IP Library › Granted Patent US 11,993,574

Granted Patent B2

US 11,993,574 · App. 17/251,295 · Granted May 28, 2024

Pyrazole and imidazole compounds for inhibition of IL-17 and RORgamma

Inventors: Xin Jiang (Irving, TX); Melean Visnick (Irving, TX); Christopher F. Bender (Irving, TX); Gary Bolton (Irving, TX); Bradley Caprathe (Irving, TX); Chitase Lee (Irving, TX); Brian Kornberg (Irving, TX); Patrick O'Brien (Irving, TX); Martha R. Hotema (Irving, TX)

Assignee: REATA PHARMACEUTICALS, INC

C07D231/54 C07D235/02 C07D401/04 C07D401/06 C07D401/10 C07D401/14 C07D403/04 C07D403/10 C07D403/14 C07D405/04 C07D409/04 C07D413/10 C07D413/14 C07D417/04 C07D417/14

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Quick Facts

Patent No.: US 11,993,574
App. No.: 17/251,295
Granted: May 28, 2024
Kind: B2

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Abstract

Disclosed herein are compounds of the formula: as well as analogs thereof, wherein the variables are defined herein. Also provided are pharmaceutical compositions thereof. In some aspects, the compounds and compositions provided herein may be used to modulate the activity of IL-17 and RORγ. Also provided are methods of administering compounds and composition provided herein to a patient in need thereof, for example, for the treatment or prevention of diseases or disorders associated with inflammation or for autoimmune disorders.

Claims (167)

1. A compound of the formula:

wherein:

n is 0, 1, or 2;

R 1 is cyano, fluoro, —CF 3 , or —C(O)R a , wherein:

R a is hydroxy or amino; or

alkoxy (C≤6) , alkylamino (C≤6) , dialkylamino (C≤6) , or a substituted version of any of these groups;

R 2 is hydrogen; or

alkyl (C≤12) , cycloalkyl (C≤12) , alkenyl (C≤12) , alkynyl (C≤12) , aryl (C≤18) , aralkyl (C≤18) , heteroaryl (C≤18) , heteroaralkyl (C≤18) , or a substituted version of any of these groups;

R 2 ′ is hydrogen;

R 3 is alkyl (C≤12) , alkenyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , or a substituted version of any of these groups;

R 4 and R 5 are each independently absent; or

cycloalkyl (C≤12) , heterocycloalkyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , heteroaryl (C≤12) , heteroaralkyl (C≤12) , -arenediyl (C≤12) -alkyl (C≤12) , -arenediyl (C≤12) -aryl (C≤12) , -arenediyl (C≤12) -heteroaryl (C≤12) , -arenediyl (C≤12) -heterocycloalkyl (C≤12) , -arenediyl (C≤12) -cyclo-alkyl (C≤12) , -heteroarenediyl (C≤12) -alkyl (C≤12) , -heteroarenediyl (C≤12) -aryl (C≤12) , -hetero-arenediyl (C≤12) -heteroaryl (C≤12) , -heteroarenediyl (C≤12) -hetero-cycloalkyl (C≤12) , -heteroarenediyl (C≤12) -cycloalkyl (C≤12) , -heterocycloalkanediyl (C≤12) -aryl (C≤12) , -heterocycloalkanediyl (C≤12) -heteroaryl (C≤12) , or a substituted version of any of these groups; or

a group of the formula:

wherein 1 and m are each 0, 1, 2, or 3;

R 6 is absent or amino; or

alkylamino (C≤12) , dialkylamino (C≤12) , cycloalkylamino (C≤12) , dicycloalkylamino (C≤12) , alkyl(cycloalkyl)amino (C≤12) , arylamino (C≤12) , diarylamino (C≤12) , alkyl (C≤12) , cycloalkyl (C≤12) , -alkanediyl (C≤12) -cycloalkyl (C≤12) , -alkanediyl (C≤18) -aralkoxy (C≤18) , heterocycloalkyl (C≤12) , aryl (C≤18) , -arenediyl (C≤12) -alkyl (C≤12) , aralkyl (C≤18) , -arenediyl (C≤18) -heterocycloalkyl (C≤12) , heteroaryl (C≤18) , -heteroarenediyl (C≤12) -alkyl (C≤12) , heteroaralkyl (C≤18) , acyl (C≤12) , alkoxy (C≤12) , or a substituted version of any of these groups;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 further defined as:

wherein:

n is 0, 1, or 2;

R 1 is cyano, fluoro, —CF 3 , or —C(O)R a , wherein:

R a is hydroxy or amino; or

alkoxy (C≤6) , alkylamino (C≤6) , dialkylamino (C≤6) , or a substituted version of any of these groups;

R 2 is hydrogen; or

R 2 ′ is hydrogen;

R 3 is alkyl (C≤12) , alkenyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , or a substituted version of any of these groups;

R 4 and R 5 are each independently absent; or

a group of the formula:

wherein 1 and m are each 0, 1, 2, or 3;

R 6 is absent or amino; or

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 , further defined as:

wherein:

R 2 independently is hydrogen; or

R 2 ′ is hydrogen;

R 4 and R 5 are each independently absent; or

a group of the formula:

wherein 1 and m are each 0, 1, 2, or 3;

R 6 is absent or amino; or

or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 , further defined as:

wherein:

R 2 independently is hydrogen; or

R 2 ′ is hydrogen;

R 4 and R 5 are each independently absent; or

a group of the formula:

wherein 1 and m are each 0, 1, 2, or 3; and

R 6 is absent; or

alkyl (C≤12) , cycloalkyl (C≤12) , -alkanediyl (C≤12) -cycloalkyl (C≤12) , -alkane-diyl (C≤18) -aralkoxy (C≤18) , heterocycloalkyl (C≤12) , aryl (C≤18) , -arenediyl (C≤12) -alkyl (C≤12) , aralkyl (C≤18) , -arenediyl (C≤18) -heterocyclo-alkyl (C≤12) , heteroaryl (C≤18) , -heteroarenediyl (C≤12) -alkyl (C≤12) , heteroaralkyl (C≤18) , acyl (C≤12) , alkoxy (C≤12) , or a substituted version of any of these groups;

or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 , further defined as:

wherein:

R 4 and R 5 are each independently absent; or

a group of the formula:

wherein 1 and m are each 0, 1, 2, or 3; and

R 6 is absent; or

or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1 , wherein R 3 is alkyl (C≤12) or substituted alkyl (C≤12) or R 1 is cyano.

7. The compound of claim 1 , wherein R 2 is hydrogen, alkyl (C≤12) , or substituted alkyl (C≤12) .

8. The compound of claim 1 , wherein R 4 is aryl (C≤12) , substituted aryl (C≤12) , -arenediyl (C≤12) -aryl (C≤12) , or substituted -arenediyl (C≤12) -aryl (C≤12) .

9. The compound of claim 1 , wherein R 4 is -arenediyl (C≤12) -heterocycloalkyl (C≤12) or substituted -arenediyl (C≤12) -heterocycloalkyl (C≤12) .

10. The compound of claim 1 , wherein R 4 is heteroaryl (C≤12) , substituted heteroaryl (C≤12) , -arenediyl (C≤12) -heteroaryl (C≤12) , substituted -arenediyl (C≤12) -heteroaryl (C≤12) , -heteroarenediyl (C≤12) -aryl (C≤12) , substituted -heteroarenediyl (C≤12) -aryl (C≤12) , -heteroarenediyl (C≤12) -heteroaryl (C≤12) , or substituted -heteroarenediyl (C≤12) -heteroaryl (C≤12) .

11. The compound of claim 1 , wherein R 5 is aryl (C≤12) , substituted aryl (C≤12) , -arenediyl (C≤12) -aryl (C≤12) , or substituted -arenediyl (C≤12) -aryl (C≤12) .

12. The compound of claim 1 , wherein R 5 is -arenediyl (C≤12) -heterocycloalkyl (C≤12) or substituted -arenediyl (C≤12) -heterocycloalkyl (C≤12) .

13. The compound of claim 1 , wherein R 5 is heteroaryl (C≤12) , substituted heteroaryl (C≤12) , -arenediyl (C≤12) -heteroaryl (C≤12) , substituted -arenediyl (C≤12) -heteroaryl (C≤12) , -heteroarenediyl (C≤12) -aryl (C≤12) , substituted -heteroarenediyl (C≤12) -aryl (C≤12) , -heteroarenediyl (C≤12) -heteroaryl (C≤12) , or substituted -heteroarenediyl (C≤12) -heteroaryl (C≤12) .

14. The compound of claim 1 , wherein R 5 is -heteroarenediyl (C≤12) -heterocycloalkyl (C≤12) or substituted -heteroarenediyl (C≤12) -heterocycloalkyl (C≤12) .

15. The compound of claim 1 , wherein R 6 is aryl (C≤18) , substituted aryl (C≤18) , heteroaryl (C≤18) , or substituted heteroaryl (C≤18) .

16. The compound of claim 1 further defined as:

or a pharmaceutically acceptable salt of any of the above formulas.

17. A pharmaceutical composition comprising:

(a) a compound of claim 1 ; and

(b) an excipient.

18. The compound of claim 1 , wherein R 6 is cycloalkyl (C≤12) , substituted cycloalkyl (C≤12) , heterocycloalkyl (C≤12) , or substituted heterocycloalkyl (C≤12) .

19. A compound of the formula:

wherein:

n is 0, 1, or 2;

R 1 is cyano, fluoro, —CF 3 , or —C(O)R a , wherein:

R a is hydroxy or amino; or

alkoxy (C≤6) , alkylamino (C≤6) , dialkylamino (C≤6) , or a substituted version of any of these groups;

R 2 is hydrogen; or

R 2 ′ is hydrogen;

R 3 is alkyl (C≤12) , alkenyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , or a substituted version of any of these groups;

R 4 and R 5 are each independently absent; or

a group of the formula:

wherein 1 and m are each 0, 1, 2, or 3;

R 6 is absent or amino; or

or a pharmaceutically acceptable salt thereof.

20. The compound of claim 19 further defined as:

wherein:

n is 0, 1, or 2;

R 1 is cyano, fluoro, —CF 3 , or —C(O)R a , wherein:

R a is hydroxy or amino; or

alkoxy (C≤6) , alkylamino (C≤6) , dialkylamino (C≤6) , or a substituted version of any of these groups;

R 2 is hydrogen; or

R 2 ′ is hydrogen;

R 3 is alkyl (C≤12) , alkenyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , or a substituted version of any of these groups;

R 4 and R 5 are each independently absent; or

a group of the formula:

wherein 1 and m are each 0, 1, 2, or 3;

R 6 is absent or amino; or

or a pharmaceutically acceptable salt thereof.

21. The compound of claim 19 , further defined as:

wherein:

R 2 is hydrogen; or

cycloalkyl (C≤12) , alkenyl (C≤12) , alkynyl (C≤12) , aryl (C≤18) , aralkyl (C≤18) , heteroaryl (C≤18) , heteroaralkyl (C≤18) , or a substituted version of any of these groups;

R 2 ′ is hydrogen;

R 4 and R 5 are each independently absent; or

a group of the formula:

wherein 1 and m are each 0, 1, 2, or 3;

R 6 is absent or amino; or

or a pharmaceutically acceptable salt thereof.

22. The compound of claim 19 , further defined as:

wherein:

R 2 is hydrogen; or

R 2 ′ is hydrogen;

R 4 and R 5 are each independently absent; or

a group of the formula:

wherein 1 and m are each 0, 1, 2, or 3; and

R 6 is absent; or

or a pharmaceutically acceptable salt thereof.

23. The compound of claim 19 , further defined as:

wherein:

R 4 and R 5 are each independently absent; or

a group of the formula:

wherein 1 and m are each 0, 1, 2, or 3; and

R 6 is absent; or

or a pharmaceutically acceptable salt thereof.

24. The compound of claim 19 , wherein R 3 is alkyl (C≤12) or substituted alkyl (C≤12) or R 1 is cyano.

25. The compound of claim 19 , wherein R 2 is hydrogen, alkyl (C≤12) , or substituted alkyl (C≤12) .

26. The compound of claim 19 , wherein R 4 is aryl (C≤12) , substituted aryl (C≤12) , -arenediyl (C≤12) -aryl (C≤12) , or substituted -arenediyl (C≤12) -aryl (C≤12) .

27. The compound of claim 19 , wherein R 4 is -arenediyl (C≤12) -heterocycloalkyl (C≤12) or substituted -arenediyl (C≤12) -heterocycloalkyl (C≤12) .

28. The compound of claim 19 , wherein R 4 is heteroaryl (C≤12) , substituted heteroaryl (C≤12) , -arenediyl (C≤12) -heteroaryl (C≤12) , substituted -arenediyl (C≤12) -heteroaryl (C≤12) , -heteroarenediyl (C≤12) -aryl (C≤12) , substituted -heteroarenediyl (C≤12) -aryl (C≤12) , -heteroarenediyl (C≤12) -heteroaryl (C≤12) , or substituted -heteroarenediyl (C≤12) -heteroaryl (C≤12) .

29. The compound of claim 19 , wherein R 5 is aryl (C≤12) , substituted aryl (C≤12) , -arenediyl (C≤12) -aryl (C≤12) , or substituted -arenediyl (C≤12) -aryl (C≤12) .

30. The compound of claim 19 , wherein R 5 is -arenediyl (C≤12) -heterocycloalkyl (C≤12) or substituted -arenediyl (C≤12) -heterocycloalkyl (C≤12) .

31. The compound of claim 19 , wherein R 5 is heteroaryl (C≤12) , substituted heteroaryl (C≤12) , -arenediyl (C≤12) -heteroaryl (C≤12) , substituted -arenediyl (C≤12) -heteroaryl (C≤12) , -heteroarenediyl (C≤12) -aryl (C≤12) , substituted -heteroarenediyl (C≤12) -aryl (C≤12) , -heteroarenediyl (C≤12) -heteroaryl (C≤12) , or substituted -heteroarenediyl (C≤12) -heteroaryl (C≤12) .

32. The compound of claim 19 , wherein R 5 is -heteroarenediyl (C≤12) -heterocycloalkyl (C≤12) or substituted -heteroarenediyl (C≤12) -heterocycloalkyl (C≤12) .

33. The compound of claim 19 , wherein R 6 is aryl (C≤18) , substituted aryl (C≤18) , heteroaryl (C≤18) , or substituted heteroaryl (C≤18) .

34. The compound of claim 19 , wherein R 6 is cycloalkyl (C≤12) , substituted cycloalkyl (C≤12) , heterocycloalkyl (C≤12) , or substituted heterocycloalkyl (C≤12) .

35. The compound of claim 19 , wherein R 6 is alkylamino (C≤12) , substituted alkylamino (C≤12) , cycloalkylamino (C≤12) , substituted cycloalkylamino (C≤12) , alkyl(cycloalkyl)amino (C≤12) , or substituted alkyl(cycloalkyl)amino (C≤12) .

36. The compound of claim 19 further defined as:

or a pharmaceutically acceptable salt of any of the above formulas.

37. A pharmaceutical composition comprising:

(a) a compound of claim 19 ; and

(b) an excipient.

Assignments (7)

RELEASE OF SECURITY INTEREST Recorded Apr 9, 2025

From: BIOPHARMA CREDIT PLC

To: REATA PHARMACEUTICALS HOLDINGS, LLC; REATA PHARMACEUTICALS GLOBAL, INC.; REATA PHARMACEUTICALS, INC.

Reel/Frame 070793/0228 →

RELEASE OF SECURITY INTEREST Recorded Apr 9, 2025

From: BIOPHARMA CREDIT PLC