US 2016/0235805 A1 · HCV PROTEASE INHIBITORS AND USES THEREOF

Abstract

The present invention provides compounds, pharmaceutically acceptable compositions thereof, and methods of using the same.

Claims28

Dependent claims

1-45. (canceled)

A method for treating an HCV protease-mediated disorder in a patient, comprising the step of administering to a patient in need thereof a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:
R1 and R1′ are independently hydrogen or optionally substituted C1-6 aliphatic, or R1 and R1′ are taken together to form an optionally substituted 3-7 membered carbocyclic ring;
R2a is —OH or —NHSO2R2;
R2 is —N(R)2 or an optionally substituted group selected from C3-7 cycloalkyl, a bridged bicyclic, 6-10 membered aryl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
each R is independently hydrogen, optionally substituted C1-6 aliphatic, or:
two R on the same nitrogen atom are taken together with the nitrogen to form a 4-7 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
R3 is a warhead group -L-Y, and -L-Y is selected from the following:
(a) L is a bivalent C2-8 straight or branched, hydrocarbon chain wherein L has at least one double bond and one or two methylene units of L are independently replaced by a functional group selected from —NRC(O)—, —C(O)NR—, —N(R)SO2—, —SO2N(R)—, —S(O)—, —SO2—, —OC(O)—, —C(O)O—, or —C(O)—, wherein at least one double bond is located in an alpha-beta position relative to the carbonyl, sulfoxide, or —SO2— functional group;
and Y is hydrogen or C1-6 aliphatic optionally substituted with oxo, halogen, NO2, or CN;
or
(b) L is a bivalent C2-8 straight or branched, hydrocarbon chain wherein L has at least one double bond and at least one methylene unit of L is replaced by a functional group selected from —C(O)—, —NRC(O)—, —C(O)NR—, —N(R)SO2—, —SO2N(R)—, —S(O)—, —SO2—, —OC(O)—, or —C(O)O—, wherein at least one double bond is located in an alpha-beta position relative to the carbonyl, sulfoxide, or —SO2— functional group, and one or two additional methylene units of L are optionally and independently replaced by cyclopropylene, —O—, —N(R)—, or —C(O)—;
and Y is hydrogen or C1-6 aliphatic optionally substituted with oxo, halogen, NO2, or CN;
or
(c) L is a bivalent C2-8 straight or branched, hydrocarbon chain wherein L has at least one double bond and at least one methylene unit of L is replaced by a functional group selected from —C(O)—, wherein at least one double bond is located in an alpha-beta position relative to the functional group, and one or two additional methylene units of L are optionally and independently replaced by cyclopropylene, —O—, —N(R)—, or —C(O)—;
and Y is hydrogen or C1-6 aliphatic optionally substituted with oxo, halogen, NO2, or CN;
or
(h) L is a bivalent C2-8 straight or branched, hydrocarbon chain wherein L has at least one alkylidenyl double bond and at least one methylene unit of L is replaced by a functional group selected from —C(O)—, —NRC(O)—, —C(O)NR—, —N(R)SO2—, —SO2N(R)—, —S(O)—, —SO2—, —OC(O)—, or —C(O)O—, wherein at least one double bond is located in an alpha-beta position relative to the carbonyl, sulfoxide, or —SO2— functional group, and one or two additional methylene units of L are optionally and independently replaced by cyclopropylene, —O—, —N(R)—, or —C(O)—;
and Y is hydrogen or C1-6 aliphatic optionally substituted with oxo, halogen, NO2, or CN;
or
(i) L is a bivalent C2-8 straight or branched, hydrocarbon chain wherein L has at least one triple bond and one or two methylene units of L are optionally and independently replaced by —NRC(O)—, —C(O)NR—, —N(R)SO2—, —SO2N(R)—, —S—, —S(O)—, —SO2—, —OC(O)—, or —C(O)O—, and Y is hydrogen or C1-6 aliphatic optionally substituted with oxo, halogen, NO2, or CN;
or
(k) L is a bivalent C2-8 straight or branched, hydrocarbon chain wherein one methylene unit of L is replaced by cyclopropylene and one or two additional methylene units of L are independently replaced by —NRC(O)—, —C(O)NR—, —N(R)SO2—, —SO2N(R)—, —S—, —S(O)—, —SO2—, —OC(O)—, or —C(O)O—;
and Y is C1-6 aliphatic substituted with oxo, halogen, NO2, or CN;
or
(l) L is a covalent bond and Y is selected from:
(i) —CH2F, —CH2Cl, —CH2CN, or —CH2NO2;
or
(ii) C2-6 alkenyl substituted with oxo, NO2, or CN, and optionally substituted with halogen;
or
(iii) C2-6 alkynyl optionally substituted with oxo, halogen, NO2, or CN;
or
(iv) a saturated 3-4 membered heterocyclic ring having 1 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-2 Re groups;
or
(v) a saturated 5-6 membered heterocyclic ring having 1-2 heteroatoms selected from oxygen or nitrogen wherein said ring is substituted with 1-4 Re groups;
or
(vii) a saturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 Re groups;
or
(viii) a partially unsaturated 3-6 membered monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
or
(ix) a partially unsaturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 Re groups;
or
(xi) a partially unsaturated 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
or
(xiii) a 6-membered aromatic ring having 0-2 nitrogens wherein said ring is substituted with 1-4 Re groups;
or
(xv) a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-3 Re groups;
or
(xvii) an 8-10 membered bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
(m) L is —C(O)— and Y is selected from:
(i) C1-6 alkyl substituted with oxo, halogen, NO2, or CN;
or
(ii) C2-6 alkenyl optionally substituted with oxo, halogen, NO2, or CN;
or
(iii) C2-6 alkynyl optionally substituted with oxo, halogen, NO2, or CN;
or
(iv) a saturated 3-4 membered heterocyclic ring having 1 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-2 Re groups;
or
(v) a saturated 5-6 membered heterocyclic ring having 1-2 heteroatoms selected from oxygen or nitrogen wherein said ring is substituted with 1-4 Re groups;
or
(vii) a saturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 Re groups;
or
(viii) a partially unsaturated 3-6 membered monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
or
(ix) a partially unsaturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 Re groups;
or
(xi) a partially unsaturated 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
or
(xiii) a 6-membered aromatic ring having 0-2 nitrogens wherein said ring is substituted with 1-4 Re groups;
or
(xv) a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-3 Re groups;
or
(xvii) an 8-10 membered bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
(n) L is —N(R)C(O)— and Y is selected from:
(i) C1-6 alkyl substituted with oxo, halogen, NO2, or CN;
or
(ii) C2-6 alkenyl optionally substituted with oxo, halogen, NO2, or CN;
or
(iii) C2-6 alkynyl optionally substituted with oxo, halogen, NO2, or CN;
or
(iv) a saturated 3-4 membered heterocyclic ring having 1 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-2 Re groups;
or
(v) a saturated 5-6 membered heterocyclic ring having 1-2 heteroatoms selected from oxygen or nitrogen wherein said ring is substituted with 1-4 Re groups;
or
(vii) a saturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 Re groups;
or
(viii) a partially unsaturated 3-6 membered monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
or
(ix) a partially unsaturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 Re groups;
or
(xi) a partially unsaturated 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
or
(xiii) a 6-membered aromatic ring having 0-2 nitrogens wherein said ring is substituted with 1-4 Re groups;
or
(xv) a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-3 Re groups;
or
(xvii) an 8-10 membered bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
(o) L is a bivalent C1-8 saturated or unsaturated, straight or branched, hydrocarbon chain;
and Y is selected from:
(i) —CH2F, —CH2Cl, —CH2CN, or —CH2NO2;
or
(ii) C2-6 alkenyl substituted with oxo, NO2, or CN, and optionally substituted with halogen;
or
(iii) C2-6 alkynyl optionally substituted with oxo, halogen, NO2, or CN;
or
(iv) a saturated 3-4 membered heterocyclic ring having 1 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-2 Re groups;
or
(v) a saturated 5-6 membered heterocyclic ring having 1-2 heteroatoms selected from oxygen or nitrogen wherein said ring is substituted with 1-4 Re groups;
or
(vii) a saturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 Re groups;
or
(viii) a partially unsaturated 3-6 membered monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
or
(ix) a partially unsaturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 Re groups;
or
(xi) a partially unsaturated 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
or
(xiii) a 6-membered aromatic ring having 0-2 nitrogens wherein said ring is substituted with 1-4 Re groups;
or
(xv) a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-3 Re groups;
or
(xvii) an 8-10 membered bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
(p) L is a covalent bond, —CH2—, —NH—, —C(O)—, —CH2NH—, —NHCH2—, —NHC(O)—, —NHC(O)CH2OC(O)—, —CH2NHC(O)—, —NHSO2—, —NHSO2CH2—, or —SO2NH—;
and Y is selected from:
(i) —CH2F, —CH2Cl, —CH2CN, or —CH2NO2;
or
(ii) C2-6 alkenyl substituted with oxo, NO2, or CN, and optionally substituted with halogen;
or
(iii) C2-6 alkynyl optionally substituted with oxo, halogen, NO2, or CN;
or
(iv) a saturated 3-4 membered heterocyclic ring having 1 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-2 Re groups;
or
(v) a saturated 5-6 membered heterocyclic ring having 1-2 heteroatoms selected from oxygen or nitrogen wherein said ring is substituted with 1-4 Re groups;
or
(vii) a saturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 Re groups;
or
(viii) a partially unsaturated 3-6 membered monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
or
(ix) a partially unsaturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 Re groups;
or
(xi) a partially unsaturated 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
or
(xiii) a 6-membered aromatic ring having 0-2 nitrogens wherein said ring is substituted with 1-4 Re groups;
or
(xv) a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-3 Re groups;
or
(xvii) an 8-10 membered bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
or
(q) -L-Y is selected from:
(r) L is a bivalent C2-8 straight or branched, hydrocarbon chain wherein L has at least one double bond and one or two methylene units of L are independently replaced by —NRC(O)—, —C(O)NR—, —N(R)SO2—, —SO2N(R)—, —S(O)—, —SO2—, —OC(O)—, —C(O)O—, cyclopropylene, —O—, —N(R)—, or —C(O)—;
and
Y is hydrogen, C1-6 aliphatic optionally substituted with oxo, halogen, NO2, or CN, or a 3-10 membered monocyclic or bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein said ring is substituted with 1-4 Re groups;
or
(s) L is a bivalent C2-8 straight or branched, hydrocarbon chain wherein L has at least one triple bond and one or two methylene units of L are optionally and independently replaced by —NRC(O)—, —C(O)NR—, —N(R)SO2—, —SO2N(R)—, —O—, —N(R)—, —C(O)—, —S—, —S(O)—, —SO2—, —OC(O)—, or —C(O)O—, and
Y is hydrogen, C1-6 aliphatic optionally substituted with oxo, halogen, NO2, or CN, or a 3-10 membered monocyclic or bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein said ring is substituted with 1-4 Re groups;
or
(t) L is a bivalent C2-8 straight or branched, hydrocarbon chain wherein one methylene unit of L is replaced by cyclopropylene and one or two additional methylene units of L are independently replaced by —NRC(O)—, —C(O)NR—, —N(R)SO2—, —SO2N(R)—, —S—, —O—, —N(R)—, —C(O)—, —S(O)—, —SO2—, —OC(O)—, or —C(O)O—, and
Y is C1-6 aliphatic substituted with oxo, halogen, NO2, or CN, or a 3-10 membered monocyclic or bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein said ring is substituted with 1-4 Re groups;
each Re is independently selected from -Q-Z, oxo, NO2, halogen, CN, a suitable leaving group selected from alkoxy, sulphonyloxy, optionally substituted alkylsulphonyloxy, optionally substituted alkenylsulfonyloxy, optionally substituted arylsulfonyloxy, acyl, and diazonium, or C1-6 aliphatic substituted with oxo, halogen, NO2, or CN, wherein:
Q is a bivalent C2-6 unsaturated, straight or branched, hydrocarbon chain, wherein one or two methylene units of Q are optionally and independently replaced by —N(R)—, —S—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —SO—, —SO2—, —N(R)C(O)—, —C(O)N(R)—, —N(R)SO2—, or —SO2N(R)—;
and
each Z is independently hydrogen or C1-6 aliphatic substituted with oxo, halogen, NO2, or CN, or:
R3 and R1 are taken together with their intervening atoms to form an optionally substituted 12-18 membered ring having 2-6 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein the ring formed thereby comprises the warhead group -L-Y;
or
R3 and a ring formed by R1 and R1′ are taken together with their intervening atoms to form an optionally substituted 12-18 membered ring having 2-6 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein the ring formed thereby comprises the warhead group -L-Y;
Rw is hydrogen or an optionally substituted group selected from C1-6 aliphatic, 6-10 membered aryl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur:
or
Rw and Rx are taken together to form an optionally substituted C3-7 membered ring having 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, or:
Rw and Ry are taken together to form an optionally substituted C3-7 membered ring having 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur;
Rx is -T-Rz, wherein:
T is a covalent bond or a C1-6 bivalent hydrocarbon chain wherein one or two methylene units of T are optionally and independently replaced by —O—, —S—, —N(R)—, —N(R)C(O)—, —C(O)N(R)—, —S(O)—, —S(O)2—, —N(R)SO2—, or —SO2N(R)—;
and
Rz is hydrogen or an optionally substituted group selected from a bridged bicyclic, or 5-membered monocyclic or bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
Rx′ is hydrogen, or Rx′ and Rx are taken together with their intervening atoms to form an optionally substituted spiro-fused 5-7 membered ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
Ry is hydrogen, or Rx and Ry are taken together to form an optionally substituted C3-7 membered ring having 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur;
R4 is H, —NHC(O)R5, —NHC(O)OR6,
or a natural or unnatural amino acid side-chain group;
each R5 is independently —N(R)2 or an optionally substituted group selected from C1-6 aliphatic, a bridged bicyclic, 6-10 membered aryl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
R6 is an optionally substituted group selected from C1-6 aliphatic, a bridged bicyclic, 6-10 membered aryl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
and
R7 is an optionally substituted group selected from C1-6 aliphatic, a bridged bicyclic, 6-10 membered aryl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

177 more elements

A method for inhibiting HCV protease, or a mutant thereof, activity in a patient comprising the step of administering to a patient in need thereof a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:
R1 and R1′ are independently hydrogen or optionally substituted C1-6 aliphatic, or R1 and R1′ are taken together to form an optionally substituted 3-7 membered carbocyclic ring;
R2a is —OH or —NHSO2R2;
R2 is —N(R)2 or an optionally substituted group selected from C3-7 cycloalkyl, a bridged bicyclic, 6-10 membered aryl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
each R is independently hydrogen, optionally substituted C1-6 aliphatic, or:
two R on the same nitrogen atom are taken together with the nitrogen to form a 4-7 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
R3 is a warhead group -L-Y, and -L-Y is selected from the following:
(a) L is a bivalent C2-8 straight or branched, hydrocarbon chain wherein L has at least one double bond and one or two methylene units of L are independently replaced by a functional group selected from —NRC(O)—, —C(O)NR—, —N(R)SO2—, —SO2N(R)—, —S(O)—, —SO2—, —OC(O)—, —C(O)O—, or —C(O)—, wherein at least one double bond is located in an alpha-beta position relative to the carbonyl, sulfoxide, or —SO2— functional group;
and Y is hydrogen or C1-6 aliphatic optionally substituted with oxo, halogen, NO2, or CN;
or
(b) L is a bivalent C2-8 straight or branched, hydrocarbon chain wherein L has at least one double bond and at least one methylene unit of L is replaced by a functional group selected from —C(O)—, —NRC(O)—, —C(O)NR—, —N(R)SO2—, —SO2N(R)—, —S(O)—, —SO2—, —OC(O)—, or —C(O)O—, wherein at least one double bond is located in an alpha-beta position relative to the carbonyl, sulfoxide, or —SO2— functional group, and one or two additional methylene units of L are optionally and independently replaced by cyclopropylene, —O—, —N(R)—, or —C(O)—;
and Y is hydrogen or C1-6 aliphatic optionally substituted with oxo, halogen, NO2, or CN;
or
(c) L is a bivalent C2-8 straight or branched, hydrocarbon chain wherein L has at least one double bond and at least one methylene unit of L is replaced by a functional group selected from —C(O)—, wherein at least one double bond is located in an alpha-beta position relative to the functional group, and one or two additional methylene units of L are optionally and independently replaced by cyclopropylene, —O—, —N(R)—, or —C(O)—;
and Y is hydrogen or C1-6 aliphatic optionally substituted with oxo, halogen, NO2, or CN;
or
(h) L is a bivalent C2-8 straight or branched, hydrocarbon chain wherein L has at least one alkylidenyl double bond and at least one methylene unit of L is replaced by a functional group selected from —C(O)—, —NRC(O)—, —C(O)NR—, —N(R)SO2—, —SO2N(R)—, —S(O)—, —SO2—, —OC(O)—, or —C(O)O—, wherein at least one double bond is located in an alpha-beta position relative to the carbonyl, sulfoxide, or —SO2— functional group, and one or two additional methylene units of L are optionally and independently replaced by cyclopropylene, —O—, —N(R)—, or —C(O)—;
and Y is hydrogen or C1-6 aliphatic optionally substituted with oxo, halogen, NO2, or CN;
or
(i) L is a bivalent C2-8 straight or branched, hydrocarbon chain wherein L has at least one triple bond and one or two methylene units of L are optionally and independently replaced by —NRC(O)—, —C(O)NR—, —N(R)SO2—, —SO2N(R)—, —S—, —S(O)—, —SO2—, —OC(O)—, or —C(O)O—, and Y is hydrogen or C1-6 aliphatic optionally substituted with oxo, halogen, NO2, or CN;
or
(k) L is a bivalent C2-8 straight or branched, hydrocarbon chain wherein one methylene unit of L is replaced by cyclopropylene and one or two additional methylene units of L are independently replaced by —NRC(O)—, —C(O)NR—, —N(R)SO2—, —SO2N(R)—, —S—, —S(O)—, —SO2—, —OC(O)—, or —C(O)O—;
and Y is C1-6 aliphatic substituted with oxo, halogen, NO2, or CN;
or
(l) L is a covalent bond and Y is selected from:
(i) —CH2F, —CH2Cl, —CH2CN, or —CH2NO2;
or
(ii) C2-6 alkenyl substituted with oxo, NO2, or CN, and optionally substituted with halogen;
or
(iii) C2-6 alkynyl optionally substituted with oxo, halogen, NO2, or CN;
or
(iv) a saturated 3-4 membered heterocyclic ring having 1 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-2 Re groups;
or
(v) a saturated 5-6 membered heterocyclic ring having 1-2 heteroatoms selected from oxygen or nitrogen wherein said ring is substituted with 1-4 Re groups;
or
(vii) a saturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 Re groups;
or
(viii) a partially unsaturated 3-6 membered monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
or
(ix) a partially unsaturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 Re groups;
or
(xi) a partially unsaturated 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
or
(xiii) a 6-membered aromatic ring having 0-2 nitrogens wherein said ring is substituted with 1-4 Re groups;
or
(xv) a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-3 Re groups;
or
(xvii) an 8-10 membered bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
(m) L is —C(O)— and Y is selected from:
(i) C1-6 alkyl substituted with oxo, halogen, NO2, or CN;
or
(ii) C2-6 alkenyl optionally substituted with oxo, halogen, NO2, or CN;
or
(iii) C2-6 alkynyl optionally substituted with oxo, halogen, NO2, or CN;
or
(iv) a saturated 3-4 membered heterocyclic ring having 1 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-2 Re groups;
or
(v) a saturated 5-6 membered heterocyclic ring having 1-2 heteroatoms selected from oxygen or nitrogen wherein said ring is substituted with 1-4 Re groups;
or
(vii) a saturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 Re groups;
or
(viii) a partially unsaturated 3-6 membered monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
or
(ix) a partially unsaturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 Re groups;
or
(xi) a partially unsaturated 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
or
(xiii) a 6-membered aromatic ring having 0-2 nitrogens wherein said ring is substituted with 1-4 Re groups;
or
(xv) a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-3 Re groups;
or
(xvii) an 8-10 membered bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
(n) L is —N(R)C(O)— and Y is selected from:
(i) C1-6 alkyl substituted with oxo, halogen, NO2, or CN;
or
(ii) C2-6 alkenyl optionally substituted with oxo, halogen, NO2, or CN;
or
(iii) C2-6 alkynyl optionally substituted with oxo, halogen, NO2, or CN;
or
(iv) a saturated 3-4 membered heterocyclic ring having 1 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-2 Re groups;
or
(v) a saturated 5-6 membered heterocyclic ring having 1-2 heteroatoms selected from oxygen or nitrogen wherein said ring is substituted with 1-4 Re groups;
or
(vii) a saturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 Re groups;
or
(viii) a partially unsaturated 3-6 membered monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
or
(ix) a partially unsaturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 Re groups;
or
(xi) a partially unsaturated 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
or
(xiii) a 6-membered aromatic ring having 0-2 nitrogens wherein said ring is substituted with 1-4 Re groups;
or
(xv) a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-3 Re groups;
or
(xvii) an 8-10 membered bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
(o) L is a bivalent C1-8 saturated or unsaturated, straight or branched, hydrocarbon chain;
and Y is selected from:
(i) —CH2F, —CH2Cl, —CH2CN, or —CH2NO2;
or
(ii) C2-6 alkenyl substituted with oxo, NO2, or CN, and optionally substituted with halogen;
or
(iii) C2-6 alkynyl optionally substituted with oxo, halogen, NO2, or CN;
or
(iv) a saturated 3-4 membered heterocyclic ring having 1 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-2 Re groups;
or
(v) a saturated 5-6 membered heterocyclic ring having 1-2 heteroatoms selected from oxygen or nitrogen wherein said ring is substituted with 1-4 Re groups;
or
(vii) a saturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 Re groups;
or
(viii) a partially unsaturated 3-6 membered monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
or
(ix) a partially unsaturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 Re groups;
or
(xi) a partially unsaturated 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
or
(xiii) a 6-membered aromatic ring having 0-2 nitrogens wherein said ring is substituted with 1-4 Re groups;
or
(xv) a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-3 Re groups;
or
(xvii) an 8-10 membered bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
(p) L is a covalent bond, —CH2—, —NH—, —C(O)—, —CH2NH—, —NHCH2—, —NHC(O)—, —NHC(O)CH2OC(O)—, —CH2NHC(O)—, —NHSO2—, —NHSO2CH2—, or —SO2NH—;
and Y is selected from:
(i) —CH2F, —CH2Cl, —CH2CN, or —CH2NO2;
or
(ii) C2-6 alkenyl substituted with oxo, NO2, or CN, and optionally substituted with halogen;
or
(iii) C2-6 alkynyl optionally substituted with oxo, halogen, NO2, or CN;
or
(iv) a saturated 3-4 membered heterocyclic ring having 1 heteroatom selected from oxygen or nitrogen wherein said ring is substituted with 1-2 Re groups;
or
(v) a saturated 5-6 membered heterocyclic ring having 1-2 heteroatoms selected from oxygen or nitrogen wherein said ring is substituted with 1-4 Re groups;
or
(vii) a saturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 Re groups;
or
(viii) a partially unsaturated 3-6 membered monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
or
(ix) a partially unsaturated 3-6 membered carbocyclic ring, wherein said ring is substituted with 1-4 Re groups;
or
(xi) a partially unsaturated 4-6 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
or
(xiii) a 6-membered aromatic ring having 0-2 nitrogens wherein said ring is substituted with 1-4 Re groups;
or
(xv) a 5-membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-3 Re groups;
or
(xvii) an 8-10 membered bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein said ring is substituted with 1-4 Re groups;
or
(q) -L-Y is selected from:
or
(r) L is a bivalent C2-8 straight or branched, hydrocarbon chain wherein L has at least one double bond and one or two methylene units of L are independently replaced by —NRC(O)—, —C(O)NR—, —N(R)SO2—, —SO2N(R)—, —S(O)—, —SO2—, —OC(O)—, —C(O)O—, cyclopropylene, —O—, —N(R)—, or —C(O)—;
and
Y is hydrogen, C1-6 aliphatic optionally substituted with oxo, halogen, NO2, or CN, or a 3-10 membered monocyclic or bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein said ring is substituted with 1-4 Re groups;
or
(s) L is a bivalent C2-8 straight or branched, hydrocarbon chain wherein L has at least one triple bond and one or two methylene units of L are optionally and independently replaced by —NRC(O)—, —C(O)NR—, —N(R)SO2—, —SO2N(R)—, —O—, —N(R)—, —C(O)—, —S—, —S(O)—, —SO2—, —OC(O)—, or —C(O)O—, and
Y is hydrogen, C1-6 aliphatic optionally substituted with oxo, halogen, NO2, or CN, or a 3-10 membered monocyclic or bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein said ring is substituted with 1-4 Re groups;
or
(t) L is a bivalent C2-8 straight or branched, hydrocarbon chain wherein one methylene unit of L is replaced by cyclopropylene and one or two additional methylene units of L are independently replaced by —NRC(O)—, —C(O)NR—, —N(R)SO2—, —SO2N(R)—, —S—, —O—, —N(R)—, —C(O)—, —S(O)—, —SO2—, —OC(O)—, or —C(O)O—, and
Y is C1-6 aliphatic substituted with oxo, halogen, NO2, or CN, or a 3-10 membered monocyclic or bicyclic, saturated, partially unsaturated, or aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein said ring is substituted with 1-4 Re groups;
each Re is independently selected from -Q-Z, oxo, NO2, halogen, CN, a suitable leaving group selected from alkoxy, sulphonyloxy, optionally substituted alkylsulphonyloxy, optionally substituted alkenylsulfonyloxy, optionally substituted arylsulfonyloxy, acyl, and diazonium, or C1-6 aliphatic substituted with oxo, halogen, NO2, or CN, wherein:
Q is a bivalent C2-6 unsaturated, straight or branched, hydrocarbon chain, wherein one or two methylene units of Q are optionally and independently replaced by —N(R)—, —S—, —O—, —C(O)—, —OC(O)—, —C(O)O—, —SO—, —SO2—, —N(R)C(O)—, —C(O)N(R)—, —N(R)SO2—, or —SO2N(R)—;
and
each Z is independently hydrogen or C1-6 aliphatic substituted with oxo, halogen, NO2, or CN, or:
R3 and R1 are taken together with their intervening atoms to form an optionally substituted 12-18 membered ring having 2-6 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein the ring formed thereby comprises the warhead group -L-Y;
or
R3 and a ring formed by R1 and R1′ are taken together with their intervening atoms to form an optionally substituted 12-18 membered ring having 2-6 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein the ring formed thereby comprises the warhead group -L-Y;
Rw is hydrogen or an optionally substituted group selected from C1-6 aliphatic, 6-10 membered aryl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur:
or
Rw and Rx are taken together to form an optionally substituted C3-7 membered ring having 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, or:
Rw and Ry are taken together to form an optionally substituted C3-7 membered ring having 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur;
Rx is -T-Rz, wherein:
T is a covalent bond or a C1-6 bivalent hydrocarbon chain wherein one or two methylene units of T are optionally and independently replaced by —O—, —S—, —N(R)—, —N(R)C(O)—, —C(O)N(R)—, —S(O)—, —S(O)2—, —N(R)SO2—, or —SO2N(R)—;
and
Rz is hydrogen or an optionally substituted group selected from a bridged bicyclic, or 5-10 membered monocyclic or bicyclic heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
Rx′ is hydrogen, or Rx′ and Rx are taken together with their intervening atoms to form an optionally substituted spiro-fused 5-7 membered ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
Ry is hydrogen, or Rx and Ry are taken together to form an optionally substituted C3-7 membered ring having 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur;
R4 is H, —NHC(O)R5, —NHC(O)OR6,
or a natural or unnatural amino acid side-chain group;
each R5 is independently —N(R)2 or an optionally substituted group selected from C1-6 aliphatic, a bridged bicyclic, 6-10 membered aryl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
R6 is an optionally substituted group selected from C1-6 aliphatic, a bridged bicyclic, 6-10 membered aryl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
and
R7 is an optionally substituted group selected from C1-6 aliphatic, a bridged bicyclic, 6-10 membered aryl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

178 more elements

Dependencies are inferred from the claim text.

Facts

Application

14/887,092Filed 19 Oct 2015

Priority

21 Dec 2007

Published

18 Aug 2016

Term ends

Not estimatedThe source records don’t support an estimate.

Classification18 codes

A61K 38/06
Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof: tripeptides
A61K 38/05
Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof: dipeptides
A61K 38/12
Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof: cyclic peptides , e.g. bacitracins; Polymyxins; Gramicidins…
A61P 1/16
Drugs for disorders of the alimentary tract or the digestive system: for liver or gallbladder disorders, e.g. hepatoprotective agents,…

Family

Application61/016,110Us provisional application · filed 21 Dec 2007

Application61/016,473Us provisional application · filed 23 Dec 2007

Application61/060,371Us provisional application · filed 10 Jun 2008

Application61/098,668Us provisional application · filed 19 Sep 2008

Application12/339,680Division · filed 19 Dec 2008

Application14/887,092Division

US 2009/0306085 A1Published application

US 9,163,061 B2Related patent

US 2016/0235805 A1This patent

From the US filing history. Foreign family members aren’t listed.

Hcv protease inhibitors and uses thereof

Life of this patent

Abstract

Claims28

Hcv protease inhibitors and uses thereof

Life of this patent

Abstract

Claims28