Search

US-20260124213-A1 - STAPHYLOCOCCUS AUREUS PBP4 INHIBITORS AND METHOD OF USE

US20260124213A1US 20260124213 A1US20260124213 A1US 20260124213A1US-20260124213-A1

Abstract

Described are compounds, compositions, and method for treating Penicillin Binding Protein 4 (PBP4) related diseases and/or disorders, such as bacterial infections.

Inventors

  • Paul M. Dunman
  • Christian Melander

Assignees

  • UNIVERSITY OF ROCHESTER
  • UNIVERSITY OF NOTRE DAME DU LAC

Dates

Publication Date
20260507
Application Date
20231004

Claims (20)

  1. 1 . A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, wherein: A 1 is G 1 is a 6- to 12-membered aryl, C 3-10 carbocyclyl, a 5- to 12-membered heteroaryl, or a 4- to 12-membered heterocyclyl, wherein G 1 is optionally substituted with 1-3 R 1 ; X 1 is CHR X , C═O, or O; X 2 is CH or N; R X , at each occurrence, is C 1-6 alkyl, hydrogen, C 1-4 haloalkyl, halogen, or cyano; R 1 , at each occurrence, is independently halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, —OR 1a , —SR 1a , —CO 2 R 1a , —C(O)R 1a , —SO 2 R 1b , —N(R 1b ) 2 , —CO 2 N(R 1b ) 2 , —NO 2 , G 1a , —OG 1a , —SG 1a , —N(R 1b )-G 1b , -L 1 -Y 1 , —O-L 1 -Y 1 , —S-L 1 -Y 1 , or —N(R 1b )-L 1 -Y 1 ; L 1 , at each occurrence, is independently a C 1-6 alkylene, wherein optionally 1 or 2 methylene groups in the alkylene of L 1 are independently replaced with —O—, —S—, —SO 2 —, —C(O)—, or —N(R 1b )—, wherein 2 methylene groups replaced with —O—, —S—, —SO 2 —, or N(R 1b )— are separated by two or more carbon atoms in the alkylene; Y 1 , at each occurrence, is independently hydrogen, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, —OR 1a , —SR 1a , —CO 2 R 1a , —C(O)R 1a , —SO 2 R 1b , —N(R 1b ) 2 , —CO 2 N(R 1b ) 2 , G 1a , or —OG 1a ; R 1a , at each occurrence, is independently hydrogen, C 1-6 alkyl, or C 1-2 haloalkyl; R 1b , at each occurrence, is independently hydrogen or C 1-6 alkyl; G 1a , at each occurrence, is independently C 3-6 carbocyclyl, phenyl, a 4- to 6-membered heterocyclyl, or a 5- to 6-membered heteroaryl, wherein G 1a is optionally substituted with 1-4 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-2 haloalkyl, halogen, cyano, —OC 1-4 alkyl, and —OC 1-2 haloalkyl; G 1b , at each occurrence, is independently C 3-6 carbocyclyl or phenyl, wherein G 1b is optionally substituted with 1-4 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-2 haloalkyl, halogen, cyano, —OC 1-4 alkyl, and —OC 1-2 haloalkyl; R 10 , at each occurrence, is independently halogen, C 1-4 alkyl, —OC 1-4 alkyl, C 1-2 haloalkyl, cyano, or —OC 1-2 haloalkyl; R 100 , at each occurrence, is independently halogen, C 1-4 alkyl, —OC 1-4 alkyl, C 1-2 haloalkyl, cyano, or —OC 1-2 haloalkyl; m is 0, 1, 2, 3, or 4; n is 0, 1, or 2; and p is 0, 1, 2, or 3.
  2. 2 . The pharmaceutical composition of claim 1 , wherein the compound of formula (I) is a compound of formula (I-a):
  3. 3 . The pharmaceutical composition of claim 1 , wherein G 1 is the 6- to 12-membered aryl.
  4. 4 . The pharmaceutical composition of claim 3 , wherein the 6- to 12-membered aryl at G 1 is phenyl.
  5. 5 . The pharmaceutical composition of claim 1 , wherein G 1 is substituted with 1-2 substituents selected from the group consisting of halogen, C 1-6 alkyl, —OC 1-4 alkyl, —NH 2 , —OC 1-2 fluoroalkyl, C 1-2 fluoroalkyl, or —NO 2 .
  6. 6 . The pharmaceutical composition of claim 1 , wherein G 1 is
  7. 7 . The pharmaceutical composition of claim 1 , wherein m is 0.
  8. 8 . The pharmaceutical composition of claim 1 , wherein A 1 is
  9. 9 . The pharmaceutical composition of claim 8 , wherein n is 1.
  10. 10 . The pharmaceutical composition of claim 8 , wherein X 1 is CHR X .
  11. 11 . The pharmaceutical composition of claim 10 , wherein R X is C 1-6 alkyl.
  12. 12 . The pharmaceutical composition of claim 11 , wherein R X is methyl.
  13. 13 . The pharmaceutical composition of claim 8 , wherein X 1 is C═O.
  14. 14 . The pharmaceutical composition of claim 8 , wherein X 1 is O.
  15. 15 . The pharmaceutical composition of claim 1 , wherein A 1 is
  16. 16 . The pharmaceutical composition of claim 15 , wherein X 2 is CH.
  17. 17 . The pharmaceutical composition of claim 15 , wherein p is 1 or 2.
  18. 18 . The pharmaceutical composition of claim 15 , wherein R 100 is F, Cl, —CH 3 , or —OCH 3 .
  19. 19 . The pharmaceutical composition of claim 15 , wherein X 2 is N.
  20. 20 . The pharmaceutical composition of claim 1 , wherein the compound of formula (I) is selected from the group consisting of:

Description

CROSS-REFERENCE TO RELATED APPLICATION(S) This application claims priority to U.S. Provisional Patent Application No. 63/378,335, filed on Oct. 4, 2022, the entire contents of which are fully incorporated herein by reference. STATEMENT OF GOVERNMENT INTEREST This invention was made with government support under grants AR072000, AI134685, AR069655, AR081050, and DE022350 awarded by the National Institutes of Health. The government has certain rights in this invention. The government has certain rights in this invention. TECHNICAL FIELD The present disclosure relates to compounds, compositions, and methods for treating Penicillin Binding Protein 4 (PBP4) related diseases and/or disorders, such as bacterial infections. INTRODUCTION Penicillin Binding Protein 4 (PBP4), which is a sub-type of the penicillin binding protein family, is an enzyme that participates in the production of peptidoglycan, the major component of cell walls in bacteria. PBP4 is overexpressed in antibiotic resistance strains and inactivation of PBP4 activity decreases bacterial migration. SUMMARY In some aspects, the present disclosure provides compounds of formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, wherein: A1 is G1 is a 6- to 12-membered aryl, C3-10carbocyclyl, a 5- to 12-membered heteroaryl, or a 4- to 12-membered heterocyclyl, wherein G1 is optionally substituted with 1-3 R1;X1 is CHRX, C═O, or O;X2 is CH or N;RX, at each occurrence, is C1-6alkyl, hydrogen, C1-4haloalkyl, halogen, or cyano;R1, at each occurrence, is independently halogen, cyano, C1-6alkyl, C1-6haloalkyl, —OR1a, —SR1a, —CO2R1a, —C(O)R1a, —SO2R1b, —N(R1b)2, —CO2N(R1b)2, —NO2, G1a, —OG1a, —SG1a, N(R1b)-G1b, -L1-Y1, —O-L1-Y1, —S-L1-Y1, or N(R1b)-L1-Y1;L1, at each occurrence, is independently a C1-6alkylene, wherein optionally 1 or 2 methylene groups in the alkylene of L1 are independently replaced with —O—, —S—, —SO2—, —C(O)—, or —N(R1b)—, wherein 2 methylene groups replaced with —O—, —S—, —SO2—, or —N(R1b)— are separated by two or more carbon atoms in the alkylene,Y1, at each occurrence, is independently hydrogen, halogen, cyano, C1-6alkyl, C1-6haloalkyl, —OR1a, —SR1a, —CO2R1a, —C(O)R1a, —SO2R1b, —N(R1b)2, —CO2N(R1b)2, G1a, or —OG1a;R1a, at each occurrence, is independently hydrogen, C1-6alkyl, or C1-2haloalkyl;R1b, at each occurrence, is independently hydrogen or C1-6alkyl;G1a, at each occurrence, is independently C3-6carbocyclyl, phenyl, a 4- to 6-membered heterocyclyl, or a 5- to 6-membered heteroaryl, wherein G1a is optionally substituted with 1-4 substituents independently selected from the group consisting of C1-4alkyl, C1-2haloalkyl, halogen, cyano, —OC1-4alkyl, and —OC1-2haloalkyl;G1b, at each occurrence, is independently C3-6carbocyclyl or phenyl, wherein G1b is optionally substituted with 1-4 substituents independently selected from the group consisting of C1-4alkyl, C1-2haloalkyl, halogen, cyano, —OC1-4alkyl, and —OC1-2haloalkyl;R10, at each occurrence, is independently halogen, C1-4alkyl, —OC1-4alkyl, C1-2haloalkyl, cyano, or —OC1-2haloalkyl;R100, at each occurrence, is independently halogen, C1-4alkyl, —OC1-4alkyl, C1-2haloalkyl, cyano, or —OC1-2haloalkyl;m is 0, 1, 2, 3, or 4;n is 0, 1, or 2; andp is 0, 1, 2, or 3. In other aspects, the present disclosure provides compounds selected from the group consisting of: or a pharmaceutically acceptable salt thereof. In other aspects, the present disclosure provides pharmaceutical compositions comprising a compound of formula (II), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, wherein: G2 is a 5- to 12-membered heteroaryl, a 6- to 12-membered aryl, C3-10carbocyclyl, or a 4- to 12-membered heterocyclyl, wherein G2 is optionally substituted with 1-3 R2;L2 is —(CH2)0-4—C(O)—(CH2)0-4—N(H)—;G3 is a 5- to 12-membered heteroaryl, a 6- to 12-membered aryl, C3-10carbocyclyl, or a 4- to 12-membered heterocyclyl, wherein G3 is optionally substituted with 1-3 R3;R2, at each occurrence, is independently halogen, cyano, C1-6alkyl, C1-6haloalkyl, —OR2a, —SR2a, —CO2R2a, —C(O)R2a, —SO2R2b, —N(R2b)2, —CO2N(R2b)2, —NO2, G2a, —OG2a, —SG2a, or —N(R2b)-G2b;R3, at each occurrence, is independently halogen, cyano, C1-6alkyl, C1-6haloalkyl, —OR3a, —SR3a, —CO2R3a, —C(O)R3a, —SO2R3b, —N(R3b)2, —CO2N(R3b)2, —NO2, G3a, —OG3a, —SG3a, or —N(R2b)-G2b;R2a and R3a, at each occurrence, are each independently hydrogen or C1-6alkyl;R2b and R3b, at each occurrence, are each independently hydrogen or C1-6alkyl;G2a and G3a, at each occurrence, are each independently C3-6carbocyclyl, phenyl, a 4- to 6-membered heterocyclyl, or a 5- to 6-membered heteroaryl, wherein G2a and G3a are each optionally substituted with 1-4 substituents independently selected from the group consisting of C1-4alkyl, C1-2haloalkyl, halogen, cyano, —OC1-4alkyl, and —OC1-2haloalkyl; andG2b and G3b, at each occurrence, are each independently C3-6carbocyclyl or phenyl, wherein G2b and