5-cyano-4-(pyrrolo [2,3B] pyridine-3-yl)-pyrimidine derivatives useful as protein kinase inhibitors

• US 8,247,421 B2
• Filed: 12/21/2007
• Issued: 08/21/2012
• Est. Priority Date: 12/21/2006
• Status: Expired due to Fees

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Mortimore, Michael, Young, Stephen Clinton, Knegtel, Ronald, Pinder, Joanne Louise, Rutherford, Alistair Peter, Durrant, Steven, Brenchley, Guy, Charrier, Jean-Damien, O'Donnell, Michael, Everitt, Simon Robert Lorrie
• Primary Examiner(s): Wilson, James O
• Assistant Examiner(s): Pagano, Alexander R
• Application Number:
  US12/448,489
• Publication Number:
  US 20100189773A1
• Time in Patent Office: 1,705 Days
• Field of Search: 544/333, 514/256
• US Class Current: 514/256
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/04 Immunostimulants
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/00 : Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 5/14 : of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems

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.

Claims

1. A compound of formula I:

2. The compound of claim 1, wherein R¹ is halogen.

3. The compound of claim 2, wherein R¹ is —

Cl.

4. The compound of claim 1, wherein R¹ is C_1-6 aliphatic optionally substituted with 1-3 of R³, and each R³ is independently halo, aryl, or heteroaryl.

5. The compound of claim 4, wherein R¹ is C_1-6 alkyl optioanlly substituted with 1-3 of R³, and each R³ is independently halo, aryl, or heteroaryl.

6. The compound of claim 5, wherein R¹ is methyl optionally substituted with 1-3 R³ and each R³ is independently halo.

7. The compound of claim 5, wherein R¹ is —

CF₃.

8. The compound of claim 5, wherein R¹ is —

CH₃.

9. The compound of claim 1, wherein R¹ is —

NHR and R is H, C_1-6 aliphatic, aryl, or C_3-8 cycloalkyl.

10. The compound of claim 9, wherein R is H, C_1-6 alkyl, or aryl.

11. The compound of claim 1, wherein R² is —

NR⁴R⁵ or —

NR¹⁰R¹¹.

12. The compound of claim 11, wherein R² is —

NR⁴R⁵ , wherein R⁴ is H or C_1-6 aliphatic optionally substituted with 1-3 R⁷, and R⁵ is C_1-6 aliphatic optionally substituted with 1-4 R⁷ or a 3- to 6-membered monocyclic or 6- to 10-membered bicyclic ring optionally substituted with 1-4 R⁷.

13. The compound of claim 12, wherein R⁴ is H or C_1-6 aliphatic, and R⁵ is C_1-6 alkyl that is optionally substituted with 1-4 of R⁷.

14. The compound of claim 13, wherein R⁴ is H, and R⁵ is C_1-4 alkyl and optionally substituted with 1-4 R⁷.

15. The compound of claim 14, wherein R⁵ is ethyl substituted at the carbon atom attached to the nitrogen atom with R⁷.

16. The compound of claim 15, wherein R⁷ is an aryl or heteroaryl, and is optionally substituted with 1-3 of R⁸.

17. The compound of claim 16, wherein R⁷ is phenyl, pyridyl, or pyrimidyl, and is optionally substituted with 1-3 of R⁸.

18. The compound of claim 17, wherein R⁷ is phenyl optionally substituted with 1-3 of R⁸.

19. The compound of claim 18, wherein R⁷ is phenyl optionally substituted at the ortho- or meta-position with R⁸ and also optionally substituted at the para-position with R⁸.

20. The compound of claim 19, wherein the optional substituent R⁸ at an ortho- or meta-position, when present, is halo.

21. The compound of claim 19, wherein

R⁷ is phenyl substituted at the para-position with —

R or —

N(R⁹)₂;

R is 4- to 8-membered heterocyclic ring optionally containing 1-3 groups each independently selected from —

N(R¹⁷)—

, —

O—

, or —

S—

, and the heterocyclic ring is optionally substituted with 1-3 of Q;

Each Q is independently selected from halogen, hydroxy, C_1-6 alkyl, benzyl, —

CF₃, W, —

C(O)—

W, —

C(O)—

N(W)₂, —

C(O)—

O —

W;

Each W is independently selected from —

H, C_1-6 alkyl, or cycloalkyl;

Each R⁹ is independently —

H, C_3-6 heterocyclic ring, or C_1-3 aliphatic, wherein C_3-6 heterocyclic ring and C_1-3 aliphatic are each optionally substituted with 1-3 Q;

or

Two R⁹ 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(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 R⁷ 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 R⁹ is independently —

H, C_3-6 heterocyclic ring, or C_1-3 aliphatic, wherein C_3-6 heterocyclic ring and C₁-C₃ aliphatic are each optionally substituted with 1-3 of Q;

or

Two R⁹ 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 R⁷ is

26. The compound of claim 19, wherein R⁷ is phenyl substituted at the para-position with —

OR⁹.

27. The compound of claim 26, wherein R⁹ is —

H, C_3-6 heterocycloalkyl ring, or C_1-3 alkyl, wherein C_3-6 heterocycloalkyl ring and C_1-3 alkyl are each optionally substituted with 1-3 of Q.

28. The compound of claim 27, wherein R⁹ is pyrrolidinyl or piperidinyl and optioanlly substituted with 1-3 of Q.

29. The compound of claim 28, wherein R⁹ is

30. The compound of claim 29, wherein R⁹ is

31. The compound of claim 17, wherein R⁷ is pyrimidinyl optionally substituted with 1-3 of R⁸.

32. The compound of claim 17, wherein R⁷ is 5-pyrimidyl optionally substituted at the 2-position with R⁸.

33. The compound of claim 32, wherein

R⁸ is —

R⁹, —

OR⁹, —

SR⁹, —

N(R⁹)₂, halogen, or —

CN;

Each R⁹ is independently —

H, C_3-6 carbocyclic ring, C_3-6 heterocyclic ring, or C_1-3 aliphatic, wherein C_3-6 carbocyclic ring, C_3-6 heterocyclic ring and C_1-3 aliphatic are each optionally substituted with 1-3 of Q.

34. The compound of claim 33, wherein R⁷ is

35. The compound of claim 17, wherein R⁷ is pyridinyl optionally substituted with 1-3 of R⁸.

36. The compound of claim 35, wherein R⁷ is 3-pyridinyl optionally substituted with 1-3 of R⁸.

37. The compound of claim 35, wherein R⁷ is 3-pyridinyl optionally substituted at the 6-position with R⁸.

38. The compound of claim 37, wherein. R⁸ is -Q, —

R⁹,—

OR⁹, —

N(R⁹)₂, halogen, or —

CN;

Each R⁹ is independently —

H, C_3-6 heterocyclic ring, or C_1-3 aliphatic, wherein C_3-6 heterocyclic ring and C_1-3 aliphatic are each optionally substituted with 1-3 of Q;

or

Two R⁹ 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(R¹⁷)—

, —

O—

, or —

S—

, wherein the 4- to 8- membered heterocycloalkyl ring is optionally and independently substituted with 1-3 of W;

Each R¹⁷ is independently, hydrogen, or C_1-4 aliphatic, wherein each C_1-4 aliphatic is optionally substituted with 1-3 of Q;

Each Q is independently selected from halogen, hydroxy, C_1-6 alkyl, —

CF₃, —

NH₂, —

N(H)—

W, or —

N(W)₂;

Each W is independently selected from —

H, C_1-6 alkyl, aralkyl, cycloalkyl or heterocyclic ring;

each C_1-6 alkyl, aralkyl, cycloalkyl or heterocyclic ring is optionally substituted with 1-3 of halogen, —

OR⁶, —

CN, C_1-6 alkyl or —

NR¹⁸R¹⁹;

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 R⁷ is

40. The compound of claim 17, wherein one R⁸ is aryl, heteroaryl, C₃-C₈ cycloalkyl, or 4- to 8-membered heterocyclic ring each optionally substituted with 1-3 of Q.

41. The compound of claim 40, wherein one R⁸ is a 4- to 8-membered heterocyclic ring optionally substituted with 1-3 of Q.

42. The compound of claim 41, wherein one R⁸ is a 5- to 6-membered heterocyclic ring optionally substituted with 1-3 of Q.

43. The compound of claim 42, wherein one R⁸ is a piperazine ring optionally substituted with 1-3 of Q.

44. The compound of claim 17, wherein one R⁸ is Q.

45. The compound of claim 44, wherein Q is —

NHW, —

NW₂, —

NH—

SO₂W, —

NH—

COW, —

CO—

NHW, —

CO—

NW₂, —

SO₂NHW, —

SO₂—

NW₂, —

SW, —

OW, or —

W.

46. The compound of claim 45, wherein Q is —

NHW, —

NW₂ or —

OW.

47. The compound of claim 46, wherein W is C_1-6 alkyl, aralkyl, cycloalkyl or heterocyclic ring;

each C_1-6 alkyl, aralkyl, cycloalkyl or heterocyclic ring is optionally substituted with 1-3 of halogen, —

OR⁶, —

CN, C_1-6 alkyl, C_1-6 alkyl or —

NR¹⁸R¹⁹.

48. The compound of claim 47, wherein W is C_1-6 alkyl or heterocyclic ring;

each C_1-6 alkyl, aralkyl, cycloalkyl or heterocyclic ring is optionally substituted with 1-3 of halogen, —

OR⁶, —

CN, C_1-6 alkyl, C_1-6 alkyl or —

NR¹⁸R¹⁹.

49. The compound of claim 17, wherein one R⁸ is —

R⁹, —

OR⁹ or —

N(R⁹)₂.

50. The compound of claim 49, wherein R⁹ is independently H, C_3-6 carbocyclic ring, C_3-6 heterocyclic ring, or C_1-3 aliphatic, wherein C_3-6 carbocyclic ring, C_3-6 heterocyclic ring and C_1-3 aliphatic are each optionally substituted with 1-3 Q;

or

Two R⁹ 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(R¹⁷)—

, —

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 R⁷ is a 4- to 10-membered heterocyclic monocyclic or bicyclic ring optionally substituted with 1-3 of R⁸.

52. The compound of claim 51, wherein R⁷ is a 4- to 6-membered heterocyclic monocyclic ring optionally substituted with 1-3 of R⁸.

53. The compound of claim 52, wherein R⁸ is Q.

54. The compound of claim 53, wherein Q is selected from —

C(O)—

W, —

C(O)—

N(W)₂—

C(O)—

O—

W or —

SO₂—

W.

55. The compound of claim 54, wherein Q is selected from —

C(O)—

W.

56. The compound of claim 15, wherein R⁷ is a C₃-C₈ carbocycle optionally substituted with 1-3 R⁸.

57. The compound of claim 56, wherein one R⁸ is Q.

58. The compound of claim 57, wherein Q is selected from hydroxy, —

NH₂, —

N(H)—

W, —

N(W)₂, —

N(H)—

SO₂—

W, —

C(O)—

N(W)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 R² is —

NR¹⁰R¹¹.

61. The compound of claim 60, wherein R¹⁰ is —

H and R¹¹ is —

C(R¹²R¹³)C(═

O)NR¹⁴R¹⁵.

62. The compound of claim 61, wherein R¹² is H;

R¹³ is C_1-3 alkyl;

R¹⁴ is H; and

R¹⁵ is alkyl substituted with trifluoromethyl or hydroxy, or R¹⁵ is cycloalkyl substituted with hydroxy.

63. The compound of claim 62, wherein R¹⁵ is

64. The compound of claim 1, wherein R² is —

OR⁶ or —

SR⁶.

65. The compound of claim 64, wherein R⁶ is optionally substituted phenyl.

67. The compound of claim 1, selected from

68. The compound of claim 1, selected from

69. The compound of claim 1, selected from

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™

(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 17β

-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 interferonlβ

, an interleukin selected from a group consisting of IL-10 and IL-12;

an anti-TNFα

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™

(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-buten-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)methylene]-6-fluoro-2-indolinone, or a pharmaceutically acceptable salt thereof.

66. A compound selected from

75. A process for preparing a compound of formula I

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-tosyl-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 R² is —

SCH₃, further comprising the steps of

a) oxidizing a compound of formula 26