(19) United States
`(12) Patent Application Publication (10) Pub. No.: US 2006/0276511 A1
`(43) Pub. Date:
`Dec. 7, 2006
`Serrano-Wu et al.
`
`US 2006027651 1A1
`
`(54) INHIBITORS OF HCV REPLICATION
`
`Publication Classi?cation
`
`(51) Int. Cl.
`(2006.01)
`A611; 31/444
`(2006.01)
`A611; 31/4439
`(2006.01)
`A611; 31/42
`(2006.01)
`A611; 31/416
`(2006.01)
`A611; 31/4025
`(2006.01)
`0070 413/14
`(2006.01)
`0070 403/14
`(2006.01)
`0070 409/14
`(52) U.S. c1. ....................... .. 514/332;514/422; 548/518;
`546/2771; 514/343; 514/414;
`548/465; 514/397; 548/3111;
`514/378; 548/248; 514/406;
`548/3657; 546/256
`
`ABSTRACT
`(57)
`Compounds having the structure of formula I are described.
`
`(76) Inventors: Michael Serrano-Wu, Belmont, MA
`(US); Makonen Belema, North Haven,
`CT (US); Lawrence B. Snyder,
`KillingWorth, CT (US); Nicholas A.
`MeanWell, East Hampton, CT (US);
`Denis R. St. Laurent, NeWington, CT
`(US); Ramesh Kakarla, South
`Glastonbury, CT (US); Van N. Nguyen,
`NeW Britain, CT (US); Yuping Qiu,
`Glastonbury, CT (US); Xuejie Yang,
`Cheshire, CT (US); John E. Leet,
`Madison, CT (US); Min Gao, Madison,
`CT (US); Donald R. O’Boyle II,
`KillingWorth, CT (US); Julie A. Lemm,
`Durham, CT (US); Fukang Yang,
`Madison, CT (US)
`
`Correspondence Address:
`LOUIS J. WILLE
`BRISTOL-MYERS SQUIBB COMPANY
`PATENT DEPARTMENT
`P 0 BOX 4000
`PRINCETON, NJ 08543-4000 (US)
`
`(21) Appl. No.:
`
`11/446,788
`
`(22) Filed:
`
`Jun. 5, 2006
`
`O
`
`Related US. Application Data
`
`(60) Provisional application No. 60/687,760, ?led on Jun.
`6, 2005.
`
`The compounds can inhibit hepatitis C virus (HCV) repli
`cation, and in particular can inhibit the function of the HCV
`NS5A protein.
`
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`US 2006/0276511 A1
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`
`INHIBITORS OF HCV REPLICATION
`
`CROSS REFERENCE TO RELATED
`APPLICATION
`
`[0001] This application claims priority from US. Provi
`sional Application Ser. No. 60/687,760, ?led Jun. 6, 2005.
`
`FIELD OF THE INVENTION
`
`[0002] The present invention is generally directed to anti
`viral compounds, and more speci?cally directed to com
`pounds Which can inhibit the function of the NS5A protein
`encoded by Hepatitis C virus (HCV), compositions com
`prising such compounds, and methods for inhibiting the
`function of the NS5A protein.
`
`BACKGROUND OF THE INVENTION
`
`[0003] HCV is a major human pathogen, infecting an
`estimated 170 million persons WorldWideiroughly ?ve
`times the number infected by human immunode?ciency
`virus type 1. A substantial fraction of these HCV infected
`individuals develop serious progressive liver disease,
`including cirrhosis and hepatocellular carcinoma (Lauer, G.
`M.; Walker, B. D. N. Engl. J. Med. 2001, 345, 41-52).
`[0004] Presently, the most e?‘ective HCV therapy employs
`a combination of alpha-interferon and ribavirin, leading to
`sustained ef?cacy in 40% of patients (Poynard, T. et al.
`Lancet 1998, 352, 1426-1432). Recent clinical results dem
`onstrate that pegylated alpha-interferon is superior to
`unmodi?ed alpha-interferon as monotherapy (ZeuZem, S. et
`al. N. Engl. J. Med. 2000, 343, 1666-1672). HoWever, even
`With experimental therapeutic regimens involving combina
`tions of pegylated alpha-interferon and ribavirin, a substan
`tial fraction of patients do not have a sustained reduction in
`viral load. Thus, there is a clear and long-felt need to develop
`e?‘ective therapeutics for treatment of HCV infection.
`
`[0005] HCV is a positive-stranded RNA virus. Based on a
`comparison of the deduced amino acid sequence and the
`extensive similarity in the 5' untranslated region, HCV has
`been classi?ed as a separate genus in the Flaviviridae family.
`All members of the Flaviviridae family have enveloped
`virions that contain a positive stranded RNA genome encod
`ing all knoWn virus-speci?c proteins via translation of a
`single, uninterrupted, open reading frame.
`[0006] Considerable heterogeneity is found Within the
`nucleotide and encoded amino acid sequence throughout the
`HCV genome. At least six major genotypes have been
`characterized, and more than 50 subtypes have been
`described. The major genotypes of HCV dilfer in their
`distribution WorldWide, and the clinical signi?cance of the
`genetic heterogeneity of HCV remains elusive despite
`numerous studies of the possible e?fect of genotypes on
`pathogenesis and therapy.
`[0007] The single strand HCV RNA genome is approxi
`mately 9500 nucleotides in length and has a single open
`reading frame (ORF) encoding a single large polyprotein of
`about 3000 amino acids. In infected cells, this polyprotein is
`cleaved at multiple sites by cellular and viral proteases to
`produce the structural and non-structural (NS) proteins. In
`the case of HCV, the generation of mature non-structural
`proteins (NS2, NS3, NS4A, NS4B, NS5A, and NS5B) is
`e?fected by tWo viral proteases. The ?rst one is believed to
`
`be a metalloprotease and cleaves at the NS2-NS3 junction;
`the second one is a serine protease contained Within the
`N-terminal region of NS3 (also referred to herein as NS3
`protease) and mediates all the subsequent cleavages doWn
`stream of NS3, both in cis, at the NS3-NS4A cleavage site,
`and in trans, for the remaining NS4A-NS4B, NS4B-NS5A,
`NS5A-NS5B sites. The NS4A protein appears to serve
`multiple functions, acting as a cofactor for the NS3 protease
`and possibly assisting in the membrane localiZation of NS3
`and other viral replicase components. The complex forma
`tion of the NS3 protein With NS4A seems necessary to the
`processing events, enhancing the proteolytic ef?ciency at all
`of the sites. The NS3 protein also exhibits nucleoside
`triphosphatase and RNA helicase activities. NS5B (also
`referred to herein as HCV polymerase) is a RNA-dependent
`RNA polymerase that is involved in the replication of HCV.
`
`[0008] Among the compounds that have demonstrated
`ef?cacy in inhibiting HCV replication as selective HCV
`serine protease inhibitors are the peptide compounds dis
`closed in US. Patent No. 6,323,180. NS5B polymerase
`inhibitors have also demonstrated activity. HoWever, none of
`these compounds have, to date, progressed beyond clinical
`trials (De Clercq, E. J Clin. l/zrol. 2001, 22, 73-89).
`[0009] Compounds useful for treating HCV-infected
`patients are desired Which selectively inhibit HCV viral
`replication. In particular, compounds Which are e?‘ective to
`inhibit the function of the NS5A protein are desired. The
`HCV NS5A protein is described, for example, in Tan, S.-L.,
`KatZel, M.G. Wrology 2001, 284, 1-12; and in Park, K.-J.;
`Choi, S.-H, JBiological Chemistry 2003.
`
`SUMMARY OF THE INVENTION
`
`[0010] The present invention relates to compounds of
`formula (I)
`
`b X 4
`
`7
`
`R8\\ is
`II{\ \ \ U 0
`N /
`is
`
`O
`
`(I)
`
`R2
`p
`
`0
`
`R1
`
`a
`
`R3X—y
`(
`N
`
`0
`
`or pharmaceutically acceptable salts thereof, Wherein
`[0011]
`
`is a single or double bond;
`
`[0012]
`
`is a single or double bond;
`
`. is a single bond, X is selected from the
`[0013] When .
`group consisting of 0, CH2, and CHR3;
`
`. is a double bond, X is selected from the
`[0014] When .
`group consisting of CH and CR3;
`
`. is a single bond, Y is selected from the
`[0015] When .
`group consisting of 0, CH2, and CHR4;
`
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`. is a double bond, Y is selected from the
`[0016] When .
`group consisting of CH and CR4;
`
`[0017] n and m are independently 0, l, 2, or 3;
`
`[0018] p is 0 or 1;
`
`[0019] R1 and R2 are independently selected from the
`group consisting of alkoxy, alkoxyalkoxyalkyl, alkoxyalkyl,
`alkyl, alkylsulfenylalkyl, alkylsul?nylalkyl, alkylsulfonyla
`lkyl, aryl, arylalkoxy, arylalkoxyalkyl, arylalkyl, arylcarbo
`nyl, aryloxy, aryloxyalkyl, arylsulfenylalkyl, arylsul?nyla
`lkyl,
`arylsulfonylalkyl,
`carboxyalkyl,
`cycloalkenyl,
`cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,
`heterocyclylalkoxy, heterocyclylalkoxyalkyl, heterocyclyla
`lkyl, heterocyclylcarbonyl, heterocyclyloxy, heterocycly
`loxyalkyl, iNRaRb, and (NRaRb)alkyl;
`[0020] R3 and R4 are independently selected from the
`group consisting of hydrogen, alkenyl, alkoxy, alkoxycar
`bonyloxy, alkyl, alkylsulfonyl, alkylsulfonyloxy, aryl, ary
`lalkyl, aZido, hydroxy, iNRaRb, (N RaRb)alkyl, and (NRaR
`b)carbonyloxy; Wherein the alkenyl and the alkyl can
`optionally form a saturated or unsaturated cyclic structure,
`respectively, With an adjacent carbon atom;
`
`[0021] R5 and R6 are independently selected from the
`group consisting of hydrogen, alkenyl, alkoxycarbonyl,
`alkyl, alkylcarbonyl, aryl, arylalkyl, heterocyclylalkylcarbo
`nyl, and heterocyclylcarbonyl;
`
`[0022] R7 and R8 are independently selected from the
`group consisting of hydrogen, alkenyl, alkoxy, alkyl, halo,
`and haloalkyl; and
`
`[0023] Ra and Rb are independently selected from the
`group consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl,
`aryl, arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkyla
`lkyl, heterocyclyl, and heterocyclylalkyl.
`[0024] The present invention also provides compositions
`comprising the compounds of the invention or pharmaceu
`tically acceptable enantiomers, diastereomers, salts, or sol
`vates thereof and a pharmaceutically acceptable carrier. In
`particular, the present invention provides pharmaceutical
`compositions useful for inhibiting the function of the HCV
`NSSA protein comprising a compound of the present inven
`tion, or a pharmaceutically acceptable enantiomer, diastere
`omer, salt, or solvate thereof, and a pharmaceutically accept
`able carrier.
`
`[0025] The present invention fuirther provides methods
`for treating patients infected With HCV comprising admin
`istering to the patient a therapeutically effective amount of
`a compound of the present invention, or a pharmaceutically
`acceptable enantiomer, diastereomer, salt, or solvate thereof.
`Additionally, the present invention provides methods of
`inhibiting the function of HCV NSSA protein by contacting
`the HCV NSSA protein With a compound of the present
`invention.
`
`[0026] By virtue of the present invention, it is noW pos
`sible to provide improved drugs comprising the compounds
`of the invention Which can be effective in the treatment of
`patients infected With HCV. Speci?cally, the present inven
`tion provides compounds that can inhibit the function of the
`NSSA protein. Further, the present invention makes it pos
`sible to administer combination therapy to a patient Whereby
`
`a compound in accordance With the present invention, Which
`is effective to inhibit the HCV NSSA protein, can be
`administered With another compound having anti-HCV
`activity, e.g., a compound Which is effective to inhibit the
`function of a target selected from the group consisting of
`HCV metalloprotease, HCV serine protease, HCV poly
`merase, HCV helicase, HCV NS4B protein, HCV entry,
`HCV assembly, HCV egress, HCV NSSB protein, IMPDH,
`and a nucleoside analog for the treatment of an HCV
`infection.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`[0027] As used in the present speci?cation the folloWing
`terms have the meanings indicated:
`
`[0028] The term “alkenyl,” as used herein, refers to a
`straight or branched chain group of tWo to six carbon atoms
`containing at least one carbon-carbon double bond.
`Examples of alkenyl groups include, but are not limited to,
`ethenyl, 2-propenyl, and isobutenyl.
`[0029] The term “alkoxy,” as used herein, refers to an
`alkyl group attached to the parent molecular moiety through
`an oxygen atom.
`
`[0030] The term “alkoxyalkoxy,” as used herein, refers to
`an alkoxyalkyl group attached to the parent molecular
`moiety through an oxygen atom.
`
`[0031] The term “alkoxyalkoxyalkyl,” as used herein,
`refers to an alkyl group substituted With one, tWo, or three
`alkoxyalkoxy groups.
`
`[0032] The term “alkoxyalkyl,” as used herein, refers to an
`alkyl group substituted With one, tWo, or three alkoxy
`groups.
`
`[0033] The term “alkoxycarbonyl,” as used herein, refers
`to an alkoxy group attached to the parent molecular moiety
`through a carbonyl group.
`
`[0034] The term “alkoxycarbonyloxy,” as used herein,
`refers to an alkoxycarbonyl group attached to the parent
`molecular moiety through an oxygen atom.
`
`[0035] The term “alkyl,” as used herein, refers to a group
`derived from a straight or branched chain saturated hydro
`carbon containing from one to six carbon atoms. Examples
`of alkyl groups include, but are not limited to, methyl, ethyl,
`isopropyl, and tert-butyl.
`[0036] The term “alkylcarbonyl,” as used herein, refers to
`an alkyl group attached to the parent molecular moiety
`through a carbonyl group.
`
`[0037] The term “alkylsulfenyl,” as used herein, refers to
`an alkyl group attached to the parent molecular moiety
`through a sulfur atom.
`
`[0038] The term “alkylsulfenylalkyl,” as used herein,
`refers to an alkyl group substituted With one, tWo, or three
`alkylsulfenyl groups.
`[0039] The term “alkylsul?nyl,” as used herein, refers to
`an alkyl group attached to the parent molecular moiety
`through a sul?nyl group.
`
`[0040] The term “alkylsul?nylalkyl,” as used herein,
`refers to an alkyl group substituted With one, tWo, or three
`alkylsul?nyl groups.
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`[0041] The term “alkylsulfonyl,” as used herein, refers to
`an alkyl group attached to the parent molecular moiety
`through a sulfonyl group.
`
`[0042] The term “alkylsulfonylalkyl,” as used herein,
`refers to an alkyl group substituted With one, tWo, or three
`alkylsulfonyl groups.
`
`[0043] The term “alkylsulfonyloxy,” as used herein, refers
`to an alkylsulfonyl group attached to the parent molecular
`moiety through an oxygen atom.
`
`[0044] The term “alkynyl,” as used herein, refers to a
`straight or branched chain hydrocarbon of tWo to six carbon
`atoms containing at least one carbon-carbon triple bond.
`Examples of alkynyl groups include, but are not limited to,
`ethynyl, propynyl, and 4-methyl-l-pentynyl.
`
`[0045] The term “aryl,” as used herein, refers to a phenyl
`group, or a bicyclic or tricyclic fused ring system Wherein
`one or more of the rings is a phenyl group. Bicyclic fused
`ring systems consist of a phenyl group fused to a monocyclic
`cycloalkenyl group, a monocyclic cycloalkyl group, or
`another phenyl group. Tricyclic fused ring systems consist
`of a bicyclic fused ring system fused to a monocyclic
`cycloalkenyl group, a monocyclic cycloalkyl group, or
`another phenyl group. The aryl groups of the present inven
`tion can be attached to the parent molecular moiety through
`any substitutable carbon atom in the group. Representative
`examples of aryl groups include, but are not limited to,
`anthracenyl, aZulenyl, bicyclooctatrienyl, ?uorenyl, indanyl,
`indenyl, naphthyl, phenyl, and tetrahydronaphthyl. Preferred
`aryl groups of the present invention are bicyclooctatrienyl,
`?uorenyl, naphthyl, and phenyl. The aryl groups of the
`present invention can be optionally substituted With one,
`tWo, three, four, or ?ve substituents independently selected
`from the group consisting of alkenyl, alkoxy, alkoxycarbo
`nyl, alkyl, alkylcarbonyl, alkylsulfenyl, alkylsulfonyl, alky
`nyl, a second aryl group, arylalkoxy, arylalkyl, arylcarbonyl,
`aryloxy, arylsulfenyl, arylsulfonyl, aZido, cyano, cycloalk
`enyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, halo,
`haloalkoxy, haloalkyl, heterocyclyl, heterocyclylalkoxy, het
`erocyclylalkyl,
`heterocyclylcarbonyl,
`heterocyclyloxy,
`iNRCRd, (NR°Rd)alkyl, (NR°Rd)carbonyl, and oxo;
`Wherein the aryloxy, the arylsulfenyl, and the arylsulfonyl,
`the cycloalkenyl, the cycloalkenyl part of the cycloalkeny
`lalkyl, the cycloalkyl, the cycloalkyl part of the cycloalky
`lalkyl, the heterocyclyl, and the heterocyclyl part of the
`heterocyclylalkoxy, the heterocyclylalkyl, the heterocyclyl
`carbonyl, and the heterocyclyloxy can be fuirther heterocy
`clylalkyl, the heterocyclylcarbonyl, and the heterocyclyloxy
`can be further selected from the group consisting of alkoxy,
`alkyl, cyano, halo, haloalkoxy, haloalkyl, and oxo; and
`Wherein Rc and Rd are each independently selected from the
`haloalkyl, and oxo; and Wherein RC and R“1 are each inde
`pendently selected from the unsubstituted aryl, unsubstituted
`arylalkyl, unsubstituted cycloalkyl, unsubstituted cycloalky
`lalkyl, unsubstituted heterocyclyl, and unsubstituted hetero
`cyclylalkyl.
`
`[0046] The term “arylalkoxy,” as used herein, refers to an
`aryl group attached to the parent molecular moiety through
`an alkoxy group.
`
`[0047] The term “arylalkoxyalkyl,” as used herein, refers
`to an alkyl group substituted With one, tWo, or three aryla
`lkoxy groups.
`
`[0048] The term “arylalkyl,” as used herein, refers to an
`alkyl group substituted With one, tWo, or three aryl groups.
`The alkyl part of the arylalkyl can be optionally substituted
`With one or tWo additional groups selected from the group
`consisting of alkenyl, alkoxy, alkynyl, arylalkoxy, aryloxy,
`heterocyclyl, heterocyclylalkoxy, heterocyclyloxy, hydroxy,
`and iNRCRd; Wherein RC and R“1 are independently selected
`from the group consisting of hydrogen, alkoxyalkyl, alkoxy
`carbonyl, alkyl, alkylcarbonyl, unsubstituted aryl, unsubsti
`tuted arylalkyl, unsubstituted cycloalkyl, unsubstituted
`cycloalkylalkyl, unsubstituted heterocyclyl, and unsubsti
`tuted heterocyclylalkyl.
`[0049] The term “arylalkylcarbonyl,” as used herein,
`refers to an arylalkyl group attached to the parent molecular
`moiety through a carbonyl group.
`
`[0050] The term “arylcarbonyl,” as used herein, refers to
`an aryl group attached to the parent molecular moiety
`through a carbonyl group.
`
`[0051] The term “aryloxy,” as used herein, refers to an aryl
`group attached to the parent molecular moiety through an
`oxygen atom.
`
`[0052] The term “aryloxyalkyl,” as used herein, refers to
`an alkyl group substituted With one, tWo, or three aryloxy
`groups.
`
`[0053] The term “arylsulfenyl,” as used herein, refers to an
`aryl group attached to the parent molecular moiety through
`a sulfur atom.
`
`[0054] The term “arylsulfenylalkyl,” as used herein, refers
`to an alkyl group substituted With one, tWo, or three aryl
`sulfenyl groups.
`
`[0055] The term “arylsul?nyl,” as used herein, refers to an
`aryl group attached to the parent molecular moiety through
`a sul?nyl group.
`
`[0056] The term “arylsul?nylalkyl,” as used herein, refers
`to an alkyl group substituted With one, tWo, or three aryl
`sul?nyl groups.
`
`[0057] The term “arylsulfonyl,” as used herein, refers to
`an aryl group attached to the parent molecular moiety
`through a sulfonyl group.
`
`[0058] The term “arylsulfonylalkyl,” as used herein, refers
`to an alkyl group substituted With one, tWo, or three aryl
`sulfonyl groups.
`
`[0059] The term “aZido,” as used herein, refers to iN3.
`
`[0060] The term “carbonyl,” as used herein, refers to
`%(O)i.
`[0061] The term “carboxy,” as used herein, refers to
`%O2H.
`[0062] The term “carboxyalkyl,” as used herein, refers to
`an alkyl group substituted With one, tWo, or three carboxy
`groups.
`
`[0063] The term “cyano,” as used herein, refers to iCN.
`
`[0064] The term “cycloalkenyl,” as used herein, refers to
`a non-aromatic, partially unsaturated monocyclic, bicyclic,
`or tricyclic ring system having three to fourteen carbon
`atoms and Zero heteroatoms. Representative examples of
`cycloalkenyl groups include, but are not limited to, cyclo
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`hexenyl, octahydronaphthalenyl, and norbornylenyl. A pre
`ferred cycloalkenyl of the present invention is cyclopente
`nyl. The cycloalkenyl groups of the present invention can be
`optionally substituted With one, tWo, three, four, or ?ve
`substituents independently selected from the group consist
`ing of alkenyl, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl,
`cyano, halo, haloalkoxy, haloalkyl, iNRCRd, (N R°Rd)alkyl,
`(NR°Rd)carbonyl, and oxo; Wherein RC and R“1 are each
`independently selected from the group consisting of hydro
`gen, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl,
`unsubstituted aryl, unsubstituted arylalkyl, unsubstituted
`cycloalkyl, unsubstituted cycloalkylalkyl, unsubstituted het
`erocyclyl, and unsubstituted heterocyclylalkyl.
`
`[0065] The term “cycloalkenylalkyl,” as used herein,
`refers to an alkyl group substituted With one, tWo, or three
`cycloalkenyl groups.
`
`[0066] The term “cycloalkyl,” as used herein, refers to a
`saturated monocyclic, bicyclic, or tricyclic hydrocarbon ring
`system having three to fourteen carbon atoms and Zero
`heteroatoms. Representative examples of cycloalkyl groups
`include, but are not limited to, adamantyl, bicyclo[3.l.l]
`heptyl, cyclobutyl, cyclopentyl, and cyclopropyl. Preferred
`cycloalkyl groups of the present invention are cyclobutyl,
`cyclopentyl, and cyclopropyl. The cycloalkyl groups of the
`present invention can be optionally substituted With one,
`tWo, three, four, or ?ve substituents independently selected
`from the group consisting of alkenyl, alkoxy, alkoxycarbo
`nyl, alkyl, alkylcarbonyl, cyano, halo, haloalkoxy, haloalkyl,
`iNRCRd, (NR°Rd)alkyl, (NR°Rd)carbonyl, and oxo;
`Wherein RC and R“1 are each independently selected from the
`group consisting of hydrogen, alkoxyalkyl, alkoxycarbonyl,
`alkyl, alkylcarbonyl, unsubstituted aryl, unsubstituted ary
`lalkyl, unsubstituted cycloalkyl, unsubstituted cycloalkyla
`lkyl, unsubstituted heterocyclyl, and unsubstituted hetero
`cyclylalkyl.
`[0067] The term “cycloalkylalkyl,” as used herein, refers
`to an alkyl group substituted With one, tWo, or three
`cycloalkyl groups.
`[0068] The terms “halo,” and “halogen,” as used herein,
`refer to Br, Cl, F, or I.
`
`[0069] The term “haloalkoxy,” as used herein, refers to a
`haloalkyl group attached to the parent molecular moiety
`through an oxygen atom.
`
`[0070] The term “haloalkyl,” as used herein, refers to an
`alkyl group substituted With one, tWo, three, or four halogen
`atoms.
`
`[0071] The term “heterocyclyl,” as used herein, refers to a
`three-, four-, ?ve-, six-, or seven-membered ring containing
`one, tWo, or three heteroatoms independently selected from
`the group consisting of nitrogen, oxygen, and sulfur. The
`three- and four-membered rings have Zero or one double
`bond. The ?ve-membered ring has Zero to tWo double bonds
`and the six- and seven-membered rings have Zero to three
`double bonds. The term “heterocyclyl” also includes bicy
`clic groups in Which the heterocyclyl ring is fused to a
`phenyl group, a monocyclic cycloalkenyl group, a monocy
`clic cycloalkyl group, or another monocyclic heterocyclyl
`group; and tricyclic groups in Which a bicyclic system is
`fused to a phenyl group, a monocyclic cycloalkenyl group,
`a monocyclic cycloalkyl group, or another monocyclic het
`erocyclyl group. The heterocyclyl groups of the present
`
`invention can be attached to the parent molecular moiety
`through a carbon atom or a nitrogen atom in the group.
`Examples of heterocyclyl groups include, but are not limited
`to, aZetidinyl, benZimidaZolyl, benZothienyl, diaZirenyl,
`furyl, hexahydrothienoimidaZolyl, imidaZolyl, imidaZopy
`ridinyl, imidaZothiaZolyl, indolinyl, indolyl, isothiaZolyl,
`isoxaZolyl, morpholinyl, oxaZolyl, piperaZinyl, piperidinyl,
`pyraZinyl, pyraZolyl, pyridinyl, pyrrolidinyl, pyrrolopyridi
`nyl, pyrrolyl, tetrahydrofuryl, thiadiaZolyl, thiaZolyl, thie
`nyl, and thiomorpholinyl. Preferred heterocyclyl groups of
`the present invention are aZetidinyl, benZimidaZolyl, diaZ
`irenyl, furyl, hexahydrothienoimidaZolyl, imidaZolyl, imi
`daZopyridinyl, imidaZothiaZolyl, indolinyl, indolyl, isox
`aZolyl, morpholinyl, oxaZolyl, piperidinyl, pyraZinyl,
`pyraZolyl, pyridinyl, tetrahydro?iryl, thiadiaZolyl, and thie
`nyl. The heterocyclyl groups of the present invention can be
`optionally substituted With one, tWo, three, four, or ?ve
`substituents independently selected from the group consist
`ing of alkenyl, alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl,
`alkylsulfenyl, alkylsulfonyl, alkynyl, aryl, arylalkoxy, ary
`lalkyl, arylcarbonyl, aryloxy, arylsulfenyl, arylsulfonyl,
`aZido, cyano, cycloalkenyl, cycloalkenylalkyl, cycloalkyl,
`cycloalkylalkyl, halo, haloalkoxy, haloalkyl, a second het
`erocyclyl group, heterocyclylalkoxy, heterocyclylalkyl, het
`erocyclylcarbonyl,
`heterocyclyloxy,
`iNRCRd,
`(NR°Rd)alkyl, (NR°Rd)carbonyl, and oxo, Wherein the aryl,
`the aryl part of the arylalkoxy, the arylalkyl, the arylcarbo
`nyl, the aryloxy, the arylsulfenyl, and the arylsulfonyl, the
`cycloalkenyl, the cycloalkenyl part of the cycloalkenylalkyl,
`the cycloalkyl, the cycloalkyl part of the cycloalkylalkyl, the
`second heterocyclyl group, and the heterocyclyl part of the
`heterocyclylalkoxy, the heterocyclylalkyl, the heterocyclyl
`carbonyl, and the heterocyclyloxy can be further optionally
`substituted With one, tWo, three, four, or ?ve substituents
`independently selected from the group consisting of alkoxy,
`alkyl, cyano, halo, haloalkoxy, haloalkyl, and oxo; and
`Wherein RC and R“1 are each independently selected from the
`group consisting of hydrogen, alkoxyalkyl, alkoxycarbonyl,
`alkyl, alkylcarbonyl, unsubstituted aryl, unsubstituted ary
`lalkyl, unsubstituted cycloalkyl, unsubstituted cycloalkyla
`lkyl, unsubstituted heterocyclyl, and unsubstituted hetero
`cyclylalkyl.
`[0072] The term “heterocyclylalkoxy,” as used herein,
`refers to a heterocyclyl group attached to the parent molecu
`lar moiety through an alkoxy group.
`[0073] The term "heterocyclylalkoxyalkyl,” as used
`herein, refers to an alkyl group substituted With one, tWo, or
`three heterocyclylalkoxy groups.
`[0074] The term “heterocyclylalkyl,” as used herein,
`refers to an alkyl group substituted With one, tWo, or three
`heterocyclyl groups. The alkyl part of the heterocyclylalkyl
`can be optionally substituted With one or tWo additional
`groups selected from the group consisting of alkenyl,
`alkoxy, alkynyl, arylalkoxy, aryloxy, heterocyclylalkoxy,
`heterocyclyloxy, hydroxy, and iNR°Rd; Wherein RC and R“1
`are independently selected from the group consisting of
`hydrogen, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbo
`nyl, unsubstituted aryl, unsubstituted arylalkyl, unsubsti
`tuted cycloalkyl, unsubstituted cycloalkylalkyl, unsubsti
`tuted heterocyclyl, and unsubstituted heterocyclylalkyl.
`[0075] The term “heterocyclylalkylcarbonyl,” as used
`herein, refers to a heterocyclylalkyl group attached to the
`parent molecular moiety through a carbonyl group.
`
`IPR2018-00211
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`US 2006/0276511 A1
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`Dec. 7, 2006
`
`[0076] The term “heterocyclylcarbonyl,” as used herein,
`refers to a heterocyclyl group attached to the parent molecu
`lar moiety through a carbonyl group.
`
`[0077] The term “heterocyclyloxy,” as used herein, refers
`to a heterocyclyl group attached to the parent molecular
`moiety through an oxygen atom.
`
`[0078] The term “heterocyclyloxyalkyl,” as used herein,
`refers to an alkyl group substituted With one, tWo, or three
`heterocyclyloxy groups.
`
`[0079] The term “hydroxy,” as used herein, refers to iH.
`
`[0080] The term “iNRaRb,” as used herein, refers to tWo
`groups, Ra and Rb, Which are attached to the parent molecu
`lar moiety through a nitrogen atom. Ra and Rb are each
`independently selected from the group consisting of hydro
`gen, alkenyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylalky
`lcarbonyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, and
`heterocyclylalkyl.
`
`[0081] The term “(NRaRb)alkyl,” as used herein, refers to
`an alkyl group substituted With one, tWo, or three iNRaRb
`groups. Ra and Rb are each independently selected from the
`group consisting of hydrogen, alkenyl, alkyl, alkylcarbonyl,
`aryl, arylalkyl, arylalkylcarbonyl, cycloalkyl, cycloalkyla
`lkyl, heterocyclyl, and heterocyclylalkyl.
`
`[0082] The term “(NRaRb)carbonyl,” as used herein,
`refers to an iNRaRb group attached to the parent molecular
`moiety through a carbonyl group. Ra and Rb are each
`independently selected from the group consisting of hydro
`gen, alkenyl, alkyl, alkylcarbonyl, aryl, arylalkyl, arylalky
`lcarbonyl, cycloalkyl, cycloalkylalkyl,
`
`[0083] The term “(NRaRb)carbonyloxy,” as used herein,
`refers to an (NRaRb)carbonyl group attached to the parent
`molecular moiety through an oxygen atom.
`
`[0084] The term “iNRCRd,” as used herein, refers to tWo
`groups, RC and Rd, Which are attached to the parent molecu
`lar moiety through a nitrogen atom. RC and R“1 are indepen
`dently selected from the group consisting of hydrogen,
`alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl, unsubsti
`tuted aryl, unsubstituted arylalkyl, unsubstituted cycloalkyl,
`unsubstituted cycloalkylalkyl, unsubstituted heterocyclyl,
`and unsubstituted heterocyclylalkyl.
`
`[0085] The term “(NR°Rd)alkyl,” as used herein, refers to
`an alkyl group substituted With one, tWo, or three iNR°Rd1
`groups. RC and R“1 are each independently selected from the
`group consisting of hydrogen, alkoxyalkyl, alkoxycarbonyl,
`alkyl, alkylcarbonyl, unsubstituted aryl, unsubstituted ary
`lalkyl, unsubstituted cycloalkyl, unsubstituted cycloalkyla
`lkyl, unsubstituted heterocyclyl, and unsubstituted hetero
`cyclylalkyl.
`
`[0086] The term “(NR°Rd)carbonyl,” as used herein,
`refers to an iNRCRG1 group attached to the parent molecular
`moiety through a carbonyl group. RC and R“1 are each
`independently selected from the group consisting of hydro
`gen, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylcarbonyl,
`unsubstituted aryl, unsubstituted arylalkyl, unsubstituted
`cycloalkyl, unsubstituted cycloalkylalkyl, unsubstituted het
`erocyclyl, and unsubstituted heterocyclylalkyl.
`
`[0087] The term “oxo,” as used herein, refers to =0.
`
`[0088] The term “sul?nyl,” as used herein, refers to
`iS(O)i.
`[0089] The term “sulfonyl,” as used herein, refers to
`isozi.
`[0090] Asymmetric centers exist in the compounds of the
`present invention. These centers are designated by the
`symbols “R” or “S”, depending on the con?guration of
`substituents around the chiral carbon atom. In the com
`pounds of the present invention at least one of the proline
`moieties is in the L con?guration. Preferably, the compounds
`of the invention contain tWo L-proline moieties. It should be
`understood that the invention encompasses all stereochemi
`cal isomeric forms, or mixtures thereof, Which possess the
`ability to inhibit NSSA. Individual stereoisomers of com
`pounds can be prepared synthetically from commercially
`available starting materials Which contain chiral centers or
`by preparation of mixtures of enantiomeric products fol
`loWed by separation such as conversion to a mixture of
`diastereomers folloWed by separation or recrystallization,
`chromatographic techniques, or direct separation of enanti
`omers on chiral chromatographic columns. Starting com
`pounds of particular stereochemistry are either commer
`cially available or can be made and resolved by techniques
`knoWn in the art.
`
`[0091] Certain compounds of the present invention may
`also exist in different stable conformational forms Which
`may be separable. Torsional asymmetry due to restricted
`rotation about an asymmetric single bond, for example
`because of steric hindrance or ring strain, may permit
`separation of different conformers. The present invention
`includes each conformational isomer of these compounds
`and mixtures thereof.
`
`[0092] Because carbon-carbon double bonds exist in the
`present compounds, the invention contemplates various geo
`metric isomers and mixtures thereof resulting from the
`arrangement of substituents around these carbon-carbon
`double bonds. It is Well knoWn in the art that stilbenes
`isomeriZe under a variety of reaction conditions (see, for
`Example WO02/50007). It should be understood that the
`invention encompasses both isomeric forms, and mixtures
`thereof, Which possess the ability to inhibit NSSA. The
`symbol “WW” is used to indicate that the compound can be
`the “E” isomer, the “Z” isomer, or a mixture of both. The
`term “E” represents higher order substituents on opposite
`sides of the carbon-carbon double bond, and the term “Z”
`represents higher order substituents on the same side of the
`carbon-carbon double bond.
`
`[0093] The term “compounds of the invention”, and
`equivalent expressions, are meant to embrace compounds of
`formula I, and pharmaceutically acceptable enantiomers,
`diastereomers, salts, solvates, e.g. hydrates, thereof. Simi
`larly, references to intermediates are meant to embrace their
`salts and solvates Where the context so permits. The term
`“solvate” means a physical association of a compound of
`this invention With one or more solvent molecules, Whether
`organic or inorganic. This physical association