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Details for Patent: 6,891,044

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Details for Patent: 6,891,044

Title: Indazole compounds and pharmaceutical compositions for Inhibiting protein kinases, and methods for their use
Abstract:Indazole compounds that modulate and/or inhibit the activity of certain protein kinases are described. These compounds and pharmaceutical compositions containing them are capable of mediating tyrosine kinase signal transduction and thereby modulate and/or inhibit unwanted cell proliferation. The invention is also directed to the therapeutic or prophylactic use of pharmaceutical compositions containing such compounds, and to methods of treating cancer and other disease states associated with unwanted angiogenesis and/or cellular proliferation, such as diabetic retinopathy, neovascular glaucoma, rheumatoid arthritis, and psoriasis, by administering effective amounts of such compounds.
Inventor(s): Kania; Robert Steven (San Diego, CA), Bender; Steven Lee (Oceanside, CA), Borchardt; Allen J. (San Diego, CA), Cripps; Stephan James (San Diego, CA), Hua; Ye (La Jolla, CA), Johnson; Michael David (San Diego, CA), Johnson, Jr.; Theodore Otto (San Diego, CA), Luu; Hiep The (San Diego, CA), Palmer; Cynthia Louise (La Mesa, CA), Reich; Siegfried Heinz (Solana Beach, CA), Tempczyk-Russell; Anna Maria (Ramona, CA), Teng; Min (San Diego, CA), Thomas; Christine (West Borough, MA), Varney; Michael David (Solana Beach, CA), Wallace; Michael Brennan (San Diego, CA), Collins; Michael Raymond (San Diego, CA)
Assignee: Agouron Pharmaceuticals, Inc. (San Diego, CA)
Filing Date:Feb 15, 2003
Application Number:10/326,037
Claims:1. A method of preparing a compound or a salt of formula I: ##STR1259##

wherein: R.sup.1 is a substituted or unsubstituted (C.sub.3 -C.sub.8)aryl or 4 to 10 membered heteroaryl, or a group of the formula --CH.dbd.CH--R.sup.3 or CH.dbd.N--R.sup.3 ; R.sup.3 is a substituted or unsubstituted (C.sub.1 -C.sub.8)alkyl, (C.sub.3 -C.sub.8)cycloalkyl, (C.sub.1 -C.sub.8)aryl, 4-10 membered heterocycloalkyl, or 4-10 membered heteroaryl; Y is O, S, C.dbd.CH.sub.2, C.dbd.O, S.dbd.O, SO.sub.2, CH.sub.2, CHCH.sub.3, NH, or N--(C.sub.1 -C.sub.8 alkyl); R.sup.8 is a substituted or unsubstituted (C.sub.1 -C.sub.8)alkyl, (C.sub.2 -C.sub.8)alkenyl, (C.sub.3 -C.sub.8)cycloalkyl, (C.sub.3 -C.sub.8)aryl, 4-10 membered heterocycloalkyl, 4-10 membered heteroaryl, 4-10 membered alkoxyl, or 4-10 membered aryloxyl; and R.sup.10, R.sup.11, and R.sup.12 are independently selected from hydrogen, halogen, and (C.sub.1 -C.sub.8)alkyl; comprising the step of: treating a compound of formula Xa: ##STR1260## wherein R.sup.1, R.sup.10, R.sup.11, R.sup.12 and Y are as described above; with a compound of formula Xb: ##STR1261## wherein R.sup.8 is as described above; in the presence of a suitable coupling agent, optionally in the presence of a suitable catalyst, a suitable base, and a suitable solvent.

2. The method according to claim 1, wherein R.sup.1 is a group of the formula ##STR1262##

3. The method according to claim 1, wherein Y is NH; R.sup.8 is a 1,3-dimethylpyrazole; R.sup.10 and R.sup.11 are each hydrogen; and R.sup.12 is fluorine.

4. The method according to claim 1, wherein the coupling agent is O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU).

5. The method according to claim 1, wherein the catalyst is 4-Dimethylaminopyridine (DMAP).

6. The method according to claim 1, wherein the base is diisopropyl-ethylamine.

7. A method according to claim 1, wherein the method further comprises the step of preparing the compound of formula (Xa) as described above; comprising: treating a compound of formula X: ##STR1263## wherein R.sup.1, R.sup.10, R.sup.11, R.sup.12 and Y are as described above; and each Pg and Pg.sup.1 are independently a protecting group; with a deprotecting agent, optionally in the presence of scavenger, in a solvent.

8. The method according to claim 7, wherein the Pg is (trimethyl-silanyl)-ethoxymethyl.

9. The method according to claim 7, wherein the Pg.sup.1 is (trimethyl-silanyl)-ethoxycarbonyl.

10. The method according to claim 7, wherein the deprotecting agent is tetrabutyl ammonium fluoride (TBAF).

11. The method according to claim 7, wherein the solvent is tetrahydrofuran.

12. The method according to claim 7, wherein said method is performed at a temperature of about 70.degree. C.

13. A method according to claim 8, wherein the method further comprises the step of preparing said compound of formula X as described above: comprising: treating a compound of formula IXe: ##STR1264## wherein Pg and R.sup.1 are as described in the compound of formula X; and Lg is a leaving group; with a compound of formula IXb: ##STR1265## wherein each of R.sup.10, R.sup.11, R.sup.12, Y, and Pg.sup.1 are as described above; in the presence of a suitable catalyst ligand complex optionally in the presence of a suitable base and a solvent.

14. The method according to claim 13, wherein the Lg is selected from the group consisting of halo or sulfonic ester.

15. The method according to claim 13, wherein the suitable catalyst ligand complex is di-palladium tri(dibenzylidene acetone) (Pd.sub.2 (dba).sub.3) in the presence of 2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl(BINAP).

16. The method according to claim 13 wherein the suitable base is Cs/CO.sub.3.

17. The method according to claim 13, wherein the suitable solvent is dioxane.

18. The method according to claim 13, wherein the method is performed at about 80.degree..

19. A method according to claim 8, wherein in the compound of formula X, R.sup.1 is ##STR1266##

and the method further comprises the step of preparing the compound of formula IXa: comprising: treating a compound of formula IXd: ##STR1267## wherein Pg and Lg are as described above; with a compound of formula IXc: ##STR1268## in the presence of a solvent.

20. A method according to claim 19, wherein said solvent is tetrahydrofuran.

21. A method according to claim 19, further comprises the step of preparing the compound of formula IXd: comprising: treating a compound of formula IXe: ##STR1269## wherein Pg and Lg are as described above; with an oxidizing agent in the presence of a solvent, followed by a reducing agent.

22. A method according to claim 19, wherein said oxidizing agent is ozone gas.

23. A method according to claim 19, wherein said solvent is methylene chloride.

24. A method according to claim 19, wherein said reducing agent is dimethylsulfide.

25. A method according to claim 19, wherein said method is performed at a temperature of about -40.degree. C.

26. A method according to claim 13, wherein the method further comprises the step of preparing said compound of formula IXe as described above: comprising: treating a compound of formula VIII: ##STR1270## wherein Pg and R.sup.t are as described above; with a leaving group producing agent in the presence of a catalyst in a solvent.

27. A method according to claim 26, wherein the leaving group producing agent is a combination of NaNO.sub.2 and KI.

28. A method according to claim 26, wherein the catalyst is aqueous HCl.

29. A method according to claim 26, wherein the method further comprises the step of preparing said compound of formula VIII as described above: comprising: treating a compound of formula VII: ##STR1271## wherein Pg and R.sup.1 are as described above; with a reducing agent in a solvent.

30. A method according to claim 29, wherein the reducing agent is SnCl.sub.2 /H.sub.2 O.

31. The method according to claim 29, wherein the solvent is dimethylformamide.

32. The method according to claim 29, wherein the method is performed at a temperature of about 60.degree. C.

33. A method according to claim 29, wherein the method further comprises the step of preparing said compound of formula VII as described above, from a compound of formula VI: comprising: treating a compound of formula VI: ##STR1272## wherein Pg is as described above and R.sup.14 is a leaving group; with a suitable organometallic reagent having a formula R.sup.1 --M, in the presence of a suitable catalyst, optionally in the presence of a suitable base and a suitable solvent.

34. The method according to claim 33, wherein R.sup.14 is iodo.

35. The method according to claim 33, wherein the organometallic reagent is R.sup.1 -boronic acid.

36. The method according to claim 33, wherein the suitable catalyst is Pd(PPH.sub.3).sub.2.

37. The method according to claim 33, wherein the base is Na.sub.2 CO.sub.3.

38. The method according to claim 33, wherein the solvent is a mixture of toluene and methanol.

39. The method according to claim 33, wherein the method is performed at a temperature of about 80.degree. C.

40. A method according to claim 33, wherein the method further comprises the step of preparing said compound of formula VI as described above, from a compound of formula V: comprising: treating a compound of formula V: ##STR1273## with a leaving group producing agent and a protecting group producing agent in a solvent.

41. The method according to claim 40, wherein the suitable protecting group producing agent is trimethylsilyl-ethoxymethyl chloride/tetrabutyl ammonium bromide.

42. The method according to claim 40, wherein the leaving group producing agent is a combination of iodine and base.

43. The method according to claim 40, wherein the suitable solvent is dioxane.
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