Pyrrolopyrimidine derivatives and analogs and their use in the treatment and prevention of diseases

A method for treating a disease comprising administering to a subject in need thereof an effective amount of an EGFR kinase modulating compound corresponding to Formula (I):

• wherein:
• a. X1 is S or O;
• b. each of X2 and X3 is independently N, O, S, NR4, or CR6;
• c. R1 is —(CHR1a)z—R1b, where
• i. each R1a is independently H, (C1-C4)alkyl, F, (C1-C4)fluoroalkyl, (C1-C4)alkoxy, —C(O)OH, —C(O)—NH2, —C(O)—(C1-C4)alkyl, —C(O)—(C1-C4)fluoralkyl, —C(O)—(C1-C4)alkyl amine, —(C1-C4)alkylamine, —(C1-C4)dialkylamine, or —C(O)—(C1-C4)alkoxy,
• ii. z is 0, 1, 2, or 3, and
• iii. R1b is
• where each Ra is independently H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, —CN, -L1-OH, -L1-NH2, -L1-(C1-C4)alkyl, -L1-(C3-C6)cycloalkyl, -L1-(C1-C4)fluoroalkyl, -L1-(C1-C4)alkoxy, -L1-(C1-C4)alkylamine, -L1-(C1-C4)dialkylamine and -L1-phenyl, wherein L1 is a bond, —C(O)—, or —S(O)2—;
• or
• R1b is H, —(C1-C4)alkyl, an optionally substituted —(C3-C6)cycloalkyl, —(C1-C4)fluoroalkyl, or an optionally substituted 5-membered or 6-membered unsaturated heterocycle;
• d. R3 is H or L3-(CHR3a)x—R3b, where
• i. L3 is a bond, NH, O, or S,
• ii. R3a is H, (C1-C4)alkyl, F, (C1-C4)fluoroalkyl, (C1-C4)alkoxy, —(C1-C4)alkylamine, or —(C1-C4)dialkylamine,
• iii. x is 0, 1, 2, or 3, and
• iv. R3b is phenyl, optionally substituted with 1-2 substituents independently selected from the group consisting of halogen, —(C1-C4)alkyl, —(C1-C4)fluoroalkyl, —(C1-C4)alkoxy, —(C1-C4)alkylamine, and —(C1-C4)dialkylamine;
• e. R4 is H or —(CHR4a)y—R4b, where
• i. R4a is H, (C1-C4)alkyl, F, (C1-C4)fluoroalkyl, (C1-C4)alkoxy, —(C1-C4)alkylamine, or —(C1-C4)dialkylamine;
• ii. y is 0, 1, 2, or 3, and
• iii. R4b is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5-membered or 6-membered unsaturated heterocycle;
• or
• R4 and R5, taken together, form a 5- or 6-membered heterocyclic aromatic ring structure, optionally substituted with 1-2 moieties independently selected from the group consisting of halogen, —CN, —OH, —NH2, —(C1-C4)alkyl, —(C3-C6)cycloalkyl, —(C1-C4)fluoroalkyl, —(C1-C4)alkoxy, —(C1-C4)alkylamine, and —(C1-C4)dialkylamine;
• or
• when X2 is NR4 and X3 is CR6, R1 and R4, taken together, form a 5- or 6-membered aromatic heterocycle optionally substituted with 1-2 moieties independently selected from the group consisting of halogen, —CN, —OH, —NH2, —(C1-C4)alkyl, —(C3-C6)cycloalkyl, —(C1-C4)fluoroalkyl, —(C1-C4)alkoxy, —(C1-C4)alkylamine, and —(C1-C4)dialkylamine;
• or
• f. R5 is H or
• where each Rb is independently H, halogen, —CN, —OH, —NH2, —(C1-C4)alkyl, —(C3-C6)cycloalkyl, —(C1-C4)fluoroalkyl, —(C1-C4)alkoxy, —(C1-C4)alkylamine, —(C1-C4)dialkylamine, —C(O)OH, —C(O)—NH2, —C(O)—(C1-C4)alkyl, —C(O)—(C1-C4)fluoralkyl, —C(O)—(C1-C4)alkylamine, or —C(O)—(C1-C4)alkoxy;
• and
• g. R6 is H, heteroaryl, or phenyl, wherein the phenyl and the heteroaryl are optionally substituted with 1-2 moieties independently selected from the group consisting of halogen, —(C1-C4)alkyl, —(C1-C4)fluoroalkyl, —(C1-C4)alkoxy, —(C1-C4)alkylamine, and —(C1-C4)dialkylamine;
• or
• R6 and R5, taken together, form an aromatic carbocycle or heterocycle optionally substituted with 1-2 moieties independently selected from the group consisting of halogen, —CN, —OH, —NH2, —(C1-C4)alkyl, —(C3-C6)cycloalkyl, —(C1-C4)fluoroalkyl, —(C1-C4)alkoxy, —(C1-C4)alkylamine, and —(C1-C4)dialkylamine, or
• when X2 is CR6 and X3 is NR4, R6 and R1, taken together, form a 5- or 6-membered aromatic heterocycle optionally substituted with 1-2 moieties independently selected from the group consisting of halogen, —CN, —OH, —NH2, —(C1-C4)alkyl, —(C3-C6)cycloalkyl, —(C1-C4)fluoroalkyl, —(C1-C4)alkoxy, —(C1-C4)alkylamine, and —(C1-C4)dialkylamine;
• or a pharmaceutically acceptable salt, pharmaceutcaly acceptable N-oxide, pharmaceutically acitve metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof.

A method for treating a disease comprising administering to a subject in need thereof an effective amount of an epidermal growth factor receptor modulating compound corresponding to:

• wherein:
• a. X1I is or O;
• b. each of X2I and X3I is independently N, O, S, NR4I, or CR6I;
• c. R1I is —(CHR1aI)zI—R1bI, where
• i. each R1aI is independently H, halogen or a substituted or unsubstituted moiety selected from alkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, alkoxy, alkylamine, dialkylamine, —C(O)OH, —C(O)NH2, —C(O)-alkyl, —C(O)-haloalkyl, —C(O)-alkylamine, and —C(O)-alkoxy,
• ii. zI is 0, 1, 2, 3, or 4 and
• iii. R1bI is
• where each RaI is independently H, halogen, —CN, —OH, or a substituted or unsubstituted moiety selected from the group consisting of alkyl, alkoxy, haloalkyl, alkenyl, alkynyl, heteroalkyl, -L1-OH, -L1-NH2, -L1-alkyl, -L1-cycloalkyl, -L1-haloalkyl, -L1-alkoxy, -L1-alkylamine, -L1-dialkylamine and -L1-phenyl, wherein L1 is a bond, —C(O)—, or —S(O)2—;
• or
• R1bI is H, alkyl, or a substituted or unsubstituted moiety selected from cycloalkyl, haloalkyl, and heterocycle;
• d. R3I is H or L3I-(CHR3aI)x—R3bI, where
• i. L3I is a bond, NH, O, or S,
• ii. R3aI is H, alkyl, halogen, haloalkyl, alkoxy, alkylamine, or dialkylamine,
• iii. xI is 0, 1, 2, 3, or 4 and
• iv. R3bI is H or substituted or unsubstituted aryl or heteroaryl group;
• e. R4I is H or —(CHR4aI)yI—R4bI, where
• i. R4aI is H, alkyl, halogen, haloalkyl, alkoxy, alkylamine, or dialkylamine;
• ii. yI is 0, 1, 2, 3, or 4 and
• iii. R4bI is a substituted or unsubstituted moiety selected from alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl;
• or
• R4I and R5I, taken together, form a substituted or unsubstitued heteroaryl moiety;
• or
• when X1I is NR4I and X2I is CR6I, R1I and R4I, taken together, form a substituted or
• unsubstituted heterocycle;
• or
• f. R5I is H or
• where each RbI is independently H, halogen, —CN, —OH, —NH2, or a substituted or unsubstituted moiety selected from alkyl, cycloalkyl, haloalkyl, alkoxy, alkylamine, dialkylamine, —C(O)OH, —C(O)—NH2, —C(O)-alkyl, —C(O)-haloalkyl, —C(O)-alkylamine, and —C(O)-alkoxy;
• and
• g. R6I is H, substituted or unsubstituted heteroaryl, or substituted or unsubstituted aryl;
• or
• R6I and R5I, taken together, form a substituted or unsubstituted aryl or heteroaryl moiety, or
• when X1I is CR6I and X2I is NR4I, R6I and R1I, taken together, form a substituted or unsubstituted heterocycle;
• or a pharmaceutically acceptable salt, pharmaceutcaly acceptable N-oxide, pharmaceutically acitve metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof.