Amino-substituted pyrimidinyl derivatives and methods of use

A compound of Formula II

• 35
• wherein R10 is selected from phenyl, and 5-10 membered heterocyclyl;
• wherein R10 is optionally substituted with 1-2 substituents selected from R11;
• wherein R11 is selected from C1-C4 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3-C6 cycloalkyl, C4-C6 cycloalkenyl, phenyl, 5-6 membered heterocyclyl, fluoro, chloro, CF3, —OR12, —OC(O)R12, —NR12R12, —COOR2, —C(O)R12, —C(O)NR12R12, —SO2R12, —SO2NR12R12, —NR12C(O)NR12R12, —NR12C(O)R2, —NR12(COOR12), —NR12SO2NR12R12, —NR12SO2R12, —OC(O)NR12R12, C1-C3 alkyl substituted with 1-3 substituents independently selected from optionally substituted phenyl and optionally substituted 5-6 membered heterocyclyl;
• and
• C2-C3 alkenyl substituted with 1-3 substituents independently selected from optionally substituted phenyl and optionally substituted 5-6 membered heterocyclyl;
• wherein R12 is selected from H, C1-6-alkyl, and phenyl optionally substituted with 1-3 substituents independently selected from C1-4-alkyl, chloro, fluoro, —CF3, hydroxy, C1-4-alkoxy, amino, C1-4-alkylamino, carboxy, C1-4-alkoxycarbonyl, nitro, cyano , C1-4-alkylcarbonyl, C1-4-alkylaminocarbonyl, aminocarbonyl, aminosulfonyl and acetyl;
• and pharmaceutically acceptable derivative thereof.

A compound of Formula III

• 36
• wherein R10 is selected from phenyl, and 5-10 membered heterocyclyl;
• wherein R10 is optionally substituted with 1-2 substituents selected from R11;
• wherein R11 is selected from C1-C4 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3-C6 cycloalkyl, C4-C6 cycloalkenyl, phenyl, 5-6 membered heterocyclyl, fluoro, chloro, CF3, —OR12, —OC(O)R12, NR12R12, —COOR2, —C(O)R12, —C(O)NR12R12, —SO2R12, —SO2NR12R12, —NR12C(O)NR12R12, —NR12C(O)R2, —NR12(COOR12), —NR12SO2NR12R12, —NR12SO2R12, —OC(O)NR12R12, C1-C3 alkyl substituted with 1-3 substituents independently selected from optionally substituted phenyl and optionally substituted 5-6 membered heterocyclyl;
• and
• C2-C3 alkenyl substituted with 1-3 substituents independently selected from optionally substituted phenyl and optionally substituted 5-6 membered heterocyclyl;
• wherein R12 is selected from H, C1-6-alkyl, and phenyl optionally substituted with 1-3 substituents independently selected from C1-4-alkyl, chloro, fluoro, CF3, hydroxy, C1-4-alkoxy, amino, C1-4-alkylamino, carboxy, C1-4-alkoxycarbonyl, nitro, cyano, C1-4-alkylcarbonyl, C1-4-alkylaminocarbonyl, aminocarbonyl, aminosulfonyl and acetyl;
• and pharmaceutically acceptable derivatives thereof.

A compound of Formula I′

• 37
• wherein R′ is heteroaryl containing at least one oxygen or sulfur heteroatom, wherein R1 is optionally substituted with 1-4 substituents
• wherein R2 is selected from R4 and aryl optionally substituted with 1-5 substituents independently selected from R3;
• wherein R3 is independently selected from
• H,
• C1-10-alkyl,
• C2-10-alkenyl,
• C2-10-alkynyl,
• C1-10-haloalkyl,
• C3-10-cycloalkyl,
• C4-10-cycloalkenyl,
• aryl,
• R4,
• halo,
• SR5,
• OR5,
• OC(O)R5,
• NR5R5,
• NR5R6,
• COOR5,
• nitro,
• cyano,
• C(O)R5,
• C(O)C(O)R5,
• C(O)NR5R5,
• S(O)nR5,
• S(O)nNR5R5,
• S(O)nNR5R6,
• NR5C(O)NR5R5,
• NR5C(O)C(O)R5,
• NR5C(O)R5,
• NR5(COOR5),
• NR5C(O)R4,
• NR5S(O)nNR5R5,
• NR5S(O)nR5,
• NR5S(O)nR4,
• NR5C(O)C(O)NR5R5,
• NR5C(O)C(O)NR5R6,
• C1-10-alkyl substituted with 1-3 substituents independently selected from aryl, R7 and R4;
• and
• C2-10-alkenyl substituted with 1-3 substituents independently selected from aryl, R7 and R4;
• wherein R4 is independently a 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic saturated, partially saturated or unsaturated ring system comprising 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms independently selected from O, N, or S, which may be saturated or unsaturated, and wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent independently selected from C1-10-alkyl, C2-10-alkenyl, C2-10-alkynyl, C3-10-cycloalkyl, C4-10-cycloalkenyl, halo, haloalkyl, sulfo, oxo, SR5, OR5, NR5R5, NR5R6, NR6R6, COOR5, nitro, cyano, S(O)nR5, S(O)nNR5R5, C(O)R5, C(O)NR5R5 and 6-membered heteroaryl optionally substituted with 1-3 substituents independently selected from R3;
• wherein R5 is independently selected from H, C1-10-alkyl, C2-10-alkenyl, C2-10-alkynyl, C3-10-cycloalkyl, C4-10-cycloalkenyl, R4, aryl optionally substituted with 1-3 substituents independently selected from R3,
• C1-C10 alkyl substituted with 1-3 substituents independently selected from aryl, R7 and R4;
• C3-C10 cycloalkyl substituted with 1-3 substituents independently selected from aryl, R7 and R4;
• and
• C2-C10 alkenyl substituted with 1-3 substituents independently selected from aryl, R7 and R4;
• wherein R6 is selected from —C(O)R5, —COOR5, —C(O)NR5R5 and —S(O)nR5;
• wherein R7 is independently halo, —CF3, —SR5, —OR5, —OC(O)R5, —NR5R5, —NR5R6, —NR6R6, —COOR5, —NO2, —CN, —C(O)R5, —OC(O)NR5R5, —C(O)NR5R5, —N(R5)C(O)R5, —N(R5)(COOR5) and —S(O)nNR5R5;
• and wherein n is 1 or 2;
• and pharmaceutically acceptable derivative thereof;
• provided R1 and R2 are not both 5-t-butyl-3-isoxazolyl.

A compound of Formula II′

• 38
• wherein R10 is selected from phenyl, and 5-10 membered heterocyclyl;
• wherein R10 is optionally substituted with 1-2 substituents selected from R11;
• wherein R11 is selected from C1-C4 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3-C10 cycloalkyl, C4-C6 cycloalkenyl, phenyl, 5-6 membered heterocyclyl, fluoro, chloro, CF3, —OC(O)R12, —NR12R12, —COOR2, —C(O)R12, —C(O)NR12R12, —SO2R12, —SO2NR12R12, —NR12C(O)NR12R12, —NR12C(O)R2, —NR12(COOR12), —NR12SO2NR12R12, —NR12SO2R12, —OC(O)NR12R12, —OR13, C1-C3 alkyl substituted with 1-3 substituents independently selected from optionally substituted phenyl and optionally substituted 5-6 membered heterocyclyl;
• and
• C2-C3 alkenyl substituted with 1-3 substituents independently selected from optionally substituted phenyl and optionally substituted 5-6 membered heterocyclyl;
• wherein R12 is selected from H, C1-6-alkyl, and phenyl optionally substituted with 1-3 substituents independently selected from C1-4-alkyl, chloro, fluoro, CF3, hydroxy, C1-4-alkoxy, amino, C1-4-alkylamino, carboxy, C1-4-alkoxycarbonyl, NO2, CN, C1-4-alkylcarbonyl, C1-4-alkylaminocarbonyl, aminocarbonyl, aminosulfonyl and acetyl;
• and
• wherein R13 is selected from H, C1-6-alkyl, amino-C1-6-alkyl, C1-6-alkylamino-C1-6-alkyl, aminocarbonyl-C1-6-alkyl, C1-6-alkylaminocarbonyl-C1-6-alkyl, and phenyl optionally substituted with 1-3 substituents independently selected from C1-4-alkyl, chloro, fluoro, CF3, hydroxy, C1-4-alkoxy, amino, C1-4-alkylamino, carboxy, C1-4-alkoxycarbonyl, NO2, CN, C1-4-alkylcarbonyl, C1-4-alkylaminocarbonyl, aminocarbonyl, aminosulfonyl and acetyl;
• and pharmaceutically acceptable salts thereof;
• provided R1 and R2 are not both 5-t-butyl-3-isoxazolyl.

A compound of Formula III′

• 39
• wherein R10 is selected from phenyl, and 5-10 membered heterocyclyl;
• wherein R10 is optionally substituted with 1-2 substituents selected from R11;
• wherein R11 is selected from C1-C4 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3-C10 cycloalkyl, C4-C6 cycloalkenyl, phenyl, 5-6 membered heterocyclyl, fluoro, chloro, CF3, —OC(O)R12, —NR12R12, —COOR2, —C(O)R12, —C(O)NR12R12, —SO2R12, —SO2NR12R12, —NR12C(O)NR12R12, —NR12C(O)R2, —NR12(COOR12), —NR12SO2NR12R12, —NR12SO2R12, —OC(O)NR12R12, —OR13, C1-C3 alkyl substituted with 1-3 substituents independently selected from optionally substituted phenyl and optionally substituted 5-6 membered heterocyclyl;
• and
• C2-C3 alkenyl substituted with 1-3 substituents independently selected from optionally substituted phenyl and optionally substituted 5-6 membered heterocyclyl;
• wherein R12 is selected from H, C1-6-alkyl, and phenyl optionally substituted with 1-3 substituents independently selected from C1-4-alkyl, chloro, fluoro, CF3, hydroxy, C1-4-alkoxy, amino, C1-4-alkylamino, carboxy, C1-4-alkoxycarbonyl, NO2, CN, C1-4-alkylcarbonyl, C1-4-alkylaminocarbonyl, aminocarbonyl, aminosulfonyl and acetyl;
• and
• wherein R13 is selected from H, C1-6-alkyl, amino-C1-6-alkyl, C1-6-alkylamino-C1-6-alkyl, aminocarbonyl-C1-6-alkyl, C1-6-alkylaminocarbonyl-C1-6-alkyl, and phenyl optionally substituted with 1-3 substituents independently selected from C1-4-alkyl, chloro, fluoro, CF3, hydroxy, C1-4-alkoxy, amino, C1-4-alkylamino, carboxy, C1-4-alkoxycarbonyl, NO2, CN, C1-4-alkylcarbonyl, C1-4-alkylaminocarbonyl, aminocarbonyl, aminosulfonyl and acetyl;
• and pharmaceutically acceptable salts thereof;
• provided R1 and R2 are not both 5-t-butyl-3-isoxazolyl.

A compound of Formula IV

• 40
• wherein R10 is selected from phenyl, and 5-10 membered heterocyclyl;
• wherein R10 is optionally substituted with 1-2 substituents selected from R11;
• wherein R11 is selected from C1-C4 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3-C10 cycloalkyl, C4-C6 cycloalkenyl, phenyl, 5-6 membered heterocyclyl, fluoro, chloro, CF3, —OC(O)R12, —NR12R12, —COOR2, —C(O)R12, —C(O)NR12R12, —SO2R12, —SO2NR12R12, —NR12C(O)NR12R12, —NR12C(O)R2, —NR12(COOR12), —NR12SO2NR12R1, —NR12SO2R12, —OC(O)NR12R12, —OR13, C1-C3 alkyl substituted with 1-3 substituents independently selected from optionally substituted phenyl and optionally substituted 5-6 membered heterocyclyl;
• and C2-C3 alkenyl substituted with 1-3 substituents independently selected from optionally substituted phenyl and optionally substituted 5-6 membered heterocyclyl;
• wherein R12 is selected from H, C1-6-alkyl, and phenyl optionally substituted with 1-3 substituents independently selected from C1-4-alkyl, chloro, fluoro, CF3, hydroxy, C1-4-alkoxy, amino, C1-4-alkylamino, carboxy, C1-4-alkoxycarbonyl, NO2, CN, C1-4-alkylcarbonyl, C1-4-alkylaminocarbonyl, aminocarbonyl, aminosulfonyl and acetyl;
• and
• wherein R13 is selected from H, C1-6-alkyl, amino-C1-6-alkyl, C1-6-alkylamino-C1-6-alkyl, aminocarbonyl-C1-6-alkyl, C1-6-alkylaminocarbonyl-C1-6-alkyl, and phenyl optionally substituted with 1-3 substituents independently selected from C1-4-alkyl, chloro, fluoro, CF3, hydroxy, C1-4-alkoxy, amino, C1-4-alkylamino, carboxy, C1-4-alkoxycarbonyl, NO2, CN, C1-4-alkylcarbonyl, C1-4-alkylaminocarbonyl, aminocarbonyl, aminosulfonyl and acetyl;
• and
• pharmaceutically acceptable salts thereof.