Claims for Patent: 8,357,693

Summary for Patent: 8,357,693

Title:	Pharmacokinetically improved compounds
Abstract:	The present invention relates to inhibitors of ROCK1 and ROCK2 and methods of modulating the pharmacokinetic and/or pharmacodynamic properties of such compounds. Also provided are methods of inhibiting ROCK1 and or ROCK2 that are useful for the treatment of disease.
Inventor(s):	Alessandra Bartolozzi, Stewart Campbell, Hope Foudoulakis, Brian Kirk, Siya Ram, Paul Sweetnam
Assignee:	Surface Logix LLC
Application Number:	US11/887,218
Patent Claims:	1. A compound of formula I: or a pharmaceutically acceptable salt thereof, wherein: R1 is selected from the group consisting of —O—(CH2)y—CO2R12, —O—(CH2)y—C(═O)NR13R14, —O—(CH2)y-heteroaryl, —O—(CH2)y-cycloalkyl, —O—C(═O)—(CH2)y—NR13R14, —O—(CH2)z—NR13R14, —NH—C(═O)—(CH2)y—NR13R14, —NH—C(═O)—X—R15, —NH—(CH2)y—NR13R14; R12 is selected from the group consisting of C1-C6 alkyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR16R17, —(C1-C6 alkyl)-C(═O)NR16R17, —(C1-C6 alkyl)-O—(C1-C6 alkyl)-O—(C1-C6 alkyl), aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted at one or more carbon atoms by from 1 to 3 substituents independently selected from halo, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; R13 and R14 are independently selected from the group consisting of H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR16R17, —(C1-C6 alkyl)-C(═O)NR16R17, aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; or R13 and R14 may be taken together to form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C3-C7 cycloalkyl, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; X is selected from a covalent bond, O, NH, and C1-C6 alkyl; R15 is selected from the group consisting of heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl, or R15 is selected from —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR16R17, —CO2R18, —O—(CH2)x—CO2R18, and —C(═O)NR16R17; R16 and R17 are independently selected from the group consisting of H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; or R16 and R17 may be taken together to form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; R18 is selected from the group consisting of H, aryl, aralkyl, heteroaryl, C1-C6 alkyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR16R17, —(C1-C6 alkyl)-O—(C1-C6 alkyl)-O—(C1-C6 alkyl), each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoroalkyl; x is selected from 0 to 6; y is selected from 0 to 6; z is selected from 2 to 6; each R2 is independently selected from the group consisting of lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, and perfluoro lower alkyl; each R3 is independently selected from the group consisting of lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, and perfluoro lower alkyl; R4 is selected from H, —(CH2)a—NR43R44, —Y—R42, —O—(CH2)a—CO2R42, —O—(CH2)a—C(═O)NR43R44,—O—(CH2)a-heteroaryl, —O—(CH2)a-cycloalkyl, —O—C(═O)—(CH2)a—NR43R44, —O—(CH2)c—NR43R44, —NH—C(═O)—(CH2)a—NR43R44, —NH—C(═O)—Y—R45, —NH—C(═O)—(CH2)a—NR43R44; R42 is selected from the group consisting of C1-C6 alkyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR46R47, —(C1-C6 alkyl)-C(═O)NR46R47, —(C1-C6 alkyl)-O—(C1-C6 alkyl)-O—(C1-C6 alkyl), each of which may be optionally substituted at one or more carbon atoms by from 1 to 3 substituents independently selected from halo, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; R43 and R44 are independently selected from the group consisting of H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR46R47, —(C1-C6 alkyl)-C(═O)NR46R47, aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; or R43 and R44 may be taken together to form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; Y is selected from a covalent bond, O, NH, and C1-C6 alkyl; R45 is selected from the group consisting of H, aryl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR46R47, —CO2R48, —O—(CH2)b—CO2R48, and —C(═O)NR46R47, R46 and R47 independently selected from the group consisting of H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; or R46 and R47 may be taken together to form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; R48 is selected from the group consisting of H, aryl, aralkyl, heteroaryl, C1-C6 alkyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR46R47, —(C1-C6 alkyl)-O—(C1-C6 alkyl)-O—(C1-C6 alkyl), each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoroalkyl; a is selected from 0 to 6; b is selected from 0 to 6; c is selected from 2 to 6; R5 is selected from the group consisting of H, C1-C6 alkyl, —(CH2)d—C(═O)—NR53R54, —C(═O)—(CH2)d—NR53R54, —C(═O)—X—R55, and —C(═O)—(CH2)d—NR53R54; R53 and R54 are independently selected from the group consisting of H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR56R57, —(C1-C6 alkyl)-C(═O)NR56R57, aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; or R53 and R54 may be taken together to form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C3-C7 cycloalkyl, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; R55 is selected from the group consisting of H, aryl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR56R57, —CO2R58, —O—(CH2)e—CO2R58, and —C(═O)NR56R57, R56 and R57 independently selected from the group consisting of H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; or R56 and R57 may be taken together to form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; R58 is selected from the group consisting of H, aryl, aralkyl, heteroaryl, C1-C6 alkyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR56R57, —(C1-C6 alkyl)-O—(C1-C6 alkyl)-O—(C1-C6 alkyl), each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoroalkyl; d is selected from 0 to 6; e is selected from 0 to 6; R6 is selected from the group consisting of H, C1-C6 alkyl, —(CH2)r—C(═O)—NR63R64, —C(═O)—(CH2)r—NR63R64, —C(═O)—X—R65, and —C(═O)—(CH2)r—NR63R64; R63 and R64 are independently selected from the group consisting of H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR66R67, —(C1-C6 alkyl)-C(═O)NR66R67, aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; or R63 and R64 may be taken together to form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C3-C7 cycloalkyl, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; R65 is selected from the group consisting of H, aryl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR66R67, —CO2R68, —O—(CH2)s—CO2R68, and —C(═O)NR66R67, R66 and R67 independently selected from the group consisting of H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; or R66 and R67 may be taken together to form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; R68 is selected from the group consisting of H, aryl, aralkyl, heteroaryl, C1-C6 alkyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR66R67, —(C1-C6 alkyl)-O—(C1-C6 alkyl)-O—(C1-C6 alkyl), each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoroalkyl; r is selected from 0 to 6; s is selected from 0 to 6; n is selected from 0 to 4; m is selected from 0 to 3; and p is selected from 0 and 1. 2. The compound of claim 1, wherein R4 and R5 are independently selected from H and C1-C6 alkyl. 3. The compound of claim 1, wherein R4 and R5 are H. 4. The compound of claim 1, having the formula II: or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, n and m are as for the compound of the formula I. 5. The compound of claim 1, having the formula III: or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, n and m are as for the compound of the formula I. 6. The compound of claim 1, having the formula IV, or a pharmaceutically acceptable salt thereof, wherein: R13 and R14 are independently selected from the group consisting of H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR16R17, —(C1-C6 alkyl)-C(═O)NR16R17, aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; or R13 and R14 may be taken together to form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C3-C7 cycloalkyl, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; X is selected from a covalent bond, O, NH, and C1-C6 alkyl; R16 and R17 are independently selected from the group consisting of H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; or R16 and R17 may be taken together to form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; each R2 is independently selected from the group consisting of lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, and perfluoro lower alkyl; each R3 is independently selected from the group consisting of lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, and perfluoro lower alkyl; n is selected from 0 to 4; and m is selected from 0 to 3. 7. The compound of claim 1, having the formula IVa: or a pharmaceutically acceptable salt thereof, wherein: R13 and R14 are independently selected from the group consisting of H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR16R17, —(C1-C6 alkyl)-C(═O)NR16R17, aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; or R13 and R14 may be taken together to form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; R16 and R17 are independently selected from the group consisting of H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; or R16 and R17 may be taken together to form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl. 8. The compound of claim 1, having the formula V: or a pharmaceutically acceptable salt thereof, wherein: R12 is selected from the group consisting of C1-C6 alkyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR16R17, —(C1-C6 alkyl)-C(═O)NR16R17, —(C1-C6 alkyl)-O—(C1-C6 alkyl)-O—(C1-C6 alkyl), aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted at one or more carbon atoms by from 1 to 3 substituents independently selected from halo, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; each R2 is independently selected from the group consisting of lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, and perfluoro lower alkyl; each R3 is independently selected from the group consisting of lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, and perfluoro lower alkyl; n is selected from 0 to 4; and m is selected from 0 to 3. 9. The compound of claim 1, having the formula Va: or a pharmaceutically acceptable salt thereof, wherein: R12 is selected from the group consisting of C1-C6 alkyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR16R17, —(C1-C6 alkyl)-C(═O)NR16R17, —(C1-C6 alkyl)-O—(C1-C6 alkyl)-O—(C1-C6 alkyl), aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted at one or more carbon atoms by from 1 to 3 substituents independently selected from halo, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl. 10. A compound of formula VI: or a pharmaceutically acceptable salt thereof, wherein: R13 and R14 are independently selected from the group consisting of H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR16R17, —(C1-C6 alkyl)-C(═O)NR16R17, aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; or R13 and R14 may be taken together to form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C3-C7 cycloalkyl, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; R16 and R17 are independently selected from the group consisting of H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; or R16 and R17 may be taken together to form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; each R2 is independently selected from the group consisting of lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, and perfluoro lower alkyl; each R3 is independently selected from the group consisting of lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, and perfluoro lower alkyl; n is selected from 0 to 4; and m is selected from 0 to 3. 11. The compound of claim 10, having the formula VIa: or a pharmaceutically acceptable salt thereof, wherein: R13 and R14 are independently selected from the group consisting of H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR16R17, —(C1-C6 alkyl)-C(═O)NR16R17, aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; or R13 and R14 may be taken together to form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C3-C7 cycloalkyl, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; R16 and R17 are independently selected from the group consisting of H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; or R16 and R17 may be taken together to form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl. 12. The compound of claim 1, having the formula VII: or a pharmaceutically acceptable salt thereof, wherein: R13 and R14 are independently selected from the group consisting of H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR16R17, —(C1-C6 alkyl)-C(═O)NR16R17, aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; or R13 and R14 may be taken together to form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; R16 and R17 are independently selected from the group consisting of H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; or R16 and R17 may be taken together to form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; each R2 is independently selected from the group consisting of lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, and perfluoro lower alkyl; each R3 is independently selected from the group consisting of lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, and perfluoro lower alkyl; n is selected from 0 to 4; and m is selected from 0 to 3. 13. The compound of claim 1, having the formula VIIa: or a pharmaceutically acceptable salt thereof, wherein: R13 and R14 are independently selected from the group consisting of H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR16R17, —(C1-C6 alkyl)-C(═O)NR16R17, aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6-alkenyl, C3-C7 cycloalkyl, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; or R13 and R14 may be taken together to form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; R16 and R17 are independently selected from the group consisting of H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; or R16 and R17 may be taken together to form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl. 14. The compound of claim 1, having the formula VIII: or a pharmaceutically acceptable salt thereof, wherein: X is selected from a covalent bond, O, NH, and C1-C6 alkyl; R15 is selected from the group consisting of heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl, or R15 is selected from —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR16R17, CO2R18, —O—(CH2)x—CO2R18, and —C(═O)NR16R17; R16 and R17 are independently selected from the group consisting of H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; or R16 and R17 may be taken together to form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; R18 is selected from the group consisting of H, aryl, aralkyl, heteroaryl, C1-C6 alkyl, —(C1-C6 alkyl)-O—-(C1-C6 alkyl), —(C1-C6 alkyl)-NR16R17, —(C1-C6 alkyl)-O—(C1-C6 alkyl)-O—(C1-C6 alkyl), each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoroalkyl; x is selected from 0 to 6, each R2 is independently selected from the group consisting of lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, and perfluoro lower alkyl; each R3 is independently selected from the group consisting of lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, and perfluoro lower alkyl; n is selected from 0 to 4; and m is selected from 0 to 3. 15. The compound of claim 1, having the formula VIIIa: or a pharmaceutically acceptable salt thereof, wherein: X is selected from a covalent bond, O, NH, and C1-C6 alkyl; R15 is selected from the group consisting of H, aryl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl, or R15 is selected from —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR16R17, —CO2R18, —O—(CH2)x—CO2R18, and —C(═O)NR16R17; R16 and R17 are independently selected from the group consisting of H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; or R16 and R17 may be taken together to form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; R18 is selected from the group consisting of H, aryl, aralkyl, heteroaryl, C1-C6 alkyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR16R17, —(C1-C6 alkyl)-O—(C1-C6 alkyl)-O—(C1-C6 alkyl), each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoroalkyl; and x is selected from 0 to 6. 16. A compound of formula IX: or a pharmaceutically acceptable salt thereof, wherein: R1 is selected from the group consisting of aryl, —(CH2)y—NR13R14, —X—R12, —O—(CH2)y—CO2R12, —O—(CH2)y—C(═O)NR13R14, —O—(CH2)y-heteroaryl, —O—(CH2)y-cycloalkyl, —O—C(═O)—(CH2)y—NR13R14, —O—(CH2)z—NR13R14, —NH—C(═O)—(CH2)y—NR13R14, —NH—C(═O)—X—R15, —NH—(CH2)y—NR13R14; R12 is selected from the group consisting of C1-C6 alkyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR16R17, —(C1-C6 alkyl)-C(═O)NR16R17, —(C1-C6 alkyl)-O—(C1-C6 alkyl)-O—(C1-C6 alkyl), aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted at one or more carbon atoms by from 1 to 3 substituents independently selected from halo, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; R13 and R14 are independently selected from the group consisting of H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR16R17, —(C1-C6 alkyl)-C(═O)NR16R17, aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; or R13 and R14 may be taken together to form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; X is selected from a covalent bond, O, NH, and C1-C6 alkyl; R15 is selected from the group consisting of H, aryl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl, or R15 is selected from —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR16R17, —CO2R18, —O—(CH2)x—CO2R18, and —C(═O)NR16R17; R16 and R17 are independently selected from the group consisting of H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; or R16 and R17 may be taken together to form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; R18 is selected from the group consisting of H, aryl, aralkyl, heteroaryl, C1-C6 alkyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR16R17, —(C1-C6 alkyl)-O—(C1-C6 alkyl)-O—(C1-C6 alkyl), each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoroalkyl; x is selected from 0 to 6; y is selected from 0 to 6; z is selected from 2 to 6; each R2 is independently selected from the group consisting of lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, and perfluoro lower alkyl; each R3 is independently selected from the group consisting of lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, and perfluoro lower alkyl; R43 and R44 are independently selected from the group consisting of H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR46R47, —(C1-C6 alkyl)-C(═O)NR46R47, aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; or R43 and R44 may be taken together to form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; R46 and R47 independently selected from the group consisting of H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; or R46 and R47 may be taken together to form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; c is selected from 2 to 6; n is selected from 0 to 4; and m is selected from 0 to 3. 17. The compound of claim 1, having the formula X: or a pharmaceutically acceptable salt thereof, wherein: R1 is selected from the group consisting of —O—(CH2)y—CO2R12, —O—(CH2)y—C(═O)NR13R14, —O—(CH2)y-heteroaryl, —O—(CH2)y-cycloalkyl, —O—C(═O)—(CH2)y—NR13R14, —O—(CH2)z—NR13R14, —NH—C(═O)—(CH2)y—NR13R14, —NH—C(═O)—X—R15, —NH—(CH2)y—NR13R14; R12 is selected from the group consisting of C1-C6 alkyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR16R17, —(C1-C6 alkyl)-C(═O)NR16R17, —(C1-C6 alkyl)-O—(C1-C6 alkyl)-O—(C1-C6 alkyl), aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted at one or more carbon atoms by from 1 to 3 substituents independently selected from halo, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; R13 and R14 are independently selected from the group consisting of H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR16R17, —(C1-C6 alkyl)-C(═O)NR16R17, aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; or R13 and R14 may be taken together to form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; X is selected from a covalent bond, O, NH, and C1-C6 alkyl; R15 is selected from the group consisting of heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl, or le is selected from —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR16R17, —CO2R18, —O—(CH2)x—CO2R18, and —C(═O)NR16R17; R16 and R17 are independently selected from the group consisting of H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; or R16 and R17 may be taken together to form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; R18 is selected from the group consisting of H, aryl, aralkyl, heteroaryl, C1-C6 alkyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR16R17, —(C1-C6 alkyl)-O—(C1-C6 alkyl)-O—(C1-C6 alkyl), each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoroalkyl; x is selected from 0 to 6; y is selected from 0 to 6; z is selected from 2 to 6; each R2 is independently selected from the group consisting of lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, and perfluoro lower alkyl; each R3 is independently selected from the group consisting of lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, and perfluoro lower alkyl; R42 is selected from the group consisting of C1-C6 alkyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR46R47, —(C1-C6 alkyl)-C(═O)NR46R47, —(C1-C6 alkyl)-O—(C1-C6 alkyl)-O—(C1-C6 alkyl), each of which may be optionally substituted at one or more carbon atoms by from 1 to 3 substituents independently selected from halo, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; R46 and R47 independently selected from the group consisting of H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; or R46 and R47 may be taken together to form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; n is selected from 0 to 4; and m is selected from 0 to 3. 18. A compound of formula XI: or a pharmaceutically acceptable salt thereof, wherein: R1 is selected from the group consisting of aryl, —(CH2)y—NR13R14, —X—R12, —O—(CH2)y—CO2R12, —O—(CH2)y—C(═O)NR13R14, —O—(CH2)y-heteroaryl, —O—(CH2)y-cycloalkyl, —O—C(═O)—(CH2)y—NR13R14, —O—(CH2)z—NR13R14, —NH—C(═O)—(CH2)y—NR13R14, —NH—C(═O)—X—R15, —NH—(CH2)y—NR13R14; R12 is selected from the group consisting of C1-C6 alkyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR16R17, —(C1-C6 alkyl)-C(═O)NR16R17, —(C1-C6 alkyl)-O—(C1-C6 alkyl)-O—(C1-C6 alkyl), aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted at one or more carbon atoms by from 1 to 3 substituents independently selected from halo, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; R13 and R14 are independently selected from the group consisting of H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR16R17, —(C1-C6 alkyl)-C(═O)NR16R17, aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; or R13 and R14 may be taken together to form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; X is selected from a covalent bond, O, NH, and C1-C6 alkyl; R15 is selected from the group consisting of H, aryl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl, or R15 is selected from —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR16R17, —CO2R18, —O—(CH2), CO2R18, and —C(═O)NR16R17; R16 and R17 are independently selected from the group consisting of H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; or R16 and R17 may be taken together to form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; R18 is selected from the group consisting of H, aryl, aralkyl, heteroaryl, C1-C6 alkyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR16R17, —(C1-C6 alkyl)-O—(C1-C6 alkyl)-O—(C1-C6 alkyl), each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoroalkyl; x is selected from 0 to 6; y is selected from 0 to 6; z is selected from 2 to 6; each R2 is independently selected from the group consisting of lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, and perfluoro lower alkyl; each R3 is independently selected from the group consisting of lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, and perfluoro lower alkyl; R43 and R44 are independently selected from the group consisting of H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR46R47, —(C1-C6 alkyl)-C(═O)NR46R47, aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; or R43 and R44 may be taken together to form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; R46 and R47 independently selected from the group consisting of H, C1-C8 alkyl, C2-C8 alkenyl, C1-C8 alkynyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; or R46 and R47 may be taken together to form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; n is selected from 0 to 4; and m is selected from 0 to 3. 19. A compound of formula XII: or a pharmaceutically acceptable salt thereof, wherein: R1 is selected from the group consisting of —O—(CH2)y—CO2R12, —O—(CH2)y—C(═O)NR13R14, —O—(CH2)y-heteroaryl, —O—(CH2)y-cycloalkyl, —O—C(═O)—(CH2)y—NR13R14, —O—(CH2)z—NR13R14, —NH—C(═O)—(CH2)y—NR13R14, —NH—C(═O)—X—R15, —NH—(CH2)y—NR13R14; R12 is selected from the group consisting of C1-C6 alkyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR16R17, —(C1-C6 alkyl)-C(═O)NR16R17, —(C1-C6 alkyl)-O—(C1-C6 alkyl)-O—(C1-C6 alkyl), aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted at one or more carbon atoms by from 1 to 3 substituents independently selected from halo, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; R13 and R14 are independently selected from the group consisting of H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR16R17, —(C1-C6 alkyl)-C(═O)NR16R17, aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; or R13 and R14 may be taken together to form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C3-C7 cycloalkyl, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; X is selected from a covalent bond, O, NH, and C1-C6 alkyl; R15 is selected from the group consisting of heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl, or R15 is selected from —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR16R17, —CO2R18, —O—(CH2)x—CO2R18, and —C(═O)NR16R17; R16 and R17 are independently selected from the group consisting of H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; or R16 and R17 may be taken together to form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; R18 is selected from the group consisting of H, aryl, aralkyl, heteroaryl, C1-C6 alkyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR16R17, —(C1-C6 alkyl)-O—(C1-C6 alkyl)-O—(C1-C6 alkyl), each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoroalkyl; x is selected from 0 to 6; y is selected from 0 to 6; z is selected from 2 to 6; each R2 is independently selected from the group consisting of lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, and perfluoro lower alkyl; each R3 is independently selected from the group consisting of lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, and perfluoro lower alkyl; R4 is selected from H, —(CH2)a—NR43R44, —Y—R42, —O—(CH2)a—CO2R42, —O—(CH2)a—C(═O)NR43R44, —O—(CH2)a-heteroaryl, —O—(CH2)a-cycloalkyl, —O—C(═O)—(CH2)a—NR43R44, —O—(CH2)c—NR43R44, —NH—C(═O)—(CH2)a—NR43R44, —NH—C(═O)—Y—R45, —NH—C(═O)—(CH2)a—NR43R44; R42 is selected from the group consisting of C1-C6 alkyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR46R47, —(C1-C6 alkyl)-C(═O)NR46R47, —(C1-C6 alkyl)-O—(C1-C6 alkyl)-O—(C1-C6 alkyl), each of which may be optionally substituted at one or more carbon atoms by from 1 to 3 substituents independently selected from halo, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; R43 and R44 are independently selected from the group consisting of H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR46R47, —(C1-C6 alkyl)-C(═O)NR46R47, aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; or R43 and R44 may be taken together to form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; Y is selected from a covalent bond, O, NH, and C1-C6 alkyl; R45 is selected from the group consisting of H, aryl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR46R47, —CO2R48, —O—(CH2)b—CO2R48, and —C(═O)NR46R47, R46 and R47 independently selected from the group consisting of H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; or R46 and R47 may be taken together to form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; R48 is selected from the group consisting of H, aryl, aralkyl, heteroaryl, C1-C6 alkyl, —(C1-C6 alkyl)-O—C1-C6 alkyl), —(C1-C16 alkyl)-NR46R47, —(C1-C6 alkyl)-O—(C1-C6 alkyl)-O—(C1-C16 alkyl), each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoroalkyl; a is selected from 0 to 6; b is selected from 0 to 6; c is selected from 2 to 6; R5 is selected from the group consisting of H, C1-C6 alkyl, —(CH2)d—C(═O)—NR53R54, —C(═O)—(CH2)d—NR53R54, —C(═O)—X—R55, and —C(═O)—(CH2)d—NR53R54; R53 and R54 are independently selected from the group consisting of H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR56R57, —(C1-C6 alkyl)-C(═O)NR56R57, aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; or R53 and R54 may be taken together to form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C3-C7 cycloalkyl, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; R55 is selected from the group consisting of H, aryl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR56R57, —CO2R58, —O—(CH2)e—CO2R58, and —C(═O)NR56R57, R56 and R57 independently selected from the group consisting of H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; or R56 and R57 may be taken together to form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; R58 is selected from the group consisting of H, aryl, aralkyl, heteroaryl, C1-C6 alkyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C16 alkyl)-NR56R57, —(C1-C6 alkyl)-O—(C1-C6 alkyl)-O—(C1-C16 alkyl), each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoroalkyl; d is selected from 0 to 6; e is selected from 0 to 6; R6 is selected from the group consisting of H, C1-C6 alkyl, —(CH2)r—C(═O)—NR63R64, —C(═O)—(CH2), NR63R64, —C(═O)—X—R65, and —C(═O)—(CH2)r—NR63R64; R63 and R64 are independently selected from the group consisting of H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR66R67, —(C1-C6 alkyl)-C(═O)NR66R67, aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; or R63 and R64 may be taken together to form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C3-C7 cycloalkyl, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; R65 is selected from the group consisting of H, aryl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR66R67, —CO2R68, —O—(CH2)s—CO2R68, and —C(═O)NR66R67, R66 and R67 independently selected from the group consisting of H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; or R66 and R67 may be taken together to form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; R68 is selected from the group consisting of H, aryl, aralkyl, heteroaryl, C1-C6 alkyl, —(C1-C6 alkyl)-O—C1-C6 alkyl), —(C1-C6 alkyl)-NR66R67, —(C1-C6 alkyl)-O—(C1-C6 alkyl)-O—(C1-C6 alkyl), each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoroalkyl; r is selected from 0 to 6; s is selected from 0 to 6; n is selected from 0 to 4; m is selected from 0 to 3; and p is selected from 0 and 1. 20. A compound of formula XIIa: or a pharmaceutically acceptable salt thereof, wherein: R1 is selected from the group consisting of —O—(CH2)y—CO2R12, —O—(CH2)y—C(═O)NR13R14, —O—(CH2)y-heteroaryl, —O—(CH2)y-cycloalkyl, —O—C(═O)—(CH2)y—NR13R14, —O—(CH2)z—NR13R14, —NH—C(═O)—(CH2)y—NR13R14, —NH—C(═O)—X—R15, —NH—(CH2)y—NR13R14; R12 is selected from the group consisting of C1-C6 alkyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR16R17, —(C1-C6 alkyl)-C(═O)NR16R17, —(C1-C6 alkyl)-O—(C1-C6 alkyl)-O—(C1-C6 alkyl), aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted at one or more carbon atoms by from 1 to 3 substituents independently selected from halo, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; R13 and R14 are independently selected from the group consisting of H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR16R17, —(C1-C6 alkyl)-C(═O)NR16R17, aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; or R13 and R14 may be taken together to form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C3-C7 cycloalkyl, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; X is selected from a covalent bond, O, NH, and C1-C6 alkyl; R15 is selected from the group consisting of heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl, or R15 is selected from —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR16R17, —CO2R18, —O—(CH2), CO2R18, and —C(═O)NR16R17; R16 and R17 are independently selected from the group consisting of H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; or R16 and R17 may be taken together to form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; R18 is selected from the group consisting of H, aryl, aralkyl, heteroaryl, C1-C6 alkyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR16R17, —(C1-C6 alkyl)-O—(C1-C6 alkyl)-O—(C1-C6 alkyl), each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoroalkyl; x is selected from 0 to 6; y is selected from 0 to 6; z is selected from 2 to 6; each R2 is independently selected from the group consisting of lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, and perfluoro lower alkyl; each R3 is independently selected from the group consisting of lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, and perfluoro lower alkyl; n is selected from 0 to 4; and m is selected from 0 to 3. 21. The compound of claim 20, wherein R1 is selected from —NH—C(═O)—(CH2)y—NR13R14, —NH—C(═O)—X—R15, and —NH—(CH2)y—NR13R14. 22. The compound of claim 1, having the formula XIIb: or a pharmaceutically acceptable salt thereof, wherein: R7 is selected from the group consisting of —(CH2)y—NR13R14, and X—R15; R13 and R14 are independently selected from the group consisting of H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR16R17, —(C1-C6 alkyl)-C(═O)NR16R17, aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; or R13 and R14 may be taken together to form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, C3-C7 cycloalkyl, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; X is selected from a covalent bond, O, NH, and C1-C6 alkyl; R15 is selected from the group consisting of heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl, or R15 is selected from —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR16R17, —CO2R18, —O—(CH2)x—CO2R18, and —C(═O)NR16R17; R16 and R17 are independently selected from the group consisting of H, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), aryl, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve membered heterocyclic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; or R16 and R17 may be taken together to form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkyl, C2-C6 alkenyl, C1-C6 alkoxy, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl; R18 is selected from the group consisting of H, aryl, aralkyl, heteroaryl, C1-C6 alkyl, —(C1-C6 alkyl)-O—(C1-C6 alkyl), —(C1-C6 alkyl)-NR16R17, —(C1-C6 alkyl)-O—(C1-C6 alkyl)-O—(C1-C6 alkyl), each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C1-C6 alkoxy, hydroxy, amino, cyano and C1-C3 perfluoroalkyl; x is selected from 0 to 6; y is selected from 0 to 6; each R2 is independently selected from the group consisting of lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, and perfluoro lower alkyl; each R3 is independently selected from the group consisting of lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, and perfluoro lower alkyl; n is selected from 0 to 4; and m is selected from 0 to 3. 23. The compound according to claim 1, wherein the compound is selected from the group consisting of 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-isopropylacetamide, 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-(2-methoxyethyl)acetamide, 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-(pyridin-3-yl)acetamide, 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-1-(4-methylpiperazin-1-yl)ethanone, 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-1-morpholinoethanone, 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-methylacetamide, 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N—((R)-pyrrolidin-3-yl)acetamide, 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N—((S)-pyrrolidin-3-yl)acetamide, 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N—((R)-tetrahydrofuran-3-yl)acetamide, 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-1-(piperidin-1-yl)ethanone, 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-tert-butylacetamide, 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-ethylacetamide, 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-(cyanomethyl)acetamide, 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-cyclobutylacetamide, 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-isobutylacetamide, 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-(2,2,2-trifluoroethyl)acetamide, 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-cyclohexylacetamide, 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-neopentylacetamide, 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-(prop-2-ynyl)acetamide, N-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenyl)-4-methylpiperazine-1-carboxamide, 3-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenyl)-1,1-dimethylurea, N-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenyl)-2-methoxyacetamide, methyl 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenylamino)-2-oxoacetate, 1-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenyl)-3-(2-(dimethylamino)ethyl)urea, N-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenyl)-2-morpholinoacetamide, N-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenyl)-3-(4-isopropylpiperazin-1-yl)propanamide, N-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenyl)piperidine-4-carboxamide, and N-(3-(4-(1H-indazol-5-ylamino)-6-(2-methoxyethoxy)quinazolin-2-yl)phenyl)butyramide. 24. The compound of claim 1, having the formula: 25. The compound of claim 1, having the formula: 26. The compound of claim 1, having the formula: 27. The compound of claim 1, having the formula: 28. The compound of claim 1, having the formula: 29. The compound of claim 1, having the formula: 30. The compound of claim 1, having the formula: 31. A pharmaceutical composition comprising a compound according to any one of claims 1 to 23 or 24 to 30 or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier. 32. A method of inhibiting the activity of a Rho kinase comprising contacting the Rho kinase with a compound according to any one of claims 1 to 23 or 24 to 30 or a pharmaceutically acceptable salt thereof.