Modular synthesis of 1,2-azaborines via ring-opening BN-isostere benzannulation

A method for making a 1,2-disubstituted azaborine having the structure:

• or a pharmaceutically-acceptable salt thereof, or a solvate thereof, wherein
• R1 is a carbon-linked substituent having no more than 40 non-H atoms;
• R2 is a carbon-linked substituent having no more than 40 non-H atoms;
• R3 is H or a substituent having no more than 40 non-H atoms, and
• L3 is selected from the group consisting of a bond, —C(O)—, —S—, —S(O)1-2—, —O—, —NR7—, —C(O)NR7—, —NR7C(O)—, —C(S)NR7—, —NR7C(S)—, —C(O)O—, —OC(O)—, —C(O)S—, —SC(O)—, —C(S)O—, —OC(S)—, —C(S)S—, —SC(S)—, —S(O)1-2O—, —OS(O)1-2—, —S(O)1-2NR7—, and —NR7S(O)1-2—, or
• -L3-R3 is halo, nitro, or cyano;
• R4 is H or a substituent having no more than 40 non-H atoms, and
• L4 is selected from the group consisting of a bond, —C(O)—, —S—, —S(O)1-2—, —O—, —NR7—, —C(O)NR7—, —NR7C(O)—, —C(S)NR7—, —NR7C(S)—, —C(O)O—, —OC(O)—, —C(O)S—, —SC(O)—, —C(S)O—, —OC(S)—, —C(S)S—, —SC(S)—, —S(O)12O—, —OS(O)1-2—, —S(O)1-2NR7—, and —NR7S(O)1-2—, or
• -L4-R4 is halo, nitro, or cyano;
• R6 is H or a substituent having no more than 40 non-H atoms, and
• L6 is selected from the group consisting of a bond, —C(O)—, —S—, —S(O)1-2—, —O—, —NR7—, —C(O)NR7—, —NR7C(O)—, —C(S)NR7—, —NR7C(S)—, —C(O)O—, —OC(O)—, —C(O)S—, —SC(O)—, —C(S)O—, —OC(S)—, —C(S)S—, —SC(S)—, —S(O)1-2O—, —OS(O)1-2—, —S(O)1-2NR7—, and —NR7S(O)1-2—, or
• -L6-R6 is halo, nitro, or cyano:
• wherein
• each R7 is independently selected from —(C1-C6 alkyl), —(C1-C6 haloalkyl), —(C0-C6 alkyl)-Ar, —(C0-C6 alkyl)-Het, —(C0-C6 alkyl)-Cak, —(C0-C6 alkyl)-Hca, —(C0-C6 alkyl)-L-R8, —(C0-C6 alkyl)-NR10R9, —(C0-C6 alkyl)-OR11, —(C0-C6 alkyl)-C(O)R11, —(C0-C6 alkyl)-S(O)0-2R11, -halogen, —NO2, and —CN, wherein
• each L is independently selected
• from —NR9C(O)O—, —OC(O)NR9—, —NR9C(O)—NR9—, —NR9C(O)S—, —SC(O)NR9—, —NR9C(O)—,
• —C(O)—NR9—, —NR9C(S)O—, —OC(S)NR9—, —NR9C(S)—NR9—, —NR9C(S)S—, —SC(S)NR9—, —NR9C(S)—, —C(S)NR9—, —SC(O)NR9—, —NR9C(S)—, —S(O)0-2—, —C(O)0, —OC(O)—, —C(S)O—,
• —OC(S)—, —C(O)S—, —SC(O)—, —C(S)S—, —SC(S)—, —OC(O)O—,
• —SC(O)O—, —OC(O)S—, —SC(S)O—, —OC(S)S—, —NR9C(NR2)NR9—, —NR9SO2—, —SO2NR9—, and —NR9SO2NR9—,
• each R8, R10, and R11 is independently selected from H, —(C1-C6 alkyl), —(C1-C6 haloalkyl), —(C0-C6 alkyl)-Ar, —(C0-C6 alkyl)-Het, —(C0-C6 alkyl)-Cak, —(C0-C6 alkyl)-Hca, —(C0-C6 alkyl)-L-(C0-C6 alkyl), —(C0-C6 alkyl)-NR9—(C0-C6 alkyl), —(C0-C6 alkyl)-O—(C0-C6 alkyl), —(C0-C6 alkyl)-C(O)—(C0-C6 alkyl), and —(C0-C6 alkyl)-S(O)0-2—(C0-C6 alkyl),
• each R9 is independently selected from —H, —(C1-C4 alkyl), —C(O)—(C1-C4 alkyl), and —C(O)O—(C1-C4 alkyl),
• each Ar is an optionally substituted aryl,
• each Het is an optionally substituted heteroaryl,
• each Cak is an optionally substituted cycloalkyl,
• each Hca is an optionally substituted heterocycloalkyl, and
• each alkyl is optionally substituted, the method comprising:
• combining a Lewis acid, an N-substituted 1-cyclopropyl imine, and a B-substituted dihaloborane and allowing them to react to form a B-substituted, N-substituted, 1-halo-N-(6-halohex-3-enyl)boranamine;
• then
• treating the B-substituted, N-substituted, 1-halo-N-(6-halohex-3-enyl)boranamine with a base to provide the 1,2-disubstituted azaborine.