Compounds and methods for kinase modulation, and indications therefor

A compound having the chemical structure of Formula I,

• all salts, prodrugs, tautomers and isomers thereof,
• wherein:
• L1 is —O—, —S—, —S(O)—, or —S(O)2—;
• R1 is selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and -L-R3,
• R3 is selected from the group consisting of hydrogen, provided, however, that hydrogen is not bound to any of S(O), S(O)2, C(O) or C(S) of L, optionally substituted lower alkyl, optionally substituted lower alkenyl, provided, however, that when R3 is optionally substituted lower alkenyl, no alkene carbon thereof is bound to N, S, O, S(O), S(O)2, C(O) or C(S) of L, optionally substituted lower alkynyl, provided, however, that when R3 is optionally substituted lower alkynyl, no alkyne carbon thereof is bound to N, S, O, S(O), S(O)2, C(O) or C(S) of L, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
• R2 is selected from the group consisting of -Cy, -alk-Cy, -alk-X-(alk)b-Cy, -alk-NR4-(alk)b-Cy, -alk-C(X)-(alk)b-Cy, -alk-S(O)-(alk)h-Cy, -alk-S(O)2-(alk)b-Cy, -alk-OC(X)-(alk)b-Cy, -alk-C(X)O-(alk)b-Cy, -alk-C(X)NR4-(alk)b-Cy, -alk-S(O)2NR4-(alk)b-Cy, -alk-NR4C(X)-(alk)b-Cy, -alk-NR4S(O)2-(alk)b-Cy, -alk-NR4C(X)O-(alk)b-Cy, -alk-OC(X)NR4-(alk)b-Cy, -alk-NR4C(X)NR4-(alk)b-Cy, -alk-NR4S(O)2NR4-(alk)b-Cy, and C2-4 alkyl, wherein C2-4 alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, —OH, —NH2, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, and di-alkylamino;
• L at each occurrence is independently selected from the group consisting of -(alk), —X-(alk)b-, -(alk), —NR4-(alk)b-, -(alk)a-C(X)-(alk)b-, -(alk), —S(O)-(alk)b-, -(alk)-S(O)2-(alk)b-, -(alk), —OC(X)-(alk)b-, -(alk), —C(X)O-(alk)b-, -(alk), —C(X)NR4-(alk)b-, -(alk), —S(O)2NR4-(alk)b-, -(alk)-NR4C(X)-(alk)h-, -(alk)a-NR4S(O)2-(alk)b-, -(alk)a-NR4C(X)O-(alk)b-, -(alk)a-OC(X)NR4-(alk)b-, -(alk)a-NR4C(X)NR4-(alk)b-, and -(alk)a-NR4S(O)NR4-(alk)b-;
• a and b are independently 0 or 1;
• alk is C1-3 alkylene or C1-3 alkylene substituted with one or more substituents selected from the group consisting of fluoro, —OH, —NH2, lower alkyl, lower alkoxy, lower alkylthio, monoalkylamino, di-alkylamino, and —NR5R6, wherein lower alkyl or the alkyl chain(s) of lower alkoxy, lower alkylthio, mono-alkylamino or di-alkylamino are optionally substituted with one or more substituents selected from the group consisting of fluoro, —OH, —NH2, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino and cycloalkylamino, provided, however, that any substitution of the alkyl chain carbon bound to O of alkoxy, S of thioalkyl or N of mono- or di-alkylamino is fluoro;
• X is O or S;
• Cy is optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
• R4 at each occurrence is independently selected from the group consisting of hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
• and
• R5 and R6 combine with the nitrogen to which they are attached to form a 5-7 membered heterocycloalkyl optionally substituted with one or more substituents selected from the group consisting of fluoro, —OH, —NH2, lower alkyl fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, and fluoro substituted lower alkylthio;
• provided, however, that the compound is not