Compounds and methods of use
Selected compounds are effective for prophylaxis and treatment of diseases, such as VEGF mediated diseases. The invention encompasses novel compounds, analogs, prodrugs and pharmaceutically acceptable salts thereof, pharmaceutical compositions and methods for prophylaxis and treatment of diseases and other maladies or conditions involving, cancer and the like. The subject invention also relates to processes for making such compounds as well as to intermediates useful in such processes.
1. A compound of formula I
or a salt thereof wherein
X is CH;
Y is (C 1 -C 6 )alkylene, or (C 1 -C 6 )alkenylene wherein substituents on the same carbon atom or on adjacent carbon atoms may optionally combine to form a C 3 to C 6 -membered cycloalkyl ring, or a C 5 -C 6 heterocyclyl ring;
Z is
p and p* are each independently absent or a bond;
R 1 and R 2 together with the ring to which they are bonded combine to form quinoline, optionally independently substituted with one or more R 10 ;
R 3 is H, NHR 7 , C(═O)NHR 7 , NHC(═O)NR 8 R 9 , or NHC(═S)NR 8 R 9 ;
R 4 and R 4a are independently selected from H, and alkyl, or R 4 and R 4a combine to form ═O;
R 5 is H, C(═O)NHR 7 , NHC(═O)NHR 7 or NHC(═O)R 7 ;
R 6 is H, halo, C(═O)NHR 7 , NHC(═O)R 7 , or NHC(═O)NR 8 R 9 ;
R 7 is independently at each occurrence
a) H, or
b) alkyl, cycloalkyl, heterocyclo, aryl, heteroaryl, cycloalkyl, alkyl, arylalkyl, alkoxyalkyl, heteroarylalkyl, cycloalklyalkyl, or 2,3-dihydroindole, any of which can be optionally substituted with one or more R 10 ;
R 10 is halo, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, cycloalkyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, cyano, nitro, —NR 8 R 9 , —C(═O)NR 8 R 9 , or NHC(═O)NR 8 R 9 ;
R 8 and R 9 are independently H, alkyl, haloalkyl, cycloalkyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, or heterocycloalkyl, any of which may be optionally independently substituted with one or more R 10
provided R 5 is not H, C(═O)NHR 7 , or NHC(═O)R 7 when Z is piperidinyl.
2. A compound of claim 1 wherein Z is
3. A compound of claim 1 wherein Z is
4. A compound of claim 2 wherein p is a bond.
5. A compound of claim 2 wherein p is absent.
6. A compound of claim 1 wherein Y is CH 2 .
7. A compound of claim 5 wherein R 1 and R 2 together with the ring to which they are bonded combine to form a ring selected from 6,7-dimethoxyquinoline, and quinoline.
8. A compound of claim 7 wherein Y is CH 2 ; and R 5 is C(═O)NHR 7 , NHC(═O)R 7 or NHC(═O)NHR 7 .
9. A compound of claim 8 wherein R 7 is independently phenyl, cycloalkyl or 2,3-dihydroindole, any of which may be optionally independently substituted with one or more R 10 .
10. A compound of claim 1 selected from
11. A compound of claim 1 selected from
12. A compound of formula II
or a salt thereof wherein
R 1 and R 2 are independently H or alkoxy;
R 4 and R 4a are each hydrogen, or R 4 and R 4a combine to form ═O;
p is absent or a bond;
X is —C(═O)NH—, —NHC(═O)NH— or —NHC(═O)—;
R 10 is independently selected at each occurrence from halo, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, cycloalkyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl, cyano, nitro, —NR 8 R 9 or —C(═O)NR 8 R 9 ;
R 8 and R 9 are independently H, alkyl, haloalkyl, cycloalkyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl, any of which may be optionally independently substituted with one or more R 10 ; and
n is 0, 1, 2 or 3.
13. A compound of claim 12 wherein R 1 and R 2 are independently H or C 1-6 alkoxy; R 4 and R 4a are each hydrogen, or R 4 and R 4a combine to form ═O; p is absent or a bond; X is —C(═O)NH—, —NHC(═O)NH— or —NHC(═O)—; R 10 is independently selected at each occurrence from halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclo, phenyl, naphthyl, indenyl, tetrahydronaphthyl, indanyl, 5- to 6-membered heteroaryl, aryl-C 1-6 -alkyl, C 5-6 cycloalkyl- C 1-6 -alkyl, 5- or 6-membered heteroaryl- C 1-6 -alkyl, cyano, nitro, —NR 8 R 9 or —C(═O)NR 8 R 9 , R 8 and R 9 are independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, 3- to 6-membered heterocyclo, phenyl, naphthyl, indenyl, tetrahydronaphthyl, indanyl, 5 to 6 membered heteroaryl, aryl- C 1-6 -alkyl, heteroaryl- C 1-6 -alkyl, C 5-6 cycloalkyl- C 1-6 -alkyl, and 5- or 6-membered heteroaryl- C 1-6 -alkyl; and n is 0, 1, or 2; or a salt thereof.
14. A compound of claim 12 wherein R 1 and R 2 are independently H or C 1-3 alkoxy; R 4 and R 4a are each hydrogen, or R 4 and R 4a combine to form ═O; p is absent or a bond; X is —C(═O)NH—, —NHC(═O)NH— or —NHC(═O)—; R 10 is independently selected at each occurrence from halo, C 1-2 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-3 alkoxy, C 1-2 haloalkyl, cyclopentyl, cyclopropyl, cyclohexyl, 3- to 6-membered heterocyclo, phenyl, 5- or 6-membered heteroaryl, benzyl, diphenylmethyl, phenylethyl, C 5-6 cycloalkyl—C 1-3 -alkyl, 5- or 6-membered heteroaryl-C 1-3 -alkyl, cyano, nitro, —NR 8 R 9 or —C(═O)NR 8 R 9 , R 8 and R 9 are independently H, C 1-2 alkyl, C 1-2 haloalkyl, cyclopentyl, cyclopropyl, cyclohexyl, 3- to 6-membered heterocyclo, phenyl, heteroaryl, benzyl, diphenylmethyl, phenylethyl, C 5-6 cycloalkyl-C 1-3 -alkyl, and 5- or 6-membered heteroaryl-C 1-6 -alkyl; and n is 0, 1, or 2; or a salt thereof.
15. A compound of claim 3 wherein p is absent.
16. A pharmaceutical composition comprising a pharmaceutically-acceptable carrier and a compound of claim 1 .
17. A pharmaceutical composition comprising a pharmaceutically-acceptable carrier and a compound of claim 12 .