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Details for Patent: 8,106,197

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Details for Patent: 8,106,197

Title:Aminoheteroaryl compounds as protein kinase inhibitors
Abstract: 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. ##STR00001##
Inventor(s): Cui; Jingrong Jean (San Diego, CA), Bhumralkar; Dilip (San Diego, CA), Botrous; Iriny (San Diego, CA), Chu; Ji Yu (Fremont, CA), Funk; Lee A. (Oceanside, CA), Hanau; Cathleen Elizabeth (Chesterfield, MO), Harris; G. Davis (Chesterfield, MO), Jia; Lei (San Diego, CA), Johnson; Joanne (Guilderland, NY), Kolodziej; Stephen A. (Ballwin, MO), Kung; Pei-Pei (San Diego, CA), Li; Xiaoyuan (Sharon) (Los Altas, CA), Lin; Jason (Qishen) (San Diego, CA), Meng; Jerry Jialun (San Diego, CA), Nambu; Mitchell David (San Diego, CA), Nelson; Christopher G. (Fresno, CA), Pairish; Mason Alan (San Diego, CA), Shen; Hong (San Diego, CA), Tran-Dube; Michelle (La Jolla, CA), Walter; Allison (Rexford, NY), Zhang; Fang-Jie (Sunnyvale, CA), Zhang; Jennifer (Foster City, CA)
Assignee: Pfizer Inc. (New York, NY)
Filing Date:Nov 14, 2006
Application Number:11/598,765
Claims:1. A compound of formula ##STR01625## wherein: Y is N; R.sup.1 is selected from C.sub.6-12 aryl, 5-12 membered heteroaryl, C.sub.3-12 cycloalkyl, 3-12 membered heteroalicyclic, --O(CR.sup.6R.sup.7).sub.nR.sup.4, --C(O)R.sup.4, --C(O)OR.sup.4, --CN, --NO.sub.2, --S(O).sub.mR.sup.4, --SO.sub.2NR.sup.4R.sup.5, --C(O)NR.sup.4R.sup.5, --C(.dbd.NR.sup.6)NR.sup.4R.sup.5, C.sub.1-8 alkyl, C.sub.2-8 alkenyl, and C.sub.2-8 alkynyl; and each hydrogen in R.sup.1 is optionally substituted by one or more R.sup.3 groups; R.sup.2 is hydrogen, halogen, C.sub.1-12 alkyl, C.sub.2-12 alkenyl, C.sub.2-12 alkynyl, C.sub.3-12 cycloalkyl, C.sub.6-12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, --S(O).sub.mR.sup.4, --SO.sub.2NR.sup.4R.sup.5, --S(O).sub.2OR.sup.4, --NO.sub.2, --NR.sup.4R.sup.5, --(CR.sup.6R.sup.7).sub.nOR.sup.4, --CN, --C(O)R.sup.4, --OC(O)R.sup.4, --O(CR.sup.6R.sup.7).sub.nR.sup.4, --NR.sup.4C(O)R.sup.5, --(CR.sup.6R.sup.7).sub.nC(O)OR.sup.4, --C(.dbd.NR.sup.6)NR.sup.4R.sup.5, --NR.sup.4C(O)NR.sup.5R.sup.6, --NR.sup.4S(O).sub.pR.sup.5 or --C(O)NR.sup.4R.sup.5, and each hydrogen in R.sup.2 is optionally substituted by one or more R.sup.8 groups; each R.sup.3 is independently selected from the group consisting of halogen, C.sub.1-12 alkyl, C.sub.2-12 alkenyl, C.sub.2-12 alkynyl, C.sub.3-12 cycloalkyl, C.sub.6-12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, --S(O).sub.mR.sup.4, --SO.sub.2NR.sup.4R.sup.5, --S(O).sub.2OR.sup.4, --NO.sub.2, --NR.sup.4R.sup.5, --(CR.sup.6R.sup.7).sub.nOR.sup.4, --CN, --C(O)R.sup.4, --OC(O)R.sup.4, --O(CR.sup.6R.sup.7).sub.nR.sup.4, --(CR.sup.6R.sup.7).sub.nC(O)OR.sup.4, --C(.dbd.NR.sup.6)NR.sup.4R.sup.5, --NR.sup.4C(O)NR.sup.5R.sup.6, and --NR.sup.4S(O).sub.pR.sup.5, each hydrogen in R.sup.3 is optionally substituted by one or more R.sup.8 groups, and R.sup.3 groups on adjacent atoms may combine to form a C.sub.6-12 aryl, 5-12 membered heteroaryl, C.sub.3-12 cycloalkyl or 3-12 membered heteroalicyclic group; each R.sup.4, R.sup.5, R.sup.6 and R.sup.7 is independently hydrogen, halogen, C.sub.1-12 alkyl, C.sub.2-12 alkenyl, C.sub.2-12 alkynyl, C.sub.3-12 cycloalkyl, C.sub.6-12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl; or any two of R.sup.4, R.sup.5, R.sup.6 and R.sup.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.sup.4, R.sup.5, R.sup.6 and R.sup.7 bound to the same carbon atom may be combined to form a C.sub.3-12 cycloalkyl, C.sub.6-12 aryl, 3-12 membered heteroalicyclic or 5-12 membered heteroaryl group; and each hydrogen in R.sup.4, R.sup.5, R.sup.6 and R.sup.7 is optionally substituted by one or more R.sup.8 groups; each R.sup.8 is independently halogen, C.sub.1-12 alkyl, C.sub.2-12 alkenyl, C.sub.2-12 alkynyl, C.sub.3-12 cycloalkyl, C.sub.6-12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, --CN, --O--C.sub.1-12 alkyl, --O--(CH.sub.2).sub.nC.sub.3-12 cycloalkyl, --O--(CH.sub.2).sub.nC.sub.6-12 aryl, --O--(CH.sub.2).sub.n(3-12 membered heteroalicyclic) or --O--(CH.sub.2).sub.n(5-12 membered heteroaryl); and each hydrogen in R.sup.8 is optionally substituted by one or more R.sup.11 groups; A.sup.1 is --(CR.sup.9R.sup.10).sub.n-A.sup.2 except that: (i) when Y is N and R.sup.1 is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, A.sup.1 is --(CR.sup.9R.sup.10).sub.n-A.sup.2 and n is not zero; and (ii) when Y is N and R.sup.2 is H and A.sup.1 is m-chlorobenzyl, R.sup.1 is not unsubstituted piperazine; each R.sup.9 and R.sup.10 is independently hydrogen, halogen, C.sub.1-12 alkyl, C.sub.3-12 cycloalkyl, C.sub.6-12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, --S(O).sub.mR.sup.4, --SO.sub.2NR.sup.4R.sup.5, --S(O).sub.2OR.sup.4, --NO.sub.2, --NR.sup.4R.sup.5, --(CR.sup.6R.sup.7).sub.nOR.sup.4, --CN, --C(O)R.sup.4, --OC(O)R.sup.4, --NR.sup.4C(O)R.sup.5, --(CR.sup.6R.sup.7).sub.nC(O)OR.sup.4, --NR.sup.4C(O)NR.sup.5R.sup.6, --NR.sup.4S(O).sub.pR.sup.5 or --C(O)NR.sup.4R.sup.5; R.sup.9 and R.sup.10 combine to form a C.sub.3-12 cycloalkyl, or 3-12 membered heteroalicyclic, ring; and each hydrogen in R.sup.9 and R.sup.10 is optionally substituted by one or more R.sup.3 groups; A.sup.2 is C.sub.6-12 aryl, 5-12 membered heteroaryl, C.sub.3-12 cycloalkyl or 3-12 membered heteroalicyclic, and A.sup.2 is optionally substituted by one or more R.sup.3 groups; each R.sup.11 is independently halogen, C.sub.1-12 alkyl, C.sub.1-12 alkoxy, C.sub.3-12 cycloalkyl, C.sub.6-12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, --O--C.sub.1-12 alkyl, --O--(CH.sub.2).sub.nC.sub.3-12 cycloalkyl, --O--(CH.sub.2).sub.nC.sub.6-12 aryl, --O--(CH.sub.2).sub.n(3-12 membered heteroalicyclic), --O--(CH.sub.2).sub.n(5-12 membered heteroaryl) or --CN, and each hydrogen in R.sup.11 is optionally substituted by one or more groups selected from halogen, --OH, --CN, --C.sub.1-12 alkyl which may be partially or fully halogenated, --O--C.sub.1-12 alkyl which may be partially or fully halogenated, --CO, --SO and --SO.sub.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 ##STR01626## wherein A.sup.2 is C.sub.6-12 aryl or 5-12 membered heteroaryl optionally substituted by one or more R.sup.3 groups.

3. The compound of claim 2, wherein R.sup.1 is selected from C.sub.6-12 aryl and 5-12 membered heteroaryl, and each hydrogen in R.sup.1 is optionally substituted by one or more R.sup.3 groups.

4. The compound of claim 2, wherein R.sup.1 is selected from C.sub.3-12 cycloalkyl, 3-12 membered heteroalicyclic, --O(CR.sup.6R.sup.7).sub.nR.sup.4, --C(O)R.sup.4, --C(O)OR.sup.4, --CN, --NO.sub.2, --S(O).sub.mR.sup.4, --SO.sub.2NR.sup.4R.sup.5, --C(O)NR.sup.4R.sup.5, --C(.dbd.NR.sup.6)NR.sup.4R.sup.5, C.sub.1-8 alkyl, C.sub.2-8 alkenyl, and C.sub.2-8 alkynyl; and each hydrogen in R.sup.1 is optionally substituted by one or more R.sup.3 groups.

5. The compound of claim 2, wherein A.sup.2 is substituted by at least one halogen atom.

6. The compound of claim 2, wherein R.sup.2 is hydrogen, R.sup.9 and R.sup.10 are independently C.sub.1-4 alkyl, and A.sup.2 is phenyl substituted by at least one halogen atom.

7. The compound of claim 1, wherein R.sup.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.sup.1 is optionally substituted by one or more R.sup.3 groups.

8. The compound of claim 1, wherein R.sup.1 is a fused ring heteroaryl group, and each hydrogen in R.sup.1 is optionally substituted by one or more R.sup.3 groups.

9. The compound of claim 1, wherein R.sup.1 is a --SO.sub.2NR.sup.4R.sup.5 group.

10. A compound of formula ##STR01627## wherein: R.sup.1 is selected from C.sub.6-12 aryl, 5-12 membered heteroaryl, C.sub.3-12 cycloalkyl, 3-12 membered heteroalicyclic, --O(CR.sup.6R.sup.7).sub.nR.sup.4, --C(O)R.sup.4, --C(O)OR.sup.4, --CN, --NO.sub.2, --S(O).sub.mR.sup.4, --SO.sub.2NR.sup.4R.sup.5, --C(O)NR.sup.4R.sup.5, --C(.dbd.NR.sup.6)NR.sup.4R.sup.5, C.sub.1-8 alkyl, C.sub.2-8 alkenyl, and C.sub.2-8 alkynyl; and each hydrogen in R.sup.1 is optionally substituted by one or more R.sup.3 groups; R.sup.3 is independently selected from the group consisting of halogen, C.sub.1-12 alkyl, C.sub.2-12 alkenyl, C.sub.2-12 alkynyl, C.sub.3-12 cycloalkyl, C.sub.6-12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, --S(O).sub.mR.sup.4, --SO.sub.2NR.sup.4R.sup.5, --S(O).sub.2OR.sup.4, --NO.sub.2, --NR.sup.4R.sup.5, --(CR.sup.6R.sup.7).sub.nOR.sup.4, --CN, --C(O)R.sup.4, --OC(O)R.sup.4, --O(CR.sup.6R.sup.7).sub.nR.sup.4, --(CR.sup.6R.sup.7).sub.nC(O)OR.sup.4, --C(.dbd.NR.sup.6)NR.sup.4R.sup.5, --NR.sup.4C(O)NR.sup.5R.sup.6, and --NR.sup.4S(O).sub.pR.sup.5, each hydrogen in R.sup.3 is optionally substituted by one or more R.sup.8 groups, and R.sup.3 groups on adjacent atoms may combine to form a C.sub.6-12 aryl, 5-12 membered heteroaryl, C.sub.3-12 cycloalkyl or 3-12 membered heteroalicyclic group; each R.sup.4, R.sup.5, R.sup.6 and R.sup.7 is independently hydrogen, halogen, C.sub.1-12 alkyl, C.sub.2-12 alkenyl, C.sub.2-12 alkynyl, C.sub.3-12 cycloalkyl, C.sub.6-12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl; or any two of R.sup.4, R.sup.5, R.sup.6 and R.sup.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.sup.4, R.sup.5, R.sup.6 and R.sup.7 bound to the same carbon atom may be combined to form a C.sub.3-12 cycloalkyl, C.sub.6-12 aryl, 3-12 membered heteroalicyclic or 5-12 membered heteroaryl group; and each hydrogen in R.sup.4, R.sup.5, R.sup.6 and R.sup.7 is optionally substituted by one or more R.sup.8 groups; each R.sup.8 is independently halogen, C.sub.1-12 alkyl, C.sub.2-12 alkenyl, C.sub.2-12 alkynyl, C.sub.3-12 cycloalkyl, C.sub.6-12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, --CN, --O--C.sub.1-12 alkyl, --O--(CH.sub.2).sub.nC.sub.3-12 cycloalkyl, --O--(CH.sub.2).sub.nC.sub.6-12 aryl, --O--(CH.sub.2).sub.n(3-12 membered heteroalicyclic) or --O--(CH.sub.2).sub.n(5-12 membered heteroaryl); and each hydrogen in R.sup.8 is optionally substituted by one or more R.sup.11 groups; each R.sup.9 and R.sup.10 is independently hydrogen, halogen, C.sub.1-12 alkyl, C.sub.3-12 cycloalkyl, C.sub.6-12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, --S(O).sub.mR.sup.4, --SO.sub.2NR.sup.4R.sup.5, --S(O).sub.2OR.sup.4, --NO.sub.2, --NR.sup.4R.sup.5, --(CR.sup.6R.sup.7).sub.nOR.sup.4, --CN, --C(O)R.sup.4, --OC(O)R.sup.4, --NR.sup.4C(O)R.sup.5, --(CR.sup.6R.sup.7).sub.nC(O)OR.sup.4, --NR.sup.4C(O)NR.sup.5R.sup.6, --NR.sup.4S(O).sub.pR.sup.5 or --C(O)NR.sup.4R.sup.5; R.sup.9 and R.sup.10 combine to form a C3-12 cycloalkyl, or 3-12 membered heteroalicyclic, ring; and each hydrogen in R.sup.9 and R.sup.10 is optionally substituted by one or more R.sup.3 groups; A.sup.2 is C.sub.6-12 aryl, 5-12 membered heteroaryl, C.sub.3-12 cycloalkyl or 3-12 membered heteroalicyclic, and A.sup.2 is optionally substituted by one or more R.sup.3 groups; except that when R.sup.2,R.sup.9 and R.sup.10 are all H and A.sup.2 is m-chlorophenyl, R.sup.1 is not unsubstituted piperazine; each R.sup.11 is independently halogen, C.sub.1-12 alkyl, C.sub.1-12 alkoxy, C.sub.3-12 cycloalkyl, C.sub.6-12 aryl, 3-12 membered heteroalicyclic, 5-12 membered heteroaryl, --O--C.sub.1-12 alkyl, --O--(CH.sub.2).sub.nC.sub.3-12 cycloalkyl, --O--(CH.sub.2).sub.nC.sub.6-12 aryl, --O--(CH.sub.2).sub.n(3-12 membered heteroalicyclic), --O--(CH.sub.2).sub.n(5-12 membered heteroaryl) or --CN, and each hydrogen in R.sup.11 is optionally substituted by one or more groups selected from halogen, --OH, --CN, --C.sub.1-12 alkyl which may be partially or fully halogenated, --O--C.sub.1-12 alkyl which may be partially or fully halogenated, --CO, --SO and --SO.sub.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.sup.2 is C.sub.6-12 aryl or 5-12 membered heteroaryl optionally substituted by one or more R.sup.3 groups.
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