Fusion of bicyclic 2,4-diaminopyrimidine derivatives as using ALK and c-Met inhibitors

摘要

A compound of formula I or II ** Formula ** or a pharmaceutically acceptable salt form thereof, wherein R 1 is chlorine; R2 is a group selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-15 aryl, C3-10 cycloalkyl, 3-15 membered heterocycloalkyl, and 5-15 membered heteroaryl, in which the group R2 is optionally substituted by one or more members independently selected from halogen, -NO2, -OR20, = O, - C ( = O) R20, -C ( = O) OR20, -C ( = O) NR22R23, -NR20R21, C1-6- (R25) x alkyl, C6-15- (R25) x aryl, 5-15 membered heteroaryl- (R25) x, C3-10- (R25) x cycloalkyl, 3-heterocycloalkyl -15 members- (R25) x, pseudohalogen, - S ( = O) nR20, -S ( = O) 2NR22R23, -OCH2F, -OCHF2, -OCF3, NHOH, -OC ( = O) R20, OC ( = O) NR22R23, - NR20C ( = O) R21, -NR20C ( = O) OR21, -NR20S ( = O) 2R21, NR20C ( = O) NR22R23, -NR20S ( = O) 2NR22R23 , and -SCF3; R3, R4, and R5 are independently selected from H, halogen, -NO2, -OR30, -C ( = O) R30, -C ( = O) OR30, - C ( = O) NR32R33, -NR30R31, C 1-6 alkyl- (R35) x, C6-15 aryl- (R35) x, 5-15 membered heteroaryl- (R35) x, C3-10 cycloalkyl- (R35) x, 3-15 membered heterocycloalkyl- ( R35) x, pseudohalogen, -S ( = O) nR30, - S ( = O) 2NR32R33, -OCH2F, -OCHF2, -OCF3, NHOH, -OC ( = O) R30, -OC ( = O ) NR32R33, NR30C ( = O) R31, - NR30C ( = O) OR31, -NR30S ( = O) 2R31, - NR30C ( = O) NR12R33, -NR30S ( = O) 2NR32R33, and -SCF3 ; A1, A2, A3, A4, and A5 are each independently -CZ1Z2-, - (CZ1Z2) 2- -C ( = O) -, - NZ3-, -S-, -S ( = O) -, -S ( = O) 2-, or -O-, with the condition at most of A1, A2, A3, A4, and A5 is - (CZ1Z2) 2-, in which: (a) when any of Z1, Z2, and Z3 are found in adjacent atoms, they can form a bond between the atoms, (b) any of Z1, Z2, and Z3 can be independently selected from H, halogen, -NO2, -OR40, - C ( = O) R40, -C ( = O) OR40, -C ( = O) NR42R43, -NR40R41, C1-6 alkyl- (R45) x, C6-15 aryl- (R45) x, 5- heteroaryl 15 members- (R45) x, C3-10 cycloalkyl- (R45) x, 3-15 membered heterocycloalkyl- (R45) x, C2-6 alkenyl- (R45) x, C2-6 alkynyl- (R45) x, pseudohalogen, -S ( = O) nR40, -S ( = O) 2NR42R43, -OCH2F, -OCHF2, -OCF3, NHOH, - OC ( = O) R40, -OC ( = O) NR42R43, - NR40C ( = O) R41, -NR40C ( = O) OR41, -NR40S ( = O) 2R41, - NR40C ( = O) NR42R43, - NR40S ( = O) 2NR42R43, and -SCF3, and ( c) any two of Z1, Z2, and Z3 can form together a group of the formula -A6-A7-A8-A9-A10-, in which A6, A7, A8, A9 , and A10 are independently selected from, -CZ4Z5-, -C ( = O) -, NZ6-, -S-, -S ( = O) -, -S ( = O) 2-, or -O -, in which: (i) when any of two of Z1, Z2, Z3, Z4, Z5, and Z6 are located in adjacent atoms, they can form a bond between the atoms, and (ii) any Z4, Z5, and Z6 can be independently selected from H, halogen, NO2, -OR50, -C ( = O) R50, - C ( = O) OR50, -C ( = O) NR52R53, -NR50R51, C1-6 alkyl- ( R25) x, C6-15 aryl- (R55) x, 5-15 membered heteroaryl- (R55) x, C3-10 cycloalkyl- (R55) x, 3-15 membered heterocycloalkyl- (R55) x, pseudohalogen, -S ( = O) nR50, -S ( = O) 2NR52R53, -OCH2F, -OCHF2, -OCF3, NHOH, -OC ( = O) R50, -OC ( = O) NR52R53, -NR50C ( = O) R51, - NR50C ( = O) OR51, -NR50S ( = O) 2R51, NR50C ( = O) NR52R53, -NR50S ( = O) 2NR52R53, and -SCF3; R25, R35, R45, and R55 at each occurrence are independently selected from halogen, -NO2, -OR60, = O, - C ( = O) R60, -C ( = O) OR60, -C ( = O) NR62R63, -NR60R61, C1-6 alkyl, C1-6 alkyl-O C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-15 aryl, 5-15 membered heteroaryl, C3-10 cycloalkyl, 3-15 membered heterocycloalkyl, pseudohalogen, -S ( = O) nR60, -S ( = O) 2NR62R63, -OCH2F, -OCHF2, -OCF3, NHOH, -OC ( = O) R60, - OC ( = O) NR62R63, -OP ( = O) (OH) 2, -NR60C ( = O) R61, -NR60C ( = O) OR61, NR60S ( = O) 2R61, NR60C ( = O) NR62R63, - NR60S ( = O) 2NR62R63, and -SCF3, wherein said groups C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-15 aryl, 5-15 member heteroaryl, C3-10 cycloalkyl, and 3-15 member heterocycloalkyl are optionally substituted by one or more substituents independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, halogen, cyano, phenyl , 5-10 membered heteroaryl- (R79) x, 3-10 membered heterocycloalkyl bros, -N (R76) 2, -C ( = O) OR76, -C ( = O) N (R76) 2, = O, and -OR76; R10, R11, R20, R21, R30, R31, R40, R41, R50 R51, R60, and R61 at each occurrence are independently selected from H, C1-6 alkyl, C2-6 alkynyl, C1-6 haloalkyl, C6- aryl 15, 5-15 membered heteroaryl, C3-10 cycloalkyl, and 3-15 membered heterocycloalkyl, wherein said C1-6 alkyl groups, alkynyl. C2-6, C1-6 haloalkyl, C6-15 aryl, 5-15 membered heteroaryl, C3-10 cycloalkyl, and 3-15 membered heterocycloalkyl are optionally substituted by one or more substituents independently selected from C1-6 alkyl, alkenyl C2-6, C2-6 alkynyl, halogen, cyano, phenyl, 5-10 membered heteroaryl- (R79) x, 3-10 membered heterocycloalkyl, -N (R76) 2, -C ( = O) OR76, -C ( = O) N (R76) 2, = O, and -OR76; R12, R13, R22, R23, R32, R33, R42, R43, R52, R53, R62, and R63 at each occurrence are independently selected from H, C1-6 alkyl, C2-6 alkynyl, C1-6 haloalkyl, C6 aryl -15, 5-15 membered heteroaryl, C3-10 cycloalkyl, and 3-15 membered heterocycloalkyl, wherein said C1-6 alkyl, C2-6 alkynyl, C1-6 haloalkyl, C6-15 aryl, heteroaryl groups 5-15 membered, C3-10 cycloalkyl, and 3-15 membered heterocycloalkyl are optionally substituted by one or more substituents independently selected from C1-6 alkyl, halogen, C3-10 cycloalkyl, 3-10 membered heterocycloalkyl- (R87 ) x, -N (R86) 2, cyano, C2-6 alkynyl, = O, and 10 -OR86; or R12 and R13, R22 and R23, R32 and R33, R42 and R43, R52 and R53, or R62 and R63 can form, together with the nitrogen atom to which they are attached, a 3-15-membered heterocycloalkyl group or a group 5-15 membered heteroaryl, wherein said 3-15 membered heterocycloalkyl group or 5-15 membered heteroaryl group is optionally substituted by one or more substituents independently selected from C1-6 alkyl, halogen, and -OH; R76 and R86 at each occurrence are independently selected from H, C1-6 alkyl- (R78) x, and -C ( = O) - C1-6 alkyl; R78 at each occurrence is independently selected from = O and phenyl; R79 in each occurrence is = O; R87 at each occurrence is independently selected from C1-6 alkyl; n in each occurrence is independently selected between 0, 1, and 2; and x in each occurrence is independently selected from 0, 1, 2, 3, 4, 5, and 6; wherein "alkenyl" includes unsaturated straight and branched chain alkyl groups having two (2) or more carbon atoms and at least one double bond; "alkynyl" includes unsaturated straight and branched chain alkyl groups having two (2) or more carbon atoms and at least one triple bond; "cycloalkyl" includes monocyclic, bicyclic, tricyclic, bridged bicyclic and bridged tricyclic non-aromatic carbocyclic rings, which may be saturated or unsaturated; "heterocycloalkyl" includes monocyclic, bicyclic, and tricyclic 3-15 membered non-aromatic rings, which may be saturated or unsaturated, and which contain, in addition to carbon atom (s), at least one heteroatom, such as nitrogen, oxygen or sulfur; "aryl" or "aryl group" includes phenyl and 7-15 membered bicyclic or tricyclic hydrocarbon ring systems in which at least one of the rings is aromatic; and heteroaryl "includes (a) 5 and 6 membered monocyclic aromatic rings, which contain, in addition to carbon atom (s), at least one heteroatom, such as nitrogen, oxygen or sulfur, and (b) bicyclic and tricyclic rings of 7-15 members, which contain, in addition to carbon atom (s), at least one heteroatom, such as nitrogen, oxygen or sulfur, and in which at least one of the rings is aromatic; with the proviso that the compound is not: ** Formula ** in which R = CI; ** Formula ** (b) in which R = CI.