Rho kinase inhibitors
View Patent ↗The invention relates to inhibitors of ROCK1 and/or ROCK2. Also provided are methods of treating diseases and disorders involving inhibiting ROCK1 and/or ROCK2.
1. A compound of Formula XVI:
or pharmaceutically acceptable salt thereof, wherein:
R 13 and R 14 are independently selected from the group consisting of H, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, —(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), heteroaryl, C 3 -C 7 cycloalkyl, a three to twelve membered heterocyclic or aromatic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, oxo, C 1 -C 6 alkyl, C 2 -C 6 , alkenyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy, CN and C 1 -C 3 perfluoro alkyl;
or R 13 and R 14 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, C 1 -C 6 alkyl, C 2 -C 6 , alkenyl, C 1 -C 6 alkoxy, C 3 -C 7 cycloalkyl, oxo, —OH, —NH 2 , CN and C 1 -C 3 perfluoro alkyl;
R 2 is selected from H and halo;
each R 3 and R 4 is independently selected from the group consisting of H, C 1 -C 8 alkyl, —CN, halo, —OH, —O—(C 1 -C 6 alkyl), —O—(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), —NR 31 R 32 , C 1 -C 3 perfluoro alkyl, —O—(CH 2 ) a NR 31 R 32 , —NR 31 —(CH 2 ) a NR 33 R 34 , —NR 31 —(CH 2 ) a OR 33 , aryl, C 3 -C 7 cycloalkyl, a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted from 1 to 3 substituents independently selected from halo, C 1 -C 6 alkyl, and —(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl);
R 31 and R 32 are independently selected from the group consisting of H, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, and —(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl);
or R 31 and R 32 may be taken together to form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted from 1 to 3 substituents independently selected from halo and C 1 -C 6 alkyl;
R 33 and R 34 are independently selected from the group consisting of H and C 1 -C 8 alkyl;
a is selected from 0 to 6;
R 5 is selected from H and C 1 -C 6 alkyl;
R 6 is selected from the group consisting of H, halo, and C 1 -C 6 alkyl.
2. A compound of Formula XVII:
or pharmaceutically acceptable salt thereof, wherein:
X is selected from the group consisting of —NH—C(═O)—CHR 13 R 14 ; —NH—C(═O)—(CH 2 ) b —NR 13 R 14 ; —C(═O)—NR 13 R 14 ;
R 13 and R 14 are independently selected from the group consisting of H, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, —(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), aryl, heteroaryl, C 3 -C 7 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, oxo, C 1 -C 6 alkyl, C 2 -C 6 , alkenyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy, CN and C 1 -C 3 perfluoro alkyl;
each R 3 and R 4 is independently selected from the group consisting of H, C 1 -C 8 alkyl, —CN, halo, —OH, —O—(C 1 -C 6 alkyl), —O—(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), —NR 31 R 32 , C 1 -C 3 perfluoro alkyl, —O—(CH 2 ) a NR 31 R 32 , aryl, C 3 -C 7 cycloalkyl, a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted from 1 to 3 substituents independently selected from halo and C 1 -C 6 alkyl;
R 31 and R 32 are independently selected from the group consisting of H, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, and —(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl);
a is selected from 0 to 6;
b is selected from 0 to 1.
3. A compound of Formula XVIII:
or pharmaceutically acceptable salt thereof, wherein:
each R 3 and R 4 is independently selected from the group consisting of H, C 1 -C 8 alkyl, —CN, halo, —OH, —O—(C 1 -C 6 alkyl), —O—(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), —NR 31 R 32 , C 1 -C 3 perfluoro alkyl, —O—(CH 2 ) a NR 31 R 32 , aryl, C 3 -C 7 cycloalkyl, a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted from 1 to 3 substituents independently selected from halo and C 1 -C 6 alkyl;
R 31 and R 32 are independently selected from the group consisting of H, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, and —(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl);
a is selected from 0 to 6;
R 15 is selected from the group consisting of H, C 1 -C 8 alkyl, —CN, halo, —OH, —O—(C 1 -C 6 alkyl), —O—(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), —C(═O)—O—C(R) 331 , C 1 -C 3 perfluoro alkyl, C 3 -C 7 cycloalkyl, a three to twelve membered heterocyclic or aromatic ring having up to 3 heteroatoms which is optionally substituted from 1 to 3 substituents independently selected from halo and C 1 -C 6 alkyl;
x is selected from 1 to 3;
y is selected from 0 to 3;
z is selected from 0 to 3;
wherein y or z are independently selected and one of which is at least 1.
4. A compound of Formula XIX:
or pharmaceutically acceptable salt thereof, wherein:
R 13 and R 14 are independently selected from the group consisting of H, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, —(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), heteroaryl, C 3 -C 7 cycloalkyl, a three to twelve membered heterocyclic or aromatic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, oxo, C 1 -C 6 alkyl, C 2 -C 6 , alkenyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy, CN and C 1 -C 3 perfluoro alkyl;
or R 13 and R 14 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, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkoxy, C 3 -C 7 cycloalkyl, oxo, —OH, —NH 2 , CN and C 1 -C 3 perfluoro alkyl;
Y is selected from the group consisting of S, CH 2 , and —CR 31 R 32 —;
R 2 is selected from H and halo;
each R 3 and R 4 is independently selected from the group consisting of H, C 1 -C 8 alkyl, —CN, halo, —OH, —O—(C 1 -C 6 alkyl), —O—(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), —NR 31 R 32 , C 1 -C 3 perfluoro alkyl, —O—(CH 2 ) a NR 31 R 32 , —NR 31 —(CH 2 ) a NR 33 R 34 , —NR 31 —(CH 2 ) a OR 33 , aryl, C 3 -C 7 cycloalkyl, a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted from 1 to 3 substituents independently selected from halo, C 1 -C 6 alkyl, and —(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl);
R 31 and R 32 are independently selected from the group consisting of H, halo, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, and —(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl);
or R 31 and R 32 may be taken together to form a three to twelve membered cycloalkyl or heterocyclic ring having up to 3 heteroatoms which is optionally substituted from 1 to 3 substituents independently selected from halo and C 1 -C 6 alkyl;
R 33 and R 34 are independently selected from the group consisting of H and C 1 -C 8 alkyl;
a is selected from 0 to 6.
5. A compound of Formula XX:
or pharmaceutically acceptable salt thereof, wherein:
R 13 and R 14 are independently selected from the group consisting of H, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, —(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), heteroaryl, C 3 -C 7 cycloalkyl, a three to twelve membered heterocyclic or aromatic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, oxo, C 1 -C 6 alkyl, C 2 -C 6 , alkenyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy, CN and C 1 -C 3 perfluoro alkyl;
or R 13 and R 14 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, C 1 -C 6 alkyl, C 2 -C 6 , alkenyl, C 1 -C 6 alkoxy, C 3 -C 7 cycloalkyl, oxo, —OH, —NH 2 , CN and C 1 -C 3 perfluoro alkyl;
R 4 is selected from the group consisting of H, C 1 -C 8 alkyl, —CN, halo, —OH, —O—(C 1 -C 6 alkyl), —O—(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), —NR 31 R 32 , C 1 -C 3 perfluoro alkyl, —O—(CH 2 ) a NR 31 R 32 , aryl, C 3 -C 7 cycloalkyl, a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted from 1 to 3 substituents independently selected from halo and C 1 -C 6 alkyl;
R 31 and R 32 are independently selected from the group consisting of H, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, and —(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl);
or R 31 and R 32 may be taken together to form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted from 1 to 3 substituents independently selected from halo and C 1 -C 6 alkyl;
R 5 is selected from H and C 1 -C 6 alkyl.
6. A compound of Formula XXI:
or pharmaceutically acceptable salt thereof, wherein:
R 13 and R 14 are independently selected from the group consisting of H, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, —(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), heteroaryl, C 3 -C 7 cycloalkyl, a three to twelve membered heterocyclic or aromatic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, oxo, C 1 -C 6 alkyl, C 2 -C 6 , alkenyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy, CN and C 1 -C 3 perfluoro alkyl;
or R 13 and R 14 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, C 1 -C 6 alkyl, C 2 -C 6 , alkenyl, C 1 -C 6 alkoxy, C 3 -C 7 cycloalkyl, oxo, —OH, —NH 2 , CN and C 1 -C 3 perfluoro alkyl;
R 4 is selected from the group consisting of H, C 1 -C 8 alkyl, —CN, halo, —OH, —O—(C 1 -C 6 alkyl), —O—(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), —NR 31 R 32 , C 1 -C 3 perfluoro alkyl, —O—(CH 2 ) a NR 31 R 32 , aryl, C 3 -C 7 cycloalkyl, a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted from 1 to 3 substituents independently selected from halo and C 1 -C 6 alkyl;
R 31 and R 32 are independently selected from the group consisting of H, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, and —(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl);
or R 31 and R 32 may be taken together to form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted from 1 to 3 substituents independently selected from halo and C 1 -C 6 alkyl;
a is selected from 0 to 6.
7. A compound of Formula XXII:
or pharmaceutically acceptable salt thereof, wherein:
R 13 and R 14 are independently selected from the group consisting of H, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, —(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), heteroaryl, C 3 -C 7 cycloalkyl, a three to twelve membered heterocyclic or aromatic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, oxo, C 1 -C 6 alkyl, C 2 -C 6 , alkenyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy, CN and C 1 -C 3 perfluoro alkyl;
or R 13 and R 14 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, C 1 -C 6 alkyl, C 2 -C 6 , alkenyl, C 1 -C 6 alkoxy, C 3 -C 7 cycloalkyl, oxo, —OH, —NH 2 , CN and C 1 -C 3 perfluoro alkyl;
R 3 is H;
R 4 is selected from the group consisting of H, C 1 -C 8 alkyl, —CN, halo, —OH, —O—(C 1 -C 6 alkyl), —O—(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), —NR 31 R 32 , C 1 -C 3 perfluoro alkyl, —O—(CH 2 ) a NR 31 R 32 , aryl, C 3 -C 7 cycloalkyl, a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted from 1 to 3 substituents independently selected from halo and C 1 -C 6 alkyl;
R 31 and R 32 are independently selected from the group consisting of H, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, and —(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl);
or R 31 and R 32 may be taken together to form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted from 1 to 3 substituents independently selected from halo and C 1 -C 6 alkyl;
a is selected from 0 to 6.
8. A compound of Formula XXIII:
or pharmaceutically acceptable salt thereof, wherein:
R 13 and R 14 are independently selected from the group consisting of H, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, —(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), heteroaryl, C 3 -C 7 cycloalkyl, a three to twelve membered heterocyclic or aromatic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, oxo, C 1 -C 6 alkyl, C 2 -C 6 , alkenyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy, CN and C 1 -C 3 perfluoro alkyl;
or R 13 and R 14 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, C 1 -C 6 alkyl, C 2 -C 6 , alkenyl, C 1 -C 6 alkoxy, C 3 -C 7 cycloalkyl, oxo, —OH, —NH 2 , CN and C 1 -C 3 perfluoro alkyl;
x is selected from 0 to 1;
R 2 is selected from the group consisting of cyclohexylpyridine, 1H-pyrazole, and pyridine;
X is selected from N or CR 3 ;
Y is selected from N or CR 3 ;
Z is selected from N or CR 4 ;
wherein at least one of X, Y, and Z is N;
R 4 is selected from the group consisting of H, C 1 -C 8 alkyl, —CN, halo, —OH, —O—(C 1 -C 6 alkyl), —O—(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), —NR 31 R 32 , C 1 -C 3 perfluoro alkyl, —O—(CH 2 ) a NR 31 R 32 , —NR 31 —(CH 2 ) a NR 33 R 34 , —NR 31 —(CH 2 ) a OR 33 , aryl, C 3 -C 7 cycloalkyl, a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted from 1 to 3 substituents independently selected from halo, C 1 -C 6 alkyl, and —(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl);
R 31 and R 32 are independently selected from the group consisting of H, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, and —(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl);
or R 31 and R 32 may be taken together to form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted from 1 to 3 substituents independently selected from halo and C 1 -C 6 alkyl;
a is selected from 0 to 6;
Q is selected from the group NR 5 and O;
R 5 is selected from H and C 1 -C 6 alkyl.
9. A compound of Formula XXIV:
or pharmaceutically acceptable salt thereof, wherein:
R 12 is selected from the group consisting of H, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, —(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), amino, NR 31 R 32 , heteroaryl, C 3 -C 7 cycloalkyl, a three to twelve membered heterocyclic or aromatic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, oxo, C 1 -C 6 alkyl, C 2 -C 6 , alkenyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy, CN and C 1 -C 3 perfluoro alkyl;
x is selected from 0 to 2;
each R 3 and R 4 is independently selected from the group consisting of H, C 1 -C 8 alkyl, —CN, halo, —OH, —O—(C 1 -C 6 alkyl), —O—(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), —NR 31 R 32 , C 1 -C 3 perfluoro alkyl, —O—(CH 2 ) a NR 31 R 32 , aryl, C 3 -C 7 cycloalkyl, a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted from 1 to 3 substituents independently selected from halo and C 1 -C 6 alkyl;
R 31 and R 32 are independently selected from the group consisting of H, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 3 -C 7 cycloalkyl and C 3 -C 7 cycloalkyl —(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl);
or R 31 and R 32 may be taken together to form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted from 1 to 3 substituents independently selected from halo and C 1 -C 6 alkyl;
a is selected from 1 to 6.
10. A compound of Formula XXV:
or pharmaceutically acceptable salt thereof, wherein:
R 13 and R 14 are independently selected from the group consisting of H, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, —(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), heteroaryl, C 3 -C 7 cycloalkyl, a three to twelve membered heterocyclic or aromatic ring containing up to 3 heteroatoms, each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, oxo, C 1 -C 6 alkyl, C 2 -C 6 , alkenyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy, CN and C 1 -C 3 perfluoro alkyl;
or R 13 and R 14 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, C 1 -C 6 alkyl, C 2 -C 6 , alkenyl, C 1 -C 6 alkoxy, C 3 -C 7 cycloalkyl, oxo, —OH, —NH 2 , CN and C 1 -C 3 perfluoro alkyl;
x is selected from 0 to 3;
R 15 is selected from the group consisting of H, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, aryl, heteroaryl, heterocyclic ring, and C 3 -C 7 cycloalkyl;
each R 3 and R 4 is independently selected from the group consisting of H, C 1 -C 8 alkyl, —CN, halo, —OH, —O—(C 1 -C 6 alkyl), —O—(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), —NR 31 R 32 , C 1 -C 3 perfluoro alkyl, —O—(CH 2 ) a NR 31 R 32 , aryl, C 3 -C 7 cycloalkyl, a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted from 1 to 3 substituents independently selected from halo and C 1 -C 6 alkyl;
R 31 and R 32 are independently selected from the group consisting of H, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, and —(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl);
or R 31 and R 32 may be taken together to form a three to twelve membered heterocyclic ring having up to 3 heteroatoms which is optionally substituted from 1 to 3 substituents independently selected from halo and C 1 -C 6 alkyl;
a is selected from 1 to 6.
11. A method of treating an autoimmune disorder in a subject comprising: administering to the subject a therapeutically effective amount of a compound that inhibits ROCK2.
12. The method of claim 1 , wherein the autoimmune disorder is rheumatoid arthritis, (multiple sclerosis), systemic lupus erythematosus (SLE; lupus), psoriasis, Crohn's disease, atopic dermatitis, eczema, or graft-versus-host disease (GVHD).
13. The method of claim 11 , wherein the compound that inhibits ROCK2 is a compound of the formula:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is selected from the group consisting of —O—(CH 2 ) y —CO 2 R 12 , —O—(CH 2 ) y —C(═O)NR 13 R 14 , —O—(CH 2 )-heteroaryl, —O—(CH 2 )-cycloalkyl, —O—C(═O)—(CH 2 ) y —NR 13 R 14 , —O—(CH 2 ) z -NR 13 R 14 , —NH—C(═O)—(CH 2 )—NR 13 R 14 , —NH—C(═O)—X—R 5 , —NH—(CH 2 ) y —NR 13 R 14 ;
R 12 is selected from the group consisting of C 1 -C 6 alkyl, —(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), —(C 1 -C 6 alkyl)-NR 16 R 17 , —(C 1 -C 6 alkyl)-C(═O)NR 16 R 17 , —(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), aryl, aralkyl, heteroaryl, C 3 -C 7 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, C 1 -C 6 alkoxy, hydroxy, amino, cyano and C 1 -C 3 perfluoro alkyl;
R 13 and R 14 are independently selected from the group consisting of H, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, —(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), —(C 1 -C 6 alkyl)-NR 16 R 17 , —(C 1 -C 6 alkyl)-C(═O)NR 16 R 17 , aryl, aralkyl, heteroaryl, C 3 -C 7 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, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy, hydroxy, amino, cyano and C 1 -C 3 perfluoro alkyl;
or R 13 and R 14 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, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkoxy, C 3 -C 7 cycloalkyl, oxo, hydroxy, amino, cyano and C 1 -C 3 perfluoro alkyl;
X is selected from a covalent bond, O, NH, and C 1 -C 6 alkyl;
R 15 is selected from the group consisting of heteroaryl, C 3 -C 7 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, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkoxy, hydroxy, amino, cyano and C 1 -C 3 perfluoro alkyl,
or R 15 is selected from —(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), —(C 1 -C 6 alkyl)-NR 16 R 17 , —CO 2 R 18 , —O—(CH 2 ) x -CO 2 R 18 , and —C(═O)NR 16 R 17 ;
R 16 and R 17 are independently selected from the group consisting of H, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, —(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), aryl, aralkyl, heteroaryl, C 3 -C 7 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, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkoxy, hydroxy, amino, cyano and C 1 -C 3 perfluoro alkyl;
or R 16 and R 17 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, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkoxy, oxo, hydroxy, amino, cyano and C 1 -C 3 perfluoro alkyl;
R 18 is selected from the group consisting of H, aryl, aralkyl, heteroaryl, C 1 -C 6 alkyl, —(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), —(C 1 -C 6 alkyl)-NR 16 R 17 , —(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C 1 -C 6 alkoxy, hydroxy, amino, cyano and C 1 -C 3 perfluoroalkyl;
x is selected from 0 to 6;
y is selected from 0 to 6;
z is selected from 2 to 6;
each R 2 is independently selected from the group consisting of lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, and perfluoro lower alkyl;
each R 3 is independently selected from the group consisting of lower alkyl, CN, halo, hydroxy, lower alkoxy, amino, and perfluoro lower alkyl;
R 4 is selected from H, —(CH 2 ) a —NR 43 R 44 , —Y—R 42 , —O—(CH 2 ) a —CO 2 R 42 , —O—(CH 2 ) a —C(═O)NR 43 R 44 , —O—(CH 2 ) a -heteroaryl, —O—(CH 2 ) a -cycloalkyl, —O—C(═O)—(CH 2 ) a —NR 43 R 44 , —O—(CH 2 ) c —NR 43 R 44 , —NH—C(═O)—(CH 2 ) a —NR 43 R 44 , —NH—C(═O)—Y—R 45 , —NH—C(═O)—(CH 2 ) a —NR 43 R 44 ;
R 42 is selected from the group consisting of C 1 -C 6 alkyl, —(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), —(C 1 -C 6 alkyl)-NR 46 R 47 , —(C 1 -C 6 alkyl)-C(═O)NR 46 R 47 , —(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), each of which may be optionally substituted at one or more carbon atoms by from 1 to 3 substituents independently selected from halo, C 1 -C 6 alkoxy, hydroxy, amino, cyano and C 1 -C 3 perfluoro alkyl;
R 43 and R 44 are independently selected from the group consisting of H, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, —(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), —(C 1 -C 6 alkyl)-NR 46 R 47 , —(C 1 -C 6 alkyl)-C(═O)NR 46 R 47 , aryl, aralkyl, heteroaryl, C 3 -C 7 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, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy, hydroxy, amino, cyano and C 1 -C 3 perfluoro alkyl;
or R 43 and R 44 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, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkoxy, oxo, hydroxy, amino, cyano and C 1 -C 3 perfluoro alkyl;
Y is selected from a covalent bond, O, NH, and C 1 -C 6 alkyl;
R 45 is selected from the group consisting of H, aryl, —(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), —(C 1 -C 6 alkyl)-NR 46 R 47 , —CO 2 R 48 , —O—(CH 2 ) b —CO 2 R 48 , and —C(═O)NR 46 R 47 ,
R 46 and R 47 independently selected from the group consisting of H, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, —(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), aryl, aralkyl, heteroaryl, C 3 -C 7 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, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkoxy, hydroxy, amino, cyano and C 1 -C 3 perfluoro alkyl;
or R 46 and R 47 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, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkoxy, oxo, hydroxy, amino, cyano and C 1 -C 3 perfluoro alkyl;
R 48 is selected from the group consisting of H, aryl, aralkyl, heteroaryl, C 1 -C 6 alkyl, —(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), —(C 1 -C 6 alkyl)-NR 46 R 47 , —(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C 1 -C 6 alkoxy, hydroxy, amino, cyano and C 1 -C 3 perfluoroalkyl;
a is selected from 0 to 6;
b is selected from 0 to 6;
c is selected from 2 to 6;
R 5 is selected from the group consisting of H, C 1 -C 6 alkyl, —(CH 2 ) d —C(═O)—NR 53 R 54 , —C(═O)—(CH 2 ) d —NR 53 R 54 , —C(═O)—X—R 55 , and —C(═O)—(CH 2 ) d —NR 53 R 54 ;
R 53 and R 54 are independently selected from the group consisting of H, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, —(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), —(C 1 -C 6 alkyl)-NR 56 R 57 , —(C 1 -C 6 alkyl)-C(═O)NR 56 R 57 , aryl, aralkyl, heteroaryl, C 3 -C 7 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, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy, hydroxy, amino, cyano and C 1 -C 3 perfluoro alkyl;
or R 53 and R 54 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, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkoxy, C 3 -C 7 cycloalkyl, oxo, hydroxy, amino, cyano and C 1 -C 3 perfluoro alkyl;
R 55 is selected from the group consisting of H, aryl, —(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), —(C 1 -C 6 alkyl)-NR 56 R 57 , —CO 2 R 58 , —O—(CH 2 ) e —CO 2 R 58 , and —C(═O)NR 56 R 57 ,
R 56 and R 57 independently selected from the group consisting of H, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, —(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), aryl, aralkyl, heteroaryl, C 3 -C 7 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, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkoxy, hydroxy, amino, cyano and C 1 -C 3 perfluoro alkyl;
or R 56 and R 57 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, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkoxy, oxo, hydroxy, amino, cyano and C 1 -C 3 perfluoro alkyl;
R 58 is selected from the group consisting of H, aryl, aralkyl, heteroaryl, C 1 -C 6 alkyl, —(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), —(C 1 -C 6 alkyl)-NR 56 R 57 , —(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C 1 -C 6 alkoxy, hydroxy, amino, cyano and C 1 -C 3 perfluoroalkyl;
d is selected from 0 to 6;
e is selected from 0 to 6;
R 6 is selected from the group consisting of H, C 1 -C 6 alkyl, —(CH 2 ) r —C(═O)—NR 63 R 64 , —C(═O)—(CH 2 ) r —NR 63 R 64 , —C(═O)—X—R 65 , and —C(═O)—(CH 2 ) r —NR 63 R 64 ;
R 63 and R 64 are independently selected from the group consisting of H, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, —(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), —(C 1 -C 6 alkyl)-NR 66 R 67 , —(C 1 -C 6 alkyl)-C(═O)NR 66 R 67 , aryl, aralkyl, heteroaryl, C 3 -C 7 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, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkoxy, hydroxy, amino, cyano and C 1 -C 3 perfluoro alkyl;
or R 63 and R 64 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, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkoxy, C 3 -C 7 cycloalkyl, oxo, hydroxy, amino, cyano and C 1 -C 3 perfluoro alkyl;
R 65 is selected from the group consisting of H, aryl, —(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), —(C 1 -C 6 alkyl)-NR 66 R 67 , —CO 2 R 68 , —O—(CH 2 ) s —CO 2 R 68 , and —C(═O)NR 66 R 67 ,
R 66 and R 67 independently selected from the group consisting of H, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, —(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), aryl, aralkyl, heteroaryl, C 3 -C 7 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, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkoxy, hydroxy, amino, cyano and C 1 -C 3 perfluoro alkyl;
or R 66 and R 67 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, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkoxy, oxo, hydroxy, amino, cyano and C 1 -C 3 perfluoro alkyl;
R 68 is selected from the group consisting of H, aryl, aralkyl, heteroaryl, C 1 -C 6 alkyl, —(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), —(C 1 -C 6 alkyl)-NR 66 R 67 , —(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl)-O—(C 1 -C 6 alkyl), each of which may be optionally substituted by from 1 to 3 substituents independently selected from halo, C 1 -C 6 alkoxy, hydroxy, amino, cyano and C 1 -C 3 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.
14. The method of claim 11 , wherein the compound that inhibits ROCK2 is a compound of the formula