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WO2008099020A1 - 1,1-dioxo-1-thia-5,10-diazadibenzocycloheptenes useful as hepatitis c virus inhibitors - Google Patents

1,1-dioxo-1-thia-5,10-diazadibenzocycloheptenes useful as hepatitis c virus inhibitors Download PDF

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Publication number
WO2008099020A1
WO2008099020A1 PCT/EP2008/051903 EP2008051903W WO2008099020A1 WO 2008099020 A1 WO2008099020 A1 WO 2008099020A1 EP 2008051903 W EP2008051903 W EP 2008051903W WO 2008099020 A1 WO2008099020 A1 WO 2008099020A1
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optionally substituted
aryl
het
alkyl
phenyl
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French (fr)
Inventor
Pierre Jean-Marie Bernard Raboisson
Koen Vandyck
Origène NYANGUILE
David Craig Mc Gowan
Sandrine Marie Helene Vendeville
Katie Ingrid Eduard Amssoms
Carlo Willy Maurice Boutton
Pedro Miguel Jales Lory
Lili Hu
Walter Marcel Mathilde Van Den Broeck
Maxwell David Cummings
Klara Rombauts
Stefaan Julien Last
Abdellah Tahri
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Janssen R&D Ireland ULC
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Tibotec Pharmaceuticals Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses

Definitions

  • the present invention is concerned with 1 , 1 -dioxo- 1 -thia-5 , 10-diazadibenzo- cycloheptenes having inhibitory activity on the replication of the hepatitis C virus (HCV). It further concerns compositions comprising these compounds as active ingredients as well as processes for preparing these compounds and compositions.
  • HCV hepatitis C virus
  • Hepatitis C virus is the leading cause of chronic liver disease worldwide and has become a focus of considerable medical research.
  • HCV is a member of the Flaviviridae family of viruses in the hepacivirus genus, and is closely related to the flavivirus genus, which includes a number of viruses implicated in human disease, such as dengue virus and yellow fever virus, and to the animal pestivirus family, which includes bovine viral diarrhoea virus (BVDV).
  • BVDV bovine viral diarrhoea virus
  • HCV is a positive-sense, single- stranded RNA virus, with a genome of around 9,600 bases.
  • the genome comprises both 5' and 3' untranslated regions that adopt RNA secondary structures, and a central open reading frame that encodes a single polyprotein of around 3,010-3,030 amino acids.
  • the polyprotein encodes ten gene products, which are generated from the precursor polyprotein by an orchestrated series of co- and posttranslational endoproteolytic cleavages mediated by both host and viral proteases.
  • the viral structural proteins include the core nucleocapsid protein, and two envelope glycoproteins El and E2.
  • the non- structural (NS) proteins encode some essential viral enzymatic functions (helicase, polymerase, protease), as well as proteins of unknown function.
  • Replication of the viral genome is mediated by an RNA-dependent RNA polymerase, encoded by non-structural protein 5b (NS5B).
  • NS5B non-structural protein 5b
  • the viral helicase and protease functions both encoded in the bifunctional NS3 protein, have been shown to be essential for replication of HCV RNA.
  • HCV also encodes a metalloproteinase in the NS2 region.
  • HCV replicates preferentially in hepatocytes but is not directly cytopathic, leading to persistent infection. In particular, the lack of a vigorous T-lymphocyte response and the high propensity of the virus to mutate appear to promote a high rate of chronic infection.
  • HCV type 1 is the predominant genotype in the US and Europe. For instance, HCV type 1 accounts for 70 to 75 percent of all HCV infections in the United States.
  • the extensive genetic heterogeneity of HCV has important diagnostic and clinical implications, perhaps explaining difficulties in vaccine development and the lack of response to therapy. An estimated 170 million persons worldwide are infected with hepatitis C virus (HCV).
  • HCV hepatitis C virus
  • liver fibrosis leading to cirrhosis, end-stage liver disease, and HCC hepatocellular carcinoma
  • HCC hepatocellular carcinoma
  • Liver cirrhosis due to HCV infection is responsible for about 10,000 deaths per year in the U.S.A. alone, and is the leading cause for liver transplantations.
  • Transmission of HCV can occur through contact with contaminated blood or blood products, for example following blood transfusion or intravenous drug use.
  • the introduction of diagnostic tests used in blood screening has led to a downward trend in post-transfusion HCV incidence.
  • the existing infections will continue to present a serious medical and economic burden for decades (Kim, W.R. Hepatology, 36, 5 Suppl. S30-S34, 2002).
  • HCV therapies are based on (pegylated) interferon-alpha (IFN- ⁇ ) in combination with ribavirin.
  • This combination therapy yields a sustained viro logic response in more than 40% of patients infected by genotype 1 viruses and about 80% of those infected by genotypes 2 and 3.
  • combination therapy has significant side effects and is poorly tolerated in many patients. For instance, in registration trials of pegylated interferon and ribavirin, significant side effects resulted in discontinuation of treatment in approximately 10 to 14 percent of patients.
  • Major side effects of combination therapy include influenza- like symptoms, hematologic abnormalities, and neuropsychiatric symptoms.
  • the development of more effective, convenient and tolerated treatments is a major public health objective. Thus, the treatment of this chronic disease is an unmet clinical need, since current therapy is only partially effective and limited by undesirable side effects.
  • NIs nucleoside inhibitors
  • NNIs non-nucleoside inhibitors
  • the present invention concerns inhibitors of HCV replication, which can be represented by formula (I):
  • R la is hydrogen, hydroxy, amino, Ci_6alkoxy, halo or Ci_6alkyl optionally substituted with hydroxyl
  • R lb is hydrogen, hydroxy, amino, Ci_6alkoxy, -O-CH2-thiazolyl, halo, trifluoromethyl, or Ci_ 6 alkyl optionally substituted with cyano
  • R 3 is Ci_ 6 alkyl optionally substituted with C 3 - 7 cycloalkyl, aryl, or Het; C 3 - 7 cycloalkyl; aryl; or Het; each R 4a and R 4b is, independently, hydrogen, C ⁇ alkyl, C 2 - 6 alkenyl, or both R 4a and R 4b together with the carbon atom of the tricyclic ring to which they are attached may form a C 3 _ 7 Cycloalkyl or an oxetanyl; R , 5 is Ci_6alkyl optionally substituted with one or two substituents selected from halo, C3-7cycloalkyl, phenylCi- ⁇ alkylthio, cyan
  • each R 7a and R 7b is, independently, hydrogen;
  • R 8 is Ci_ 6 alkyl, C 3 _ 7 Cycloalkyl, di(Ci_ 3 alkyl)amino, or aryl;
  • R 9 is hydrogen; Ci_6alkyl optionally substituted with one, two or three substituents each independently selected from halo, hydroxyl, C 3 _ 7 Cycloalkenyl, C 3 _ 7 Cycloalkyl, cyano, Ci_ 6 alkoxy, phenyl, or Het, wherein the phenyl may optionally be substituted with halo, hydroxyl, Ci_6alkoxy, Ci_6alkyl, Ci_6alkoxyCi_6alkoxy, nitro, or amino; C2-6alkenyl optionally substituted with one or two substituents selected from halo and polyhaloCi- ⁇ alkyl; C 2 - 6 alkynyl; C 3 _ 7 Cycloalkenyl; or phenyl optionally substituted with one or two substituents selected from
  • the present invention concerns inhibitors of HCV replication and the salts and stereoisomers thereof, wherein R la is hydrogen, hydroxy, amino, or halo; R lb is hydrogen, hydroxy, halo, trifluoromethyl, or Ci_ 6 alkyl optionally substituted with cyano;
  • R 3 is Ci_ 6 alkyl optionally substituted with C 3 - 7 cycloalkyl, aryl, or Het; C 3 - 7 cycloalkyl; aryl; or Het; each R 4a and R 4b is, independently, C 1-6 alkyl, or both R 4a and R 4b together with the carbon atom of the tricyclic ring to which they are attached may form a
  • each R 7a and R 7b is, independently, hydrogen;
  • R 8 is d- ⁇ alkyl, C3-7cycloalkyl, di(Ci_3alkyl)amino, or aryl;
  • R 9 is hydrogen; Ci_ 6 alkyl optionally substituted with Ci_ 6 alkoxy, phenyl, or Het, wherein the phenyl may optionally be substituted with halo, Ci_6alkoxy, nitro, or amino; or phenyl optionally substituted with one or two substituents selected from halo, amino, nitro, d ⁇ alkyl, and phenyl; aryl as a group or part of a group is phenyl, naphthyl, indanyl, or 1,2,3,4-tetrahydro-naphthyl, each of which may be optionally substituted with one or two substituents each independently selected from the group consisting of halo, polyhaloCi_ 6 alkyl, cyano, Ci_ 6 alkyl, polyhaloCi_ 6 alk
  • R 10b together with the nitrogen to which they are attached, may form a saturated, partially unsaturated, or completely unsaturated 5-8 membered monocycle, wherein said monocycle optionally contains one additional heteroatom selected from the group consisting of oxygen, sulfur and nitrogen, and wherein the remaining monocycle members are carbon atoms; wherein said monocycle may be optionally substituted on any carbon atom with one or two substituents each independently selected from halo, Ci_ 6 alkyl, hydroxy, or oxo.
  • the invention further relates to methods for the preparation of the compounds of formula (I), the //-oxides, quaternary amines, metal complexes, and stereochemically isomeric forms thereof, their intermediates, and the use of the intermediates in the preparation of the compounds of formula (I).
  • the invention therefore encompasses a process for the preparation of a compound according to the invention having formula (1-8), comprising the steps of : reacting a compound of formula (1-2) with a compound of formula (1-4) thereby obtaining compound of formula (1-5), and
  • R la , R lb , R 4a , R 4b , and R 3 have the same meaning as that defined herein.
  • the invention also encompasses a process for the preparation of a compound according to the invention having formula (1-9), comprising the step of:
  • the invention also encompasses a process for the preparation of a compound according to the invention having formula (I- 10), comprising the steps of :
  • the invention also encompasses a process for the preparation of a compound according to the invention having formula (1-11), comprising the step of : reacting a compound of formula (1-8) with a chloroformate of formula (I-8d) in the presence of a base, in an inert solvent thereby obtaining a compound of formula (I- 11), wherein R la , R lb , R 4a , R 4b , R 3 and R 6 have the same meaning as that defined herein.
  • the invention relates to the compounds of formula (I) per se, the iV-oxides, salts, hydrates, solvates, quaternary amines, metal complexes, prodrugs, and stereochemically isomeric forms thereof, for use as a medicament.
  • the invention relates to the compounds of formula (J) per se, the iV-oxides, salts, hydrates, solvates, quaternary amines, metal complexes, prodrugs, and stereochemically isomeric forms thereof, for treating hepatitis C.
  • the invention further relates to pharmaceutical compositions comprising a carrier and an anti-virally effective amount of a compound of formula (I) as specified herein.
  • the pharmaceutical compositions may comprise combinations of the aforementioned compounds with other anti-HCV agents.
  • the pharmaceutical compositions may comprise combinations of the aforementioned compounds with anti-HIV agents.
  • the invention further relates to the aforementioned pharmaceutical compositions for administration to a subject suffering from HCV infection.
  • the invention also relates to the use of a compound of formula (I), or a JV-oxide, salt, hydrate, solvate, quaternary amine, metal complex, prodrug, or stereochemically isomeric forms thereof, for the manufacture of a medicament for inhibiting HCV replication.
  • the invention relates to a method of inhibiting HCV replication in a warm-blooded animal said method comprising the administration of an effective amount of a compound of formula (I), or a prodrug, iV-oxide, salt, hydrate, solvate, quaternary amine, metal complex, or stereochemically isomeric forms thereof.
  • halo is generic to fluoro, chloro, bromo and iodo.
  • Ci_ 4 alkyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as for example methyl, ethyl, prop-1-yl, prop-2-yl, but-l-yl, but-2-yl, isobutyl, 2-methyl- prop-1-yl;
  • Ci_3alkyl as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 1 to 3 carbon atoms such as for example methyl, ethyl, prop-1-yl, prop-2-yl;
  • Ci_ 6 alkyl encompasses Ci_ 3 alkyl and Ci_ 4 alkyl radicals and the higher homologues thereof having 5 or 6 carbon atoms such as, for example, pent-1-yl, pent-2-yl, pent-3-yl, hex-l-yl, hex-2-yl, 2-methylbut-l-y
  • C2-6alkenyl refers to an unsaturated hydrocarbyl group, which may be linear, or branched, comprising one or more carbon- carbon double bonds.
  • Examples of C 2 - 6 alkenyl groups are ethenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl and its isomers, 2-hexenyl and its isomers,
  • polyhaloCi- ⁇ alkyl refers to a Ci_ 6 alkyl radical having the meaning as defined above wherein one or more hydrogens are replaced with one or more halogens as defined above.
  • Non- limiting examples of such polyhalo- C i_ 6 alkyl radicals include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, and 1,1,1-trifluoroethyl.
  • C 3 7 cycloalkyl is generic to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • Ci_6alkoxy or "Ci_6alkyloxy” as a group or part of a group refers to a radical having the Formula -OR a wherein R a is Ci_ 6 alkyl as defined above.
  • suitable Ci_6alkoxy include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy.
  • Suitable Ci_4alkoxy include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec- butoxy, and tert-butoxy.
  • polyhaloCi- ⁇ alkoxy refers to a Ci_6alkoxy radical having the meaning as defined above wherein one or more hydrogens are replaced with one or more halogens as defined above.
  • Non- limiting examples of such polyhaloCi- ⁇ alkoxy radicals include chloromethoxy, 1-bromoethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, and 1,1,1-trifluoroethoxy.
  • the carbon atom to which the oxo is linked is a saturated carbon.
  • Non-limiting examples of Ci_ 6 alkylsulfonyl groups include methylsulfonyl, ethylsulfonyl, butylsulfonyl, prop-1-ylsulfonyl, n-pentylsulfonyl, and hexylsulfonyl.
  • Ci_6alkylthio refers to a group consisting of a sulfur atom attached to a Ci_6alkyl group.
  • Non- limiting examples of Ci_6alkylthio groups include methylthio (SCH 3 ), ethylthio (SCH 2 CH 3 ), n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, te/t-butylthio, and the like.
  • radical positions on any molecular moiety used in the definitions may be anywhere on such moiety as long as it is chemically stable.
  • Radicals used in the definitions of the variables include all possible isomers unless otherwise indicated.
  • piperidinyl includes piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, and piperidin-4-yl
  • pentyl includes pent-1-yl, pent-2-yl and pent-3-yl.
  • each definition is independent.
  • the term "compounds of formula (I)”, or “the present compounds” or similar terms it is meant to include the compounds of formula (I), their prodrugs, JV-oxides, salts, quaternary amines, metal complexes, and stereochemically isomeric forms.
  • One embodiment comprises the compounds of formula (I) or any subgroup of compounds of formula (I) specified herein, as well as the JV-oxides, salts, as the possible stereoisomeric forms thereof.
  • Another embodiment comprises the compounds of formula (I) or any subgroup of compounds of formula (I) specified herein, as well as the salts as the possible stereoisomeric forms thereof.
  • the compounds of formula (I) may have one or more centers of chirality and may exist as stereochemically isomeric forms.
  • stereochemically isomeric forms as used herein defines all the possible compounds made up of the same atoms bonded by the same sequence of bonds but having different three-dimensional structures, which the compounds of formula (I) may possess.
  • the chemical designation of a compound encompasses the mixture of all possible stereochemically isomeric forms, which said compound may possess. Said mixture may contain all diastereomers and/or enantiomers of the basic molecular structure of said compound. All stereochemically isomeric forms of the compounds of the present invention both in pure form or mixed with each other are intended to be embraced within the scope of the present invention.
  • stereoisomerically pure concerns compounds or intermediates having a stereoisomeric excess of at least 80% (i.e. minimum 90% of one isomer and maximum 10% of the other possible isomers) up to a stereoisomeric excess of 100% (i.e.
  • enantiomers may be separated from each other by the selective crystallization of their diastereomeric salts with optically active acids or bases. Examples thereof are tartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid and camphosulfonic acid.
  • enantiomers may be separated by chromatographic techniques using chiral stationary phases.
  • Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically.
  • said compound will be synthesized by stereospecif ⁇ c methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.
  • the diastereomeric racemates of the compounds of formula (I) can be obtained separately by conventional methods.
  • Appropriate physical separation methods that may advantageously be employed are, for example, selective crystallization and chromatography, e.g. column chromatography.
  • the absolute stereochemical configuration was not experimentally determined.
  • a person skilled in the art is able to determine the absolute configuration of such compounds using art-known methods such as, for example, X-ray diffraction.
  • the present invention encompasses compounds of Formula (II) and (III).
  • preferred configuration has Formula (II).
  • R la , R lb , R 2 , R 3 , R 4a and R 4b have the same meaning as that defined herein.
  • the present invention is also intended to include all isotopes of atoms occurring on the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include tritium and deuterium.
  • Isotopes of carbon include C- 13 and C- 14.
  • prodrug as used throughout this text means the pharmacologically acceptable derivatives such as esters, amides and phosphates, such that the resulting in vivo biotransformation product of the derivative is the active drug as defined in the compounds of formula (I).
  • the reference by Goodman and Gilman The Pharmacological Basis of Therapeutics, 8 th ed, McGraw-Hill, Int. Ed. 1992,
  • Prodrugs preferably have excellent aqueous solubility, increased bioavailability and are readily metabolized into the active inhibitors in vivo.
  • Prodrugs of a compound of the present invention may be prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either by routine manipulation or in vivo, to the parent compound.
  • ester prodrugs that are hydrolysable in vivo and are derived from those compounds of formula (I) having a hydroxy or a carboxyl group.
  • An in vivo hydrolysable ester is an ester, which is hydro lyzed in the human or animal body to produce the parent acid or alcohol.
  • Suitable pharmaceutically acceptable esters for carboxy include Ci_6alkoxymethyl esters for example methoxy— methyl, Ci_ 6 alkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidyl esters, C 3 _ 8 CycloalkoxycarbonyloxyCi_ 6 alkyl esters for example 1-cyclohexylcarbonyl- oxyethyl; l,3-dioxolen-2-onylmethyl esters for example 5-methyl-l,3-dioxolen-2- onylmethyl; and Ci_ 6 alkoxycarbonyloxyethyl esters for example 1-methoxycarbonyl- oxyethyl which may be formed at any carboxy group in the compounds of this invention.
  • An in vivo hydrolysable ester of a compound of the formula (I) containing a hydroxy group includes inorganic esters such as phosphate esters and ⁇ -acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxy group.
  • inorganic esters such as phosphate esters and ⁇ -acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxy group.
  • ⁇ -acyloxyalkyl ethers include acetoxy-methoxy and 2,2-dimethylpropionyloxy-methoxy.
  • a selection of in vivo hydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and 7V-(dialkylaminoethyl)-7V-alkylcarbamoyl (to give carbamates), dialkylaminoacetyl and carboxyacetyl.
  • substituents on benzoyl include morpholino and piperazino linked from a ring nitrogen atom via a methylene group to the 3- or 4-position of the benzoyl ring.
  • salts of the compounds of formula (I) are those wherein the counter-ion is pharmaceutically acceptable.
  • salts of acids and bases which are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. All salts, whether pharmaceutically acceptable or not are included within the ambit of the present invention.
  • the pharmaceutically acceptable acid and base salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid and base addition salt forms which the compounds of formula (I) are able to form.
  • the pharmaceutically acceptable acid addition salts can conveniently be obtained by treating the base form with such appropriate acid.
  • Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e.
  • butanedioic acid maleic, fumaric, malic (i.e. hydroxybutanedioic acid), tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, /?-toluenesulfonic, cyclamic, salicylic, /?-amino- salicylic, pamoic and the like acids.
  • salt forms can be converted by treatment with an appropriate base into the free base form.
  • the compounds of formula (I) containing an acidic proton may also be converted into their non-toxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases.
  • Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. the benzathine, JV-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like.
  • quaternary amine as used hereinbefore defines the quaternary ammonium salts which the compounds of formula (I) are able to form by reaction between a basic nitrogen of a compound of formula (I) and an appropriate quaternizing agent, such as, for example, an optionally substituted alkylhalide, arylhalide or arylalkylhalide, e.g. methyliodide or benzyliodide.
  • Other reactants with good leaving groups may also be used, such as alkyl trifluoromethanesulfonates, alkyl methanesulfonates, and alkyl p-toluenesulfonates.
  • a quaternary amine has a positively charged nitrogen.
  • Pharmaceutically acceptable counterions include chloro, bromo, iodo, trifluoroacetate and acetate. The counterion of choice can be introduced using ion exchange resins.
  • N-oxide forms of the present compounds are meant to comprise the compounds of formula (I) wherein one or several nitrogen atoms are oxidized to the so-called N-oxide.
  • the compounds of formula (I) may have metal binding, chelating, complex forming properties and therefore may exist as metal complexes or metal chelates. Such metalated derivatives of the compounds of formula (I) are intended to be included within the scope of the present invention.
  • One embodiment of the present invention concerns compounds of formula (I) or of any subgroup thereof, wherein:
  • R 3 is Ci_ 6 alkyl optionally substituted with C 3 - 7 cycloalkyl, aryl, or Het; C 3 - 7 cycloalkyl; aryl; or Het; preferably R 3 is aryl; or Het; most preferably R 3 is aryl; each R 4a and R 4b is, independently, hydrogen, C 2 - 6 alkenyl,Ci_ 6 alkyl; or both R 4a and R 4b together with the carbon atom of the tricyclic ring to which they are attached may form an oxetanyl; preferably each R 4a and R 4b is, independently, hydrogen,
  • each R 4a and R 4b is, independently,
  • R , 5 is Ci_6alkyl optionally substituted with one or two substituents selected from halo,
  • Het is selected from pyridinyl, quinolinyl, isoquinolinyl, pyrazinyl, furanyl, thiophenyl, oxazolyl, thiazolyl, pyrimidinyl, pyridazinyl, imidazolyl, 2,3-dihydrobenzofuranyl, tetrahydrofuran, and wherein the group Het as a whole may be optionally substituted with one or two substituents each independently selected from the group consisting of halo; polyhaloCi- ⁇ alkyl; Ci_6alkylthio, oxo; -OR 9 ; -CN;
  • One embodiment of the present invention concerns compounds of formula (I) or of any subgroup of compounds of formula (I), wherein
  • R la is hydrogen, hydroxy, amino, or hydroxyCi- ⁇ alkyl
  • R lb is hydrogen, hydroxy, halo, amino, Ci_6alkoxy, -O-CH2-thiazolyl, trifluoromethyl, or Ci_ 6 alkyl optionally substituted with cyano;
  • R is Ci_ 6 alkyl optionally substituted with C 3 _ 7 Cycloalkyl, aryl, or Het; C 3 _ 7 Cycloalkyl; aryl; or Het; each R 4a and R 4b is, independently, hydrogen, C 2 - 6 alkenyl, or Ci_ 6 alkyl; or both R 4a and R 4b together with the carbon atom of the tricyclic ring to which they are attached may form an oxetanyl;
  • R 8 is d- ⁇ alkyl, C3-7cycloalkyl, di(Ci_3alkyl)amino, or aryl;
  • R 9 is hydrogen; Ci_6alkyl optionally substituted with one, two or three substituents each independently selected from halo, hydroxyl, C 3 - 7 cycloalkenyl, C 3 - 7 cycloalkyl, cyano, Ci_ 6 alkoxy, phenyl, or Het, wherein the phenyl may optionally be substituted with halo, hydroxyl, Ci_6alkoxy, Chalky!, Ci_6alkoxyCi_6alkoxy, nitro, or amino; C2-6alkenyl optionally substituted with one or two substituents selected from halo and polyhaloCi- ⁇ alkyl; C 2 - 6 alkynyl; C 3 _ 7 Cycloalkenyl;or phenyl optionally substituted with one or two substituents selected from hydroxyl
  • R la is hydrogen, hydroxy, or amino
  • R lb is hydrogen, hydroxy, halo, trifluoromethyl, or Ci_ 6 alkyl optionally substituted with cyano;
  • R is Ci_ 6 alkyl optionally substituted with C 3 _ 7 Cycloalkyl, aryl, or Het; C 3 _ 7 Cycloalkyl; aryl; or Het; each R 4a and R 4b is, independently, Ci_ 6 alkyl;
  • R 5 is Ci_6alkyl optionally substituted with one or two substituents selected from halo,
  • each R 7a and R 7b is, independently, hydrogen;
  • R 8 is Ci_ 6 alkyl, C 3 _ 7 Cycloalkyl, di(Ci_ 3 alkyl)amino, or aryl;
  • R 9 is hydrogen; Ci_6alkyl optionally substituted with one, two or three substituents each independently selected from halo, hydroxyl, C 3 _ 7 Cycloalkenyl, C 3 _ 7 Cycloalkyl, Ci_ 6 alkoxy, phenyl, or Het, wherein the phenyl may optionally be substituted with halo, Ci_6alkoxy, Ci_6alkyl, Ci_6alkoxyCi_6alkoxy, nitro, or amino; C2-6alkenyl;
  • C 2 _6alkynyl or phenyl optionally substituted with one or two substituents selected from halo, Ci_ 6 alkoxy, polyhaloCi- ⁇ alkyl, amino, nitro, Ci_ 6 alkyl, and phenyl; aryl as a group or part of a group is phenyl, naphthyl, indanyl, or 1,2,3,4-tetrahydro- naphthyl, each of which may be optionally substituted with one, two, three or four substituents each independently selected from the group consisting of
  • One embodiment of the present invention concerns compounds of formula (I) or of any subgroup of compounds of formula (I), wherein one or more of the following restrictions apply:
  • R la is hydrogen, hydroxy, amino, or halo
  • R lb is hydrogen, hydroxy, halo, trifluoromethyl, or Ci_ 6 alkyl optionally substituted with cyano;
  • R 3 is Ci_ 6 alkyl optionally substituted with C 3 _ 7 Cycloalkyl, aryl, or Het; C 3 _ 7 Cycloalkyl; aryl; or Het;
  • each R 4a and R 4b is, independently, C h alky!;
  • R 8 is Ci_ 6 alkyl, C 3 _ 7 Cycloalkyl, di(Ci_ 3 alkyl)amino, or aryl;
  • R 9 is hydrogen; Ci_ 6 alkyl optionally substituted with Ci_ 6 alkoxy, phenyl, or Het, wherein the phenyl may optionally be substituted with halo, Ci_6alkoxy, nitro, or amino; or phenyl optionally substituted with one or two substituents selected from halo, amino, nitro, Ci_6alkyl, and phenyl;
  • Ci_ 6 alkylthio, Ci_ 6 alkylsulfonyl, -S( O) 2 NH 2 , and pyrrolyl;
  • R la is hydrogen, hydroxy, or amino
  • R lb is hydrogen, hydroxy, halo, trifluoromethyl, or Ci_ 6 alkyl optionally substituted with cyano
  • R 3 is Ci_ 6 alkyl optionally substituted with C 3 - 7 cycloalkyl, aryl, or Het
  • each R 4a and R 4b is, independently, Ci_ 6 alkyl
  • R 6 is aryl or Ci_ 6 alkyl; each R 7a and R 7b is, independently, hydrogen; Ci_ 6 alkyl; aryl; or Het;
  • R 9 is hydrogen; Ci_6alkyl optionally substituted with one, two or three substituents each independently selected from halo, hydroxyl, C 3-7 Cy cloalkenyl, C 3-7 Cy cloalkyl,
  • Ci_ 6 alkoxy, phenyl, or Het wherein the phenyl may optionally be substituted with halo, Ci_6alkoxy, nitro, Ci_6alkyl, Ci_6alkoxyCi_6alkoxy, or amino; C2-6alkenyl; C2- ⁇ alkynyl; or phenyl optionally substituted with one or two substituents selected from halo, Ci_6alkoxy, polyhaloCi- ⁇ alkyl, amino, nitro, Ci_6alkyl, and phenyl; aryl as a group or part of a group is phenyl optionally substituted with one two, three or four substituents each independently selected from the group consisting of C 3 _ 7 cycloalkyl, phenylCi- ⁇ alkyl, phenylpolyhaloCi- ⁇ alkyl, phenylCi- ⁇ alkyloxy, halo, polyhaloCi- ⁇ alkyl, cyano
  • One embodiment of the present invention concerns compounds of formula (I) or of any subgroup of compounds of formula (I), wherein one or more of the following restrictions apply: (a) R la is hydrogen, hydroxy, amino, or halo;
  • R lb is hydrogen, hydroxy, halo, trifluoromethyl, or Ci_ 6 alkyl optionally substituted with cyano;
  • R 3 is Ci_ 6 alkyl optionally substituted with C 3 _ 7 cycloalkyl, aryl, or Het; C 3 _ 7 cy cloalkyl; aryl; or Het;
  • each R 4a and R 4b is, independently, C h alky!;
  • R > 6 0 is d-ealkyl
  • each R 7a and R 7b is, independently, hydrogen; Ci_ 6 alkyl; aryl; or Het;
  • R 9 is hydrogen; Ci_ 6 alkyl optionally substituted with Ci_ 6 alkoxy, phenyl, or Het, wherein the phenyl may optionally be substituted with halo, Ci_6alkoxy, nitro, or amino; or phenyl optionally substituted with one or two substituents selected from halo, amino, nitro, C ⁇ aUcyl, and phenyl;
  • Het as a group or part of a group is a 5 to 12 membered saturated, partially unsaturated or completely unsaturated mono- or bicyclic ring containing 1 to 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, and wherein the group Het as a whole may be optionally substituted with one or two substituents each independently selected from the group consisting of halo, oxo, -OR 9 , -CN, and Chalky!.
  • R la , R lb , R 3 , R 5 and R 6 are as specified in the definitions of the compounds of formula (I) or any subgroups thereof.
  • Particular subgroups of compounds of formula (I) are those represented by any of the following structural formula (I-f), (I-g) or (I-h): and the salts and stereoisomers thereof, wherein R la , R lb , R 2 , R 5 , R 6 and aryl are as specified in the definitions of the compounds of formula (I) or any subgroups thereof.
  • One embodiment of the present invention concerns compounds of formula (I) or of any subgroup thereof, wherein:
  • R la is hydrogen, hydroxy, or amino
  • R lb is hydrogen, hydroxy, amino, Ci_3alkoxy, or Ci_3alkyl
  • R is aryl; or Het; each R 4a and R 4b is, independently, hydrogen, C 2 - 6 alkenyl, or Ci_ 6 alkyl;
  • R 5 is selected from the group comprising Ci_6alkyl; polyhaloCi- ⁇ alkyl;
  • R 6 is phenyl optionally substituted with Ci_ 6 alkyloxy; or Ci_ 6 alkyl optionally substituted with -OR 9 , aryl, or Het;
  • R 9 is hydrogen; Ci_6alkyl optionally substituted with one, two or three substituents each independently selected from halo, hydroxyl, C 3 - 7 cycloalkenyl, C 3 - 7 cycloalkyl,
  • Ci_ 6 alkoxy, phenyl, or Het wherein the phenyl may optionally be substituted with halo, hydroxyl, Ci_6alkoxy, Ci_6alkyl, Ci_6alkoxyCi_6alkoxy; C2-6alkenyl; C2- ⁇ alkynyl; or phenyl optionally substituted with one or two substituents selected from hydroxyl, Ci_ 6 alkoxy, halo, polyhaloCi- ⁇ alkyl, C h alky!, and phenyl; aryl as a group or part of a group is phenyl, optionally substituted with one, two , three or four substituents each independently selected from the group consisting of C 3 _ 7 Cycloalkyl, phenylCi- ⁇ alkyl, phenylpolyhaloCi- ⁇ alkyl, phenylCi- ⁇ alkyloxy, halo, polyhaloCi- ⁇ alkyl, cyano,
  • One embodiment of the present invention concerns compounds of formula (I) or of any subgroup thereof, wherein:R la is hydrogen or hydroxy; R lb is hydrogen or hydroxy;
  • R 3 is aryl;
  • eaacch R 4a and R 4b is, independently, C h alky!;
  • R 9 is Ci_6alkyl optionally substituted with one, two or three substituents each independently selected from halo, hydroxyl, C 3 - 7 cycloalkenyl, C 3 - 7 cycloalkyl, or phenyl; or phenyl optionally substituted with one or two substituents selected from halo, polyhaloCi- ⁇ alkyl, or C ⁇ aUcyl, aryl as a group or part of a group is phenyl optionally substituted with one, two, three or four substituents each independently selected from the group consisting of halo, polyhaloCi- ⁇
  • R 5 is selected from the group comprising Ci_ 6 alkyl; polyhaloCi- ⁇ alkyl;
  • R 6 is phenyl optionally substituted with Ci_ 3 alkyloxy; or Ci_ 6 alkyl;
  • R 9 is hydrogen; Ci_6alkyl optionally substituted with one, two or three substituents each independently selected from halo, C 3 - 7 cycloalkenyl, C 3 - 7 cycloalkyl, phenyl, or Het, wherein the phenyl may optionally be substituted with halo, hydroxyl, Ci_6alkoxy, Ci_ 6 alkyl, Ci_ 6 alkoxyCi_ 6 alkoxy; C 2 - 6 alkenyl; C 2 - ⁇ alkynyl; or phenyl optionally substituted with one or two substituents selected from hydroxyl, Ci_6alkoxy, halo, polyhaloCi- ⁇ alkyl, Ci_ 6 alkyl; aryl as a group or part of a group is phenyl, optionally substituted with one, two , three or four substituents each independently selected from the group consisting of C 3 _ 7 Cycloalkyl, phenylCi- ⁇ alkyl
  • One embodiment of the present invention concerns compounds of formula (I) or of any subgroup of compounds of formula (I), wherein one or more of the following restrictions apply:
  • R la is hydrogen or hydroxy
  • R lb is hydrogen or hydroxy
  • R 3 is aryl
  • each R 4a and R 4b is, independently, Ci_ 6 alkyl;
  • R 5 is Ci_ 6 alkyl or Het;
  • R 9 is Ci_ 6 alkyl optionally substituted with phenyl;
  • aryl as a group or part of a group is phenyl optionally substituted with one or two substituents each independently selected from the group consisting of halo, polyhaloCi- ⁇ alkyl, cyano, Chalky!, polyhaloCi- ⁇ alkoxy, and -OR 9 ;
  • Het as a group or part of a group is a 5 to 6 membered saturated, partially unsaturated or completely unsaturated monocyclic ring containing 1 to 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, and wherein the group Het may be optionally substituted with one or two substituents each independently selected from the group consisting of halo, oxo, -OR 9 , -CN, and Ci_ 6 alkyl.
  • R 9 is Ci_ 6 alkyl optionally substituted with phenyl; aryl as a group or part of a group is phenyl optionally substituted with one or two halo or -OR 9 ; Het as a group or part of a group is a 5 to 6 membered saturated, partially unsaturated or completely unsaturated monocyclic ring containing 1 to 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, and wherein the group Het may be optionally substituted with one or two substituents each independently selected from the group consisting of halo, -OR 9 , and Ci_6alkyl.
  • R la , R lb , R 2 and R 3 are as specified in the definitions of the compounds of formula (I) or in any of the subgroups of compounds of formula (I) specified herein.
  • the present invention encompasses compounds of Formula (II-a) and (III-a).
  • preferred configuration has Formula (II-a).
  • R la , R lb , R 2 , and aryl are as specified in the definitions of the compounds of formula (I) or in any of the subgroups of compounds of formula (I) specified herein.
  • the present invention encompasses compounds of Formula (II -b) and (III-b).
  • preferred configuration has Formula (II -b).
  • Particular subgroups of compounds of formula (I) are those represented by any of the following structural formula (I-i), (I-j) or (I-k): and the salts and stereoisomers thereof, wherein R la , R lb , R 3 , R 5 and R 6 are as specified in the definitions of the compounds of formula (I) or any subgroups thereof.
  • Particular subgroups of compounds of formula (I) are those represented by any of the following structural formula (1-1), (I-m) or (I-n):
  • R la , R lb , R 2 , R 5 , R 6 and aryl are as specified in the definitions of the compounds of formula (I) or any subgroups thereof.
  • the present invention encompasses compounds of Formula (II-l), (III-l), (II-m), (III-m), (II-n) and (III-n).
  • compounds of Formula (1-1), (I-m) or (I-n) preferred configuration has Formula (II-l), (II-m), (II-n) respectively.
  • compounds of Formula I or any subgroup thereof that in the inhibition assays described below have an inhibition value of less than 100 ⁇ M, preferably less than 50 ⁇ M, more preferably less than 10 ⁇ M, preferably less than 5 ⁇ M, even more preferably less than l ⁇ M preferably less than 100 nM, and in particular less than 10 nM, as determined by a suitable assay, such as the assays used in the Examples below.
  • Step 1-1 -> 1-2 Intermediate (1-1) may be synthesized following the procedure reported in (i) Lansbury, P.T.; Scharf, D. J. J. Am. Chem. Soc. 1968, 90, 2, 536-53 and (ii) Lansbury, P.T.; Nienhouse, E. J.; Scharf, D. J.; Hilfiker, F. R. J. Am. Chem. Soc. 1970, 92, 19, 5649-5657 or following the procedure described in scheme 4.
  • Intermediate (1-1) is reacted with a strong oxidizing agent in order to oxidize the cyclic sulfide into the sulfone derivative (1-2).
  • a strong oxidizing agent for carrying out this reaction include, amongst other, m-chloroperbenzoic acid, hydrogen peroxide-ZrCU, or hydrogen peroxide- Acetic acid.
  • the solvent may be selected from chloroform or dichloromethane.
  • Step 1-2 + 1-4 -> 1-5 + 1-6
  • Intermediate (1-5) may then be reacted with an aldehyde of formula R 3 -CHO (1-7). Such reaction occurs in the presence of an acid, such as acetic acid, and in an appropriate solvent.
  • an acid such as acetic acid
  • Step 1-8 -> 1-9: Procedure to introduce substituent -Cf O)-R 5
  • Compound of formula (1-8), which is itself an intermediate as well, is acylated with an acid or an activated acid such as acyl anhydride or acyl chloride (for instance picolinoylchloride), in the presence of a suitable solvent, in order to acylate the amines thereby forming amides.
  • an activated acid such as acyl anhydride or acyl chloride (for instance picolinoylchloride)
  • acyl chloride for instance picolinoylchloride
  • HATU (2-( 1 H-7-azabenzotriazo 1- 1 -yl) ⁇ 1 , 1 ,3 ,3 -tetramethyl uranium hexafluorophosphate methanaminium ), and the like optionally in the presence of an appropriate base such as triethylamine or diisopropylethylamine.
  • the acyl chloride can be activated in situ with DMAP (4-dimethylaminopyridine) and the like and the reaction can be carried out in the presence of an appropriate base such as triethylamine or diisopropylethylamine.
  • an acid catalyst such as p-TSA (p-toluenesulfonic acid), may be added.
  • the suitable solvent for the acylation reaction may be selected from pyridine, dichloromethane, chloroform, THF, and DMF.
  • an isocyanate is used, a compound of formula (I- 10) wherein R 7b represents a hydrogen is obtained.
  • a base such as an alkali or alkaline metal hydride such as LiH or sodium hydride, or alkali metal alkoxide such as sodium or potassium methoxide or ethoxide, potassium tert-butoxidc, in an inert solvent like a dipolar aprotic solvent, e.g. DMA (dimethylacetamide), DMF, THF, and the like.
  • a base such as an alkali or alkaline metal hydride such as LiH or sodium hydride, or alkali metal alkoxide such as sodium or potassium methoxide or ethoxide, potassium tert-butoxidc
  • an inert solvent like a dipolar aprotic solvent, e.g. DMA (dimethylacetamide), DMF, THF, and the like.
  • DMA dimethylace
  • More than one acyl group can be introduced on compound of formula (1-8), when R la represents a hydroxyl group, or (1-12), as depicted in Scheme 3 below.
  • R la represents a hydroxyl group, or (1-12)
  • Scheme 3 depicted in Scheme 3 below.
  • a compound of structure (I- 13 a), (I- 13b) or (I- 13 c) is obtained.
  • a mixture of compounds (I- 13a), (I- 13b) or (I- 13c) can be obtained.
  • acyl groups can be cleaved by treating the corresponding compounds of formula (1-9), (1-10), (1-11), (I- 13a), (I-13b) and (I- 13c) with an hydroxide such as sodium hydroxide, potassium hydroxide, or lithium hydroxide in a suitable solvent such as water, C ⁇ alcohol, THF, 2-methyltetrahydrofuran (MeTHF), or any mixture thereof.
  • an hydroxide such as sodium hydroxide, potassium hydroxide, or lithium hydroxide in a suitable solvent such as water, C ⁇ alcohol, THF, 2-methyltetrahydrofuran (MeTHF), or any mixture thereof.
  • Protection of the hydroxy group may be performed with benzyl or substituted benzyl ethers, e.g. 4-methoxybenzyl ether, benzoyl or substituted benzoyl esters, e.g. 4-nitrobenzoyl ester, or with trialkylsilyl goups (e.g. trimethylsilyl or te/t-butyldimethylsilyl) or by intramolecular cyclisation with CDI (l,l'-carbonyldiimidazole) to form a cyclic carbamate derivative.
  • CDI l,l'-carbonyldiimidazole
  • Compound of formula (1-1) may be synthesized following the three-step procedure of scheme 4.
  • compound of formula IV-4 can be prepared from 2,3-dichloropropene IV-I via intermediates IV-5 and IV-6 as shown in Scheme 4.
  • 2,3-dichloropropene IV-I (commercially available at Aldrich) is reacted with thiourea in a suitable solvent such as ethanol at a temperature between 0 0 C and 120 0 C, preferably around 80 0 C, to provide the intermediate IV-5.
  • hydrolysis of intermediate IV-5 to the thiol derivative IV-6 is performed in presence of an hydroxide, for instance sodium hydroxide, in an appropriate solvent such as water, at a temperature between 20 and 120 0 C, preferably around 100 0 C.
  • an hydroxide for instance sodium hydroxide
  • an appropriate solvent such as water
  • intermediate IV-6 Treatment of intermediate IV-6 with a disubstituted epoxide of formula IV-3 in presence of a suitable base such as sodium methanolate in methanol at a temperature between 0 0 C and 50 0 C, preferably around 20 0 C, provides the intermediate IV-4.
  • a suitable base such as sodium methanolate in methanol at a temperature between 0 0 C and 50 0 C, preferably around 20 0 C
  • a substituent R 9 may be introduced as described in scheme 5, from a precursor V-3 whose hydroxyl group R la is protected with an acyl protecting group, for example a cyclic carbamate protecting group like in the structure below where X is for example halogen.
  • an acyl protecting group for example a cyclic carbamate protecting group like in the structure below where X is for example halogen.
  • Step V-I- ⁇ V-2 protection of the hydroxyl group with PGi
  • Step V-2 -> V-3 removal of the PG 2 group
  • Step V-3 -> V-4 introduction of a R 9 substituent
  • a R 9 substituent may be introduced via for example a SN2 reaction, or Mitsunobu reaction from intermediate V-3.
  • the resulting intermediate V-3 is further reacted with an alkali metal hydroxide (LiOH, NaOH, KOH), in an aqueous medium comprising water and a water-soluble organic solvent such as an alkanol (methanol, ethanol) and THF to afford a compound of formula V-5.
  • an alkali metal hydroxide LiOH, NaOH, KOH
  • the compounds of formula (I) may be converted to the corresponding JV-oxide forms following art-known procedures for converting a trivalent nitrogen into its iV-oxide form.
  • Said JV-oxidation reaction may generally be carried out by reacting the starting material of formula (I) with an appropriate organic or inorganic peroxide.
  • Appropriate inorganic peroxides comprise, for example, hydrogen peroxide, alkali metal or earth alkaline metal peroxides, e.g. sodium peroxide, potassium peroxide;
  • appropriate organic peroxides may comprise peroxy acids such as, for example, benzenecarbo- peroxoic acid or halo substituted benzenecarboperoxoic acid, e.g.
  • Suitable solvents are, for example, water, lower alcohols, e.g. ethanol and the like, hydrocarbons, e.g. toluene, ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g. dichloromethane, and mixtures of such solvents.
  • Diastereomers may be separated by physical methods such as selective crystallization and chromatographic techniques, e.g., counter-current distribution, liquid chromatography and the like.
  • the compounds of formula (I) may be obtained as racemic mixtures of enantiomers, which can be separated from one another following art-known resolution procedures.
  • the racemic compounds of formula (I), which are sufficiently basic or acidic may be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid, respectively chiral base. Said diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated therefrom by alkali or acid.
  • An alternative manner of separating the enantiomeric forms of the compounds of formula (I) involves liquid chromatography, in particular liquid chromatography using a chiral stationary phase.
  • Said pure stereochemical ⁇ isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecif ⁇ cally.
  • said compound may be synthesized by stereospecif ⁇ c methods of preparation. These methods may advantageously employ enantiomerically pure starting materials.
  • the present invention concerns a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) as specified herein, or a compound of any of the subgroups of compounds of formula (I) as specified herein, and a pharmaceutically acceptable carrier.
  • a therapeutically effective amount in this context is an amount sufficient to prophylactically act against, to stabilize or to reduce viral infection, and in particular HCV viral infection, in infected subjects or subjects being at risk of being infected.
  • this invention relates to a process of preparing a pharmaceutical composition as specified herein, which comprises intimately mixing a pharmaceutically acceptable carrier with a therapeutically effective amount of a compound of formula (I), as specified herein, or of a compound of any of the subgroups of compounds of formula (I) as specified herein.
  • compositions of the present invention may be formulated into various pharmaceutical forms for administration purposes.
  • compositions there may be cited all compositions usually employed for systemically administering drugs.
  • an effective amount of the particular compound, optionally in salt form or metal complex, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration.
  • a pharmaceutically acceptable carrier which carrier may take a wide variety of forms depending on the form of preparation desired for administration.
  • These pharmaceutical compositions are desirable in unitary dosage form suitable, particularly, for administration orally, rectally, percutaneously, or by parenteral injection.
  • any of the usual pharmaceutical media may be employed such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs, emulsions and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules, and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid pharmaceutical carriers are obviously employed.
  • the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included.
  • Injectable solutions may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution.
  • Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. Also included are solid form preparations that are intended to be converted, shortly before use, to liquid form preparations.
  • the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not introduce a significant deleterious effect on the skin.
  • the compounds of the present invention may also be administered via oral inhalation or insufflation by means of methods and formulations employed in the art for administration via this way.
  • the compounds of the present invention may be administered to the lungs in the form of a solution, a suspension or a dry powder, a solution being preferred. Any system developed for the delivery of solutions, suspensions or dry powders via oral inhalation or insufflation are suitable for the administration of the present compounds.
  • the present invention also provides a pharmaceutical composition adapted for administration by inhalation or insufflation through the mouth comprising a compound of formula (I) and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition adapted for administration by inhalation or insufflation through the mouth comprising a compound of formula (I) and a pharmaceutically acceptable carrier.
  • the compounds of the present invention are administered via inhalation of a solution in nebulized or aerosolized doses.
  • Unit dosage form refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • unit dosage forms are tablets (including scored or coated tablets), capsules, pills, suppositories, powder packets, wafers, injectable solutions or suspensions and the like, and segregated multiples thereof.
  • Viral infections and their associated diseases treatable using the compounds and methods of the present invention include those infections brought on by HCV and other pathogenic flaviviruses such as Yellow fever, Dengue fever (types 1-4), St. Louis encephalitis, Japanese encephalitis, Murray valley encephalitis, West Nile virus and Kunjin virus.
  • the diseases associated with HCV include progressive liver fibrosis, inflammation and necrosis leading to cirrhosis, end-stage liver disease, and HCC; and for the other pathogenic flaviviruses the diseases include yellow fever, dengue fever, hemorrhagic fever and encephalitis.
  • the compounds of formula (I) or any subgroup thereof, their prodrugs, //-oxides, salts, quaternary amines, metal complexes and stereochemically isomeric forms are useful in the treatment of individuals experiencing a viral infection, particularly a HCV infection, and for the prophylaxis of these infections.
  • the compounds of the present invention may be useful in the treatment of warm-blooded animals infected with viruses, in particular flaviviruses such as HCV.
  • the compounds of the present invention or any subgroup thereof may therefore be used as medicines.
  • Said use as a medicine or method of treatment comprises the systemic administration to virally infected subjects or to subjects susceptible to viral infections of an amount effective to combat the conditions associated with the viral infection, in particular the HCV infection.
  • the present invention also relates to the use of the present compounds or any subgroup thereof in the manufacture of a medicament for the treatment or the prevention of viral infections, particularly HCV infection.
  • the present invention furthermore relates to a method of treating a warm-blooded animal infected by a virus, or being at risk of infection by a virus, in particular by HCV, said method comprising the administration of an anti- virally effective amount of a compound of formula (I), as specified herein, or of a compound of any of the subgroups of compounds of formula (I), as specified herein.
  • the present invention also concerns combinations of a compound of formula (I) or any subgroup thereof, as specified herein with other anti-HCV agents.
  • the invention concerns combination of a compound of Formula (I) or any subgroup thereof with at least one anti-HCV agent.
  • the invention concerns combination of a compound of Formula (I) or any subgroup thereof with at least two anti-HCV agents.
  • the invention concerns combination of a compound of Formula (I) or any subgroup thereof with at least three anti-HCV agents.
  • the invention concerns combination of a compound of Formula (I) or any subgroup thereof with at least four anti-HCV agents.
  • combination of previously known anti-HCV compound such as, for instance, interferon- ⁇ (IFN- ⁇ ), pegylated interferon- ⁇ , ribavirin or a combination thereof, and a compound of formula (I) can be used as a medicine in a combination therapy.
  • the term "combination therapy” relates to a product containing mandatory (a) a compound of formula (I), and (b) at least one other anti-HCV compound, as a combined preparation for simultaneous, separate or sequential use in treatment of HCV infections, in particular, in the treatment of infections with HCV.
  • Anti-HCV compounds encompass agents selected from HCV polymerase inhibitors, R-7128, MK-0608, VCH759, PF-868554, GS9190, NM283, R803, R-1626, BILB- 1941, HCV-796, JTK- 109 and JTK-003; HCV proteases (NS2-NS3 and NS3-NS4A) inhibitors, the compounds of WO02/18369 (see, e.g., page 273, lines 9-22 and page 274, line 4 to page 276, line 11), BI-1335, TMC435350, MK70009, ITMN-191, BILN-2061, VX-950, VX-500, SCH 503034; inhibitors of other targets in the HCV life cycle, including helicase, and metalloprotease inhibitors, ISIS- 14803; immunomodulatory agents such as, ⁇ -, ⁇ -, and ⁇ - interferons, pegylated derivatized interferon- ⁇ compounds, compounds
  • the compounds of formula (I) may be co-administered in combination with for instance, interferon- ⁇ (IFN- ⁇ ), pegylated interferon- ⁇ , ribavirin or a combination thereof, as well as therapeutics based on antibodies targeted against HCV epitopes, small interfering RNA (si RNA), ribozymes, DNAzymes, antisense RNA, small molecule antagonists of for instance NS3 protease,
  • the combinations of the present invention may be used as medicaments. Accordingly, the present invention relates to the use of a compound of formula (I) or any subgroup thereof as defined above for the manufacture of a medicament useful for inhibiting HCV activity in a mammal infected with HCV viruses, wherein said medicament is used in a combination therapy, said combination therapy preferably comprising a compound of formula (I) and at least one other HCV inhibitory compound, e.g. IFN- ⁇ , pegylated IFN- ⁇ , ribavirin or a combination thereof.
  • a compound of formula (I) or any subgroup thereof as defined above for the manufacture of a medicament useful for inhibiting HCV activity in a mammal infected with HCV viruses, wherein said medicament is used in a combination therapy, said combination therapy preferably comprising a compound of formula (I) and at least one other HCV inhibitory compound, e.g. IFN- ⁇ , pegylated IFN- ⁇ , ribavirin or a combination thereof
  • HIV infection appears to adversely affect all stages of HCV infection, leading to increased viral persistence and accelerated progression of HCV-related liver disease.
  • HCV infection may affect the management of HIV infection, increasing the incidence of liver toxicity caused by antiviral medications.
  • the present invention therefore also concerns combinations of a compound of Formula (I) or any subgroup thereof with anti-HIV agents. Also, the combination of one or more additional anti-HIV compounds and a compound of Formula (I) can be used as a medicine.
  • combination therapy also encompasses a product comprising (a) a compound of Formula (I) or any subgroup thereof, and (b) at least one anti-HIV compound, and (c) optionally at least one other anti-HCV compound, as a combined preparation for simultaneous, separate or sequential use in treatment of HCV and HIV infections, in particular, in the treatment of infections with HCV and HIV.
  • the present invention also relates to a product containing (a) at least one compound of Formula (I) or any subgroup thereof, and (b) one or more additional anti- HIV compounds, as a combined preparation for simultaneous, separate or sequential use in anti-HCV and anti-HIV treatment.
  • the different drugs may be combined in a single preparation together with pharmaceutically acceptable carriers.
  • Said other anti- HIV compounds may be any known antiretroviral compounds such as suramine, pentamidine, thymopentin, castanospermine, dextran (dextran sulfate), foscarnet- sodium (trisodium phosphono formate); nucleoside reverse transcriptase inhibitors (NRTIs), e.g.
  • NRTIs non-nucleoside reverse transcriptase inhibitors
  • NcRTIs nucleotide-competing reverse transcriptase inhibitors
  • TAT-inhibitors e.g. RO-5-3335, BI-201, and the like
  • REV inhibitors e.g. RO-5-3335, BI-201, and the like
  • protease inhibitors e.g.
  • saquinavir SQV
  • lopinavir ABT-378 or LPV
  • indinavir IDV
  • amprenavir VX-478
  • TMC 126 TMC 126
  • nelf ⁇ navir AG- 1343
  • atazanavir BMS 232,632
  • darunavir TMC 126
  • fosamprenavir GW433908 or VX- 175
  • brecanavir GW-640385, VX-385
  • P-1946, PL-337, PL-100, tipranavir PNU-140690
  • entry inhibitors which comprise fusion inhibitors (e.g. enfuvirtide (T-20)), attachment inhibitors and co-receptor inhibitors, the latter comprise the CCR5 antagonists (e.g. ancriviroc, CCR5mAb004, maraviroc
  • entry inhibitors are PRO-542, TNX-355, BMS-488,043, BlockAide/CRTM, FP 21399, hNMOl, nonakine, VGV-I; a maturation inhibitor for example is PA-457; inhibitors of the viral integrase e.g.
  • HCV infected patients also suffering from conditions associated with HIV or even other pathogenic retroviruses, such as AIDS, AIDS-related complex (ARC), progressive generalized lymphadenopathy (PGL), as well as chronic CNS diseases caused by retroviruses, such as, for example HIV mediated dementia and multiple sclerosis, can conveniently be treated with the present composition.
  • retroviruses such as AIDS, AIDS-related complex (ARC), progressive generalized lymphadenopathy (PGL), as well as chronic CNS diseases caused by retroviruses, such as, for example HIV mediated dementia and multiple sclerosis.
  • compositions may be formulated into suitable pharmaceutical dosage forms such as the dosage forms described above.
  • Each of the active ingredients may be formulated separately and the formulations may be co-administered or one formulation containing both and if desired further active ingredients may be provided.
  • composition is intended to encompass a product comprising the specified ingredients, as well as any product that results, directly or indirectly, from the combination of the specified ingredients.
  • therapeutically effective amount means that amount of active compound or component or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought, in the light of the present invention, by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease being treated. Since the instant invention refers as well to combinations comprising two or more agents, the "therapeutically effective amount” in the context of combinations is also that amount of the agents taken together so that the combined effect elicits the desired biological or medicinal response.
  • the therapeutically effective amount of a composition comprising (a) the compound of formula (I) and (b) another anti-HCV agent, would be the amount of the compound of formula (I) and the amount of the other anti-HCV agent that when taken together have a combined effect that is therapeutically effective.
  • an antiviral effective daily amount would be from 0.01 mg/kg to 500 mg/kg body weight, more preferably from 0.1 mg/kg to 50 mg/kg body weight. It may be appropriate to administer the required dose as two, three, four or more sub-doses at appropriate intervals throughout the day. Said sub-doses may be formulated as unit dosage forms, for example, containing 1 to 1000 mg, and in particular 5 to 200 mg of active ingredient per unit dosage form.
  • the exact dosage and frequency of administration depends on the particular compound of formula (I) used, the particular condition being treated, the severity of the condition being treated, the age, weight, sex, extent of disorder and general physical condition of the particular patient as well as other medication the individual may be taking, as is well known to those skilled in the art. Furthermore, it is evident that said effective daily amount may be lowered or increased depending on the response of the treated subject and/or depending on the evaluation of the physician prescribing the compounds of the instant invention. The effective daily amount ranges mentioned hereinabove are therefore only guidelines.
  • an article of manufacture comprising a composition effective to treat an HCV infection or to inhibit the NS5B polymerase of HCV; and packaging material comprising a label which indicates that the composition can be used to treat infection by the hepatitis C virus; wherein the composition comprises a compound of the formula (I) or any subgroup thereof, or the combination as described herein.
  • kits or containers comprising a compound of the formula (I) or any subgroup thereof, in an amount effective for use as a standard or reagent in a test or assay for determining the ability of potential pharmaceuticals to inhibit HCV NS5B polymerase, HCV growth, or both.
  • This aspect of the invention may find its use in pharmaceutical research programs.
  • the compounds and combinations of the present invention can be used in high- throughput target-analyte assays such as those for measuring the efficacy of said combination in HCV treatment.
  • Example 1 10-acetyl-l l-(2,4-dichlorophenyl)-3,3-dimethyl-l,l-dioxo- 1,2,3,4,5,1 l-hexahvdro-l ⁇ 6 -thia-5J0-diazadibenzor ⁇ , ⁇ cvcloheptene (10).
  • m-CPBA m-chloroperbenzoic acid; 1.5 g, 70-75 w/w %, 6.52 mmol
  • cyclic sulfide (4) 800 mg, 5.55 mmol
  • additional m-CPBA 750 mg, 70-75 w/w %, 3.26 mmol
  • the reaction mixture was diluted with CH 2 Cl 2 then washed with IM NaHCO 3 (2 x 125 mL). The water layer was extracted with CH 2 Cl 2 (2 x 150 mL) and the combined organic layers were successively dried (MgSO 4 ) and evaporated.
  • Example 2 10-acetyl-l l-(4-benzyloxy-2-fluorophenyl)-3,3-dimethyl-l,l-dioxo- 1,2,3,4,5,1 l-hexahvdro-l ⁇ 6 -thia-5J0-diazadibenzor ⁇ , ⁇ cvcloheptene (13).
  • Example 5 1 l-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl-l,l-dioxo- 1,2,3,4,5,1 l-hexahydro-l ⁇ 6 -thia-5,10-diazadibenzo
  • Example 6 10-acetyl-l l-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl- 1 , 1 -dioxo- 1,2,3,4,5,11 -hexahydro- 1 ⁇ 6 -thia-5 , 10-diazadibenzor ⁇ , ⁇ Hcycloheptene (20).
  • Example 7 10-isobutyryl-l l-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl- 1, 1-dioxo-l, 2,3,4,5, I l-hexahvdro-l ⁇ 6 -thia-5,10-diazadibenzor ⁇ , ⁇ cvcloheptene (21).
  • Example 8 1 l-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl-l,l-dioxo- 10-(2-pyridylcarbonvO- 1.2.3.4.5.11 -hexahydro- 1 ⁇ 6 -thia- 5,10-diazadibenzo
  • Example 9 1 l-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl-l,l-dioxo- 10-r(2.5-dimethyloxazol-4-yl)carbonyl1-1.2.3.4.5.11-hexahvdro-l ⁇ 6 -thia- 5,10-diazadibenzor ⁇ , ⁇ cycloheptene (23).
  • Example 10 1 l-(4-benzyloxy-2-fluorophenyl)-6-hvdroxy-3,3-dimethyl-l,l-dioxo- 1100--((tthhiiaazzooll--44--yyllccaarrbboonnvyrn)--11..22..33A.4.55..1111--hheexxahydro- 1 ⁇ 6 -thia- 5,10-diazadibenzor ⁇ , ⁇ cycloheptene (24).
  • Example 11 1 l-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl-l,l-dioxo- 10-(6-methyl-2-pyridylcarbonyD- 1,2,3.4,5,11 -hexahydro- 1 ⁇ 6 -thia- 5,10-diazadibenzo[ ⁇ , ⁇ cycloheptene (25).
  • Example 12 (R)-I l-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl-l,l-dioxo- 10-r(2.5-dimethyloxazol-4-yl)carbonyl1-1.2.3.4.5.11-hexahvdro-l ⁇ 6 -thia- 5,10-diazadibenzo
  • Example 15 1-[1 l-(4-Benzyloxy-2-fluoro-phenyl)-9-hydroxy-3,3-dimethyl-l,l-dioxo- 1,2,3,4,5,11 -hexahydro- 1 ⁇ 6 -thia-5 , 10-diaza-dibenzo
  • Example 16 1-[1 l-(4-Benzyloxy-2-fluoro-phenyl)-3,3-dimethyl-l,l-dioxo-9-(thiazol- 4-ylmethoxy)- 1 ,2,3 ,4,5 , 11 -hexahydro- 1 ⁇ 6 -thia-5 , 1 Q-diaza-dibenzo[a,dlcyclohepten- 10-yll-ethanone (192)
  • Example 18 11 -(4-Benzyloxy-2-fluoro-phenyl)-3 ,3 ,9-trimethyl- 1 , 1 -dioxo- 2,3.4,5.10.1 l-hexahvdro-lH-l ⁇ 6 -thia-5.10-diaza-dibenzora,dlcvclohepten-6-oU197)
  • Example 19 [1 l-(4-Benzyloxy-2-fluoro-phenyl)-6-hydroxy-3,3,9-trimethyl-l,l-dioxo- 1,2,3,4,5,11 -hexahydro- 1 ⁇ 6 -thia-5 , 1 Q-diaza-dibenzo
  • Example 22 6-(2,5-Dimethyl-oxazole-4-carbonyl)-7-(2-fluoro-4-hydroxy-pheny0- 10J0-dimethyl-8.8-dioxo-6.7.8.9J0J l-hexahvdro-2-oxa-8 ⁇ 6 -thia-6J lb-diaza- dibenzo[cd,hlazulen-l-one (261)
  • Example 23 [1 l-(4-Allyloxy-2-fluoro-phenyl)-6-hydroxy-3,3-dimethyl-l,l-dioxo- 1,2,3,4,5,11 -hexahydro- 1 ⁇ 6 -thia-5 , 1 Q-diaza-dibenzo[a,dlcyclohepten- 10-yl]- (2,5-dimethyl-oxazol-4-yl)-methanone (263)
  • Example 25 (2.5-Dimethyl-oxazol-4-yl)-(l l-r2-fluoro-4-(2-thiophen-2-yl-ethoxy)- phenyll-6-hydroxy-3 ,3-dimethyl- 1 , 1 -dioxo- 1,2,3,4,5,11 -hexahydro- 1 ⁇ 6 -thia- 5,10-diaza-dibenzora ⁇ lcyclohepten- 10-vU -methanone (272)
  • Example 26 (1 l-[4-(2-Cyclopropyl-ethoxy)-2-fluoro-phenyll-6-hydroxy-3,3-dimethyl- 1 , 1 -dioxo- 1,2,3,4,5,11 -hexahydro- 1 ⁇ 6 -thia-5 , 1 Q-diaza-dibenzo
  • Example 27 (2,5-Dimethyl-oxazol-4-yl)- ⁇ l l-[2-fluoro-4-(3-methoxymethoxy- benzyloxy)-phenyll-6-hydroxy-3 ,3-dimethyl- 1 , 1 -dioxo- 1,2,3,4,5,11 -hexahydro- 1 ⁇ 6 -thia-5, 10-diaza-dibenzora,d1cvclohepten- 10-vU -methanone (274)
  • Example 28 (2,5-Dimethyl-oxazol-4-yl)- ⁇ l l-[2-fluoro-4-(3-hydroxy-benzyloxy)- phenyl]-6-hydroxy-3 ,3-dimethyl- 1 , 1 -dioxo- 1,2,3,4,5,11 -hexahydro- 1 ⁇ 6 -thia- 5,10-diaza-dibenzora,d1cyclohepten- 10-vU -methanone (275)
  • the title compound (279) was prepared in 55% yield following the procedure reported for the synthesis of 5,5-dimethyldihydrothiopyran-3-one (4), using l-(2-chloroallyl- sulfanyl)-2-methyl-butan-2-ol (278) instead of l-(2-chloro-allylsulfanyl)-2-methyl- propan-2-ol (3).
  • the title compound (280) was prepared in 8% yield following the procedure reported for the synthesis of compound 5,5-dimethyl-l,l-dioxo-tetrahydro-thiopyran-3-one (5), using 5-ethyl-5-methyl-dihydro-thiopyran-3-one instead of 5,5-dimethyl-dihydro- thiopyran-3-one.
  • Example 31 [1 l-(4-Benzyloxy-2-fluoro-phenyl)-3-ethyl-6-hydroxy-3-methyl- 1 , 1 -dioxo- 1,2,3,4,5,11 -hexahydro- 1 ⁇ 6 -thia-5 , 10-diaza-dibenzo[a.dlcyclohepten- 10-yl]- (2-fluoro-phenyl)-methanone (282)
  • the title compound (283) was prepared in 70% yield following the procedure reported for the synthesis of 10-isobutyryl-l l-(4-benzyloxy-2-fluorophenyl)-6-hydroxy- 3 ,3-dimethyl- 1 , 1 -dioxo- 1,2,3,4,5,11 -hexahydro- 1 ⁇ 6 -thia-5 , 10-diazadibenzo[ ⁇ , d ⁇ - cycloheptene (21), starting from compound (281) and 2,5-dimethyloxazole-4- ylcarbonyl chloride, instead of 1 l-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3- dimethyl- 1 , 1 -dioxo- 1 ,2,3 ,4,5 , 11 -hexahydro- 1 ⁇ 6 -thia-5 , 10-diazadibenzo[ ⁇ , d ⁇ cyc ⁇ o- heptene (18) and iso
  • Example 37 1 l-(4-Benzyloxy-2-fluoro-phenyl)-3-methyl-l,l-dioxo-3-propyl- 2.3.4.5.10.1 l-hexahvdro-lH-l ⁇ 6 -thia-5J0-diaza-dibenzora.dlcvclohepten-6-ol (288)
  • Example 38 [1 l-(4-Benzyloxy-2-fluoro-phenyl)-6-hydroxy-3-methyl-l,l-dioxo- 3-propyl- 1 ,2,3 ,4,5 , 11 -hexahydro- 1 ⁇ 6 -thia-5 , 10-diaza-dibenzo[a.dlcyclohepten- 10-yl]- (2-fluoro-phenyl)-methanone (289)
  • Example 40 synthesis of [6-Amino-l l-(4-benzyloxy-2-fluorophenyl)-3,3-dimethyl- 1 , 1 -dioxo- 1,2,3,4,5,11 -hexahydro- 1 ⁇ 6 -thia-5 , 1 Q-diaza-dibenzo[a,dlcyclohepten- 10-yl]- (6-methylpyridin-2-yl)-methanone (353).
  • Example 41 synthesis of [l l-(4-benzyloxy-2-fluoro-phenyl)-3,3-dimethyl-l,l-dioxo- 2,3,4,5,10,1 l-hexahydro-lH-l ⁇ 6 -thia-5,10-diaza-dibenzo[a,dlcyclohepten-6-yll- methanol (354)
  • Example 42 synthesis of [l l-(4-Benzyloxy-2-fluoro-phenyl)-6-hydroxymethyl- 3, 3-dimethyl- 1,1 -dioxo- 1, 2,3,4,5, I l-hexahydro-l ⁇ 6 -thia-5,10-diaza-dibenzo
  • Reagent 1 indicated in the table was acylated following the procedure reported for the synthesis of 10-isobutyryl-l l-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl- 1 , 1 -dioxo- 1,2,3,4,5,11 -hexahydro- 1 ⁇ 6 -thia-5 , 10-diazadibenzo[ ⁇ , J]cycloheptene (21), using the acid chloride indicated in table 7 instead of isobutyryl chloride.
  • Reagent 1 indicated in the table was alkylated following the procedure reported for the synthesis of [1 l-(4-allyloxy-2-fluoro-phenyl)-6-hydroxy-3,3-dimethyl-l,l-dioxo- 1,2,3,4,5,11 -hexahydro- 1 ⁇ 6 -thia-5 , 10-diaza-dibenzo[a,d]cyclohepten- 10-yl]- (2,5-dimethyl-oxazol-4-yl)-methanone (263), starting from 6-(2,5-dimethyl-oxazole- 4-carbonyl)-7-(2-fluoro-4-hydroxy-phenyl)- 10,10-dimethyl-8,8-dioxo- 6,7,8,9,10,1 l-hexahydro-2-oxa-8 ⁇ 6 -thia-6,l lb-diaza-dibenzo[cd,h]azulen-l -one (261) and
  • Reagent 1 indicated in the table was alkylated following the procedure reported for the synthesis of (2,5-dimethyl-oxazol-4-yl)- ⁇ 11 -[2-fluoro-4-(2-thiophen-2-yl-ethoxy)- phenyl]-6-hydroxy-3 ,3-dimethyl- 1 , 1 -dioxo- 1,2,3,4,5,11 -hexahydro- 1 ⁇ 6 -thia- 5,10-diazadibenzo[a,d]cyclohepten-10-yl ⁇ -methanone (272), starting from 6-(2,5-dimethyl-oxazole-4-carbonyl)-7-(2-fluoro-4-hydroxy-phenyl)- 10,10-dimethyl- 8,8-dioxo-6,7,8,9,10,l l-hexahydro-2-oxa-8 ⁇ 6 -thia-6,l lb-diaza-dibenzo[cd,h]
  • Reagent 1 (racemic mixture) indicated in the table was purified by SFC with a chiral column, as described in Example 12 for the enantiomeric separation of the racemic mixture 11 -(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3 ,3-dimethyl- 1 , 1 -dioxo-
  • the residual oil was purified by column chromatography (gradient heptanes/ethyl acetate, 1 :0 to 0:1) to give a yellow oil.
  • a 100 mL round-bottomed flask was loaded with the oil previously obtained (3700 mg, 18.03 mmol) and sodium thiomethoxide (1895 mg, 27.0 mmol) in DMF (20 mL).
  • the resulting solution was heated at 65°C for 3 hours. Then, the reaction mixture was filtered, evaporated to give (3-methylsulfanylmethyloxetan-3-yl)acetonitrile (456), wish was used as such in the next step.
  • m-CPBA was added at 0 0 C to a solution of intermediate (456) in CH 2 CL 2 . The solution was allowed to warm up to room temperature overnight. Then, additional m-CPBA was added and the reaction mixture was stirred for another 4 hours. Next, the reaction mixture was quenched with a solution of NaHCO 3 and the product was extracted with ethyl acetate. The combined organic layers were dried over MgSO 4 and the solvent removed under reduced pressure.
  • Example 49 synthesis of l l-(4-Benzyloxy-2-fluoro-phenyl)-3-methyl-l,l-dioxo- 3-vinyl-2.3.4.5.10.11-hexahvdro-lH-l ⁇ 6 -thia-5.10-diaza-dibenzora.d1cvclohepten-6-ol
  • Example 51 synthesis of l l-(4-Benzyloxy-2-fluoro-phenyl)-l,l-dioxo-2,3,4,5J0J l- hexahvdro-lH-l ⁇ 6 -thia-5,10-diaza-dibenzora,d1cvclohepten-6-ol (471)
  • Example 52 synthesis of aldehydes Aldehydes of example 52 were synthesized by nucleophilic substitution of a suitable halide derivative by a phenol derivative, in the presence of a base, as described for the synthesis of aldehyde (11).
  • Example 53 Representative procedure: synthesis of 4-(2-Bromo-phenoxy)-2-chloro- benzaldehyde
  • aldehydes were synthesized according to the representative procedure of example 53, using suitable haloaryl or haloheteroaryl derivatives and substituted phenols.
  • Example 55 Representative procedure: synthesis of 4-Benzyloxy-2-trifluoromethyl- benzaldehyde
  • aldehydes were synthesized according to the representative procedure of example 55, using suitable haloaryl or haloheteroaryl derivatives and phenylmethanol.
  • Example 57 Representative procedure: synthesis of 2-Fluoro-4-(Yl£)-l-phenyl- ethoxy)benzaldehyde
  • the target aldehyde was synthesized in 40% yield as a slightly yellow liquid following the representative procedure disclosed in example 57, using thiophen-3-yl methanol instead of (R)-(+)-phenylethanol.
  • the target aldehyde was synthesized in 25% yield as a white solid following the representative procedure disclosed for the synthesis of 2-Fluoro-4-((lS)-l-phenyl- ethoxy)-benzaldehyde, using 3,4-difluorobenzyl alcohol instead of (R)-(+)-phenyl- ethanol.
  • reaction mixture was then filtered on decalite, evaporated on silica and purified by flash chromatography (eluent: heptane/CH 2 Cl2 75:25) to give 4.18 g (56%) of the desired product 1 -(4-bromo-3-fluoro-phenyl)-2-phenyl-ethanone.
  • reaction mixture was stirred during 2h, then was diluted with CH 2 Cl 2 , filtered on basic alumina, washed with a saturated solution of NaHCO 3 , then with a 10% solution OfNa 2 S 2 O 3 , dried over MgSO 4 , filtered and concentrated. Purification by flash chromatography afforded 1.2 g (36%) of the desired product l-bromo-4-(l,l-difluoro-2-phenyl-ethyl)-2-fluoro-benzene as a colorless solid that solidifies upon standing.
  • Example 64 synthesis of compounds 510. 547-569 and 571-573. 575. 576. and 583- 585.
  • Reagent 1 indicated in the table was acylated following the procedure reported for the synthesis of 10-isobutyryl-l l-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl- 1,1-dioxo- 1,2,3, 4,5,1 l-hexahydro-l ⁇ 6 -thia-5,10-diazadibenzo[ ⁇ , ⁇ i]cycloheptene (21), using the acid chloride indicated in table 7 instead of isobutyryl chloride.
  • Reagent 1 indicated in the table was alkylated following the procedure reported for the synthesis of [1 l-(4-allyloxy-2-fluoro-phenyl)-6-hydroxy-3,3-dimethyl-l,l-dioxo- 1 ,2,3,4,5, 11 -hexahydro- 1 ⁇ 6 -thia-5, 10-diaza-dibenzo[a,d]cyclohepten- 10-yl]-(2,5-di- methyloxazol-4-yl)-methanone (263), starting from 6-(2,5-dimethyl-oxazole- 4-carbonyl)-7-(2-fluoro-4-hydroxy-phenyl)- 10, 10-dimethyl-8,8-dioxo-6,7,8,9, 10,11- hexahydro-2-oxa-8 ⁇ 6 -thia-6,l lb-diaza-dibenzo[cd,h]azulen-l-one (261) and the appropriate
  • Reagent 1 indicated in the table was alkylated following the procedure reported for the synthesis of (2,5-dimethyl-oxazol-4-yl)- ⁇ 11 -[2-fluoro-4-(2-thiophen-2-yl-ethoxy)- phenyl] -6-hydroxy-3 ,3-dimethyl- 1 , 1 -dioxo- 1 ,2,3 ,4,5 , 11 -hexahydro- 1 ⁇ 6 -thia- 5,10-diazadibenzo[a,d]cyclohepten-10-yl ⁇ -methanone (272), starting from 6-(2,5-dimethyl-oxazole-4-carbonyl)-7-(2-fluoro-4-hydroxy-phenyl)- 10,10-dimethyl- 8,8-dioxo-6,7,8,9,10,l l-hexahydro-2-oxa-8 ⁇ 6 -thia-6,l lb-diaza-dibenzo
  • Reagent 1 (racemic mixture) indicated in the table was purified by SFC with a chiral column, as described in Example 12 for the enantiomeric separation of the racemic mixture 11 -(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3 ,3-dimethyl- 1 , 1 -dioxo-
  • Example 65 synthesis of l l-r2,3-difluoro-4-(2-methyl-allyloxy)-phenyll-3,3-dimethyl- ll,Jl--ddiiooxxoo--22 ,3,4,5J0J l-hexahydro-lH-l ⁇ 6 -thia-5J0-diaza-dibenzora,dlcvclohepten-
  • Example 66 synthesis of ⁇ l l-[2,3-difluoro-4-(2-methylallyloxy)phenyll-6-hydroxy- 3, 3-dimethyl- 1,1 -dioxo- 1,2,3,4,5, 11-hexahydro- I ⁇ 6 -thia-5,l Q-diaza-dibenzo[a,dl- cyclohepten-10-yl
  • Example 67 synthesis of (S)-[I l-[2,3-difluoro-4-(2-methylallyloxy)phenyl]- 6-hydroxy-3 ,3-dimethyl- 1 , 1 -dioxo- 1,2,3.4,5,11 -hexahydro- 1 ⁇ 6 -thia-5 , 10-diaza- dibenzo[a,d]cyclohepten-10-yU(2,5-dimethyloxazol-4-yl)methanone (578) and (R)- ⁇ 11 -[2,3-difluoro-4-(2-methylallyloxy)phenyll-6-hydroxy-3,3-dimethyl- 1 , 1 -dioxo- 1.2,3.4,5.1 l-hexahvdro-l ⁇ 6 -thia-5.10-diaza-dibenzora,dlcvclohepten-10-yl
  • Example 68 alternative synthesis for (5V(2,5-Dimethyl-oxazol-4-yl)- ⁇ l l-[2-fiuoro- 4-(2-methyl-allyloxy)-phenyll-6-hydroxy-3 ,3-dimethyl- 1 , 1 -dioxo- 1,2,3-4,5.11- hexahydro- 1 ⁇ 6 -thia-5 , 10-diaza-dibenzo
  • Step 1 synthesis of l l-[2-fluoro-4-(2-methylallyloxy)phenyl]-3,3-dimethyl-l,l-dioxo- 2,3,4,5,10,1 l-hexahydro-lH-l ⁇ 6 -thia-5,10-diazadibenzo[a,d]cyclohepten-6-ol (579) and 1 -[2-Fluoro-4-(2-methyl-allyloxy)-phenyl]-3,3-dimethyl- 1 , 1 -dioxo- 2,3,4,5,10,1 l-hexahydro-l ⁇ -l ⁇ 6 -thia-5,10-diaza-dibenzo[a,d]cyclohepten-9-ol (580).
  • the title compounds (579) and (580) were prepared from 2-fluoro-4-(2-methylallyl- oxy)benzaldehyde and a mixture of compounds (16) and (17) following the procedure reported in example 5 for the preparation of 1 l-(4-benzyloxy-2-fluorophenyl)-6- hydroxy-3 ,3-dimethyl- 1 , 1 -dioxo- 1,2,3,4,5,11 -hexahydro- 1 ⁇ 6 -thia-5 , 10-diazadibenzo- [ ⁇ ,d]cycloheptene (18) and l l-(4-benzyloxy-2-fluorophenyl)-9-hydroxy-3,3-dimethyl- 1,1 -dioxo- 1,2,3, 4,5,1 l-hexahydro-l ⁇ 6 -thia-5,10-diazadibenzo[ ⁇ , ⁇ i]cycloheptene (19).
  • Step 2 synthesis of l l-[2-fluoro-4-(2-methylallyloxy)-phenyl]-8,8-dimethyl- 10,10-dioxo-6,7,8,9, 10,11 -hexahydro-2-oxa- 10 ⁇ 6 -thia-6, 11 a-diaza- dibenzo[cd,g]azulen-l-one (581) and 7-[2-fluoro-4-(2-methylallyloxy)phenyl]- 10,10-dimethyl-8,8-dioxo-6,7,8,9,10,l l-hexahydro-2-oxa-8 ⁇ 6 -thia-6,l lb-diaza- dibenzo[cd,h]azulen-l-one (582).
  • CDI (1.5 eq.) was added to a stirred solution of compounds (579) and (580) in DMF. After 45 minutes at room temperature, the reaction mixture was filtered on decalite, then quenched with water. The resulting solution was concentrated under reduced pressure, then diluted with water. The solid obtained was collected by filtration.
  • Step 3 synthesis of 1 l-[2-fluoro-4-(2-methylallyloxy)phenyl]-3,3-dimethyl-l,l-dioxo- 2,3,4,5,10,1 l-hexahydro-lH-l ⁇ 6 -thia-5,10-diazadibenzo[a,d]cyclohepten-6-ol (579).
  • Step 4 synthesis of (5)-(2,5-dimethyl-oxazol-4-yl)- ⁇ l l-[2-fluoro-4-(2-methyl- allyloxy)phenyl]-6-hydroxy-3 ,3-dimethyl- 1 , 1 -dioxo- 1 ,2,3 ,4,5 , 11 -hexahydro- 1 ⁇ 6 -thia- 5,10-diaza-dibenzo[a,d]cyclohepten- 10-yl ⁇ -methanone (383).
  • Example 69 synthesis of (2,5-dimethyl-oxazol-4-yl)-[l l-(2-fluoro-4-hydroxy-phenyl)- 6-hydroxy-3 ,3-dimethyl- 1 , 1 -dioxo- 1,2,3.4,5,11 -hexahydro- 1 ⁇ 6 -thia-5 , 10-diaza- dibenzora,dlcyclohepten- 10-yll-methanone (528).
  • Example 70 synthesis of l l-[4-fluoro-2-(2-fluoro-phenoxy)-phenyl]-3,3-dimethyl- l,l-dioxo-2, 3,4, 5, 10, 11 -hexahydro- IH- I ⁇ 6 -thia-5,10-diaza-dibenzo[a,dlcyclohepten- 6-ol (542).
  • Step 1 synthesis of 2-chloroprop-2-ene-l -thiol (544).
  • the compounds of formula (I) were examined for inhibitory activity of HCV RNA replication in a cellular assay.
  • the assay demonstrated that the compounds of formula (I) inhibited a HCV functional cellular replicating cell line, also known as HCV replicons.
  • the cellular assay was based on a bicistronic expression construct, as described by Lohmann et al. (1999) Science vol. 285 pp. 110-113 with the modifications described by Krieger et al. (2001) Journal of Virology 75: 4614-4624, in a multi-target screening strategy. In essence, the method was as follows: The assay utilized the stably transfected cell line Huh-7 luc/neo (hereafter referred to as Huh-Luc).
  • This cell line harbors an RNA encoding a bi-cistronic expression construct comprising the wild type NS3-NS5B regions of HCV type Ib translated from an Internal Ribosome Entry Site (IRES) from encephalomyocarditis virus (EMCV), preceded by a reporter portion (FfL-luciferase), and a selectable marker portion (neo R , neomycine phosphotransferase). The construct is bordered by 5' and 3' NTRs (non-translated regions) from HCV type Ib.
  • G418 neo R
  • the stably transfected replicon cells that express HCV RNA which replicates autonomously and to high levels, encoding inter alia luciferase, are used for screening the antiviral compounds.
  • the replicon cells were plated in 384-well plates in the presence of the test and control compounds which were added in increasing concentrations. Following an incubation of three days, HCV replication was measured by assaying luciferase activity (using standard luciferase assay substrates and reagents and a Perkin Elmer ViewLuxTM ultraHTS microplate imager). Replicon cells in the control cultures have high luciferase expression in the absence of any inhibitor. The inhibitory activity of the compounds was monitored on the Huh-Luc cells, enabling a dose-response curve to be generated for each test compound. EC50 values were then calculated, which value represents the amount of the compound required to decrease by 50% the level of detected luciferase activity, or more specifically, the ability of the genetically linked HCV replicon RNA to replicate.
  • NS5B amino acid 1-570 (HC-J4, genotype Ib, pCV-J4L6S, genebank accession number AF054247) was subcloned into the Nhe I and Xho I restriction sites of pET-21b. Expression of the subsequent His-tagged C-terminal 21 amino acid deleted NS5B was performed as follows:
  • the NS5B expression construct was transformed into E. coli BL21(DE3) (Novagen, Madison, WI). Five milliliter of LB-medium supplemented with ampicillin (50 ⁇ g/mL) was inoculated with one colony. When the pre-culture reached an optical density of 0.6 measured at 600 nm, it was transferred to fresh LB-medium supplemented with ampicillin, at a ratio of 1 :200.
  • Cells were grown to an optical density at 600 nm of 0.6, after which the expression cultures were shifted to a growth temperature of 20 0 C following induction with ispopropyl-1-thio- ⁇ -D-galactopyranoside and MgCl 2 at a final concentration of 0.4 mM and 10 ⁇ M, respectively. After ten hours of induction, cells were harvested by centrifugation and resuspended in 20 mM Tris-HCl, pH 7.5, 300 mM NaCl, 10% glycerol, 0.1% NP40, 4 mM MgCl 2 , 5 mM DTT supplemented with EDTA- free Complete Protease Inhibitor (Roche, Basel, Switzerland).
  • Clarified cell lysate was thawed and subsequently loaded onto a 5 mL pre-packed HisTrap FF column equilibrated with 25 mM HEPES, pH 7.5, 500 mM NaCl, 10% glycerol and 5 mM DTT. Proteins were eluted with 500 mM imidazole at a flow rate of 1 mL/min. Fractions containing the protein of interest were applied onto a pre-packed 26/10 HiPrep Desalting Column equilibrated with 25 mM HEPES, pH 7.5, 150 mM NaCl, 10% glycerol and 5 mM DTT.
  • the buffer-exchanged NS5B peak was then applied onto a 20 mL PoIy-U Sepharose column. Protein was eluted with an increasing salt gradient and fractions collected. Protein purity was assessed on Nu-PAGE pre-cast gels (Invitrogen, Carlsbad, CA). Purified NS5B samples were concentrated using Centri-Prep concentrators (Millipore, Billerica, MA, USA) and protein concentrations were determined by Bradford assay (Pierce, Rockford, IL, USA).
  • HCV NS5B polymerization activity was performed by evaluating the amount of radiolabeled GTP incorporated by the enzyme in a newly synthesized RNA using heteropolymeric RNA template/primer.
  • the RdRp assay was carried out in 384-well plates using 50 nM enzyme, 300 nM 5'-biotinylated oligo(rGi 3 )/poly(rC) primer-template, 600 nM of GTP, and 0.1 ⁇ Ci of [ 3 H]GTP in 25 mM Tris-HCl, pH 7.5, 5 mM MgCl 2 , 25 mM KCl, 17 mM NaCl and 3 mM of DTT.
  • Test compounds were dissolved in DMSO. The test compounds were added to the preformed polymerase- template complex, and incubated at room temperature for 15 min before the addition of NTPs. The 30 ⁇ l reaction was terminated after 2h at 25°C upon addition of 30 ⁇ l streptavidin-coated SPA beads (GE Heathcare, Uppsala, Sweden 5 mg/ml in 0.5 M EDTA). After incubation at 25°C for 30 min, the plate was counted using a Packard TopCount microplate reader (30 sec/well, 1 min count delay) and IC50 values were calculated. IC50 values represent the concentration of compound required to decrease by 50% the amount of RNA produced which is measured by the detection of incorporated radiolabeled GTP. The following Table 14 the activities of compounds that were prepared according to any one of the above examples, in the replicon (EC50) and enzymatic (IC 50 ) assay.
  • EC50 replicon
  • IC 50 enzymatic

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Abstract

Inhibitors of HCV replication of formula (I) the stereoisomers, prodrugs, tautomers, racemics, salts, hydrates or solvates thereof wherein R1a; R1b R2; R3; R4a and R4b have the meaning defined in the claims. The present invention also relates to processes for preparing said compounds, pharmaceutical compositions containing them and their use in HCV therapy.

Description

1,1-DIOXO-I-THIA-S9IO-DIAZADIBENZOCYCLOHEPTENES USEFUL AS HEPATITIS C VIRUS INHIBITORS
Field of the invention The present invention is concerned with 1 , 1 -dioxo- 1 -thia-5 , 10-diazadibenzo- cycloheptenes having inhibitory activity on the replication of the hepatitis C virus (HCV). It further concerns compositions comprising these compounds as active ingredients as well as processes for preparing these compounds and compositions.
Background of the invention
Hepatitis C virus is the leading cause of chronic liver disease worldwide and has become a focus of considerable medical research. HCV is a member of the Flaviviridae family of viruses in the hepacivirus genus, and is closely related to the flavivirus genus, which includes a number of viruses implicated in human disease, such as dengue virus and yellow fever virus, and to the animal pestivirus family, which includes bovine viral diarrhoea virus (BVDV). HCV is a positive-sense, single- stranded RNA virus, with a genome of around 9,600 bases. The genome comprises both 5' and 3' untranslated regions that adopt RNA secondary structures, and a central open reading frame that encodes a single polyprotein of around 3,010-3,030 amino acids. The polyprotein encodes ten gene products, which are generated from the precursor polyprotein by an orchestrated series of co- and posttranslational endoproteolytic cleavages mediated by both host and viral proteases. The viral structural proteins include the core nucleocapsid protein, and two envelope glycoproteins El and E2. The non- structural (NS) proteins encode some essential viral enzymatic functions (helicase, polymerase, protease), as well as proteins of unknown function. Replication of the viral genome is mediated by an RNA-dependent RNA polymerase, encoded by non-structural protein 5b (NS5B). In addition to the polymerase, the viral helicase and protease functions, both encoded in the bifunctional NS3 protein, have been shown to be essential for replication of HCV RNA. In addition to the NS3 serine protease, HCV also encodes a metalloproteinase in the NS2 region.
HCV replicates preferentially in hepatocytes but is not directly cytopathic, leading to persistent infection. In particular, the lack of a vigorous T-lymphocyte response and the high propensity of the virus to mutate appear to promote a high rate of chronic infection. There are 6 major HCV genotypes and more than 50 subtypes, which are differently distributed geographically. HCV type 1 is the predominant genotype in the US and Europe. For instance, HCV type 1 accounts for 70 to 75 percent of all HCV infections in the United States. The extensive genetic heterogeneity of HCV has important diagnostic and clinical implications, perhaps explaining difficulties in vaccine development and the lack of response to therapy. An estimated 170 million persons worldwide are infected with hepatitis C virus (HCV). Following the initial acute infection, a majority of infected individuals develops chronic hepatitis, which can progress to liver fibrosis leading to cirrhosis, end-stage liver disease, and HCC (hepatocellular carcinoma) (National Institutes of Health Consensus Development Conference Statement: Management of Hepatitis C. Hepatology, 36, 5 Suppl. S3-S20, 2002). Liver cirrhosis due to HCV infection is responsible for about 10,000 deaths per year in the U.S.A. alone, and is the leading cause for liver transplantations. Transmission of HCV can occur through contact with contaminated blood or blood products, for example following blood transfusion or intravenous drug use. The introduction of diagnostic tests used in blood screening has led to a downward trend in post-transfusion HCV incidence. However, given the slow progression to the end-stage liver disease, the existing infections will continue to present a serious medical and economic burden for decades (Kim, W.R. Hepatology, 36, 5 Suppl. S30-S34, 2002).
Current HCV therapies are based on (pegylated) interferon-alpha (IFN-α) in combination with ribavirin. This combination therapy yields a sustained viro logic response in more than 40% of patients infected by genotype 1 viruses and about 80% of those infected by genotypes 2 and 3. Beside the limited efficacy on HCV type 1, combination therapy has significant side effects and is poorly tolerated in many patients. For instance, in registration trials of pegylated interferon and ribavirin, significant side effects resulted in discontinuation of treatment in approximately 10 to 14 percent of patients. Major side effects of combination therapy include influenza- like symptoms, hematologic abnormalities, and neuropsychiatric symptoms. The development of more effective, convenient and tolerated treatments is a major public health objective. Thus, the treatment of this chronic disease is an unmet clinical need, since current therapy is only partially effective and limited by undesirable side effects.
One area of particular focus has been the search for inhibitors of the NS5b RNA- dependent RNA polymerase (RdRp) . Close structural homo logs of this polymerase do not exist within the uninfected host cell and the finding of inhibitors of said polymerase would provide a more specific mode of action. Inhibitors which are currently under investigation can be classified as either nucleoside inhibitors (NIs) or non-nucleoside inhibitors (NNIs). NIs directly compete with nucleotide substrates for binding to highly conserved active sites. Greater specificity may be achieved by NNIs, which may interact outside of the highly conserved active site at a unique allosteric site common only to structurally related polymerases. Preliminary clinical trials have resulted in a high failure rate, thereby highlighting the need to pursue the search for novel NS5b inhibitors.
Summary of the invention It has been found that certain 1 , 1 -dioxo- 1 -thia-5 , 10-diazadibenzo-cycloheptene derivatives exhibit antiviral activity in mammals infected with HCV. These compounds are therefore useful in treating or combating HCV infections.
The present invention concerns inhibitors of HCV replication, which can be represented by formula (I):
Figure imgf000004_0001
(I) and the stereoisomers, prodrugs, tautomers, racemics, salts, hydrates or solvates thereof, wherein Rla is hydrogen, hydroxy, amino, Ci_6alkoxy, halo or Ci_6alkyl optionally substituted with hydroxyl; Rlb is hydrogen, hydroxy, amino, Ci_6alkoxy, -O-CH2-thiazolyl, halo, trifluoromethyl, or Ci_6alkyl optionally substituted with cyano;
R2 is hydrogen, -C(=O)-R5, -C(=O)-C(=O)-R5, -C(=O)-OR6, or -C(=O)-NR7aR7b; R3 is Ci_6alkyl optionally substituted with C3-7cycloalkyl, aryl, or Het; C3-7cycloalkyl; aryl; or Het; each R4a and R4b is, independently, hydrogen, C^alkyl, C2-6alkenyl, or both R4a and R4b together with the carbon atom of the tricyclic ring to which they are attached may form a C3_7Cycloalkyl or an oxetanyl; R , 5 is Ci_6alkyl optionally substituted with one or two substituents selected from halo, C3-7cycloalkyl, phenylCi-βalkylthio, cyano, polyhaloCi-βalkyl, oxo, -OR9, -C(=O)-Het, -C(=O)-OR6, -C(=O)-OH, -C(=O)-NR7aR7b, -C(=O)-NH-S(=O)2-R8, -NR7aR7b, -S(=O)2-aryl, aryl, and Het; C2-6alkenyl optionally substituted with aryl; polyhaloCi-βalkyl; C3_7Cycloalkyl; aryl; or Het; R6 is aryl or Ci_6alkyl optionally substituted with -OR9, -C(=O)-OR9, -C(=O)-NR7aR7b,
-C(=O)-NH-S(=O)2-R8, aryl, or Het; each R7a and R7b is, independently, hydrogen; Ci_6alkyl optionally substituted with one or two substituents selected from -OR9, mono- or diCi_6alkylamino, -C(=O)-OR9, -C(=O)-NH2, -C(=O)-NH-Ci_6alkyl, -C(=O)-NH-hydroxyCi_6alkyl, -C(=O)-Het, C3_7Cycloalkyl, aryl, and Het; C2-6alkenyl; C3_7Cycloalkyl optionally substituted with hydroxy; aryl; or Het;
R8 is Ci_6alkyl, C3_7Cycloalkyl, di(Ci_3alkyl)amino, or aryl; R9 is hydrogen; Ci_6alkyl optionally substituted with one, two or three substituents each independently selected from halo, hydroxyl, C3_7Cycloalkenyl, C3_7Cycloalkyl, cyano, Ci_6alkoxy, phenyl, or Het, wherein the phenyl may optionally be substituted with halo, hydroxyl, Ci_6alkoxy, Ci_6alkyl, Ci_6alkoxyCi_6alkoxy, nitro, or amino; C2-6alkenyl optionally substituted with one or two substituents selected from halo and polyhaloCi-βalkyl; C2-6alkynyl; C3_7Cycloalkenyl; or phenyl optionally substituted with one or two substituents selected from hydroxyl, Ci_6alkoxy, halo, polyhaloCi-βalkyl, amino, nitro, Ci_6alkyl, and phenyl; aryl as a group or part of a group is phenyl, naphthyl, indanyl, or
1,2,3,4-tetrahydro-naphthyl, each of which may be optionally substituted with one two, three or four substituents each independently selected from the group consisting of C3_7Cycloalkyl, phenylCi-βalkyl, phenylpolyhaloCi-βalkyl, phenylCi-βalkyloxy, halo, polyhaloCi-βalkyl, cyano, Chalky!, polyhaloCi-βalkoxy, -OR9, -C(=O)OH, Ci_6alkylcarbonyl, Ci_6alkylthio, Ci_6alkylsulfonyl, -S(=O)2NH2, and pyrrolyl, wherein the phenyl may optionally be substituted with halo ; or two substituents on the aryl ring may form -0-CH2-O- or a -0-C(C^)2-CH2-;
Het as a group or part of a group is a 5 to 12 membered saturated, partially unsaturated or completely unsaturated mono- or bicyclic ring containing 1 to 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, being optionally condensed with one benzene ring, and wherein the group Het as a whole may be optionally substituted with one or two substituents each independently selected from the group consisting of halo; polyhaloCi-βalkyl; Ci_6alkylthio, oxo; -OR9; -NR10aR10b; -CN; Ci_6alkyl optionally substituted with -OR9, -CN, -NR10aR10b, or phenyl;-C(=O)-NH2; -C(=O)-phenyl; C3_7Cycloalkyl; phenyl optionally substituted with Ci_6alkoxy; morpholinyl; pyrrolidinyl; pyrrolyl; furanyl; tetrazolyl; and thiophenyl; and each R1Oa and R10b is, independently, hydrogen, Ci_6alkyl, arylCi_6alkyl, or R1Oa and R10b, together with the nitrogen to which they are attached, may form a saturated, partially unsaturated, or completely unsaturated 5-8 membered monocycle, wherein said monocycle optionally contains one additional heteroatom selected from the group consisting of oxygen, sulfur and nitrogen, and wherein the remaining monocycle members are carbon atoms; wherein said monocycle may be optionally substituted on any carbon atom with one or two substituents each independently selected from halo, Ci_6alkyl, hydroxy, or oxo. In one embodiment, the present invention concerns inhibitors of HCV replication and the salts and stereoisomers thereof, wherein Rla is hydrogen, hydroxy, amino, or halo; Rlb is hydrogen, hydroxy, halo, trifluoromethyl, or Ci_6alkyl optionally substituted with cyano;
R2 is hydrogen, -C(=O)-R5, -C(=O)-C(=O)-R5, -C(=O)-OR6, or -C(=O)-NR7aR7b; R3 is Ci_6alkyl optionally substituted with C3-7cycloalkyl, aryl, or Het; C3-7cycloalkyl; aryl; or Het; each R4a and R4b is, independently, C1-6alkyl, or both R4a and R4b together with the carbon atom of the tricyclic ring to which they are attached may form a
C3-7cycloalkyl; R5 is Ci_6alkyl optionally substituted with one or two substituents selected from cyano, polyhaloCi_6alkyl, oxo, -OR9, -C(=O)-Het, -C(=O)-OR6, -C(=O)-OH, -C(=O)-NR7aR7b, -C(=O)-NH-S(=O)2-R8, -NR7aR7b, aryl, and Het; C2-6alkenyl optionally substituted with aryl; polyhaloCi-βalkyl; C3-7cycloalkyl; aryl; or Het; R6 is Ci_6alkyl optionally substituted with -OR9, -C(=O)-OR9, -C(=O)-NR7aR7b,
-C(=O)-NH-S(=O)2-R8, aryl, or Het; each R7a and R7b is, independently, hydrogen; Ci_6alkyl optionally substituted with one or two substituents selected from -OR9, mono- or diCi_6alkylamino, -C(=O)-OR9,
-C(=O)-NH2, -C(=O)-NH-Ci_6alkyl, -C(=O)-NH-hydroxyCi_6alkyl, -C(=O)-Het,
C3-7cycloalkyl, aryl, and Het; C2_6alkenyl; C3-7cycloalkyl optionally substituted with hydroxy; aryl; or Het;
R8 is d-βalkyl, C3-7cycloalkyl, di(Ci_3alkyl)amino, or aryl; R9 is hydrogen; Ci_6alkyl optionally substituted with Ci_6alkoxy, phenyl, or Het, wherein the phenyl may optionally be substituted with halo, Ci_6alkoxy, nitro, or amino; or phenyl optionally substituted with one or two substituents selected from halo, amino, nitro, d^alkyl, and phenyl; aryl as a group or part of a group is phenyl, naphthyl, indanyl, or 1,2,3,4-tetrahydro-naphthyl, each of which may be optionally substituted with one or two substituents each independently selected from the group consisting of halo, polyhaloCi_6alkyl, cyano, Ci_6alkyl, polyhaloCi_6alkoxy, -OR9, -C(=O)OH,
Ci_6alkylcarbonyl, Ci_6alkylthio, Ci_6alkylsulfonyl, -S(=O)2NH2, and pyrrolyl; Het as a group or part of a group is a 5 to 12 membered saturated, partially unsaturated or completely unsaturated mono- or bicyclic ring containing 1 to 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, being optionally condensed with one benzene ring, and wherein the group Het as a whole may be optionally substituted with one or two substituents each independently selected from the group consisting of halo; oxo; -OR9; -NR10aR10b; -CN; Ci_6alkyl optionally substituted with -OR9, -CN, -NR10aR10b, or phenyl;-C(=O)-NH2; -C(=O)-phenyl; C3-7cycloalkyl; phenyl optionally substituted with Ci_6alkoxy; morpholinyl; pyrrolidinyl; pyrrolyl; furanyl; tetrazolyl; and thiophenyl; and each R , 1l0uaa and R , 110UbB is, independently, hydrogen, Ci_6alkyl, arylCi_6alkyl, or R 1l0uaa and
R10b, together with the nitrogen to which they are attached, may form a saturated, partially unsaturated, or completely unsaturated 5-8 membered monocycle, wherein said monocycle optionally contains one additional heteroatom selected from the group consisting of oxygen, sulfur and nitrogen, and wherein the remaining monocycle members are carbon atoms; wherein said monocycle may be optionally substituted on any carbon atom with one or two substituents each independently selected from halo, Ci_6alkyl, hydroxy, or oxo.
The invention further relates to methods for the preparation of the compounds of formula (I), the //-oxides, quaternary amines, metal complexes, and stereochemically isomeric forms thereof, their intermediates, and the use of the intermediates in the preparation of the compounds of formula (I).
The invention therefore encompasses a process for the preparation of a compound according to the invention having formula (1-8), comprising the steps of : reacting a compound of formula (1-2) with a compound of formula (1-4) thereby obtaining compound of formula (1-5), and
Figure imgf000007_0001
reacting a compound of formula (1-5) with an aldehyde of formula (1-7), optionally in the presence of an acid, thereby obtaining a compound of formula (1-8),
Figure imgf000007_0002
wherein Rla, Rlb, R4a , R4b, and R3 have the same meaning as that defined herein. The invention also encompasses a process for the preparation of a compound according to the invention having formula (1-9), comprising the step of:
Figure imgf000008_0001
acylating a compound of formula (1-8) with an acid or an activated acid thereby obtaining a compound of formula (I) having formula (1-9), wherein Rla, Rlb, R4a , R4b, R3 and R5 have the same meaning as that defined herein.
The invention also encompasses a process for the preparation of a compound according to the invention having formula (I- 10), comprising the steps of :
Figure imgf000008_0002
reacting a compound of formula (1-8) with an isocyanate of formula (I-8a) thereby obtaining a compound of formula (I- 10) with R7b being hydrogen, or reacting a compound of formula (1-8) with phosgene or an equivalent of phosgene of formula (I-8b), wherein LG represent a leaving group, followed by the treatment with an amine of formula (I-8c) thereby obtaining a compound of formula (I- 10), wherein Rla, Rlb, R4a , R4b, R3 , R7a' and R7b have the same meaning as that defined herein.
The invention also encompasses a process for the preparation of a compound according to the invention having formula (1-11), comprising the step of :
Figure imgf000009_0001
reacting a compound of formula (1-8) with a chloroformate of formula (I-8d) in the presence of a base, in an inert solvent thereby obtaining a compound of formula (I- 11), wherein Rla, Rlb, R4a , R4b, R3 and R6 have the same meaning as that defined herein.
The invention relates to the compounds of formula (I) per se, the iV-oxides, salts, hydrates, solvates, quaternary amines, metal complexes, prodrugs, and stereochemically isomeric forms thereof, for use as a medicament. The invention relates to the compounds of formula (J) per se, the iV-oxides, salts, hydrates, solvates, quaternary amines, metal complexes, prodrugs, and stereochemically isomeric forms thereof, for treating hepatitis C. The invention further relates to pharmaceutical compositions comprising a carrier and an anti-virally effective amount of a compound of formula (I) as specified herein. The pharmaceutical compositions may comprise combinations of the aforementioned compounds with other anti-HCV agents. The pharmaceutical compositions may comprise combinations of the aforementioned compounds with anti-HIV agents. The invention further relates to the aforementioned pharmaceutical compositions for administration to a subject suffering from HCV infection.
The invention also relates to the use of a compound of formula (I), or a JV-oxide, salt, hydrate, solvate, quaternary amine, metal complex, prodrug, or stereochemically isomeric forms thereof, for the manufacture of a medicament for inhibiting HCV replication. Or the invention relates to a method of inhibiting HCV replication in a warm-blooded animal said method comprising the administration of an effective amount of a compound of formula (I), or a prodrug, iV-oxide, salt, hydrate, solvate, quaternary amine, metal complex, or stereochemically isomeric forms thereof.
Detailed description
The present invention will now be further described. In the following passages, different aspects of the invention are defined in more detail. Each aspect so defined may be combined with any other aspect or aspects unless clearly indicated to the contrary. In particular, any feature indicated as being preferred or advantageous may be combined with any other feature or features indicated as being preferred or advantageous.
As used in the foregoing and hereinafter, the following definitions apply unless otherwise noted.
The term halo is generic to fluoro, chloro, bromo and iodo.
As used herein "Ci_4alkyl" as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as for example methyl, ethyl, prop-1-yl, prop-2-yl, but-l-yl, but-2-yl, isobutyl, 2-methyl- prop-1-yl; "Ci_3alkyl" as a group or part of a group defines straight or branched chain saturated hydrocarbon radicals having from 1 to 3 carbon atoms such as for example methyl, ethyl, prop-1-yl, prop-2-yl; "Ci_6alkyl" encompasses Ci_3alkyl and Ci_4alkyl radicals and the higher homologues thereof having 5 or 6 carbon atoms such as, for example, pent-1-yl, pent-2-yl, pent-3-yl, hex-l-yl, hex-2-yl, 2-methylbut-l-yl, 2-methylpent-l-yl, 2-ethylbut-l-yl, 3-methylpent-2-yl, and the like. Of interest amongst Ci_6alkyl is Ci_4alkyl and Ci_3alkyl.
The term "C2-6alkenyl" as a group or part of a group refers to an unsaturated hydrocarbyl group, which may be linear, or branched, comprising one or more carbon- carbon double bonds. Examples of C2-6alkenyl groups are ethenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl and its isomers, 2-hexenyl and its isomers,
2,4-pentadienyl and the like.
The term "polyhaloCi-βalkyl" as a group or part of a group, refers to a Ci_6alkyl radical having the meaning as defined above wherein one or more hydrogens are replaced with one or more halogens as defined above. Non- limiting examples of such polyhalo- C i_6alkyl radicals include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, and 1,1,1-trifluoroethyl.
C3 7cycloalkyl is generic to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
The term "Ci_6alkoxy" or "Ci_6alkyloxy" as a group or part of a group refers to a radical having the Formula -ORa wherein Ra is Ci_6alkyl as defined above. Non-limiting examples of suitable Ci_6alkoxy include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy. Suitable Ci_4alkoxy include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec- butoxy, and tert-butoxy.
The term "polyhaloCi-βalkoxy" as a group or part of a group, refers to a Ci_6alkoxy radical having the meaning as defined above wherein one or more hydrogens are replaced with one or more halogens as defined above. Non- limiting examples of such polyhaloCi-βalkoxy radicals include chloromethoxy, 1-bromoethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, and 1,1,1-trifluoroethoxy.
As used herein before, the term (=0) or oxo forms a carbonyl moiety when attached to a carbon atom, a sulfoxide moiety when attached to a sulfur atom and a sulfonyl moiety when two of said terms are attached to a sulfur atom. Whenever a ring or ring system is substituted with an oxo group, the carbon atom to which the oxo is linked is a saturated carbon.
The term "Ci_6alkylsulfonyl" as a group or part of a group, refers to a group of Formula -S(=O)2-Rb wherein Rb is Ci_6alkyl as defined herein. Non-limiting examples of Ci_6alkylsulfonyl groups include methylsulfonyl, ethylsulfonyl, butylsulfonyl, prop-1-ylsulfonyl, n-pentylsulfonyl, and hexylsulfonyl.
The term " Ci_6alkylcarbonyl" as a group or part of a group, refers to a group of Formula -C(=O)-RC, wherein Rc is as defined above for Ci_6alkyl.
The term "Ci_6alkylthio" as a group or part of a group, refers to a group consisting of a sulfur atom attached to a Ci_6alkyl group. Non- limiting examples of Ci_6alkylthio groups include methylthio (SCH3), ethylthio (SCH2CH3), n-propylthio, isopropylthio, n-butylthio, isobutylthio, sec-butylthio, te/t-butylthio, and the like.
It should be noted that the radical positions on any molecular moiety used in the definitions may be anywhere on such moiety as long as it is chemically stable.
Radicals used in the definitions of the variables include all possible isomers unless otherwise indicated. For instance piperidinyl includes piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, and piperidin-4-yl; pentyl includes pent-1-yl, pent-2-yl and pent-3-yl.
When any variable occurs more than one time in any constituent, each definition is independent. Whenever used hereinafter, the term "compounds of formula (I)", or "the present compounds" or similar terms, it is meant to include the compounds of formula (I), their prodrugs, JV-oxides, salts, quaternary amines, metal complexes, and stereochemically isomeric forms. One embodiment comprises the compounds of formula (I) or any subgroup of compounds of formula (I) specified herein, as well as the JV-oxides, salts, as the possible stereoisomeric forms thereof. Another embodiment comprises the compounds of formula (I) or any subgroup of compounds of formula (I) specified herein, as well as the salts as the possible stereoisomeric forms thereof.
The compounds of formula (I) may have one or more centers of chirality and may exist as stereochemically isomeric forms. The term "stereochemically isomeric forms" as used herein defines all the possible compounds made up of the same atoms bonded by the same sequence of bonds but having different three-dimensional structures, which the compounds of formula (I) may possess.
With reference to the instances where (R) or (S) is used to designate the absolute configuration of a chiral atom within a substituent, the designation is done taking into consideration the whole compound and not the substituent in isolation.
Unless otherwise mentioned or indicated, the chemical designation of a compound encompasses the mixture of all possible stereochemically isomeric forms, which said compound may possess. Said mixture may contain all diastereomers and/or enantiomers of the basic molecular structure of said compound. All stereochemically isomeric forms of the compounds of the present invention both in pure form or mixed with each other are intended to be embraced within the scope of the present invention.
Pure stereoisomeric forms of the compounds and intermediates as mentioned herein are defined as isomers substantially free of other enantiomeric or diastereomeric forms of the same basic molecular structure of said compounds or intermediates. In particular, the term "stereoisomerically pure" concerns compounds or intermediates having a stereoisomeric excess of at least 80% (i.e. minimum 90% of one isomer and maximum 10% of the other possible isomers) up to a stereoisomeric excess of 100% (i.e. 100% of one isomer and none of the other), more in particular, compounds or intermediates having a stereoisomeric excess of 90% up to 100%, even more in particular having a stereoisomeric excess of 94% up to 100% and most in particular having a stereoisomeric excess of 97% up to 100%. The terms "enantiomerically pure" and "diastereomerically pure" should be understood in a similar way, but then having regard to the enantiomeric excess, and the diastereomeric excess, respectively, of the mixture in question. Pure stereoisomeric forms of the compounds and intermediates of this invention may be obtained by the application of art-known procedures. For instance, enantiomers may be separated from each other by the selective crystallization of their diastereomeric salts with optically active acids or bases. Examples thereof are tartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid and camphosulfonic acid. Alternatively, enantiomers may be separated by chromatographic techniques using chiral stationary phases. Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically. Preferably, if a specific stereoisomer is desired, said compound will be synthesized by stereospecifϊc methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.
The diastereomeric racemates of the compounds of formula (I) can be obtained separately by conventional methods. Appropriate physical separation methods that may advantageously be employed are, for example, selective crystallization and chromatography, e.g. column chromatography.
For some of the compounds of formula (I), their prodrugs, JV-oxides, salts, hydrates, solvates, quaternary amines, or metal complexes, and the intermediates used in the preparation thereof, the absolute stereochemical configuration was not experimentally determined. A person skilled in the art is able to determine the absolute configuration of such compounds using art-known methods such as, for example, X-ray diffraction.
In an embodiment, the present invention encompasses compounds of Formula (II) and (III). In a particular embodiment, for the compounds of Formula (I) preferred configuration has Formula (II).
Figure imgf000013_0001
wherein Rla, Rlb, R2, R3, R4a and R4b have the same meaning as that defined herein. The present invention is also intended to include all isotopes of atoms occurring on the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C- 13 and C- 14.
The term "prodrug" as used throughout this text means the pharmacologically acceptable derivatives such as esters, amides and phosphates, such that the resulting in vivo biotransformation product of the derivative is the active drug as defined in the compounds of formula (I). The reference by Goodman and Gilman (The Pharmacological Basis of Therapeutics, 8th ed, McGraw-Hill, Int. Ed. 1992,
"Biotransformation of Drugs", p 13-15) describing prodrugs generally is hereby incorporated. Prodrugs preferably have excellent aqueous solubility, increased bioavailability and are readily metabolized into the active inhibitors in vivo. Prodrugs of a compound of the present invention may be prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either by routine manipulation or in vivo, to the parent compound.
Preferred are pharmaceutically acceptable ester prodrugs that are hydrolysable in vivo and are derived from those compounds of formula (I) having a hydroxy or a carboxyl group. An in vivo hydrolysable ester is an ester, which is hydro lyzed in the human or animal body to produce the parent acid or alcohol. Suitable pharmaceutically acceptable esters for carboxy include Ci_6alkoxymethyl esters for example methoxy— methyl, Ci_6alkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidyl esters, C3_8CycloalkoxycarbonyloxyCi_6alkyl esters for example 1-cyclohexylcarbonyl- oxyethyl; l,3-dioxolen-2-onylmethyl esters for example 5-methyl-l,3-dioxolen-2- onylmethyl; and Ci_6alkoxycarbonyloxyethyl esters for example 1-methoxycarbonyl- oxyethyl which may be formed at any carboxy group in the compounds of this invention.
An in vivo hydrolysable ester of a compound of the formula (I) containing a hydroxy group includes inorganic esters such as phosphate esters and α-acyloxyalkyl ethers and related compounds which as a result of the in vivo hydrolysis of the ester breakdown to give the parent hydroxy group. Examples of α-acyloxyalkyl ethers include acetoxy-methoxy and 2,2-dimethylpropionyloxy-methoxy. A selection of in vivo hydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and 7V-(dialkylaminoethyl)-7V-alkylcarbamoyl (to give carbamates), dialkylaminoacetyl and carboxyacetyl. Examples of substituents on benzoyl include morpholino and piperazino linked from a ring nitrogen atom via a methylene group to the 3- or 4-position of the benzoyl ring.
For therapeutic use, salts of the compounds of formula (I) are those wherein the counter-ion is pharmaceutically acceptable. However, salts of acids and bases which are non-pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound. All salts, whether pharmaceutically acceptable or not are included within the ambit of the present invention.
The pharmaceutically acceptable acid and base salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid and base addition salt forms which the compounds of formula (I) are able to form. The pharmaceutically acceptable acid addition salts can conveniently be obtained by treating the base form with such appropriate acid. Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e. butanedioic acid), maleic, fumaric, malic (i.e. hydroxybutanedioic acid), tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, /?-toluenesulfonic, cyclamic, salicylic, /?-amino- salicylic, pamoic and the like acids.
Conversely said salt forms can be converted by treatment with an appropriate base into the free base form.
The compounds of formula (I) containing an acidic proton may also be converted into their non-toxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases. Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. the benzathine, JV-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like.
The term "quaternary amine" as used hereinbefore defines the quaternary ammonium salts which the compounds of formula (I) are able to form by reaction between a basic nitrogen of a compound of formula (I) and an appropriate quaternizing agent, such as, for example, an optionally substituted alkylhalide, arylhalide or arylalkylhalide, e.g. methyliodide or benzyliodide. Other reactants with good leaving groups may also be used, such as alkyl trifluoromethanesulfonates, alkyl methanesulfonates, and alkyl p-toluenesulfonates. A quaternary amine has a positively charged nitrogen. Pharmaceutically acceptable counterions include chloro, bromo, iodo, trifluoroacetate and acetate. The counterion of choice can be introduced using ion exchange resins.
The N-oxide forms of the present compounds are meant to comprise the compounds of formula (I) wherein one or several nitrogen atoms are oxidized to the so-called N-oxide.
It will be appreciated that the compounds of formula (I) may have metal binding, chelating, complex forming properties and therefore may exist as metal complexes or metal chelates. Such metalated derivatives of the compounds of formula (I) are intended to be included within the scope of the present invention.
Some of the compounds of formula (I) may also exist in their tautomeric form. Such forms although not explicitly indicated in the above formula are intended to be included within the scope of the present invention.
One embodiment of the present invention concerns compounds of formula (I) or of any subgroup thereof, wherein:
Rla is hydrogen, hydroxy, amino, hydroxyCi-βalkyl, or halo; preferably Rla is hydrogen, hydroxy, amino, or hydroxyCi_4alkyl, more preferably Rla is hydrogen, hydroxy, or amino, most preferably Rla is hydrogen or hydroxy; yet most preferably Rla is hydroxy, Rlb is hydrogen, hydroxy, halo, amino, Ci_6alkoxy, -O-CH2-thiazolyl, trifluoromethyl, or Ci_6alkyl optionally substituted with cyano; preferably Rlb is hydrogen, hydroxy, amino, Ci_6alkoxy, -O-CH2-thiazolyl, or Ci_6alkyl; more preferably Rlb is hydrogen, hydroxy, amino, Ci_3alkoxy, or Ci_3alkyl; most preferably Rlb is hydrogen, hydroxy, or amino; yet most preferably Rlb is hydrogen, or hydroxy, R2 is hydrogen, -C(=O)-R5, -C(=O)-C(=O)-R5, -C(=O)-OR6, or -C(=O)-NR7aR7b; preferably R2 is hydrogen, -C(=O)-R5, or -C(=O)-OR6; most preferably R2 is hydrogen, or -C(=O)-R5;
R3 is Ci_6alkyl optionally substituted with C3-7cycloalkyl, aryl, or Het; C3-7cycloalkyl; aryl; or Het; preferably R3 is aryl; or Het; most preferably R3 is aryl; each R4a and R4b is, independently, hydrogen, C2-6alkenyl,Ci_6alkyl; or both R4a and R4b together with the carbon atom of the tricyclic ring to which they are attached may form an oxetanyl; preferably each R4a and R4b is, independently, hydrogen,
C2-6alkenyl, or Ci_6alkyl; most preferably each R4a and R4b is, independently,
Chalky!;
R , 5 is Ci_6alkyl optionally substituted with one or two substituents selected from halo,
C3-7cycloalkyl, phenylCi-βalkylthio, cyano, polyhaloCi-βalkyl, oxo, -OR 9 , -C(=O)-Het, -C(=O)-OR6, -C(=O)-OH, -C(=O)-NR7aR7b, -C(=O)-NH-S(=O)2-R8, -NR7aR7b, -S(=O)2-aryl, aryl, and Het; C2-6alkenyl optionally substituted with aryl; polyhaloCi-βalkyl; C3-7cycloalkyl; aryl; or Het; preferably R5 is Ci_6alkyl optionally substituted with one or two substituents selected from halo, C3_7cycloalkyl, phenyl- Ci_6alkylthio, cyano, polyhaloCi-βalkyl, -OR9, -S(=O)2-aryl, aryl, and Het;
C2-6alkenyl optionally substituted with aryl; polyhaloCi-βalkyl; C3_7Cycloalkyl; aryl; or Het; most preferably R5 is selected from the group comprising Ci_6alkyl; polyhaloCi-βalkyl; C3_7CycloalkylCi_6alkyl; phenylCi_6alkylthioCi_6alkyl; cyano Ci_6alkyl; R9-Oalkyl; polyhaloCi.6alkylCi.6alkyl, aryl-S(=O)2-Ci.6alkyl; aryl- Ci_6alkyl; HetCi_6alkyl; C2-6alkenyl; arylC2-6alkenyl; C3_7Cycloalkyl; aryl; or Het; most preferably R5 is selected from the group comprising Ci_6alkyl; polyhalo- Ci_6alkyl; C3_7CycloalkylCi_6alkyl; phenylCi_6alkylthioCi_6alkyl; cyanoCi-βalkyl; R9-Oalkyl; polyhaloCi_6alkyl Ci_6alkyl, aryl-S(=O)2-Ci.6alkyl; arylCi_6alkyl; HetCi_6alkyl; C2-6alkenyl; arylC2-6alkenyl; C3_7Cycloalkyl; aryl; or Het; R6 is aryl or Ci_6alkyl optionally substituted with -OR9, -C(=O)-OR9, -C(=O)-NR7aR7b, -C(=O)-NH-S(=O)2-R8, aryl, or Het; preferably R6 is phenyl optionally substituted with Ci_6alkyloxy; or Ci_6alkyl optionally substituted with -OR9, aryl, or Het; preferably R6 is phenyl optionally substituted with Ci_3alkyloxy; or Ci_6alkyl; each R7a and R7b is, independently, hydrogen; Ci_6alkyl optionally substituted with one or two substituents selected from -OR9, mono- or diCi_6alkylamino, -C(=O)-OR9,
-C(=O)-NH2, -C(=O)-NH-Ci_6alkyl, -C(=O)-NH-hydroxyCi_6alkyl, -C(=O)-Het, C3_7Cycloalkyl, aryl, and Het; C2-6alkenyl; C3_7Cycloalkyl optionally substituted with hydroxy; aryl; or Het; R8 is Ci_6alkyl, C3_7Cycloalkyl, di(Ci_3alkyl)amino, or aryl; R9 is hydrogen; Ci_6alkyl optionally substituted with one, two or three substituents each independently selected from halo, hydroxyl, C3_7Cycloalkenyl, C3_7Cycloalkyl, cyano, Ci_6alkoxy, phenyl, or Het, wherein the phenyl may optionally be substituted with halo, hydroxyl, Ci_6alkoxy, Ci_6alkyl, Ci_6alkoxyCi_6alkoxy, nitro, or amino; C2-6alkenyl optionally substituted with one or two substituents selected from halo and polyhaloCi-βalkyl; C2-βalkynyl; C3_7Cycloalkenyl;or phenyl optionally substituted with one or two substituents selected from hydroxyl, Ci_6alkoxy, halo, polyhaloCi-βalkyl, amino, nitro, Ci_6alkyl, and phenyl; preferably R9 is hydrogen; Ci_6alkyl optionally substituted with one, two or three substituents each independently selected from halo, hydroxyl, C3_7Cycloalkenyl, C3_7Cycloalkyl, Ci_6alkoxy, phenyl, or Het, wherein the phenyl may optionally be substituted with halo, hydroxyl, Ci_6alkoxy, Ci_6alkyl, Ci_6alkoxyCi_6alkoxy; C2-6alkenyl; C2-βalkynyl; or phenyl optionally substituted with one or two substituents selected from hydroxyl, Ci_6alkoxy, halo, polyhaloCi-βalkyl, Ci_6alkyl, and phenyl; more preferably R9 is hydrogen; Ci_6alkyl optionally substituted with one, two or three substituents each independently selected from halo, C3_7cycloalkenyl, C3-7cycloalkyl, phenyl, or Het, wherein the phenyl may optionally be substituted with halo, hydroxyl, Ci_6alkoxy, Ci_6alkyl, Ci_6alkoxyCi_6alkoxy; C2-6alkenyl; C2-βalkynyl; or phenyl optionally substituted with one or two substituents selected from hydroxyl, Ci_6alkoxy, halo, polyhaloCi-βalkyl, Ci_6alkyl; aryl as a group or part of a group is phenyl, naphthyl, indanyl, or 1,2,3,4-tetrahydro- naphthyl, each of which may be optionally substituted with one, two , three or four substituents each independently selected from the group consisting of C3-7cyclo- alkyl, phenylCi-βalkyl, phenylpolyhaloCi-βalkyl, phenylCi-βalkyloxy, halo, polyhaloCi_6alkyl, cyano, Ci_6alkyl, polyhaloCi_6alkoxy, -OR9, -C(=O)OH, Ci_6alkylcarbonyl, Ci_6alkylthio, Ci_6alkylsulfonyl, -S(=O)2NH2, and pyrrolyl, wherein the phenyl may optionally be substituted with halo ; or two substituents on the aryl ring may form -0-CH2-O- or a -0-C(CHs)2-CH2-; preferably aryl as a group or part of a group is phenyl, optionally substituted with one, two , three or four substituents each independently selected from the group consisting of C3-7cycloalkyl, phenylCi-βalkyl, phenylpolyhaloCi-βalkyl, phenylCi-βalkyloxy, halo, polyhaloCi-βalkyl, cyano, Ci_6alkyl, polyhaloCi-βalkoxy, -OR9, Ci_6alkylthio, -S(=O)2NH2, and pyrrolyl; more preferably aryl as a group or part of a group is phenyl, optionally substituted with one, two , three or four substituents each independently selected from the group consisting of C3-7cycloalkyl, phenyl- Ci_6alkyl, phenylpolyhaloCi-βalkyl, phenylCi-βalkyloxy, halo, polyhaloCi-βalkyl, cyano, d_6alkyl, polyhaloCi_6alkoxy, -OR9, Ci_6alkylthio, -S(=O)2NH2; Het as a group or part of a group is a 5 to 12 membered saturated, partially unsaturated or completely unsaturated mono- or bicyclic ring containing 1 to 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, being optionally condensed with one benzene ring, and wherein the group Het as a whole may be optionally substituted with one or two substituents each independently selected from the group consisting of halo; polyhaloCi-βalkyl; Ci_6alkylthio, oxo; -OR9; -CN; Ci_6alkyl optionally substituted with -OR9, -CN, or phenyl;-C(=O)-NH2;
-C(=O)-phenyl; C3-7cycloalkyl; phenyl optionally substituted with Ci_6alkoxy; morpholinyl; pyrrolidinyl; pyrrolyl; furanyl; tetrazolyl; and thiophenyl; preferably Het is selected from pyridinyl, quinolinyl, isoquinolinyl, pyrazinyl, furanyl, thiophenyl, oxazolyl, thiazolyl, pyrimidinyl, pyridazinyl, imidazolyl, 2,3-dihydrobenzofuranyl, tetrahydrofuran, and wherein the group Het as a whole may be optionally substituted with one or two substituents each independently selected from the group consisting of halo; polyhaloCi-βalkyl; Ci_6alkylthio, oxo; -OR9; -CN; d_6alkyl optionally substituted with -OR9, -CN, or phenyl; -C(=O)-NH2; -C(=O)-phenyl; C3-7cycloalkyl; phenyl optionally substituted with Ci_6alkoxy; morpholinyl; pyrrolidinyl; pyrrolyl; furanyl; tetrazolyl; and thiophenyl; more preferably Het is selected from pyridinyl, quinolinyl, isoquinolinyl, pyrazinyl, furanyl, thiophenyl, oxazolyl, thiazolyl, pyrimidinyl, pyridazinyl, imidazolyl, 2,3-dihydrobenzofuranyl, tetrahydrofuran, and wherein the group Het as a whole may be optionally substituted with one or two substituents each independently selected from the group consisting of halo; polyhaloCi-βalkyl; Ci_6alkylthio, oxo; -OR9; Ci_6alkyl optionally substituted with -OR9, -CN, or phenyl; C3-7cycloalkyl.
One embodiment of the present invention concerns compounds of formula (I) or of any subgroup of compounds of formula (I), wherein
Rla is hydrogen, hydroxy, amino, or hydroxyCi-βalkyl;
Rlb is hydrogen, hydroxy, halo, amino, Ci_6alkoxy, -O-CH2-thiazolyl, trifluoromethyl, or Ci_6alkyl optionally substituted with cyano;
R2 is hydrogen, -C(=O)-R5, -C(=O)-C(=O)-R5, -C(=O)-OR6, or -C(=O)-NR7aR7b;
R is Ci_6alkyl optionally substituted with C3_7Cycloalkyl, aryl, or Het; C3_7Cycloalkyl; aryl; or Het; each R4a and R4b is, independently, hydrogen, C2-6alkenyl, or Ci_6alkyl; or both R4a and R4b together with the carbon atom of the tricyclic ring to which they are attached may form an oxetanyl;
R5 is Ci_6alkyl optionally substituted with one or two substituents selected from halo, C3_7Cycloalkyl, phenylCi-βalkylthio, cyano, polyhaloCi-βalkyl, oxo, -OR9, -C(=O)-Het, -C(=O)-OR6, -C(=O)-OH, -C(=O)-NR7aR7b, -C(=O)-NH-S(=O)2-R8, -NR7aR7b, -S(=O)2-aryl, aryl, and Het; C2-6alkenyl optionally substituted with aryl; polyhaloCi-βalkyl; C3-7cycloalkyl; aryl; or Het;
R6 is aryl or Ci_6alkyl optionally substituted with -OR9, -C(=O)-OR9, -C(=O)-NR7aR7b, -C(=O)-NH-S(=O)2-R8, aryl, or Het; each R7a and R7b is, independently, hydrogen; Ci_6alkyl optionally substituted with one or two substituents selected from -OR9, mono- or diCi_6alkylamino, -C(=O)-OR9,
-C(=O)-NH2, -C(=O)-NH-Ci_6alkyl, -C(=O)-NH-hydroxyCi_6alkyl, -C(=O)-Het, C3-7cycloalkyl, aryl, and Het; C2-6alkenyl; C3-7cycloalkyl optionally substituted with hydroxy; aryl; or Het;
R8 is d-βalkyl, C3-7cycloalkyl, di(Ci_3alkyl)amino, or aryl; R9 is hydrogen; Ci_6alkyl optionally substituted with one, two or three substituents each independently selected from halo, hydroxyl, C3-7cycloalkenyl, C3-7cycloalkyl, cyano, Ci_6alkoxy, phenyl, or Het, wherein the phenyl may optionally be substituted with halo, hydroxyl, Ci_6alkoxy, Chalky!, Ci_6alkoxyCi_6alkoxy, nitro, or amino; C2-6alkenyl optionally substituted with one or two substituents selected from halo and polyhaloCi-βalkyl; C2-6alkynyl; C3_7Cycloalkenyl;or phenyl optionally substituted with one or two substituents selected from hydroxyl, Ci_6alkoxy, polyhaloCi-βalkyl, halo, amino, nitro, Ci_6alkyl, and phenyl; aryl as a group or part of a group is phenyl, naphthyl, indanyl, or 1 ,2,3,4-tetrahydro- naphthyl, each of which may be optionally substituted with one, two , three or four substituents each independently selected from the group consisting of C3-7cyclo- alkyl, phenylCi-βalkyl, phenylpolyhaloCi-βalkyl, phenylCi-βalkyloxy, halo, polyhaloCi_6alkyl, cyano, Ci_6alkyl, polyhaloCi_6alkoxy, -OR9, -C(=O)OH, Ci_6alkylcarbonyl, Ci_6alkylthio, Ci_6alkylsulfonyl, -S(=O)2NH2, and pyrrolyl, wherein the phenyl may optionally be substituted with halo ; or two substituents on the aryl ring may form -0-CH2-O- or a -O-C(CH3)2-CH2-; Het as a group or part of a group is a 5 to 12 membered saturated, partially unsaturated or completely unsaturated mono- or bicyclic ring containing 1 to 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, being optionally condensed with one benzene ring, and wherein the group Het as a whole may be optionally substituted with one or two substituents each independently selected from the group consisting of halo; polyhaloCi-βalkyl; Ci_6alkylthio, oxo; -OR9; -CN; Ci_6alkyl optionally substituted with -OR9, -CN, or phenyl; -C(=O)-NH2; -C(=O)-phenyl; C3_7Cycloalkyl; phenyl optionally substituted with Ci_6alkoxy; morpholinyl; pyrrolidinyl; pyrrolyl; furanyl; tetrazolyl; and thiophenyl.
One embodiment of the present invention concerns compounds of formula (I) or of any subgroup thereof, wherein: Rla is hydrogen, hydroxy, or amino;
Rlb is hydrogen, hydroxy, halo, trifluoromethyl, or Ci_6alkyl optionally substituted with cyano;
R2 is hydrogen, -C(=O)-R5, -C(=O)-C(=O)-R5, -C(=O)-OR6, or -C(=O)-NR7aR7b; R is Ci_6alkyl optionally substituted with C3_7Cycloalkyl, aryl, or Het; C3_7Cycloalkyl; aryl; or Het; each R4a and R4b is, independently, Ci_6alkyl;
R5 is Ci_6alkyl optionally substituted with one or two substituents selected from halo,
C3-7cycloalkyl, cyano, polyhaloCi_6alkyl, oxo, -OR9, -C(=O)-Het, -C(=O)-OR6,
-C(=O)-OH, -C(=O)-NR7aR7b, -C(=O)-NH-S(=O)2-R8, -NR7aR7b, -S(=O)2-aryl, aryl, and Het; C2-6alkenyl optionally substituted with aryl; polyhaloCi-βalkyl;
C3-7cycloalkyl; aryl; or Het; R6 is aryl or Ci_6alkyl optionally substituted with -OR9, -C(=O)-OR9, -C(=O)-NR7aR7b,
-C(=O)-NH-S(=O)2-R8, aryl, or Het; each R7a and R7b is, independently, hydrogen; Ci_6alkyl optionally substituted with one or two substituents selected from -OR9, mono- or diCi_6alkylamino, -C(=O)-OR9, -C(=O)-NH2, -C(=O)-NH-Ci_6alkyl, -C(=O)-NH-hydroxyCi_6alkyl, -C(=O)-Het, C3_7Cycloalkyl, aryl, and Het; C2-6alkenyl; C3_7Cycloalkyl optionally substituted with hydroxy; aryl; or Het;
R8 is Ci_6alkyl, C3_7Cycloalkyl, di(Ci_3alkyl)amino, or aryl;
R9 is hydrogen; Ci_6alkyl optionally substituted with one, two or three substituents each independently selected from halo, hydroxyl, C3_7Cycloalkenyl, C3_7Cycloalkyl, Ci_6alkoxy, phenyl, or Het, wherein the phenyl may optionally be substituted with halo, Ci_6alkoxy, Ci_6alkyl, Ci_6alkoxyCi_6alkoxy, nitro, or amino; C2-6alkenyl;
C2_6alkynyl; or phenyl optionally substituted with one or two substituents selected from halo, Ci_6alkoxy, polyhaloCi-βalkyl, amino, nitro, Ci_6alkyl, and phenyl; aryl as a group or part of a group is phenyl, naphthyl, indanyl, or 1,2,3,4-tetrahydro- naphthyl, each of which may be optionally substituted with one, two, three or four substituents each independently selected from the group consisting of
C3_7Cycloalkyl, phenylCi-βalkyl, phenylpolyhaloCi-βalkyl, phenylCi-βalkyloxy, halo, polyhaloCi_6alkyl, cyano, Ci_6alkyl, polyhaloCi_6alkoxy, -OR9, -C(=O)OH, Ci_6alkylcarbonyl, Ci_6alkylthio, Ci_6alkylsulfonyl, -S(=O)2NH2, and pyrrolyl;
Het as a group or part of a group is a 5 to 12 membered saturated, partially unsaturated or completely unsaturated mono- or bicyclic ring containing 1 to 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, being optionally condensed with one benzene ring, and wherein the group Het as a whole may be optionally substituted with one or two substituents each independently selected from the group consisting of halo; polyhaloCi-βalkyl; Ci_6alkylthio,oxo; -OR9; -CN; Ci_6alkyl optionally substituted with -OR9, -CN, or phenyl;-C(=O)-NH2;
-C(=O)-phenyl; C3_7Cycloalkyl; phenyl optionally substituted with Ci_6alkoxy; morpholinyl; pyrrolidinyl; pyrrolyl; furanyl; tetrazolyl; and thiophenyl.
One embodiment of the present invention concerns compounds of formula (I) or of any subgroup of compounds of formula (I), wherein one or more of the following restrictions apply:
(a) Rla is hydrogen, hydroxy, amino, or halo;
(b) Rlb is hydrogen, hydroxy, halo, trifluoromethyl, or Ci_6alkyl optionally substituted with cyano; (c) R2 is hydrogen, -C(=O)-R5, -C(=O)-C(=O)-R5, -C(=O)-OR6, or -C(=O)-NR7aR7b;
(d) R3 is Ci_6alkyl optionally substituted with C3_7Cycloalkyl, aryl, or Het; C3_7Cycloalkyl; aryl; or Het;
(e) each R4a and R4b is, independently, Chalky!; (f) R5 is Ci_6alkyl optionally substituted with one or two substituents selected from cyano, polyhaloCi_6alkyl, oxo, -OR9, -C(=O)-Het, -C(=O)-OR6, -C(=O)-OH, -C(=O)-NR7aR7b, -C(=O)-NH-S(=O)2-R8, -NR7aR7b, aryl, and Het; C2-6alkenyl optionally substituted with aryl; polyhaloCi-βalkyl; C3_7Cycloalkyl; aryl; or Het; (g) R6 is Ci_6alkyl optionally substituted with -OR9, -C(=O)-OR9, -C(=O)-NR7aR7b, -C(=O)-NH-S(=O)2-R8, aryl, or Het;
(h) each R7a and R7b is, independently, hydrogen; Ci_6alkyl optionally substituted with one or two substituents selected from -OR9, mono- or diCi_6alkylamino, -C(=O)-OR9, -C(=O)-NH2, -C(=O)-NH-Ci_6alkyl, -C(=O)-NH-hydroxyCi_6alkyl, -C(=O)-Het, C3_7Cycloalkyl, aryl, and Het; C2_6alkenyl; C3_7Cycloalkyl optionally substituted with hydroxy; aryl; or Het;
(i) R8 is Ci_6alkyl, C3_7Cycloalkyl, di(Ci_3alkyl)amino, or aryl;
(J) R9 is hydrogen; Ci_6alkyl optionally substituted with Ci_6alkoxy, phenyl, or Het, wherein the phenyl may optionally be substituted with halo, Ci_6alkoxy, nitro, or amino; or phenyl optionally substituted with one or two substituents selected from halo, amino, nitro, Ci_6alkyl, and phenyl;
(k) aryl as a group or part of a group is phenyl, naphthyl, indanyl, or 1,2,3,4-tetrahydro- naphthyl, each of which may be optionally substituted with one or two substituents each independently selected from the group consisting of halo, polyhaloCi-βalkyl, cyano, Ci_6alkyl, polyhaloCi-βalkoxy, -OR9, -C(=O)OH, Ci_6alkylcarbonyl,
Ci_6alkylthio, Ci_6alkylsulfonyl, -S(=O)2NH2, and pyrrolyl;
(1) Het as a group or part of a group is a 5 to 12 membered saturated, partially unsaturated or completely unsaturated mono- or bicyclic ring containing 1 to 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, being optionally condensed with one benzene ring, and wherein the group Het as a whole may be optionally substituted with one or two substituents each independently selected from the group consisting of halo; oxo; -OR9; -CN; Ci_6alkyl optionally substituted with -OR9, -CN, or phenyl;-C(=O)-NH2; -C(=O)-phenyl; C3-7cycloalkyl; phenyl optionally substituted with Ci_6alkoxy; morpholinyl; pyrrolidinyl; pyrrolyl; furanyl; tetrazolyl; and thiophenyl.
One embodiment of the present invention concerns compounds of formula (I) or of any subgroup of compounds of formula (I), wherein: Rla is hydrogen, hydroxy, or amino; Rlb is hydrogen, hydroxy, halo, trifluoromethyl, or Ci_6alkyl optionally substituted with cyano; R2 is hydrogen, -C(=O)-R5, -C(=O)-OR6, or -C(=O)-NR7aR7b; R3 is Ci_6alkyl optionally substituted with C3-7cycloalkyl, aryl, or Het; C3-7cycloalkyl; aryl; or Het; each R4a and R4b is, independently, Ci_6alkyl;
R5 is Ci_6alkyl optionally substituted with one or two substituents selected from halo, Cs-vcycloalkyl, cyano, polyhaloCi_6alkyl, oxo, -OR9, -C(=O)-OR6, -C(=O)OH,
-S(=O)2-aryl, aryl, and Het; C3_7Cycloalkyl; aryl; or Het;
R6 is aryl or Ci_6alkyl; each R7a and R7b is, independently, hydrogen; Ci_6alkyl; aryl; or Het;
R9 is hydrogen; Ci_6alkyl optionally substituted with one, two or three substituents each independently selected from halo, hydroxyl, C3-7Cy cloalkenyl, C3-7Cy cloalkyl,
Ci_6alkoxy, phenyl, or Het, wherein the phenyl may optionally be substituted with halo, Ci_6alkoxy, nitro, Ci_6alkyl, Ci_6alkoxyCi_6alkoxy, or amino; C2-6alkenyl; C2-βalkynyl; or phenyl optionally substituted with one or two substituents selected from halo, Ci_6alkoxy, polyhaloCi-βalkyl, amino, nitro, Ci_6alkyl, and phenyl; aryl as a group or part of a group is phenyl optionally substituted with one two, three or four substituents each independently selected from the group consisting of C3_7cycloalkyl, phenylCi-βalkyl, phenylpolyhaloCi-βalkyl, phenylCi-βalkyloxy, halo, polyhaloCi-βalkyl, cyano, Ci_6alkyl, polyhaloCi-βalkoxy, -OR9, -C(=O)OH, Ci_6alkylcarbonyl, Ci_6alkylthio, Ci_6alkylsulfonyl, and -S(=O)2NH2; Het as a group or part of a group is a 5 to 12 membered saturated, partially unsaturated or completely unsaturated mono- or bicyclic ring containing 1 to 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, and wherein the group Het as a whole may be optionally substituted with one or two substituents each independently selected from the group consisting of halo, polyhaloCi-βalkyl; Ci-ealkylthio, oxo, -OR9, -CN, and Ci-6alkyl.
One embodiment of the present invention concerns compounds of formula (I) or of any subgroup of compounds of formula (I), wherein one or more of the following restrictions apply: (a) Rla is hydrogen, hydroxy, amino, or halo;
(b) Rlb is hydrogen, hydroxy, halo, trifluoromethyl, or Ci_6alkyl optionally substituted with cyano;
(c) R2 is hydrogen, -C(=O)-R5, -C(=O)-OR6, or -C(=O)-NR7aR7b;
(d) R3 is Ci_6alkyl optionally substituted with C3_7cycloalkyl, aryl, or Het; C3_7cy cloalkyl; aryl; or Het;
(e) each R4a and R4b is, independently, Chalky!; (f) R , 5 is Ci_6alkyl optionally substituted with one or two substituents selected from ccyyaannoo,, ppoollyyhhaallooCCii-_β6aallkkyyll,, oo?xo, -OR9, -C(=O)-OR6, -C(=O)-OH, aryl, and Het; C3-7cycloalkyl; aryl; or Het;
(g) R > 60 is d-ealkyl; (h) each R7a and R7b is, independently, hydrogen; Ci_6alkyl; aryl; or Het; (j) R9 is hydrogen; Ci_6alkyl optionally substituted with Ci_6alkoxy, phenyl, or Het, wherein the phenyl may optionally be substituted with halo, Ci_6alkoxy, nitro, or amino; or phenyl optionally substituted with one or two substituents selected from halo, amino, nitro, C^aUcyl, and phenyl;
(k) aryl as a group or part of a group is phenyl optionally substituted with one or two substituents each independently selected from the group consisting of halo, polyhaloCi-βalkyl, cyano, Ci_6alkyl, polyhaloCi-βalkoxy, -OR9, -C(=O)OH, Ci_6alkylcarbonyl, Ci_6alkylthio, Ci_6alkylsulfonyl, and -S(=O)2NH2; (1) Het as a group or part of a group is a 5 to 12 membered saturated, partially unsaturated or completely unsaturated mono- or bicyclic ring containing 1 to 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, and wherein the group Het as a whole may be optionally substituted with one or two substituents each independently selected from the group consisting of halo, oxo, -OR9, -CN, and Chalky!.
In an embodiment, the present invention relates to compounds of formula (I) or any subgroup thereof, wherein R2 is hydrogen, -C(=O)-R5 or -C(=O)-OR6, such as compounds represented by any of the following structural formula (I-c), (I-d) or (I-e):
Figure imgf000024_0001
and the salts and stereoisomers thereof, wherein Rla, Rlb, R3, R5 and R6 are as specified in the definitions of the compounds of formula (I) or any subgroups thereof.
Particular subgroups of compounds of formula (I) are those represented by any of the following structural formula (I-f), (I-g) or (I-h):
Figure imgf000025_0001
and the salts and stereoisomers thereof, wherein Rla, Rlb, R2, R5, R6 and aryl are as specified in the definitions of the compounds of formula (I) or any subgroups thereof.
One embodiment of the present invention concerns compounds of formula (I) or of any subgroup thereof, wherein:
Rla is hydrogen, hydroxy, or amino;
Rlb is hydrogen, hydroxy, amino, Ci_3alkoxy, or Ci_3alkyl; R2 is hydrogen, -C(=O)-R5, or -C(=O)-OR6;
R is aryl; or Het; each R4a and R4b is, independently, hydrogen, C2-6alkenyl, or Ci_6alkyl;
R5 is selected from the group comprising Ci_6alkyl; polyhaloCi-βalkyl;
C3-7cycloalkylCi_6alkyl; phenylCi_6alkylthioCi_6alkyl; cyano Ci_6alkyl; R9-Oalkyl; polyhaloCi_6alkylCi_6alkyl, aryl-S(=O)2-Ci_6alkyl; arylCi_6alkyl; HetCi_6alkyl;
C2-6alkenyl; arylC2-6alkenyl; C3-7cycloalkyl; aryl; or Het;
R6 is phenyl optionally substituted with Ci_6alkyloxy; or Ci_6alkyl optionally substituted with -OR9, aryl, or Het;
R9 is hydrogen; Ci_6alkyl optionally substituted with one, two or three substituents each independently selected from halo, hydroxyl, C3-7cycloalkenyl, C3-7cycloalkyl,
Ci_6alkoxy, phenyl, or Het, wherein the phenyl may optionally be substituted with halo, hydroxyl, Ci_6alkoxy, Ci_6alkyl, Ci_6alkoxyCi_6alkoxy; C2-6alkenyl; C2-βalkynyl; or phenyl optionally substituted with one or two substituents selected from hydroxyl, Ci_6alkoxy, halo, polyhaloCi-βalkyl, Chalky!, and phenyl; aryl as a group or part of a group is phenyl, optionally substituted with one, two , three or four substituents each independently selected from the group consisting of C3_7Cycloalkyl, phenylCi-βalkyl, phenylpolyhaloCi-βalkyl, phenylCi-βalkyloxy, halo, polyhaloCi-βalkyl, cyano, Chalky!, polyhaloCi-βalkoxy, -OR9, Ci_6alkylthio, -S(=O)2NH2, and pyrrolyl; Het is selected from pyridinyl, quinolinyl, isoquinolinyl, pyrazinyl, furanyl, thiophenyl, oxazolyl, thiazolyl, pyrimidinyl, pyridazinyl, imidazolyl, 2,3-dihydrobenzofuranyl, tetrahydrofuranyl, and wherein the group Het as a whole may be optionally substituted with one or two substituents each independently selected from the group consisting of halo; polyhaloCi-βalkyl; Ci_6alkylthio, oxo; -OR9; -CN; Ci_6alkyl optionally substituted with -OR9, -CN, or phenyl;-C(=O)-NH2; -C(=O)-phenyl; C3-7cycloalkyl; phenyl optionally substituted with Ci_6alkoxy; morpholinyl; pyrrolidinyl; pyrrolyl; furanyl; tetrazolyl; and thiophenyl.
One embodiment of the present invention concerns compounds of formula (I) or of any subgroup thereof, wherein:Rla is hydrogen or hydroxy; Rlb is hydrogen or hydroxy;
RR22 iiss hhyyddrroc gen, -C(=O)-R5 or -C(=O)-OR6; R3 is aryl; eaacch R4a and R4b is, independently, Chalky!;
R5 is Ci_6alkyl optionally substituted with one or two substituents selected from halo, C3_7Cycloalkyl, cyano, polyhaloCi-βalkyl, oxo, -OR9, -S(=O)2-aryl, aryl, and Het; aryl; or Het; R9 is Ci_6alkyl optionally substituted with one, two or three substituents each independently selected from halo, hydroxyl, C3-7cycloalkenyl, C3-7cycloalkyl, or phenyl; or phenyl optionally substituted with one or two substituents selected from halo, polyhaloCi-βalkyl, or C^aUcyl, aryl as a group or part of a group is phenyl optionally substituted with one, two, three or four substituents each independently selected from the group consisting of halo, polyhaloCi-βalkyl, cyano, Ci_6alkyl, polyhaloCi-βalkoxy, and -OR9; Het as a group or part of a group is a 5 to 6 membered saturated, partially unsaturated or completely unsaturated monocyclic ring containing 1 to 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, and wherein the group Het may be optionally substituted with one or two substituents each independently selected from the group consisting of halo, oxo, -OR9, -CN, and Ci_6alkyl. One embodiment of the present invention concerns compounds of formula (I) or of any subgroup thereof, wherein:
Rla is hydrogen or hydroxy; preferably Rla is hydroxy, Rlb is hydrogen, hydroxy, or amino; preferably Rlb is hydrogen, or hydroxy, R2 is hydrogen, or -C(=O)-R5; R3 is aryl; each R4a and R4b is, independently, Ci_6alkyl;
R5 is selected from the group comprising Ci_6alkyl; polyhaloCi-βalkyl;
C3_7CycloalkylCi_6alkyl; phenylCi_6alkylthioCi_6alkyl; cyanoCi-βalkyl; R9-Oalkyl; polyhaloCi_6alkyl Ci_6alkyl, aryl-S(=O)2-Ci.6alkyl; arylCi_6alkyl; HetCi_6alkyl; C2-6alkenyl; arylC2-6alkenyl; C3_7Cycloalkyl; aryl; or Het;
R6 is phenyl optionally substituted with Ci_3alkyloxy; or Ci_6alkyl;
R9 is hydrogen; Ci_6alkyl optionally substituted with one, two or three substituents each independently selected from halo, C3-7cycloalkenyl, C3-7cycloalkyl, phenyl, or Het, wherein the phenyl may optionally be substituted with halo, hydroxyl, Ci_6alkoxy, Ci_6alkyl, Ci_6alkoxyCi_6alkoxy; C2-6alkenyl; C2-βalkynyl; or phenyl optionally substituted with one or two substituents selected from hydroxyl, Ci_6alkoxy, halo, polyhaloCi-βalkyl, Ci_6alkyl; aryl as a group or part of a group is phenyl, optionally substituted with one, two , three or four substituents each independently selected from the group consisting of C3_7Cycloalkyl, phenylCi-βalkyl, phenylpolyhaloCi-βalkyl, phenylCi-βalkyloxy, halo, polyhaloCi-βalkyl, cyano, Chalky!, polyhaloCi-βalkoxy, -OR9, Ci_6alkylthio, -S(=O)2NH2; Het is selected from pyridinyl, quinolinyl, isoquinolinyl, pyrazinyl, furanyl, thiophenyl, oxazolyl, thiazolyl, pyrimidinyl, pyridazinyl, imidazolyl, 2,3-dihydrobenzofuranyl, tetrahydro furanyl, and wherein the group Het as a whole may be optionally substituted with one or two substituents each independently selected from the group consisting of halo; polyhaloCi-βalkyl; Ci_6alkylthio, oxo; -OR9; Ci_6alkyl optionally substituted with -OR9, -CN, or phenyl; C3_7Cycloalkyl.
One embodiment of the present invention concerns compounds of formula (I) or of any subgroup of compounds of formula (I), wherein one or more of the following restrictions apply:
(a) Rla is hydrogen or hydroxy; (b) Rlb is hydrogen or hydroxy;
(c) R2 is hydrogen or -C(=O)-R5;
(d) R3 is aryl;
(e) each R4a and R4b is, independently, Ci_6alkyl; (f) R5 is Ci_6alkyl or Het; (g) R9 is Ci_6alkyl optionally substituted with phenyl;
(h) aryl as a group or part of a group is phenyl optionally substituted with one or two substituents each independently selected from the group consisting of halo, polyhaloCi-βalkyl, cyano, Chalky!, polyhaloCi-βalkoxy, and -OR9; (i) Het as a group or part of a group is a 5 to 6 membered saturated, partially unsaturated or completely unsaturated monocyclic ring containing 1 to 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, and wherein the group Het may be optionally substituted with one or two substituents each independently selected from the group consisting of halo, oxo, -OR9, -CN, and Ci_6alkyl.
One embodiment of the present invention concerns compounds of formula (I) or of any subgroup of compounds of formula (I), wherein Rla is hydroxy; Rlb is hydrogen; R2 is hydrogen or -C(=O)-R5; R is aryl; each R4a and R4b is, independently, Ci_6alkyl; R5 is Ci_6alkyl or Het;
R9 is Ci_6alkyl optionally substituted with phenyl; aryl as a group or part of a group is phenyl optionally substituted with one or two halo or -OR9; Het as a group or part of a group is a 5 to 6 membered saturated, partially unsaturated or completely unsaturated monocyclic ring containing 1 to 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, and wherein the group Het may be optionally substituted with one or two substituents each independently selected from the group consisting of halo, -OR9, and Ci_6alkyl.
Particular subgroups of compounds of formula (I) are those represented by the following structural formula (I-a):
Figure imgf000028_0001
and the salts and stereoisomers thereof, wherein Rla, Rlb, R2 and R3 are as specified in the definitions of the compounds of formula (I) or in any of the subgroups of compounds of formula (I) specified herein.
In an embodiment, the present invention encompasses compounds of Formula (II-a) and (III-a). In a particular embodiment, for the compounds of Formula (I-a) preferred configuration has Formula (II-a).
Figure imgf000029_0001
Particular subgroups of compounds of formula (I) are those represented by the following structural formula (I-b):
Figure imgf000029_0002
(I-b)
and the salts and stereoisomers thereof, wherein Rla, Rlb, R2, and aryl are as specified in the definitions of the compounds of formula (I) or in any of the subgroups of compounds of formula (I) specified herein.
In an embodiment, the present invention encompasses compounds of Formula (II -b) and (III-b). In a particular embodiment, for the compounds of Formula (I-b) preferred configuration has Formula (II -b).
Figure imgf000029_0003
Particular subgroups of compounds of formula (I) are those represented by any of the following structural formula (I-i), (I-j) or (I-k):
Figure imgf000030_0001
and the salts and stereoisomers thereof, wherein Rla, Rlb, R3, R5 and R6 are as specified in the definitions of the compounds of formula (I) or any subgroups thereof.
Particular subgroups of compounds of formula (I) are those represented by any of the following structural formula (1-1), (I-m) or (I-n):
Figure imgf000030_0002
and the salts and stereoisomers thereof, wherein Rla, Rlb, R2, R5, R6 and aryl are as specified in the definitions of the compounds of formula (I) or any subgroups thereof.
In an embodiment, the present invention encompasses compounds of Formula (II-l), (III-l), (II-m), (III-m), (II-n) and (III-n). In a particular embodiment, for the compounds of Formula (1-1), (I-m) or (I-n) preferred configuration has Formula (II-l), (II-m), (II-n) respectively.
Figure imgf000030_0003
Figure imgf000030_0005
(II-m)
Figure imgf000030_0004
Figure imgf000031_0001
In the invention, particular preference is given to compounds of Formula I or any subgroup thereof, that in the inhibition assays described below have an inhibition value of less than 100 μM, preferably less than 50 μM, more preferably less than 10 μM, preferably less than 5 μM, even more preferably less than lμM preferably less than 100 nM, and in particular less than 10 nM, as determined by a suitable assay, such as the assays used in the Examples below.
It is to be understood that the above defined subgroups of compounds of formulae (I-a) to (I-n) as well as any other subgroup defined herein, are meant to also comprise any JV-oxides, salts, quaternary amines, prodrugs, tautomers, hydrates, solvates, metal complexes and stereo chemically isomeric forms of such compounds.
Preparation of the compounds of formula (I)
The compounds of formula (I) and the salts and stereoisomers thereof of the present invention may be prepared according to Schemes 1, 2, 3, and 5 as depicted below.
Figure imgf000031_0002
1-1 I-2 I-3
Figure imgf000031_0003
Figure imgf000032_0001
Scheme 1
Step 1-1 -> 1-2 Intermediate (1-1) may be synthesized following the procedure reported in (i) Lansbury, P.T.; Scharf, D. J. J. Am. Chem. Soc. 1968, 90, 2, 536-53 and (ii) Lansbury, P.T.; Nienhouse, E. J.; Scharf, D. J.; Hilfiker, F. R. J. Am. Chem. Soc. 1970, 92, 19, 5649-5657 or following the procedure described in scheme 4.
Intermediate (1-1) is reacted with a strong oxidizing agent in order to oxidize the cyclic sulfide into the sulfone derivative (1-2). Useful oxidizing agents for carrying out this reaction include, amongst other, m-chloroperbenzoic acid, hydrogen peroxide-ZrCU, or hydrogen peroxide- Acetic acid.
The solvent may be selected from chloroform or dichloromethane.
Step 1-2 + 1-4 -> 1-5 + 1-6
Intermediate (1-2) is then reacted with a o-phenylenediamine derivative bearing substituents Rla and Rlb (1-4). The reaction of (1-2) and (1-4) is usually carried out in a solvent selected from tetrahydrofuran (THF), methyltetrahydrofuran (MeTHF), methyl isobutyl ketone, Ci-4alcohol, dimethylformamide (DMF), methyl t-butylether (MTBE), toluene, or any mixture thereof. The condensation of (1-2) and (1-4) is optionally performed in a Dean-Stark apparatus. Optionally, an acid or Lewis acid is added to the reaction mixture to catalyze the reaction. Isomers (1-5) and (1-6) are obtained.
Step 1-5 + 1-7 -> 1-8
Intermediate (1-5) may then be reacted with an aldehyde of formula R3-CHO (1-7). Such reaction occurs in the presence of an acid, such as acetic acid, and in an appropriate solvent.
Compound of formula (1-8) is obtained, which may be further reacted to introduce other R2 substituents than hydrogen, according to the procedures described below in Scheme 2.
Figure imgf000033_0001
Figure imgf000033_0002
Figure imgf000033_0003
Scheme 2
Step 1-8 -> 1-9: Procedure to introduce substituent -Cf=O)-R5
Compound of formula (1-8), which is itself an intermediate as well, is acylated with an acid or an activated acid such as acyl anhydride or acyl chloride (for instance picolinoylchloride), in the presence of a suitable solvent, in order to acylate the amines thereby forming amides. The acid can be activated in situ with a coupling agent such as
EDC (l-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride) /HOBT
( 1 -hydroxybenzotriazo Ie), HATU (2-( 1 H-7-azabenzotriazo 1- 1 -yl)~ 1 , 1 ,3 ,3 -tetramethyl uranium hexafluorophosphate methanaminium ), and the like optionally in the presence of an appropriate base such as triethylamine or diisopropylethylamine. The acyl chloride can be activated in situ with DMAP (4-dimethylaminopyridine) and the like and the reaction can be carried out in the presence of an appropriate base such as triethylamine or diisopropylethylamine. When the activated acid is an anhydride, an acid catalyst, such as p-TSA (p-toluenesulfonic acid), may be added.
The suitable solvent for the acylation reaction may be selected from pyridine, dichloromethane, chloroform, THF, and DMF.
Compound of formula (1-9) is obtained.
Step 1-8 ^ 1-10: Procedure to introduce substituent -C(=OVNR7aR7b Compound of formula (1-8) may then be reacted with an isocyanate, thereby affording compound of formula (I- 10). When an isocyanate is used, a compound of formula (I- 10) wherein R7b represents a hydrogen is obtained. Alternatively, a compound of formula (I- 10) is obtained by reacting a compound of formula (1-8) with phosgene or an equivalent of phosgene of formula LG-C(=O)-LG, wherein LG represent a leaving group, followed by the treatment with an amine of formula HNR7aR7b, optionally in the presence of a base, in a suitable solvent.
Step 1-8 -> 1-11 : Procedure to introduce substituent -Cf=O)-OR6
Compound of formula (1-8) may then be reacted with a chloroformate to introduce the desired -C(=O)-OR6 substituent. Such reaction is conveniently carried out in the presence of a base such as an alkali or alkaline metal hydride such as LiH or sodium hydride, or alkali metal alkoxide such as sodium or potassium methoxide or ethoxide, potassium tert-butoxidc, in an inert solvent like a dipolar aprotic solvent, e.g. DMA (dimethylacetamide), DMF, THF, and the like. Compound of formula (I- 11) is obtained.
More than one acyl group can be introduced on compound of formula (1-8), when Rla represents a hydroxyl group, or (1-12), as depicted in Scheme 3 below. In this case a compound of structure (I- 13 a), (I- 13b) or (I- 13 c) is obtained. In some cases, a mixture of compounds (I- 13a), (I- 13b) or (I- 13c) can be obtained.
Figure imgf000035_0001
Scheme 3
These additional acyl groups can be cleaved by treating the corresponding compounds of formula (1-9), (1-10), (1-11), (I- 13a), (I-13b) and (I- 13c) with an hydroxide such as sodium hydroxide, potassium hydroxide, or lithium hydroxide in a suitable solvent such as water, C^alcohol, THF, 2-methyltetrahydrofuran (MeTHF), or any mixture thereof.
As such, for intermediates (1-8) or (1-12), when R a is hydroxy, it may be desirable to protect such hydroxy group prior to introducing substituents -C(=O)-R 5 or
-C(=O)-NR7aR7b or -C(=O)-OR6. Protection of the hydroxy group may be performed with benzyl or substituted benzyl ethers, e.g. 4-methoxybenzyl ether, benzoyl or substituted benzoyl esters, e.g. 4-nitrobenzoyl ester, or with trialkylsilyl goups (e.g. trimethylsilyl or te/t-butyldimethylsilyl) or by intramolecular cyclisation with CDI (l,l'-carbonyldiimidazole) to form a cyclic carbamate derivative.
Introduction of the -C(=O)-R5 or -C(=O)-NR7aR7b or -C(=O)-OR6 groups is performed as explained above. Thereafter, the resulting intermediate is further reacted with an alkali metal hydroxide (LiOH, NaOH, KOH), in an aqueous medium comprising water and a water-soluble organic solvent such as an alkanol (methanol, ethanol) and THF. Such reaction allows the removal of the acyl hydroxyl-protecting group (e.g. benzoyl or substituted benzoyl esters or cyclic carbamate), thereby affording compounds of formula (I- 10) or (1-11) wherein Rla represents hydroxy. Intermediate (1-9), (I- 10) and (1-11) bearing a trialkylsilyl protecting group in Rla is further reacted with tetraalkyl- ammonium fluoride to deprotect the silyl group thereby affording a compound of formula (1-14) or (1-9), (1-10) and (I- 11) wherein Rla represents a hydroxyl group. Intermediate (1-9), (I- 10) and (I- 11) bearing a 4-methoxybenzyl ether protecting group in Rla is further reacted with DDQ (2,3-dicyano-5,6-dichloro-parabenzoquinone) to afford a compound of formula (1-14) or (1-9), (1-10) and (I- 11) wherein Rla represents a hydroxyl group.
Scheme 4
Compound of formula (1-1) may be synthesized following the three-step procedure of scheme 4.
Figure imgf000036_0001
Scheme 4.
Step IV-I^ IV-2
2,3-dichloropropene IV-I (commercially available at Aldrich) is monosubstituted by potassium thioacetate in an organic solvent, for example acetone, to give (IV-2).
Step IV-2^ IV-4
A one-pot reaction consisting of 1) thioester hydrolysis to the sulfide in basic conditions, i.e. sodium methanolate in methanol then 2) reaction of the obtained sulfide with a disubstituted epoxide (IV-3) is carried out to afford a compound of formula IV-4. Step IV-4 ^ 1-1
Cyclisation of a compound IV-4 under acidic conditions, for example aqueous sulfuric acid, methane sulfonic acid in an organic solvent like DCM (CH2Cl2), or more preferably formic acid, gives a compound of formula 1-1.
Alternatively, compound of formula IV-4 can be prepared from 2,3-dichloropropene IV-I via intermediates IV-5 and IV-6 as shown in Scheme 4.
Step IV- l-MV-5
2,3-dichloropropene IV-I (commercially available at Aldrich) is reacted with thiourea in a suitable solvent such as ethanol at a temperature between 00C and 1200C, preferably around 800C, to provide the intermediate IV-5.
Step IV-5-»IV-6
The hydrolysis of intermediate IV-5 to the thiol derivative IV-6 is performed in presence of an hydroxide, for instance sodium hydroxide, in an appropriate solvent such as water, at a temperature between 20 and 1200C, preferably around 1000C.
Step IV-6-»IV-4
Treatment of intermediate IV-6 with a disubstituted epoxide of formula IV-3 in presence of a suitable base such as sodium methanolate in methanol at a temperature between 00C and 500C, preferably around 200C, provides the intermediate IV-4.
Scheme 5
Figure imgf000037_0001
Figure imgf000038_0001
Scheme 5
A substituent R9 may be introduced as described in scheme 5, from a precursor V-3 whose hydroxyl group Rla is protected with an acyl protecting group, for example a cyclic carbamate protecting group like in the structure below where X is for example halogen.
Figure imgf000038_0002
Step V-I-^ V-2: protection of the hydroxyl group with PGi
Introduction of PGi from a compound (V-I) or (1-14), where PG2 is another hydroxyl protecting group like benzylether, to form a compound (V-2) is achieved using for example CDI in an organic solvent.
Step V-2 -> V-3: removal of the PG2 group
Removal of PG2, for example by catalytic hydrogenation gives a phenol V-3.
Step V-3 -> V-4 : introduction of a R9 substituent
A R9 substituent may be introduced via for example a SN2 reaction, or Mitsunobu reaction from intermediate V-3. Step V-4-> V-5: removal of the PGi group
The resulting intermediate V-3 is further reacted with an alkali metal hydroxide (LiOH, NaOH, KOH), in an aqueous medium comprising water and a water-soluble organic solvent such as an alkanol (methanol, ethanol) and THF to afford a compound of formula V-5.
Compounds of formula (I) may be converted into each other following art-known functional group transformation reactions. For example, amino groups may be jV-alkylated, nitro groups reduced to amino groups, a halo atom may be exchanged for another halo. The procedures described in the example section further provide with methods to introduce the substituents constituting the scope of the present invention.
The compounds of formula (I) may be converted to the corresponding JV-oxide forms following art-known procedures for converting a trivalent nitrogen into its iV-oxide form. Said JV-oxidation reaction may generally be carried out by reacting the starting material of formula (I) with an appropriate organic or inorganic peroxide. Appropriate inorganic peroxides comprise, for example, hydrogen peroxide, alkali metal or earth alkaline metal peroxides, e.g. sodium peroxide, potassium peroxide; appropriate organic peroxides may comprise peroxy acids such as, for example, benzenecarbo- peroxoic acid or halo substituted benzenecarboperoxoic acid, e.g. 3-chlorobenzene- carboperoxoic acid, peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides, e.g. tert-butyi hydro-peroxide. Suitable solvents are, for example, water, lower alcohols, e.g. ethanol and the like, hydrocarbons, e.g. toluene, ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g. dichloromethane, and mixtures of such solvents.
Pure stereochemically isomeric forms of the compounds of formula (I) may be obtained by the application of art-known procedures. Diastereomers may be separated by physical methods such as selective crystallization and chromatographic techniques, e.g., counter-current distribution, liquid chromatography and the like.
The compounds of formula (I) may be obtained as racemic mixtures of enantiomers, which can be separated from one another following art-known resolution procedures. The racemic compounds of formula (I), which are sufficiently basic or acidic may be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid, respectively chiral base. Said diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated therefrom by alkali or acid. An alternative manner of separating the enantiomeric forms of the compounds of formula (I) involves liquid chromatography, in particular liquid chromatography using a chiral stationary phase. Said pure stereochemical^ isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifϊcally. Preferably if a specific stereoisomer is desired, said compound may be synthesized by stereospecifϊc methods of preparation. These methods may advantageously employ enantiomerically pure starting materials.
In a further aspect, the present invention concerns a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) as specified herein, or a compound of any of the subgroups of compounds of formula (I) as specified herein, and a pharmaceutically acceptable carrier. A therapeutically effective amount in this context is an amount sufficient to prophylactically act against, to stabilize or to reduce viral infection, and in particular HCV viral infection, in infected subjects or subjects being at risk of being infected. In still a further aspect, this invention relates to a process of preparing a pharmaceutical composition as specified herein, which comprises intimately mixing a pharmaceutically acceptable carrier with a therapeutically effective amount of a compound of formula (I), as specified herein, or of a compound of any of the subgroups of compounds of formula (I) as specified herein.
Therefore, the compounds of the present invention or any subgroup thereof may be formulated into various pharmaceutical forms for administration purposes. As appropriate compositions there may be cited all compositions usually employed for systemically administering drugs. To prepare the pharmaceutical compositions of this invention, an effective amount of the particular compound, optionally in salt form or metal complex, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirable in unitary dosage form suitable, particularly, for administration orally, rectally, percutaneously, or by parenteral injection. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs, emulsions and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules, and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. Also included are solid form preparations that are intended to be converted, shortly before use, to liquid form preparations. In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not introduce a significant deleterious effect on the skin.
The compounds of the present invention may also be administered via oral inhalation or insufflation by means of methods and formulations employed in the art for administration via this way. Thus, in general the compounds of the present invention may be administered to the lungs in the form of a solution, a suspension or a dry powder, a solution being preferred. Any system developed for the delivery of solutions, suspensions or dry powders via oral inhalation or insufflation are suitable for the administration of the present compounds.
Thus, the present invention also provides a pharmaceutical composition adapted for administration by inhalation or insufflation through the mouth comprising a compound of formula (I) and a pharmaceutically acceptable carrier. Preferably, the compounds of the present invention are administered via inhalation of a solution in nebulized or aerosolized doses.
It is especially advantageous to formulate the aforementioned pharmaceutical compositions in unit dosage form for ease of administration and uniformity of dosage. Unit dosage form as used herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such unit dosage forms are tablets (including scored or coated tablets), capsules, pills, suppositories, powder packets, wafers, injectable solutions or suspensions and the like, and segregated multiples thereof.
The compounds of formula (I) and any subgroup thereof show antiviral properties. Viral infections and their associated diseases treatable using the compounds and methods of the present invention include those infections brought on by HCV and other pathogenic flaviviruses such as Yellow fever, Dengue fever (types 1-4), St. Louis encephalitis, Japanese encephalitis, Murray valley encephalitis, West Nile virus and Kunjin virus. The diseases associated with HCV include progressive liver fibrosis, inflammation and necrosis leading to cirrhosis, end-stage liver disease, and HCC; and for the other pathogenic flaviviruses the diseases include yellow fever, dengue fever, hemorrhagic fever and encephalitis.
Due to their antiviral properties, particularly their anti-HCV properties, the compounds of formula (I) or any subgroup thereof, their prodrugs, //-oxides, salts, quaternary amines, metal complexes and stereochemically isomeric forms, are useful in the treatment of individuals experiencing a viral infection, particularly a HCV infection, and for the prophylaxis of these infections. In general, the compounds of the present invention may be useful in the treatment of warm-blooded animals infected with viruses, in particular flaviviruses such as HCV.
The compounds of the present invention or any subgroup thereof may therefore be used as medicines. Said use as a medicine or method of treatment comprises the systemic administration to virally infected subjects or to subjects susceptible to viral infections of an amount effective to combat the conditions associated with the viral infection, in particular the HCV infection.
The present invention also relates to the use of the present compounds or any subgroup thereof in the manufacture of a medicament for the treatment or the prevention of viral infections, particularly HCV infection.
The present invention furthermore relates to a method of treating a warm-blooded animal infected by a virus, or being at risk of infection by a virus, in particular by HCV, said method comprising the administration of an anti- virally effective amount of a compound of formula (I), as specified herein, or of a compound of any of the subgroups of compounds of formula (I), as specified herein.
The present invention also concerns combinations of a compound of formula (I) or any subgroup thereof, as specified herein with other anti-HCV agents. In an embodiment, the invention concerns combination of a compound of Formula (I) or any subgroup thereof with at least one anti-HCV agent. In a particular embodiment, the invention concerns combination of a compound of Formula (I) or any subgroup thereof with at least two anti-HCV agents. In a particular embodiment, the invention concerns combination of a compound of Formula (I) or any subgroup thereof with at least three anti-HCV agents. In a particular embodiment, the invention concerns combination of a compound of Formula (I) or any subgroup thereof with at least four anti-HCV agents.
The combination of previously known anti-HCV compound, such as, for instance, interferon-α (IFN-α), pegylated interferon-α, ribavirin or a combination thereof, and a compound of formula (I) can be used as a medicine in a combination therapy. In an embodiment the term "combination therapy" relates to a product containing mandatory (a) a compound of formula (I), and (b) at least one other anti-HCV compound, as a combined preparation for simultaneous, separate or sequential use in treatment of HCV infections, in particular, in the treatment of infections with HCV.
Anti-HCV compounds encompass agents selected from HCV polymerase inhibitors, R-7128, MK-0608, VCH759, PF-868554, GS9190, NM283, R803, R-1626, BILB- 1941, HCV-796, JTK- 109 and JTK-003; HCV proteases (NS2-NS3 and NS3-NS4A) inhibitors, the compounds of WO02/18369 (see, e.g., page 273, lines 9-22 and page 274, line 4 to page 276, line 11), BI-1335, TMC435350, MK70009, ITMN-191, BILN-2061, VX-950, VX-500, SCH 503034; inhibitors of other targets in the HCV life cycle, including helicase, and metalloprotease inhibitors, ISIS- 14803; immunomodulatory agents such as, α-, β-, and γ- interferons, pegylated derivatized interferon-α compounds, compounds that stimulate the synthesis of interferon in cells, interleukins, Toll like receptor (TLR) agonists, compounds that enhance the development of type 1 helper T cell response, and thymosin; other antiviral agents such as ribavirin, amantadine, and telbivudine, inhibitors of internal ribosome entry, broad- spectrum viral inhibitors, such as IMPDH inhibitors (e.g., compounds of US5, 807,876, US6,498,178, US6,344,465, US6,054,472, WO97/40028, WO98/40381, WO00/56331, and mycophenolic acid and derivatives thereof, and including, but not limited to VX-497, VX-148, and/or VX-944); or combinations of any of the above.
Thus, to combat or treat HCV infections, the compounds of formula (I) may be co-administered in combination with for instance, interferon-α (IFN-α), pegylated interferon-α , ribavirin or a combination thereof, as well as therapeutics based on antibodies targeted against HCV epitopes, small interfering RNA (si RNA), ribozymes, DNAzymes, antisense RNA, small molecule antagonists of for instance NS3 protease,
NS3 helicase and NS5B polymerase.
The combinations of the present invention may be used as medicaments. Accordingly, the present invention relates to the use of a compound of formula (I) or any subgroup thereof as defined above for the manufacture of a medicament useful for inhibiting HCV activity in a mammal infected with HCV viruses, wherein said medicament is used in a combination therapy, said combination therapy preferably comprising a compound of formula (I) and at least one other HCV inhibitory compound, e.g. IFN-α, pegylated IFN-α , ribavirin or a combination thereof.
Furthermore, it is known that a large percentage of patients infected with human immunodeficiency virus 1 (HIV) are also infected with HCV, i.e. they are HCV/HIV co-infected. HIV infection appears to adversely affect all stages of HCV infection, leading to increased viral persistence and accelerated progression of HCV-related liver disease. In turn, HCV infection may affect the management of HIV infection, increasing the incidence of liver toxicity caused by antiviral medications.
The present invention therefore also concerns combinations of a compound of Formula (I) or any subgroup thereof with anti-HIV agents. Also, the combination of one or more additional anti-HIV compounds and a compound of Formula (I) can be used as a medicine.
The term "combination therapy" also encompasses a product comprising (a) a compound of Formula (I) or any subgroup thereof, and (b) at least one anti-HIV compound, and (c) optionally at least one other anti-HCV compound, as a combined preparation for simultaneous, separate or sequential use in treatment of HCV and HIV infections, in particular, in the treatment of infections with HCV and HIV.
Thus, the present invention also relates to a product containing (a) at least one compound of Formula (I) or any subgroup thereof, and (b) one or more additional anti- HIV compounds, as a combined preparation for simultaneous, separate or sequential use in anti-HCV and anti-HIV treatment. The different drugs may be combined in a single preparation together with pharmaceutically acceptable carriers. Said other anti- HIV compounds may be any known antiretroviral compounds such as suramine, pentamidine, thymopentin, castanospermine, dextran (dextran sulfate), foscarnet- sodium (trisodium phosphono formate); nucleoside reverse transcriptase inhibitors (NRTIs), e.g. zidovudine (AZT), didanosine (ddl), zalcitabine (ddC), lamivudine (3TC), stavudine (d4T), emtricitabine (FTC), abacavir (ABC), amdoxovir (DAPD), elvucitabine (ACH- 126,443), AVX 754 ((-)-dOTC), fozivudine tidoxil (FZT), phosphazide, HDP-990003, KP-1461, MIV-210, racivir (PSI-5004), UC-781 and the like; non-nucleoside reverse transcriptase inhibitors (NNRTIs) such as delavirdine (DLV), efavirenz (EFV), nevirapine (NVP), dapivirine (TMC 120), etravirine (TMC125), rilpivirine (TMC278), DPC-082, (+)-Calanolide A, BILR-355, and the like; nucleotide reverse transcriptase inhibitors (NtRTIs), e.g. tenofovir ((R)-PMPA) and tenofovir disoproxil fumarate (TDF), and the like; nucleotide-competing reverse transcriptase inhibitors (NcRTIs), e.g. NcRTI-I and the like; inhibitors of trans- activating proteins, such as TAT-inhibitors, e.g. RO-5-3335, BI-201, and the like; REV inhibitors; protease inhibitors e.g. saquinavir (SQV), lopinavir (ABT-378 or LPV), indinavir (IDV), amprenavir (VX-478), TMC 126, nelfϊnavir (AG- 1343), atazanavir (BMS 232,632), darunavir (TMCl 14), fosamprenavir (GW433908 or VX- 175), brecanavir (GW-640385, VX-385), P-1946, PL-337, PL-100, tipranavir (PNU-140690), AG- 1859, AG- 1776, Ro-0334649 and the like; entry inhibitors, which comprise fusion inhibitors (e.g. enfuvirtide (T-20)), attachment inhibitors and co-receptor inhibitors, the latter comprise the CCR5 antagonists (e.g. ancriviroc, CCR5mAb004, maraviroc
(UK-427,857), PRO-140, TAK-220, TAK-652, vicriviroc (SCH-D, SCH-417,690)) and CXR4 antagonists (e.g. AMD-070, KRH-27315), examples of entry inhibitors are PRO-542, TNX-355, BMS-488,043, BlockAide/CR™, FP 21399, hNMOl, nonakine, VGV-I; a maturation inhibitor for example is PA-457; inhibitors of the viral integrase e.g. raltegravir (MK-0518), elvitegravir (JTK-303, GS-9137), BMS-538,158; ribozymes; immunomodulators; monoclonal antibodies; gene therapy; vaccines; siRNAs; antisense RNAs; microbicides; Zinc-finger inhibitors. Therefore, HCV infected patients also suffering from conditions associated with HIV or even other pathogenic retroviruses, such as AIDS, AIDS-related complex (ARC), progressive generalized lymphadenopathy (PGL), as well as chronic CNS diseases caused by retroviruses, such as, for example HIV mediated dementia and multiple sclerosis, can conveniently be treated with the present composition.
The compositions may be formulated into suitable pharmaceutical dosage forms such as the dosage forms described above. Each of the active ingredients may be formulated separately and the formulations may be co-administered or one formulation containing both and if desired further active ingredients may be provided.
As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients, as well as any product that results, directly or indirectly, from the combination of the specified ingredients.
The term "therapeutically effective amount" as used herein means that amount of active compound or component or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought, in the light of the present invention, by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease being treated. Since the instant invention refers as well to combinations comprising two or more agents, the "therapeutically effective amount" in the context of combinations is also that amount of the agents taken together so that the combined effect elicits the desired biological or medicinal response. For example, the therapeutically effective amount of a composition comprising (a) the compound of formula (I) and (b) another anti-HCV agent, would be the amount of the compound of formula (I) and the amount of the other anti-HCV agent that when taken together have a combined effect that is therapeutically effective.
In general it is contemplated that an antiviral effective daily amount would be from 0.01 mg/kg to 500 mg/kg body weight, more preferably from 0.1 mg/kg to 50 mg/kg body weight. It may be appropriate to administer the required dose as two, three, four or more sub-doses at appropriate intervals throughout the day. Said sub-doses may be formulated as unit dosage forms, for example, containing 1 to 1000 mg, and in particular 5 to 200 mg of active ingredient per unit dosage form.
The exact dosage and frequency of administration depends on the particular compound of formula (I) used, the particular condition being treated, the severity of the condition being treated, the age, weight, sex, extent of disorder and general physical condition of the particular patient as well as other medication the individual may be taking, as is well known to those skilled in the art. Furthermore, it is evident that said effective daily amount may be lowered or increased depending on the response of the treated subject and/or depending on the evaluation of the physician prescribing the compounds of the instant invention. The effective daily amount ranges mentioned hereinabove are therefore only guidelines.
In one embodiment of the present invention there is provided an article of manufacture comprising a composition effective to treat an HCV infection or to inhibit the NS5B polymerase of HCV; and packaging material comprising a label which indicates that the composition can be used to treat infection by the hepatitis C virus; wherein the composition comprises a compound of the formula (I) or any subgroup thereof, or the combination as described herein.
Another embodiment of the present invention concerns a kit or container comprising a compound of the formula (I) or any subgroup thereof, in an amount effective for use as a standard or reagent in a test or assay for determining the ability of potential pharmaceuticals to inhibit HCV NS5B polymerase, HCV growth, or both. This aspect of the invention may find its use in pharmaceutical research programs. The compounds and combinations of the present invention can be used in high- throughput target-analyte assays such as those for measuring the efficacy of said combination in HCV treatment.
Examples
The following examples are intended to illustrate the present invention and not to limit it thereto.
Example 1 : 10-acetyl-l l-(2,4-dichlorophenyl)-3,3-dimethyl-l,l-dioxo- 1,2,3,4,5,1 l-hexahvdro-lλ6-thia-5J0-diazadibenzorα,άπcvcloheptene (10).
Figure imgf000047_0001
(1)
To a mixture of potassium thioacetate (1.23 g, 10.8 mmol) in acetone (10 mL) was added 2,3-dichloropropene (1 g, 9.01 mmol). The reaction mixture was refluxed for 3h, then cooled down to room temperature, diluted with water and extracted with CH2Cl2. The organic layer was then dried over MgSO4, filtered and concentrated. The slightly yellow liquid was filtrated on a plug of silica with CH2Cl2/pentane 50:50. After evaporation (250 mbar, 45°C), 1.29 g (95% yield) of the target product thioacetic acid S-^-chloroallyl) ester (1) was obtained as a colorless liquid.
Step 2 o NaOMe
Λ, ,cι
OH ^y
O (1) (2) (3) To a solution of thioacetic acid S-^-chloroallyl) ester (1) (1.29 g, 8.56 mmol) in dry methanol was added sodium methanolate (463 mg, 1 eq). The reaction mixture was stirred for 40 minutes, then 2,2-dimethyl-oxirane (2) (618 mg, 1 eq) was added and the reaction mixture was stirred at room temperature during 16h. After addition OfH2O, the pH was adjusted to 7 with IN HCl and the mixture was extracted with ethyl acetate (χ3). The combined organic layers were dried with MgSO4, filtered and concentrated in vacuo to afford 1.22 g (79% yield) of the target product l-(2-chloroallylsulfanyl)- 2-methylpropan-2-ol (3) as a colorless oil.
Figure imgf000048_0001
l-(2-Chloroallylsulfanyl)-2-methylpropan-2-ol (3) (5 g, 27.7 mmol) was refluxed in formic acid for 4h. After cooling, the mixture was poured in H2O and then extracted with CH2Cl2. The organic layer was then washed with H2O, dried on MgSO4, filtered and concentrated. Purification of the obtained oil by flash chromatography (eluent CH2Cl2) afforded 2.4 g (60% yield) of the target product 5,5-dimethyl-dihydro- thiopyran-3-one (4).
Figure imgf000048_0002
(4) (5) (6)
m-CPBA (m-chloroperbenzoic acid; 1.5 g, 70-75 w/w %, 6.52 mmol) was added to the cyclic sulfide (4) (800 mg, 5.55 mmol) in CHCl3 (50 mL). After 3 hours, additional m-CPBA (750 mg, 70-75 w/w %, 3.26 mmol) was added. After Ih, the reaction mixture was diluted with CH2Cl2 then washed with IM NaHCO3 (2 x 125 mL). The water layer was extracted with CH2Cl2 (2 x 150 mL) and the combined organic layers were successively dried (MgSO4) and evaporated. The residue was purified by column chromatography (gradient CH2Cl2/ethyl acetate 1 :0 to 1 : 1) to give 652 mg (67%) of the cyclic sulfone (5) as a white solid: Rf (CH2Cl2) = 0.19, Rf (ethyl acetate) = 0.48; 1U NMR (400 MHz, CDCl3) δ ppm 1.24 (s, 6 H), 2.52 (s, 2 H), 3.23 (s, 2 H), 3.99 (s, 2 H), followed by sulfoxide (6): Rf (ethyl acetate) = 0.12; 1H NMR (400 MHz, CDCl3) δ ppm 1.04 (s, 3 H), 1.25 (s, 3 H), 2.34 (d, J= 13.1 Hz, 1 H), 2.50 (d, J= 13.1 Hz, 1 H), 2.95 (d, J= 13.1 Hz, 1 H), 3.22 (d, J= 13.1 Hz, 1 H), 3.61 (d, J= 11.9 Hz, 1 H), 3.98 (d, J= 11.9 Hz, 1 H).
Figure imgf000049_0001
(5) (7)
A mixture of (5) (51.3 mg, 0.291 mmol), o-phenylenediamine (31.5 mg, 0.291 mmol), 4 A molecular sieves and acetic acid (17 μL, 0.291 mmol) in toluene was stirred at room temperature for 3 h, then heated at reflux. After 12h, the reaction mixture was successively cooled down to room temperature, filtered on decalite, and evaporated to give the target product (7), which was used as such in the next reaction: m/z = 267 (M+H)+.
Step 6
Figure imgf000049_0002
A solution of the enamine (7) (77.5 mg, 0.291 mmol),/?-TSA (2.5 mg, 0.015 mmol) and 2,4-dichlorobenzaldehyde (8) (51 mg, 0.291 mmol) in DMSO (dimethyl sulfoxide; 2 mL) was heated at 75 0C under nitrogen. After 12h, the reaction mixture was successively cooled down to room temperature, then diluted with water. The precipitate was collected by filtration and washed with H2O and diethylether to give 75 mg of (9) as a brown solid: RT = 2.33, m/z = 423 (M+H)+. 1U NMR (400 MHz, DMSO-J6) δ ppm 1.19 (s, 3 H), 1.20 (s, 3 H), 2.57 (d, J= 16.7 Hz, 1 H), 2.68 (d, J= 16.7 Hz, 1 H), 3.11 (d, J= 13.5 Hz, 1 H), 3.18 (d, J= 13.5 Hz, 1 H), 5.71 (d, J= 6.2 Hz, 1 H), 5.92 (d, J = 6.2 Hz, 1 H), 6.46 (d, J= 7.6 Hz, 1 H), 6.58 (t, J= 7.6 Hz, 1 H), 6.66 (t, J= 7.6 Hz, 1 H), 6.89 (d, J= 8.3 Hz, 1 H), 6.93 (d, J= 7.6 Hz, 1 H), 7.13 (d, J= 8.3 Hz, 1 H), 7.52 (s, 1 H), 8.55 (s, 1 H). 13C NMR (101 MHz, DMSO-J6) δ ppm 27.9 (CH3), 28.2 (CH3), 31.4 (C), 42.8 (CH2), 52.9 (CH), 60.4 (CH2), 105.6 (C), 119.6 (CH), 121.2 (CH), 121.3 (CH), 122.4 (CH), 126.5 (CH), 128.6 (CH), 129.3 (CH), 132.0 (C), 132.5 (C), 133.4 (C), 136.2 (C), 139.4 (C), 144.9 (C)
Step 7
Figure imgf000050_0001
(9) (10)
A solution of (9) (15 mg, 0.035 mmol) and/?-TSA (10 mg, 0.058 mmol) in acetic anhydride (1.5 rnL) was stirred at 700C under nitrogen. After 6 hours, the reaction mixture was cooled down to room temperature and evaporated. The residue was purified by column chromatography (C^Cyethyl acetate, 70:30) to give 4.3 mg
(26 %) of the title product 10-acetyl-l l-(2,4-dichlorophenyl)-3,3-dimethyl-l,l-dioxo- 1,2,3,4,5,1 l-hexahydro-lλ6-thia-5,10-diazadibenzo[α,<i]cycloheptene (10): Rf (CH2Cl2/ethyl acetate, 70:30) = 0.1; RT = 2.21, m/z = 465 (M+H)+.
Example 2: 10-acetyl-l l-(4-benzyloxy-2-fluorophenyl)-3,3-dimethyl-l,l-dioxo- 1,2,3,4,5,1 l-hexahvdro-lλ6-thia-5J0-diazadibenzorα,άπcvcloheptene (13).
Figure imgf000050_0002
Step l
Figure imgf000050_0003
A mixture of 2-fluoro-4-hydroxybenzaldehyde (2.92 mmol), benzylbromide (534 μL, 4.38 mmol) and Cs2CO3 (1.14 g, 3.50 mmol) in dry DMF (N,N-dimethylformamide; 10 niL) was stirred at room temperature for 3 days. Then, the reaction mixture was diluted with water (200 mL). The resulting precipitate was filtered off, then dried under vacuum to give the desired product 4-benzyloxy-2-fluorobenzaldehyde (11) (94.4 %) as a white solid: m/z = 231 (M+H)+.
Step 2
Figure imgf000051_0001
A solution of the enamine (7) (159 mg, 0.597 mmol),/?-TSA (5 mg, 0.030 mmol) and the aldehyde (11) (137 mg, 0.597 mmol) in DMSO (5 mL) was heated at 75°C under nitrogen. After 4h, the reaction mixture was allowed to cool down to room temperature, then diluted with water. The resulting mixture was successively extracted with CH2Cl2 and AcOEt. The resulting organic layer was successively washed with brine, dried (Na2SO4) and evaporated. The residue was triturated in water. The precipitate was collected by filtration, washed with water and dried under vacuum to give 243 mg of the target product (12): Rt = 2.48 min, m/z = 479 (M+H)+.
Step 3
Figure imgf000051_0002
A solution of (12) (54 mg, 0.113 mmol) and/?-TSA (21 mg, 0.124 mmol) in acetic anhydride (5 mL) was stirred at 75°C under nitrogen. After 2.5 h, the reaction mixture was allowed to cool down to room temperature and was then concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate/ CH2Cl2, 30:70) to give 19 mg (32%) of the title product 10-acetyl-l l-(4-benzyloxy-2- fluorophenyl)-3 ,3-dimethyl- 1 , 1 -dioxo- 1,2,3,4,5,11 -hexahydro- 1 λ -thia-5 , 10- diazadibenzo[α,<i]cycloheptene (13) as a white solid: Rt = 2.42 min, m/z = 521 (M+H)4
Example 3: [1 l-(4-Benzyloxy-2-fluoro-phenyl)-3,3-dimethyl-l,l-dioxo- 1,2,3,4,5,11 -hexahydro- 1 λ6-thia-5 , 1 Q-diaza-dibenzo|"a,dlcyclohepten- 10-yl]-pyridin- 2-yl-methanone (14)
Figure imgf000052_0001
To a solution of 1 l-(4-benzyloxy-2-fluoro-phenyl)-3,3-dimethyl-2,3,4,5,10,l 1-hexa- hydro-l-thia-5,10-diaza-dibenzo[a,d]cycloheptene 1,1-dioxide (12) (36 mg, 0.075 mmol) and Hunig's base (Λ/,jV-diisopropylethylamine, DIPEA; 68 mg, 7 eq) in CH2Cl2 was added picolinoyl chloride (40 mg, 3 eq) at room temperature. After 4h, the reaction mixture was diluted with CH2Cl2 and extracted with brine. The organic layer was separated, dried over MgSO4, filtered and concentrated in vacuo. Purification by flash chromatography (eluent CH2Cl2/ethyl acetate 50:50 to 30:70) afforded 16 mg (36% yield) of the desired product (14) as a yellow solid; m/z = 584 (M+H)+.
Example 4: [1 l-(4-Benzyloxy-2-fluoro-phenyl)-3,3-dimethyl-l,l-dioxo- 1,2,3,4,5,11 -hexahydro- 1 λ6-thia-5 , 10-diaza-dibenzo[a,d]cyclohepten- 10-yl]-pyrazin- 2-yl-methanone (15)
Figure imgf000052_0002
The title compound (15) was prepared in 71% yield following the procedure reported for the preparation of [1 l-(4-benzyloxy-2-fluoro-phenyl)-3,3-dimethyl-l,l-dioxo- 1,2,3,4,5,11 -hexahydro- 1 λ6-thia-5 , 10-diaza-dibenzo[a,d]cyclohepten- 10-yl]-pyridin- 2-yl-methanone (14), using pyrazine carbonyl chloride instead of picolinoyl chloride; m/z = 585 (M+H)+. Example 5: 1 l-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl-l,l-dioxo- 1,2,3,4,5,1 l-hexahydro-lλ6-thia-5,10-diazadibenzo|"α,άπcycloheptene (18) and 11 -(4-benzyloxy-2-fluorophenyl)-9-hydroxy-3 ,3-dimethyl- 1 , 1 -dioxo- 1,2,3,4,5,1 l-hexahvdro-lλ6-thia-5,10-diazadibenzorα,άπcycloheptene (19).
Figure imgf000053_0001
(5) (16) (17)
TFA (trifluoroacetic acid; 230 μL, 3.07 mmol) was added to a solution of the sulfone (5) (541.3 mg, 3.07 mmol), 2,3-diaminophenol (381.3 mg, 3.07 mmol) and 4 A powder sieves in DMF (30 mL). The resulting mixture was stirred at 500C for 6 h to give the desired product (16): Rt = 1.00 min, m/z = 283 (M+H)+, contaminated with the regioisomer (17). The mixture was used without further purification in the next step.
Step 2
Figure imgf000053_0002
(16) (17) (18) (19)
NaHCθ3 (232 mg, 2.76 mmol) was added to the above reaction mixture of (16) and (17) obtained via step 1. Then, the aldehyde (11) (707 mg, 3.07 mmol) was added and the resulting mixture was stirred at 500C. After 12h, the reaction mixture was successively cooled down to room temperature, filtered and washed with CH2Cl2 and saturated NaHCO3. The water layer was extracted with CH2Cl2. Combined organic layers were dried over MgSO4, filtered, and evaporated. The residue was purified by column chromatography (gradient: ethyl acetate/CH2Cl2, 20:80 to 30:70) to give 292 mg of the target product 1 l-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl- 1 , 1 -dioxo- 1,2,3,4,5,11 -hexahydro- 1 λ6-thia-5 , 10-diazadibenzo[α, J]cycloheptene (18) : Rt = 2.26 min, m/z = 495 (M+H)+. 1H NMR (400 MHz, DMSO-J6) δ ppm 1.18 (s, 3H), 1.19 (s, 3 H), 2.64 (d, J= 16.2 Hz, 1 H), 2.70 (d, J= 16.2 Hz, 1 H), 3.09 (d, J= 13.4 Hz, 1 H), 3.15 (d, J= 13.4 Hz, 1 H), 4.98 (s, 2 H), 5.58 (d, J= 6.0 Hz, 1 H), 5.86 (d, J = 6.0 Hz, 1 H), 6.02 (dd, J= 7.8; 1.1 Hz, 1 H), 6.26 (dd, J= 7.8, 1.1 Hz, 1 H), 6.40 (t, J = 7.8 Hz, 1 H), 6.55 (dd, J= 8.6, 2.5 Hz, 1 H), 6.74-6.83 (2 H), 7.00 (s, 1 H), 7.27-7.44 (m, 5 H), 9.22 (s, 1 H); 13C NMR (101 MHz, DMSO-J6) ppm 27.6 (CH3), 28.3 (CH3), 31.5 (C), 43.1 (CH2), 49.3 (CH), 60.5 (CH2), 69.5 (CH2), 101.8 (CH, d, J= 25.6 Hz), 106.2 (C), 106.8 (CH), 109.6 (CH, d, J= 1.5 Hz), 111.9 (CH), 119.7 (C), 121.8 (CH), 122.7 (C, d, J= 14.6 Hz), 127.9 (CH), 128.0 (CH), 128.4 (CH), 128.8 (CH, d, J= 5.9 Hz), 136.6 (C), 137.8 (C), 143.9 (C), 146.1 (C), 158.3 (C, d, J= 11.0 Hz), 160.3 (C, d, J= 245.2 Hz); and 210 mg of 1 l-(4-benzyloxy-2-fluorophenyl)-9-hydroxy-3,3- dimethyl- 1 , 1 -dioxo- 1 ,2,3 ,4,5 , 11 -hexahydro- 1 λ6-thia-5 , 10- diazadibenzo[α,<i]cycloheptene (19): Rt = 2.26 min, m/z = 495 (M+H)+.
Example 6: 10-acetyl-l l-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl- 1 , 1 -dioxo- 1,2,3,4,5,11 -hexahydro- 1 λ6-thia-5 , 10-diazadibenzorα, άHcycloheptene (20).
Figure imgf000054_0001
(18) (20)
A solution of 1 l-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl-l,l-dioxo- 1,2,3,4,5,1 l-hexahydro-lλ6-thia-5,10-diazadibenzo[α,d]cycloheptene (18) (40.8 mg, 0.082 mmol) and/?-TSA (16 mg, 0.091 mmol) in acetic anhydride (1.5 mL) was stirred at 75°C under argon. After 3 hours, the mixture was cooled to room temperature and the solvent was evaporated. The mixture was dissolved in THF (tetrahydrofuran) /H2O and 15 mg LiOH.H2O was added. After 20 min, the pH of the resulting mixture was adjusted to ~3 (with 1 N HCl) and the resulting mixture was extracted with CH2Cl2. The organic layer was washed with brine, dried on MgSO4, filtered and evaporated. The residue was purified by chromatography (gradient: CH2Cl2/ethyl acetate, 50:50 to 25/75) to give 7.3 mg of the title product (20): Rt = 2.21 min, m/z = 537 (M+H)+.
Example 7: 10-isobutyryl-l l-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl- 1, 1-dioxo-l, 2,3,4,5, I l-hexahvdro-lλ6-thia-5,10-diazadibenzorα,άπcvcloheptene (21).
Figure imgf000055_0001
(18) (21)
Isobutyrylchloride (33.8 μL, 0.323 mmol) was added to a solution of 1 l-(4-benzyloxy- 2-fluorophenyl)-6-hydroxy-3 ,3-dimethyl- 1 , 1 -dioxo- 1 ,2,3 ,4,5 , 11 -hexahydro- 1 λ6-thia- 5,10-diazadibenzo[α, JJcycloheptene (18) (39.9 mg, 0.081 mmol) and DIPEA (70.3 μL, 0.403 mmol) in CH2Cl2 (5 mL). After 3h, the solvent was evaporated and the residue was reconstituted in THF/H2O. Then, 50 mg LiOH was added. After stirring for 3 h, H2O was added and the pH was adjusted to ~5 with diluted HCl. Then, the reaction mixture was successively concentrated under reduced pressure, extracted with CH2Cl2, dried (Na2SO4) and evaporated. The residue was purified by silicagel chromatography with (CH2Cl2/ethyl acetate, 70:30) to give 35.3 mg of the target product (21) as a white solid: Rt = 2.40 min, m/z = 565 (M+H)+.
Example 8: 1 l-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl-l,l-dioxo- 10-(2-pyridylcarbonvO- 1.2.3.4.5.11 -hexahydro- 1 λ6-thia- 5,10-diazadibenzo|"α,<i]cycloheptene (22).
(22)
Figure imgf000055_0002
The title compound (22) was prepared from l l-(4-benzyloxy-2-fluorophenyl)- 6-hydroxy-3 ,3-dimethyl- 1 , 1 -dioxo- 1 ,2,3 ,4,5 , 11 -hexahydro- 1 λ6-thia-5 , 10-diazadibenzo- [a, d]cycloheptene (18) and picolinoylchloride following the procedure reported for the preparation of 10-isobutyryl-l l-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3- dimethyl- 1 , 1 -dioxo- 1 ,2,3 ,4,5 , 11 -hexahydro- 1 λ6-thia-5 , 10-diazadibenzo[α, d\- cycloheptene (21): Rt = 2.21 min, m/z = 600 (M+H)+.
Example 9: 1 l-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl-l,l-dioxo- 10-r(2.5-dimethyloxazol-4-yl)carbonyl1-1.2.3.4.5.11-hexahvdro-lλ6-thia- 5,10-diazadibenzorα,άπcycloheptene (23).
Figure imgf000056_0001
The title compound (23) was prepared from l l-(4-benzyloxy-2-fluorophenyl)- 6-hydroxy-3 ,3-dimethyl- 1 , 1 -dioxo- 1 ,2,3 ,4,5 , 11 -hexahydro- 1 λ6-thia-5 , 10-diazadibenzo- [α,J]cycloheptene (18) and 2,5-dimethyloxazol-4-carbonyl chloride following the procedure reported for the preparation of 10-isobutyryl- 11 -(4-benzyloxy-2-fluoro- phenyl)6-hydroxy-3 ,3-dimethyl- 1 , 1 -dioxo- 1,2,3,4,5,11 -hexahydro- 1 λ6-thia-5 , 10- diazadibenzo[α,φycloheptene (21): Rt = 2.28 min, m/z = 618 (M+H)+; 1H NMR (400 MHz, DMSO-J6) δ ppm 1.15 (s, 3H), 1.22 (s, 3 H), 2.13 (s, 3H), 2.18 (s, 3H), 2.76 (d, J = 16.0 Hz, 1 H), 2.84 (d, J= 16.0 Hz, 1 H), 3.08-3.19 (m, 2 H), 4.98 (s, 2 H), 5.82 (d, J = 7.5 Hz, 1 H), 6.42 (t, J= 7.5 Hz, 1 H), 6.52-6.61 (m, 2 H), 6.72-6.83 (m, 2 H), 7.27- 7.40 (m, 5 H), 7.45 (s, 1 H), 7.66 (s, 1 H), 10.16 (bs, 1 H); 13C NMR (101 MHz, DMSO-J6) δ ppm 10.6 (CH3), 13.1 (CH3), 28.1 (CH3), 29.0 (CH3), 32.0 (C), 42.3 (CH2), 49.2 (CH), 61.3 (CH2), 69.5 (CH2), 101.9 (CH, d, J= 24.9 Hz), 104.6 (C), 109.8 (CH), 112.9 (CH), 118.9 (C, d, J= 14.6 Hz), 119.5 (CH), 122.2 (CH), 125.6 (C), 127.8 (CH), 127.9 (CH), 128.4 (CH), 130.1 (C), 130.9 (CH, d, J= 5.1 Hz), 131.1 (C), 136.4 (C), 146.1 (C), 147.1 (C), 150.0 (C), 157.6 (C), 159.1 (C, d, J= 11.0 Hz), 160.0 (C, d, J = 247.4 Hz), 160.2 (C).
Example 10: 1 l-(4-benzyloxy-2-fluorophenyl)-6-hvdroxy-3,3-dimethyl-l,l-dioxo- 1100--((tthhiiaazzooll--44--yyllccaarrbboonnvyrn)--11..22..33A.4.55..1111--hheexxahydro- 1 λ6-thia- 5,10-diazadibenzorα,άπcycloheptene (24).
Figure imgf000057_0001
The title compound (24) was prepared from l l-(4-benzyloxy-2-fluorophenyl)- 6-hydroxy-3 ,3-dimethyl- 1 , 1 -dioxo- 1 ,2,3 ,4,5 , 11 -hexahydro- 1 λ6-thia-5 , 10-diazadi- benzo[α,</]cycloheptene (18) and thiazole-4-carbonyl chloride following the procedure reported for the preparation of 10-isobutyryl-l l-(4-benzyloxy-2-fluorophenyl)-6- hydroxy-3 ,3-dimethyl- 1 , 1 -dioxo- 1,2,3,4,5,11 -hexahydro- 1 λ6-thia-5 , 10- diazadibenzo[α,</Jcycloheptene (21): Rt = 2.19 min, m/z = 606 (M+H)+.
Example 11 : 1 l-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl-l,l-dioxo- 10-(6-methyl-2-pyridylcarbonyD- 1,2,3.4,5,11 -hexahydro- 1 λ6-thia- 5,10-diazadibenzo[α,άπcycloheptene (25).
Figure imgf000057_0002
The title compound (25) was prepared from l l-(4-benzyloxy-2-fluorophenyl)- 6-hydroxy-3 ,3-dimethyl- 1 , 1 -dioxo- 1 ,2,3 ,4,5 , 11 -hexahydro- 1 λ6-thia- 5,10-diazadibenzo[α, J]cycloheptene (18) and 6-methylpicolinoylchloride following the procedure reported for the preparation of 10-isobutyryl-l l-(4-benzyloxy- 2-fluorophenyl)-6-hydroxy-3 ,3-dimethyl- 1 , 1 -dioxo- 1 ,2,3 ,4,5 , 11 -hexahydro- 1 λ6-thia- 5,10-diazadibenzo[α,<i]cycloheptene (21): Rt = 2.30 min, m/z = 614 (M+H)+.
Example 12: (R)-I l-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl-l,l-dioxo- 10-r(2.5-dimethyloxazol-4-yl)carbonyl1-1.2.3.4.5.11-hexahvdro-lλ6-thia- 5,10-diazadibenzo|"α,<i]cycloheptene (26) and (61-l l-(4-benzyloxy-2-fluorophenyl)- 6-hydroxy-3,3-dimethyl- 1 , 1 -dioxo- 10-[(2,5-dimethyloxazol-4-yl)carbonyll- 1,2,3,4,5,1 l-hexahydro-lλ6-thia-5J0-diazadibenzorα,άπcvcloheptene (27).
Figure imgf000058_0001
The 2 enantiomers of 1 l-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl- 1 , 1 -dioxo- 10-[(2,5-dimethyloxazol-4-yl)carbonyl]- 1 ,2,3,4,5, 11 -hexahydro- 1 λ6-thia- 5,10-diazadibenzo[a,d]cycloheptene (23) were purified by SFC (supercritical fluid chromatography) with a chiral column AD-H (eluent: CCVisopropanol 50:50). Two fractions were collected and the solvent was evaporated to give (27): retention time 1.28 min, m/z = 618 (M+H)+; and (28): retention time 1.47 min, m/z = 618 (M+H)+.
Example 13: synthesis of compounds (28)-(142)
The compounds (28)-(142) reported in Table 1 were prepared according to the procedure used in example 7 for the preparation of 10-isobutyryl-l l-(4-benzyloxy-
2-fluorophenyl)-6-hydroxy-3 ,3-dimethyl- 1 , 1 -dioxo- 1 ,2,3 ,4,5 , 11 -hexahydro- 1 λ6-thia-
5,10-diazadibenzo[α,d]cycloheptene (21), using l l-(4-benzyloxy-2-fluoro-phenyl)-
3,3-dimethyl-l,l-dioxo-2,3,4,5,10,l l-hexahydro-lH-lλ6-thia-5,10-diaza-dibenzo[a,d]- cyclohepten-6-ol (18) and the appropriate acid chloride as indicated in Table 1.
Table 1.
Figure imgf000058_0002
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
Example 14: synthesis of compounds (143)-(190)
Pure enantiomers (143)-(190) were obtained from the corresponding racemic mixtures as indicated in Table 2, after purification on chiral column as described in example 12.
Table 2.
Figure imgf000084_0002
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Example 15: 1-[1 l-(4-Benzyloxy-2-fluoro-phenyl)-9-hydroxy-3,3-dimethyl-l,l-dioxo- 1,2,3,4,5,11 -hexahydro- 1 λ6-thia-5 , 10-diaza-dibenzo|"a,d1cyclohepten- 10-yl]-ethanone
Figure imgf000089_0001
The title compound (191) was prepared from l l-(4-benzyloxy-2-fluoro-phenyl)- 3,3-dimethyl-l,l-dioxo-2,3,4,5,10,l l-hexahydro-lH-lλ6-thia-5,10-diaza-dibenzo[a,d]- cyclohepten-9-ol (19) (103 mg, 0.208 mmol) following the procedure reported for the synthesis of 1-[1 l-(4-benzyloxy-2-fluoro-phenyl)-6-hydroxy-3,3-dimethyl-l,l-dioxo- 1,2,3,4,5,11 -hexahydro- 1 λ6-thia-5 , 10-diaza-dibenzo[a,d]cyclohepten- 10-yl]-ethanone (20), affording 104 mg (93% yield) of an off-white solid; m/z = 537 (M+H)+.
Example 16: 1-[1 l-(4-Benzyloxy-2-fluoro-phenyl)-3,3-dimethyl-l,l-dioxo-9-(thiazol- 4-ylmethoxy)- 1 ,2,3 ,4,5 , 11 -hexahydro- 1 λ6-thia-5 , 1 Q-diaza-dibenzo[a,dlcyclohepten- 10-yll-ethanone (192)
Figure imgf000089_0002
(191) (192)
A mixture of compound (191) (40 mg, 0.075 mmol), 4-chloromethyl-thiazole hydrochloride (16 mg, 1.3 eq) and cesium carbonate (73 mg, 3 eq) in DMF was stirred at room temperature. After 16h, 8 mg of 4-chloromethyl-thiazole hydrochloride was added and the reaction mixture was heated at 600C for 2h. The reaction mixture was then diluted with water and extracted with CH2Cl2, then ethyl acetate. The organic layers were dried on MgSO4, filtered and concentrated. Purification by flash chromatography (eluent: ethyl acetate) afforded 23 mg (49% yield) of the desired product (192) as an off-white solid; m/z = 634 (M+H)+. Example 17: 1-[1 l-(4-Benzyloxy-2-fluoro-phenyl)-9-methoxy-3,3-dimethyl-l,l-dioxo- 1,2,3,4,5,11 -hexahydro- 1 λ6-thia-5 , 1 Q-diaza-dibenzo|"a,d]cyclohepten- 10-yl]-ethanone (193)
Figure imgf000090_0001
A mixture of compound (191) (24 mg, 0.045 mmol), iodomethane (7 mg, 1.1 eq) and cesium carbonate (22 mg, 1.5 eq) in DMF was heated at 75°C for Ih. The reaction mixture was then cooled down to room temperature, diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried with MgSO4, filtered and concentrated in vacuo. The obtained solid was washed with isopropylether to afford 13 mg (54% yield) of the desired product (193); m/z = 551 (M+H)+.
Example 18: 11 -(4-Benzyloxy-2-fluoro-phenyl)-3 ,3 ,9-trimethyl- 1 , 1 -dioxo- 2,3.4,5.10.1 l-hexahvdro-lH-lλ6-thia-5.10-diaza-dibenzora,dlcvclohepten-6-oU197)
Figure imgf000090_0002
Step l
Figure imgf000090_0003
(5) (195) (196) A mixture of the sulfone (5) (191 mg, 1.084 mmol), 2,3-diamino-4-methyl-phenol (194) (150 mg, 1 eq), trifluoroacetic acid (138 mg, 1.1 eq) and 4 A molecular sieves in DMF (10 mL) was heated at 500C for 6h. After cooling to room temperature, the reaction mixture was filtered and the solid washed with DMF. The filtrate containing i the 2 regioisomers (195) and (196) was used directly in the next step without further purification; m/z = 297 (M+H)+.
Figure imgf000091_0001
(195) (196) (11) (197) (198)
To the above reaction mixture containing (195) and (196) were added 4-benzyloxy- 2-fluorobenzaldehyde (11) (251 mg, 1 eq) and NaHCO3 (81 mg, 0.9 eq). The reaction mixture was heated at 500C for 16h. After cooling to room temperature, the reaction mixture was diluted with saturated NaHCO3 solution, extracted with CH2Cl2 several times and the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography (eluent: ethyl acetate/CH2Cl2 30:70) afforded the mixture of the 2 regioisomers (197) and (198); m/z = 509 (M+H)+.
Example 19: [1 l-(4-Benzyloxy-2-fluoro-phenyl)-6-hydroxy-3,3,9-trimethyl-l,l-dioxo- 1,2,3,4,5,11 -hexahydro- 1 λ6-thia-5 , 1 Q-diaza-dibenzo|"a,dlcyclohepten- 10-yl]-(6-methyl- pyridin-2-yl)-methanone (199)
Figure imgf000091_0002
(199)
To the above mixture of regioisomers (197) and (198) dissolved in CH2Cl2 were added 6-methyl-pyridine-2-carbonyl chloride (99 mg, 4.7 eq) and Hunig's base (219 mg, 12.7 eq) at room temperature. After 15 min, the solvent was evaporated and the residue was reconstituted in THFZH2O. Then, 50 mg of LiOH were added. After stirring for 16h, H2O was added and the pH was adjusted to ~4 with diluted HCl. Then, the reaction mixture was successively concentrated under reduced pressure, extracted with CH2Cl2, dried (Na2SO4) and evaporated. The residue was purified by silicagel chromatography with (CH2Cl2/ethyl acetate 70:30) to give 14 mg of the target product (199) as a single regioisomer; m/z = 628 (M+H)+.
Example 20: synthesis of compounds (200)-(217)
Compounds (200) to (217) were prepared following the procedure reported for the synthesis of 1 l-(4-benzyloxy-2-fluoro-phenyl)-3,3-dimethyl-l,l-dioxo-2,3,4,5,10,l 1- hexahydro-lH-lλ6-thia-5,10-diaza-dibenzo[a,d]cyclohepten-6-ol (18), using the appropriate aldehyde as shown in table 3, instead of 4-benzyloxy-2-fluoro- benzaldehyde.
Table 3.
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
Example 21 : synthesis of compounds (219)-(259)
Compounds (219)-(259) were prepared following the procedure reported for the synthesis of 10-isobutyryl-l l-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl- 1 , 1 -dioxo- 1,2,3,4,5,11 -hexahydro- 1 λ6-thia-5 , 10-diazadibenzo[α, Jjcycloheptene (21), starting from the 3,3-dimethyl-l,l-dioxo-2,3,4,5,10,l 1 -hexahydro -IH-I λ6-thia- 5,10-diaza-dibenzo[a,d]cyclohepten-6-ol derivatives (200)-(218) and acid chlorides indicated in table 4, instead of 1 l-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-di- methyl- 1 , 1 -dioxo- 1,2,3,4,5,11 -hexahydro- 1 λ6-thia-5 , 10-diazadibenzo [a, JJcycloheptene (18) and isobutyryl chloride.
Table 4.
Figure imgf000095_0002
Figure imgf000096_0001
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
Figure imgf000105_0001
Example 22: 6-(2,5-Dimethyl-oxazole-4-carbonyl)-7-(2-fluoro-4-hydroxy-pheny0- 10J0-dimethyl-8.8-dioxo-6.7.8.9J0J l-hexahvdro-2-oxa-8λ6-thia-6J lb-diaza- dibenzo[cd,hlazulen-l-one (261)
Figure imgf000105_0002
Figure imgf000106_0001
(23) (260)
A solution of [1 l-(4-benzyloxy-2-fluoro-phenyl)-6-hydroxy-3,3-dimethyl-l,l-dioxo- 1,2,3,4,5,11 -hexahydro- 1 λ6-thia-5 , 10-diaza-dibenzo[a,d]cyclohepten- 10-yl]- (2,5-dimethyl-oxazol-4-yl)-methanone (23) (1.561 g, 2.53 mmol) and carbonyl diimidazole (574 mg, 1.4 eq) in CH2Cl2 (50 mL) was stirred at room temperature for 16h. The reaction mixture was then diluted with CH2Cl2, washed with a saturated solution of NaHCOs, dried over MgSO4, filtered and concentrated to dryness to give 1.62 g (quantitative yield) of 7-(4-benzyloxy-2-fluoro-phenyl)-6-(2,5-dimethyl- oxazole-4-carbonyl)- 10,10-dimethyl-8,8-dioxo-6,7,8 ,9, 10,11 -hexahydro-2-oxa- 8λ6-thia-6,l lb-diaza-dibenzo[cd,h]azulen-l-one (260); m/z = 644 (M+H)+.
Figure imgf000106_0002
(260) (261)
A solution of compound (260) (1.56 g, 2.424 mmol) in ethyl acetate (100 mL) was catalytically hydrogenated with Pd/C (258 mg, 0.1 eq). After completion, the reaction mixture was filtered and concentrated. The obtained white precipitate was filtered off to give 1.17 g (87% yield) of the desired product 6-(2,5-dimethyl-oxazole-4-carbonyl)- 7-(2-fluoro-4-hydroxy-phenyl)- 10, 10-dimethyl-8,8-dioxo-6,7,8,9, 10, 11-hexahydro- 2-oxa-8λ6-thia-6,l lb-diaza-dibenzo[cd,h]azulen-l-one (261); m/z = 554 (M+H)+.
Example 23: [1 l-(4-Allyloxy-2-fluoro-phenyl)-6-hydroxy-3,3-dimethyl-l,l-dioxo- 1,2,3,4,5,11 -hexahydro- 1 λ6-thia-5 , 1 Q-diaza-dibenzo[a,dlcyclohepten- 10-yl]- (2,5-dimethyl-oxazol-4-yl)-methanone (263)
Figure imgf000107_0001
(261) (262) (263)
To a solution of compound (261) (300 mg, 0.542 mmol) in acetonitrile were added cesium carbonate (177 mg, 1 eq) and 3-bromoprop-l-ene (328 mg, 5 eq). The reaction mixture was stirred at room temperature for Ih, then successively concentrated in vacuo, redissolved in ethyl acetate and extracted with water. The organic layer was dried over MgSO4, filtered and concentrated to dryness to afford 320 mg (99% yield) of 7-(4-allyloxy-2-fluoro-phenyl)-6-(2,5-dimethyl-oxazole-4-carbonyl)- 10,10-dimethyl- 8,8-dioxo-6,7,8,9,10,l l-hexahydro-2-oxa-8λ6-thia-6,l lb-diaza-dibenzo[cd,h]azulen- 1-one (262); m/z = 594 (M+H)+.
To a solution of (262) in a mixture of THF/methanol 1 :1 (10 mL), LiOH (13 mg, 1 eq) in water (2 mL) was added at room temperature. After completion of the reaction, H2O was added and the pH was adjusted to ~5 with diluted HCl. Then, the reaction mixture was successively concentrated under reduced pressure, extracted with CH2Cl2, dried (Na2SO4), filtered and concentrated to dryness to give 293 mg (96% yield) of the target product (263); m/z = 568 (M+H)+.
Example 24: synthesis of compounds (264)-(270)
Compounds (264)-(270) were prepared following the 2-step procedure reported for the synthesis of [1 l-(4-allyloxy-2-fluoro-phenyl)-6-hydroxy-3,3-dimethyl-l,l-dioxo- 1,2,3,4,5,11 -hexahydro- 1 λ6-thia-5 , 10-diaza-dibenzo[a,d]cyclohepten- 10-yl]- (2,5-dimethyl-oxazol-4-yl)-methanone (263), starting from 6-(2,5-dimethyloxazole- 4-carbonyl)-7-(2-fluoro-4-hydroxyphenyl)- 10,10-dimethyl-8,8-dioxo-6,7,8 ,9, 10,11- hexahydro-2-oxa-8λ6-thia-6,l lb-diazadibenzo[cd,h]azulen-l-one (261) and the appropriate alkylating agent indicated in Table 5.
Table 5.
Figure imgf000108_0001
Figure imgf000109_0002
Example 25: (2.5-Dimethyl-oxazol-4-yl)-(l l-r2-fluoro-4-(2-thiophen-2-yl-ethoxy)- phenyll-6-hydroxy-3 ,3-dimethyl- 1 , 1 -dioxo- 1,2,3,4,5,11 -hexahydro- 1 λ6-thia- 5,10-diaza-dibenzora^lcyclohepten- 10-vU -methanone (272)
Figure imgf000109_0001
To a solution of 6-(2,5-dimethyl-oxazole-4-carbonyl)-7-(2-fluoro-4-hydroxy-phenyl)- 10,10-dimethyl-8,8-dioxo-6,7,8,9,10,l l-hexahydro-2-oxa-8λ6-thia-6,l lb-diaza- dibenzo[cd,h]azulen-l-one (261) (50 mg, 0.09 mmol) in THF (2 niL) were added 2-(thiophen-2-yl)ethanol (23 mg, 2 eq), triphenylphosphine (71 mg, 3 eq) and DIAD (diisopropylazodicarboxylate; 55 mg, 3 eq) at 0°C under N2. The reaction mixture was stirred at 00C for Ih, then at room temperature for 16h. The resulting solution was successively concentrated under reduced pressure, then purified by flash chromatography to afford 24 mg (40% yield) of 6-(2,5-dimethyl-oxazole-4-carbonyl)-7-[2- fluoro-4-(2-thiophen-2-yl-ethoxy)-phenyl]- 10, 10-dimethyl-8,8-dioxo-6,7,8,9, 10,11- hexahydro-2-oxa-8λ6-thia-6,l lb-diaza-dibenzo[cd,h]azulen-l-one (271); m/z = 664 (M+H)+.
To a solution of (271) in a mixture of THF/methanol 1 : 1 (5 mL) was added at room temperature a solution of LiOH (1 eq) in water (1 mL). After completion of the reaction, H2O was added and the pH was adjusted to ~4 with diluted HCl. Then, the reaction mixture was successively concentrated under reduced pressure, extracted with CH2Cl2, dried (Na2SO4), filtered and concentrated to dryness to give the target product (272); m/z = 638 (M+H)+.
Example 26: (1 l-[4-(2-Cyclopropyl-ethoxy)-2-fluoro-phenyll-6-hydroxy-3,3-dimethyl- 1 , 1 -dioxo- 1,2,3,4,5,11 -hexahydro- 1 λ6-thia-5 , 1 Q-diaza-dibenzo|"a,dlcyclohepten- 1 Q-ylj - (2,5-dimethyl-oxazol-4-yl)-methanone (273; )
Figure imgf000110_0001
The title compound (273) was prepared following the 2-step procedure reported for the synthesis of compound (272), using 2-cyclopropylethanol instead of 2-(thiophen-2-yl)- ethanol; m/z = 596 (M+H)+.
Example 27: (2,5-Dimethyl-oxazol-4-yl)-{l l-[2-fluoro-4-(3-methoxymethoxy- benzyloxy)-phenyll-6-hydroxy-3 ,3-dimethyl- 1 , 1 -dioxo- 1,2,3,4,5,11 -hexahydro- 1 λ6-thia-5, 10-diaza-dibenzora,d1cvclohepten- 10-vU -methanone (274)
Figure imgf000111_0001
The title compound (274) was prepared following the 2-step procedure reported for the synthesis of compound (272), using (3-methoxymethoxy-phenyl)methanol instead of 2-(thiophen-2-yl)ethanol; m/z = 678 (M+H)+.
Example 28: (2,5-Dimethyl-oxazol-4-yl)-{l l-[2-fluoro-4-(3-hydroxy-benzyloxy)- phenyl]-6-hydroxy-3 ,3-dimethyl- 1 , 1 -dioxo- 1,2,3,4,5,11 -hexahydro- 1 λ6-thia- 5,10-diaza-dibenzora,d1cyclohepten- 10-vU -methanone (275)
Figure imgf000111_0002
To a solution of compound (274) (54 mg, 0.08 mmol) in THF (5 mL) was added concentrated HCl (1 mL) and the reaction mixture was stirred at room temperature for 16h. The reaction mixture was then concentrated in vacuo, redissolved in CH2Cl2, washed with a saturated NaHCO3 solution, then brine, dried over MgSO4, filtered and concentrated. Purification by flash chromatography afforded the desired product (275); m/z = 634 (M+H)+.
Example 29: 5-Ethyl-5-methyl-l,l-dioxo-tetrahvdro-thiopyran-3-one (280)
(280)
Figure imgf000111_0003
Figure imgf000112_0001
(276) (277) (278)
To 2-chloroprop-2-ene-l -thiol (276) (10.11 g, 93.1 mmol), synthesized as described in (i) Lansbury, P.T.; Scharf, D. J. J. Am. Chem. Soc. 1968, 90, 2, 536-53 and (ii) Lansbury, P.T.; Nienhouse, E. J.; Scharf, D. J.; Hilfϊker, F. R. J. Am. Chem. Soc. 1970, 92, 19, 5649-5657, in methanol, was added sodium methanolate (5.03 g, 1 eq). After 30 minutes at room temperature, 2-ethyl-2-methyl-oxirane (277) (7.82 g, 1 eq) was added and the reaction mixture was stirred for 16h, then was diluted with water and basified until pH 10 with a saturated solution of NaHCOs. The aqueous layer was extracted with ethyl acetate and the organic layer was subsequently dried over MgSO4, filtered and concentrated in vacuo to afford 10.02 g (60% yield) of product (278) 1- (2-chloro-allylsulfanyl)-2-methyl-butan-2-ol as colorless oil.
Figure imgf000112_0002
(278) (279)
The title compound (279) was prepared in 55% yield following the procedure reported for the synthesis of 5,5-dimethyldihydrothiopyran-3-one (4), using l-(2-chloroallyl- sulfanyl)-2-methyl-butan-2-ol (278) instead of l-(2-chloro-allylsulfanyl)-2-methyl- propan-2-ol (3).
Step 3
mCPBA
Figure imgf000112_0004
Figure imgf000112_0003
(279) (280)
The title compound (280) was prepared in 8% yield following the procedure reported for the synthesis of compound 5,5-dimethyl-l,l-dioxo-tetrahydro-thiopyran-3-one (5), using 5-ethyl-5-methyl-dihydro-thiopyran-3-one instead of 5,5-dimethyl-dihydro- thiopyran-3-one.
Example 30: 1 l-(4-Benzyloxy-2-fluoro-phenyl)-3-ethyl-3-methyl-l,l-dioxo-
2.3.4.5.10.1 l-hexahvdro-lH-lλ^thia-SJO-diaza-dibenzora.dlcvclohepten-β-oUlSl)
Figure imgf000113_0001
The title compound (281) was prepared in 32% overall yield following the 2-step procedure reported for the synthesis of compound (18) 1 l-(4-benzyloxy-2-fluoro- phenyl)-6-hydroxy-3 ,3-dimethyl- 1 , 1 -dioxo- 1,2,3,4,5,11 -hexahydro- 1 λ6-thia-5 , 10- diazadibenzo[α,<i]cycloheptene, using 5-ethyl-5-methyl-l,l-dioxo-tetrahydro- thiopyran-3-one (280) instead of compound (5); m/z = 509 (M+H)+.
Example 31 : [1 l-(4-Benzyloxy-2-fluoro-phenyl)-3-ethyl-6-hydroxy-3-methyl- 1 , 1 -dioxo- 1,2,3,4,5,11 -hexahydro- 1 λ6-thia-5 , 10-diaza-dibenzo[a.dlcyclohepten- 10-yl]- (2-fluoro-phenyl)-methanone (282)
Figure imgf000113_0002
The title compound (282) was prepared in 65% yield as a racemic mixture following the procedure reported for the synthesis of 10-isobutyryl-l l-(4-benzyloxy-2-fluoro- phenyl)-6-hydroxy-3 ,3-dimethyl- 1 , 1 -dioxo- 1,2,3,4,5,11 -hexahydro- 1 λ6-thia-5 , 10- diazadibenzo[α,<i]cycloheptene (21), starting from compound (281) and 2-fluoro- benzoyl chloride, instead of 1 l-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl- 1 , 1 -dioxo- 1,2,3,4,5,11 -hexahydro- 1 λ6-thia-5 , 10-diazadibenzo[α, Jjcycloheptene (18) and isobutyryl chloride; m/z = 631 (M+H)+. The four stereoisomers of (282) were further isolated by SFC chiral separation, leading to compounds (282a), (282b), (282c), (282d).
Example 32: [1 l-(4-Benzyloxy-2-fluoro-phenyl)-3-ethyl-6-hydroxy-3-methyl-
1 , 1 -dioxo- 1,2,3,4,5,11 -hexahydro- 1 λ6-thia-5 , 1 Q-diaza-dibenzo[a,dlcyclohepten- 10-yl]-
(2,5-dimethyl-oxazol-4-yl)-rnethanone (283)
Figure imgf000114_0001
The title compound (283) was prepared in 70% yield following the procedure reported for the synthesis of 10-isobutyryl-l l-(4-benzyloxy-2-fluorophenyl)-6-hydroxy- 3 ,3-dimethyl- 1 , 1 -dioxo- 1,2,3,4,5,11 -hexahydro- 1 λ6-thia-5 , 10-diazadibenzo[α, d\- cycloheptene (21), starting from compound (281) and 2,5-dimethyloxazole-4- ylcarbonyl chloride, instead of 1 l-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3- dimethyl- 1 , 1 -dioxo- 1 ,2,3 ,4,5 , 11 -hexahydro- 1 λ6-thia-5 , 10-diazadibenzo[α, d\cyc\o- heptene (18) and isobutyryl chloride; m/z = 632 (M+H)+.
Example 33: 5-Isobutyl-5-methyl-l,l-dioxo-tetrahvdro-thiopyran-3-one (284)
Figure imgf000114_0002
The title compound (284) was prepared following the 3 -step procedure reported for the synthesis of compound (280), using 2-isobutyl-2-methyl-oxirane instead of 2-ethyl- 2-methyloxirane (277). Example 34: 1 l-(4-Benzyloxy-2-fluoro-phenyl)-3-isobutyl-3-methyl-l,l-dioxo- 2.3.4.5.10.1 l-hexahvdro-lH-lλ6-thia-5J0-diaza-dibenzora.dlcvclohepten-6-oU285)
Figure imgf000115_0001
The title compound (285) was prepared in 30% overall yield following the 2-step procedure reported for the synthesis of compound 1 l-(4-benzyloxy-2-fluorophenyl)- 6-hydroxy-3 ,3-dimethyl- 1 , 1 -dioxo- 1 ,2,3 ,4,5 , 11 -hexahydro- 1 λ6-thia-5 , 10-diazadibenzo- [α,J]cycloheptene (18), using compound (284) instead of 5,5-dimethyl-l,l-dioxo- tetrahydro-thiopyran-3-one (5); m/z = 537 (M+H)+.
Example 35: [1 l-(4-Benzyloxy-2-fluoro-phenyl)-6-hydroxy-3-isobutyl-3-methyl-
1 , 1 -dioxo- 1,2,3,4,5,11 -hexahydro- 1 λ6-thia-5 , 10-diaza-dibenzo[a.dlcyclohepten- 10-yl]-
(2-fluoro-phenyl)-methanone (286)
Figure imgf000115_0002
The title compound (286) was prepared following the procedure reported for the synthesis of 10-isobutyryl-l l-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl- 1 , 1 -dioxo- 1,2,3,4,5,11 -hexahydro- 1 λ6-thia-5 , 10-diazadibenzo[α, J]cycloheptene (21), starting from compound (285) and 2-fluorobenzoyl chloride, instead of 1 l-(4-benzyl- oxy-2-fluorophenyl)-6-hydroxy-3 ,3-dimethyl- 1 , 1 -dioxo- 1,2,3,4,5,11 -hexahydro- 1 λ6- thia-5,10-diazadibenzo[α,<i]cycloheptene (18) and isobutyryl chloride; m/z = 659 (M+H)+. Example 36: 5-Methyl-l,l-dioxo-5-propyl-tetrahvdro-thiopyran-3-one (287)
Figure imgf000116_0001
The title compound (287) was prepared following the 3 -step procedure reported for the synthesis of compound (280), using 2-methyl-2-propyloxirane instead of 2-ethyl- 2-methyloxirane.
Example 37: 1 l-(4-Benzyloxy-2-fluoro-phenyl)-3-methyl-l,l-dioxo-3-propyl- 2.3.4.5.10.1 l-hexahvdro-lH-lλ6-thia-5J0-diaza-dibenzora.dlcvclohepten-6-ol (288)
Figure imgf000116_0002
The title compound (288) was prepared following the 2-step procedure reported for the synthesis of compound 1 l-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl- 1 , 1 -dioxo- 1,2,3,4,5,11 -hexahydro- 1 λ6-thia-5 , 10-diazadibenzo[α, J]cycloheptene (18), using compound (287) instead of 5,5-dimethyl-l,l-dioxo-tetrahydro-thiopyran-3-one (5); m/z = 523 (M+H)+.
Example 38: [1 l-(4-Benzyloxy-2-fluoro-phenyl)-6-hydroxy-3-methyl-l,l-dioxo- 3-propyl- 1 ,2,3 ,4,5 , 11 -hexahydro- 1 λ6-thia-5 , 10-diaza-dibenzo[a.dlcyclohepten- 10-yl]- (2-fluoro-phenyl)-methanone (289)
Figure imgf000116_0003
The title compound (289) was prepared following the procedure reported for the synthesis of 10-isobutyryl-l l-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl- 1 , 1 -dioxo- 1,2,3,4,5,11 -hexahydro- 1 λ6-thia-5 , 10-diazadibenzo[α, J]cycloheptene (21), starting from compound (288) and 2-fluorobenzoyl chloride, instead of 1 l-(4-benzyl- oxy-2-fluorophenyl)-6-hydroxy-3 ,3-dimethyl- 1 , 1 -dioxo- 1,2,3,4,5,11 -hexahydro- 1 λ6- thia-5,10-diazadibenzo[α,<i]cycloheptene (18) and isobutyryl chloride; m/z = 645 (M+H)+.
The four stereoisomers of (289) were further isolated by SFC chiral chromatography, leading to compounds (289a), (289b), (289c), (289d).
Example 39: synthesis of compounds 290-348
Compounds 290-348 were prepared following the procedure reported for the synthesis of 10-isobutyryl- 11 -(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3 ,3-dimethyl- 1 , 1 -dioxo-
1,2,3,4,5,1 l-hexahydro-lλ6-thia-5,10-diazadibenzo[α,d]cycloheptene (21), starting from the 2,3,4,5,10,1 l-hexahydro-l-thia-5,10-diaza-dibenzo[a,d]cycloheptene
1,1 -dioxide derivatives (reagent 1) and acid chlorides indicated in table 6, instead of
11 -(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3 ,3-dimethyl- 1 , 1 -dioxo- 1 ,2,3 ,4,5 , 11 -hexa- hydro-lλ6-thia-5,10-diazadibenzo[α,d]cycloheptene (18) and isobutyryl chloride.
Table 6.
Figure imgf000117_0001
Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0001
Figure imgf000121_0001
Figure imgf000122_0001
Figure imgf000123_0001
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0001
Figure imgf000130_0001
Figure imgf000131_0001
Figure imgf000132_0002
Example 40: synthesis of [6-Amino-l l-(4-benzyloxy-2-fluorophenyl)-3,3-dimethyl- 1 , 1 -dioxo- 1,2,3,4,5,11 -hexahydro- 1 λ6-thia-5 , 1 Q-diaza-dibenzo[a,dlcyclohepten- 10-yl]- (6-methylpyridin-2-yl)-methanone (353).
Figure imgf000132_0001
(349)
A solution of 2,3-dinitroaniline (10 g, 54.61 mmol) was catalytically hydrogenated on Pd/C to yield, after filtration and concentration to dryness, 6420 mg (95% yield) of the target product (349); m/z = 124 (M+H)+.
Figure imgf000133_0001
The title compound (350) Λ/-(5,5-dimethyl-l,l-dioxo-l,4,5,6-tetrahydro-thiopyran- 3-yl)-benzene-l,2,6-triamine was prepared following the procedure reported for the synthesis of compound (16), by shortening the reaction time to 1 hour and using 1,2,3-trianiline (349) instead of 2,3-diaminophenol and was obtained as a mixture with the regioisomer (351); m/z = 282 (M+H)+. This mixture was used without further purification in the next step.
Figure imgf000133_0002
(350) (351) (352)
To a mixture of regioisomers (350) and (351) (3200 mg, 5.67 mmol) in DMF (200 mL) was added Fmoc-CI (9-fluorenylmethyl carbamate chloride; 1468 mg, 1 eq). The reaction mixture was then heated at 500C for Ih. Aldehyde (11) (1306 mg, 1 eq) and NaHCθ3 (477 mg, 1 eq) were then added and the reaction mixture was further heated for 16h, then was then filtered on decalite, diluted with a saturated aqueous solution of NaHCθ3 and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. Purification of the crude by flash chromatography on silical gel (eluent: CF^C^/ethyl acetate) afforded 1200 mg (21% overall yield) of the target product [1 l-(4-Benzyloxy-2-fluoro-phenyl)-3,3-dimethyl- l,l-dioxo-2, 3,4, 5, 10,11 -hexahydro- IH-I λ6-thia-5,l 0-diaza-dibenzo[a,d]cyclohepten- 6-yl]-carbamic acid 9H-fluoren-9-ylmethyl ester (352); m/z = 716 (M+Η)+. Step 4
Figure imgf000134_0001
To a solution of intermediate (352) (300 mg, 0.419 mmol) in THF (50 mL) were added 6-methyl-pyridine-2-carbonyl chloride (326 mg, 5 eq) and Hunig's base (0.69 mL, 10 eq). After 4 h at room temperature, lithium hydroxide (5 eq) dissolved in water was added and the reaction mixture was stirred during Ih, then diluted with brine and extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified by flash chromatography to give 4 mg of the desired target product (353); m/z = 613 (M+H)+.
Example 41 : synthesis of [l l-(4-benzyloxy-2-fluoro-phenyl)-3,3-dimethyl-l,l-dioxo- 2,3,4,5,10,1 l-hexahydro-lH-lλ6-thia-5,10-diaza-dibenzo[a,dlcyclohepten-6-yll- methanol (354)
Figure imgf000134_0002
The title compound (354) was prepared following the 2-step procedure reported for the synthesis of compound 1 l-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl- 1 , 1 -dioxo- 1,2,3,4,5,11 -hexahydro- 1 λ6-thia-5 , 10-diazadibenzo[α, J]cycloheptene (18), using (2,3-diaminophenyl)methanol instead of 2,3-diaminophenol and was obtained in 34% overall yield as an off-white solid; m/z = 509 (M+H)+. Example 42: synthesis of [l l-(4-Benzyloxy-2-fluoro-phenyl)-6-hydroxymethyl- 3, 3-dimethyl- 1,1 -dioxo- 1, 2,3,4,5, I l-hexahydro-lλ6-thia-5,10-diaza-dibenzo|"a,d]- cyclohepten- 10-yll-(2-fluoro-phenyl)-methanone (355)
Figure imgf000135_0001
The title compound (355) was prepared in 69% yield following the procedure reported for the synthesis of 10-isobutyryl-l l-(4-benzyloxy-2-fluorophenyl)-6-hydroxy- 3 ,3-dimethyl- 1 , 1 -dioxo- 1,2,3,4,5,11 -hexahydro- 1 λ6-thia-5 , 10-diazadibenzo[α, d\- cycloheptene (21), starting from compound (354) and 2-fluorobenzoyl chloride, instead of 1 l-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl-l,l-dioxo-l,2,3,4,5,l 1- hexahydro-lλ6-thia-5,10-diazadibenzo[α,ύT]cycloheptene (18) and isobutyryl chloride; m/z = 631 (M+H)+.
Example 43: synthesis of compounds 356-440 and 472-473
Compounds 356-440 and 472-473 were prepared from the 2,3,4,5,10,11-hexahydro- l-thia-5,10-diaza-dibenzo[a,d]cycloheptene-l,l-dioxide derivative (reagent 1) and optionally reagent 2 indicated in the table below, following the protocol indicated in table 7.
Protocol A: Reagent 1 indicated in the table was acylated following the procedure reported for the synthesis of 10-isobutyryl-l l-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl- 1 , 1 -dioxo- 1,2,3,4,5,11 -hexahydro- 1 λ6-thia-5 , 10-diazadibenzo[α, J]cycloheptene (21), using the acid chloride indicated in table 7 instead of isobutyryl chloride.
Protocol B:
Reagent 1 indicated in the table was alkylated following the procedure reported for the synthesis of [1 l-(4-allyloxy-2-fluoro-phenyl)-6-hydroxy-3,3-dimethyl-l,l-dioxo- 1,2,3,4,5,11 -hexahydro- 1 λ6-thia-5 , 10-diaza-dibenzo[a,d]cyclohepten- 10-yl]- (2,5-dimethyl-oxazol-4-yl)-methanone (263), starting from 6-(2,5-dimethyl-oxazole- 4-carbonyl)-7-(2-fluoro-4-hydroxy-phenyl)- 10,10-dimethyl-8,8-dioxo- 6,7,8,9,10,1 l-hexahydro-2-oxa-8λ6-thia-6,l lb-diaza-dibenzo[cd,h]azulen-l -one (261) and the appropriate alkylating reagent indicated in Table 7 as reagent 2.
Protocol C:
Reagent 1 indicated in the table was alkylated following the procedure reported for the synthesis of (2,5-dimethyl-oxazol-4-yl)- { 11 -[2-fluoro-4-(2-thiophen-2-yl-ethoxy)- phenyl]-6-hydroxy-3 ,3-dimethyl- 1 , 1 -dioxo- 1,2,3,4,5,11 -hexahydro- 1 λ6-thia- 5,10-diazadibenzo[a,d]cyclohepten-10-yl}-methanone (272), starting from 6-(2,5-dimethyl-oxazole-4-carbonyl)-7-(2-fluoro-4-hydroxy-phenyl)- 10,10-dimethyl- 8,8-dioxo-6,7,8,9,10,l l-hexahydro-2-oxa-8λ6-thia-6,l lb-diaza-dibenzo[cd,h]azulen- 1-one (261) and the appropriate alcohol indicated in Table 7 as reagent 2 instead of 2-(thiophen-2-yl)ethano 1.
Protocol D:
Reagent 1 (racemic mixture) indicated in the table was purified by SFC with a chiral column, as described in Example 12 for the enantiomeric separation of the racemic mixture 11 -(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3 ,3-dimethyl- 1 , 1 -dioxo-
10-[(2,5-dimethyloxazol-4-yl)carbonyl]- 1 ,2,3,4,5, 11 -hexahydro- 1 λ6-thia-5, 10-diazadi- benzo[a,d]cycloheptene (23) and the obtained stereochemistry is indicated in the table.
Table 7.
Figure imgf000136_0001
Figure imgf000137_0001
Figure imgf000138_0001
Figure imgf000139_0001
Figure imgf000140_0001
Figure imgf000141_0001
Figure imgf000142_0001
Figure imgf000143_0001
Figure imgf000144_0001
Figure imgf000145_0001
Figure imgf000146_0001
Figure imgf000147_0001
Figure imgf000148_0001
Figure imgf000149_0001
Figure imgf000150_0001
Figure imgf000151_0001
Nc Chemistry Protocol Reagent 1 Reagent 2 or m/z stereochemistry (M+H)'
428 A 452 pyrazme 637.65 carbonyl chloride
429 A 452 2-methyl- 663.73 phenacetyl chloride
430 A 452 2,5-dimethoxy- 709.75 phenacetyl chloride
431 A 452 6-methyl- 650.69 pyridine-
2-carbonyl chloride
Figure imgf000152_0001
Nc Chemistry Protocol Reagent 1 Reagent 2 or m/z stereochemistry (M+H)+
432 A 467 2,5-dimethyl- 630.71 oxazole-
4-carbonyl chloride
433 A 467 pyrazme 613.68 carbonyl chloride
434 A 467 2-methyl- 639.76 phenacetyl chloride
435 A 467 2,5-dimethoxy- 685.78 phenacetyl chloride
Figure imgf000153_0001
Figure imgf000154_0001
Figure imgf000155_0002
Example 44: synthesis of compounds (441)-(453)
Compounds (441) to (453) were prepared following the procedure reported for the synthesis of 1 l-(4-benzyloxy-2-fluoro-phenyl)-3,3-dimethyl-l,l-dioxo-2,3,4,5,10,l 1- hxahydro-lH-lλ6-thia-5,10-diaza-dibenzo[a,d]cyclohepten-6-ol (18), using the appropriate aldehyde as described in the table below, instead of 4-benzyloxy-2-fluoro- benzaldehyde.
Table 8.
Figure imgf000155_0001
Figure imgf000156_0001
Figure imgf000157_0001
Figure imgf000158_0001
Example 45: synthesis of 6,6-dioxo-2-oxa-6λ6-thia-spiro|"3.5]nonan-8-one (458)
Figure imgf000158_0002
Step 1
Figure imgf000158_0003
(455)
A mixture of 2,2-bis(bromomethyl)propane-l,3-diol (25 g, 95 mmol) and potassium hydroxide (6.1 g, 92 mmol) in ethanol (250 mL) was stirred at room temperature during 2h. The reaction mixture was then filtered over decalite and concentrated to dryness to give a yellowish oil, which was used in the next step without further purification.
To the previous intermediate (3-(bromomethyl)oxetan-3-yl)methanol dissolved in EtOH (175 mL) was added cyanosodium (5.39 g, 1.15 eq). The reaction mixture was refluxed overnight. After cooling to room temperature, the reaction mixture was filtered and concentrated to give 3.8 g (31% overall yield) of the desired product 2-(3 -(hydroxymethyl)oxetan-3 -yl)acetonitrile (455) .
Step 2
Figure imgf000159_0001
2. NaSMe, DMF, 6O0C
455 456
A 250 mL round-bottomed flask was loaded with intermediate (455) (3.8 g, 29.9 mmol), methanesulfonyl chloride (6.94 ml, 90 mmol), and Hunig's Base (24.76 ml, 149 mmol) in CH2Cl2 (100 mL) at -200C to give a colorless solution. The resulting solution was allowed to warm to room temperature overnight. Then, the solution was poured in ice-cold water. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over MgSO4, filtered over decalite, then solvent was removed under reduced pressure. The residual oil was purified by column chromatography (gradient heptanes/ethyl acetate, 1 :0 to 0:1) to give a yellow oil. A 100 mL round-bottomed flask was loaded with the oil previously obtained (3700 mg, 18.03 mmol) and sodium thiomethoxide (1895 mg, 27.0 mmol) in DMF (20 mL). The resulting solution was heated at 65°C for 3 hours. Then, the reaction mixture was filtered, evaporated to give (3-methylsulfanylmethyloxetan-3-yl)acetonitrile (456), wish was used as such in the next step.
Step 3
Figure imgf000159_0002
456 457
m-CPBA was added at 00C to a solution of intermediate (456) in CH2CL2. The solution was allowed to warm up to room temperature overnight. Then, additional m-CPBA was added and the reaction mixture was stirred for another 4 hours. Next, the reaction mixture was quenched with a solution of NaHCO3 and the product was extracted with ethyl acetate. The combined organic layers were dried over MgSO4 and the solvent removed under reduced pressure. The residue was purified by column chromatography (gradient heptanes/ethyl acetate, 1 :0 to 0:1) to give (3-methanesulfonylmethyloxetan- 3-yl)acetonitrile (457) : 1H-NMR (400 MHz, CDCl3): 4.80 (2H, d, J= 7.3 Hz); 4.52 (2H, d, J= 7.4 Hz); 3.61 (2H, s); 3.29 (2H, s); 3.04 (3H, s).
Step 4
Figure imgf000160_0001
457 458
Potassium tert-butoxidc was added to a stirred solution of intermediate (457) in dry THF. After 1.5h, TLC analysis (CH2Cl2/methanol 90:10) showed complete conversion of the starting material. Then, water and CH2Cl2 were added and the aqueous layer was acidified slowly with concentrated HCl. The organic layer was dried over MgSO4, evaporated to dryness and purified by column chromatography. Fractions containing the product were combined and the solvent was removed under reduced pressure to give 6,6-dioxo-2-oxa-6λ6-thia-spiro[3.5]nonan-8-one (458): 1H-NMR (400 MHz, DMSO): 4.60 (2H, d, J= 6.4Hz); 4.28 (2H, s); 4.19 (2H, d, J= 6.4Hz); 3.93 (2H, s); 3.04 (2H, s). 13C-NMR (40 MHz, DMSO): 36.6 (C); 49.1 (CH2); 55.4 (CH2); 64.8 (CH2); 78.4 (CH2); 78.4 (CH2); 195.8 (C).
Example 46: synthesis of (459)
Figure imgf000160_0002
The title compound (459) was prepared following the 2-step procedure reported for the synthesis of compound (18) l l-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl- 1 , 1 -dioxo- 1 ,2,3 ,4,5, 11 -hexahydro- 1 λ6-thia-5 , 10-diazadibenzo[α, d]cycloheptene, using compound (458) instead of 5,5-dimethyl-l,l-dioxo-tetrahydro-thiopyran-3-one (5); m/z = 509 (M+H)+. Example 47: synthesis of (461)-(465)
Compounds (461)-(465) were prepared following the procedure reported for the synthesis of 10-isobutyryl-l l-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl- 1 , 1 -dioxo- 1,2,3,4,5,11 -hexahydro- 1 λ6-thia-5 , 10-diazadibenzo[α, Jjcycloheptene (21), starting from 1 l-[4-(2-Bromo-phenoxy)-2-fluoro-phenyl]-3,3-dimethyl-l,l-dioxo- 2,3,4,5,10,1 l-hexahydro-lH-lλ6-thia-5,10-diaza-dibenzo[a,d]cyclohepten-6-ol (207) and the acid chlorides indicated in the table below, instead of 1 l-(4-benzyloxy- 2-fluorophenyl)-6-hydroxy-3 ,3-dimethyl- 1 , 1 -dioxo- 1 ,2,3 ,4,5 , 11 -hexahydro- 1 λ6-thia- 5,10-diazadibenzo[α, J]cycloheptene (18) and isobutyryl chloride.
Table 9.
Nc Structure Acid chloride m/z (M+H)+
461 2-fluorobenzoyl 682 chloride
462 6-methyl-pyridine- 679 2-carbonyl chloride
463 2,5-dimethyl- 683 oxazole-4-carbonyl chloride
Figure imgf000161_0001
Nc Structure Acid chloride m/z (M+H)+
464 pyrazine carbonyl 666 chloride
465 oxazole-4-carbonyl 655 chloride
Figure imgf000162_0001
Example 48: synthesis of 5-Methyl-l J-dioxo-5-vinyl-tetrahvdro-thiopyran-3-one (466)
Figure imgf000162_0002
The title compound (466) was prepared following the 3 -step procedure reported for the synthesis of compound (280), using 2-methyl-2-vinyl-oxirane instead of 2-ethyl- 2-methyl-oxirane.
Example 49: synthesis of l l-(4-Benzyloxy-2-fluoro-phenyl)-3-methyl-l,l-dioxo- 3-vinyl-2.3.4.5.10.11-hexahvdro-lH-lλ6-thia-5.10-diaza-dibenzora.d1cvclohepten-6-ol
Figure imgf000162_0003
The title compound (467) was prepared following the 2-step procedure reported for the synthesis of 1 l-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl-l,l-dioxo- 1,2,3,4,5,1 l-hexahydro-lλ6-thia-5,10-diazadibenzo[α,d]cycloheptene (18), using compound (466) instead of 5,5-dimethyl-l,l-dioxo-tetrahydro-thiopyran-3-one (5); m/z = 507 (M+H)+.
Example 50: synthesis of 1 J-Dioxo-tetrahydro-thiopyran-3-one (470)
Figure imgf000163_0001
468 469
To a solution of methyl 4-(methylthio)butanoate (468) (27.62 g, 186 mmol) in chloro- form was added portion wise m-cPBA (84 g, 2 eq), at 00C. After 4h, a saturated solution of NaHCOs was added, then solid bicarbonate was added in portions until no gas evolution was observed. The reaction mixture was then extracted with CH2Cl2, the organic layer was washed with saturated bicarbonate solution, then brine, dried over MgSO4, filtered and concentrated under reduced pressure to give a quantitative yield of product 4-methanesulfonyl-butyric acid methyl ester (469) as a colorless oil.
Figure imgf000163_0002
469 470
To a solution of compound (469) (1.5 g, 8.32 mmol) in THF (100 niL) was added potassium tert-butoxide (2.34 g, 2.5 eq). After 1.5h, 5N HCl was added until a milky solution was obtained. Silica was then added and the reaction mixture was concentrated under reduced pressure. Purification by flash chromatography (eluent: ClHkCk/ethyl acetate 1 :1) afforded the desired product (470) as a white solid.
Example 51 : synthesis of l l-(4-Benzyloxy-2-fluoro-phenyl)-l,l-dioxo-2,3,4,5J0J l- hexahvdro-lH-lλ6-thia-5,10-diaza-dibenzora,d1cvclohepten-6-ol (471)
Figure imgf000164_0001
The title compound (471) was prepared following the 2-step procedure reported for the synthesis of 1 l-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl-l,l-dioxo- 1,2,3,4,5,1 l-hexahydro-lλ6-thia-5,10-diazadibenzo[α,d]cycloheptene (18), using compound (470) instead of 5,5-dimethyl-l,l-dioxo-tetrahydro-thiopyran-3-one (5); m/z = 467 (M+H)+.
Example 52: synthesis of aldehydes Aldehydes of example 52 were synthesized by nucleophilic substitution of a suitable halide derivative by a phenol derivative, in the presence of a base, as described for the synthesis of aldehyde (11).
Table 10.
Figure imgf000164_0002
Figure imgf000165_0001
Figure imgf000166_0002
The synthesis of bromodifluoromethylbenzene was performed according to the procedure of Journal of Fluorine Chemistry (2004), 125(4), 595-601. Nd: not detected.
Example 53: Representative procedure: synthesis of 4-(2-Bromo-phenoxy)-2-chloro- benzaldehyde
Figure imgf000166_0001
To a solution of 2-bromophenol (5.57 g, 32.2 mmol) in DMF were added cesium carbonate (11.31 g, 1.1 eq) and 2-chloro-4-fluorobenzaldehyde (4.96 g, 31.3 mmol). The reaction mixture was stirred at 75°C during 16h, was then cooled down to room temperature, diluted with water (500 mL) and extracted with ether. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 9.44 g (97%) of the target product as a yellow oil; m/z = 311 (M+H)+.
Example 54: synthesis of aldehydes
The following aldehydes were synthesized according to the representative procedure of example 53, using suitable haloaryl or haloheteroaryl derivatives and substituted phenols.
Table 11.
Figure imgf000167_0001
Figure imgf000168_0001
The synthesis of 4,5-dichloro-thiophene-2-carbaldehyde was performed according to the procedure of J. Prakt. Chemie 1964, 4, 24, p38.
Example 55: Representative procedure: synthesis of 4-Benzyloxy-2-trifluoromethyl- benzaldehyde
KOtBu
Figure imgf000168_0003
Figure imgf000168_0002
To a solution of benzylalcohol (619 mg, 5.73 mmol) in DMF (4 mL) was added potassium tert-butoxide (438 mg, 5.99 mmol) at room temperature. After 15 min, 4-fluoro-2-trifluoromethylbenzaldehyde was added, then the mixture was stirred at room temperature. After 2h, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over MgSO4, filtered and concentrated. The crude product was purified by flash chromatography on silica gel (eluent: gradient OfCH2Cl2 in heptane: 0:100 to 100:0) to afford the target aldehyde in 20% yield; m/z = 281 (M+H)+.
Example 56: synthesis of aldehydes
The following aldehydes were synthesized according to the representative procedure of example 55, using suitable haloaryl or haloheteroaryl derivatives and phenylmethanol.
Table 12.
Figure imgf000169_0002
Example 57: Representative procedure: synthesis of 2-Fluoro-4-(Yl£)-l-phenyl- ethoxy)benzaldehyde
Figure imgf000169_0001
To a mixture of 2-fluoro-4-hydroxybenzaldehyde (250 mg, 1.4 eq), (R)-(+)-phenyl- ethanol (156 mg, 1.274 mmol) and triphenylphosphine (468 mg, 1.4 eq) in dry THF, under N2, was added DIAD (361 mg, 1.4 eq). After stirring for 4h at room temperature, the reaction mixture was concentrated under reduced pressure and the crude was purified by flash chromatography on silica gel (eluent: CH2Cl2/heptane 6:4) to afford 244 mg (55% yield) of the target aldehyde. Example 58: Synthesis of 2-Fluoro-4-(thiophen-3-ylmethoxy)benzaldehyde
Figure imgf000170_0001
The target aldehyde was synthesized in 40% yield as a slightly yellow liquid following the representative procedure disclosed in example 57, using thiophen-3-yl methanol instead of (R)-(+)-phenylethanol.
Example 59: Synthesis of 4-(3,4-Difluoro-benzyloxy)-2-fluoro-benzaldehyde
Figure imgf000170_0002
The target aldehyde was synthesized in 25% yield as a white solid following the representative procedure disclosed for the synthesis of 2-Fluoro-4-((lS)-l-phenyl- ethoxy)-benzaldehyde, using 3,4-difluorobenzyl alcohol instead of (R)-(+)-phenyl- ethanol.
Example 60: synthesis of 4-Benzyloxy-2-isopropyl-benzaldehvde
Figure imgf000170_0003
To a solution of 4-benzyloxy-l-bromo-2-isopropyl-benzene (56.5 g, 185.12 mmol, synthesized as described in WO98/34919 PCT/IB98/00112) in dry THF (400 mL), under N2, at -78°C, was added n-BuLi (n-butyllithium; 135 mL, 1.6 M in hexane) in portions of 10 mL over several minutes. The reaction mixture was then stirred at -78°C during 30 minutes, and anhydrous DMF (21.6 mL, 1.5 eq) was added. After 20 minutes at -78°C, the reaction mixture was quenched by addition of IM HCl (200 mL). Water (100 mL) was added and the two layers were separated. The aqueous layer was extracted with ether and the combined organic layers were washed with IN NaOH, then brine, dried over MgSO4, filtered and concentrated. Purification by flash chromatography on silica gel (eluent: gradient Of CH2Cl2 in heptane 1 :9 to 10:0) afforded 28 g (60% yield) of the target product as a slightly yellow liquid; m/z = 255 (M+H)+. Example 61 : synthesis of 4-Benzyloxy-2-fluoro-5-methoxy-benzaldehyde
Figure imgf000171_0001
Step l
Figure imgf000171_0002
A mixture of 5-fluoro-2-methoxy-phenol (5 g, 35.18 mmol), benzylbromide (6.1 g, 1.01 eq) and K2CO3 (6.3 g, 1.3 eq) in ethanol was stirred at 500C during 17h. The reaction mixture was then filtered and concentrated to dryness to afford 4.8 g (59% yield) of the target product 2-benzyloxy-4-fluoro-l-methoxy-benzene.
Figure imgf000171_0003
To a solution of 2-benzyloxy-4-fluoro-l-methoxy-benzene (4.8 g, 20.67 mmol) in acetonitrile (100 mL), at 00C, was added N-bromosuccinimide (4.05 g, 1.1 eq). The ice bath was removed and the reaction mixture was stirred at room temperature during 16h. The reaction mixture was then concentrated and the residue was filtered through a pad of silica gel with CE^Cyheptane to afford 5.2 g (81% yield) of the target product l-benzyloxy-4-bromo-5-fluoro-2-methoxy-benzene as a white solid; m/z = 311 (M+H)+.
Figure imgf000172_0001
The target product 4-benzyloxy-2-fluoro-5-methoxy-benzaldehyde was synthesized in 90% yield following the procedure described in example 47, using 1-benzyloxy- 4-bromo-5-fluoro-2-methoxy-benzene instead of 4-benzyloxy- 1 -bromo-2-isopropyl- benzene; m/z = 261 (M+H)+.
Example 62: synthesis of 4-Benzyloxy-2-cyclopropyl-benzaldehyde
Figure imgf000172_0002
A mixture of 4-benzyloxy-2-hydroxy-benzaldehyde (2.4 g, 10.53 mmol), N,N-bis(tri- fluoromethylsulfonyl)aniline (3.95 g, 1.05 eq) and K2CO3 (4.365 g, 3 eq) in dry THF (1.5 mL) was stirred in a microwave oven at 1200C for 12 minutes. After cooling to room temperature, the reaction mixture was diluted with CH2Cl2, washed with water, then with a IN NaOH solution, then brine, dried over MgSO4, filtered and concentrated to afford 3.77 g (99% yield) of the target product trifluoro-methanesulfonic acid 5-benzyloxy-2-formyl-phenyl ester, which was used without further purification in the next step; m/z = 361 (M+H)+.
Step 2
Figure imgf000173_0001
A mixture of trifluoro-methanesulfonic acid 5-benzyloxy-2-formyl-phenyl ester (2.25 g, 6.245 mmol), KF (1.524 g, 4.2 eq), KBr (743 mg, 1 eq), tetrakis(triphenyl- phosphine) palladium(O) (361 mg, 0.05 eq) and cyclopropylboronic acid (1 g, 1.86 eq) in toluene, degassed by bubbling through nitrogen, was stirred in a microwave oven at 1200C during 15 minutes. After cooling to room temperature, the reaction mixture was diluted with CH2Cl2, washed with water, then brine, dried over MgSO4, filtered and concentrated to afford 1.3 g (83% yield) of the target product 4-benzyloxy-2-cyclo- propylbenzaldehyde; m/z = 253 (M+H)+.
Example 63: synthesis of 4-0 J-Difluoro-2-phenyl-ethyl)-2-fluoro-benzaldehvde
Figure imgf000173_0002
4-Bromo-3-fluorobenzoic acid (5.6 g, 25.6 mmol) was refluxed in thionyl chloride
(50 mL) during 2h. The reaction mixture was then concentrated under reduced pressure to afford 4-bromo-3-fluorobenzoyl chloride (6.07 g, quantitative yield) as an oil, which was used directly in the next step. A mixture of 4-bromo-3-fluorobenzoyl chloride (6.07 g, 25.6 mmol), benzylbromide (4.81 g, 1.1 eq), zinc (2.34 g, 1.4 eq) and (PPh3)2PdCl2 (0.9 g, 0.05 eq) in DME (dimethoxy ethane; 55 niL) was stirred at room temperature during 2.5h. The reaction mixture was then filtered on decalite, evaporated on silica and purified by flash chromatography (eluent: heptane/CH2Cl2 75:25) to give 4.18 g (56%) of the desired product 1 -(4-bromo-3-fluoro-phenyl)-2-phenyl-ethanone.
Figure imgf000174_0001
A mixture of l-(4-bromo-3-fluoro-phenyl)-2-phenyl-ethanone (4.18 g, 14.26 mmol), ethane- 1,2-dithiol (2.69 g, 2 eq), boron trifluoride etherate (2.02 g, 1 eq) and acetic acid (1.71 g, 2 eq) in CH2Cl2 was stirred at room temperature. After Ih, more boron trifluoride etherate (0.5 eq) was added and the reaction mixture was stirred at room temperature overnight. It was then diluted with CH2Cl2, and a saturated solution of NaHCO3 was carefully added under vigorous stirring. The organic layer was then washed with a 15% NaOH solution, then brine, dried over MgSO4, filtered and concentrated to give 3.86 g (73%) of the desired product 2-benzyl-2-(4-bromo- 3-fluoro-phenyl)-[l,3]dithiolane.
Figure imgf000174_0002
To l-iodopyrrolidine-2,5-dione (9.41 g, 41.8 mmol) in CH2Cl2 (15 mL) was carefully added pyridine hydrofluoride (10 mL) at -300C, under N2. To this mixture was then added a solution of 2-benzyl-2-(4-bromo-3-fluoro-phenyl)-[l,3]dithiolane (3.86 g, 10.45 mmol) in CH2Cl2 (20 mL). The reaction mixture was stirred during 2h, then was diluted with CH2Cl2, filtered on basic alumina, washed with a saturated solution of NaHCO3, then with a 10% solution OfNa2S2O3, dried over MgSO4, filtered and concentrated. Purification by flash chromatography afforded 1.2 g (36%) of the desired product l-bromo-4-(l,l-difluoro-2-phenyl-ethyl)-2-fluoro-benzene as a colorless solid that solidifies upon standing.
Figure imgf000175_0001
The title product 4-(l,l-difluoro-2-phenyl-ethyl)-2-fluoro-benzaldehyde was synthesized following the procedure used for the preparation of 4-benzyloxy-
2-isopropyl-benzaldehyde, using 1 -bromo-4-( 1 , 1 -difluoro-2-phenyl-ethyl)-2-fluoro- benzene (1.21 g, 3.84 mmol) instead of 4-benzyloxy-l-bromo-2-isopropylbenzene, and was obtained in 80% yield as a colorless oil that solidified upon standing.
Example 64: synthesis of compounds 510. 547-569 and 571-573. 575. 576. and 583- 585.
Compounds 510, 547-569 and 571-573, 575, 576, and 583-585 were prepared from the 2, 3, 4, 5, 10, 11 -hexahydro- 1 -thia-5 , 10-diaza-dibenzo[a,d]cycloheptene- 1 , 1 -dioxide derivative (reagent 1) and optionally reagent 2 indicated in the table below, following the protocol indicated in table 7.
Protocol A:
Reagent 1 indicated in the table was acylated following the procedure reported for the synthesis of 10-isobutyryl-l l-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl- 1,1-dioxo- 1,2,3, 4,5,1 l-hexahydro-lλ6-thia-5,10-diazadibenzo[α,<i]cycloheptene (21), using the acid chloride indicated in table 7 instead of isobutyryl chloride.
Protocol B:
Reagent 1 indicated in the table was alkylated following the procedure reported for the synthesis of [1 l-(4-allyloxy-2-fluoro-phenyl)-6-hydroxy-3,3-dimethyl-l,l-dioxo- 1 ,2,3,4,5, 11 -hexahydro- 1 λ6-thia-5, 10-diaza-dibenzo[a,d]cyclohepten- 10-yl]-(2,5-di- methyloxazol-4-yl)-methanone (263), starting from 6-(2,5-dimethyl-oxazole- 4-carbonyl)-7-(2-fluoro-4-hydroxy-phenyl)- 10, 10-dimethyl-8,8-dioxo-6,7,8,9, 10,11- hexahydro-2-oxa-8λ6-thia-6,l lb-diaza-dibenzo[cd,h]azulen-l-one (261) and the appropriate alkylating reagent indicated in Table 7 as reagent 2.
Protocol C:
Reagent 1 indicated in the table was alkylated following the procedure reported for the synthesis of (2,5-dimethyl-oxazol-4-yl)- { 11 -[2-fluoro-4-(2-thiophen-2-yl-ethoxy)- phenyl] -6-hydroxy-3 ,3-dimethyl- 1 , 1 -dioxo- 1 ,2,3 ,4,5 , 11 -hexahydro- 1 λ6-thia- 5,10-diazadibenzo[a,d]cyclohepten-10-yl}-methanone (272), starting from 6-(2,5-dimethyl-oxazole-4-carbonyl)-7-(2-fluoro-4-hydroxy-phenyl)- 10,10-dimethyl- 8,8-dioxo-6,7,8,9,10,l l-hexahydro-2-oxa-8λ6-thia-6,l lb-diaza-dibenzo[cd,h]azulen- 1-one (261) and the appropriate alcohol indicated in Table 7 as reagent 2 instead of 2-(thiophen-2-yl)ethano 1.
Protocol D:
Reagent 1 (racemic mixture) indicated in the table was purified by SFC with a chiral column, as described in Example 12 for the enantiomeric separation of the racemic mixture 11 -(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3 ,3-dimethyl- 1 , 1 -dioxo-
10-[(2,5-dimethyloxazol-4-yl)carbonyl]- 1 ,2,3,4,5, 11 -hexahydro- 1 λ6-thia-5, 10-diaza- dibenzo[a,d]cycloheptene (23) and the obtained stereochemistry is indicated in table
13.
Table 13.
Figure imgf000176_0001
Figure imgf000177_0001
Figure imgf000178_0001
Figure imgf000179_0001
Figure imgf000180_0001
Figure imgf000181_0001
Figure imgf000182_0001
Figure imgf000183_0001
Figure imgf000184_0001
Figure imgf000185_0001
Figure imgf000186_0001
Example 65: synthesis of l l-r2,3-difluoro-4-(2-methyl-allyloxy)-phenyll-3,3-dimethyl- ll,Jl--ddiiooxxoo--22 ,3,4,5J0J l-hexahydro-lH-lλ6-thia-5J0-diaza-dibenzora,dlcvclohepten-
6-ol (570V
Figure imgf000187_0001
Step 1: synthesis of 2,3-difluoro-4-(2-methylallyloxy)benzaldehyde
Figure imgf000187_0002
The target product 2,3-difluoro-4-(2-methylallyloxy)benzaldehyde was synthesized in quantitative yield from 2,3-difluoro-4-hydroxybenzaldehyde and 3-chloro-2-methyl- propene following the procedure reported for the preparation of intermediate (11); m/z = 213 (M+H)+.
Step 2: the target product (570) was synthesized from 2,3-difluoro-4-(2-methylallyl- oxy)benzaldehyde and intermediate (16) following the procedure reported for the preparation of 1 l-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl-l,l-dioxo- 1,2,3,4,5,1 l-hexahydro-lλ6-thia-5,10-diazadibenzo[α,<i]cycloheptene (18): m/z = All (M+H)+.
Example 66: synthesis of {l l-[2,3-difluoro-4-(2-methylallyloxy)phenyll-6-hydroxy- 3, 3-dimethyl- 1,1 -dioxo- 1,2,3,4,5, 11-hexahydro- Iλ6-thia-5,l Q-diaza-dibenzo[a,dl- cyclohepten-10-yl|(2,5-dimethyloxazol-4-yl)methanone (574).
Figure imgf000187_0003
The title compound (574) was prepared from compound (570) and 2,5-dimethyloxazol- 4-carbonyl chloride following the procedure reported for the preparation of 10-isobutyryl- 11 -(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3 ,3-dimethyl- 1 , 1 -dioxo- 1,2,3,4,5,1 l-hexahydro-lλ6-thia-5,10-diazadibenzo[α,<i]cycloheptene (21): m/z = 600 (M+H)+.
Example 67: synthesis of (S)-[I l-[2,3-difluoro-4-(2-methylallyloxy)phenyl]- 6-hydroxy-3 ,3-dimethyl- 1 , 1 -dioxo- 1,2,3.4,5,11 -hexahydro- 1 λ6-thia-5 , 10-diaza- dibenzo[a,d]cyclohepten-10-yU(2,5-dimethyloxazol-4-yl)methanone (578) and (R)- { 11 -[2,3-difluoro-4-(2-methylallyloxy)phenyll-6-hydroxy-3,3-dimethyl- 1 , 1 -dioxo- 1.2,3.4,5.1 l-hexahvdro-lλ6-thia-5.10-diaza-dibenzora,dlcvclohepten-10-yl|(2,5- dimethyloxazol-4-yl)methanone (577).
Figure imgf000188_0001
The title compounds (578) and (577) were prepared from compound (574) following the procedure reported in example 12 for the preparation of (R)-I l-(4-benzyloxy- 2-fluorophenyl)-6-hydroxy-3,3-dimethyl- 1 , 1 -dioxo- 10-[(2,5-dimethyloxazol-4-yl)- carbonyl]- 1 ,2,3 ,4,5 , 11 -hexahydro- 1 λ6-thia-5 , 10-diazadibenzo[α, Jjcycloheptene (26) and (S)- 11 -(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl- 1 , 1 -dioxo- 10-[(2,5- dimethyloxazol-4-yl)carbonyl]- 1 ,2,3 ,4,5 , 11 -hexahydro- 1 λ6-thia-5 , 10-diazadibenzo- [a, JJcycloheptene (27): (577) m/z = 600 (M+H)+; (578); m/z = 600 (M+H)+; Rt = 4.34 min; 1H NMR (400 MHz, DMSO-J6) δ ppm 1H NMR (400 MHz, DMSO-J6) δ ppm 1.14 (s, 3H), 1.22 (s, 3 H), 1.70 (s, 3H), 2.12 (s, 3H), 2.21 (s, 3H), 2.78 (d, J= 16.0 Hz, IH), 2.83 (d, J= 16.0 Hz, IH), 3.20-3.13 (m, 2 H), 4.45 (s, 2H), 4.93 (m, IH) 4.98 (m, IH), 5.84 (d, J= 7.8 Hz, IH), 6.45 (t, J= 7.8 Hz, 1 H), 6.55 (d, J= 7.8 Hz, IH), 6.60 (m, IH), 6.74 (m, IH), 7.48 (s, IH), 7.75 (s, IH), 10.21 (bs, IH); Rt on SFC using a ADH column with 20% MeOH: 1.68 min. Example 68: alternative synthesis for (5V(2,5-Dimethyl-oxazol-4-yl)-{l l-[2-fiuoro- 4-(2-methyl-allyloxy)-phenyll-6-hydroxy-3 ,3-dimethyl- 1 , 1 -dioxo- 1,2,3-4,5.11- hexahydro- 1 λ6-thia-5 , 10-diaza-dibenzo |"a,d]cyclohepten- 10-yl| -methanone (383).
Figure imgf000189_0001
Step 1: synthesis of l l-[2-fluoro-4-(2-methylallyloxy)phenyl]-3,3-dimethyl-l,l-dioxo- 2,3,4,5,10,1 l-hexahydro-lH-lλ6-thia-5,10-diazadibenzo[a,d]cyclohepten-6-ol (579) and 1 -[2-Fluoro-4-(2-methyl-allyloxy)-phenyl]-3,3-dimethyl- 1 , 1 -dioxo- 2,3,4,5,10,1 l-hexahydro-lΗ-lλ6-thia-5,10-diaza-dibenzo[a,d]cyclohepten-9-ol (580).
Figure imgf000189_0002
The title compounds (579) and (580) were prepared from 2-fluoro-4-(2-methylallyl- oxy)benzaldehyde and a mixture of compounds (16) and (17) following the procedure reported in example 5 for the preparation of 1 l-(4-benzyloxy-2-fluorophenyl)-6- hydroxy-3 ,3-dimethyl- 1 , 1 -dioxo- 1,2,3,4,5,11 -hexahydro- 1 λ6-thia-5 , 10-diazadibenzo- [α,d]cycloheptene (18) and l l-(4-benzyloxy-2-fluorophenyl)-9-hydroxy-3,3-dimethyl- 1,1 -dioxo- 1,2,3, 4,5,1 l-hexahydro-lλ6-thia-5,10-diazadibenzo[α,<i]cycloheptene (19).
Step 2: synthesis of l l-[2-fluoro-4-(2-methylallyloxy)-phenyl]-8,8-dimethyl- 10,10-dioxo-6,7,8,9, 10,11 -hexahydro-2-oxa- 10λ6-thia-6, 11 a-diaza- dibenzo[cd,g]azulen-l-one (581) and 7-[2-fluoro-4-(2-methylallyloxy)phenyl]- 10,10-dimethyl-8,8-dioxo-6,7,8,9,10,l l-hexahydro-2-oxa-8λ6-thia-6,l lb-diaza- dibenzo[cd,h]azulen-l-one (582).
Figure imgf000190_0001
CDI (1.5 eq.) was added to a stirred solution of compounds (579) and (580) in DMF. After 45 minutes at room temperature, the reaction mixture was filtered on decalite, then quenched with water. The resulting solution was concentrated under reduced pressure, then diluted with water. The solid obtained was collected by filtration. Purification by column chromatography (CH2Cl2) gave the desired products: (581); m/z = 485 (M + H)+, (582); m/z = 485 (M + H)+; 1H NMR (400 MHz, DMSO-J6) δ ppm 1.21 (s, 3H), 1.24 (s, 3 H), 1.70 (s, 3H), 2.79 (d, J= 17.7 Hz, 1 H), 3.41 (d, J= 13.5 Hz, 1 H), 3.52 (d, J= 17.7 Hz, 1 H), 3.55 (d, J= 13.5 Hz, 1 H), 4.40 (s, 2 H), 4.91 (m, IH) 4.99 (m, 1 H), 5.59 (d, J= 6.0 Hz, 1 H), 6.54-6.66 (m, 3H), 6.78 (dd, J= 2.5, 12.9 Hz, 1 H), 6.88 (t, J= 8.0 Hz, 1 H), 6.93 (d, J= 6.0 Hz, 1 H), 7.07 (t, J= 9.0 Hz, 1 H); 13C NMR (101 MHz, DMSO-J6) δ ppm 19.1 (CH3), 25.1 (CH3), 29.7 (CH3), 31.8 (C), 39.2 (CH2), 48.7 (CH), 58.4 (CH2), 71.2 (CH2), 100.1 (CH), 102.8 (CH, d, J= 25.6 Hz),
110.1 (CH), 112.5 (CH), 112.7 (CH2), 115.4 (C), 118.0 (C, d, J=13.2 Hz), 124.5 (CH), 125.9 (C), 128.7 (CH), 135.4 (C), 140.4 (C), 141.6 (C), 142.2 (C), 150.3 (C), 159.2 (C, d, J= 11.7 Hz), 160.7 (C, d, J= 247.4 Hz).
Step 3: synthesis of 1 l-[2-fluoro-4-(2-methylallyloxy)phenyl]-3,3-dimethyl-l,l-dioxo- 2,3,4,5,10,1 l-hexahydro-lH-lλ6-thia-5,10-diazadibenzo[a,d]cyclohepten-6-ol (579).
Figure imgf000190_0002
An aqueous solution of LiOH (51.7 mmol) was added to a stirred solution of compound (582) (8.35 g, 17.2 mmol) in THF (200 mL) and methanol (5 mL). After 30 minutes at room temperature, the pH of the resulting solution was adjusted to 6 with 2M HCl. The reaction mixture was concentrated under vacuum. The precipitate formed was collected by filtration, then dried to give the title product (579) as a white powder in quantitative yield: m/z = 459 (M+H)+.
Step 4: synthesis of (5)-(2,5-dimethyl-oxazol-4-yl)-{l l-[2-fluoro-4-(2-methyl- allyloxy)phenyl]-6-hydroxy-3 ,3-dimethyl- 1 , 1 -dioxo- 1 ,2,3 ,4,5 , 11 -hexahydro- 1 λ6-thia- 5,10-diaza-dibenzo[a,d]cyclohepten- 10-yl} -methanone (383).
Figure imgf000191_0001
The title product (383) was prepared from compound (579) following the procedures reported in Table 7: m/z = 582.66 (M + H)+; 1H NMR (400 MHz, DMSO-J6) δ ppm 1.14 (s, 3H), 1.22 (s, 3 H), 1.69 (s, 3H), 2.12 (s, 3H), 2.18 (s, 3H), 2.76 (d, J= 16.0 Hz, 1 H), 2.83 (d, J= 16.0 Hz, 1 H), 3.10-3.19 (m, 2 H), 4.36 (s, 2H), 4.90 (m, IH) 4.97 (m, 1 H), 5.80 (d, J= 7.8 Hz, 1 H), 6.41 (t, J= 7.8 Hz, 1 H), 6.47-6.57 (m, 2 H), 6.68 (dd, J = 12.4, 2.2 Hz, 1 H), 6.76 (t, J= 8.8 Hz, 1 H), 7.44 (s, 1 H), 7.67 (s, 1 H), 10.15 (bs, 1 H). 13C NMR (101 MHz, DMSO-J6) δ ppm 10.6 (CH3), 13.1 (CH3), 19.1 (CH3), 28.1 (CH3), 29.0 (CH3), 32.0 (C), 42.3 (CH2), 49.2 (CH), 61.3 (CH2), 71.1 (CH2), 101.8 (CH, d, J= 24.9 Hz), 104.6 (C), 109.7 (CH), 112.6 (CH2), 112.9 (CH), 118.8 (C, d, J= 14.6 Hz), 119.5 (CH), 122.2 (CH), 125.6 (C), 130.1 (C), 130.8 (CH, d, J= 5.1 Hz), 131.1 (C), 140.4 (C), 146.2 (C), 147.1 (C), 150.0 (C), 157.5 (C), 159.0 (C, d, J= 11.0 Hz), 159.9 (C, d, J= 247.4 Hz), 160.3 (C). Example 69: synthesis of (2,5-dimethyl-oxazol-4-yl)-[l l-(2-fluoro-4-hydroxy-phenyl)- 6-hydroxy-3 ,3-dimethyl- 1 , 1 -dioxo- 1,2,3.4,5,11 -hexahydro- 1 λ6-thia-5 , 10-diaza- dibenzora,dlcyclohepten- 10-yll-methanone (528).
Figure imgf000192_0001
A solution of 6-(2,5-dimethyl-oxazole-4-carbonyl)-7-(2-fluoro-4-hydroxy-phenyl)- 10,10-dimethyl-8,8-dioxo-6,7,8,9,10,l l-hexahydro-2-oxa-8λ6-thia-6,l lb-diaza- dibenzo[cd,h]azulen-l-one (261) in THF was treated with an aqueous solution of LiOH (5 eq.). After Ih at room temperature, the pH of the reaction mixture was adjusted to 6 with HCl. The reaction mixture was extracted with ethyl acetate, the organic layer was dried (Na2SO4) and then evaporated. The residue was purified by column chromatography to give the title product (528) as a white powder: m/z = 528 (M + H)+.
Example 70: synthesis of l l-[4-fluoro-2-(2-fluoro-phenoxy)-phenyl]-3,3-dimethyl- l,l-dioxo-2, 3,4, 5, 10, 11 -hexahydro- IH- Iλ6-thia-5,10-diaza-dibenzo[a,dlcyclohepten- 6-ol (542).
Figure imgf000192_0002
The title product (542) was synthesized from intermediate (16) and 4-fluoro- 2-(2-fluorophenoxy)benzaldehyde, following the procedure reported for the preparation of 11 -(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3 ,3-dimethyl- 1 , 1 -dioxo-
1,2,3,4,5,1 l-hexahydro-lλ6-thia-5,10-diazadibenzo[α,d]cycloheptene (18): m/z = 499 (M + H)+. Example 71: Alternative preparation of l-(2-chloro-allylsulfanyl)-2-methyl-propan-2-ol
Step 1: synthesis of 2-chloroprop-2-ene-l -thiol (544).
S «. EtOH Ii _ r^\
H2N NNHH2 Il NaOH H2N s T || water H-Cl "
(543) (544)
Thiourea (164.85 g, 1 eq.) was added to a suspension of 2,3-dichloropropene (240.32 g, 2.17 mol) in ethanol (1.2 L). The reaction mixture was heated to reflux for 12h, then cooled down to room temperature. A solution of NaOH in water (650 mL) was added drop-wise. The reaction mixture was then heated at 700C for 5h, then cooled down to room temperature for 78h. The brown oil obtained was separated from the aqueous layer. The pH of the aqueous layer was acidified with H2SO4 (~75 mL). The resulting solution was extracted with ether. The ether fraction was combined with the brown oil previously obtained. This organic fraction was dried (Na2SO4) and used as such in the next step of the synthesis.
Step 2:
Figure imgf000193_0001
Methanol (1.5 L) was added to a fraction of the solution obtained in Step 1 and containing (544). Then, sodium methoxide (43 g, 0.8 mol) was added portion-wise at 00C. After Ih, 2,2-dimethyloxirane (60 g, 0.8 mol) was slowly added at 00C. The resulting solution was stirred at room temperature for 12h. Then, the pH of the reaction mixture was adjusted to 7 with diluted HCl (0.5 N in water). The organic layer was successively separated, washed with water and brine, and dried (Na2SO4). Then, the solvent was evaporated to give HO g (75%) of the target product (3) as a brown oil. Table 14.
Figure imgf000194_0001
Example 72: Activity of compounds of formula (I) Replicon assay
The compounds of formula (I) were examined for inhibitory activity of HCV RNA replication in a cellular assay. The assay demonstrated that the compounds of formula (I) inhibited a HCV functional cellular replicating cell line, also known as HCV replicons. The cellular assay was based on a bicistronic expression construct, as described by Lohmann et al. (1999) Science vol. 285 pp. 110-113 with the modifications described by Krieger et al. (2001) Journal of Virology 75: 4614-4624, in a multi-target screening strategy. In essence, the method was as follows: The assay utilized the stably transfected cell line Huh-7 luc/neo (hereafter referred to as Huh-Luc). This cell line harbors an RNA encoding a bi-cistronic expression construct comprising the wild type NS3-NS5B regions of HCV type Ib translated from an Internal Ribosome Entry Site (IRES) from encephalomyocarditis virus (EMCV), preceded by a reporter portion (FfL-luciferase), and a selectable marker portion (neoR, neomycine phosphotransferase). The construct is bordered by 5' and 3' NTRs (non-translated regions) from HCV type Ib. Continued culture of the replicon cells in the presence of G418 (neoR) is dependent on the replication of the HCV RNA. The stably transfected replicon cells that express HCV RNA, which replicates autonomously and to high levels, encoding inter alia luciferase, are used for screening the antiviral compounds.
The replicon cells were plated in 384-well plates in the presence of the test and control compounds which were added in increasing concentrations. Following an incubation of three days, HCV replication was measured by assaying luciferase activity (using standard luciferase assay substrates and reagents and a Perkin Elmer ViewLux™ ultraHTS microplate imager). Replicon cells in the control cultures have high luciferase expression in the absence of any inhibitor. The inhibitory activity of the compounds was monitored on the Huh-Luc cells, enabling a dose-response curve to be generated for each test compound. EC50 values were then calculated, which value represents the amount of the compound required to decrease by 50% the level of detected luciferase activity, or more specifically, the ability of the genetically linked HCV replicon RNA to replicate.
Enzymatic assay a) Protein purification
The cDNA encoding NS5B amino acid 1-570 (HC-J4, genotype Ib, pCV-J4L6S, genebank accession number AF054247) was subcloned into the Nhe I and Xho I restriction sites of pET-21b. Expression of the subsequent His-tagged C-terminal 21 amino acid deleted NS5B was performed as follows:
The NS5B expression construct was transformed into E. coli BL21(DE3) (Novagen, Madison, WI). Five milliliter of LB-medium supplemented with ampicillin (50 μg/mL) was inoculated with one colony. When the pre-culture reached an optical density of 0.6 measured at 600 nm, it was transferred to fresh LB-medium supplemented with ampicillin, at a ratio of 1 :200. Cells were grown to an optical density at 600 nm of 0.6, after which the expression cultures were shifted to a growth temperature of 200C following induction with ispopropyl-1-thio-β-D-galactopyranoside and MgCl2 at a final concentration of 0.4 mM and 10 μM, respectively. After ten hours of induction, cells were harvested by centrifugation and resuspended in 20 mM Tris-HCl, pH 7.5, 300 mM NaCl, 10% glycerol, 0.1% NP40, 4 mM MgCl2, 5 mM DTT supplemented with EDTA- free Complete Protease Inhibitor (Roche, Basel, Switzerland). Cell suspensions were disrupted by sonication and incubated with 10-15 mg/L of DNase I (Roche, Basel, Switzerland) for 30 minutes. Cell debris was removed through ultracentrifugation at 30,000 x g for 1 hour and clarified cell lysate was flash frozen and stored at -800C prior to purification.
Clarified cell lysate was thawed and subsequently loaded onto a 5 mL pre-packed HisTrap FF column equilibrated with 25 mM HEPES, pH 7.5, 500 mM NaCl, 10% glycerol and 5 mM DTT. Proteins were eluted with 500 mM imidazole at a flow rate of 1 mL/min. Fractions containing the protein of interest were applied onto a pre-packed 26/10 HiPrep Desalting Column equilibrated with 25 mM HEPES, pH 7.5, 150 mM NaCl, 10% glycerol and 5 mM DTT. The buffer-exchanged NS5B peak was then applied onto a 20 mL PoIy-U Sepharose column. Protein was eluted with an increasing salt gradient and fractions collected. Protein purity was assessed on Nu-PAGE pre-cast gels (Invitrogen, Carlsbad, CA). Purified NS5B samples were concentrated using Centri-Prep concentrators (Millipore, Billerica, MA, USA) and protein concentrations were determined by Bradford assay (Pierce, Rockford, IL, USA).
b) Protein Sequence PDB: Inb4, Apo form . The protein sequence is as described in WO 2007/026024. CaIc. MoI. Properties: 64941.4 g/mol.
c) Inhibition assay
Measurement of HCV NS5B polymerization activity was performed by evaluating the amount of radiolabeled GTP incorporated by the enzyme in a newly synthesized RNA using heteropolymeric RNA template/primer. The RdRp assay was carried out in 384-well plates using 50 nM enzyme, 300 nM 5'-biotinylated oligo(rGi3)/poly(rC) primer-template, 600 nM of GTP, and 0.1 μCi of [3H]GTP in 25 mM Tris-HCl, pH 7.5, 5 mM MgCl2 , 25 mM KCl, 17 mM NaCl and 3 mM of DTT. Test compounds were dissolved in DMSO. The test compounds were added to the preformed polymerase- template complex, and incubated at room temperature for 15 min before the addition of NTPs. The 30 μl reaction was terminated after 2h at 25°C upon addition of 30 μl streptavidin-coated SPA beads (GE Heathcare, Uppsala, Sweden 5 mg/ml in 0.5 M EDTA). After incubation at 25°C for 30 min, the plate was counted using a Packard TopCount microplate reader (30 sec/well, 1 min count delay) and IC50 values were calculated. IC50 values represent the concentration of compound required to decrease by 50% the amount of RNA produced which is measured by the detection of incorporated radiolabeled GTP. The following Table 14 the activities of compounds that were prepared according to any one of the above examples, in the replicon (EC50) and enzymatic (IC50) assay.
Table 14
Figure imgf000197_0001
Figure imgf000198_0001
Figure imgf000199_0001
Figure imgf000200_0001
Figure imgf000201_0001
Figure imgf000202_0001
Figure imgf000203_0001
Figure imgf000204_0001
Figure imgf000205_0001
Figure imgf000206_0001
Figure imgf000207_0001
Figure imgf000208_0001
Figure imgf000209_0001

Claims

Claims
1. A compound having the formula (I):
Figure imgf000210_0001
and the stereoisomers, prodrugs, tautomers, racemics, salts, hydrates or solvates thereof, wherein Rla is hydrogen, hydroxy, amino, Ci_6alkoxy, halo or Ci_6alkyl optionally substituted with hydroxyl;
Rlb is hydrogen, hydroxy, amino, Ci_6alkoxy, -O-CH2-thiazolyl, halo, trifluoromethyl, or Ci_6alkyl optionally substituted with cyano;
R2 is hydrogen, -C(=O)-R5, -C(=O)-C(=O)-R5, -C(=O)-OR6, or -C(=O)-NR7aR7b; R3 is Ci_6alkyl optionally substituted with C3_7Cycloalkyl, aryl, or Het;
C3-7cycloalkyl; aryl; or Het; each R4a and R4b is, independently, hydrogen, Ci_6alkyl, C2-6alkenyl, or both R4a and R4b together with the carbon atom of the tricyclic ring to which they are attached may form a C3_7Cycloalkyl or an oxetanyl;
R5 is Ci_6alkyl optionally substituted with one or two substituents selected from halo, C3_7Cycloalkyl, phenylCi-βalkylthio, cyano, polyhaloCi-βalkyl, oxo, -OR9, -C(=O)-Het, -C(=O)-OR6, -C(=O)-OH, -C(=O)-NR7aR7b, -C(=O)-NH-S(=O)2-R8, -NR7aR7b, -S(=O)2-aryl, aryl, and Het; C2-6alkenyl optionally substituted with aryl; polyhaloCi-βalkyl; C3-7cycloalkyl; aryl; or Het; R6 is aryl or Ci_6alkyl optionally substituted with -OR9, -C(=O)-OR9,
-C(=O)-NR7aR7b, -C(=O)-NH-S(=O)2-R8, aryl, or Het; each R7a and R7b is, independently, hydrogen; Ci_6alkyl optionally substituted with one or two substituents selected from -OR9, mono- or diCi_6alkylamino,
-C(=O)-OR9, -C(=O)-NH2, -C(=O)-NH-Ci_6alkyl, -C(=O)-NH-hydroxy- Ci_6alkyl, -C(=O)-Het, C3-7cycloalkyl, aryl, and Het; C2-6alkenyl; C3-7cycloalkyl optionally substituted with hydroxy; aryl; or Het; R8 is Ci_6alkyl, C3-7cycloalkyl, di(Ci_3alkyl)amino, or aryl; R9 is hydrogen; Ci_6alkyl optionally substituted with one, two or three substituents each independently selected from halo, hydroxyl, C3-7cycloalkenyl, C3-7cycloalkyl, cyano, Ci_6alkoxy, phenyl, or Het, wherein the phenyl may optionally be substituted with halo, hydroxyl, Ci_6alkoxy, Ci_6alkoxyCi_6alkoxy, Ci_6alkyl, nitro, or amino; C2-6alkenyl optionally substituted with one or two substituents selected from halo and polyhaloCi-βalkyl; C2-6alkynyl; C3-7cycloalkenyl; or phenyl optionally substituted with one or two substituents selected from hydroxyl, Ci_6alkoxy, halo, polyhaloCi-βalkyl, amino, nitro, d-βalkyl, and phenyl; aryl as a group or part of a group is phenyl, naphthyl, indanyl, or 1,2,3,4-tetrahydro- naphthyl, each of which may be optionally substituted with one two, three or four substituents each independently selected from the group consisting of
C3-7cycloalkyl, phenylCi-βalkyl, phenylpolyhaloCi-βalkyl, phenylCi-βalkyloxy, halo, polyhaloCi-βalkyl, cyano, Ci_6alkyl, polyhaloCi-βalkoxy, -OR9, - C(=O)OH, Ci_6alkylcarbonyl, Ci_6alkylthio, Ci_6alkylsulfonyl, -S(=O)2NH2, and pyrrolyl, wherein the phenyl may optionally be substituted with halo ; or two substituents on the aryl ring may form -0-CH2-O- or a -0-C(CHs)2-CH2-;
Het as a group or part of a group is a 5 to 12 membered saturated, partially unsaturated or completely unsaturated mono- or bicyclic ring containing 1 to 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, being optionally condensed with one benzene ring, and wherein the group Het as a whole may be optionally substituted with one or two substituents each independently selected from the group consisting of halo; polyhaloCi-βalkyl; Ci_6alkylthio, oxo; -OR9; -NR10aR10b; -CN; Ci_6alkyl optionally substituted with -OR9, -CN, -NR10aR10b, or phenyl;-C(=O)-NH2; -C(=O)-phenyl; C3_7Cycloalkyl; phenyl optionally substituted with Ci_6alkoxy; morpholinyl; pyrrolidinyl; pyrrolyl; furanyl; tetrazolyl; and thiophenyl; and each R1Oa and R10b is, independently, hydrogen, Ci_6alkyl, arylCi-βalkyl, or R1Oa and R10b, together with the nitrogen to which they are attached, may form a saturated, partially unsaturated, or completely unsaturated 5-8 membered monocycle, wherein said monocycle optionally contains one additional heteroatom selected from the group consisting of oxygen, sulfur and nitrogen, and wherein the remaining monocycle members are carbon atoms; wherein said monocycle may be optionally substituted on any carbon atom with one or two substituents each independently selected from halo, Ci_6alkyl, hydroxy, or oxo.
2. A compound according to claim 1, wherein Rla is hydrogen, hydroxy, amino, or halo; Rlb is hydrogen, hydroxy, halo, trifluoromethyl, or Ci_6alkyl optionally substituted with cyano; R2 is hydrogen, -C(=O)-R5, -C(=O)-C(=O)-R5, -C(=O)-OR6, or -C(=O)-NR7aR7b;
R3 is Ci_6alkyl optionally substituted with C3_7Cycloalkyl, aryl, or Het;
C3-7cycloalkyl; aryl; or Het; each R4a and R4b is, independently, Ci_6alkyl, or both R4a and R4b together with the carbon atom of the tricyclic ring to which they are attached may form a C3-ycy cloalkyl;
R5 is Ci_6alkyl optionally substituted with one or two substituents selected from cyano, polyhaloCi_6alkyl, oxo, -OR9, -C(=O)-Het, -C(=O)-OR6, -C(=O)-OH, -C(=O)-NR7aR7b, -C(=O)-NH-S(=O)2-R8, -NR7aR7b, aryl, and Het; C2-6alkenyl optionally substituted with aryl; polyhaloCi-βalkyl; C3_7Cy cloalkyl; aryl; or Het; R6 is Ci_6alkyl optionally substituted with -OR9, -C(=O)-OR9, -C(=O)-NR7aR7b,
-C(=O)-NH-S(=O)2-R8, aryl, or Het; each R7a and R7b is, independently, hydrogen; Ci_6alkyl optionally substituted with one or two substituents selected from -OR9, mono- or diCi_6alkylamino, -C(=O)-OR9, -C(=O)-NH2, -C(=O)-NH-Ci_6alkyl, -C(=O)-NH-hydroxyCi_6alkyl, -C(=O)-Het, C3-7cycloalkyl, aryl, and Het;
C2_6alkenyl; C3-7cycloalkyl optionally substituted with hydroxy; aryl; or Het; R8 is Ci_6alkyl, C3_7Cycloalkyl, di(Ci_3alkyl)amino, or aryl; R9 is hydrogen; Ci_6alkyl optionally substituted with Ci_6alkoxy, phenyl, or Het, wherein the phenyl may optionally be substituted with halo, Ci_6alkoxy, nitro, or amino; or phenyl optionally substituted with one or two substituents selected from halo, amino, nitro, Ci_6alkyl, and phenyl; aryl as a group or part of a group is phenyl, naphthyl, indanyl, or 1,2,3,4-tetrahydro- naphthyl, each of which may be optionally substituted with one or two substituents each independently selected from the group consisting of halo, polyhaloCi_6alkyl, cyano, d_6alkyl, polyhaloCi_6alkoxy, -OR9, -C(=O)OH,
Ci_6alkylcarbonyl, Ci_6alkylthio, Ci_6alkylsulfonyl, -S(=O)2NH2, and pyrrolyl; Het as a group or part of a group is a 5 to 12 membered saturated, partially unsaturated or completely unsaturated mono- or bicyclic ring containing 1 to 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, being optionally condensed with one benzene ring, and wherein the group Het as a whole may be optionally substituted with one or two substituents each independently selected from the group consisting of halo; oxo; -OR9; -NR10aR10b; -CN; d_6alkyl optionally substituted with -OR9, -CN, -NR10aR10b, or phenyl;-C(=O)-NH2; -C(=O)-phenyl; C3-7cycloalkyl; phenyl optionally substituted with Ci_6alkoxy; morpholinyl; pyrrolidinyl; pyrrolyl; furanyl; tetrazolyl; and thiophenyl; and each R1Oa and R10b is, independently, hydrogen, Ci_6alkyl, arylCi-βalkyl, or R1Oa and R10b, together with the nitrogen to which they are attached, may form a saturated, partially unsaturated, or completely unsaturated 5-8 membered monocycle, wherein said monocycle optionally contains one additional heteroatom selected from the group consisting of oxygen, sulfur and nitrogen, and wherein the remaining monocycle members are carbon atoms; wherein said monocycle may be optionally substituted on any carbon atom with one or two substituents each independently selected from halo, C^alkyl, hydroxy, or oxo.
3. A compound according to claim 1 or 2, having one of the structural Formula (II) or
Figure imgf000213_0001
(II) (III)
wherein Rla, Rlb, R2, R3, R4a and R4b are as specified in any one of claims 1 or 2.
4. A compound according to claim 1 or 3, wherein:
Rla is hydrogen, hydroxy, amino, or hydroxyCi-βalkyl;
Rlb is hydrogen, hydroxy, halo, amino, Ci_6alkoxy, -O-CH2-thiazolyl, trifluoromethyl, or Ci_6alkyl optionally substituted with cyano; R2 is hydrogen, -C(=O)-R5, -C(=O)-C(=O)-R5, -C(=O)-OR6, or -C(=O)-NR7aR7b; R3 is Ci_6alkyl optionally substituted with C3_7Cycloalkyl, aryl, or Het;
C3-7cycloalkyl; aryl; or Het; each R4a and R4b is, independently, hydrogen, C2-6alkenyl, or Ci_6alkyl; or both R4a and R4b together with the carbon atom of the tricyclic ring to which they are attached may form an oxetanyl; R5 is Ci_6alkyl optionally substituted with one or two substituents selected from halo, C3_7Cycloalkyl, phenylCi-βalkylthio, cyano, polyhaloCi-βalkyl, oxo, -OR9,
-C(=O)-Het, -C(=O)-OR6, -C(=O)-OH, -C(=O)-NR7aR7b, -C(=O)-NH-S(=O)2-R8, -NR7aR7b, -S(=O)2-aryl, aryl, and Het; C2-6alkenyl optionally substituted with aryl; polyhaloCi-βalkyl; C3_7Cycloalkyl; aryl; or Het; R6 is aryl or Ci_6alkyl optionally substituted with -OR9, -C(=O)-OR9,
-C(=O)-NR7aR7b, -C(=O)-NH-S(=O)2-R8, aryl, or Het; each R7a and R7b is, independently, hydrogen; Ci_6alkyl optionally substituted with one or two substituents selected from -OR9, mono- or diCi_6alkylamino, -C(=O)-OR9, -C(=O)-NH2, -C(=O)-NH-Ci_6alkyl,
-C(=O)-NH-hydroxyCi_6alkyl, -C(=O)-Het, C3-7cycloalkyl, aryl, and Het; C2_6alkenyl; C3-7cycloalkyl optionally substituted with hydroxy; aryl; or Het; R8 is Ci_6alkyl, C3_7cycloalkyl, di(Ci_3alkyl)amino, or aryl;
R9 is hydrogen; Ci_6alkyl optionally substituted with one, two or three substituents each independently selected from halo, hydroxyl, C3_7cycloalkenyl, C3-7cycloalkyl, cyano, Ci_6alkoxy, phenyl, or Het, wherein the phenyl may optionally be substituted with halo, hydroxyl, Ci_6alkoxy, Ci_6alkyl, Ci_6alkoxyCi_6alkoxy, nitro, or amino; C2_6alkenyl optionally substituted with one or two substituents selected from halo and polyhaloCi-βalkyl; C2_6alkynyl; C3_7cycloalkenyl;or phenyl optionally substituted with one or two substituents selected from hydroxyl, Ci_6alkoxy, polyhaloCi-βalkyl, halo, amino, nitro, d-βalkyl, and phenyl; aryl as a group or part of a group is phenyl, naphthyl, indanyl, or 1,2,3,4-tetrahydro- naphthyl, each of which may be optionally substituted with one, two, three or four substituents each independently selected from the group consisting of C3-7cycloalkyl, phenylCi-βalkyl, phenylpolyhaloCi-βalkyl, phenylCi-βalkyloxy, halo, polyhaloCi-βalkyl, cyano, Ci_6alkyl, polyhaloCi-βalkoxy, -OR9, - C(=O)OH, Ci_6alkylcarbonyl, Ci_6alkylthio, Ci_6alkylsulfonyl, -S(=O)2NH2, and pyrrolyl, wherein the phenyl may optionally be substituted with halo ; or two substituents on the aryl ring may form -0-CH2-O- or a -O-C(CH3)2-CH2-; Het as a group or part of a group is a 5 to 12 membered saturated, partially unsaturated or completely unsaturated mono- or bicyclic ring containing 1 to 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, being optionally condensed with one benzene ring, and wherein the group Het as a whole may be optionally substituted with one or two substituents each independently selected from the group consisting of halo; polyhaloCi-βalkyl; Ci_6alkylthio, oxo; -OR9; -CN; Ci_6alkyl optionally substituted with -OR9, -CN, or phenyl; -C(=O)-NH2; -C(=O)-phenyl; C3-7cycloalkyl; phenyl optionally substituted with Ci_6alkoxy; morpholinyl; pyrrolidinyl; pyrrolyl; furanyl; tetrazolyl; and thiophenyl.
5. A compound according to any one of claims 1, 3-4, wherein: Rla is hydrogen, hydroxy, or amino; Rlb is hydrogen, hydroxy, halo, trifluoromethyl, or Ci_6alkyl optionally substituted with cyano; i R2 is hydrogen, -C(=O)-R5, -C(=O)-C(=O)-R5, -C(=O)-OR6, or -C(=O)-NR7aR7b;
R3 is Ci_6alkyl optionally substituted with C3_7Cycloalkyl, aryl, or Het;
C3-7cycloalkyl; aryl; or Het; eac ]h R4a and R4b is, independently, Chalky!; R5 is Ci_6alkyl optionally substituted with one or two substituents selected from halo, C3_7Cycloalkyl, cyano, polyhaloCi-βalkyl, oxo, -OR9, -C(=O)-Het,
-C(=O)-OR6, -C(=O)-OH, -C(=O)-NR7aR7b, -C(=O)-NH-S(=O)2-R8, -NR7aR7b,
-S(=O)2-aryl, aryl, and Het; C2-6alkenyl optionally substituted with aryl; polyhaloCi-βalkyl; C3-7cycloalkyl; aryl; or Het; R6 is aryl or Ci_6alkyl optionally substituted with -OR9, -C(=O)-OR9, -C(=O)-NR7aR7b, -C(=O)-NH-S(=O)2-R8, aryl, or Het; each R7a and R7b is, independently, hydrogen; Ci_6alkyl optionally substituted with one or two substituents selected from -OR9, mono- or diCi_6alkylamino, -C(=O)-OR9, -C(=O)-NH2, -C(=O)-NH-Ci_6alkyl, -C(=O)-NH- hydroxyCi-βalkyl, -C(=O)-Het, C3-7cycloalkyl, aryl, and Het; C2-6alkenyl; C3_7Cycloalkyl optionally substituted with hydroxy; aryl; or Het;
R8 is d-βalkyl, C3-7cycloalkyl, di(Ci_3alkyl)amino, or aryl;
R9 is hydrogen; Ci_6alkyl optionally substituted with one, two or three substituents each independently selected from halo, hydroxyl, C3-7cycloalkenyl, C3_7Cycloalkyl, Ci_6alkoxy, phenyl, or Het, wherein the phenyl may optionally be substituted with halo, Ci_6alkoxy, Chalky!, Ci_6alkoxyCi_6alkoxy, nitro, or amino; C2-6alkenyl; C2-6alkynyl; or phenyl optionally substituted with one or two substituents selected from halo, Ci_6alkoxy, polyhaloCi-βalkyl, amino, nitro, Ci_6alkyl, and phenyl; aryl as a group or part of a group is phenyl, naphthyl, indanyl, or 1,2,3,4-tetrahydro- naphthyl, each of which may be optionally substituted with one, two, three or four substituents each independently selected from the group consisting of C3_7Cycloalkyl, phenylCi-βalkyl, phenylpolyhaloCi-βalkyl, phenylCi-βalkyloxy, halo, polyhaloCi-βalkyl, cyano, d^alkyl, polyhaloCi-βalkoxy, -OR9, -C(=O)OH, Ci_6alkylcarbonyl, Ci_6alkylthio, Ci_6alkylsulfonyl, -S(=O)2NH2, and pyrrolyl;
Het as a group or part of a group is a 5 to 12 membered saturated, partially unsaturated or completely unsaturated mono- or bicyclic ring containing 1 to 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, being optionally condensed with one benzene ring, and wherein the group Het as a whole may be optionally substituted with one or two substituents each independently selected from the group consisting of halo; polyhaloCi-βalkyl; Ci_6alkylthio, oxo; -OR9; -CN; Ci_6alkyl optionally substituted with -OR9, -CN, or phenyl;-C(=O)-NH2; -C(=O)-phenyl; C3-7cycloalkyl; phenyl optionally substituted with Ci_6alkoxy; morpholinyl; pyrrolidinyl; pyrrolyl; furanyl; tetrazolyl; and thiophenyl.
6. A compound according to any one of claims 1, 3-5, wherein: Rla is hydrogen, hydroxy, or amino;
Rlb is hydrogen, hydroxy, halo, trifluoromethyl, or Ci_6alkyl optionally substituted with cyano;
R2 is hydrogen, -C(=O)-R5, -C(=O)-OR6, or -C(=O)-NR7aR7b; R3 is Ci_6alkyl optionally substituted with C3_7cycloalkyl, aryl, or Het; C3-7cycloalkyl; aryl; or Het; each R4a and R4b is, independently, Ci_6alkyl;
R5 is Ci_6alkyl optionally substituted with one or two substituents selected from halo, C3_7cycloalkyl, cyano, polyhaloCi-βalkyl, oxo, -OR9, -C(=O)-OR6, -C(=O)-OH, -S(=O)2-aryl, aryl, and Het; C3-7cycloalkyl; aryl; or Het; R > 6 is aryl or Ci_6alkyl; each R7a and R7b is, independently, hydrogen; Ci_6alkyl; aryl; or Het; R9 is hydrogen; Ci_6alkyl optionally substituted with one, two or three substituents each independently selected from halo, hydroxyl, C3-7cycloalkenyl, C3-7cyclo- alkyl, Ci_6alkoxy, phenyl, or Het, wherein the phenyl may optionally be substituted with halo, Ci_6alkoxy, nitro, Chalky!, Ci_6alkoxyCi_6alkoxy, or amino; C2-6alkenyl; C2_6alkynyl; or phenyl optionally substituted with one or two substituents selected from halo, Ci_6alkoxy, polyhaloCi-βalkyl, amino, nitro, Ci_6alkyl, and phenyl; aryl as a group or part of a group is phenyl optionally substituted with one, two, three or four substituents each independently selected from the group consisting of C3-7cycloalkyl, phenylCi-βalkyl, phenylpolyhalo Chalky!, phenylCi-βalkyl- oxy, halo, polyhaloCi-βalkyl, cyano, Ci_6alkyl, polyhaloCi-βalkoxy, -OR9, -C(=O)OH, Ci_6alkylcarbonyl, Ci_6alkylthio, Ci_6alkylsulfonyl, and -S(=O)2NH2; Het as a group or part of a group is a 5 to 12 membered saturated, partially unsaturated or completely unsaturated mono- or bicyclic ring containing 1 to 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, and wherein the group Het as a whole may be optionally substituted with one or two substituents each independently selected from the group consisting of halo, polyhaloCi-βalkyl; Ci_6alkylthio, oxo, -OR9, -CN, and Ci_6alkyl.
7. A compound according to any one of claims 1-6, wherein R is hydrogen, -C(=O)-R5 or -C(=O)-OR6.
8. A compound according to any one of claims 1, 3-7, wherein:
R , 1aa is hydrogen or hydroxy; Rlb is hydrogen or hydroxy; R 22 is hydrogen, -C(=O)-R5 or -C(=O)-OR6;
R3 is aryl; ea 1Cch R4a and R4b is, independently, Chalky!;
R5 is Ci_6alkyl optionally substituted with one or two substituents selected from halo, C3_7Cycloalkyl, cyano, polyhaloCi-βalkyl, oxo, -OR9, -S(=O)2-aryl, aryl, and Het; aryl; or Het;
R9 is Ci_6alkyl optionally substituted with one, two or three substituents each independently selected from halo, hydroxyl, C3-7cycloalkenyl, C3-7cycloalkyl, or phenyl; or phenyl optionally substituted with one or two substituents selected from halo, polyhaloCi-βalkyl, or C^alkyl, aryl as a group or part of a group is phenyl optionally substituted with one, two, three or four substituents each independently selected from the group consisting of halo, polyhaloCi-βalkyl, cyano, Ci_6alkyl, polyhaloCi-βalkoxy, and -OR9; Het as a group or part of a group is a 5 to 6 membered saturated, partially unsaturated or completely unsaturated monocyclic ring containing 1 to 4 heteroatoms each independently selected from nitrogen, oxygen and sulfur, and wherein the group Het may be optionally substituted with one or two substituents each independently selected from the group consisting of halo, oxo, -OR9, -CN, and Ci_6alkyl.
9. A compound according to any one of claims 1-8, wherein the compound has the formula (I-a)
Figure imgf000217_0001
wherein R , 1aa, T R-) Ib , τ R-) 2 and R are as specified in any one of claims 1-8.
10. A compound according to any one of claims 1-8, wherein the compound has the formula (I-b)
Figure imgf000218_0001
wherein Rla, Rlb, R2, and aryl are as specified in any one of claims 1-8.
11. A compound according to any one of claims 1-8, wherein the compound has the formula (I-i), (I-j) or (I-k)
Figure imgf000218_0002
wherein Rla, Rlb, R3, R5 and R6 are as specified in any one of claims 1-8.
12. A compound according to any one of claims 1-8, wherein the compound has the formula (1-1), (I-m) or (I-n),
Figure imgf000218_0003
wherein Rla, Rlb, R2, R5, R6 and aryl are as specified in any one of claims 1-8.
13. A pharmaceutical composition comprising a carrier, and as active ingredient an anti-virally effective amount of a compound as claimed in any one of claims 1-12.
14. A pharmaceutical composition according to claim 13, further comprising at least one other anti HCV compound.
15. A pharmaceutical composition according to claim 13, further comprising at least one other anti HIV compound.
16. A compound according to any of claims 1-12, or a pharmaceutical composition according to any of claims 13-15, for use as a medicament.
17. A compound according to any of claims 1-12, or a pharmaceutical composition according to any of claims 13-15, for inhibiting HCV replication.
18. A compound according to any of claims 1-12 or a pharmaceutical composition according to any of claims 13-15, for treating hepatitis C.
19. A pharmaceutical composition according to claim 15, for inhibiting HCV and HIV replication.
20. Use of a compound according to any of claims 1-12, for the manufacture of a medicament for inhibiting HCV replication.
21. A method of inhibiting HCV replication in a warm-blooded animal said method comprising the administration of an effective amount of a compound according to any of claims 1-12 or a pharmaceutical composition according to any of claims 13- 15.
22. A combination comprising a compound according to any one of claims 1-12, and at least one other anti-HCV compound.
23. A process for the preparation of a compound according to any one of claims 1-12 having formula (1-8), comprising the steps of reacting a compound of formula (1-2) with a compound of formula (1-4) thereby obtaining compound of formula (1-5), and
Figure imgf000220_0001
1-2 1-4 1-5
reacting a compound of formula (1-5) with an aldehyde of formula (1-7); optionally in the presence of an acid, thereby obtaining a compound of formula (1-8),
Figure imgf000220_0002
wherein R , 1aa, T R-) Ib , r R> 4aa , r R> 4b , and j r R> 3 have the same meaning as in any one of claims 1-12.
24. A process for the preparation of a compound according to any one of claims 1-12 having formula (1-9), comprising the step of
Figure imgf000220_0003
acylating a compound of formula (1-8) with an acid or an activated acid thereby obtaining a compound of formula (I) having formula (1-9) wherein Rla, Rlb, R4a R4b, R3 and R5 have the same meaning as in any one of claims 1-12.
25. A process for the preparation of a compound according to any one of claims 1-12 having formula (I- 10), comprising the steps of
Figure imgf000221_0001
1-10
reacting a compound of formula (1-8) with an isocyanate of formula (I-8a) thereby obtaining a compound of formula (I- 10) with R7b being hydrogen, or reacting a compound of formula (1-8) with phosgene or an equivalent of phosgene of formula (I-8b), wherein LG represent a leaving group, followed by the treatment with an amine of formula (I-8c) thereby obtaining a compound of formula (I- 10), wherein Rla, Rlb, R4a , R4b, R3 , R7a' and R7b have the same meaning as in any one of claims 1-12.
26. A process for the preparation of a compound according to any one of claims 1-12 having formula (1-11), comprising the step of
Figure imgf000221_0002
reacting a compound of formula (1-8) with a chloroformate of formula (I-8d) in the presence of a base, in an inert solvent thereby obtaining a compound of formula (I- 11), wherein Rla, Rlb, R4a , R4b, R3 and R6 have the same meaning as in any one of claims 1-12.
PCT/EP2008/051903 2007-02-16 2008-02-15 1,1-dioxo-1-thia-5,10-diazadibenzocycloheptenes useful as hepatitis c virus inhibitors Ceased WO2008099020A1 (en)

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WO2021030278A1 (en) * 2019-08-12 2021-02-18 Aligos Therapeutics, Inc. Bicyclic compounds

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WO2000066106A2 (en) * 1999-04-30 2000-11-09 The Regents Of The University Of Michigan Use of benzodiazepines for treating autoimmune diseases induced by apoptosis
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WO2000066106A2 (en) * 1999-04-30 2000-11-09 The Regents Of The University Of Michigan Use of benzodiazepines for treating autoimmune diseases induced by apoptosis
WO2006046030A2 (en) * 2004-10-26 2006-05-04 Istituto Di Ricerche Di Biologia Molecolare P Angeletti Spa Tetracyclic indole derivatives as antiviral agents

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8198305B2 (en) 2007-04-13 2012-06-12 Concert Pharmaceuticals Inc. 1,2-benzisoxazol-3-yl compounds
WO2021030278A1 (en) * 2019-08-12 2021-02-18 Aligos Therapeutics, Inc. Bicyclic compounds

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