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

Patent metadata

Field	Value
Publication number	US-9783505-B2
Application number	US-201615241232-A
Country	US
Kind code	B2
Filing date	Aug 19, 2016
Priority date	Dec 20, 2013
Publication date	Oct 10, 2017
Grant date	Oct 10, 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 method for the treatment of a PKC-theta mediated disorder comprising administering to a subject having a PKC-theta mediated disorder an effective amount of 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,
wherein the PKC-theta mediated disorder is graft-versus-host disease, organ transplant rejection, psoriasis, Duchenne muscular dystrophy, rheumatoid arthritis, insulin resistance, myasthenia gravis, multiple sclerosis, colitis, psoriatic arthritis, ankylosing spondylitis, atopic dermatitis, Sjogren syndrome, asthma, or lupus.

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

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

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

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

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

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

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

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

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

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

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

24. The method 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

• A61P37/08

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

• A61P43/00

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

• A61P37/06

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

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title