Claims for Patent: 7,423,148

Summary for Patent: 7,423,148

Title:	Small molecule PI 3-kinase inhibitors and methods of their use
Abstract:	Compounds having formula I are provided where the variables have the values described herein. ##STR00001## Pharmaceutical formulations include the compounds or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier and combinations with other agents. A method of treating a patient comprises administering a pharmaceutical formulation according to the invention to a patient in need thereof.
Inventor(s):	Nuss; John N. (Danville, CA), Pecchi; Sabina (Oakland, CA), Renhowe; Paul A. (Danville, CA)
Assignee:	Chiron Corporation (Emeryville, CA)
Application Number:	10/719,896
Patent Claims:	1. A compound having the formula I: ##STR00238## or a stereoisomer, tautomer, or pharmaceutically acceptable salt-thereof, wherein Y is selected from the group consisting of (1) substituted or unsubstituted aryl, (2) substituted or unsubstituted heterocyclyl, and (3) substituted or unsubstituted heteroaryl; X is selected from the group consisting of (1) --N(R.sup.1x)--, (2) --(CH.sub.2).sub.m--C(R.sup.2x, R.sup.3x)--N(R.sup.1x)--, (3) --O--, (4) --S--, (5) --SO--, (6) --SO.sub.2--, (7) --C(R.sup.2X, R.sup.3x)--, and (8) ##STR00239## wherein R.sup.1x, R.sup.2x, and R.sub.3x are selected from the group consisting of (a) H, (b) substituted or unsubstituted C.sub.1-C.sub.6-alkyl, (c) substituted or unsubstituted C.sub.2-C.sub.6-alkenyl, (d) substituted or unsubstituted C.sub.2-C.sub.6-alkynyl, (e) substituted or unsubstituted aryl, (f) substituted or unsubstituted heterocyclyl, (g) substituted or unsubstituted heteroaryl; and m is 0, 1, 2, 3, or 4; R.sub.1 is selected from the group consisting of (1) H, (2) substituted or unsubstituted C.sub.1-C.sub.6-alky1, (3) --COOH, (4) halo, (5) --OR.sup.1t, and (6) --NHR.sup.1t, wherein R.sup.1t is H or C.sub.1-C.sub.6-alkyl; R.sub.2 is selected from the group consisting of (1) substituted or unsubstituted aryl, (2) substituted or unsubstituted heteroaryl, and W is selected from the group consisting of (1) --N(R.sup.lw, R.sup.2w), and (2) ##STR00240## wherein R.sup.1w and R.sup.2W are selected from the group consisting of (a) substituted or unsubstituted aryl, (b) substituted or unsubstituted heterocyclyl, and (c) substituted or unsubstituted heteroaryl, Z is selected from the group consisting of (a) --O--, (b) --NR.sup.z--, (c) --S--, (d) --SO--, (e) --SO.sub.2--, and (f) --CH.sub.2--, wherein R.sup.z is H or substituted or unsubstituted alkyl group; and R.sup.4w is selected from the group consisting of (a) H, (b) substituted or unsubstituted C.sub.1-C.sub.6-alkyl, (c) --COOR.sup.5w, (d) --CONH.sub.2, (e) --OR.sup.5w, and (f) --NHR.sup.5w, wherein R.sup.5w is H or C.sub.1-C.sub.6-alkyl; and r is 0, 1, or 2; with the proviso that when R.sub.2 is phenyl independently substituted with one to five substituents selected from hydrogen, cycloalkyl, heterocycloalkyl, halo, nitro, amino, sulphonamido, or alkylsulphonylamino, R.sub.1 is hydrogen, haloalkyl, alkyl, or halo, and X is NR.sup.1x, then Y is substituted or unsubstituted heteroaryl or substituted or unsubstituted heterocyclyl. 2. The compound of claim 1, wherein Y is selected from the group consisting of (1) substituted or unsubstituted aryl, (2) substituted or unsubstituted heterocyclyl, and (3) substituted or unsubstituted heteroaryl; X is selected from the group consisting of (1) --N(R.sup.1x)--, (2) --(CH.sub.2).sub.m--C(R.sup.2x, R.sup.3x)--N(R.sup.1x)--, and (3) ##STR00241## wherein R.sup.1x, R.sup.2x, R.sup.3x are independently H or substituted or unsubstituted C.sub.1-C.sub.6-alkyl; and W is selected from the group consisting of ##STR00242## wherein Z is --O-- or --NR.sup.z--, wherein R.sup.4w is H or substituted or unsubstituted C.sub.1-C.sub.6-alkyl. 3. The compound of claim 1, wherein Y is selected from the group consisting of (1) substituted or unsubstituted heterocyclyl, (2) substituted or unsubstituted heteroaryl; X is selected from the group consisting of (1) --N(R.sup.1x)--, (2) --(CH.sub.2).sub.m--C(R.sup.2x, R.sup.3x)--N(R.sup.1x)--, and (3) ##STR00243## wherein R.sup.1x, R.sup.2x, R.sup.3x are independently H or substituted or unsubstituted C.sub.1-C.sub.6-alkyl; and W is selected from the group consisting of ##STR00244## wherein Z is --O-- or --NR.sup.z--, wherein R.sup.4w is H or substituted or unsubstituted C.sub.1-C.sub.6-alkyl. 4. The compound of claim 1, wherein Y is substituted or unsubstituted aryl; X is selected from the group consisting of (1) --N(R.sup.1x)--, (2) --(CH.sub.2).sub.m--C(R.sup.2x, R.sup.3x)--N(R.sup.1x)--, and (3) ##STR00245## wherein R.sup.1x, R.sup.2x, R.sup.3x are independently H or substituted or unsubstituted C.sub.1-C.sub.6-alkyl; and W is selected from the group consisting of ##STR00246## wherein Z is --O-- or --NR.sup.z, wherein R.sup.4w is H or substituted or unsubstituted C.sub.1-C.sub.6-alkyl. 5. The compound of claim 1, wherein X is selected from the group consisting of (1) --N(R.sup.1x)--, (2) --(CH.sub.2).sub.m--C(R.sup.2x, R.sup.3x)--N(R.sup.1x)--, and (3) ##STR00247## wherein R.sup.1x, R.sup.2x, R.sup.3x are independently H or substituted or unsubstituted C.sub.1-C.sub.6-alkyl; and W is selected from the group consisting of ##STR00248## wherein Z is --O-- or --NR.sup.z, wherein R.sup.4w is H or substituted or unsubstituted C.sub.1-C.sub.6-alkyl. 6. The compound of claim 1, wherein Y is selected from the group consisting of (1) substituted or unsubstituted heterocyclyl, (2) substituted or unsubstituted heteroaryl; X is selected from the group consisting of (1) --N(R.sup.1x)--, (2) --(CH.sub.2).sub.m--C(R.sup.2x, R.sup.3x)--N(R.sup.1x)--, and (3) ##STR00249## wherein R.sup.1x, R.sup.2x, R.sup.3x are independently H or substituted or unsubstituted C.sub.1-C.sub.6-alkyl; R.sub.2 is substituted or unsubstituted aryl; and W is ##STR00250## wherein Z is --O-- or --NH--. 7. The compound of claim 1, wherein Y is substituted or unsubstituted aryl; X is selected from the group consisting of (1) --N(R.sup.1x)--, (2) --(CH.sub.2).sub.m--C(R.sup.2x, R.sup.3x)--N(R.sup.1x)--, and (3) ##STR00251## wherein R.sup.1x, R.sup.2x, R.sup.3x are independently H or substituted or unsubstituted C.sub.1-C.sub.6-alkyl; R.sub.2 is substituted or unsubstituted aryl; and W is ##STR00252## wherein Z is --O-- or --NH--. 8. The compound of claim 1, wherein X is selected from the group consisting of (1) --N(R.sup.1x)--, (2) --(CH.sub.2).sub.m--C(R.sup.2x, R.sup.3x)--N(R.sup.1x)--, and (3) ##STR00253## wherein R.sup.lx, R.sup.2x, R.sub.3x are independently H or substituted or unsubstituted C.sub.1-C.sub.6-alkyl; R.sub.2 is substituted or unsubstituted aryl; and W is ##STR00254## wherein Z is --O-- or --NH--. 9. The compound of claim 1, having the formula II: ##STR00255## wherein Y is selected from the group consisting of (1) substituted or unsubstituted aryl, (2) substituted or unsubstituted heterocyclyl, and (3) substituted or unsubstituted heteroaryl; and X is selected from the group consisting of (1) --N(R.sup.1x)--, (2) --(CH.sub.2).sub.m--C(R.sup.2x, R.sup.3x)--N(R.sup.1x)--, and (3) ##STR00256## 10. The compound of claim 1, having the formula II: ##STR00257## wherein Y and X, taken together, are selected from the group consisting of ##STR00258## ##STR00259## 11. The compound of claim 1, having the formula II: ##STR00260## wherein Y and X, taken together, are selected from the group consisting of ##STR00261## ##STR00262## 12. A compound having the formula II: ##STR00263## wherein, Y and X, taken together, are selected from the group consisting of ##STR00264## R.sub.1 is selected from the group consisting of (1) H, (2) substituted or unsubstituted C.sub.1-C.sub.6-alkyl, (3) --COOH, (4) halo, (5) --OR.sup.1t, and (6) --NHR.sup.1t, wherein R.sup.1t is H or C.sub.1-C.sub.6-alkyl; and R.sub.2 is selected from the group consisting of (1) substituted or unsubstituted aryl, and (2) substituted or unsubstituted heteroaryl. 13. The compound of claim 1, having the formula III: ##STR00265## wherein R.sub.3, R.sub.4, R.sub.5, R.sub.6 are selected from the group consisting of (1) H, (2) substituted or unsubstituted C.sub.1-C.sub.6-alkyl, (3) --COORt.sup.1, (4) --CONH.sub.2, (5) --OR.sup.1t, and (6) --NHR.sup.1t. 14. The compound of claim 1, having the formula IV: ##STR00266## wherein R.sub.3, R.sub.4, R.sub.5, R.sub.6 are selected from the group consisting of (1) H, (2) substituted or unsubstituted C.sub.1-C.sub.6-alkyl, (3) --COOR.sup.1t, (4) --CONH.sub.2 (5) --OR.sup.1t, and (6) --NHR.sup.1t. 15. The compound of claim 1, having the formula V: ##STR00267## wherein R.sub.3, R.sub.4, R.sub.5, R.sub.6 are selected from the group consisting of (1) H, (2) substituted or unsubstituted C.sub.1-C.sub.6-alkyl, (3) --COOR.sup.1t, (4) --CONH.sub.2 (5) --OR.sup.1t, and (6) --NHR.sup.1t; and R.sup.2a and R.sup.2b are selected from the group consisting of (1) H, (2) substituted or unsubstituted alkyl, (3) halo, (4) --(CH.sub.2).sub.q--N(R.sup.2c, R.sup.2d), (5) --(CH.sub.2).sub.q--N(R.sup.2c, R.sup.2d)COR.sup.2e, (6) --(CH.sub.2).sub.q--OR.sup.2e, (7) --(CH.sub.2).sub.q--OCOR.sup.2e, (8) --(CH.sub.2).sub.q--OCOOR.sup.2e, (9) --(CH.sub.2).sub.q--COOR.sup.2e, (10) --(CH.sub.2).sub.q--CONR.sup.2c, (11) --CN, (12) --NO.sub.2, (13) --SO.sub.2NH.sub.2, (14) --NHSO.sub.2CH.sub.3, and (15) --SO.sub.2R.sup.2f, wherein R.sup.2c, R.sup.2d, R.sup.2e, and R.sup.2f are selected from the group consisting of (a) H, (b) substituted or unsubstituted alkyl, and (c) substituted or unsubstituted phenyl; and q is 0, 1, 2, 3, or 4. 16. A compound having the formula VI: ##STR00268## wherein R.sub.2 is selected from the group consisting of ##STR00269## ##STR00270## 17. The compound of claim 1, having the formula VII: ##STR00271## wherein R.sub.7, R.sub.8, R.sub.9, and R.sub.10 are selected from the group consisting of (1) H, (2) substituted or unsubstituted C.sub.1-C.sub.6-alkyl, (3) --COOR.sup.1t, (4) --CONH.sub.2 (5) --OR.sup.1t, and (6) --NHR.sup.1t. 18. The compound of claim 1, having the formula VIII: ##STR00272## wherein R.sub.7, R.sub.8, R.sub.9, R.sub.10 are selected from the group consisting of (1) H, (2) substituted or unsubstituted C.sub.1-C.sub.6-alkyl, (3) --COOR.sup.1t, (4) --CONH.sub.2, (5) --OR.sup.1t, and (6) --NHR.sup.1t. 19. A compound having the formula IX: ##STR00273## wherein R.sup.1a and R.sup.1b are selected from the group consisting of (1) H, (2) substituted or unsubstituted alkyl, (3) halo, (4) --(CH.sub.2).sub.q--N(R.sup.2c, R.sup.2d), (5) --(CH.sub.2).sub.q--N(R.sup.2c, R.sup.2d)COR.sup.2e, (6) --(CH.sub.2).sub.q--OR.sup.2e, (7) --(CH.sub.2).sub.q--OCOR.sup.2e, (8) --(CH.sub.2).sub.q--OCOOR.sup.2e, (9) --(CH.sub.2).sub.q--COOR.sup.2e, (10) --(CH.sub.2).sub.q--CONR.sup.2c, (11) --CN, (12) --NO.sub.2, (13) --SO.sub.2NH.sub.2, (14) --NHSO.sub.2CH.sub.3, and (15) --SO.sub.2R.sup.2f, wherein R.sup.2c, R.sup.2d, R.sup.2e, and R.sup.2f are selected from the group consisting of (a) H, (b) substituted or unsubstituted alkyl, and (c) substituted or unsubstituted phenyl; and wherein R.sub.7 is selected from the group consisting of (1) H, (2) substituted or unsubstituted C.sub.1-C.sub.6-alkyl, (3) --COOR.sup.1t, (4) --CONH.sub.2, and (5) --OR.sup.1t, and (6) --NHR.sup.1t. 20. A compound having the formula X: ##STR00274## wherein R.sub.2 is selected from the group consisting of ##STR00275## ##STR00276## 21. A compound having the formula XI: ##STR00277## wherein R.sup.2g is selected from the group consisting of (1) H, (2) substituted or unsubstituted alkyl, (3) --CONHR.sup.2h, (4) --CON(R.sup.2h)--(CH.sub.2).sub.2-3--N(R.sup.2h, R.sup.2i), (5) --COR.sup.2j, (6) --CO.sub.2R.sup.2j, (7) --COC.sub.1-C.sub.6-alkyl-CO.sub.2H, (8) --CH.sub.2--OC(.dbd.O)R.sup.2i, (9) --CH.sub.2--OC(.dbd.O)NHCHR.sup.2iCO.sub.2R.sup.2j, (10) --P(.dbd.O)(OR.sup.2k, OR.sup.2p), ##STR00278## wherein R.sup.2h, R.sup.2i, R.sup.2j, R.sup.2k, and R.sup.2p are selected from the group consisting of (a) H, (b) substituted or unsubstituted alkyl, and (c) substituted or unsubstituted aryl. 22. A compound having the formula XII: ##STR00279## wherein R.sup.2g is selected from the group consisting of (1) H, (2) substituted or unsubstituted alkyl, (3) --CONHR.sup.2h, (4) --CON(R.sup.2h)--(CH.sub.2).sub.2-3--N(R.sup.2h, R.sup.2i), (5) --COR.sup.2j, (6) --CO.sub.2R.sup.2j, (7) --COC.sub.1-C.sub.6-alkyl-CO.sub.2H, (8) --CH.sub.2--OC(.dbd.O)R.sup.2i, (9) --CH.sub.2--OC(.dbd.O)NHCHR.sup.2iCO.sub.2R.sup.2j, (10) --P(.dbd.O)(OR.sup.2k, OR.sup.2p), ##STR00280## wherein R.sup.2h, R.sup.2i, R.sup.2j, R.sup.2k, and R.sup.2p are selected from the group consisting of (a) H, (b) substituted or unsubstituted alkyl, and (c) substituted or unsubstituted aryl. 23. A composition, comprising a compound of claim 1 and a pharmaceutically acceptable carrier. 24. The composition of claim 23 further comprising at least one additional agent for the treatment of breast cancer. 25. The composition of claim 24, wherein the at least one additional agent for the treatment of breast cancer is selected from irinotecan, topotecan, gemcitabine, imatinib mesylate, herceptin, 5-fluorouracil, lencovorin, carboplatin, cisplatin, taxanes, tezacitabine, cyclophosphamide, vinca alkaloids, imatinib, anthracyclines, rituximab, tamoxifen, CPT 11, and trastuzumab. 26. A method for treating breast cancer comprising administering to a subject in need of such treatment an effective amount of a compound of claim 1. 27. The method of claim 26, wherein the compound has an IC.sub.50 value of less than about 20 .mu.M in a cell proliferation assay. 28. The method of claim 26 further comprising administering to the human or animal subject at least one additional agent for the treatment of breast cancer. 29. The method of claim 28, wherein the at least one additional agent for the treatment of breast cancer is selected from irinotecan, topotecan, gemcitabine, imatinib mesylate, herceptin, 5-fluorouracil, leucovorin, carboplatin, cisplatin, taxanes, tezacitabine, cyclophosphamide, vinca alkaloids, imatinib, anthracyclines, rituximab, tamoxifen, CPT 11, and trastuzumab. 30. A compound of claim 1, wherein R.sub.2 is hydroxy-substituted phenyl. 31. A compound of claim 1, wherein R.sub.2 is substituted or unsubstituted pyridinyl. 32. A compound of claim 1, wherein R.sub.2 is substituted or unsubstituted pyrimidinyl. 33. A compound of claim 1, wherein W is ##STR00281## 34. A compound of claim 33, wherein R.sup.4w is H, r is 1, and Z is O. 35. A compound of claim 1, wherein Y is substituted or unsubstituted heterocyclyl. 36. A compound of claim 1, wherein X is a O and Y is substituted or unsubstituted heterocyclyl. 37. A compound of claim 33, wherein R.sup.4w is H, r is 1, Z is O, Y is substituted or unsubstituted heterocyclyl, R.sub.1 is H, and R.sub.2 is substituted or unsubstituted heteroaryl. 38. A compound of claim 33, wherein R.sup.4w is H, r is 1, Z is O, X is O, Y is substituted or unsubstituted heterocyclyl, R.sub.1 is H, and R.sub.2 is substituted or unsubstituted heteroaryl.

Details for Patent 7,423,148

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	RITUXAN	rituximab	Injection	103705	11/26/1997		2022-11-21
Idec Pharmaceuticals Corp.	RITUXAN	rituximab	Injection	103737	02/19/2002		2022-11-21
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	09/25/1998		2022-11-21
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	02/10/2017		2022-11-21
Genentech, Inc.	RITUXAN HYCELA	rituximab and hyaluronidase human	Injection	761064	06/22/2017		2022-11-21
Genentech, Inc.	HERCEPTIN HYLECTA	trastuzumab and hyaluronidase-oysk	Injection	761106	02/28/2019		2022-11-21