PYRROLO[2,3-b]PYRIDIN-4-YL-AMINES AND PYRROLO[2,3-b]PYRIMIDIN-5-YL-AMINES AS JANUS KINASE INHIBITORS

US 20150315185A1
Filed: 07/15/2015
Published: 11/05/2015
Est. Priority Date: 12/22/2004
Status: Active Grant

First Claim

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1. A compound of Formula I:

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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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60 Claims

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)
- - 2. The compound of claim 1 wherein R¹is H.
  - 3. The compound of claim 1 wherein R²is H.
  - 4. The compound of claim 1 wherein R³is H.
  - 5. The compound of claim 1 wherein R⁴is H or C_1-4alkyl.
  - 6. The compound of claim 1 wherein R⁴is methyl.
  - 7. The compound of claim 1 wherein R⁵is 3-8 membered heterocycloalkyl substituted by one R⁶and 0, 1 or 2 R⁷.
  - 8. The compound of claim 1 wherein R⁵is 6-membered heterocycloalkyl substituted by one R⁶and 0, 1 or 2 R⁷.
  - 9. The compound of claim 1 wherein R⁵is piperidinyl substituted by one R⁶and 0, 1 or 2R⁷.
  - 10. The compound of claim 1 wherein R⁵is piperidin-3-yl substituted by one R⁶and 0, 1 or 2 R⁷.
  - 11. The compound of claim 10 wherein R⁶is substituted on the piperidinyl N-atom.
  - 12. The compound of claim 1 wherein R⁵is L-pyrrolidinyl;
    - L is C_1-4alkylenyl; and
      
      said pyrrolidinyl is substituted by one R⁶and 0, 1 or 2 R⁷.
  - 13. The compound of claim 1 wherein R⁵is -L-pyrrolidin-2-yl;
    - L is C_1-4alkylenyl and said pyrrolidin-2-yl is substituted by one R⁶and 0, 1 or 2 R⁷.
  - 14. The compound of claim 1 wherein W²is SO₂, CO, COO, C(S)NR¹², or CONR¹².
  - 15. The compound of claim 1 wherein W²is SO₂, CO, COO, C(S)NH, CONH or —
    - CON(C_1-4alkyl)-.
  - 16. The compound of claim 1 wherein W²is SO₂or CO.
  - 17. The compound of claim 1 wherein W³is C_1-4alkylenyl or cycloalkyl.
  - 18. The compound of claim 1 wherein R¹³is C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl or heterocycloalkylalkyl, each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from:
    - C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, halo, CN, NO₂, OR^a″, SR^a″, C(O)R^b″, C(O)NR^c″R^d″, C(O)OR^a″, OC(O)R^b″, OC(O)NR^c″R^d″, NR^c″R^d″, NR^c″C(O)R^d″, NR^c″C(O)OR^a″, S(O)R^b″, S(O)NR^c″R^d″, S(O)₂R^b″, S(O)₂NR^c″R^d″, —
      
      (C_1-6alkyl)-CN, —
      
      (C_1-6alkyl)-NO₂, —
      
      (C_1-6alkyl)-OR^a″, —
      
      (C_1-6alkyl)-SR^a″, —
      
      (C_1-6alkyl)-C(O)R^b″, —
      
      (C_1-6alkyl)-C(O)NR^c″R^d″, —
      
      (C_1-6alkyl)-C(O)OR^a″, —
      
      (C_1-6alkyl)-OC(O)R^b″, —
      
      (C_1-6alkyl)-OC(O)NR^c″R^d″, —
      
      (C_1-6alkyl)-NR^c″R^d″, —
      
      (C_1-6alkyl)-NR^c″C(O)R^d″, —
      
      (C_1-6alkyl)-NR^c″C(O)OR^a″,—
      
      (C_1-6alkyl)-S(O)R^b″, —
      
      (C_1-6alkyl)-S(O)NR^c″R^d″, —
      
      (C_1-6alkyl)-S(O)₂R^b″, and —
      
      (C_1-6alkyl)-S(O)₂NR^c″R^d″.
  - 19. The compound of claim 1 wherein R¹³is C_1-6alkyl, C_1-6haloalkyl, aryl, cycloalkyl, hetero aryl, heterocycloalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl or heterocycloalkylalkyl, each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from:
    - C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, halo, CN, NO₂, OR^a″, SR^a″, C(O)R^b″, C(O)NR^c″R^d″, C(O)OR^a″, OC(O)R^b″, OC(O)NR^c″R^d″, NR^c″R^d″, NR^c″C(O)R^d″, NR^c″C(O)OR^a″, S(O)R^b″, S(O)NR^c″R^d″, S(O)₂R^b″, S(O)₂NR^c″R^d″, —
      
      (C_1-6alkyl)-CN, —
      
      (C_1-6alkyl)-NO₂, —
      
      (C_1-6alkyl)-OR^a″, —
      
      (C_1-6alkyl)-SR^a″, —
      
      (C_1-6alkyl)-C(O)R^b″, —
      
      (C_1-6alkyl)-C(O)NR^c″R^d″, —
      
      (C_1-6alkyl)-C(O)OR^a″, —
      
      (C_1-6alkyl)-OC(O)R^b″, —
      
      (C_1-6alkyl)-OC(O)NR^c″R^d″, —
      
      (C_1-6alkyl)-NR^c″R^d″, —
      
      (C_1-6alkyl)-NR^c″C(O)R^d″, —
      
      (C_1-6alkyl)-NR^c″C(O)OR^a″, —
      
      (C_1-6alkyl)-S(O)R^b″, —
      
      (C_1-6alkyl)-S(O)NR^c″R^d″, —
      
      (C_1-6alkyl)-S(O)₂R^b″, and —
      
      (C_1-6alkyl)-S(O)₂NR^c″R^d″.
  - 20. The compound of claim 1 wherein R¹³is C_1-6alkyl, C_1-6haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl or heterocycloalkylalkyl, each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from C_1-6alkyl, C_1-6haloalkyl, aryl, heteroaryl, halo, CN, OR^a″
    - , SR^a″, C(O)R^b″, C(O)OR^a″, NR^c″C(O)R^d″, S(O)₂R^b″, and —
      
      (C_1-6alkyl)-CN.
  - 21. The compound of claim 1 wherein R¹³is C_1-6alkyl, C_1-6haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl or heterocycloalkylalkyl, each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from C_1-6alkyl, C_1-6haloalkyl, aryl, heteroaryl, halo, CN, OH, C_1-4alkoxy, C_1-4haloalkoxy, heteroaryloxy, aryloxy, —
    - SC_1-6alkyl, —
      
      C(O)—
      
      C_1-6alkyl, —
      
      C(O)OC_1-6alkyl, —
      
      S(O)₂C_1-6alkyl, —
      
      NHC(O)—
      
      C_1-6alkyl, and —
      
      (C_1-6alkyl)-CN.
  - 22. The compound of claim 1 where R¹³is OH or CN.
  - 23. The compound of claim 1 wherein W¹is absent, W²is CO or SO₂, W³is C_1-4alkyleneyl or cycloalkyl, W⁴is absent, W⁵is absent, W⁶is absent, and R¹³is CN or OH.
  - 24. The compound of claim 1 wherein R⁶is —
    - W²—
      
      W³—
      
      R¹³.
  - 25. The compound of claim 1 wherein R⁶is —
    - CO—
      
      CH₂—
      
      CN.
  - 26. The compound of claim 1 wherein R⁶is —
    - W²—
      
      R¹³.
  - 27. The compound of claim 1 wherein:
    - R⁶is —
      
      W²—
      
      R¹³;
      
      W²is SO₂, CO, COO, C(S)NR¹², or CONR¹²; and
      
      R¹³is C_1-6alkyl, C_1-6haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl or heterocycloalkylalkyl, each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from;
      
      C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, halo, CN, NO₂, OR^a″, SR^a″, C(O)R^b″, C(O)NR^c″R^d″, C(O)OR^a″, OC(O)R^b″, OC(O)NR^c″R^d″, NR^c″R^d″, NR^c″C(O)R^d″, NR^c″C(O)OR^a″, S(O)R^b″, S(O)NR^c″R^d″, S(O)₂R^b″, S(O)₂NR^c″R^d″, —
      
      (C_1-6alkyl)-CN, —
      
      (C_1-6alkyl)-NO₂, —
      
      (C_1-6alkyl)-OR^a″, —
      
      (C_1-6alkyl)-SR^a″, —
      
      (C_1-6alkyl)-C(O)R^b″, —
      
      (C_1-6alkyl)-C(O)NR^c″R^d″, —
      
      (C_1-6alkyl)-C(O)OR^a″, —
      
      (C_1-6alkyl)-OC(O)R^b″, —
      
      (C_1-6alkyl)-OC(O)NR^c″R^d″, —
      
      (C_1-6alkyl)-NR^c″R^d″, —
      
      (C_1-6alkyl)-NR^c″C(O)R^d″, —
      
      (C_1-6alkyl)-NR^c″C(O)OR^a′, —
      
      (C_1-6alkyl)-S(O)R^b″, —
      
      (C_1-6alkyl)-S(O)NR^c″R^d″, —
      
      (C_1-6alkyl)-S(O)₂R^b″, and —
      
      (C_1-6alkyl)-S(O)₂NR^c″R^d″.
  - 28. The compound of claim 1 having the structure of Formula I-A:
  - 29. The compound of claim 28 wherein:
    - W²is SO₂, CO, COO, C(S)NR¹², or CONR¹²; and
      
      R¹³is C_1-6alkyl, C_1-6haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl or heterocycloalkylalkyl, each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from;
      
      C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, C_1-6haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocycloalkylalkyl, halo, CN, NO₂, OR^a″, SR^a″, C(O)R^b″, C(O)NR^c″R^d″, C(O)OR^a″, OC(O)R^b″, OC(O)NR^c″R^d″, NR^c″R^d″, NR^c″C(O)R^d″, NR^c″C(O)OR^a″, S(O)R^b″, S(O)NR^c″R^d″, S(O)₂R^b″, S(O)₂NR^c″R^d″, —
      
      (C_1-6alkyl)-CN, —
      
      (C_1-6alkyl)-NO₂, —
      
      (C_1-6alkyl)-OR^a″, —
      
      (C_1-6alkyl)-SR^a″, —
      
      (C_1-6alkyl)-C(O)R^b″, —
      
      (C_1-6alkyl)-C(O)NR^c″R^d″, —
      
      (C_1-6alkyl)-C(O)OR^a″, —
      
      (C_1-6alkyl)-OC(O)R^b″, —
      
      (C_1-6alkyl)-OC(O)NR^c″R^d″, —
      
      (C_1-6alkyl)-NR^c″R^d″, —
      
      (C_1-6alkyl)-NR^c″C(O)R^d″, —
      
      (C_1-6alkyl)-NR^c″C(O)OR^a″, —
      
      (C_1-6alkyl)-S(O)R^b″, —
      
      (C_1-6alkyl)-S(O)NR^c″R^d″, —
      
      (C_1-6alkyl)-S(O)₂R^b″, and —
      
      (C_1-6alkyl)-S(O)₂NR^c″R^d″.
  - 30. The compound of claim 1 having the structure of Formula I-B:
  - 31. The compound of claim 30 whereinR¹³is C_1-6alkyl, C_1-6haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl or heterocycloalkylalkyl, each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from C_1-6alkyl, C_1-6haloalkyl, aryl, heteroaryl, halo, CN, OR^a″
    - , SR^a″, C(O)R^b″, C(O)OR^a″, NR^c″C(O)R^d″, S(O)₂R^b″, and —
      
      (C_1-6alkyl)-CN;
      
      W²is SO₂, CO, COO, C(S)NH, CONH or —
      
      CON(C_1-4alkyl)-; and
      
      R⁴is C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, S(O)₂R⁹, SOR⁹, cycloalkyl, or heterocycloalkyl, wherein said C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, cycloalkyl, heterocycloalkyl are each optionally substituted with 1, 2 or 3 substituents selected from halo, C_1-4alkyl, C_2-4alkenyl, C_2-4alkynyl, C_1-4haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO₂, OR^a, SR^a, C(O)R^b, C(O)NR^cR^d, C(O)OR^a, OC(O)R^b, OC(O)NR^cR^d, NR^cR^d, NR^cC(O)R^d, NR^cC(O)OR^a, S(O)R^b, S(O)NR^cR^d, S(O)₂R^b, and S(O)₂NR^cR^d.
  - 32. A compound of claim 1 selected from:
    - 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.
  - 33. A composition comprising a compound of claim 1, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  - 34. A method of modulating an activity of JAK comprising contacting JAK with a compound of claim 1, or pharmaceutically acceptable salt thereof.
  - 35. The method of claim 34 wherein said JAK is in a cell.
  - 36. The method of claim 34 wherein said JAK is JAK1, JAK2, JAK3 or TYK2.
  - 37. The method of claim 34 wherein said JAK is JAK1 or JAK2.
  - 38. The method of claim 34 wherein said JAK is JAK2.
  - 39. The method of claim 34 wherein said modulating is inhibiting.
  - 40. The method of claim 34 wherein said compound is a selective inhibitor of JAK2 over JAK1, JAK2, JAK3 and TYK2.
  - 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.
  - 42. The method of claim 41 wherein said disease is allograft rejection or graft versus host disease.
  - 43. The method of claim 41 wherein said disease is an autoimmune disease.
  - 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.
  - 45. The method of claim 41 wherein said disease is a viral disease.
  - 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).
  - 47. The method of claim 41 wherein said disease is cancer.
  - 48. The method of claim 47 wherein said cancer is prostate cancer, lymphoma, leukemia, or multiple myeloma.
  - 49. The method of claim 47 wherein said cancer is multiple myeloma.

50. A pharmaceutical composition for topical administration comprising a compound of Formula II:
- View Dependent Claims (51, 52, 53, 54)
- - 51. The composition of claim 50 wherein said topical administration comprises transdermal administration.
  - 52. The composition of claim 50 which is in the form of a transdermal patch, ointment, lotion, cream, or gel.
  - 53. The composition of claim 50 wherein A is CR¹.
  - 54. The composition of claim 50 wherein A is N.

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)
- - 56. The method of claim 55 wherein said skin disorder is atopic dermatitis or psoriasis.
  - 57. The method of claim 55 wherein said skin disorder is skin sensitization, skin irritation, skin rash, contact dermatitis or allergic contact sensitization.
  - 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.
  - 59. The method of claim 55 wherein A is CR¹.
  - 60. The method of claim 55 wherein A is N.

Specification

Resources

Litigation Campaign Assessment

Current Assignee
Incyte Corporation, Incyte Holdings Corporation (Incyte Corporation)
Original Assignee
Incyte Corporation
Inventors
Rodgers, James D., Wang, Haisheng, Combs, Andrew P., Sparks, Richard B.

Granted Patent

US 9,580,419 B2
Time in Patent Office

Days
Field of Search
US Class Current

1/1
CPC Class Codes

A61P 1/04   for ulcers, gastritis or re...

A61P 17/00   Drugs for dermatological di...

A61P 17/06   Antipsoriatics

A61P 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   Antivirals

A61P 31/14   for RNA viruses

A61P 31/18   for HIV

A61P 31/20   for DNA viruses

A61P 35/00   Antineoplastic agents

A61P 37/00   Drugs for immunological or ...

A61P 37/02   Immunomodulators

A61P 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 systems

C07D 487/04   Ortho-condensed systems

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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PYRROLO[2,3-b]PYRIDIN-4-YL-AMINES AND PYRROLO[2,3-b]PYRIMIDIN-5-YL-AMINES AS JANUS KINASE INHIBITORS

First Claim

2 Assignments

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0 Petitions

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Accused Products

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Abstract

37 Citations

60 Claims

Specification

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Solutions

Use Cases

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