IP Library › Granted Patent US 8,916,576

Granted Patent B2

US 8,916,576 · App. 13/715,644 · Granted Dec 23, 2014

Pharmacokinetically improved compounds

View Patent ↗

Loading inventors, assignments & file history…

Monitor This Case

Get email alerts when status or documents change.

Order Certified Copies

Most orders are placed with the USPTO same day — all within 24 business hours.

Order via The Patent Place →

Pre-filled with this patent's details

Quick Facts

Patent No.: US 8,916,576
App. No.: 13/715,644
Granted: Dec 23, 2014
Kind: B2

External Links

USPTO Patent Center↗ Full Patent PDF↗

Abstract

The present invention relates to inhibitors of ROCK1 and ROCK2 and methods of modulating the pharmacokinetic and/or pharmacodynamic properties of such compounds. Also provided are methods of inhibiting ROCK1 and or ROCK2 that are useful for the treatment of disease.

Claims (323)

1. A method of treating a disease selected from the group consisting of hypertension, atherosclerosis, restenosis, cardiac hypertrophy, cerebral ischemia, cerebral vasospasm, glaucoma, ocular hypertension, liver fibrosis, and cardiac fibrosis, which comprises administering to a patient an effective amount of a compound of formula I:

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 ) y -heteroaryl, —O—(CH 2 ) y -cycloalkyl, —O—C(═O)—(CH 2 ) y —NR 13 R 14 , —O—(CH 2 ) z —NR 13 R 14 , —NH—C(═O)—(CH 2 ) y —NR 13 R 14 , —NH—C(═O)—X—R 15 , —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.

2. The method of claim 1 , wherein R 4 and R 5 are independently selected from H and C 1 -C 6 alkyl.

3. The method of claim 1 , wherein R 4 and R 5 are H.

4. The method of claim 1 , wherein the compound of formula I has the formula II:

or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , n and m are as for the compound of the formula I.

5. The method of claim 1 , wherein the compound of formula I has the formula

or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , n and m are as for the compound of the formula I.

6. The method of claim 1 , wherein the compound of formula I has the formula IV:

or a pharmaceutically acceptable salt thereof, wherein:

X is selected from a covalent bond, O, NH, and C 1 -C 6 alkyl;

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;

n is selected from 0 to 4; and

m is selected from 0 to 3.

7. The method of claim 1 , wherein the compound of formula I has the formula IV a :

or a pharmaceutically acceptable salt thereof, wherein:

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, oxo, hydroxy, amino, cyano and C 1 -C 3 perfluoro alkyl;

8. The method of claim 1 , wherein the compound of formula I has the formula V:

or a pharmaceutically acceptable salt thereof, wherein:

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;

n is selected from 0 to 4; and

m is selected from 0 to 3.

9. The method of claim 1 , wherein the compound of formula I has the formula V a :

or a pharmaceutically acceptable salt thereof, wherein:

10. A method of treating a disease selected from the group consisting of hypertension, atherosclerosis, restenosis, cardiac hypertrophy, cerebral ischemia, cerebral vasospasm, glaucoma, ocular hypertension, liver fibrosis, and cardiac fibrosis, which comprises administering to a patient an effective amount of a compound of formula VI:

or a 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 6 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;

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;

n is selected from 0 to 4; and

m is selected from 0 to 3.

11. The method of claim 10 , wherein the compound of formula VI has the formula VI a :

or a pharmaceutically acceptable salt thereof, wherein:

12. The method of claim 1 , wherein the compound of formula I has the formula VII:

or a pharmaceutically acceptable salt thereof, wherein:

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, oxo, hydroxy, amino, cyano and C 1 -C 3 perfluoro alkyl;

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;

n is selected from 0 to 4; and

m is selected from 0 to 3.

13. The method of claim 1 , wherein the compound of formula I has the formula VII a :

or a 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 6 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, oxo, hydroxy, amino, cyano and C 1 -C 3 perfluoro alkyl;

14. The method of claim 1 , wherein the compound of formula I has the formula VIII:

or a pharmaceutically acceptable salt thereof, wherein:

X is selected from a covalent bond, O, NH, and C 1 -C 6 alkyl;

x is selected from 0 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;

n is selected from 0 to 4; and

m is selected from 0 to 3.

15. The method of claim 1 , wherein the compound of formula I has the formula VIII a :

or a pharmaceutically acceptable salt thereof, wherein:

X is selected from a covalent bond, O, NH, and C 1 -C 6 alkyl;

x is selected from 0 to 6.

16. A method of treating a disease selected from the group consisting of hypertension, atherosclerosis, restenosis, cardiac hypertrophy, cerebral ischemia, cerebral vasospasm, glaucoma, ocular hypertension, liver fibrosis, and cardiac fibrosis, which comprises administering to a patient an effective amount of a compound of formula IX:

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is selected from the group consisting of aryl, —(CH 2 ) y —NR 13 R 14 , —X—R 12 , —O—(CH 2 ) y —CO 2 R 12 , —O—(CH 2 ) y —C(═O)NR 13 R 14 , —O—(CH 2 ) y -heteroaryl, —O—(CH 2 ) y -cycloalkyl, —O—C(═O)—(CH 2 ) y —NR 13 R 14 , —O—(CH 2 ) z —NR 13 R 14 , —NH—C(═O)—(CH 2 ) y —NR 13 R 14 , —NH—C(═O)—X—R 15 , —NH—(CH 2 ) y —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), —(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, 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 H, 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, 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 ;

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;

c is selected from 2 to 6;

n is selected from 0 to 4; and

m is selected from 0 to 3.

17. The method of claim 1 , wherein the compound of formula I has the formula X:

or a 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), —(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, 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;

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;

n is selected from 0 to 4; and

m is selected from 0 to 3.

18. A method of treating a disease selected from the group consisting of hypertension, atherosclerosis, restenosis, cardiac hypertrophy, cerebral ischemia, cerebral vasospasm, glaucoma, ocular hypertension, liver fibrosis, and cardiac fibrosis, which comprises administering to a patient an effective amount of a compound of formula XI:

or a 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), —(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, 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;

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 ;

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;

n is selected from 0 to 4; and

m is selected from 0 to 3.

19. A method of treating a disease selected from the group consisting of hypertension, atherosclerosis, restenosis, cardiac hypertrophy, cerebral ischemia, cerebral vasospasm, glaucoma, ocular hypertension, liver fibrosis, and cardiac fibrosis, which comprises administering to a patient an effective amount of a compound of formula XII:

or a pharmaceutically acceptable salt thereof, wherein:

X is selected from a covalent bond, O, NH, and C 1 -C 6 alkyl;

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 ) a —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 ;

Y is selected from a covalent bond, O, NH, and C 1 -C 6 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;

d is selected from 0 to 6;

e is selected from 0 to 6;

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.

20. A method of treating a disease selected from the group consisting of hypertension, atherosclerosis, restenosis, cardiac hypertrophy, cerebral ischemia, cerebral vasospasm, glaucoma, ocular hypertension, liver fibrosis, and cardiac fibrosis, which comprises administering to a patient an effective amount of a compound of formula XII a :

or a pharmaceutically acceptable salt thereof, wherein:

X is selected from a covalent bond, O, NH, and C 1 -C 6 alkyl;

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;

n is selected from 0 to 4; and

m is selected from 0 to 3.

21. The method of claim 20 , wherein R 1 is selected from —NH—C(═O)—(CH 2 ) y —NR 13 R 14 , —NH—C(═O)—X—R 15 , and —NH—(CH 2 ) y —NR 13 R 14 .

22. The method of claim 1 , wherein the compound of formula I has the formula XII b :

or a pharmaceutically acceptable salt thereof, wherein:

R 7 is selected from the group consisting of —(CH 2 ) y —NR 13 R 14 , and X—R′ 5 ;

X is selected from a covalent bond, O, NH, and C 1 -C 6 alkyl;

x is selected from 0 to 6;

y is selected from 0 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;

n is selected from 0 to 4; and

m is selected from 0 to 3.

23. A method of treating a disease selected from the group consisting of hypertension, atherosclerosis, restenosis, cardiac hypertrophy, cerebral ischemia, cerebral vasospasm, glaucoma, ocular hypertension, liver fibrosis, and cardiac fibrosis, which comprises administering to a patient an effective amount of a compound selected from the group consisting of:

2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-isopropylacetamide,

2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-(2-methoxyethyl)acetamide,

2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-(pyridin-3-yl)acetamide,

2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-1-(4-methylpiperazin-1-yl)ethanone,

2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-1-morpholinoethanone,

2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-methylacetamide,

2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N—((R)-pyrrolidin-3-yl)acetamide,

2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N—((S)-pyrrolidin-3-yl)acetamide,

2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N—((R)-tetrahydrofuran-3-yl)acetamide,

2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-1-(piperidin-1-yl)ethanone,

2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-tert-butylacetamide,

2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-ethylacetamide,

2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-(cyanomethyl)acetamide,

2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-cyclobutylacetamide,

2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-isobutylacetamide,

2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-(2,2,2-trifluoroethyl)acetamide,

2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-cyclohexylacetamide,

2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-neopentylacetamide,

2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-(prop-2-ynyl)acetamide,

N-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenyl)-4-methylpiperazine-1-carboxamide,

3-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenyl)-1,1-dimethylurea,

N-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenyl)-2-methoxyacetamide,

methyl 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenylamino)-2-oxoacetate,

1-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenyl)-3-(2-(dimethylamino)ethyl)urea,

N-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenyl)-2-morpholinoacetamide,

N-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenyl)-3-(4-isopropylpiperazin-1-yl)propanamide, N-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenyl)piperidine-4-carboxamide, and N-(3-(4-(1H-indazol-5-ylamino)-6-(2-methoxyethoxy)quinazolin-2-yl)phenyl)butyramide.

24. A method of treating a disease selected from the group consisting of hypertension, atherosclerosis, restenosis, cardiac hypertrophy, cerebral ischemia, cerebral vasospasm, glaucoma, ocular hypertension, liver fibrosis, and cardiac fibrosis, which comprises administering to a patient an effective amount of a compound having the formula:

25. The method of claim 24 , wherein the disease is liver fibrosis.

26. The method of claim 24 , wherein the disease is asthma.

27. The method of claim 24 , wherein the disease is atherosclerosis.

28. A method of treating a disease selected from the group consisting of hypertension, atherosclerosis, restenosis, cardiac hypertrophy, cerebral ischemia, cerebral vasospasm, glaucoma, ocular hypertension, liver fibrosis, and cardiac fibrosis, which comprises administering to a patient an effective amount of a compound having the formula:

29. A method of treating a disease selected from the group consisting of hypertension, atherosclerosis, restenosis, cardiac hypertrophy, cerebral ischemia, cerebral vasospasm, glaucoma, ocular hypertension, liver fibrosis, and cardiac fibrosis, which comprises administering to a patient an effective amount of a compound having the formula:

30. A method of treating a disease selected from the group consisting of hypertension, atherosclerosis, restenosis, cardiac hypertrophy, cerebral ischemia, cerebral vasospasm, glaucoma, ocular hypertension, liver fibrosis, and cardiac fibrosis, which comprises administering to a patient an effective amount of a compound having the formula:

31. A method of treating a disease selected from the group consisting of hypertension, atherosclerosis, restenosis, cardiac hypertrophy, cerebral ischemia, cerebral vasospasm, glaucoma, ocular hypertension, liver fibrosis, and cardiac fibrosis, which comprises administering to a patient an effective amount of a compound having the formula:

32. A method of treating a disease selected from the group consisting of hypertension, atherosclerosis, restenosis, cardiac hypertrophy, cerebral ischemia, cerebral vasospasm, glaucoma, ocular hypertension, liver fibrosis, and cardiac fibrosis, which comprises administering to a patient an effective amount of a compound having the formula:

33. A method of treating a disease selected from the group consisting of hypertension, atherosclerosis, restenosis, cardiac hypertrophy, cerebral ischemia, cerebral vasospasm, glaucoma, ocular hypertension, liver fibrosis, and cardiac fibrosis, which comprises administering to a patient an effective amount of a compound having the formula:

Assignments (8)

RELEASE OF SECURITY INTEREST Recorded Oct 29, 2021

From: MACQUARIE US TRADING LLC

To: KADMON CORPORATION, LLC

Reel/Frame 057973/0751 →

TERMINATION OF PATENT AND TRADEMARK SECURITY AGREEMENT Recorded Nov 25, 2019

From: PERCEPTIVE CREDIT OPPORTUNITIES FUND, LP

To: KADMON CORPORATION, LLC

Reel/Frame 051106/0677 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 16, 2016

From: BARTOLOZZI, ALESSANDRA; CAMPBELL, STEWART; FOUDOULAKIS, HOPE; KIRK, BRIAN; RAM, SIYA; SWEETNAM, PAUL; SESHARDRI, HEMALATHA

To: SURFACE LOGIX, INC.,