Substituted pyrimidinyl derivatives and methods of use

Compound of Formula I′

• wherein X is selected from O, NH and NR;
• wherein R is selected from methyl, optionally substituted phenyl, —(CH2)2-3—Ra, —C2-3-alkenyl-Ra, and —C2-3-alkynyl-Ra;
• wherein Ra is independently selected from H, optionally substituted phenyl, optionally substituted 5-6-membered heterocyclyl, and —NRbRb;
• wherein Rb is independently selected from H, C1-3 alkyl, optionally substituted phenyl, and optionally substituted 5-6-membered heterocyclyl;
• wherein R1 is selected from 3-quinolyl, wherein R1 is optionally substituted with 1-3 substituents independently selected from R3;
• wherein R2 is selected from R4 and aryl optionally substituted with 1-3 substituents independently selected from R3;
• wherein R3 is independently selected from H, halo, C1-3-alkyl, C2-3-alkenyl, C2-3-alkynyl, phenyl, hydroxy, C1-3-haloalkoxy, C1-3-alkoxy, —C(O)—C1-3-alkyl, and C1-3-haloalkyl;
• and
• wherein R4 is independently selected from 2,3-dihydro-indolyl, 1,3-benzodioxolyl, indolyl, 1,3-dioxo-isoindolyl, indazolyl, pyridyl, quinolyl, isoquinolyl, benzothiazolyl, 1,2,3-benzotriazolyl, benzimidazolyl, and pyridyl;
• wherein R4 is optionally substituted with hydroxy, C1-3-alkoxy, cyano, nitro, halo, C1-3-alkyl, di-C1-3-alkylamino, di-C1-3-alkylamino-C1-3-alkyl, di-C1-3-alkylamino-C1-3-alkoxy, C1-3-alkylcarbonyl, C1-3-alkoxycarbonyl, C1-3-alkylcarbonylamino, pyrrolidinylcarbonyl-C2-3-alkenyl, pyrrolidinylcarbonyl-C1-3-alkyl, pyrrolidinyl-C1-3-alkyl, C2-3-alkynyl, acetyl, C1-3-alkylcarbonyl-C1-3-alkyl, carboxy-C1-3-alkyl, (piperidinyl)-C1-3-alkoxy, (piperazinyl)-C1-3-alkoxy, 2-morpholinyl-C1-3-alkoxy, C1-3-haloalkyl, C1-3-haloalkoxy, aminocarbonyl, aminosulfonyl, C1-3-alkylaminosulfonyl, hydroxy-C1-3-alkylaminosulfonyl, (thiazolyl)aminosulfonyl, C1-4-alkylaminosulfonyl, C1-3-alkylcarbonylaminosulfonyl, C1-3-alkylsulfonyl, C1-3-alkoxycarbonyl-piperazinyl, morpholinyl, piperazinyl, C1-3-alkylpiperazinyl, and oxazolyl;
• or pharmaceutically acceptable salts thereof.

A compound of Formula IV

• wherein R10 is selected from phenyl, naphthyl, and 5-10 membered heterocyclyl;
• wherein R10 is optionally substituted with 1-4 substituents selected from R13;
• wherein R11 is one or more substituents selected from H, C1-C4 alkyl, C1-C4 haloalkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3-C6 cycloalkyl, C4-C6 cycloalkenyl, phenyl, 5-6 membered heterocyclyl, fluoro, chloro, bromo, CF3, —OR14, —OC(O)R12, —NR12R12, —COOR12, —C(O)R12, —C(O)NR12R12, —SO2R12, —SO2NR12R12, —NR12C(O)NR12R12, —NR12C(O)R12, —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 R11 can be attached in either ring of the quinolyl substituent;
• wherein R12 is selected from H, C1-6-alkyl, C1-6-haloalkyl, C1-C3 alkyl substituted with 1-3 substituents independently selected from optionally substituted phenyl and optionally substituted 5-6 membered heterocyclyl;
• wherein optionally substituted phenyl and optionally substituted 5-6 membered heterocyclyl are 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, phenyl, 5-6 membered heterocyclyl optionally substituted with one or more substituents selected from alkyl, C1-4-alkylaminocarbonyl, aminocarbonyl, aminosulfonyl, acetyl, phenyl, and 5-6 membered heterocyclyl optionally substituted with one or more substituents 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, phenyl, 5-6 membered heterocyclyl optionally substituted with one or more substituents selected from alkyl, C1-4-alkylaminocarbonyl, aminocarbonyl, aminosulfonyl, acetyl, phenyl, and 5-6 membered heterocyclyl;
• 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;
• wherein R13 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, bromo, CF3, —OR12, —OC(O)R12, —NR12R12, —COOR12, —C(O)R12, —C(O)NR12R12, —SO2R12, —SO2NR12R12, —NR12C(O)NR12R12, —NR12C(O)R12, —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;
• and
• wherein R14 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;
• or pharmaceutically acceptable derivatives thereof.

A compound of Formula V

• wherein R10 is selected from phenyl, naphthyl, and 5-10 membered heterocyclyl;
• wherein R10 is optionally substituted with 1-4 substituents selected from R13;
• wherein R11 is one or more substituents selected from H, C1-C4 alkyl, C1-C4 haloalkyl, C2-C3 alkenyl, C2-C3 alkynyl, C3-C6 cycloalkyl, C4-C6 cycloalkenyl, phenyl, 5-6 membered heterocyclyl, fluoro, chloro, bromo, CF3, —OR14, —OC(O)R12, —NR12R12, —COOR12, —C(O)R12, —C(O)NR12R12, —SO2R12, —SO2NR12R12, —NR12C(O)NR12R12, —NR12C(O)R12, —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 R11 can be attached in either ring of the quinolyl substituent;
• wherein R12 is selected from H, C1-6-alkyl, C1-6-haloalkyl, C1-C3 alkyl substituted with 1-3 substituents independently selected from optionally substituted phenyl and optionally substituted 5-6 membered heterocyclyl;
• wherein optionally substituted phenyl and optionally substituted 5-6 membered heterocyclyl are 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, phenyl, 5-6 membered heterocyclyl optionally substituted with one or more substituents selected from alkyl, C1-4-alkylaminocarbonyl, aminocarbonyl, aminosulfonyl, acetyl, phenyl, and 5-6 membered heterocyclyl optionally substituted with one or more substituents 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, phenyl, 5-6 membered heterocyclyl optionally substituted with one or more substituents selected from alkyl, C1-4-alkylaminocarbonyl, aminocarbonyl, aminosulfonyl, acetyl, phenyl, and 5-6 membered heterocyclyl;
• 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;
• wherein R13 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, bromo, CF3, —OR12, —OC(O)R12, —NR12R12, —COOR12, —C(O)R12, —C(O)NR12R12, —SO2R12, —SO2NR12R12, —NR12C(O)NR12R12, —NR12C(O)R12, —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;
• and
• wherein R14 is selected from H, C1-6-alkyl, amino-C1-6-alkyl, C1-6-alkylamino-C1-6-alkyl, aminocarbonyl-C1-6-alkyl, C1-6-alkylaminocarbonyl-C1-16-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;
• or pharmaceutically acceptable derivatives thereof;
• provided R10 is not 4-amino-2-methylquinol-6-yl when R11 is 4-amino-2-methyl substitution.