally substituted (C 0 -C 4 alkylene)-SO 2 N(R 11 ) 2 , optionally substituted (C 0 -C 4 alkylene)-SO 2 R 11 , optionally substituted (C 0 -C 4 alkylene)N(R 12 )—SO 2 N(R 11 ) 2 , optionally substituted (C 0 -C 4 alkylene)N(R 12 )—SO 2 R 11 , optionally substituted (C 0 -C 4 alkylene)-O—SO 2 N(R 11 ) 2 , optionally substituted (C 1 -C 4 alkylene)-N(R 12 )—SO 2 R 11 , optionally substituted (C 1 -C 4 alkylene)-SO 2 R 11 , or optionally substituted (C 0 -C 4 alkylene)N(R 11 )—PO (optionally substituted C 1 -C 4 alkyl) 2 ;

R 2 , R 4 , and R 5 are each independently H or optionally substituted C 1 -C 3 alkyl;

R 6 is H;

is phenyl,

W is a bond, —S—, —SO—, —SO 2 —, —O—, —CR 1 R 3 —, —C(═CR 1 H)—, *—CR 1 ═CR 3 —; *—CR 1 R 2 —CR 3 R 4 —; *—N(R 5 )—CR 3 R 4 —; *—CR 1 R 2 —N(R 5 )—; *—O—CR 3 R 4 —; *—CR 1 R 2 —O—; *—S—CR 3 R 4 —; *—CR 1 R 2 —S—; *—N(R 5 )—C(O)—; *—C(O)—N(R 5 )—; *—N(R 5 )—S(O) 2 —; or *—S(O) 2 —N(R 5 )—, wherein the * denotes a bond to

is phenyl, cycloalkyl,

provided that if

is phenyl, then

is not phenyl; and

is phenyl, then

is not phenyl;

X is halogen or optionally substituted C 1 -C 3 alkyl;

Y is halogen or optionally substituted C 1 -C 3 alkyl;

L2 is a bond, optionally substituted C 1 -C 4 alkylene, —C(O)—, or —SO 2 —;

G is optionally substituted heterocyclyl, optionally substituted heteroaryl, —N(R 13 ) 2 , —OR 13 , halogen, or —CN;

each R 11 is independently H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted carbocyclyl, optionally substituted carbocyclylalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heterocyclyl, optionally substituted heterocyclylalkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl; or two R 11 groups together with the nitrogen to which they are attached join to form an optionally substituted N-heterocyclyl;

each R 12 is independently H or optionally substituted alkyl;

each R 14 is independently selected from H or optionally substituted alkyl.

13. The compound of claim 12 , or a pharmaceutically acceptable salt thereof, wherein:

L is selected from *—CR 1 R 2 —CR 3 R 4 —; *—CR 1 R 2 —N(R 5 )—; or *—C(O)—N(R 5 )—;

R 2 , R 4 , and R 5 are each independently H or optionally substituted C 1 -C 3 alkyl;

n is 0; and

m is 0.

14. The compound of claim 12 , or a pharmaceutically acceptable salt thereof, wherein Z is -L2-G, optionally substituted (C 1 -C 4 alkylene)-OCON(R 13 ) 2 , optionally substituted (C 1 -C 4 alkylene)-N(R 14 )CON(R 13 ) 2 , or optionally substituted (C 1 -C 4 alkylene)-SO 2 N(R 13 ) 2 .

15. The compound of claim 12 , or a pharmaceutically acceptable salt thereof, wherein:

is phenyl,

is phenyl, cycloalkyl,

and

W is —C≡C— or —C≡C—C≡C—.

16. The compound of claim 12 , or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

2-(1-(4-(benzofuro[6,5-d][1,3]dioxol-6-yl)phenyl)-3-(2-fluoroethylamino)propan-2-yl)-3-hydroxy-4H-pyran-4-one;

2-(1-(4-(benzofuran-2-yl)phenylthio)-2-(2-fluoroethylamino)ethyl)-3-hydroxy-4H-pyran-4-one;

N-(2-fluoroethyl)-2-(3-hydroxy-4-oxo-4H-pyran-2-yl)-3-(6-(4-(2-hydroxyethyl)phenyl)-3-oxo-1H-pyrrolo[1,2-c]imidazol-2(3H)-yl)propanamide;

2-(1-(5-(cyclopropylethynyl)-2H-indazol-2-yl)-3-(2-fluoroethylamino)propan-2-yl)-3-hydroxy-4H-pyran-4-one;

2-(1-(6-(cyclopropylethynyl)imidazo[1,2-a]pyridin-2-yl)-3-(2-fluoroethylamino)propan-2-yl)-3-hydroxy-4H-pyran-4-one;

2-(1-(5-(cyclopropylbuta-1,3-diynyl)-1H-indazol-1-yl)-3-(2-fluoroethylamino)propan-2-yl)-3-hydroxy-4H-pyran-4-one;

5-(cyclopropylethynyl)-2-(3-(2-fluoroethylamino)-2-(3-hydroxy-4-oxo-4H-pyran-2-yl)propyl)isoindolin-1-one;

2-(1-(6-(cyclopropylethynyl)indolizin-2-yl)-3-(2-fluoroethylamino)propan-2-yl)-3-hydroxy-4H-pyran-4-one;

3-hydroxy-2-(6-(phenylethynyl)-2,3-dihydrobenzofuran-2-yl)-4H-pyran-4-one;

N-(2,2-difluoroethyl)-3-(4-((4-(1,2-dihydroxyethyl)phenyl)ethynyl)-2-oxopyridin-1(2H)-yl)-2-(3-hydroxy-4-oxo-4H-pyran-2-yl)propanamide; and

5-(6-(3-(2-fluoroethylamino)-2-(3-hydroxy-4-oxo-4H-pyran-2-yl)propyl)pyridin-3-yl)isoindolin-1-one.

17. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

18. A method of inhibiting LpxC comprising contacting LpxC with a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

19. A method of treating a gram-negative bacterial infection in a patient in need thereof comprising administering to the patient the pharmaceutical composition of claim 17 .

Assignments (2)

MERGER AND CHANGE OF NAME Recorded Jan 13, 2023

From: FORGE THERAPEUTICS, INC.; BLACKSMITH MEDICINES, INC.

To: BLACKSMITH MEDICINES, INC.

Reel/Frame 062376/0817 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 17, 2020

From: TENG, MIN; NAMMALWAR, BASKAR; TAGANOV, KONSTANTIN; LI, XIAOMING; PUERTA, DAVID T.

To: FORGE THERAPEUTICS, INC.

Reel/Frame 051550/0573 →

Continuity (2)

Provisional Application 62504218 · May 10, 2017

Related Publication 20200255413A1 · Aug 13, 2020

Cited By (2)

US 12,187,754 US 12,325,699