IP Library › Granted Patent US 11,332,485

Granted Patent B2

US 11,332,485 · App. 16/616,294 · Granted May 17, 2022

Penicillin-binding protein inhibitors

Inventors: Christopher J. Burns (Malvern, PA); Denis Daigle (Street, MD); Guo-Hua Chu (Exton, PA); Jodie Hamrick (New Holland, PA); Matthew Lucas (Cambridge, MA); Steven A. Boyd (Chester Springs, PA); Allison L. Zulli (Chesterbrook, PA); Eugen F. Mesaros (Wallingford, PA); Stephen M. Condon (Glenmoore, PA); Robert E. Lee Trout (Collegeville, PA); Cullen L. Myers (Exton, PA)

Assignee: VENATORX PHARMACEUTICALS, INC.

C07F5/027 A61K9/205 A61K9/2009 A61K9/2013 A61K9/2018 A61K9/2059 A61K9/4858 A61P31/04

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Quick Facts

Patent No.: US 11,332,485
App. No.: 16/616,294
Granted: May 17, 2022
Kind: B2

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Abstract

Described herein are certain boron-containing compounds, compositions, preparations and their use as modulators of the transpeptidase function of bacterial penicillin-binding proteins and as antibacterial agents. In some embodiments, the compounds described herein inhibit penicillin-binding proteins. In certain embodiments, the compounds described herein are useful in the treatment of bacterial infections.

Claims (64)

1. A compound of Formula (VIa) or (VIb), or a pharmaceutically acceptable salt, solvate, stereoisomer, tautomer, N-oxide, dimer, or trimer thereof:

wherein:

L 1 is —(CR 1 R 2 ) n —;

L 2 is —(CR 1 R 2 ) m —;

L 3 is —C(═O)—, —S(═O)—, or —S(═O) 2 —;

A 1 is

Ring A is thiazole;

each R 1 and R 2 are independently hydrogen, halogen, optionally substituted alkyl, —OH, —OR 34 , —SR 35 , —NR 32 R 33 , —NR 32 C(═O)R 34 , —C(═O)NR 32 R 33 , —NR 32 S(═O) 2 R 34 , —C(═O)OH, —C(═O)OR 34 , optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; or

R 1 and R 2 are taken together with the carbon to which they are attached to form an optionally substituted cycloalkyl;

R 8 is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

each R 20 and R 21 are independently hydrogen, halogen, or optionally substituted alkyl;

R 22 and R 23 are independently hydrogen or optionally substituted alkyl; or

R 22 and R 23 are taken together with the nitrogen to which they are attached to form an optionally substituted heterocycloalkyl;

R 24 is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

R 25 is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl;

each R 30 , R 31 , R 50 , and R 51 are independently hydrogen, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, —OH, —OR 24 , —SR 25 , —NR 22 R 23 , —NR 22 C(═O)R 24 , —C(═O)NR 22 R 23 , —NR 22 S(═O) 2 R 24 , —C(═O)OH, or —C(═O)OR 24 ; or

R 30 and R 31 , or R 50 and R 51 are taken together with the carbon atom to which they are attached form an optionally substituted cycloalkyl; or

two R 30 or two R 50 on adjacent carbons are taken together to form an alkenyl; or

two R 30 and two R 31 , or two R 50 and two R 51 on adjacent carbons are taken together to form an alkynyl;

R 32 , R 33 , R 52 , R 53 , R 82 , and R 83 are independently hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, (poly-ethylene-glycol)-ethyl, optionally substituted saccharide, —CN, —OH, —S(═O) 2 R 24 , —S(═O) 2 NR 22 R 23 , or —C(═O)R 24 ; or

R 32 and R 33 , or R 52 and R 53 , or R 82 and R 83 are taken together with the nitrogen to which they are attached to form an optionally substituted heterocycloalkyl;

R 34 , R 54 , and R 84 are independently optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

R 35 and R 55 are independently hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl;

R 36 and R 56 are independently hydrogen, —OH, —OR 24 , —CN, —NO 2 , —NR 22 R 23 , or optionally substituted alkyl;

Z is hydrogen, R 61 , —(R 60 ) q OR 61 , —(R 60 ) q O(R 60 ) q OR 61 , —R 60 OC(═O)R 61 , —R 60 OC(═O)OR 61 , —R 60 OC(═O)NHR 61 , —R 60 OC(═O)N(R 61 ) 2 , optionally substituted alkyloxyalkyl, optionally substituted acyloxyalkyl, optionally substituted alkyloxycarbonyloxyalkyl, optionally substituted cycloalkyloxycarbonyloxyalkyl, optionally substituted aryloxycarbonyloxyalkyl, or optionally substituted alkyl-[1,3]dioxol-2-one;

each R 60 is independently —CH 2 —, —CH(CH 3 )—, —C(CH 3 ) 2 —, or optionally substituted 1,1′-cyclopropylene;

each R 61 is independently optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; or

two R 61 are taken together with the nitrogen to which they are attached to form an optionally substituted heterocycloalkyl;

R 74 is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, —OH, —OR 84 , —NR 82 R 83 , —C(═O)OH, or —C(═O)OR 84 ;

R a , R b , and R c are independently hydrogen, halogen, cyano, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, —OH, —OR 54 , —O(CR 50 R 51 ) w NR 52 R 53 , —O(CR 50 R 51 ) w OH, —O(CR 50 R 51 ) w OR 54 , —O(CR 50 R 51 ) v C(═O)OH, —O(CR 50 R 51 ) v C(═O)OR 54 , —O(CR 50 R 51 ) v C(═O)NR 52 R 53 , —NR 52 R 53 , —NR 52 (CR 50 R 51 ) w NR 52 R 53 , —NR 52 (CR 50 R 51 )C(═O)OH, —NR 52 (CR 50 R 51 ) v C(═O)OR 54 , —NR 52 (CR 50 R 51 )C(═O)NR 52 R 53 , —NR 52 S(═O) 1,2 R 54 , —S(═O) 1,2 R 54 , —SR 55 , —S(CR 50 R 51 ) v NR 52 C(═NR 56 )NR 52 R 53 , —S(CR 50 R 51 ) v NR 52 CR 50 (═NR 56 ), —S(CR 50 R 51 ) v C(═NR 56 )NR 52 R 53 , —S(CR 50 R 51 ) w OH, —S(CR 50 R 51 ) w OR 54 , —S(CR 50 R 51 ) w NR 52 R 53 , —S(CR 50 R 51 ) v C(═O)OH, —S(CR 50 R 51 )C(═O)OR 54 , —S(CR 50 R 51 )C(═O)NR 52 R 53 , —C(═O)H, —C(═O)R 54 , —C(═O)OH, —C(═O)OR 54 , —C(═O)NR 52 R 53 , —(CR 50 R 51 ) v N(R 52 )(CR 50 R 51 ) v C(═O)OH, —(CR 50 R 51 ) v OH, —(CR 50 R 51 )OR 54 , —(CR 50 R 51 ) v C(═O)OH, —(CR 50 R 51 ) v C(═O)OR 54 , —(CR 50 R 51 ) v C(═O)NR 52 R 53 , —(CR 50 R 51 ) v OC(═O)R 54 , —(CR 50 R 51 ) v SR 55 , —(CR 50 R 51 ) v NR 52 C(═NR 56 ), —(CR 50 R 51 ) v NR 52 R 53 , —(CR 50 R 51 ) v C(═NR 56 )NR 52 R 53 , —(CR 50 R 51 ) v C(═O)NR 52 R 53 , —(CR 50 R 51 ) v heterocycloalkyl, or —(CR 50 R 51 )heteroaryl;

R d is hydrogen, —CN, —OH, —S(═O) 2 R 24 , —S(═O) 2 NR 22 R 23 , —(CR 20 R 21 ) v C(═O)OH, —C(═O)R 24 , optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, (poly-ethylene-glycol)-ethyl, an optionally substituted saccharide;

R X is optionally substituted alkyl or optionally substituted cycloalkyl;

X 1 and X 2 are independently —OH, —OR X , or F; or

X 1 and X 2 are taken together with the boron atom to which there are attached to form a cyclic boronate ester;

each Y is independently halogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -heteroaryl-NR 32 R 33 , -heterocycloalkyl-NR 32 R 33 , -heteroaryl-N(R 32 )C(═NR 32 )NR 32 R 33 , -heterocycloalkyl-N(R 32 )C(═NR 32 )NR 32 R 33 , —OH, —OR 34 , —O(CR 30 R 31 ) w OH, —O(CR 30 R 31 ) w OR 34 , —O(CR 30 R 31 ) w NR 32 R 33 , —O(CR 30 R 31 ) w NR 32 C(═O)R 34 , —O(CR 30 R 31 ) w NR 32 C(═O)OR 34 , —O(CR 30 R 31 ) w NR 32 C(═O)NR 32 R 33 , —O(CR 30 R 31 ) w C(═O)NR 32 R 33 , —O(CR 30 R 31 ) w NR 32 S(═O) 0,1,2 R 34 , —O(CR 30 R 31 ) w NR 32 S(═O) 0,1,2 NR 32 R 33 , —O(CR 30 R 31 ) w S(═O) 0,1,2 R 34 , —O(CR 30 R 31 ) w S(═O) 0,1,2 NR 32 R 33 , —O(CR 30 R 31 ) v C(═NR 36 )NR 32 R 33 , —O(CR 30 R 31 ) w N(R 32 )C(═NR 36 )R 34 , —O(CR 30 R 31 ) v C(═NR 36 )NR 32 C(═NR 36 )NR 32 R 33 , —O(CR 30 R 31 ) w N(R 32 )C(═NR 36 )NR 32 R 33 , —O(CR 30 R 31 ) w S(═O) 0,1,2 R 34 , —O(CR 30 R 31 ) w S(═O) 0,1,2 NR 32 R 33 , —OC(═O)R 34 , —OC(═O)(CR 30 R 31 ) v NR 32 R 33 , —OC(═O)NR 32 R 33 , —OC(═O)OR 34 , —OC(═O)NR 32 (CR 30 R 31 ) w NR 32 R 33 , —O-heteroaryl, —O-heterocycloalkyl, —O(CR 30 R 31 ) v heteroaryl, —O(CR 30 R 31 ) v heterocycloalkyl, —O(CR 30 R 31 ) w NR 32 -heteroaryl, —O(CR 30 R 31 ) w NR 32 -heterocycloalkyl, —O(CR 30 R 31 ) w O-heterocycloalkyl, —NR 32 R 33 , —NR 32 (CR 30 R 31 ) w NR 32 R 33 , —NR 32 (CR 30 R 31 ) w O, —NR 32 (CR 30 R 31 ) w OR 34 , —NR 32 C(═O)R 34 , —NR 32 C(═O)OR 34 , —N(R 32 )C(═O)(CR 30 R 31 ) v NR 32 R 33 , —NR 32 C(═O)NR 32 R 33 , —NR 32 C(═O)NR 32 (CR 30 R 31 ) w NR 32 R 33 , —NR 32 (CR 30 R 31 ) w S(═O) 0,1,2 R 34 , —NR 32 (CR 30 R 31 ) w S(═O) 0,1,2 NR 32 R 33 , —NR 32 (CR 30 R 31 ) w NR 32 R 33 S(═O) 0,1,2 R 34 , —NR 32 (CR 30 R 31 ) w NR 32 S(═O) 0,1,2 NR 32 R 33 , —NR 32 C(═NR 36 )NR 32 R 33 , —N(R 32 )C(═NR 36 )R 34 , —NR 32 (CR 30 R 31 ) w N(R 32 )C(═NR 36 )R 34 , —NR 32 (CR 30 R 31 ) v C(═NR 36 )NR 32 R 33 , —NR 32 (CR 30 R 31 ) w N(R 32 )C(═NR 36 )NR 32 R 33 , —NR 32 (CR 30 R 31 ) w NR 32 C(═O)NR 32 R 33 , —NR 32 (CR 30 R 31 ) w NR 32 C(═O)OR 34 , —NR 32 S(═O) 0,1,2 R 34 , —NR 32 (CR 30 R 31 )CO 2 H, —NR 32 (CR 30 R 31 )CO 2 R 34 , —NR 32 (CR 30 R 31 )C(═O)NR 32 R 33 , —N(R 32 )-heteroaryl-NR 32 R 33 , —N(R 32 )-heterocycloalkyl-NR 32 R 33 , —NR 32 (CR 30 R 31 ) v heteroaryl, —NR 32 (CR 30 R 31 ) v heterocycloalkyl, —NR 32 (CR 30 R 31 ) w NR 32 -heteroaryl, —NR 32 (CR 30 R 31 ) w NR 32 heterocycloalkyl, —CN, —(CR 30 R 31 ) v CN, —(CR 30 R 31 ) v NR 32 R 33 , —(CR 30 R 31 ) v OH, —(CR 30 R 31 ) v OR 34 , —(CR 30 R 31 )OC(═O)R 34 , —(CR 30 R 31 ) v OC(═O)NR 32 R 33 , —(CR 30 R 31 ) v O(CR 30 R 31 ) w OR 34 , —(CR 30 R 31 ) v O(CR 30 R 31 ) w OH, —(CR 30 R 31 ) v O(CR 30 R 31 ) w NR 32 R 33 , —(CR 30 R 31 ) v NR 32 (CR 30 R 31 ) w OH, —(CR 30 R 31 ) v NR 32 (CR 30 R 31 ) w OR 34 , —(CR 30 R 31 ) v C(═O)NR 32 R 33 , —(CR 30 R 31 ) v C(═O)NR 32 (CR 30 R 31 ) w NR 32 R 33 , —(CR 30 R 31 ) v C(═O)NR 32 (CR 30 R 31 ) w OR 34 , —(CR 30 R 31 ) v N(R 32 )C(═O)R 34 , —(CR 30 R 31 ) v N(R 32 )C(═O)OR 34 , —(CR 30 R 31 ) v N(R 12 )C(═O)NR 32 R 33 , —(CR 30 R 31 ) v N(R 32 )C(═O) (CR 30 R 31 ) w NR 32 R 33 , —(CR 30 R 31 ) v N(R 32 )S(═O) 0,1,2 R 34 , —(CR 30 R 31 ) v N(R 32 )S(═O) 0,1,2 NR 32 R 33 , —(CR 30 R 31 ) v S(═O) 0,1,2 NR 32 R 33 , —(CR 30 R 31 ) v NR 32 (CR 30 R 31 ) w NR 32 R 33 , —(CR 30 R 31 ) v N(R 32 )CH(═NR 36 ), —(CR 30 R 31 ) v N(R 32 )C(═NR 36 )R 34 , —(CR 30 R 31 ) v C(═NR 36 )NR 32 R 33 , —(CR 30 R 31 ) v N(R 32 )C(═NR 36 )NR 32 R 33 , —(CR 30 R 31 ) v C(═NR 36 )NR 32 C(═NR 36 )NR 32 R 33 , —(CR 30 R 31 ) v heteroaryl-NR 32 R 33 , —(CR 30 R 31 ) v heterocycloalkyl-NR 32 R 33 , —(CR 30 R 31 ) v heteroaryl-N(R 32 )C(═NR 36 )NR 32 R 33 , —(CR 30 R 31 ) v heterocycloalkyl-N(R 32 )C(═NR 36 )NR 32 R 33 , —(CR 30 R 31 ) v heteroaryl, —(CR 30 R 31 ) v heterocycloalkyl, —C(═O)OH, —C(═O)OR 34 , —C(═O)NR 32 R 33 , —C(═O)NR 32 (CR 30 R 31 ) w NR 32 R 33 , —C(═O)NR 32 (CR 30 R 31 ) w OH, —C(═O)NR 32 (CR 30 R 31 ) w OR 34 , —C(═NR 36 )NR 32 R 33 , —C(═NR 36 )NR 32 C(═O)R 34 , —S(═O) 1,2 R 34 , —SR 35 , —S(═O) 0,1,2 (CR 30 R 31 ) w NR 32 R 33 , —S(═O) 0,1,2 (CR 30 R 31 ) w OH, —S(═O) 0,1,2 (CR 30 R 31 ) w OR 34 , —S(═O) 0,1,2 NR 32 R 33 , —S(═O) 0,1,2 NR 32 (CR 30 R 31 ) w NR 32 R 33 , —S(═O) 0,1,2 (CR 30 R 31 ) w N(R 32 )C(═NR 36 )R 34 , —S(═O) 0,1,2 (CR 30 R 31 )C(═NR 36 )NR 32 R 33 , —S(═O) 0,1,2 (CR 30 R 31 ) w N(R 32 )C(═NR 36 )NR 32 R 33 , —S(═O) 0,1,2 (CR 30 R 31 ) v C(═NR 36 )NR 32 C(═NR 36 )NR 32 R 33 , —Si(R 34 ) 3 , —NR 32 R 33 R 34+ Q − , —(CR 30 R 31 ) v NR 32 R 33 R 34+ Q − , —NR 32 (CR 30 R 31 ) w NR 32 R 33 R 34+ Q − , —NR 32 R 34+ (CR 30 R 31 ) w NR 32 R 33 R 34+ Q − 2 , —(CR 30 R 31 )(T) + Q − , or —O(CR 30 R 31 ) w NR 32 R 33 R 34+ Q − ;

or two Ys taken together with the atoms to which they are attached form an optionally substituted cycloalkyl or an optionally substituted heterocycloalkyl;

T is pyridin-1-yl, pyrimidin-1-yl, or thiazol-3-yl;

Q is a pharmaceutically acceptable counterion;

n is 0-3;

m is 0-3;

p is 0-3;

each q is independently 2-6;

each v is independently 1-5; and

each w is independently 2-5.

2. The compound of claim 1 , wherein L 3 is —C(═O)—.

3. The compound of claim 1 , wherein R 8 is hydrogen.

4. The compound of claim 1 , wherein R 74 is:

wherein

R 90 is hydrogen, —OH, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted aralkyl, optionally substituted heteroaralkyl, —S(═O) 2 R 24 , —S(═O) 2 NR 22 R 23 , or —C(═O)R 24 ;

each R 91 is independently hydrogen, halogen, —OH, —CN, NH 2 , NO 2 , optionally substituted alkyl, optionally substituted alkoxy, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; and

t is 1-4.

5. The compound of claim 4 , wherein R 74 is:

6. The compound of claim 1 , wherein R a , R b , and R c are hydrogen.

7. The compound of claim 1 , wherein X 1 is —OH and X 2 is —OH when present.

8. The compound of claim 1 , wherein R d is alkyl or hydrogen.

9. The compound of claim 1 , wherein each R 1 and R 2 are hydrogen.

10. The compound of claim 1 , wherein Z is hydrogen.

11. The compound of claim 1 , wherein each Y is independently halogen, optionally substituted heteroaryl, —NR 32 R 33 , —OH, —OR 34 , —NR 32 (CR 30 R 31 ) w NR 32 R 33 , —NR 32 C(═NR 36 )NR 32 R 33 , —(CR 30 R 31 ) v NR 32 R 33 , —SR 35 , —NR 32 (CR 31 R 31 ) v CO 2 H, —NR 32 (CR 30 R 31 ) v C(═O)NR 32 R 33 , or —NR 32 (CR 30 R 31 )heteroaryl; or two Ys taken together with the atoms to which they are attached form an optionally substituted heterocycloalkyl.

12. The compound of claim 1 , wherein each Y is independently halogen, —NR 32 R 33 , —OH, —OR 34 , —NR 32 (CR 30 R 31 ) w NR 32 R 33 , —C(═O)OH, or —C(═O)NR 32 R 33 .

13. The compound of claim 1 wherein p is 0-2.

14. The compound of claim 1 selected from the group consisting of:

or a pharmaceutically acceptable salt, solvate, stereoisomer, tautomer, N-oxide, dimer, or trimer thereof.

15. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt, solvate, stereoisomer, tautomer, N-oxide, dimer, or trimer thereof, and a pharmaceutically acceptable excipient.

16. A method of treating a bacterial infection in a subject, comprising administering to the subject an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt, solvate, stereoisomer, tautomer, N-oxide, dimer, or trimer thereof.

Assignments (2)

CONFIRMATORY LICENSE Recorded Sep 8, 2023

From: VENATORX PHARMACEUTICALS, INC

To: NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT

Reel/Frame 064852/0178 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 9, 2020

From: BURNS, CHRISTOPHER J.; DAIGLE, DENIS; CHU, GUO-HUA; HAMRICK, JODIE; LUCAS, MATTHEW; BOYD, STEVEN A.; ZULLI, ALLISON L.; MESAROS, EUGEN F.; CONDON, STEPHEN M.; TROUT, ROBERT E. LEE; MYERS, CULLEN L.

To: VENATORX PHARMACEUTICALS, INC.

Reel/Frame 052128/0042 →

Continuity (2)

Provisional Application 62511613 · May 26, 2017

Related Publication 20200157123A1 · May 21, 2020