O-linked pyrimidin-4-amine-based compounds, compositions comprising them, and methods of their use to treat cancer

1. A compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein:

L 1 is a bond, —C(O)—, —SO 2 —, or —C(R 4 ) 2—;

L 2 is a bond, —O—, —C(O)—, —SO 2 —, —C(NOH)—, or —C(R 5 ) 2—;

A 2 is optionally substituted cycloalkyl, aryl or heterocycle;

R 1 is hydrogen, halogen, —OH, —NH 2 , —NO 2 , —CN, —C(O)OR 4 , or optionally substituted alkyl;

R 2 is hydrogen, halogen, —OH, —NH 2 , —NO 2 , —CN, —C(O)OR 4 , or optionally substituted alkyl;

each R 3 is independently ═O or optionally substituted lower alkyl;

each R 4 is independently hydrogen or lower alkyl;

each R 5 is independently hydrogen, fluoro, hydroxyl or lower alkyl, provided that when one of R 5 is hydroxyl, the other is neither hydroxyl nor fluoro;

each R 6 is halogen, —OH, —NH 2 , —NO 2 , —CN, or optionally substituted alkyl;

m is 0-4; and

p is 0-2.

2. The compound of claim 1 , which is of the formula:

3. A compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein:

L 1 is a bond, —C(O)—, —SO 2 —, or —C(R 4 ) 2 —;

L 2 is a bond, —O—, —C(O)—, —SO 2 —, —C(NOH)—, or —C(R 5 ) 2 —;

A 2 is optionally substituted cycloalkyl, aryl or heterocycle;

R 1 is hydrogen, halogen, —OH, —NH 2 , —NO 2 , —CN, —C(O)OR 4 , or optionally substituted alkyl;

R 2 is hydrogen, halogen, —OH, —NH 2 , —NO 2 , —CN, —C(O)OR 4 , or optionally substituted alkyl;

each R 3 is independently ═O or optionally substituted lower alkyl;

each R 4 is independently hydrogen or lower alkyl;

each R 5 is independently hydrogen, fluoro, hydroxyl or lower alkyl, provided that when one of R 5 is hydroxyl, the other is neither hydroxyl nor fluoro;

each R 6 is halogen, —OH, —NH 2 , —NO 2 , —CN, or optionally substituted alkyl;

m is 0-4; and

q is 0-4.

4. The compound of claim 1 or 3 , wherein A 2 is optionally substituted phenyl, pyridine, quinoline, thiophene, indole, pyrazole, piperidine, morpholine, or pyrrolidine.

5. The compound of claim 1 or 3 , wherein L 2 is —O—.

6. The compound of claim 1 or 3 , wherein L 2 is —C(O)— or —C(NOH)—.

7. The compound of claim 1 or 3 , wherein L 2 is —C(R 5 ) 2 —.

8. A compound of the formula:

or a pharmaceutically acceptable salt or solvate thereof, wherein:

L 2 is a bond, —O—, —C(O)—, —SO 2 —, —C(NOH)—, or —C(R 5 ) 2 —;

A 1 is optionally substituted cycloalkyl, aryl or heterocycle;

R 1 is hydrogen, halogen, —OH, —NH 2 , —NO 2 , —CN, —C(O)OR 4 , or optionally substituted alkyl;

R 2 is hydrogen, halogen, —OH, —NH 2 , —NO 2 , —CN, —C(O)OR 4 , or optionally substituted alkyl;

each R 3 is independently ═O or optionally substituted lower alkyl;

each R 4 is independently hydrogen or lower alkyl;

each R 5 is independently hydrogen, fluoro, hydroxyl or lower alkyl, provided that when one of R 5 is hydroxyl, the other is neither hydroxyl nor fluoro;

each R 7 is halogen, —OR 8 , —NH 2 , —NO 2 , —C(O)N(R 8 ) 2 , —CN, or optionally substituted alkyl, aryl or heterocycle;

each R 8 is hydrogen or optionally substituted alkyl;

n is 1-3;

m is 0-3 if n is 1, m is 0-4 if n is 2, or m is 0-5 if n is 3; and

r is 0-5.

9. The compound of claim 8 , wherein A 1 is optionally substituted imidazole, pyridine, pyrimidine, purine, triazine, or thiazole.

10. The compound of claim 8 , wherein R 7 is —OR 8 , C(O)N(R 8 ) 2 , or —CN.

11. The compound of claim 8 , wherein R 7 is an optionally substituted non-aromatic heterocycle.

12. The compound of claim 11 , wherein the heterocycle is hexahydropyrimidine, morpholine, piperidine, pyrrolidine, or 1,2,3,4-tetrahydropyrrolo[1,2-a]pyrimidine.

13. The compound of claim 8 , wherein L 2 is —O—.

14. The compound of claim 8 , wherein L 2 is —C(O)— or —C(NOH)—.

15. The compound of claim 8 , wherein L 2 is —C(R 5 ) 2 —.

16. The compound of claim 8 , wherein R 1 is halogen.

17. The compound of claim 8 , wherein R 2 is hydrogen.

18. A composition comprising a compound of claim 1 , 3 , or 8 and a pharmaceutically acceptable excipient or diluent.