Macrocyclic indoles as Mcl-1 inhibitors

A compound of Formula I:

• wherein:
• R is selected from the group consisting of hydrogen and C1-C6 alkyl;
• R1a is selected from the group consisting of hydrogen, halo, C1-C4 alkyl, C1-C4 haloalkyl, C2-C4 alkynyl, C3-C6 cycloalkyl, and —(CH2),N(R2a)(R2b);
• R2a is selected from the group consisting of hydrogen and C1-C4 alkyl;
• R2b is selected from the group consisting of hydrogen, C1-C4 alkyl, —C(═O)R3a, and —S(═O)2R3b;
• or
• R2a and R2b taken together with the nitrogen atom to which they are attached form a 3- to 6-membered optionally substituted heterocyclo;
• m is 1, 2, or 3;
• R3a is selected from the group consisting of C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, optionally substituted 4- to 8-membered heterocyclo, optionally substituted C6-C10 aryl, and optionally substituted 5- to 10-membered heteroaryl;
• R3b is selected from the group consisting of C1-C4 alkyl, C1-C4 haloalkyl, C3-C6 cycloalkyl, optionally substituted 4- to 8-membered heterocyclo, optionally substituted C6-C10 aryl, and optionally substituted 5- to 10-membered heteroaryl;
• R1b is selected from the group consisting of hydrogen, halo, and C1-C4 alkyl;
• R1h is selected from the group consisting of hydrogen, halo, and C1-C4 alkyl;
• is selected from the group consisting of:
• R4a, R4b, R4c, and R4d are each independently selected from the group consisting of hydrogen, halo, cyano, amino, hydroxyl, C1-C4 alkyl, C1-C4 haloalkyl, and C1-C4 alkoxy;
• R5a, R5b, R5c, R5d, R5e, and R5f are each independently selected from the group consisting of hydrogen, halo, cyano, amino, hydroxyl, C1-C4 alkyl, C1-C4 haloalkyl, and C1-C4 alkoxy;
• is selected from the group consisting of arylene and heteroarylene;
• is selected from the group consisting of:
• wherein —X— is attached to L3;
• R1c is selected from the group consisting of hydrogen, C1-C4 alkyl, halo, C1-C4 haloalkyl, and C3-06 cycloalkyl;
• R1d is selected from the group consisting of hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, (C1-C4 alkoxy)C1-C4 alkyl, and (carboxamido)C1-C4 alkyl;
• or
• R1c and R1d taken together with the atoms to which they are attached form an optionally substituted 4- to 8-membered heterocyclo;
• R1c is selected from the group consisting of hydrogen, halo, C1-C4 alkyl, C1-C4 haloalkyl, and C3-C6 cycloalkyl;
• R1f is selected from the group consisting of hydrogen, C1-C4 alkyl, C3-C6 cycloalkyl, (C1-C4 alkoxy)C1-C4 alkyl, and (carboxamido)C1-C4 alkyl;
• X is selected from the group consisting of —O—, —S—, —S(═O)—, —S(═O)2—, and —N(R6)—;
• R6 is selected from the group consisting of hydrogen, C1-C4 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C6-C10 aryl, (C6-C10 aryl)C1-C4 alkyl, optionally substituted 5- to 10-membered heteroaryl, —C(═O)R7a, —S(═O)2R8a, (hydroxyl)C1-C4 alkyl, (5- to 10-membered heteroaryl)C1-C4 alkyl, (C1-C4 alkoxy)C1-C4 alkyl, (carboxamido)C1-C4 alkyl, —(CH2)qN(R13a)C(═O)R7b, and —(CH2)1N(R13b)S(=O)2R8b;
• R7a is selected from the group consisting of amino, C1-C4 alkyl, C1-C4 alkoxy, optionally substituted C3-C6 cycloalkyl, optionally substituted C6-C10 aryl, optionally substituted 5- to 10-membered heteroaryl, and (C6-C10 aryl)C1-C4 alkyl;
• R7b is selected from the group consisting of amino, C1-C4 alkyl, C1-C4 alkoxy, optionally substituted C3-C6 cycloalkyl, optionally substituted C6-C10 aryl, optionally substituted 5- to 10-membered heteroaryl, and (C6-C10 aryl)C1-C4 alkyl;
• R8a is selected from the group consisting of amino, C1-C4 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C6-C10 aryl, optionally substituted 5- to 10-membered heteroaryl, and (C6-C10 aryl)C1-C4 alkyl;
• R8b is selected from the group consisting of amino, C1-C4 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted C6-C10 aryl, optionally substituted 5- to 10-membered heteroaryl, and (C6-C10 aryl)C1-C4 alkyl;
• R13a is selected from the group consisting of hydrogen and C1-04 alkyl;
• R13b is selected from the group consisting of hydrogen and C1-04 alkyl;
• q is 1, 2, 3, or 4;
• r is 1, 2, 3, or 4;
• L1 is —(CR14aR14b)s—;
• each R14a and R14b are independently selected from the group consisting of hydrogen and C1-C4 alkyl;
• s is 2, 3, 4, 5, or 6;
• L2 is —(CR14cR14d)t—;
• each R14c and R14d are independently selected from the group consisting of hydrogen and C1-C4 alkyl;
• t is 1, 2, 3, or 4;
• L3 is —(CR14eR14f)v—;
• each R14e and R14f are independently selected from the group consisting of hydrogen and C1-C4 alkyl;
• and
• v is 1, 2, 3, or 4,
• wherein the C3-C6 cycloalkyl optionally is substituted with one, two, or three substituents independently selected from the group consisting of from halo, nitro, cyano, hydroxy, amino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, amido, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, carboxy, carboxyalkyl, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclo, alkoxyalkyl, (amino)alkyl, (carboxamido)alkyl, mercaptoalkyl, and (heterocyclo)alkyl;
• wherein aryl is a monocyclic or bicyclic aromatic ring system having an indicated number of carbon atoms, optionally substituted with one to five substituents independently selected from the group consisting of halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, amido, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, carboxy, carboxyalkyl, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclo, alkoxyalkyl, (amino)alkyl, (carboxamido)alkyl, mercaptoalkyl, and (heterocyclo)alkyl;
• wherein heteroaryl is a monocyclic or bicyclic aromatic ring systems having 5 to 14 ring atoms, wherein at least one carbon atom of one of the rings is replaced with 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur, optionally substituted with one to four substituents independently selected from the group consisting of halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, amido, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, carboxy, carboxyalkyl, alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclo, alkoxyalkyl, (amino)alkyl, (carboxamido)alkyl, mercaptoalkyl, and (heterocyclo)alkyl;
• and
• wherein heterocyclo is a saturated or partially unsaturated cyclic group containing one, two, or three rings having an indicated number of ring members, wherein at least one carbon atom of one of the rings is replaced with a heteroatom selected from the group consisting of oxygen, sulfur, and/or nitrogen atoms with, optionally substituted with one to four substituents independently selected from halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, amido, carboxamido, sulfonamido, alkylcarbonyl, alkoxycarbonyl, CF3C(=O)—, arylcarbonyl, alkylsulfonyl, arylsulfonyl, carboxy, carboxyalkyl, alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, substituted aryl, substituted heteroaryl, substituted heterocyclo, alkoxyalkyl, (amino)alkyl, (carboxamido)alkyl, mercaptoalkyl, and (heterocyclo)alkyl,
• or a pharmaceutically acceptable salt thereof.