Pyrimidine tricyclic enone derivatives for inhibition of ROR-gamma and other uses

Patent metadata

Field	Value
Publication number	US-12195443-B2
Application number	US-202217577456-A
Country	US
Kind code	B2
Filing date	Jan 18, 2022
Priority date	Dec 16, 2016
Publication date	Jan 14, 2025
Grant date	Jan 14, 2025

Abstract

Disclosed herein are compounds of the formulas:

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 inhibit RORγ and/or reduce the expression of IL-17. 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 autoimmune disorders.

First claim

What is claimed is:

1. A compound of the formula:

wherein:
the bond between carbon atoms 1 and 2 is a single bond, an epoxidized double bond, or a double bond;
the bond between carbon atoms 4 and 5 is a single bond or a double bond;
a is 0, 1, or 2;
R 1 is cyano, heteroaryl (c≤8), substituted heteroaryl (c≤8), —CF 3 , or —C(O)R a ; wherein:
R a is hydroxy, amino, or alkoxy (C≤8), alkylamino (c≤8), dialkylamino (c≤8), alkylsulfonylamino (c≤8), or a substituted version of any of these groups;

R 2 is hydrogen, alkyl (c≤12), cycloalkyl (C≤12), alkenyl (c≤12), alkynyl (c≤12), or a substituted version of the last four groups, or -alkanediyl (c≤8)-cycloalkyl (c≤12) or a substituted version of this group;
R 2 ′ is absent, hydrogen, alkyl (c≤12), cycloalkyl (c≤12), alkenyl (c≤12), alkynyl (c≤12), or a substituted version of the last four groups, provided that when the bond between carbon atoms 4 and 5 is a double bond then R 2 ′ is absent;
R 3 is alkyl (c≤12), aryl (c≤12), aralkyl (c≤12), or a substituted version of any of these groups;
R 4 is cycloalkyl (c≤18), substituted cycloalkyl (c≤18), heteroaryl (c≤18), substituted heteroaryl (c≤18), heterocycloalkyl (<18), substituted heterocycloalkyl (c≤18), or

wherein:
n is 0, 1, 2, 3, or 4; and
R 4 ″ is —H, —OH, —F, —Cl, —Br, —I, —NH 2 , —NO 2 , —CN, —SH, —S(O) 2 OH, or —S(O) 2 NH 2 , or alkyl (C≤8), cycloalkyl (c≤8), aryl (c≤8), heteroaryl (c≤8), heterocycloalkyl (c≤8), acyl (c≤8), amido (C≤8), alkoxy (C≤8), acyloxy (C≤8), alkylamino (C≤8), dialkylamino (C≤8), —C(O)-alkoxy (c≤8), —C(O)-alkylamino (C≤8), —C(O)-dialkyl-amino (c≤8), alkylsulfonyl (c≤8), arylsulfonyl (c≤8), alkoxysulfonyl (c≤8), or a substituted version of any of these groups; or
— X 2 —( CH 2 ) p —R 4 ″;

wherein:
X 2 is arenediyl (c≤12), substituted arenediyl (c≤12), heterocycloalkanediyl (c≤12), substituted heterocycloalkanediyl (c≤12), heteroarenediyl (C≤12), or substituted heteroarenediyl (C≤12),
p is 0, 1, 2, 3, or 4; and
R 4 ″ is alkyl (c≤8), cycloalkyl (c≤8), aryl (c≤8), heteroaryl (c≤8), heterocycloalkyl (c≤8), acyl (c≤8), alkoxy (C≤8), acyloxy (C≤8), —C(O)-alkoxy (c≤8), —C(O)-alkylamino (C≤8), —C(O)-dialkyl-amino (C≤8), alkylsulfonyl (c≤8), arylsulfonyl (c≤8), alkoxysulfonyl (c≤8), or a substituted version of any of these groups; and

R 5 is cycloalkoxy (C≤12), aryl (c≤12), heteroaryl (c≤12), or a substituted version of any of these groups, or
—OY 1 -A 1 ;

wherein:
Y 1 is alkanediyl (c≤8) or substituted alkanediyl (c≤8); and
A 1 is cycloalkyl (c≤8) or substituted cycloalkyl (c≤8);

provided that when carbon atoms 4 and 5 are joined by a double bond, then R 2 ′ and the hydrogen atom at carbon atom 5 are absent;
or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein the bond between carbon atom 1 and carbon atom 2 is a double bond.

3. The compound of claim 1 , wherein the bond between carbon atom 4 and carbon atom 5 is a single bond.

4. The compound of claim 1 , wherein a is 1.

5. The compound of claim 1 , wherein R 1 is cyano.

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

7. The compound of claim 6 , wherein R 2 is methyl, ethyl, propyl, or 3-hydroxypropyl.

8. The compound of claim 1 , wherein R 2 ′ is hydrogen, alkyl (c≤12), or substituted alkyl (c≤12).

9. The compound of claim 1 , wherein R 3 is alkyl (c≤12) or substituted alkyl (c≤12).

10. The compound of claim 9 , wherein R 3 is methyl.

11. The compound of claim 1 , wherein R 4 is heteroaryl (c≤18) or substituted heteroaryl (c≤18).

12. The compound of claim 11 , wherein R 4 is a heteroaryl (c≤12) or a substituted heteroaryl (c≤12) group wherein at least one of the heteroatoms in the aromatic ring is a nitrogen atom.

13. The compound of claim 11 , wherein R 4 is heteroaryl (c≤18).

14. The compound of claim 13 , wherein R 4 is 3-pyridinyl, 4-pyridinyl, 4-(2-cyclopropyl)-pyridinyl, 5-(2-cyclopropyl)-pyridinyl, 4-(2-morpholino)-pyridinyl, 4-(2-phenyl)-pyridinyl, 3-(5-methyl)-pyridinyl, 3-(6-methyl)-pyridinyl, 4-(2-methyl)-pyridinyl, 4-(3-methyl)-pyridinyl, 3-pyrazolo [1,5-a] pyridinyl, 3-(N-methyl)-pyrrolo [2,3-b] pyridinyl, 5-isoquinolinyl, 2-isoquinolinyl, 1-isoquinolinyl, 4-(3-phenyl)-pyridinyl, 5-(2-phenyl)-pyridinyl, 4-(3,5-dimethyl)-isoxazolyl, 3-(4-methyl)-pyridinyl, 4-(6-methyl)-pyrimidinyl, 6-(4-methyl)-pyrimidinyl, 4-pyridazinyl, 2-quinazolinyl, 4-quinazolinyl, 2-quinolinyl, 3-quinolinyl, 4-quinolinyl, 5-quinolinyl, 6-quinolinyl, 8-quinolinyl, 4-isoquinolinyl, 3-(8-methyl)-quinolinyl, 3-(1-methyl)-quinolinyl, 4-(2-methyl)-quinolinyl, 4-(2-isopropyl)-quinolinyl, 4-(6-methyl)-quinolinyl, 4-(7-methyl)-quinolinyl, 4-(8-methyl)-quinolinyl, 2-(N-methyl)-indolyl, 5-(2,4-dimethyl)-thiazolyl, or 3-(5-methyl)-oxadizolyl.

15. The compound of claim 11 , wherein R 4 is substituted heteroaryl (c≤18).

16. The compound of claim 15 , wherein R 4 is 4-(2-trifluoromethyl)-pyridinyl, 4-(3-fluoro)-pyridinyl, 4-(2-methoxy)-pyridinyl, 4-(2-hydroxymethyl)-pyridinyl, 4-(2-acetylamino)-pyridinyl, 4-(2-fluoromethyl)-pyridinyl, 4-(2-acetamidylethyl)-pyridinyl, 4-(2-fluoromethyl)-quinolinyl, 4-(2-acetoxymethyl)-quinolinyl, 4-(2-formyl)-quinolinyl, 4-(6-fluoro)-quinolinyl, 4-(7-fluoro)-quinolinyl, 4-(8-fluoro)-quinolinyl, 4-(6,8-difluoro)-quinolinyl, 4-(6-fluoro-2-methyl)-quinolinyl, or 4-(8-fluoro-2-methyl)-quinolinyl.

17. The compound of claim 1 , wherein R 4 is —X 2 —(CH 2 ) p —R 4 ″;
wherein:
X 2 is arenediyl (c≤12), substituted arenediyl (c≤12), heterocycloalkanediyl (C≤12), substituted heterocycloalkanediyl (C≤12), heteroarenediyl (c≤12), or substituted heteroarenediyl (C≤12);
p is 0, 1, 2, 3, or 4; and
R 4 ″ is alkyl (c≤8), cycloalkyl (c≤8), aryl (c≤8), heteroaryl (c≤8), heterocycloalkyl (c≤8), acyl (c≤8), alkoxy (C=8), acyloxy (c≤8), —C(O)-alkoxy (c≤8), —C(O)-alkylamino (c≤8), —C(O)-dialkylamino (c≤8), alkylsulfonyl (c≤8), arylsulfonyl (c≤8), alkoxysulfonyl (c≤8), or a substituted version of any of these groups.

18. The compound of claim 17 , wherein X 2 is heteroarenediyl (c≤12) or substituted heteroarenediyl (C≤12).

19. The compound of claim 17 , wherein R 4 ″ is cycloalkyl (c≤8) or substituted cycloalkyl (c≤8).

20. The compound of claim 19 , wherein R 4 ″ is cycloalkyl (c≤8).

21. The compound of claim 20 , wherein R 4 ″ is cyclopropyl.

22. The compound of claim 1 , wherein R 5 is aryl (c≤12) or substituted aryl (c≤12).

23. The compound of claim 22 , wherein R 5 is aryl (c≤12).

24. The compound of claim 23 , wherein R 5 is phenyl, 4-methylphenyl, 3-isopropylphenyl, 4-isopropylphenyl, 1,3-biphenyl, or 1,4-biphenyl.

25. The compound of claim 22 , wherein R 5 is substituted aryl (c≤12), wherein one or more hydrogen atoms has been replaced with one or more fluorine atoms.

26. The compound of claim 22 , wherein R 5 is substituted aryl (c≤12).

27. The compound of claim 26 , wherein R 5 is 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 4-hydroxymethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 4-methoxyphenyl, 4-chlorophenyl, or 3,4-dichlorophenyl.

Assignees

• Reata Pharmaceuticals Inc

Inventors

• Jiang Xin
• Bender Christopher F
• Visnick Melean
• Hotema Martha R
• Sheldon Zachary S
• Lee Chitase
• Caprathe Bradley William
• Bolton Gary
• Kornberg Brian

Classifications

• C07D417/14

  containing three or more hetero rings · CPC title

• C07D413/14

  containing three or more hetero rings · CPC title

• C07D413/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D403/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title