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CA2700988A1 - Rho kinase inhibitors - Google Patents

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CA2700988A1
CA2700988A1 CA2700988A CA2700988A CA2700988A1 CA 2700988 A1 CA2700988 A1 CA 2700988A1 CA 2700988 A CA2700988 A CA 2700988A CA 2700988 A CA2700988 A CA 2700988A CA 2700988 A1 CA2700988 A1 CA 2700988A1
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alkyl
independently selected
hydroxy
halo
amino
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Alessandra Bartolozzi
Stewart Campbell
Bridget Cole
James Ellis
Hope Foudoulakis
Brian Kirk
Siya Ram
Paul Sweetnam
Martin Hauer-Jensen
Marjan Boerma
Junru Wang
Qiang Fu
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Surface Logix Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

The present invention relates to inhibitors of ROCK1 and ROCK2, which may be selective for ROCK2, and methods of modulating the pharmacokinetic and/or pharmacodynamic properties of such compounds. Also provided are methods of inhibiting ROCK1 and/or ROCK2. Also provided are treatments combining inhibitors of ROCK1 and/or ROCK2 with statins.

Claims (40)

1. A compound having the formula I:

or pharmaceutically acceptable salt or hydrate thereof, wherein:
Ring A is a 5- or 6-membered aromatic ring which may comprise 0-3 heteroatoms selected from N, O, and S;
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)2-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-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-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 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-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 H, C1-C8 alkyl, aryl, heteroaryl, 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 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 R16 and R17 may be taken together 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-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 -(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-NR43e, -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-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-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, C1-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 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-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, 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 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-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)--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 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-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, 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 R56 and R57 may be taken together 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-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 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-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, CI-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 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-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, having the formula Ia:

or pharmaceutically acceptable salt or hydrate 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-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-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 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-alkoxy, C3-C7 cycloalkyl, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl;
each X is selected from a covalent bond, O, NH, and C1-C6 alkyl;

R15 is selected from the group consisting of H, C1-C8 alkyl, aryl, heteroaryl, 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;

16 and R17 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 R16 and R17 may be taken together 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-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 -(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-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-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, C1-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 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-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, 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 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-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;

.alpha. 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 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-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, 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 R56 and R57 may be taken together 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-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 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-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, -C02R68, -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, 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 R66 and R67 may be taken together 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-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.
3. The compound of claim 1, wherein R1 is selected from the group consisting of:
-O-(CH2)y-C(=O)NR13R14, -NH-C(=O)-(CH2)y-NR13R14, and -NH-C(=O)-X-R15.
4. The compound of claim 3, wherein R4 and R5 are independently selected from H and alkyl.
5. The compound of claim 1, having the formula II or III:
or pharmaceutically acceptable salt or hydrate 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 IIa or IIIa:
or pharmaceutically acceptable salt or hydrate thereof, wherein R1, R2, R4, n and p are as for the compound of the formula I.
7. The compound of claim 1, having the formula IV:
or pharmaceutically acceptable salt or hydrate 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 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-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 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 R16 and R17 may be taken together 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.
8. The compound of claim 7, having the formula IVa:
or pharmaceutically acceptable salt or hydrate 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 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-alkoxy, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl;

R16 and R17 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 R16 and R17 may be taken together 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.
9. The compound of claim 1, having the formula V:

or pharmaceutically acceptable salt or hydrate 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.
10. The compound of claim 9, having the formula Va:
or pharmaceutically acceptable salt or hydrate 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.
11. The compound of claim 1, having the formula VI:
or pharmaceutically acceptable salt or hydrate 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 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-alkoxy, C3-C7 cycloalkyl, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl;

R16 and R17 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 R16 and R17 may be taken together 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.
12. The compound of claim 11, having the formula VIa:
or pharmaceutically acceptable salt or hydrate 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)--(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 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-alkoxy, C3-C7 cycloalkyl, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl;

R16 and R17 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 R16 and R17 may be taken together 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-alkoxy, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl.
13. The compound of claim 1, having the formula VII:
or pharmaceutically acceptable salt or hydrate 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 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-alkoxy, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl;

R16 and R17 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 R16 and R17 may be taken together 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.
14. The compound of claim 13, having the formula VIIa:
or pharmaceutically acceptable salt or hydrate 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 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-alkoxy, oxo, hydroxy, amino, cyano and C1-C3 perfluoro alkyl;

R16 and R17 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 R16 and R17 may be taken together 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.
15. The compound of claim 1, having the formula VIII:

or pharmaceutically acceptable salt or hydrate thereof, wherein:

X is selected from a covalent bond, O, NH, and C1-C6 alkyl;

R15 is selected from the group consisting of H, C1-C8 alkyl, aryl, heteroaryl, 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 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 R16 and R17 may be taken together 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-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.
16. The compound of claim 15, wherein X is a covalent bond and R15 is C1-C8 alkyl.
17. The compound of claim 15, having the formula VIIIa:

or pharmaceutically acceptable salt or hydrate thereof, wherein:
X is selected from a covalent bond, O, NH, and C1-C6 alkyl;

R15 is selected from the group consisting of H, C1-C8 alkyl, aryl, heteroaryl, 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 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 R16 and R17 may be taken together 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-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.
18. The compound of claim 1, having the formula IX:
or pharmaceutically acceptable salt or hydrate 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-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-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)--(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 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-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, C1-C8 alkyl, aryl, heteroaryl, 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 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 R16 and R17 may be taken together 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-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, C1-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 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 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-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;

c is selected from 2 to 6;
n is selected from 0 to 4; and m is selected from 0 to 3.
19. The compound of claim 1, having the formula X:

or pharmaceutically acceptable salt or hydrate 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)2-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-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-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 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-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, C1-C8 alkyl, aryl, heteroaryl, 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 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 R16 and R17 may be taken together 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-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, 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 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-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.
20. The compound of claim 1, having the formula XI:

or pharmaceutically acceptable salt or hydrate 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-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-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 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-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, C1-C8 alkyl, aryl, heteroaryl, 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 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 R16 and R17 may be taken together 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-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, C1-C8 alkynyl, -(C1-C6 alkyl)-O-(C1-C6 alkyl), -(C1-C6 alkyl)-NR46R47, -(C1-C6 alkyl)-C(=O)NR46R47, aralkyl, heteroaryl, C3-C7 cycloalkyl, a three to twelve aryl, 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 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 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-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;

n is selected from 0 to 4; and m is selected from 0 to 3.
21. The compound of claim 1, having the formula XII:

or pharmaceutically acceptable salt or hydrate 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-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-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 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-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 H, C1-C8 alkyl, aryl, heteroaryl, 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 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 R16 and R17 may be taken together 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-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 -(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-alkyl), -(C1-C6 alkyl)-NR46R47, -(CI-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-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, C1-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 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-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, 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 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-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 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-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, 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 R56 and R57 may be taken together 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-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)-NR66R61, -(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 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-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, -CO2 R68, -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, 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 R66 and R67 may be taken together 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-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.
22. The compound of claim 21, having the formula XII a:

or pharmaceutically acceptable salt or hydrate 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-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-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 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-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 H, C1-C8 alkyl, aryl, heteroaryl, 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 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 R16 and R17 may be taken together 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-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.
23. The compound of claim 22, wherein R1 is selected from -NR13R14, -NH-R12, -NH-C(=O)-(CH2)y-NR13R14, -NH-C(=O)-X-R15, and -NH-(CH2)y-NR13R14.
24. The compound of claim 21, having the formula XII b:

or pharmaceutically acceptable salt or hydrate 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 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-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 H, C1-C8 alkyl, aryl, heteroaryl, 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 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 R16 and R17 may be taken together 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-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.
25. The compound of claim 1, which is selected from:

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-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, methyl2-(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-yl)propanamide, N-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenyl)piperidine-4-carboxamide, 2-(3-fluoro-4-(phenyl)phenyl)-N-(1H-indazol-5-yl)-7-methoxy-6-(2-(4-methylpiperazin-1-yl)ethoxy)quinazolin-4-amine, 6-(2-(dimethylamino)ethoxy)-2-(3-fluoro-4-(phenyl)phenyl)-N-(1H-indazol-5-yl)-methoxyquinazolin-4-amine, 2-(3-fluoro-4-(phenyl)phenyl)-N-(1H-indazol-5-yl)-7-methoxy-6-(2-(pyrrolidin-1-yl)ethoxy)quinazolin-4-amine, 2-(4-(1H-indazol-5-ylamino)-2-[(3-phenyl)phenyl)-7-methoxyquinazolin-6-yloxy)-1-(4-methylpiperazin-1-yl)ethanone, 2-[(3-(phenyl)phenyl)-N-(1H-indazol-5-yl)-7-methoxy-6-(2-methoxyethoxy)quinazolin-4-amine, 6-(2-(dimethylamino)ethoxy)-N-(1H-indazol-5-yl)-7-methoxy-2-(3-(phenyl)phenyl)quinazolin-4-amine, 2-[(3-phenyl)phenyl)-N-(1H-indazol-5-yl)-7-methoxy-6-(2-(pyrrolidin-1-yl)ethoxy)quinazolin-4-amine, 2-((2-(4-(1H-indazol-5-ylamino)-2-[(3-phenyl)phenyl)-7-methoxyquinazolin-6-yloxy)ethyl)(methyl)amino)-N,N-dimethylacetamide, 2-[(3-phenyl)phenyl)-N-(1H-indazol-5-yl)-7-methoxy-6-(2-(4-methylpiperazin-1-yl)ethoxy)quinazolin-4-amine, 2-[(3-phenyl)phenyl)-N-(1H-indazol-5-yl)-7-methoxy-6-(2-morpholinoethoxy)quinazolin-4-amine, 2-[(3-phenyl)phenyl)-N-(1H-indazol-5-yl)-7-methoxy-6-(2-(4-methyl-1,4-diazepan-yl)ethoxy)quinazolin-4-amine, N-(3-(4-(1H-indazol-5-ylamino)-6-(2-(dimethylamino)ethoxy)quinazolin-2-yl)phenyl)nicotinamide, N-(3-(4-(1H-indazol-5-ylamino)-6-(2-methoxyethoxy)quinazolin-2-yl)phenyl)nicotinamide, N-(3-(4-(1H-indazol-5-ylamino)-6-(2-(dimethylamino)ethoxy)quinazolin-2-yl)phenyl)butyramide, N-(3-(4-(1H-indazol-5-ylamino)-6-(3-(dimethylamino)propoxy)quinazolin-2-yl)phenyl)butyramide, N-(3-(4-(1H-indazol-5-ylamino)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-2-yl)phenyl)butyramide, N-(3-(4-(1H-indazol-5-ylamino)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-2-yl)phenyl)isonicotinamide, N-(3-(4-(1H-indazol-5-ylamino)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-2-yl)phenyl)nicotinamide, N-(3-(4-(1H-Indazol-5-ylamino)-7-methoxy-6-(2-(pyrrolidin-1-yl)ethoxy)quinazolin-2-yl)phenyl)-2-morpholinoacetamide, N-(3-(4-(1H-indazol-5-ylamino)-6-(2-(dimethylamino)ethoxy)-7-methoxyquinazolin-yl)phenyl)butyramide, N-(3-(4-(1H-indazol-5-ylamino)-6-(2-(dimethylamino)-2-oxoethoxy)-7-methoxyquinazolin-2-yl)phenyl)nicotinamide, N-(3-(4-(1H-Indazol-5-ylamino)-6-(2-(dimethylamino)ethoxy)-7-methoxyquinazolin-yl)phenyl)nicotinamide, N-(3-(4-(1H-Indazol-5-ylamino)-7-methoxy-6-(2-methoxyethoxy)quinazolin-2-yl)phenyl)nicotinamide, N-(3-(4-(1H-indazol-5-ylamino)-7-methoxy-6-(2-methoxyethoxy)quinazolin-2-yl)phenyl)-2-morpholinoacetamide, 2-(3-(4-(1H-indazol-5-ylamino)-7-methoxy-6-(2-methoxyethoxy)quinazolin-2-yl)phenoxy)-N-isopropylacetamide, N-(3-(4-(1H-Indazol-5-ylamino)-6-(2-(pyrrolidin-1-yl)ethoxy)quinazolin-2-yl)phenyl)butyramide, N-(3-(4-(1H-indazol-5 -ylamino)-6-(2-(piperidin-1-yl)ethoxy)quinazolin-2-yl)phenyl)butyramide, N-(3-(4-(1H-indazol-5-ylamino)-6-(2-methoxyethoxy)quinazolin-2-yl)phenyl)butyramide, N-(3-(4-(1H-indazol-5-ylamino)-6-(2-((2-methoxyethyl)(methyl)amino)ethoxy)-quinazolin-2-yl)phenyl)butyramide, N-(3-(4-(1H-indazol-5-ylamino)-6-(2-(4-methylpiperazin-1-yl)ethoxy)quinazolin-yl)phenyl)butyramide, N-(3-(4-(1H-indazol-5-ylamino)-6-(2-(2-oxopyrrolidin-1-yl)ethoxy)quinazolin-2-yl)phenyl)butyramide, N-(3-(4-(1H-indazol-5-ylamino)-6-(2-(3-hydroxypyrrolidin-1-yl)ethoxy)quinazolin-2-yl)phenyl)butyramide, N-(3-(4-(1H-indazol-5-ylamino)-7-methoxy-6-(2-(2-oxopyrrolidin-1-yl)ethoxy)quinazolin-2-yl)phenyl)butyramide, N-(3-(4-(1H-indazol-5-ylamino)-7-methoxy-6-(2-methoxyethoxy)quinazolin-2-yl)phenyl)butyramide, N-(3-(4-(1H-indazol-5-ylamino)-7-methoxy-6-(2-(4-methylpiperazin-1-yl)ethoxy)quinazolin-2-yl)phenyl)butyramide, and N-(3-(4-(1H-indazol-5-ylamino)-6-(2-((S)-3-(dimethylamino)pyrrolidin-1-yl)ethoxy)-7-methoxyquinazolin-2-yl)phenyl)butyramide.
26. A method of treating or ameliorating fibrosis, comprising administering to a subject an effective amount of a ROCK inhibitor of claims 1 to 25.
27. The method of claim 26, which further comprises administering an effective amount of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor.
28. A method of treating or ameliorating a cardiovascular disease, comprising administering to a subject an effective amount of a ROCK inhibitor of claims 1 to 25.
29. The method of claim 28, which further comprises administering an effective amount of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor.
30. A method of treating or ameliorating inflammation comprising administering to a subject an effective amount of a ROCK inhibitor of claims 1 to 25.
31. The method of claim 30, which further comprises administering an effective amount of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor.
32. A method of treating radiation-exposure in a mammal, comprising administering an effective amount of a ROCK inhibitor of claims 1 to 25.
33. A method of claim 32, which further comprises administering an effective amount of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor.
34. A method of reducing or preventing tissue injury in a mammal subsequently exposed to ionizing radiation, comprising administering an effective amount of a ROCK
inhibitor of claims 1 to 25.
35. A method of claim 34, which further comprises administering an effective amount of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor.
36. A method of treating or ameliorating a neoplastic disease, comprising administering to an individual in need thereof an effective amount of a ROCK inhibitor of claims 1 to 25 and treating said individual with radiation therapy.
37. A method of claim 36, which further comprises administering an effective amount of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor.
38. The method of any one of claims 26 to 37, wherein the ROCK inhibitor is selective for ROCK2.
39. The method of any one of claims 27, 29, 31, 33, 35 or 37 wherein the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor is a statin.
40. The method of claim 39, wherein the statin is selected from the group consisting of lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, mevastatin, rivastatin, pitavastatin, and rosuvastatin.
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