Claims
- 1. An isolated compound having the structure (I):
- 2. The compound of claim 1, wherein one or more of the following groups do not occur simultaneously as defined:
(i) R′, R0, R3 and R3′ are each hydrogen; R2 is alkyl, cycloalkylalkyl or aralkyl; —X2—X3—R4 together represents —CHReC(═O)NHCH(Rw)C(═O)NRxRy, wherein Re is hydrogen or alkyl, Rw is alkyl, and one of Rx or Ry represents hydrogen and the other represents hydrogen, alkyl, aryl, aralkyl, 1-alkoxycarbonyl-2-phenylethyl, 1-alkoxycarbonyl-2-(imidazol-4-yl)ethyl, 2-(imidazol-1-yl)ethyl, indanyl, heterocyclyl-alkyl, carboxyalkyl, alkoxycarbonylalkyl, aryloxycarbonylalkyl, aralkoxycarbonylalkyl or a group of the formula —A—N(Ra)(Rb) in which A represents alkylene and Ra and Rb each represents alkyl or Ra and Rb together represent a pentamethylene group in which one methylene group can be replaced by NH, N-alkyl, N-alkanoyl, N-aralkoxycarbonyl, O, S, SO, or SO2; or Rx and Ry together with the nitrogen atom to which they are attached represent a 1,2,3,4-tetrahydroisoquinoline ring; and —X1—R1 together represents an alkoxycarbonyl, aralkoxycarbonyl, alkanoyl, aralkanoyl, aroyl, cycloalkylcarbonyl, heterocyclylcarbonyl, heterocyclyl-alkanoyl, 6-(dibenylcarbamoyl)-4-oxohexanoyl moiety or an acyl group of an α-amino acid in which the amino group is substituted by an alkoxycarbonyl, aralkoxycarbonyl, diaralkylcarbamoyl, diaralkylalkanoyl, or aralkanoyl moiety; wherein the term “aroyl” refers to an acyl group derived from from an arylcarboxylic acid such as benzoyl, 1-naphthoyl, 2-naphthoyl, etc., and the term “aralkanoyl” refers to an acyl group derived from an aryl-substituted alkanecarboxylic acid; whereby the term “aryl” alone or in each of the aralkyl, aryloxycarbonylalkyl, aralkoxycarbonylalkyl or N-aralkoxycarbonyl moieties refers to a phenyl or naphthyl group optionally substituted with one or emore substituents selected from alkyl, hydroxy, alkoxy and halogen; (ii) R′, R0, R3 and R3′ are each hydrogen; X1 is —C(═O)—, —SO2—, N(Rx)SO2, N(Rx)C(═O) or SC(═O), wherein Rx is hydrogen, C1-5alkyl or joined together with R1 either directly to form a 5-7 membered heterocycle such as pyrrolidinyl or piperidinyl, or through a heteroatom selected from N, O and S, to form a 6-membered heterocycle with the nitrogen to which they are attached such as morpholinyl, piperazyl, or N—C1-3alkyl-piperazyl; R1 is a substituted or unsubstituted C1-6alkyl, a 5-6 membered heterocycle or a 6-10 carbon atoms aryl moiety substituted with C1-4alkyl, C1-3alkoxy, hydroxy, halogen, N(Ra)2, C(═O)ORa, —C(═O)N(Ra)2, —SO2N(Ra)2, CH2N(Ra)2, N(Ra)C(═O)Ra or N(Ra)SO2Ra; R2 is ORa, N(Ra)2, C1-4alkenyl-Rc or —[CRbRc]nRc; and —X2—X3—R4 together represent —CH(Rd)C(═O)NHCH(Re)C(═O)—Y—[CRfRg]mRg, wherein m is an integer from 0 to 5, Y is O or NH, Rd and Re are independently hydrogen, ORa, N(Ra)2, C1-4alkenyl-Rc or —[CRbRc]nRc wherein n is an integer from 0 to 5, Ra is hydrogen or C1-4alkyl, Rb is hydrogen, hydroxy or C1-4alkyl and Rc is hydrogen, substituted or unsubstituted aryl, 5- or 6-membered heterocycle, C1-6alkyl or C1-6alkenyl, C3-7cycloalkyl, 5- to 7-membered carbocyclic or 7- to 10-membered bicyclic carbocyclic ring, benzofuryl, indolyl, azabicyclo C7-11cycloalkyl or benzopiperidinyl; Rf is hydrogen, substituted or unsubstituted C1-6alkyl or (CH2CH2O)pCH3 or (CH2CH2O)pH wherein p is an integer from 0 to 5, and Rg is hydrogen, or substituted or unsubstituted aryl, heterocycle, 5- to 7-membered carbocyclic or 7- to 10-membered bicyclic carbocyclic ring; (iii) R′, R0, R3 and R3′ are each hydrogen; X1 is —C(═O)—, —SO2—, N(Rx)SO2, N(Rx)C(═O) or SC(═O), wherein Rx is hydrogen, C1-5alkyl or joined together with R1 either directly to form a 5-7 membered heterocycle such as pyrrolidinyl or piperidinyl, or through a heteroatom selected from N, O and S, to form a 6-membered heterocycle with the nitrogen to which they are attached such as morpholinyl, piperazyl, or N—C1-3alkyl-piperazyl; R1 is a substituted or unsubstituted C1-6alkyl, a 5-6 membered heterocycle or a 6-10 carbon atoms aryl moiety substituted with C1-4alkyl, C1-3alkoxy, hydroxy, halogen, N(Ra)2, C(═O)ORa, —C(═O)N(Ra)2, —SO2N(Ra)2, CH2N(Ra)2, N(Ra)C(═O)Ra or N(Ra)SO2Ra; R2 is ORa, N(Ra)2, C1-4alkenyl-Rc or —[CRbRc]nRc; and —X2—X3—R4 together represent —CH(Rd)C(═O)—Y—[CRfRg]mRg, wherein m is an integer from 0 to 5, Y is O or NH, Rd is hydrogen, ORa, N(Ra)2, C1-4alkenyl-Rc or —[CRbRc]nRc; wherein n is an integer from 0 to 5, Ra is hydrogen or C1-4alkyl, Rb is hydrogen, hydroxy or C1-4alkyl and Rc is hydrogen, substituted or unsubstituted aryl, 5- or 6-membered heterocycle, C1-6alkyl or C1-6alkenyl, C3-7cycloalkyl, 5- to 7-membered carbocyclic or 7- to 10-membered bicyclic carbocyclic ring, benzofuryl, indolyl, azabicyclo C7-11cycloalkyl or benzopiperidinyl; Rf is hydrogen, substituted or unsubstituted C1-6alkyl or (CH2CH2O)pCH3 or (CH2CH2O)pH wherein p is an integer from 0 to 5, and Rg is hydrogen, or substituted or unsubstituted aryl, heterocycle, 5- to 7-membered carbocyclic or 7- to 10-membered bicyclic carbocyclic ring; (iv) R′ and R3′ are each hydrogen; R0 is hydrogen, —C(═O)H, —C1-4alkyl or —COORa; X1 is —C(═O)—, —SO2—, N(Rx)SO2, N(Rx)C(═O) or SC(═O), wherein Rx is hydrogen, C1-5alkyl or joined together with R1 either directly to form a 5-7 membered heterocycle such as pyrrolidinyl or piperidinyl, or through a heteroatom selected from N, O and S, to form a 6-membered heterocycle with the nitrogen to which they are attached such as morpholinyl, piperazyl, or N—C1-3alkyl-piperazyl; R1 is a substituted or unsubstituted C1-6alkyl, a 5-6 membered heterocycle or a 6-10 carbon atoms aryl moiety substituted with C1-4alkyl, C1-3alkoxy, hydroxy, halogen, N(Ra)2, C(═O)ORa, —C(═O)N(Ra)2, —SO2N(Ra)2, CH2N(Ra)2, N(Ra)C(═O)Ra or N(Ra)SO2Ra; R2 is ORa, N(Ra)2, C1-4alkenyl-Rc or —[CRbRc]nRc; R3 is hydrogen, ORa, N(Ra)2, C1-4alkenyl-Rc or —[CRbRc]nRc; and —X2—X3—R4 together represent —CH(Rd)C(═O)NHCH(Re)C(═O)—Y—[CRfRg]mRg, wherein m is an integer from 0 to 5, Y is O or NH, Rd and Re are independently hydrogen, ORa, N(Ra)2, C1-4alkenyl-Rc or —[CRbRc]nRc wherein n is an integer from 0 to 5, Ra is hydrogen or C1-4alkyl, Rb is hydrogen, hydroxy or C1-4alkyl and Rc is hydrogen, substituted or unsubstituted aryl, 5- or 6-membered heterocycle, C1-6alkyl or C1-6alkenyl, C3-7cycloalkyl, 5- to 7-membered carbocyclic or 7- to 10-membered bicyclic carbocyclic ring, benzofuryl, indolyl, azabicyclo C7-11cycloalkyl or benzopiperidinyl; Rf is hydrogen, substituted or unsubstituted C1-6alkyl or (CH2CH2O)pCH3 or (CH2CH2O)pH wherein p is an integer from 0 to 5, and Rg is hydrogen, or substituted or unsubstituted aryl, heterocycle, 5- to 7-membered carbocyclic or 7- to 10-membered bicyclic carbocyclic ring; (v) R′ and R3′ are each hydrogen; R0 is hydrogen, —C(═O)H, —C1-4alkyl or —COORa; X1 is —C(═O)—, —SO2—, N(Rx)SO2, N(Rx)C(═O) or SC(═O), wherein Rx is hydrogen, C1-5alkyl or joined together with R1 either directly to form a 5-7 membered heterocycle such as pyrrolidinyl or piperidinyl, or through a heteroatom selected from N, O and S, to form a 6-membered heterocycle with the nitrogen to which they are attached such as morpholinyl, piperazyl, or N—C1-3alkyl-piperazyl; R1 is a substituted or unsubstituted C1-6alkyl, a 5-6 membered heterocycle or a 6-10 carbon atoms aryl moiety substituted with C1-4alkyl, C1-3alkoxy, hydroxy, halogen, N(Ra)2, C(═O)ORa, —C(═O)N(Ra)2, —SO2N(Ra)2, CH2N(Ra)2, N(Ra)C(═O)Ra or N(Ra)SO2Ra; R2 is ORa, N(Ra)2, C1-4alkenyl-Rc or —[CRbRc]nRc; R3 is hydrogen, ORa, N(Ra)2, C1-4alkenyl-Rc or —[CRbRc]nRc; and —X2—X3—R4 together represent —CH(Rd)C(═O)—Y—[CRfRg]mRg, wherein m is an integer from 0 to 5, Y is O or NH, Rd is hydrogen, ORa, N(Ra)2, C1-4alkenyl-Rc or —[CRbRc]nRc; wherein n is an integer from 0 to 5, Ra is hydrogen or C1-4alkyl, Rb is hydrogen, hydroxy or C1-4alkyl and Rc is hydrogen, substituted or unsubstituted aryl, 5- or 6-membered heterocycle, C1-6alkyl or C1-6alkenyl, C3-7cycloalkyl, 5- to 7-membered carbocyclic or 7- to 10-membered bicyclic carbocyclic ring, benzofuryl, indolyl, azabicyclo C7-11cycloalkyl or benzopiperidinyl; Rf is hydrogen, substituted or unsubstituted C1-6alkyl or (CH2CH2O)pCH3 or (CH2CH2O)pH wherein p is an integer from 0 to 5, and Rg is hydrogen, or substituted or unsubstituted aryl, heterocycle, 5- to 7-membered carbocyclic or 7- to 10-membered bicyclic carbocyclic ring; and (vi) R0, R′, R3 and R3′ are each hydrogen; R2 is C1-6alkyl, C2-6alkenyl, C3-7cycloalkyl, aryl, heteroaryl, T—C1-6alkyl, T—C2-6alkenyl, wherein T is aryl, heteroaryl or C3-7cycloalkyl; R1—X1 together represent W wherein W is Rx, RxCO, RxOCO, RxOCH(Ry)CO, RxNHCH(Ry)CO, RxSCH(Ry)CO, RxSO2, RxSO or an amino acid with a blocked or unblocked amino terminus, wherein Rx and Ry are each independently hydrogen, C1-6alkyl, C3-7cycloalkyl, aryl, heteroaryl, T—C1-6alkyl or T—(CH2)nCH(T)(CH2)n wherein n is an integer from 1 to 4; and —X2—X3—R4 together represent —CH(Ra)C(═X)CHRbRc, wherein X is (OH,H) or O; Ra is hydrogen, C1-6alkyl, C2-6alkenyl, C3-7cycloalkyl, aryl, heteroaryl, T—C1-6alkyl or T—C2-6alkenyl; Rb is hydrogen or OH; and Rc is Y, (CHRw)n—Y or ═CRz(CHRw)n—Y, wherein Y is hydrogen, OH, —NRwRq, aryl, heteroaryl or CO—Z, n is an integer from 1 to 4, Z is OH, —NRwRq, ORw or an amino acid with a blocked or unblocked carboxy terminus, Rq is H, C1-6alkyl or arylC1-6alykl, and Rz and Rw are each independently hydrogen, C1-6alkyl, C3-7cycloalkyl, aryl, heteroaryl, T—C1-6alkyl or T—C2-6alkenyl.
- 3. The compound of claim 1, wherein:
R0 is hydrogen, an aliphatic, heteroaliphatic, aromatic or heteroaromatic moiety, a nitrogen protecting group, or a prodrug moiety; R′ is hydrogen or an aliphatic, heteroaliphatic, aromatic or heteroaromatic moiety; R1 is an aliphatic, heteroaliphatic, aromatic or heteroaromatic moiety; X1 is —C(═O)—, —S(═O)—, —C(═NH)—, —C(═S)—, —NC(═O)—, —NC(═S)—, —N—C(═N—C≡N)—, —NS(O2)—, —CHRX1A—, —SO2—, —COO—, —C(═O)C(RX1A)2—, or —SC(═O)— wherein each occurrence of RX1A is independently hydrogen, or an aliphatic, heteroaliphatic, aromatic or heteroaromatic moiety; R2 is an aliphatic, heteroaliphatic, aromatic or heteroaromatic moiety; R3 is hydrogen, halogen, or an aliphatic, heteroaliphatic, aromatic or heteroaromatic moiety; R3′ is hydrogen, halogen, or lower alkyl; R4 is an aliphatic, heteroaliphatic, aromatic or heteroaromatic moiety; X2 is absent, —NRX2A—, —(CHRX2A)j—, —NRX2AY—, or —(CHRX2A)jY— wherein each occurrence of RX2A is independently hydrogen or an aliphatic, heteroaliphatic, aromatic or heteroaromatic moiety, each occurrence of Y is independently 1812wherein, for each independent occurrence of t, RX2B is hydrogen, or an aliphatic, heteroaliphatic, aromatic or heteroaromatic moiety, and wherein each occurrence of j and t is independently an integer from 1 to 4; and X3 is absent, —NHCO—, —NHSO2—, —NHCONH—, —NHCOO—, —CH2NH—, —C(═O)—, —S(═O)—, —C(═NH)—, —C(═S)—, —NC(═S)N—, —N—C(═N—C≡N)N—, —NS(O2)N—, —SO2—, —CONRX3A—, —COO—, —(CHRX3A)k—, —O—, or —NRX3A—, wherein each occurrence of RX3A is independently hydrogen, an aliphatic, heteroaliphatic, aromatic or heteroaromatic moiety, and k is an integer from 1 to 3; wherein each of the foregoing aliphatic or heteroaliphatic moieties may be independently substituted or unsubstituted, linear or branched, cyclic or acyclic, and each of the foregoing aromatic, heteroaromatic, aryl and heteroaryl moieties may be substituted or unsubstituted.
- 4. The compound of claim 1, wherein the compound has the structure:
- 5. The compound of claim 4, wherein R3′ is hydrogen, X2 is CHRX2A, R0 and R′, taken together, form a 5-membered heterocyclic moiety and the compound has the structure:
- 6. The compound of claim 2, wherein R3′ is hydrogen, X2 is CHRX2A, R0 and R′, taken together, form a 6-membered heterocyclic moiety and the compound has the structure:
- 7. The compound of claim 1, wherein R3′ is hydrogen, X2 is CHMe and the compound has the structure:
- 8. The compound of claim 1, wherein R3′ is hydrogen, X3 is absent, X2 is —CH(Me)Y— where Y is
- 9. The compound of claim 1, wherein R′ and R3′ are each hydrogen, X2 is CHRX2A, and the compound has the structure:
- 10. The compound of claim 9, wherein the compound has the structure:
- 11. The compound of claim 10, wherein R0 and RX2A, taken together, form a 5-membered heterocyclic moiety and the compound has the structure:
- 12. The compound of claim 10, wherein R0 and RX2A, taken together, form a 6-membered heterocyclic moiety and the compound has the structure:
- 13. The compound of claim 9, wherein RX2A is methyl and the compound has the structure:
- 14. The compound of claim 1, wherein R′ and R3′ are each hydrogen, X2 is CHRX2A and X3 is —C(═O)NH— and the compound has the structure:
- 15. The compound of claim 14, wherein the compound has the structure:
- 16. The compound of claim 15, wherein R0 and RX2A, taken together, form a 5-membered heterocyclic moiety and the compound has the structure:
- 17. The compound of claim 15, wherein R0 and RX2A, taken together, form a 6-membered heterocyclic moiety and the compound has the structure:
- 18. The compound of claim 14, wherein RX2A is methyl and the compound has the structure:
- 19. The compound of claim 1, wherein R′ and R3′ are each hydrogen, X2 is CHRX2A, X1 is —C(═O)— and the compound has the structure:
- 20. The compound of claim 19, wherein the compound has the structure:
- 21. The compound of claim 20, wherein R0 and RX2A, taken together, form a 5-membered heterocyclic moiety and the compound has the structure:
- 22. The compound of claim 20, wherein R0 and RX2A, taken together, form a 6-membered heterocyclic moiety and the compound has the structure:
- 23. The compound of claim 19, wherein RX2A is methyl and the compound has the structure:
- 24. The compound of claim 1, wherein R′ and R3′ are each hydrogen, X1 is —C(═O)—, X2 is CHRX2A and X3 is —C(═O)NH— and the compound has the structure:
- 25. The compound of claim 24, wherein the compound has the structure:
- 26. The compound of claim 25, wherein R0 and RX2A, taken together, form a 5-membered heterocyclic moiety and the compound has the structure:
- 27. The compound of claim 25, wherein R0 and RX2A, taken together, form a 6-membered heterocyclic moiety and the compound has the structure:
- 28. The compound of claim 24, wherein RX2A is methyl and the compound has the structure:
- 29. The compound of claim 1, wherein R′ and R3′ are each hydrogen, and X2 is —NRX2A— and the compound has the structure:
- 30. The compound of claim 29, wherein the compound has the structure:
- 31. The compound of claim 30, wherein R0 and RX2A, taken together form a heterocyclic moiety and the compound has the structure:
- 32. The compound of claim 1, wherein R′ and R3′ are each hydrogen, X1 is —C(═O)— and X2 is —NRX2A—, and the compound has the structure:
- 33. The compound of claim 32, wherein the compound has the structure:
- 34. The compound of claim 1, wherein R′ and R3′ are each hydrogen, X1 is —C(═O)— and X2 is NH, and the compound has the structure:
- 35. The compound of claim 34, wherein the compound has the structure:
- 36. The compound of claim 1, wherein R′ and R3′ are each hydrogen, X1 is —C(═O)—, X2 and X3 are both absent and R4 is a cyclic moiety
- 37. The compound of claim 36, wherein
- 38. The compound of claim 1, wherein R0 is hydrogen.
- 39. The compound of claim 1, wherein R3 is hydrogen; R2 is substituted or unsubstituted lower alkyl, lower alkylamino, lower heteroaryl, —(CH2)cycloalkyl, —(CH2)heterocycloalkyl, —(CH2)aryl, —(CH2)heteroaryl, optionally substituted with one or more occurrences of R2A, wherein R2A is hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, —OR2B, —SR2B, —N(R2B)2, —SO2N(R2B)2, —C(═O)N(R2B)2, halogen, —CN, —NO2, —C(═O)OR2B, —N(R2B)C(═O)R2C, wherein each occcurrence of R2B and R2C is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl; R1 is alkyl, alkenyl, heteroalkyl, heteroalkenyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, -(heteroalkyl)aryl, or -(heteroalkyl)heteroaryl, wherein R1 is optionally substituted with one or more occurrences of R1A, wherein R1A is hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, —OR1B, —SR1B, —N(R1B)2, —SO2N(R1B)2, —C(═O)N(R1B)2, halogen, —CN, —NO2, —C(═O)OR1B, N(R1B)C(═O)R1C or —N(R1B)SO2R1C; wherein each occcurrence of R1B and R1C is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl; or R1B and R1C, taken together with the atoms to which they are attached, form a substituted or unsubstituted heterocyclic moiety; and R4 is alkyl, alkenyl, heteroalkyl, heteroalkenyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl -(heteroalkyl)aryl, or -(heteroalkyl)heteroaryl, optionally substituted with one or more occurrences of R4A, wherein R4A is hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl, -(alkyl)heteroaryl, —OR4B, —SR4B, —N(R4B)2, —SO2N(R4B)2, —C(═O)N(R4B)2, halogen, —CN, —NO2, —C(═O)OR4B, —N(R4B)C(═O)R4C, wherein each occcurrence of R4B and R4C is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl.
- 40. The compound of claim 1 wherein R3′ is hydrogen, X1 is C(═O), X2 is CHRX2A—Y and the compound has the structure (and pharmaceutically acceptable derivatives thereof):
- 41. The compound of claim 40 wherein Y is C(═O), X3 is absent and the compound has the structure:
- 42. The compound of claim 41 wherein RX2A is methyl and R0 is a prodrug moiety.
- 43. The compound of claim 1 wherein R3′ is hydrogen, X1 is C(═O), X2 is CHRX2A[C(═O)NHCH(RX2B)]t, X3 is absent and the compound has the structure (and pharmaceutically acceptable derivatives thereof):
- 44. The compound of claim 43 wherein t is 2, R1 is AR1, RX2A is methyl, one occurrence of RX2B is isopropyl and the compound has the structure:
- 45. The compound of claim 40, 41, 43 or 44 wherein R3 is hydrogen, lower alkyl or halogen.
- 46. The compound of claim 40, 41, 43 or 44 wherein R3 is hydrogen, methyl or F.
- 47. The compound of claim 40, 41, 43 or 44 wherein R3 is F.
- 48. The compound of claim 1 wherein R3′ is hydrogen, X1 is C(═O), X2 is NHRX2ACH(RX2A′)—Y, X3 is absent and the compound has the structure (and pharmaceutically acceptable derivatives thereof):
- 49. The compound of claim 48 wherein R1 is AR1, RX2A and RX2A′ are each hydrogen, Y is absent and the compound has the structure:
- 50. The compound of claim 48 wherein R3 is hydrogen, Y is [C(═O)NHCHRX2B)]t and the compound has the structure:
- 51. The compound of claim 50 wherein t is 2, R1 is AR1, RX2A′ is methyl, one occurrence of RX2B is isopropyl and the compound has the structure:
- 52. The compound of claim 1, 40, 41, 43, 44, 48, 49, 50 or 51, wherein R′ is hydrogen.
- 53. The compound of claim 41, 44, 49 or 51, wherein AR1 is one of:
- 54. The compound of claim 41, 44, 49 or 51, wherein AR1 is one of:
- 55. The compound of claim 41, 44, 49 or 51, wherein AR1 is one of:
- 56. The compound of claim 41, wherein AR1 is one of:
- 57. The compound of claim 56, wherein R1A is methyl, methoxy or halide.
- 58. The compound of claim 57, wherein R1A is methyl, methoxy or F.
- 59. The compound of claim 41, wherein AR1 is a moiety having the structure:
- 60. The compound of claim 41, wherein AR1 is a moiety having the structure:
- 61. The compound of claim 41, wherein AR1 is one of:
- 62. The compound of claim 41, wherein AR1 is one of:
- 63. The compound of claim 41, 44, 49 or 51, wherein R2 is lower alkyl, —CH2NR2AR2B or —(CH2)phenyl, wherein the phenyl group is optionally substituted with one or more occurrences of R2C, wherein R2C is hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, —OR2D, —SR2D, —N(R2D)2, —SO2N(R2D)2, —C(═O)N(R2D)2, halogen, —CN, —NO2, —C(═O)OR2D, —N(R2D)C(═O)R2E, wherein each occcurrence of R2D and R2E is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl; and wherein R2A and R2B are each independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl; whereby each of the foregoing alkyl and heteroalkyl moieties may be linear or branched, substituted or unsubstituted, cyclic or acylic, and each of the foregoing aryl, heteroaryl, -(alkyl)aryl and -(alkyl)heteroaryl moieties may be substituted or unsusbtituted.
- 64. The compound of claim 41, 44, 49 or 51, wherein R2 is is one of:
- 65. The compound of claim 41, 44, 49 or 51, wherein R2 is one of:
- 66. The compound of claim 41, 44, 49 or 51, wherein R2 is one of:
- 67. The compound of claim 41, wherein R2 is one of:
- 68. The compound of claim 41, wherein R2 is one of:
- 69. The compound of claim 41, 44, 49 or 51, wherein R3 and R3′ are each independently hydrogen, methyl or F.
- 70. The compound of claim 41, 44, 49 or 51, wherein R3′ and R3′ are each independently hydrogen or F.
- 71. The compound of claim 41, 44, 49 or 51, wherein R3 and R3′ are each hydrogen.
- 72. The compound of claim 41, wherein RX2A is methyl, ethyl or isopropyl.
- 73. The compound of claim 41, 44, 49 or 51, wherein R4 is substituted or unsubstituted, linear or branched, cyclic or acyclic alkyl, phenyl or —(CH2)phenyl, wherein the phenyl group is optionally substituted with one or more occurrences of R4A, wherein R4A is hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, -(alkyl)aryl or -(alkyl)heteroaryl, —OR4B, —SR4B, —N(R4B)2, —SO2N(R4B)2, —C(═O)N(R4B)2, halogen, —CN, —NO2, —C(═O)OR4B, —N(R4B)C(═O)R4C, wherein each occcurrence of R4B and R4C is independently hydrogen, lower alkyl, lower heteroalkyl, aryl, heteoraryl, -(alkyl)aryl or -(alkyl)heteroaryl.
- 74. The compound of claim 41, 44, 49 or 51, wherein R4 is substituted or unsubstituted, linear or branched, cyclic or acyclic alkyl, phenyl or —(CH2)phenyl, wherein the phenyl group is optionally substituted with one or more occurrences of R4A, wherein R4A is hydrogen, hydroxyl, alkyl, alkoxy or halogen.
- 75. The compound of claim 41, 44, 49 or 51, wherein R4 is one of:
- 76. The compound of claim 41, 44, 49 or 51, wherein R4 is one of:
- 77. The compound of claim 41, 44, 49 or 51, wherein R4 is one of:
- 78. The compound of claim 41, 44, 49 or 51, wherein R4 is one of:
- 79. The compound of claim 41, 44, 49 or 51, wherein R4 is one of:
- 80. The compound of claim 41, 44, 49 or 51, wherein R4 is one of:
- 81. The compound of claim 41, wherein R4 is one of:
- 82. The compound of claim 41, wherein R4 is one of:
- 83. A pharmaceutical composition comprising a compound 1, 41, 44, 49 or 51, and a pharmaceutically acceptable carrier or diluent, optionally further comprising an additional therapeutic agent.
- 84. The pharmaceutical composition of claim 83, wherein the compound is present in an amount effective to inhibit β-secretase activity.
- 85. The pharmaceutical composition of claim 83, wherein the additional therapeutic agent is an agent for the treatment of Alzheimer's Disease.
- 86. A method for inhibiting β-secretase activity in a patient or a biological sample, comprising administering to said patient, or contacting said biological sample with an effective inhibitory amount of a compound of claim 1.
- 87. A method for treating or preventing a disease characterized by β-amyloid deposits in the brain comprising administering to a patient a therapeutically effective amount of a compound of claim 1.
- 88. The method of claim 87, wherein the disease is Alzheimer's disease MCI (mild cognitive impairment), Down's syndrome, Hereditary Cerebral Hemmorhage with Amyloidosis of the Dutch-Type, cerebral amyloid angiopathy, other degenerative dementias, including dementias of mixed vascular and degenerative origin, dementia associated with Parkinson's disease, dementia associated with progressive supranuclear palsy, dementia associated with cortical basal degeneration, and diffuise Lewy body type Alzheimer's disease.
- 89. A method for synthesizing a compound having the structure:
- 90. The method of claim 89, wherein the method comprises synthesizing a compound having the structure:
- 91. A method for synthesizing a compound having the structure:
- 92. The method of claim 91, wherein the method comprises synthesizing a compound having the structure:
PRIORITY CLAIM
[0001] The present application claims priority under 35 U.S.C. § 119 to U.S. Ser. No. 60/430,693, filed Dec. 3, 2002, and U.S. Ser. No. 60/389,194, filed Jun. 17, 2002; the entire contents of each of these applications are incorporated herein by reference.
Provisional Applications (2)
|
Number |
Date |
Country |
|
60430693 |
Dec 2002 |
US |
|
60389194 |
Jun 2002 |
US |