1′-substituted pyrimidine N-nucleoside analogs for antiviral treatment

A compound of Formula I:

• or a pharmaceutically acceptable salt thereof;
• wherein:
• Base is a naturally occurring or modified pyrimidine base;
• R1 is H, CN, ORa, (C1-C4)alkyl, (C1-C4)substituted alkyl, (C2-C4)alkenyl, (C2-C4)substituted alkenyl, (C2-C4)alkynyl, (C2-C4)substituted alkynyl or S(O)nRa;
• R2 is H, ORa, N(Ra)2, N3, CN, NO2, S(O)nRa, (C1-C4)alkyl, (C4-C6)cycloalkylalkyl, (C1-C4)substituted alkyl, (C2-C4)alkenyl, (C2-C4)substituted alkenyl, (C2-C4)alkynyl, or (C2-C4)substituted alkynyl;
• or R1 and R2 taken together with the carbon to which they are attached form a 3- to 6-membered cycloalkyl ring wherein 1 to 3 carbon atoms of said cycloalkyl ring is optionally replaced by O or S(O)n;
• R3, R4, and R5 are each independently H, ORa, N(Ra)2, N3, CN, NO2, S(O)nRa, halogen, (C1-C4)alkyl, (C4-C8)cycloalkylalkyl, (C1-C4)substituted alkyl, (C2-C4)alkenyl, (C2-C4)substituted alkenyl, (C2-C4)alkynyl, or (C2-C4)substituted alkynyl;
• or any two of R3, R4 or R5 on adjacent carbon atoms when taken together are —O(CO)O— or when taken together with the ring carbon atoms to which they are attached to form a double bond;
• R6 is CN, 2-haloethen-1-yl, or (C2-C8)alkyn-1-yl,
• each n is independently 0, 1, or 2;
• each Ra is independently H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, aryl(C1-C8)alkyl, (C4-C8)cycloalkylalkyl, —C(═O)R11, —C(═O)OR11, —C(═O)NR11R12, —C(═O)SR11, —S(O)R11, —S(O)(OR11), —S(O)2(OR11), or —SO2NR11R12;
• R7 is H, —C(═O)OR11, —C(═O)NR11R12, —C(═O)SR11, —S(O)R11, —S(O)2R11, —S(O)(OR11), —S(O)2(OR11), —SO2NR11R12, or the group of Formula Ia
• wherein
• Y is O, S, NR, +N(O)(R), N(OR), +N(O)(OR), or N—NR2;
• W1 and W2, when taken together, are —Y3(C(Ry)2)3Y3—;
• or one of W1 or W2 together with either R3 or R4 is —Y3— and the other of W1 or W2 is Formula Ib;
• or W1 and W2 are each, independently, a group of Formula Ib:
• wherein:
• each Y1 is independently 0, S, NR, +N(O)(R), N(OR), +N(O)(OR), or N—NR2;
• each Y2 is independently a bond, 0, CR2, NR, +N(O)(R), N(OR), +N(O)(OR), N—NR2, S, S—S, S(O), or S(O)2;
• each Y3 is independently 0, S, or NR;
• M2 is 0, 1, or 2;
• each Rx is a group of Formula Ic
• wherein:
• each M1a, M1c, and M1d is independently 0 or 1;
• M1b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
• each Ry is independently H, F, Cl, Br, I, —CN, —N3, —NO2, —OR, —C(R)2—O—C(R)3, —C(═Y1)R, —C(═Y1)R13, —C(═Y1)OR, —C(═Y1)N(R)2, —N(R)2, —N(R)3, —SR, —S(O)R, —S(O)2R, —S(O)2R13, —S(O)(OR), —S(O)2(OR), —OC(═Y1)R, —OC(═Y1)OR, —OC(═Y1)(N(R)2), —SC(═Y1)R, —SC(═Y1)OR, —SC(═Y1)(N(R)2), —N(R)C(═Y1)R, —N(R)C(═Y1)OR, —N(R)C(═Y1)N(R)2, —SO2NR2, (C1-C8) alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, C6-C20 aryl, C3-C20 cycloalkyl, (C2-C20) heterocyclyl, arylalkyl, or heteroarylalkyl,
• wherein each (C1-C8) alkyl, (C2-C8)alkenyl, (C2-C8) alkynyl, (C6-C20) aryl, (C3-C20) cycloalkyl, (C2-C20) heterocyclyl, arylalkyl, or heteroarylalkyl is optionally substituted with 1-3 R20 groups;
• or when taken together, two Ry groups on the same carbon atom form a cycloalkyl ring of 3 to 7 carbon atoms;
• each R is independently H, (C1-C8) alkyl, (C2-C8)alkenyl, (C2-C8) alkynyl, (C6-C20) aryl, (C3-C20) cycloalkyl, (C2-C20) heterocyclyl, or arylalkyl;
• R8 is H, (C1-C4) alkyl, or (C1-C4) substituted alkyl;
• each R11 or R12 is independently H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C4-C8)cycloalkylalkyl, (C3-C20)cycloalkyl, (C2-C20)heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —C(═O)(C1-C8)alkyl, —S(O)n(C1-C8)alkyl or aryl(C1-C8)alkyl;
• or R11 and R12 taken together with a nitrogen to which they are both attached form a 3- to 7-membered heterocyclic ring wherein any one carbon atom of said heterocyclic ring can optionally be replaced with —O—, —S— or —NH—;
• each R13 is independently a cycloalkyl or heterocyclyl optionally substituted with 1-3 R or R20 groups;
• each R20 is independently, halogen, CN, N3, N(R)2, OR, —SR, —S(O)R, —S(O)2R, —S(O)(OR), —S(O)2(OR), —C(═Y1)R, —C(═Y1)OR, or C(═Y1)N(R)2;
• wherein each alkyl, alkenyl, alkynyl, aryl or heteroaryl of each of R1, R2, R3, R4, R5, or R8 is, independently, optionally substituted with 1 to 3 halo, hydroxy, CN, N3, N(Ra)2 or ORa;
• and wherein 1 to 3 of the non-terminal carbon atoms of each said (C1-C8)alkyl may be optionally replaced with —O—, —S— or —NRa—;
• wherein each R11 or R12 is, independently, optionally substituted with 1 to 3 halo, hydroxy, CN, N3, NH2 or OH;
• and wherein 1 to 3 of the non-terminal carbon atoms of each said (C1-C8)alkyl may be optionally replaced with —O—, —S— or —NH—;
• with the following provisos:
• a) when R1, R3, and R5 are H, R2 and R4 are hydroxy, R6 is cyano and R7 and R8 are H, then Base is not uracil or thymine;
• b) when R1 and R4 are hydroxy, R2, R3, and R5 are H, R6 is cyano and R7 and R8 are H, then Base is not uracil or cytosine;
• c) when R1, R2, R3, and R5 are H, R4 is hydroxy, R6 is cyano and R7 and R8 are H, then Base is not uracil, cytosine, thymine or 5-iodo-uracil;
• d) when R5 is other than H, then R8 is H;
• e) when R1 is hydroxy, R2, R3, R5, and R8 are H, R6 is cyano, R4 is H or benzoyl, and R7 is H or benzoyl, then Base is not cytosine;
• f) when R1 is acetyl or hydroxy, R2, R3, R5, R7, and R8 are H, R4 is hydroxy or —OC(O)phenyl, then Base is not 2-oxo-4-hydroxypyrimidinyl;
• g) when R1 is acetoxy, R4 is benzoyloxy, R6 is cyano, R7 is benzoyl, and R2, R3, R5, and R8 are H, then base is not uracil;
• and
• h) at least one of R1, R2, R3, R4 and R5 is not H.