1. A compound of the formula I
wherein
R1 is selected from alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, and alkynyl of 2-8 carbon atoms, or
R1 is aryl of 6-10 carbon atoms, which may be substituted with 1-3 of R10;
R10 is selected from nitro, nitrile, hydroxy, halogen, acyl of 1-6 carbon atoms, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, haloalkoxy of 1-6 carbon atoms, cycloalkoxy of 3-6 carbon atoms, aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(\u2550O)0-2 and O, NR11R2, C(\u2550O)OR11, C(\u2550O)NHR11, NHC(\u2550O)R13, NHS(\u2550O)2R13, S(\u2550O)O2R13, S(\u2550O)2NHR11, cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(\u2550O)0-2 and O, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(\u2550O)0-2 and O, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(\u2550O)0-2 and O, andor wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(\u2550O);
R13 is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, and cycloalkenyl of 4-6 carbon atoms;
R11 and R12 are independently selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, cycloalkyl of 3-6 carbon atoms, and cycloalkenyl of 4-6 carbon atoms;
A is selected from alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, and haloalkyl of 1-8 carbon atoms;
R2 is NR15R16;
R15 is selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, cylcoalkyl of 3-8 carbon atoms, and cycloalkenyl of 4-8 carbon atoms;
R16 is selected from alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, and alkynyl of 2-8 carbon atoms, or
R16 is aryl of 6-10 carbon atoms, which may be substituted with 1-3 of R10;
R3 is selected from aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(\u2550O)0-2 and O, cylcoalkyl of 3-8 carbon atoms, heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(O)0-2, and O, cycloalkenyl of 4-8 carbon atoms, and heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(O)0-2 and O, all of which may be substituted with 1-3 of R10, or
R3 is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, hydrogen, nitro, halogen, NR19R20, A\u2014OR19, A\u2014NR19R20, and A\u2014R20;
R19 and R20 are independently selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, and A\u2014R9, or
R19 and R20 are independently selected from aryl of 6-10 carbon atoms, heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(O)0-2 and O, cylcoalkyl of 3-8 carbon atoms, cycloalkenyl of 5-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(O)0-2 and O, 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(O)0-2 and O, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 56 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(\u2550O)0-2 and O, andor wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(\u2550O), all of which may be substituted with 1-3 of R10;
R4 is selected from \u2550OH, \u2550S, and OR21;
R21 is hydrogen, or
R21 is selected from alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, cycloalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(\u2550O)0-2 and O, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(\u2550O)0-2 and O, all of which may be substituted with 1-3 of R10;
R5 and R6 are independently selected from cycloalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, aryl of 6-10 carbon atoms, which may be substituted with 1-3 of R10, or
R5 and R6 are independently selected from hydrogen, halogen, nitrile, nitro, hydroxy, alkyl of 1-8 carbon atoms, alkenyl of 2-8 carbon atoms, alkynyl of 2-8 carbon atoms, haloalkyl of 1-8 carbon atoms, alkoxy of 1-8 carbon atoms, haloalkoxy of 1-8 carbon atoms;
R22 is selected from hydrogen, alkyl of 1-8 carbon atoms, haloalkyl of 1-8 carbon atoms, and cycloalkyl of 3-8 carbon atoms;
R23 is selected from hydroxy, alkoxy of 1-8 carbon atoms, haloalkoxy of 1-8 carbon atoms, and cycloalkoxy of 3-8 carbon atoms, or
R23 is selected from cycloalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, aryl of 6-10 carbon atoms, and heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(\u2550O)0-2, and O, all of which may be substituted with 1-3 of R10, or
R23 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(\u2550O)0-2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(\u2550O)0-2, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(\u2550O)0-2 and O, andor wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(\u2550O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10;
with the proviso for A(OR22)\u2014R23 that when R23 is selected from hydroxy, alkoxy of 1-8 carbon atoms, haloalkoxy of 1-8 carbon atoms, and cycloalkoxy of 3-8 carbon atoms, A is not CH;
R24 and R25 are independently selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, and A\u2014R23, or
R24 and R25 are independently selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, aryl of 6-10 carbon atoms, and heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(\u2550O)0-2, and O, all of which may be substituted with 1-3 of R10, or
R24 and R25 are independently selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(\u2550O)0-2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(\u2550O)0-2, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(\u2550O)0-2 and O, andor wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(\u2550O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10, or
R24 and R25 combine, together with the nitrogen atom to which they are attached, to form a 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(\u2550O)0-2, and O, a 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(\u2550O),2, and O, or a heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(\u2550O)0-2 and O, andor wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(\u2550O), all of which may be substituted with 1-3 of R10;
R26 is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, A(OR22)-R23, and A\u2014R23, or
R26 is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, aryl of 6-10 carbon atoms, and heteroaryl of 2-9 carbon atoms and 1-4 heteroatoms selected from N, S(\u2550O)0-2, and O, all of which may be substituted with 1-3 of R10, or
R is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(\u2550O)0-2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(\u2550O)0-2, wherein said heterocycloalkyl and said heterocycloakenyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(\u2550O)0-2 and O, andor wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(\u2550O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10;
R7 is selected from cycloalkyl of 3-8 carbon atoms, cycloalkenyl of 4-8 carbon atoms, aryl of 6-10 carbon atoms, all of which may be substituted with 1-3 of R10, or
R7 is a 6 membered heterocycloalkyl of 4-5 carbon atoms and 1-2 heteroatoms selected from N and O wherein said heterocycloalkyl may further be fused with phenyl or a 5-6 membered heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(\u2550O)0-2 and O, andor wherein one or more of the carbon atoms in said heterocycloalkyl may be oxidized to C(\u2550O), wherein said heterocycloalkyl may be substituted with 1-3 of R10, A(OR22)\u2014R23, A\u2014R23, A\u2014NR24R25, C(\u2550O)R24, C(\u2550O)OR24, C(\u2550O)NR24R25, S(\u2550O)2R26, A\u2014C(\u2550O)R24, A\u2014C(\u2550)OR24, or A\u2014C(\u2550O)NR24R25,
and pharmaceutically acceptable salts thereof.
2. The compound of claim 1, wherein R4 is \u2550O.
3. The compound of claim 1, wherein R3 is selected from cycloalkyl of 3-6 carbon atoms, heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(O)0-2 and O, both of which may be substituted with 1-3 of R10, or
R3 is selected from alkyl of 1-6 carbon atoms, haloalkyl of 1-6 carbon atoms, hydrogen, nitro, halogen, NR19R20, A\u2014OR19, A\u2014NR19R20 and A\u2014R20.
4. The compound of claim 3, wherein R19 and R20 are independently selected from hydrogen, alkyl of 1-6 carbon atoms, haloalkyl of 1-6 carbon atoms and A\u2014R9, or wherein R19 and R20 are independently selected from phenyl, monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(O)0-2 and O, cycloalkyl of 3-6 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(O)0-2 and O, wherein one or more of the carbon atoms in said heterocycloalkyl may be oxidized to C(\u2550O), all of which may be substituted with 1-3 of R10.
5. The compound of claim 1, wherein R3 is selected from cycloalkyl of 3-6 carbon atoms, heterocycloalkyl of 3-6 carbon atoms and 1-2 hetcroatoms selected from N, S(O)0-2 and O, both of which may be substituted with 1-3 of R10, or
R3 is selected from alkyl of 1-6 carbon atoms, haloalkyl of 1-6 carbon atoms, hydrogen, nitro, halogen, NR19R20, A\u2014OR19, A\u2014NR19R20 and A\u2014R20; and
R4 is \u2550O.
6. The compound of claim 5, wherein R19 and R20 are independently selected from hydrogen, alkyl of 1-6 carbon atoms, haloalkyl of 1-6 carbon atoms and A\u2014R9, or wherein R19 and R20 are independently selected from phenyl, monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(O)0-2 and O, cycloalkyl of 3-6 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(O)0-2 and O, wherein one or more of the carbon atoms in said heterocycloalkyl may be oxidized to C(\u2550O), all of which may be substituted with 1-3 of R10.
7. The compound of claim 1, wherein R2 is NR15R16.
8. The compound of claim 7, wherein
R15 is selected from hydrogen, alkyl of 1-6 carbon atoms, cylcoalkyl of 3-8 carbon atoms; and
R16 is alkyl of 1-6 carbon atoms, or
R16 is phenyl, which may be substituted with 1-3 of R10.
9. The compound of claim 1, wherein R2 is NR15R16;
R3 is selected from cycloalkyl of 3-6 carbon atoms, heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(O)0-2 and O, both of which may be substituted with 1-3 of R10, or
R3 is selected from alkyl of 1-6 carbon atoms, haloalkyl of 1-6 carbon atoms, hydrogen, nitro, halogen, NR19R20, A\u2014OR19, A\u2014NR19R20 and A\u2014R20; and
R4 is \u2550O.
10. The compound of claim 9, wherein
R15 is selected from hydrogen, alkyl of 1-6 carbon atoms, cylcoalkyl of 3-8 carbon atoms;
R16 is alkyl of 1-6 carbon atoms, or
R16 is phenyl, which may be substituted with 1-3 of R10.
11. The compound of claim 10, selected from the group consisting of:
12. The compound of claim 9, wherein R19 and R20 are independently selected from hydrogen, alkyl of 1-6 carbon atoms, haloalkyl of 1-6 carbon atoms and A\u2014R9, or wherein R19 and R20 are independently selected from phenyl, monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(O)0-2 and O, cycloalkyl of 3-6 carbon atoms, 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(O)0-2 and O, wherein one or more of the carbon atoms in said heterocycloalkyl may be oxidized to C(\u2550O), all of which may be substituted with 1-3 of R10.
13. The compound of claim 1 or 9, wherein R5 is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 4-6 carbon atoms, phenyl, all of which may be substituted with 1-3 of R10, or
R5 is selected from hydrogen, halogen, nitrile, nitro, hydroxy, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, haloalkoxy of 1-6 carbon atoms.
14. The compound of claim 13, wherein R5 is selected from cycloalkyl of 3-6 carbon atoms, and phenyl, all of which may be substituted with 1-3 of R10, or
R5 is selected from hydrogen, halogen, nitrile, nitro, hydroxy, alkyl of 1-6 carbon atoms, haloalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, haloalkoxy of 1-6 carbon atoms.
15. The compound of claim 14 selected from the group consisting of:
16. The compound of claim 1 or 9, wherein R6 is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 4-6 carbon atoms, and phenyl, all of which may be substituted with 1-3 of R10, or
R6 is selected from hydrogen, halogen, nitrile, nitro, hydroxy, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, haloalkoxy of 1-6 carbon atoms.
17. The compound of claim 16, wherein R6 is selected from cycloalkyl of 3-6 carbon atoms, all of which maybe substituted with 1-3 of R10, or
R6 is selected from hydrogen, halogen, nitrile, nitro, hydroxy, alkyl of 1-4 carbon atoms, haloalkyl of 1-6 carbon atoms.
18. The compound of claim 17 selected from the group consisting of:
19. The compound of claim 1 or 9, wherein R7 is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 4-6 carbon atoms, phenyl, all of which may be substituted with 1-3 of R10, or
R7 is selected from 6 membered heterocycloalkyl of 4-5 carbon atoms and 1-2 heteroatoms selected from N, and O, andor wherein one or more of the carbon atoms in said heterocycloalkyl may be oxidized to C(\u2550O), wherein said heterocycloalkyl may be substituted with 1-3 of R10, A\u2014R23, A\u2014NR24R25, C(\u2550O)R24, C(\u2550O)OR24, C(\u2550O)NR24R25, S(\u2550O)2R26, A\u2014C(\u2550O)R24, A\u2014C(\u2550O)OR24, or A\u2014C(\u2550O)NR24R25, or
R22 is selected from hydrogen, alkyl of 1-6 carbon atoms, haloalkyl of 1-6 carbon atoms, and cycloalkyl of 3-6 carbon atoms;
R23 is selected from hydroxy, alkoxy of 1-6 carbon atoms, haloalkoxy of 1-6 carbon atoms, and cycloalkoxy of 3-6 carbon atoms, or
R23 is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 4-6 carbon atoms, phenyl, and monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(\u2550O)2, and O, all of which may be substituted with 1-3 of R10, or
R23 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(\u2550O)s2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(\u2550O)0-2, andor wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(\u2550O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10;
with the proviso for A(OR22)\u2014R23 that when R23 is selected from hydroxy, alkoxy of 1-6 carbon atoms, haloalkoxy of 1-6 carbon atoms, and cycloalkoxy of 3-6 carbon atoms, A is not CH;
R24 and R25 are independently selected from hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, and A\u2014R23, or
R24 and R25 are independently selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, phenyl, and monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(\u2550O)0-2, and O, all of which may be substituted with 1-3 of R10, or
R24 and R25 are independently selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(\u2550O)2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(\u2550O)0-2, andor wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(\u2550O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10, or
R24 and R25 combine, together with the nitrogen atom to which they are attached, to form a 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(\u2550O)0-2, and O, a 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(\u2550O)0-2, and O, or a monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms, andor wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(\u2550O), all of which may be substituted with 1-3 of R10;
R26 is selected from alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, haloalkyl of 1-6 carbon atoms, A(OR22)\u2014R23, and A\u2014R23, or
R26 is selected from cycloalkyl of 3-6 carbon atoms, cycloalkenyl of 3-6 carbon atoms, phenyl, and monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(\u2550O)0-2, and O, all of which may be substituted with 1-3 of R10, or
R26 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(\u2550O)0-2, and 5-7 membered heterocycloalkenyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(\u2550O)0-2, andor wherein one or more of the carbon atoms in said heterocycloalkyl or heterocycloalkenyl may be oxidized to C(\u2550O), wherein said heterocycloalkyl or said heterocycloalkenyl may be substituted with 1-3 of R10.
20. The compound of claim 19, wherein R7 is selected from cycloalkyl of 3-6 carbon atoms and phenyl, all of which may be substituted with 1-3 of R10, or
R7 is selected from 6 membered heterocycloalkyl of 4-5 carbon atoms and 1-2 heteroatoms selected from N, andor wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C(\u2550O), wherein said heterocycloalkyl may be substituted with 1-3 of R10, A\u2014R23, A\u2014NR24R25, C(\u2550O)R24, C(\u2550O)OR24, C(O)NR24R25, S(\u2550O)2R26, A\u2014C(\u2550O)R24, A\u2014C(\u2550O)OR24, or A\u2014C(\u2550O)NR24R25, or
R22 is selected from hydrogen, alkyl of 1-6 carbon atoms, haloalkyl of 1-6 carbon atoms, and cycloalkyl of 3-6 carbon atoms;
R23 is selected from hydroxy, alkoxy of 1-6 carbon atoms, haloalkoxy of 1-6 carbon atoms, and cycloalkoxy of 3-6 carbon atoms, or
R23 is selected from cycloalkyl of 3-6 carbon atoms, phenyl, and monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(\u2550O)0-2, and O, all of which may be substituted with 1-3 of R10, or
R23 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(\u2550O)0-2, andor wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C(\u2550O), wherein said heterocycloalkyl may be substituted with 1-3 of R10;
with the proviso for A(OR22)\u2014R23 that when R23 is selected from hydroxy, alkoxy of 1-6 carbon atoms, haloalkoxy of 1-6 carbon atoms, and cycloalkoxy of 3-6 carbon atoms, A is not CH;
R24 and R25 are independently selected from hydrogen, alkyl of 1-6 carbon atoms, haloalkyl of 1-6 carbon atoms, and A\u2014R23, or
R24 and R25 are independently selected from cycloalkyl of 3-6 carbon atoms, phenyl, and monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(\u2550O)0-2, and O, all of which may be substituted with 1-3 of R10, or
R24 and R25 are independently selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(\u2550O)0-2, andor wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C(\u2550O), wherein said heterocycloalkyl may be substituted with 1-3 of R10, or
R24 and R25 combine, together with the nitrogen atom to which they are attached, to form a 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, S(\u2550O)0-2, or a monocyclic heteroaryl of 2-S carbon atoms and 1-3 heteroatoms, andor wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C(\u2550O), all of which may be substituted with 1-3 of R10;
R26 is selected from alkyl of 1-6 carbon atoms, haloalkyl of 1-6 carbon atoms, A(OR22)\u2014R23, and A\u2014R23, or
R26 is selected from cycloalkyl of 3-6 carbon atoms, phenyl, and monocyclic heteroaryl of 2-5 carbon atoms and 1-3 heteroatoms selected from N, S(\u2550O)0-2, and O, all of which may be substituted with 1-3 of R10, or
R26 is selected from 5-7 membered heterocycloalkyl of 3-6 carbon atoms and 1-2 heteroatoms selected from N, O, S(\u2550O)0-2, andor wherein one of the carbon atoms in said heterocycloalkyl may be oxidized to C(\u2550O), wherein said heterocycloalkyl may be substituted with 1-3 of R10.
21. The compound of claim 20 selected from the group consisting of:
22. A method of treating a disease or condition selected from the group consisting of diabetes (Type 1 or Type 2), maturity-onset diabetes of the young (MODY), latent autoimmune diabetes adult (LADA), impaired glucose tolerance (IGT), impaired fasting glucose (IFG), gestational diabetes, and metabolic syndrome X, comprising administering to a mammal an effective amount of a compound of claim 1.
23. The method of claim 22, wherein said disease or condition is diabetes (Type 1 or Type 2).
24. The method of claim 23, wherein said disease or condition is Type 2 diabetes.
25. The method of claim 22, further comprising administering a PPAR-agonist, an insulin sensitizer, a sulfonylurea, an insulin secretagogue, a hepatic glucose output lowering compound, an \u03b1-glucosidase inhibitor or insulin in combination with said compound of claim 1.
26. The method of claim 25, wherein said PPAR-agonist is selected from rosiglitazone and pioglitazone.
27. The method of claim 25, wherein said sulfonylurea is selected from glibenclamide, glimepiride, chlorpropamide, and glipizide.
28. The method of claim 25, wherein said insulin secretagogue is selected from GLP-1, GIP, PACVPAC receptor agonists, secretin, nateglinide, meglitinide, repaglinide, glibenclamide, glimepiride, chlorpropamide, and glipizide.
29. The method of claim 25, wherein said \u03b1-glucosidase inhibitor is selected from acarbose, miglitol and voglibose.
30. The method of claim 25, wherein said hepatic glucose output lowering compound is metformin.
31. The method of claim 22, further comprising administering an HMG-CoA reductase inhibitor, nicotinic acid, a bile acid sequestrant, a fibric acid derivative, antihypertensive drug, or an anti-obesity drug in combination with said compound of claim 1.
32. The method of claim 31, wherein said anti-obesity drug is selected from a \u03b2-3 agonist, a CB-1 antagonist, and a lipase inhibitor.
33. A method of treating secondary causes of diabetes selected from glucocorticoid excess, growth hormone excess, pheochromocytoma, and drug-induced diabetes, comprising administering to a mammal an effective amount of a compound of claim 1.
34. A method of increasing the sensitivity of pancreatic beta cells to an insulin secretagogue, comprising administering to a mammal an effective amount of a compound of claim 1.
35. The method of claim 34, wherein said insulin secretagogue is selected from GLP-1, GIP, PACVPAC receptor agonists, secretin, nateglinide, meglitinide, repaglinide, glibenclamide, glimepiride, chlorpropamide, and glipizide.
36. A pharmaceutical composition, comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1. A method of coating a substrate to provide a transparent, abrasion-resistant coating, the method comprising the steps of providing a coating composition comprising:
a) the hydrolysis product of an epoxy-functional alkoxy silane,
b) a curing agent for polymerizing epoxy compounds, the curing agent comprising a cationic photoinitiator,
c) an ethylenically unsaturated monomer and photoactivated free-radical initiator therefore, and
d) a viscosity-reducing amount up to 50% by weight, solids basis, of an unhydrolyzed epoxy-functional alkoxy silane,
and applying the composition to the substrate in order to form a transparent, abrasion-resistant coating.
2. The method of claim 1 wherein said ethylenically unsaturated monomer comprises an acrylic monomer.
3. The method of claim 2 wherein said acrylic monomer has an acrylic functionality not greater than two.
4. The method of claim 1 including an essentially non-reactive polyether surfactant in sufficient quantity to improve tintability of a cured coating formed from said composition.
5. The method of claim 4 wherein said polyether surfactant is a siloxane.
6. The method of claim 4 wherein said polyether surfactant is a polyalkaleneoxide siloxane.
7. The method of claim 4 wherein said polyether surfactant is an alkoxy polyethylene oxyalkanol.
8. The method of claim 4 in which the surfactant is at least partially water soluble.
9. The method of claim 4 in which the surfactant is insoluble in water.
10. The method of claim 1 wherein the epoxyfunctional alkoxy silanes of parts a) and d) are independently prepared from the group consisting of glycidoxymethyl-trimethoxysilane, glycidoxymethyltriethoxysilane, glycidoxymethyl-tripropoxysilane, glycidoxymethyl-tributoxysilane, \u03b2-glycidoxyethyltrimethoxysilane, \u03b2-glycidoxyethyltriethoxysilane, \u03b2-glycidoxyethyl-tripropoxysilane, \u03b2-glycidoxyethyl-tributoxysilane, \u03b2-glycidoxyethyltrimethoxysilane, \u03b1-glycidoxyethyl-triethoxysilane, \u03b1-glycidoxyethyl-tripropoxysilane, \u03b1-glycidoxyethyltributoxysilane, \u03b3-glycidoxypropyl-trimethoxysilane, \u03b3-glycidoxypropyl-triethoxysilane, \u03b3-glycidoxypropyl-tripropoxysilane, \u03b3-glycidoxypropyltributoxysilane, \u03b2-glycidoxypropyl-trimethoxysilane, \u03b2-glycidoxypropyl-triethoxysilane, \u03b2-glycidoxypropyl-tripropoxysilane, \u03b2-glycidoxypropyltributoxysilane, \u03b1-glycidoxypropyl-trimethoxysilane, \u03b1-glycidoxypropyl-triethoxysilane, \u03b1-glycidoxypropyl-tripropoxysilane, \u03b1-glycidoxypropyltributoxysilane, \u03b3-glycidoxybutyl-trimethoxysilane, \u03b4-glycidoxybutyl-triethoxysilane, \u03b4-glycidoxybutyl-tripropoxysilane, \u03b4-glycidoxybutyl-tributoxysilane, \u03b4-glycidoxybutyl-trimethoxysilane, \u03b3-glycidoxybutyl-triethoxysilane, \u03b3-glycidoxybutyl-tripropoxysilane, \u03b3-propoxybutyl-tributoxysilane, \u03b4-glycidoxybutyl-trimethoxysilane, \u03b4-glycidoxybutyl-triethoxysilane, \u03b4-glycidoxybutyl-tripropoxysilane, \u03b1-glycidoxybutyl-trimethoxysilane, \u03b1-glycidoxybutyl-triethoxysilane, \u03b1-glycidoxybutyl-tripropoxysilane, \u03b1-glycidoxybutyl-tributoxysilane, (3,4-epoxycyclohexyl)-methyl-trimethoxysilane, (3,4-epoxycyclohexyl)methyl-triethoxysilane, (3,4-epoxycyclohexyl)methyl-tripropoxysilane, (3,4-epoxycyclohexyl)-methyl-tributoxysilane, (3,4-epoxycyclohexyl)ethyl-trimethoxysilane, (3,4-epoxycyclohexyl)ethyl-triethoxysilane, (3,4-epoxycyclohexyl)ethyl-tripropoxysilane, (3,4-epoxycyclohexyl)-ethyl-tributoxysilane, (3,4-epoxycyclohexyl)propyl-trimethoxysilane, (3,4-epoxycyclohexyl)propyl-triethoxysilane, (3,4-epoxycyclohexyl)propyl-tripropoxysilane, (3,4-epoxycyclohexyl)propyl-tributoxysilane, (3,4-epoxycyclohexyl)butyl-trimethoxysilane, (3,4-epoxycyclohexy) butyl-triethoxysilane, (3,4-epoxycyclohexyl)-butyl-tripropoxysilane, and (3,4-epoxycyclohexyl)butyl-tributoxysilane.
11. The method of claim 1 wherein the silane of part a) is added in an amount sufficient to provide a concentration in the composition, based on weight (solids basis), of between about 10% to about 75%, and the silane of part d) is added in an amount sufficient to provide a concentration of not less than about 10%.
12. The method of claim 1 wherein the ethylenically unsaturated monomers comprise acrylic monomers and oligomers having acrylic functionalities of not greater than two.
13. The method of claim 11 wherein the monomers are selected from the group consisting of ethyl acrylate, butyl acrylate, 2-hydroxypropyl acrylate, cyclohexyl acrylate, 2-ethylhexyl acrylate, methyl methacrylate, ethyl methacrylate, neopentylglycol diacrylate, pentaerythritol triacrylate, 1,6-hexanediol diacrylate, trimethylolpropane triacrylate, tetraethylene glycol diacrylate, 1,3-butylene glycol diacrylate, trimethylolpropane trimethacrylate, 1,3-butylene glycol dimethacrylate, ethylene glycol dimethacrylate, pentaerythritol tetraacrylate, tetraethylene glycol dimethacrylate, 1,6-hexanediol dimethacrylate, ethylene glycol diacrylate, diethylene glycol diacrylate, glycerol diacrylate, glycerol triacrylate, 1,3-propanediol diacrylate, 1,3-propanediol dimethacrylate, 1,2,4-butanetriol trimethacrylate, 1,4-cyclohexanediol diacrylate, 1,4-cyclohexanediol dimethacrylate, pentaerythritol diacrylate, and 1,5-pentanediol dimethacrylate.
14. The method of claim 12 wherein the monomers are employed at a weight concentration in the composition from about 10% to about 25%, on a solids basis.
15. The method of claim 1 wherein the cationic photoinitiator is selected from the group consisting of salts of Group Va elements, salts of Group VIa elements, and salts of Group VIa elements.
16. The method according to claim 14 wherein the cationic photoinitiator comprises a diaryl iodonium hexafluoroantimonate.
17. The method according to claim 1 wherein the photoactivated free-radical initiator is selected from the group consisting of haloalkylated aromatic ketones, chloromethylbenzophenones, benzoin ethers, and acetophenone derivatives.
18. The method according to claim 16 wherein the initiator is selected from the group consisting of diethoxyacetophenone, 2-hydroxy-2-methyl-1-phenylpropan-1-one, benzil ketals, \u03b1,\u03b1-dimethoxy-\u03b1-phenyl acetophenone, 2-hydroxy-2-methyl-1-phenylpropane-1-one, ethyl benzoin ether, isopropyl benzoin ether, dimethoxyphenyl acetophenone, diethoxy acetophenone, and benzophenone.
19. The method according to claim 1 wherein the composition is substantially free of volatile solvents.
20. The method according to claim 1 wherein the composition can be cured using ultraviolet radiation.
21. The method of claim 1 wherein the epoxyfunctional alkoxy silanes of parts a) and d) are independently prepared from the group consisting of glycidoxymethyl-trimethoxysilane, glycidoxymethyltriethoxysilane, glycidoxymethyl-tripropoxysilane, glycidoxymethyl-tributoxysilane, \u03b2-glycidoxyethyltrimethoxysilane, \u03b2-glycidoxyethyltriethoxysilane, \u03b2-glycidoxyethyl-tripropoxysilane, \u03b2-glycidoxyethyl-tributoxysilane, \u03b2-glycidoxyethyltrimethoxysilane, \u03b1-glycidoxyethyl-triethoxysilane, \u03b1-glycidoxyethyl-tripropoxysilane, \u03b1-glycidoxyethyltributoxysilane, \u03b3-glycidoxypropyl-trimethoxysilane, \u03b3-glycidoxypropyl-triethoxysilane, \u03b3-glycidoxypropyl-tripropoxysilane, \u03b3-glycidoxypropyltributoxysilane, \u03b2-glycidoxypropyl-trimethoxysilane, \u03b2-glycidoxypropyl-triethoxysilane, \u03b2-glycidoxypropyl-tripropoxysilane, \u03b2-glycidoxypropyltributoxysilane, \u03b1-glycidoxypropyl-trimethoxysilane, \u03b1-glycidoxypropyl-triethoxysilane, \u03b1-glycidoxypropyl-tripropoxysilane, \u03b1-glycidoxypropyltributoxysilane, \u03b3-glycidoxybutyl-trimethoxysilane, \u03b4-glycidoxybutyl-triethoxysilane, \u03b4-glycidoxybutyl-tripropoxysilane, \u03b4-glycidoxybutyl-tributoxysilane, \u03b4-glycidoxybutyl-trimethoxysilane, \u03b3-glycidoxybutyl-triethoxysilane, \u03b3-glycidoxybutyl-tripropoxysilane, \u03b3-propoxybutyl-tributoxysilane, \u03b4-glycidoxybutyl-trimethoxysilane, \u03b4-glycidoxybutyl-triethoxysilane, \u03b4-glycidoxybutyl-tripropoxysilane, \u03b1-glycidoxybutyl-trimethoxysilane, \u03b1-glycidoxybutyl-triethoxysilane, \u03b1-glycidoxybutyl-tripropoxysilane, \u03b1-glycidoxybutyl-tributoxysilane, (3,4-epoxycyclohexyl)-methyl-trimethoxysilane, (3,4-epoxycyclohexyl)methyl-triethoxysilane, (3,4-epoxycyclohexyl)methyl-tripropoxysilane, (3,4-epoxycyclohexyl)-methyl-tributoxysilane, (3,4-epoxycyclohexyl)ethyl-trimethoxysilane, (3,4-epoxycyclohexyl)ethyl-triethoxysilane, (3,4-epoxycyclohexyl)ethyl-tripropoxysilane, (3,4-epoxycyclohexyl)-ethyl-tributoxysilane, (3,4-epoxycyclohexyl)propyl-trimethoxysilane, (3,4-epoxycyclohexyl)propyl-triethoxysilane, (3,4-epoxycyclohexyl)propyl-tripropoxysilane, (3,4-epoxycyclohexyl)propyl-tributoxysilane, (3,4-epoxycyclohexyl)butyl-trimethoxysilane, (3,4-epoxycyclohexy) butyl-triethoxysilane, (3,4-epoxycyclohexyl)-butyl-tripropoxysilane, and (3,4-epoxycyclohexyl)butyl-tributoxysilane,
and wherein the ethylenically unsaturated monomers are selected from the group consisting of ethyl acrylate, butyl acrylate, 2-hydroxypropyl acrylate, cyclohexyl acrylate, 2-ethylhexyl acrylate, methyl methacrylate, ethyl methacrylate, neopentylglycol diacrylate, pentaerythritol triacrylate, 1,6-hexanediol diacrylate, trimethylolpropane triacrylate, tetraethylene glycol diacrylate, 1,3-butylene glycol diacrylate, trimethylolpropane trimethacrylate, 1,3-butylene glycol dimethacrylate, ethylene glycol dimethacrylate, pentaerythritol tetraacrylate, tetraethylene glycol dimethacrylate, 1,6-hexanediol dimethacrylate, ethylene glycol diacrylate, diethylene glycol diacrylate, glycerol diacrylate, glycerol triacrylate, 1,3-propanediol diacrylate, 1,3-propanediol dimethacrylate, 1,2,4-butanetriol trimethacrylate, 1,4-cyclohexanediol diacrylate, 1,4-cyclohexanediol dimethacrylate, pentaerythritol diacrylate, and 1,5-pentanediol dimethacrylate,
and wherein the cationic photoinitiator is selected from the group consisting of salts of Group Va elements, salts of Group VIa elements, and salts of Group VIIa elements,
and wherein the photoactivated free-radical initiator is selected from the group consisting of diethoxyacetophenone, 2-hydroxy-2-methyl-1-phenylpropan-1-one, benzil ketals, \u03b1,\u03b1-dimethoxy-\u03b1-phenyl acetophenone, 2-hydroxy-2-methyl-1-phenylpropane-1-one, ethyl benzoin ether, isopropyl benzoin ether, dimethoxyphenyl acetophenone, diethoxy acetophenone, and benzophenone,
and wherein the composition is substantially free of volatile solvents and can be cured using ultraviolet radiation.
22. The method according to claim 1 wherein the substrate comprises an eyeglass lens.
23. The method according to claim 22 wherein the lens is prepared from a material selected from polycarbonate or poly (methylmethacrylate).
24. The method according to claim 10 wherein the substrate comprises an eyeglass lens.
25. The method according to claim 24 wherein the lens is prepared from a material selected from polycarbonate or poly (methylmethacrylate).
26. The method according to claim 21 wherein the substrate comprises an eyeglass lens.
27. A coated substrate according to claim 26 wherein the lens is prepared from a material selected from polycarbonate or poly (methylmethacrylate).
28. A method according to claim 1 wherein parts a) and d) are separately prepared and blended to form the composition, and the substrate comprises an eyeglass lens prepared from a material selected from polycarbonate or poly (methylmethacrylate).
29. A method according to claim 28 wherein the composition is photocured.