Compounds and methods for kinase modulation, and indications therefor
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Abstract
Compounds active on protein kinases are described, as well as methods of using such compounds to treat diseases and conditions associated with aberrant activity of protein kinases.
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Citations
24 Claims
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1. A compound having the chemical structure of Formula I,
- View Dependent Claims (2, 3, 4, 5, 6, 19, 20)
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2. The compound of claim 1, wherein:
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R1 is selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —
OH, —
NH2, —
CN, —
NO2, —
C(O)OH, —
S(O)2NH2, —
C(O)NH2, —
C(S)NH2, —
NHC(O)NH2, —
NHC(S)NH2, —
NHS(O)2NH2, —
OR7, —
SR7, —
NR8R7, —
C(O)R7, —
C(S)R7, —
C(O)OR7, —
C(O)NR8R7, —
C(S)NR8R7, S(O)2NR8R7, —
NR8C(O)R7, —
NR8C(S)R7, —
NR8S(O)2R7, —
NR8C(O)NH2, —
NR8C(O)NR8R7, —
NR8C(S)NH2, —
NR8C(S)NR8R7, —
NR8S(O)2NH2, —
NR8S(O)2NR8R7, —
S(O)R7, and —
S(O)2R7, wherein lower alkyl, lower alkenyl or lower alkynyl are optionally substituted with one or more substituents selected from fluoro, —
OH, —
NH2, C(O)OH, —
C(O)NH2, —
OR7, —
NR8R7, —
C(O)OR7, —
C(O)NR8R7, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R1 or as substituents of lower alkyl, lower alkenyl or lower alkynyl are optionally substituted with one or more substituents selected from the group consisting of —
OH, —
NH2, —
CN, —
NO2, —
S(O)2NH2, —
C(O)NH2, —
OR9, —
SR9, —
NHR9, —
NR8R9, —
NR8C(O)R9, —
NR8S(O)2R9, —
S(O)2R9, —
S(O)2NR8R9, —
C(O)R9, —
C(O)NR8R9, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino;R2 is selected from the group consisting of halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —
OH, —
NH2, —
CN, —
NO2, —
C(O)OH, S(O)2NH2, —
C(O)NH2, —
C(S)NH2, —
NHC(O)NH2, —
NHC(S)NH2, —
NHS(O)2NH2, —
OR7, —
SR7, —
NR8R7, —
C(O)R7, —
C(S)R7, —
C(O)OR7, —
C(O)NR8R7, —
C(S)NR8R7, —
S(O)2NR8R7, —
NR8C(O)R7, —
NR8C(S)R7, —
NR8S(O)2R7, —
NR8C(O)NH2, —
NR8C(O)NR8R7, —
NR8C(S)NH2, —
NR8C(S)NR8R7, —
NR8S(O)2NH2, —
NR8S(O)2NR8R7, —
S(O)R7, and —
S(O)2R7, wherein lower alkyl is optionally substituted with one or more substituents selected from fluoro, —
OR7, —
NR8R7, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R2 or as substituents of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of —
OH, —
NH2, —
CN, —
NO2, —
S(O)2NH2, —
C(O)NH2, —
OR9, —
SR9, —
NHR9—
NR8R9, —
NR8C(O)R9, —
NR8S(O)2R9, —
S(O)2R9, —
S(O)2NR8R9, —
C(O)R9, —
C(O)NR8R9, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino;R7 is selected from the group consisting of lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R7 or as substituents of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of —
OH, —
NH2, —
CN, —
NO2, —
S(O)NH), —
C(O)NH2, —
OR9, —
SR9, —
NHR9, —
NR8R9, —
NR8C(O)R9, —
NR8S(O)2R9, —
S(O)2R9, —
S(O)2NR8R9, —
C(O)R9, —
C(O)NR8R9, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino;R8 at each occurrence is independently hydrogen or lower alkyl; and R9 at each occurrence is independently selected from the group consisting of lower alkyl, heterocycloalkyl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino, and heterocycloalkyl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, —
CN, lower alkyl, fluoro substituted lower alkyl, lower alkoxy and fluoro substituted lower alkoxy.
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3. The compound of claim 2, wherein:
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R1 is selected from the group consisting of hydrogen, —
CN, —
OR7, —
SR7, —
NR8R7, —
NR8C(O)R7, —
NR8S(O)2R7—
C(O)NR8R7, —
C(O)R7, —
S(O)2NR8R7, —
S(O)R7, —
S(O)2R7, halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R1 or as substituents of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of —
OH, —
NH2, —
CN, —
NO2, —
S(O)2NH2, —
C(O)NH2, —
OR9, —
SR9, —
NR8R9, —
NR8C(O)R9, —
NR8S(O)2R9, —
S(O)2R9, —
S(O)2NR8R9, —
C(O)R9, —
C(O)NR8R9, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino; andR2 is selected from the group consisting of —
CN, —
OR7, —
SR7, —
NR8R7, —
NR8C(O)R7, —
NR8S(O)2R7, —
(CO)NR8R7, —
C(O)R7, —
S(O)2NR8R7, —
S(O)R7, —
S(O)2R7, halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, as R2 or as a substituent of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of —
OH, —
NH2, —
CN, —
NO2, —
S(O)2NH2, —
C(O)NH2, —
OR9, —
SR9, —
NR8R9, —
NR8C(O)R9, —
NR8S(O)2R9, —
S(O)2R9, —
S(O)2NR8R9, —
C(O)R9, —
C(O)NR8R9, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino.
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4. The compound of claim 3, wherein:
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R1 is hydrogen, —
CN, —
NR8R7, —
OR7, —
S(O)2R7, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, —
NR8R7, —
OR7 and —
S(O)2R7, andR2 is —
CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, —
NR8R7, —
OR7 or —
S(O)2R7.
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5. The compound of claim 4, wherein:
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R1 is hydrogen, —
CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkoxy substituted C2-6alkoxy, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, mono-alkylamino, di-alkylamino, and cycloalkylamino, andR2 is —
CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, mono-alkylamino, di-alkylamino, or cycloalkylamino.
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6. The compound of claim 1, wherein the compound is selected from the group consisting of:
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4-Butoxy—
N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-benzenesulfonamide,N-[3-(5—
Chloro-1r-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-pyrazol-1-yl benzenesulfonamide,N-[3-(5—
Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-isopropoxy-benzenesulfonamide,4-tert-Butyl—
N-[3-(5-chloro-1-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-benzenesulfonamide,N-[3-(5—
Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-propyl-benzenesulfonamide,N-{2,4-Difluoro-3-[5-(2-methoxy-ethoxy)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-4-isopropyl-benzenesulfonamide, N-{2,4-Difluoro-3-[5-(4-methyl-1H-imidazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-4-isopropyl-benzenesulfonamide, 4-Difluoromethoxy—
N-{2,4-difluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-benzenesulfonamide,N-{2,4-Difluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-4-propyl-benzenesulfonamide, N-{2,4-Difluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-4-isopropyl-benzenesulfonamide, N-{2,4-Difluoro-3-[5-(5-methyl-1H-imidazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-4-propyl-benzenesulfonamide, N-{2,4-Difluoro-3-[5-(5-methyl-1H-imidazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-4-trifluoromethyl-benzenesulfonamide, N-{2,4-Difluoro-3-[5-(1-methyl-1H-imidazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-4-propyl-benzenesulfonamide, N-{3-[5-(1,5-Dimethyl-1H-imidazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-4-propyl-benzenesulfonamide, N-[2,4-Difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-trifluoromethyl-benzenesulfonamide, N-[3-(5—
Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-trifluoromethyl-benzenesulfonamide,(E)-3-{3-[2,6-Difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-acrylic acid methyl ester, 3-{3-[2,6-Difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-propionic acid methyl ester, 3-{3-[2,6-Difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-propionic acid, 3-{3-[2,6-Difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}—
N-ethyl-propionamide; andall salts, tautomers, and isomers thereof.
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19. A composition comprising a pharmaceutically acceptable carrier;
- and a compound according to claim 1.
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20. A kit comprising a compound according to claim 1.
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2. The compound of claim 1, wherein:
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7. A compound having the chemical structure of Formula II,
- View Dependent Claims (8, 9, 10, 11, 12, 21, 22)
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8. The compound of claim 7, wherein:
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R1 is selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —
OH, —
NH2, —
CN, —
NO2, —
C(O)OH, —
S(O)2NH2, —
C(O)NH2, —
C(S)NH2, —
NHC(O)NH2, —
NHC(S)NH2, —
NHS(O)2NH2, —
OR7, —
SR7, —
NR8R7, —
C(O)R7, —
C(S)R7, —
C(O)OR7, —
C(O)NR8R7, —
C(S)NR8R7, —
S(O)2NR8R7, —
NR8C(O)R7, —
NR8C(S)R7, —
NR8S(O)2R7, —
NR8C(O)NH2, —
NR8C(O)NR8R7, —
NR8C(S)NH2, —
NR8C(S)NR8R7, —
NR8S(O)2NH2, —
NR8S(O)2NR8R7, —
S(O)R7, and —
S(O)2R7, wherein lower alkyl, lower alkenyl or lower alkynyl are optionally substituted with one or more substituents selected from fluoro, —
OH, —
NH2, C(O)OH, —
C(O)NH2, —
OR7, —
NR8R7, —
C(O)OR7, —
C(O)NR8R7, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R1 or as substituents of lower alkyl, lower alkenyl or lower alkynyl are optionally substituted with one or more substituents selected from the group consisting of —
OH, —
NH2, —
CN, —
NO2, —
S(O)2NH2, —
C(O)NH2, —
OR9, —
SR9, —
NR8R9, —
NR8C(O)R9, —
NR8S(O)—
R9, —
S(O)2R9, —
S(O)2NR8R9, —
C(O)R9, —
C(O)NR8R9, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino;R2a is selected from the group consisting of halogen, lower alkyl, cycloalkyl, heterocycloalkyl aryl, heteroaryl, —
OH, —
NH2, —
CN, —
NO2, —
C(O)OH, —
S(O)2NH2, —
C(O)NH2, —
C(S)NH, —
NHC(O)NH2, —
NHC(S)NH2, —
NHS(O)2NH2, —
OR7, —
SR7, —
NR8R7, —
C(O)R7, —
C(S)R7, —
C(O)OR7, —
C(O)NR8R7, —
C(S)NR8R7, —
S(O)2NR8R7, —
NR8C(O)R7, NR8C(S)R7, —
NR7S(O)2R7, —
NR8C(O)NH2, —
NR8C(O)NR8R7, —
NR8C(S)NH2, —
NR8C(S)NR8R7, —
NR8S(O)2NH2, —
NR8S(O)2NR8R7, —
S(O)R7, and —
S(O)2R7, wherein lower alkyl is optionally substituted with one or more substituents selected from fluoro, —
OR7, —
NR8R7, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R2a or as substituents of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of —
OH, —
NH2, —
CN, —
NO2, —
S(O)2NH2, —
C(O)NH2, —
OR9, —
SR9, —
NHR9—
NR8R8, —
NR8C(O)R8, —
NR8S(O)2R9, —
S(O)2R9, —
S(O)2NR8R9,—
C(O)R9, —
C(O)NR8R9, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino;R7 is selected from the group consisting of lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R7 or as substituents of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of —
OH, —
NH2, —
CN, —
NO2, —
S(O)2NH2, —
C(O)NH2, —
OR9, —
SR9,—
NHR9—
NR8R9, —
NR8C(O)R9, —
NR8S(O)2R9, —
S(O)2R9, —
S(O)2NR8R9, —
C(O)R9, —
C(O)NR8R9, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino;R8 at each occurrence is independently hydrogen or lower alkyl; and R9 at each occurrence is independently selected from the group consisting of lower alkyl, heterocycloalkyl and heteroaryl, wherein lower alkyl is optionally substituted with one of more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino, and heterocycloalkyl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, —
CN, lower alkyl, fluoro substituted lower alkyl, lower alkoxy and fluoro substituted lower alkoxy.
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9. The compound of claim 8, wherein:
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R1 is selected from the group consisting of hydrogen, —
CN, —
OR7, —
SR7, —
NR8R7, —
NR8C(O)R7, —
NR8S(O)2R7, —
C(O)NR8R7, —
C(O)R7, —
S(O)2NR8R7, —
S(O)R7, —
S(O)—
R7, halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R1 or as substituents of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of —
OH, —
NH2, —
CN, —
NO2, —
S(O)2NH2, —
C(O)NH2, —
OR9, —
SR9, —
NR8R9, —
NR8C(O)R9, —
NR8S(O)2R9, —
S(O)2R9, —
S(O)2NR8R9, —
C(O)R9, —
C(O)NR8R9, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino; andR2a is selected from the group consisting of —
CN, —
OR7, —
SR7, —
NR8R7, —
NR8C(O)R7, —
NR8S(O)2R7, —
C(O)NR8R7, —
C(O)R7, —
S(O)2NR8R7, —
S(O)R7, —
S(O)2R7, halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R2a or as a substituent of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of —
OH, —
NH2, —
CN, —
NO2, —
S(O)2 N2, —
C(O)NH2, —
OR9, —
SR9, —
NR8R9, —
NR8C(O)R9, —
NR8S(O)2R9, —
S(O)2R9, —
S(O)2NR8R9, —
—
C(O)R9, —
C(O)NR8R9, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino.
-
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10. The compound of claim 9, wherein:
-
R1 is hydrogen, —
CN, —
NR8R7, —
OR7, —
S(O)2R7, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, —
NR8R7, —
OR7 and —
S(O)2R7, andR2a is —
CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, —
NR8R7, —
OR7 or —
S(O)2R7.
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11. The compound of claim 10, wherein:
-
R1 is hydrogen, —
CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkoxy substituted C2-6alkoxy, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, mono-alkylamino, di-alkylamino, and cycloalkylamino, andR2a is —
CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, mono-alkylamino, di-alkylamino, or cycloalkylamino.
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12. The compound of claim 7, wherein the compound is selected from the group consisting of:
-
3-[3-(5—
Chloro-1-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenylsulfamoyl]-benzoic acid,N-[3-(5—
Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-3-difluoromethoxy-benzenesulfonamide,3-Difluoromethoxy—
N-{2,4-difluoro-3-[5-(5-methyl-1H-imidazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-benzenesulfonamide; andall salts, tautomers, and isomers thereof.
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21. A composition comprising a pharmaceutically acceptable carrier;
- and a compound according to claim 7.
-
22. A kit comprising a compound according to claim 7.
-
8. The compound of claim 7, wherein:
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13. A compound having the chemical structure of Formula III,
- View Dependent Claims (14, 15, 16, 17, 18, 23, 24)
-
14. The compound of claim 13, wherein:
-
R1 is selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —
OH, —
NH—
, —
CN, —
NO2, —
C(O)OH, —
S(O)2NH2, —
C(O)NH2, —
C(S)NH2, —
NHC(O)NH2, —
NHC(S)NH2, —
NHS(O)2NH2, —
OR7, —
SR7, —
NR8R7, —
C(O)R7, —
C(S)R7, —
C(O)OR7, —
C(O)NR8R7, —
C(S)NR8R7, —
S(O)2NR8R7, —
NR8C(O)R7, —
NR8C(S)R7, —
NR8S(O)2R7, —
NR8C(O)NH2, —
NR8C(O)NR8R7, —
NR8C(S)NH2, —
NR8C(S)NR8R7, —
NR5S(O)2NH2, —
NR8S(O)2NR8R7, —
S(O)R7, and —
S(O)2R7, wherein lower alkyl, lower alkenyl or lower alkynyl are optionally substituted with one or more substituents selected from fluoro, —
OH, —
NH2, C(O)OH, —
C(O)NH2, —
OR7, —
NR8R7, —
C(O)OR7, —
C(O)NR8R7, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R1 or as substituents of lower alkyl, lower alkenyl or lower alkynyl are optionally substituted with one or more substituents selected from the group consisting of —
OH, —
NH2, —
CN, —
NO2, —
S(O)2NH2, —
C(O)NH2, —
OR9, —
SR9, —
NR8R9, —
NR8C(O)R9, —
NR8S(O)2R9, —
S(O)2R9, —
S(O)2NR8R9, —
C(O)R9, —
C(O)NR8R9, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino;R6 is heteroaryl optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —
OH, —
NH2, —
CN, —
NO2, —
C(O)OH, —
S(O)2NH2, —
C(O)NH2, —
C(S)NH2, —
NHC(O)NH2, —
NHC(S)NH2, —
NHS(O)2NH2, —
OR7, —
SR7, —
NR8R7, —
C(O)R7, —
C(S)R7, —
C(O)OR7, —
C(O)NR8R7, —
S(O)2NR8R7, —
NR8C(O)R7, —
NR8C(S)R7, —
NR8S(O)2R7, —
NR8C(O)NH2, —
NR8C(O)NR8R7, —
NR8C(S)NH2, —
NR8C(S)NR8R7, —
NR8S(O)2NH2, —
NR8S(O)2NR8R7, —
S(O)R8, and —
S(O)2R7, wherein lower alkyl is optionally substituted with one or more substituents selected from fluoro, —
OR7, —
NR8R7, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as a substituent of R6 or as a substituent of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of —
OH, —
NH2, —
CN, —
NO2, —
S(O)2NH2, —
C(O)NH2, —
OR9, —
SR9, —
NR8R9, —
NR8C(O)R9, —
NR8S(O)2R9, —
S(O)2R9, —
S(O)2NR8R9, —
C(O)R9, —
C(O)NR9R9, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino;R7 is selected from the group consisting of lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R7 or as substituents of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of —
OH, —
NH2, —
CN, —
NO2, —
S(O)2NH2,—
C(O)NH2, —
OR9, —
SR9,—
NHR9, —
NR8R9, —
NR8C(O)R9, —
NR8S(O)2R9, —
S(O)2R9, —
S(O)2NR8R9, —
C(O)R9, —
C(O)NR8R9, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino;R8 at each occurrence is independently hydrogen or lower alkyl; and R9 at each occurrence is independently selected from the group consisting of lower alkyl, heterocycloalkyl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino, and heterocycloalkyl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, —
CN, lower alkyl, fluoro substituted lower alkyl, lower alkoxy and fluoro substituted lower alkoxy.
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15. The compound of claim 14, wherein:
-
R1 is selected from the group consisting of hydrogen, —
CN, —
OR7, —
SR7, —
NR8R7, —
NR8C(O)R7, —
NR8S(O)2R7, —
C(O)NR8R7, —
C(O)R7, —
S(O)2NR8R7, —
S(O)R7, —
S(O)2R7, halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R1 or as substituents of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of —
OH, —
NH2, —
CN, —
NO2, —
S(O)2NH2, —
C(O)NH2, —
OR9, —
SR8, —
NR8R9, —
NR8C(O)R9, —
NR8S(O)2R9, —
S(O)2R9, —
S(O)2NR8R9, —
C(O)R9, —
C(O)NR8R9, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino; andR6 is heteroaryl optionally substituted with one or more substituents selected from the group consisting of —
CN, —
OR7, —
SR7, —
NR8R7, —
NR8C(O)R7, —
NR8S(O)2R7, —
C(O)NR8R7, —
C(O)R7, —
S(O)2NR8R7, —
S(O)R7, —
S(O)2R7, halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as a substituent of R6 or as a substituent of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of —
OH, —
NH2, —
CN, —
NO2, —
S(O)2NH2, —
C(O)NH2, —
OR9, —
SR9, —
NR8R9, —
NR8C(O)R9, —
NR8S(O)2R9, —
S(O)2R9, —
S(O)2NR8R9, —
C(O)R9, —
C(O)NR8R9, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino.
-
-
16. The compound of claim 15, wherein:
-
R1 is hydrogen, —
CN, —
NR8R7, —
OR7, —
S(O)2R7, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, —
NR8R7, —
OR7 and —
S(O)2R7, andR6 is heteroaryl optionally substituted with one or more of —
CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, —
NR8R7, —
OR7 or —
S(O)2R7.
-
-
17. The compound of claim 16, wherein:
-
R1 is hydrogen, —
CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkoxy substituted C2-6alkoxy, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, mono-alkylamino, di-alkylamino, and cycloalkylamino, andR6 is heteroaryl optionally substituted with one or more of —
CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, mono-alkylamino, di-alkylamino, or cycloalkylamino.
-
-
18. The compound of claim 13, wherein the compound is selected from the group consisting of:
-
Benzo[b]thiophene-3-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide, 5-Methyl-2-trifluoromethyl-furan-3-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide, 5—
Oxazol-5-yl-thiophene-2-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide,2—
Oxo-2H-chromene-6-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide,5-Isoxazol-5-yl-thiophene-2-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide, Benzothiazole-6-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide, 1-Methyl-3-trifluoromethyl-1H-pyrazole-4-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide, Benzo[1,2,5]thiadiazoe-5-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide, 5-Methyl-benzo[b]thiophene-2-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide, 5-Methyl-thiophene-2-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide, 1-Methyl-1-pyrazole-3-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide, Pyridine-2-sulfonic acid [2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide; and all salts, tautomers, and isomers thereof.
-
-
23. A composition comprising:
- a pharmaceutically acceptable carrier; and
a compound according to claim 13.
- a pharmaceutically acceptable carrier; and
-
24. A kit comprising a compound according to claim 13.
-
14. The compound of claim 13, wherein:
Specification
- Resources
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Current AssigneePlexxikon Inc (Daiichi Sankyo Company Limited)
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Original AssigneePlexxikon Inc (Daiichi Sankyo Company Limited)
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InventorsZhu, Hongyao, Spevak, Wayne, Shi, Shenghua, Mamo, Shumeye, Ibrahim, Prabha N., Gillette, Samuel J., Cho, Hanna
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Primary Examiner(s)Seaman; D. Margaret
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Assistant Examiner(s)Rahmani; Niloofar
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Application NumberUS11/960,590Publication NumberTime in Patent Office1,112 DaysField of Search514/300, 546/113US Class Current514/300CPC Class CodesA61P 1/00 Drugs for disorders of the ...A61P 1/04 for ulcers, gastritis or re...A61P 11/00 Drugs for disorders of the ...A61P 11/06 AntiasthmaticsA61P 13/08 of the prostateA61P 13/12 of the kidneysA61P 15/00 Drugs for genital or sexual...A61P 15/10 for impotenceA61P 17/00 Drugs for dermatological di...A61P 17/06 AntipsoriaticsA61P 17/14 for baldness or alopeciaA61P 19/02 for joint disorders, e.g. a...A61P 19/08 for bone diseases, e.g. rac...A61P 19/10 for osteoporosisA61P 21/00 Drugs for disorders of the ...A61P 21/04 for myasthenia gravisA61P 25/00 Drugs for disorders of the ...A61P 25/02 for peripheral neuropathiesA61P 25/04 Centrally acting analgesics...A61P 25/06 Antimigraine agentsA61P 25/16 : Anti-Parkinson drugsA61P 25/28 : for treating neurodegenerat...A61P 29/00 : Non-central analgesic, anti...A61P 3/00 : Drugs for disorders of the ...A61P 3/04 : Anorexiants; Antiobesity ag...A61P 3/10 : for hyperglycaemia, e.g. an...A61P 3/14 : for calcium homeostasis vit...A61P 31/04 : Antibacterial agentsA61P 31/12 : AntiviralsA61P 31/14 : for RNA virusesA61P 31/16 : for influenza or rhinovirusesA61P 35/00 : Antineoplastic agentsA61P 35/02 : specific for leukemiaA61P 35/04 : specific for metastasisA61P 37/02 : ImmunomodulatorsA61P 37/06 : Immunosuppressants, e.g. dr...A61P 37/08 : Antiallergic agents antiast...A61P 5/14 : of the thyroid hormones, e....A61P 7/02 : Antithrombotic agents; Anti...A61P 9/00 : Drugs for disorders of the ...A61P 9/04 : Inotropic agents, i.e. stim...A61P 9/10 : for treating ischaemic or a...C07D 471/04 : Ortho-condensed systems