Substituted diaminopyrimidyl compounds, compositions thereof, and methods of treatment therewith

Patent metadata

Field	Value
Publication number	US-9556126-B2
Application number	US-201414576197-A
Country	US
Kind code	B2
Filing date	Dec 19, 2014
Priority date	Dec 20, 2013
Publication date	Jan 31, 2017
Grant date	Jan 31, 2017

Abstract

Provided herein are diaminopyrimidyl Compounds having the following structures:

wherein X, L, R 1 , and R 2 are as defined herein, compositions comprising an effective amount of a Diaminopyrimidyl Compound, and methods for treating or preventing PKC-theta-mediated disorders, or a condition treatable or preventable by inhibition of a kinase, for example, PKC-theta.

First claim

What is claimed is:

1. A compound of formula (I):

or a pharmaceutically acceptable salt, tautomer, or stereoisomer thereof,
wherein:
X is CN or CF 3 ;
L is (C 1-4 alkyl);
R 1 is substituted or unsubstituted heteroaryl; and
R 2 is substituted or unsubstituted cycloalkyl.

2. The compound of claim 1 , wherein X is CN.

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

4. The compound of claim 1 , wherein L is CH 2 , CH 2 CH 2 or CH 2 CH 2 CH 2 .

5. The compound of claim 1 , wherein R 1 is a substituted or unsubstituted pyridyl, pyridyl-1-oxide, or pyrimidyl.

6. The compound of claim 5 , wherein R 1 is substituted with one or more halogen, —OR 3 , substituted or unsubstituted C 1-4 alkyl, or substituted or unsubstituted aryl, wherein each R 3 is independently H, substituted or unsubstituted C 1-6 alkyl, or substituted or unsubstituted aryl.

7. The compound of claim 5 , wherein R 1 is substituted with one or more F, Cl, Br, I, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, phenyl, naphthyl, —CH 2 F, —CHF 2 , —CF 3 , —CHFCH 3 , —CF 2 CH 3 , —C(CH 3 ) 2 F, —OCH 3 , —OCH 2 F, —OCHF 2 , —OCF 3 , —OCH 2 CH 3 , —OCH 2 CH 2 F, —OCH 2 CHF 2 , —OCH 2 CF 3 , —OCH 2 CH(CH 3 )F, —OCH 2 C(CH 3 ) 2 F, —OCH 2 C(CH 3 )F 2 , —OCH 2 CH 2 CF 3 , or —O-phenyl, wherein each phenyl is optionally substituted with halogen or substituted or unsubstituted C 1-4 alkyl.

8. The compound of claim 5 , wherein R 1 is substituted with one or more F, Cl, methyl, ethyl, isopropyl, phenyl, —CF 3 , —CF 2 CH 3 , —C(CH 3 ) 2 F, —OCH 3 , —OCH 2 CH 3 , —OCH 2 CF 3 , —OCH 2 CH 2 F, —OCH 2 CHF 2 , —OCH 2 C(CH 3 )F 2 , —OCH 2 CH 2 CF 3 , or —O-phenyl, wherein each phenyl is optionally substituted with F or methyl.

9. The compound of claim 1 , wherein R 1 is a substituted or unsubstituted indolyl, indolinonyl, benzoxazolyl, pyrrolopyridyl, indazolyl, benzimidazolyl, dihydrobenzimidazolonyl, or quinolyl.

10. The compound of claim 9 , wherein R 1 is substituted with one or more halogen, CN, —OR 3 , substituted or unsubstituted C 1-4 alkyl, or substituted or unsubstituted aryl, wherein each R 3 is independently H, substituted or unsubstituted C 1-6 alkyl, or substituted or unsubstituted aryl.

11. The compound of claim 9 , wherein R 1 is substituted with one or more F, Cl, CN, methyl, ethyl, —CH 2 SO 2 NHCH 3 , —OH, —OCH 3 , or OCF 3 .

12. The compound of claim 1 , wherein R 1 is a substituted or unsubstituted furanyl, pyrrolyl, thiophenyl, oxazolyl, pyrazolyl, imidazolyl, oxadiazolyl, or triazolyl.

13. The compound of claim 12 , wherein R 1 is substituted with one or more halogen, CN, —OR 3 , substituted or unsubstituted C 1-4 alkyl, or substituted or unsubstituted aryl, wherein each R 3 is independently H, substituted or unsubstituted C 1-6 alkyl, or substituted or unsubstituted aryl.

14. The compound of claim 12 , wherein R 1 is substituted with one or more CN, methyl, ethyl, —CF 3 , or —CH 2 OCH 3 .

15. The compound of claim 1 , wherein R 2 is substituted or unsubstituted C 3-12 cycloalkyl.

16. The compound of claim 15 , wherein R 2 is substituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or adamantyl.

17. The compound of claim 15 , wherein R 2 is substituted with one or more C 1-4 alkyl, —OR 4 , or —C(═O)NR 2 , wherein each R 4 is independently H or C 1-6 alkyl, and each R is independently H or C 1-4 alkyl.

18. The compound of claim 15 , wherein R 2 is substituted with one or more methyl, ethyl, propyl, isopropyl, —CH 2 OH, —CH(CH 3 )OH, —C(CH 3 ) 2 OH, —OH, —OCH 3 , —OCH 2 CH 3 , —C(═O)NH 2 , —C(═O)NHCH 3 , or —C(═O)N(CH 3 ) 2 .

19. The compound of claim 15 , wherein R 2 is substituted with one or more methyl, —CH 2 OH, —C(CH 3 ) 2 OH, —OH, —OCH 3 , or —C(═O)NHCH 3 .

20. The compound of claim 15 , wherein R 2 is substituted or unsubstituted spiro[3.3]heptyl, or bicyclooctyl.

21. The compound of claim 15 , wherein R 2 is substituted with one or more C 1-4 alkyl, —OR 4 , —C(═O)NR 2 , or triazolyl, wherein each R 4 is independently H or C 1-6 alkyl, and each R is independently H or C 1-4 alkyl.

22. The compound of claim 15 , wherein R 2 is substituted with one or more methyl, triazolyl, —CH 2 OH, —C(CH 3 ) 2 OH, —OH, —OCH 3 , —C(═O)NH 2 , —C(═O)NHCH 3 , or —C(═O)N(CH 3 ) 2 .

23. The compound of claim 1 , wherein the compound at a concentration of 10 μM inhibits PKC-theta by at least about 50%.

24. The compound of claim 1 , wherein the compound is

Assignees

• Signal Pharm Llc

Inventors

• Papa Patrick
• Cathers Brian Edwin
• Calabrese Andrew Antony
• Whitefield Brandon Wade
• Bennett Brydon
• Cashion Daniel
• Mortensen Deborah
• Huang Dehua
• Torres Eduardo
• Parnes Jason
• Sapienza John
• Hansen Joshua
• Leftheris Katerina
• Correa Matthew
• Delgado Maria Mercedes
• Raheja Raj K
• Bahmanyar Sogole
• Hegde Sayee
• Norris Stephen
• Plantevin-Krenitsky Veronique

Classifications

• A61P5/50

  for increasing or potentiating the activity of insulin · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title