Pyrazolo[1,5-A]pyrimidines for antiviral treatment

摘要

The invention provides compounds of Formula I or Formula II:;
or a pharmaceutically acceptable salt or ester, thereof, as described herein. The compounds and compositions thereof are useful for treating Pneumovirinae virus infections. The compounds, compositions, and methods provided are particularly useful for the treatment of Human respiratory syncytial virus infections.

主权项

1. A compound of Formula I or Formula II: or a pharmaceutically acceptable salt, thereof;wherein:
A is —(C(R4)2)n— wherein any one C(R4)2 of said —(C(R4)2)n— may be optionally replaced with —O—, —S—, —S(O)p—, NH or NRa; n is 3, 4, 5 or 6; each p is 1 or 2; Ar is a monocyclic heterocyclyl group having 3 to 7 ring atoms or a bicyclic heterocyclyl group having 7 to 12 ring atoms, the monocyclic and bicyclic heterocyclyl groups having 1, 2, 3, or 4 hetero ring atoms selected from O, N, or S, or a C6-C20 aryl group, wherein the monocyclic heterocyclyl group having 3 to 7 ring atoms, the bicyclic heterocyclyl group having 7 to 12 ring atoms, or the C6-C20 aryl group is optionally substituted with 1 to 5 R6; X is —C(R13)(R14)—, —N(CH2R14)— or X is absent; Y is N or CR7; each R1, R2, R3, R4, R5, R6, R7 or R8 is independently H, oxo, OR11, NR11R12, NR11C(O)R11, NR11C(O)R11, NR11C(O)NR11R12, N3, CN, NO2, SR11, S(O)pRa, NR11S(O)pRa, —C(═O)R11, —C(═O)OR11, —C(═O)NR11R12, —C(═O)SR11, —S(O)p(OR11), —SO2NR11R12, —NR11S(O)p(OR11), —NR11SOpNR11R12, NR11C(═NR11)NR11R12, halogen, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, aryl(C1-C8)alkyl, C6-C20 aryl, (C3-C7)cycloalkyl, (C4-C8)carbocyclylalkyl, a monocyclic heterocyclyl group having 3 to 7 ring atoms, a bicyclic heterocyclyl group having 7 to 12 ring atoms, the monocyclic and bicyclic heterocyclyl groups having 1, 2, 3, or 4 hetero ring atoms selected from O, N, or S; two R4 on adjacent carbon atoms, when taken together, may form a double bond between the two carbons to which they are attached or may form a (C3-C7)cycloalkyl ring wherein one carbon atom of said (C3-C7)cycloalkyl ring may be optionally replaced by —O—, —S—, —S(O)p—, —NH— or —NRa—; four R4 on adjacent carbon atoms, when taken together, may form an optionally substituted C6 aryl ring; two R4 on the same carbon atom, when taken together, may form a (C3-C7)cycloalkyl ring wherein one carbon atom of said (C3-C7)cycloalkyl ring may be optionally replaced by —O—, —S—, —S(O)p—, —NH— or —NRa—; two R6 on adjacent carbon atoms, when taken together, may form a (C3-C7)cycloalkyl ring wherein one carbon atom of said (C3-C7)cycloalkyl ring may be optionally replaced by —O—, —S—, —S(O)p—, —NH— or —NRa—; any R6 adjacent to the obligate carbonyl group of said Ar, when taken together with R3, may form a bond or a—(C(R5)2)m— group wherein m is 1 or 2; any R6 adjacent to the obligate carbonyl group of said Ar, when taken together with R2, may form a bond; each Ra is independently (C1-C8)alkyl, (C1-C8)haloalkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, aryl(C1-C8)alkyl, C6-C20 aryl, (C3-C7)cycloalkyl, (C4-C8)carbocyclylalkyl, a monocyclic heterocyclyl group having 3 to 7 ring atoms, or a bicyclic heterocyclyl group having 7 to 12 ring atoms, the monocyclic and bicyclic heterocyclyl groups having 1, 2, 3, or 4 hetero ring atoms selected from O, N, or S, wherein any (C1-C8)alkyl, (C1-C8)haloalkyl, (C2-C8)alkenyl or (C2-C8)alkynyl of Ra is optionally substituted with one or more OH, NH2, CO2H, a monocyclic heterocyclyl group having 3 to 7 ring atoms, or a bicyclic heterocyclyl group having 7 to 12 ring atoms, the monocyclic and bicyclic heterocyclyl groups having 1, 2, 3, or 4 hetero ring atoms selected from O, N, or S, and wherein any aryl(C1-C8)alkyl, C6-C20 aryl, (C3-C7)cycloalkyl, (C4-C8)carbocyclylalkyl, monocyclic heterocyclyl group, or bicyclic heterocyclyl group of Ra is optionally substituted with one or more substituents selected from OH, NH2, CO2H, (C1-C8)alkyl, a monocyclic heterocyclyl group having 3 to 7 ring atoms, and a bicyclic heterocyclyl group having 7 to 12 ring atoms, the monocyclic and bicyclic heterocyclyl groups having 1, 2, 3, or 4 hetero ring atoms selected from O, N, or S; each R11 or R12 is independently H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, aryl(C1-C8)alkyl, C6-C20 aryl, (C3-C7)cycloalkyl, (C4-C8)carbocyclylalkyl, —C(═O)Ra, —S(O)pRa, aryl(C1-C8)alkyl, a monocyclic heterocyclyl group having 3 to 7 ring atoms, a bicyclic heterocyclyl group having 7 to 12 ring atoms, the monocyclic and bicyclic heterocyclyl groups having 1, 2, 3, or 4 hetero ring atoms selected from O, N, or S; 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—, —S(O)p—, —NH—, —NRa—or —C(O)—; R13 is H or (C1-C8)alkyl; R14 is H, (C1-C8)alkyl, NR11R12, NR11C(O)R11, NR11C(O)OR11, NR11C(O)NR11R12, NR11S(O)pRa, —NR11S(O)p(OR11) or NR11SOpNR11R12; and wherein each (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, aryl(C1-C8)alkyl, C6-C20 aryl, monocyclic heterocyclyl group having 3 to 7 ring atoms, bicyclic heterocyclyl group having 7 to 12 ring atoms, (C3-C7)cycloalkyl or (C4-C8)carbocyclylalkyl of each R1, R2, R3, R4, R5, R6, R7, R8, R11 or R12 is, independently, optionally substituted with one or more oxo, halogen, hydroxy, NH2, CN, N3, N(Ra)2, NHRa, SH, SRa, S(O)pRa, ORa, (C1-C8)alkyl, (C1-C8)haloalkyl, —C(O)Ra, —C(O)H, —C(═O)ORa, —C(═O)OH, —C(═O)N(Ra)2, —C(═O)NHRa, —C(═O)NH2, NHS(O)pRa, NRaS(O)pRa, NHC(O)Ra, NRaC(O)Ra, NHC(O)ORa, NRaC(O)ORa, NRaC(O)NHRa, NRaC(O)N(Ra)2, NRaC(O)NH2, NHC(O)NHRa, NHC(O)N(Ra)2, NHC(O)NH2, ═NH, ═NOH, ═NORa, NRaS(O)pNHRa, NRaS(O)pN(Ra)2, NRaS(O)pNH2, NHS(O)pNHRa, NHS(O)pN(Ra)2, NHS(O)pNH2, —OC(═O)Ra, —OP(O)(OH)2 or Ra.