US 8,785,487 B2 · Hepatitis C virus inhibitors

Abstract

The present invention discloses compounds of Formula (I), and pharmaceutically acceptable salts, esters, or prodrugs thereof: Q-G-A-L-B—W (I), which inhibit RNA-containing virus, particularly the hepatitis C virus (HCV). Consequently, the compounds of the present invention interfere with the life cycle of the hepatitis C virus and are also useful as antiviral agents. The present invention further relates to pharmaceutical compositions comprising the aforementioned compounds for administration to a subject suffering from HCV infection. The invention also relates to methods of treating an HCV infection in a subject by administering a pharmaceutical composition comprising the compounds of the present invention.

A compound represented by Formula (I):

Q-G-A-L-B—W (I)
or a pharmaceutically acceptable salt thereof, wherein:
A and B are each independently absent or a monocyclic or polycyclic group independently selected from the group consisting of aryl, heteroaryl, heterocyclic, C3-C8 cycloalkyl, and C3-C8 cycloalkenyl, each optionally substituted;
L is absent or an aliphatic group;
wherein at least one of A, B and L is present;
W is
G is an optionally substituted 5-membered heteroaryl containing one or more nitrogen atoms, or an optionally substituted 5-membered heteroaryl fused to a mono- or bicyclic ring, wherein the mono- or bicyclic ring is aromatic or non-aromatic, wherein the mono- or bicyclic ring is attached to one of groups A, L and B and wherein the 5-membered heteroaryl contains one or more nitrogen atoms;
Q is hydrogen or
X1 is N;
X2 is N(R1);
R1 is hydrogen;
R11 at each occurence is independently hydrogen, halogen or optionally substituted C1-C4 alkyl;
Y at each occurence is independently C(O);
L1-L2-L3 is a linker selected from:
wherein RX is hydrogen, amino, hydroxy, protected amino or O(C1-C4alkyl);
RY is hydrogen or C1-C8 alkyl;
R3 and R4 are hydrogen;
R5 is hydrogen
Alternatively R3, R4 and R5 are taken together with the carbon atom and nitrogen atom to which they are attached to form
U is selected from C(R7)2 and C═C(R2)2;
R2 at each occurrence is independently hydrogen, halogen, optionally substituted C1-C4 alkyl, optionally substituted aryl, or optionally substituted heteroaryl;
R7 at each occurrence is independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, O(C1-C4 alkyl), S(C1-C4 alkyl), amino optionally substituted with one or two C1-C4 alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C1-C4 alkyl, and optionally substituted C3-C8 cycloalkyl;
Alternatively two geminal R7 groups are taken together with the carbon atom to which they are attached to form a spiro, optionally substituted 3- to 7-membered cyclic group selected from the group consisting of C3-C7 cycloalkyl, C3-C7 cycloalkenyl or 3- to 7-membered heterocyclic;
R7a and R7b at each occurrence are each independently selected from the group consisting of hydrogen, optionally substituted aryl, optionally substituted C1-C4 alkyl, and optionally substituted C3-C8 cycloalkyl;
Alternatively, CHR7a—U or CHR7b—U are taken together to form a group selected from CH═CH, fused and optionally substituted C3-C8 cycloalkyl, fused and optionally substituted aryl, or fused and optionally substituted heterocyclic;
and
R6 at each occurrence is independently selected from the group consisting of O(C1-C8 alkyl), amino, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, heterocyclic, aryl, and heteroaryl, each optionally substituted;
wherein heteroaryl refers to a mono- or polycyclic aromatic radical having one or more ring atom selected from S, O and N;
and the remaining ring atoms are carbon, wherein any N or S contained within the ring may be optionally oxidized;
“heterocyclic” refers to a non-aromatic ring or a bi- or tri-cyclic group fused system, where (i) each ring system contains at least one heteroatom independently selected from oxygen, sulfur and nitrogen, (ii) each ring system can be saturated or unsaturated (iii) the nitrogen and sulfur heteroatoms may optionally be oxidized, (iv) the nitrogen heteroatom may optionally be quaternized, (v) any of the above rings may be fused to an aromatic ring, and (vi) the remaining ring atoms are carbon atoms which may be optionally oxo-substituted;
and
“substituted” refers to substitution by independent replacement of one, two, or three or more of the hydrogen atoms with substituents selected from —F, —Cl, —Br, —I, —OH, protected hydroxy, —NO2, —N3, —CN, —NH2, protected amino, oxo, thioxo, —NH—C1-C12-alkyl, —NH—C2-C8-alkenyl, —NH—C2-C8-alkynyl, —NH—C3-C12-cycloalkyl, —NH-aryl, —NH-heteroaryl, -dialkylamino, -diarylamino, -diheteroarylamino, —O—C1-C12-alkyl, —O—C2-C8-alkenyl, —O—C2-C8-alkynyl, —O—C3-C12-cycloalkyl, —O-aryl, —O-heteroaryl, —C(O)—C1-C12-alkyl, —C(O)—C2-C8-alkenyl, —C(O)—C2-C8-alkynyl, —C(O)—C3-C12-cycloalkyl, —C(O)-aryl, —C(O)-heteroaryl, —CONH2, —CONH—C1-C12-alkyl, —CONH—C2-C8-alkenyl, —CONH—C2-C8-alkynyl, —CONH—C3-C12-cycloalkyl, —CONH-aryl, —CONH-heteroaryl, —OCO2—C1-C12-alkyl, —OCO2—C2-C8-alkenyl, —OCO2—C2-C8-alkynyl, —OCO2—C3-C12-cycloalkyl, —OCO2-aryl, —OCO2-heteroaryl, —CO2—C1-C12 alkyl, —CO2—C2-C8 alkenyl, —CO2—C2-C8 alkynyl, CO2—C3-C12-cycloalkyl, —CO2- aryl, CO2-heteroaryl, CO2-heterocyloalkyl, —OCONH2, —OCONH—C1-C12-alkyl, —OCONH—C2-C8-alkenyl, —OCONH—C2-C8-alkynyl, —OCONH—C3-C12-cycloalkyl, —OCONH-aryl, —OCONH-heteroaryl, —NHC(O)H, —NHC(O)—C1-C12-alkyl, —NHC(O)—C2-C8-alkenyl, —NHC(O)—C2-C8-alkynyl, —NHC(O)—C3-C12-cycloalkyl, —NHC(O)-aryl, —NHC(O)-heteroaryl, —NHCO2—C1-C12-alkyl, —NHCO2—C2-C8-alkenyl, —NHCO2—C2-C8-alkynyl, —NHCO2—C3-C12-cycloalkyl, —NHCO2-aryl, —NHCO2-heteroaryl, —NHC(O)NH2, —NHC(O)NH—C1-C12-alkyl, —NHC(O)NH—C2-C8-alkenyl, —NHC(O)NH—C2-C8-alkynyl, —NHC(O)NH—C3-C12-cycloalkyl, —NHC(O)NH-aryl, —NHC(O)NH-heteroaryl, NHC(S)NH2, —NHC(S)NH—C1-C12-alkyl, —NHC(S)NH—C2-C8-alkenyl, —NHC(S)NH—C2-C8-alkynyl, —NHC(S)NH—C3-C12-cycloalkyl, —NHC(S)NH-aryl, —NHC(S)NH-heteroaryl, —NHC(NH)NH2, —NHC(NH)NH—C1-C12-alkyl, —HC(NH)NH—C2-C8-alkenyl, —NHC(NH)NH—C2-C8-alkynyl, —NHC(NH)NH—C3-C12-cycloalkyl, —NHC(NH)NH-aryl, —NHC(NH)NH-heteroaryl, —NHC(NH)—C1-C12-alkyl, —NHC(NH)—C2-C8-alkenyl, —NHC(NH)—C2-C8-alkynyl, —NHC(NH)—C3-C12-cycloalkyl, —NHC(NH)-aryl, —NHC(NH)-heteroaryl, —C(NH)NH—C1-C12-alkyl, —C(NH)NH—C2-C8-alkenyl, —C(NH)NH—C2-C8-alkynyl, —C(NH)NH—C3-C12-cycloalkyl, —C(NH)NH-aryl, —C(NH)NH-heteroaryl, —S(O)—C1-C12-alkyl, —S(O)—C2-C8-alkenyl, —S(O)—C2-C8-alkynyl, —S(O)—C3-C12-cycloalkyl, —S(O)-aryl, —S(O)-heteroaryl, —SO2NH2, —SO2NH—C1-C12-alkyl, —SO2NH—C2-C8-alkenyl, —SO2NH—C2-C8-alkynyl, —SO2NH—C3-C12-cycloalkyl, —SO2NH-aryl, —SO2NH-heteroaryl, —NHSO2—C1-C12-alkyl, —NHSO2—C2-C8-alkenyl, —NHSO2—C2-C8-alkynyl, —NHSO2—C3-C12-cycloalkyl, —NHSO2-aryl, —NHSO2-heteroaryl, —CH2NH2, —CH2SO2CH3, -aryl, -arylalkyl, -heteroaryl, -heteroarylalkyl, —C3-C12-cycloalkyl, polyalkoxyalkyl, polyalkoxy, —methoxymethoxy, -methoxyethoxy, —SH, —S—C1-C12-alkyl, —S—C2-C8-alkenyl, —S—C2-C8-alkynyl, —S—C3-C12-cycloalkyl, —S-aryl, —S-heteroaryl, and methylthio-methyl.

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Hepatitis C virus inhibitors

Life of this patent

Hepatitis C virus inhibitors

Life of this patent

Abstract

Claims19