SUBSTITUTED HETEROCYCLES AS JANUS KINASE INHIBITORS
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Abstract
The present invention provides substituted tricyclic heteroaryl compounds, including, for example, pyridoindoles, pyrimidinoindoles and triazinoindoles that modulate the activity of Janus kinases and are useful in the treatment of diseases related to activity of Janus kinases such as immune-related diseases, skin disorders, myeloid proliferative disorders, cancer, and other diseases.
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Citations
100 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, 50, 51, 52, 53, 54, 55, 56, 57)
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2. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein Y1 is N and Y2 is CR4.
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3. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein Y2 is N and Y1 is CR3.
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4. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein Y2 is N.
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5. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein Y2 is CR4.
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6. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein Y3 is N.
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7. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein Y3 is CR5.
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8. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein Z1 is N.
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9. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein Z1 is CR6.
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10. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein Z2 is N.
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11. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein Z2 is CR7.
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12. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein R1 is H, C1-6 alkyl, or C(O)C1-6 alkyl.
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13. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein R1 is H
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14. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein R2 is H
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15. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein Cya is arylene or heteroarylene, each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Cy, C1-6 haloalkyl, halosulfanyl, CN, NO2, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, C(═
- NRi)NRc1Rd1, NRc1C(═
NRi)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1C(O)NRc1Rd1, NRc1S(O)Rb1, NRc1S(O)2Rb1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1;
wherein said C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl is optionally substituted with 1, 2, 3, 4, or 5 substituents selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Cy, C1-6 haloalkyl, halosulfanyl, CN, NO2, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, C(═
NRi)NRc1Rd1, NRc1C(═
NRi)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1C(O)NRc1Rd1, NRc1S(O)Rb1, NRc1S(O)2Rb1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1.
- NRi)NRc1Rd1, NRc1C(═
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16. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein Cya is arylene optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Cy, C1-6 haloalkyl, halosulfanyl, CN, NO2, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, C(═
- NRi)NRc1Rd1, NRc1C(═
NRi)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1C(O)NRc1Rd1, NRc1S(O)Rb1, NRc1S(O)2Rb1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1;
wherein said C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl is optionally substituted with 1, 2, 3, 4, or 5 substituents selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Cy, C1-6 haloalkyl, halosulfanyl, CN, NO2, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Ra1, OC(O)NRc1Rd1, C(═
NRi)NRc1Rd1, NRc1C(═
NRi)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1C(O)NRc1Rd1, NRc1S(O)Rb1, NRc1S(O)2Rb1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1.
- NRi)NRc1Rd1, NRc1C(═
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17. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein Cya is arylene optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Cy, C1-6 haloalkyl, halosulfanyl, CN, NO2, ORb1, SRb1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, C(═
- NRi)NRc1Rd1, NRc1C(═
NRi)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1C(O)NRc1Rd1, NRc1S(O)Rb, NRc1S(O)2Rb1, S(O)Rb1 S(O)NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1.
- NRi)NRc1Rd1, NRc1C(═
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18. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein Cya is arylene optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Cy, C1-6 haloalkyl, CN, NO2, ORa1, SRa1, and NRc1Rd1.
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19. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein Cya is arylene optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from halo, C1-6 alkyland ORa1.
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20. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein Cya is a substituted aryl or substituted heteroaryl ring according to Formula IA:
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21. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein Cya is a substituted aryl or substituted heteroaryl ring according to Formula IB:
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22. A compound of claim 21, or pharmaceutically acceptable salt thereof, wherein R is selected from H, halo, CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Cy, C1-6 haloalkyl, and ORa1;
- wherein said C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl is optionally substituted with 1, 2, 3, 4, or 5 substituents selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Cy, C1-6 haloalkyl, halosulfanyl, CN, NO2, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, C(═
NRi)NRc1Rd1, NRc1C(═
NRi)NRc1Rd1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1C(O)NRc1Rd1, NRc1S(O)Rb1, NRc1S(O)2Rb1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1.
- wherein said C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl is optionally substituted with 1, 2, 3, 4, or 5 substituents selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Cy, C1-6 haloalkyl, halosulfanyl, CN, NO2, ORa1, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, C(═
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23. A compound of claim 21, or pharmaceutically acceptable salt thereof, wherein R is selected from halosulfanyl, NO2, SRa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, OC(O)Rb1, OC(O)NRc1Rd1, C(═
- NRi)NRc1Rd1, NRc1C(═
NRi)NRc1Rd1, NRc1Rd, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1C(O)NRc1Rd1, NRc1S(O)Rb1, NRc1S(O)2Rb1, S(O)Rb1, S(O)NRc1Rd1, S(O)2Rb1, and S(O)2NRc1Rd1.
- NRi)NRc1Rd1, NRc1C(═
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24. A compound of claim 21, or pharmaceutically acceptable salt thereof, wherein R is selected from H, halo, CN, C1-6 alkyl and ORa1.
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25. A compound of claim 21, or pharmaceutically acceptable salt thereof, wherein Q1 is CRQ.
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26. A compound of claim 21, or pharmaceutically acceptable salt thereof, wherein Q2 is CRQ.
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27. A compound of claim 21, or pharmaceutically acceptable salt thereof, wherein Q3 is CRQ.
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28. A compound of claim 21, or pharmaceutically acceptable salt thereof, wherein Q3 is N.
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29. A compound of claim 21, or pharmaceutically acceptable salt thereof, wherein RQ is H.
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30. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein Cyb is aryl or heteroaryl, each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Cy, C1-6 haloalkyl, halosulfanyl, CN, NO2, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)OR2, OC(O)Rb2, OC(O)NRc2Rd2, C(═
- NRi)NRc2Rd2, NRc2C(═
NRi)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)ORa2, NRc2C(O)NRc2Rd2, NRc2S(O)Rb2, NRc2S(O)2Rb2, S(O)b2, S(O)NRc2Rd2, S(O)2Rb2, and S(O)2NRc2Rd2;
wherein said C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl is optionally substituted with 1, 2, 3, 4, or 5 substituents selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Cy, C1-6 haloalkyl, halosulfanyl, CN, NO2, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, C(═
NRi)NRc2Rd2, NRc2C(═
NRi)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)ORa2, NRc2C(O)NRc2Rd2, NRc2S(O)Rb2, NRc2S(O)2Rb2, NRc2C(O)NRc2Rd2, NRc2S(O)Rb2, NRc2S(O)2Rb2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, and S(O)2NRc2Rd2.
- NRi)NRc2Rd2, NRc2C(═
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31. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein Cyb is aryl or heteroaryl, each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Cy, C1-6 haloalkyl, halosulfanyl, CN, NO2, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, C(═
- NRi)NRc2Rd2, NRc2C(═
NRi)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)ORa2, NRc2C(O)NRc2Rd2, NRc2S(O)Rb2, NRc2S(O)2, S(O)b2 S(O)NRc2Rd2, S(O)2Rb2, and S(O)2NRc2Rd2.
- NRi)NRc2Rd2, NRc2C(═
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32. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein Cyb is aryl or heteroaryl, each optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from halo, C1-6 alkyl, Cy, C1-6 haloalkyl, halosulfanyl, CN, NO2, ORa2, and NRc2Rd2.
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33. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein Cyb is aryl, optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Cy, C1-6 haloalkyl, halosulfanyl, CN, NO2, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, C(═
- NRi)NRc2Rd2, NRc2C(═
NRi)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)ORa2, NRc2C(O)NRc2Rd2, NRc2S(O)Rb2, NRc2S(O)Rb2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, and S(O)2NRc2Rd2;
wherein said C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl is optionally substituted with 1, 2, 3, 4, or 5 substituents selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Cy, C1-6 haloalkyl, halosulfanyl, CN, NO2, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, C(═
NRi)NRc2Rd2, NRc2C(═
NRi)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)ORa2, NRc2C(O)NRc2Rd2, NRc2S(O)Rb2, NRc2S(O)2Rb2, NRc2C(O)NRc2Rd2, NRc2S(O)Rb2, NRc2S(O)2Rb2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, and S(O)2NRc2Rd2.
- NRi)NRc2Rd2, NRc2C(═
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34. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein Cyb is heteroaryl, optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Cy, C1-6 haloalkyl, halosulfanyl, CN, NO2, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, C(═
- NRi)NRc2Rd2, NRc2C(═
NRi)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)ORa2, NRc2C(O)NRc2Rd2, NRc2S(O)Rb2, NRc2S(O)2Rb2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, and S(O)2NRc2Rd2;
wherein said C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl is optionally substituted with 1, 2, 3, 4, or 5 substituents selected from halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, Cy, C1-6 haloalkyl, halosulfanyl, CN, NO2, ORa2, SRa2, C(O)Rb2, C(O)NRc2Rd2, C(O)ORa2, OC(O)Rb2, OC(O)NRc2Rd2, C(═
NRi)NRc2Rd2, NRc2C(═
NRi)NRc2Rd2, NRc2Rd2, NRc2C(O)Rb2, NRc2C(O)ORa2, NRc2C(O)NRc2Rd2, NRc2S(O)Rb2, NRc2S(O)2Rb2, NRc2C(O)NRc2Rd2, NRc2S(O)Rb2, NRc2S(O)2Rb2, S(O)Rb2, S(O)NRc2Rd2, S(O)2Rb2, and S(O)2NRc2Rd2.
- NRi)NRc2Rd2, NRc2C(═
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35. A compound of claim 1, wherein Cyb is a substituted aryl or substituted heteroaryl ring according to Formula IF:
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36. A compound of claim 35, or pharmaceutically acceptable salt thereof, wherein W1 is CRW.
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37. A compound of claim 35, or pharmaceutically acceptable salt thereof, wherein W1 is N.
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38. A compound of claim 35, or pharmaceutically acceptable salt thereof, wherein W2 is CRW.
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39. A compound of claim 35, or pharmaceutically acceptable salt thereof, wherein W2 is N.
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40. A compound of claim 35, or pharmaceutically acceptable salt thereof, wherein A1 is CRW.
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41. A compound of claim 35, or pharmaceutically acceptable salt thereof, wherein A1 is N.
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42. A compound of claim 35, or pharmaceutically acceptable salt thereof, wherein A2 is CRW.
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43. A compound of claim 35, or pharmaceutically acceptable salt thereof, wherein A2 is N.
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44. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein L is a divalent moiety selected from C1-6 alkylene, (C1-6 alkylene)p-O—
- (C1-6 alkylene)q, (C1-6 alkylene)p-S—
(C1-6 alkylene)q, (C1-6 alkylene)p-NRc3—
(C1-6 alkylene)q, (C1-6 alkylene)p-C(O)—
(C1-6 alkylene)q, (C1-6 alkylene)p-OC(O)—
(C1-6 alkylene)q, (C1-6 alkylene)p-C(O)NRc3—
(C1-6 alkylene)q, (C1-6 alkylene)p-OC(O)NRc3—
(C1-6 alkylene)q, (C1-6 alkylene)p-SO—
(C1-6 alkylene)q, (C1-6 alkylene)p-SO2—
(C1-6 alkylene)q, (C1-6 alkylene)p-SONRc3—
(C1-6 alkylene)q, (C1-6 alkylene)p-SO2NRc3—
(C1-6 alkylene)q, (C1-6 alkylene)p-NRc3CONRd3—
(C1-6 alkylene)q, (C1-6 alkylene)p-NRc3SONRd3—
(C1-6 alkylene)q, and (C1-6 alkylene)p-NRc3SO2NRd3—
(C1-6 alkylene)q, wherein the C1-6 alkylene is optionally substituted by 1, 2 or 3 substituents independently selected from C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 hydroxyalkyl, C1-4 cyanoalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halo, CN, NO2, SCN, OH, C1-4 haloalkyl, halosulfanyl, C1-4 alkoxy-C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkoxy, amino, C1-4 alkylamino, and C2-8 dialkylamino.
- (C1-6 alkylene)q, (C1-6 alkylene)p-S—
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45. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein L is a divalent moiety selected from (C1-6 alkylene)p-C(O)NRc3—
- (C1-6 alkylene)q and (C1-6 alkylene)p-NRc3CONRd3—
(C1-6 alkylene)q, wherein the C1-6 alkylene is optionally substituted by 1, 2 or 3 substituents independently selected from C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 hydroxyalkyl, C1-4 cyanoalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, halo, CN, NO2, SCN, OH, C1-4 haloalkyl, halosulfanyl, C1-4 alkoxy-C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkoxy, amino, C1-4 alkylamino, and C2-8 dialkylamino.
- (C1-6 alkylene)q and (C1-6 alkylene)p-NRc3CONRd3—
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46. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein L is a divalent moiety selected from (C1-6 alkylene)p-C(O)NRc3—
- (C1-6 alkylene)q and (C1-6 alkylene)p-NRc3CONRd3—
(C1-6 alkylene)q.
- (C1-6 alkylene)q and (C1-6 alkylene)p-NRc3CONRd3—
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47. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein L is a divalent moiety selected from C(O)NH, C(O)NH—
- (C1-6 alkylene) and NHCONH.
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48. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein L is C(O)NH.
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49. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein L is C(O)NH—
- (C1-6 alkylene).
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50. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein L is NHCONH.
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51. A compound of claim 1, or pharmaceutically acceptable salt thereof, having Formula II:
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52. The compound of claim 1, or pharmaceutically acceptable salt thereof, having Formula III:
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53. The compound of claim 1, or pharmaceutically acceptable salt thereof, having Formula IIIK:
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54. The compound of claim 1, or pharmaceutically acceptable salt thereof, having Formula IVA or IVB:
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55. The compound of claim 1, selected from:
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N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-3-(trifluoromethyl)benzamide; 3-(4-Methyl-1H-imidazol-1-yl)-N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-5-(tri-fluoromethyl)benzamide; 3-fluoro-N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-5-(trifluoromethyl)-benzamide; 3-(4-formyl-1H-imidazol-1-yl)-N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-5-(trifluoromethyl)benzamide; 3-[4-(hydroxymethyl)-1H-imidazol-1-yl]-N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)-phenyl]-5-(trifluoromethyl)benzamide; 3-4-[(methylamino)methyl]-1H-imidazol-1-yl-N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-5-(trifluoromethyl)benzamide; 3-(4-methylpiperazin-1-yl)-N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-5-(trifluoromethyl)benzamide; N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-6-yl)phenyl]-3-(trifluoromethyl)benzamide; 4-fluoro-N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-6-yl)phenyl]-3-(trifluoromethyl)-benzamide; N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-N′
-[3-(trifluoromethyl)phenyl]urea;N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-6-yl)phenyl]-N′
-[3-(trifluoromethyl)phenyl]urea;4-methyl-3-(9H-pyrimido[4,5-b]indol-6-yl)-N-[3-(trifluoromethyl)phenyl]benzamide; 4-chloro-3-(9H-pyrimido[4,5-b]indol-7-yl)-N-[3-(trifluoromethyl)phenyl]benzamide; 4-cyano-3-(9H-pyrimido[4,5-b]indol-7-yl)-N-[3-(trifluoromethyl)phenyl]benzamide; 2-fluoro-N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-3-(trifluoromethyl)-benzamide; 4-fluoro-N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-3-(trifluoromethyl)-benzamide; 2-fluoro-N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-5-(trifluoromethyl)-benzamide; 3-fluoro-N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-6-yl)phenyl]benzamide; N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-2,5-bis(trifluoromethyl)benzamide; 3-chloro-2-fluoro-N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-5-(trifluoromethyl)-benzamide; N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-3,5-bis(trifluoromethyl)benzamide; 4-methoxy-N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-3-(trifluoromethyl)-benzamide; 3-methoxy-N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]benzamide; N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-2-(trifluoromethyl)benzamide; N-[4-fluoro-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-3-(trifluoromethyl)benzamide; N-[3-(9H-pyrimido[4,5-b]-indol-7-yl)phenyl]-3-(trifluoromethyl)benzamide; 3-chloro-N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]benzamide; N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-3-(pentafluoro-λ
(6)-sulfanyl)-benzamide;N-[4-chloro-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-3-(trifluoromethyl)benzamide; N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-4-(trifluoromethyl)pyridine-2-carboxamide; 3-(1H-imidazol-1-yl)-N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-5-(trifluoro-methyl)benzamide; N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-3-(1H-1,2,4-triazol-1-yl)-5-(trifluoro-methyl)benzamide; 3-{4-[(dimethylamino)methyl]-1H-imidazol-1-yl}-N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-5-(trifluoromethyl)benzamide; N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-3-morpholin-4-yl-5-(trifluoromethyl)-benzamide; N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-3-piperazin-1-yl-5-(trifluoromethyl)-benzamide; 3-(4-hydroxypiperidin-1-yl)-N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-5-(trifluoromethyl)benzamide; 3-(3-hydroxypiperidin-1-yl)-N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-5-(trifluoromethyl)benzamide; N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-3-[(2-morpholin-4-ylethyl)amino]-5-(trifluoromethyl)benzamide; 3-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-5-(trifluoromethyl)benzamide; 3-{[3-(dimethylamino)propyl]amino}-N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-5-(trifluoromethyl)benzamide; 3-(3-hydroxypyrrolidin-1-yl)-N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-5-(trifluoromethyl)benzamide; 3-{[3-(1H-imidazol-1-yl)-propyl]amino}-N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)-phenyl]-5-(trifluoromethyl)benzamide; 3-(dimethylamino)-N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-5-(trifluoro-methyl)benzamide; 3-[3-(dimethylamino)-pyrrolidin-1-yl]-N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)-phenyl]-5-(trifluoromethyl)benzamide; 3-{[2-(dimethylamino)ethyl]amino}-N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)phenyl]-5-(trifluoromethyl)benzamide; 4-fluoro-N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-6-yl)phenyl]-3-(trifluoromethyl)-benzamide; 3-fluoro-N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-6-yl)phenyl]-5-(trifluoromethyl)-benzamide; 3-fluoro-N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-6-yl)phenyl]benzamide; N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-6-yl)phenyl]-2,5-bis(trifluoromethyl)benzamide; 3-chloro-2-fluoro-N-[4-methyl-3-(9H-pyrimido[4,5-b]indol-6-yl)phenyl]-5-(trifluoromethyl)-benzamide; 4-methyl-3-(9H-pyrimido-[4,5-b]indol-7-yl)-N-[3-(trifluoromethyl)phenyl]benzamide; 4-methyl-N-(3-methyl-phenyl)-3-(9H-pyrimido[4,5-b]indol-7-yl)benzamide; 4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)-N-[3-(trifluoromethoxy)phenyl]benzamide; N-(2,5-difluorobenzyl)-4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)benzamide; 4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)-N-[3-(trifluoromethyl)benzyl]benzamide; 4-methyl-N-(5-methyl-1,3-thiazol-2-yl)-3-(9H-pyrimido[4,5-b]indol-7-yl)benzamide; 4-chloro-3-(9H-pyrimido[4,5-b]indol-7-yl)-N-[3-(trifluoromethyl)phenyl]benzamide; 3-(9H-pyrimido[4,5-b]indol-7-yl)-N-[3-(trifluoromethyl)phenyl]benzamide; 4-methoxy-3-(9H-pyrimido[4,5-b]indol-7-yl)-N-[3-(trifluoromethyl)phenyl]benzamide; 4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)-N-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]-benzamide; 4-methyl-N-[3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl]-3-(9H-pyrimido[4,5-b]indol-7-yl)benzamide; 4-methyl-N-[(1R)-1-phenylethyl]-3-(9H-pyrimido[4,5-b]indol-7-yl)benzamide; 4-methyl-N-[(1S)-1-phenylethyl]-3-(9H-pyrimido[4,5-b]indol-7-yl)benzamide; 4-methyl-N-[3-(pentafluoro-λ
(6)-sulfanyl)phenyl]-3-(9H-pyrimido[4,5-b]indol-7-yl)-benzamide;4-methyl-3-(9H-pyrimido[4,5-b]indol-7-yl)-N-[5-(trifluoromethyl)pyridin-3-yl]benzamide; N-[3-(2-amino-9H-pyrimido[4,5-b]indol-7-yl)-4-methylphenyl]-3-(trifluoromethyl)-benzamide; 4-methyl-3-(9H-pyrido[2,3-b]indol-7-yl)-N-[3-(trifluoromethyl)phenyl]benzamide; 4-methyl-3-(9H-pyrido[3′
,2′
;
4,5]pyrrolo[2,3-d]pyrimidin-7-yl)-N-[3-(trifluoromethyl)phenyl]-benzamide;N-[6-methyl-5-(9H-pyrimido[4,5-b]indol-7-yl)pyridin-3-yl]-3-(trifluoromethyl)benzamide; 3-fluoro-N-[6-methyl-5-(9H-pyrimido[4,5-b]indol-7-yl)pyridin-3-yl]-5-(trifluoromethyl)benzamide; 3-(1H-imidazol-1-yl)-N-[6-methyl-5-(9H-pyrimido[4,5-b]indol-7-yl)pyridin-3-yl]-5-(trifluoromethyl)benzamide; N-[6-methyl-5-(9H-pyrimido[4,5-b]indol-7-yl)pyridin-3-yl]-3-(1H-1,2,4-triazol-1-yl)-5-(trifluoromethyl)benzamide; 3-(4-formyl-1H-imidazol-1-yl)-N-[6-methyl-5-(9H-pyrimido[4,5-b]indol-7-yl)pyridin-3-yl]-5-(trifluoromethyl)benzamide; 3-[4-(hydroxymethyl)-1H-imidazol-1-yl]-N-[6-methyl-5-(9H-pyrimido[4,5-b]indol-7-yl)pyridin-3-yl]-5-(trifluoromethyl)benzamide; 3-[2-(dimethylamino)ethyl]amino-N-[6-methyl-5-(9H-pyrimido[4,5-b]indol-7-yl)pyridin-3-yl]-5-(trifluoromethyl)benzamide; 3-[3-(dimethylamino)propyl]amino-N-[6-methyl-5-(9H-pyrimido[4,5-b]indol-7-yl)pyridin-3-yl]-5-(trifluoromethyl)benzamide; and pharmaceutically acceptable salts thereof.
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56. A composition comprising a compound according to claim 1, or pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
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57. The composition of claim 56 which is suitable for topical administration.
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2. A compound of claim 1, or pharmaceutically acceptable salt thereof, wherein Y1 is N and Y2 is CR4.
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58. A method of treating a disease in a patient, wherein said disease is associated with abnormal activities of one or more kinases, comprising administering to said patient a therapeutically effective amount of a compound of Formula I:
- View Dependent Claims (59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99)
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59. The method of claim 58 wherein the disease is characterized by the abnormal activity of ABL.
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60. The method of claim 58 wherein the disease is characterized by the abnormal activity of JAK.
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61. The method of claim 58 wherein the disease is characterized by the abnormal activity of ABL and JAK.
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62. The method of claim 58 wherein more than one compound of Formula I is administered
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63. The method of claim 58 wherein the compound is administered in combination with another kinase inhibitor.
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64. The method of claim 58 wherein said disease is allograft rejection or graft versus host disease.
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65. The method of claim 58 wherein said disease is an autoimmune disease.
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66. The method of claim 65 wherein said autoimmune disease is a skin disorder, multiple sclerosis, rheumatoid arthritis, juvenile arthritis, type I diabetes, lupus, inflammatory bowel disease, Crohn'"'"'s disease, myasthenia gravis, immunoglobulin nephropathies, myocarditis, or autoimmune thyroid disorder.
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67. The method of claim 65 wherein said autoimmune disease is bullous skin disorder.
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68. The method of claim 67 wherein said bullous skin disorder is pemphigus vulgaris (PV) or bullous pemphigoid (BP).
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69. The method of claim 65 wherein said disease is a skin disorder.
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70. The method of claim 69 wherein said skin disorder is atopic dermatitis, psoriasis, skin sensitization, skin irritation, skin rash, contact dermatitis or allergic contact sensitization.
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71. The method of claim 65 wherein said disease is a viral disease.
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72. The method of claim 71 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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73. The method of claim 65 wherein said disease is cancer.
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74. The method of claim 73 wherein said cancer is a solid tumor.
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75. The method of claim 73 wherein said cancer is prostate cancer, renal cancer, hepatic cancer, breast cancer, lung cancer, thyroid cancer, Kaposi'"'"'s sarcoma, Castleman'"'"'s disease or pancreatic cancer.
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76. The method of claim 73 wherein said cancer is prostate cancer.
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77. The method of claim 73 wherein said cancer is hematological.
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78. The method of claim 73 wherein said cancer is lymphoma, leukemia, or multiple myeloma.
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79. The method of claim 73 wherein said cancer is acute lymphoblastic leukemia (ALL), chronic myelomonocytic leukemia (CMML), chronic myeloid leukemia (CML), atypical CML or CMML.
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80. The method of claim 73 wherein said cancer is a skin cancer.
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81. The method of claim 80 wherein said skin cancer is cutaneous T-cell lymphoma or cutaneous B-cell lymphoma.
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82. The method of claim 73 wherein said cancer is multiple myeloma.
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83. The method of claim 65 said disease is characterized by a mutant JAK2.
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84. The method of claim 83 wherein at least one mutation of said mutant JAK2 resides in the pseudo-kinase domain of said JAK2.
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85. The method of claim 58 wherein said disease is characterized by a mutant ABL.
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86. The method of claim 85 wherein at least one mutation of said mutant ABL resides in the kinase domain of said mutant ABL.
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87. The method of claim 65 wherein said disease is a myeloproliferative disorder.
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88. The method of claim 87 wherein said myeloproliferative disorder (MPD) is polycythemia vera (PV), essential thrombocythemia (ET), myeloid metaplasia with myelofibrosis (MMM), chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), hypereosinophilic syndrome (HES), idiopathic myelofibrosis (IMF), or systemic mast cell disease (SMCD).
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89. The method of claim 65 wherein said disease is an inflammatory disease.
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90. The method of claim 89 wherein said disease is an inflammatory disease of the eye.
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91. The method of claim 90 wherein said disease is iritis, uveitis, scleritis, or conjunctivitis.
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92. The method of claim 89 wherein said disease is an inflammatory disease of the respiratory tract.
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93. The method of claim 92 wherein said inflammatory disease concerns the upper respiratory tract.
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94. The method of claim 92 wherein said inflammatory disease concerns the lower respiratory tract.
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95. The method of claim 89 wherein said inflammatory disease is an inflammatory myopathy.
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96. The method of claim 89 wherein said inflammatory disease is myocarditis.
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97. The method of claim 65 wherein said disease is ischemia reperfusion or related to an ischemic event.
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98. The method of claim 65 wherein said disease is anorexia or cachexia resulting from or associated with cancer.
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99. The method of claim 65 wherein said disease is fatigue resulting from or associated with cancer.
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59. The method of claim 58 wherein the disease is characterized by the abnormal activity of ABL.
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100. A method of treating autoimmune disease, skin disorder, viral disease, cancer, or myeloproliferative disorder in a patient, comprising administering to said patient a therapeutically effective amount of a compound of Formula I:
Specification
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Current AssigneeIncyte Holdings Corporation And Incyte Corporation
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Original AssigneeIncyte Corporation
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InventorsRodgers, James D., Storace, Louis, Arvanitis, Argyrios G., Folmer, Beverly
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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 Current514/267
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CPC Class CodesA61K 31/437 the heterocyclic ring syste...A61P 1/04 for ulcers, gastritis or re...A61P 11/06 AntiasthmaticsA61P 17/00 Drugs for dermatological di...A61P 17/06 AntipsoriaticsA61P 19/02 for joint disorders, e.g. a...A61P 21/04 for myasthenia gravisA61P 25/00 Drugs for disorders of the ...A61P 27/02 Ophthalmic agentsA61P 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 31/22 for herpes virusesA61P 35/00 Antineoplastic agentsA61P 35/02 specific for leukemiaA61P 37/06 Immunosuppressants, e.g. dr...A61P 43/00 Drugs for specific purposes...A61P 5/14 : of the thyroid hormones, e....A61P 9/04 : Inotropic agents, i.e. stim...C07D 471/14 : Ortho-condensed systemsC07D 487/04 : Ortho-condensed systemsC07D 487/14 : Ortho-condensed systems