IP Library › Granted Patent US 10,138,241

Granted Patent B2

US 10,138,241 · App. 15/696,540 · Granted Nov 27, 2018

Substituted benzamides as RIPK2 inhibitors

Inventors: Pingrong Liu (Southbury, CT); Craig Andrew Miller (New Milford, CT); Maolin Yu (Brookfield, CT); Zhonghua Zhang (Ridgefield, CT); Sabine Ruppel (New Milford, CT); Anil K. Padyana (Lexington, MA)

Assignee: Boehringer Ingelheim International GmbH

C07D471/04 C07D231/12 C07D401/04 C07D403/04 C07D417/04 C07D417/14 C07D487/04

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Quick Facts

Patent No.: US 10,138,241
App. No.: 15/696,540
Granted: Nov 27, 2018
Kind: B2

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Abstract

The present invention relates to compounds of formula (I): or pharmaceutically acceptable salts thereof, wherein R 1 , R 2 , X, Y, and HET are as defined herein. The invention also relates to pharmaceutical compositions comprising these compounds, methods of using these compounds in the treatment of various diseases and disorders, processes for preparing these compounds and intermediates useful in these processes.

Claims (234)

1. A compound of Formula (I):

or pharmaceutically acceptable salts thereof, wherein:

X is N and Y is CH; or

X is CH and Y is N;

HET is a 5-membered heteroaryl ring containing one to three heteroatoms selected from nitrogen and sulfur, wherein each heteroaryl ring is optionally substituted with one or two substituents groups independently selected from R 3 and R 4 ; or

HET is a 5-membered heteroaryl ring containing one to three heteroatoms selected from nitrogen and sulfur, wherein each heteroaryl ring is substituted with two substituents groups selected from R a and R b , wherein R a and R b together with the atoms to which they are attached form a 5-6 membered heterocyclic or heteroaryl ring which may be optionally substituted with one or two substituents selected from R 3 and R 4 ;

R 1 is hydrogen or F;

R 2 is C 1-3 alkyl or Cl;

R 3 and R 4 are each independently selected from:

(a) —H,

(b) —O R 5 ,

(d) —O—C 3-6 cycloalkyl,

(e) —C(O)R 5 ,

(f) C 1-6 alkyl optionally substituted with one to three —OH, fluoro, heterocyclyl optionally substituted with oxo, C 3-6 cycloalkyl, —CO 2 R 5 , —O— C 1-6 alkyl, aryl, —N(R 5 )(R 6 ), or —C(O)N(R 5 )(R 6 ),

(g) C 3-6 cycloalkyl optionally substituted with one to three —OH, one to three fluoro, C 1-6 alkyl, —OC 1-6 alkyl, C 1-6 alkyl-OC 1-6 alkyl, C 1-6 alkyl-OH, CF 3 , —OC 3-6 cycloalkyl, —CO 2 H, —CO 2 R 5 , C 3-6 cycloalkyl, 5-6 membered heteroaryl, C 3-6 heterocyclyl, N(R 5 )(R 6 ),

or —C(O)N(R 5 )(R 6 ),

(h) —CO 2 R 5 ,

(i) —C(O)N(R 5 )(R 6 ),

(j) —S(O) 2 N(R 5 )(R 6 ),

(k) —S(O) n -R 5 ,

(l) a 5-6 membered heteroaryl group optionally substituted with one to three groups selected from C 1-6 alkyl, C 3-6 cycloalkyl, halogen, —CF 3 , —OH, —(CH 2 ) n CO 2 R 5 , —C(O)N(R 5 )(R 6 ), —N(R 5 )(R 6 ), —NH—S(O) 2 C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl-O— C 1-3 alkyl, C 1-6 alkylhydroxy, C 1-3 alkyl-CN, oxo, phenyl optionally substituted with halogen and —S(O) n C 1-6 alkyl,

(m) 4-10 membered monocyclic, bicyclic or spirocyclic heterocyclyl group containing nitrogen, sulfur, or oxygen, wherein each heterocyclyl is optionally substituted with with 1-3 substituents selected from 3-6 membered monocyclic heterocyclyl group, halogen, —C 1-3 alkyl, —C 1-3 alkyl —O— C 1-3 alkyl and —C 1-3 alkyl- C(O)N(R 5 )(R 6 ),

(n) aryl, and

(o) —N(R 5 )(R 6 );

R 5 and R 6 are each independently selected from —H, 4-6 membered heterocyclyl, —C(O)—C 1-3 alkyl—C(O)—C 1-3 cycloalkyl and —(C 1 -C 6 )alkyl, wherein each R 5 and R 6 is independently and optionally substituted with —OH, C 3-6 cycloalkyl, —C 1-3 alkyl, —O— C 1-3 alkyl, —NH—C 1-3 alkyl or —N—(C 1-3 -alkyl) 2 ; or

R 5 and R 6 together with the nitrogen atom to which they are attached form a 4-6 membered heterocyclic ring optionally substituted with methyl; and

n is 0, 1 or 2.

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

X is N and Y is CH.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein: X is CH and Y is N.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

HET is a 5-membered heteroaryl ring selected from pyrazolyl and imidazolyl, wherein each heteroaryl ring is substituted with two substituents groups selected from R a and R b ; wherein R a and R b together with the atoms to which they are attached form a 5-6 membered heteroaryl ring such that HET is a bicyclic heteroaryl ring selected from imidazopyridine and pyrazolopyridine which may be optionally substituted one or two substituents selected from R 3 and R 4 .

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein: HET is pyrazolyl optionally substituted with one or two substituents groups selected from R 3 and R 4 .

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

HET is:

optionally substituted one or two substituents selected from R 3 and R 4 .

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

HET is:

optionally substituted one or two substituents selected from R 3 and R 4 .

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

HET is selected from:

optionally substituted one or two substituents selected from R 3 and R 4 .

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

Het is a 5-membered heteroaryl ring selected from pyrazolyl, imidazolyl, thiazolyl and thiadiazolyl, wherein each heteroaryl ring is optionally substituted with one or two substituents groups independently selected from R 3 and R 4 ; or

Het is a 5-membered heteroaryl ring selected from pyrazolyl and imidazolyl, wherein each heteroaryl ring is substituted with two substituents groups selected from R a and R b , wherein R a and R b together with the atoms to which they are attached form a 5-6 membered heterocyclic or heteroaryl ring which may be optionally substituted with one or two substituents selected from R 3 and R 4 ;

R 3 and R 4 are each independently selected from:

(a) —H,

(b) —O R 5 ,

(d) —O—C 3-6 cycloalkyl,

(e) —C(O)R 5 ,

(h) —CO 2 R 5 ,

(i) —C(O)N(R 5 )(R 6 ),

(j) —S(O) 2 N(R 5 )(R 6 ),

(k) —S(O) n -R 5

(m) 4-10 membered monocyclic, bicyclic or spirocyclic heterocyclyl group containing nitrogen, sulfur, or oxygen, wherein each heterocyclyl is optionally substituted with 1-3 substituents selected from 3-6 membered monocyclic heterocyclyl group, halogen, C 1-3 alkyl, and C 1-3 alkyl- C(O)N(R 5 )(R 6 ).

(n) aryl, and

(o) —N(R 5 )(R 6 );

R 5 and R 6 are each independently selected from —H, 4-6 membered heterocyclyl, —C(O)—C 1-3 alkyl —C(O)—C 1-3 cycloalkyl and —(C 1 -C 6 )alkyl optionally substituted with —OH, C 3-6 cycloalkyl, —NH—C 1-3 alkyl or —N—(C 1-3 -alkyl) 2 ; or

R 5 and R 6 together with the nitrogen atom to which they are attached form a 5-6 membered heterocyclic ring optionally substituted with methyl; and

n is 0 or 2.

10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

HET is a 5-membered heteroaryl ring selected from pyrazolyl, imidazolyl, thiazolyl and thiadiazolyl, wherein each heteroaryl ring is optionally substituted with one or two substituents groups independently selected from R 3 and R 4 ;

R 3 and R 4 are each independently selected from:

(a) —H,

(b) —O R 5 ,

(d) —O—C 3-6 cycloalkyl,

(e) —C(O)R 5 ,

or —C(O)N(R 5 )(R 6 ),

(h) —CO 2 R 5 ,

(i) —C(O)N(R 5 )(R 6 ),

(j) —S(O) 2 N(R 5 )(R 6 ),

(k) —S(O) n -R 5

(n) aryl, and

(o) —N(R 5 )(R 6 );

R 5 and R 6 together with the nitrogen atom to which they are attached form a 5-6 membered heterocyclic ring optionally substituted with methyl; and

n is 0 or 2.

11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

HET is a 5-membered heteroaryl ring selected from pyrazolyl and imidazolyl, wherein each heteroaryl ring is substituted with two substituents groups selected from R a and R b ; wherein R a and R b together with the atoms to which they are attached form a 5-6 membered heterocyclic or heteroaryl ring which may be optionally substituted with one or two substituents selected from R 3 and R 4 ;

R 3 and R 4 are each independently selected from:

(a) —H,

(b) —O R 5 ,

(d) —O—C 3-6 cycloalkyl,

(e) —C(O)R 5 ,

or —C(O)N(R 5 )(R 6 ),

(h) —CO 2 R 5 ,

(i) —C(O)N(R 5 )(R 6 ),

(j) —S(O) 2 N(R 5 )(R 6 ),

(k) —S(O) n —R 5

(n) aryl, and

(o) —N(R 5 )(R 6 );

R 5 and R 6 together with the nitrogen atom to which they are attached form a 6 membered heterocyclic ring optionally substituted with methyl; and

n is 0 or 2.

12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

X is N and Y is CH;

R 1 is F;

R 2 is CH 3 or Cl;

HET is imidazopyridinyl which may be optionally substituted with one or two substituents selected from R 3 and R 4 ;

R 3 and R 4 are each independently selected from:

(a) —H,

(b) —O R 5 ,

(d) —O—C 3-6 cycloalkyl,

(e) —C(O)R 5 ,

or —C(O)N(R 5 )(R 6 ),

(h) —CO 2 R 5 ,

(i) —C(O)N(R 5 )(R 6 ),

(j) —S(O) 2 N(R 5 )(R 6 ),

(k) —S(O) 2 -R 5

(l) a 5-6 membered heteroaryl group optionally substituted with one to three groups selected from C 1-6 alkyl, C 3-6 cycloalkyl, halogen, —CF 3 , —OH, —(CH 2 ) CO 2 R 5 , —C(O)N(R 5 )(R 6 ), —N(R 5 )(R 6 ), —NH—S(O) 2 C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkyl-O— C 1-3 alkyl, C 1-6 alkylhydroxy, C 1-3 alkyl-CN, oxo, phenyl optionally substituted with halogen and —S(O) 2 C 1-6 alkyl,

(m) 6 membered monocyclic heterocyclyl group containing nitrogen wherein the heterocycle is optionally substituted with 1-3 substituents selected from 3-6 membered monocyclic heterocyclyl group halogen, C 1-3 alkyl, and C 1-3 alkyl- C(O)N(R 5 )(R 6 ).

(n) aryl, and

(o) —N(R 5 )(R 6 );

R 5 and R 6 together with the nitrogen atom to which they are attached form a 6 membered heterocyclic ring optionally substituted with methyl.

13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

X is N and Y is CH;

R 1 is F;

R 2 is CH 3 or Cl;

HET is imidazopyridinyl or pyrazolopyridinyl which may be optionally substituted one or two substituents selected from R 3 and R 4 ;

R 3 and R 4 are each independently selected from:

(a) —H,

(b) —O R 5 ,

(d) —O—C 3-6 cycloalkyl,

(e) —C(O)R 5 ,

(g) C 3-6 cycloalkyl optionally substituted with one to three —OH, one to three fluoro, C 1-6 alkyl, —OC 1-6 alkyl, C 1-6 alkyl-OC 1-6 alkyl, C 1-6 alkyl-OH, CF 3 , —O C 3-6 cycloalkyl, —CO 2 H, —CO 2 R 5 , C 3-6 cycloalkyl, 5-6membered heteroaryl, C 3-6 heterocyclyl, N(R 5 )(R 6 ),

or —C(O)N(R 5 )(R 6 ),

(h) —CO 2 R 5 ,

(i) —C(O)N(R 5 )(R 6 ),

(j) —S(O) 2 N(R 5 )(R 6 ),

(k) —S(O) 2 -R 5

(n) aryl, and

(o) —N(R 5 )(R 6 );

R 5 and R 6 together with the nitrogen atom to which they are attached form a 6 membered heterocyclic ring optionally substituted with methyl.

14. The compound of claim 13 or a pharmaceutically acceptable salt thereof, wherein:

HET is:

optionally substituted one or two substituents selected from R 3 and R 4 ;

R 3 and R 4 are each independently selected from:

(a) —H,

(b) —O R 5 ,

(d) —O—C 3-6 cycloalkyl,

(e) —C(O)R 5 ,

or —C(O)N(R 5 )(R 6 ),

(h) —CO 2 R 5 ,

(i) —C(O)N(R 5 )(R 6 ),

(j) —S(O) 2 N(R 5 )(R 6 ),

(k) —S(O) 2 —R 5

(n) aryl, and

(o) —N(R 5 )(R 6 );

R 5 and R 6 together with the nitrogen atom to which they are attached form a 6 membered heterocyclic ring optionally substituted with methyl.

15. The compound of claim 13 , or a pharmaceutically acceptable salt thereof, wherein:

HET is:

optionally substituted one or two substituents selected from R 3 and R 4 .

16. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

X is N and Y is CH;

R 1 is F;

R 2 is CH 3 ;

HET is selected from:

17. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

18. A method for modulating receptor interacting serine/threonine-protein kinase 2 activity in a patient comprising administering to said patient a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

19. The method of claim 18 , wherein the patient has an autoimmune disease or allergic disorder.

20. The method of claim 19 , wherein the autoimmune disease or allergic disorder is selected from the group consisting of: rheumatoid arthritis, psoriasis, systemic lupus erythromatosis, lupus nephritis, scleroderma, asthma, chronic obstructive pulmonary disease, allergic rhinitis, allergic eczema, multiple sclerosis, juvenile rheumatoid arthritis, juvenile idiopathic arthritis, type I diabetes, inflammatory bowel disease, graft versus host disease, psoriatic arthritis, reactive arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, uveitis and non-radiographic spondyloarthropathy.

21. A compound selected from the group consisting of:

or the pharmaceutically acceptable salts thereof.

22. A pharmaceutical composition comprising a compound of claim 21 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

23. A compound of formula: