Modulators of rho-associated protein kinase

A compound of formula (I) and pharmaceutically acceptable salts thereof:

• X1 and X2 are each independently selected from carbon and nitrogen;
• wherein at least one of X1 and X2 is carbon;
• X3 is selected from carbon and nitrogen;
• R1 and R2 are each independently selected from H, halo, nitro, cyano, NR8R8, OR10, SR8, SO2R8, SO2NR8R8, CO2R8, C(O)R8, CONR8R8, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl, C1-C4-alkyl substituted with NR8R9, C1-C4-alkyl substituted with OR10, and cyclopropyl;
• R3 is independently selected from C1-C4-alkyl, C1-C4-haloalkyl, C0-C3-alkylene-R3a, and C2-C4-alkylene-R3b;
• wherein R3a is independently at each occurrence selected from cyclopropyl and azetidinyl, said cyclopropyl or azetidinyl groups being optionally substituted with from 1 to 4 R1 groups;
• wherein R3b is independently at each occurrence selected from NR8R9, OR10 and SR8;
• R4 and R12 are each independently at each occurrence selected from halo, nitro, cyano, NR8R9, OR10, SR8, SO2R8, SO2NR8R8, CO2R8, C(O)R8, CONR8R8, CR8R8NR8R8, CR8R8OR8, C1-C4- alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl;
• R5 is independently selected from CONR8R8, unsubstituted phenyl, phenyl substituted with from 1 to 4 R11 groups, and 4- to 10-membered heterocyclyl, wherein said heterocyclyl group may be monocyclic or bicyclic and wherein any given ring of said heterocyclyl group may be saturated, unsaturated or partially unsaturated;
• wherein any saturated ring or partially unsaturated ring is optionally substituted with a single R13 group and/or from 1 to 4 R11 groups and wherein any unsaturated ring is optionally substituted with a single R13 group and/or from 1 to 3 R12 groups;
• R6 is independently at each occurrence selected from H, halo, C1-C4-alkyl, C1-C4-alkyl substituted with NR8R9, C1-C4-alkyl substituted with OR10, and cyclopropyl, or the two R6 groups and the carbon atom to which they are attached may together form a C3-C6 cycloalkyl ring;
• R7 and R8 are each independently selected from H, C1-C4-alkyl and C1-C4-haloalkyl;
• R9 is independently at each occurrence selected from H, C1-C4-alkyl, C(O)—C1-C4-alkyl and S(O)2—C1-C4-alkyl;
• or R8 and R9, together with the nitrogen atom to which they are attached together form a C5-C8-heterocycloalkyl group optionally substituted with from 0 to 4 R11 groups;
• R10 is independently at each occurrence selected from H, C1-C4-alkyl, C(O)—C1-C4-alkyl and C1-C4-haloalkyl;
• R11 is independently at each occurrence selected from ═O, halo, nitro, cyano, NR8R9, OR14, SR8, SO2NR8R8, CO2R8, C(O)R8, CONR8R8, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-haloalkyl and cyclopropyl;
• R13 is independently selected from C3-C6-cycloalkyl, 3- to 6-membered-heterocycloalkyl, CR8R8NR8R9 and CR8R8OR8;
• wherein where R13 is cycloalkyl or heterocycloalkyl, R13 is optionally substituted with from 1 to 4 R11 groups;
• R14 is independently at each occurrence selected from H, C1-C4-alkyl;
• C1-C4-haloalkyl and C(O)—C1-C4-alkyl;
• and
• m is an integer selected from 0, 1, 2, 3 and 4;
• wherein any of the aforementioned alkyl or cycloalkyl (e.g. cyclopropyl) groups is optionally substituted, where chemically possible, by 1 to 5 substituents which are each independently at each occurrence selected from the group consisting of:
• halo, oxo, nitro, cyano, NRaRb, ORa, SRa, CO2Ra, C(O)Ra, CONRaRa;
• wherein Ra is independently at each occurrence selected from H, C1-C4-alkyl and C1-C4-haloalkyl;
• and Rb is independently at each occurrence selected from H, C1-C4-alkyl, C(O)—C1-C4-alkyl and S(O)2—C1-C4-alkyl.