US2009148407A1PendingUtilityA1
Novel Macrocyclic Inhibitors of Hepatitis C Virus Replication
Est. expiryJul 25, 2025(expired)· nominal 20-yr term from priority
Inventors:Lawrence M. BlattScott D. SeiwertSteven W. AndrewsPierre MartinAndreas SchumacherBradley BarnettC. Todd EaryRobert J. KausTimothy KercherWeidong LiuMichael LyonPaul NicholsBin WangTarek SammakiaApril L. KennedyYutong Jiang
A61P 31/14A61P 31/12A61P 43/00A61K 38/1793C07K 5/0804A61K 38/00A61K 38/2292A61K 38/217C07K 5/0806C07D 487/04A61P 1/16A61K 38/55A61K 38/212C07D 471/04A61K 31/407Y02A50/30
58
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Claims
Abstract
The embodiments provide compounds of the general Formulae (I) through general Formula (VIII), as well as compositions, including pharmaceutical compositions, comprising a subject compound. The embodiments further provide treatment methods, including methods of treating a hepatitis C virus infection and methods of treating liver fibrosis, the methods generally involving administering to an individual in need thereof an effective amount of a subject compound or composition.
Claims
exact text as granted — not AI-modified1 . A compound of the general formula (Ia) or (Ib)
or a pharmaceutically acceptable salt, prodrug, or ester thereof wherein:
R 1 is
p is 1;
R 2 is hydroxyl or NHR 5 ;
R 3 is selected from the group consisting of H, CH 2 R 6 , COR 6 CO 2 R 7 , CSNH 2 , optionally substituted 2-thiazole, and
R 4 is hydrogen or cyclopropylmethyl;
R 5 is selected from the group consisting of phenyl, CH 2 C(CF 3 ) 2 OH, C 3 -C 7 alkyl, cyclopropylcarbonyl, SO 2 R 8 , CN, and
R 6 is selected from the group consisting of R 9 , optionally-substituted phenyl, cyclopropyl, cyclobutyl, optionally-substituted furanyl, fluorinated alkyl, and hydroxylated alkyl;
R 7 is cyclopentyl or C 1 -C 6 alkyl;
R 8 is selected from the group consisting of NR 11 R 12 , tert-butyl, chloropyridinyl,
R 9 is selected from the group consisting of tert-butyl, trifluoromethyl, trifluoroethyl, and methyl trifluoromethyl;
R 10 is selected from the group consisting of H, C 1 to C 3 alkyl, 3-propenyl, methylmethoxyl, and benzyl;
R 11 is H, methyl, C 1-4 alkyl or C 1-4 fluorinated alkyl
R 12 is selected from the group consisting of C 1 to C 3 alkyl, 3-propenyl, phenyl,
chlorophenyl, dichlorophenyl, benzyl, pyridinyl, CH 2 R 13 , CH 2 R 16 R 17 , and fluorinated alkyl
or R 11 and R 12 taken together can form a 4 or 5 membered ring optionally substituted with 2 fluorines;
R 13 is pyridinyl or R 14 ;
R 14 is selected from the group consisting of pyridinyl, chlorophenyl, naphthyl, and anisolyl;
R 15 is NR 11 R 12 or alkyl or cycloalkyl;
R 16 is pyridinyl;
R 17 is H or methyl.
R 18 and R 19 are each independently H, halogen, methyl or CF 3 .
2 . A compound of the formula (Ic) or (Id):
or a pharmaceutically acceptable salt, prodrug, or ester thereof wherein:
R 1 is
wherein R 18 is H, fluoro, or trifluoromethyl, and p is 1
R 2 is hydroxyl or NHR 5 ;
R 3 is selected from the group consisting of H, CH 2 R 6 , COR 6 CO 2 R 7 ′, CSNH 2 , optionally substituted 2-thiazole, and
R 4 is hydrogen or cyclopropylmethyl;
R 5 is selected from the group consisting of phenyl, CH 2 C(CF 3 ) 2 OH, C 3 alkyl, cyclopropylcarbonyl, SO 2 R 8 , CN, and
R 6 is selected from the group consisting of R 9 , optionally-substituted phenyl, cyclopropyl, cyclobutyl, optionally-substituted furanyl, fluorinated alkyl, and hydroxylated alkyl;
R 7 is cyclopentyl or C 1 -C 6 alkyl;
R 8 is selected from the group consisting of NR 11 R 12 , tert-butyl, chloropyridinyl,
wherein R 18 and R 19 is independently H, halogen, methyl or CF 3 ;
R 9 is selected from the group consisting of tert-butyl, trifluoromethyl, and methyltrifluoromethyl;
R 10 is selected from the group consisting of H, C 1 to C 3 alkyl, 3-propenyl, methylmethoxyl, and benzyl;
R 11 is H, methyl, C 1-4 alkyl or C 1-4 fluorinated alkyl;
R 12 is selected from the group consisting of C 1 to C 3 alkyl, 3-propenyl, phenyl,
chlorophenyl, dichlorophenyl, benzyl, pyridinyl, CH 2 R 13 , CH 2 R 16 R 17 , and fluorinated alkyl,
or R 11 and R 12 taken together can form a 4 or 5 membered ring optionally substituted with 2 fluorines;
R 13 is pyridinyl or CH 2 R 14 ;
R 14 is selected from the group consisting of pyridinyl, chlorophenyl, naphthyl, and anisolyl;
R 15 is NR 11 R 12 or alkyl or cycloalkyl;
R 16 is pyridinyl;
R 17 is H or methyl.
3 . (canceled)
4 . The compound of claim 1 , wherein R 1 is:
5 . A compound of the general formula (II):
or a pharmaceutically acceptable salt, prodrug, or ester thereof wherein:
R 3 is selected from the group consisting of H, CH 2 R 6 , COR 6 , CO 2 R 7 , and optionally substituted 2-thiazole;
R 5 is selected from the group consisting of cyclopropylmethyl or SO 2 R 8 ;
R 6 is selected from the group consisting of R 9 , optionally-substituted phenyl, cyclopropyl, cyclobutyl, optionally-substituted furanyl, fluorinated alkyl, and hydroxylated alkyl;
R 7 is cyclopentyl or C 1 -C 6 alkyl;
R 8 is selected from the group consisting of NR 11 R 12 , optionally substituted phenyl, and
R 9 is selected from the group consisting of tert-butyl, trifluoromethyl, trifluoroethyl, and methyl trifluoromethyl;
R 10 is selected from the group consisting of H, C 1 to C 3 alkyl, 3-propenyl, methylmethoxyl, and benzyl;
R 11 is H, methyl, C 1-4 alkyl, or C 1-4 fluorinated alkyl;
R 12 is selected from the group consisting of C 1 to C 3 alkyl, 3-propenyl, phenyl,
chlorophenyl, dichlorophenyl, benzyl, pyridinyl, CH 2 R 13 , CH 2 R 16 R 17 , and fluorinated alkyl,
or R 11 and R 12 taken together can form a 4 or 5 membered ring optionally substituted with 2 fluorines;
R 13 is pyridinyl or R 14 ;
R 14 is selected from the group consisting of pyridinyl, chlorophenyl, naphthyl, and anisolyl;
R 16 is pyridinyl;
R 17 is H or methyl;
R 18 and R 19 are independently H, halogen, methyl, or CF 3 ;
W is
R 20 is H, CH 3 , alkyl, fluorinated alkyl, or SO 2 Ar; and
the 12-13 bond is a single or double bond.
6 . The compound of claim 5 having the structure:
or a pharmaceutically acceptable salt, prodrug, or ester thereof.
7 . The compound of claim 1 , wherein R 2 is NHR 5 .
8 . The compound of claim 5 , wherein R 5 is SO 2 R 8 .
9 . The compound of claim 8 , wherein R 8 is NR 11 R 12 .
10 . The compound of claim 8 , wherein R 8 is
11 . The compound of claim 1 , wherein R 3 is CO 2 R 7 .
12 . The compound of claim 1 , wherein R 3 is CH 2 R 6 .
13 . The compound of claim 1 , wherein R 3 is H.
14 . A compound of claim 1 , wherein R 3 is a substituted thiazole of the general structure:
wherein:
R 19 is independently H, halogen, methyl or CF 3 ; and
R 20 is independently H or an optionally substituted phenyl ring.
15 . (canceled)
16 . A compound having the Formula III:
or a pharmaceutically acceptable salt, prodrug, or ester thereof wherein:
B ring is
Z is bond, O, or S;
R 1 is H, C 1-7 alkyl, C 3-7 cycloalkyl, pyridyl, thioazolo, naphthyl, fused heterocycle, phenyl, substituted phenyl, benzyloxy, or substituted benzyloxy;
W is
R 3 is H, C 1-8 alkyl, C 3-7 cycloalkyl, C 4-10 cycloalkyl-alkyl, C 1-6 alkyl, C 4-10 cycloalkyl-alkyl, C 7-10 arylalkyl, or C 6-12 heteroarylalkyl;
R 4 and R 5 are each independently substituted or unsubstituted groups selected from H, C 1-6 alkyl, C(O)R 8 , C(O)OR 8 , C 3-7 cycloalkyl, alkyl-C 4-10 cycloalkyl, phenyl, benzyl, C(O)NR 8 R 8 , C(S)NR 8 R 8 , S(O) 2 R 8 , or (CO)CHR 21 NH(CO)R 22 ;
wherein R 8 is a substituted or unsubstituted group selected from H, C 1-6 alkyl, C 3-7 cycloalkyl, alkyl-C 3-7 cycloalkyl, C 6 or 10 aryl, alkyl-C 6 or 10 aryl, C 3-7 cycloalkyl fused to C 6 aryl or C 6 aryl heterocyclyl, tetrahydrofuran ring, tetrahydropyranyl ring, benzyl, or phenyl;
R 21 is a substituted or unsubstituted group selected from C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 cycloalkyl-alkyl, phenyl, C 6-10 aryl, pyridyl, pyrimidyl, pyrazinyl, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, or thiophenoxy;
R 22 is a substituted or unsubstituted group selected from C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 cycloalkyl-alkyl, or phenyl;
Y has a formula selected from —C(O)NHS(O) 2 R 1a , —C(O)NHS(O) 2 NR 1a R 1b , —C(O)NHR 1a , —C(O)R 1a , —C(O)NHC(O)R 1a , —C(O)NHS(O) 2 R 1a , —C(O)NHS(O) 1a , or —C(O)OH;
wherein R 1a and R 1b are each independently substituted or unsubstituted groups selected from H, CN, CF 3 , C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, C 3-7 cycloalkyl, alkyl-C 3-10 cycloalkyl, C 6 or 10 aryl, alkyl-C 6 or 10 aryl, alkenyl-C 6 or 10 aryl, heterocycle, heteroaromatic ring, or alkyl-heteroaryl, alkyl-heterocycle,
or NR 1a R 1b form a substituted or unsubstituted three- to seven-membered ring, or NR 1a R 1b is a heteroaryl selected from the group consisting of:
wherein R 1c is H, halo, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, NO 2 , N(R 1d ) 2 , NH(CO)R 1d , or NH(CO)NHR 1d , wherein each R 1d is independently H, C 1-6 alkyl, or C 3-6 cycloalkyl,
or R 1c is NH(CO)OR 1e , wherein R 1e is C 1-6 alkyl or C 3-6 cycloalkyl; and the dashed line represents an optional double bond.
17 . The compound of claim 16 , wherein:
W is
R 3 is H or C 1-3 alkyl;
R 4 and R 5 are each independently substituted or unsubstituted groups selected from H, C 1-6 alkyl, C(O)R 8 , C(O)OR 8 , C 3-7 cycloalkyl, alkyl-C 4-10 cycloalkyl, phenyl, or benzyl;
R 8 is a substituted or unsubstituted group selected from C 1-6 alkyl, C 3-7 cycloalkyl, alkyl-C 3-7 cycloalkyl, C 6 or 10 aryl, or alkyl-C 6 or 10 aryl; and
R 1a and R 1b are each independently substituted or unsubstituted groups selected from H, CN, CF 3 , C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, C 3-7 cycloalkyl, alkyl-C 3-10 cycloalkyl, C 6 or 10 aryl, alkyl-C 6 or 10 aryl, alkenyl-C 6 or 10 aryl, heterocycle, or alkyl-heterocycle,
or NR 1a R 1b form a substituted or unsubstituted three- to seven-membered ring.
18 . A compound having the Formula IV:
or a pharmaceutically acceptable salt, prodrug, or ester thereof wherein:
W is
R 3 is H or C 1-3 alkyl;
R 4 and R 5 are independently substituted or unsubstituted groups selected from H, C 1-6 alkyl, C(O)R 8 , C(O)OR 8 , C 3-7 cycloalkyl alkyl-C 4-10 cycloalkyl, phenyl, or benzyl;
wherein R 8 is a substituted or unsubstituted group selected from C 1-6 alkyl, C 3-7 cycloalkyl, alkyl-C 3-7 cycloalkyl, C 6 or 10 aryl, or alkyl-C 6 or 10 aryl;
Y has a formula selected from —C(O)NHS(O) 2 R 1a , —C(O)NHS(O) 2 NR 1a R 1b , —C(O)NHR 1a , —C(O)R 1a , —C(O)NHC(O)R 1a , —C(O)NHS(O) 2 R 1a , —C(O)NHS(O)R 1a , or —C(O)OH;
wherein R 1a and R 1b are each independently substituted or unsubstituted groups selected from H, CN, CF 3 , C 1-6 alkyl, C 1-6 alkenyl, C 1-6 alkynyl, C 3-7 cycloalkyl, alkyl-C 3-10 cycloalkyl, C 6 or 10 aryl, alkyl-C 6 or 10 aryl, alkenyl-C 6 or 10 aryl, heterocycle, or alkyl-heterocycle,
or NR 1a R 1b form a substituted or unsubstituted three- to seven-membered ring, and
the dashed line represents an optional double bond.
19 - 36 . (canceled)
37 . A compound having the Formula VII:
or a pharmaceutically acceptable salt, prodrug, or ester thereof wherein:
Q is a unsubstituted or substituted core ring
where p is 0,
or Q is R 1 -R 2 , wherein R 1 is a substituted or unsubstituted group selected from C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 cycloalkyl-alkyl, phenyl, pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, furan, thiophene, thiazole, oxazole, imidazole, isoxazole, pyrazole, isothiazole, naphthyl, quinoline, isoquinoline, quinoxaline, benzothiazole, benzothiophene, benzofuran, indole, or benzimidazole; and R 2 is a substituted or unsubstituted group selected from H, phenyl, pyridine, pyrazine, pyrimidine, pyridazine, pyrrole, furan, thiophene, thiazole, oxazole, imidazole, isoxazole, pyrazole, isothiazole, naphthyl, quinoline, isoquinoline, quinoxaline, benzothiazole, benzothiophene, benzofuran, indole, or benzimidazole;
R 4 is selected from H, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 cycloalkyl-alkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted benzyl;
R 5 is H, C 1-6 alkyl, C(O)NR 6 R 7 , C(S)NR 6 R 7 , C(O)R 8 , C(O)OR 8 , S(O) 2 R 8 , or (CO)CHR 21 NH(CO)R 22 ;
R 6 and R 7 are each independently H, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 cycloalkyl-alkyl, or substituted or unsubstituted phenyl, or R 6 and R 7 are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
R 8 is a substituted or unsubstituted group selected from C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 cycloalkyl-alkyl, phenyl, C 6 or 10 aryl, C 1-6 alkoxy, C 1-6 alkyl, tetrahydrofuran ring, or tetrahydropyranyl ring;
V is selected from O;
W is selected from O,
Y is an amide of the formula C(O)NHR 9 , wherein R 9 is a substituted or unsubstituted group selected from C 1-6 alkyl, phenyl, cyano, C 3-7 cycloalkyl, or C 4-10 cycloalkyl-alkyl, C 5-10 arylalkyl, or heteroarylalkyl;
or Y is an acyl sulfonimide of the formula —C(O)NHS(O)R 9 , wherein R 9 is a substituted or unsubstituted group selected from C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 cycloalkyl-alkyl, C 5-10 arylalkyl, C 6 or 10 aryl, or heteroaromatic ring;
the dashed line represents an optional double bond;
R 21 is a substituted or unsubstituted group selected from C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 cycloalkyl-alkyl, phenyl, C 6 or 10 aryl, pyridyl, pyrimidyl, pyrazinyl, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, or thiophenoxy; and
R 22 is a substituted or unsubstituted group selected from C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 cycloalkyl-alkyl, or phenyl.
38 . The compound of claim 37 , wherein the core ring is substituted with H, halo, cyano, nitro, hydroxy, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 cycloalkyl-alkyl, C 2-6 alkenyl, C 1-6 alkoxy, hydroxy-C 1-6 alkyl, C 1-6 alkyl, substituted C 1-6 alkyl, C 1-6 alkoxy, substituted C 1-6 alkoxy, C 6 or 10 aryl, pyridyl, pyrimidyl, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, thiophenoxy, sulphonamido, urea, thiourea, amido, keto, carboxyl, carbamyl, sulphide, sulphoxide, sulphone, amino, alkoxyamino, alkyoxyheterocyclyl, alkylamino, alkylcarboxy, carbonyl, spirocyclic cyclopropyl, spirocyclic cyclobutyl, spirocyclic cyclopentyl, or spirocyclic cyclohexyl.
39 . The compound of claim 37 , wherein R 1 or R 2 is substituted with NR 6 R 7 , halo, cyano, nitro, hydroxy, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 cycloalkyl-alkyl, C 2-6 alkenyl, C 1-6 alkoxy, hydroxy-C 1-6 alkyl, C 1-6 alkyl optionally substituted with up to 5 fluoro, or C 1-6 alkoxy optionally substituted with up to 5 fluoro.
40 . The compound of claim 37 , wherein phenyl or benzyl groups are substituted with up to three halo, cyano, nitro, hydroxy, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 cycloalkyl-alkyl, C 2-6 alkenyl, C 1-6 alkoxy, hydroxy-C 1-6 alkyl, C 1-6 alkyl optionally substituted with up to 5 fluoro, or C 1-6 alkoxy optionally substituted with up to 5 fluoro.
41 . The compound of claim 37 , wherein R 8 is substituted with halo, cyano, nitro, hydroxy, phenyl, C 3-7 cycloalkyl, C 4-10 cycloalkyl-alkyl, C 2-6 alkenyl, hydroxy-C 1-6 alkyl, C 1-6 alkyl, substituted C 1-6 alkyl with up to 5 fluoro, C 1-6 alkoxy, or substituted C 1-6 alkoxy with up to 5 fluoro.
42 . The compound of claim 37 , wherein R 8 is a tetrahydrofuran ring linked through the C 3 or C 4 position of the tetrahydrofuran ring; or R 8 is a tetrahydropyranyl ring linked through the C 4 position of the tetrahydropyranyl ring.
43 . The compound of claim 37 , wherein R 9 is substituted with alkyl, trifluoromethyl, halo, cyano, nitro, hydroxy, C 1-6 alkoxy, carboxylic acid, carboxylic ester, carboxyamide, phenyl, cycloalkyl, cycloalkyl-alkyl, alkenyl, hydroxyalkyl, substituted C 1-6 alkyl with up to 5 fluoro, substituted C 1-6 alkoxy with up to 5 fluoro.
44 . The compound of claim 37 , wherein R 21 is substituted with halo, cyano, nitro, hydroxy, C 1-6 alkoxy, C 1-6 alkyl optionally substituted with up to 5 fluoro, phenyl, C 3-7 cycloalkyl, C 4-10 cycloalkyl-alkyl, C 2-6 alkenyl, hydroxy-C 1-6 alkyl, substituted C 1-6 alkyl substituted with up to 5 fluoro, or substituted C 1-6 alkoxy substituted with up to 5 fluoro.
45 . The compound of claim 37 , wherein R 22 is substituted with halo, cyano, nitro, hydroxy, C 1-6 alkyl optionally substituted with up to 5 fluoro, or phenyl.
46 . (canceled)
47 . The compound of claim 37 have the structure of the Formula VIIa.
wherein the dashed line between positions 13 and 14 represents an optional cis double bond.
48 . A compound of claim 47 , wherein Y is an amide of the formula —C(O)NHR 9 , where R 9 is selected from the group consisting CH 2 —C 3-6 cycloalkyl, CH(CH 3 )C 6-10 cycloalkyl, CH 2 C 6-10 aryl, CH(CH 3 )C 6-10 aryl CH 2 heteroaryl, CH(CH 3 ) heteroaryl which are all optionally substituted from one to two times with alkyl, trifluoromethyl, halo, cyano or C 1-3 alkoxy.
49 . A compound of claim 47 , wherein Y is an acyl sulfoxide of the formula —C(O)NHS(O)R 9 , where R 9 is C 1-6 alkyl, C 3-7 cycloalkyl, or C 4-10 cycloalkyl-alkyl, C 5-10 arylalkyl which are all optionally substituted from one to two times with alkyl, halo, cyano, nitro, hydroxy, or C 1-6 alkoxy, or R 9 is C 6 or 10 aryl which is optionally substituted by up to two times by alkyl, halo, cyano, nitro, hydroxy, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 cycloalkyl-alkyl, C 2-6 alkenyl, hydroxy-C 1-6 alkyl, or C 1-6 alkyl optionally substituted with up to 5 fluoro, C 1-6 alkoxy optionally substituted with up to 3 fluoro.
50 . The compound of claim 47 , wherein Q is a core ring selected from:
optionally substituted with up to two NR 6 R 7 , halo, cyano, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 cycloalkyl-alkyl, C 2-6 alkenyl, C 1-6 alkoxy, hydroxy-C 1-6 alkyl, or C 1-6 alkyl optionally substituted with up to 5 fluoro, C 1-6 alkoxy optionally substituted with up to 5 fluoro.
51 . A compound having the structure of Formula VIII:
or a pharmaceutically acceptable salt, prodrug, or ester thereof wherein:
Q is an unsubstituted or substituted core ring selected from:
Z is a C 5-7 saturated or unsaturated chain containing one or two heteroatoms selected from O, S, or NR 6 ;
R 4 is H, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 cycloalkyl-alkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted benzyl;
R 5 is H, C 1-6 alkyl, C(O)NR 6 R 7 , C(O)NHR 8 , C(S)NR 6 R 7 , C(O)R 8 , C(O)OR 8 , S(O) 2 R 8 , or (CO)CHR 21 NH(CO)R 22 ;
R 6 and R 7 are each independently H, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 cycloalkyl-alkyl, or substituted or unsubstituted phenyl;
R 8 is a substituted or unsubstituted group selected from C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 cycloalkyl-alkyl, phenyl, C 6 or 10 aryl, C 1-6 alkyl, tetrahydrofuran ring, tetrahydropyranyl ring;
Y is a sulfonimide of the formula —C(O)NHS(O) 2 R 9 , wherein R 9 is a substituted or unsubstituted group selected from C 1-6 alkyl, C 3-7 cycloalkyl, or C 4-10 cycloalkyl-alkyl, C 6 or 10 aryl, C 1-6 alkyl, NR 6 R 7 , NR 1a R 1b , or a heteroaromatic ring,
or Y is a carboxylic acid or pharmaceutically acceptable salt, solvate, or prodrug thereof;
wherein R 1a and R 1b are each independently H or a substituted or unsubstituted group selected from C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 cycloalkyl-alkyl, or C 6 or 10 aryl,
or R 1a and R 1b are each independently H, heterocycle, which is a five-, six-, or seven-membered, saturated or unsaturated heterocyclic molecule, containing from one to four heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur,
or NR 1a R 1b is a three- to six-membered optionally substituted alkyl cyclic secondary amine,
or NR 1a R 1b is a heteroaryl selected from the group consisting of:
wherein R 1c is H, halo, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, NO 2 , N(R 1d ) 2 , NH(CO)R 1d , or NH(CO)NHR 1d , wherein each R 1d is independently H, C 1-6 alkyl, or C 3-6 cycloalkyl,
or R 1c is NH(CO)OR 1e , wherein R 1c is C 1-6 alkyl or C 3-6 cycloalkyl;
V is selected from O;
W is selected from O;
the dashed lines represent an optional double bond;
R 21 is a substituted or unsubstituted group selected from C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 cycloalkyl-alkyl, phenyl, C 6 or 10 aryl, pyridyl, pyrimidyl, pyrazinyl, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, or thiophenoxy; and
R 22 is a substituted or unsubstituted group selected from C 1-6 alkyl, C 3-7 cycloalkyl, or C 4-10 cycloalkyl-alkyl, or phenyl.
52 . The compound of claim 51 , wherein the core ring is substituted with H, halo, cyano, nitro, hydroxy, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 cycloalkyl-alkyl, C 2-6 alkenyl, C 1-6 alkoxy, hydroxy-C 1-6 alkyl, C 1-6 alkyl, substituted C 1-6 alkyl, C 1-6 alkoxy, substituted C 6-6 alkoxy, C 6 or 10 aryl, pyridyl, pyrimidyl, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, thiophenoxy, sulphonamido, urea, thiourea, amido, keto, carboxyl, carbamyl, sulphide, sulphoxide, sulphone, amino, alkoxyamino, alkyoxyheterocyclyl, alkylamino, alkylcarboxy, carbonyl, spirocyclic cyclopropyl, spirocyclic cyclobutyl, spirocyclic cyclopentyl, or spirocyclic cyclohexyl.
53 . (canceled)
54 . The compound of claim 51 , wherein phenyl or benzyl groups are substituted with up to three halo, cyano, nitro, hydroxy, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 cycloalkyl-alkyl, C 2-6 alkenyl, C 1-46 alkoxy, hydroxy-C 1-6 alkyl, C 1-6 alkyl optionally substituted with up to 5 fluoro, or C 1-6 alkoxy optionally substituted with up to 5 fluoro.
55 . The compound of claim 51 , wherein R 8 is substituted with halo, cyano, nitro, hydroxy, phenyl, C 3-7 cycloalkyl, C 4-10 cycloalkyl-alkyl, C 2-6 alkenyl, hydroxy-C 1-6 alkyl, C 1-6 alkyl, substituted C 1-6 alkyl with up to 5 fluoro, C 1-6 alkoxy, or substituted C 6-34 alkoxy with up to 5 fluoro.
56 . The compound of claim 51 , wherein R 5 is a tetrahydrofuran ring linked through the C 3 or C 4 position of the tetrahydrofuran ring; or R 8 is a tetrahydropyranyl ring linked through the C 4 position of the tetrahydropyranyl ring.
57 . The compound of claim 51 , wherein R 9 is substituted with alkyl, trifluoromethyl, halo, cyano, nitro, hydroxy, C 1-6 alkoxy, carboxylic acid, carboxylic ester, carboxyamide, phenyl, cycloalkyl, cycloalkyl-alkyl, alkenyl, hydroxyalkyl, substituted C 1-6 alkyl substituted with up to 5 fluoro, or substituted C 1-6 alkoxy substituted with up to 5 fluoro.
58 . The compound of claim 51 , wherein R 21 is substituted with halo, cyano, nitro, hydroxy, C 1-6 alkoxy, C 1-6 alkyl optionally substituted with up to 5 fluoro, phenyl, C 3-7 cycloalkyl, C 4-10 cycloalkyl-alkyl, C 2-6 alkenyl, hydroxy-C 1-6 alkyl, substituted C 1-6 alkyl with up to 5 fluoro, or substituted C 1-6 alkoxy with up to 5 fluoro.
59 . The compound of claim 51 , wherein R 22 is substituted with halo, cyano, nitro, hydroxy, C 1-6 alkyl optionally substituted with up to 5 fluoro, or phenyl.
60 . The compound of claim 51 , wherein W is selected from O, NH, or CH 2 .
61 . (canceled)
62 . The compound of claim 51 , wherein R 1a or R 1b is substituted with halo, cyano, nitro, C 1-6 alkoxy, amido, phenyl, hydroxy, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 cycloalkyl-alkyl, C 2-6 alkenyl, hydroxy-C 1-6 alkyl, substituted C 1-6 alkyl with up to 5 fluoro, or substituted C 1-6 alkoxy with up to 5 fluoro.
63 . The compound of claim 51 , wherein NR 1a R 1b is a three- to six-membered alkyl cyclic secondary amine substituted with halo, cyano, nitro, C 1-6 alkoxy, amido, or phenyl.
64 . (canceled)
65 . A compound having the general Formula VIIIb:
or a pharmaceutically acceptable salt, prodrug, or ester thereof wherein:
R 1 and R 2 are each independently H, halo, cyano, hydroxy, C 1-3 alkyl, or C 1-3 alkoxy;
R 5 is H, C(O)OR 8 or C(O)NHR 8 ;
R 8 is C 1-6 alkyl, C 5-6 cycloalkyl, or 3-tetrahydrofuryl;
R 9 is C 1-3 alkyl, C 3-5 cycloalkyl, or phenyl which is optionally substituted by up to two halo, cyano, hydroxy, C 1-3 alkyl, or C 1-3 alkoxy;
R 10 and R 11 are each independently H, C 1-3 alkyl, or C 4-5 cycloalkyl;
W is O; and
Z is a C 5-7 saturated or unsaturated chain
R 6 is H, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 cycloalkyl-alkyl or substituted or unsubstituted phenyl.
66 . (canceled)
67 . The compound of claim 65 , wherein:
R 1 is F; R 2 is H; W is O; R 5 is C(O)OR 8 ; R 6 is cyclopropyl R 8 is tert-butyl; and R 9 is cyclopropyl;
68 . A compound having the Formula VIIIc:
or a pharmaceutically acceptable salt, prodrug, or ester thereof wherein:
R 1a and R 1b are each independently H, C 1-6 alkyl, C 3-7 cycloalkyl, or C 4-10 cycloalkyl-alkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, C 1-6 alkoxy, amido, or phenyl;
or R 1a and R 1b are each independently H and C 6 or 10 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 cycloalkyl-alkyl, C 2-6 alkenyl, C 1-6 alkoxy, hydroxy-C 1-6 alkyl, C 1-6 alkyl optionally substituted with up to 5 fluoro, or C 1-6 alkoxy optionally substituted with up to 5 fluoro;
or R 1a and R 1b are each independently H or optionally substituted heterocycle, which is a five-, six-, or seven-membered, saturated or unsaturated heterocyclic molecule, containing from one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur;
or NR 1a R 1b is a three- to six-membered optionally substituted alkyl cyclic secondary amine, which optionally has one to three hetero atoms incorporated in the ring, and which is optionally substituted from one to three times with halo, cyano, nitro, C 1-6 alkoxy, amido, or phenyl;
or NR 1a R 1b is a heteroaryl selected from the group consisting of:
wherein R 1c is H, halo, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, NO 2 , N(R 1d ) 2 , NH(CO)R 1d , or NH(CO)NHR 1d , wherein each R 1d is independently H, C 1-6 alkyl, or C 3-6 cycloalkyl;
or R 1c is NH(CO)OR 1e wherein R 1e is C 1-6 alkyl, or C 3-6 cycloalkyl;
V is selected from O;
W is selected from O;
Q is a bicyclic secondary amine with the structure of:
wherein R 21 and R 22 are each independently H, halo, cyano, nitro, hydroxy, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 cycloalkyl-alkyl, C 2-6 alkenyl, C 1-6 alkoxy, hydroxy-C 1-6 alkyl, C 1-6 alkyl optionally substituted with up to 5 fluoro, C 1-6 alkoxy optionally substituted with up to 5 fluoro, C 6 or 10 aryl, pyridyl, pyrimidyl, thienyl, furanyl, thiazolyl, oxazolyl, phenoxy, thiophenoxy, S(O) 2 NR 6 R 7 , NHC(O)NR 6 R 7 , NHC(S)NR 6 R 7 , C(O)NR 6 R 7 , NR 6 R 7 , C(O)R 8 , C(O)OR 8 , NHC(O)R 8 , NHC(O)OR 8 , SO m R 8 (m=0, 1 or 2), or NHS(O) 2 R 8 ; said thienyl, pyrimidyl, furanyl, thiazolyl and oxazolyl in the definition of R 21 and R 22 are optionally substituted by up to two halo, cyano, nitro, hydroxy, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 cycloalkyl-alkyl, C 2-6 alkenyl, C 1-6 alkoxy, hydroxy-C 1-6 alkyl, C 1-6 alkyl optionally substituted with up to 5 fluoro, or C 1-6 alkoxy optionally substituted with up to 5 fluoro; said C 6 or 10 aryl, pyridyl, phenoxy and thiophenoxy in the definition of R 21 and R 22 are optionally substituted by up to three halo, cyano, nitro, hydroxy, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 cycloalkyl-alkyl, C 2-6 alkenyl, C 1-6 alkoxy, hydroxy-C 1-6 alkyl, C 1-6 alkyl optionally substituted with up to 5 fluoro, or C 1-6 alkoxy optionally substituted with up to 5 fluoro;
wherein R 10 and R 11 are each independently H, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 cycloalkyl-alkyl, C 6 or 10 aryl, hydroxy-C 1-6 alkyl, C 1-6 alkyl optionally substituted with up to 5 fluoro, (CH 2 ) n NR 6 R 7 , or (CH 1 ) n C(O)OR 14 where R 14 is H, C 1-6 alkyl, C 3-7 cycloalkyl, or C 4-10 cycloalkyl-alkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C 1-6 alkoxy, or phenyl; or R 14 is C 6 or 10 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 cycloalkyl-alkyl, C 2-6 alkenyl, C 1-6 alkoxy, hydroxy-C 1-6 alkyl, C 1-6 alkyl optionally substituted with up to 5 fluoro, C 1-6 alkoxy optionally substituted with up to 5 fluoro; said C 6 or 10 aryl, in the definition of R 10 and R 11 is optionally substituted by up to three halo, cyano, nitro, hydroxy, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 cycloalkyl-alkyl, C 2-6 alkenyl, C 1-6 alkoxy, hydroxy-C 1-6 alkyl, C 1-6 alkyl optionally substituted with up to 5 fluoro, or C 1-6 alkoxy optionally substituted with up to 5 fluoro; or R 10 and R 11 are taken together with the carbon to which they are attached to form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; or R 10 and R 11 are combined as O;
wherein p=0;
wherein R 12 and R 13 are each independently H1, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 cycloalkyl-alkyl, C 6 or 10 aryl, hydroxy-C 1-6 alkyl, C 1-6 alkyl optionally substituted with up to 5 fluoro, (CH 2 ) n NR 6 R 7 , (CH 2 ) n C(O)OR 14 where R 14 is H, C 1-6 alkyl, C 3-7 cycloalkyl, or C 4-10 cycloalkyl-alkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C 1-6 alkoxy, or phenyl; or R 14 is C 6 or 10 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 cycloalkyl-alkyl, C 2-6 alkenyl, C 1-6 alkoxy, hydroxy-C 1-6 alkyl, C 1-6 alkyl optionally substituted with up to 5 fluoro, C 1-6 alkoxy optionally substituted with up to 5 fluoro; said C 6 or 10 aryl, in the definition of R 12 and R 13 is optionally substituted by up to three halo, cyano, nitro, hydroxy, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 cycloalkyl-alkyl, C 2-6 alkenyl, C 1-6 alkoxy, hydroxy-C 1-6 alkyl, C 1-6 alkyl optionally substituted with up to 5 fluoro, or C 1-6 alkoxy optionally substituted with up to 5 fluoro; or R 12 and R 13 are taken together with the carbon to which they are attached to form cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;
wherein R 20 is H, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 cycloalkyl-alkyl, C 6 or 10 aryl, hydroxy-C 1-6 alkyl, C 1-6 alkyl optionally substituted with up to 5 fluoro, (CH 2 ) n NR 6 R 7 , or (CH 2 ) n C(O)OR 14 where R 14 is H, C 1-6 alkyl, C 3-7 cycloalkyl, or C 4-10 cycloalkyl-alkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C 1-6 alkoxy, or phenyl; or R 14 is C 6 or 10 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 cycloalkyl-alkyl, C 2-6 alkenyl, C 1-6 alkoxy, hydroxy-C 1-6 alkyl, C 1-6 alkyl optionally substituted with up to 5 fluoro, or C 1-6 alkoxy optionally substituted with up to 5 fluoro; said C 6 or 10 aryl, in the definition of R 12 and R 13 is optionally substituted by up to three halo, cyano, nitro, hydroxy, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 cycloalkyl-alkyl, C 2-6 alkenyl, C 1-6 alkoxy, hydroxy-C 1-6 alkyl, C 1-6 alkyl optionally substituted with up to 5 fluoro, or C 1-6 alkoxy optionally substituted with up to 5 fluoro;
wherein n=0-4;
wherein R 6 and R 7 are each independently H, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 cycloalkyl-alkyl, or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 cycloalkyl-alkyl, C 2-6 alkenyl, hydroxy-C 1-6 alkyl, C 1-6 alkyl optionally substituted with up to 5 fluoro, or C 1-6 alkoxy optionally substituted with up to 5 fluoro; or R 6 and R 7 are taken together with the nitrogen to which they are attached to form indolinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl;
Z is a C 5-7 saturated or unsaturated chain;
R 4 is H, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 cycloalkyl-alkyl, or phenyl, said phenyl optionally substituted by up to three halo, cyano, nitro, hydroxy, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 cycloalkyl-alkyl, C 2-6 alkenyl, C 1-6 alkoxy, hydroxy-C 1-6 alkyl, C 1-6 alkyl optionally substituted with up to 5 fluoro, or C 1-6 alkoxy optionally substituted with up to 5 fluoro;
R 5 is H, C 1-6 alkyl, C(O)NR 6 R 7 , C(S)NR 6 R 7 , C(O)R 8 , C(O)OR 8 , or S(O) 2 R 8 ; and
R 8 is C 1-6 alkyl, C 3-7 cycloalkyl, or C 4-10 cycloalkyl-alkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, hydroxy, C 1-6 alkoxy, or phenyl; or R 8 is C 6 or 10 aryl which is optionally substituted by up to three halo, cyano, nitro, hydroxy, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 cycloalkyl-alkyl, C 2-6 alkenyl, C 1-6 alkoxy, hydroxy-C 1-6 alkyl, C 1-6 alkyl optionally substituted with up to 5 fluoro, or C 1-6 alkoxy optionally substituted with up to 5 fluoro.
69 . A compound having the Formula VIIId:
or a pharmaceutically acceptable salt, prodrug, or ester thereof wherein:
(a) R 1a and R 1b are each independently H, C 1-6 alkyl, C 3-7 cycloalkyl, or C 4-10 cycloalkyl-alkyl, which are all optionally substituted from one to three times with halo, cyano, nitro, C 1-6 alkoxy, amido, or phenyl;
or R 1a and R 1b are each independently H or heteroaryl selected from the group consisting of:
wherein R 1c is H, halo, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, NO 2 , N(R 1d ) 2 , NH(CO)R 1d , or NH(CO)NHR 1d , wherein each R 1d is independently H, C 1-6 alkyl, or C 3-6 cycloalkyl;
or NR 1a R 1b is a three- to six-membered alkyl cyclic secondary amine, which optionally has one to three hetero atoms incorporated in the ring, and which is optionally substituted from one to three times with halo, cyano, nitro, C 1-6 alkoxy, amido, or phenyl;
(b) R 21 and R 22 are each independently H, halo, cyano, hydroxy, C 1-3 alkyl, or C 1-3 alkoxy;
(e) R 5 is H, C(O)NR 6 R 7 , C(O)R 8 , or C(O)OR 8 ;
(d) R 6 and R 7 are each independently H, C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 cycloalkyl-alkyl, or phenyl;
(e) R 8 is C 1-6 alkyl, C 3-7 cycloalkyl, C 4-10 cycloalkyl-alkyl, or 3-tetrahydrofuryl; and
(f) Z is a C 5-7 saturated or unsaturated chain.
70 - 83 . (canceled)
84 . A compound having a formula selected from the group consisting of the compounds numbered 100-105, 107-116, 121-138, 141-145, 153-154, 156-182, 184, 185, 192-207, 209-230, 234-241, 243-244, 246-254, 261-269, 600-643, 645-648, 701-705, 900-929, 1001-1012, 1015-1032, 2501-2502, and 2601-2604 as described in the specification.
85 . A compound of claim 1 that is a salt.
86 . A compound of claim 1 that is a prodrug.
87 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound claim 1 .
88 . A method of inhibiting NS3/NS4 protease activity, comprising contacting a NS3/NS4 protease with a compound of claim 1 .
89 . The method of claim 88 in which the contacting is conducted in vivo.
90 . The method of claim 88 , further comprising identifying a subject suffering from a hepatitis C infection and administering the compound or composition to the subject in an amount effective to treat the infection.
91 . The method of claim 88 in which the contacting is conducted ex vivo.
92 . A method of treating an individual, the method comprising administering to the individual an amount of a composition comprising a compound of claim 1 that is effective to treat a least one condition selected from the group consisting of a hepatitis C virus infection, liver fibrosis, and impaired liver function.
93 . The method of claim 92 , wherein a sustained viral response is achieved.
94 . The method of claim 92 , wherein the method further comprises administering to the individual an effective amount of a nucleoside analog.
95 . The method of claim 94 , wherein the nucleoside analog is selected from ribavirin, levovirin, viramidine, an L-nucleoside, and isatoribine.
96 . The method of claim 92 , wherein the method further comprises administering to the individual pirfenidone or a pirfenidone analog administered orally daily in an amount of from about 400 mg to about 3600 mg.
97 . The method of claim 92 , wherein the method further comprises administering to the individual an effective amount of an NS5B RNA-dependent RNA polymerase inhibitor.
98 . The method of claim 92 , wherein the method further comprises administering to the individual an effective amount of a tumor necrosis factor antagonist selected from the group consisting of etanercept, infliximab, and adalimumab.
99 . The method of claim 92 , wherein the method further comprises administering to the individual an effective amount of thymosin-α.
100 . The method of claim 99 , wherein the thymosin-α is administered subcutaneously twice weekly in an amount of from about 1.0 mg to about 1.6 mg.
101 . The method of claim 92 , wherein the method further comprises administering to the individual an effective amount of interferon-gamma (IFN-γ).
102 . The method of claim 101 , wherein the IFN-γ is administered subcutaneously in an amount of from about 10 μg to about 300 μg.
103 . The method of claim 92 , wherein the method further comprises administering to the individual an effective amount of interferon-alpha (IFN-α).
104 . The method of claim 103 , wherein the IFN-α is monoPEG (30 kD, linear)-ylate consensus IFN-α administered at a dosing interval of every 8 days to every 14 days.
105 . The method of claim 103 , wherein the IFN-α is monoPEG (30 kD, linear)-ylated consensus IFN-α administered at a dosing interval of once every 7 days.
106 . The method of claim 105 , wherein the IFN-α INFERGEN consensus IFN-α.
107 . The method of claim 92 , further comprising administering an effective amount of an agent selected from 3′-azidothymidine, 2′,3′-dideoxyinosine, 2′,3′-dideoxycytidine, 2-,3-didehydro-2′,3′-dideoxythymidine, combivir, abacavir, adefovir dipoxil, cidofovir, ritonavir, and an inosine monophosphate dehydrogenase inhibitor.
108 . The method of claim 92 , further comprising administering interferon, another NS3 protease inhibitor, a NS5b polymerase inhibitor, or a NS3 helicase inhibitor.
109 . The method of claim 108 , wherein the another NS3 protease inhibitor is selected from
110 - 129 . (canceled)Join the waitlist — get patent alerts
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