Substituted pyrimidinyl derivatives and methods of use

A compound of Formula II

• 202
• wherein Y and Z are N or CH, provided one of Y and Z is N and the other is CH;
• wherein R10 is selected from phenyl, and 5-10 membered heterocyclyl;
• wherein R10 is optionally substituted with 1-4 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, bromo, CF3, —OR12, —OC(O)R12, —NR12R12, —COOR2, —C(O)R12, —C(O)NR12R12, —SO2R12, —SO2NR12R12, —NR12C(O)NR12R12, —NR12C(O)R12, —NR(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 bicyclic substituent;
• 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 pharmaceutically acceptable derivatives thereof.

A compound of Formulas IIIa and IIIb

• 203
• wherein R10 is selected from phenyl and 5-10 membered heterocyclyl;
• wherein R10 is optionally substituted with 1-4 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, bromo, CF3, —OR12, —OC(O)R12, —NR12R12, —COOR2, —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, 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′

• 204
• wherein X is selected from S, O and NR;
• wherein R is selected from C1-3-alkoxycarbonyl-C1-3-alkyl-, —(CH2)0-4—Ra, —C2-4-alkenyl-Ra, and —C2-4-alkynyl-Ra;
• wherein Ra is independently selected from H, optionally substituted phenyl, optionally substituted 5-6-membered heterocyclyl, —ORb 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 quinolyl, isoquinolyl, purinyl, benzimidazolyl, benzthiazolyl, benzoxadiazolyl, benzothiadiazolyl, benzisoxazolyl, benzisothiazolyl, benzotriazolyl, indolizinyl, benzoxazolyl, pteridinyl, acridinyl, carbazolyl, indolinyl, imidazo[1,2-a]pyridinyl, benzofuryl, 1,1-dioxo-benzothienyl, benzthienyl, quinolizinyl, pyridyl, triazinyl, pyrazinyl, pyrimidinyl, pyridazinyl, phthalazinyl, naphthyridinyl, tetrazolyl, quinoxalinyl, quinazolinyl, cinnolinyl, dibenzofuryl, phenanthrolinyl, and perimidinyl, wherein R1 is optionally substituted with 1-4 substituents independently selected from R3;
• 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-C10alkenyl 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 R2 is not 4-amino-2-methylquinol-6-yl when R1 is 4-amino-2-methylquinol-6-yl and when X is NH;
• further provided R is not methyl when R1 is 1-methyl-5-benzimidazolyl and when R2 is 3-aminosulfonylphenyl.

A compound of Formula IV

• 205
• 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 substitutents 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, —NR12S2R12, —OC(O)NR12 R12, 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-C1-16-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 derivatives thereof.

A compound of Formula V

• 206
• 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;
• and pharmaceutically acceptable derivatives thereof;
• provided R10 is not 4-amino-2-methylquinol-6-yl when R” is 4-amino-2-methyl substitution.

A compound of Formula VI

• 207
• 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;
• and pharmaceutically acceptable derivatives thereof.