Certain amino-substituted monocycles as kinase modulators
View Patent ↗A composition comprises a compound of Formula 1: a pharmaceutically acceptable salt, hydrate, solvate, crystal form, diastereomer, prodrug, or mixture thereof, wherein W is a nitrogen-substituted 5- or 6-membered monocyclic ring. The compounds are of utility as modulators of kinase activity.
1. At least one chemical entity chosen from compounds of the formula:
and pharmaceutically acceptable salts thereof, wherein
R 1 is chosen from
benzyl, and
substituted benzyl chosen from mono-, di-, and tri-substituted benzyl wherein the substituents are independently chosen from
hydroxy,
nitro,
cyano,
amino,
halo,
(C 1 –C 6 )alkyl,
(C 1 –C 6 )perhaloalkyl,
(C 1 –C 6 )alkoxy,
(C 1 –C 6 )alkyloxy-(C 1 –C 6 )alkoxy,
mono-((C 1 –C 6 )alkyl)amino,
di((C 1 –C 6 )alkyl)amino,
mono-((C 1 –C 6 )alkyl)amino(C 1 –C 6 )alkyl,
di((C 1 –C 6 )alkyl)amino(C 1 –C 6 )alkyl,
amino(C 1 –C 6 )alkyl,
benzamido,
substituted benzamido chosen from mono-, di-, and tri-substituted benzamido and wherein the substituents are independently chosen from hydroxy, nitro, cyano, amino, halo, (C 1 –C 6 )alkyl, and (C 1 –C 6 )alkoxy,
benzenesulfonamido,
substituted benzenesulfonamido chosen from mono-, di-, and tri-substituted benzenesulfonamido wherein the substituents are independently chosen from hydroxy, nitro, cyano, amino, halo, (C 1 –C 6 )alkyl, (C 1 –C 6 )perhaloalkyl, and (C 1 –C 6 )alkoxy,
heteroaryl,
substituted heteroaryl chosen from mono-, di-, and trisubstituted heteroaryl wherein the substituents are independently chosen from hydroxy, nitro, cyano, amino, halo, (C 1 –C 6 )alkyl, (C 1 –C 6 )perhaloalkyl, (C 1 –C 6 )alkoxy, (C 1 –C 6 )alkyloxy-(C 1 –C 6 )alkoxy, mono-((C 1 –C 6 )alkyl)amino, di((C 1 –C 6 )alkyl)amino, mono-((C 1 –C 6 )alkyl)amino(C 1 –C 6 )alkyl, and di((C 1 –C 6 )alkyl)amino(C 1 –C 6 )alkyl,
benzylamino(C 1 –C 6 )alkyl,
dibenzylamino(C 1 –C 6 )alkyl,
substituted benzylamino(C 1 –C 6 )alkyl chosen from mono-, di-, and trisubstituted benzylamino(C 1 –C 6 )alkyl wherein the substituents on the benzyl are independently chosen from hydroxy, nitro, cyano, amino, and halo,
substituted dibenzylamino(C 1 –C 6 )alkyl chosen from mono-, di-, and trisubstituted dibenzylamino(C 1 – 06 )alkyl wherein the substituents on the benzyl are independently chosen from hydroxy, nitro, cyano, amino, and halo,
amino(C 1 –C 6 )alkyl, and
heteroaryl linked to the benzyl by a group chosen from ether, sulfide, (C 1 –C 3 )carbonyl, and secondary amino;
R 2 is chosen from phenyloxyphenyl, and
substituted phenyloxyphenyl chosen from mono-, di-, and tri-substituted phenyloxyphenyl wherein the substituents are independently chosen from hydroxy, nitro, cyano, amino, halo, sulfonamido, (C 1 –C 6 )alkyl, (C 1 –C 6 )perhaloalkyl, (C 1 –C 6 )alkoxy, (C 1 –C 6 )alkyloxy-(C 1 –C 6 )alkoxy, mono-((C 1 –C 6 )alkyl)amino, di((C 1 –C 6 )alkyl)amino, and amino(C 1 –C 6 )alkyl;
R 4 is chosen from
hydrogen,
straight chain (C 1 –C 6 )alkyl,
branched chain (C 3 –C 6 )alkyl,
phenyl,
substituted phenyl chosen from mono-, di-, and tri-substituted phenyl wherein the substituents are chosen from hydroxy, nitro, cyano, amino, halo, (C 1 –C 6 )alkyl, (C 1 –C 6 )perhaloalkyl, (C 1 –C 6 )alkoxy, (C 1 –C 6 )alkyloxy-(C 1 –C 6 )alkoxy, mono-((C 1 –C 6 )alkyl)amino, di((C 1 –C 6 )alkyl)amino, and amino(C 1 –C 6 )alkyl,
heteroaryl, and
substituted heteroaryl chosen from mono-, di-, and tri-substituted heteroaryl wherein the substituents are chosen from hydroxy, nitro, cyano, amino, halo, (C 1 – 6 )alkyl, (C 1 –C 6 )alkoxy, (C 1 –C 6 )alkyloxy-(C 1 –C 6 )alkoxy, mono-((C 1 –C 6 )alkyl)amino, di((C 1 –C 6 )alkyl)amino, and amino(C 1 –C 6 )alkyl; and
R 11 and R 12 are independently chosen from
hydrogen,
straight chain (C 1 –C 7 )alkyl,
branched chain (C 3 –C 7 )alkyl, in which the branched alkyl chains are allowed to also form a 3–7 membered ring chosen from heterocycloalkyl and cycloalkyl rings,
(cyclo(C 3 –C 6 )alkyl)methyl,
(C 1 –C 6 )perhaloalkyl,
sulfonamido,
mono-((C 1 –C 6 )alkyl)amino,
di((C 1 –C 6 )alkyl)amino,
mono-((C 1 –C 6 )alkyl)amino(C 1 –C 6 alkyl),
di((C 1 –C 6 )alkyl)amino(C 1 –C 6 alkyl),
phenyl,
substituted phenyl chosen from mono-, di-, and tri-substituted phenyl wherein the substituents are chosen from hydroxy, nitro, cyano, amino, halo, (C 1 –C 6 )alkyl, (C 1 –C 6 )perhaloalkyl, (C 1 –C 6 )alkoxy, (C 1 –C 6 )alkyloxy-(C 1 –C 6 )alkoxy, mono-((C 1 –C 6 )alkyl)amino, di((C 1 –C 6 )alkyl)amino, mono-((C 1 –C 6 )alkyl)amino(C 1 –C 6 )alkyl, di((C 1 –C 6 )alkyl)amino(C 1 –C 6 )alkyl, and amino((C 1 –C 6 )alkyl),
benzyl,
substituted benzyl chosen from mono-, di-, and tri-substituted benzyl wherein the substituents are chosen from hydroxy, nitro, cyano, amino, halo, (C 1 –C 6 )alkyl, (C 1 –C 6 )perhaloalkyl, (C 1 –C 6 )alkoxy, (C 1 –C 6 )alkyloxy-(C 1 –C 6 )alkoxy, mono-((C 1 –C 6 )alkyl)amino, di((C 1 –C 6 )alkyl)amino, mono-((C 1 –C 6 )alkyl)amino(C 1 –C 6 )alkyl, di((C 1 –C 6 )alkyl)amino(C 1–C 6 )alkyl, and amino((C 1 –C 6 )alkyl),
heteroaryl,
substituted heteroaryl chosen from mono-, di-, and tri-substituted heteroaryl wherein the substituents are chosen from hydroxy, nitro, cyano, amino, halo, (C 1 –C 6 )alkyl, (C 1 –C 6 )perhaloalkyl, (C 1 –C 6 )alkoxy, (C 1 –C 6 )alkyloxy-(C 1 –C 6 )alkoxy, mono-((C 1 –C 6 )alkyl)amino, di((C 1 –C 6 )alkyl)amino, mono-((C 1 –C 6 )alkyl)amino(C 1 –C 6 )alkyl, di((C 1 –C 6 )alkyl)amino(C 1 –C 6 )alkyl, and amino((C 1 –C 6 )alkyl),
heteroaryloxyphenyl,
substituted heteroaryloxyphenyl chosen from mono-, di-, and tri-substituted heteroaryloxyphenyl wherein the substituents are independently chosen from hydroxy, nitro, cyano, amino, halo, sulfonamido, (C 1 –C 6 )alkyl, (C 1 –C 6 )perhaloalkyl, (C 1 –C 6 )alkoxy, (C 1 –C 6 )alkyloxy-(C 1 –C 6 )alkoxy, mono-((C 1 –C 6 )alkyl)amino, di((C 1 –C 6 )alkyl)amino, and amino(C 1 –C 6 alkyl),
phenoxyphenyl,
substituted phenoxyphenyl chosen from mono-, di-, and tri-substituted phenoxyphenyl wherein the substituents are independently chosen from hydroxy, nitro, cyano, amino, halo, sulfonamido, (C 1 –C 6 )alkyl, (C 1 –C 6 )perhaloalkyl, (C 1 –C 6 )alkoxy, (CC 1 –C 6 )alkyloxy-(C 1 –C 6 )alkoxy, mono-((C 1 –C 6 )alkyl)amino, di((C 1 –C 6 )alkyl)amino, and amino(C 1 –C 6 alkyl),
phenyl-piperazinyl,
substituted phenyl-piperazinyl chosen from mono-, di-, and tri-substituted phenyl-piperazinyl wherein the substituents on the phenyl ring are independently chosen from hydroxy, nitro, cyano, amino, halo, sulfonamido, (C 1 –C 6 )alkyl, (C 1 –C 6 )perhaloalkyl, (C 1 –C 6 )alkoxy, (C 1 –C 6 )alkyloxy(C 1 –C 6 )alkoxy, mono-((C 1 –C 6 )alkyl)amino, di((C 1 –C 6 )alkyl)amino, mono-(C 1 –C 6 alkyl)amino(C 1 –C 6 alkyl), and di(C 1 –C 6 alkyl)amino(C 1 –C 6 alkyl),
heteroaryl-piperazinyl, and
substituted heteroaryl-piperazinyl chosen from mono-, di-, and tri-substituted heteroaryl-piperazinyl wherein the substituents on the heteroaryl ring are independently chosen from hydroxy, nitro, cyano, amino, halo, sulfonamido, (C 1 –C 6 )alkyl, (C 1 –C 6 )perhaloalkyl, (C 1 –C 6 )alkoxy, (C 1 –C 6 )alkyloxy(C 1 –C 6 )alkoxy, mono-((C 1 –C 6 )alkyl)amino, di((C 1 –C 6 )alkyl)amino, mono-(C 1 –C 6 alkyl)amino(C 1 –C 6 alkyl), and di(C 1 –C 6 alkyl)amino(C 1 –C 6 alkyl).
2. At least one chemical entity of claim 1 , wherein
R 11 and R 12 are independently chosen from
hydrogen,
straight chain (C 1 –C 7 )alkyl,
branched chain (C 3 –C 7 )alkyl, in which the branched alkyl chains are allowed to also form a 3 –7 member ring chosen from heterocycloalkyl and cycloalkyl rings;
phenyl,
benzyl,
heteroaryl,
substituted phenyl chosen from mono-, di-, and tri-substituted phenyl wherein the substituents are independently chosen from hydroxy, nitro, cyano, amino, halo, (C 1 –C 6 )alkyl, (C 1 –C 6 )perfluoroalkyl, and (C 1 –C 6 )alkoxy,
substituted benzyl chosen from mono-, di-, and tn-substituted benzyl wherein the substituents are independently chosen from hydroxy, nitro, cyano, amino, halo, (C 1 –C 6 )alkyl, (C 1 –C 6 )perfluoroalkyl, and (C 1 –C 6 )alkoxy,
substituted heteroaryl chosen from mono-, di-, and tri-substituted heteroaryl wherein the substituents are independently chosen from hydroxy, nitro, cyano, amino, halo, (C 1 –C 6 )alkyl, (C 1 –C 6 )perfluoroalkyl, and (C 1 –C 6 )alkoxy,
heteroaryloxyphenyl,
phenyloxyphenyl,
substituted heteroaryloxyphenyl chosen from mono-, di-, and tri-substituted heteroaryloxyphenyl wherein the substituents are independently chosen from hydroxy, nitro, cyano, amino, halo, sulfonamido, (C 1 –C 6 )alkyl, (C 1 –C 6 )perhaloalkyl, and (C 1 –C 6 )alkoxy, and
substituted phenyloxyphenyl chosen from mono-, di-, and tri-substituted phenyloxyphenyl wherein the substituents are independently chosen from hydroxy, nitro, cyano, amino, halo, sulfonamido, (C 1 –C 6 )alkyl, (C 1 –C 6 )perhaloalkyl, and (C 1 –C 6 )alkoxy.
3. At least one chemical entity of claim 1 , wherein R 4 is hydrogen.
4. At least one chemical entity chosen from N3-(2-methoxybenzyl)-5-(4-phenoxyphenyl)-pyrazine-2,3-diamine and pharmaceutically acceptable salts thereof.
5. A pharmaceutical composition comprising at least one chemical entity of claim 1 and at least one vehicle chosen from pharmaceutically acceptable carriers and excipients.
6. A pharmaceutical composition comprising at least one chemical entity of claim 4 and at least one vehicle chosen from pharmaceutically acceptable carriers and excipients.