Indole carboxamide derivatives and uses thereof

A method of treating tuberculosis comprising the step of administering to a human in need thereof a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient, and at least one additional pharmaceutical agent, wherein said human has (i) a sputum smear-positive, sputum smear-negative, or extrapulmonary tuberculosis;

• (ii) tuberculosis caused by drug resistant Mycobacterium tuberculosis complex (M. tuberculosis) organisms;
• or (iii) tuberculosis combined with human immunodeficiency virus (HIV) infection, and wherein the compound of Formula I is:
• wherein
• R1 is H or methyl;
• R2 is H, methyl, halo, cyano, trifluoromethyl, or methoxy;
• R3 is H, methyl, or methoxy;
• R4 is H, methyl, halo, cyano, trifluoromethoxy, methoxy, —(O(CH2)m)n-morpholinyl, piperidinyl, ((C1-C4)alkyl)NH—, or (phenyl)NH—, where m is 1 or 2 and n is 0 or 1;
• or
• R3 and R4 taken together with the aromatic carbon atoms to which they are attached form a fused 1,3-dioxolo group;
• R5 is H or halo;
• provided that R2, R3, R4 and R5 are not all hydrogen;
• R6 is
• (i) (C4-C6)alkyl, where said (C4-C6)alkyl is optionally substituted with phenyl which is optionally substituted with one to two substituents each independently selected from (C1-C4)alkyl, fluoro-substituted (C1-C4)alkyl, methoxy, hydroxy(C1-C4)alkyl, methoxy(C1-C4)alkyl, ethynyl, cyano, halo, or hydroxy;
• (ii) (C5-C7)cycloalkyl, or —CH2—(C5-C7)cycloalkyl, where said (C5-C7)cycloalkyls are optionally substituted with one to two substituents each independently selected from (C1-C4)alkyl, fluoro-substituted (C1-C4)alkyl, methoxy, hydroxy(C1-C4)alkyl, methoxy(C1-C4)alkyl, ethynyl, cyano, halo, or hydroxy, provided that R6 is not an unsubstituted cyclohexyl, when R2 and R4 are both methyl;
• (iii) spiral(C8-C11)cycloalkyl;
• or
• (iv) phenyl, where said phenyl is optionally substituted with one to two substituents each independently selected from (C1-C4)alkyl, fluoro-substituted (C1-C4)alkyl, methoxy, hydroxy(C1-C4)alkyl, methoxy(C1-C4)alkyl, ethynyl, cyano, halo, or hydroxy, provided that R6 is not an unsubstituted phenyl, when R2 and R4 are both methyl.

A compound for use in therapy, wherein the compound is of Formula I:

• wherein
• R1 is H or methyl;
• R2 is H, methyl, halo, cyano, trifluoromethyl, or methoxy;
• R3 is H, methyl, or methoxy;
• R4 is H, methyl, halo, cyano, trifluoromethyl, methoxy, —(O(CH2)m)n-morpholinyl, piperidinyl, ((C1-C4)alkyl)NH—, or (phenyl)NH—, where m is 1 or 2 and n is 0 or 1;
• or
• R3 and R4 taken together with the aromatic carbon atoms to which they are attached form a fused 1,3-dioxolo group;
• R5 is H or halo;
• provided that R2, R3, R4 and R5 are not all hydrogen;
• R6 is
• (i) (C4-C6)alkyl, where said (C4-C6)alkyl is optionally substituted with phenyl which is optionally substituted with one to two substituents each independently selected from (C1-C4)alkyl, fluoro-substituted (C1-C4)alkyl, methoxy, hydroxy(C1-C4)alkyl, methoxy(C1-C4)alkyl, ethynyl, cyano, halo, or hydroxy;
• (ii) (C5-C7)cycloalkyl, or —CH2—(C5-C7)cycloalkyl, where said (C5-C7)cycloalkyls are optionally substituted with one to two substituents each independently selected from (C1-C4)alkyl, fluoro-substituted (C1-C4)alkyl, methoxy, hydroxy(C1-C4)alkyl, methoxy(C1-C4)alkyl, ethynyl, cyano, halo, or hydroxy, provided that R6 is not an unsubstituted cyclohexyl, when R2 and R4 are both methyl;
• (iii) spiral(C8-C11)cycloalkyl;
• or
• (iv) phenyl, where said phenyl is optionally substituted with one to two substituents each independently selected from (C1-C4)alkyl, fluoro-substituted (C1-C4)alkyl, methoxy, hydroxy(C1-C4)alkyl, methoxy(C1-C4)alkyl, ethynyl, cyano, halo, or hydroxy, provided that R6 is not an unsubstituted phenyl, when R2 and R4 are both methyl:
• or a pharmaceutically acceptable salt thereof.

A method for treating a disease, disorder or syndrome mediated by the transportation of essential molecules in the mmpL3 pathway comprising the step of administering to a patient in need thereof,

• (i) a first composition comprising a compound, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient;
• and
• (ii) a second composition comprising at least one additional pharmaceutical agent and a pharmaceutically acceptable carrier or excipient;
• wherein the compound is of Formula I:
• wherein
• R1 is H or methyl;
• R2 is H, methyl, halo, cyano, trifluoromethyl, or methoxy;
• R3 is H, methyl, or methoxy;
• R4 is H, methyl, halo, cyano, trifluoromethyl, methoxy, —O(CH2)m)n-morpholinyl, piperidinyl, ((C1-C4)alkyl)NH—, or (phenyl)NH—, where m is 1 or 2 and n is 0 or 1;
• or
• R3 and R4 taken together with the aromatic carbon atoms to which they are attached form a fused 1,3-dioxolo group;
• R5 is H or halo;
• provided that R2, R3, R4 and R5 are not all hydrogen;
• R6 is
• (i) (C4-C6)alkyl, where said (C4-C6)alkyl is optionally substituted with phenyl which is optionally substituted with one to two substituents each independently selected from (C1-C4)alkyl, fluoro-substituted (C1-C4)alkyl, methoxy, hydroxy(C1-C4)alkyl, methoxy(C1-C4)alkyl, ethynyl, cyano, halo, or hydroxy;
• (ii) (C5-C7)cycloalkyl, or —CH2—(C5-C7)cycloalkyl, where said (C5-C7)cycloalkyls are optionally substituted with one to two substituents each independently selected from (C1-C4)alkyl, fluoro-substituted (C1-C4)alkyl, methoxy, hydroxy(C1-C4)alkyl, methoxy(C1-C4)alkyl, ethynyl, cyano, halo, or hydroxy, provided that R6 is not an unsubstituted cyclohexyl, when R2 and R4 are both methyl;
• (iii) spiral(C8-C11)cycloalkyl;
• or
• (iv) phenyl, where said phenyl is optionally substituted with one to two substituents each independently selected from (C1-C4)alkyl, fluoro-substituted (C1-C4)alkyl, methoxy, hydroxy(C1-C4)alkyl, methoxy(C1-C4)alkyl, ethynyl, cyano, halo, or hydroxy, provided that R6 is not an unsubstituted phenyl, when R2 and R4 are both methyl.