C-Met Modulators and Method of Use
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, KDF, 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.
1 - 52 . (canceled)
52 . A compound according to formula XIVa:
or a pharmaceutically acceptable salt thereof,
wherein:
Q is selected from ═N— or ═C(H)—;
R 2 is halogen, trihalomethyl, —CN, —NH 2 , —NO 2 , —OR 3 , —NR 3 R 3 , —S(O) 0-2 R 3 , —SO 2 NR 3 R 3 , —CO 2 R 3 , —C(O)NR 3 R 3 , —N(R 3 )SO 2 R 3 , —N(R 3 )C(O)R 3 , —N(R 3 )CO 2 R 3 , —C(O)R 3 and optionally substituted lower alkyl;
R 3 is independently selected from —H, or R 4 ;
R 4 is independently selected from optionally substituted C 1-6 alkyl, optionally substituted aryl, optionally substituted aryl C 1-6 alkyl, optionally substituted heterocyclyl and optionally substituted heterocyclyl C 1-6 alkyl;
R 20 is selected from halogen, trihalomethyl, —CN, —NO 2 , —NH 2 , —OR 3 , —NR 3 R 3 , S(O) 0-2 R 3 , —SO 2 NR 3 R 3 , —CO 2 R 3 , —C(O)NR 3 R 3 , —N(R 3 )SO 2 R 3 , —N(R 3 )C(O)R 3 , —N(R 3 )CO 2 R 3 , —C(O)R 3 and optionally substituted lower alkyl;
R 30 is independently selected from halogen, trihalomethyl, —CN, —NO 2 , —NH 2 , —OR 3 , —NR 3 R 3 , —S(O) 0-2 R 3 , —SO 2 NR 3 R 3 , —CO 2 R 3 , —C(O)NR 3 R 3 , —N(R 3 )SO 2 R 3 , —N(R 3 )C(O)R 3 , —N(R 3 )CO 2 R 3 , —C(O)R 3 , and optionally substituted C 1-6 alkyl; and
R 50 is lower alkyl.
53 . The compound according to claim 52 , or a pharmaceutically acceptable salt thereof, wherein Q is —N═.
54 . The compound according to claim 52 , or a pharmaceutically acceptable salt thereof, wherein Q is —CH═.
55 . The compound according to claim 54 , or a pharmaceutically acceptable salt thereof, wherein (R 30 ) 0-4 is (R 30 ) 0 , or methyl.
56 . The compound according to claim 54 , or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from C 1-6 alkyl, perfluoro C 1-6 alkyl, hydrogen, and halogen.
57 . The compound according to claim 54 , or a pharmaceutically acceptable salt thereof, wherein R 2 is halogen.
58 . The compound according to claim 54 , or a pharmaceutically acceptable salt thereof, wherein R 2 is hydrogen.
59 . The compound according to claim 53 , or a pharmaceutically acceptable salt thereof, wherein R 20 is selected from halogen, —CN, —NO 2 , —NH 2 , —OR 3 , —NR 3 R 4 , —N(R 3 )SO 2 R 3 , —N(R 3 )C(O)R 3 , —N(R 3 )CO 2 R 3 , optionally substituted heterocyclyl, and optionally substituted heterocyclyl C 1-6 alkyl, and (two of R 20 ) together with the atom or atoms to which they are attached, form an optionally substituted three- to six-membered heteroalicyclic, said optionally substituted three- to six-membered heteroalicyclic fused to the phenyl as in formula XIVa.
60 . The compound according to claim 59 , or a pharmaceutically acceptable salt thereof, wherein R 20 is selected from halogen, —NR 3 R 4 , optionally substituted heterocyclyl and optionally substituted heterocyclyl C 1-6 alkyl, and (two of R 20 ) together with the atom or atoms to which they are attached, form an optionally substituted five- to six-membered heteroalicyclic, said optionally substituted five- to six-membered heteroalicyclic fused to the phenyl as in XIVa.
61 . The compound according to claim 60 , or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from C 1-6 alkyl, perfluoro C 1-6 alkyl, and halogen.
62 . The compound according to claim 61 , or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from perfluoro C 1-3 alkyl, and halogen.
63 . The compound according to claim 52 selected from the following:
Name
Structure
4
N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-chloropyridin- 3-yl)-N′- phenylcyclopropane-1,1- dicarboxamide
12
N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}phenyl)-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
13
N-(4-{[6,7- bis(methyloxy)quinazolin- 4-yl]oxy}phenyl)-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
14
N-(4-{[6,7- bis(methyloxy)quinazolin- 4-yl]oxy}-3- fluorophenyl)-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
22
N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-2-methylphenyl)- N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
24
N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)- N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
27
N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3,5- difluorophenyl)-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
28
N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-2,5- difluorophenyl)-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
33
N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-2,3,5- trifluorophenyl)-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
34
N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-fluoro-2- methylphenyl)-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
35
N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-2-chloro-5- methylphenyl)-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
43
N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-2-chloro-5- fluorophenyl)-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide
104
N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}phenyl)-N′- phenylcyclopropane-1,1- dicarboxamide
64 . A pharmaceutical composition comprising a compound according to claim 52 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
65 . The pharmaceutical composition comprising a compound according to claim 63 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.