| 主权项 |
1. A method for prevention or treatment of malaria, comprising administering to a subject in need thereof a therapeutically effective amount of a compound and optionally in combination with one or more therapeutic agents, wherein the compound is of Formula 1a:or a pharmaceutically acceptable salt thereof; in which:
Ra is selected from —X3NR7R8, —X3OR8, —X3S(O)0-2R8, —X3C(O)NR7R8, and benzyl optionally substituted with 1 to 3 radicals independently selected from halo, C1-4alkyl, halo-substituted-C1-4alkyl, C1-4alkoxy and halo-substituted-C1-4alkoxy; wherein X3 is selected from a bond and C1-4alkylene; R1 is selected from —ORB, —C(O)OR13, —NR13R14, C6-10aryl and a saturated, unsaturated or partially unsaturated 4-9 member heterocyclic ring containing up to three nitrogens; wherein
R13 is selected from hydrogen, C1-6alkyl, halo-substituted-C1-6alkyl, hydroxy-substituted-C1-6alkyl, C6-10aryl-C0-4alkyl, C3-8cycloalkyl-C0-4alkyl, —X1NHC(O)R15, —X1C(NH)NHR15, —X1C(O)NHR15, —X1NHR15, —X1OR15, —C(O)R15 and —C(O)OR15; wherein X1 is selected from a bond and C1-4alkylene; R15 is selected from hydrogen, C1-6alkyl, halo-substituted-C1-6alkyl, and benzyl; andR14 is selected from hydrogen, C1-6alkyl and hydroxy-substituted-C1-6alkyl;any aryl or heterocyclic of R1 is optionally substituted with 1-3 radicals independently selected from halo, C1-6alkyl, halo-substituted-C1-6alkyl, C1-6alkoxy and halo-substituted-C1-6alkoxy;or R13 and R14 together with the nitrogen to which R13 and R14 are attached form a saturated, unsaturated or partially unsaturated 5-9 member heterocyclic ring containing up to three heteroatoms selected from N, NR30, S(O)0-2 and O; wherein R30 is selected from hydrogen and C1-6alkyl; wherein said heterocyclic form the combination of R13 and R14 is optionally substituted with 1 to 3 radicals independently selected from halo, hydroxy, C1-6alkyl, amino-substituted-C1-6alkyl and halo-substituted-C1-6alkyl; R2 is selected from hydrogen, C1-6alkyl, amino, C3-8cycloalkyl-C0-4alkyl, C6-10aryl-C0-4alkyl, halo-substituted-C1-6alkyl, hydroxy-substituted-C1-6alkyl and heterocyclyl-C0-4alkyl; wherein
said heterocyclyl is a saturated, unsaturated or partially unsaturated 5-9 member heterocyclic ring containing up to three heteroatoms selected from N, NR30, S(O)0-2 and O; wherein R30 is selected from hydrogen and C1-6alkyl;said C6-10aryl or heterocyclic of R2 is optionally substituted with 1 to 3 radicals independently selected from halo, hydroxy, cyano, nitro, —NHR17, —(CH2)0-2NHC(O)R17, C1-6alkyl, halo-substituted-C1-6alkyl, amino-substituted-C1-6alkyl and C1-6alkoxy; wherein R17 is selected from hydrogen and C1-6alkyl; R3 is selected from hydrogen, C1-6alkyl, C6-10aryl-C0-4alkyl, —X2C(O)OR16, —X2S(O)0-2R16, —X2OR16, —X2C(O)NHR16 and —X2NHC(O)R16; wherein
X2 is selected from a bond and C1-4alkylene; andR16 is selected from hydrogen, C1-6alkyl and C6-10aryl-C0-4alkyl; wherein-said aryl of R16 is optionally substituted with 1 to 3 radicals independently selected from halo, C1-6alkyl, halo-substituted-C1-6alkyl, C1-6alkoxy and halo-substituted-C1-6alkoxy; or R2 and R3 together with the carbon atom to which R2 and R3 are attached forms C3-8cycloalkyl; or R2 and R13 together with the atoms to which R2 and R13 are attached form a ring selected from C3-8cycloalkyl and a saturated, unsaturated or partially unsaturated 5-9 member mono or fused heterocyclic ring containing up to three heteroatoms or groups selected from N, C(O), NR30, S(O)0-2 and O; wherein R30 is selected from hydrogen and C1-6alkyl; wherein said heterocyclic form the combination of R2 and R13 is optionally substituted with 1 to 3 radicals independently selected from halo, hydroxy, C1-6alkyl and halo-substituted-C1-6alkyl; R4 is selected from hydrogen and C1-6alkyl; R5 is selected from hydrogen and C1-6alkyl; or R4 and R5 together with the carbon atom to which R4 and R5 are attached forms C3-8cycloalkyl; R6 is selected from C6-10aryl, C3-8cycloalkyl and a saturated, unsaturated or partially unsaturated 5-9 member mono or fused heterocyclic ring containing up to three heteroatoms or groups selected from N, C(O), NR30, S(O)0-2 and O; wherein R30 is selected from hydrogen and C1-6alkyl; wherein said aryl or heterocyclic of R6 is optionally substituted by 1 to 3 radicals independently selected from halo, hydroxy, C1-6alkyl and C1-6alkoxy; R7 is selected from hydrogen, methyl, ethyl and isopropyl; and R8 is selected from phenyl, benzyl, benzo[d][1,3]dioxol-5-yl, cyclobutyl, cyclopentyl, cycloheptyl, cyclohexyl, bicyclo[2.2.1]heptyl, tetrahydro-2H-pyranyl, pyridinyl, piperidinyl, piperazinyl, quinolinyl, pyrrolidinyl and pyrazolyl; wherein said phenyl, benzyl, benzo[d][1,3]dioxol-5-yl, cyclobutyl, cyclopentyl, cycloheptyl, cyclohexyl, bicyclo[2.2.1]heptyl, tetrahydro-2H-pyranyl, pyridinyl, piperidinyl, piperazinyl, quinolinyl, pyrrolidinyl or pyrazolyl of R8 is optionally substituted by 1 to 3 radicals independently selected from halo, cyano, methyl, ethyl, t-butyl, trifluoromethyl, trifluoromethoxy, dimethyl-amino, difluoromethoxy, carboxy, methoxy-carbonyl, methyl-sulfonyl-amino, methyl-sulfonyl, methyl-amino-carbonyl, phenyl, piperidinyl, piperidinyl-methyl, piperazinyl and piperazinyl-methyl; R9 is selected from hydrogen and C1-6alkyl; R10 is selected from hydrogen and C1-6alkyl; R11 is selected from hydrogen and C1-6alkyl; R12 is selected from hydrogen and C1-6alkyl; or R11 and R12 combine to form C(O). |
