PYRROLO[2,3-b]PYRIDIN-4-YL-AMINES AND PYRROLO[2,3-b]PYRIMIDIN-5-YL-AMINES AS JANUS KINASE INHIBITORS
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Abstract
The present invention provides pyrrolo[2,3-b]pyridine-4-yl amines pyrrolo[2,3-b]pyrimidin-4-yl amines that modulate the activity of Janus kinases and are useful in the treatment of diseases related to activity of Janus kinases including, for example, immune-related diseases and cancer.
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Citations
60 Claims
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1. A compound of Formula I:
- 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)
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2. The compound of claim 1 wherein R1 is H.
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3. The compound of claim 1 wherein R2 is H.
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4. The compound of claim 1 wherein R3 is H.
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5. The compound of claim 1 wherein R4 is H or C1-4 alkyl.
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6. The compound of claim 1 wherein R4 is methyl.
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7. The compound of claim 1 wherein R5 is 3-8 membered heterocycloalkyl substituted by one R6 and 0, 1 or 2 R7.
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8. The compound of claim 1 wherein R5 is 6-membered heterocycloalkyl substituted by one R6 and 0, 1 or 2 R7.
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9. The compound of claim 1 wherein R5 is piperidinyl substituted by one R6 and 0, 1 or 2R7.
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10. The compound of claim 1 wherein R5 is piperidin-3-yl substituted by one R6 and 0, 1 or 2 R7.
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11. The compound of claim 10 wherein R6 is substituted on the piperidinyl N-atom.
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12. The compound of claim 1 wherein R5 is L-pyrrolidinyl;
- L is C1-4 alkylenyl; and
said pyrrolidinyl is substituted by one R6 and 0, 1 or 2 R7.
- L is C1-4 alkylenyl; and
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13. The compound of claim 1 wherein R5 is -L-pyrrolidin-2-yl;
- L is C1-4 alkylenyl and said pyrrolidin-2-yl is substituted by one R6 and 0, 1 or 2 R7.
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14. The compound of claim 1 wherein W2 is SO2, CO, COO, C(S)NR12, or CONR12.
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15. The compound of claim 1 wherein W2 is SO2, CO, COO, C(S)NH, CONH or —
- CON(C1-4 alkyl)-.
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16. The compound of claim 1 wherein W2 is SO2 or CO.
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17. The compound of claim 1 wherein W3 is C1-4 alkylenyl or cycloalkyl.
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18. The compound of claim 1 wherein R13 is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl or heterocycloalkylalkyl, each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from:
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C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, halo, CN, NO2, ORa″
, SRa″
, C(O)Rb″
, C(O)NRc″
Rd″
, C(O)ORa″
, OC(O)Rb″
, OC(O)NRc″
Rd″
, NRc″
Rd″
, NRc″
C(O)Rd″
, NRc″
C(O)ORa″
, S(O)Rb″
, S(O)NRc″
Rd″
, S(O)2Rb″
, S(O)2NRc″
Rd″
, —
(C1-6 alkyl)-CN, —
(C1-6 alkyl)-NO2, —
(C1-6 alkyl)-ORa″
, —
(C1-6 alkyl)-SRa″
, —
(C1-6 alkyl)-C(O)Rb″
, —
(C1-6 alkyl)-C(O)NRc″
Rd″
, —
(C1-6 alkyl)-C(O)ORa″
, —
(C1-6 alkyl)-OC(O)Rb″
, —
(C1-6 alkyl)-OC(O)NRc″
Rd″
, —
(C1-6 alkyl)-NRc″
Rd″
, —
(C1-6 alkyl)-NRc″
C(O)Rd″
, —
(C1-6 alkyl)-NRc″
C(O)ORa″
,—
(C1-6 alkyl)-S(O)Rb″
, —
(C1-6 alkyl)-S(O)NRc″
Rd″
, —
(C1-6 alkyl)-S(O)2Rb″
, and —
(C1-6 alkyl)-S(O)2NRc″
Rd″
.
-
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19. The compound of claim 1 wherein R13 is C1-6 alkyl, C1-6 haloalkyl, aryl, cycloalkyl, hetero aryl, heterocycloalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl or heterocycloalkylalkyl, each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from:
C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, halo, CN, NO2, ORa″
, SRa″
, C(O)Rb″
, C(O)NRc″
Rd″
, C(O)ORa″
, OC(O)Rb″
, OC(O)NRc″
Rd″
, NRc″
Rd″
, NRc″
C(O)Rd″
, NRc″
C(O)ORa″
, S(O)Rb″
, S(O)NRc″
Rd″
, S(O)2Rb″
, S(O)2NRc″
Rd″
, —
(C1-6 alkyl)-CN, —
(C1-6 alkyl)-NO2, —
(C1-6 alkyl)-ORa″
, —
(C1-6 alkyl)-SRa″
, —
(C1-6 alkyl)-C(O)Rb″
, —
(C1-6 alkyl)-C(O)NRc″
Rd″
, —
(C1-6 alkyl)-C(O)ORa″
, —
(C1-6 alkyl)-OC(O)Rb″
, —
(C1-6 alkyl)-OC(O)NRc″
Rd″
, —
(C1-6 alkyl)-NRc″
Rd″
, —
(C1-6 alkyl)-NRc″
C(O)Rd″
, —
(C1-6 alkyl)-NRc″
C(O)ORa″
, —
(C1-6 alkyl)-S(O)Rb″
, —
(C1-6 alkyl)-S(O)NRc″
Rd″
, —
(C1-6 alkyl)-S(O)2Rb″
, and —
(C1-6 alkyl)-S(O)2NRc″
Rd″
.
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20. The compound of claim 1 wherein R13 is C1-6 alkyl, C1-6 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl or heterocycloalkylalkyl, each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from C1-6 alkyl, C1-6 haloalkyl, aryl, heteroaryl, halo, CN, ORa″
- , SRa″
, C(O)Rb″
, C(O)ORa″
, NRc″
C(O)Rd″
, S(O)2Rb″
, and —
(C1-6 alkyl)-CN.
- , SRa″
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21. The compound of claim 1 wherein R13 is C1-6 alkyl, C1-6 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl or heterocycloalkylalkyl, each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from C1-6 alkyl, C1-6 haloalkyl, aryl, heteroaryl, halo, CN, OH, C1-4 alkoxy, C1-4 haloalkoxy, heteroaryloxy, aryloxy, —
- SC1-6 alkyl, —
C(O)—
C1-6 alkyl, —
C(O)OC1-6 alkyl, —
S(O)2C1-6 alkyl, —
NHC(O)—
C1-6 alkyl, and —
(C1-6 alkyl)-CN.
- SC1-6 alkyl, —
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22. The compound of claim 1 where R13 is OH or CN.
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23. The compound of claim 1 wherein W1 is absent, W2 is CO or SO2, W3 is C1-4 alkyleneyl or cycloalkyl, W4 is absent, W5 is absent, W6 is absent, and R13 is CN or OH.
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24. The compound of claim 1 wherein R6 is —
- W2—
W3—
R13.
- W2—
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25. The compound of claim 1 wherein R6 is —
- CO—
CH2—
CN.
- CO—
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26. The compound of claim 1 wherein R6 is —
- W2—
R13.
- W2—
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27. The compound of claim 1 wherein:
-
R6 is —
W2—
R13;W2 is SO2, CO, COO, C(S)NR12, or CONR12; and R13 is C1-6 alkyl, C1-6 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl or heterocycloalkylalkyl, each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from; C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, halo, CN, NO2, ORa″
, SRa″
, C(O)Rb″
, C(O)NRc″
Rd″
, C(O)ORa″
, OC(O)Rb″
, OC(O)NRc″
Rd″
, NRc″
Rd″
, NRc″
C(O)Rd″
, NRc″
C(O)ORa″
, S(O)Rb″
, S(O)NRc″
Rd″
, S(O)2Rb″
, S(O)2NRc″
Rd″
, —
(C1-6 alkyl)-CN, —
(C1-6 alkyl)-NO2, —
(C1-6 alkyl)-ORa″
, —
(C1-6 alkyl)-SRa″
, —
(C1-6 alkyl)-C(O)Rb″
, —
(C1-6 alkyl)-C(O)NRc″
Rd″
, —
(C1-6 alkyl)-C(O)ORa″
, —
(C1-6 alkyl)-OC(O)Rb″
, —
(C1-6 alkyl)-OC(O)NRc″
Rd″
, —
(C1-6 alkyl)-NRc″
Rd″
, —
(C1-6 alkyl)-NRc″
C(O)Rd″
, —
(C1-6 alkyl)-NRc″
C(O)ORa′
, —
(C1-6 alkyl)-S(O)Rb″
, —
(C1-6 alkyl)-S(O)NRc″
Rd″
, —
(C1-6 alkyl)-S(O)2Rb″
, and —
(C1-6 alkyl)-S(O)2NRc″
Rd″
.
-
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28. The compound of claim 1 having the structure of Formula I-A:
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29. The compound of claim 28 wherein:
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W2 is SO2, CO, COO, C(S)NR12, or CONR12; and R13 is C1-6 alkyl, C1-6 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl or heterocycloalkylalkyl, each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from; C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, halo, CN, NO2, ORa″
, SRa″
, C(O)Rb″
, C(O)NRc″
Rd″
, C(O)ORa″
, OC(O)Rb″
, OC(O)NRc″
Rd″
, NRc″
Rd″
, NRc″
C(O)Rd″
, NRc″
C(O)ORa″
, S(O)Rb″
, S(O)NRc″
Rd″
, S(O)2Rb″
, S(O)2NRc″
Rd″
, —
(C1-6 alkyl)-CN, —
(C1-6 alkyl)-NO2, —
(C1-6 alkyl)-ORa″
, —
(C1-6 alkyl)-SRa″
, —
(C1-6 alkyl)-C(O)Rb″
, —
(C1-6 alkyl)-C(O)NRc″
Rd″
, —
(C1-6 alkyl)-C(O)ORa″
, —
(C1-6 alkyl)-OC(O)Rb″
, —
(C1-6 alkyl)-OC(O)NRc″
Rd″
, —
(C1-6 alkyl)-NRc″
Rd″
, —
(C1-6 alkyl)-NRc″
C(O)Rd″
, —
(C1-6 alkyl)-NRc″
C(O)ORa″
, —
(C1-6 alkyl)-S(O)Rb″
, —
(C1-6 alkyl)-S(O)NRc″
Rd″
, —
(C1-6 alkyl)-S(O)2Rb″
, and —
(C1-6 alkyl)-S(O)2NRc″
Rd″
.
-
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30. The compound of claim 1 having the structure of Formula I-B:
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31. The compound of claim 30 wherein
R13 is C1-6 alkyl, C1-6 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl or heterocycloalkylalkyl, each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from C1-6 alkyl, C1-6 haloalkyl, aryl, heteroaryl, halo, CN, ORa″ - , SRa″
, C(O)Rb″
, C(O)ORa″
, NRc″
C(O)Rd″
, S(O)2Rb″
, and —
(C1-6 alkyl)-CN;W2 is SO2, CO, COO, C(S)NH, CONH or —
CON(C1-4 alkyl)-; andR4 is C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, S(O)2R9, SOR9, cycloalkyl, or heterocycloalkyl, wherein said C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, cycloalkyl, heterocycloalkyl are each optionally substituted with 1, 2 or 3 substituents selected from halo, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rd, NRcC(O)ORa, S(O)Rb, S(O)NRcRd, S(O)2Rb, and S(O)2NRcRd.
- , SRa″
-
32. A compound of claim 1 selected from:
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3-{3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile; 3-{(3R,4R)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidin-1-yl}-3-oxopropanenitrile; N-methyl-N-[(3R,4R)-4-methyl-1-(phenylsulfonyl)piperidin-3-yl]-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine; N-[(3R,4R)-1-(methoxyacetyl)-4-methylpiperidin-3-yl]-N-methyl-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine; (3R,4R)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]-N-phenylpiperidine-1-carboxamide; (3R,4R)—
N-benzyl-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidine-1-carboxamide;(3R,4R)—
N-ethyl-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidine-1-carboxamide;(3R,4R)—
N-isopropyl-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidine-1-carboxamide;N-[(3R,4R)-1-isobutyryl-4-methylpiperidin-3-yl]-N-methyl-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine; N-methyl-N-[(3R,4R)-4-methyl-1-(morpholin-4-ylcarbonyl)piperidin-3-yl]-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine; N-[(3R,4R)-1-acetyl-4-methylpiperidin-3-yl]-N-methyl-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine; N-methyl-N-[(3R,4R)-4-methyl-1-(3-methylbutanoyl)piperidin-3-yl]-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine; N-[(3R,4R)-1-benzoyl-4-methylpiperidin-3-yl]-N-methyl-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine; (3R,4R)—
N,N,4-trimethyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidine-1-carboxamide;4-({(3R,4R)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidin-1-yl}carbonyl)benzonitrile; N-[(3R,4R)-1-(cyclopropylcarbonyl)-4-methylpiperidin-3-yl]-N-methyl-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine; N-[(3R,4R)-1-isonicotinoyl-4-methylpiperidin-3-yl]-N-methyl-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine; N-{(3R,4R)-1-[(1-acetylpiperidin-4-yl)carbonyl]-4-methylpiperidin-3-yl}-N-methyl-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine; Phenyl(3R,4R)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidine-1-carboxylate; Methyl(3R,4R)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidine-1-carboxylate; N-methyl-N-[(3R,4R)-4-methyl-1-(trifluoroacetyl)piperidin-3-yl]-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine; N-[(3R,4R)-1-(2-furoyl)-4-methylpiperidin-3-yl]-N-methyl-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine; (3R,4R)—
N-(4-cyanophenyl)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidine-1-carboxamide;(3R,4R)—
N-(3-cyanophenyl)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidine-1-carboxamide;(3R,4R)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]-N-(2-phenyl ethyl)piperidine-1-carboxamide; (3R,4R)—
N-(2-furylmethyl)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidine-1-carboxamide;N-methyl-N-[(3R,4R)-4-methyl-1-(propylsulfonyl)piperidin-3-yl]-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine; N-[(3R,4R)-1-(isopropylsulfonyl)-4-methylpiperidin-3-yl]-N-methyl-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine; 4-({(3R,4R)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidin-1-yl}sulfonyl)benzonitrile; 2-({(3R,4R)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidin-1-yl}sulfonyl)benzonitrile; N-methyl-N-[(3R,4R)-4-methyl-1-(methylsulfonyl)piperidin-3-yl]-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine; N-methyl-N-{(3R,4R)-4-methyl-1-[(trifluoromethyl)sulfonyl]piperidin-3-yl}-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine; N-methyl-N-[(3R,4R)-4-methyl-1-(pyridin-3-ylsulfonyl)piperidin-3-yl]-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine; 2-fluoro-5-({(3R,4R)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidin-1-yl}sulfonyl)benzonitrile; N-methyl-N-[(3R,4R)-4-methyl-1-(3-pyridin-3-ylpropanoyl)piperidin-3-yl]-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine; N-methyl-N-[(3R,4R)-4-methyl-1-(3,3,3-trifluoropropanoyl)piperidin-3-yl]-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine; N-methyl-N-[(3R,4R)-4-methyl-1-(tetrahydrofuran-2-ylcarbonyl)piperidin-3-yl]-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine; (2R)-1-{(3R,4R)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidin-1-yl}-1-oxopropan-2-ol; (2S)-1-{(3R,4R)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidin-1-yl}-1-oxopropan-2-ol; N-methyl-N-[(3R,4R)-4-methyl-1-(3-phenylpropanoyl)piperidin-3-yl]-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine; (3R,4R)—
N-(4-cyanophenyl)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidine-1-carbothioamide;N-methyl-N-{(3R,4R)-4-methyl-1-[(5-methylisoxazol-4-yl)sulfonyl]piperidin-3-yl}-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine; N-methyl-N-{(3R,4R)-4-methyl-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]piperidin-3-yl}-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine; N-{(3R,4R)-1-[(3,5-dimethylisoxazol-4-yl)carbonyl]-4-methylpiperidin-3-yl}-N-methyl-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine; (3R,4R)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]-N-2-thienylpiperidine-1-carboxamide; N-[(3R,4R)-1-(isoxazol-5-yl)carbonyl)-4-methylpiperidin-3-yl]-N-methyl-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine; N-{(3R,4R)-1-[(1,2-dimethyl-1H-imidazol-4-yl)sulfonyl]-4-methylpiperidin-3-yl}-N-methyl-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine; N-[4-methyl-5-({(3R,4R)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidin-1-yl}sulfonyl)-1,3-thiazol-2-yl]acetamide; N-{(3R,4R)-1-[(2,4-dimethyl-1,3-thiazol-5-yl)sulfonyl]-4-methylpiperidin-3-yl}-N-methyl-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine; N-methyl-N-{(3R,4R)-4-methyl-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidin-3-yl}-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine; N-{(3R,4R)-1-[(3,5-dimethylisoxazol-4-yl)sulfonyl]-4-methylpiperidin-3-yl}-N-methyl-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine; N-methyl-N-{(3R,4R)-4-methyl-1-[(pyridin-4-ylmethyl)sulfonyl]piperidin-3-yl}-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine; N-methyl-N-{(3R,4R)-4-methyl-1-[(pyridin-3-ylmethyl)sulfonyl]piperidin-3-yl}-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine; N-methyl-N-{(3R,4R)-4-methyl-1-[(pyridin-2-ylmethyl)sulfonyl]piperidin-3-yl}-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine; 4-({(3R,4R)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidin-1-yl}sulfonyl)benzonitrile; (3R,4R)—
N-(4-cyanophenyl)-N,4-dimethyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidine-1-carboxamide;(3R,4R)—
N-(4-cyanophenyl)-N-ethyl-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidine-1-carboxamide;(3R,4R)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]-N-1,3-thiazol-2-ylpiperidine-1-carboxamide; (3R,4R)-4-methyl-N-(3-methylisoxazol-5-yl)-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidine-1-carboxamide; 3-chloro-4-({(3R,4R)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidin-1-yl}sulfonyl)benzonitrile; (3R,4R)-4-methyl-N-(5-methylisoxazol-3-yl)-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidine-1-carboxamide; (3R,4R)—
N-isoxazol-3-yl-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidine-1-carboxamide;N-methyl-N-{(3R,4R)-4-methyl-1-[(5-pyridin-3-yl-2-thienyl)sulfonyl]piperidin-3-yl}-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine; (3R,4R)—
N-(3-cyano-2-thienyl)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidine-1-carboxamide;(3R,4R)—
N-1,3-benzothiazol-2-yl-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidine-1-carboxamide;N-[(3R,4R)-1-(2,3-dihydro-1H-indol-1-ylcarbonyl)-4-methylpiperidin-3-yl]-N-methyl-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine; N-methyl-N-{(3R,4R)-4-methyl-1-[(methylthio)acetyl]piperidin-3-yl}-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine; (3R,4R)—
N-(4,5-dihydro-1,3-thiazol-2-yl)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidine-1-carboxamide;(3R,4R)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]-N-(1,3-thiazol-2-ylmethyl)piperidine-1-carboxamide; 1-({(3R,4R)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidin-1-yl}carbonyl)piperidine-4-carbonitrile; 1-({(3R,4R)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidin-1-yl}carbonyl)piperidine-3-carbonitrile; 1-({(3R,4R)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidin-1-yl}carbonyl)pyrrolidine-3-carbonitrile; (3R,4R)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]-N-(3-thienylmethyl)piperidine-1-carboxamide; (3R,4R)—
N-(2-benzothien-1-ylmethyl)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidine-1-carboxamide;(3R,4R)—
N-(1,3-benzothiazol-2-ylmethyl)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidine-1-carboxamide;N-[(3R,4R)-1-(3-furylacetyl)-4-methylpiperidin-3-yl]-N-methyl-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine; 3-(2-{(3R,4R)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidin-1-yl}-2-oxoethyl)-1,3-thiazolidine-2,4-dione; 3-(2-{(3R,4R)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidin-1-yl}-2-oxoethyl)-1,3-benzothiazol-2(3H)-one; (3R,4R)—
N-[5-(cyanomethyl)-4,5-dihydro,-1,3-thiazol-2-yl]-3-[methyl-(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]-4-methyl-piperidine-1-carboxamide;(3S)-1-({(3R,4R)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidin-1-yl}carbonyl)pyrrolidine-3-carbonitrile; (3R)-1-({(3R,4R)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidin-1-yl}carbonyl)pyrrolidine-3-carbonitrile; 1-({(3R,4R)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidin-1-yl}carbonyl)-4-phenylpiperidine-4-carbonitrile; N-methyl-N-((3R,4R)-4-methyl-1-{[3-(trifluoromethyl)pyrrolidin-1-yl]carbonyl}piperidin-3-yl)-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine; 1-({(3R,4R)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidin-1-yl}carbonyl)azetidine-3-carbonitrile; 4-methyl-1-({(3R,4R)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidin-1-yl}carbonyl)pyrrolidine-3-carbonitrile; 1-({(3R,4R)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidin-1-yl}carbonyl)pyrrolidine-3,4-dicarbonitrile; 3-methyl-1-({(3R,4R)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidin-1-yl}carbonyl)pyrrolidine-3-carbonitrile; (3R,4R)—
N-(2-cyano ethyl)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidine-1-carboxamide;4-methoxy-1-({(3R,4R)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidin-1-yl}carbonyl)pyrrolidine-3-carbonitrile; N-{(3R,4R)-1-[(2R)-2-aminopropanoyl]-4-methylpiperidin-3-yl}-N-methyl-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine; N-[(3R,4R)-1-(aminoacetyl)-4-methylpiperidin-3-yl]-N-methyl-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine; 1-(2-{(3R,4R)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidin-1-yl}-2-oxoethyl)piperidine-4-carbonitrile; N-methyl-N-[(3R,4R)-4-methyl-1-(1,3-thiazol-4-ylcarbonyl)piperidin-3-yl]-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine bis(trifluoroacetate); 4-(2-2S-{[methyl-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amino]-methyl}-pyrrolidin-1-yl-sulfonyl)-benzonitrile trifluoroacetate; N-[(1-methanesulfonyl-2S-pyrrolidin-2-yl)-methyl]-N-methyl-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine trifluoroacetate; 3-((2S)-2-{[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]methyl}pyrrolidin-1-yl)-3-oxopropanenitrile trifluoroacetate; Methyl 3-[({(3R,4R)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidine-1-yl}carbonyl)-amino]benzoate; (3R,4R)—
N-(4-trifluoromethoxyphenyl)-4-methyl-3-[methyl-(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidine-1-carboxamide;(3R,4R)—
N-(4-fluorophenyl)-4-methyl-3-[methyl-(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidine-1-carboxamide;(3R,4R)—
N-(3-fluorophenyl)-4-methyl-3-[methyl-(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidine-1-carboxamide;(3R,4R)—
N-(2-fluorophenyl)-4-methyl-3-[methyl-(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidine-1-carboxamide;(3R,4R)—
N-(4-trifluoromethylphenyl)-4-methyl-3-[methyl-(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidine-1-carboxamide;(3R,4R)—
N-(2-methoxyphenyl)-4-methyl-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)amino]piperidine-1-carboxamide;(3R,4R)-4-methyl-N-(4-methylphenyl)-3-[methyl(1H-pyrrolo[2,3-b]pyridin-4-yl)-amino]piperidine-1-carboxamide; N-methyl-N-{(3R,4R)-4-methyl-1-[4-(pyridin-2-yloxy)phenyl]sulfonyl-piperidin-3-yl}-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine; N-methyl-N-{(3R,4R)-4-methyl-1-[4-(1,3-oxazol-5-yl)phenyl]sulfonyl-piperidin-3-yl}-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine; N-methyl-N-{(3R,4R)-4-methyl-1-[5-(1,3-oxazol-5-yl)thienyl]sulfonyl-piperidin-3-yl}-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine; N-methyl-N-{(3R,4R)-4-methyl-1-[(6-phenoxy-pyridin-3-yl)sulfonyl]piperidin-3-yl}-(1H-pyrrolo[2,3-b]pyridin-4-yl)amine; N-{(3R,4R)-1-[(2,6-dichlorophenyl)sulfonyl]-4-methylpiperidin-3-yl}-N-methyl-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine; N-{(3R,4R)-1-[(4-fluorophenyl)sulfonyl]-4-methylpiperidin-3-yl}-N-methyl-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine; N-{(3R,4R)-1-[(3-fluorophenyl)sulfonyl]-4-methylpiperidin-3-yl}-N-methyl-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine; N-{(3R,4R)-1-[(2-fluorophenyl)sulfonyl]-4-methylpiperidin-3-yl}-N-methyl-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine; N-{(3R,4R)-4-methyl-1-[4-(trifluoromethyl)phenyl]sulfonyl-piperidin-3-yl}-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine; N-{(3R,4R)-4-methyl-1-[3-(trifluoromethyl)phenyl]sulfonyl-piperidin-3-yl}-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine; N-{(3R,4R)-4-methyl-1-[2-(trifluoromethyl)phenyl]sulfonyl-piperidin-3-yl}-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine; N-{(3R,4R)-1-[(4-methoxyphenyl)sulfonyl]-4-methylpiperidin-3-yl}-N-methyl-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine; N-{(3R,4R)-1-[(3-methoxyphenyl)sulfonyl]-4-methylpiperidin-3-yl}-N-methyl-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine; N-methyl-N-{(3R,4R)-4-methyl-1-[(4-methylphenyl)sulfonyl]piperidin-3-yl}-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine; N-methyl-N-{(3R,4R)-4-methyl-1-[(3-methylphenyl)sulfonyl]piperidin-3-yl}-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine; N-methyl-N-{(3R,4R)-4-methyl-1-[(2-methylphenyl)sulfonyl]piperidin-3-yl}-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine; N-{(3R,4R)-1-[(4-chlorophenyl)sulfonyl]-4-methylpiperidin-3-yl}-N-methyl-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine; N-{(3R,4R)-1-[(3-chlorophenyl)sulfonyl]-4-methylpiperidin-3-yl}-N-methyl-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine; and N-{(3R,4R)-1-[(2-chlorophenyl)sulfonyl]-4-methylpiperidin-3-yl}-N-methyl-N-(1H-pyrrolo[2,3-b]pyridin-4-yl)-amine, or a pharmaceutically acceptable salt thereof.
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33. A composition comprising a compound of claim 1, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
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34. A method of modulating an activity of JAK comprising contacting JAK with a compound of claim 1, or pharmaceutically acceptable salt thereof.
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35. The method of claim 34 wherein said JAK is in a cell.
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36. The method of claim 34 wherein said JAK is JAK1, JAK2, JAK3 or TYK2.
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37. The method of claim 34 wherein said JAK is JAK1 or JAK2.
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38. The method of claim 34 wherein said JAK is JAK2.
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39. The method of claim 34 wherein said modulating is inhibiting.
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40. The method of claim 34 wherein said compound is a selective inhibitor of JAK2 over JAK1, JAK2, JAK3 and TYK2.
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41. A method of treating a disease in a patient, wherein said disease is associated with JAK activity, comprising administering to said patient a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.
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42. The method of claim 41 wherein said disease is allograft rejection or graft versus host disease.
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43. The method of claim 41 wherein said disease is an autoimmune disease.
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44. The method of claim 43 wherein said autoimmune disease is a skin disorder, multiple sclerosis, rheumatoid arthritis, juvenile arthritis, type I diabetes, lupus, psoriasis, inflammatory bowel disease, Crohn'"'"'s disease, or autoimmune thyroid disorder.
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45. The method of claim 41 wherein said disease is a viral disease.
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46. The method of claim 45 wherein said viral disease is Epstein Barr Virus (EBV), Hepatitis B, Hepatitis C, HIV, HTLV 1, Varicell-Zoster Virus (VZV) or Human Papilloma Virus (HPV).
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47. The method of claim 41 wherein said disease is cancer.
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48. The method of claim 47 wherein said cancer is prostate cancer, lymphoma, leukemia, or multiple myeloma.
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49. The method of claim 47 wherein said cancer is multiple myeloma.
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2. The compound of claim 1 wherein R1 is H.
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50. A pharmaceutical composition for topical administration comprising a compound of Formula II:
- View Dependent Claims (51, 52, 53, 54)
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51. The composition of claim 50 wherein said topical administration comprises transdermal administration.
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52. The composition of claim 50 which is in the form of a transdermal patch, ointment, lotion, cream, or gel.
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53. The composition of claim 50 wherein A is CR1.
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54. The composition of claim 50 wherein A is N.
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51. The composition of claim 50 wherein said topical administration comprises transdermal administration.
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55. A method of treating a skin disorder in a patient comprising topically administering to said patient a therapeutically effective amount of a compound of Formula II:
- View Dependent Claims (56, 57, 58, 59, 60)
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56. The method of claim 55 wherein said skin disorder is atopic dermatitis or psoriasis.
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57. The method of claim 55 wherein said skin disorder is skin sensitization, skin irritation, skin rash, contact dermatitis or allergic contact sensitization.
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58. The method of claim 55 wherein said compound of Formula II is administered in the form of a transdermal patch, ointment, lotion, cream, or gel.
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59. The method of claim 55 wherein A is CR1.
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60. The method of claim 55 wherein A is N.
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56. The method of claim 55 wherein said skin disorder is atopic dermatitis or psoriasis.
Specification
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Current AssigneeIncyte Corporation, Incyte Holdings Corporation (Incyte Corporation)
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Original AssigneeIncyte Corporation
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InventorsRodgers, James D., Wang, Haisheng, Combs, Andrew P., Sparks, Richard B.
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Granted Patent
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Time in Patent OfficeDays
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Field of Search
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US Class Current1/1
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CPC Class CodesA61P 1/04 for ulcers, gastritis or re...A61P 17/00 Drugs for dermatological di...A61P 17/06 AntipsoriaticsA61P 19/02 for joint disorders, e.g. a...A61P 25/00 Drugs for disorders of the ...A61P 29/00 Non-central analgesic, anti...A61P 3/10 for hyperglycaemia, e.g. an...A61P 31/12 AntiviralsA61P 31/14 for RNA virusesA61P 31/18 for HIVA61P 31/20 for DNA virusesA61P 35/00 Antineoplastic agentsA61P 37/00 Drugs for immunological or ...A61P 37/02 ImmunomodulatorsA61P 37/06 Immunosuppressants, e.g. dr...A61P 37/08 Antiallergic agents antiast...A61P 43/00 Drugs for specific purposes...A61P 5/14 of the thyroid hormones, e....C07D 471/04 Ortho-condensed systemsC07D 487/04 Ortho-condensed systems