Pyrrolo[2,3-b]pyridin-4-yl-amines and pyrrolo[2,3-b]pyrimidin-5-yl-amines as janus kinase inhibitors

US 9,090,611 B2
Filed: 04/17/2014
Issued: 07/28/2015
Est. Priority Date: 12/22/2004
Status: Active Grant

First Claim

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1. A method of treating rheumatoid arthritis in a patient, comprising administering to said patient a therapeutically effective amount of 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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32 Claims

1. A method of treating rheumatoid arthritis in a patient, comprising administering to said patient a therapeutically effective amount of 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)
- - 2. The method of claim 1, wherein R¹is H.
  - 3. The method of claim 1, wherein R²is H.
  - 4. The method of claim 1, wherein R³is H.
  - 5. The method of claim 1, wherein R⁴is H or C_1-4alkyl.
  - 6. The method of claim 1, wherein R⁴is methyl.
  - 7. The method of claim 1, wherein R⁵is 3-8 membered heterocycloalkyl substituted by one R⁶and 0, 1 or 2 R⁷.
  - 8. The method of claim 1, wherein R⁵is 6-membered heterocycloalkyl substituted by one R⁶and 0, 1 or 2 R⁷.
  - 9. The method of claim 1, wherein R⁵is piperidinyl substituted by one R⁶and 0, 1 or 2 R⁷.
  - 10. The method of claim 1, wherein R⁵is piperidin-3-yl substituted by one R⁶and 0, 1 or 2 R⁷.
  - 11. The method of claim 1, wherein R⁶is substituted on the piperidinyl N-atom.
  - 12. The method 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 method 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 method of claim 1, wherein W²is SO₂, CO, COO, C(S)NR¹², or CONR¹².
  - 15. The method of claim 1, wherein W²is SO₂, CO, COO, C(S)NH, CONH or —
    - CON(C_1-4alkyl)-.
  - 16. The method of claim 1, wherein W²is SO₂or CO.
  - 17. The method of claim 1, wherein W³is C_1-4alkylenyl or cycloalkyl.
  - 18. The method 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, ORB″
      
      , 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 method 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_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^r, —
      
      (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 method 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 method 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 method of claim 1, wherein R¹³is OH or CN.
  - 23. The method 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 method of claim 1, wherein R⁶is —
    - W²—
      
      W³—
      
      R¹³.
  - 25. The method of claim 1, wherein R⁶is —
    - CO—
      
      CH₂—
      
      CN.
  - 26. The method of claim 1, wherein R⁶is —
    - W²—
      
      R¹³.
  - 27. The method 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 method of claim 1, having the structure of Formula I-A:
  - 29. The method of claim 1, 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 method of claim 1, having the structure of Formula I-B:
  - 31. The method of claim 1, 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. The method of claim 1, wherein the compound of Formula I is 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-phenylethyl)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-(1 H-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-ylcarbonyl)-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-(1 H-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;
      
      (3 S)-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-cyanoethyl)-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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Current Assignee
Incyte Holdings Corporation And Incyte Corporation
Original Assignee
Incyte Corporation
Inventors
Rodgers, James D., Wang, Haisheng, Combs, Andrew P., Sparks, Richard B.
Primary Examiner(s)
Rahmani, Niloofar

Application Number

US14/255,092
Publication Number

US 20140228346A1
Time in Patent Office

467 Days
Field of Search

546/113, 514/233.8, 514/300, 544/116
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

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3 Assignments

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Abstract

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32 Claims

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