IP Library › Granted Patent US 11,524,959

Granted Patent B1

US 11,524,959 · App. 17/265,842 · Granted Dec 13, 2022

Indole and azaindole inhibitors of pad enzymes

Inventors: Anurag S. Srivastava (Belle Mead, NJ); Robert J. Cherney (Newtown, PA); Khehyong Ngu (Pennington, NJ)

Assignee: Bristol-Myers Squibb Company

C07D471/08 A61K45/06 C07D519/00

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Quick Facts

Patent No.: US 11,524,959
App. No.: 17/265,842
Granted: Dec 13, 2022
Kind: B1

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Abstract

The present invention provides compounds of Formula (I) useful as inhibitors of PAD4, compositions thereof, and methods of treating PAD4-related disorders, wherein each of Ring A, L, Q, R1, R2, R3, R4, R7, and R8 along with other variables are as defined herein.

Claims (172)

1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

Q is selected from N and CH;

Ring A is 4- to 15-membered heterocyclyl substituted with 1-4 R 7 ;

R 1 is selected from CH 3 , CD 3 , and —CH 2 -5 membered heterocyclyl comprising carbon atoms and 1-3 heteroatoms selected from N, NC 1-4 alkyl, O, and S;

R 2 is selected from H, C 1-3 alkyl substituted with 0-5 R e , and —(CH 2 ) r —C 3-6 cycloalkyl substituted with 0-5 R e ;

R 3 is selected from H, F, Cl, Br, —OR b , and C 1-3 alkyl substituted with 0-5 R e ;

L is absent or selected from —NR d —, —O—, —C(═O)NR d —, and —S(O) p —;

R 4 is selected from —(CH 2 ) r -aryl substituted with 1-7 R 5 , —(CH 2 ) r —C 3-12 cycloalkyl (substituted with 1-2 OR b , C(═O)OR b , —C(═O)NR a R a , —NR a C(═O)R b ), —(CH 2 ) r -heterocyclyl comprising carbon atoms and 1-3 heteroatoms selected from N, NR 6 , O, and S and substituted with 1-7 R 5 ;

R 5 , at each occurrence, is independently selected from H, F, Cl, Br, CN, ═O, nitro, C 1-4 alkyl substituted with 0-5 R e , C 2-4 alkenyl substituted with 0-5 R e , C 2-4 alkynyl substituted with 0-5 R e , —(CHR d ) r OR b , —(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 NR a R a , —(CHR d ) r NR a C(═O)R b , —(CHR d ) r NR a C(═O)OR b , —(CHR d ) r NR a C(═O)NR a R a , —(CHR d ) r C(═O)R b , —(CHR d ) r C(═O)OR b , —(CHR d ) r C(═O)NR a R a , —(CHR d ) r OC(═O)R b , —(CHR d ) r OC(═O)OR b , —(CHR d ) r O(CH 2 ) r C(═O)NR a R a , C 3-6 cycloalkyl substituted with 0-4 R e , aryl substituted with 0-4 R e , and heterocyclyl substituted with 0-4 R e ;

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

R 7 is selected from H, F, Cl, CN, C 1-3 alkyl, ═N—OR b , —(CH 2 )OR b , —(CH 2 ) r NR a R a , —NR a C(═NH)C 1-3 alkyl, —NR a C(═O)OR b , carbocyclyl, and heterocyclyl; alternatively, two R 7 groups are taken together to form carbocyclyl or heterocyclyl;

R 8 , at each occurrence, is independently selected from H, F, Cl, Br, and C 1-4 alkyl substituted with 0-5 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 , —(CH 2 ) r —C 3-6 carbocyclyl substituted with 0-5 R e , and —(CH 2 ) r -heterocyclyl substituted with 0-5 R e ;

R d , at each occurrence, is independently selected from H, C 1-6 alkyl substituted with 0-5 R e , and OH,

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 -aryl, —(CH 2 ) r -heterocyclyl, Si(C 1-4 alkyl) 3 , 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 , S(O) p 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 optionally substituted with OH, C 2-5 alkenyl, C 2-5 alkynyl, 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;

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

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

provided:

(1) when L is absent, R 4 is not

(2) when L is —NR d —, R 4 is not

and

(3) when L is —O—, R 4 is not C 3-6 cycloalkyl.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein:

is selected from

R 1 is selected from CH 3 and CD 3 ;

R 2 is selected from methyl, ethyl and —CH 2 -cyclopropyl substituted with 0-3 R e ;

R 3 is selected from H, F, Cl, Br, and —OC 1-4 alkyl;

L is absent or selected from —NR d —, —O—, —C(═O)NH—, —S—, and —S(O) 2 —;

R 4 is selected from

R 5 , at each occurrence, is independently selected from H, F, Cl, Br, CN, ═O, C 1-4 alkyl substituted with 0-5 R e , C 2-4 alkenyl, C 2-4 alkynyl, —(CHR d ) r OR b , —(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 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 NR a C(═O)NR a R a , —(CH 2 ) r C(═O)R b , —(CH 2 ) r C(═O)OR b , —(CHR d ) r C(═O)NR a R a , —(CH 2 ) r OC(═O)R b , —(CH 2 ) r OC(═O)OR b , —(CH 2 ) r O(CH 2 ) r C(═O)NR a R a , C 3-6 cycloalkyl substituted with 0-4 R e , aryl substituted with 0-4 R e , and heterocyclyl substituted with 0-4 R e ;

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

R d , at each occurrence, is independently selected from H, C 1-6 alkyl substituted with 0-5 R e , and OH;

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 -aryl, —(CH 2 ) r -heterocyclyl, F, Cl, Br, CN, NO 2 , ═O, —NH 2 , —NHC 1-4 alkyl, —N(C 1-4 alkyl) 2 , —C(═O)OH, —C(═O)OC 1-4 alkyl, —(CH 2 ) r OH, and —(CH 2 ) r OC 1-4 alkyl;

R f , at each occurrence, is independently selected from H, F, Cl, Br, CN, OH, C 1-5 alkyl optionally substituted with OH, C 3-6 cycloalkyl, and phenyl;

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.

3. The compound according to claim 2 of Formula (II):

or a pharmaceutically acceptable salt thereof, wherein:

is selected from

R 2 is selected from CH 3 , CH 2 CH 3 and —CH 2 -cyclopropyl substituted with 0-2 F, Cl, and CH 3 ;

R 3 is selected from H, F, and —OC 1-4 alkyl;

R 4 is selected from

R 5 , at each occurrence, is independently selected from H, F, Cl, Br, CN, ═O, C 1-4 alkyl substituted with 0-4 R e , —(CHR d ) r OR b , —(CH 2 ) r S(O) p R c , —S(O) p NR a R a , —(CH 2 ) r NR a S(O) p R c , —(CH 2 ) r NR a R a , —(CH 2 ) r NR a C(═O)R b , —NR a C(═O)OR b , —NR a C(═O)NR a R a , —(CH 2 ) r C(═O)R b , —(CH 2 ) r C(═O)OR b , —(CHR d ) r C(═O)NR a R a , —(CH 2 ) r OC(═O)R b , —(CH 2 ) r OC(═O)OR b , —(CH 2 ) r O(CH 2 ) r C(═O)NR a R a , C 3-6 cycloalkyl substituted with 0-4 R e , aryl substituted with 0-4 R e , and heterocyclyl substituted with 0-4 R e ;

R 6 , at each occurrence, is independently selected from H, C 1-3 alkyl substituted with 0-4 R e , —S(O) p R c , —C(═O)R b , —(CH 2 ) r C(═O)OR b , —(CH 2 ) r C(═O)NR a R a , —C(═O)(CH 2 ) r NR a C(═O)R b , —S(O) p NR a R a , aryl substituted with 0-4 R e , and heterocyclyl substituted with 0-4 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 , —(CH 2 ) r —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 d , at each occurrence, is independently selected from H and C 1-6 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 -aryl, —(CH 2 ) r -heterocyclyl, F, Cl, Br, CN, NO 2 , ═O, —NH 2 , —NHC 1-4 alkyl, —N(C 1-4 alkyl) 2 , —C(═O)OH, —C(═O)OC 1-4 alkyl, —(CH 2 ) r OH, and —(CH 2 ) r OC 1-4 alkyl;

R f , at each occurrence, is independently selected from H, F, Cl, Br, CN, OH, C 1-5 alkyl optionally substituted with OH, C 3-6 cycloalkyl, and phenyl;

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.

4. The compound according to claim 3 of Formula (III):

or a pharmaceutically acceptable salt thereof, wherein:

is selected from

R 2 is —CH 2 -cyclopropyl;

R 3 is —OC 1-4 alkyl;

R 5 , at each occurrence, is independently selected from H, F, Cl, Br, CN, C 1-4 alkyl substituted with 0-4 R e , —(CHR d ) r OR b , —(CH 2 ) r S(O) p R c , —S(O) p NR a R a , —(CH 2 ) r NHS(O) p R c , —(CH 2 ) r NR a R a , —(CH 2 ) r NHC(═O)R b , —NHC(═O)OR b , —(CHR d ) r C(═O)NR a R a , —(CH 2 ) r C(═O)OR b , —OC(═O)OR b , —O(CH 2 ) 0-1 C(═O)NR a R a , C 3-6 cycloalkyl substituted with 0-4 R e , aryl substituted with 0-4 R e , and heterocyclyl substituted with 0-4 R e ;

R d , at each occurrence, is independently selected from H, C 1-4 alkyl, and OH;

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 -aryl, —(CH 2 ) r -heterocyclyl, F, Cl, Br, CN, NO 2 , ═O, —NH 2 , —NHC 1-4 alkyl, —N(C 1-4 alkyl) 2 , —C(═O)OH, —C(═O)OC 1-4 alkyl, —(CH 2 ) r OH, —(CH 2 ) r OC 1-4 alkyl, and SO 2 C 1-4 alkyl;

R f , at each occurrence, is independently selected from H, F, Cl, Br, CN, OH, C 1-5 alkyl optionally substituted with OH, C 3-6 cycloalkyl, and phenyl;

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 according to claim 4 , or a pharmaceutically acceptable salt thereof, wherein:

R 3 is —OCH 3 ;

R 5 , at each occurrence, is independently selected from H, F, Cl, Br, CN, C 1-4 alkyl, —(CH 2 ) 0-1 OR b , —S(O) 2 NH 2 , —NHS(O) 2 C 1-3 alkyl, —NHS(O) 2 C 2-4 alkenyl, —NHC(═O)R b , —C(═O)NH 2 and heterocyclyl selected from

R b , at each occurrence, is independently selected from H and C 1-6 alkyl substituted with 0-5 R e ,

R e , at each occurrence, is independently selected from C 1-6 alkyl, F, Cl, Br, CN, NO 2 , ═O, —NH 2 , —NHC 1-4 alkyl, —N(C 1-4 alkyl) 2 , —C(═O)OH, —C(═O)OC 1-4 alkyl, —(CH 2 ) r OH, —(CH 2 )OC 1-4 alkyl, and SO 2 C 1-4 alkyl; and

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

6. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein:

is selected from and

R 2 is —CH 2 -cyclopropyl;

R 3 is —OC 1-4 alkyl;

R 4 is selected from

R 5 , at each occurrence, is independently selected from H, F, Cl, Br, CN, C 1-4 alkyl substituted with 0-4 R e , —(CH 2 ) r OR b , —S(O) p R c , —S(O) p NR a R a , —(CH 2 ) r NR a S(O) p R c , —(CH 2 ) r NR a R a , —(CH 2 ) r NR a C(═O)R b , —NR a C(═O)OR b , —NR a C(═O)NR a R a , —(CH 2 ) r C(═O)R b , —(CH 2 ) r C(═O)OR b , —(CH 2 ) r C(═O)NR a R a , —(CH 2 OC(═O)R b , C 3-6 cycloalkyl substituted with 0-4 R e , aryl substituted with 0-4 R e , and heterocyclyl substituted with 0-4 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 -aryl, F, Cl, Br, CN, NO 2 , ═O, —NH 2 , —NHC 1-4 alkyl, —N(C 1-4 alkyl) 2 , —C(═O)OH, —C(═O)OC 1-4 alkyl, —(CH 2 ) r OH, and —(CH 2 ) r OC 1-4 alkyl;

R f , at each occurrence, is independently selected from H, F, Cl, Br, CN, OH, C 1-5 alkyl optionally substituted with OH, C 3-6 cycloalkyl, and phenyl;

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. The compound according to claim 6 , or a pharmaceutically acceptable salt thereof, wherein:

R 3 is —OCH 3 ;

R 5 , at each occurrence, is independently selected from H, F, Cl, Br, C 1-4 alkyl, —OH, —OC 1-3 alkyl, —NHS(O) 2 C 2-4 alkenyl, NHC(═O)OC 1-4 alkyl, C(═O)NH 2 , C(═O)NHC 1-4 alkyl, and heterocyclyl selected from

and

8. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein:

is selected from

R 2 is —CH 2 -cyclopropyl;

R 3 is —OC 1-4 alkyl;

R 4 is selected from

R 5 , at each occurrence, is independently selected from H, F, Cl, Br, CN C 1-4 alkyl, —OR b , —S(O) p R c —(CH 2 ) r NR a S(O) p R c , —(CH 2 ) r NR a R a , —(CH 2 ) r NR a C(═O)R b , —NR a C(═O)OR b , —C(═O)OR b , C(═O)NR a R a , C 3-6 cycloalkyl substituted with 0-4 R e , aryl substituted with 0-4 R e , and heterocyclyl substituted with 0-4 R e ;

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

R f , at each occurrence, is independently selected from H, F, Cl, Br, CN, OH, C 1-5 alkyl optionally substituted with OH, C 3-6 cycloalkyl, and phenyl;

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 according to claim 8 , or a pharmaceutically acceptable salt thereof, wherein:

R 4 is selected from

R 5 , at each occurrence, is independently selected from H, F, Cl, Br, C 1-4 alkyl, OH, and —C(═O)OH.

10. The compound according to claim 2 of Formula (IV):

or a pharmaceutically acceptable salt thereof, wherein:

is selected from

R 2 is selected from CH 3 and —CH 2 -cyclopropyl;

R 3 is selected from H, F, and —OC 1-4 alkyl;

R 4 is selected from

R 5 , at each occurrence, is independently selected from H, F, Cl, Br, CN, C 1-4 alkyl, —(CH 2 ) r OR b , —NR a S(O) p R c , —NR a R a , —NR a C(═O)R b , —NR a C(═O)OR b , —C(═O)OR b , —C(═O)NR a R a , —NR a C(═O)NR a R a , C 3-6 cycloalkyl substituted with 0-4 R e , aryl substituted with 0-4 R e , and heterocyclyl substituted with 0-4 R e ;

R 6 , at each occurrence, is independently selected from H and C 1-3 alkyl;

R d , at each occurrence, is independently selected from H and C 1-3 alkyl;

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 -aryl, F, Cl, Br, CN, NO 2 , ═O, N(C 1-4 alkyl) 2 , —C(═O)OH, —C(═O)OC 1-4 alkyl, —(CH 2 ) r OH, and —(CH 2 )OC 1-4 alkyl;

R f , at each occurrence, is independently selected from H, F, Cl, Br, CN, OH, C 1-5 alkyl optionally substituted with OH, C 3-6 cycloalkyl, and phenyl;

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 according to claim 10 , or a pharmaceutically acceptable salt thereof, wherein:

R 2 is CH 2 -cyclopropyl;

R 3 is —OCH 3 ;

R 4 is

R 5 , at each occurrence, is independently selected from H, F, Cl, Br, C 1-4 alkyl, and —(CH 2 ) 0-1 OH; and

R d is H.

12. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein:

L is —C(═O)NH—;

R 2 is —CH 2 -cyclopropyl;

R 3 is —OC 1-4 alkyl;

R 4 is selected from

R 5 , at each occurrence, is independently selected from H, F, Cl, Br, C 1-4 alkyl, —OH, and —CN; and

R 6 , at each occurrence, is independently selected from H and C 1-3 alkyl.

13. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein:

L is —O—;

R 2 is —CH 2 -cyclopropyl;

R 3 is —OC 1-4 alkyl;

R 4 is selected from

and

R 5 , at each occurrence, is independently selected from H, F, Cl, Br, C 1-4 alkyl, —OH, and —CN.

14. The compound according to claim 2 of Formula (VI):

or a pharmaceutically acceptable salt thereof, wherein:

is selected from

R 2 is —CH 2 -cyclopropyl;

R 4 is selected from

and

R 5 is selected from H, OH, CH 2 OH, and —C(CH 3 ) 2 OH.

15. The compound according to claim 2 of Formula (VII):

or a pharmaceutically acceptable salt thereof, wherein:

is selected from

R 2 is —CH 2 -cyclopropyl;

R 4 is selected from

R 5 , at each occurrence, is independently selected from F, Cl, C 1-4 alkyl, —(CH 2 OR b , —S(O) 2 NR a R a , —NR a S(O) 2 R c , and —C(═O)NR a R a ;

R 6 , at each occurrence, is independently selected from H and C 1-3 alkyl;

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

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

R c , at each occurrence, is independently C 1-4 alkyl substituted with 0-5 R e ;

R e , at each occurrence, is independently selected from F, Cl, Br, —OH, and —OC 1-4 alkyl;

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

16. A pharmaceutical composition comprising the compound according to claim 1 and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

17. The composition according to claim 16 , in combination with an additional therapeutic agent.

18. A method of inhibiting PAD4 in a subject or in a biological sample comprising the step of contacting the PAD4 with a compound according to claim 1 .

Continuity (1)

Provisional Application 62715850 · Aug 8, 2018