Pyrrolopyrimidines and related analogs as HSP90-inhibitors
The present invention provides compounds represented by Formula I. R 0 is selected from hydrogen, halogen, lower alkyl, —SR 8 , —OR 8 , —CN, and —NHR 8 , R 1 is halogen, or lower alkyl; R 2 is —NHR 8 ; R 3 is selected from the group consisting of hydrogen, halogen, —SR 8 , —OR 8 , —CN, —C(O)R 9 , —C(O)OH, —NO 2 , —NR 8 R 10 , lower alkyl, lower alkenyl, lower alkynyl, lower perhaloalkyl, aryl, heteroaryl, alicyclic and heterocyclic, all optionally substituted, and R 5 is aryl, heteroaryl, alicyclic, or heterocyclic:
1. A compound represented by Formula I, or a polymorph, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof:
wherein:
R 0 is selected from hydrogen, halogen, lower alkyl, —SR 8 , —OR 8 , —CN, and —NHR 8 ,
R 1 is halogen, or lower alkyl;
R 2 is —NHR 8 ;
R 3 is selected from the group consisting of hydrogen, halogen, —SR 8 , —OR 8 , —CN, —C(O)R 9 , —C(O)OH, —NO 2 , —NR 8 R 10 , lower alkyl, lower alkenyl, lower alkynyl, lower perhaloalkyl, aryl, heteroaryl, alicyclic and heterocyclic, all optionally substituted, wherein:
the aryl, heteroaryl, alicyclic and heterocyclic groups are optionally mono-, bi- or tri-cyclic,
R 8 and R 10 taken together with the N to which they are attached optionally form a ring of 3–7 ring atoms and 1–3 of the ring atoms are heteroatoms selected from the group of O, S and N, and
the optional substituents on R 3 are selected from the group consisting of halogen, lower alkyl, lower alkenyl, lower alkynyl, —SR 8 , —OR 8 , —CN, —C(O)OH, —C(O)R 9 , —NO 2 , —NR 8 R 10 , lower aryl, heteroaryl, alicyclic, lower heterocyclic, arylalkyl, heteroarylalkyl, amino, alkylamino, dialkylamino, oxo, perhaloalkyl, perhaloalkoxy, perhaloacyl, guanidinyl, pyridinyl, thiophenyl, furanyl, indolyl, and indazolyl, wherein R 8 and R 10 taken together with the N to which they are attached optionally form a ring of 3–7 ring atoms and 1–3 of the ring atoms are heteroatoms selected from the group of O, S and N;
When R 0 or R 3 is —OH or —SH, the compound may exist as the corresponding (thio)keto tautomer or a mixture of keto-enol tautomers;
R 4 is —CHR 12 —, —C(O)—, —C(S)—, —S(O)— or —SO 2 —;
R 5 is aryl, heteroaryl, alicyclic, or heterocyclic, wherein
the aryl group is substituted with 3 to 5 substituents,
the heteroaryl group is substituted with 2 to 5 substituents,
the alicyclic group is substituted with 3 to 5 substituents,
the heterocyclic group is substituted with 3 to 5 substituents, and
the substituents are selected from the group consisting of halogen, lower alkyl, lower alkenyl, lower alkynyl, —SR 8 , —OR 8 , —CN, —C(O)OH, —C(O)R 9 , —NO 2 , —NR 8 R 10 , lower aryl, heteroaryl, alicyclic, lower heterocyclic, arylalkyl, heteroarylalkyl, amino, alkylamino, dialkylamino, oxo, perhaloalkyl, perhaloalkoxy, perhaloacyl, guanidinyl, pyridinyl, thiophenyl, furanyl, indolyl, and indazolyl, wherein R 8 and R 10 taken together with the N to which they are attached optionally form a ring of 3–7 ring atoms and 1–3 of the ring atoms are heteroatoms selected from the group of O, S and N;
R 8 is hydrogen, lower alkyl, lower alkenyl, or lower alkynyl, lower aryl, lower heteroaryl, or —C(O)R 9 ;
R 9 is H, lower alkyl, lower alkenyl, lower alkynyl, lower aryl, lower heteroaryl, —NR 10 R 10 , or —OR 11 , wherein R 10 and R 10 taken together with the N to which they are attached optionally form a ring of 3–7 ring atoms and 1–3 of the ring atoms are heteroatoms selected from the group of O, S and N;
R 10 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl or lower heteroaryl;
R 11 is lower alkyl, lower alkenyl, or lower alkynyl, lower heteroaryl or lower aryl; and
R 12 is hydrogen or lower alkyl.
2. The compound of claim 1 , or a polymorph, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, wherein each of said aryl, heteroaryl, alicyclic or heterocyclic group is monocyclic or bicyclic.
3. The compound of claim 1 or a polymorph, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, wherein:
R 0 is hydrogen, halogen, —SH, —OH, or —CN;
R 1 is halogen; and
R 2 is —NHR 8 , where R 8 is hydrogen or —C(O)R 9 .
4. The compound of claim 1 , or a polymorph, ester, tautomer, enantiomer pharmaceutically acceptable salt or prodrug thereof, wherein:
R 1 is chloro or bromo,
R 2 is —NHR 8 , where R 8 is hydrogen or —C(O)R 9 ; and
R 3 is hydrogen, halogen, —OR 8 , —SR 8 , —NR 8 R 10 , lower alkyl, lower alkenyl, or lower alkynyl, lower perhaloalkyl, lower aryl, or lower heteroaryl.
5. The compound of claim 1 , or a polymorph, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, wherein:
R 0 is hydrogen, halogen or —CN;
R 2 is —NHR 8 , where R 8 is hydrogen or —C(O)R 9 ; and
R 4 is —CH 2 —.
6. The compound of claim 1 , or a polymorph, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, wherein:
R 0 is hydrogen, halogen, —SH, —OH or —CN;
R 1 is halogen;
R 2 is —NH 2 ;
R 3 is hydrogen, halogen, —OR 8 , —SR 8 , —NR 8 R 10 , lower alkyl, lower alkenyl, lower alkynyl, lower perhaloalkyl, lower aryl, or lower heteroaryl, wherein R 8 is hydrogen, lower alkyl, lower aryl, or —C(O)R 9 ;
R 4 is —CH 2 —; and
R 5 is aryl or heteroaryl, wherein each of said aryl and heteroaryl is monocyclic or bicyclic and is substituted with 3 to 5 substituents.
7. The compound of claim 6 , or a polymorph, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, wherein R 1 is chloro or bromo, R 2 is —NH 2 , and R 5 is a phenyl having at least three substituents.
8. The compound of claim 6 , or a polymorph, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, wherein R 1 is chloro or bromo, R 2 is —NH 2 and R 5 is a pyridyl having at least two substituents.
9. The compound of claim 6 , or a polymorph, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, wherein R 1 is chloro or bromo, R 2 is —NH 2 , and R 5 is 1-oxy-pyridyl (N-oxy-pyridyl) having at least two substituents.
10. The compound of claim 6 , wherein said compound is a member selected from the group below, or a polymorph, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof:
11. The compound of claim 6 , wherein said compound is a member selected from the group below, or a polymorph, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof:
12. The compound of claim 6 , wherein the compound is a member selected from the group of compounds below, or a polymorph, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof:
13. The compound of claim 6 , wherein said compound is a member selected from the group below, or a polymorph, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof:
14. The compound of claim 6 , wherein said compound is a member selected from the group below, or a polymorph, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof:
15. The compound of claim 6 , wherein said compound is a member selected from the group below, or a polymorph, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof:
16. The compound of claim 6 , wherein said compound is a member selected from the group below, or a polymorph, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof:
17. The compound of claim 6 , wherein said compound is a member selected from the group below, or a polymorph, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof:
18. The compound of claim 6 , wherein said compound is a member selected from the group below, or a polymorph, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof:
19. The compound of claim 6 , wherein said compound is a member selected from the group below, or a polymorph, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof:
20. The compound of claim 6 , wherein said compound is a member selected from the group below, or a polymorph, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof:
21. The compound of claim 6 , wherein said compound is a member selected from the group below, or a polymorph, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof:
22. The compound of claim 6 , wherein said compound is a member selected from the group below wherein Py is pyridinyl, a polymorph, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof:
23. The compound of claim 6 , wherein said compound is a member selected from the group below, or a polymorph, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof:
24. The compound of claim 6 , wherein said compound is represented by the formula below, or a polymorph, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof:
25. The compound of claim 6 , wherein said compound is represented by the formula below, or a polymorph, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof:
26. The compound of claim 6 , wherein said compound is represented by the formula below, or a polymorph, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof:
27. The compound of claim 6 , wherein said compound is represented by the formula below, or a polymorph, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof:
28. The compound of claim 6 , wherein said compound is represented by the formula below, or a polymorph, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof:
29. The compound of claim 6 , wherein said compound is represented by the formula below, or a polymorph, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof:
30. The compound of claim 6 , wherein said compound is represented by the formula below, or a polymorph, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof:
31. The compound of claim 6 , wherein said compound is represented by the formula below, or a polymorph, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof:
32. The compound of claim 6 , wherein said compound is represented by the formula below, or a polymorph, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof:
33. The compound of claim 6 , wherein said compound is represented by the formula below, or a polymorph, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof:
34. The compound of claim 6 , wherein said compound is represented by the formula below, or a polymorph, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof:
35. The compound of claim 6 , wherein said compound is represented by the formula below, or a polymorph, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof:
36. The compound of claim 6 , wherein said compound is represented by the formula below, or a polymorph, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof:
37. The compound of claim 6 , wherein said compound is represented by the formula below, or a polymorph, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof:
38. The compound of claim 6 , wherein said compound is represented by the formula below, or a polymorph, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof:
39. The compound of claim 6 , wherein said compound is represented by the formula below, or a polymorph, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof:
40. The compound of claim 6 , wherein said compound is represented by the formula below, or a polymorph, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof:
41. The compound of claim 6 , wherein said compound is represented by the formula below, or a polymorph, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof:
42. The compound of claim 6 , wherein said compound is represented by the formula below, or a polymorph, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof:
43. A pharmaceutical composition comprising one or more pharmaceutically acceptable excipients and at least one compound represented by Formula I below, or a polymorph, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof:
wherein:
R 0 is selected from hydrogen, halogen, lower alkyl, —SR 8 , —OR 8 , —CN, and —NHR 8 ,
R 1 is halogen, or lower alkyl;
R 2 is —NHR 8 ;
R 3 is selected from the group consisting of hydrogen, halogen, —SR 8 , —OR 8 , —CN, —C(O)R 9 , —C(O)OH, —NO 2 , —NR 8 R 10 , lower alkyl, lower alkenyl, lower alkynyl, lower perhaloalkyl, aryl, heteroaryl, alicyclic and heterocyclic, all optionally substituted, wherein:
the aryl, heteroaryl, alicyclic and heterocyclic groups are optionally mono-, bi- or tri-cyclic,
R 8 and R 10 taken together with the N to which they are attached optionally form a ring of 3–7 ring atoms and 1–3 of the ring atoms are heteroatoms selected from the group of O, S and N, and
the optional substituents on R 3 are selected from the group consisting of halogen, lower alkyl, lower alkenyl, lower alkynyl, —SR 8 , —OR 8 , —CN, —C(O)OH, —C(O)R 9 , —NO 2 , —NR 8 R 10 lower aryl, heteroaryl, alicyclic, lower heterocyclic, arylalkyl, heteroarylalkyl, amino, alkylamino, dialkylamino, oxo, perhaloalkyl, perhaloalkoxy, perhaloacyl, guanidinyl, pyridinyl, thiophenyl, furanyl, indolyl, and indazolyl, wherein R 8 and R 10 taken together with the N to which they are attached optionally form a ring of 3–7 ring atoms and 1–3 of the ring atoms are heteroatoms selected from the group of O, S and N;
When R 0 or R 3 is —OH or —SH, the compound may exist as the corresponding (thio)keto tautomer or a mixture of keto-enol tautomers;
R 4 is —CHR 12 —, —C(O)—, —C(S)—, —S(O)— or —SO 2 —;
R 5 is aryl, heteroaryl, alicyclic, or heterocyclic, wherein
the aryl group is substituted with 3 to 5 substituents,
the heteroaryl group is substituted with 2 to 5 substituents,
the alicyclic group is substituted with 3 to 5 substituents,
the heterocyclic group is substituted with 3 to 5 substituents, and
the substituents are selected from the group consisting of halogen, lower alkyl, lower alkenyl, lower alkynyl, —SR 8 , —OR 8 , —CN, —C(O)OH, —C(O)R 9 , —NO 2 , —NR 8 R 10 , lower aryl, heteroaryl, alicyclic, lower heterocyclic, arylalkyl, heteroarylalkyl, amino, alkylamino, dialkylamino, oxo, perhaloalkyl, perhaloalkoxy, perhaloacyl, guanidinyl, pyridinyl, thiophenyl, furanyl, indolyl, and indazolyl, wherein R 8 and R 10 taken together with the N to which they are attached optionally form a ring of 3–7 ring atoms and 1–3 of the ring atoms are heteroatoms selected from the group of O, S and N;
R 8 is hydrogen, lower alkyl, lower alkenyl, or lower alkynyl, lower aryl, lower heteroaryl, or —C(O)R 9 ;
R 9 is H, lower alkyl, lower alkenyl, lower alkynyl, lower aryl, lower heteroaryl, —NR 10 R 10 , or —OR 11 , wherein R 10 and R 10 taken together with the N to which they are attached optionally form a ring of 3–7 ring atoms and 1–3 of the ring atoms are heteroatoms selected from the group of O, S and N;
R 10 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl or lower heteroaryl;
R 11 is lower alkyl, lower alkenyl, or lower alkynyl, lower heteroaryl or lower aryl; and
R 12 is hydrogen or lower alkyl.
44. The pharmaceutical composition of claim 43 , wherein:
R 0 is hydrogen, halogen, —SH, —OH, or —CN,
R 1 is halogen; and
R 2 is —NHR 8 , where R 8 is hydrogen or —C(O)R 9 .
45. The pharmaceutical composition of claim 43 , wherein:
R 0 is hydrogen, halogen or —CN,
R 2 is —NHR 8 , where R 8 is hydrogen or —C(O)R 9 ; and
R 4 is —CH 2 —.
46. The pharmaceutical composition of claim 43 , wherein:
R 0 is hydrogen, halogen, —SH, —OH or —CN,
R 1 is halogen;
R 2 is —NH 2 ,
R 3 is hydrogen, halogen, OR 8 , SR 8 , NR 8 R 10 , lower alkyl, lower alkenyl, lower alkynyl, lower perhaloalkyl, lower aryl, or lower heteroaryl, wherein R 8 is hydrogen, lower alkyl, lower aryl, or —C (O)R 9 ;
R 4 is —CH 2 —; and
R 5 is aryl or heteroaryl, wherein each of the aryl and heteroaryl is monocyclic or bicyclic and is substituted with 3 to 5 substituents.
47. The pharmaceutical composition of claim 43 , wherein:
R 1 is chloro or bromo;
R 2 is —NH 2 ; and
R 5 is a phenyl having at least three substituents, a pyridyl having at least two substituents, or 1-oxy-pyridyl (N-oxy-pyridyl), each of which has at least two substituents.
48. A compound represented by Formula II, or a polymorph, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof:
wherein:
R 0 is hydrogen, halogen, lower alkyl, —SR 8 , —OR 8 , —CN or —NHR 8 ;
R 1 is halogen, or lower alkyl;
R 2 is —NH 2 ;
R 4 is —CHR 12 —, —C(O)—, —C(S)—, —S(O)— or —SO 2 —;
R 5 is aryl, heteroaryl, alicyclic, or heterocyclic, wherein:
the aryl group is substituted with 3 to 5 substituents,
the heteroaryl group is substituted with 2 to 5 substituents,
the alicyclic group is substituted with 3 to 5 substituents,
the heterocyclic group is substituted with 3 to 5 substituents, and
the substituents on R 5 are selected from the group consisting of halogen, lower alkyl, lower alkenyl, lower alkynyl, —SR 8 , —OR 8 , —CN, —C(O)OH, —C(O)R 9 , —NO 2 , —NR 8 R 10 , lower aryl, heteroaryl, alicyclic, lower heterocyclic, arylalkyl, heteroarylalkyl, amino, alkylamino, oxo, perhaloalkyl, perhaloalkoxy, perhaloacyl, guanidinyl, pyridinyl, thiophenyl, furanyl, indolyl, and indazolyl, wherein R 8 and R 10 taken together with the N to which they are attached optionally form a ring of 3–7 ring atoms and 1–3 of the ring atoms are heteroatoms selected from the group of O, S and N;
R 8 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl, lower heteroaryl, or —C(O)R 9 ;
R 9 is H, lower alkyl, lower aryl, lower heteroaryl, —NR 10 R 10 , or —OR 11 , wherein R 10 and R 10 taken together with the N to which they are attached optionally form a ring of 3–7 ring atoms and 1–3 of the ring atoms are heteroatoms selected from the group of O, S and N;
R 10 is hydrogen, lower alkyl, lower heteroaryl, lower aryl, lower alkenyl, or lower alkynyl;
R 11 is lower alkyl, lower alkenyl, or lower alkynyl, lower heteroaryl or lower aryl;
R 12 is hydrogen or lower alkyl; and
R 0 and R 10 taken together optionally form an exocyclic double bond which is optionally substituted, or optionally form a ring of 3–7 ring atoms and optionally 1–3 of the ring atoms are heteroatoms selected from the group of O, S and N.
49. The compound of claim 48 , or a polymorph, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, wherein:
R 1 is halogen or lower alkyl;
R 4 is —CHR 12 —; and
R 5 is aryl or heteroaryl, wherein each of said aryl and heteroaryl is monocyclic or bicyclic and is substituted with 3 to 5 substituents.
50. The compound of claim 49 , or a polymorph, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, wherein
R 0 is hydrogen or —NHR 8 ;
R 1 is halogen, or lower alkyl;
R 10 is hydrogen or lower alkyl.
51. The compound of claim 49 , or a polymorph, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, wherein:
R 0 is hydrogen;
R 1 is halogen;
R 4 is —CH 2 —;
R 5 is aryl or heteroaryl, wherein each of said aryl and heteroaryl is monocyclic or bicyclic and is substituted with 3 to 5 substituents; and
R 10 is hydrogen.
52. The compound of claim 51 , or a polymorph, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, wherein: R 1 is chloro or bromo; R 5 is phenyl, pyridyl or 1-oxy-pyridyl (N-oxy-pyridyl), each R 5 has at least two substituents.
53. The compound of claim 51 , wherein said compound is a member selected from the group below, or a polymorph, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof:
54. The compound of claim 51 , wherein said compound is a member selected from the group below, or a polymorph, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof:
55. The compound of claim 51 , wherein said compound is a member selected from the group below, or a polymorph, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof:
56. The compound of claim 51 , wherein said compound is a member selected from the group below, or a polymorph, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof:
57. A pharmaceutical composition comprising one or more pharmaceutical acceptable excipients and at least one compound represented by Formula II below, or a polymorph, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof:
wherein:
R 0 is hydrogen, halogen, lower alkyl, —SR 8 , —OR 8 , —CN or —NHR 8 ;
R 1 is halogen, or lower alkyl;
R 2 is —NH 2 ;
R 4 is —CHR 12 —, —C(O)—, —C(S)—, —S(O)— or —SO 2 —;
R 5 is aryl, heteroaryl, alicyclic, or heterocyclic, wherein:
the aryl group is substituted with 3 to 5 substituents,
the heteroaryl group is substituted with 2 to 5 substituents,
the alicyclic group is substituted with 3 to 5 substituents,
the heterocyclic group is substituted with 3 to 5 substituents, and
the substituents on R 5 are selected from the group consisting of halogen, lower alkyl, lower alkenyl, lower alkynyl, —SR 8 , —OR 8 , —CN, —C(O)OH, —C(O)R 9 , —NO 2 , —NR 8 R 10 , lower aryl, heteroaryl, alicyclic, lower heterocyclic, arylalkyl, heteroarylalkyl, amino, alkylamino, dialkylamino, oxo, perhaloalkyl, perhaloalkoxy, perhaloacyl, guanidinyl, pyridinyl, thiophenyl, furanyl, indolyl, and indazolyl, wherein R 8 and R 10 taken together with the N to which they are attached optionally form a ring of 3–7 ring atoms and 1–3 of the ring atoms are heteroatoms selected from the group of O, S and N;
R 8 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl, lower heteroaryl, or —C(O)R 9 .
R 9 is H, lower alkyl, lower aryl, lower heteroaryl, —NR 10 R 10 , or —OR 11 , wherein R 10 and R 10 taken together with the N to which they are attached optionally form a ring of 3–7 ring atoms and 1–3 of the ring atoms are heteroatoms selected from the group of O, S and N;
R 10 is hydrogen, lower alkyl, lower heteroaryl, lower aryl, lower alkenyl, or lower alkynyl,
R 11 is lower alkyl, lower alkenyl, lower alkynyl, lower heteroaryl or lower aryl;
R 12 is hydrogen or lower alkyl; and
R 0 and R 10 taken together optionally form an exocyclic double bond which is optionally substituted, or optionally form a ring of 3–7 ring atoms and optionally 1–3 of the ring atoms are heteroatoms selected from the group of O, S and N.
58. A compound represented by Formula III, or a polymorph, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof:
wherein:
R 1 is halogen, or lower alkyl;
R 2 is —NH 2 ;
R 3 is selected from the group consisting of hydrogen, halogen, —SR 8 , —OR 8 , —CN, —C(O)R 9 , —C(O)OH, —NO 2 , —NR 8 R 10 , lower alkyl, lower alkenyl, lower alkynyl, lower perhaloalkyl, aryl, heteroaryl, alicyclic, heterocyclic, all optionally substituted, wherein:
the aryl, heteroaryl, alicyclic and heterocyclic groups are optionally mono-, bi- or tri-cyclic,
R 8 and R 10 taken together with the N to which they are attached optionally form a ring of 3–7 ring atoms and 1–3 of the ring atoms are heteroatoms selected from the group of O, S and N, and
the optional substituents on R 3 are selected from the group consisting of halogen, lower alkyl, lower alkenyl, lower alkynyl, —SR 8 , —OR 8 , —CN, —C(O)OH, —C(O)R 9 , —NO 2 , —NR 8 R 10 , lower aryl, heteroaryl, alicyclic, lower heterocyclic, arylalkyl, heteroarylalkyl, amino, alkylamino, dialkylamino, oxo, perhaloalkyl, perhaloalkoxy, perhaloacyl, guanidinyl, pyridinyl, thiophenyl, furanyl, indolyl, and indazolyl, wherein R 8 and R 10 with the N to which they are attached together optionally form a ring of 3–7 ring atoms and 1–3 of the ring atoms are heteroatoms selected from the group of O, S and N;
R 4 is —CHR 12 —, —C(O)—, —C(S)—, —S(O)— or —SO 2 —;
R 5 is aryl, heteroaryl, alicyclic, or heterocyclic, wherein
the aryl group is substituted with 3 to 5 substituents,
the heteroaryl group is substituted with 2 to 5 substituents,
the alicyclic group is substituted with 3 to 5 substituents,
the heterocyclic group is substituted with 3 to 5 substituents, and
the substituents on R 5 are selected from the group consisting of halogen, lower alkyl, lower alkenyl, lower alkynyl, —SR 8 , —OR 8 , —CN, —C(O)OH, —C(O)R 9 , —NO 2 , —NR 8 R 10 , lower aryl, heteroaryl, alicyclic, lower heterocyclic, arylalkyl, heteroarylalkyl, amino, alkylamino, dialkylamino, oxo, perhaloalkyl, perhaloalkoxy, perhaloacyl, guanidinyl, pyridinyl, thiophenyl, furanyl, indolyl, and indazolyl, wherein R 8 and R 10 taken together with the N to which they are attached optionally form a ring of 3–7 ring atoms and 1–3 of the ring atoms are heteroatoms selected from the group of O, S and N;
R 8 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl, lower heteroaryl, or —C(O)R 9 ;
R 9 is H, lower alkyl, lower aryl, lower heteroaryl, —NR 10 R 10 , or —OR 11 , wherein R 10 and R 10 taken together with the N to which they are attached optionally form a ring of 3–7 ring atoms and 1–3 of the ring atoms are heteroatoms selected from the group of O, S and N;
R 10 is hydrogen, lower alkyl, lower heteroaryl, lower aryl, lower alkenyl, or lower alkynyl,
R 11 is lower alkyl, lower alkenyl, lower alkynyl, lower heteroaryl or lower aryl;
R 12 is hydrogen or lower alkyl; and
R 3 and R 10 taken together optionally form an exocyclic double bond which is optionally substituted, or optionally form a ring of 3–7 ring atoms and 1–3 of the ring atoms are heteroatoms selected from the group of O, S and N.
59. The compound of claim 58 , or a polymorph, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, wherein:
R 1 is halogen;
R 3 is hydrogen, halogen, —OR 8 , —SR 8 , —NR 8 R 10 , lower alkyl, lower alkenyl, lower alkynyl, lower perhaloalkyl, lower aryl, or lower heteroaryl, wherein R 8 is hydrogen, lower alkyl, lower alkenyl, or lower alkynyl, lower aryl, lower heteroaryl, or —C(O)R 9 ;
R 4 is —CH 2 —;
R 5 is aryl or heteroaryl, wherein each of said aryl and heteroaryl is monocyclic or bicyclic and is substituted with 3 to 5 substituents, and
R 10 is hydrogen or lower alkyl.
60. The compound of claim 58 , or a polymorph, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, wherein:
R 1 is halogen;
R 4 is —CH 2 —;
R 5 is aryl or heteroaryl, wherein each of said aryl and heteroaryl is monocyclic or bicyclic and is substituted with 3 to 5 substituents; and
R 10 is hydrogen.
61. The compound of claim 58 , or a polymorph, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, wherein:
R 1 is halogen;
R 3 is hydrogen;
R 4 is —CH 2 —;
R 5 is aryl or heteroaryl, wherein each of said aryl and heteroaryl is monocyclic or bicyclic and is substituted with 3 to 5 substituents; and
R 10 is hydrogen.
62. The compound of claim 61 , or a polymorph, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, wherein: R 1 is chloro or bromo; and R 5 is phenyl, pyridyl or 1-oxy-pyridyl (N-oxy-pyridyl), wherein each R 5 has at least two substituents.
63. A pharmaceutical composition comprising one or more pharmaceutically acceptable excipients and at least one compound represented by Formula III below, or a polymorph, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof:
wherein:
R 1 is halogen, or lower alkyl;
R 2 is —NH 2 ;
R 3 is selected from the group consisting of hydrogen, halogen, —SR 8 , —OR 8 —CN, —C(O)R 9 , —C(O)OH, —NO 2 , —NR 8 R 10 , lower alkyl, lower alkenyl, lower alkynyl, lower perhaloalkyl, aryl, heteroaryl, alicyclic, heterocyclic, all optionally substituted, wherein:
the aryl, heteroaryl, alicyclic and heterocyclic groups are optionally mono-, bi- or tri-cyclic,
R 8 and R 10 taken together with the N to which they are attached optionally form a ring of 3–7 ring atoms and 1–3 of the ring atoms are heteroatoms selected from the group of O, S and N, and
the optional substituents on R 3 are selected from the group consisting of halogen, lower alkyl, lower alkenyl, lower alkynyl, —SR 8 , —OR 8 , —CN, —C(O)OH, —C(O)R 9 , —NO 2 , —NR 8 R 10 , lower aryl, heteroaryl, alicyclic, lower heterocyclic, arylalkyl, heteroarylalkyl, amino, alkylamino, dialkylamino, oxo, perhaloalkyl, perhaloalkoxy, perhaloacyl, guanidinyl, pyridinyl, thiophenyl, furanyl, indolyl, and indazolyl, wherein R 8 and R 10 taken together with the N to which they are attached optionally form a ring of 3–7 ring atoms and 1–3 of the ring atoms are heteroatoms selected from the group of O, S and N;
R 4 is —CHR 12 —, —C(O)—, —C(S)—, —S(O)— or —SO 2 —;
R 5 is aryl, heteroaryl, alicyclic, or heterocyclic, wherein
the aryl group is substituted with 3 to 5 substituents,
the heteroaryl group is substituted with 2 to 5 substituents,
the alicyclic group is substituted with 3 to 5 substituents,
the heterocyclic group is substituted with 3 to 5 substituents, and
the substituents on R 5 are selected from the group consisting of halogen, lower alkyl, lower alkenyl, lower alkynyl, —SR 8 , —OR 8 , —CN, —C(O)OH, —C(O)R 9 , —NO 2 and —NR 8 R 10 lower aryl, heteroaryl, alicyclic, lower heterocyclic, arylalkyl, heteroarylalkyl, amino, alkylamino, dialkylamino, oxo, perhaloalkyl, perhaloalkoxy, perhaloacyl, guanidinyl, pyridinyl, thiophenyl, furanyl, indolyl, and indazolyl, wherein R 8 and R 10 taken together with the N to which they are attached optionally form a ring of 3–7 ring atoms and 1–3 of the ring atoms are heteroatoms selected from the group of O, S and N;
R 8 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl, lower heteroaryl, or —C(O)R 9 ;
R 9 is H, lower alkyl, lower aryl, lower heteroaryl, —NR 10 R 10 , or —OR 11 , wherein R 10 and R 10 taken together with the N to which they are attached optionally form a ring of 3–7 ring atoms and 1–3 of the ring atoms are heteroatoms selected from the group of O, S and N;
R 10 is hydrogen, lower alkyl, lower heteroaryl, lower aryl, lower alkenyl, or lower alkynyl,
R 11 is lower alkyl, lower alkenyl, lower alkynyl, lower heteroaryl or lower aryl;
R 12 is hydrogen or lower alkyl; and
R 3 and R 10 taken together optionally form an exocyclic double bond which is optionally substituted, or optionally form a ring of 3–7 ring atoms and 1–3 of the ring atoms are heteroatoms selected from the group of O, S and N.
64. A compound represented by Formula IV, or a polymorph, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof:
wherein:
R 1 is halogen, or lower alkyl;
R 2 is —NH 2 ;
R 4 is —CHR 12 —, —C(O)—, —C(S)—, —S(O)— or —SO 2 —;
R 5 is aryl, heteroaryl, alicyclic, or heterocyclic, wherein
the aryl group is substituted with 3 to 5 substituents,
the heteroaryl group is substituted with 2 to 5 substituents,
the alicyclic group is substituted with 3 to 5 substituents,
the heterocyclic group is substituted with 3 to 5 substituents, and
the substituents on R 5 are selected from the group consisting of halogen, lower alkyl, lower alkenyl, lower alkynyl, —SR 8 , —OR 8 , —CN, —C(O)OH, —C(O)R 9 , —NO 2 , —NR 8 R 10 , lower aryl, heteroaryl, alicyclic, lower heterocyclic, arylalkyl, heteroarylalkyl, amino, alkylamino, dialkylamino, oxo, perhaloalkyl, perhaloalkoxy, perhaloacyl, guanidinyl, pyridinyl, thiophenyl, furanyl, indolyl, and indazolyl, wherein R 8 and R 10 taken together with the N to which they are attached optionally form a ring of 3–7 ring atoms and 1–3 of the ring atoms are heteroatoms selected from the group of O, S and N;
R 8 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl, lower heteroaryl, or —C(O)R 9 ;
R 9 is H, lower alkyl, lower aryl, lower heteroaryl, —NR 10 R 10 , or —OR 11 , wherein R 10 and R 10 taken together with the N to which they are attached optionally form a ring of 3–7 ring atoms and 1–3 of the ring atoms are heteroatoms selected from the group of O, S and N;
R 10 is hydrogen, lower alkyl, lower heteroaryl, lower aryl, lower alkenyl, or lower alkynyl,
R 11 is lower alkyl, lower alkenyl, lower alkynyl, lower heteroaryl or lower aryl; and
R 12 is hydrogen or lower alkyl.
65. The compound of claim 64 , or a polymorph, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, wherein:
R 1 is halogen;
R 4 is —CH 2 —; and
R 5 is aryl or heteroaryl, wherein each of said aryl and heteroaryl is monocyclic or bicyclic and is substituted with 3 to 5 substituents.
66. The compound of claim 65 , or a polymorph, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, wherein R 1 is chloro or bromo, R 5 is phenyl, pyridyl or 1-oxy-pyridyl (N-oxy-pyridyl), wherein each R 5 has at least two substituents.
67. A pharmaceutical composition comprising one or more pharmaceutically acceptable excipients and at least one compound represented by Formula IV below, or a polymorph, ester, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof:
wherein:
R 1 is halogen, or lower alkyl;
R 2 is —NH 2 ;
R 4 is —CHR 12 —, —C(O)—, —C(S)—, —S(O)— or —SO 2 —;
R 5 is aryl, heteroaryl, alicyclic, or heterocyclic, wherein
the aryl group is substituted with 3 to 5 substituents,
the heteroaryl group is substituted with 2 to 5 substituents,
the alicyclic group is substituted with 3 to 5 substituents,
the heterocyclic group is substituted with 3 to 5 substituents, and
the substituents on R 5 are selected from the group consisting of halogen, lower alkyl, lower alkenyl, lower alkynyl, —SR 8 , —OR 8 , —CN, —C(O)OH, —C(O)R 9 , —NO 2 and —NR 8 R 10 lower aryl, heteroaryl, alicyclic, lower heterocyclic, arylalkyl, heteroarylalkyl, amino, alkylamino, dialkylamino, oxo, perhaloalkyl, perhaloalkoxy, perhaloacyl, guanidinyl, pyridinyl, thiophenyl, furanyl, indolyl, and indazolyl, wherein R 8 and R 10 taken together with the N to which they are attached optionally form a ring of 3–7 ring atoms and 1–3 of the ring atoms are heteroatoms selected from the group of O, S and N;
R 8 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl, lower heteroaryl, or —C(O)R 9 ;
R 9 is H, lower alkyl, lower aryl, lower heteroaryl, —NR 10 R 10 , or —OR 11 , wherein R 10 and R 10 taken together with the N to which they are attached optionally form a ring of 3–7 ring atoms and 1–3 of the ring atoms are heteroatoms selected from the group of O, S and N;
R 10 is hydrogen, lower alkyl, lower heteroaryl, lower aryl, lower alkenyl, or lower alkynyl,
R 11 is lower alkyl, lower alkenyl, lower alkynyl, lower heteroaryl or lower aryl; and
R 12 is hydrogen or lower alkyl.
68. The compound of claim 6 , wherein said compound is a member selected from the group below, or a polymorph, tautomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof