Small-molecule inhibitors targeting G-protein-coupled Rho guanine nucleotide exchange factors

A method of inhibiting Rho GTPase activation comprising contacting a RhoGEF with a compound having the structure of Formula I:

• or a pharmaceutically acceptable salt thereof,
• wherein:
• R1 is
• or 1H-isoindolyl;
• each R6 is independently selected from the group consisting of fluoro, chloro, methyl, ethoxy, and C1-3 alkoxy substituted with R1B;
• each R1B is independently selected from the group consisting of —OR1C, aryl, and heteroaryl, said aryl or heteroaryl each optionally substituted with one or more R1D;
• each R1C is independently selected from the group consisting of aryl, and heteroaryl, said aryl or heteroaryl each optionally substituted with one or more R1E;
• each R1D is independently selected from the group consisting of hydroxy, cyano, nitro, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, amino, optionally substituted C3-7 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, and C1-6 alkoxy optionally substituted with up to 5 fluoro;
• each R1E is independently selected from the group consisting of hydroxy, halo, cyano, nitro, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, amino, optionally substituted C3-7 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, C1-6 alkyl optionally substituted with up to 5 fluoro, and C1-6 alkoxy optionally substituted with up to 5 fluoro;
• R2 is H (hydrogen), aryl, or heteroaryl, said aryl or heteroaryl each optionally substituted with one or more R2A;
• each R2A is independently selected from the group consisting of hydroxy, halo, cyano, optionally substituted C3-7 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, C1-6 alkyl substituted with up to 5 fluoro, and C1-6 alkoxy optionally substituted with up to 5 fluoro;
• and
• R3 is H (hydrogen), aryl, or heteroaryl, said aryl or heteroaryl each optionally substituted with one or more R3A, provided that one of R2 and R3 is H (hydrogen) and one of R2 and R3 is not H (hydrogen);
• each R3A is independently selected from the group consisting of hydroxy, halo, cyano, optionally substituted C3-7 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, C1-6 alkyl substituted with up to 5 fluoro, and C1-6 alkoxy optionally substituted with up to 5 fluoro;
• R4 is H (hydrogen), or C1-6 alkyl;
• and
• R5 is H (hydrogen), or C1-6 alkyl, or optionally R4 and R5 together are oxo.

A method of inhibiting Rho GTPase activation comprising contacting a RhoGEF with a compound having the structure of Formula Ia:

• or a pharmaceutically acceptable salt thereof,
• wherein:
• R1 is
• or 1H-isoindolyl;
• each R6 is independently selected from the group consisting of fluoro, chloro, bromo, methyl, methoxy, and C1-4 alkoxy substituted with R1B;
• each R1B is independently selected from the group consisting of —OR1C, aryl, and heteroaryl, said aryl or heteroaryl each optionally substituted with one or more R1D;
• each R1C is independently selected from the group consisting of aryl, and heteroaryl, said aryl or heteroaryl each optionally substituted with one or more R1E;
• each R1D is independently selected from the group consisting of hydroxy, halo, cyano, nitro, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, amino, optionally substituted C3-7 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, C1-6 alkyl optionally substituted with up to 5 fluoro, and C1-6 alkoxy optionally substituted with up to 5 fluoro;
• each R1E is independently selected from the group consisting of hydroxy, halo, cyano, nitro, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, amino, optionally substituted C3-7 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, C1-6 alkyl optionally substituted with up to 5 fluoro, and C1-6 alkoxy optionally substituted with up to 5 fluoro;
• R2 is aryl optionally substituted with one or more R2A;
• each R2A is independently selected from the group consisting of hydroxy, bromo, cyano, optionally substituted C3-7 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, C1-6 alkyl substituted with up to 5 fluoro, and C1-6 alkoxy optionally substituted with up to 5 fluoro;
• and
• R3 is H (hydrogen);
• each R3A is independently selected from the group consisting of hydroxy, bromo, cyano, optionally substituted C3-7 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, C1-6 alkyl substituted with up to 5 fluoro, and C1-6 alkoxy optionally substituted with up to 5 fluoro;
• R4 is H (hydrogen), or C1-6 alkyl;
• and
• R5 is H (hydrogen), or C1-6 alkyl, or optionally R4 and R5 together are oxo.