Toll like receptor modulator compounds
This application relates generally to toll like receptor modulator compounds and pharmaceutical compositions which, among other things, modulate toll-like receptors (e.g. TLR8), and methods of making and using them.
1. A compound of Formula I
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is —H, C 1-4 alkyl, or C 1-4 haloalkyl;
R 2 is C 1-6 alkyl or C 1-6 haloalkyl;
Q is CR 4 ;
R 3 and R 4 are taken together to form 5 to 6 membered heterocyclyl having 1 to 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein:
the 5 to 6 membered heterocyclyl is optionally substituted with 1 to 3 R 7 ;
R 7 is halogen, —OH, C 1-4 alkyl, C 1-4 alkoxy, or —C(O)R 8 ;
each R 8 is independently C 1-4 alkyl optionally substituted with —CN or —NH 2 ; C 1-4 haloalkyl;
C 5-6 cycloalkyl; 5 to 6 membered heterocyclyl having 1 to 3 heteroatoms selected from oxygen, nitrogen, and sulfur optionally substituted with 1 to 3 R Z ; or 5 to 10 membered heteroaryl having 1 to 3 heteroatoms selected from oxygen, nitrogen, and sulfur optionally substituted with 1 to 3 R Z ; and
each R Z is independently —NH 2 , C 1-4 alkyl, halogen, —CN, —OC 1-4 alkyl, C 1-4 haloalkyl, or —C(O)NH 2 .
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is —H or C 1-4 alkyl.
3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is methyl.
4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is C 3-6 alkyl.
5. The compound of claim 1 , wherein R 3 and R 4 are taken together to form tetrahydropyridinyl optionally substituted with —C(O)R 8 wherein R 8 is C 1-4 alkyl optionally substituted with —CN or —NH 2 ; C 1-3 haloalkyl; tetrahydropyranyl; thienyl optionally substituted with 1 to 3 C 1-3 alkyl; thiazolyl; imidazolyl optionally substituted with 1 to 3 C 1-2 alkyl;
oxazolyl; isoxazolyl optionally substituted with 1 to 3 C 1-2 alkyl; thiadiazolyl; pyrazinyl; or
quinolinyl.
6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
R 1 is —H or C 1-4 alkyl;
R 2 is C 3-6 alkyl; and
R 3 and R 4 are taken together to form 5 to 6 membered heterocyclyl having 1 to 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein:
the 5 to 6 membered heterocyclyl is optionally substituted with 1 to 3—C(O)C 1-4 alkyl.
7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Formula I is represented by Formula II
8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Formula I is represented by Formula III
9. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 are taken together to form tetrahydropyridinyl optionally substituted with 1 to 3 C(O)C 1-2 alkyl.
10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 are taken together to form:
11. The compound of claim 1 , selected from
or a pharmaceutically acceptable salt thereof.
12. A pharmaceutical composition comprises a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
13. The pharmaceutical composition of claim 12 , further comprising one or more additional therapeutic agents.
14. A kit comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof.