Details for Patent: 9,174,947

Title:	c-Met modulators and methods of use
Abstract:	The present invention provides compounds for modulating protein kinase enzymatic activity for modulating cellular activities such as proliferation, differentiation, programmed cell death, migration and chemoinvasion. More specifically, the invention provides quinazolines and quinolines which inhibit, regulate and/or modulate kinase receptor, particularly c-Met, KDR, c-Kit, flt-3 and flt-4, signal transduction pathways related to the changes in cellular activities as mentioned above, compositions which contain these compounds, and methods of using them to treat kinase-dependent diseases and conditions. The present invention also provides methods for making compounds as mentioned above, and compositions which contain these compounds.
Inventor(s):	Bannen; Lynne Canne (Pacifica, CA), Chan; Diva Sze-Ming (San Francisco, CA), Chen; Jeff (San Francisco, CA), Dalrymple; Lisa Esther (San Francisco, CA), Forsyth; Timothy Patrick (Hayward, CA), Huynh; Tai Phat (Oakland, CA), Jammalamadaka; Vasu (Pleasanton, CA), Khoury; Richard George (Redwood City, CA), Leahy; James William (San Leandro, CA), Mac; Morrison B. (San Francisco, CA), Mann; Grace (Brisbane, CA), Mann; Larry W. (Redwood City, CA), Nuss; John M. (Danville, CA), Parks; Jason Jevious (Sacramento, CA), Takeuchi; Craig Stacy (Burlingame, CA), Wang; Yong (Foster City, CA), Xu; Wie (Danville, CA)
Assignee:	Exelixus, Inc. (South San Francisco, CA)
Filing Date:	Oct 26, 2006
Application Number:	11/586,751
Claims:	1. A process for preparing a compound of formula XXIb: ##STR00755## comprising reaction of a compound of Formula XXIIb, with a compound of Formula XXIIIb: ##STR00756## wherein: J is .dbd.C(H)--; R.sup.2 is selected from --H, halogen, trihalomethyl, --CN, --NO.sub.2, --NH.sub.2, --OR.sup.3, --NR.sup.3R.sup.3, --S(O).sub.0-2R.sup.3, --SO.sub.2NR.sup.3R.sup.3, --CO.sub.2R.sup.3, --C(O)NR.sup.3R.sup.3, --N(R.sup.3)SO.sub.2R.sup.3, --N(R.sup.3)C(O)R.sup.3, --N(R.sup.3)CO.sub.2R.sup.3, --C(O)R.sup.3, and optionally substituted C.sub.1-6alkyl; each R.sup.3 is independently selected from --H, --Si(R.sup.5)(R.sup.5)R.sup.5, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted arylalkyl, and optionally substituted heteroarylalkyl; two R.sup.3, together with the nitrogen to which they are attached, form a four- to seven-membered heteroalicyclic, said four- to seven-membered heteroalicyclic optionally containing one additional heteroatom; when one said additional heteroatom is a nitrogen, then said nitrogen is optionally substituted with a group selected from --H, trihalomethyl, --SO.sub.2R.sup.5, --SO.sub.2NR.sup.5R.sup.5, --CO.sub.2R.sup.5, --C(O)NR.sup.5R.sup.5, --C(O)R.sup.5, and optionally substituted lower alkyl; each R.sup.20 is independently selected from --H, halogen, trihalomethyl, --CN, --NO.sub.2, --NH.sub.2, --OR.sup.3, --NR.sup.3R.sup.3, --S(O).sub.0-2R.sup.3, --SO.sub.2NR.sup.3R.sup.3, --CO.sub.2R.sup.3, --C(O)NR.sup.3R.sup.3, --N(R.sup.3)SO.sub.2R.sup.3, --N(R.sup.3)C(O)R.sup.3, --N(R.sup.3)CO.sub.2R.sup.3, --C(O)R.sup.3, optionally substituted C.sub.1-6alkyl, optionally substituted aryl, optionally substituted aryl C.sub.1-6alkyl, optionally substituted heterocyclyl, and optionally substituted heterocyclyl C.sub.1-6alkyl; two of R.sup.20, together with the atom or atoms to which they are attached, combine to form an optionally substituted three- to seven-membered heteroalicyclic; R.sup.50 is lower alkyl; and P.sup.1 is selected from chlorine, bromine, a toluene sulfonate, and trifluoromethansulfonate. 2. A process for preparing the compound: ##STR00757## comprising reaction of the compound: ##STR00758## with the compound: ##STR00759## wherein P.sub.1 is selected from chlorine, bromine, a toluene sulfonate, and trifluoromethansulfonate. 3. The process of claim 2, further comprising the step of preparing the compound ##STR00760## by either: reacting ##STR00761## in the presence of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) and removing the Bn group using Pd/C and 1,4-cyclohexadiene; or reacting ##STR00762## in the presence of EDCI. 4. The process of claim 3, further comprising the step of preparing the compound ##STR00763## by reacting ##STR00764## in the presence of thionyl cloride. 5. A process for preparing the compound: ##STR00765## comprising: (a) preparing the compound ##STR00766## by reacting ##STR00767## in the presence of thionyl chloride: (b) preparing the compound ##STR00768## by either: (b1) reacting ##STR00769## in the presence of EDCI to form ##STR00770## and removing the Bn group using Pd/C and 1,4-cyclohexadiene; or (b2) reacting ##STR00771## in the presence of EDCI; and (c) preparing ##STR00772## by reacting ##STR00773## wherein P.sub.1 is selected from chlorine, bromine, a toluene sulfonate and trifluoromethansulfonate. 6. The compounds ##STR00774## and ##STR00775##