Claims
- 1. A method of inhibiting AKT, PKA, PDK1, p70S6K, or ROCK kinase in:
(a) a patient; or (b) a biological sample; which method comprises administering to said patient, or contacting said biological sample with, a compound of formula I′: 428 or a pharmaceutically acceptable salt thereof, wherein:
R1 is selected from halogen, CN, N(R4)2, T-R, or T′-Ar; T is selected from a valence bond or a C1-6 alkylidene chain, wherein up to two methylene units of T are optionally, and independently, replaced by —O—, —N(R)—, —S—, —N(R)C(O)—, —C(O)N(R)—, —C(O)—, or —SO2—; T′ is a C1-6 alkylidene chain, wherein up to two methylene units of T′ are optionally, and independently, replaced by —O—, —N(R)—, —S—, —N(R)C(O)—, —C(O)N(R)—, —C(O)—, or —SO2—; each R is independently selected from hydrogen or an optionally substituted C1-6 aliphatic group, or:
two R groups on the same nitrogen, taken together with the nitrogen atom attached thereto, form a 5-7 membered saturated, partially unsaturated, or aromatic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R2 is selected from Q-Ar, Q-N(R5)2, or Q-C(R)(Q-Ar)R3, wherein:
R and R3 optionally form a 5-7 membered saturated or partially unsaturated ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each Q is independently selected from a valence bond or a C1-4 alkylidene chain; each Ar is independently an optionally substituted ring selected from a 5-7 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 front nitrogen, oxygen, or sulfur; R3 is selected from R′, Ar1, Q-OR5, Q-OC(O)R5, Q-CONHR5, Q-OC(O)NHR5, Q-SR5, Q-N(R4)2, N(R)(Q-Ar), N(R)C(O)Q-N(R4)2, or N(R)Q-N(R4)2; R′ is an optionally substituted C1-6 aliphatic group; each R4 is independently selected from R, COR5, CO2R5, CON(R5)2, SO2R5, SO2N(R5)2, or Ar1; each R5 is independently selected from R or Ar; V1, V2 and V3 are each independently selected from nitrogen or C(R6); each R6 is independently selected from R, Ar1, halogen, CN, NO2, OR, SR, N(R4)2, N(R)COR, N(R)CON(R4)2, N(R)C(O)OR, CON(R4)2, OC(O)N(R4)2, CO2R, OC(O)R, N(R)SO2R, N(R)SO2N(R4)2, SO2R, or SO2N(R4)2; and each Ar1 is independently selected from an optionally substituted 5-7 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; provided that:
when V1, V2, and V3 are each CH and R1 is hydrogen, then R2 is Q-C(R)(Q-Ar)R3, wherein R3 is other than R′, Q-OC(O)R5, or OCH2phenyl.
- 2. The method according to claim 1, wherein:
R1 is selected from halogen, CN, N(R4)2, or optionally substituted C1-6 aliphatic; and R2 is selected from Q-Ar or Q-N(R5)2; wherein:
R and R3 optionally form a 5-7 membered saturated or partially unsaturated ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Ar is an optionally substituted ring selected from a 5-6 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 9-10 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
- 3. The method according to claim 1, wherein:
R1 is selected from halogen, CN, N(R4)2, or T-R; and R2 is selected from Q-C(R)(Q-Ar)R3, wherein:
R and R3 optionally form a 5-7 membered saturated or partially unsaturated ring having, 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Ar is an optionally substituted 5-6 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-4 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; and R3 is selected from Q-OR5, Q-N(R4)2, Ar1, N(R)C(O)Q-N(R4)2, or N(R)Q-N(R4)2.
- 4. The method according to claim 1, wherein:
R1 is T′-Ar, wherein:
Ar is an optionally substituted 5-6 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and T′ is selected from —NHC(O)—, —NH—, —NHCH2—, —NHSO2—, —CH2NH—, —C≡C—, —CH2— or —CH2CH2—;
- 5. The method according to claim 4, wherein:
R2 is Q-C(R)(Q-Ar)R3, wherein:
R and R3 optionally form a 5-7 membered saturated or partially unsaturated ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Ar is an optionally substituted 5-6 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-4 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; and R3 is R′, Q-OR5, Q-N(R4)2, Ar1, N(R)C(O)Q-N(R4)2, or N(R)Q-N(R4)2.
- 6. The method according to either of claims 3 or 5, wherein said compound has the formula III or IV:
- 7. The method according to claim 1, wherein said compound has the formula V:
- 8. A compound of formula Ia:
- 9. The compound according to claim 8, wherein:
R1 is selected from halogen, N(R4)2, or optionally substituted C1-6 aliphatic; and R2 is Q-C(R)(Q-Ar)R3, wherein:
R and R3 optionally form a 5-7 membered saturated or partially unsaturated ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R3 is selected from R′, Q-OR5, Q-N(R4)2, Ar1, N(R)C(O)Q-N(R4)2, or N(R)Q-N(R4)2; and Ar is an optionally substituted 5-6 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or all optionally substituted 9-10 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
- 10. The compound according to claim 9, wherein:
R1 is selected from chloro, bromo, fluoro, NH2, NHMe, NHEt, NH-cyclohexyl, methyl, ethyl, propyl, isopropyl, cyclopropyl, acetylenyl, or d t-butyl; and R3 is selected from CH2OH, OH, NH2, CH2NH2, CH2NHMe, CH2N(Me)2, CH2CH2NH2, CH2CH2NHMe, CH2CH2N(Me)2, CH2CH2NH2, NHCO2t-butyl, phenyl, cyclopentyl, methyl, ethyl, isopropyl, cyclopropyl, NH(CH2)3NH2, NH(CH2)2NH2, CH2C(Me)2NH2, CH2C(Me)2CHMe, NH(CH2)2NHEt, NHCH2pyridyl, NHSO2phenyl, NHC(O)CH2C(O)Ot-butyl, NHC(O)CH2NH3, or NHCH2-imidazol-4-yl.
- 11. The compound according to claim 8, wherein:
R1 is hydrogen; and R2 is Q-C(R)(Q-Ar)R3, wherein:
R and R3 optionally form a 5-7 membered saturated or partially unsaturated ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R3 is selected from Q-0R5, Q-N(R4)2, Ar1, N(R)C(O)Q-N(R4)2, or N(R)Q-N(R4)2; and Ar is an optionally substituted 5-6 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-4 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.
- 12. The compound according to claim 11, wherein:
R3 is selected from OH, NH2, CH2NH2, CH2NHMe, CH2N(Me)2, CH2CH2NH2, CH2CH2NHMe, CH2CH2N(Me)2, NHCO2t-butyl, phenyl, NH(CH2)3NH2, CH2C(Me)2NH2, CH2C(Me)2CHMe, NH(CH2)2NH2, NH(CH2)2NHEt, NHCH2pyridyl, NHSO2phenyl, NHC(O)CH2C(O)Ot-butyl, NHC(O)CH2NH3, or NHCH2-imidazol-4-yl.
- 13. Thc compound according to claim 8, wherein said compound is selected from the group consisting of:
- 14. A compound of formula IIb:
- 15. The compound according to claim 14, wherein:
R1 is T-Ar, wherein:
T is selected from —NHC(O)—, —NH—, —NHCH—, NHSO2, —CH2NH—, —C≡—, —CH2— or —CH2CH2—; and Ar is an optionally substituted 5-6 membered aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an optionally substituted 9-10 membered aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and R2 is Q-C(R)(Q-Ar)R3, wherein:
R3 is R′, Q-OR5, Q-N(R4)2, Ar1, N(R)C(O)Q-N(R4)2, or N(R)Q-N(R4)2; each Q is independently selected from a valence bond, —CH2—, or —CH2CH2—; and Ar is an optionally substituted 5-6 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-4 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.
- 16. The compound according to claim 15, wherein:
R3 is CH2OH, OH, NH2, CH2NH2, CH2NHMe, CH2N(Me)2, CH2CH2NH2, CH2CH2NHMe, CH2CH2N(Me)2, CH2CH2NH2, NHCO2t-butyl, phenyl, cyclopentyl, methyl, ethyl, isopropyl, cyclopropyl, NH(CH2)3NH2, NH(CH2)2NH2, CH2C(Me)2NH2, CH2C(Me)2CHMe, NH(CH2)2NHEt, NHCH2pyridyl, NHSO2phenyl, NHC(O)CH2C(O)Ot-butyl, NHC(O)CH2NH3, and NHCH2-imidazol-4-yl.
- 17. The compound according to claim 14, wherein:
T is a valence bond; and R2 is Q-C(R)(Q-Ar)R3, wherein:
R and R3 optionally form a 5-7 membered saturated or partially unsaturated ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R3 is Q-N(R4)2, Ar1, N(R)C(O)Q-N(R4)2, or N(R)Q-N(R4)2; and Ar is an optionally substituted 5-6 membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-4 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.
- 18. The compound according to claim 17, wherein:
R3 is CH2NHMe, CH2N(Me)2, CH2CH2NH2, CH2CH2NHMe, CH2CH2N(Me)2, CH2C(Me)2NH2, CH2C(Me)2CHMe, NHCO2(t butyl), phenyl, NH(CH2)3NH2, NH(CH2)2NH2, NH(CH2)2NHEt, NHCH2pyridyl, NHSO2phenyl, NHC(O)CH2C(O)Ot-butyl, NHC(O)CH2NH3, and NHCH2-imidazol-4-yl.
- 19. The compound according to claim 14, wherein said compound is selected from the group consisting of:
- 20. The compound according to claim 14, wherein said compound has the formula V:
- 20. A composition comprising a compound according to either of claims 8 or 14, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.
- 21. The composition according to claim 20, 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.
- 22. A method of inhibiting AKT, PKA, PDK1, p70S6K, or ROCK kinase activity in a biological sample comprising the step of contacting said biological sample with:
a) a compound according to claim 8;b) a compound according to claim 14; or c) a composition according to claim 20.
- 23. A method of treating or lessening the severity of a disease or condition selected from a proliferative disorder, a cardiac disorder, an inflammatory disorder, an autoimmune disorder, a neurodegenerative disorder, a viral disease, or a bone disorder, wherein said method comprises the step of administering an effective amount a composition according to claim 20.
- 24. The method according to claim 23, wherein said disease or condition is selected from cancer, rheumatoid arthritis, asthma, HIV, angina pectoris, peripheral circulation disorder, hypertension, arteriosclerosis, tuberous sclerosis, or osteoporosis.
- 25. The method according to claim 24, wherein said disease or condition is selected from cancer.
- 26. The method according to claim 25, wherein said cancer is selected from brain (gliomas), breast, colon, head and neck, kidney, lung, liver, melanoma, ovarian, pancreatic, prostate, sarcoma, or thyroid.
- 27. The method according to claim 26, wherein said cancer is selected from pancreatic, prostate, or ovarian.
- 28. The method according to claim 23, comprising the additional step of administering to said patient an additional 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, wherein:
said additional therapeutic agent is appropriate for the disease being treated; and said additional therapeutic agent is administered together with said composition as a single dosage form or separately from said composition as part of a multiple dosage form.
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional Patent Application No. 60/351,597 filed Jan. 25, 2002, the contents of which are incorporated herein by reference.
Provisional Applications (1)
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Number |
Date |
Country |
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60351597 |
Jan 2002 |
US |