Pyrido-[2,3-D] Pyrimidines and Their Use as Kinase Inhibitors
The present invention provides derivatives of pyrido[2,3-d]pyrimidin-7-one. These compounds are kinase inhibitors, including compounds that show anti-proliferative activity, including against tumor cells, and are useful in the treatment of diseases including cancer.
1 . A compound having a structure represented by formula (V)
or any tautomeric or stereoisomeric form thereof, wherein
R 7 is selected from —S(O) m —R 17 , with m=0, 1 or 2, and —N(R 1 )—V—R 2 ;
R 18 is taken from the list of —W—R 4 , —COOH, —COOR 17 , and —Br; and
R 17 is independently selected from —C 1-6 -alkyl, —CH 2 -aryl, or -aryl;
with R 1 is selected from hydrogen, —C 1-6 alkyl, —C 2-6 -alkenyl, —C 2-6 -alkynyl, —C 3-6 -cycloalkyl and —C 3-6 -cycloalkenyl;
V is selected from a bond, —O—, —N(R 11 )—, —C(═X)—, —S(O) n —, —C(═X)—O—, —C(═X)—N(R 11 )—, —C(═X)—S—, —C(═X)—N(R 11 )—N(R 11 )—, —N(R 11 )—C(═X)—, —N(R 11 )—C(═X)—N(R 11 )—, and —N(R 11 )—S(O) n —, with n=1 or 2;
R 2 is selected from hydrogen, -alkyl, -alkenyl, -alkynyl, -cycloalkyl, -cycloalkenyl, -heterocycloalkyl, -heterocycloalkenyl, -aryl and -heteroaryl;
or, R 1 and R 2 , together with V and the nitrogen atom they are attached to, form a heterocycle;
R 3 is selected from hydrogen, —C 1-6 alkyl, —C 2-6 -alkenyl, —C 2-6 -alkynyl, —C 3-6 -cycloalkyl, —C 3-6 -cycloalkenyl and halogen;
W is a bond, or —C(═O)—;
R 4 is selected from hydrogen, phenyl ans substituted phenyl;
R 5 is selected from -alkyl, -alkenyl, -alkynyl, -cycloalkyl, -cycloalkenyl, —(C-linked-heterocycloalkyl), —(C-linked-heterocycloalkenyl), -aryl, and -heteroaryl;
X is independently selected from ═O, ═S, ═NR 12 , ═N—OR 13 , ═N—N(R 11 ) 2 , ═N—N(R 11 )(R 12 ), and ═N—N(R 12 ) 2 ;
R 10 is independently selected from —C 1-6 alkyl, —C 2-6 -alkenyl, —C 2-6 -alkynyl, —C 3-6 -cycloalkyl and —C 3-6 -cycloalkenyl;
R 11 is independently selected from hydrogen and R 10 ;
R 12 is independently selected from -alkyl, -alkenyl, -alkynyl, -cycloalkyl, -cycloalkenyl, -heterocycloalkyl, -heterocycloalkenyl, -aryl and -heteroaryl;
R 13 is independently selected from hydrogen and R 12 ;
wherein R 2 , R 4 , R 5 , R 10 , and R 12 may optionally be substituted;
provided that if R 7 is —N(R 1 )—V—R 2 , then R 18 is not —W—R 4 .
2 . The compound of claim 1 , wherein one or more hydrogen atoms in any of R 2 , R 4 , R 5 , R 10 , and R 12 are independently substituted with substituents R 6 , with R 6 being independently taken from the list of: Y—R 14 and R 15 ;
with R 14 being independently selected from —R 13 , —OR 13 , —SR 13 , —N(R 13 ) 2 , —N(R 13 )N(R 13 ) 2 , —N═C(R 13 ) 2 , and —N═NR 13 ;
with R 15 being independently selected from —F, —Cl, —Br, —I, —CN, —NO 2 , and ═Z;
with Y being independently selected from a bond, —C(═Z)—, —O—, —O—C(═Z)—, —N(R 13 )—, —N(R 13 )—C(═Z)—, —N(R 13 )—N(R 13 )—C(═Z)—, —N(R 13 )—S(O) n —, —S—, and —S(O) n —, with n=1 or 2; provided that if Y is a bond, then R 14 is not hydrogen; and
with Z being independently selected from ═O, ═S, ═NR 12 , ═N—OR 13 , and ═N—N(R 11 ) 2 .
3 . The compound of claim 1 , wherein one or more hydrogen atoms in any of R 2 , R 4 , R 5 , R 10 , and R 12 are independently substituted with substituents R 7 , with R 7 being independently taken from R 6 , wherein one or more hydrogens of R 6 are substituted by substituents independently taken from the list of: Y—R 14 and R 15 .
4 . The compound of claim 1 , wherein R 1 is hydrogen.
5 . The compound of claim 1 , wherein V is a bond.
6 . The compound of claim 5 , wherein R 2 is selected from -aryl and -heteroaryl, substituted with 0, 1, 2, 3, 4 or 5 substituents R 8 , wherein R 8 is independently selected from R 6 and R 7 .
7 . The compound of claim 6 , wherein R 2 is -phenyl substituted with one substituent R 8 in position 3 or 4.
8 . The compound of claim 6 , wherein any R 8 is independently selected from —O—C 1-3 -alkyl, —S—C 1-3 -alkyl, —C 1-3 -alkyl-OH, —SO 2 —NH 2 , and —N-linked-heterocycloalkyl.
9 . The compound of claim 1 , wherein R 3 is hydrogen.
10 . The compound of claim 1 , wherein W is a bond.
11 . The compound of claim 10 , wherein R 4 is -phenyl that is substituted with 0, 1, 2, 3, 4, or 5 substituents R 9 , wherein R 9 is independently selected from R 6 and R 7 .
12 . The compound of claim 11 , wherein R 9 is selected from -methyl, —O-Me, —CF 3 , N(R 13 ) 2 , —NH—C(═X)—R 13 and halogen.
13 . The compound of claim 1 , wherein X is ═O.
14 . The compound of claim 1 , wherein R 5 is selected from R 10 and phenyl, in each case substituted with 0, 1, 2, or 3 substituents R 16 , wherein R 16 is independently selected from R 6 and R 7 .
15 . The compound of claim 14 , wherein R 5 is —C 1-4 -alkyl substituted with 0 or 1 substituent R 16 .
16 . A pharmaceutical composition, including a compound of claim 1 , and a pharmaceutically acceptable diluent, excipient or carrier.
17 . The pharmaceutical composition of claim 16 , comprising a therapeutically effective amount of the compound.
18 . The pharmaceutical composition of claim 16 for the treatment of an individual in need thereof.
19 . The pharmaceutical composition of claim 18 , wherein said individual is a human.
20 . A pharmaceutical composition for the treatment of cancer, said compound comprising a compound of claim 1 , and a pharmaceutically acceptable carrier, diluent or excipient.