IP Library › Granted Patent US 8,987,311
Granted Patent B2
US 8,987,311 · App. 14/371,281 · Granted Mar 24, 2015

Triazolyl-substituted pyridyl compounds useful as kinase inhibitors

Inventors: Dharmpal S. Dodd (Princeton, NJ); Christopher P. Mussari (Princeton, NJ); Rajeev S. Bhide (Princeton Junction, NJ); Satheesh Kesavan Nair (Bangalore, IN); Venkatram Reddy Paidi (Bangalore, IN); Sreekantha Ratna Kumar (Bangalore, IN); Abhisek Banerjee (West Bengal, IN); Ramesh Sistla (Bangalore, IN); William J. Pitts (Newtown, PA); John Hynes (Washington Crossing, PA)
Assignee: Bristol-Myers Squibb Company
C07D471/10C07D417/14
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Quick Facts
Patent No.
US 8,987,311
App. No.
14/371,281
Granted
Mar 24, 2015
Kind
B2
Abstract

Compounds having the following formula: (I) wherein: A is an optionally substituted triazole, or a stereoisomer or a pharmaceutically-acceptable salt thereof, are useful as kinase modulators, including IRAK-4 modulation.

Claims (64)

1. A compound according to formula (I):

or a stereoisomer or pharmaceutically-acceptable salt thereof, wherein

A is a triazole optionally substituted by 0-2 R;

X is N or C—R 7 ;

R is hydrogen, R 1 , halogen, cyano, nitro, —OR 1 , —C(═O)—R 1 , —C(═O)O—R 1 , —C(═O)NR 11 —R 1 , —S(═O) 2 —R 1 , —NR 11 C(═O)—R 1 , —NR 11 C(═O)NR 11 R 1 , —NR 11 C(═O)O—R 1 , —NR 11 S(═O) 2 R 1 or —NR 11 R 1 ;

R 1 is C 1-6 alkyl substituted with 0-4 R 1a , C 1-6 haloalkyl, C 2-6 alkenyl substituted with 0-3 R 1a , C 2-6 alkynyl substituted with 0-3 R 1a , C 3-10 cycloalkyl substituted with 0-3 R 1a , C 6-10 aryl substituted with 0-3 R 1a , a 5-10 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R 1a , or a 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R 1a ;

R 1a is hydrogen, ═O, F, Cl, Br, OCF 3 , CN, NO 2 , —(CH 2 ) r OR b , —(CH 2 ) r SR b , —(CH 2 ) r C(O)R b , —(CH 2 ) r C(O)OR b , —(CH 2 ) r OC(O)R b , —(CH 2 ) r NR 11 R 11 , —(CH 2 ) r C(O)NR 11 R 11 , —(CH 2 ) r NR b C(O)R c , —(CH 2 ) r NR b C(O)OR c , —NR b C(O)NR 11 R 11 , —S(O) p NR 11 R 11 , —NR b S(O) p R c , —S(O)R c , —S(O) 2 R c , C 1-6 alkyl substituted with 0-2 R a , C 1-6 haloalkyl, —(CH 2 ) r -3-14 membered carbocycle substituted with 0-3 R a , or —(CH 2 ) r -5-7 membered heterocycle or heteroaryl, each comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O) p substituted with 0-3 R a ;

R 2 is C 6-10 aryl substituted with 0-4 R 2a , a 5-10 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S, substituted with 1-4 R 2a , or a 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-4 R 2a ;

R 2a at each occurrence is independently selected from hydrogen, ═O, halo, OCF 3 , CN, NO 2 , —(CH 2 ) r OR b , —(CH 2 ) r SR b , —(CH 2 ) r C(O)R b , —(CH 2 ) r C(O)OR b , —(CH 2 ) r OC(O)R b , —(CH 2 ) r NR 11 R 11 , —(CH 2 ) r C(O)NR 11 R 11 , —(CH 2 ) r NR b C(O)R c , —(CH 2 ) r NR b C(O)OR c , —NR b C(O)NR 11 R 11 , —S(O) p NR 11 R 11 , —NR b S(O) p R c , —S(O)R c , —S(O) 2 R c , C 1-6 alkyl substituted with 0-2 R a , C 1-6 haloalkyl, —(CH 2 ) r -3-14 membered carbocycle substituted with 0-1 R a , or —(CH 2 ) r -5-7 membered heterocycle or heteroaryl, each comprising carbon atoms and 1-4 heteroatoms selected from N, 0, and S(O) p substituted with 0-2 R a ;

R 3 is C 1-6 alkyl substituted with 0-3 R 3a , C 1-6 haloalkyl, C 2-6 alkenyl substituted with 0-3 R 3a , C 2-6 alkynyl substituted with 0-3 R 3a , C 3-10 cycloalkyl substituted with 0-3 R 3a , C 6-10 aryl substituted with 0-3 R 3a , a 5-10 membered heterocyclyl containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R 3a or a 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R 3a ;

R 3a is hydrogen, ═O, F, Cl, Br, OCF 3 , CN, NO 2 , —(CH 2 ) r OR b , —(CH 2 ) r SR b , —(CH 2 ) r C(O)R b , —(CH 2 ) r C(O)OR b , —(CH 2 ) r OC(O)R b , —(CH 2 ) r NR 11 R 11 , —(CH 2 ) r C(O)NR 11 R 11 , —(CH 2 ) r NR b C(O)R c , —(CH 2 ) r NR b C(O)OR c , —NR b C(O)NR 11 R 11 , —S(O) p NR 11 R 11 , —NR b S(O) p R c , —S(O)R c , —S(O) 2 R c , C 1-6 alkyl substituted with 0-2 R a , C 1-6 haloalkyl, —(CH 2 ) r -3-14 membered carbocycle substituted with 0-1 R a , or —(CH 2 ) r -5-7 membered heterocycle or heteroaryl, each comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O) p substituted with 0-1 R a ;

R 4 and R 5 are independently selected from hydrogen, C 1-4 alkyl substituted with 0-1 R f , (CH 2 )-phenyl substituted with 0-3 R d , and a —(CH 2 )-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O) p ;

R 6 and R 7 are independently at each occurrence is selected from hydrogen, ═O, F, Cl, Br, OCF 3 , CN, NO 2 , —(CH 2 ) r OR b , —(CH 2 ) r SR b , —(CH 2 ) r C(O)R b , —(CH 2 ) r C(O)OR b , —(CH 2 ) r OC(O)R b , —(CH 2 ) r NR 11 R 11 , —(CH 2 ) r C(O)NR 11 R 11 , —(CH 2 ) r NR b C(O)R c , —(CH 2 ) r NR b C(O)OR c , —NR b C(O)NR 11 R 11 , —S(O) p NR 11 R 11 , —NR b S(O) p R c , —S(O)R c , —S(O) 2 R c , C 1-6 alkyl substituted with 0-2 R a , C 1-6 haloalkyl, —(CH 2 ) r -3-14 membered carbocycle substituted with 0-3 R a , or —(CH 2 ) r -5-7 membered heterocycle or heteroaryl, each comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O) p substituted with 0-3 R a , provided R 6 and R 7 are not both hydrogen;

R 11 at each occurrence is independently hydrogen, R e , C 1-4 alkyl substituted with 0-1 R f , CH 2 -phenyl substituted with 0-3 R d , or —(CH 2 )-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O) p substituted with 0-3 R d ; or

R 11 and along with another R 11 , R 1 , or R 2 on the same nitrogen atom may join to form an optionally substituted heterocycle;

R a is hydrogen, F, Cl, Br, OCF 3 , CF 3 , CHF 2 , CN, NO 2 , —(CH 2 ) r OR b , —(CH 2 ) r SR b , —(CH 2 ) r C(O)R b , —(CH 2 ) r C(O)OR b , —(CH 2 ) r OC(O)R b , —(CH 2 ) r NR 11 R 11 , —(CH 2 ) r C(O)NR 11 R 11 , —(CH 2 ) r NR b C(O)R c , —(CH 2 ) r NR b C(O)OR c , —NR b C(O)NR 11 R 11 , —S(O) p NR 11 R 11 , —NR b S(O) p R c , —S(O)R c , —S(O) 2 R c , C 1-6 alkyl substituted with 0-1 R f , C 1-6 haloalkyl, —(CH 2 ) r -3-14 membered carbocycle, or —(CH 2 ) r -5-7 membered heterocycle or heteroaryl, each comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O) p ; or two R a on adjacent or the same carbon atom form a cyclic acetal of the formula —O—(CH 2 ) n —O—, or —O—CF 2 —O—, wherein n is selected from 1 or 2;

R b is hydrogen, R e , C 1-6 alkyl substituted with 0-2 R d , C 1-6 haloalkyl, C 3-6 cycloalkyl substituted with 0-2 R d , or (CH 2 ) r -phenyl substituted with 0-3 R d ;

R c is C 1-6 alkyl substituted with 0-1 R f , C 3-6 cycloalkyl, or (CH 2 ) r -phenyl substituted with 0-3 R f ;

R d is hydrogen, F, Cl, Br, OCF 3 , CF 3 , CN, NO 2 , —OR e , —(CH 2 ) r C(O)R c , —NR e R e , —NR e C(O)OR c , C 1-6 alkyl, or (CH 2 ) r -phenyl substituted with 0-3 R f ;

R e is selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, and (CH 2 ) r -phenyl substituted with 0-3 R f ;

R f is hydrogen, halo, NH 2 , OH, or O(C 1-6 alkyl);

p is 0, 1, or 2;

r is 0, 1, 2, 3, or 4; and

m is 0,1, or 2.

2. The compound of claim 1 , or a stereoisomer or pharmaceutically-acceptable salt thereof,

wherein A is

and X 1 and X 2 are independently selected from N or C—R, provided that one of X 1 and X 2 is selected from N and the other from C—R.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is phenyl, pyridyl, pyrimidinyl, naphthyl, indolinyl, benzothiazolyl, pyrazolopyridinyl, benzoisothiazolyl, triazolopyridinyl, imidazopyridinyl, benzooxazolyl, triazolopyridinyl, imidazopyridinyl, pyridopyrazinyl, quinazolinyl, pyridopyrazinyl, benzooxadiazolyl, benzothiadiazolyl, benzoimidazolyl, triazolopyridinyl, imdazopyridazinyl, pyridopyrazinyl, naphthyridinyl, quinoxalinyl, phthalazinyl, quinolinyl, indolyl, benzothiazolyl, benzodioxolyl, benzothienyl, isoquinolinyl, benzopyranyl, indolizinyl, benzofuranyl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, pyrrolopyridyl, furopyridyl, isoindolyl, or quinazolinyl, each group substituted by 1-4 groups selected from R 2a .

4. The compound of claim 1 , or a stereoisomer or pharmaceutically-acceptable salt thereof, wherein m is 0.

5. The compound of claim 1 , or a stereoisomer or pharmaceutically-acceptable salt thereof, wherein both R 4 and R 5 are hydrogen.

6. The compound of claim 1 having the following formula

or a stereoisomer or pharmaceutically salt thereof, wherein:

X 1 and X 2 are independently selected from N or C—R, provided one of X 1 and X 2 is selected from N and the other from C—R;

R is hydrogen, R 1 , halogen, —C(═O)—R 1 , —C(═O)OR 1 , —C(═O)NR 11 R 1 or —NR 11 R 1 ;

R 1 is C 1-6 alkyl substituted with 0-4 R 1a , C 1-6 haloalkyl, C 2-6 alkenyl substituted with 0-3 R 1a , C 2-6 alkynyl substituted with 0-3 R 1a , C 3-10 cycloalkyl substituted with 0-3 R 1a , C 6-10 aryl substituted with 0-3 R 1a , a 5-10 membered heterocycle containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R 1a , or a 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R 1a ;

R 1a is hydrogen, ═O, F, Cl, Br, OCF 3 , CN, NO 2 , —(CH 2 ) r OR b , —(CH 2 ) r SR b , —(CH 2 ) r C(O)R b , —(CH 2 ) r C(O)OR b , —(CH 2 ) r OC(O)R b , —(CH 2 ) r NR 11 R 11 , —(CH 2 ) r C(O)NR 11 R 11 , —(CH 2 ) r NR b C(O)R c , —(CH 2 ) r NR b C(O)OR c , —NR b C(O)NR 11 R 11 , —S(O) p NR 11 R 11 , —NR b S(O) p R c , —S(O)R c , —S(O) 2 R c , C 1-6 alkyl substituted with 0-2 R a , C 1-6 haloalkyl, —(CH 2 ) r -3-14 membered carbocycle substituted with 0-1 R a , or —(CH 2 ) r -5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O) p substituted with 0-1 R a ;

R 2 is phenyl, pyridyl, pyrimidinyl, naphthyl, indolinyl, benzothiazolyl, pyrazolopyridinyl, benzoisothiazolyl, triazolopyridinyl, imidazopyridinyl, benzooxazolyl, triazolopyridinyl, imidazopyridinyl, pyridopyrazinyl, quinazolinyl, pyridopyrazinyl, benzooxadiazolyl, benzothiadiazolyl, benzoimidazolyl, triazolopyridinyl, imdazopyridazinyl, pyridopyrazinyl, naphthyridinyl, quinoxalinyl, phthalazinyl, quinolinyl, indolyl, benzothiazolyl, benzodioxolyl, benzothienyl, isoquinolinyl, benzopyranyl, indolizinyl, benzofuranyl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl, pyrrolopyridyl, furopyridyl, isoindolyl, or quinazolinyl each group substituted by 1-4 groups selected from R 2a ;

R 2a is hydrogen, ═O, F, Cl, Br, OCF 3 , CN, NO 2 , —(CH 2 ) r OR b , —(CH 2 ) r SR b , —(CH 2 ) r C(O)R b , —(CH 2 ) r C(O)OR b , —(CH 2 ) r OC(O)R b , —(CH 2 ) r NR 11 R 11 , —(CH 2 ) r C(O)NR 11 R 11 , —(CH 2 ) r NR b C(O)R c , —(CH 2 ) r NR b C(O)OR c , —NR b C(O)NR 11 R 11 , —S(O) p NR 11 R 11 , —NR b S(O) p R c , —S(O)R c , —S(O) 2 R c , C 1-6 alkyl substituted with 0-2 R a , C 1-6 haloalkyl, —(CH 2 ) r -3-14 membered carbocycle substituted with 0-1 R a , or —(CH 2 ) r -5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O) p substituted with 0-1 R a ;

R 3 is C 1-6 alkyl substituted with 0-3 R 3a ; or a C 3-7 cycloalkyl, phenyl, tetrahydropyranyl, tetrahydrofuranyl, or oxetane ring, each ring optionally substituted with 0-3 R 3a ;

R 3a is hydrogen, ═O, F, Cl, Br, OCF 3 , CF 3 , CHF 2 , CN, NO 2 , —(CH 2 ) r OR b , —(CH 2 ) r SR b , —(CH 2 ) r C(O)R b , —(CH 2 ) r C(O)OR b , —(CH 2 ) r OC(O)R b , —(CH 2 ) r NR 11 R 11 , —(CH 2 ) r C(O)NR 11 R 11 , —(CH 2 ) r NR b C(O)R c , —(CH 2 ) r NR b C(O)OR c , —NR b C(O)NR 11 R 11 , —S(O) p NR 11 R 11 , —NR b S(O) p R c , —S(O)R c , —S(O) 2 R c , C 1-6 alkyl substituted with 0-2 R a , C 1-6 haloalkyl, —(CH 2 ) r -3-14 membered carbocycle substituted with 0-1 R a , or —(CH 2 ) r -5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O) p substituted with 0-1 R a ;

R 11 at each occurrence is independently hydrogen, C 1-4 alkyl substituted with 0-1 R f , CH 2 -phenyl substituted with 0-3 R d , or —(CH 2 )-5-7 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O) p substituted with 0-3 R d ;

R a is hydrogen, Cl, Br, OCF 3 , CF 3 , CHF 2 , CN, NO 2 , —(CH 2 ) r OR b , —(CH 2 ) r SR b , —(CH 2 ) r C(O)R b , —(CH 2 ) r C(O)OR b , —(CH 2 ) r OC(O)R b , —(CH 2 ) r NR 11 R 11 , —(CH 2 ) r C(O)NR 11 R 11 , —(CH 2 ) r NR b C(O)R c , —(CH 2 ) r NR b C(O)OR c , —NR b C(O)NR 11 R 11 , —S(O) p NR 11 R 11 , —NR b S(O) p R c , —S(O)R c , —S(O) 2 R c , C 1-6 alkyl, C 1-6 haloalkyl, —(CH 2 ) r -3-14 membered carbocycle, or —(CH 2 ) r -5-7 membered heterocycle or heteroaryl, each comprising carbon atoms and 1-4 heteroatoms selected from N, O, and S(O) p , alternatively two R a on adjacent or the same carbon atom form a cyclic acetal of the formula —O—(CH 2 ) n —O—, or —O—CF 2 —O—, wherein n is selected from 1 or 2;

R b is hydrogen, C 1-6 alkyl substituted with 0-2 R d , C 1-6 haloalkyl, C 3-6 cycloalkyl substituted with 0-2 R d , or (CH 2 ) r -phenyl substituted with 0-3 R d ;

R c is C 1-6 alkyl, C 3-6 cycloalkyl, or (CH 2 ) r -phenyl substituted with 0-3 R f ;

R d is hydrogen, F, Cl, Br, OCF 3 , CF 3 , CN, NO 2 , —OR e , —(CH2) r C(O)R e , —NR e R e , —NR e C(O)OR c , C 1-6 alkyl, or (CH 2 ) r -phenyl substituted with 0-3 R f ;

R e is hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, or (CH 2 ) r -phenyl substituted with 0-3 R f ;

R f is hydrogen, halo, NH 2 , OH, or O(C 1-6 alkyl);

r is 0, 1, 2, 3, or 4; and

p is 0,1, or 2.

7. The compound of claim 1 , or a stereoisomer or pharmaceutically-acceptable salt thereof, wherein R 2 is selected from

each group substituted by 0-4 R 2a .

8. The compound of claim 1 , or a stereoisomer or pharmaceutically-acceptable salt thereof, wherein R 2 is selected from

each group optionally substituted by 0-3 R 2a .

9. The compound of claim 1 , or a stereoisomer or pharmaceutically-acceptable salt thereof wherein R 2 is selected

or

each group optionally substituted by 0-3 R 2a .

10. The compound of claim 1 , or a stereoisomer or pharmaceutically-acceptable salt thereof wherein R 2 is

and Y is Cl, F, Br, CN, —OC 1-6 alkyl, C 1-6 alkyl, -haloC 1-6 alkyl, or NH 2 .

11. The compound of claim 1 , or a stereoisomer or pharmaceutically-acceptable salt thereof, wherein R is selected from the following groups:

12. The compound of claim 1 , or a stereoisomer or pharmaceutically-acceptable salt thereof wherein X 2 is N and X 1 is CR; and R is hydrogen or C 1-6 alkyl.

13. The compound of claim 1 , or a stereoisomer or pharmaceutically-acceptable salt thereof R 3 is C 1-6 alkyl substituted with 0-3 R 3a or phenyl optionally substituted with 0-3 R 3a .

14. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier or diluent.

15. A method of treating a disease, comprising administering to a patient a therapeutically-effective amount of a compound according to claim 1 , wherein the disease is an inflammatory or autoimmune disease.

16. The method of claim 15 wherein the disease is selected from Crohn's disease, ulcerative colitis, asthma, graft versus host disease, allograft rejection, chronic obstructive pulmonary disease, Graves' disease, rheumatoid arthritis, systemic lupus erythematosis, psoriasis, adult onset stills, systemic onset juvenile idiopathic arthritis, multiple sclerosis, neuropathic pain, gout, and gouty arthritis.

Continuity (2)
Provisional Application 61586139 · Jan 13, 2012
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