US 2021/0198288 A1 · PENICILLIN-BINDING PROTEIN INHIBITORS

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.

A compound of Formula (Ia) or (Ib), or a pharmaceutically acceptable salt, solvate, stereoisomer, tautomer, N-oxide, dimer, or trimer thereof:

wherein:
L1 is —(CR1R2)n—;
L2 is —(CR1R2)m—;
L2′ is absent, —C(═O)NH—, —NHC(═O)—, or —CH2NH—;
L3 is —C(═O)—, —S(═O)—, or —S(═O)2—;
A1 is
Ring A is a 6-membered aryl or a 6-membered heteroaryl;
each R1 and R2 is independently hydrogen, halogen, optionally substituted alkyl, —OH, —OR34, —SR35, —NR32R33, —NR32C(═O)R34, —C(═O)NR32R33, —NR32S(═O)2R34, —C(═O)OH, —C(═O)OR34, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
or
R1 and R2 are taken together with the carbon to which they are attached to form an optionally substituted cycloalkyl;
R8 is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
each R20 and R21 is independently hydrogen, halogen, or optionally substituted alkyl;
R22 and R23 are independently hydrogen or optionally substituted alkyl;
or
R22 and R23 are taken together with the nitrogen to which they are attached to form an optionally substituted heterocycloalkyl;
R24 is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
R25 is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
each R30, R31, R50, and R51 is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, —OH, —OR24, —SR25, —NR22R23, —NR22C(═O)R24, —C(═O)NR22R23, —NR22S(═O)2R24, —C(═O)OH, or —C(═O)OR24;
or
R30 and R31, or R50 and R51 are taken together with the carbon atom to which they are attached to form an optionally substituted cycloalkyl;
or
two R30 or two R50 on adjacent carbons are taken together to form an alkenyl;
or
two R30 and two R31, or two R50 and two R51 on adjacent carbons are taken together to form an alkynyl;
R32, R33, R52, R53, R82, and R83 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)2R24, —S(═O)2NR22R23, or —C(═O)R24;
or
R32 and R33, or R52 and R53, or R82 and R83 are taken together with the nitrogen to which they are attached to form an optionally substituted heterocycloalkyl;
R34, R54, and R84 are independently optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
R35 and R55 are independently hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
R36 and R56 are independently hydrogen, —OH, —OR24, —CN, —NO2, —NR22R23, or optionally substituted alkyl;
Z is hydrogen, R61, —(R60)qOR61, —(R60)qO(R60)qOR61, —R60OC(═O)R61, —R60OC(═O)OR61, —R60OC(═O)NHR61, —R60OC(═O)N(R61)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 R60 is independently —CH2—, —CH(CH3)—, —C(CH3)2—, or optionally substituted 1,1′-cyclopropylene;
each R61 is independently optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
or
two R61 are taken together with the nitrogen to which they are attached to form an optionally substituted heterocycloalkyl;
R74 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, —OR84, —NR82R83, —C(═O)OH, or —C(═O)OR84;
Ra, Rb, and Rc are independently hydrogen, halogen, cyano, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, —OH, —OR54, —O(CR50R51)wNR52R53, —O(CR50R51)wOH, —O(CR50R51)wOR54, —O(CR50R51)vC(═O)OH, —O(CR50R51)vC(═O)OR54, —O(CR50R51)vC(═O)NR52R53, —NR52R53, —NR52(CR50R51)wNR52R53, —NR52(CR50R51)vC(═O)OH, —NR52(CR50R51)vC(═O)OR54, —NR52(CR50R51)vC(═O)NR52R53, —NR52S(═O)1,2R54, —S(═O)1,2R54, —SR55, —S(CR50R51)vNR52C(═NR56)NR52R53, —S(CR50R51)vNR52CR50(═NR56), —S(CR50R51)vC(═NR56)NR52R53, —S(CR50R51)wOH, —S(CR50R51)wOR54, —S(CR50R51)wNR52R53, —S(CR50R51)vC(═O)OH, —S(CR50R51)vC(═O)OR54, —S(CR50R51)vC(═O)NR52R53, —C(═O)H, —C(═O)R54, —C(═O)OH, —C(═O)OR54, —C(═O)NR52R53, —(CR50R51)vN(R52)(CR50R51)vC(═O)OH, —(CR50R51)vOH, —(CR50R51)vOR54, —(CR50R51)vC(═O)OH, —(CR50R51)vC(═O)OR54, —(CR50R51)vC(═O)NR52R53, —(CR50R51)vOC(═O)R54, —(CR50R51)vSR55, —(CR50R51)vNR52C(═NR56), —(CR50R51)vNR52R53, —(CR50R51)vC(═NR56)NR52R53, —(CR50R51)vC(═O)NR52R53, —(CR50R51)vheterocycloalkyl, or —(CR50R51)vheteroaryl;
Rd is hydrogen, —CN, —OH, —S(═O)2R24, —S(═O)2NR22R23, —(CR20R21)vC(═O)OH, —C(═O)R24, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, (poly-ethylene-glycol)-ethyl, or an optionally substituted saccharide;
each Re is independently hydrogen, —CN, —OH, optionally substituted alkyl, or optionally substituted cycloalkyl;
RX is optionally substituted alkyl or optionally substituted cycloalkyl;
X1 and X2 are independently —OH, —ORX, or F;
or
X1 and X2 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-NR32R33, -heterocycloalkyl-NR32R33, -heteroaryl-N(R32)C(═NR32)NR32R33, -heterocycloalkyl-N(R32)C(═NR32)NR32R33, —OH, —OR34, —O(CR30R31)wOH, —O(CR30R31)wOR34, —O(CR30R31)wNR32R33, —O(CR30R31)wNR32C(═O)R34, —O(CR30R31)wNR32C(═O)OR34, —O(CR30R31)wNR32C(═O)NR32R33, —O(CR30R31)wC(═O)NR32R33, —O(CR30R31)wNR32S(═O)0,1,2R34, —O(CR30R31)wNR32S(═O)0,1,2NR32R33, —O(CR30R31)wS(═O)0,1,2R34, —O(CR30R31)wS(═O)0,1,2NR32R33, —O(CR30R31)vC(═NR36)NR32R33, —O(CR30R31)wN(R32)C(═NR36)R34, —O(CR30R31)vC(═NR36)NR32C(═NR36)NR32R33, —O(CR30R31)wN(R32)C(═NR36)NR32R33, —O(CR30R31)wS(═O)0,1,2R34, —O(CR30R31)wS(═O)0,1,2NR32R33, —OC(═O)R34, —OC(═O)(CR30R31)wNR32R33, —OC(═O)NR32R33, —OC(═O)OR34, —OC(═O)NR32(CR30R31)wNR32R33, —O-heteroaryl, —O-heterocycloalkyl, —O(CR30R31)vheteroaryl, —O(CR30R31)vheterocycloalkyl, —O(CR30R31)wNR32-heteroaryl, —O(CR30R31)wNR32-heterocycloalky, —O(CR30R31)vO-heterocycloalkyl, —NR32R33, —NR32(CR30R31)wNR32R33, —NR32(CR30R31)wOH, —NR32(CR30R31)wOR34, —NR32C(═O)R34, —NR32C(═O)OR34, —N(R32)C(═O)(CR31R31)vNR32R33, —NR32C(═O)NR32R33, —NR32C(═O)NR32(CR30R31)wNR32R33, —NR32(CR30R31)wS(═O)0,1,2R34, —NR32(CR30R31)wS(═O)0,1,2NR32R33, —NR32(CR30R31)wNR32R33S(═O)0,1,2R34, —NR32(CR30R31)wNR32S(═O)0,1,2NR32R33, —NR32C(═NR36)NR32R33, —N(R32)C(═NR36)R34, —NR32(CR30R31)wN(R32)C(═NR36)R34, —NR32(CR30R31)vC(═NR36)NR32R33, —NR32(CR30R31)wN(R32)C(═NR36)NR32R33, —NR32(CR30R31)wNR32C(═O)NR32R33, —NR32(CR30R31)wNR32C(═O)OR34, —NR32S(═O)0,1,2NR32R33, —NR32S(═O)0,1,2R34, —NR32(CR30R31)vCO2H, —NR32(CR30R31)vCO2R34, —NR32(CR30R31)vC(═O)NR32R33, —N(R32)-heteroaryl- NR32R33, —N(R32)-heterocycloalkyl-NR32R33, —NR32(CR30R31)vheteroaryl, —NR32(CR30R31)vheterocycloalkyl, —NR32(CR30R31)wNR32-heteroaryl, —NR32(CR30R31)wNR32-heterocycloalkyl, —CN, —(CR30R31)vCN, —(CR30R31)vNR32R33, —(CR30R31)vOH, —(CR30R31)vOR34, —(CR30R31)vOC(═O)R34, —(CR30R31)vOC(═O)NR32R33, —(CR30R31)vO(CR30R31)wOR34, —(CR30R31)vO(CR30R31)wOH, —(CR30R31)vO(CR30R31)wNR32R33, —(CR30R31)vNR32(CR30R31)wOH, —(CR30R31)vNR32(CR30R31)wOR34, —(CR30R31)vC(═O)NR32R33, —(CR30R31)vC(═O)OH, —(CR30R31)vC(═O)OR34, —(CR30R31)vC(═O)NR32(CR30R31)wNR32R33, —(CR30R31)vC(═O)NR32(CR30R31)wOR34, —(CR30R31)vN(R32)C(═O)R34, —(CR30R31)vN(R32)C(═O)OR34, —(CR30R31)vN(R32)C(═O)NR32R33, —(CR30R31)vN(R32)C(═O) (CR30R31)vNR32R33, —(CR30R31)vN(R32)S(═O)0,1,2R34, —(CR30R31)vN(R32)S(═O)0,1,2NR32R33 —(CR30R31)vS(═O)0,1,2NR32R33, —(CR30R31)vNR32(CR30R31)wNR32R33, —(CR30R31)vN(R32)CH(═NR36), —(CR30R31)vN(R32)C(═NR36)R34, —(CR30R31)vC(═NR36)NR32R33, —(CR30R31)vN(R32)C(═NR36)NR32R33, —(CR30R31)vC(═NR36)NR32C(═NR36)NR32R33, —(CR30R31)vheteroaryl-NR32R33, —(CR30R31)vheterocycloalkyl-NR32R33, —(CR30R31)vheteroaryl-N(R32)C(═NR36)NR32R33, —(CR30R31)vheterocycloalkyl-N(R32)C(═NR36)NR32R33, —(CR30R31)vheteroaryl, —(CR30R31)vheterocycloalkyl, —C(═O)OH, —C(═O)OR34, —C(═O)NR32R33, —C(═O)NR32(CR30R31)wNR32R33, —C(═O)NR32(CR30R31)wOH, —C(═O)NR32(CR30R31)wOR34, —C(═NR36)NR32R33, —C(═NR36)NR32C(═O)R34, —S(═O)1,2R34, —SR35, —S(═O)0,1,2(CR30R31)wNR32R33, —S(═O)0,1,2(CR30R31)wOH, —S(═O)0,1,2(CR30R31)wOR34, —S(═O)0,1,2NR32R33, —S(═O)0,1,2NR32(CR30R31)wNR32R33, —S(═O)0,1,2(CR30R31)wN(R32)C(═NR36)R34, —S(═O)0,1,2(CR30R31)vC(═NR36)NR32R33, —S(═O)0,1,2(CR30R31)wN(R32)C(═NR36)NR32R33, —S(═O)0,1,2(CR30R31)vC(═NR36)NR32C(═NR36)NR32R33, —Si(R34)3, —NR32R33R34+Q−, —(CR30R31)vNR32R33R34+Q−, —NR32(CR30R31)wNR32R33R34+Q−, —NR32R34+(CR30R31)wNR32R33R34+Q−2, —(CR30R31)v(T)+Q−, or —O(CR30R31)wNR32R33R34+Q−;
or two Ys are taken together with the atoms to which they are attached to 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 1-3;
each q is independently 2-6;
each v is independently 1-5;
and
each w is independently 2-5.

51 more elements

Penicillin-binding protein inhibitors

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Penicillin-binding protein inhibitors

Life of this patent

Abstract

Claims72