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Last Updated: March 28, 2024

Claims for Patent: 8,247,421


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Summary for Patent: 8,247,421
Title:5-cyano-4-(pyrrolo [2,3B] pyridine-3-yl)-pyrimidine derivatives useful as protein kinase inhibitors
Abstract: The present invention relates to compounds useful as inhibitors of protein kinase. The invention also provides pharmaceutically acceptable compositions comprising said compounds and methods of using the compositions in the treatment of various disease, conditions, or disorders. The invention also provides processes for preparing compounds of the inventions.
Inventor(s): Mortimore; Michael (Oxfordshire, GB), Young; Stephen Clinton (Oxfordshire, GB), Everitt; Simon Robert Lorrie (Oxfordshire, GB), Knegtel; Ronald (Oxfordshire, GB), Pinder; Joanne Louise (Oxfordshire, GB), Rutherford; Alistair Peter (Oxfordshire, GB), Durrant; Steven (Oxfordshire, GB), Brenchley; Guy (Oxfordshire, GB), Charrier; Jean-Damien (Oxfordshire, GB), O\'Donnell; Michael (Oxfordshire, GB)
Assignee: Vertex Pharmaceuticals Incorporated (Cambridge, MA)
Application Number:12/448,489
Patent Claims:1. A compound of formula I: ##STR00481## or a pharmaceutically acceptable salt thereof; wherein: R.sup.1 is --H, halogen, C.sub.l-6 aliphatic optionally substituted with 1-3 R.sup.3, --O(C.sub.1-6 aliphatic) optionally substituted with 1-3 R.sup.3, or --N(H)R; Each R is independently H, C.sub.1-6 aliphatic, aryl, heteroaryl, C.sub.3-8 cycloalkyl, or 4-12 membered heterocyclic ring optionally containing 1-3 groups selected from --N(R.sub.17)--, --O--, or --S--; wherein each of the aliphatic, aryl, heteroaryl, cycloalkyl, and heterocyclic ring are optionally substituted with 1-3 of Q; Each Q is independently selected from halogen, hydroxy, C.sub.1-6 alkyl, benzyl, oxo, --CF.sub.3, W, --CN, --NH.sub.2, --N(H)--W, --N(W).sub.2, --N(H)--SO.sub.2--W, --S(O).sub.2--N(H)--W, --S(O).sub.2--N(W).sub.2, --C(O)--W, --C(O)--N(W).sub.2, --N(H)--C(O)--W, --O--C(O)--W, --C(O)--O--W, --SO.sub.2--W, SW or --OW; Two Q can be linked together to form a 4- to 8-membered carbocyclic or heterocyclic ring optionally substituted with C.sub.1-3 alkyl or CF.sub.3; Each W is independently selected from --H, C.sub.1-6 alkyl, aralkyl, cycloalkyl or heterocyclic ring; each C.sub.1-6 alkyl, aralkyl, cycloalkyl or heterocyclic ring is optionally substituted with 1-3 of halogen, --OR.sup.6, --CN, C.sub.1-6 alkyl or NR.sup.18R.sup.19; or One W, together with the nitrogen atom to which it is attached and a carbon atom of R, form a 4- to 8-membered ring; or Two W, together with the same or different nitrogen atom or carbon atom to which they are attached, form a 4- to 8-membered heterocyclic ring; Each R.sup.18 and R.sup.19 is independently hydrogen or C.sub.1-3 alkyl; or R.sup.18 and R.sup.19, together with the nitrogen atom to which they are attached, form a 4- to 8-memebered heterocyclic ring, optionally substituted with C.sub.1-3 alkyl or CF.sub.3; Two W can be linked together to form a 4- to 8-membered cycloalkyl or heterocycloalkyl optionally substituted with C.sub.1-3 alkyl or CF.sub.3; R.sup.2 is --NR.sup.4R.sup.5, --OR.sup.6, --SR.sup.6, or --NR.sup.10R.sup.11; Each R.sup.3 is independently halogen, C.sub.1-6 alkyl, aryl, or heteroaryl; Each R.sup.4 is independently --H or C.sub.1-6 aliphatic optionally substituted with 1-3 R.sup.7; Each R.sup.5 is independently C.sub.1-6 aliphatic optionally substituted with 1-4 R.sup.7or a 4-to 8- membered monocyclic or 6- to 10-membered bicyclic ring optionally substituted with 1-4 R.sup.7, or R.sup.4 and R.sup.5 can be joined together to form a monocyclic or bicyclic ring optionally substituted with 1-3 R.sup.9; Each R.sup.6 is independently H, C.sub.1-6 alkyl, -L-aryl, or -L-heteroaryl, wherein each of the C.sub.1-6 alkyl, -L-aryl, or -L-heteroaryl is optionally and independently substituted with 1-3 R.sup.8; L is C.sub.0-3 alkyl; Each R.sup.7 is independently oxo, alkyl, halogen, --CN, --OR.sup.9, --SR.sup.9, --N(R.sup.9).sub.2, C.sub.3-8cycloalkyl, aryl, heteroaryl or a 4- to 8-membered heterocyclic ring containing 1-3 groups selected from --N(R.sup.17)--, --O--, or --S--, wherein each alkyl, cycloalkyl, 4-8 membered heterocyclic monocyclic or bicyclic ring, aryl, and heteroaryl is optionally and independently substituted with 1-3 R.sup.8, or Two R.sup.7 on the same atom or adjacent atoms is joined to form a carbocyclic ring or a 4- to 8-membered heterocyclic ring containing 1-3 groups selected from --N(R.sup.17)--, --O--, or --S--, wherein each of the carbocyclic ring and the 4- to 8-membered heterocyclic ring is optionally and independently substituted with 1-3 R.sup.8; Each R.sup.8 is independently --R, -Q, --R.sup.9, --OR.sup.9, --N(R.sup.9).sub.2, halogen, or --CN; Each R.sup.9 is independently --H, --N(R.sup.16).sub.2, C.sub.3-6 carbocyclic ring, C.sub.3-6 heterocyclic ring, or C.sub.1-3 aliphatic, wherein C.sub.3-6 carbocyclic ring, C.sub.3-6 heterocyclic ring and C.sub.1-3 aliphatic are each optionally substituted with 1-3 Q; or Two R.sup.9 groups together with the N atom to which they are bound form a 4-8 membered ring additionally containing 1 or 2 groups each independently selected from --N(R.sup.17)--, --O--, or --S--, wherein the 4- to 8-membered ring is optionally and independently substituted with 1-3 of W; Each R.sup.16 is independently hydrogen or C.sub.1-6 alkyl, or Two R.sup.16 groups together with the N atom to which they are bound form a 4- to 8-membered ring containing 1or 2 groups selected from NR.sup.17, O, or S; Each R.sup.17 is independently, hydrogen, Q.sub.1 or C.sub.1-4 aliphatic or cycloaliphatic, wherein each C.sub.-4 aliphatic or cycloaliphatic is optionally substituted with 1-3 of Q; Q.sub.1 is C.sub.1-6 alkyl, benzyl, --SO.sub.2--W, --S(O).sub.2--N(H)--W, --S(O).sub.2--N(W).sub.2, --C(O)--W, --C(O)--N(W).sub.2, --C(O)--N(H)--W, --N(H)--C(O)--W, --O--C(O)--W, --C(O)--O--W, or --SO.sub.2--W; R.sup.10 is --H or C.sub.1-6 aliphatic optionally substituted with 1-3 of R.sup.7; R.sup.11 is --C(R.sup.12R.sup.13)C(=O)NR.sup.14R.sup.15; Each of R.sup.12 and R.sup.13 is independently H or C.sub.1-6 aliphatic optionally substituted with 1-3 R.sup.7; or R.sup.12 and R.sup.13 can be joined together to form a ring optionally substituted with 1-3 of R.sup.9; or R.sup.10 and R.sup.12 can be joined together to form a ring optionally substituted with 1-3 of R.sup.9 ; and Each R.sup.14 and R.sup.15 is independently H, C.sub.1-6 alkyl, carbocyclic, or heterocyclic optionally substituted with 1-3 of R.sup.7; or R.sup.14 and R.sup.15 can be joined together to form a ring optionally substituted with 1-3 of R.sup.9.

2. The compound of claim 1, wherein R.sup.1 is halogen.

3. The compound of claim 2, wherein R.sup.1 is --Cl.

4. The compound of claim 1, wherein R.sup.1 is C.sub.1-6 aliphatic optionally substituted with 1-3 of R.sup.3, and each R.sup.3 is independently halo, aryl, or heteroaryl.

5. The compound of claim 4, wherein R.sup.1 is C.sub.1-6 alkyl optioanlly substituted with 1-3 of R.sup.3, and each R.sup.3 is independently halo, aryl, or heteroaryl.

6. The compound of claim 5, wherein R.sup.1 is methyl optionally substituted with 1-3 R.sup.3 and each R.sup.3 is independently halo.

7. The compound of claim 5, wherein R.sup.1 is --CF.sub.3.

8. The compound of claim 5, wherein R.sup.1 is --CH.sub.3.

9. The compound of claim 1, wherein R.sup.1 is --NHR and R is H, C.sub.1-6 aliphatic, aryl, or C.sub.3-8 cycloalkyl.

10. The compound of claim 9, wherein R is H, C.sub.1-6 alkyl, or aryl.

11. The compound of claim 1, wherein R.sup.2 is --NR.sup.4R.sup.5 or --NR.sup.10R.sup.11.

12. The compound of claim 11, wherein R.sup.2 is --NR.sup.4R.sup.5 , wherein R.sup.4 is H or C.sub.1-6 aliphatic optionally substituted with 1-3 R.sup.7, and R.sup.5 is C.sub.1-6 aliphatic optionally substituted with 1-4 R.sup.7 or a 3- to 6-membered monocyclic or 6- to 10-membered bicyclic ring optionally substituted with 1-4 R.sup.7.

13. The compound of claim 12, wherein R.sup.4 is H or C.sub.1-6 aliphatic, and R.sup.5 is C.sub.1-6 alkyl that is optionally substituted with 1-4 of R.sup.7.

14. The compound of claim 13, wherein R.sup.4 is H, and R.sup.5 is C.sub.1-4 alkyl and optionally substituted with 1-4 R.sup.7.

15. The compound of claim 14, wherein R.sup.5 is ethyl substituted at the carbon atom attached to the nitrogen atom with R.sup.7.

16. The compound of claim 15, wherein R.sup.7 is an aryl or heteroaryl, and is optionally substituted with 1-3 of R.sup.8.

17. The compound of claim 16, wherein R.sup.7 is phenyl, pyridyl, or pyrimidyl, and is optionally substituted with 1-3 of R.sup.8.

18. The compound of claim 17, wherein R.sup.7 is phenyl optionally substituted with 1-3 of R.sup.8.

19. The compound of claim 18, wherein R.sup.7 is phenyl optionally substituted at the ortho- or meta-position with R.sup.8 and also optionally substituted at the para-position with R.sup.8.

20. The compound of claim 19, wherein the optional substituent R.sup.8 at an ortho- or meta-position, when present, is halo.

21. The compound of claim 19, wherein R.sup.7 is phenyl substituted at the para-position with --R or --N(R.sup.9).sub.2; R is 4- to 8-membered heterocyclic ring optionally containing 1-3 groups each independently selected from --N(R.sup.17)--, --O--, or --S--, and the heterocyclic ring is optionally substituted with 1-3 of Q; Each Q is independently selected from halogen, hydroxy, C.sub.1-6 alkyl, benzyl, --CF.sub.3, W, --C(O)--W, --C(O)--N(W).sub.2, --C(O)--O --W; Each W is independently selected from --H, C.sub.1-6 alkyl, or cycloalkyl; Each R.sup.9 is independently --H, C.sub.3-6 heterocyclic ring, or C.sub.1-3 aliphatic, wherein C.sub.3-6 heterocyclic ring and C.sub.1-3 aliphatic are each optionally substituted with 1-3 Q; or Two R.sup.9 groups together with the N atom to which they are bound form a 4- to 8-membered ring containing additional 1 or 2 groups each independently selected from --N(.sup.17)--,--O--, or --S--, wherein the 4- to 8-membered ring is optionally and independently substituted with 1-3 of W.

22. The compound of claim 21, wherein R.sup.7 is optionally substituted at an ortho-position with fluorine.

23. The compound of claim 21, wherein R is 5- to 7-membered heterocyclic ring optionally containing 2 nitrogen atoms and optionally substituted with 1-3 of Q; Each R.sup.9 is independently --H, C.sub.3-6 heterocyclic ring, or C.sub.1-3 aliphatic, wherein C.sub.3-6 heterocyclic ring and C.sub.1-C.sub.3 aliphatic are each optionally substituted with 1-3 of Q; or Two R.sup.9 groups together with the N atom to which they are bound form a 6- to 7-membered ring containing 1 additional nitrogen atom and optionally substituted with 1-3 of W.

24. The compound of claim 23, wherein R is piperazine optionally substituted with 1-3 of Q.

25. The compound of claim 21, wherein R.sup.7 is ##STR00482##

26. The compound of claim 19, wherein R.sup.7 is phenyl substituted at the para-position with --OR.sup.9.

27. The compound of claim 26, wherein R.sup.9 is --H, C.sub.3-6 heterocycloalkyl ring, or C.sub.1-3 alkyl, wherein C.sub.3-6 heterocycloalkyl ring and C.sub.1-3 alkyl are each optionally substituted with 1-3 of Q.

28. The compound of claim 27, wherein R.sup.9 is pyrrolidinyl or piperidinyl and optioanlly substituted with 1-3 of Q.

29. The compound of claim 28, wherein R.sup.9 is ##STR00483##

30. The compound of claim 29, wherein R.sup.9 is ##STR00484##

31. The compound of claim 17, wherein R.sup.7 is pyrimidinyl optionally substituted with 1-3 of R.sup.8.

32. The compound of claim 17, wherein R.sup.7 is 5-pyrimidyl optionally substituted at the 2-position with R.sup.8.

33. The compound of claim 32, wherein R.sup.8 is --R.sup.9, --OR.sup.9, --SR.sup.9, --N(R.sup.9).sub.2, halogen, or --CN; Each R.sup.9 is independently --H, C.sub.3-6 carbocyclic ring, C.sub.3-6 heterocyclic ring, or C.sub.1-3 aliphatic, wherein C.sub.3-6 carbocyclic ring, C.sub.3-6 heterocyclic ring and C.sub.1-3 aliphatic are each optionally substituted with 1-3 of Q.

34. The compound of claim 33, wherein R.sup.7 is ##STR00485##

35. The compound of claim 17, wherein R.sup.7 is pyridinyl optionally substituted with 1-3 of R.sup.8.

36. The compound of claim 35, wherein R.sup.7 is 3-pyridinyl optionally substituted with 1-3 of R.sup.8.

37. The compound of claim 35, wherein R.sup.7 is 3-pyridinyl optionally substituted at the 6-position with R.sup.8.

38. The compound of claim 37, wherein. R.sup.8 is -Q, --R.sup.9,--OR.sup.9, --N(R.sup.9).sub.2, halogen, or --CN; Each R.sup.9 is independently --H, C.sub.3-6 heterocyclic ring, or C.sub.1-3 aliphatic, wherein C.sub.3-6 heterocyclic ring and C.sub.1-3 aliphatic are each optionally substituted with 1-3 of Q; or Two R.sup.9 groups together with the N atom to which they are bound form a 4- to 8-membered hetercycloalkyl ring optioanlly containing an additional 1 or 2 groups selected from --N(R.sup.17)--, --O--, or --S--, wherein the 4- to 8- membered heterocycloalkyl ring is optionally and independently substituted with 1-3 of W; Each R.sup.17 is independently, hydrogen, or C.sub.1-4 aliphatic, wherein each C.sub.1-4 aliphatic is optionally substituted with 1-3 of Q; Each Q is independently selected from halogen, hydroxy, C.sub.1-6 alkyl, --CF.sub.3, --NH.sub.2, --N(H)--W, or --N(W).sub.2; Each W is independently selected from --H, C.sub.1-6 alkyl, aralkyl, cycloalkyl or heterocyclic ring; each C.sub.1-6 alkyl, aralkyl, cycloalkyl or heterocyclic ring is optionally substituted with 1-3 of halogen, --OR.sup.6, --CN, C.sub.1-6 alkyl or --NR.sup.18R.sup.19; or One W group, together with the nitrogen atom to which it is attached and a carbon atom of R, form a 4- to 8-membered ring; or Two W groups, together with the same or different nitrogen atom or carbon atom to which they are attached, form a 4 - to 8-membered heterocyclic ring.

39. The compound of claim 35, wherein R.sup.7 is ##STR00486##

40. The compound of claim 17, wherein one R.sup.8 is aryl, heteroaryl, C.sub.3-C.sub.8 cycloalkyl, or 4- to 8-membered heterocyclic ring each optionally substituted with 1-3 of Q.

41. The compound of claim 40, wherein one R.sup.8 is a 4- to 8-membered heterocyclic ring optionally substituted with 1-3 of Q.

42. The compound of claim 41, wherein one R.sup.8 is a 5- to 6-membered heterocyclic ring optionally substituted with 1-3 of Q.

43. The compound of claim 42, wherein one R.sup.8 is a piperazine ring optionally substituted with 1-3 of Q.

44. The compound of claim 17, wherein one R.sup.8 is Q.

45. The compound of claim 44, wherein Q is --NHW, --NW.sub.2, --NH--SO.sub.2W, --NH--COW, --CO--NHW, --CO--NW.sub.2, --SO.sub.2NHW, --SO.sub.2--NW.sub.2, --SW, --OW, or --W.

46. The compound of claim 45, wherein Q is --NHW, --NW.sub.2 or --OW.

47. The compound of claim 46, wherein W is C.sub.1-6 alkyl, aralkyl, cycloalkyl or heterocyclic ring; each C.sub.1-6 alkyl, aralkyl, cycloalkyl or heterocyclic ring is optionally substituted with 1-3 of halogen, --OR.sup.6, --CN, C.sub.1-6 alkyl, C.sub.1-6 alkyl or --NR.sup.18R.sup.19.

48. The compound of claim 47, wherein W is C.sub.1-6 alkyl or heterocyclic ring; each C.sub.1-6 alkyl, aralkyl, cycloalkyl or heterocyclic ring is optionally substituted with 1-3 of halogen, --OR.sup.6, --CN, C.sub.1-6 alkyl, C.sub.1-6 alkyl or --NR.sup.18R.sup.19.

49. The compound of claim 17, wherein one R.sup.8 is --R.sup.9, --OR.sup.9 or --N(R.sup.9).sub.2.

50. The compound of claim 49, wherein R.sup.9 is independently H, C.sub.3-6 carbocyclic ring, C.sub.3-6 heterocyclic ring, or C.sub.1-3 aliphatic, wherein C.sub.3-6 carbocyclic ring, C.sub.3-6 heterocyclic ring and C.sub.1-3 aliphatic are each optionally substituted with 1-3 Q; or Two R.sup.9 groups, together with the N atom to which they are bound, form a 4- to 8-membered ring optionally containing additional 1or 2 groups selected from --N(R.sup.17)--, --O--, or --S--, wherein the 4- to 8-membered ring is optionally and independently substituted with 1-3 of W.

51. The compound of claim 15, wherein R.sup.7 is a 4- to 10-membered heterocyclic monocyclic or bicyclic ring optionally substituted with 1-3 of R.sup.8.

52. The compound of claim 51, wherein R.sup.7 is a 4- to 6-membered heterocyclic monocyclic ring optionally substituted with 1-3 of R.sup.8.

53. The compound of claim 52, wherein R.sup.8 is Q.

54. The compound of claim 53, wherein Q is selected from --C(O)--W, --C(O)--N(W).sub.2--C(O)--O--W or --SO.sub.2--W.

55. The compound of claim 54, wherein Q is selected from --C(O)--W.

56. The compound of claim 15, wherein R.sup.7 is a C.sub.3-C.sub.8 carbocycle optionally substituted with 1-3 R.sup.8.

57. The compound of claim 56, wherein one R.sup.8 is Q.

58. The compound of claim 57, wherein Q is selected from hydroxy, --NH.sub.2, --N(H)--W, --N(W).sub.2, --N(H)--SO.sub.2--W, --C(O)--N(W).sub.2, --N(H)--C(O)--W, or --O--C(O)--W.

59. The compound of claim 58, wherein Q is selected from --N(H)--C(O)--W.

60. The compound of claim 11, wherein R.sup.2 is --NR.sup.10R.sup.11.

61. The compound of claim 60, wherein R.sup.10 is --H and R.sup.11 is --C(R.sup.12R.sup.13)C(.dbd.O)NR.sup.14R.sup.15.

62. The compound of claim 61, wherein R.sup.12 is H; R.sup.13 is C.sub.1-3 alkyl; R.sup.14 is H; and R.sup.15 is alkyl substituted with trifluoromethyl or hydroxy, or R.sup.15 is cycloalkyl substituted with hydroxy.

63. The compound of claim 62, wherein R.sup.15 is ##STR00487##

64. The compound of claim 1, wherein R.sup.2 is --OR.sup.6 or --SR.sup.6.

65. The compound of claim 64, wherein R.sup.6 is optionally substituted phenyl.

66. A compound selected from ##STR00488## ##STR00489## ##STR00490## ##STR00491## ##STR00492## ##STR00493## ##STR00494## ##STR00495## ##STR00496## ##STR00497## ##STR00498## ##STR00499## ##STR00500## ##STR00501## ##STR00502## ##STR00503## ##STR00504## ##STR00505## ##STR00506## ##STR00507## ##STR00508## ##STR00509## ##STR00510## ##STR00511## ##STR00512## ##STR00513## ##STR00514## ##STR00515## ##STR00516## ##STR00517## ##STR00518## ##STR00519## ##STR00520## ##STR00521## ##STR00522## ##STR00523## ##STR00524## ##STR00525## ##STR00526## ##STR00527## ##STR00528## ##STR00529## ##STR00530## ##STR00531## ##STR00532## ##STR00533## ##STR00534## ##STR00535## ##STR00536## ##STR00537## ##STR00538## ##STR00539## ##STR00540## ##STR00541## ##STR00542## ##STR00543## ##STR00544## ##STR00545## ##STR00546## ##STR00547## ##STR00548## ##STR00549## ##STR00550## or a pharmaceutically acceptable salt thereof.

67. The compound of claim 1, selected from ##STR00551## ##STR00552## ##STR00553## or a pharmaceutically acceptable salt thereof.

68. The compound of claim 1, selected from ##STR00554## ##STR00555## ##STR00556## or a pharmaceutically acceptable salt thereof.

69. The compound of claim 1, selected from ##STR00557## or a pharmaceutically acceptable salt thereof.

70. A composition comprising a compound of claim 1, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

71. The composition of claim 70, further comprising another therapeutic agent selected from the group consisting of synthetic small molecule VEGF receptor antagonists, small molecule growth factor receptor antagonists, inhibitors of the EGF receptor or VEGF receptor or integrin receptor or any other protein tyrosine kinase receptors which are not classified under the synthetic small-molecules, inhibitors directed to EGF receptor or VEGF receptor or integrin receptors or any other protein tyrosine kinase receptors, which are fusion proteins, compounds which interact with nucleic acids and which are classified as alkylating agents or platinum compounds, compounds which interact with nucleic acids and which are classified as anthracyclines, as DNA intercalators or as DNA cross-linking agents, including DNA minor-groove binding compounds, anti-metabolites, naturally occurring, semi-synthetic or synthetic bleomycin type antibiotics, inhibitors of DNA transcribing enzymes, and especially the topoisomerase I or topoisomerase II inhibitors, chromatin modifying agents, mitosis inhibitors, anti-mitotic agents, cell-cycle inhibitors, proteasome inhibitors, enzymes, hormones, hormone antagonists, hormone inhibitors, inhibitors of steroid biosynthesis, steroids, cytokines, hypoxia-selective cytotoxins, inhibitors of cytokines, lymphokines, antibodies directed against cytokines, oral and parenteral tolerance induction agents, supportive agents, chemical radiation sensitizers and protectors, photo-chemically activated drugs, synthetic poly- or oligonucleotides, optionally modified or conjugated, non-steroidal anti-inflammatory drugs, cytotoxic antibiotics, antibodies targeting growth factors or their receptors, antibodies targeting the surface molecules of cancer cells, inhibitors of metalloproteinases, metals, inhibitors of oncogenes, inhibitors of gene transcription or of RNA translation or protein expression, complexes of rare earth elements, compounds which reduces the transport of hyaluronan mediated by one or more ABC transporters, and photo-chemotherapeutic agents.

72. The composition of claim 70, further comprising another therapeutic agent selected from the group consisting of a small molecule VEGF receptor antagonist selected from a group consisting of vatalanib (PTK-787/ZK222584), SU-5416, SU-6668, SU-11248, SU-14813, AZD-6474, AZD-2171, CP-547632, CEP-7055, AG-013736, IM-842 and GW-786034; a dual EGFR/HER2 antagonist selected from a group consisting of gefitinib, erlotinib, CI-1033, and GW-2016; an EGFR antagonist selected from a group consisting of iressa (ZD-1839), tarceva (OSI-774), PKI-166, EKB-569, HKI-272, and herceptin; an antagonist of the mitogen-activated protein kinase selected from a group consisting of BAY-43-9006 and BAY-57-9006; a quinazoline derivative selected from a group consisting of 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute- - n-1-yl]amino}-7 -((S)-tetrahydrofuran-3-yloxy)-quinazoline or 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-(homomorpholin-4-yl)-1-oxo-2-bu- - ten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline, and their pharmaceutically acceptable salts; a protein kinase receptor antagonist selected from a group consisting of atrasentan, rituximab, cetuximab, Avastin.TM. (bevacizumab), IMC-1C11, erbitux (C-225), DC-101, EMD-72000, vitaxin, and imatinib; a protein tyrosine kinase inhibitor which is a fusion protein and is VEGFtrap; an alkylating agent or a platinum compound selected from a group consisting of melphalan, cyclophosphamide, an oxazaphosphorine, cisplatin, carboplatin, oxaliplatin, satraplatin, tetraplatin, iproplatin, mitomycin, streptozocin, carmustine (BCNU), lomustine (CCNU), busulfan, ifosfamide, streptozocin, thiotepa, and chlorambucil; a nitrogen mustard selected from a group consisting of mechlorethamine; an ethyleneimine compound, an alkylsulphonate, daunorubicin, doxorubicin (adriamycin), liposomal doxorubicin (doxil), epirubicin, idarubicin, mitoxantrone, amsacrine, dactinomycin, distamycin or a derivative thereof, netropsin, pibenzimol, mitomycin, CC-1065, a duocarmycin, mithramycin, chromomycin, olivomycin, a phtalanilide selected from a group consisting of propamidine and stilbamidine; an anthramycin, an aziridine, a nitrosourea or a derivative thereof, a pyrimidine or purine analogue or antagonist or an inhibitor of the nucleoside diphosphate reductase selected from a group consisting of cytarabine, 5-fluorouracile (5-FU), pemetrexed, tegafur/uracil, uracil mustard, fludarabine, gemcitabine, capecitabine, mercaptopurine, cladribine, thioguanine, methotrexate, pentostatin, hydroxyurea, or folic acid, a phleomycin, a bleomycin or a derivative or salt thereof, CHPP, BZPP, MTPP, BAPP, liblomycin, an acridine or a derivative thereof, a rifamycin, an actinomycin, adramycin, a camptothecin selected from a group consisting of irinotecan and topotecan, an amsacrine or analogue thereof, a tricyclic carboxamide, an histonedeacetylase inhibitor selected from a group consisting of SAHA, MD-275, trichostatin A, CBHA, LAQ824, and valproic acid; an anti-cancer drug from plants selected from a group consisting of paclitaxel (taxol), docetaxel and taxotere; a vinca alkaloid selected from a group consisting of navelbine, vinbiastin, vincristin, vindesine, and vinorelbine; a tropolone alkaloid selected from a group consisting of colchicine or a derivative thereof; a macrolide selected from a group consisting of maytansine, an ansamitocin and rhizoxin; an antimitotic peptide selected from a group consisting of phomopsin and dolastatin; an epipodophyllotoxin or a derivative of podophyllotoxin selected from a group consisting of etoposide and teniposide; a steganacin, an antimitotic carbamate derivative selected from a group consisting of combretastatin and amphetinile; procarbazine, a proteasome inhibitor selected from a group consisting of bortezomib, an enzyme selected from a group consisting of asparaginase, pegylated asparaginase (pegaspargase), and a thymidine-phosphorylase inhibitor; a gestagen or an estrogen selected from a group consisting of estramustine (T-66) and megestrol, an anti-androgen selected from a group consisting of flutamide, casodex, anandron and cyproterone acetate, an aromatase inhibitor such as aminogluthetimide, anastrozole, formestan, and letrozole; a GNrH analogue selected from a group consisting of leuprorelin, buserelin, goserelin, and triptorelin; an anti-estrogen selected from a group consisting of tamoxifen or its citrate salt, droloxifene, trioxifene, raloxifene or zindoxifene, a derivative of 17.beta.-estradiol selected from a group consisting of ICI 164,384 and ICI 182,780; aminoglutethimide, formestane, fadrozole, finasteride, ketoconazole, a LH-RH antagonist selected from a group consisting of leuprolide, a steroid selected from a group consisting of prednisone, prednisolone, methylprednisolone, dexamethasone, budenoside, fluocortolone, and triamcinolone; an interferon selected from a group consisting of interferonl.beta., an interleukin selected from a group consisting of IL-10 and IL-12; an anti-TNF.alpha. antibody selected from a group consisting of etanercept, an immunomodulatory drug selected from a group consisting of thalidomide, its R- and S-enantiomers and its derivatives, and revimid (CC-5013), a leukotrien antagonist, mitomycin C, an aziridoquinone selected from a group consisting of BMY-42355, AZQ and EO-9; a 2-nitroimidazole selected from a group consisting of misonidazole, NLP-1, and NLA-1; a nitroacridine, a nitroquinoline, a nitropyrazoloacridine, a "dual-function" nitro aromatic selected from a group consisting of RSU-1069 and RB-6145; CB-1954, a N-oxide of nitrogen mustard selected from a group consisting of nitromin, a metal complex of a nitrogen mustard, an anti-CD3, and anti-CD25 antibody, a tolerance induction agent, a biphosphonate or derivative thereof selected from a group consisting of minodronic acid or its derivatives (YM-529, Ono-5920, YH-529), zoledronic acid monohydrate, ibandronate sodium hydrate, and clodronate disodium; a nitroimidazole selected from a group consisting of metronidazole, misonidazole, benznidazole, and nimorazole; a nitroaryl compound selected from a group consisting of RSU-1069, a nitroxyl, and SR-4233; an halogenated pyrimidine analogue selected from a group consisting of bromodeoxyuridine, iododeoxyuridine, a thiophosphate selected from a group consisting of WR-272 1, a photo-chemically activated drug selected from a group consisting of porfimer, photofrin, a benzoporphyrin derivative, a pheophorbide derivative, merocyanin 540 (MC-540) and tin etioporpurin; an ant-template or an anti-sense RNA or DNA selected from a group consisting of oblimersen, a non-steroidal inflammatory drug selected from a group consisting of acetylsalicyclic acid, mesalazin, ibuprofen, naproxen, flurbiprofen, fenoprofen, fenbufen, ketoprofen, indoprofen, pirprofen, carprofen, oxaprozin, pranoprofen, miroprofen, tioxaprofen, suprofen, alminoprofen, tiaprofenic acid, fluprofen, indomethacin, sulindac, tolmetin, zomepirac, nabumetone, diclofenac, fenclofenac, alclofenac, bromfenac, ibufenac, aceclofenac, acemetacin, fentiazac, clidanac, etodolac, oxpinac, mefenamic acid, meclofenamic acid, flufenamic acid, nifluminic acid, tolfenamic acid, diflunisal, flufenisal, piroxicam, tenoxicam, lomoxicam, nimesulide, meloxicam, celecoxib, rofecoxib, and a pharmaceutically acceptable salt of a non-steroidal inflammatory drug; a cytotoxic antibiotic, an antibody targeting the surface molecules of cancer cells selected from a group consisting of apolizumab or 1D09C3; an inhibitor of metalloproteinases selected from a group consisting of TIMP-1 and TIMP-2; Zinc, an inhibitor of oncogenes selected from a group consisting of P53 and Rb; a complex of rare earth elements selected from a group consisting of the heterocyclic complexes of lanthanides; a photo-chemotherapeutic agent selected from a group consisting of PUVA, an inhibitor of the transcription factor complex ESX/DRIP130/Sur-2, an inhibitor of HER-2 expression selected from a group consisting of the heat shock protein HSP90 modulator geldanamycin and its derivative 17-allylaminogeldanamycin, and 17-AAG; a compound which reduces the transport of hyaluronan mediated by one or more ABC transporters selected from a P-glycoprotein (P-gp) inhibitor molecule or inhibitor peptide, an MRP1 inhibitor, an antibody directed against and capable of blocking the ABC transporter, an antisense oligomer, iRNA, siRNA or aptamer directed against one or more ABC transporters, or a therapeutic agent selected from a group consisting of IM-842, tetrathiomolybdate, squalamine, combrestatin A4, TNP-470, marimastat, neovastat, bicalutamide, abarelix, oregovomab, mitumomab, TLK-286, alemtuzumab, ibritumomab, temozolomide, denileukin diftitox, aldesleukin, dacarbazine, floxuridine, plicamycin, mitotane, pipobroman, plicamycin, tamLoxifen, and testolactone.

73. The composition of claim 70, further comprising another therapeutic agent selected from the group consisting of an anti-cancer drug from plants selected from a group consisting of paclitaxel (taxol), docetaxel, and taxotere; a vinca alkaloid selected from a group consisting ofnavelbine, vinblastin, vincristin, vindesine and vinorelbine; a vinca alkaloid selected from a group consisting of navelbine, vinblastin, vincristin, vindesine and vinorelbine; an alkylating agent or a platinum compound selected from a group consisting ofmelphalan, cyclophosphamide, an oxazaphosphorine, cisplatin, carboplatin, oxaliplatin, satraplatin, tetraplatin, iproplatin, mitomycin, streptozocin, carmustine (BCNU), lomustine (CCNU), busulfan, ifosfamide, streptozocin, thiotepa, chlorambucil, a nitrogen mustard selected from a group consisting of mechlorethamine; an immunomodulatory drug selected from a group consisting of thalidomide, its R- and S-enantiomers and its derivatives, or revimid (CC-5013)), an ethyleneimine compound, an alkylsulphonate, daunorubicin, doxorubicin (adriamycin), liposomal doxorubicin (doxil), epirubicin, idarubicin, mitoxantrone, amsacrine, dactinomycin, distamycin or a derivative thereof, netropsin, pibenzimol, mitomycin, CC-1065, a duocarmycin, mithramycin, chromomycin, olivomycin, a phtalanilide selected from a group consisting of propamidine or stilbamidine, an anthramycin, an aziridine, a nitrosourea or a derivative thereof, a pyrimidine or purine analogue; an antagonist or an inhibitor of the nucleoside diphosphate reductase selected from a group consisting of cytarabine, 5-fluorouracile (5-FU), pemetrexed, tegafur/uracil, uracil mustard, fludarabine, gemcitabine, capecitabine, mercaptopurine, cladribine, thioguanine, methotrexate, pentostatin, hydroxyurea, or folic acid, an acridine or a derivative thereof, a rifamycin, an actinomycin, adramycin, a camptothecin selected from a group consisting of irinotecan and topotecan, an amsacrine or analogue thereof, a tricyclic carboxamide, an histonedeacetylase inhibitor selected from a group consisting of SAHA, MD-275, trichostatin A, CBHA, LAQ824, and valproic acid; a proteasome inhibitor selected from a group consisting of bortezomib, a small molecule VEGF receptor antagonist selected from a group consisting of vatalanib (PTK-787/ZK222584), SU-5416, SU-6668, SU-11248, SU-14813, AZD-6474, AZD-2171, CP-547632, CEP-7055, AG-013736, IM-842 and GW-786034; an antagonist of the mitogen-activated protein kinase selected from a group consisting of BAY-43-9006 and BAY-57-9006; a dual EGFR/HER2 antagonist selected from a group consisting of gefitinib, erlotinib, CI-1033 and GW-2016; an EGFR antagonist selected from a group consisting of iressa (ZD-1839), tarceva (OSI-774), PKI-166, EKB-569, HKI-272 and herceptin; a quinazoline derivative selected from a group consisting of 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute- - n-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline or 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-(homomorpholin-4-yl)-1-oxo-2-bu- - ten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-y)oxy]-quinazoline, or a pharmaceutically acceptable salt thereof, an inhibitor of the transcription factor complex ESX/DRIP130/Sur-2, an inhibitor of HER-2 expression, selected from a group consisting of the heat shock protein HSP90 modulator geldanamycin and its derivative 17-allylaminogeldanamycin and 17-AAG; a protein kinase receptor antagonist which is not classified under the synthetic small molecules selected from a group consisting of atrasentan, rituximab, cetuximab, Avastin.TM. (bevacizumab), IMC-1C11, erbitux (C-225), DC-1 01, EMD-72000, vitaxin, and imatinib; a P-glycoprotein (P-gp) inhibitor molecule selected from a group consisting of zosuquidar (LY 335973), its salts (especially the trichloride salt) and its polymorphs, cyclosporin A, verapamil or its R-isomer, tamoxifen, quinidine, d-alpha tocopheryl polyethylene glycol 1000 succinate, VX-710, PSC833, phenothiazine, GF120918 (II), SDZ PSC 833, TMBY, MS-073, S-9788, SDZ 280-446, XR(9051) and functional derivatives, analogues and isomers of these; or an antibody targeting the surface molecules of cancer cells selected from a group consisting of apolizumab and ID09C3.

74. The composition of claim 70, further comprising 4[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute -n-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-bute- - n-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-(homomorpholin-4-yl)-1-oxo-2-bu- ten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-(homomorpholin-4-yl)-1-oxo-2-bu- - ten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline, 3-Z-[1 -(4-(N-((4-methyl-piperazin-1-yl) -methylcarbonyl)-N-methyl-amino)-anilino- )-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone, 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-a- -nilino) -1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone, 3-Z-[1-(4-dimethylaminomethylanilino)-1-(4-(2-carboxyethyl)phenyl)methyle- ne]-6-fluoro-2-indolinone, or a pharmaceutically acceptable salt thereof.

75. A process for preparing a compound of formula I ##STR00558## or a pharmaceutically acceptable salt thereof, wherein R.sup.1 is --H, halogen, C.sub.1-6 aliphatic optionally substituted with 1-3 R.sup.3, --O(C.sub.1-6 aliphatic) optionally substituted with 1-3 of R.sup.3 , or --N(H)R; Each R is independently H, C.sub.1-6 aliphatic, aryl, heteroaryl, C.sub.3-8 cycloalkyl, or 4- to 8-membered heterocyclic ring optionally containing 1-3 groups selected from --N(R.sup.17)--, --O--, or --S--; wherein each of the aliphatic, aryl, heteroaryl, cycloalkyl, and heterocyclic ring are optionally substituted with 1-3 of Q; Each Q is independently selected from halogen, hydroxy, C.sub.1-6 alkyl, benzyl, oxo, --CF.sub.3, --CN, --NH.sub.2, --N(H)--W, --N(W).sub.2, --N(H)--SO.sub.2--W, --S(O).sub.2--N(H)--W, --S(O).sub.2--N(W).sub.2, --C(O)--W, --C(O)--N(W).sub.2, --N(H)--C(O)--W, --O --C(O)--W, --C(O)--O--W, --SO.sub.2--W, SW or --OW; Two Q can be linked together to form a 4- to 8-membered carbocyclic or heterocyclic ring optionally substituted with C.sub.1-3alkyl or CF.sub.3; Each W is independently selected from --H, C.sub.1-6 alkyl, aralkyl, cycloalkyl or heterocyclic ring; each C.sub.1-6 alkyl, aralkyl, cycloalkyl or heterocyclic ring is optionally substituted with 1-3 of halogen, --OR.sup.6, --CN, C.sub.1-6 alkyl or NR.sup.18R.sup.19; or One W, together with the nitrogen atom to which it is attached and a carbon atom of R, form a 4- to 8-membered ring; or Two W, together with the same or different nitrogen atom or carbon atom to which they are attached, form a 4 - to 8-membered heterocyclic ring; Each R.sup.18 and R.sup.19 is independently hydrogen or C.sub.1-3 alkyl; or R.sup.18 and R.sup.19 , together with the nitrogen atom to which they are attached, form a 4- to 8-memebered heterocyclic ring, optionally substituted with C.sub.1-3 alkyl or CF.sub.3; Two W can be linked together to form a 4- to 8-membered cycloalkyl or heterocycloalkyl optionally substituted with C.sub.1-3 alkyl or CF.sub.3; R.sup.2 is --NR.sup.4R.sup.5, --OR.sup.6, --SR.sup.6, or --NR.sup.10R.sup.11; Each R.sup.3 is independently halogen, C.sub.1-6 alkyl, aryl, or heteroaryl; Each R.sup.4 is independently --H or C.sub.1-6 aliphatic optionally substituted with 1-3 of R.sup.7; Each R.sup.5 is independently C.sub.1-6 aliphatic optionally substituted with 1-4 R.sup.7 or a 3-to 6-membered monocyclic or 6- to 10-membered bicyclic ring optionally substituted with 1-4 of R.sup.7, or R.sup.4 and R.sup.5 can be joined together to form a monocyclic or bicyclic ring optionally substituted with 1-3 R.sup.9; Each R.sup.6 is independently H, C.sub.1-3 alkyl, -L-aryl, or -L-heteroaryl, wherein each of the C.sub.1-C.sub.3 alkyl, -L-aryl, or -L-heteroaryl is optionally and independently substituted with 1-3R.sup.8; L is C.sub.0-3 alkyl; Each R.sup.7 is independently oxo, alkyl, halogen, --CN, --OR.sup.9, --N(R.sup.9).sub.2, C.sub.3--C.sub.8 cycloalkyl, aryl, heteroaryl or a 4-8 membered heterocyclic ring containing 1-3 groups selected from --N(R.sup.17)--, --O--, or --S--, wherein each alkyl, cycloalkyl, 4-8 membered heterocyclic monocyclic or bicyclic ring, aryl, and heteroaryl is optionally and independently substituted with 1-3 R.sup.8, or Two R.sup.7 on the same atom or adjacent atoms is joined to form a carbocyclic ring or a 4-8 membered heterocyclic ring containing 1-3 groups selected from --N(R.sup.17)--, --O--, or --S--, wherein each of the carbocyclic ring and the 4-8 membered heterocyclic ring is optionally and independently substituted with 1-3 R.sup.8; Each R.sup.8 is independently --R, -Q, --R.sup.9, --OR.sup.9, --N(R.sup.9).sub.2, halogen, or --CN; Each R.sup.9is independently --H, --N(R.sup.16).sub.2, C.sub.3-6 carbocyclic ring, C.sub.3-6 heterocyclic ring, or C.sub.1-3 aliphatic, wherein C.sub.3-6 carbocyclic ring, C.sub.3-6 heterocyclic ring and C.sub.1-3 aliphatic are each optionally substituted with 1-3 Q; or Two R.sup.9 groups together with the N atom to which they are bound form a 4-8 membered ring containing an additional 1 or 2 groups selected from --N(R.sup.17)--,--O--, or --S--, wherein the 4- to 8-membered ring is optionally and independently substituted with 1-3 of W; Each R.sup.16 is independently hydrogen or C.sub.1-6 alkyl, or Two R.sup.16 groups together with the N atom to which they are bound form a 4- to 8-membered ring containing 1 or 2 groups selected from NR.sup.17, O, or S; Each R.sup.17 is independently, hydrogen, Q.sub.1or C.sub.1-4 aliphatic or cycloaliphatic, wherein each C.sub.1-4 aliphatic or cycloaliphatic is optionally substituted with 1-3 of Q; Q.sub.1 is C.sub.1-6 alkyl, benzyl, --SO.sub.2--W, --S(O).sub.2--N(H)--W, --S(O).sub.2--N(W).sub.2, --C(O)--W, --C(O)--N(W).sub.2, --C(O)--N(H)--W, --N(H)--C(O)--W, --O--C(O)--W, --C(O)--O--W, or --SO.sub.2--W; R.sup.10 is --H or C.sub.1-6 aliphatic optionally substituted with 1-3 of R.sup.7; R.sup.11 is --C(R.sup.12R.sup.13)C(.dbd.O)NR.sup.14R.sup.15; Each of R.sup.12 and R.sup.13 is independently H or C.sub.1-6 aliphatic optionally substituted with 1-3 of R.sup.7; or R.sup.12 and R.sup.13 can be joined together to form a ring optionally substituted with 1-3 of R.sup.9; or R.sup.10 and R.sup.12 can be joined together to form a ring optionally substituted with 1-3 of R.sup.9; and Each R.sup.14 and R.sup.15 is independently H, C.sub.1-6 alkyl, carbocyclic, or heterocyclic optionally substituted with 1-3 R.sup.7; or R.sup.14 and R.sup.15 can be joined together to form a ring optionally substituted with 1-3 of R.sup.9, comprising contacting a mixture of a compound of formula 8 ##STR00559## wherein each R' is independently H, C.sub.1-3 alkyl, or two R' together with the atoms to which they are attached fom a 5- or 6-membered ring optionally substituted with 1 to 4 methyl groups, a pyrimidine of formula 7 ##STR00560## and an alkali metal carbonate with a palladium catalyst in a suitable solvent.

76. The process of claim 75, wherein the palladium catalyst is bis-(tri-tert-butylphosphine) palladium(0).

77. The process of claim 75 , wherein the pyrimidine is 4-chloro-2-(methylthio)pyrimidine-5-carbonitrile and the boronate ester is 5-Trifluoromethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)-1-to- syl-1H-pyrrolo[2,3-b]pyridine.

78. The process of claim 75, wherein the suitable solvent is dioxane and the alkali metal carbonate is potassium carbonate.

79. The process of claim 75, wherein R.sup.2 is --SCH.sub.3, further comprising the steps of a) oxidizing a compound of formula 26 ##STR00561## wherein R.sup.1 is as previously described, with chlorine in aqueous ethanol to provide a compound of formula 27 ##STR00562## b) reacting a compound of formula 27 with a compound of formula R.sup.2H, wherein R.sup.2 is HNR.sup.4R.sup.5, HOR.sup.6 or HSR.sup.6 and R.sup.4, R.sup.5 and R.sup.6 are as previously described, in the presence of microwave irradiation to provide a compound of formula 28 ##STR00563## c) removing the Tos protecting group to provide compounds of formula I.

Details for Patent 8,247,421

Applicant Tradename Biologic Ingredient Dosage Form BLA Approval Date Patent No. Expiredate
Recordati Rare Diseases, Inc. ELSPAR asparaginase For Injection 101063 01/10/1978 ⤷  Try a Trial 2039-02-26
Clinigen, Inc. PROLEUKIN aldesleukin For Injection 103293 05/05/1992 ⤷  Try a Trial 2039-02-26
Servier Pharmaceuticals Llc ONCASPAR pegaspargase Injection 103411 02/01/1994 ⤷  Try a Trial 2039-02-26
Genentech, Inc. RITUXAN rituximab Injection 103705 11/26/1997 ⤷  Try a Trial 2039-02-26
Idec Pharmaceuticals Corp. RITUXAN rituximab Injection 103737 02/19/2002 ⤷  Try a Trial 2039-02-26
Eisai, Incorporated ONTAK denileukin diftitox Injection 103767 02/05/1999 ⤷  Try a Trial 2039-02-26
Genentech, Inc. HERCEPTIN trastuzumab For Injection 103792 09/25/1998 ⤷  Try a Trial 2039-02-26
>Applicant >Tradename >Biologic Ingredient >Dosage Form >BLA >Approval Date >Patent No. >Expiredate

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