IP Library › Granted Patent US 11,459,331
Granted Patent B2
US 11,459,331 · App. 16/775,596 · Granted Oct 4, 2022

Chemical compounds

Inventors: Jason D. Speake (Winston-Salem, NC); Brent Christopher Beck (Apex, NC); Bharathi Pandi (Cary, NC); Jennifer C. Freeman (Durham, NC)
Assignee: Avista Pharma Solutions, Inc.
C07D487/04C07D471/04A61K45/06
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Quick Facts
Patent No.
US 11,459,331
App. No.
16/775,596
Granted
Oct 4, 2022
Kind
B2
Abstract

The present disclosure describes novel compounds, or their pharmaceutically acceptable salts, pharmaceutical compositions containing them, and their medical uses. The compounds of the disclosure have activity as prostaglandin EP4 receptor antagonists, and are useful in the treatment or alleviation of pain and inflammation and other inflammation-associated disorders, such as arthritis, treating or preventing disorders or medical conditions selected from pain, inflammatory diseases and the like. Also described herein are methods of treating pain by administering the compounds of the disclosure, which are EP4 receptor antagonists.

Claims (94)

1. A compound of Formula (II), or a veterinary, or pharmaceutically acceptable salt thereof:

wherein

X is N or CR 1 , where each R 1 individually is hydrogen, halogen, CN, C 1-3 alkyl, or C 1-3 haloalkyl;

R 2 is hydrogen, halogen, C 1-3 alkyl, C 1-3 haloalky, CN, aryl, or heteroaryl;

R 3 is hydrogen, halogen, C 1-3 alkyl, C 1-3 haloalkyl or CN;

R 4 is hydrogen, C 1-3 alkyl, C 1-3 haloalkyl, C 3-6 cycloalkyl, heterocyclyl, heteroaryl, or aryl;

Z is phenyl or C 6-7 cycloalkyl, each substituted with one or more R 5 , where R 5 is hydrogen, halogen, CN, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 haloalkoxy, or C 1-3 alkoxy;

Ar is phenyl, pyridyl, or thiophenyl, each optionally substituted with one or more halogen, CN, NO 2 , NH 2 , N(C 1-3 alkyl) 2 , OH, C 1-3 alkoxy, C 1-3 alkyl, or C 1-3 haloalkyl;

L is —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, or —OCH 2 CH 2 —; and

n is 0 or 1.

2. The compound of claim 1 , wherein:

a) Ar is phenyl and the group L is arranged para to the depicted imidazopyridine/pyrazine core;

b) Ar is pyridyl and the group L is arranged para to the depicted imidazopyridine/pyrazine core; or

c) Ar is thiophene and the group L is arranged 2,4, 2,5, or 3,5 to the depicted imidazopyridine/pyrazine core.

3. The compound of claim 1 , wherein X is N.

4. The compound of claim 1 , wherein R 2 is C 1-3 alkyl.

5. The compound of claim 1 , wherein R 3 is C 1-3 alkyl.

6. The compound of claim 1 , wherein R 4 is C 1-3 alkyl or C 1-3 haloalkyl.

7. The compound of claim 1 , wherein R 5 is C 1-3 alkyl or halogen.

8. The compound of claim 1 , wherein R 5 is CH 3 , F, or Cl.

9. The compound of claim 1 , wherein Ar is phenyl.

10. The compound of claim 1 , wherein Ar is 1,4-phenyl.

11. The compound of claim 10 , wherein Ar is unsubstituted or substituted at one or more of 2 and 3 positions.

12. The compound of claim 1 , wherein L is —CH 2 CH 2 —.

13. The compound of claim 1 , wherein n is 0.

14. The compound of claim 1 , wherein n is 1.

15. A compound selected from:

a) 1-(4-chlorophenyl)sulfonyl-3-[2-[4-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]urea;

b) 1-[2-[4-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(o-tolylsulfonyl)urea;

c) 1-(benzenesulfonyl)-3-[2-[4-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]urea;

d) 1-cyclopentylsulfonyl-3-[2-[4-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]urea;

e) 1-[2-[4-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-[4-(trifluoromethoxy)phenyl]sulfonyl-urea;

f) 1-[2-[5-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)-2-pyridyl]ethyl]-3(p-tolylsulfonyl)urea;

g) 1-[2-[5-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)-2-thienyl]ethyl]-3-(p-tolylsulfonyl)urea;

h) 1-[2-[4-(6,8-dichloro-2-ethyl-imidazo[1,2-a]pyridin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea;

i) 1-[2-[4-(6-cyano-2-ethyl-8-methyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea;

j) 1-[2-[4-(2-ethyl-8-methyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl) urea;

k) 1-[2-[4-(2-ethyl-8-methyl-6-phenyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea;

l) 1-[2-[4-[2-ethyl-8-methyl-6-(3-pyridyl)imidazo[1,2-a]pyrazin-3-yl]phenyl]ethyl]-3-(p-tolylsulfonyl)urea;

m) 1-[2-[4-[2-ethyl-8-methyl-6-(4-pyridyl)imidazo[1,2-a]pyrazin-3-yl]phenyl]ethyl]-3-(p-tolylsulfonyl)urea;

n) 1-[2-[4-(6,8-dimethyl-2-phenyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea;

o) 1-[2-[4-(2-isoxazol-3-yl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea;

p) 1-[2-[4-(6,8-dimethyl-2-tetrahydrofuran-3-yl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea;

q) 1-[2-[4-(2-ethyl-6,8-difluoro-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea; and

r) 1-[2-[4-[6,8-dimethyl-2-(1-methylsulfonyl-4-piperidyl)imidazo[1,2-a]pyrazin-3-yl]phenyl]ethyl]-3-(p-tolylsulfonyl)urea,

or a veterinary, or pharmaceutically acceptable salt thereof.

16. A composition comprising a compound of claim 1 , and a pharmaceutically or veterinary acceptable carrier.

17. A combination comprising a compound of claim 1 , and one or more other pharmaceutically or veterinary active substances.

18. A method for treating pain comprising administering to a subject in need thereof an effective amount of a compound of claim 1 .

19. The method of claim 18 , wherein the subject is a mammal.

20. The method of claim 19 , where in the mammal is a companion animal.

21. The method of claim 18 , wherein the pain is associated with one or more of joint pain, musculoskeletal pain, lower back pain, neck pain, skeletal pain, sprain, strain, myositis, neuralgia, fibromyalgia, synovitis, arthritis, rheumatoid arthritis, degenerative joint disease, osteoarthritis, gout, ankylosing spondylitis, and bursitis.

22. A composition comprising

a) a compound selected from:

(1) 1-(4-chlorophenyl)sulfonyl-3-[2-[4-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]urea;

(2) 1-[2-[4-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(o-tolylsulfonyl)urea;

(3) 1-(benzenesulfonyl)-3-[2-[4-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]urea;

(4) 1-cyclopentylsulfonyl-3-[2-[4-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]urea;

(5) 1-[2-[4-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-[4-(trifluoromethoxy)phenyl]sulfonyl-urea;

(6) 1-[2-[5-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)-2-pyridyl]ethyl]-3-(p-tolylsulfonyl)urea;

(7) 1-[2-[5-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)-2-thienyl]ethyl]-3-(p-tolylsulfonyl)urea;

(8) 1-[2-[4-(6,8-dichloro-2-ethyl-imidazo[1,2-a]pyridin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea;

(9) 1-[2-[4-(6-cyano-2-ethyl-8-methyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea;

(10) 1-[2-[4-(2-ethyl-8-methyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea;

(11) 1-[2-[4-(2-ethyl-8-methyl-6-phenyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea;

(12) 1-[2-[4-[2-ethyl-8-methyl-6-(3-pyridyl)imidazo[1,2-a]pyrazin-3-yl]phenyl]ethyl]-3-(p-tolylsulfonyl)urea;

(13) 1-[2-[4-[2-ethyl-8-methyl-6-(4-pyridyl)imidazo[1,2-a]pyrazin-3-yl]phenyl]ethyl]-3-(p-tolylsulfonyl)urea;

(14) 1-[2-[4-(6,8-dimethyl-2-phenyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea;

(15) 1-[2-[4-(2-isoxazol-3-yl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea;

(16) 1-[2-[4-(6,8-dimethyl-2-tetrahydrofuran-3-yl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea;

(17) 1-[2-[4-(2-ethyl-6,8-difluoro-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea; and

(18) 1-[2-[4-[6,8-dimethyl-2-(1-methylsulfonyl-4-piperidyl)imidazo[1,2-a]pyrazin-3-yl]phenyl]ethyl]-3-(p-tolylsulfonyl)urea;

or a veterinary, or pharmaceutically acceptable salt thereof; and

b) one or more veterinary or pharmaceutically acceptable carrier.

23. A method for treating pain comprising administering to a subject in need thereof an effective amount of a compound selected from:

i) 1-(4-chlorophenyl)sulfonyl-3-[2-[4-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]urea;

ii) 1-[2-[4-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(o-tolylsulfonyl)urea;

iii) 1-(benzenesulfonyl)-3-[2-[4-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]urea;

iv) 1-cyclopentylsulfonyl-3-[2-[4-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]urea;

v) 1-[2-[4-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-[4-(trifluoromethoxy)phenyl]sulfonyl-urea;

vi) 1-[2-[5-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)-2-pyridyl]ethyl]-3-(p-tolylsulfonyl)urea;

vii) 1-[2-[5-(2-ethyl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)-2-thienyl]ethyl]-3-(p-tolylsulfonyl)urea;

viii) 1-[2-[4-(6,8-dichloro-2-ethyl-imidazo[1,2-a]pyridin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea;

ix) 1-[2-[4-(6-cyano-2-ethyl-8-methyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea;

x) 1-[2-[4-(2-ethyl-8-methyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea;

xi) 1-[2-[4-(2-ethyl-8-methyl-6-phenyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea;

xii) 1-[2-[4-[2-ethyl-8-methyl-6-(3-pyridyl)imidazo[1,2-a]pyrazin-3-yl]phenyl]ethyl]-3-(p-tolylsulfonyl)urea;

xiii) 1-[2-[4-[2-ethyl-8-methyl-6-(4-pyridyl)imidazo[1,2-a]pyrazin-3-yl]phenyl]ethyl]-3-(p-tolylsulfonyl)urea;

xiv) 1-[2-[4-(6,8-dimethyl-2-phenyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea;

xv) 1-[2-[4-(2-isoxazol-3-yl-6,8-dimethyl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea;

xvi) 1-[2-[4-(6,8-dimethyl-2-tetrahydrofuran-3-yl-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea;

xvii) 1-[2-[4-(2-ethyl-6,8-difluoro-imidazo[1,2-a]pyrazin-3-yl)phenyl]ethyl]-3-(p-tolylsulfonyl)urea; and

xviii) 1-[2-[4-[6,8-dimethyl-2-(1-methylsulfonyl-4-piperidyl)imidazo[1,2-a]pyrazin-3-yl]phenyl]ethyl]-3-(p-tolylsulfonyl)urea,

or a veterinary, or pharmaceutically acceptable salt thereof.

Assignments (2)
ASSIGNMENT AND ASSUMPTION OF INTELLECTUAL PROPERTY SECURITY AGREEMENT Recorded Apr 11, 2025
From: ARES AGENT SERVICES, L.P., AS FORMER AGENT
To: BLUE OWL CAPITAL CORPORATION, AS NEW AGENT
Reel/Frame 070821/0302 →
SECURITY INTEREST Recorded Mar 6, 2025
From: AVISTA PHARMA SOLUTIONS, INC.
To: ARES AGENT SERVICES, L.P., AS COLLATERAL AGENT
Reel/Frame 070421/0835 →