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Details for Patent: 6,884,890

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Details for Patent: 6,884,890

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 (San Diego, CA), Reich; Siegfried Heinz (Solana Beach, CA), Tempczyk-Russell; Anna Marie (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 13, 2003
Application Number:10/326,755
Claims:1. A method to prepare a compound or a salt of formula I, ##STR1261##

wherein R.sup.1 is a substituted or unsubstituted aryl or heteroaryl, or a group of the formula CH.dbd.CH--R.sup.3 or CH.dbd.N--R.sup.3, where R.sup.3 is a substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R.sup.2 is Y--X, where 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); X is ##STR1262## where R.sup.9 is a substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxyl, aryloxyl, cycloalkoxyl, NH--(C.sub.1 -C.sub.8 alkyl), NH-(aryl), NH-(heteroaryl), N.dbd.CH-(alkyl), NH(C.dbd.O)R.sup.11, or NH.sub.2, where R.sup.11 is selected from hydrogen, substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; and R.sup.10 is independently selected from hydrogen, halogen, and lower-alkyl;

the method comprising converting a compound of formula IX into a compound of formula X by a cross coupling reaction in the presence of a metal catalyst or a stoichiometric metal reagent: ##STR1263##

where Pg is a protecting group; and removing the protecting group to form the compound of formula I.

2. The method of claim 1, wherein the step of converting the compound of formula IX to the compound of formula X comprises: (i) reacting the compound of formula IX with a nucleophilic R.sup.2 compound in the presence of a metal catalyst; or (ii) treating the compound of formula IX with a stochiometric organometallic reagent in a halogen-metal exchange reaction to form a metal containing intermediate, and treating the intermediate with an electrophilic R.sup.2 compound to form the compound of formula X.

3. The method of claim 1, wherein the Pg is 1-(2-trimethylsilanyl-ethoxymethyl).

4. The method of claim 2, wherein the nucleophilic R.sup.2 compound is an R.sup.2 -boronic acid.

5. The method of claim 2, wherein the organometallic reagent is an organolithium compound.

6. The method of claim 1, wherein the compound of formula IX is prepared by treating the compound of formula VIII with an oxidizing reagent and a halogenating reagent: ##STR1264##

7. The method of claim 6, wherein the oxidizing reagent is a nitrite compound.

8. The method of claim 6, wherein the compound of formula VIII is prepared from a compound of formula VII by reducing the nitro group of the compound of formula VII to the amino group of the compound of formula VIII ##STR1265##

9. The method of claim 8, wherein the step of reducing the nitro group is carried out in the presence of SnCl.sub.2.

10. The method of claim 8, wherein the compound of formula VII is prepared from a compound of formula VI by a metal catalyzed cross coupling reaction ##STR1266##

11. The method of claim 10, wherein the metal catalyzed cross coupling reaction is carried out in the presence of an R.sup.1 -organometallic reagent and a catalyst.

12. The method of claim 11, wherein the R.sup.1 -organometallic reagent is an R.sup.1 -boronic acid and the catalyst is a palladium catalyst.

13. The method of claim 10, wherein the compound of formula VI is prepared from a compound of formula V ##STR1267##

by a process that comprises: treating the compound of formula V with a strong base and an iodination reagent to form an intermediate; and subsequently treating the intermediate with a strong base and a Pg-halide.

14. The method of claim 13, wherein the Pg-halide is 1-(2-trimethylsilanyl-ethoxymethyl) chloride.

15. A method to prepare a compound or a salt of formula I, ##STR1268##

wherein R.sup.1 is a substituted or unsubstituted aryl or heteroaryl, or a group of the formula CH.dbd.CH--R.sup.3 or CH.dbd.N--R.sup.3, where R.sup.3 is a substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R.sup.2 is Y--X, where 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); X is ##STR1269## where R.sup.9 is a substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxyl, aryloxyl, cycloalkoxyl, NH--(C.sub.1 -C.sub.8 alkyl), NH-(aryl), NH-(heteroaryl), N.dbd.CH-(alkyl), NH(C.dbd.O)R.sup.11, or NH.sub.2, where R.sup.11 is selected from hydrogen, substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; and R.sup.10 is independently selected from hydrogen, halogen, and lower-alkyl;

the method comprising converting a compound of formula XIV into a compound of formula XV by a metal catalyzed cross coupling reaction: ##STR1270##

where Pg is a protecting group; and removing the protecting group to form the compound of formula I.

16. The method of claim 15, wherein the metal catalyzed cross coupling reaction is carried out by treating the compound of formula XIV with an R.sup.1 -organometallic reagent in the presence of a metal catalyst.

17. The method of claim 16, wherein the R.sup.1 -organometallic reagent is an R.sup.1 -boronic acid or an R.sup.1 --ZnCl, and the metal catalyst is a palladium catalyst.

18. The method of claim 15, wherein the compound of formula XIV is prepared from a compound of formula XIII by a metal catalyzed cross coupling reaction: ##STR1271##

19. The method of claim 18, wherein the metal catalyzed cross coupling reaction is carried out by treating the compound of formula XIII with an R.sup.2 -organometallic reagent in the presence of a metal catalyst.

20. The method of claim 19, wherein the R.sup.2 -organometallic reagent is an R.sup.2 -boronic acid reagent, or a R.sup.2 --ZnCl reagent, and the metal catalyst is a palladium catalyst.

21. The method of claim 18, wherein the compound of formula XIII is prepared by reacting a compound of formula XII with a protecting group reagent: ##STR1272##

22. The method of claim 21, wherein the protecting group reagent is 1-(2-trimethylsilanyl-ethoxymethyl) chloride.

23. The method of claim 21, wherein the compound of formula XII is prepared from a compound of formula XI by an iodination reaction: ##STR1273##

24. The method of claim 23, wherein the iodination reaction is carried out by treating the compound of formula XI with I.sub.2 in the presence of a strong base.

25. A method to prepare a compound or a salt of formula I, ##STR1274##

wherein R.sup.1 is a substituted or unsubstituted aryl or heteroaryl, or a group of the formula CH.dbd.CH--R.sup.3 or CH.dbd.N--R.sup.3, where R.sup.3 is a substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R.sup.2 is Y--X, where 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); X is ##STR1275## where R.sup.9 is a substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxyl, aryloxyl, cycloalkoxyl, NH-(C.sub.1 -C.sub.8 alkyl), NH-(aryl), NH-(heteroaryl), N.dbd.CH-(alkyl), NH(C.dbd.O)R.sup.11, or NH.sub.2, where R.sup.11 is selected from hydrogen, substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; and R.sup.10 is independently selected from hydrogen, halogen, and lower-alkyl;

the method comprising dehydrogenation of a compound of formula XVIII to form the compound of formula I: ##STR1276##

26. The method of claim 25, wherein the dehydrogenation reaction is carried out by treating the compound of formula XVIII with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ).

27. The method of claim 25, wherein the compound of formula XVIII is prepared by an annulation reaction of a 1,3-diketone compound of formula XVII: ##STR1277##

28. The method of claim 27, wherein the annulation reaction is carried out in the presence of hydrazine.

29. The method of claim 27, wherein the compound of formula XVII is prepared from a compound of formula XVI by an acylation reaction: ##STR1278##

30. The method of claim 29, wherein the acylation reaction is carried out by treating a compound of formula XVI with a strong base and an acylation reagent LCO-R.sup.1, where L is a leaving group.

31. The method of claim 29, wherein the compound of formula XVI is prepared from a compound of formula XV by a nucleophilic substitution reaction ##STR1279##

32. The method of claim 31, wherein the nucleophilic substitution reaction is carried out by contacting the compound of formula XV with a strong base and a nucleophile R.sup.2 --H.
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