Aminofurazan compounds useful as protein kinase inhibitors
The present invention relates to compounds useful of inhibitors of protein kinases. The invention also provides pharmaceutically acceptable compositions comprising said compounds and methods of using the compositions in the treatment of various disease, conditions, or disorders.
1. A compound of formula I:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is R, SO 2 R, —SO 2 N(R) 2 , —C(O)R, —CO 2 R, or —CON(R) 2 ;
each R is independently selected from hydrogen or an optionally substituted C 1-6 aliphatic group, or:
two R groups on the same nitrogen atom are taken together with said nitrogen to form a 3–8 membered saturated, partially unsaturated, or fully unsaturated ring having 1–3 heteroatoms, in addition to said nitrogen, independently selected from nitrogen, oxygen, or sulfur;
Ring A is
wherein said ring is substituted with one, two or three L-R 2 groups;
each R 2 is independently selected from C 1-6 aliphatic, CN, halogen, NO 2 , or Ar;
each L is independently selected from a valence bond or an optionally substituted C 1-6 alkylidene chain, wherein up to two methylene units of L are optionally, and independently, replaced by —O—, —S—, —NR—, —NRC(O)—, —NRC(O)NR—, —OC(O)NR—, —C(O)—, —CO 2 —, —NRCO 2 —, —C(O)NR—, —SO 2 NR—, —NRSO 2 —, or —NRSO 2 NR—; and
Ar is an optionally substituted 3–8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8–10 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring having 0–4 hereroatoms independently selected from nitrogen, oxygen, or sulfur.
2. The compound according to claim 1 , wherein L is a valence bond or an optionally substituted C 1-6 alkylidene chain wherein one or two methylene units of L are independently replaced by —NR—, —S—, —O—, —NRC(O)—, —C(O)NR—, —C(O)O—, or —O(O)—.
3. The compound according to claim 1 , wherein R 2 is optionally substituted C 1-4 aliphatic.
4. The compound according to claim 1 , wherein R 2 Ar wherein Ar is an optionally substituted 5–6 membered saturated, partially unsaturated, or fully unsaturated monocycle ring having 0–2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an optionally substituted 9–10 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
5. The compound according to claim 4 , wherein Ar is optionally substituted phenyl, pyridyl, benzofuranyl, tetrahydroisoquinolinyl, quinolinyl, or naphthyl.
6. The compound according to claim 1 , wherein said compound is selected from:
7. A composition comprising a compound of formula I:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is R, —SO 2 R, —SO 2 N(R) 2 , —C(O)R, —CO 2 R, or —CON(R) 2 ;
each R is independently selected from hydrogen or an optionally substituted C 1-6 aliphatic group, or:
two R groups on the same nitrogen atom are taken together with said nitrogen to form a 3–8 membered saturated, partially unsaturated, or fully unsaturated ring having 1–3 heteroatoms, in addition to said nitrogen, independently selected from nitrogen, oxygen, or sulfur;
Ring A is
wherein said ring is substituted with one, two or three L-R 2 groups;
each R 2 is independently selected from C 1-6 aliphatic, CN, halogen, NO 2 , or Ar;
each L is independently selected from a valence bond or an optionally substituted C 1-6 alkylidene chain, wherein up to two methylene units of L are optionally, and independently, replaced by —O—, —S—, —NR—, —NRC(O)—, —NRC(O)NR—, —OC(O)NR—, —C(O)—, —CO 2 —, —NRCO 2 —, —C(O)NR—, —SO 2 NR—, —NRSO 2 —, or NRSO 2 NR—; and
Ar is an optionally substituted 3–8 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8–10 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
8. The composition according to claim 7 , additionally comprising a therapeutic agent selected from an anti-proliferative agent, an anti-inflammatory agent, an immunomodulatory agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating liver disease, an anti-viral agent, an agent for treating blood disorders, an agent for treating diabetes, or an agent for treating immunodeficiency disorders, premature birth, cerebral vasospasm, coronary vasospasm, retinopathy, erectile dysfunction, osteoporosis, Crohn's Disease, colitis, neurite outgrowth, or Raynaud's Disease.
9. A method of treating or lessening the severity of a disease, condition or disorder comprising the step of administering to said patient the compound of claim 1 or the composition of claim 7 , wherein said disease, condition, or disorder is glaucoma, atherosclerosis, hypertension, erectile dysfunction, reperfusion/ischemia injury, stroke, cerebral vasospasm, or coronary vasospasm.
10. A method of treating or lessening the severity of diabetes in a patient in need thereof, wherein said method comprises administering to said patient a composition according to claim 7 .