Aminoheteroaryl compounds as protein kinase inhibitors
View Patent ↗Aminopyridine and aminopyrazine compounds of formula (1), compositions including these compounds, and methods of their use are provided. Preferred compounds of formula 1 have activity as protein kinase inhibitors, including as inhibitors of c-MET.
1. A compound of formula
wherein:
Y is N;
R 1 is selected from C 6-12 aryl, 5-12 membered heteroaryl, C 3-12 cycloalkyl, 3-12 membered heteroalicyclic, —O(CR 6 R 7 ) n R 4 , —C(O)R 4 , —C(O)OR 4 , —CN, —NO 2 , —S(O) m R 4 , —SO 2 NR 4 R 5 , —C(O)NR 4 R 5 , —C(═NR 6 )NR 4 R 5 , C 1-8 alkyl, C 2-8 alkenyl, and C 2-8 alkynyl; and each hydrogen in R 1 is optionally substituted by one or more R 3 groups;
R 2 is hydrogen, halogen, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-12 cycloalkyl, C 6-12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, —S(O) m R 4 , —SO 2 NR 4 R 5 , —S(O) 2 OR 4 , —NO 2 , —NR 4 R 5 , —(CR 6 R 7 ) n OR 4 , —CN, —C(O)R 4 , —OC(O)R 4 , —O(CR 6 R 7 ) n R 4 , —NR 4 C(O)R 5 , —(CR 6 R 7 ) n C(O)OR 4 , —C(═NR 6 )NR 4 R 5 , —NR 4 C(O)NR 5 R 6 , —NR 4 S(O) p R 5 or —C(O)NR 4 R 5 , and each hydrogen in R 2 is optionally substituted by one or more R 8 groups;
each R 3 is independently selected from the group consisting of halogen, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-12 cycloalkyl, C 6-12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, —S(O) m R 4 , —SO 2 NR 4 R 5 , —S(O) 2 OR 4 , —NO 2 , —NR 4 R 5 , —(CR 6 R 7 ) n OR 4 , —CN, —C(O)R 4 , —OC(O)R 4 , —O(CR 6 R 7 ) n R 4 , —(CR 6 R 7 ) n C(O)OR 4 , —C(═NR 6 )NR 4 R 5 , —NR 4 C(O)NR 5 R 6 , and —NR 4 S(O) p R 5 , each hydrogen in R 3 is optionally substituted by one or more R 8 groups, and R 3 groups on adjacent atoms may combine to form a C 6-12 aryl, 5-12 membered heteroaryl, C 3-12 cycloalkyl or 3-12 membered heteroalicyclic group;
each R 4 , R 5 , R 6 and R 7 is independently hydrogen, halogen, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-12 cycloalkyl, C 6-12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl; or any two of R 4 , R 5 , R 6 and R 7 bound to the same nitrogen atom may, together with the nitrogen to which they are bound, be combined to form a 3 to 12 membered heteroalicyclic or 5-12membered heteroaryl group optionally containing 1 to 3 additional heteroatoms selected from N, O, and S; or any two of R 4 , R 5 , R 6 and R 7 bound to the same carbon atom may be combined to form a C 3-12 cycloalkyl, C 6-12 aryl, 3-12 membered heteroalicyclic or 5-12 membered heteroaryl group; and each hydrogen in R 4 , R 5 , R 6 and R 7 is optionally substituted by one or more R 8 groups;
each R 8 is independently halogen, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-12 cycloalkyl, C 6-12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, —CN, —O—C 1-12 alkyl, —O—(CH 2 ) n C 3-12 cycloalkyl, —O—(CH 2 ) n C 6-12 aryl, —O—(CH 2 ) n (3-12 membered heteroalicyclic) or —O—(CH 2 ) n (5-12 membered heteroaryl); and each hydrogen in R 8 is optionally substituted by one or more R 11 groups;
A 1 is —(CR 9 R 10 ) n -A 2 except that:
(i) when Y is N and R 1 is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, A 1 is —(CR 9 R 10 ) n -A 2 and n is not zero; and
(ii) when Y is N and R 2 is H and A 1 is m-chlorobenzyl, R 1 is not unsubstituted piperazine;
each R 9 and R 10 is independently hydrogen, halogen, C 1-12 alkyl, C 3-12 cycloalkyl, C 6-12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, —S(O) m R 4 , —SO 2 NR 4 R 5 , —S(O) 2 OR 4 , —NO 2 , —NR 4 R 5 , —(CR 6 R 7 ) n OR 4 , —CN, —C(O)R 4 , —OC(O)R 4 , —NR 4 C(O)R 5 , —(CR 6 R 7 ) n C(O)OR 4 , —NR 4 C(O)NR 5 R 6 , —NR 4 S(O) p R 5 or —C(O)NR 4 R 5 ; R 9 and R 10 combine to form a C 3-12 cycloalkyl, or 3-12 membered heteroalicyclic, ring; and each hydrogen in R 9 and R 10 is optionally substituted by one or more R 3 groups;
A 2 is C 6-12 aryl, 5-12 membered heteroaryl, C 3-12 cycloalkyl or 3-12 membered heteroalicyclic, and A 2 is optionally substituted by one or more R 3 groups;
each R 11 is independently halogen, C 1-12 alkyl, C 1-12 alkoxy, C 3-12 cycloalkyl, C 6-12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, —O—C 1-12 alkyl, —O—(CH 2 ) n C 3-12 cycloalkyl, —O—(CH 2 ) n C 6-12 aryl, —O—(CH 2 ) n (3-12 membered heteroalicyclic), —O—(CH 2 ) n (5-12 membered heteroaryl) or —CN, and each hydrogen in R 11 is optionally substituted by one or more groups selected from halogen, —OH, —CN, —C 1-12 alkyl which may be partially or fully halogenated, —O—C 1-12 alkyl which may be partially or fully halogenated, —CO, —SO and —SO 2 ;
m is 0, 1 or 2;
n is 0, 1, 2, 3 or 4; and
p is 1 or 2;
wherein 3-12 membered heteroalicyclic group is selected from pyrroline, pyrrolidine, dioxolane, imidazoline, imidazolidine, pyrazoline, pyrazolidine, pyran, piperidine, dioxane, morpholine, dithiane, thiomorpholine, piperazine and trithiane and 5-12 membered heteroaryl group is selected from furan, thiophene, pyrrole, oxazole, thiazole, imidazole, pyrazole, isoxazole, isothiazole, oxadiazole, triazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine and triazine;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , wherein the compound has formula
wherein A 2 is C 6-12 aryl or 5-12 membered heteroaryl optionally substituted by one or more R 3 groups.
3. The compound of claim 2 , wherein R 1 is selected from C 6-12 aryl and 5-12 membered heteroaryl, and each hydrogen in R 1 is optionally substituted by one or more R 3 groups.
4. The compound of claim 2 , wherein R 1 is selected from C 3-12 cycloalkyl, 3-12 membered heteroalicyclic, —O(CR 6 R 7 ) n R 4 , —C(O)R 4 , —C(O)OR 4 , —CN, —NO 2 , —S(O) m R 4 , —SO 2 NR 4 R 5 , —C(O)NR 4 R 5 , —C(═NR 6 )NR 4 R 5 , C 1-8 alkyl, C 2-8 alkenyl, and C 2-8 alkynyl; and each hydrogen in R 1 is optionally substituted by one or more R 3 groups.
5. The compound of claim 2 , wherein A 2 is substituted by at least one halogen atom.
6. The compound of claim 2 , wherein R 2 is hydrogen, R 9 and R 10 are independently C 1-4 alkyl, and A 2 is phenyl substituted by at least one halogen atom.
7. The compound of claim 1 , wherein R 1 is a furan, thiopene, pyrrole, pyrroline, pyrrolidine, dioxolane, oxazole, thiazole, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyrazolidine, isoxazole, isothiazole, oxadiazole, triazole, thiadiazole, pyran, pyridine, piperidine, dioxane, morpholine, dithiane, thiomorpholine, pyridazine, pyrimidine, pyrazine, piperazine, triazine, trithiane or phenyl group, and each hydrogen in R 1 is optionally substituted by one or more R 3 groups.
8. The compound of claim 1 , wherein R 1 is a fused ring heteroaryl group, and each hydrogen in R 1 is optionally substituted by one or more R 3 groups.
9. The compound of claim 1 , wherein R 1 is a —SO 2 NR 4 R 5 group.
10. A compound of formula
wherein:
R 1 is selected from C 6-12 aryl, 5-12 membered heteroaryl, C 3-12 cycloalkyl, 3-12 membered heteroalicyclic, —O(CR 6 R 7 ) n R 4 , —C(O)R 4 , —C(O)OR 4 , —CN, —NO 2 , —S(O) m R 4 , —SO 2 NR 4 R 5 , —C(O)NR 4 R 5 , —C(═NR 6 )NR 4 R 5 , C 1-8 alkyl, C 2-8 alkenyl, and C 2-8 alkynyl; and each hydrogen in R 1 is optionally substituted by one or more R 3 groups;
R 3 is independently selected from the group consisting of halogen, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-12 cycloalkyl, C 6-12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, —S(O) m R 4 , —SO 2 NR 4 R 5 , —S(O) 2 OR 4 , —NO 2 , —NR 4 R 5 , —(CR 6 R 7 ) n OR 4 , —CN, —C(O)R 4 , —OC(O)R 4 , —O(CR 6 R 7 ) n R 4 , —(CR 6 R 7 ) n C(O)OR 4 , —C(═NR 6 )NR 4 R 5 , —NR 4 C(O)NR 5 R 6 , and —NR 4 S(O) p R 5 , each hydrogen in R 3 is optionally substituted by one or more R 8 groups, and R 3 groups on adjacent atoms may combine to form a C 6-12 aryl, 5-12 membered heteroaryl, C 3-12 cycloalkyl or 3-12 membered heteroalicyclic group;
each R 4 , R 5 , R 6 and R 7 is independently hydrogen, halogen, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-12 cycloalkyl, C 6-12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl; or any two of R 4 , R 5 , R 6 and R 7 bound to the same nitrogen atom may, together with the nitrogen to which they are bound, be combined to form a 3 to 12 membered heteroalicyclic or 5-12membered heteroaryl group optionally containing 1 to 3 additional heteroatoms selected from N, O, and S; or any two of R 4 , R 5 , R 6 and R 7 bound to the same carbon atom may be combined to form a C 3-12 cycloalkyl, C 6-12 aryl, 3-12 membered heteroalicyclic or 5-12 membered heteroaryl group; and each hydrogen in R 4 , R 5 , R 6 and R 7 is optionally substituted by one or more R 8 groups;
each R 8 is independently halogen, C 1-12 alkyl, C 2-12 alkenyl, C 2-12 alkynyl, C 3-12 cycloalkyl, C 6-12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, —CN, —O—C 1-12 alkyl, —O—(CH 2 ) n C 3-12 cycloalkyl, —O—(CH 2 ) n C 6-12 aryl, —O—(CH 2 ) n (3-12 membered heteroalicyclic) or —O—(CH 2 ) n (5-12 membered heteroaryl); and each hydrogen in R 8 is optionally substituted by one or more R 11 groups;
each R 9 and R 10 is independently hydrogen, halogen, C 1-12 alkyl, C 3-12 cycloalkyl, C 6-12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, —S(O) m R 4 , —SO 2 NR 4 R 5 , —S(O) 2 OR 4 , —NO 2 , —NR 4 R 5 , —(CR 6 R 7 ) n OR 4 , —CN, —C(O)R 4 , —OC(O)R 4 , —NR 4 C(O)R 5 , —(CR 6 R 7 ) n C(O)OR 4 , —NR 4 C(O)NR 5 R 6 , —NR 4 S(O) p R 5 or —C(O)NR 4 R 5 ; R 9 and R 10 combine to form a C3-12 cycloalkyl, or 3-12 membered heteroalicyclic, ring; and each hydrogen in R 9 and R 10 is optionally substituted by one or more R 3 groups;
A 2 is C 6-12 aryl, 5-12 membered heteroaryl, C 3-12 cycloalkyl or 3-12 membered heteroalicyclic, and A 2 is optionally substituted by one or more R 3 groups; except that when R 2 ,R 9 and R 10 are all H and A 2 is m-chlorophenyl, R 1 is not unsubstituted piperazine;
each R 11 is independently halogen, C 1-12 alkyl, C 1-12 alkoxy, C 3-12 cycloalkyl, C 6-12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, —O—C 1-12 alkyl, —O—(CH 2 ) n C 3-12 cycloalkyl, —O—(CH 2 ) n C 6-12 aryl, —O—(CH 2 ) n (3-12 membered heteroalicyclic), —O—(CH 2 ) n (5-12 membered heteroaryl) or —CN, and each hydrogen in R 11 is optionally substituted by one or more groups selected from halogen, —OH, —CN, —C 1-12 alkyl which may be partially or fully halogenated, —O—C 1-12 alkyl which may be partially or fully halogenated, —CO, —SO and —SO 2 ;
m is 0, 1 or 2;
n is 0, 1, 2, 3 or 4; and
p is 1 or 2;
or a pharmaceutically acceptable salt thereof.
11. The compound of claim 10 , wherein A 2 is C 6-12 aryl or 5-12 membered heteroaryl optionally substituted by one or more R 3 groups.