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US 11,261,201 B2Granted
TRNA synthetase inhibitors
AssigneePresident and Fellows of Harvard College
InventorsDaniel E. Kahne, Vadim Baidin
Life of this patent
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Abstract
Disclosed herein are secondary amine compounds that inhibit tRNA synthetase. The compounds of the invention are useful in inhibiting tRNA synthetase in Gram-negative bacteria and are useful in killing Gram-negative bacteria. The secondary amine compounds of the invention are also useful in the treatment of tuberculosis.
Claims27
A compound having the structure of formula (II′):
- or a pharmaceutically acceptable salt thereof;
- wherein:
- X is O or S;
- each of R10, R11, R12, and R13 is independently selected from H, OH, —NH2, halide, sulfonamido, (C1-C6)alkylsulfonyl, —OC(O)((C1-C8)alkyl), —C(O)O((C1-C8)alkyl), —C(O)OH, optionally substituted —NHC(O)(aryl), —C(O)NH2, —B(OH)2, tri((C1-C8)alkyl)silyl, optionally substituted (C1-C8)alkyl, optionally substituted (C1-C8)alkoxy, optionally substituted (C1-C8)aminoalkyl, optionally substituted (C1-C8)hydroxyalkyl, optionally substituted (C1-C8)haloalkyl, optionally substituted (C1-C8)haloalkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aryloxy, optionally substituted arylalkoxy, optionally substituted heteroaryloxy, optionally substituted heteroarylalkoxy, optionally substituted (C3-C10)cycloalkyl, optionally substituted (C3-C10)cycloalkoxy, optionally substituted (C2-C9)heterocycloalkyl, optionally substituted (C2-C9)heterocycloalkoxy, (H3CSO2)(C1-C8)alkylene, (H2NSO2)(C1-C8)alkylene, optionally substituted di((C1-C8)alkyl)amino;
- or R10 and R11, R11 and R12, or R12 and R13, taken together with the intervening atoms, form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group;
- R14 is H or (C1-C6)alkyl;
- R15 is optionally substituted (C3-C10)cycloalkyl or (C3-C10)cycloalkenyl;
- represents a heterocyclic group substituted by oxo (═O) and optionally substituted by one or more additional substituents;
- and
- n is an integer from 1-3.
7 more elements
A compound having the structure of formula (III′):
- or a pharmaceutically acceptable salt thereof;
- wherein:
- each of R40, R41, R42, and R43 is independently selected from H, OH, —NH2, halide, sulfonamido, (C1-C6)alkylsulfonyl, —OC(O)((C1-C8)alkyl), —C(O)O((C1-C8)alkyl), —C(O)OH, optionally substituted —NHC(O)(aryl), —C(O)NH2, —B(OH)2, tri((C1-C8)alkyl)silyl, optionally substituted (C1-C8)alkyl, optionally substituted (C1-C8)alkoxy, optionally substituted (C1-C8)aminoalkyl, optionally substituted (C1-C8)hydroxyalkyl, optionally substituted (C1-C8)haloalkyl, optionally substituted (C1-C8)haloalkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aryloxy, optionally substituted arylalkoxy, optionally substituted heteroaryloxy, optionally substituted heteroarylalkoxy, optionally substituted (C3-C10)cycloalkyl, optionally substituted (C3-C10)cycloalkoxy, optionally substituted (C2-C9)heterocycloalkyl, optionally substituted (C2-C9)heterocycloalkoxy, (H3CSO2)(C1-C8)alkylene, (H2NSO2)(C1-C8)alkylene, optionally substituted di((C1-C8)alkyl)amino;
- or R40 and R41, R41 and R42, or R42 and R43, taken together with the intervening atoms, form an aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group;
- R44 is H or (C1-C6)alkyl;
- R45 is optionally substituted (C3-C10)cycloalkyl or (C3-C10)cycloalkenyl;
- Rc, independently for each occurrence, is selected from H, (C1-C8)alkyl, (C1-C8)haloalkyl, (C1-C8)alkoxyl, (C1-C8)hydroxyalkyl, (C3-C10)cycloalkyl, (C3-C10)cycloalkyl(C1-C8)alkyl, aryl, and aryl(C1-C8) alkyl;
- Rd, independently for each occurrence, is selected from H, optionally substituted —C(O)(C1-C8)alkyl, optionally substituted —C(O)NH—(C3-C10)cycloalkyl, optionally substituted (C1-C8)alkyl, optionally substituted (C1-C8)haloalkyl, optionally substituted (C1-C8)hydroxyalkyl, optionally substituted (C3-C10)cycloalkyl, optionally substituted heterocyclyl, optionally substituted (C3-C10)cycloalkyl(C1-C8)alkyl, optionally substituted aryl, and optionally substituted aryl(C1-C8) alkyl, or
- two Rd are taken together with the nitrogen atom to which they are attached to form an optionally substituted 5-6-membered heterocyclyl;
- and
- m is an integer from 1-3.
8 more elements
Dependencies are inferred from the claim text.