IP Library › Granted Patent US 10,123,993

Granted Patent B2

US 10,123,993 · App. 15/541,725 · Granted Nov 13, 2018

Cyclic ureas as inhibitors of rock

Inventors: Peter W. Glunz (Yardley, PA); Doree F. Sitkoff (Dresher, PA); Navnath Dnyanoba Yadav (Bangalore, IN); Mandar Shrikrishna Bodas (Bangalore, IN); Rajeev S. Bhide (Princeton Junction, NJ); Sharanabasappa Patil (Raichur, IN); Kumaresan Chinnakotti (Sankarankovil, IN); Prasanna Savanor Maddu Rao (Shimoga, IN); Jeevan Prakash Shetty (Bangalore, IN)

Assignee: Bristol-Myers Squibb Company

A61K31/4178 A61K31/422 A61K31/498 C07D401/10 C07D401/14 C07D403/10 C07D413/10 C07D471/04 C07D487/04 H05K999/99

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Quick Facts

Patent No.: US 10,123,993
App. No.: 15/541,725
Granted: Nov 13, 2018
Kind: B2

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Abstract

The present invention provides compounds of Formula (I): or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, wherein all the variables are as defined herein. These compounds are selective ROCK inhibitors. This invention also relates to pharmaceutical compositions comprising these compounds and methods of treating cardiovascular, smooth muscle, oncologic, neuropathologic, autoimmune, fibrotic, and/or inflammatory disorders using the same.

Claims (253)

1. A compound according to Formula (I):

or an enantiomer, a diastereomer, a stereoisomer, a tautomer, a pharmaceutically acceptable salt thereof, wherein

is an optional bond;

Ring A is independently selected from

J 1 , J 2 , J 3 , and J 4 are independently selected from N and CR 3 ; provided one of J 1 , J 2 , J 3 , and J 4 is N and no more than two of J 1 , J 2 , J 3 , and J 4 are N;

K is independently selected from N and CR 1 ;

R 1 is independently selected from H, F, Cl, Br, OH, CN, NR a R a , —OC 1-4 alkyl substituted with 0-3 R e , and C 1-4 alkyl substituted with 0-3 R e ;

R 2 is independently selected from H, —(CH 2 ) r OR b , (CH 2 ) r S(O) p R c , —(CH 2 ) r C(═O)R b , —(CH 2 ) r NR a R a , —(CH 2 ) r CN, —(CH 2 ) r C(═O)NR a R a , —(CH 2 ) r NR a C(═O)R b , —(CH 2 ) r NR a C(═O)NR a R a , —(CH 2 ) r NR a C(═O)OR b , —(CH 2 ) r OC(═O)NR a R a , —(CH 2 ) r C(═O)OR b , —(CH 2 ) r S(O) p NR a R a , —(CH 2 ) r NR a S(O) p NR a R a , —(CH 2 ) r NR a S(O) p R c , (CH 2 ) r —C 3-6 carbocyclyl substituted with 0-3 R e , and —(CH 2 ) r -heterocyclyl substituted with 0-3 R e ;

R 3 is independently selected from H, F, Cl, Br, CN, C 1-4 alkyl substituted with 0-3 R e , —(CH 2 ) r OR b , (CH 2 ) r S(O) p R c , —(CH 2 ) r C(═O)R b , —(CH 2 ) r NR a R a , —(CH 2 ) r C(═O)NR a R a , —(CH 2 ) r C(═O)(CH 2 ) r NR a R a , —(CH 2 ) r CN, —(CH 2 ) r NR a C(═O)R b , —(CH 2 ) r NR a C(═O)OR b , —(CH 2 ) r OC(═O)NR a R a , —(CH 2 ) r NR a C(═O)NR a R a , —(CH 2 ) r C(═O)OR b , —(CH 2 ) r S(O) p NR a R a , —(CH 2 ) r NR a S(O) p NR a R a , —(CH 2 ) r NR a S(O) p R c , (CH 2 ) r —C 3-6 carbocyclyl substituted with 0-3 R e , and —(CH 2 ) r -heterocyclyl substituted with 0-3 R e ;

R 4 is independently selected from H, F, Cl, Br, OH, CN, OC 1-4 alkyl substituted with 0-3 R e , NR a R a , and C 1-4 alkyl substituted with 0-3 R e ;

R 5 is independently selected from H, ═O, C 1-4 alkyl substituted with 0-4 R e , —(CH 2 ) r OR b , (CH 2 ) r S(O) p R c , —(CH 2 ) r C(═O)R b , —(CH 2 ) r NR a R a , —(CH 2 ) r CN, —(CH 2 ) r C(═O)NR a R a , —(CH 2 ) r NR a C(═O)R b , —(CH 2 ) r NR a C(═O)NR a R a , —(CH 2 ) r NR a C(═O)OR b , —(CH 2 ) r OC(═O)NR a R a , —(CH 2 ) r C(═O)OR b , —(CH 2 ) r S(O) p NR a R a , —(CH 2 ) r NR a S(O) p NR a R a , —(CH 2 ) r NR a S(O) p R c , (CH 2 ) r —C 3-6 carbocyclyl substituted with 0-3 R e , and —(CH 2 ) r -heterocyclyl substituted with 0-3 R e ;

R 6 and R 7 are independently selected from H, C 1-4 alkyl substituted with 0-4 R e , —(CH 2 ) r OR b , —(CH 2 ) r S(O) p R c , —(CH 2 ) r C(═O)R b , —(CH 2 ) r NR a R a , —(CH 2 ) r C(═O)NR a R a , —(CH 2 ) r C(═O)(CH 2 ) r NR a R a , —(CH 2 ) r NR a C(═O)R b , —(CH 2 ) r NR a C(═O)OR b , —(CH 2 ) r OC(═O)NR a R a , —(CH 2 ) r NR a C(═O)NR a R a , —(CH 2 ) r C(═O)OR b , —(CH 2 ) r S(O) p NR a R a , —(CH 2 ) r NR a S(O) p NR a R a , —(CH 2 ) r NR a S(O) p R c , (CH 2 ) r —C 3-6 carbocyclyl substituted with 0-3 R e , and —(CH 2 ) r -heterocyclyl substituted with 0-3 R e ;

R 8 is independently selected from C 3-6 cycloalkyl, heterocyclyl, aryl and heteroaryl, each substituted with 0-5 R 9 ;

R 9 is independently selected from F, Cl, Br, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, nitro, —(CHR d ) r S(O) p R c , —(CHR d ) r S(O) p NR a R a , —(CHR d ) r NR a S(O) p R c , —(CHR d ) r OR b , —(CHR d ) r CN, —(CHR d ) r NR a R a , —(CHR d ) r NR a C(═O)R b , —(CHR d ) r NR a C(═O)NR a R a , —(CHR d ) r C(═O)OR b , —(CHR d ) r C(═O)R b , —(CHR d ) r OC(═O)R b , —(CHR d ) r -cycloalkyl, —(CHR d ) r -heterocyclyl, —(CHR d ) r -aryl, and —(CHR d ) r -heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is substituted with 0-4 R e ;

R a , at each occurrence, is independently selected from H, C 1-6 alkyl substituted with 0-5 R e , C 2-6 alkenyl substituted with 0-5 R e , C 2-6 alkynyl substituted with 0-5 R e , —(CH 2 ) r —C 3-10 carbocyclyl substituted with 0-5 R e , and —(CH 2 ) r -heterocyclyl substituted with 0-5 R e ; or R a and R a together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0-5 R e ;

R b , at each occurrence, is independently selected from H, C 1-6 alkyl substituted with 0-5 R e , C 2-6 alkenyl substituted with 0-5 R e , C 2-6 alkynyl substituted with 0-5 R e , —(CH 2 ) r —C 3-10 carbocyclyl substituted with 0-5 R e , and —(CH 2 ) r -heterocyclyl substituted with 0-5 R e ;

R c , at each occurrence, is independently selected from C 1-6 alkyl substituted with 0-5 R e , C 2-6 alkenyl substituted with 0-5 R e , C 2-6 alkynyl substituted with 0-5 R e , C 3-6 carbocyclyl, and heterocyclyl;

R d , at each occurrence, is independently selected from H and C 1-4 alkyl substituted with 0-5 R e ;

R e , at each occurrence, is independently selected from C 1-6 alkyl substituted with 0-5 R f , C 2-6 alkenyl, C 2-6 alkynyl, —(CH 2 ) r —C 3-6 cycloalkyl, —(CH 2 ) r —C 4-6 heterocyclyl, —(CH 2 ) r -aryl, —(CH 2 ) r -heteroaryl, F, Cl, Br, CN, NO 2 , ═O, CO 2 H, —(CH 2 ) r OR f , S(O) p R f , C(═O)NR f R f , NR f C(═O)R d , S(O) p NR f R f , NR f S(O) p R d , NR f C(═O)OR d , OC(═O)NR f R f and —(CH 2 ) r NR f R f ;

R f , at each occurrence, is independently selected from H, F, Cl, Br, CN, OH, C 1-5 alkyl, C 3-6 cycloalkyl, and phenyl, or R f and R f together with the nitrogen atom to which they are both attached form a heterocyclic ring optionally substituted with C 1-4 alkyl;

n is independently selected from 1, 2, and 3;

p, at each occurrence, is independently selected from zero, 1, and 2; and

r, at each occurrence, is independently selected from zero, 1, 2, 3, and 4.

2. The compound of claim 1 or an enantiomer, a diastereomer, a stereoisomer, a tautomer, a pharmaceutically acceptable salt thereof, wherein

R 1 is independently selected from H, F, Cl, Br, OH, CN, NR a R a , —OC 1-4 alkyl substituted with 0-3 R e , and C 1-4 alkyl substituted with 0-3 R e ;

R 2 is independently selected from H, —(CH 2 ) r OR b , (CH 2 ) r S(O) p R c , —(CH 2 ) r C(═O)R b , —(CH 2 ) r NR a R a , —(CH 2 ) r CN, —(CH 2 ) r NR a C(═O)OR b , —(CH 2 ) r OC(═O)NR a R a , —(CH 2 ) r C(═O)OR b , —(CH 2 ) r NR a S(O) p NR a R a , and —(CH 2 ) r NR a S(O) p R c ;

R 3 is independently selected from H, F, Cl, Br, CN, C 1-4 alkyl substituted with 0-3 R e , —(CH 2 ) r OR b , —(CH 2 ) r S(O) p R c , —(CH 2 ) r C(═O)R b , —(CH 2 ) r NR a R a , —(CH 2 ) r C(═O)NR a R a , —(CH 2 ) r NR a C(═O)R b , —(CH 2 ) r OC(═O)NR a R a , —(CH 2 ) r NR a C(═O)NR a R a , —(CH 2 ) r C(═O)OR b , —(CH 2 ) r S(O) p NR a R a , —(CH 2 ) r —C 3-6 carbocyclyl substituted with 0-3 R e , and —(CH 2 ) r -heterocyclyl substituted with 0-3 R e ;

R 4 is independently selected from H, F, Cl, Br, OH, CN, and C 1-4 alkyl substituted with 0-3 R e ;

R 5 is independently selected from H, ═O, C 1-4 alkyl substituted with 0-4 R e , —(CH 2 ) r OR b , C(═O)R b , and —C(═O)OR b ;

R 6 and R 7 are independently selected from H, C 1-4 alkyl substituted with 0-4 R e , —(CH 2 ) r OR b , —(CH 2 ) r C(═O)R b , —(CH 2 ) r NR a R a , —(CH 2 ) r C(═O)NR a R a , —(CH 2 ) r NR a C(═O)R b , —(CH 2 ) r C(═O)OR b , (CH 2 ) r —C 3-6 carbocyclyl substituted with 0-3 R e , and —(CH 2 ) r -heterocyclyl substituted with 0-3 R e ;

R 8 is independently selected from

3. A compound according to Formula (IIa):

or an enantiomer, a diastereomer, a stereoisomer, a tautomer, a pharmaceutically acceptable salt thereof, wherein

is an optional bond;

Ring A is independently selected from

R 1 is independently selected from H, F, Cl, Br, CN, NR a R a , and C 1-4 alkyl substituted with 0-4 R e ;

R 2 is independently selected from H, F, Cl, Br, OH, CN, NR a R a , and C 1-4 alkyl substituted with 0-4 R e ;

R 3 is independently selected from H, F, Cl, Br, CN, C 1-4 alkyl substituted with 0-3 R e , —(CH 2 ) r OR b , and —C 3 6 cycloalkyl;

R 4 is independently selected from H, F, Cl, Br, OH, CN, OC 1-4 alkyl substituted with 0-3 R e , and C 1-4 alkyl substituted with 0-3 R e ;

R 5 , R 10 , and R 11 are independently selected from H, ═O, and C 1-4 alkyl substituted with 0-4 R e ;

provided R 5 , R 10 , and R 11 are not all H;

R 9 is independently selected from F, Cl, Br, C 1-4 alkyl, nitro, —(CH 2 ) r S(O) p R c , —(CH 2 ) r S(O) p NR a R a , —(CH 2 ) r NR a S(O) p R c , —(CH 2 ) r OR b , —(CH 2 ) r CN, —(CH 2 ) r NR a R a , —(CH 2 ) r NR a C(═O)R b , —(CH 2 ) r NR a C(═O)NR a R a , —(CH 2 ) r C(═O)OR b , —(CH 2 ) r C(═O)R b , —(CH 2 ) r OC(═O)R b , —(CH 2 ) r -cycloalkyl, —(CH 2 ) r -heterocyclyl, —(CH 2 ) r -aryl, and —(CH 2 ) r -heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is substituted with 0-4 R e ; R a , at each occurrence, is independently selected from H, C 1-6 alkyl substituted with 0-5 R e , C 2-6 alkenyl substituted with 0-5 R e , C 2-6 alkynyl substituted with 0-5 R e , —(CH 2 ) r —C 3-10 cycloalkyl substituted with 0-5 R e , —(CH 2 ) r -aryl substituted with 0-5 R e , and —(CH 2 ) r -heterocyclyl substituted with 0-5 R e ; or R a and R a together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0-5 R e ;

R e , at each occurrence, is independently selected from C 1-6 alkyl substituted with 0-5 R f , C 2-6 alkenyl, C 2-6 alkynyl, —(CH 2 ) r —C 3-6 cycloalkyl, —(CH 2 ) r —C 4-6 heterocyclyl, F, Cl, Br, CN, NO 2 , ═O, CO 2 H, —(CH 2 ) r OR f , S(O) p R f , S(O) p NR f R f , and —(CH 2 ) r NR f R f ;

n is independently selected from 1, 2, and 3;

p, at each occurrence, is independently selected from zero, 1, and 2; and

r, at each occurrence, is independently selected from zero, 1, 2, 3, and 4; and

provided

(1) R 9 is not a substituted piperazine;

(2) when n is 3, R 8 is not

and

(3) when A

R 2 is not —C(═O)NR a R a , —NR a C(═O)R b , and —NR a C(═O)NR a R a .

4. The compound of claim 3 , having Formula (IIIa):

or an enantiomer, a diastereomer, a stereoisomer, a tautomer, a pharmaceutically acceptable salt thereof, wherein

R 1 is independently selected from H, F, Cl, Br, CN, NR a R a , and C 1-4 alkyl substituted with 0-4 R e ;

R 2 is independently selected from H and C 1-4 alkyl substituted with 0-4 R e ;

R 3 is independently selected from H, F, Cl, Br, CN, C 1-4 alkyl substituted with 0-3 R e , —(CH 2 ) r OR b , and —C 3-6 cycloalkyl;

R 4 is independently selected from H, F, Cl, Br, OH, CN, OC 1-4 alkyl substituted with 0-3 R e , and C 1-4 alkyl substituted with 0-3 R e ;

R 5 , R 10 , and R 1 are independently selected from H, ═O, and C 1-4 alkyl substituted with 0-4 R e ;

provided R 5 , R 10 , and R 11 are not all H;

R 6 is independently selected from H, C 1-4 alkyl substituted with 0-4 R e , —CH 2 OR b , —C(═O)R b , NR a C(═O)R b , —CH 2 NR a R a , —C(═O)NR a R a , — r C(═O)OR b , and heterocyclyl substituted with 0-3 R e ;

R 7 is independently selected from H and C 1-4 alkyl;

R a , at each occurrence, is independently selected from H, C 1-6 alkyl substituted with 0-5 R e , C 2-6 alkenyl substituted with 0-5 R e , C 2-6 alkynyl substituted with 0-5 R e , —(CH 2 ) r —C 3-10 cycloalkyl substituted with 0-5 R e , —(CH 2 ) r -aryl substituted with 0-5 R e , and —(CH 2 ) r -heterocyclyl substituted with 0-5 R e ; or R a and R a together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0-5 R e ;

n is independently selected from 1 and 2;

p, at each occurrence, is independently selected from zero, 1, and 2; and

r, at each occurrence, is independently selected from zero, 1, 2, 3, and 4.

5. The compound of claim 4 , having Formula (IVa):

or enantiomer, a diastereomer, a stereoisomer, a tautomer, a pharmaceutically acceptable salt thereof, wherein

R 1 is independently selected from H and CF 3 ;

R 3 is independently selected from H, CN, C 1-4 alkyl, —OC 1-3 alkyl, and —C 3-6 cycloalkyl;

R 5 is independently selected from H, ═O, C 1-4 alkyl substituted with 0-4 R e , —CH 2 OR b , C(═O)R b , and —C(═O)OR b ;

R 6 is independently selected from H, C 1-4 alkyl substituted with 0-3 R e , —(CH 2 ) r OR b , —CH 2 NR a R a , —C(═O)NR a R a and —(CH 2 ) r C(═O)OR b ;

R 7 is independently selected from H and C 1-4 alkyl;

R 9 is independently selected from F, Cl, C 1-4 alkyl substituted with 0-3 R e , —OR b , and heterocyclyl substituted with 0-3 R e ;

R 10 , and R 11 are independently selected from H, C 1-4 alkyl substituted with 0-4 R e ; provided R 10 and R 11 are not all H;

R b , at each occurrence, is independently selected from H, C 1-6 alkyl substituted with 0-5 R e , —(CH 2 ) r —C 3-10 carbocyclyl substituted with 0-5 R e , and —(CH 2 ) r -heterocyclyl substituted with 0-5 R e ;

R e , at each occurrence, is independently selected from C 1-6 alkyl substituted with 0-5 R f , F, Cl, Br, CN, NO 2 , ═O, CO 2 H, OH, and OC 1-4 alkyl;

n is independently selected from 1 and 2; and

r, at each occurrence, is independently selected from zero, 1, 2, and 3.

6. A compound according to Formula (Va):

or an enantiomer, a diastereomer, a stereoisomer, a tautomer, a pharmaceutically acceptable salt thereof, wherein

R 1 is independently selected from H, F, Cl, Br, CN, NR a R a , and C 1-4 alkyl substituted with 0-4 R e ;

R 3 is independently selected from H, CN, C 1-4 alkyl substituted with 0-3 R e , and —OR b ;

R 5 is independently selected from H, ═O, C 1-4 alkyl substituted with 0-4 R e , —(CH 2 ) r OR b , C(═O)R b , and —C(═O)OR b ;

R 6 is independently selected from H, C 1-4 alkyl substituted with 0-4 R e , —(CH 2 ) r OR b , —(CH 2 ) r C(═O)R b , —(CH 2 ) r NR a C(═O)R b , —(CH 2 ) r C(═O)OR b , and heterocyclyl substituted with 0-3 R e ;

R 9 is independently selected from F, Cl, Br, C 1-4 alkyl, nitro, —S(O) p R c , —S(O) p NR a R a , —OR b , —NR a R a , —C(═O)OR b , —(CH 2 ) r C(═O)R b , —(CH 2 ) r -cycloalkyl, —(CH 2 ) r -heterocyclyl, —(CH 2 ) r -aryl, and —(CH 2 ) r -heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is substituted with 0-4 R e ;

R a , at each occurrence, is independently selected from H, C 1-6 alkyl substituted with 0-5 R e , —(CH 2 ) r —C 3-6 cycloalkyl substituted with 0-5 R e , —(CH 2 ) r -aryl substituted with 0-5 R e , and —(CH 2 ) r -heterocyclyl substituted with 0-5 R e ; or R a and R a together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0-5 R e ;

n is independently selected from 1 and 2;

p, at each occurrence, is independently selected from zero, 1, and 2; and

r, at each occurrence, is independently selected from zero, 1, 2, 3, and 4.

7. A compound according to Formula (VIa):

or an enantiomer, a diastereomer, a stereoisomer, a tautomer, a pharmaceutically acceptable salt thereof, wherein

K is independently selected from N and CH;

R 1 is independently selected from H, F, Cl, Br, CN, NR a R a , and C 1-4 alkyl substituted with 0-4 R e ;

R 3 is independently selected from H, CN, C 1-4 alkyl substituted with 0-3 R e , and —OR b ;

R 5 is independently selected from H, ═O, C 1-4 alkyl substituted with 0-4 R e , —(CH 2 ) r OR b , C(═O)R b , and —C(═O)OR b ;

n is independently selected from 1, and 2;

p, at each occurrence, is independently selected from zero, 1, and 2; and

r, at each occurrence, is independently selected from zero, 1, 2, 3, and 4.

8. The compound of claim 1 , having Formula (VII):

or an enantiomer, a diastereomer, a stereoisomer, a tautomer, a pharmaceutically acceptable salt thereof, wherein

Ring A is independently selected from

R 1 is independently selected from H, F, Cl, Br, CN, NR a R a , and C 1-4 alkyl substituted with 0-4 R e ;

R 2 is independently selected from H, F, Cl, Br, OH, CN, NR a R a , and C 1-4 alkyl substituted with 0-4 R e ;

R 4 is independently selected from H, F, Cl, Br, OH, CN, OC 1-4 alkyl substituted with 0-3 R e , and C 1-4 alkyl substituted with 0-3 R e ;

R 5 is independently selected from H, ═O, C 1-4 alkyl substituted with 0-4 R e , —(CH 2 ) r OR b , C(═O)R b , and —C(═O)OR b ;

R 6 and R 7 are independently selected from H, C 1-4 alkyl substituted with 0-4 R e , —(CH 2 ) r OR b , —(CH 2 ) r C(═O)R b , —(CH 2 ) r NR a C(═O)R b , —(CH 2 ) r C(═O)OR b , (CH 2 ) r —C 3-6 carbocyclyl substituted with 0-3 R e , and —(CH 2 ) r -heterocyclyl substituted with 0-3 R e ;

R 8 is independently selected from

R a , at each occurrence, is independently selected from H, C 1-6 alkyl substituted with 0-5 R e , C 2-6 alkenyl substituted with 0-5 R e , C 2-6 alkynyl substituted with 0-5 R e , —(CH 2 ) r —C 3-10 cycloalkyl substituted with 0-5 R e , —(CH 2 ) r -aryl substituted with 0-5 R e , and —(CH 2 ) r -heterocyclyl substituted with 0-5 R e ; or R a and R a together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0-5 R e ;

n is independently selected from 1, 2, and 3;

p, at each occurrence, is independently selected from zero, 1, and 2; and

r, at each occurrence, is independently selected from zero, 1, 2, 3, and 4.

9. The compound of claim 1 , having Formula (VIII):

or an enantiomer, a diastereomer, a stereoisomer, a tautomer, a pharmaceutically acceptable salt thereof, wherein

Ring A is independently selected from

R 1 is independently selected from H, F, Cl, Br, CN, NR a R a , and C 1-4 alkyl substituted with 0-4 R e ;

R 2 is independently selected from H, F, Cl, Br, OH, CN, NR a R a , and C 1-4 alkyl substituted with 0-4 R e ;

R 4 is independently selected from H, F, Cl, Br, OH, CN, OC 1-4 alkyl substituted with 0-3 R e , and C 1-4 alkyl substituted with 0-3 R e ;

R 5 is independently selected from H, ═O, C 1-4 alkyl substituted with 0-4 R e , —(CH 2 ) r OR b , C(═O)R b , and —C(═O)OR b ;

R 8 is independently selected from

R a , at each occurrence, is independently selected from H, C 1-6 alkyl substituted with 0-5 R e , C 2-6 alkenyl substituted with 0-5 R e , C 2-6 alkynyl substituted with 0-5 R e , —(CH 2 ) r —C 3-10 cycloalkyl substituted with 0-5 R e , —(CH 2 ) r -aryl substituted with 0-5 R e , and —(CH 2 ) r -heterocyclyl substituted with 0-5 R e ; or R a and R a together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0-5 R e ;

n is independently selected from 1, 2, and 3;

p, at each occurrence, is independently selected from zero, 1, and 2; and

r, at each occurrence, is independently selected from zero, 1, 2, 3, and 4.

10. The compound of claim 1 , having Formula (IX):

or an enantiomer, a diastereomer, a stereoisomer, a tautomer, a pharmaceutically acceptable salt thereof, wherein

Ring A is independently selected from

R 1 is independently selected from H, F, Cl, Br, CN, NR a R a , and C 1-4 alkyl substituted with 0-4 R e ;

R 2 is independently selected from H, F, Cl, Br, OH, CN, NR a R a , and C 1-4 alkyl substituted with 0-4 R e ;

R 4 is independently selected from H, F, Cl, Br, OH, CN, OC 1-4 alkyl substituted with 0-3 R e , and C 1-4 alkyl substituted with 0-3 R e ;

R 5 is independently selected from H, ═O, C 1-4 alkyl substituted with 0-4 R e , —(CH 2 ) r OR b , C(═O)R b , and —C(═O)OR b ;

R 8 is independently selected from

R a , at each occurrence, is independently selected from H, C 1-6 alkyl substituted with 0-5 R e , C 2-6 alkenyl substituted with 0-5 R e , C 2-6 alkynyl substituted with 0-5 R e , —(CH 2 ) r —C 3-10 cycloalkyl substituted with 0-5 R e , —(CH 2 ) r -aryl substituted with 0-5 R e , and —(CH 2 ) r -heterocyclyl substituted with 0-5 R e ; or R a and R a together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0-5 R e ;

n is independently selected from 1, 2, and 3;

p, at each occurrence, is independently selected from zero, 1, and 2; and

r, at each occurrence, is independently selected from zero, 1, 2, 3, and 4.

11. The compound of claim 1 , having Formula (X):

or an enantiomer, a diastereomer, a stereoisomer, a tautomer, a pharmaceutically acceptable salt thereof, wherein

Ring A is independently selected from

R 1 is independently selected from H, F, Cl, Br, CN, NR a R a , and C 1-4 alkyl substituted with 0-4 R e ;

R 2 is independently selected from H, F, Cl, Br, OH, CN, NR a R a , and C 1-4 alkyl substituted with 0-4 R e ;

R 4 is independently selected from H, F, Cl, Br, OH, CN, OC 1-4 alkyl substituted with 0-3 R e , and C 1-4 alkyl substituted with 0-3 R e ;

R 5 is independently selected from H, ═O, C 1-4 alkyl substituted with 0-4 R e , —(CH 2 ) r OR b , C(═O)R b , and —C(═O)OR b ;

R 8 is independently selected from

R a , at each occurrence, is independently selected from H, C 1-6 alkyl substituted with 0-5 R e , C 2-6 alkenyl substituted with 0-5 R e , C 2-6 alkynyl substituted with 0-5 R e , —(CH 2 ) r —C 3-10 cycloalkyl substituted with 0-5 R e , —(CH 2 ) r -aryl substituted with 0-5 R e , and —(CH 2 ) r -heterocyclyl substituted with 0-5 R e ; or R a and R a together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0-5 R e ;

n is independently selected from 1, 2, and 3;

p, at each occurrence, is independently selected from zero, 1, and 2; and

r, at each occurrence, is independently selected from zero, 1, 2, 3, and 4.

12. A compound according to Formula (XI):

or an enantiomer, a diastereomer, a stereoisomer, a tautomer, a pharmaceutically acceptable salt thereof, wherein

R 1 is independently selected from H, F, Cl, Br, CN, NR a R a , and C 1-4 alkyl substituted with 0-4 R e ;

R 2 is independently selected from H and C 1-4 alkyl substituted with 0-4 R e ;

R 3 is independently selected from H, F, Cl, Br, CN, C 1-4 alkyl substituted with 0-3 R e , —(CH 2 ) r OR b , and —C 3-6 cycloalkyl;

R 4 is independently selected from H, F, Cl, Br, OH, CN, OC 1-4 alkyl substituted with 0-3 R e , and C 1-4 alkyl substituted with 0-3 R e ;

R 6 is independently selected from H, C 1-4 alkyl substituted with OH, —CH 2 OR b , —C(═O)R b , NR a C(═O)R b , —CH 2 NR a R a , —C(═O)NR a R a , — r C(═O)OR b , and heterocyclyl substituted with 0-3 R e ;

R 7 is independently selected from H and C 1-4 alkyl; provided R 6 and R 7 are not both H; when R 7 is C 1-4 alkyl, R 6 is not H;

R a , at each occurrence, is independently selected from H, C 1-6 alkyl substituted with 0-5 R e , C 2-6 alkenyl substituted with 0-5 R e , C 2-6 alkynyl substituted with 0-5 R e , —(CH 2 ) r —C 3-10 cycloalkyl substituted with 0-5 R e , —(CH 2 ) r -aryl substituted with 0-5 R e , and —(CH 2 ) r -heterocyclyl substituted with 0-5 R e ; or R a and R a together with the nitrogen atom to which they are both attached form a heterocyclic ring substituted with 0-5 R e ;

n is independently selected from 1 and 2;

p, at each occurrence, is independently selected from zero, 1, and 2; and

r, at each occurrence, is independently selected from zero, 1, 2, 3, and 4.

13. A compound according to Formula (XII):

or an enantiomer, a diastereomer, a stereoisomer, a tautomer, a pharmaceutically acceptable salt thereof, wherein

R 1 is independently selected from F, Cl, Br, CN, NR a R a , and C 1-4 alkyl substituted with 0-4 R e ;

R 3 is independently selected from H, CN, C 1-4 alkyl substituted with 0-3 R e , and —OR b ;

R 5 is independently selected from H, ═O, C 1-4 alkyl substituted with 0-4 R e , —(CH 2 ) r OR b , C(═O)R b , and —C(═O)OR b ;

n is independently selected from 1 and 2;

p, at each occurrence, is independently selected from zero, 1, and 2; and

r, at each occurrence, is independently selected from zero, 1, 2, 3, and 4.

14. A compound according to Formula (XIII):

or an enantiomer, a diastereomer, a stereoisomer, a tautomer, a pharmaceutically acceptable salt thereof, wherein

Ring A is independently selected from

J 1 , J 2 , J 3 , and J 4 are independently selected from N and CR 3 ;

K is independently selected from N and CR 1 ;

R 1 is independently selected from H, F, Cl, Br, OH, CN, NR a R a , —OC 1-4 alkyl substituted with 0-3 R e , and C 1-4 alkyl substituted with 0-3 R e ;

R 4 is independently selected from H, F, Cl, Br, OH, CN, OC 1-4 alkyl substituted with 0-3 R e , NR a R a , and C 1-4 alkyl substituted with 0-3 R e ;

R 5 is independently selected from H, ═O, C 1-4 alkyl substituted with 0-4 R e , —(CH 2 ) r OR b , (CH 2 ) r S(O) p R c , —(CH 2 ) r C(═O)R b , —(CH 2 ) r NR a R a , —(CH 2 ) r CN, —(CH 2 ) r C(═O)NR a R a , —(CH 2 ) r NR a C(═O)R b , —(CH 2 ) r NR a C(═O)R a R a , —(CH 2 ) r NR a C(═O)OR b , —(CH 2 ) r OC(═O)NR a R a , —(CH 2 ) r C(═O)OR b , —(CH 2 ) r S(O) p NR a R a , —(CH 2 ) r NR a S(O) p NR a R a , —(CH 2 ) r NR a S(O) p R c , (CH 2 ) r —C 3-6 carbocyclyl substituted with 0-3 R e , and —(CH 2 ) r -heterocyclyl substituted with 0-3 R e ;

R 8 is independently selected from C 3-6 cycloalkyl, heterocyclyl, aryl and heteroaryl, each substituted with 0-5 R 9 ;

R d , at each occurrence, is independently selected from H and C 1-4 alkyl substituted with 0-5 R e ;

n is independently selected from 1, 2, and 3;

p, at each occurrence, is independently selected from zero, 1, and 2; and

r, at each occurrence, is independently selected from zero, 1, 2, 3, and 4; and

provided R 9 is not a substituted piperazine.

15. A pharmaceutical composition comprising one or more compounds according to claim 1 and a pharmaceutically acceptable carrier or diluent.

16. A method for treatment of a disorder associated with aberrant Rho kinase activity, comprising administrating to a patient in need thereof a therapeutically effective amount of the compound of claim 1 .

17. The method of claim 16 , wherein said disorder is selected from the group consisting of a cardiovascular disorder, a smooth muscle related disorder, a fibrotic disease, an inflammatory disease, a neuropathic disorder, an oncologic disorder, and an autoimmune disorder.

18. The method of claim 17 , wherein said cardiovascular disorder is selected from the group consisting of angina, atherosclerosis, stroke, cerebrovascular disease, heart failure, coronary artery disease, myocardial infarction, peripheral vascular disease, stenosis, vasospasm, hypertension and pulmonary hypertension.

Continuity (2)

Provisional Application 62101434 · Jan 9, 2015

Related Publication 20180000788A1 · Jan 4, 2018

Cited By (1)

US 12,630,534