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US 11,993,571 B2Granted
Indole derivatives as efflux pump inhibitors
AssigneeRutgers, The State University of New Jersey
InventorsEdmond J. LaVoie, Ajit Parhi, Yi Yuan, Yongzheng Zhang, Yangsheng Sun
Life of this patent
Estimating the term…
Abstract
Disclosed herein are compounds of formula (I): and salts thereof. Also disclosed are compositions comprising compounds of formula I and compounds of formula I for use in treating or preventing bacterial infections.
Claims26
A compound of formula I:
- wherein:
- A is —C(═O)N(Ra1)—R1, —(C1-C3)alkyl-C(═O)N(Ra1)R1, —(C1-C3)alkyl-O—R1, or —O—R1, and B is hydrogen, halogen, or (C1-C4)alkyl;
- each R1 is independently:
- (a) (C2-C8)alkyl substituted with two or more —NRb2Rc2 and wherein (C2-C8)alkyl is optionally substituted independently with one or more halo, (C1-C4)alkyl or (C3-C7)carbocyclyl;
- or
- (b) pyrrolidinyl-(CH2), (C3-C7)carbocyclyl-NRe—(C1-C4)alkyl- or 4-7 membered monocyclic heterocyclyl-NRe—(C1-C4)alkyl- wherein each (C3-C7)carbocyclyl-NRe—(C1-C4)alkyl- is independently substituted with one or more Z1 or Z2, and wherein each pyrrolidinyl-(CH2)— or 4-7 membered monocyclic heterocyclyl-NRe—(C1-C4)alkyl- is independently substituted with one or more Z1 or Z2, and wherein any pyrrolidinyl-(CH2), (C3-C7)carbocyclyl NRe—(C1-C4)alkyl- or 4-7 membered monocyclic heterocyclyl-NRe—(C1-C4)alkyl-of R1 is independently optionally substituted with one or more halo, (C1-C4)alkyl, (C3-C7)carbocyclyl, —C(═O)NH2, —C(═O)NH(C1-C4)alkyl, —C(═O)N((C1-C4)alkyl)2, —NHC(═O)(C1-C4)alkyl-NH2, or 3-7 membered monocyclic heterocyclyl wherein (C1-C4)alkyl, (C3-C7)carbocyclyl or 3-7 membered monocyclic heterocyclyl is optionally substituted with one or more halogen, (C1-C4)alkyl, —NH2, —NH(C1-C4)alkyl or —N((C1-C4)alkyl)2;
- R2 is hydrogen or (C1-C4)alkyl;
- R3 is hydrogen, halo, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, (C1-C4)haloalkoxy, aryl, or heteroaryl wherein the aryl or heteroaryl is optionally substituted with one or more groups independently selected from the group consisting of halo, —OH, —NO2, —CN, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, and (C1-C4)haloalkoxy;
- R4 is hydrogen, halo, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, (C1-C4)haloalkoxy, aryl, heteroaryl, aryl(C1-C4)alkyl-, heteroaryl(C1-C4)alkyl-, (C3-C7)carbocyclyl(C1-C4)alkyl-, (C3-C7)carbocyclyl(C2-C4)alkynyl-, phenoxy or heteroaryloxy, wherein the aryl, heteroaryl, aryl(C1-C4)alkyl-, heteroaryl(C1-C4)alkyl-, (C3-C7)carbocyclyl(C1-C4)alkyl-, (C3-C7)carbocyclyl(C2-C4)alkynyl-, phenoxy or heteroaryloxy, is optionally substituted with one or more groups independently selected from the group consisting of halo, —OH, —NO2, —CN, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, (C1-C4)haloalkoxy, methylenedioxy (—OCH2O—), and (C3-C7)carbocyclyl;
- R5 is hydrogen, halo, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, (C1-C4)haloalkoxy, aryl, heteroaryl, aryl(C1-C4)alkyl-, heteroaryl(C1-C4)alkyl-, (C3-C7)carbocyclyl(C1-C4)alkyl-, (C3-C7)carbocyclyl(C2-C4)alkynyl-, phenoxy or heteroaryloxy, wherein the aryl, heteroaryl, aryl(C1-C4)alkyl-, heteroaryl(C1-C4)alkyl-, (C3-C7)carbocyclyl(C1-C4)alkyl-, (C3-C7)carbocyclyl(C2-C4)alkynyl-, phenoxy or heteroaryloxy, is optionally substituted with one or more groups independently selected from the group consisting of halo, —OH, —NO2, —CN, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, (C1-C4)haloalkoxy, methylenedioxy (—OCH2O—), and (C3-C7)carbocyclyl;
- R6 is hydrogen, halo, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, (C1-C4)haloalkoxy, aryl, or heteroaryl wherein the aryl or heteroaryl is optionally substituted with one or more groups independently selected from the group consisting of halo, —OH, —NO2, —CN, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, and (C1-C4)haloalkoxy;
- each Z1 is independently selected from the group consisting
- of —NRb3Rc3, —NHNH2, —C(═NRa3)(NRb3Rc3), —NRa3C(═NRa3)(Rd3),
- and —NRa3C(═NRa3)(NRb3Rc3);
- each Z2 is independently —(C1-C6)alkyl substituted with one or more Z1 and optionally substituted with one or more Z3;
- each Z3 is independently halo or (C3-C7)carbocyclyl;
- each Ra1 is independently hydrogen, (C1-C4)alkyl, (C3-C7)carbocyclyl or 3-7 membered monocyclic heterocyclyl optionally substituted with one or more halogen or (C1-C4)alkyl;
- each Rb2 and Rc2 is independently hydrogen, (C1-C4)alkyl or (C3-C7)carbocyclyl;
- each Ra3 is independently hydrogen, (C1-C4)alkyl or (C3-C7)carbocyclyl;
- each Rb3 is hydrogen;
- each Rc3 is independently hydrogen, (C1-C4)alkyl, or (C3-C7)carbocyclyl;
- Rd3 is (C1-C4)alkyl or (C3-C7)carbocyclyl;
- and
- each Re is independently hydrogen, (C1-C4)alkyl or (C3-C7)carbocyclyl;
- or a salt thereof;
- and
- wherein any carbocyclyl is saturated or partially unsaturated.
24 more elements
A compound of formula Ia:
- wherein:
- R1 is:
- (a) (C2-C8)alkyl substituted with two or more —NRb2Rc2 and wherein (C2-C8)alkyl is optionally substituted independently with one or more halo, (C1-C4)alkyl or (C3-C7)carbocyclyl;
- or
- (b) pyrrolidinyl-(C1-C4)alkyl-, (C3-C7)carbocyclyl-NRe—(C1-C4)alkyl- or 4-7 membered monocyclic heterocyclyl-NRe—(C1-C4)alkyl- wherein each (C3-C7)carbocyclyl-NRe—(C1-C4)alkyl- is independently substituted with one or more Z1 or Z2, and wherein each pyrrolidinyl-(C1-C4)alkyl- or 4-7 membered monocyclic heterocyclyl-NRe—(C1-C4)alkyl- is independently substituted with one or more Z1 or Z2, and wherein any pyrrolidinyl-(C1-C4)alkyl-, (C3-C7)carbocyclyl NRe—(C1-C4)alkyl- or 4-7 membered monocyclic heterocyclyl-NRe—(C1-C4)alkyl- of R1 is independently optionally substituted with one or more halo, (C1-C4)alkyl, (C3-C7)carbocyclyl, —C(═O)NH2, —C(═O)NH(C1-C4)alkyl, —C(═O)N((C1-C4)alkyl)2, —NHC(═O)(C1-C4)alkyl-NH2, or 3-7 membered monocyclic heterocyclyl wherein (C1-C4)alkyl, (C3-C7)carbocyclyl or 3-7 membered monocyclic heterocyclyl is optionally substituted with one or more halogen, (C1-C4)alkyl, —NH2, —NH(C1-C4)alkyl or —N((C1-C4)alkyl)2;
- R3 is hydrogen, halo, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, (C1-C4)haloalkoxy, aryl, or heteroaryl wherein the aryl or heteroaryl is optionally substituted with one or more groups independently selected from the group consisting of halo, —OH, —NO2, —CN, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, and (C1-C4)haloalkoxy;
- R4 is hydrogen, halo, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, (C1-C4)haloalkoxy, aryl, heteroaryl, aryl(C1-C4)alkyl-, heteroaryl(C1-C4)alkyl-, (C3-C7)carbocyclyl(C1-C4)alkyl-, (C3-C7)carbocyclyl(C2-C4)alkynyl-, phenoxy or heteroaryloxy, wherein the aryl, heteroaryl, aryl(C1-C4)alkyl-, heteroaryl(C1-C4)alkyl-, (C3-C7)carbocyclyl(C1-C4)alkyl-, (C3-C7)carbocyclyl(C2-C4)alkynyl-, phenoxy or heteroaryloxy, is optionally substituted with one or more groups independently selected from the group consisting of halo, —OH, —NO2, —CN, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, (C1-C4)haloalkoxy, methylenedioxy (—OCH2O—), and (C3-C7)carbocyclyl;
- R5 is hydrogen, halo, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, (C1-C4)haloalkoxy, aryl, heteroaryl, aryl(C1-C4)alkyl-, heteroaryl(C1-C4)alkyl-, (C3-C7)carbocyclyl(C1-C4)alkyl-, (C3-C7)carbocyclyl(C2-C4)alkynyl-, phenoxy or heteroaryloxy, wherein the aryl, heteroaryl, aryl(C1-C4)alkyl-, heteroaryl(C1-C4)alkyl-, (C3-C7)carbocyclyl(C1-C4)alkyl-, (C3-C7)carbocyclyl(C2-C4)alkynyl-, phenoxy or heteroaryloxy, is optionally substituted with one or more groups independently selected from the group consisting of halo, —OH, —NO2, —CN, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, (C1-C4)haloalkoxy, methylenedioxy (—OCH2O—), and (C3-C7)carbocyclyl;
- R6 is hydrogen, halo, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, (C1-C4)haloalkoxy, aryl, or heteroaryl wherein the aryl or heteroaryl is optionally substituted with one or more groups independently selected from the group consisting of halo, —OH, —NO2, —CN, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, and (C1-C4)haloalkoxy;
- each Z1 is independently selected from the group consisting
- of —NRb3Rc3, —NHNH2, —C(═NRa3)(NRb3Rc3);
- —NRa3 (═NRa3)(Rd3);
- and —NRa3C(═NRa3)(NRb3Rc3);
- each Z2 is independently —(C1-C6)alkyl substituted with one or more Z1 and optionally substituted with one or more Z3;
- each Z3 is independently halo or (C3-C7)carbocyclyl;
- each Rb2 and Rc2 is independently hydrogen, (C1-C4)alkyl or (C3-C7)carbocyclyl;
- each Ra3 is independently hydrogen, (C1-C4)alkyl or (C3-C7)carbocyclyl;
- each Rb3 is hydrogen;
- each Rc3 is independently hydrogen, (C1-C4)alkyl, or (C3-C7)carbocyclyl;
- Rd3 is (C1-C4)alkyl or (C3-C7)carbocyclyl;
- and
- each Re is independently hydrogen, (C1-C4)alkyl or (C3-C7)carbocyclyl;
- or a salt thereof;
- and
- wherein any carbocyclyl is saturated or partially unsaturated.
22 more elements
A compound or salt thereof that is:
- or a salt thereof.
Dependencies are inferred from the claim text.