TREATMENT OF PLURIPOTENT CELLS
First Claim
Patent Images
1. A method to expand and differentiate pluripotent cells, comprising the steps of:
- a. Culturing pluripotent cells, andb. Treating the pluripotent cells with an inhibitor of GSK-3B enzyme activity.
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Abstract
The present invention is directed to methods to treat pluripotent cells, whereby the pluripotent cells can be efficiently expanded in culture and differentiated by treating the pluripotent cells with an inhibitor of GSK-3B enzyme activity.
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Citations
126 Claims
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1. A method to expand and differentiate pluripotent cells, comprising the steps of:
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a. Culturing pluripotent cells, and b. Treating the pluripotent cells with an inhibitor of GSK-3B enzyme activity. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126)
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2. The method of claim 1, wherein the pluripotent cells are embryonic stem cells.
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3. The method of claim 1, wherein the pluripotent cells are cells expressing pluripotency markers derived from embryonic stem cells.
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4. The method of claim 3, wherein the cells expressing pluripotency markers express at least one of the following pluripotency markers selected from the group consisting of:
- ABCG2, cripto, FoxD3, Connexin43, Connexin45, Oct4, SOX-2, Nanog, hTERT, UTF-1, ZFP42, SSEA-3, SSEA-4, Tra1-60, and Tra1-81.
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5. The method of claim 1, wherein the pluripotent cells are differentiated into cells expressing markers characteristic of the definitive endoderm lineage.
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6. The method of claim 1, wherein the pluripotent cells are treated with the inhibitor of GSK-3B enzyme activity for about one to about 72 hours.
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7. The method of claim 1, wherein the pluripotent cells are treated with the inhibitor of GSK-3B enzyme activity for about 12 to about 48 hours.
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8. The method of claim 1, wherein the pluripotent cells are treated with the inhibitor of GSK-3B enzyme activity for about 48 hours.
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9. The method of claim 1, wherein the inhibitor of GSK-3B enzyme activity is used at a concentration of about 100 nM to about 100 μ
- M.
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10. The method of claim 1, wherein the inhibitor of GSK-3B enzyme activity is used at a concentration of about 1 μ
- M to about 10 μ
M.
- M to about 10 μ
-
11. The method of claim 1, wherein the inhibitor of GSK-3B enzyme activity is used at a concentration of about 10 μ
- M.
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12. The method of claim 1, wherein the inhibitor of GSK-3B enzyme activity is a compound of the Formula (I):
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13. The method of claim 12, wherein R1 is phenyl, substituted phenyl wherein the phenyl substituents are selected from the group consisting of C1-5alkyl, halogen, nitro, trifluoromethyl and nitrile, or pyrimidinyl.
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14. The method of claim 12, wherein R2 is phenyl, substituted phenyl wherein the phenyl substituents are selected from the group consisting of C1-5alkyl, halogen, nitro, trifluoromethyl and nitrile, or pyrimidinyl which is optionally C1-4alkyl substituted, and at least one of R1 and R2 is pyrimidinyl.
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15. The method of claim 12, wherein R3 is hydrogen, 2-(trimethylsilyl)ethoxymethyl, C1-5alkoxycarbonyl, aryloxycarbonyl, arylC1-5alkyloxycarbonyl, arylC1-5alkyl, substituted arylC1-5alkyl wherein the one or more aryl substituents are independently selected from the group consisting of C1-5alkyl, C1-5alkoxy, halogen, amino, C1-5alkylamino, and diC1-5alkylamino, phthalimidoC1-5alkyl, aminoC1-5alkyl, diaminoC1-5alkyl, succinimidoC1-5alkyl, C1-5alkylcarbonyl, arylcarbonyl, C1-5alkylcarbonylC1-5alkyl and aryloxycarbonylC1-5alkyl.
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16. The method of claim 12, wherein R4 is -(A)-(CH2)q—
- X.
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17. The method of claim 16, wherein A is vinylene, ethynylene or
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18. The method of claim 17, wherein R5 is selected from the group consisting of hydrogen, C1-5alkyl, phenyl and phenylC1-5alkyl.
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19. The method of claim 16, wherein q is 0-9.
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20. The method of claim 16, wherein X is selected from the group consisting of hydrogen, hydroxy, vinyl, substituted vinyl wherein one or more vinyl substituents are each selected from the group consisting of fluorine, bromine, chlorine and iodine, ethynyl, substituted ethynyl wherein the ethynyl substituents are selected from the group consisting of fluorine, bromine chlorine and iodine, C1-5alkyl, substituted C1-5alkyl wherein the one or more alkyl substituents are each selected from the group consisting of C1-5alkoxy, trihaloalkyl, phthalimido and amino, C3-7cycloalkyl, C1-5alkoxy, substituted C1-5alkoxy wherein the alkyl substituents are selected from the group consisting of phthalimido and amino, phthalimidooxy, phenoxy, substituted phenoxy wherein the one or more phenyl substituents are each selected from the group consisting of C1-5alkyl, halogen and C1-5alkoxy, phenyl, substituted phenyl wherein the one or more phenyl substituents are each selected from the group consisting of C1-5alkyl, halogen and C1-5alkoxy, arylC1-5alkyl, substituted arylC1-5alkyl wherein the one or more aryl substituents are each selected from the group consisting of C1-5alkyl, halogen and C1-5alkoxy, aryloxyC1-5alkylamino, C1-5alkylamino, diC1-5alkylamino, nitrile, oxime, benxyloxyimino, C1-5alkyloxyimino, phthalimido, succinimido, C1-5alkylcarbonyloxy, phenylcarbonyloxy, substituted phenylcarbonyloxy wherein the one or more phenyl substituents are each selected from the group consisting of C1-5alkyl, halogen and C1-5alkoxy, phenylC1-5alkylcarbonyloxy wherein the one or more phenyl substituents are each selected from the group consisting of C1-5alkyl, halogen and C1-5alkoxy, aminocarbonyloxy, C1-5alkylaminocarbonyloxy, diC1-5alkylaminocarbonyloxy, C1-5alkoxycarbonyloxy, substituted C1-5alkoxycarbonyloxy wherein the one or more alkyl substituents are each selected from the group consisting of methyl, ethyl, isopropyl and hexyl, phenoxycarbonyloxy, substituted phenoxycarbonyloxy wherein the one or more phenyl substituents are each selected from the group consisting of C1-5alkyl, C1-5alkoxy and halogen, C1-5alkylthio, substituted C1-5alkylthio wherein the alkyl substituents are selected from the group consisting of hydroxy and phthalimido, C1-5alkylsulfonyl, phenylsulfonyl, substituted phenylsulfonyl wherein the one or more phenyl substituents are each selected from the group consisting of bromine, fluorine, chloride, C1-5alkoxy and trifluoromethyl;
- with the proviso that if A is
q is 0 and X is H, then R3 may not be 2-(trimethylsilyl)ethoxymethyl; and
pharmaceutically acceptable salts thereof.
- with the proviso that if A is
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21. The method of claim 12, wherein R1 is substituted phenyl and R2 is pyrimidin-3-yl.
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22. The method of claim 12, wherein R1 is 4-fluorophenyl.
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23. The method of claim 12, wherein R3 is hydrogen, arylC1-5alkyl, or substituted arylC1-5alkyl.
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24. The method of claim 12, wherein R3 is hydrogen or phenylC1-5alkyl.
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25. The method of claim 16, wherein A is ethynylene and q is 0-5.
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26. The method of claim 16, wherein X is succinimido, hydroxy, methyl, phenyl, C1-5alkylsulfonyl, C3-6cycloalkyl, C1-5alkylcarbonyloxy, C1-5alkoxy, phenylcarbonyloxy, C1-5alkylamino, diC1-5alkylamino or nitrile.
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27. The method of claim 12, wherein the compound of the Formula I is 4-(4-fluorophenyl)-2-(4-hydroxybutyn-1-yl)-1-(3-phenylpropyl)-5-(4-pyridyl)imidazole.
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28. The method of claim 1, wherein the inhibitor of GSK-3B enzyme activity is a compound of the Formula (II):
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29. The method of claim 28, wherein R is selected from the group consisting of Ra, —
- C1-8alkyl-Ra, —
C2-8alkenyl-Ra, —
C2-8alkynyl-Ra and cyano.
- C1-8alkyl-Ra, —
-
30. The method of claim 29, wherein Ra is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl.
-
31. The method of claim 28, wherein R1 is selected from the group consisting of hydrogen, —
- C1-8alkyl-R5, —
C2-8alkenyl-R5, —
C2-8alkynyl-R5, —
C(O)—
(C1-8)alkyl-R9, —
C(O)-aryl-R8, —
C(O)—
O—
(C1-8)alkyl-R9, —
C(O)—
O-aryl-R8, —
C(O)—
NH(C1-8alkyl-R9), —
C(O)—
NH(aryl-R8), —
C(O)—
N(C1-8alkyl-R9)2, —
SO2—
(C1-8)alkyl-R9, —
SO2-aryl-R8, -cycloalkyl-R6, -heterocyclyl-R6, -aryl-R6 and -heteroaryl-R6;
wherein heterocyclyl and heteroaryl are attached to the azaindole nitrogen atom in the one position via a heterocyclyl or heteroaryl ring carbon atom.
- C1-8alkyl-R5, —
-
32. The method of claim 31, wherein R5 is 1 to 2 substituents independently selected from the group consisting of hydrogen, —
- O—
(C1-8)alkyl, —
O—
(C1-8)alkyl-OH, —
O—
(C1-8)alkyl-O—
(C1-8)alkyl, —
O—
(C1-8)alkyl-NH2, —
O—
(C1-8)alkyl-NH(C1-8alkyl), —
O—
(C1-8)alkyl-N(C1-8alkyl)2, —
O—
(C1-8)alkyl-S—
(C1-8)alkyl, —
O—
(C1-8)alkyl-SO2—
(C1-8)alkyl, —
O—
(C1-8)alkyl-SO2—
NH2, —
O—
(C1-8)alkyl-SO2—
NH(C1-8alkyl), —
O—
(C1-8)alkyl-SO2—
N(C1-8alkyl)2, —
O—
C(O)H, —
O—
C(O)—
(C1-8)alkyl, —
O—
C(O)—
NH2, —
O—
C(O)—
NH(C1-8alkyl), —
O—
C(O)—
N(C1-8alkyl)2, —
O—
(C1-8)alkyl-C(O)H, —
O—
(C1-8)alkyl-C(O)—
(C1-8)alkyl, —
O—
(C1-8)alkyl-CO2H, —
O—
(C1-8)alkyl-C(O)—
O—
(C1-8)alkyl, —
O—
(C1-8)alkyl-C(O)—
NH2, —
O—
(C1-8)alkyl-C(O)—
NH(C1-8alkyl), —
O—
(C1-8)alkyl-C(O)—
N(C1-8alkyl)2, —
C(O)H, —
C(O)—
(C1-8)alkyl, —
CO2H, —
C(O)—
O—
(C1-8)alkyl, —
C(O)—
NH2, —
C(NH)—
NH2, —
C(O)—
NH(C1-8alkyl), —
C(O)—
N(C1-8alkyl)2, —
SH, —
S—
(C1-8)alkyl, —
S—
(C1-8)alkyl-S—
(C1-8)alkyl, —
S—
(C1-8)alkyl-O—
(C1-8)alkyl, —
S—
(C1-8)alkyl-O—
(C1-8)alkyl-OH, —
S—
(C1-8)alkyl-O—
(C1-8)alkyl-NH2, —
S—
(C1-8)alkyl-O—
(C1-8)alkyl-NH(C1-8alkyl), —
S—
(C1-8)alkyl-O—
(C1-8)alkyl-N(C1-8alkyl)2, —
S—
(C1-8)alkyl-NH(C1-8alkyl), —
SO2—
(C1-8)alkyl, —
SO2—
NH2, —
SO2—
NH(C1-8alkyl), —
SO2—
N(C1-8alkyl)2, —
N—
R7, cyano, (halo)1-3, hydroxy, nitro, oxo, -cycloalkyl-R6, -heterocyclyl-R6, -aryl-R6 and -heteroaryl-R6.
- O—
-
33. The method of claim 31, wherein R6 is 1 to 4 substituents attached to a carbon or nitrogen atom independently selected from the group consisting of hydrogen, —
- C1-8alkyl, —
C2-8alkenyl, —
C2-8alkynyl, —
C(O)H, —
C(O)—
(C1-8)alkyl, —
CO2H, —
C(O)—
O—
(C1-8)alkyl, —
C(O)—
NH2, —
C(NH)—
NH2, —
C(O)—
NH(C1-8alkyl), —
C(O)—
N(C1-8)alkyl)2, —
SO2—
(C1-8)alkyl, —
SO2—
NH2, —
SO2—
NH(C1-8alkyl), —
SO2—
N(C1-8alkyl)2, —
(C1-8)alkyl-N—
R7, —
(C1-8)alkyl-(halo)1-3, —
(C1-8)alkyl-OH, -aryl-R8, —
(C1-8)alkyl-aryl-R8 and —
(C1-8)alkyl-heteroaryl-R8;
with the proviso that, when R6 is attached to a carbon atom, R6 is further selected from the group consisting of —
C1-8alkoxy, —
(C1-8)alkoxy-(halo)1-3, —
SH, —
S—
(C1-8)alkyl, —
N—
R7, cyano, halo, hydroxy, nitro, oxo and -heteroaryl-R8.
- C1-8alkyl, —
-
34. The method of claim 33, wherein R7 is 2 substituents independently selected from the group consisting of hydrogen, —
- C1-8alkyl, —
C2-8alkenyl, —
C2-8alkynyl, -(C1-8)alkyl-OH, —
(C1-8)alkyl-O—
(C1-8)alkyl, —
(C1-8)alkyl-NH2, —
(C1-8)alkyl-NH(C1-8alkyl), —
(C1-8)alkyl-N(C1-8alkyl)2, —
(C1-8)alkyl-S—
(C1-8)alkyl, —
C(O)H, —
C(O)—
(C1-8)alkyl, —
C(O)—
O—
(C1-8)alkyl, —
C(O)—
NH2, —
C(O)—
NH(C1-8alkyl), —
C(O)—
N(C1-8alkyl)2, —
SO2—
(C1-8)alkyl, —
SO2—
NH2, —
SO2—
NH(C1-8alkyl), —
SO2—
N(C1-8alkyl)2, —
C(N)—
NH2, -cycloalkyl-R8, —
(C1-8)alkyl-heterocyclyl-R8, -aryl-R8, —
(C1-8)alkyl-aryl-R8 and —
(C1-8)alkyl-heteroaryl-R8.
- C1-8alkyl, —
-
35. The method of claim 31, wherein R8 is 1 to 4 substituents attached to a carbon or nitrogen atom independently selected from the group consisting of hydrogen, —
- C1-8alkyl, —
(C1-8)alkyl-(halo)1-3 and —
(C1-8)alkyl-OH;
with the proviso that, when R8 is attached to a carbon atom, R8 is further selected from the group consisting of —
C1-8alkoxy, —
NH2, —
NH(C1-8alkyl), —
N(C1-8alkyl)2, cyano, halo, —
(C1-8)alkoxy-(halo)1-3, hydroxy and nitro.
- C1-8alkyl, —
-
36. The method of claim 31, wherein R9 is 1 to 2 substituents independently selected from the group consisting of hydrogen, —
- C1-8alkoxy, —
NH2, —
NH(C1-8alkyl), —
N(C1-8alkyl)2, cyano, (halo)1-3, hydroxy and nitro.
- C1-8alkoxy, —
-
37. The method of claim 28, wherein R2 is one substituent attached to a carbon or nitrogen atom selected from the group consisting of hydrogen, —
- C1-8alkyl-R5, —
C2-8alkenyl-R5, —
C2-8alkynyl-R5, —
C(O)H, —
C(O)—
(C1-8)alkyl-R9, —
C(O)—
NH2, —
C(O)—
NH(C1-8alkyl-R9), —
C(O)—
N(C1-8alkyl-R9)2, —
C(O)—
NH(aryl-R8), —
C(O)-cycloalkyl-R8, —
C(O)-heterocyclyl-R8, —
C(O)-aryl-R8, —
C(O)-heteroaryl-R8, —
CO2H, —
C(O)—
O—
(C1-8)alkyl-R9, —
C(O)—
O-aryl-R8, —
SO2—
(C1-8)alkyl-R9, —
SO2-aryl-R8, -cycloalkyl-R6, -aryl-R6 and —
(C1-8)alkyl-N—
R7;
with the proviso that, when R2 is attached to a carbon atom, R2 is further selected from the group consisting of —
C1-8alkoxy-R5—
N—
R7, cyano, halogen, hydroxy, nitro, oxo, -heterocyclyl-R6 and -heteroaryl-R6.
- C1-8alkyl-R5, —
-
38. The method of claim 28, wherein R3 is 1 to 3 substituents attached to a carbon atom independently selected from the group consisting of hydrogen, —
- C1-8alkyl-R10, —
C2-8alkenyl-R10, —
C2-8alkynyl-R10, —
C1-8alkoxy-R10, —
C(O)H, —
C(O)—
(C1-8)alkyl-R9, —
C(O)—
NH2, —
C(O)—
NH(C1-8alkyl-R9), —
C(O)—
N(C1-8alkyl-R9)2, —
C(O)-cycloalkyl-R8, —
C(O)-heterocyclyl-R8, —
C(O)-aryl-R8, —
C(O)-heteroaryl-R8, —
C(NH)—
NH2, —
CO2H, —
C(O)—
O—
(C1-8)alkyl-R9, —
C(O)—
O-aryl-R8, —
SO2—
(C1-8)alkyl-R9, —
SO2-aryl-R8, —
N—
R7, cyano, halogen, hydroxy, nitro, -cycloalkyl-R8, -heterocyclyl-R8, -aryl-R8 and -heteroaryl-R8.
- C1-8alkyl-R10, —
-
39. The method of claim 38, wherein R10 is 1 to 2 substituents independently selected from the group consisting of hydrogen, —
- NH2, —
NH(C1-8alkyl), —
N(C1-8alkyl)2, cyano, (halo)1-3, hydroxy, nitro and oxo.
- NH2, —
-
40. The method of claim 28, wherein R4 is 1 to 4 substituents attached to a carbon atom independently selected from the group consisting of hydrogen, —
- C1-8alkyl-R10, —
C2-8alkenyl-R10, —
C2-8alkynyl-R10, —
C1-8alkoxy-R10, —
C(O)H, —
C(O)—
(C1-8)alkyl-R9, —
C(O)—
NH2, —
C(O)—
NH(C1-8alkyl-R9), —
C(O)—
N(C1-8alkyl-R9)2, —
C(O)-cycloalkyl-R8, —
C(O)-heterocyclyl-R8, —
C(O)-aryl-R8, —
C(O)-heteroaryl-R8, —
C(NH)—
NH2, —
CO2H, —
C(O)—
O—
(C1-8)alkyl-R9, —
C(O)—
O-aryl-R8, —
SH, —
S—
(C1-8)alkyl-R10, —
SO2—
(C1-8)alkyl-R9, —
SO2-aryl-R8, —
SO2—
NH2, —
SO2—
NH(C1-8alkyl-R9), —
SO2—
N(C1-8alkyl-R9)2, —
N—
R7, cyano, halogen, hydroxy, nitro, -cycloalkyl-R8, -heterocyclyl-R8, -aryl-R8 and -heteroaryl-R8.
- C1-8alkyl-R10, —
-
41. The method of claim 40, wherein R10 is 1 to 2 substituents independently selected from the group consisting of hydrogen, —
- NH2, —
NH(C1-8alkyl), —
N(C1-8alkyl)2, cyano, (halo)1-3, hydroxy, nitro and oxo.
- NH2, —
-
42. The method of claim 28, wherein Y and Z are independently selected from the group consisting of O, S, (H,OH) and (H,H);
- with the proviso that one of Y and Z is O and the other is selected from the group consisting of O, S, (H,OH) and (H,H); and
pharmaceutically acceptable salts thereof.
- with the proviso that one of Y and Z is O and the other is selected from the group consisting of O, S, (H,OH) and (H,H); and
-
43. The method of claim 28, wherein R is selected from the group consisting of Ra, —
- C1-4alkyl-Ra, —
C2-4alkenyl-Ra, —
C2-4alkynyl-Ra and cyano.
- C1-4alkyl-Ra, —
-
44. The method of claim 29, wherein Ra is selected from the group consisting of heterocyclyl, aryl and heteroaryl.
-
45. The method of claim 29, Ra is selected from the group consisting of dihydro-pyranyl, phenyl, naphthyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, pyridinyl, azaindolyl, indazolyl, benzofuryl, benzothienyl, dibenzofuryl and dibenzothienyl.
-
46. The method of claim 28, wherein R1 is selected from the group consisting of hydrogen, —
- C1-4alkyl-R5, —
C2-4alkenyl-R5, —
C2-4alkynyl-R5, —
C(O)—
(C1-4)alkyl-R9, —
C(O)-aryl-R8, —
C(O)—
O—
(C1-4)alkyl-R9, —
C(O)—
O-aryl-R8, —
C(O)—
NH(C1-4alkyl-R9), —
C(O)—
NH(aryl-R8), —
C(O)—
N(C1-4alkyl-R9)2, —
SO2—
(C1-4)alkyl-R9, —
SO2-aryl-R8, -cycloalkyl-R6, -heterocyclyl-R6, -aryl-R6 and -heteroaryl-R6;
wherein heterocyclyl and heteroaryl are attached to the azaindole nitrogen atom in the one position via a heterocyclyl or heteroaryl ring carbon atom.
- C1-4alkyl-R5, —
-
47. The method of claim 28, wherein R1 is selected from the group consisting of hydrogen, —
- C1-4alkyl-R5, -aryl-R6 and -heteroaryl-R6;
wherein heteroaryl is attached to the azaindole nitrogen atom in the one position via a heteroaryl ring carbon atom.
- C1-4alkyl-R5, -aryl-R6 and -heteroaryl-R6;
-
48. The method of claim 28, wherein R1 is selected from the group consisting of hydrogen, —
- C1-4alkyl-R5 and -naphthyl-R6.
-
49. The method of claim 31, wherein R5 is 1 to 2 substituents independently selected from the group consisting of hydrogen, —
- O—
(C1-4)alkyl, —
O—
(C1-4)alkyl-OH, —
O—
(C1-4)alkyl-O—
(C1-4)alkyl, —
O—
(C1-4)alkyl-NH2, —
O—
(C1-4)alkyl-NH(C1-4alkyl), —
O—
(C1-4)alkyl-N(C1-4alkyl)2, —
O—
(C1-4)alkyl-S—
(C1-4)alkyl, —
O—
(C1-4)alkyl-SO2—
(C1-4)alkyl, —
O—
(C1-4)alkyl-SO2—
NH2, —
O—
(C1-4)alkyl-SO2—
NH(C1-4alkyl), —
O—
(C1-4)alkyl-SO2—
N(C1-4alkyl)2, —
O—
C(O)H, —
O—
C(O)—
(C1-4)alkyl, —
O—
C(O)—
NH2, —
O—
C(O)—
NH(C1-4alkyl), —
O—
C(O)—
N(C1-4alkyl)2, —
O—
(C1-4)alkyl-C(O)H, —
O—
(C1-4)alkyl-C(O)—
(C1-4)alkyl, —
O—
(C1-4)alkyl-CO2H, —
O—
(C1-4)alkyl-C(O)—
O—
(C1-4)alkyl, —
O—
(C1-4)alkyl-C(O)—
NH2, —
O—
(C1-4)alkyl-C(O)—
NH(C1-4alkyl), —
O—
(C1-4)alkyl-C(O)—
N(C1-4alkyl)2, —
C(O)H, —
C(O)—
(C1-4)alkyl, —
CO2H, —
C(O)—
O—
(C1-4)alkyl, —
C(O)—
NH2, —
C(NH)—
NH2, —
C(O)—
NH(C1-4alkyl), —
C(O)—
N(C1-4alkyl)2, —
SH, —
S—
(C1-4)alkyl, —
S—
(C1-4)alkyl-S—
(C1-4)alkyl, —
S—
(C1-4)alkyl-O—
(C1-4)alkyl, —
S—
(C1-4)alkyl-O—
(C1-4)alkyl-OH, —
S—
(C1-4)alkyl-O—
(C1-4)alkyl-NH2, —
S—
(C1-4)alkyl-O—
(C1-4)alkyl-NH(C1-4alkyl), —
S—
(C1-4)alkyl-O—
(C1-4)alkyl-N(C1-4alkyl)2, —
S—
(C1-4)alkyl-NH(C1-4alkyl), —
SO2—
(C1-4)alkyl, —
SO2—
NH2, —
SO2—
NH(C1-4alkyl), —
SO2—
N(C1-4alkyl)2, —
N—
R7, cyano, (halo)1-3, hydroxy, nitro, oxo, -cycloalkyl-R6, -heterocyclyl-R6, -aryl-R6 and -heteroaryl-R6.
- O—
-
50. The method of claim 31, wherein R5 is 1 to 2 substituents independently selected from the group consisting of hydrogen, —
- O—
(C1-4)alkyl, —
N—
R7, hydroxy and -heteroaryl-R6.
- O—
-
51. The method of claim 31, wherein R5 is 1 to 2 substituents independently selected from the group consisting of hydrogen, —
- O—
(C1-4)alkyl, —
N—
R7, hydroxy, -imidazolyl-R6, -triazolyl-R6 and -tetrazolyl-R6.
- O—
-
52. The method of claim 31, wherein R6 is 1 to 4 substituents attached to a carbon or nitrogen atom independently selected from the group consisting of hydrogen, —
- C1-4alkyl, —
C2-4alkenyl, —
C2-4alkynyl, —
C(O)H, —
C(O)—
(C1-4)alkyl, —
CO2H, —
C(O)—
O—
(C1-4)alkyl, —
C(O)—
NH2, —
C(NH)—
NH2, —
C(O)—
NH(C1-4alkyl), —
C(O)—
N(C1-4)alkyl)2, —
SO2—
(C1-4)alkyl, —
SO2—
NH2, —
SO2—
NH(C1-4alkyl), —
SO2—
N(C1-4alkyl)2, —
(C1-4)alkyl-N—
R7, —
(C1-4)alkyl-(halo)1-3, —
(C1-4)alkyl-OH, -aryl-R8, —
(C1-4)alkyl-aryl-R8 and —
(C1-4)alkyl-heteroaryl-R8;
with the proviso that, when R6 is attached to a carbon atom, R6 is further selected from the group consisting of —
C1-4alkoxy, —
(C1-4)alkoxy-(halo)1-3, —
SH, —
S—
(C1-4)alkyl, —
N—
R7, cyano, halo, hydroxy, nitro, oxo and -heteroaryl-R8.
- C1-4alkyl, —
-
53. The method of claim 31, wherein R6 is hydrogen.
-
54. The method of claim 33, wherein R7 is 2 substituents independently selected from the group consisting of hydrogen, —
- C1-4alkyl, —
C2-4alkenyl, —
C2-4alkynyl, —
(C1-4)alkyl-OH, —
(C1-4)alkyl-O—
(C1-4)alkyl, —
(C1-4)alkyl-NH2, —
(C1-4)alkyl-NH(C1-4alkyl), —
(C1-4)alkyl-N(C1-4alkyl)2, —
(C1-4)alkyl-S—
(C1-4)alkyl, —
C(O)H, —
C(O)—
(C1-4)alkyl, —
C(O)—
O—
(C1-4)alkyl, —
C(O)—
NH2, —
C(O)—
NH(C1-4alkyl), —
C(O)—
N(C1-4alkyl)2, —
SO2—
(C1-4)alkyl, —
SO2—
NH2, —
SO2—
NH(C1-4alkyl), —
SO2—
N(C1-4alkyl)2, —
C(N)—
NH2, -cycloalkyl-R8, —
(C1-4)alkyl-heterocyclyl-R8, -aryl-R8, —
(C1-4)alkyl-aryl-R8 and —
(C1-4)alkyl-heteroaryl-R8.
- C1-4alkyl, —
-
55. The method of claim 33, wherein R7 is 2 substituents independently selected from the group consisting of hydrogen, —
- C1-4alkyl, —
C(O)H, —
C(O)—
(C1-4)alkyl, —
C(O)—
O—
(C1-4)alkyl, —
SO2—
NH2, —
SO2—
NH(C1-4alkyl) and —
SO2—
N(C1-4alkyl)2.
- C1-4alkyl, —
-
56. The method of claim 31, wherein R8 is 1 to 4 substituents attached to a carbon or nitrogen atom independently selected from the group consisting of hydrogen, —
- C1-4alkyl, —
(C1-4)alkyl-(halo)1-3 and —
(C1-4)alkyl-OH;
with the proviso that, when R8 is attached to a carbon atom, R8 is further selected from the group consisting of —
C1-4alkoxy, —
NH2, —
NH(C1-4alkyl), —
N(C1-4alkyl)2, cyano, halo, —
(C1-4)alkoxy-(halo)1-3, hydroxy and nitro.
- C1-4alkyl, —
-
57. The method of claim 31, wherein R8 is hydrogen.
-
58. The method of claim 31, wherein R9 is 1 to 2 substituents independently selected from the group consisting of hydrogen, —
- C1-4alkoxy, —
NH2, —
NH(C1-4alkyl), —
N(C1-4alkyl)2, cyano, (halo)1-3, hydroxy and nitro.
- C1-4alkoxy, —
-
59. The method of claim 31, wherein R9 is hydrogen.
-
60. The method of claim 28, wherein R2 is one substituent attached to a carbon or nitrogen atom selected from the group consisting of hydrogen, —
- C1-4alkyl-R5, —
C2-4alkenyl-R5, —
C2-4alkynyl-R5, —
C(O)H, —
C(O)—
(C1-4)alkyl-R9, —
C(O)—
NH2, —
C(O)—
NH(C1-4alkyl-R9), —
C(O)—
N(C1-4alkyl-R9)2, —
C(O)—
NH(aryl-R8), —
C(O)-cycloalkyl-R8, —
C(O)-heterocyclyl-R8, —
C(O)-aryl-R8, —
C(O)-heteroaryl-R8, —
CO2H, —
C(O)—
O—
(C1-4)alkyl-R9, —
C(O)—
O-aryl-R8, —
SO2—
(C1-4)alkyl-R9, —
SO2-aryl-R8, -cycloalkyl-R6, -aryl-R6 and —
(C1-4)alkyl-N—
R7;
with the proviso that, when R2 is attached to a carbon atom, R2 is further selected from the group consisting of —
C1-4alkoxy-R5—
N—
R7, cyano, halogen, hydroxy, nitro, oxo, -heterocyclyl-R6 and -heteroaryl-R6.
- C1-4alkyl-R5, —
-
61. The method of claim 28, wherein R2 is one substituent attached to a carbon or nitrogen atom selected from the group consisting of hydrogen, —
- C1-4alkyl-R5, —
C2-4alkenyl-R5, —
C2-4alkynyl-R5, —
CO2H, —
C(O)—
O—
(C1-4)alkyl-R9, -cycloalkyl-R6, -aryl-R6 and —
(C1-4)alkyl-N—
R7;
with the proviso that, when R2 is attached to a nitrogen atom, a quaternium salt is not formed; and
, with the proviso that, when R2 is attached to a carbon atom, R2 is further selected from the group consisting of —
C1-4alkoxy-R5, —
N—
R7, cyano, halogen, hydroxy, nitro, oxo, -heterocyclyl-R6 and -heteroaryl-R6.
- C1-4alkyl-R5, —
-
62. The method of claim 28, wherein R2 is one substituent attached to a carbon or nitrogen atom selected from the group consisting of hydrogen, —
- C1-4alkyl-R5 and -aryl-R6;
with the proviso that, when R2 is attached to a nitrogen atom, a quaternium salt is not formed; and
, with the proviso that when R2 is attached to a carbon atom, R2 is further selected from the group consisting of —
N—
R7, halogen, hydroxy and -heteroaryl-R6.
- C1-4alkyl-R5 and -aryl-R6;
-
63. The method of claim 28, wherein R3 is 1 to 3 substituents attached to a carbon atom independently selected from the group consisting of hydrogen, —
- C1-4alkyl-R10, —
C2-4alkenyl-R10, —
C2-4alkynyl-R10, —
C1-4alkoxy-R10, —
C(O)H, —
C(O)—
(C1-4)alkyl-R9, —
C(O)—
NH2, —
C(O)—
NH(C1-4alkyl-R9), —
C(O)—
N(C1-4alkyl-R9)2, —
C(O)-cycloalkyl-R8, —
C(O)-heterocyclyl-R8, —
C(O)-aryl-R8, —
C(O)-heteroaryl-R8, —
C(NH)—
NH2, —
CO2H, —
C(O)—
O—
(C1-4)alkyl-R9, —
C(O)—
O-aryl-R8, —
SO2—
(C1-8)alkyl-R9, —
SO2-aryl-R8, —
N—
R7, —
(C1-4)alkyl-N—
R7, cyano, halogen, hydroxy, nitro, -cycloalkyl-R8, -heterocyclyl-R8, -aryl-R8 and -heteroaryl-R8.
- C1-4alkyl-R10, —
-
64. The method of claim 28, wherein R3 is one substituent attached to a carbon atom selected from the group consisting of hydrogen, —
- C1-4alkyl-R10, —
C2-4alkenyl-R10, —
C2-4alkynyl-R10, —
C1-4alkoxy-R10, —
C(O)H, —
CO2H, —
NH2, —
NH(C1-4alkyl), —
N(C1-4alkyl)2, cyano, halogen, hydroxy and nitro.
- C1-4alkyl-R10, —
-
65. The method of claim 28, wherein R3 is one substituent attached to a carbon atom selected from the group consisting of hydrogen, —
- C1-4alkyl-R10, —
NH2, —
NH(C1-4alkyl), —
N(C1-4alkyl)2, halogen and hydroxy.
- C1-4alkyl-R10, —
-
66. The method of claim 28, wherein R4 is 1 to 4 substituents attached to a carbon atom independently selected from the group consisting of hydrogen, —
- C1-4alkyl-R10, —
C2-4alkenyl-R10, —
C2-4alkynyl-R10, —
C1-4alkoxy-R10, —
C(O)H, —
C(O)—
(C1-4)alkyl-R9, —
C(O)—
NH2, —
C(O)—
NH(C1-4alkyl-R9), —
C(O)—
N(C1-4alkyl-R9)2, —
C(O)-cycloalkyl-R8, —
C(O)-heterocyclyl-R8, —
C(O)-aryl-R8, —
C(O)-heteroaryl-R8, —
C(NH)—
NH2, —
CO2H, —
C(O)—
O—
(C1-4)alkyl-R9, —
C(O)—
O-aryl-R8, —
SH, —
S—
(C1-4)alkyl-R10, —
SO2—
(C1-4)alkyl-R9, —
SO2-aryl-R8, —
SO2—
NH2, —
SO2—
NH(C1-4alkyl-R9), —
SO2—
N(C1-4alkyl-R9)2, —
N—
R7, cyano, halogen, hydroxy, nitro, -cycloalkyl-R8, -heterocyclyl-R8, -aryl-R8 and -heteroaryl-R8.
- C1-4alkyl-R10, —
-
67. The method of claim 28, wherein R4 is 1 to 4 substituents attached to a carbon atom independently selected from the group consisting of hydrogen, —
- C1-4alkyl-R10, —
C2-4alkenyl-R10, —
C2-4alkynyl-R10, —
C1-4alkoxy-R10, —
C(O)H, —
CO2H, —
NH2, —
NH(C1-4alkyl), —
N(C1-4alkyl)2, cyano, halogen, hydroxy, nitro, -cycloalkyl, -heterocyclyl, -aryl and -heteroaryl.
- C1-4alkyl-R10, —
-
68. The method of claim 28, wherein R4 is 1 to 4 substituents attached to a carbon atom independently selected from the group consisting of hydrogen, C1-4alkyl-R10, C1-4alkoxy-R10, —
- NH2, —
NH(C1-4alkyl), —
N(C1-4alkyl)2, halogen and hydroxy.
- NH2, —
-
69. The method of claim 28, wherein R4 is 1 to 4 substituents attached to a carbon atom independently selected from the group consisting of hydrogen, C1-4alkyl-R10, C1-4alkoxy-R10, —
- NH2, —
NH(C1-4alkyl), —
N(C1-4alkyl)2, chlorine, fluorine and hydroxy.
- NH2, —
-
70. The method of claims 38 and 41, wherein R10 is 1 to 2 substituents independently selected from the group consisting of hydrogen, —
- NH2, —
NH(C1-4alkyl), —
N(C1-4alkyl)2, cyano, (halo)1-3, hydroxy, nitro and oxo.
- NH2, —
-
71. The method of claims 38 and 41, wherein R10 is 1 to 2 substituents independently selected from the group consisting of hydrogen and (halo)1-3.
-
72. The method of claims 38 and 41, wherein R10 is 1 to 2 substituents independently selected from the group consisting of hydrogen and (fluoro)3.
-
73. The method of claim 28, wherein Y and Z are independently selected from the group consisting of O, S, (H,OH) and (H,H);
- with the proviso that one of Y and Z is O and the other is selected from the group consisting of O, S, (H,OH) and (H,H).
-
74. The method of claim 28, wherein Y and Z are independently selected from the group consisting of O and (H,H);
- with the proviso that one of Y and Z is O, and the other is selected from the group consisting of O and (H,H).
-
75. The method of claim 28, wherein Y and Z are independently selected from O.
-
76. The method of claim 28, where the compound of the Formula II is 3-[1-(3-hydroxypropyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-4-[2-(trifluoromethyl)phenyl]-1H-pyrrole-2,5-dione.
-
77. The method of claim 28, where the compound of the Formula II is 3-[1-(3-hydroxypropyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-4-(1-methyl-1H-pyrazol-3-yl)-1H-pyrrole-2,5-dione.
-
78. The method of claim 28, where the compound of the Formula II is 3-[1-(3-hydroxy-propyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-4-pyrazin-2-yl-pyrrole-2,5-dione.
-
79. The method of claim 28, where the compound of the Formula II is 3-(2,4-dimethoxy-pyrimidin-5-yl)-4-[1-(3-hydroxy-propyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-pyrrole-2,5-dione.
-
80. The method of claim 28, where the compound of the Formula II is 4-{3-[4-(2,4-dimethoxy-pyrimidin-5-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl]-pyrrolo[2,3-b]pyridin-1-yl}-butyronitrile.
-
81. The method of claim 28, where the compound of the Formula II is 4-{3-[4-(1-methyl-1H-pyrazol-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl]-pyrrolo[2,3-b]pyridin-1-yl}-butyronitrile.
-
82. The method of claim 28, where the compound of the Formula II is 3-(2,4-dimethoxy-pyrimidin-5-yl)-4-(1-phenethyl-1H-pyrrolo[2,3-b]pyridine-3-yl)-pyrrole-2,5-dione.
-
83. The method of claim 1, wherein the inhibitor of GSK-3B enzyme activity is a compound of the Formula (III):
-
84. The method of claim 83, wherein A and E are independently selected from the group consisting of a hydrogen substituted carbon atom and a nitrogen atom;
- wherein
is independently selected from the group consisting of 1H-indole, 1H-pyrrolo[2,3-b]pyridine, 1H-pyrazolo[3,4-b]pyridine and 1H-indazole.
- wherein
-
85. The method of claim 83, wherein Z is selected from O;
- alternatively, Z is selected from dihydro;
wherein each hydrogen atom is attached by a single bond.
- alternatively, Z is selected from dihydro;
-
86. The method of claim 83, wherein R4 and R5 are independently selected from C1-8alkyl, C2-8alkenyl and C2-8alkynyl optionally substituted with oxo.
-
87. The method of claim 83, wherein R2 is selected from the group consisting of —
- C1-8alkyl-, —
C2-8alkenyl-, —
C2-8alkynyl-, —
O—
(C1-8)alkyl-O—
, —
O—
(C2-8)alkenyl-O—
, —
O—
(C2-8)alkynyl-O—
, —
C(O)—
(C1-8)alkyl-C(O)—
(wherein any of the foregoing alkyl, alkenyl and alkynyl linking groups are straight carbon chains optionally substituted with one to four substituents independently selected from the group consisting of C1-8alkyl, C1-8alkoxy, C1-8alkoxy(C1-8)alkyl, carboxyl, carboxyl(C1-8)alkyl, —
C(O)O—
(C1-8)alkyl, —
C1-8alkyl-C(O)O—
(C1-8)alkyl, amino (substituted with a substituent independently selected from the group consisting of hydrogen and C1-4alkyl), amino(C1-8)alkyl (wherein amino is substituted with a substituent independently selected from the group consisting of hydrogen and C1-4alkyl), halogen, (halo)1-3(C1-8)alkyl, (halo)1-3(C1-8)alkoxy, hydroxy, hydroxy(C1-8)alkyl and oxo; and
, wherein any of the foregoing alkyl, alkenyl and alkynyl linking groups are optionally substituted with one to two substituents independently selected from the group consisting of heterocyclyl, aryl, heteroaryl, heterocyclyl(C1-8)alkyl, aryl(C1-8)alkyl, heteroaryl(C1-8)alkyl, spirocycloalkyl and spiroheterocyclyl (wherein any of the foregoing cycloalkyl, heterocyclyl, aryl and heteroaryl substituents are optionally substituted with one to four substituents independently selected from the group consisting of C1-8alkyl, C1-8alkoxy, C1-8alkoxy(C1-8)alkyl, carboxyl, carboxyl(C1-8)alkyl, amino (substituted with a substituent independently selected from the group consisting of hydrogen and C1-4alkyl), amino(C1-8)alkyl (wherein amino is substituted with a substituent independently selected from the group consisting of hydrogen and C1-4alkyl), halogen, (halo)1-3(C1-8)alkyl, (halo)1-3(C1-8)alkoxy, hydroxy and hydroxy(C1-8)alkyl; and
, wherein any of the foregoing heterocyclyl substituents are optionally substituted with oxo)), cycloalkyl, heterocyclyl, aryl, heteroaryl (wherein cycloalkyl, heterocyclyl, aryl and heteroaryl are optionally substituted with one to four substituents independently selected from the group consisting of C1-8alkyl, C1-8alkoxy, C1-8alkoxy(C1-8)alkyl, carboxyl, carboxyl(C1-8)alkyl, amino (substituted with a substituent independently selected from the group consisting of hydrogen and C1-4alkyl), amino(C1-8)alkyl (wherein amino is substituted with a substituent independently selected from the group consisting of hydrogen and C1-4alkyl), halogen, (halo)1-3(C1-8)alkyl, (halo)1-3(C1-8)alkoxy, hydroxy and hydroxy(C1-8)alkyl; and
, wherein heterocyclyl is optionally substituted with oxo), —
(O—
(CH2)1-6)0-5—
O—
, —
O—
(CH2)1-6—
O—
(CH2)1-6—
O—
, —
O—
(CH2)1-6—
O—
(CH2)1-6—
O—
(CH2)1-6—
O—
, —
(O—
(CH2)1-6)0-5—
NR6—
, —
O—
(CH2)1-6—
NR6—
(CH2)1-6—
O—
, —
O—
(CH2)1-6—
O—
(CH2)1-6—
NR6—
, —
(O—
(CH2)1-6)0-5—
S—
, —
O—
(CH2)1-6—
S—
(CH2)1-6—
O—
, —
O—
(CH2)1-6—
O—
(CH2)1-6—
S—
, —
NR6—
, —
NR6—
NR7—
, —
NR6—
(CH2)1-6—
NR7—
, —
NR6—
(CH2)1-6—
NR7—
(CH2)1-6—
NR8—
, —
NR6—
C(O)—
, —
C(O)—
NR6—
, —
C(O)—
(CH2)0-6—
NR6—
(CH2)0-6—
C(O)—
, —
NR6—
(CH2)0-6—
C(O)—
(CH2)1-6—
C(O)—
(CH2)0-6—
NR7—
, —
NR6—
C(O)—
NR7—
, —
NR6—
C(NR7)—
NR8—
, —
O—
(CH2)1-6—
NR6—
(CH2)1-6—
S—
, —
S—
(CH2)1-6—
NR6—
(CH2)1-6—
O—
, —
S—
(CH2)1-6—
NR6—
(CH2)1-6—
S—
, —
NR6—
(CH2)1-6—
S—
(CH2)1-6—
NR7— and
—
SO2—
(wherein R6, R7 and R8 are independently selected from the group consisting of hydrogen, C1-8alkyl, C1-8alkoxy(C1-8)alkyl, carboxyl(C1-8)alkyl, amino(C1-8)alkyl (wherein amino is substituted with a substituent independently selected from the group consisting of hydrogen and C1-4alkyl), hydroxy(C1-8)alkyl, heterocyclyl(C1-8)alkyl, aryl(C1-8)alkyl and heteroaryl(C1-8)alkyl (wherein the foregoing heterocyclyl, aryl and heteroaryl substituents are optionally substituted with one to four substituents independently selected from the group consisting of C1-8alkyl, C1-8alkoxy, C1-8alkoxy(C1-8)alkyl, carboxyl, carboxyl(C1-8)alkyl, amino (substituted with a substituent independently selected from the group consisting of hydrogen and C1-4alkyl), amino(C1-8)alkyl (wherein amino is substituted with a substituent independently selected from the group consisting of hydrogen and C1-4alkyl), halogen, (halo)1-3(C1-8)alkyl, (halo)1-3(C1-8)alkoxy, hydroxy and hydroxy(C1-8)alkyl; and
, wherein heterocyclyl is optionally substituted with oxo));
with the proviso that, if A and E are selected from a hydrogen substituted carbon atom, then R2 is selected from the group consisting of —
C2-8alkynyl-, —
O—
(C1-8)alkyl-O—
, —
O—
(C2-8)alkenyl-O—
, —
O—
(C2-8)alkynyl-O—
, —
C(O)—
(C1-8)alkyl-C(O)—
(wherein any of the foregoing alkyl, alkenyl and alkynyl linking groups are straight carbon chains optionally substituted with one to four substituents independently selected from the group consisting of C1-8alkyl, C1-8alkoxy, C1-8alkoxy(C1-8)alkyl, carboxyl, carboxyl(C1-8)alkyl, —
C(O)O—
(C1-8)alkyl, —
C1-8alkyl-C(O)O—
(C1-8)alkyl, amino (substituted with a substituent independently selected from the group consisting of hydrogen and C1-4alkyl), amino(C1-8)alkyl (wherein amino is substituted with a substituent independently selected from the group consisting of hydrogen and C1-4alkyl), halogen, (halo)1-3(C1-8)alkyl, (halo)1-3(C1-8)alkoxy, hydroxy, hydroxy(C1-8)alkyl and oxo; and
, wherein any of the foregoing alkyl, alkenyl and alkynyl linking groups are optionally substituted with one to two substituents independently selected from the group consisting of heterocyclyl, aryl, heteroaryl, heterocyclyl(C1-8)alkyl, aryl(C1-8)alkyl, heteroaryl(C1-8)alkyl, spirocycloalkyl and spiroheterocyclyl (wherein any of the foregoing cycloalkyl, heterocyclyl, aryl and heteroaryl substituents are optionally substituted with one to four substituents independently selected from the group consisting of C1-8alkyl, C1-8alkoxy, C1-8alkoxy(C1-8)alkyl, carboxyl, carboxyl(C1-8)alkyl, amino (substituted with a substituent independently selected from the group consisting of hydrogen and C1-4alkyl), amino(C1-8)alkyl (wherein amino is substituted with a substituent independently selected from the group consisting of hydrogen and C1-4alkyl), halogen, (halo)1-3(C1-8)alkyl, (halo)1-3(C1-8)alkoxy, hydroxy and hydroxy(C1-8)alkyl; and
, wherein any of the foregoing heterocyclyl substituents are optionally substituted with oxo)), cycloalkyl (wherein cycloalkyl is optionally substituted with one to four substituents independently selected from the group consisting of C1-8alkyl, C1-8alkoxy, C1-8alkoxy(C1-8)alkyl, carboxyl, carboxyl(C1-8)alkyl, amino (substituted with a substituent independently selected from the group consisting of hydrogen and C1-4alkyl), amino(C1-8)alkyl (wherein amino is substituted with a substituent independently selected from the group consisting of hydrogen and C1-4alkyl), halogen, (halo)1-3(C1-8)alkyl, (halo)1-3(C1-8)alkoxy, hydroxy and hydroxy(C1-8)alkyl), —
(O—
(CH2)1-6)1-5—
O—
, —
O—
(CH2)1-6—
O—
(CH2)1-6—
O—
, —
O—
(CH2)1-6—
O—
(CH2)1-6—
O—
(CH2)1-6—
O—
, —
(O—
(CH2)1-6)1-5—
NR6—
, —
O—
(CH2)1-6—
NR6—
(CH2)1-6—
O—
, —
O—
(CH2)1-6—
O—
(CH2)1-6—
NR6—
, —
(O—
(CH2)1-6)0-5—
S—
, —
O—
(CH2)1-6—
S—
(CH2)1-6—
O—
, —
O—
(CH2)1-6—
O—
(CH2)1-6—
S—
, —
NR6—
NR7—
, —
NR6—
(CH2)1-6—
NR7—
, —
NR6—
(CH2)1-6—
NR7—
(CH2)1-6—
NR8—
, —
NR9—
C(O)—
, —
C(O)—
NR9—
, —
C(O)—
(CH2)0-6—
NR6—
(CH2)0-6—
C(O)—
, —
NR6—
(CH2)0-6—
C(O)—
(CH2)1-6—
C(O)—
(CH2)0-6—
NR7—
, —
NR6—
C(O)—
NR7—
, —
NR6—
C(NR7)—
NR8—
, —
O—
(CH2)1-6—
NR6—
(CH2)1-6—
S—
, —
S—
(CH2)1-6—
NR6—
(CH2)1-6—
O—
, —
S—
(CH2)1-6—
NR6—
(CH2)1-6—
S— and
—
NR6—
(CH2)1-6—
S—
(CH2)1-6—
NR7—
(wherein R6, R7 and R8 are independently selected from the group consisting of hydrogen, C1-8alkyl, C1-8alkoxy(C1-8)alkyl, carboxyl(C1-8)alkyl, amino(C1-8)alkyl (wherein amino is substituted with a substituent independently selected from the group consisting of hydrogen and C1-4alkyl), hydroxy(C1-8)alkyl, heterocyclyl(C1-8)alkyl, aryl(C1-8)alkyl and heteroaryl(C1-8)alkyl (wherein the foregoing heterocyclyl, aryl and heteroaryl substituents are optionally substituted with one to four substituents independently selected from the group consisting of C1-8alkyl, C1-8alkoxy, C1-8alkoxy(C1-8)alkyl, carboxyl, carboxyl(C1-8)alkyl, amino (substituted with a substituent independently selected from the group consisting of hydrogen and C1-4alkyl), amino(C1-8)alkyl (wherein amino is substituted with a substituent independently selected from the group consisting of hydrogen and C1-4alkyl), halogen, (halo)1-3(C1-8)alkyl, (halo)1-3(C1-8)alkoxy, hydroxy and hydroxy(C1-8)alkyl; and
, wherein heterocyclyl is optionally substituted with oxo); and
, wherein R9 is selected from the group consisting of C1-8alkyl, C1-8alkoxy(C1-8)alkyl, carboxyl(C1-8)alkyl, amino(C1-8)alkyl (wherein amino is substituted with a substituent independently selected from the group consisting of hydrogen and C1-4alkyl), hydroxy(C1-8)alkyl, heterocyclyl(C1-8)alkyl, aryl(C1-8)alkyl and heteroaryl(C1-8)alkyl (wherein the foregoing heterocyclyl, aryl and heteroaryl substituents are optionally substituted with one to four substituents independently selected from the group consisting of C1-8alkyl, C1-8alkoxy, C1-8alkoxy(C1-8)alkyl, carboxyl, carboxyl(C1-8)alkyl, amino (substituted with a substituent independently selected from the group consisting of hydrogen and C1-4alkyl), amino(C1-8)alkyl (wherein amino is substituted with a substituent independently selected from the group consisting of hydrogen and C1-4alkyl), halogen, (halo)1-3(C1-8)alkyl, (halo)1-3(C1-8)alkoxy, hydroxy and hydroxy(C1-8)alkyl; and
, herein heterocyclyl is optionally substituted with oxo)).
- C1-8alkyl-, —
-
88. The method of claim 83, wherein R1 and R3 are independently selected from the group consisting of hydrogen, C1-8alkyl, C2-8alkenyl, C2-8alkynyl (wherein alkyl, alkenyl and alkynyl are optionally substituted with a substituent selected from the group consisting of C1-8alkoxy, alkoxy(C1-8)alkyl, carboxyl, carboxyl(C1-8)alkyl, amino (substituted with a substituent independently selected from the group consisting of hydrogen and C1-4alkyl), amino(C1-8)alkyl (wherein amino is substituted with a substituent independently selected from the group consisting of hydrogen and C1-4alkyl), (halo)1-3, (halo)1-3(C1-8)alkyl, (halo)1-3(C1-8)alkoxy, hydroxy, hydroxy(C1-8)alkyl and oxo), C1-8alkoxy, C1-8alkoxycarbonyl, (halo)1-3(C1-8)alkoxy, C1-8alkylthio, aryl, heteroaryl (wherein aryl and heteroaryl are optionally substituted with a substituent selected from the group consisting of C1-8alkyl, C1-8alkoxy, alkoxy(C1-8)alkyl, carboxyl, carboxyl(C1-8)alkyl, amino (substituted with a substituent independently selected from the group consisting of hydrogen and C1-4alkyl), amino(C1-8)alkyl (wherein amino is substituted with a substituent independently selected from the group consisting of hydrogen and C1-4alkyl), halogen, (halo)1-3(C1-8)alkyl, (halo)1-3(C1-8)alkoxy, hydroxy and hydroxy(C1-8)alkyl), amino (substituted with a substituent independently selected from the group consisting of hydrogen and C1-4alkyl), cyano, halogen, hydroxy and nitro;
- and pharmaceutically acceptable salts thereof.
-
89. The method of claim 83, wherein the compound of the Formula (III) is 6,7,9,10,12,13,15,16-octahydro-23H-5,26:
- 17,22-dimetheno-5H-dipyrido[2,3-k;
3′
,2′
-q]pyrrolo[3,4-n][1,4,7,10,19]trioxadiazacyclohenicosine-23,25(24H)-dione.
- 17,22-dimetheno-5H-dipyrido[2,3-k;
-
90. The method of claim 83, wherein the compound of the Formula (III) is 10,11,13,14,16,17,19,20,22,23-decahydro-9,4:
- 24,29-dimetheno-1H-dipyrido[2,3-n;
3′
,2′
-t]pyrrolo[3,4-q][1,4,7,10,13,22]tetraoxadiazacyclotetracosine-1,3(2H)-dione.
- 24,29-dimetheno-1H-dipyrido[2,3-n;
-
91. The method of claim 83, wherein the compound of the Formula (III) is 10,11,13,14,16,17,19,20,22,23,25,26-dodecahydro-9,4:
- 27,32-dimetheno-1H-dipyrido[2,3-q;
3′
,2′
-w]pyrrolo[3,4-t][1,4,7,10,13,16,25]pentaoxadiazacycloheptacosine-1,3(2H)-dione.
- 27,32-dimetheno-1H-dipyrido[2,3-q;
-
92. The method of claim 83, wherein the compound of the Formula (III) is 6,7,9,10,12,13-hexahydro-20H-5,23:
- 14,19-dimetheno-5H-dibenzo[h,n]pyrrolo[3,4-k][1,4,7,16]dioxadiazacyclooctadecine-20,22(21H)-dione.
-
93. The method of claim 83, wherein the compound of the Formula (III) is 6,7,9,10,12,13,15,16-octahydro-23H-5,26:
- 17,22-dimetheno-5H-dibenzo[k,q]pyrrolo[3,4-n][1,4,7,10,19]trioxadiazacycloheneicosine-23,25(24H)-dione.
-
94. The method of claim 83, wherein the compound of the Formula (III) is 10,11,13,14,16,17,19,20,22,23-decahydro-9,4:
- 24,29-dimetheno-1H-dibenzo[n,t]pyrrolo[3,4-q][1,4,7,10,13,22]tetraoxadiazacyclotetracosine-1,3(2H)-dione.
-
95. The method of claim 83, wherein the compound of the Formula (III) is Compound 1a.
-
96. The method of claim 83, wherein the compound of the Formula (III) is 3-[1-[3-[(2-hydroxyethyl)methylamino]propyl]-1H-indazol-3-yl]-4-[1-(3-pyridinyl)-1H-indol-3-yl]-1H-pyrrole-2,5-dione.
-
97. The method of claim 83, wherein the compound of the Formula (III) is 3,5-dichloro-N-[3-chloro-4-[(3,4,12,12a-tetrahydro-1H-[1,4]thiazino[3,4-c][1,4]benzodiazepin-11(6H)-yl)carbonyl]phenyl]-benzamide.
-
98. The method of claim 83, wherein the compound of the Formula (III) is 3-[1-(2-hydroxy-ethyl)-1H-indol-3-yl]-4-(1-pyridin-3-yl-1H-indol-3-yl)-pyrrole-2,5-dione.
-
99. The method of claim 83, wherein the compound of the Formula (III) is 3-(2-methoxy-phenyl)-4-(1-pyridin-3-yl-1H-indol-3-yl)-pyrrole-2,5-dione.
-
100. The method of claim 83, wherein the compound of the Formula (III) is 6-[[2-[[4-(2,4-dichlorophenyl)-5-(4-methyl-1H-imidazol-2-yl)-2-pyrimidinyl]amino]ethyl]amino]-3-pyridinecarbonitrile.
-
101. The method of claim 83, wherein the compound of the Formula (III) is 3-(5-chloro-1-methyl-1H-indol-3-yl)-4-[1-(3-imidazol-1-yl-propyl)-1H-indazol-3-yl]-pyrrole-2,5-dione.
-
102. The method of claim 83, wherein the compound of the Formula (III) is 3-(5-chloro-1-methyl-1H-indol-3-yl)-4-[1-(3-[1,2,3]triazol-1-yl-propyl)-1H-indazol-3-yl]-pyrrole-2,5-dione.
-
103. The method of claim 83, wherein the compound of the Formula (III) is 3-[1-(3-hydroxy-propyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]-4-(1-methyl-1H-pyrazol-3-yl)-pyrrole-2,5-dione.
-
104. The method of claim 83, wherein the compound of the Formula (III) is Compound 10a.
-
105. The method of claim 83, wherein the compound of the Formula (III) is 3-[1-(3-hydroxy-3-methyl-butyl)-1H-indazol-3-yl]-4-(1-pyridin-3-yl-1H-indol-3-yl)-pyrrole-2,5-dione.
-
106. The method of claim 83, wherein the compound of the Formula (III) is 3-[1-(2-hydroxy-ethyl)-1H-indazol-3-yl]-4-(1-pyrimidin-5-yl-1H-indol-3-yl)-pyrrole-2,5-dione.
-
107. The method of claim 83, wherein the compound of the Formula (III) is 3-[1-(2-hydroxy-ethyl)-1H-indol-3-yl]-4-(1-pyrimidin-5-yl-1H-indol-3-yl)-pyrrole-2,5-dione.
-
108. The method of claim 83, wherein the compound of the Formula (III) is (11Z)-8,9,10,13,14,15-hexahydro-2,6:
- 17,21-di(metheno)pyrrolo[3,4-h][1,15,7]dioxazacyclotricosine-22,24(1H,23H)-dione.
-
109. The method of claim 83, wherein the compound of the Formula (III) is 3-(5-chloro-1-pyridin-3-yl-1H-indol-3-yl)-4-[1-(3-hydroxy-propyl)-1H-indazol-3-yl]-pyrrole-2,5-dione.
-
110. The method of claim 83, wherein the compound of the Formula (III) is 3-(2-methoxy-phenyl)-4-[1-(3-methoxy-propyl)-1H-pyrrolo[3,2-c]pyridin-3-yl]-pyrrole-2,5-dione.
-
111. The method of claim 83, wherein the compound of the Formula (III) is 3-[1-(3-hydroxy-propyl)-1H-indazol-3-yl]-4-[1-(tetrahydro-pyran-4-yl)-1H-indol-3-yl]-pyrrole-2,5-dione.
-
112. The method of claim 83, wherein the compound of the Formula (III) is 2-{3-[4-(5-chloro-1-methyl-1H-indol-3-yl)-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl]-indazol-1-yl}-N-(2-hydroxy-ethyl)-acetamide.
-
113. The method of claim 83, wherein the compound of the Formula (III) is 4-(3-chloro-phenyl)-6-(3-dimethylamino-propyl)-5,6-dihydro-4H-2,4,6-triaza-cyclopenta[c]fluorine-1,3-dione.
-
114. The method of claim 83, wherein the compound of the Formula (III) is 14-ethyl-6,7,9,10,13,14,15,16-octahydro-12H,23H-5,26:
- 17,22-dimethenodibenzo[k,q]pyrrolo[3,4-n][1,4,7,10,19]dioxatriazacycloheneicosine-23,25(24H)-dione.
-
115. The method of claim 83, wherein the compound of the Formula (III) is 14-benzyl-6,7,9,10,13,14,15,16-octahydro-12H,23H-5,26:
- 17,22-di(metheno)dibenzo[k,q]pyrrolo[3,4-n][1,4,7,10,19]dioxatriazacyclohenicosine-23,25(24H)-dione.
-
116. The method of claim 83, wherein the compound of the Formula (III) is 3-(1-{2-[2-(2-hydroxy-ethoxy)-ethoxy]-ethyl}-1H-indol-3-yl)-4-[1-(2-hydroxy-ethyl)-1H-indol-3-yl]-pyrrole-2,5-dione.
-
117. The method of claim 83, wherein the compound of the Formula (III) is 6,7,8,9,10,11,12,13-octahydro-8,11-dimethyl-5,23:
- 14,19-dimetheno-20H-dibenzo[k,q]pyrrolo[3,4-n][1,4,7,10]tetraazacyclooctadecine-20,22(21H)-dione.
-
118. The method of claim 83, wherein the compound of the Formula (III) is 7,8,9,10,12,13,16,17,18,19-decahydro-8,17-dimethyl-15H,26H-5,29:
- 20,25-dimetheno-6H-dibenzo[k,q]pyrrolo[3,4-n][1,4,7,10,19,22]dioxatetraazacyclotetracosine-26,28(27H)-dione.
-
119. The method of claim 83, wherein the compound of the Formula (III) is 14-(2-furylmethyl)-6,7,9,10,13,14,15,16-octahydro-12H,23H-5,26:
- 17,22-di(metheno)dibenzo[k,q]pyrrolo[3,4-n][1,4,7,10,19]dioxatriazacyclohenicosine-23,25(24H)-dione.
-
120. The method of claim 83, wherein the compound of the Formula (III) is 14-(2-thienylmethyl)-6,7,9,10,13,14,15,16-octahydro-12H,23H-5,26:
- 17,22-di(metheno)dibenzo[k,q]pyrrolo[3,4-n][1,4,7,10,19]dioxatriazacyclohenicosine-23,25(24H)-dione.
-
121. The method of claim 83, wherein the compound of the Formula (III) is 14-(1-naphthylmethyl)-6,7,9,10,13,14,15,16-octahydro-12H,23H-5,26:
- 17,22-di(metheno)dibenzo[k,q]pyrrolo[3,4-n][1,4,7,10,19]dioxatriazacyclohenicosine-23,25(24H)-dione.
-
122. The method of claim 83, wherein the compound of the Formula (III) is 14-(pyridin-4-ylmethyl)-6,7,9,10,13,14,15,16-octahydro-12H,23H-5,26:
- 17,22-di(metheno)dibenzo[k,q]pyrrolo[3,4-n][1,4,7,10,19]dioxatriazacyclohenicosine-23,25(24H)-dione.
-
123. The method of claim 83, wherein the compound of the Formula (III) is 3-[1-(2-{2-[2-(1,2,3,4-tetrahydro-naphthalen-1-ylamino)-ethoxy]-ethoxy}-ethyl)-1H-indol-3-yl]-4-{1-[2-(1,2,3,4-tetrahydro-naphthalen-1-ylamino)-ethyl]-1H-indol-3-yl}-pyrrole-2,5-dione.
-
124. The method of claim 83, wherein the compound of the Formula (III) is 3-[1-(3-dimethylamino-phenyl)-1H-indol-3-yl]-4-[1-(2-hydroxy-ethyl)-1H-indazol-3-yl]-pyrrole-2,5-dione.
-
125. The method of claim 83, wherein the compound of the Formula (III) is 3-[5-chloro-1-(6-dimethylamino-pyridin-3-yl)-1H-indol-3-yl]-4-[1-(2-hydroxy-ethyl)-1H-indazol-3-yl]-pyrrole-2,5-dione.
-
126. The method of claim 83, wherein the compound of the Formula (III) is 5-(5-chloro-3-{4-[1-(2-hydroxy-ethyl)-1H-indazol-3-yl]-2,5-dioxo-2,5-dihydro-1H-pyrrol-3-yl}-indol-1-yl)-nicotinic acid methyl ester.
-
2. The method of claim 1, wherein the pluripotent cells are embryonic stem cells.
-
Specification
- Resources
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Current AssigneeJanssen Biotech, Inc. (Johnson & Johnson)
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Original AssigneeJanssen Biotech, Inc. (Johnson & Johnson)
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InventorsLiu, Jiajian, Davis, Janet
-
Granted Patent
-
Time in Patent OfficeDays
-
Field of Search
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US Class Current435/377
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CPC Class CodesA61K 31/00 Medicinal preparations cont...C12N 2501/105 Insulin-like growth factors...C12N 2501/115 Basic fibroblast growth fac...C12N 2501/117 Keratinocyte growth factors...C12N 2501/119 Other fibroblast growth fac...C12N 2501/16 Activin; Inhibin; Mullerian...C12N 2501/415 Wnt; FrizzeledC12N 2501/48 Regulators of apoptosisC12N 2501/70 EnzymesC12N 2506/00 Differentiation of animal c...C12N 2506/02 from embryonic cellsC12N 5/0606 Pluripotent embryonic cells...C12N 5/0676 Pancreatic cells