US2012064034A1PendingUtilityA1
Peptidomimetic protease inhibitors
Est. expiryAug 31, 2020(expired)· nominal 20-yr term from priority
Inventors:Robert E. BabineShu-Hui ChenIvan ColladoCristina Garcia-ParedesJohn I. GlassDeqi GuoLing JinJason Eric LamarRaymond Samuel Parker, IiiNancy June SnyderXicheng SunYvonne Yee Mai YipQ. May WangFrantz VictorMark J. TebbeRobert B. PerniLuc Farmer
C07K 5/1016C07K 14/005C07K 5/0205C07K 5/06052Y02P20/55C07K 7/06A61K 38/095C12N 2770/24222C07D 209/02C07K 5/0202C07K 5/0808A61P 31/12A61P 43/00A61P 31/14A61P 31/18A61P 1/16A61K 38/08C07D 209/52A61K 38/212A61K 38/07A61K 38/215A61K 45/06A61K 38/21C07K 7/02C07K 5/101C07D 401/12
57
PatentIndex Score
0
Cited by
0
References
0
Claims
Abstract
The present invention relates to peptidomimetic compounds useful as protease inhibitors, particularly as serine protease inhibitors and more particularly as hepatitis C NS3 protease inhibitors; intermediates thereto; their preparation including novel steroselective processes to intermediates. The invention is also directed to pharmaceutical compositions and to methods for using the compounds for inhibiting HCV protease or treating a patient suffering from an HCV infection or physiological condition related to the infection. Also provided are pharmaceutical combinations comprising, in addition to one or more HCV serine protease inhibitors, one or more interferons exhibiting anti-HCV activity and/or one or more compounds having anti HCV activity and a pharmaceutically acceptable carrier, and methods for treating or preventing a HCV infection in a patient using the compositions. The present invention is also directed to a kit or pharmaceutical pack for treating or preventing HCV infection in a patient.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound of formula 1
wherein:
R 0 is a bond or difluoromethylene;
R 1 is hydrogen, optionally substituted aliphatic group, optionally substituted cyclic group or optionally substituted aromatic group;
R 2 and R 9 are each independently optionally substituted aliphatic group, optionally substituted cyclic group or optionally substituted aromatic group;
R 3 , R 5 and R 7 are each independently;
optionally substituted (1,1- or 1,2-)cycloalkylene ; or
optionally substituted (1,1- or 1,2-)heterocyclylene; or
methylene or ethylene, substituted with one substituent selected from the group consisting of an optionally substituted aliphatic group, an optionally substituted cyclic group or an optionally substituted aromatic group, and wherein the methylene or ethylene is further optionally substituted with an aliphatic group substituent; or
R 4 , R 6 , R 8 and R 10 are each independently is hydrogen or optionally substituted aliphatic group;
is substituted monocyclic azaheterocyclyl or optionally substituted multicyclic azaheterocyclyl, or optionally substituted multicyclic azaheterocyclenyl wherein the unsaturatation is in the ring distal to the ring bearing the R 9 -L-(N(R 8 )—R 7 —C(O)—) n N(R 6 )—R 5 —C(O—N moiety and to which the —C(O)—N(R 4 )—R 3 —C(O)C(O)NR 2 R 1 moiety is attached;
L is —C(O)—, —OC(O)—, —NR 10 C(O)—, —S(O) 2 —, or —NR 10 S(O) 2 —; and
n is 0 or 1, or
a pharmaceutically acceptable salt or prodrug thereof, or a solvate of such a compound, its salt or its prodrug, provided
when
is substituted
then L is —OC(O)— and leis optionally substituted aliphatic; or at least one of R 3 , R 5 and R 7 is ethylene, substituted with one substituent selected from the group consisting of an optionally substituted aliphatic group, an optionally substituted cyclic group or an optionally substituted aromatic group and wherein the ethylene is further optionally substituted with an aliphatic group substituent; or R 4 is optionally substituted aliphatic.
2 . A compound of claim 1 wherein R 0 is a bond.
3 . A compound of claim 1 or 2 wherein:
optionally substituted aliphatic groups are alkyl, alkenyl or alkynyl, optionally substituted with one or more aliphatic group substituent;
optionally substituted cyclic groups are cycloalkyl, cycloalkenly, heterocyclyl or heterocyclenyl groups optionally substituted with one or more ring group substituents;
optionally substituted aromatic groups are aryl or heteroaryl groups optionally substituted with one or more ring group substituents;
optionally substituted (1,1- or 1,2) cycloalkylene groups are (1,1- or 1,2) cycloalkylene groups optionally substituted with one or more ring group substituents;
optionally substituted (1,1- or 1,2) heterocyclylene groups are (1,1- or 1,2) heterocyclylene groups optionally substituted with one or more ring group substituents;
as substituted monocyclic azaheterocyclyl is a monocyclic azaheterocyclyl group substituted directly or through a linker group by at least one substituent selected from aryl, heteroaryl, aryloxy, heteroaryloxy, aroyl or its thio analogue, heteroaryl or its thioxo analogue, aroyloxy, heteroaroyloxy, aryloxycarbonyl, heteroaryloxycarbonyl, arylsulfonyl, heteroarylsulfonyl, arylsulfinyl, heteroarylsulfinyl, arylthio, heteroarylthio, aryldiazo, heteroaryldiazo, Y 1 Y 2 N—, Y 1 Y 2 NC(O)—, Y 1 Y 2 NC(O)O—, Y 1 Y 2 NC(O)NY 3 — or Y 1 Y 2 NSO 2 — wherein at least one of Y 1 and Y 2 is aryl or heteroaryl, wherein said linker group is selected from the group consisting of —C(O)—, —OC(O)—, lower alkyl, lower alkoxy, lower alkenyl, —O—, —S—, —C(O)C(O)—, —S(O)—, —S(O) 2 —, —NR 80 —, where R 80 is hydrogen, alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl or heteroaryl;
optionally substituted multicyclic azaheterocyclyl is a multicyclic azaheterocyclyl group optionally substituted by one or more ring group substituents;
optionally substituted multicyclic azaheterocyenyll is a multicyclic azaheterocyclenyll group optionally substituted by one or more ring group substituents;
wherein:
aliphatic group substituents means aryl, heteroaryl, hydroxy, alkoxy, cyclyloxy, aryloxy, heteroaryloxy, acyl or its thioxo analogue, cyclylcarbonyl or its thioxo analogue, aroyl or its thioxo analogue, heteroaroyl or its thioxo analogue, acyloxy, cyclylcarbonyloxy, aroyloxy, heteroaroyloxy, halo, nitro, cyano, carboxy (acid), —C(O)—NHOH, —C(O)—CH 2 OH, —C(O)—CH 2 SH, —C(O)—NH—CN, sulpho, phosphono, alkylsulphonylcarbamoyl, tetrazolyl, arylsulphonylcarbamoyl, N-methoxycarbamoyl, heteroarylsulphonylcarbamoyl, 3-hydroxy-3-cyclobutene-1,2-dione, 3,5-dioxo-1,2,4-oxadiazolidinyl or hydroxyheteroaryl such as 3-hydroxyisoxazolyl, 3-hydoxy-1-methylpyrazolyl, alkoxycarbonyl, cyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylsulfonyl, cyclylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, cyclylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, cyclylthio, arylthio, heteroarylthio, cyclyl, aryldiazo, heteroaryldiazo, thiol, methylene (H 2 C═), oxo (O═), thioxo (S═), Y 1 Y 2 N—, Y 1 Y 2 NC(O)—, Y 1 Y 2 NC(O)O—, Y 1 Y 2 NC(O)NY 3 —, Y 1 Y 2 NSO 2 —, or Y 3 SO 2 NY 1 — wherein R 2 is as defined herein, Y 1 and Y 2 are independently hydrogen, alkyl, aryl or heteroaryl, and Y 3 is alkyl, cycloalkyl aryl or heteroaryl, or for where the substituent is Y 1 Y 2 N—, then one of Y 1 and Y 2 may be acyl, cyclylcarbonyl, aroyl, heteroaroyl, alkoxycarbonyl, cyclyloxycarbonyl, aryloxycarbonyl or heteroaryloxycarbonyl, as defined herein and the other of Y 1 and Y 2 is as defined previously, or for where the substituent is Y 1 Y 2 NC(O)—, Y 1 Y 2 NC(O)O—, Y 1 Y 2 NC(O)NY 3 — or Y 1 Y 2 NSO 2 —, Y 1 and Y 2 may also be taken together with the N atom through which Y 1 and Y 2 are linked to form a 4 to 7 membered azaheterocyclyl or azaheterocyclenyl; ring group substituents means aryl, heteroaryl, hydroxy, alkoxy, cyclyloxy, aryloxy, heteroaryloxy, acyl or its thioxo analogue, cyclylcarbonyl or its thioxo analogue, aroyl or its thioxo analogue, heteroaroyl or its thioxo analogue, acyloxy, cyclylcarbonyloxy, aroyloxy, heteroaroyloxy, halo, nitro, cyano, carboxy (acid), acid biostere, alkoxycarbonyl, cyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylsulfonyl, cyclylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, cyclylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, cyclylthio, arylthio, heteroarylthio, cyclyl, aryldiazo, heteroaryldiazo, thiol, Y 1 Y 2 N—, Y 1 Y 2 NC(O)—, Y 1 Y 2 NC(O)O—, Y 1 Y 2 NC(O)NY 3 — or Y 1 Y 2 NSO 2 —, wherein Y 1 , Y 2 and Y 3 are independently hydrogen, alkyl, aryl or heteroaryl, or for where the substituent is Y 1 Y 2 N—, then one of Y 1 and Y 2 may be acyl, cyclylcarbonyl, aroyl, heteroaroyl, alkoxycarbonyl, cyclyloxycarbonyl, aryloxycarbonyl or heteroaryloxycarbonyl, as defined herein and the other of Y 1 and Y 2 is as defined previously, or for where the substituent is Y 1 Y 2 NC(O)—, Y 1 Y 2 NC(O)O—, Y 1 Y 2 NC(O)NY 3 — or Y 1 Y 2 NSO 2 —, Y 1 and Y 2 may also be taken together with the N atom through which Y 1 and Y 2 are linked to form a 4 to 7 membered azaheterocyclyl or azaheterocyclenyl, or when a ring system is saturated or partially saturated, the “ring group substituents” further include, methylene (H 2 C═), oxo (O═) and thioxo (S═);
aryl means an aromatic monocyclic or multicyclic ring system of 6 to 14 carbon atoms; cycloalkyl means a non-aromatic mono- or multicyclic ring system of 3 to 10 carbon atoms;
cycloalkenyl means a non-aromatic mono- or multicyclic ring system of 3 to 10 carbon atoms which contain at least one carbon-carbon double bond;
cyclyl means cycloalkyl, cycloalkenyl, heterocyclyl or heterocyclenyl;
heterocyclyl means a non-aromatic saturated monocyclic or multicyclic ring system of about 3 to about 10 carbon atomsin which one or more of the carbon atoms in the ring system is/are hetero element(s) other than carbon;
heterocyclenyl means a non-aromatic monocyclic or multicyclic hydrocarbon ring system of about 3 to about 10 carbon atoms in which one or more of the carbon atoms in the ring system is/are hetero element(s) other than carbon and which contains at least one carbon-carbon double bond or carbon-nitrogen double bond; and
heteroaryl means an aromatic monocyclic or multicyclic ring system of about 5 to about 14 carbon atoms, in which one or more of the carbon atoms in the ring system is/are hetero element(s) other than carbon.
4 . A compound of any one of claims 1 to 3 wherein R 0 is difluoromethylene.
5 . A compound of any one of claims 1 to 4 wherein R 1 is hydrogen or optionally substituted lower aliphatic group.
6 . A compound of any one of claims 1 to 5 wherein R 1 is hydrogen or lower alkyl.
7 . A compound of any one of claims 1 to 6 wherein R 1 is hydrogen.
8 . A compound of any one of claims 1 to 7 wherein R 2 is optionally substituted lower aliphatic group or optionally substituted monocyclic group.
9 . A compound of any one of claims 1 to 8 wherein R 2 is optionally substituted lower alkyl, optionally substituted lower alkenyl, or optionally substituted monocyclic cycloalkyl.
10 . A compound of any one of claims 1 to 9 wherein R 2 is carboxymethyl, 1-carboxy-2-phenylethyl, cyclopropyl, cyclobutyl, 1-cyclohexylethyl, 1-phenylethyl, but-2-yl, 1-pyrid-4-ylethyl, propen-3-yl or 3-methylbut-2-yl.
11 . A compound of any one of claims 1 to 10 wherein R 3 is optionally substituted lower aliphatic group methylene.
12 . A compound of any one of claims 1 to 11 wherein R 3 is optionally halo substituted lower (alkyl or alkenyl)methylene.
13 . A compound as claimed in any one of claims 1 to 12 wherein R 3 is propylmethylene, 2,2-difluoroethylmethylene, 2,2,2-trifluoromethylene or propen-3-ylmethylene;
14 . A compound of claim 13 wherein R 3 is propylmethylene or 2,2-difluoroethylmethylene.
15 . A compound of claim 14 wherein R 3 is propylmethylene.
16 . A compound of any one of claims 1 to 15 wherein R 4 is hydrogen or optionally substituted lower aliphatic group.
17 . A compound of claim 16 wherein R 4 is hydrogen.
18 . A compound of any one of claims 1 to 17 wherein R 5 is optionally substituted lower aliphatic group methylene.
19 . A compound of any one of claims 1 to 18 wherein R 5 is optionally (phenyl, carboxy, carboxamido or alkoxycarbonyl) substituted lower (alkyl or alkenyl) methylene.
20 . A compound of any one of claims 1 to 19 wherein R 5 is methylmethylene, isopropylmethylene, t-butylmethylene, but-2-ylmethylene, butylmethylene, benzylmethylene, 3-methylbutylmethylene, 2-methylpropylmethylene, carboxymethylmethylene, carboxamidomethylmethylene, benzyloxycarbonylmethylmethylene, benzyloxycarbonylpropylmethylene or phenylpropen-3-ylmethylene.
21 . A compound of claim 20 wherein R 5 is isopropylmethylene or t-butylmethylene.
22 . A compound of any one of claims 1 to 21 wherein R 6 is hydrogen or optionally substituted lower aliphatic group.
23 . A compound of any one of claims 1 to 22 wherein R 6 is hydrogen or lower alkyl.
24 . A compound of claim 23 wherein R 6 is hydrogen.
25 . A compound of any one of claims 1 to 24 wherein R 1 is optionally substituted lower aliphatic group methylene, optionally substituted lower cyclic group methylene or optionally substituted monocyclic (aryl or heteroaryl) methylene.
26 . A compound of any one of claims 1 to 25 wherein R 7 is optionally substituted lower alkylmethylene, optionally substituted lower cycloalkylmethylene or optional substituted phenylmethylene.
27 . A compound of any one of claims 1 to 26 wherein R 7 is methylmethylene, isopropylmethylene, n-propylmethylene, phenylmethylene, cyclohexylmethylene, cyclopentylmethylene, t-butylmethylene, s-butylmethylene, cyclohexylmethylmethylene, or phenylmethylmethylene.
28 . A compound of claim 27 wherein R 7 is isopropylmethylene, cyclohexylmethylene, cyclopentylmethylene, t-butylmethylene or s-butylmethylene.
29 . A compound of any one of claims 1 to 28 wherein each of R 3 , R 5 , and R 7 is mono substituted methylene.
30 . A compound of any one of claims 1 to 29 wherein R 3 is mono substituted methylene and has an (S) configuration on the carbon attached to the —C(O)—R 0 —C(O)—NR 1 R 2 moiety.
31 . A compound of any one of claims 1 to 30 wherein R 8 is hydrogen or optionally substituted lower aliphatic group.
32 . A compound of claim 31 wherein R 8 is hydrogen or lower alkyl.
33 . A compound of claim 32 wherein R 8 is hydrogen.
34 . A compound of any one of claims 1 to 33 wherein R 9 is optionally substituted lower aliphatic group or optionally substituted monocyclic aromatic group.
35 . A compound of claim 34 wherein R 9 is optionally substituted lower alkyl or optionally substituted monocyclic heteroaryl.
36 . A compound of any one of claims 1 to 34 wherein R 9 is optionally (carboxy, (loweralkyl)SO 2 NH—, (lower alkyl)HNCO—, hydroxy, phenyl, heteroaryl, or (lower alkyl)OC(O)NH—)-substituted lower alkyl, or optionally substituted monocyclic heteroaryl.
37 . A compound of any one of claims 1 to 33 wherein R 9 is lower alkyl substituted by (mono- or di-)MeOC(O)NH—.
38 . A compound of any one of claims 1 to 33 wherein R 9 is (carboxy, (lower alkyl)HNCO— or tetrazolyl)substituted lower alkyl.
39 . A compound of any one of claims 1 to 33 wherein R 9 is 3-carboxypropyl, 2-tetrazol-5ylpropyl, 3-(N-methylcarboxamido)propyl or 3-carboxy-2,2-dimethylpropyl.
40 . A compound of any one of claims 1 to 33 wherein R 9 is 3-carboxypropyl, 2-tetrazol-5ylpropyl or 3-(N-methylcarboxamido)propyl.
41 . A compound of any one of claims 1 to 33 wherein R 9 is optionally subtituted lower alkyl.
42 . A compound of any one of claims 1 to 33 wherein R 9 is 1-hydroxy-2-phenylethyl, isopropyl or t-butyl.
43 . A compound of any one of claims 1 to 33 wherein R 9 is isopropyl or t-butyl.
44 . A compound of any one of claims 1 to 33 wherein R 9 is selected from the group consisting of
45 . A compound of any one of claims 1 to 33 wherein R 9 is pyrazinyl.
46 . A compound of any one of claims 1 to 45 wherein R 10 is hydrogen or optionally substituted lower aliphatic group.
47 . A compound of any one of claims 1 to 46 wherein R 10 is hydrogen or lower alkyl.
48 . A compound of any one of claims 1 to 47 wherein R 10 is hydrogen.
49 . A compound of any one of claims 1 to 48 wherein
as a substituted monocyclic azaheterocyclyl is substituted pyrrolidinyl.
50 . A compound of any one of claims 1 to 48 wherein
as a substituted monocyclic azaheterocyclyl is optionally subtituted
or optionally subtituted
wherein Ar is R 2 that comprises an aromatic moiety.
51 . A compound of any one of claims 1 to 48 wherein
as a substituted monocyclic azaheterocyclyl is optionally subtituted
52 . A compound of any one of claims 1 to 48 wherein
53 . A compound of any one of claims 1 to 48 wherein
as an optionally substituted multicyclic azaheterocyclyl is optionally substituted
54 . A compound of any one of claims 1 to 48 wherein
as an optionally substituted multicyclic azaheterocyclyl is optionally substituted
55 . A compound of any one of claims 1 to 48 wherein
as an optionally substituted multicyclic azaheterocyclenyl is optionally substituted
56 . A compound of any one of claims 1 to 48 wherein
as an optionally substituted multicyclic azaheterocyclenyl is optionally substituted
57 . A compound of any one of claims 1 to 48 wherein
as an optionally substituted multicyclic azaheterocyclenyl is optionally substituted
58 . A compound of any one of claims 1 to 57 wherein the —C(O)—N(R 4 )—R 3 —C(O)R 0 C(O)NR 2 R 1 moiety attached to
is attached a carbon α to the nitrogen atom.
59 . A compound of any one of claims 1 to 58 wherein L is —C(O)— or —OC(O)—.
60 . A compound of any one of claims 1 to 59 wherein n is 0.
61 . A compound of any one of claims 1 to 59 wherein n is 1.
62 . A compound as claimed in claim 1 selected from the group consisting of:
or a pharmaceutically acceptable salt or prodrug thereof, or a solvate of such a compound, its salt or its prodrug.
63 . A pharmaceutical compositions comprising a pharmaceutically acceptable amount of the compound of any one of the preceeding claims and a pharmaceutically acceptable carrier.
64 . A method for inhibiting HCV protease comprising contacting the protease with a compound of any one of claims 1 to 62 .
65 . A method for treating a patient suffering from an HCV infection or physiological conditions related to the infection comprising administering to the patient a pharmaceutically effective amount of a compound of any one of claims 1 to 62 .
66 . A method for treating a patient suffering from an HCV infection or physiological conditions related to the infection comprising administering to the patient a pharmaceutically effective amount of a compound of any one of claims 1 to 62 in combination with a pharmaceutically effective amount of another anti-HCV therapeutic.
67 . The method of claim 66 wherein the anti-HCV therapeutic is interferon or derivatized interferon.
68 . A pharmaceutical composition, comprising a hepatitis C virus serine protease inhibitor, an interferon having anti-hepatitis C virus activity, and a pharmaceutically acceptable carrier.
69 . The pharmaceutical composition of claim 68 , further comprising a compound having anti-hepatitis C virus activity, wherein said compound is other than an interferon.
70 . A pharmaceutical composition, comprising a hepatitis C virus serine protease inhibitor, a compound having anti-hepatitis C virus activity, and a pharmaceutically acceptable carrier, wherein said compound is other than an interferon.
71 . The pharmaceutical composition of claim 69 , wherein said hepatitis C virus serine protease inhibitor, said interferon, and said compound having anti-hepatitis C virus activity are each present in an amount selected from the group consisting of a pharmaceutically effective amount, a subclinical pharmaceutically effective amount, and a combination thereof.
72 . The pharmaceutical composition of claim 71 , wherein said hepatitis C virus serine protease inhibitor is a compound of any one of claims 1 to 62 ; said interferon is selected from the group consisting of interferon alpha 2B, pegylated interferon alpha, consensus interferon, interferon alpha 2A, lymphoblastoid interferon, and interferon tau; and said compound having anti-hepatitis C virus activity is selected from the group consisting of interleukin 2, interleukin 6, interleukin 12, a compound that enhances the development of a type 1 helper T cell response, double stranded RNA, double stranded RNA complexed with tobramycin, Imiquimod, ribavirin, an inosine 5′-monophosphate dehydrogenase inhibitor, amantadine, and rimantadine.
73 . A method of treating or preventing a hepatitis C virus infection in a patient in need thereof, comprising administering to said patient a pharmaceutically effective amount of a combination of a hepatitis C virus serine protease inhibitor and an interferon having anti-hepatitis C virus activity.
74 . The method of claim 73 , wherein said pharmaceutically effective amount of said combination further comprises a compound having anti-hepatitis C virus activity, wherein said compound is other than an interferon.
75 . A method of treating or preventing a hepatitis C virus infection in a patient in need thereof, comprising administering to said patient a pharmaceutically effective amount of a combination of a hepatitis C virus serine protease inhibitor and a compound having anti-hepatitis C virus activity, wherein said compound is other than an interferon.
76 . The method of any one of claims 74 , wherein said hepatitis C virus serine protease inhibitor, said interferon, and said compound having anti-hepatitis C virus activity are each present in an amount selected from the group consisting of a pharmaceutically effective amount, a subclinical pharmaceutically effective amount, and a combination thereof.
77 . The method of claim 76 , wherein said hepatitis C virus serine protease inhibitor is a compound of any one of claims 1 to 62 ; said interferon is selected from the group consisting of interferon alpha 2B, pegylated interferon alpha, consensus interferon, interferon alpha 2A, lymphoblastoid interferon, and interferon tau; and said compound having anti-hepatitis C virus activity is selected from the group consisting of interleukin 2, interleukin 6, interleukin 12, a compound that enhances the development of a type 1 helper T cell response, double stranded RNA, double stranded RNA complexed with tobramycin, Imiquimod, ribavirin, an inosine 5′-monophosphate dehydrogenase inhibitor, amantadine, and rimantadine.
78 . Use of a hepatitis C virus serine protease inhibitor in combination with an interferon having anti-hepatitis C virus activity to prepare a medicament for the treatment or prevention of hepatitis C virus infection in a patient in need thereof.
79 . Use of a hepatitis C virus serine protease inhibitor in combination with a compound having anti-hepatitis C virus activity to prepare a medicament for the treatment or prevention of hepatitis C virus infection in a patient in need thereof, wherein said compound is other than an interferon.
80 . Use of a hepatitis C virus serine protease inhibitor in combination with an interferon having anti-hepatitis C virus activity and a compound having anti-hepatitis C virus activity to prepare a medicament for the treatment or prevention of hepatitis C virus infection in a patient in need thereof, wherein said compound is other than an interferon.
81 . The use according to claim 80 ,wherein said hepatitis C virus serine protease inhibitor, said interferon, and said compound having anti-hepatitis C virus activity are each present in said medicament in an amount selected from the group consisting of a pharmaceutically effective amount, a subclinical pharmaceutically effective amount, and a combination thereof.
82 . The use according to claim 81 , wherein said hepatitis C virus serine protease inhibitor is a compound of any one of claims 1 to 62 ; said interferon is selected from the group consisting of interferon alpha 2B, pegylated interferon alpha, consensus interferon, interferon alpha 2A, lymphoblastoid interferon, and interferon tau; and said compound having anti-hepatitis C virus activity is selected from the group consisting of interleukin 2, interleukin 6, interleukin 12, a compound that enhances the development of a type 1 helper T cell response, double stranded RNA, double stranded RNA complexed with tobramycin, Imiquimod, ribavirin, an inosine 5′-monophosphate dehydrogenase inhibitor, amantadine, and rimantadine.
83 . A kit or pharmaceutical pack, comprising a plurality of separate containers, wherein at least one of said containers contains a hepatitis C virus serine protease inhibitor and at least another of said containers contains an interferon having anti-hepatitis C virus activity.
84 . A kit or pharmaceutical pack, comprising a plurality of separate containers, wherein at least one of said containers contains a hepatitis C virus serine protease inhibitor and at least another of said containers contains a compound having anti-hepatitis C virus activity, wherein said compound is other than an interferon.
85 . A kit or pharmaceutical pack, comprising a plurality of separate containers, wherein at least one of said containers contains a hepatitis C virus serine protease inhibitor, at least another of said containers contains an interferon having anti-hepatitis C virus activity, and at least another of said containers contains a compound having anti-hepatitis C virus activity, wherein said compound is other than an interferon.
86 . The kit or pharmaceutical pack of claim 85 , wherein said hepatitis C virus serine protease inhibitor, said interferon, and said compound having anti-hepatitis C virus activity are each present in an amount selected from the group consisting of a pharmaceutically effective amount, a subclinical pharmaceutically effective amount, and a combination thereof.
87 . The kit or pharmaceutical pack of claim 86 wherein said hepatitis C virus serine protease inhibitor is a compound of any one of claims 1 to 62 ; said interferon is selected from the group consisting of interferon alpha 2B, pegylated interferon alpha, consensus interferon, interferon alpha 2A, lymphoblastoid interferon, and interferon tau; and said compound having anti-hepatitis C virus activity is selected from the group consisting of interleukin 2, interleukin 6, interleukin 12, a compound that enhances the development of a type 1 helper T cell response, double stranded RNA, double stranded RNA complexed with tobramycin, Imiquimod, ribavirin, an inosine 5′-monophosphate dehydrogenase inhibitor, amantadine, and rimantadine.
88 . A method of inhibiting hepatitis C virus replication in a cell, comprising contacting said cell, a hepatitis C virus serine protease inhibitor, and an interferon having anti-hepatitis C virus activity.
89 . The method of claim 88 , further comprising contacting said cell and a compound having anti-hepatitis C virus activity, wherein said compound is other than an interferon.
90 . A method of inhibiting hepatitis C virus replication in a cell, comprising contacting said cell, a hepatitis C virus serine protease inhibitor, and a compound having anti-hepatitis C virus activity, wherein said compound is other than an interferon.
91 . The method of claim 88 , wherein said hepatitis C virus serine protease inhibitor, said interferon, and said compound having anti-hepatitis C virus activity are each present in an amount selected from the group consisting of a pharmaceutically effective amount, a subclinical pharmaceutically effective amount, and a combination thereof.
92 . The method of claim 91 , wherein said hepatitis C virus serine protease inhibitor is a compound of any one of claims 1 to 62 ; said interferon is selected from the group consisting of interferon alpha 2B, pegylated interferon alpha, consensus interferon, interferon alpha 2A, lymphoblastoid interferon, and interferon tau; and said compound having anti-hepatitis C virus activity is selected from the group consisting of interleukin 2, interleukin 6, interleukin 12, a compound that enhances the development of a type 1 helper T cell response, double stranded RNA, double stranded RNA complexed with tobramycin, Imiquimod, ribavirin, an inosine 5′-monophosphate dehydrogenase inhibitor, amantadine, and rimantadine.
93 . A compound of formula 24
wherein:
is optionally substituted cycloalkyl or optionally substituted fused arylcycloalkyl;
R 11 is —CO 2 R 13 ;
R 12 is an iminic glycinimide derivative adduct; and
R 13 is acid protecting group or optionally substituted aliphatic group.
94 . A compound of claim 93 wherein:
optionally substituted cycloalkyl means a non-aromatic mono- or multicyclic ring system of 3 to 10 carbon atoms optionally substituted with one or more ring group substituents;
optionally substituted fused arylcycloalkyl means a fused arylcycloalkyl optionally substituted with one or more ring group substituents;
optionally substituted aliphatic group are alkyl, alkenyl, or alkynyl optionally substituted with an aliphatic group substituent;
an iminic glycinimide derivative adduct is a compound selected from the group consisting of
wherein:
R 16 is an acid protecting group, optionally substituted aryl, or optionally substituted aliphatic group;
R 17 is optionally substituted aryl, optionally substituted aliphatic group,
R 18 is hydrogen, alkyl, or alkylthio; or optionally substituted aryl;
wherein;
ring group substituents mean substituents attached to aromatic or non-aromatic ring systems inclusive of aryl, heteroaryl, hydroxy, alkoxy, cyclyloxy, aryloxy, heteroaryloxy, acyl or its thioxo analogue, cyclylcarbonyl or its thioxo analogue, aroyl or its thioxo analogue, heteroaroyl or its thioxo analogue, acyloxy, cyclylcarbonyloxy, aroyloxy, heteroaroyloxy, halo, nitro, cyano, carboxy (acid), —C(O)—NHOH, —C(O)—CH 2 OH, —C(O)—CH 2 SH, —C(O)—NH—CN, sulpho, phosphono, alkylsulphonylcarbamoyl, tetrazolyl, arylsuiphonylcarbamoyl, N-methoxycarbamoyl, heteroarylsulphonylcarbamoyl, 3-hydroxy-3-cyclobutene-1,2-dione, 3,5-dioxo-1,2,4-oxadiazolidinyl or hydroxyheteroaryl such as 3-hydroxyisoxazolyl, 3-hydoxy-1-methylpyrazoly, alkoxycarbonyl, cyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylsulfonyl, cyclylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, cyclylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, cyclylthio, arylthio, heteroarylthio, cyclyl, aryldiazo, heteroaryldiazo, thiol, Y 1 Y 2 N—, Y 1 Y 2 NC(O)—, Y 1 Y 2 NC(O)O, Y 1 Y 2 NC(O)NY 3 — or Y 1 Y 2 NSO 2 —, wherein Y 1 , Y 2 and Y 3 are independently hydrogen, alkyl, aryl or heteroaryl, or for where the substituent is Y 1 Y 2 N—, then one of Y 1 and Y 2 may be acyl, cyclylcarbonyl, aroyl, heteroaroyl, alkoxycarbonyl, cyclyloxycarbonyl, aryloxycarbonyl or heteroaryloxycarbonyl, as defined herein and the other of Y 1 and Y 2 is as defined previously, or for where the substituent is Y 1 Y 2 NC(O)—, Y 1 Y 2 NC(O)O—, Y 1 Y 2 NC(O)NY 3 — or Y 1 Y 2 NSO 2 —, Y 1 and Y 2 may also be taken together with the N atom through which Y 1 and Y 2 are linked to form a 4 to 7 membered azaheterocyclyl or azaheterocyclenyl or when the ring system is saturated or partially saturated, the ring group substituents further include, methylene (H 2 C═), oxo (O═) and thioxo (S═); and
aliphatic group substituents means aryl, heteroaryl, hydroxy, alkoxy, cyclyloxy, aryloxy, heteroaryloxy, acyl or its thioxo analogue, cyclylcarbonyl or its thioxo analogue, aroyl or its thioxo analogue, heteroaroyl or its thioxo analogue, acyloxy, cyclylcarbonyloxy, aroyloxy, heteroaroyloxy, halo, nitro, cyano, carboxy (acid), —C(O)—NHOH, —C(O)—, CH 2 OH, —C(O)—CH 2 SH, —C(O)—NH—CN, sulpho, phosphono, alkylsulphonylcarbamoyl, tetrazolyl, arylsulphonylcarbamoyl, N-methoxycarbamoyl, heteroarylsulphonylcarbamoyl, 3-hydroxy-3-cyclobutene-1,2-dione, 3,5-dioxo-1,2,4-oxadiazolidinyl or hydroxyheteroaryl such as 3-hydroxyisoxazolyl, 3-hydoxy-1-methylpyrazolyl, alkoxycarbonyl, cyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylsulfonyl, cyclylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, cyclylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, cyclylthio, arylthio, heteroarylthio, cyclyl, aryldiazo, heteroaryldiazo, thiol, methylene (H 2 C═), oxo (O═), thioxo (S═), Y 1 Y 2 N—, Y 1 Y 2 NC(O)—, Y 1 Y 2 NC(O)O—, Y 1 Y 2 NC(O)NY 3 —, Y 1 Y 2 NSO 2 —, or Y 3 SO 2 NY 1 — wherein R 2 is as defined herein, Y 1 and Y 2 are independently hydrogen, alkyl, aryl or heteroaryl, and Y 3 is alkyl, cycloalkyl aryl or heteroaryl, or for where the substituent is Y 1 Y 2 N—, then one of Y 1 and Y 2 may be acyl, cyclylcarbonyl, aroyl, heteroaroyl, alkoxycarbonyl, cyclyloxycarbonyl, aryloxycarbonyl or heteroaryloxycarbonyl, as defined herein and the other of Y 1 and Y 2 is as defined previously, or for where the substituent is Y 1 Y 2 NC(O)—, Y 1 Y 2 NC(O)O—, Y 1 Y 2 NC(O)NY 3 — or Y 1 Y 2 NSO 2 —, Y 1 and Y 2 may also be taken together with the N atom through which Y 1 and Y 2 are linked to form a 4 to 7 membered azaheterocyclyl or azaheterocyclenyl; and
aryl means an aromatic monocyclic or multicyclic ring system of 6 to 14 carbon atoms.
95 . A compound according to claim 93 or 94 where R 11 is —CO 2 R 13 .
96 . A compound according to any one of claim 93 or 95 where R 13 is an optionally substituted aliphatic group.
97 . A compound according to any one of claims 93 to 96 where R 13 is an alkyl group.
98 . A compound according to any one of claims 93 to 97 where R 13 is lower alkyl.
99 . A compound according to any one of claims 93 to 98 where R 13 is methyl.
100 . A compound according to any one of claims 93 to 99 where R 12 is
wherein: R 14 is —CONR 15 R 15 , —CN;
or —CO 2 R 16 ;
R 15 is optionally substituted aliphatic group;
R 16 is acid protecting group, optionally substituted aryl, or optionally substituted aliphatic group;
R 17 is optionally substituted aryl, optionally substituted aliphatic group,
R 18 is hydrogen, alkyl, or alkylthio; or optionally substituted aryl;
R 17 and R 18 taken together with the carbon to which R 17 and R 18 are attached
and {circle around (S)} is a solid phase.
101 . A compound according to claim 100 where R 14 is —CO 2 R 16 .
102 . A compound according to claim 100 or 101 where R 16 is optionally substituted aliphatic.
103 . A compound according to any one of claims 100 to 102 where R 16 is alkyl.
104 . A compound according to any one of claims 100 to 103 where R 16 is lower alkyl.
105 . A compound according to any one of claims 100 to 104 where R 16 is t-Bu.
106 . A compound according to any one of claims 100 to 105 where R 17 is optionally substituted aryl.
107 . A compound according to any one of claims 100 to 106 where R 17 is phenyl.
108 . A compound according to any one of claims 100 to 107 where R 18 is optionally substituted aryl.
109 . A compound according to any one of claims 100 to 108 where R 18 is phenyl.
110 . A compound of formula 25
wherein:
R 14 is —CONR 15 R 15 , —CN;
or —CO 2 R 16 ;
R 15 is optionally substituted aliphatic group; and
R 16 is acid protecting group, optionally substituted aryl, or optionally substituted aliphatic group.
111 . A compound according to claim 110 wherein:
optionally substituted aliphatic groups are alkyl, alkenyl, or alkynyl optionally substituted with one or more aliphatic group substituents;
optionally substituted aryl means an aromatic monocyclic or mylticyclic ring systems of 6 to 14 carbon atoms optionally substituted with one or more ring group substituents;
wherein;
ring group substituents mean substituents attached to aromatic or non-aromatic ring systems inclusive of aryl, heteroaryl, hydroxy, alkoxy, cyclyloxy, aryloxy, heteroaryloxy, acyl or its thioxo analogue, cyclylcarbonyl or its thioxo analogue, aroyl or its thioxo analogue, heteroaroyl or its thioxo analogue, acyloxy, cyclylcarbonyloxy, aroyloxy, heteroaroyloxy, halo, nitro, cyano, carboxy (acid), —C(O)—NHOH, —C(O)—CH 2 OH, —C(O)—CH 2 SH, —C(O)—NH—CN, sulpho, phosphono, alkylsulphonylcarbamoyl, tetrazolyl, arylsulphonylcarbamoyl, N-methoxycarbamoyl, heteroarylsulphonylcarbamoyl, 3-hydroxy-3-cyclobutene-1,2-dione, 3,5-dioxo-1,2,4-oxadiazolidinyl or hydroxyheteroaryl such as 3-hydroxyisoxazolyl, 3-hydoxy-1-methylpyrazoly, alkoxycarbonyl, cyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylsulfonyl, cyclylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, cyclylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, cyclylthio, arylthio, heteroarylthio, cyclyl, aryldiazo, heteroaryldiazo, thiol, Y 1 Y 2 N—, Y 1 Y 2 NC(O)—, Y 1 Y 2 NC(O)O, Y 1 Y 2 NC(O)NY 3 — or Y 1 Y 2 NSO 2 —, wherein Y 1 , Y 2 and Y 3 are independently hydrogen, alkyl, aryl or heteroaryl, or for where the substituent is Y 1 Y 2 N—, then one of Y 1 and Y 2 may be acyl, cyclylcarbonyl, aroyl, heteroaroyl, alkoxycarbonyl, cyclyloxycarbonyl, aryloxycarbonyl or heteroaryloxycarbonyl, as defined herein and the other of Y 1 and Y 2 is as defined previously, or for where the substituent is Y 1 Y 2 NC(O)—, Y 1 Y 2 NC(O)O—, Y 1 Y 2 NC(O)NY 3 — or Y 1 Y 2 NSO 2 —, Y 1 and Y 2 may also be taken together with the N atom through which Y 1 and Y 2 are linked to form a 4 to 7 membered azaheterocyclyl or azaheterocyclenyl or when the ring system is saturated or partially saturated, the “ring group substituents” further include, methylene (H 2 C═), oxo (O═) and thioxo (S═); and
aliphatic group substituents means aryl, heteroaryl, hydroxy, alkoxy, cyclyloxy, aryloxy, heteroaryloxy, acyl or its thioxo analogue, cyclylcarbonyl or its thioxo analogue, aroyl or its thioxo analogue, heteroaroyl or its thioxo analogue, acyloxy, cyclylcarbonyloxy, aroyloxy, heteroaroyloxy, halo, nitro, cyano, carboxy (acid), —C(O)—NHOH, —C(O)—CH 2 OH, —C(O)—CH 2 SH, —C(O)—NH—CN, sulpho, phosphono, alkylsulphonylcarbamoyl, tetrazolyl, arylsulphonylcarbamoyl, N-methoxycarbamoyl, heteroarylsulphonylcarbamoyl, 3-hydroxy-3-cyclobutene-1,2-dione, 3,5-dioxo-1,2,4-oxadiazolidinyl or hydroxyheteroaryl such as 3-hydroxyisoxazolyl, 3-hydoxy-1-methylpyrazolyl, alkoxycarbonyl, cyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylsulfonyl, cyclylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, cyclylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, cyclylthio, arylthio, heteroarylthio, cyclyl, aryldiazo, heteroaryldiazo, thiol, methylene (H 2 C═), oxo (O═), thioxo (S═), Y 1 Y 2 N—, Y 1 Y 2 NC(O)—, Y 1 Y 2 NC(O)O—, Y 1 Y 2 NC(O)NY 3 , Y 1 Y 2 NSO 2 —, or Y 3 SO 2 NY 1 — wherein R 2 is as defined herein, Y 1 and Y 2 are independently hydrogen, alkyl, aryl or heteroaryl, and Y 3 is alkyl, cycloalkyl aryl or heteroaryl, or for where the substituent is Y 1 Y 2 N—, then one of Y 1 and Y 2 may be acyl, cyclylcarbonyl, aroyl, heteroaroyl, alkoxycarbonyl, cyclyloxycarbonyl, aryloxycarbonyl or heteroaryloxycarbonyl, as defined herein and the other of Y 1 and Y 2 is as defined previously, or for where the substituent is Y 1 Y 2 NC(O)—, Y 1 Y 2 NC(O)O—, Y 1 Y 2 NC(O)NY 3 — or Y 1 Y 2 NSO 2 —, Y 1 and Y 2 may also be taken together with the N atom through which Y 1 and Y 2 are linked to form a 4 to 7 membered azaheterocyclyl or azaheterocyclenyl.
112 . A compound according to claim 110 or 111 where R 14 is —CO 2 R 16 .
113 . A compound according to any one of claims 110 to 112 where R 16 is optionally substituted aliphatic.
114 . A compound according to any one of claims 110 to 113 where R 16 is alkyl.
115 . A compound according to any one of claims 110 to 114 where R 16 is lower alkyl.
116 . A compound according to any one of claims 110 to 115 where R 16 is t-Bu.
117 . A compound of formula 26
wherein:
p o is amide protecting group;
R 14 is —CONR 15 R 15 , —CN;
or —CO 2 R 16 ;
R 15 is optionally substituted aliphatic group; and
R 16 is acid protecting group, optionally substituted aryl, or optionally substituted aliphatic group.
118 . A compound according to claim 117 wherein:
optionally substituted aliphatic groups are alkyl, alkenyl, or alkynyl optionally substituted with one or more aliphatic group substituents;
optionally substituted aryl means an aromatic monocyclic or mylticyclic ring systems of 6 to 14 carbon atoms optionally substituted with one or more ring group substituents;
wherein;
ring group substituents mean substituents attached to aromatic or non-aromatic ring systems inclusive of aryl, heteroaryl, hydroxy, alkoxy, cyclyloxy, aryloxy, heteroaryloxy, acyl or its thioxo analogue, cyclylcarbonyl or its thioxo analogue, aroyl or its thioxo analogue, heteroaroyl or its thioxo analogue, acyloxy, cyclylcarbonyloxy, aroyloxy, heteroaroyloxy, halo, nitro, cyano, carboxy (acid), —C(O)—NHOH, —C(O)—CH 2 OH, —C(O)—CH 2 SH, —C(O)—NH—CN, sulpho, phosphono, alkylsulphonylcarbamoyl, tetrazolyl, arylsulphonylcarbamoyl, N-methoxycarbamoyl, heteroarylsulphonylcarbamoyl, 3-hydroxy-3-cyclobutene-1,2-dione, 3,5-dioxo-1,2,4-oxadiazolidinyl or hydroxyheteroaryl such as 3-hydroxyisoxazolyl, 3-hydoxy-1-methylpyrazoly, alkoxycarbonyl, cyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylsulfonyl, cyclylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, cyclylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, cyclylthio, arylthio, heteroarylthio, cyclyl, aryldiazo, heteroaryldiazo, thiol, Y 1 Y 2 N—, Y 1 Y 2 NC(O)—, Y 1 Y 2 NC(O)O, Y 1 Y 2 NC(O)NY 3 — or Y 1 Y 2 NSO 2 —, wherein Y 1 , Y 2 and Y 3 are independently hydrogen, alkyl, aryl or heteroaryl, or for where the substituent is Y 1 Y 2 N—, then one of Y 1 and Y 2 may be acyl, cyclylcarbonyl, aroyl, heteroaroyl, alkoxycarbonyl, cyclyloxycarbonyl, aryloxycarbonyl or heteroaryloxycarbonyl, as defined herein and the other of Y 1 and Y 2 is as defined previously, or for where the substituent is Y 1 Y 2 NC(O)—, Y 1 Y 2 NC(O)O—, Y 1 Y 2 NC(O)NY 3 — or Y 1 Y 2 NSO 2 —, Y 1 and Y 2 may also be taken together with the N atom through which Y 1 and Y 2 are linked to form a 4 to 7 membered azaheterocyclyl or azaheterocyclenyl or when the ring system is saturated or partially saturated, the ring group substituents further include, methylene (H 2 C═), oxo (O═) and thioxo (S═); and
aliphatic group substituents means aryl, heteroaryl, hydroxy, alkoxy, cyclyloxy, aryloxy, heteroaryloxy, acyl or its thioxo analogue, cyclylcarbonyl or its thioxo analogue, aroyl or its thioxo analogue, heteroaroyl or its thioxo analogue, acyloxy, cyclylcarbonyloxy, aroyloxy, heteroaroyloxy, halo, nitro, cyano, carboxy (acid), —C(O)—NHOH, —C(O)—CH 2 OH, —C(O)—CH 2 SH, —C(O)—NH—CN, sulpho, phosphono, alkylsulphonylcarbamoyl, tetrazolyl, arylsulphonylcarbamoyl, N-methoxycarbamoyl, heteroarylsulphonylcarbamoyl, 3-hydroxy-3-cyclobutene-1,2-dione, 3,5-dioxo-1,2,4-oxadiazolidinyl or hydroxyheteroaryl such as 3-hydroxyisoxazolyl, 3-hydoxy-1-methylpyrazolyl, alkoxycarbonyl, cyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylsulfonyl, cyclylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, cyclylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, cyclylthio, arylthio, heteroarylthio, cyclyl, aryldiazo, heteroaryldiazo, thiol, methylene (H 2 C═), oxo (O═), thioxo (S=), Y 1 Y 2 N—, Y 1 Y 2 NC(O)—, Y 1 Y 2 NC(O)O—, Y 1 Y 2 NC(O)NY 3 —, Y 1 Y 2 NSO 2 —, or Y 3 SO 2 NY 1 — wherein R 2 is as defined herein, Y 1 and Y 2 are independently hydrogen, alkyl, aryl or heteroaryl, and Y 3 is alkyl, cycloalkyl aryl or heteroaryl, or for where the substituent is Y 1 Y 2 N—, then one of Y 1 and Y 2 may be acyl, cyclylcarbonyl, aroyl, heteroaroyl, alkoxycarbonyl, cyclyloxycarbonyl, aryloxycarbonyl or heteroaryloxycarbonyl, as defined herein and the other of Y 1 and Y 2 is as defined previously, or for where the substituent is Y 1 Y 2 NC(O)—, Y 1 Y 2 NC(O)O—, Y 1 Y 2 NC(O)NY 3 —, or Y 1 Y 2 NSO 2 —, Y 1 and Y 2 may also be taken together with the N atom through which Y 1 and Y 2 are linked to form a 4 to 7 membered azaheterocyclyl or azaheterocyclenyl.
119 . A compound according to claim 117 or 118 where R 14 is —CO 2 R 16 .
120 . A compound according to any one of claims 117 to 119 where R 16 is optionally substituted aliphatic.
121 . A compound according to any one of claims 117 to 120 where R 16 is alkyl.
122 . A compound according to any one of claims 117 to 121 where R 16 is lower alkyl.
123 . A compound according to any one of claims 117 to 122 where R 16 is t-Bu.
124 . A compound according to any one of claims 117 to 123 where p 0 is selected from the group consisting of BOC, CBz, and —CO 2 alkyl.
125 . A compound according to claim 124 where p 0 is BOC.
126 . A compound of formula 27
wherein:
p o is amide protecting group;
R 14 is —CONR 15 R 15 , —CN;
or —CO 2 R 16 ;
R 15 is optionally substituted aliphatic group; and
R 16 is acid protecting group, optionally substituted aryl, or optionally substituted aliphatic group.
127 . A compound according to claim 126 wherein:
optionally substituted aliphatic groups are alkyl, alkenyl, or alkynyl optionally substituted with one or more aliphatic group substituents;
optionally substituted aryl means an aromatic monocyclic or mylticyclic ring systems of 6 to 14 carbon atoms optionally substituted with one or more ring group substituents;
wherein;
ring group substituents mean substituents attached to aromatic or non-aromatic ring systems inclusive of aryl, heteroaryl, hydroxy, alkoxy, cyclyloxy, aryloxy, heteroaryloxy, acyl or its thioxo analogue, cyclylcarbonyl or its thioxo analogue, aroyl or its thioxo analogue, heteroaroyl or its thioxo analogue, acyloxy, cyclylcarbonyloxy, aroyloxy, heteroaroyloxy, halo, nitro, cyano, carboxy (acid), —C(O)—NHOH, —C(O)—CH 2 OH, —C(O)— CH 2 SH, —C(O)—NH—CN, sulpho, phosphono, alkylsulphonylcarbamoyl, tetrazolyl, arylsulphonylcarbamoyl, N-methoxycarbamoyl, heteroarylsulphonylcarbamoyl, 3-hydroxy-3-cyclobutene-1,2-dione, 3,5-dioxo-1,2,4-oxadiazolidinyl or hydroxyheteroaryl such as 3-hydroxyisoxazolyl, 3-hydoxy-1-methylpyrazoly, alkoxycarbonyl, cyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylsulfonyl, cyclylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, cyclylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, cyclylthio, arylthio, heteroarylthio, cyclyl, aryldiazo, heteroaryldiazo, thiol, Y 1 Y 2 N—, Y 1 Y 2 NC(O)—, Y 1 Y 2 NC(O)O, Y 1 Y 2 NC(O)NY 3 — or Y 1 Y 2 NSO 2 —, wherein Y 1 , Y 2 and Y 3 are independently hydrogen, alkyl, aryl or heteroaryl, or for where the substituent is Y 1 Y 2 N—, then one of Y 1 and Y 2 may be acyl, cyclylcarbonyl, aroyl, heteroaroyl, alkoxycarbonyl, cyclyloxycarbonyl, aryloxycarbonyl or heteroaryloxycarbonyl, as defined herein and the other of Y 1 and Y 2 is as defined previously, or for where the substituent is Y 1 Y 2 NC(O)—, Y 1 Y 2 NC(O)O—, Y 1 Y 2 NC(O)NY 3 — or Y 1 Y 2 NSO 2 —, Y 1 and Y 2 may also be taken together with the N atom through which Y 1 and Y 2 are linked to form a 4 to 7 membered azaheterocyclyl or azaheterocyclenyl or when the ring system is saturated or partially saturated, the ring group substituents further include, methylene (H 2 C═), oxo (O═) and thioxo (S═); and
aliphatic group substituents means aryl, heteroaryl, hydroxy, alkoxy, cyclyloxy, aryloxy, heteroaryloxy, acyl or its thioxo analogue, cyclylcarbonyl or its thioxo analogue, aroyl or its thioxo analogue, heteroaroyl or its thioxo analogue, acyloxy, cyclylcarbonyloxy, aroyloxy, heteroaroyloxy, halo, nitro, cyano, carboxy (acid), —C(O)—NHOH, —C(O)—CH 2 OH, —C(O)—CH 2 SH, —C(O)—NH—CN, sulpho, phosphono, alkylsulphonylcarbamoyl, tetrazolyl, arylsulphonylcarbamoyl, N-methoxycarbamoyl, heteroarylsulphonylcarbamoyl, 3-hydroxy-3-cyclobutene-1,2-dione, 3,5-dioxo-1,2,4-oxadiazolidinyl or hydroxyheteroaryl such as 3-hydroxyisoxazolyl, 3-hydoxy-1-methylpyrazolyl, alkoxycarbonyl, cyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylsulfonyl, cyclylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, cyclylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, cyclylthio, arylthio, heteroarylthio, cyclyl, aryldiazo, heteroaryldiazo, thiol, methylene (H 2 C═), oxo (O═), thioxo (S═), Y 1 Y 2 N—, Y 1 Y 2 NC(O)—, Y 1 Y 2 NC(O)O—, Y 1 Y 2 NC(O)NY 3 —, Y 1 Y 2 NSO 2 —, or Y 3 SO 2 NY 1 — wherein R 2 is as defined herein, Y 1 and Y 2 are independently hydrogen, alkyl, aryl or heteroaryl, and Y 3 is alkyl, cycloalkyl aryl or heteroaryl, or for where the substituent is Y 1 Y 2 N—, then one of Y 1 and Y 2 may be acyl, cyclylcarbonyl, aroyl, heteroaroyl, alkoxycarbonyl, cyclyloxycarbonyl, aryloxycarbonyl or heteroaryloxycarbonyl, as defined herein and the other of Y 1 and Y 2 is as defined previously, or for where the substituent is Y 1 Y 2 NC(O)—, Y 1 Y 2 NC(O)O—, Y 1 Y 2 NC(O)NY 3 — or Y 1 Y 2 NSO 2 —, Y 1 and Y 2 may also be taken together with the N atom through which Y 1 and Y 2 are linked to form a 4 to 7 membered azaheterocyclyl or azaheterocyclenyl.
128 . A compound according to any one of claim 126 or 127 where R 14 is —CO 2 R 16 .
129 . A compound according to any one of claims 126 to 128 where R 16 is optionally substituted aliphatic.
130 . A compound according to any one of claims 126 to 129 where R 6 is alkyl.
131 . A compound according to any one of claims 126 to 130 where R 16 is lower alkyl.
132 . A compound according to any one of claims 126 to 131 where R 16 is t-Bu.
133 . A compound according to any one of claims 126 to 132 where p 0 is selected from the group consisting of BOC, CBz, and —CO 2 alkyl.
134 . A compound according to claim 133 where p 0 is BOC.
135 . A process for preparing a chiral bicycloprolinate compound of formula 28
comprising the steps of:
(a) cleaving and cyclizing a compound of formula 24
wherein:
is optionally substituted cycloalkyl or optionally substituted fused arylcycloalkyl;
R 11 is —CO 2 R 13 ;
R 12 is an iminic glycinimide derivative adduct;
R 13 is acid protecting group or optionally substituted aliphatic group;
under cleaving and cyclizing conditions to form a compound of formula 25
wherein:
R 14 is —CONR 15 R 15 , —CN;
or —CO 2 R 16 ;
R 15 is optionally substituted aliphatic group;
R 16 is acid protecting group, optionally substituted aryl, or optionally substituted aliphatic group; and
(b) protecting the nitrogen of the lactam moiety in the compound of formula 25 with an amide protecting group to form a compound of formula 26
wherein:
p o is amide protecting group;
R 14 is as described herein; and
(c) reducing the compound of formula 26 under reducing conditions to form a compound of formula 27
wherein:
p o and R 14 are as described herein; and
(d) deprotecting the compound of formula 27 under deprotecting conditions to form a compound of formula 28
wherein:
R 14 is as described herein.
136 . A compound according to claim 135 wherein:
optionally substituted aliphatic groups are alkyl, alkenyl, or alkynyl optionally substituted with one or more aliphatic group substituents;
optionally substituted aryl means an aromatic monocyclic or mylticyclic ring systems of 6 to 14 carbon atoms optionally substituted with one or more ring group substituents;
optionally substituted cycloalkyl means a non-aromatic mono- or multicyclic ring system of 3 to 10 carbon atoms optionally substituted with one or more ring group substituents;
optionally substituted fused arylcycloalkyl means a fused arylcycloalkyl optionally substituted with one or more ring group substituents;
an iminic glycinimide derivative adduct is a compound selected from the group consisting of
wherein:
R 16 is an acid protecting group, optionally substituted aryl, or optionally substituted aliphatic group;
R 17 is optionally substituted aryl, optionally substituted aliphatic group,
R 18 is hydrogen, alkyl, or alkylthio; or optionally substituted aryl;
wherein;
ring group substituents mean substituents attached to aromatic or non-aromatic ring systems inclusive of aryl, heteroaryl, hydroxy, alkoxy, cyclyloxy, aryloxy, heteroaryloxy, acyl or its thioxo analogue, cyclylcarbonyl or its thioxo analogue, aroyl or its thioxo analogue, heteroaroyl or its thioxo analogue, acyloxy, cyclylcarbonyloxy, aroyloxy, heteroaroyloxy, halo, nitro, cyano, carboxy (acid), —C(O)—NHOH, —C(O)—CH 2 OH, —C(O)—CH 2 SH, —C(O)—NH—CN, sulpho, phosphono, alkylsulphonylcarbamoyl, tetrazolyl, arylsulphonylcarbamoyl, N-methoxycarbamoyl, heteroarylsulphonylcarbamoyl, 3-hydroxy-3-cyclobutene-1,2-dione, 3,5-dioxo-1,2,4-oxadiazolidinyl or hydroxyheteroaryl such as 3-hydroxyisoxazolyl, 3-hydoxy-1-methylpyrazoly, alkoxycarbonyl, cyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylsulfonyl, cyclylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, cyclylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, cyclylthio, arylthio, heteroarylthio, cyclyl, aryldiazo, heteroaryldiazo, thiol, Y 1 Y 2 N—, Y 1 Y 2 NC(O)—, Y 1 Y 2 NC(O)O, Y 1 Y 2 NC(O)NY 3 — or Y 1 Y 2 NSO 2 —, wherein Y 1 , Y 2 and Y 3 are independently hydrogen, alkyl, aryl or heteroaryl, or for where the substituent is Y 1 Y 2 N—, then one of Y 1 and Y 2 may be acyl, cyclylcarbonyl, aroyl, heteroaroyl, alkoxycarbonyl, cyclyloxycarbonyl, aryloxycarbonyl or heteroaryloxycarbonyl, as defined herein and the other of Y 1 and Y 2 is as defined previously, or for where the substituent is Y'Y 2 NC(O)—, Y 1 Y 2 NC(O)O—, Y 1 Y 2 NC(O)NY 3 — or Y 1 Y 2 NSO 2 —, Y 1 and Y 2 may also be taken together with the N atom through which Y 1 and Y 2 are linked to form a 4 to 7 membered azaheterocyclyl or azaheterocyclenyl or when the ring system is saturated or partially saturated, the ring group substituents further include, methylene (H 2 C═), oxo (O═) and thioxo (S═); and
aliphatic group substituents means aryl, heteroaryl, hydroxy, alkoxy, cyclyloxy, aryloxy, heteroaryloxy, acyl or its thioxo analogue, cyclylcarbonyl or its thioxo analogue, aroyl or its thioxo analogue, heteroaroyl or its thioxo analogue, acyloxy, cyclylcarbonyloxy, aroyloxy, heteroaroyloxy, halo, nitro, cyano, carboxy (acid), —C(O)—NHOH, —C(O)—CH 2 OH, —C(O)—CH 2 SH, —C(O)—NH—CN, sulpho, phosphono, alkylsulphonylcarbamoyl, tetrazolyl, arylsulphonylcarbamoyl, N-methoxycarbamoyl, heteroarylsulphonylcarbamoyl, 3-hydroxy-3-cyclobutene-1,2-dione, 3,5-dioxo-1,2,4-oxadiazolidinyl or hydroxyheteroaryl such as 3-hydroxyisoxazolyl, 3-hydoxy-1-methylpyrazolyl, alkoxycarbonyl, cyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylsulfonyl, cyclylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, cyclylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, cyclylthio, arylthio, heteroarylthio, cyclyl, aryldiazo, heteroaryldiazo, thiol, methylene (H 2 C═), oxo (O═), thioxo (S═), Y 1 Y 2 N—, Y 1 Y 2 NC(O)—, Y 1 Y 2 NC(O)O—, Y 1 Y 2 NC(O)NY 3 —, Y 1 Y 2 NSO 2 —, or Y 3 SO 2 NY 1 — wherein R 2 is as defined herein, Y 1 and Y 2 are independently hydrogen, alkyl, aryl or heteroaryl, and Y 3 is alkyl, cycloalkyl aryl or heteroaryl, or for where the substituent is Y 1 Y 2 N—, then one of Y 1 and Y 2 may be acyl, cyclylcarbonyl, aroyl, heteroaroyl, alkoxycarbonyl, cyclyloxycarbonyl, aryloxycarbonyl or heteroaryloxycarbonyl, as defined herein and the other of Y 1 and Y 2 is as defined previously, or for where the substituent is Y'Y 2 NC(O)—, Y 1 Y 2 NC(O)O—, Y 1 Y 2 NC(O)NY 3 — or Y 1 Y 2 NSO 2 —, Y 1 and Y 2 may also be taken together with the N atom through which Y 1 and Y 2 are linked to form a 4 to 7 membered azaheterocyclyl or azaheterocyclenyl.
137 . The process of claim 136 further comprising the step wherein the compound of formula 24 is prepared by effecting a Michael addition with an iminic glycinimide compound on a compound of formula 29
wherein:
is optionally substituted cycloalkenyl or optionally substituted fused arylcycloalkenyl;
wherein:
the compound of formula 29 may be prepared by esterifying a compound of formula 29a
wherein:
R 11a is —CHO, —COR 15 , C≡N, or —CONR 15 R 15 .
138 . The process of claim 137 wherein the process is carried out at a temperature between 0° C. and −78° C.
139 . The process of claim 138 wherein the process is carried out at −60°.
140 . The process of claim 139 wherein the process is catalyzed by a chiral phase transfer catalyst.
141 . The process of claim 139 wherein the process is catalyzed by a nonchiral phase transfer catalyst.
142 . The process of any one of claims 135 to 141 wherein the protecting group is BOC.
143 . The process of claim 142 wherein the iminic glycinimide is (N-diphenylmethylene)-glycine tert-butyl ester.
143 . The process of claim 142 wherein the compound of formula 29 is 1-carboxy-1-cyclopentene methyl ester.
144 . A compound of claim 1 having the structural formula:
wherein:
R 1 is hydrogen, optionally substituted aliphatic group, optionally substituted cyclic group or optionally substituted aromatic group;
R 2 and R 9 are each independently optionally substituted aliphatic group, optionally substituted cyclic group or optionally substituted aromatic group;
R 3 , R 5 and R 7 are each independently methanediyl or ethanediyl, substituted with one substituent selected from the group consisting of an optionally substituted aliphatic group, an optionally substituted cyclic group or an optionally substituted aromatic group and wherein the methanediyl or ethanediyl is further optionally substituted with an aliphatic group substituent;
R 4 , R 6 , R 8 and R 10 are each independently is hydrogen or optionally substituted aliphatic group;
is substituted monocyclic azaheterocyclyl or optionally substituted multicyclic azaheterocyclyl, or optionally substituted multicyclic azaheterocyclenyl wherein the unsaturatation is in the ring distal to the ring bearing the R 9 -L-(N(R 8 )—R 7 —C(O)—) n N(R 6 )—R 5 —C(O)—N moiety and to which the —C(O)—N(R 4 )—R 3 —C(O)C(O)NR 2 R 1 moiety is attached;
L is —C(O)—, —OC(O)—, —NR 10 C(O)—, —S(O) 2 —, or —NR 10 S(O) 2 —; and
n is 0 or 1, or
a pharmaceutically acceptable salt or prodrug thereof, or a solvate of such a compound, its salt or its prodrug, provided
when
is substituted
then L is —OC(O)— and R 9 is optionally substituted aliphatic, or at least one of R 3 , R 5 and R 7 is methanediyl or ethanediyl, substituted with at least one substituent selected from the group consisting of an optionally substituted aliphatic group, an optionally substituted cyclic group or an optionally substituted aromatic group and wherein the methanediyl or ethanediyl is further optionally substituted with an aliphatic group substituent, or R 4 is optionally substituted aliphatic.
145 . A compound of claim 144 wherein:
optionally substituted aliphatic groups are alkyl, alkenyl or alkynyl, optionally substituted with one or more aliphatic group substituent;
optionally substituted cyclic groups are cycloalkyl, cycloalkenly, heterocyclyl or heterocyclenyl groups optionally substituted with one or more ring group substituents;
optionally substituted aromatic groups are aryl or heteroaryl groups optionally substituted with one or more ring group substituents;
optionally substituted (1,1- or 1,2) cycloalkylene groups are (1,1- or 1,2) cycloalkylene groups
optionally substituted with one or more ring group substituents;
optionally substituted (1,1- or 1,2) heterocyclylene groups are (1,1- or 1,2) heterocyclylene groups optionally substituted with one or more ring group substituents;
as substituted monocyclic azaheterocyclyl is a monocyclic azaheterocyclyl group substituted directly or through a linker group by at least one substituent selected from aryl, heteroaryl, aryloxy, heteroaryloxy, aroyl or its thio analogue, heteroaryl or its thioxo analogue, aroyloxy, heteroaroyloxy, aryloxycarbonyl, heteroaryloxycarbonyl, arylsulfonyl, heteroarylsulfonyl, arylsulfinyl, heteroarylsulfinyl, arylthio, heteroarylthio, aryldiazo, heteroaryldiazo, Y 1 Y 2 N, Y 1 Y 2 NC(O)—, Y 1 Y 2 NC(O)O—, Y 1 Y 2 NC(O)NY 3 — or Y 1 Y 2 NSO 2 — wherein at least one of Y 1 and Y 2 is aryl or heteroaryl, wherein said linker group is selected from the group consisting of —C(O)—, —OC(O)—, lower alkyl, lower alkoxy, lower alkenyl, —O—, —S—, —C(O)C(O)—, —S(O)—, —S(O) 2 —, —NR 80 —, where R 80 is hydrogen, alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl or heteroaryl;
optionally substituted multicyclic azaheterocyclyl is a multicyclic azaheterocyclyl group optionally substituted by one or more ring group substituents;
optionally substituted multicyclic azaheterocyenyl is a multicyclic azaheterocyclenyll group optionally substituted by one or more ring group substituents;
wherein:
aliphatic group substituents means aryl, heteroaryl, hydroxy, alkoxy, cyclyloxy, aryloxy, heteroaryloxy, acyl or its thioxo analogue, cyclylcarbonyl or its thioxo analogue, aroyl or its thioxo analogue, heteroaroyl or its thioxo analogue, acyloxy, cyclylcarbonyloxy, aroyloxy, heteroaroyloxy, halo, nitro, cyano, carboxy (acid), —C(O)—NHOH, —C(O)—CH 2 OH, —C(O)—CH 2 SH, —C(O)—NH—CN, sulpho, phosphono, alkylsulphonylcarbamoyl, tetrazolyl, arylsulphonylcarbamoyl, N-methoxycarbamoyl, heteroarylsulphonylcarbarnoyl, 3-hydroxy-3-cyclobutene-1,2-dione, 3,5-dioxo-1,2,4-oxadiazolidinyl or hydroxyheteroaryl such as 3-hydroxyisoxazolyl, 3-hydoxy-1-methylpyrazolyl, alkoxycarbonyl, cyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylsulfonyl, cyclylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, cyclylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, cyclylthio, arylthio, heteroarylthio, cyclyl, aryldiazo, heteroaryldiazo, thiol, methylene (H 2 C═), oxo (O═), thioxo (S═), Y 1 Y 2 N—, Y 1 Y 2 NC(O)—, Y 1 Y 2 NC(O)O 3 —, Y 1 Y 2 NY 3 —, Y 1 Y 2 NSO 2 —, or Y 3 SO 2 NY 1 — wherein R 2 is as defined herein, Y 1 and Y 2 are independently hydrogen, alkyl, aryl or heteroaryl, and Y 3 is alkyl, cycloalkyl aryl or heteroaryl, or for where the substituent is Y 1 Y 2 N—, then one of Y 1 and Y 2 may be acyl, cyclylcarbonyl, aroyl, heteroaroyl, alkoxycarbonyl, cyclyloxycarbonyl, aryloxycarbonyl or heteroaryloxycarbonyl, as defined herein and the other of Y 1 and Y 2 is as defined previously, or for where the substituent is Y 1 Y 2 NC(O)—, Y 1 Y 2 NC(O)O—, Y 1 Y 2 NC(O)NY 3 — or Y 1 Y 2 NSO 2 —, Y 1 and Y 2 may also be taken together with the N atom through which Y 1 and Y 2 are linked to form a 4 to 7 membered azaheterocyclyl or azaheterocyclenyl;
ring group substituents means aryl, heteroaryl, hydroxy, alkoxy, cyclyloxy, aryloxy, heteroaryloxy, acyl or its thioxo analogue, cyclylcarbonyl or its thioxo analogue, aroyl or its thioxo analogue, heteroaroyl or its thioxo analogue, acyloxy, cyclylcarbonyloxy, aroyloxy, heteroaroyloxy, halo, nitro, cyano, carboxy (acid), acid biostere, alkoxycarbonyl, cyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylsulfonyl, cyclylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, cyclylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, cyclylthio, arylthio, heteroarylthio, cyclyl, aryldiazo, heteroaryldiazo, thiol, Y 1 Y 2 N—, Y 1 Y 2 NC(O)—, Y 1 Y 2 NC(O)O—, Y 1 Y 2 NC(O)NY 3 — or Y 1 Y 2 NSO 2 —, wherein Y 1 , Y 2 and Y 3 are independently hydrogen, alkyl, aryl or heteroaryl, or for where the substituent is Y 1 Y 2 N—, then one of Y 1 and Y 2 may be acyl, cyclylcarbonyl, aroyl, heteroaroyl, alkoxycarbonyl, cyclyloxycarbonyl, aryloxycarbonyl or heteroaryloxycarbonyl, as defined herein and the other of Y 1 and Y 2 is as defined previously, or for where the substituent is Y 1 Y 2 NC(O)—, Y 1 Y 2 NC(O)O—, Y 1 Y 2 NC(O)NY 3 — or Y 1 Y 2 NSO 2 —, Y 1 and Y 2 may also be taken together with the N atom through which Y 1 and Y 2 are linked to form a 4 to 7 membered azaheterocyclyl or azaheterocyclenyl, or when a ring system is saturated or partially saturated, the “ring group substituents” further include, methylene (H 2 C═), oxo (O═) and thioxo (S═);
aryl means an aromatic monocyclic or multicyclic ring system of 6 to 14 carbon atoms;
cycloalkyl means a non-aromatic mono- or multicyclic ring system of 3 to 10 carbon atoms;
cycloalkenyl means a non-aromatic mono- or multicyclic ring system of 3 to 10 carbon atoms which contain at least one carbon-carbon double bond;
cyclyl means cycloalkyl, cycloalkenyl, heterocyclyl or heterocyclenyl;
heterocyclyl means a non-aromatic saturated monocyclic or multicyclic ring system of about 3 to about 10 carbon atomsin which one or more of the carbon atoms in the ring system is/are hetero element(s) other than carbon;
heterocyclenyl means a non-aromatic monocyclic or multicyclic hydrocarbon ring system of about 3 to about 10 carbon atoms in which one or more of the carbon atoms in the ring system is/are hetero element(s) other than carbon and which contains at least one carbon-carbon double bond or carbon-nitrogen double bond; and
heteroaryl means an aromatic monocyclic or multicyclic ring system of about 5 to about 14 carbon atoms, in which one or more of the carbon atoms in the ring system is/are hetero element(s) other than carbon.
146 . The compound of any one of claims 143 to 145 wherein R 2 is 1-carboxy-2-phenylethyl, cyclopropyl, carboxymethyl, cyclobutyl, 1-phenylethyl, but-2-yl, 1-pyrid-4-ylethyl, or propen-3-yl.
147 . The compound of any one of claims 143 to 146 wherein R 3 is optionally substituted lower aliphatic group methanediyl.
148 . The compound of any one of claims 143 to 147 wherein R 3 is optionally halo substituted lower (alkyl or alkenyl) group methanediyl.
149 . The compound of any one of claims 143 to 148 wherein R 3 is propylmethanediyl, 2,2-difluoroethylmethanediyl, 2,2,2-trifluoromethanediyl or propen-3-ylmethanediyl; more preferred R 3 is propylmethanediyl, 2,2-difluoroethylmethanediyl.
150 . The compound of any one of claims 143 to 149 wherein R 5 is optionally substituted lower aliphatic group methanediyl.
151 . The compound of any one of claims 143 to 150 wherein R 5 is optionally (phenyl, carboxy, carboxamido or alkoxycarbonyl) substituted lower (alkyl or alkenyl) methanediyl.
152 . The compound of any one of claims 143 to 151 wherein R 5 is methylmethanediyl, isopropylmethanediyl, t-butylmethanediyl, but-2-ylmethanediyl, butylmethanediyl, benzylmethanediyl, 3-methylbutylmethanediyl, 2-methylpropylmethanediyl, carboxymethylmethanediyl, carboxamidomethylmethanediyl, benzyloxycarbonylmethyl-methanediyl, benzyloxycarbonylpropylmethanediyl, phenylpropen-3-ylmethanediyl.
153 . The compound of any one of claims 143 to 152 wherein R 7 is optionally substituted lower aliphatic group methanediyl or optionally substituted lower cyclic group methanediyl.
154 . The compound of any one of claims 143 to 153 wherein R 7 is optionally substituted lower alkylmethanediyl or optionally substituted lower cycloalkylmethanediyl.
155 . The compound of any one of claims 143 to 154 wherein R 7 is isopropylmethanediyl or cyclohexylmethanediyl.
156 . The compound of any one of claims 143 to 155 wherein R 9 is optionally (carboxy, (lower alkyl)HNCO-,hydroxy, phenyl or heteroaryl)substituted lower alkyl or optionally substituted monocyclic heteroaryl.
157 . The compound of any one of claims 143 to 1556 wherein 9 is isopropyl or t-butyl.
158 . The compound of any one of claims 143 to 157 wherein R 9 is selected from the group consisting of:
159 . The compound of any one of claims 143 to 158 wherein
as a substituted monocyclic azaheterocyclyl is optionally substituted
or optionally substituted
wherein Ar is R 2 that comprises an aromatic moiety/substituent.
160 . The compound of claim 144 selected from the following compounds:
161 . The compound of claim 144 selected from the group consisting of:
161 . A compound of the formula
or a pharmaceutically acceptable salt or prodrug thereof, or a solvate of such a compound, its salt or its prodrug.
162 . A compound of claim 1 or 2 wherein:
R 0 is a bond;
R 1 is hydrogen;
R 2 is lower alkyl optionally substituted with 1 to 3 aliphatic group substituents; or
lower cycloalky optionally substituted with 1 to 3 cyclic group substituents;
R 3 and R 5 are each independently methylene optionally substituted with 1 to 3 aliphatic group substituents;
R 4 , R 6 , R 8 and R 10 are hydrogen;
R 7 is methylene substituted with cycloalkyl, lower alkyl or aryl; or
or (1,1- or 1,2-)cycloalkenyl optionally substituted with cycloalkyl, lower alkyl or aryl;
R9 is
lower alkyl optionally substituted with 1 to 3 aliphatic group substituents; or
heteroaryl optionally substituted with 1 to 3 cyclic group substituents;
or heterocyclic optionally substituted with 1 to 3 cyclic group substituents;
is monocyclic azaheterocyclyl, multicyclic azaheterocyclyl, or multicyclic azaheterocyclenyl optionally substituted with from 1 to 3 cyclic group substituents; and
L is —C(O)—, —OC(O)—.
163 . A compound of claim 163 wherein:
aliphatic group substituents means aryl, heteroaryl, hydroxy, alkoxy, cyclyloxy, aryloxy, heteroaryloxy, acyl or its thioxo analogue, cyclylcarbonyl or its thioxo analogue, aroyl or its thioxo analogue, heteroaroyl or its thioxo analogue, acyloxy, cyclylcarbonyloxy, aroyloxy, heteroaroyloxy, halo, nitro, cyano, carboxy (acid), —C(O)—NHOH, —C(O)—CH 2 OH, —C(O)—CH 2 SH, —C(O)—NH—CN, sulpho, phosphono, alkylsulphonylcarbamoyl, tetrazolyl, arylsulphonylcarbamoyl, N-methoxycarbamoyl, heteroarylsulphonylcarbamoyl, 3-hydroxy-3-cyclobutene-1,2-dione, 3,5-dioxo-1,2,4-oxadiazolidinyl or hydroxyheteroaryl such as 3-hydroxyisoxazolyl, 3-hydoxy-1-methylpyrazolyl, alkoxycarbonyl, cyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylsulfonyl, cyclylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, cyclylsulfinyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, cyclylthio, arylthio, heteroarylthio, cyclyl, aryldiazo, heteroaryldiazo, thiol, methylene (H 2 C═), oxo (O═), thioxo (S═), Y 1 Y 2 N—, Y 1 Y 2 NC(O)—, Y 1 Y 2 NC(O)O—, Y 1 Y 2 NC(O)NY 3 —, Y 1 Y 2 NSO 2 —, or Y 3 SO 2 NY 1 — wherein R 2 is as defined herein, Y 1 and Y 2 are independently hydrogen, alkyl, aryl or heteroaryl, and Y 3 is alkyl, cycloalkyl aryl or heteroaryl, or for where the substituent is Y 1 Y 2 N—, then one of Y 1 and Y 2 may be acyl, cyclylcarbonyl, aroyl, heteroaroyl, alkoxycarbonyl, cyclyloxycarbonyl, aryloxycarbonyl or heteroaryloxycarbonyl, as defined herein and the other of Y 1 and Y 2 is as defined previously, or for where the substituent is Y 1 Y 2 NC(O)—, Y 1 Y 2 NC(O)O—, Y 1 Y 2 NC(O)NY 3 — or Y 1 Y 2 NSO 2 —, Y 1 and Y 2 may also be taken together with the N atom through which Y 1 and Y 2 are linked to form a 4 to 7 membered azaheterocyclyl or azaheterocyclenyl;
ring group substituents means aryl, heteroaryl, hydroxy, alkoxy, cyclyloxy, aryloxy, heteroaryloxy, acyl or its thioxo analogue, cyclylcarbonyl or its thioxo analogue, aroyl or its thioxo analogue, heteroaroyl or its thioxo analogue, acyloxy, cyclylcarbonyloxy, aroyloxy, heteroaroyloxy, halo, nitro, cyano, carboxy (acid), acid biostere, alkoxycarbonyl, cyclyloxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, alkylsulfonyl, cyclylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, cyclylsulfonyl, arylsulfinyl, heteroarylsulfinyl, alkylthio, cyclylthio, arylthio, heteroarylthio, cyclyl, aryldiazo, heteroaryldiazo, thiol, Y 1 Y 2 N—, Y 1 Y 2 NC(O)—, Y 1 Y 2 NC(O)O—, Y 1 Y 2 NC(O)NY 3 — or Y 1 Y 2 NSO 2 —, wherein Y 1 , Y 2 and Y 3 are independently hydrogen, alkyl, aryl or heteroaryl, or for where the substituent is Y 1 Y 2 N—, then one of Y 1 and Y 2 may be acyl, cyclylcarbonyl, aroyl, heteroaroyl, alkoxycarbonyl, cyclyloxycarbonyl, aryloxycarbonyl or heteroaryloxycarbonyl, as defined herein and the other of Y 1 and Y 2 is as defined previously, or for where the substituent is Y 1 Y 2 NC(O)—, Y 1 Y 2 NC(O)O—, Y 1 Y 2 NC(O)NY 3 — or Y 1 Y 2 NSO 2 —, Y 1 and Y 2 may also taken together with the N atom through which Y 1 and Y 2 are linked to form a 4 to 7 membered azaheterocyclyl or azaheterocyclenyl, or when a ring system is saturated or partially saturated, the “ring group substituents” further include, methylene (H 2 C═), oxo (O═) and thioxo (S═); aryl means an aromatic monocyclic or multicyclic ring system of 6 to 14 carbon atoms; cycloalkyl means a non-aromatic mono- or multicyclic ring system of 3 to 10 carbon atoms; cycloalkenyl means a non-aromatic mono- or multicyclic ring system of 3 to 10 carbon atoms which contain at least one carbon-carbon double bond; cyclyl means cycloalkyl, cycloalkenyl, heterocyclyl or heterocyclenyl; heterocyclyl means a non-aromatic saturated monocyclic or multicyclic ring system of about 3 to about 10 carbon atomsin which one or more of the carbon atoms in the ring system is/are hetero element(s) other than carbon; and heteroaryl means an aromatic monocyclic or multicyclic ring system of about 5 to about 14 carbon atoms, in which one or more of the carbon atoms in the ring system is/are hetero element(s) other than carbon.
164 . Any compound or synthetic intermediate as substantially disclosed herein.
165 . A compound selected from the group consisting of:
or a pharmaceutically acceptable salt or prodrug thereof, or a solvate of such a compound, its salt or its prodrug.
166 . A compound of any one of claim 1 , 2 , 162 or 163 wherein the optionally substituted aliphatic group, optionally substituted cyclic group or optionally substituted aromatic group of R 9 is substituted with at least one heteroaryl substituent.
167 . A compound of any one of claim 1 , 2 , 162 or 163 wherein the optionally substituted aromatic group of R 9 is optionally substituted heteroaryl.
168 . A compound of claim 166 wherein the optionally substituted aliphatic group of R 9 is optionally substituted alkylheteroaryl.Cited by (0)
No later patents cite this yet.
References (0)
No backward citations on record.