NOVEL P13K p110 INHIBITORS AND METHODS OF USE THEREOF

摘要

The invention includes compositions that regulated PI3K p110 delta and are useful as an anti-viral therapy. The invention includes a method of inhibiting p110 delta, a component of PI3K p110 delta signaling pathway, or any combination thereof in a cell as an anti-viral therapeutic approach for treating a viral infection, for example influenza. The invention includes a method of modulating PI3K p110 delta in a cell infected with a virus by contacting the cell with an effective amount of a composition comprising an inhibitor of PI3K p110 delta.

主权项

1. A compound of Formula (I), or a salt thereof:wherein in (I):R1 is selected from the group consisting of:
6-amine-9H-purin-9-yl, (9H-purin-6-yl)amino, wherein in (Ia), (Ib) and (Ic):
A1 is N(R8), O or S;A2 and A3 are independently C(R8) or N;each occurrence of A4 and A5 is independently selected from the group consisting of H, F, Cl, Br, I, —CF3, —CN, —NO2, -(L)m-OR8, -(L)m-SR9, -(L)m-S(═O)R9, -(L)m-S(═O)2R9, -(L)m-NHS(═O)2R9, -(L)m-C(═O)R9, -(L)m-OC(═O)R9, -(L)mCO2R8, -(L)m-OCO2R8, -(L)m-CH(R8)2, -(L)m-N(R8)2, -(L)m-C(═O)N(R8)2, -(L)m-OC(═O)N(R8)2, -(L)mNHC(═O)NH(R8), -(L)m-NHC(═O)R9, -(L)m-NHC(═O)OR9, -(L)m-C(OH)(R8)2, -(L)mC(NH2)(R8)2, —C1-C6 alkyl, —C1-C6 fluoroalkyl and —C1-C6 heteroalkyl; andA6 is —C(A4)═C(A5)-, —C(A4)═N—, —N═C(A4)-, —C(A4)═C(A5)-C(═O)— and —C(═O)—C(A4)═C(A5)-; ring A is a monocyclic or bicyclic aryl ring, or a monocyclic or bicyclic heteroaryl ring, wherein the aryl or heteroaryl ring is optionally substituted with 0-3 substituents selected from R3, with the proviso that the compound of formula (I) is not: each occurrence of R2 and R3 is independently selected from the group consisting of F, Cl, Br, I, —CF3, —CN, —NO2, -(L)m-OR8, -(L)m-SR9, -(L)m-S(═O)R9, -(L)m-S(═O)2R9, -(L)mNHS(═O)2R9, -(L)m-C(═O)R9, -(L)m-OC(═O)R9, -(L)mCO2R8, -(L)m-OCO2R8, -(L)m-CH(R8)2, -(L)m-N(R8)2, -(L)m-C(═O)N(R8)2, -(L)m-OC(═O)N(R8)2, -(L)m-NHC(═O)NH(R8), -(L)m-NHC(═O)R9, -(L)m-NHC(═O)OR9, -(L)m-C(OH)(R8)2, -(L)mC(NH2)(R8)2, —C1-C6 alkyl, —C1-C6 fluoroalkyl and —C1-C6 heteroalkyl; R4 is H, —C1-C6 alkyl, —C1-C6 fluoroalkyl or —C1-C6 heteroalkyl; each R8 is independently, at each occurrence, H, C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C10 cycloalkyl, C2-C10 heterocycloalkyl, aryl, heteroaryl, —C1-C4 alkyl-(C3-C10 cycloalkyl), —C1-C4 alkyl-(C2-C10 heterocycloalkyl), —C1-C4 alkyl-(aryl), or —C1-C4alkyl(heteroaryl), and wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl is optionally substituted with 0-5 substituents selected from R2; or two R8 groups attached to the same N or C atom are taken together with the N or C atom to which they are attached to form an optionally substituted C2-C10 heterocycloalkyl or C3-C10 heterocycloalkyl, wherein the ring optionally comprises a moiety selected from O, C═O, S(O)m, NR4S(O)m, NR4(C═O) or N—R4, and wherein the ring is optionally substituted with 0-5 substituents selected from R2; R9 is C1-C6 alkyl, C1-C6 fluoroalkyl, C1-C6 heteroalkyl, C3-C10 cycloalkyl, a C2-C10 heterocycloalkyl, aryl, heteroaryl, —C1-C4 alkyl-(C3-C10 cycloalkyl), —C1-C4 alkyl-(C2-C10 heterocycloalkyl), —C1-C4 alkyl-(aryl), or —C1-C4 alkyl-(heteroaryl), and wherein the alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring is optionally substituted with 0-5 substituents selected from R2; L is independently at each occurrence a bivalent radical selected from —(C1-C3alkylene)m-, —(C3-C7 cycloalkylene), —(C1-C3 alkylene)m-O—(C1-C3 alkylene)m-, or —(C1-C3alkylene)m-NH—(C1-C3 alkylene)m-; x is 0, 1, 2 or 3; and, each occurrence of m is independently 0, 1 or 2.