WO2008099019A1 - 6-hydroxy-dibenzodiazepinones useful as hepatitis c virus inhibitors - Google Patents

6-hydroxy-dibenzodiazepinones useful as hepatitis c virus inhibitors Download PDF

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WO2008099019A1
WO2008099019A1 PCT/EP2008/051902 EP2008051902W WO2008099019A1 WO 2008099019 A1 WO2008099019 A1 WO 2008099019A1 EP 2008051902 W EP2008051902 W EP 2008051902W WO 2008099019 A1 WO2008099019 A1 WO 2008099019A1
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optionally substituted
het
aryl
alkyl
phenyl
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PCT/EP2008/051902
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French (fr)
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Pierre Jean-Marie Bernard Raboisson
David Craig Mc Gowan
Koen Vandyck
Sandrine Marie Helene Vendeville
Jean-François BONFANTI
Walter Marcel Mathilde Van Den Broeck
Origène NYANGUILE
Katie Ingrid Eduard Amssoms
Lili Hu
Carlo Willy Maurice Boutton
Abdellah Tahri
Stefaan Julien Last
Klara Rombauts
Anne-Sophie Helene Marie Rebstock
Jérôme Michel Claude FORTIN
Philippe Muller
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Tibotec Pharmaceuticals Ltd.
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Publication of WO2008099019A1 publication Critical patent/WO2008099019A1/en

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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D243/38—[b, e]- or [b, f]-condensed with six-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention is concerned with 6-hydroxy-dibenzodiazepinones 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 1 is hydrogen, 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 6-hydroxy-dibenzodiazepinone ring to which they are attached may form a C 3 _ 7 Cycloalkyl; R 5 is Ci_6alkyl optionally substituted with one or two substituents selected from cyano, polyhaloCi_ 6 alkyl,
  • 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_6alkyl optionally substituted with one, two, or three substituents selected from halo, hydroxy, Ci_6alkoxy, C3-7cycloalkenyl, phenyl, and Het, wherein the phenyl may optionally be substituted with halo, hydroxy , Ci_6alkoxy, nitro, or amino; C 2 - 6 alkenyl; C 2-6 alkynyl; C 3 - 7 cycloalkenyl; indanyl; or phenyl optionally substituted with one or two substituents selected from halo, hydroxy, amino, nitro, C ⁇ aUcyl, 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 or three substituents each independently selected from the group consisting of halo
  • each R 7a and R 7b is, independently, hydrogen;
  • 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 JV-oxides, quaternary amines, salts, hydrates, solvates, prodrugs, 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 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 (I) 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-l-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-
  • 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, 2,4-pentadienyl and the like.
  • 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 polyhaloCi- ⁇ alkyl radicals include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, and 1,1,1-trifluoroethyl.
  • 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-
  • 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 (SCH3), ethylthio (SCH2CH3), 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.
  • 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 stereospecific 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 1 , 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 methoxymethyl, 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-oxy ethyl 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 ⁇ /-(dialkylaminoethyl)- ⁇ /-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, / ⁇ -aminosalicylic, 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 1 is hydrogen, halo, trifluoromethyl, or Ci_ 6 alkyl optionally substituted with cyano; preferably R 1 is hydrogen or halo, more preferably R 1 is hydrogen;
  • R 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 Ci_ 6 alkyl optionally substituted with aryl, or Het; C 3 _ 7 Cycloalkyl; aryl; or Het; preferably R 3 is Ci_ 6 alkyl optionally substituted with aryl, C 3 - 7 cycloalkyl; aryl; or Het; preferably R 3 is C 3 - 7 cycloalkyl; aryl; or Het; yet more preferably R 3 is aryl; or Het, preferably aryl; 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 6-hydroxy-dibenzodiazepinone ring to which they are attached may form a C 3 - 7 cycloalkyl; preferably each R 4
  • Het is selected from tetrahydrofuranyl, pyridazinyl, pyrazinyl, quinoxalinyl, furanyl, benzofuranyl, thiazolyl, pyrimidinyl, quinolinyl, benzo(l,3)dioxolyl, oxazolyl, pyridinyl, pyrazolyl, 2,3-dihydrobenzo(l,4)dioxinyl, quinazolinyl, isoxazolyl, 1,2,4-triazolyl, naphthyridinyl, each Het being optionally substituted with one or two substituents selected from halo; oxo; -OR 9 ; -NR 10a R 10b ; -CN;
  • R 9 is hydrogen; Ci_6alkyl optionally substituted with one, two, or three substituents selected from halo, hydroxy, Ci_6alkoxy, C3-7cycloalkenyl, phenyl, and Het, wherein the phenyl may optionally be substituted with halo, hydroxy , Ci_6alkoxy, nitro, or amino; C 2 - 6 alkenyl; C 2-6 alkynyl; C 3 - 7 cycloalkenyl; indanyl; or phenyl optionally substituted with one or two substituents selected from halo, hydroxy, amino, nitro, d- ⁇ alkyl, and phenyl; preferably R 9 is hydrogen; Ci_6alkyl optionally substituted with one, two, or three substituents selected from halo, Ci_6alkoxy
  • R 1 is hydrogen, halo, trifluoromethyl, or Ci_ 6 alkyl optionally substituted with cyano
  • R 3 is Ci_ 6 alkyl optionally substituted with aryl; 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 6-hydroxy-dibenzodiazepinone ring to which they are attached may form a C 3 _ 7 Cycloalkyl;
  • each R 7a and R 7b is, independently, hydrogen;
  • R 8 is Ci_ 6 alkyl, C 3 _ 7 Cycloalkyl, or aryl;
  • each R 10a andR 10b is, independently, hydrogen, Ci_ 6 alkyl, arylCi- ⁇ alkyl, or aryl.
  • R is 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 6-hydroxy-dibenzodiazepinone ring to which they are attached may form a C 3 _ 7 Cycloalkyl;
  • R 5 is Ci_6alkyl optionally substituted with one or two substituents selected from cyano,
  • each R 7a and R 7b is, independently, hydrogen;
  • R 8 is Ci_ 6 alkyl, C 3-7 Cy cloalkyl, or aryl;
  • Ci_6alkylthio C 2 -6alkynyl; phenyl optionally substituted with Ci_6alkoxy; morpholinyl; pyrrolidinyl; pyrrolyl; furanyl; pyridinyl; tetrazolyl; and thiophenyl; each R 10a andR 10b is, independently, hydrogen, Ci_ 6 alkyl, arylCi- ⁇ alkyl, or aryl.
  • One embodiment of the present invention concerns compounds of formula (I) or of any subgroup thereof, wherein one or more of the following restrictions apply:
  • R 1 is hydrogen, halo, trifluoromethyl, or Ci_ 6 alkyl optionally substituted with cyano
  • R 3 is Ci_ 6 alkyl optionally substituted with aryl; 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 6-hydroxy-dibenzodiazepinone ring to which they are attached may form a C 3 _ 7 Cycloalkyl;
  • R 8 is Ci_ 6 alkyl, C 3 _ 7 Cycloalkyl, 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, Ci_ 6 alkyl, and phenyl;
  • R 1 is hydrogen
  • R 3 is 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 6-hydroxy-dibenzodiazepinone ring to which they are attached may form a C 3 _ 7 Cycloalkyl
  • R 1 is hydrogen
  • R 3 is 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 6-hydroxy-dibenzodiazepinone ring to which they are attached may form a C 3 _ 7 Cycloalkyl
  • R 1 is hydrogen
  • R 3 is 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 6-hydroxy-dibenzodiazepinone ring to which they are attached may form a C 3 _ 7 Cy
  • each R 7a and R 7b is, independently, hydrogen;
  • R 8 is d- ⁇ alkyl, C 3 - 7 cycloalkyl, or aryl;
  • R 9 is hydrogen; Ci_ 6 alkyl optionally substituted with 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 halo;
  • 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, C ⁇ aUcyl, -OR 9 , Ci_ 6 alkylsulfonyl, and pyrrolyl; and
  • 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; -OR 9 ; -CN; 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:
  • R 1 is hydrogen
  • R 3 is 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 6-hydroxy-dibenzodiazepinone ring to which they are attached may form a C 3 _ 7 cycloalkyl;
  • each R 7a and R 7b is, independently, hydrogen;
  • R 9 is hydrogen; Ci_ 6 alkyl optionally substituted with phenyl or Het, wherein the phenyl may optionally be substituted with halo, nitro, or amino; or phenyl optionally substituted with one or two halo;
  • 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, d- ⁇ alkyl, -OR 9 , and pyrrolyl; and
  • 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; -OR 9 ; -CN; Ci_6alkyl; phenyl; morpholinyl; pyrrolidinyl; pyrrolyl; furanyl; tetrazolyl; and thiophenyl.
  • One embodiment of the present invention concerns compounds of formula (I) or of any subgroup thereof, wherein:
  • R 1 is hydrogen or halo, more preferably R 1 is hydrogen;
  • R 3 is Ci_ 6 alkyl optionally substituted with aryl, C 3 - 7 cycloalkyl; aryl; or Het; preferably
  • R 3 is C 3 _ 7 Cycloalkyl; aryl; or Het; yet more preferably R 3 is aryl; or Het, preferably aryl; each R 4a and R 4b is, independently, C 1-4 alkyl, or both R 4a and R 4b together with the carbon atom of the 6-hydroxy-dibenzodiazepinone ring to which they are attached may form a C 3 _ 6 Cycloalkyl; more preferably, each R 4a and R 4b is, independently,
  • R 8 is Ci_ 6 alkyl, C 3 _ 7 cycloalkyl, or aryl; more preferably R 8 is C 3 _ 7 cycloalkyl, or aryl; R 9 hydrogen; Ci_6alkyl optionally substituted with one, two, or three substituents selected from halo, Ci_ 6 alkoxy, phenyl, and Het, wherein the phenyl may optionally be substituted with halo, Ci_6alkoxy, nitro, or amino; indanyl; or phenyl optionally substituted with one or two substituents selected from halo, amino, nitro, Ci_ 6 alkyl, and phenyl; preferably R 9 is hydrogen; Ci_ 6 alkyl optionally substituted with one, two, or three substituents selected from halo, hydroxy, Ci_6alkoxy, C 3 - 7 cycloalkenyl, phenyl, and Het, wherein the phenyl may optionally be substituted with halo
  • 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; -OR 9 ; - -CN; d_ 6 alkyl optionally substituted with -OR 9 , -NR 10a R 10b ; phenyl optionally substituted with Ci_ 6 alkoxy; morpholinyl; furanyl; and thiophenyl; preferably He
  • One embodiment of the present invention concerns compounds of formula (I) or of any subgroup thereof, wherein: R 1 is hydrogen;
  • R 3 is C 3 - 7 cycloalkyl; aryl; or Het; yet more preferably R 3 is aryl; or Het, preferably aryl; 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 cyano,
  • One embodiment of the present invention concerns compounds of formula (I) or of any subgroup thereof, wherein:
  • R 1 is hydrogen
  • R is aryl; or Het;
  • each R 4a and R 4b is, independently, Ci_ 6 alkyl;
  • 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; -OR 9 ; - -CN; Ci_6alkyl optionally substituted with -OR 9 , -NR 10a R 10b ; phenyl optionally substituted with Ci_ 6 alkoxy; morpholinyl; furanyl; and thiophenyl; preferably Het is selected from quinolinyl, furanyl, quinoxalinyl, oxazolyl, benzofuranyl, isoxazolyl, 2,3-dihydrobenzo[l,4]dioxinyl,
  • One embodiment of the present invention concerns compounds of formula (I) or of any subgroup of compounds of formula (I), wherein
  • R 1 is hydrogen
  • R 3 is aryl;
  • 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 6-hydroxy-dibenzodiazepinone ring to which they are attached may form a C 3 _ 7 Cycloalkyl;
  • each R 7a and R 7b is, independently, hydrogen or Het;
  • R 9 is Ci_ 6 alkyl substituted with phenyl, wherein the phenyl may optionally be substituted with nitro or amino;
  • 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 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; -OR 9 ; -CN; Ci_6alkyl; phenyl; morpholinyl; pyrrolidinyl; pyrrolyl; furanyl; tetrazolyl; and thiophenyl.
  • 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 11 represents -R 5 , -OR 6 , -NR 7a R 7b ; and R 3 , R 4a and R 4b , R 5 , R 6 , R 7a and R 7b 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).
  • R 11 represents -R 5 , -OR 6 , -NR 7a R 7b ; and R 3 , R 5 , R 6 , R 7a and R 7b 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-c) and (III-c).
  • preferred configuration has Formula (II-c).
  • R 1 ⁇ represents -R 5 , -OR 6 , -NR 7a R 7b ; and R 4a , R 4b , R 5 , R 6 , R 7a and R 7b are as specified in the definitions of the compounds formula (I) or in any of the subgroups of compounds of formula (I) specified herein.
  • the present invention encompasses compounds of Formula (II-d) and (III-d).
  • preferred configuration has Formula (II-d).
  • R 11 represents -R 5 , -OR 6 , -NR 7a R 7b ; and R 5 , R 6 , R 7a and R 7b 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-e) and (III-e).
  • preferred configuration has Formula (II-e).
  • 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 1 ⁇ 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.
  • 2-amino-3-nitrophenol (1-1) which is commercially available (Sigma-Aldrich catalogue nr. 45947) or can be synthesized following art-known procedures, is submitted to a catalytic hydrogenation to reduce the nitro moiety to amino.
  • the hydrogenation is carried out with a suitable catalyst, and in a solvent.
  • the nitro group of 2-amino-3-nitrophenol (1-1) is reduced by a metal such as Iron and the like in presence of a source of hydrogen such as an ammonium, and acid or an alcohol.
  • the catalyst may be selected from palladium on charcoal, palladium acetate, palladium chloride, palladium hydroxide, or palladium hydroxide on charcoal.
  • the solvent may be selected from tetrahydrofuran (THF), methyltetrahydrofuran (MeTHF), (methyl)(isobutyl)ketone, Ci-4alcohol, dimethylformamide (DMF), methyl t-butylether (MTBE), toluene, or any mixture thereof.
  • Compound of formula (1-7) which is itself an intermediate as well, is acylated with an acid or an activated acid such as acyl anhydride or acyl chloride, in the presence of a suitable solvent, in order to acylate the amines thereby forming amides.
  • this reaction is conducted in the presence of a base.
  • the acid can be activated in situ with a coupling agent such as EDC (l-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride) /HOBT (1-hydroxybenzotriazole), HATU (2-(lH-7-azabenzotriazol- l-yl)-l,l,3,3-tetramethyl uranium hexafluorophosphate methanaminium ), and the like.
  • a coupling agent such as EDC (l-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride) /HOBT (1-hydroxybenzotriazole), HATU (2-(lH-7-azabenzotriazol- l-yl)-l,l,3,3-tetramethyl uranium hexafluorophosphate methanaminium ), and the like.
  • the acyl chloride can be activated in situ with DMAP
  • the suitable solvent for the acylation reaction may be selected from pyridine, dichloromethane, chloroform, THF, and DMF.
  • a suitable hydroxide may be selected from lithium hydroxide, sodium hydroxide, or potassium hydroxide.
  • a suitable solvent may be selected from water, Ci-4alcohol, THF, 2-methyltetrahydrofuran (MeTHF), or any mixture thereof.
  • More than one acyl group can be introduced on compound of formula (1-7), as depicted in Scheme 2a below.
  • a compound of structure (1-8), (I-8a) or (I-8b) is obtained.
  • a mixture of compounds (1-8), (I-8a) or (I-8b) can be obtained.
  • acyl groups can be cleaved by treating the corresponding compounds of formula (1-8), (I-8a) or (I-8b) with an hydroxide such as sodium hydroxide, potassium hydroxide, or lithium hydroxide in a suitable solvent such as water, Ci- 4 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, Ci- 4 alcohol, THF, 2-methyltetrahydrofuran (MeTHF), or any mixture thereof.
  • Step 1-7 ⁇ 1-10 Protection of the hydroxyl group of compound of formula (1-7) may be performed in order to introduce other substituents in R 2 , thereby yielding intermediate (I- 10) wherein PG represents a protecting group.
  • Protection of the hydroxyl group may be performed with benzyl or substituted benzyl ethers, e.g. 4-methoxybenzyl ether, benzoyl or substituted benzoyl esters, e.g.
  • Intermediate (1-12) 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.
  • an alkali metal hydroxide LiOH, NaOH, KOH
  • an aqueous medium comprising water and a water-soluble organic solvent such as an alkanol (methanol, ethanol) and THF.
  • a trialkylsilyl protecting group is further reacted with tetraalkylammonium fluoride to deprotect the silyl group thereby affording a compound of formula (1-13).
  • 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.
  • the protecting group can be cleaved following the same procedures than reported for (1-12) -> (1-13).
  • a dimedone derivative 1-3 can be synthesized following the synthetic pathway described in scheme 3 below.
  • a dicarboxylic acid derivative 1-16 bearing the R 4a and R 4b substituents which is commercially available or synthesized according to procedures known by the skilled person in the art, or as described in scheme 4, is cyclized to the anhydride 1-17 under refluxing conditions in acetic anhydride.
  • Cyclic anhydride 1-17 is reacted with a grignard reagent, such as methylmagnesium bromide, at low temperature, and in the presence of a catalyst such as copper iodide, in a suitable organic solvent, to provide the methylketone derivative 1-18 bearing the R 4a and R 4b substituents and one carboxylic acid moiety.
  • a grignard reagent such as methylmagnesium bromide
  • a catalyst such as copper iodide
  • a suitable solvent may be THF or diethylether.
  • Intermediate 1-18 is then esterified to provide methylester derivative 1-19, according to procedures known by the skilled person in the art.
  • a suitable procedure is the reaction of the carboxylic acid derivative 1-18 under reflux in acidic methanol, obtained by adding acetyl chloride to methanol at low temperature.
  • a derivative 1-19 is reacted with a base, such as sodium hydride, in a suitable solvent such as THF, to provide the cyclized compound 1-3.
  • a base such as sodium hydride
  • Dicarboxylic acid derivatives 1-16 may be obtained following the synthetic pathway described in scheme 4 below.
  • Imide 1-22 may be obtained by reacting a ketone 1-20 with cyanoethylacetate 1-21 and ammonia, in the presence of a catalytic amount of a suitable base such as ammonium acetate, in a suitable solvent, such as ethanol, at low temperature.
  • a suitable base such as ammonium acetate
  • a suitable solvent such as ethanol
  • Step 1-22 ⁇ 1-16 Dicarboxylic acid derivative 1-16 can be obtained by heating imide 1-22 at elevated temperature, such as 160 0 C, in a strong acid, such as sulfuric acid, in the presence of water.
  • 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-butyl 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.
  • 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 stereospecifically.
  • said compound may be synthesized by stereospecific 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 which 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.
  • 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.
  • the compounds of formula (I) or any subgroup thereof, their prodrugs, JV-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, valopicitabine, PSI-6130, XTL-2125, NM-107, R7128 (R4048), GSK625433, R803, R-1626, BILB-1941, HCV- 796, JTK-109 and JTK-003, benzimidazole derivatives, benzo-l,2,4-thiadiazine derivatives, phenylalanine derivatives, A-831 and A-689; 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, BILN-2065, BMS
  • 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, NS3 helicase and NS5B polymerase.
  • IFN- ⁇ interferon- ⁇
  • pegylated interferon- ⁇ ribavirin or a combination thereof
  • 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.
  • si RNA small interfering RNA
  • 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.
  • 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.
  • 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.
  • ritonavir RTV
  • SQV saquinavir
  • ABT-378 or LPV indinavir
  • IDV amprenavir
  • VX-478 TMC 126
  • nelfmavir AG- 1343
  • BMS 232,632 darunavir
  • TMCl 14 fosamprenavir
  • GW433908 or VX-175 brecanavir
  • GW-640385 brecanavir
  • 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 (UK-427,857), PRO-140, TAK-220, TAK-652, vicriviroc (SCH-D, SCH-417,690)) and CXR4 antagonists (e.g.
  • 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. 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.
  • 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 which 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 1 l-(3-chlorophenyl)-6-hydroxy-3,3-dimethyl-2,3,4,5,10,l 1-hexahydro- dibenzo
  • Example 2 10-acetyl-l l-(3-chlorophenyl)-6-hydroxy-3,3-dimethyl-2,3,4,5,10,l 1-hexa- hvdro-dibenzor&,ei ⁇ ,41diazepin-l-one (8).
  • Example 3 1 l-(2,4-dichlorobenzyl)-6-hydroxy-3, 3-dimethyl-2, 3,4,5, 10,11-hexahydro- dibenzo[b,el [1 ,41diazepin- 1 -one (9).
  • Example 4 1 l-(4-benzyloxy-2-chlorophenyl)-6-hydroxy-3,3-dimethyl- 2.3.4.5.10.1 l-hexahvdro-dibenzorb.ei ⁇ .41diazepin-l-one (13).
  • Step 1 synthesis of 4-benzyloxy-2-chlorobenzaldehyde (11).
  • Step 2 Synthesis of l l-(4-benzyloxy-2-chlorophenyl)-6-hydroxy-3,3-dimethyl- 2,3,4,5,10,1 l-hexahydro-dibenzo[ ⁇ ,e][l,4]diazepin-l-one (13).
  • Example 5 10-acetyl-l l-(4-benzyloxy-2-chlorophenyl)-6-hydroxy-3,3-dimethyl- 2,3,4,5,10,1 l-hexahydro-dibenzorb,eiri,41diazepin-l-one (14).
  • Example 6 l l-(2,4-dichlorophenethyl)-6-hydroxy-3,3-dimethyl- 2,3,4,5,10,1 l-hexahydro-dibenzo
  • Example 7 10-acetyl-l l-(2,4-dichlorophenethyl)-6-hydroxy-3,3-dimethyl- 2,3,4,5,10,1 l-hexahvdro-dibenzorb,eiri,41diazepin-l-one (18).
  • Example 9 3- ⁇ [l l-(4-Benzyloxy-2-chlorophenyl)-6-hydroxy-3,3-dimethyl-l-oxo- 1,2,3,4,5,1 l-hexahydrodibenzoFb, el ri ⁇ idiazepine-lO-carbonyliaminolpropionic acid
  • Example 10 ⁇ [1 l-(4-Benzyloxy-2-chlorophenyl)-6-hydroxy-3,3-dimethyl-l-oxo- 1,2,3,4,5,1 l-hexahydrodibenzofb ⁇ lfl ⁇ ldiazepine-lO-carbonyllaminolacetic acid ethyl ester (23).
  • Example 11 1 l-(4-benzyloxy-2-chlorophenyl)-6-hydroxy-3,3-dimethyl-l-oxo- 1,2,3,4,5,1 l-hexahydrodibenzo
  • Example 12 1 l-(4-benzyloxy-2-chlorophenyl)-6-hydroxy-3,3-dimethyl-l-oxo- 1,2,3,4,5,1 l-hexahydrodibenzo
  • Example 13 ⁇ [1 l-(4-Benzyloxy-2-chlorophenyl)-6-hydroxy-3,3-dimethyl-l-oxo- 1,2,3,4,5,1 l-hexahydrodibenzoTb, el ri,41diazepine-10-carbonyllamino
  • Example 14 2- ⁇ [l l-(4-Benzyloxy-2-chlorophenyl)-6-hydroxy-3,3-dimethyl-l-oxo- 1,2,3,4,5,11 -hexahydrodibenzo
  • Example 15 2- ⁇ [l l-(4-Benzyloxy-2-chlorophenyl)-6-hydroxy-3,3-dimethyl-l-oxo- 1,2,3,4,5,1 l-hexahydrodibenzo[b,el[l,41diazepine-10-carbonyllamino
  • Example 16 4-(2- ⁇ [l l-(4-Benzyloxy-2-chloro-phenyl)-6-hydroxy-3,3-dimethyl-l-oxo- 1,2,3,4,5,1 l-hexahydrodibenzo[b,el[l,41diazepine-10-carbonyllamino
  • Example 17 1 l-(4-benzyloxy-2-chlorophenyl)-6-hydroxy-3,3-dimethyl-l-oxo- 1,2,3,4,5,1 l-hexahydrodibenzo
  • Example 18 1 l-(4-benzyloxy-2-chlorophenyl)-6-hydroxy-3,3-dimethyl-l-oxo- 1,2,3,4,5,1 l-hexahydrodibenzo
  • Example 19 1 l-(4-Benzyloxy-2-chloro-phenyl)-6-hydroxy-3,3-dimethyl-l-oxo- 1,2,3,4,5,1 l-hexahydro-dibenzo
  • Example 20 ([I l-(4-benzyloxy-2-chlorophenyl)-6-hydroxy-3,3-dimethyl-l-oxo- 1,2,3,4,5,1 l-hexahvdrodibenzorb,eiri,41diazepine-10-carbonylloxy
  • Example 21 1 l-(4-benzyloxy-2-chlorophenyl)-6-hydroxy-3,3-dimethyl-l-oxo- 1,2,3,4,5,1 l-hexahydrodibenzo
  • Example 22 1 l-(4-benzyloxy-2-chlorophenyl)-6-hydroxy-3,3-dimethyl-l-oxo- 1,2,3,4,5,1 l-hexahydrodibenzo[&,e "
  • Example 23 1 l-(4-benzyloxy-2-chlorophenyl)-6-hydroxy-3,3-dimethyl-l-oxo- 1,2,3,4,5,1 l-hexahvdrodibenzor&,eiri,41diazepine-10-carboxylic acid isopropyl ester
  • Example 24 1 l-(4-benzyloxy-2-chlorophenyl)-6-hydroxy-3,3-dimethyl-l-oxo- 1,2,3,4,5,1 l-hexahydrodibenzo[ ⁇ e "
  • Example 26 1 l-(4-benzyloxy-2-chlorophenyl)-6-hydroxy-3,3-dimethyl-l-oxo- 1,2,3,4,5,1 l-hexahydrodibenzo[ ⁇ ,el[l,41diazepine-10-carboxylic acid benzyl ester (42).
  • Example 28 ⁇ [1 l-(4-benzyloxy-2-chlorophenyl)-6-hydroxy-3,3-dimethyl-l-oxo- 1,2,3,4,5,11 -hexahydrodibenzo
  • Example 30 2- ⁇ [l l-(4-benzyloxy-2-chlorophenyl)-6-hydroxy-3,3-dimethyl-l-oxo- 1,2,3,4,5,11 -hexahydrodibenzo
  • Example 31 1 l-(4-benzyloxy-2-chlorophenyl)-6-hydroxy-3,3-dimethyl-l-oxo- 1,2,3,4,5,1 l-hexahydrodibenzor&,eiri,41diazepine-10-carboxylic acid 2-(2-methoxy- ethoxy)ethyl ester (47).
  • Example 32 3- ⁇ [l l-(4-benzyloxy-2-chlorophenyl)-6-hydroxy-3,3-dimethyl-l-oxo- 1,2,3,4,5,1 l-hexahydrodibenzorb ⁇ iri ⁇ ldiazepine-lO-carbonylloxylpropionic acid
  • Example 33 1 l-(4-benzyloxy-2-chlorophenyl)-6-hydroxy-3,3-dimethyl-l-oxo- 1,2,3,4,5,1 l-hexahvdrodibenzor ⁇ eiri,41diazepine-10-carboxylic acid phenethyl ester
  • Example 34 2- ⁇ [l l-(4-benzyloxy-2-chlorophenyl)-6-hydroxy-3,3-dimethyl-l-oxo- 1,2,3,4,5,11 -hexahydrodibenzo
  • Example 35 2- ⁇ [l l-(4-benzyloxy-2-chlorophenyl)-6-hydroxy-3,3-dimethyl-l-oxo- 1,2,3,4,5,11 -hexahydrodibenzo
  • Example 36 1 l-[4-(2-bromophenoxy)-2-chlorophenyll-6-hydroxy-3,3-dimethyl- 2,3.4,5.10.1 l-hexahvdro-dibenzorb.ei ⁇ ,41diazepin-l-one (56).
  • Example 37 10-isobutyryl-l l-[4-(2-bromophenoxy)-2-chlorophenyll-6-hydroxy- 3,3-dimethyl-2,3,4,5J0J l-hexahvdro-dibenzor ⁇ ,eiri,41diazepin-l-one (57).
  • Example 38 1 l-[4-(2-phenylphenoxy)-2-chlorophenyll-6-hydroxy-3,3-dimethyl- 2,3,4,5,10,1 l-hexahvdro-dibenzorb,eiri,41diazepin-l-one (58).
  • Example 39 1 l-[4-(2-bromo-6-fluorophenoxy)-2-chlorophenyll-6-hydroxy- 3,3-dimethyl-2,3,4,5J0J l-hexahvdro-dibenzorb,ei ⁇ ,41diazepin-l-one (60).
  • Example 40 10-acetyl-l l-[4-(2-phenylphenoxy)-2-chlorophenyll-6-hydroxy- 3,3-dimethyl-2,3,4,5J0J l-hexahvdro-dibenzorb,ei ⁇ ,41diazepin-l-one (61).
  • Example 41 10-acetyl-l l-[4-(2-bromo-6-fluorophenoxy)-2-chlorophenyll-6-hydroxy- 3,3-dimethyl-2,3,4,5J0J l-hexahvdro-dibenzor&,ei ⁇ ,41diazepin-l-one (62).
  • Example 42 10-(2-cyanoacetyl)-l l-[4-(2-bromophenoxy)-2-chlorophenyll-6-hydroxy- 3,3-dimethyl-2,3,4,5J0J l-hexahvdro-dibenzor ⁇ ,eiri,41diazepin-l-one (63).
  • Example 43 10-(3-oxo-3-methoxypropionyl)-l l-[4-(2-bromophenoxy)-2-chloro- phenyll-6-hydroxy-3,3-dimethyl-2,3,4,5J0,l l-hexahydro-dibenzo[&,el[l,41diazepin-l- one (64).
  • Example 44 3- ⁇ l l-[4-(2-bromophenoxy)-2-chlorophenyl]-6-hydroxy-3,3-dimethyl- 1 -oxo- 1,2,3,4,5,11 -hexahydrodibenzo ⁇ b, e] ⁇ 1 ,41 diazepin- 10-ylj -3 -oxopropionic acid (65).
  • Example 45 10-(2-cyanoacetyl)-l l-[4-(2-bromo-6-fluorophenoxy)-2-chlorophenyll- 6-hydroxy-3 ,3-dimethyl-2,3 ,4,5 , 10,11 -hexahydro-dibenzo
  • Example 46 10-(2-cyanoacetyl)-l l-(4-benzyloxy-2-chlorophenyl)-6-hydroxy- 3.3-dimethyl-2,3.4,5.10.11-hexahvdro-dibenzor ⁇ .eiri,41diazepin-l-one (67).
  • Example 47 1 l-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl- 2,3,4,5,10,1 l-hexahvdro-dibenzor&,e " iri,41diazepin-l-one (69).
  • Step 1 synthesis of 4-benzyloxy-2-fluorobenzaldehyde (68).
  • Step 2 Synthesis of l l-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl- 2,3,4,5,10,1 l-hexahydro-dibenzo[ ⁇ ,e][l,4]diazepin-l-one (69).
  • Example 48 (1 li?)-10-(2-cyanoacetyl)-l l-(4-benzyloxy-2-chlorophenyl)-6-hydroxy- 3.3-dimetfayl-2.3.4.5.10.11-hexahvdro-dibenzor6.eiri.41diazepin-l-one (70) and (115)- 10-(2-cyanoacetyl)-l l-(4-benzyloxy-2-chlorophenyl)-6-hydroxy-3,3-dimethyl- 2,3,4,5,10,1 l-hexahydro-dibenzor&.eiri/ ⁇ diazepin-l-one (71).
  • Example 49 (1 IR)-I l-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl- 2.3.4.5.10.1 l-hexahvdro-dibenzor6.eiri.41diazepin-l-one (72) and (US)-I l- (4-benzyloxy-2-fluorophenyl)-6-hydroxy-3 ,3-dimethyl-2,3 ,4,5 , 10,11 -hexahydro- dibenzor&,eiri,41diazepin-l-one (73).
  • Example 50 10-(2-methylpropionyl)-l l-(4-benzyloxy-2-fluorophenyl)-6-hydroxy- 3.3-dimethyl-2.3.4.5.10.11-hexahvdro-dibenzor ⁇ .eiri.41diazepin-l-one (74).
  • Example 51 (1 li?)-10-(2-methylpropionyl)-l l-(4-benzyloxy-2-fluorophenyD- 6-hydroxy-3 ,3-dimethyl-2,3 ,4,5 , 10,11 -hexahydro-dibenzo
  • Example 52 10-(quinolin-2-ylcarbonyl)-l l-(4-benzyloxy-2-fluorophenyl)-6-hydroxy- 3,3-dimethyl-2,3,4,5,10,l l-hexahvdro-dibenzor ⁇ ,eiri,41diazepin-l-one (77).
  • Example 53 10-acetyl-l l-[4-(2-bromophenoxy)-2-chlorophenyll-6-hydroxy- 3.3-dimethyl-2.3.4.5J0J l-hexahvdro-dibenzor ⁇ .ei ⁇ .41diazepin-l-one (78).
  • Example 54 10-(3-cyclopropylsulfonylamino-3-oxopropionyl)-l l-[4-(2-bromo- phenoxy)-2-chlorophenyll-6-hydroxy-3,3-dimethyl-2,3,4,5J0,l l-hexahydro- dibenzor&.ei ⁇ .41diazepin-l-one (80).
  • Step 2 Synthesis of 10-acetyl-l 1 -[4-(4-methoxybenzylo xy)-2-chlorophenyl]- 6-acetoxy-3,3-dimethyl-2,3,4,5,10,l l-hexahydro-dibenzo[ ⁇ ,e][l,4]diazepin-l-one (82).
  • Step 3 Synthesis of 10-acetyl-l l-(4-hydroxy-2-chlorophenyl)-6-acetoxy-3, 3-dimethyl- 2,3,4,5,10,1 l-hexahydro-dibenzo[ ⁇ ,e][l,4]diazepin-l-one (83).
  • Step 4 Synthesis of 10-acetyl-l l-[4-(4-bromobenzyloxy)-2-chlorophenyl]-6-hydroxy- 3,3-dimethyl-2,3,4,5,10,l l-hexahydro-dibenzo[ ⁇ ,e][l,4]diazepin-l-one (84).
  • Example 56 1 l-[5-(2-bromophenoxy)thienyl]-6-hydroxy-3,3-dimethyl- 2,3,4,5,10,1 l-hexahydro-dibenzor&,eiri,41diazepin-l-one (86).
  • Example 57 10-acetyl-l l-[5-(2-bromophenoxy)thienyll-6-hydroxy-3,3-dimethyl- 2.3.4.5.10.1 l-hexahvdro-dibenzor6.ei ⁇ .41diazepin-l-one (87).
  • Example 58 10-acetyl-l l-[4-(4-fluorobenzyloxy)-2-chlorophenyl]-6-hydroxy- 3.3-dimethyl-2.3.4.5J0J l-hexahvdro-dibenzor ⁇ .ei ⁇ .41diazepin-l-one (88).
  • Example 59 (R)-3- ⁇ l l-[4-(2-bromophenoxy)-2-chlorophenyll-6-hydroxy- 3,3-dimethyl-l-oxo-l,2,3,4,5J l-hexahydrodibenzo[ ⁇ ,el[l,41diazepin-10-yU-3-oxo- propionic acid (89) and (61-3- ⁇ l l-[4-(2-bromophenoxy)-2-chlorophenyll-6-hydroxy- 3,3-dimethyl-l-oxo-l,2,3,4,5J l-hexahydrodibenzo[ ⁇ ,el[l,41diazepin-10-yU-3- oxopropionic acid (90).
  • Example 60 1 l-[4-(3-nitrobenzyloxy)-2-chlorophenyll-6-hydroxy-3,3-dimethyl- 2.3.4.5.10.1 l-hexahvdro-dibenzor6.ei ⁇ .41diazepin-l-one (92).
  • the title product 92 was prepared from 2-chloro-4-(3-nitrobenzyloxy)benzaldehyde (91), which was obtained in 91% yield from 3-nitrobenzylbromide following the procedure (Method A) reported for the synthesis of compound 11.
  • Example 61 10-acetyl-l l-[4-(3-nitrobenzyloxy)-2-chlorophenyll-6-hydroxy- 3,3-dimethyl-2,3,4,5,10,l l-hexahvdro-dibenzor ⁇ ,ei ⁇ ,41diazepin-l-one (93).
  • Example 62 1 l-[5-(benzyloxy)thienyll-6-hydroxy-3,3-dimethyl-2,3,4,5,10,l 1-hexa- hydro-dibenzor ⁇ , e ⁇ W ,41diazepin- 1 -one (94).
  • Example 63 10-acetyl-l l-[4-(3-aminobenzyloxy)-2-chlorophenyl]-6-hydroxy- 3,3-dimethyl-2,3,4,5, 10,11 -hexahvdro-dibenzor ⁇ , e] [ 1 ,41diazepin- 1 -one (95).
  • Example 64 10-acetyl-l l-[5-(benzyloxy)thienyll-6-hydroxy-3,3-dimethyl- 2.3.4.5.10.1 l-hexahvdro-dibenzor6.ei ⁇ .41diazepin-l-one (96).
  • Example 65 4-[l l-(4-benzyloxy-2-chlorophenyl)-6-hydroxy-3,3-dimethyl-l-oxo- 1,2,3,4,5,1 l-hexahvdrodibenzor&,eiri,41diazepin-10-vH-4-oxobutyric acid (97).
  • Example 66 10-[3-(cyclopropylsulfonylamino)-3-oxopropionyll-l l-(4-benzyloxy- 2-chlorophenyl)-6-hydroxy-3, 3-dimethyl-2, 3,4,5, 10,l l-hexahydro-dibenzo[ ⁇ ,el [1,41- diazepin-1-one (100).
  • cyclopropane sulfonamide (6000 mg, 49.5 mmol), potassium carbonate (1.25 g), benzyltriethylammonium chloride (1545 mg, 5.0 mmol), and acetonitrile (75 mL).
  • the flask was sealed, equipped with a nitrogen balloon and allowed to stir at 45°C.
  • a solution of methyl malonyl chloride (8790 mg, 64.4 mmol) in acetonitrile (40 mL) was added dropwise via addition funnel. When addition was complete, the heating was removed and the reaction stirred at room temperature for Ih. LCMS showed product formed.
  • Example 67 10-[4-(phenylsulfonylamino)-4-oxobutyryll-l l-(4-benzyloxy-2-chloro- phenyl)-6-hydroxy-3, 3-dimethyl-2, 3,4,5, 10,l l-hexahydro-dibenzo
  • Example 68 4-[l l-(4-benzyloxy-2-chlorophenyl)-6-hydroxy-3,3-dimethyl-l-oxo- 1,2,3,4,5,1 l-hexahydrodibenzo
  • Example 69 10-[4-(4-methylpiperazin-l-yl)-4-oxobutyryll-l l-(4-benzyloxy-2-chloro- phenyl)-6-hydroxy-3, 3-dimethyl-2, 3,4,5, 10,l l-hexahydro-dibenzo
  • Example 70 (1 li?)-4-[l l-(4-benzyloxy-2-chlorophenyl)-6-hydroxy-3,3-dimethyl- l-oxo-1,2,3,4,5,1 l-hexahydrodibenzo[ ⁇ ,el[l,41diazepin-10-yll-4-oxobutyric acid (105) and (1151-4-[I l-(4-benzyloxy-2-chlorophenyl)-6-hydroxy-3,3-dimethyl-l-oxo- 1,2,3,4,5,1 l-hexahvdrodibenzor&,eiri,41diazepin-10-yl1-4-oxobutyric acid (106).
  • Example 71 [1 l-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl-l-oxo- 1,2,3,4,5,1 l-hexahvdrodibenzor&,eiri,41diazepin-10-vHoxoacetic acid (107).
  • Example 72 4-[l l-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl-l-oxo- 1,2,3,4,5,1 l-hexahvdrodibenzor&,eiri,41diazemn-10-vH-4-oxobutyric acid (108).
  • Example 106 (1 li?)-l l-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl- 10-(5-methylisoxazole-3-carbonyl)-2,3,4,5J0J l-hexahydrodibenzo[ ⁇ ,el[l,41diazepin- 1-one (142) and (1161-1 l-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3, 3-dimethyl- 10-(5-methylisoxazole-3-carbonyl)-2,3,4,5J0J l-hexahydrodibenzo[6,e1[l,41diazepin- 1-one (143).
  • Example 107 (i?)- ⁇ [l l-(4-benzyloxy-2-chlorophenyl)-6-hydroxy-3,3-dimethyl-l-oxo- 1,2,3,4,5,11 -hexahydrodibenzo[&, e] [ 1 ,4 "
  • Example 108 (1 IR)-I l-(4-benzyloxy-2-fluorophenyl)-10-(2,5-dimethyloxazole- 4-carbonyl)-6-hydroxy-3,3-dimethyl-2,3,4,5,10,l l-hexahydrodibenzo[ ⁇ e "
  • Example 138 10-acetyl-l l-(2,4-dichlorophenyl)-6-hydroxy-3,3-dimethyl- 2,3,4,5,10,1 l-hexahydro-dibenzor&,eiri,41diazepin-l-one (177).
  • Example 139 (1 lift- 10-acetyl-l l-(2.4-dichlorophenyl)-6-hvdroxy-3.3-dimethyl- 2,3.4,5.10.1 l-hexahvdro-dibenzor&.eiri,41diazepin-l-one (178) and (1 IS)-10-acetyl- l l-(2,4-dichlorophenyl)-6-hydroxy-3,3-dimethyl-2,3,4,5,10,l l-hexahydro- dibenzor&,ei ⁇ ,41diazepin-l-one (179).
  • Example 140 (1 Ii?)- 10-acetyl-l l-(4-benzyloxy-2-chlorophenyl)-6-hydroxy- 3, 3-dimethyl-2, 3,4,5, 10,1 l-hexahydro-dibenzo
  • Example 141 3-[l l-(2,4-dichlorophenyl)-6-hydroxy-3,3-dimethyl-l-oxo- 1,2,3,4,5,1 l-hexahvdrodibenzor ⁇ ,eiri,41diazepin-10-yll-3-oxopropionic acid (183).
  • Chlorocarbonylacetic acid ethyl ester (0.104 rnL) was added drop wise to a solution of compound 176 (0.30 mmol) and triethylamine (0.40 mmol) in THF (3 rnL). The mixture was stirred and refluxed for 12 h. Then, additional chlorocarbonylacetic acid ethyl ester (0.057 mL) was added and the resulting solution was stirred at reflux. After 6h, the reaction was cooled down to room temperature. The precipitate was collected by filtration, rinsed with THF and dried to give 0.35 g of intermediate 182, which was used directly in the next reaction without further purification.
  • Example 142 3-[l l-(2,4-dichlorophenyl)-6-hydroxy-3,3-dimethyl-l-oxo- 1,2,3,4,5,1 l-hexahydrodibenzoF ⁇ el ri,41diazepm-10-yl1-3-oxopropionamide (184).
  • Example 143 1 l-(2,4-dichlorophenyl)-6-hydroxy-3,3-dimethyl-l-oxo- 1,2,3,4,5,1 l-hexahvdrodibenzor&,eiri,41diazepine-10-carboxyric acid methylamide
  • Example 144 1 l-[2-chloro-4-(pyridin-3-ylmethoxy)phenyll-6-hydroxy-3,3-dimethyl- 2.3.4.5.10.1 l-hexahvdrodibenzor6.eiri.41diazepin-l-one (200).
  • Example 145 10-acetyl-l l-[2-chloro-4-(pyridin-3-ylmethoxy)phenyll-6-hydroxy- 3.3-dimetfayl-2.3.4.5.10.11-hexahvdrodibenzor6.eiri.41diazepin-l-one (20iy
  • Examples 146-169 The compounds in Table 4 were synthesized starting from the starting materials indicated in the table and the corresponding anhydride following the procedure (step 3) reported for the preparation of compound 61.
  • Example 170 3-[l l-(4-benzyloxy-2-methylphenyl)-6-hydroxy-3,3-dimethyl-l-oxo- 1,2,3,4,5,1 l-hexahvdrodibenzor ⁇ ,eiri,41diazepin-10-yll-3-oxopropionitrile (226).
  • Example 171 4-[l l-(4-benzyloxy-2-methylphenyl)-6-hydroxy-3,3-dimethyl-l-oxo- 1,2,3,4,5,1 l-hexahydrodibenzor&,eiri,41diazemn-10-vH-4-oxobutyric acid (227).
  • Example 229 1 l-(2,4-dichlorophenyl)-10-(2,5-dimethyloxazole-4-carbonyl)- 6-hydroxy-3 ,3-dimethyl-2,3 ,4,5 , 10,11 -hexatiydrodibenzoT ⁇ , e ⁇ ⁇ 1 ,41diazepin- 1 -one
  • Example 230 2- ⁇ 4-[l l-(4-benzyloxy-2-chlorophenyl)-6-hydroxy-3,3-dimethyl-l-oxo- 1 ,2,3,4,5, 11 -hexahydro-dibenzo
  • Example 231 (7?)-4-[l l-(4-benzyloxy-2-chlorophenyl)-6-hydroxy-3,3-dimethyl-l-oxo- 1,2,3,4,5,11 -hexahydrodibenzo
  • Example 232 (i?)-l-[l l-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl-l-oxo- 1,2,3,4,5,1 l-hexahydrodibenzo[ ⁇ ,el[l,41diazepin-10-yll-4-(4-morpholin-4-yl-piperidin- l-yl)butane-l,4-dione (289) and (61-l-[l l-(4-benzyloxy-2-fluorophenyl)-6-hydroxy- 3,3-dimethyl-l-oxo-l,2,3,4,5,l l-hexahydrodibenzo[ ⁇ ,el[l,41diazepin-10-yll- 4-(4-morpholin-4-yl-prperidin- 1 -vDbutane- 1 ,4-dione (290).
  • Protocol A generic acylation method using an anhydride
  • the benzodiazepine indicated in table 6 was acylated following the procedures described for the preparation of compound 8 or compound 57, using the anhydride indicated in the table.
  • Protocol B generic acylation method using an acid chloride The benzodiazepine indicated in the table was acylated using the acid chloride indicated in the table, following the procedure described for the preparation of compound 64 or 77.
  • Protocol C generic method for enantiomer separation
  • Protocol D generic acylation method using coupling reagents
  • the benzodiazepine indicated in the table was acylated using the carboxylic acid indicated in the table and coupling reagents as described for example for the preparation of compound 63.
  • Protocol E generic method for urea formation
  • Protocol G generic method for carbamate formation The benzodiazepine indicated in the table was reacted as its silyl-protected phenol with the chloroformate indicated in the table to form the corresponding carbamate, following the procedure described for the preparation of compound 34.
  • Protocol H The PMB-protecting group of the tetrazole moiety and the trityl-protecting group on the phenol of the benzodiazepine 520 were simultaneously deprotected in TFA at 50 0 C during 48h. After cooling down to 0 0 C, water was added to the reaction mixture, which was subsequently neutralized by addition of potassium carbonate, then extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, concentrated, and the crude was purified by flash chromatography to give 60 mg (15% yield) of the desired product as a solid, which was recrystallized from acetone; mp > 260 0 C. Protocol I:
  • Example 451 synthesis of l l-(4-Benzyloxy-2-fluoro-phenyl)-6-hydroxy-3,3-dimethyl- 10-[2-(3-oxo-piperazin-l-yl)-acetyll-2, 3,4, 5, 10,11 -hexahydro-dibenzo[b,el [1,41- diazepin- 1 -one (511)
  • the title compound 514 was prepared in 73% yield (70 mg) from compound 513 (92 mg, 0.175 mmol) by catalytic hydrogenation using Pd/C 10% in methanol; m/z : 527 (M+H) + .
  • Example 453 synthesis of l l-(2,4-Dichloro-phenyl)-10- ⁇ 3-[l-(4-methoxy-benzyl)- lH-tetrazol-5-yll-propionyl
  • the two regioisomers 517 (0.4 g, 1.52 mmol) were heated in refluxing thionyl chloride (2 rnL) during 2h. After concentration under reduced pressure, the obtained acid chloride regioisomers (518) were used without further purification in the next step.
  • Acetyl chloride (10.7 mL, 150 mmol) was added to methanol (150 mL) over 30 minutes, at 0 0 C, under N 2 atmosphere. This solution was then added to the intermediate 522 (4.94 g, 28.7 mmol) and the reaction mixture was refluxed during 6h. After concentration, the reaction mixture was diluted with water and extracted with diethylether. The organic layer was dried over sodium sulfate, filtered and concentrated.
  • the title compound 528 was synthesized following the 4-step procedure reported for the preparation of compound 524, starting from compound 527 instead of 3-ethyl- 3-methyl-pentanedioic acid.
  • the title compound 529 was synthesized in 31% overall yield following the 2-step procedure reported for the preparation of compound 527, starting from 2-pentanone instead of 3-methyl-2-butanone.
  • the title compound 530 was synthesized following the 4-step procedure reported for the preparation of compound 524, starting from compound 529 instead of 3-ethyl- 3-methyl-pentanedioic acid.
  • Example 459 synthesis of l l-(4-benzyloxy-2-fluoro-phenyl)-3-ethyl-6-hydroxy- 3-methyl-2.3.4.5.10.1 l-hexahvdro-dibenzorb.ei ⁇ .41diazepin-l-one (531)
  • Example 460 synthesis of l l-(4-benzyloxy-2-fluoro-phenyl)-6-hydroxy-3-isopropyl-3- methyl-2,3,4,5,10,l l-hexahvdro-dibenzorb,eiri,41diazepin-l-one (532)
  • Example 461 synthesis of l l-(4-Benzyloxy-2-fluoro-phenyl)-6-hydroxy-3-methyl- 3-propyl-2, 3,4,5, 10, l l-hexahvdro-dibenzorb,eiri,41diazepin-l-one (533)
  • the compounds of formula (I) were examined for activity in the inhibition 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 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).
  • IRS Internal Ribosome Entry Site
  • EMCV encephalomyocarditis virus
  • FfL-luciferase reporter portion
  • neo R neomycine phosphotransferase
  • the replicon cells were plated in 384 well plates in the presence of the test and control compounds which were added in various 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 Tm ultraHTS microplate imager). Replicon cells in the control cultures have high luciferase expression in the absence of any inhibitor. The inhibitory activity of the compound 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 milliliters 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).
  • the protein sequence is as described in WO 2007/026024. CaIc. MoI. Properties: 64941.4 g/mol.
  • 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 ⁇ 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.
  • 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).
  • streptavidin-coated SPA beads GE Heathcare, Uppsala, Sweden 5 mg/ml in 0.5 M EDTA.
  • 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.
  • Table 10 lists compounds that were prepared according to any one of the above examples. The activities of the compounds tested are also depicted in Table 10.

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Abstract

Inhibitors of HCV replication of formula (I) the stereoisomers, prodrugs, tautomers, racemics, salts, hydrates or solvates thereof wherein R1, 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

ό-HYDROXY-DIBENZODIAZEPINONES USEFUL AS HEPATITIS C VIRUS INHIBITORS
Field of the invention The present invention is concerned with 6-hydroxy-dibenzodiazepinones 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 6-hydroxy-dibenzodiazepinone derivatives exhibit antiviral activity in mammalians 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
and the stereoisomers, prodrugs, tautomers, racemics, salts, hydrates or solvates thereof, wherein
R1 is hydrogen, 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 6-hydroxy-dibenzodiazepinone 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, -S(=O)2-aryl, -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 one, two, or three substituents selected from halo, hydroxy, Ci_6alkoxy, C3-7cycloalkenyl, phenyl, and Het, wherein the phenyl may optionally be substituted with halo, hydroxy , Ci_6alkoxy, nitro, or amino; C2-6alkenyl; C2-6alkynyl; C3-7cycloalkenyl; indanyl; or phenyl optionally substituted with one or two substituents selected from halo, hydroxy, amino, nitro, C^aUcyl, 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 or three substituents each independently selected from the group consisting of halo; phenyl; polyhaloCi-βalkyl; cyano; Ci_6alkyl optionally substituted with -OR9 or phenyl; polyhaloCi-βalkoxy; polyhaloCi-βalkylphenyl; polyhaloCi-βalkylthienyl; -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 halo, -OR9, -CN, -NR10aR10b, or phenyl;-C(=O)-NH2; -C(=O)- phenyl; -C(=O)-OH; -C(=O)-Ci_6alkyl; Ci_6alkylthio; C3-7cycloalkyl; phenyl optionally substituted with Ci_6alkoxy; morpholinyl; C2-6alkynyl; pyrrolidinyl; pyrrolyl; furanyl; pyridinyl, tetrazolyl; 1,3-dioxolanyl, and thiophenyl; and each R1Oa andR1Ob is, independently, hydrogen, d_6alkyl, arylCi_6alkyl, aryl, or R1Oa and R1Ob, 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 of formula (I) and the salts and stereoisomers thereof, wherein R1 is hydrogen, 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, C1-6alkyl, or both R4a and R4b together with the carbon atom of the 6-hydroxy-dibenzodiazepinone 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 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-βalkyl, cyano, Ci_6alkyl, 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; 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 R10aandR10b 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.
The invention further relates to methods for the preparation of the compounds of formula (I), the JV-oxides, quaternary amines, salts, hydrates, solvates, prodrugs, 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 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 (I) 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-l-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 polyhaloCi-βalkyl radicals include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, and 1,1,1-trifluoroethyl.
C3 yCycloalkyl 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 "Cl-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 " Cl-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 stereospecific 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, iV-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 imgf000011_0001
wherein R1, 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 methoxymethyl, 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-oxy ethyl 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 Λ/-(dialkylaminoethyl)-Λ/-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, /^-aminosalicylic, 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:
R1 is hydrogen, halo, trifluoromethyl, or Ci_6alkyl optionally substituted with cyano; preferably R1 is hydrogen or halo, more preferably R1 is hydrogen;
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, -C(=O)-OR6, or -C(=O)-NR7aR7b; preferably R2 is hydrogen, -C(=O)-R5, or -C(=O)-OR6; preferably R2 is hydrogen, -C(=O)-R5, or -C(=O)-NR7aR7b; yet more preferably R2 is hydrogen or -C(=O)-R5, preferably -C(=O)-R5;
R is Ci_6alkyl optionally substituted with C3_7Cycloalkyl, aryl, or Het; C3_7Cycloalkyl; aryl; or Het; preferably R3 is Ci_6alkyl optionally substituted with aryl, or Het; C3_7Cycloalkyl; aryl; or Het; preferably R3 is Ci_6alkyl optionally substituted with aryl, C3-7cycloalkyl; aryl; or Het; preferably R3 is C3-7cycloalkyl; aryl; or Het; yet more preferably R3 is aryl; or Het, preferably aryl; each R4a and R4b is, independently, C1-6alkyl, or both R4a and R4b together with the carbon atom of the 6-hydroxy-dibenzodiazepinone ring to which they are attached may form a C3-7cycloalkyl; preferably each R4a and R4b is, independently, Ci_4alkyl, or both R4a and R4b together with the carbon atom of the 6-hydroxy- dibenzodiazepinone ring to which they are attached may form a C3_6Cycloalkyl; more preferably, each R4a and R4b is, independently, Ci_6alkyl;
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, -S(=O)2-aryl, -NR7aR7b, 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 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; more preferably R5 is Ci_6alkyl optionally substituted with one or two substituents selected from cyano, -OR9, -C(=O)-Het, -C(=O)-OR6, -C(=O)-OH, -C(=O)-NR7aR7b, -C(=O)-NH-S(=O)2-R8, aryl, and Het; C2-6alkenyl optionally substituted with aryl; polyhaloCi-βalkyl; C3_7Cycloalkyl; aryl; or Het; more preferably R5 is Ci_6alkyl optionally substituted with one or two substituents selected from cyano, -OR9, -C(=O)-Het, -C(=O)-OR6, -C(=O)-OH, -C(=O)-NR7aR7b, aryl, and Het; C3-7cycloalkyl; aryl; or Het; more preferably R5 is Ci_6alkyl optionally substituted with one or two substituents selected from cyano, -OR9, -C(=O)-Het, -C(=O)-NR7aR7b, and Het; aryl; or Het; more preferably R5 is
Ci_6alkyl optionally substituted with one or two substituents selected from cyano, -C(=O)-Het, and Het; aryl; or Het; more preferably R5 is Ci_6alkyl optionally substituted with one or two substituents selected from cyano, — C(=O)-Het, and Het; aryl; or Het; more preferably R5 is Ci_6alkyl optionally substituted with one or two substituents selected from cyano, — C(=O)-Het, and Het; aryl; or Het, wherein
Het is selected from tetrahydrofuranyl, pyridazinyl, pyrazinyl, quinoxalinyl, furanyl, benzofuranyl, thiazolyl, pyrimidinyl, quinolinyl, benzo(l,3)dioxolyl, oxazolyl, pyridinyl, pyrazolyl, 2,3-dihydrobenzo(l,4)dioxinyl, quinazolinyl, isoxazolyl, 1,2,4-triazolyl, naphthyridinyl, each Het being optionally substituted with one or two substituents selected from halo; oxo; -OR9; -NR10aR10b; -CN;
Ci_6alkyl optionally substituted with halo, -OR9, -CN, -NR10aR10b, or phenyl;-C(=O)-NH2; -C(=O)-phenyl; -C(=O)-OH; -C(=O)-Ci_6alkyl; Ci_6alkylthio; phenyl optionally substituted with Ci_6alkoxy; morpholinyl; C2_6alkynyl; pyrrolyl; furanyl; pyridinyl; tetrazolyl; 1,3-dioxolanyl, and thiophenyl, ; R6 is 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 Ci_6alkyl optionally substituted with -OR9,-C(=O)-NR7aR7b, -C(=O)-NH-S(=O)2-R8, phenyl, or Het; preferably R6 is Ci_6alkyl optionally substituted with -OR9,-C(=O)-NR7aR7b, phenyl, 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; preferably each R7a and R7b is, independently, hydrogen; Ci_6alkyl optionally substituted with one or two substituents selected from mono- or diCi_6alkylamino, -C(=O)-Het, aryl, and Het; C2-6alkenyl; C3-7cycloalkyl optionally substituted with hydroxy; aryl; or Het; preferably each R7a and R7b is, independently, hydrogen; Ci_6alkyl optionally substituted with one or two substituents selected from mono- or diCi_6alkylamino, and Het; C2-6alkenyl; C3_7Cycloalkyl optionally substituted with hydroxy; or Het; more preferably each R7a and R7b is, independently, hydrogen; Ci_6alkyl optionally substituted with one or two Het, or C(=O)Het substituents; or Het; R8 is Ci_6alkyl, C3_7Cycloalkyl, di(Ci_3alkyl)amino, or aryl; preferably R8 is Ci_6alkyl,
C3-7cycloalkyl, or aryl; more preferably R8 is C3-7cycloalkyl, or aryl; R9 is hydrogen; Ci_6alkyl optionally substituted with one, two, or three substituents selected from halo, hydroxy, Ci_6alkoxy, C3-7cycloalkenyl, phenyl, and Het, wherein the phenyl may optionally be substituted with halo, hydroxy , Ci_6alkoxy, nitro, or amino; C2-6alkenyl; C2-6alkynyl; C3-7cycloalkenyl; indanyl; or phenyl optionally substituted with one or two substituents selected from halo, hydroxy, amino, nitro, d-βalkyl, and phenyl; preferably R9 is hydrogen; Ci_6alkyl optionally substituted with one, two, or three substituents selected from halo, Ci_6alkoxy, phenyl, and Het, wherein the phenyl may optionally be substituted with halo, Ci_6alkoxy, nitro, or amino; indanyl; or phenyl optionally substituted with one or two substituents selected from halo, amino, nitro, d-βalkyl, and phenyl; preferably R9 is hydrogen; Ci_6alkyl optionally substituted with one, two, or three substituents selected from halo, hydroxy, Ci_6alkoxy, C3-7cycloalkenyl, phenyl, and Het, wherein the phenyl may optionally be substituted with halo, hydroxy , Ci_6alkoxy, nitro, or amino; C2-6alkenyl; C2-6alkynyl; C3-7cycloalkenyl; indanyl; or phenyl optionally substituted with one or two substituents selected from halo, hydroxy, amino, nitro, d-βalkyl, and phenyl; preferably R9 is hydrogen; Ci_6alkyl optionally substituted with one, two, or three substituents selected from halo, Ci_6alkoxy, and phenyl, wherein the phenyl may optionally be substituted with halo, nitro, amino, or Ci_6alkoxy; indanyl; or phenyl optionally substituted with one or two substituents selected from halo, d-βalkyl, and phenyl; preferably R9 is hydrogen; Ci_6alkyl optionally substituted with one, two, or three substituents selected from halo, Ci_6alkoxy, and phenyl, wherein the phenyl may optionally be substituted with halo, Ci_6alkoxy, amino or nitro; or phenyl optionally substituted with one or two halo substituents; 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 or three substituents each independently selected from the group consisting of halo; phenyl; polyhaloCi-βalkyl; cyano; Ci_6alkyl optionally substituted with -OR9 or phenyl; polyhaloCi-βalkoxy; polyhaloCi-βalkylphenyl; polyhaloCi-βalkylthienyl; -OR9; -C(=O)OH; Ci_6alkylcarbonyl; Ci_6alkylthio; Ci_6alkylsulfonyl; -S(=O)2NH2; Het and pyrrolyl; preferably aryl as a group or part of a group is phenyl, or naphthyl each of which may be optionally substituted with one, two or three substituents each independently selected from the group consisting of halo; phenyl; polyhaloCi-βalkyl; cyano; Ci_6alkyl optionally substituted with -OR9 or phenyl; polyhaloCi_6alkoxy; -OR9; -C(=O)OH; Ci_6alkylthio; -S(=O)2NH2; and pyrrolyl; preferably 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 halopolyhaloCi_6alkyl; Ci_6alkyl; polyhaloCi_6alkoxy; -OR9; -C(=O)OH; Ci_6alkylthio; -S(=O)2NH2; and pyrrolyl; preferably 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 halopolyhaloCi-βalkyl; Ci_6alkyl; -OR9; 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 halo, -OR9, -CN, -NR10aR10b, or phenyl;-C(=O)-NH2; -C(=O)-phenyl; -C(=O)-OH; -C(=O)-Ci_6alkyl; Ci_6alkylthio; C3-7cycloalkyl; phenyl optionally substituted with Ci_6alkoxy; morpholinyl; C2_6alkynyl; pyrrolidinyl; pyrrolyl; furanyl; pyridinyl, tetrazolyl; 1,3-dioxolanyl, and thiophenyl; preferably 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 halo, -OR9, -NR10aR10b, or phenyl; -C(=O)-NH2; -C(=O)-phenyl; C3-7cycloalkyl; phenyl optionally substituted with Ci_6alkoxy; morpholinyl; furanyl; pyridinyl, tetrazolyl; and thiophenyl; preferably 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, -NR10aR10b; phenyl optionally substituted with Ci_6alkoxy; morpholinyl; furanyl; and thiophenyl; preferably Het is selected from quinolinyl, furanyl, quinoxalinyl, oxazolyl, benzofuranyl, isoxazolyl, 2,3-dihydrobenzo[l,4]- dioxinyl, thiazolyl, tetrahydrofuranyl, pyridazinyl, pyrazinyl, pyrimidinyl, benzo(l,3)dioxolyl, pyridinyl, pyrazolyl, quinazolinyl, 1,2,4-triazolyl, naphthyridinyl, indolyl, tetrahydrothiophenyl, morpholinyl, thiophenyl, pyrrolidinyl, piperazinyl, pyrrolyl, tetrahydroquinolinyl, piperidinyl, isoindolinyl, tetrahydroisoquinolinyl, imidazolyl, tetrazolyl, imidazo(2,l)thiazolyl, 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, -NR10aR10b; phenyl optionally substituted with Ci_6alkoxy; morpholinyl; furanyl; and thiophenyl; each R1 Oa and R1 ob is, independently, hydrogen, C i _6alky 1, arylC i _6alkyl, aryl, or R1 Oa 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, preferably each R1Oa andR10b is, independently, hydrogen, arylCi_6alkyl, aryl, 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; preferably each R10aandR10b is, independently, hydrogen, arylCi-βalkyl, aryl.
One embodiment of the present invention concerns compounds of formula (I) or of any subgroup thereof, wherein R1 is hydrogen, 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 aryl; 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 6-hydroxy-dibenzodiazepinone 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, -OR9, -C(=O)-Het, -C(=O)-OR6, -C(=O)-OH, -C(=O)-NR7aR7b,
-C(=O)-NH-S(=O)2-R8, -S(=O)2-aryl, 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-hydroxyCi_6alkyl, -C(=O)-Het, aryl and Het; C2.6alkenyl; C3-7cycloalkyl optionally substituted with hydroxy; aryl; or Het;
R8 is Ci_6alkyl, C3_7Cycloalkyl, or aryl; R9 is hydrogen; Ci_6alkyl optionally substituted with one, two, or three substitutents selected from halo, Ci_6alkoxy, phenyl, and 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, Ci_6alkyl, and phenyl; aryl as a group or part of a group is phenyl optionally substituted with one, two or three substituents each independently selected from the group consisting of halo; phenyl; polyhaloCi-βalkyl; cyano; Ci_6alkyl_optionally substituted with -OR9 or phenyl; polyhaloCi-βalkoxy; -OR9; -C(=O)OH; Ci_6alkylcarbonyl; Ci_6alkylthio; Ci_6alkylsulfonyl; -S(=O)2NH2; and pyrrolyl; and
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 halo, -NR10aR10b, -OR9 or phenyl;-C(=O)-NH2; -C(=O)-phenyl; -C(=O)-OH;
-C(=O)-Ci_6alkyl; Ci_6alkylthio; C2_6alkynyl; phenyl optionally substituted with Ci_6alkoxy; morpholinyl; pyrrolidinyl; pyrrolyl; furanyl; pyridinyl; tetrazolyl; and thiophenyl; each R10aandR10b is, independently, hydrogen, Ci_6alkyl, arylCi-βalkyl, or aryl.
One embodiment of the present invention concerns compounds of formula (I) or any subgroup thereof, wherein R1 is hydrogen; R2 is -C(=O)-R5, -C(=O)-OR6, or -C(=O)-NR7aR7b;
R is aryl or Het; each R4a and R4b is, independently, C1-6alkyl, or both R4a and R4b together with the carbon atom of the 6-hydroxy-dibenzodiazepinone 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,
-OR9, -C(=O)-Het, -C(=O)-OR6, -C(=O)-OH, -C(=O)-NR7aR7b, -C(=O)-NH-
S(=O)2-R8, -S(=O)2-aryl, 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 mono- or diCi_6alkylamino, -C(=O)-OR9,
-C(=O)-NH2, -C(=O)-Het, aryl and Het; C2-6alkenyl; C3-7cycloalkyl optionally substituted with hydroxyl; aryl; or Het;
R8 is Ci_6alkyl, C3-7Cy cloalkyl, or aryl; R9 is hydrogen; Ci_6alkyl optionally substituted with halo, 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 halo; aryl as a group or part of a group is phenyl optionally substituted with one, two or three substituents each independently selected from the group consisting of halo; phenyl; polyhaloCi-βalkyl; cyano; Ci_6alkyl optionally substituted with -OR9 or phenyl; polyhaloCi-ealkoxy; -OR9; -C(=O)OH; Ci.6alkylthio; -S(=O)2NH2; and pyrrolyl; and 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 halo, -NR10aR10b, -OR9; -C(=O)-phenyl; -C(=O)-OH; -C(=O)-Ci.6alkyl;
Ci_6alkylthio; C2-6alkynyl; phenyl optionally substituted with Ci_6alkoxy; morpholinyl; pyrrolidinyl; pyrrolyl; furanyl; pyridinyl; tetrazolyl; and thiophenyl; each R10aandR10b is, independently, hydrogen, Ci_6alkyl, arylCi-βalkyl, or aryl.
One embodiment of the present invention concerns compounds of formula (I) or of any subgroup thereof, wherein one or more of the following restrictions apply:
(a) R1 is hydrogen, halo, trifluoromethyl, or Ci_6alkyl optionally substituted with cyano; (b) R2 is hydrogen, -C(=O)-R5, -C(=O)-C(=O)-R5, -C(=O)-OR6, or -C(=O)-NR7aR7b;
(c) R3 is Ci_6alkyl optionally substituted with aryl; C3_7Cycloalkyl; aryl; or Het;
(d) each R4a and R4b is, independently, C1-6alkyl, or both R4a and R4b together with the carbon atom of the 6-hydroxy-dibenzodiazepinone ring to which they are attached may form a C3_7Cycloalkyl;
(e) R5 is Ci_6alkyl optionally substituted with one or two substituents selected from cyano, -OR9, -C(=O)-Het, -C(=O)-OR6, -C(=O)-OH, -C(=O)-NR7aR7b, -C(=O)-NH-S(=O)2-R8, aryl, and Het; C2-6alkenyl optionally substituted with aryl; polyhaloCi-βalkyl; C3-7cycloalkyl; aryl; or Het; (f) R6 is Ci_6alkyl optionally substituted with -OR9, -C(=O)-OR9, -C(=O)-NR7aR7b,
-C(=O)-NH-S(=O)2-R8, aryl, or Het;
(g) 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)-NH-hydroxyCi_6alkyl, -C(=O)-Het, and aryl; C2.6alkenyl; C3-7cycloalkyl optionally substituted with hydroxy; aryl; or Het;
(h) R8 is Ci_6alkyl, C3_7Cycloalkyl, or aryl;
(i) 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, Ci_6alkyl, and phenyl;
(j) 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_6alkyl, cyano, Ci_6alkyl, polyhaloCi_6alkoxy, -OR9, -C(=O)OH, Ci_6alkylcarbonyl, Ci_6alkylthio, Ci_6alkylsulfonyl, -S(=O)2NH2, and pyrrolyl; and (k) 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 or phenyl;-C(=O)-NH2; -C(=O)-phenyl; 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 any subgroup thereof, wherein R1 is hydrogen; R2 is -C(=O)-R5, -C(=O)-OR6, or -C(=O)-NR7aR7b; R3 is aryl or Het; each R4a and R4b is, independently, C1-6alkyl, or both R4a and R4b together with the carbon atom of the 6-hydroxy-dibenzodiazepinone 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, -OR9, -C(=O)-Het, -C(=O)-OR6, -C(=O)-OH, aryl, Het, and -C(=O)-NR7aR7b; polyhaloCi-βalkyl; C3-7cycloalkyl; aryl; or Het;
R6 is Ci_6alkyl optionally substituted with -C(=O)-OR9, or -C(=O)-NR7aR7b; each R7a and R7b is, independently, hydrogen; Ci_6alkyl optionally substituted with one or two substituents selected from mono- or diCi_6alkylamino, -C(=O)-OR9, and
-C(=O)-Het; aryl; or Het;
R9 is hydrogen; Ci_6alkyl optionally substituted with halo, Ci_6alkoxy, phenyl or Het, wherein the phenyl may optionally be substituted with halo, nitro, or amino; or phenyl optionally substituted with one or two halo; 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; phenyl; polyhaloCi-βalkyl; Ci_6alkyl optionally substituted with -OR9 or phenyl; polyhaloCi_6alkoxy; -OR9; -C(=O)OH; Ci_6alkylthio; -S(=O)2NH2; and pyrrolyl; and 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 halo, -NR10aR10b, -OR9; -C(=O)-OH; -C(=O)-Ci_6alkyl; Ci_6alkylthio; C2-6alkynyl; phenyl; morpholinyl; pyridinyl;pyrrolidinyl; pyrrolyl; furanyl; tetrazolyl; and thiophenyl; each R10aandR10b is, independently, hydrogen, d^alkyl, arylCi-βalkyl, or aryl.
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) R1 is hydrogen; (b) R2 is -C(=O)-R5, -C(=O)-OR6, or -C(=O)-NR7aR7b; (c) R3 is aryl or Het; (d) each R4a and R4b is, independently, C1-6alkyl, or both R4a and R4b together with the carbon atom of the 6-hydroxy-dibenzodiazepinone ring to which they are attached may form a C3_7Cycloalkyl;
(e) R5 is Ci_6alkyl optionally substituted with one or two substituents selected from cyano, -C(=O)-Het, -C(=O)-OR6, -C(=O)-OH, -C(=O)-NR7aR7b,
-C(=O)-NH-S(=O)2-R8, aryl, and Het; polyhaloCi_6alkyl; C3-7cycloalkyl; aiyl; or Het;
(f) R6 is Ci_6alkyl optionally substituted with -OR9, -C(=O)-OR9, -C(=O)-NR7aR7b, or aryl; (g) each R7a and R7b is, independently, hydrogen; Ci_6alkyl optionally substituted with one or two substituents selected from mono- or diCi_6alkylamino, -C(=O)-OR9, -C(=O)-Het, and aryl; aryl; or Het; (h) R8 is d-βalkyl, C3-7cycloalkyl, or aryl; (i) R9 is hydrogen; Ci_6alkyl optionally substituted with 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 halo;
(j) 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, C^aUcyl, -OR9, Ci_6alkylsulfonyl, and pyrrolyl; and (k) 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;
-C(=O)-phenyl; 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) R1 is hydrogen;
(b) R2 is -C(=O)-R5, -C(=O)-OR6, or -C(=O)-NR7aR7b;
(c) R3 is aryl or Het; (d) each R4a and R4b is, independently, C1-6alkyl, or both R4a and R4b together with the carbon atom of the 6-hydroxy-dibenzodiazepinone ring to which they are attached may form a C3_7cycloalkyl; (e) R5 is Ci_6alkyl optionally substituted with one or two substituents selected from cyano, -C(=O)-Het, -C(=O)-OR6, -C(=O)-OH, and -C(=O)-NR7aR7b; polyhaloCi-βalkyl; C3-7cycloalkyl; aryl; or Het;
(f) R6 is Ci_6alkyl optionally substituted with -C(=O)-NR7aR7b; (g) each R7a and R7b is, independently, hydrogen; Ci_6alkyl optionally substituted with one or two substituents selected from mono- or diCi_6alkylamino, -C(=O)-OR9, and -C(=O)-Het; aryl; or Het; (h) R9 is hydrogen; Ci_6alkyl optionally substituted with phenyl or Het, wherein the phenyl may optionally be substituted with halo, nitro, or amino; or phenyl optionally substituted with one or two halo;
(i) 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, d-βalkyl, -OR9, and pyrrolyl; and
(j) 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; phenyl; morpholinyl; pyrrolidinyl; pyrrolyl; furanyl; tetrazolyl; and thiophenyl.
One embodiment of the present invention concerns compounds of formula (I) or of any subgroup thereof, wherein:
R1 is hydrogen or halo, more preferably R1 is hydrogen; R2 is hydrogen, -C(=O)-R5, or -C(=O)-OR6; preferably R2 is hydrogen, -C(=O)-R5, or
-C(=O)-NR7aR7b; yet more preferably R2 is hydrogen or -C(=O)-R5, preferably
-C(=O)-R5; R3 is Ci_6alkyl optionally substituted with aryl, C3-7cycloalkyl; aryl; or Het; preferably
R3 is C3_7Cycloalkyl; aryl; or Het; yet more preferably R3 is aryl; or Het, preferably aryl; each R4a and R4b is, independently, C1-4alkyl, or both R4a and R4b together with the carbon atom of the 6-hydroxy-dibenzodiazepinone ring to which they are attached may form a C3_6Cycloalkyl; more preferably, each R4a and R4b is, independently,
Chalky!; R , 5 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; more preferably R5 is Ci_6alkyl optionally substituted with one or two substituents selected from cyano, -OR9, -C(=O)-Het, -C(=O)-OR6, -C(=O)-OH, -C(=O)-NR7aR7b, -C(=O)-NH-S(=O)2-R8, aryl, and Het; C2-6alkenyl optionally substituted with aryl; polyhaloCi-βalkyl; C3_7Cycloalkyl; aryl; or Het; more preferably R5 is Ci_6alkyl optionally substituted with one or two substituents selected from cyano, -OR9, -C(=O)-Het, -C(=O)-OR6, -C(=O)-OH, -C(=O)-NR7aR7b, aryl, and Het; C3-7cycloalkyl; aryl; or Het; more preferably R5 is Ci_6alkyl optionally substituted with one or two substituents selected from cyano, -OR9, -C(=O)-Het, -C(=O)-NR7aR7b, and Het; aryl; or Het; more preferably R5 is Ci_6alkyl optionally substituted with one or two substituents selected from cyano,
-C(=O)-Het, and Het; aryl; or Het; more preferably R5 is Ci_6alkyl optionally substituted with one or two substituents selected from cyano, -C(=O)-Het, and Het; aryl; or Het; more preferably R5 is Ci_6alkyl optionally substituted with one or two substituents selected from cyano, -C(=O)-Het, and Het; aryl; or Het, wherein Het is selected from tetrahydrofuranyl, pyridazinyl, pyrazinyl, quinoxalinyl, furanyl, benzo furanyl, thiazolyl, pyrimidinyl, quinolinyl, benzo(l,3)dioxolyl, oxazolyl, pyridinyl, pyrazolyl, 2,3-dihydrobenzo(l,4)dioxinyl, quinazolinyl, isoxazolyl, 1,2,4-triazolyl, naphthyridinyl, each Het being optionally substituted with one or two substituents selected from halo; oxo; -OR9; -NR10aR10b; -CN; d_6alkyl optionally substituted with halo, -OR9, -CN, -NR10aR10b, or phenyl;-C(=O)-NH2;
-C(=O)-phenyl; -C(=O)-OH; -C(=O)-Ci_6alkyl; Ci_6alkylthio; phenyl optionally substituted with Ci_6alkoxy; morpholinyl; C2_6alkynyl; pyrrolyl; furanyl; pyridinyl; tetrazolyl; 1,3-dioxolanyl, and thiophenyl; R6 is Ci_6alkyl optionally substituted with -OR9,-C(=O)-NR7aR7b, -C(=O)-NH-S(=O)2-R8, phenyl, or Het; preferably R6 is Ci_6alkyl optionally substituted with -OR9,-C(=O)-NR7aR7b, phenyl, or Het; each R7a and R7b is, independently, hydrogen; Ci_6alkyl optionally substituted with one or two substituents selected from mono- or diCi_6alkylamino, and Het; C2_6alkenyl; C3_7cycloalkyl optionally substituted with hydroxy; or Het; more preferably each R7a and R7b is, independently, hydrogen; Ci_6alkyl optionally substituted with one or two Het, or C(=O)Het substituents; or Het;
R8 is Ci_6alkyl, C3_7cycloalkyl, or aryl; more preferably R8 is C3_7cycloalkyl, or aryl; R9 hydrogen; Ci_6alkyl optionally substituted with one, two, or three substituents selected from halo, Ci_6alkoxy, phenyl, and Het, wherein the phenyl may optionally be substituted with halo, Ci_6alkoxy, nitro, or amino; indanyl; or phenyl optionally substituted with one or two substituents selected from halo, amino, nitro, Ci_6alkyl, and phenyl; preferably R9 is hydrogen; Ci_6alkyl optionally substituted with one, two, or three substituents selected from halo, hydroxy, Ci_6alkoxy, C3-7cycloalkenyl, phenyl, and Het, wherein the phenyl may optionally be substituted with halo, hydroxy , Ci_6alkoxy, nitro, or amino; C2-6alkenyl; C2-6alkynyl; C3-7cycloalkenyl; indanyl; or phenyl optionally substituted with one or two substituents selected from halo, hydroxy, amino, nitro, Ci_6alkyl, and phenyl; preferably R9 is hydrogen; Ci_6alkyl optionally substituted with one, two, or three substituents selected from halo, Ci_6alkoxy, and phenyl, wherein the phenyl may optionally be substituted with halo, Ci_6alkoxy; indanyl; or phenyl optionally substituted with one or two substituents selected from halo, Ci_6alkyl, and phenyl; preferably R9 is hydrogen; Ci_6alkyl optionally substituted with one, two, or three substituents selected from halo, Ci_6alkoxy, and phenyl, wherein the phenyl may optionally be substituted with halo, Ci_6alkoxy; or phenyl optionally substituted with one or two halo substituents; aryl as a group or part of a group is phenyl, or naphthyl each of which may be optionally substituted with one, two or three substituents each independently selected from the group consisting of halo; phenyl; polyhaloCi-βalkyl; cyano;
Ci_6alkyl optionally substituted with -OR9 or phenyl; polyhaloCi-βalkoxy; -OR9; -C(=O)OH; Ci_6alkylthio; -S(=O)2NH2; and pyrrolyl; preferably 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 halopolyhaloCi-βalkyl; Ci_6alkyl; polyhaloCi_6alkoxy; -OR9; -C(=O)OH; Ci_6alkylthio; -S(=O)2NH2; and pyrrolyl; preferably 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 halopolyhaloCi-βalkyl; Ci_6alkyl; -OR9; 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; -CN; Ci_6alkyl optionally substituted with halo, -OR9, -NR10aR10b, or phenyl;-C(=O)-NH2; -C(=O)-phenyl;
C3-7cycloalkyl; phenyl optionally substituted with Ci_6alkoxy; morpholinyl; furanyl; pyridinyl, tetrazolyl; and thiophenyl; preferably 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; d_6alkyl optionally substituted with -OR9, -NR10aR10b; phenyl optionally substituted with Ci_6alkoxy; morpholinyl; furanyl; and thiophenyl; preferably Het is selected from quinolinyl, furanyl, quinoxalinyl, oxazolyl, benzo furanyl, isoxazolyl, 2,3-dihydrobenzo[l,4]dioxinyl, thiazolyl, tetrahydrofuranyl, pyridazinyl, pyrazinyl, pyrimidinyl, benzo(l,3)dioxolyl, pyridinyl, pyrazolyl, quinazolinyl, 1,2,4-triazolyl, naphthyridinyl, indolyl, tetrahydro thiophenyl, morpholinyl, thiophenyl, pyrrolidinyl, piperazinyl, pyrrolyl, tetrahydroquinolinyl, piperidinyl, isoindolinyl, tetrahydro iso quinolinyl, imidazolyl, tetrazolyl, imidazo(2,l)thiazolyl, 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, -NR10aR10b; phenyl optionally substituted with Ci_6alkoxy; morpholinyl; furanyl; and thiophenyl; each R10aandR10b is, independently, hydrogen, arylCi_6alkyl, aryl, 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; preferably each R10aandR10b is, independently, hydrogen, arylCi-βalkyl, aryl.
One embodiment of the present invention concerns compounds of formula (I) or of any subgroup thereof, wherein: R1 is hydrogen;
R2 is hydrogen, -C(=O)-R5, or -C(=O)-NR7aR7b; yet more preferably R2 is hydrogen or
-C(=O)-R5, preferably -C(=O)-R5;
R3 is C3-7cycloalkyl; aryl; or Het; yet more preferably R3 is aryl; or Het, preferably aryl; each R4a and R4b is, independently, Ci_6alkyl; R5 is Ci_6alkyl optionally substituted with one or two substituents selected from cyano,
-OR9, -C(=O)-Het, -C(=O)-OR6, -C(=O)-OH, -C(=O)-NR7aR7b,
-C(=O)-NH-S(=O)2-R8, aryl, and Het; C2-6alkenyl optionally substituted with aryl; polyhaloCi-βalkyl; C3_7Cycloalkyl; aryl; or Het; more preferably R5 is Ci_6alkyl optionally substituted with one or two substituents selected from cyano, -OR9, -C(=O)-Het, -C(=O)-OR6, -C(=O)-OH, -C(=O)-NR7aR7b, aryl, and Het; C3-7cycloalkyl; aryl; or Het; more preferably R5 is Ci_6alkyl optionally substituted with one or two substituents selected from cyano, -OR9, -C(=O)-Het, -C(=O)-NR7aR7b, and Het; aryl; or Het; more preferably R5 is Ci_6alkyl optionally substituted with one or two substituents selected from cyano, — C(=O)-Het, and Het; aryl; or Het; more preferably R5 is Ci_6alkyl optionally substituted with one or two substituents selected from cyano, — C(=O)-Het, and Het; aryl; or Het; more preferably R5 is Ci_6alkyl optionally substituted with one or two substituents selected from cyano, — C(=O)-Het, and Het; aryl; or Het, wherein Het is selected from tetrahydrofuranyl, pyridazinyl, pyrazinyl, quinoxalinyl, furanyl, benzofuranyl, thiazolyl, pyrimidinyl, quinolinyl, benzo(l,3)dioxolyl, oxazolyl, pyridinyl, pyrazolyl, 2,3-dihydrobenzo(l,4)dioxinyl, quinazolinyl, isoxazolyl, 1,2,4-triazolyl, naphthyridinyl, each Het being optionally substituted with one or two substituents selected from halo; oxo; -OR9; -NR10aR10b; -CN; d_6alkyl optionally substituted with halo, -OR9, -CN, -NR10aR10b, or phenyl;-C(=O)-NH2; -C(=O)-phenyl; -C(=O)-OH; -C(=O)-Ci_6alkyl; Ci_6alkylthio; phenyl optionally substituted with Ci_6alkoxy; morpholinyl; C2_6alkynyl; pyrrolyl; furanyl; pyridinyl; tetrazolyl; 1,3-dioxolanyl, and thiophenyl; R6 is Ci_6alkyl optionally substituted with -OR9,-C(=O)-NR7aR7b, phenyl, or Het; each R7a and R7b is, independently, hydrogen; Ci_6alkyl optionally substituted with one or two Het, or C(=O)Het substituents; or Het; R8 is C3_7Cycloalkyl, or aryl; R9 is hydrogen; Ci_6alkyl optionally substituted with one, two, or three substituents selected from halo, hydroxy, Ci_6alkoxy, C3_7Cycloalkenyl, phenyl, and Het, wherein the phenyl may optionally be substituted with halo, hydroxy, Ci_6alkoxy, nitro, or amino; C2-6alkenyl; C2_6alkynyl; C3_7Cycloalkenyl; indanyl; or phenyl optionally substituted with one or two substituents selected from halo, hydroxy, amino, nitro, Ci_6alkyl, and phenyl; preferably R9 is hydrogen; Ci_6alkyl optionally substituted with one, two, or three substituents selected from halo, Ci_6alkoxy, and phenyl, wherein the phenyl may optionally be substituted with halo, Ci_6alkoxy; indanyl; or phenyl optionally substituted with one or two substituents selected from halo, Ci_6alkyl, and phenyl; preferably R9 is hydrogen; Ci_6alkyl optionally substituted with one, two, or three substituents selected from halo, Ci_6alkoxy, and phenyl, wherein the phenyl may optionally be substituted with halo, Ci_6alkoxy; or phenyl optionally substituted with one or two halo substituents; 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 halopolyhaloCi_6alkyl; Ci_6alkyl; polyhaloCi_6alkoxy; -OR9; -C(=O)OH; Ci_6alkylthio; -S(=O)2NH2; and pyrrolyl; preferably 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 halopolyhaloCi-βalkyl; Ci_6alkyl; -OR9; 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; -CN; Ci_6alkyl optionally substituted with -OR9, -NR10aR10b; phenyl optionally substituted with Ci_6alkoxy; morpholinyl; furanyl; and thiophenyl; preferably Het is selected from quinolinyl, furanyl, quinoxalinyl, oxazolyl, benzo furanyl, isoxazolyl, 2,3-dihydrobenzo[l,4]dioxinyl, thiazolyl, tetrahydro furanyl, pyridazinyl, pyrazinyl, pyrimidinyl, benzo(l,3)dioxolyl, pyridinyl, pyrazolyl, quinazolinyl, 1,2,4-triazolyl, naphthyridinyl, indolyl, tetrahydrothiophenyl, morpholinyl, thiophenyl, pyrrolidinyl, piperazinyl, pyrrolyl, tetrahydroquinolinyl, piperidinyl, isoindolinyl, tetrahydroisoquinolinyl, imidazolyl, tetrazolyl, imidazo(2,l)thiazolyl, 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, -NR10aR10b; phenyl optionally substituted with Ci_6alkoxy; morpholinyl; furanyl; and thiophenyl; each R10aandR10b is, independently, hydrogen, arylCi-βalkyl, or aryl.
One embodiment of the present invention concerns compounds of formula (I) or of any subgroup thereof, wherein:
R1 is hydrogen;
R2 is hydrogen or -C(=O)-R5; R is aryl; or Het; each R4a and R4b is, independently, Ci_6alkyl;
R5 is Ci_6alkyl optionally substituted with one or two substituents selected from cyano, — C(=O)-Het, and Het; aryl; or Het; more preferably R5 is Ci_6alkyl optionally substituted with one or two substituents selected from cyano, — C(=O)-Het, and Het; aryl; or Het; wherein Het is selected from tetrahydro furanyl, pyridazinyl, pyrazinyl, quinoxalinyl, furanyl, benzofuranyl, thiazolyl, pyrimidinyl, quinolinyl, benzo(l,3)dioxolyl, oxazolyl, pyridinyl, pyrazolyl, 2,3-dihydrobenzo(l,4)dioxinyl, quinazolinyl, isoxazolyl, 1,2,4-triazolyl, naphthyridinyl, each Het being optionally substituted with one or two substituents selected from halo; oxo; -OR9; -NR10aR10b; -CN; Ci_6alkyl optionally substituted with halo, -OR9, -CN, -NR10aR10b, or phenyl;
-C(=O)-NH2; -C(=O)-phenyl; -C(=O)-OH; -C(=O)-Ci_6alkyl; Ci_6alkylthio; phenyl optionally substituted with Ci_6alkoxy; morpholinyl; C2-βalkynyl; pyrrolyl; furanyl; pyridinyl; tetrazolyl; 1,3-dioxolanyl, and thiophenyl; R6 is Ci_6alkyl optionally substituted with -OR9 ,-C(=O)-NR7aR7b, or Het; each R7a and R7b is, independently, hydrogen; Ci_6alkyl optionally substituted with one or two Het, or C(=O)Het substituents; or Het; preferably R9 is hydrogen; Ci_6alkyl optionally substituted with one, two, or three substituents selected from halo, Ci_6alkoxy, and phenyl, wherein the phenyl may optionally be substituted with halo, Ci_6alkoxy; indanyl; or phenyl optionally substituted with one or two substituents selected from halo, Ci_6alkyl, and 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 halopolyhaloCi-βalkyl; Ci_6alkyl; -OR9; 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; - -CN; Ci_6alkyl optionally substituted with -OR9, -NR10aR10b; phenyl optionally substituted with Ci_6alkoxy; morpholinyl; furanyl; and thiophenyl; preferably Het is selected from quinolinyl, furanyl, quinoxalinyl, oxazolyl, benzofuranyl, isoxazolyl, 2,3-dihydrobenzo[l,4]dioxinyl, thiazolyl, tetrahydrofuranyl, pyridazinyl, pyrazinyl, pyrimidinyl, benzo(l,3)dioxolyl, pyridinyl, pyrazolyl, quinazolinyl, 1,2,4-triazolyl, naphthyridinyl, indolyl, tetrahydrothiophenyl, morpholinyl, thiophenyl, pyrrolidinyl, piperazinyl, pyrrolyl, tetrahydroquinolinyl, piperidinyl, isoindolinyl, tetrahydroisoquinolinyl, imidazolyl, tetrazolyl, imidazo(2,l)thiazolyl, 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, -NR10aR10b; phenyl optionally substituted with Ci_6alkoxy; morpholinyl; furanyl; and thiophenyl; each R10aandR10b is, independently, hydrogen, arylCi-βalkyl, or aryl.
One embodiment of the present invention concerns compounds of formula (I) or of any subgroup of compounds of formula (I), wherein
(a) R1 is hydrogen;
(b) R2 is -C(=O)-R5; (c) R3 is aryl;
(d) each R4a and R4b is, independently, C1-6alkyl, or both R4a and R4b together with the carbon atom of the 6-hydroxy-dibenzodiazepinone ring to which they are attached may form a C3_7Cycloalkyl; (e) R5 is Ci_6alkyl optionally substituted with one or two substituents selected from cyano, -C(=O)-OH, and -C(=O)-NR7aR7b; polyhaloCi_6alkyl; C3-7cycloalkyl; aryl; or Het;
(f) each R7a and R7b is, independently, hydrogen or Het; (g) R9 is Ci_6alkyl substituted with phenyl, wherein the phenyl may optionally be substituted with nitro or amino; (h) aryl as a group or part of a group is phenyl optionally substituted with one or two halo or -OR9; and
(i) 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; phenyl; morpholinyl; pyrrolidinyl; pyrrolyl; furanyl; tetrazolyl; and thiophenyl.
Particular subgroups of compounds of formula (I) are those represented by the following structural formula (I-a):
Figure imgf000031_0001
and the salts and stereoisomers thereof, wherein 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 imgf000032_0001
Particular subgroups of compounds of formula (I) are those represented by the following structural formula (I-b):
Figure imgf000032_0002
and the salts and stereoisomers thereof, wherein
R11 represents -R5, -OR6, -NR7aR7b; and R3, R4a and R4b, R5, R6, R7a and R7b 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 imgf000032_0003
Particular subgroups of compounds of formula (I) are those represented by the following structural formula (I-c):
Figure imgf000033_0001
and the salts and stereoisomers thereof, wherein
R11 represents -R5, -OR6, -NR7aR7b; and R3, R5, R6, R7a and R7b 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-c) and (III-c). In a particular embodiment, for the compounds of Formula (I-c) preferred configuration has Formula (II-c).
Figure imgf000033_0002
Particular subgroups of compounds of formula (I) are those represented by the following structural formula (I-d):
Figure imgf000033_0003
and the salts and stereoisomers thereof, wherein R1 λ represents -R5, -OR6, -NR7aR7b; and R4a, R4b, R5, R6, R7a and R7b are as specified in the definitions of the compounds 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-d) and (III-d). In a particular embodiment, for the compounds of Formula (I-d) preferred configuration has Formula (II-d).
Figure imgf000034_0001
Particular subgroups of compounds of formula (I) are those represented by the following structural formula (I-e):
Figure imgf000034_0002
and the salts and stereoisomers thereof, wherein R11 represents -R5, -OR6, -NR7aR7b; and R5, R6, R7a and R7b 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-e) and (III-e). In a particular embodiment, for the compounds of Formula (I-e) preferred configuration has Formula (II-e).
Figure imgf000035_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 1 μM 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-e) as well as any other subgroup defined herein, are meant to also comprise any TV-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 and 2, as depicted below.
Figure imgf000035_0003
Figure imgf000035_0002
1-3 1-4
Figure imgf000036_0001
Step 1-1 -> 1-2
2-amino-3-nitrophenol (1-1), which is commercially available (Sigma-Aldrich catalogue nr. 45947) or can be synthesized following art-known procedures, is submitted to a catalytic hydrogenation to reduce the nitro moiety to amino. The hydrogenation is carried out with a suitable catalyst, and in a solvent. Alternatively, the nitro group of 2-amino-3-nitrophenol (1-1) is reduced by a metal such as Iron and the like in presence of a source of hydrogen such as an ammonium, and acid or an alcohol.
The catalyst may be selected from palladium on charcoal, palladium acetate, palladium chloride, palladium hydroxide, or palladium hydroxide on charcoal.
The solvent may be selected from tetrahydrofuran (THF), methyltetrahydrofuran (MeTHF), (methyl)(isobutyl)ketone, Ci-4alcohol, dimethylformamide (DMF), methyl t-butylether (MTBE), toluene, or any mixture thereof.
Step 1-2 + 1-3 -> 1-4 + 1-5
Intermediate (1-2) is then reacted with a dimedone derivative bearing substituents R > 44a and R4b (1-3). Dimedone is commercially available and can be derivatized according to procedures known by the skilled person in the art, or synthesized as described in scheme 3. The reaction of (1-2) and (1-3) is usually carried out in a solvent selected from tetrahydrofuran (THF), methyl-tetrahydrofuran (MeTHF), methyl isobutyl ketone, Ci-4alcohol, dimethylformamide (DMF), methyl t-butylether (MTBE), toluene, or any mixture thereof. The condensation of (1-2) and (1-3) 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 (1-4) and (1-5) are obtained.
Step 1-4 + 1-6 ■» 1-7
Intermediate (1-4) may then be reacted with an aldehyde of formula R3-CHO (1-6). Such reaction occurs in the presence of an acid, such as acetic acid, and in an appropriate solvent. Compound of formula (1-7) is obtained, which may be further reacted to introduce other R2 substituents than hydrogen, according to the procedures described below in Scheme 2.
Figure imgf000037_0001
Figure imgf000037_0002
Scheme 2
Step 1-7 -> 1-8 -> 1-9: Procedure to introduce substituent -Cf=O)-R5 Compound of formula (1-7), which is itself an intermediate as well, is acylated with an acid or an activated acid such as acyl anhydride or acyl chloride, in the presence of a suitable solvent, in order to acylate the amines thereby forming amides. Optionally, this reaction is conducted in the presence of a base. The acid can be activated in situ with a coupling agent such as EDC (l-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride) /HOBT (1-hydroxybenzotriazole), HATU (2-(lH-7-azabenzotriazol- l-yl)-l,l,3,3-tetramethyl uranium hexafluorophosphate methanaminium ), and the like. The acyl chloride can be activated in situ with DMAP (4-dimethylaminopyridine) and the like.
The suitable solvent for the acylation reaction may be selected from pyridine, dichloromethane, chloroform, THF, and DMF.
Intermediate (1-8) is obtained which is further reacted with a hydroxide in a suitable solvent or mixture of solvents in order to cleave the ester, thereby affording compound of formula (1-9).
A suitable hydroxide may be selected from lithium hydroxide, sodium hydroxide, or potassium hydroxide. A suitable solvent may be selected from water, Ci-4alcohol, THF, 2-methyltetrahydrofuran (MeTHF), or any mixture thereof.
More than one acyl group can be introduced on compound of formula (1-7), as depicted in Scheme 2a below. In this case a compound of structure (1-8), (I-8a) or (I-8b) is obtained. In some cases, a mixture of compounds (1-8), (I-8a) or (I-8b) can be obtained.
Figure imgf000039_0001
Scheme 2a
These additional acyl groups can be cleaved by treating the corresponding compounds of formula (1-8), (I-8a) or (I-8b) with an hydroxide such as sodium hydroxide, potassium hydroxide, or lithium hydroxide in a suitable solvent such as water, Ci- 4alcohol, THF, 2-methyltetrahydrofuran (MeTHF), or any mixture thereof.
Step 1-7 ^ 1-10 Protection of the hydroxyl group of compound of formula (1-7) may be performed in order to introduce other substituents in R2, thereby yielding intermediate (I- 10) wherein PG represents a protecting group.
Protection of the hydroxyl 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, trityl ether or with trialkylsilyl groups (e.g. trimethylsilyl or tert-bvXy ldimethylsily 1) . Step 1-10 + 1-11 -> 1-12 -> 1-13: Procedure to introduce substituent -C(=OVNR7aR7b Intermediate (I- 10) may then be reacted with an isocyanate (I- 11) to introduce the desired -C(=O)-NR7aR7b substituent, thereby obtaining intermediate (1-12) in which R7b represents H. Alternatively, a compound of formula (1-12) is obtained by reacting a compound of formula (I- 10) 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.
Intermediate (1-12) 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, thereby affording compound of formula (1-13). Intermediate (1-12) bearing a trialkylsilyl protecting group is further reacted with tetraalkylammonium fluoride to deprotect the silyl group thereby affording a compound of formula (1-13).
Step I- 10 + 1-14 -> 1-5: Procedure to introduce substituent -Cf=O)-OR6 Intermediate (I- 10) may then be reacted with the chloro formate derivative (1-14) 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. The protecting group can be cleaved following the same procedures than reported for (1-12) -> (1-13).
Scheme 3
A dimedone derivative 1-3 can be synthesized following the synthetic pathway described in scheme 3 below.
Figure imgf000040_0001
Scheme 3 Step 1-16 -> 1-17:
A dicarboxylic acid derivative 1-16 bearing the R4a and R4b substituents, which is commercially available or synthesized according to procedures known by the skilled person in the art, or as described in scheme 4, is cyclized to the anhydride 1-17 under refluxing conditions in acetic anhydride.
Step 1-17 -> 1-18:
Cyclic anhydride 1-17 is reacted with a grignard reagent, such as methylmagnesium bromide, at low temperature, and in the presence of a catalyst such as copper iodide, in a suitable organic solvent, to provide the methylketone derivative 1-18 bearing the R4a and R4b substituents and one carboxylic acid moiety. A suitable solvent may be THF or diethylether.
Step 1-18 -> 1-19:
Intermediate 1-18 is then esterified to provide methylester derivative 1-19, according to procedures known by the skilled person in the art. A suitable procedure is the reaction of the carboxylic acid derivative 1-18 under reflux in acidic methanol, obtained by adding acetyl chloride to methanol at low temperature.
Step 1-19 -> 1-3:
A derivative 1-19 is reacted with a base, such as sodium hydride, in a suitable solvent such as THF, to provide the cyclized compound 1-3.
Dicarboxylic acid derivatives 1-16 may be obtained following the synthetic pathway described in scheme 4 below.
Figure imgf000041_0001
Scheme 4.
Step 1-20 + 1-21-» 1-22:
Imide 1-22 may be obtained by reacting a ketone 1-20 with cyanoethylacetate 1-21 and ammonia, in the presence of a catalytic amount of a suitable base such as ammonium acetate, in a suitable solvent, such as ethanol, at low temperature. The product thus obtained is an ammonium salt and can be transformed to the free imide in hot water after acidification until pH 2 with HCl.
Step 1-22^ 1-16: Dicarboxylic acid derivative 1-16 can be obtained by heating imide 1-22 at elevated temperature, such as 1600C, in a strong acid, such as sulfuric acid, in the presence of water.
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 Examples 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-butyl 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 stereospecifically. Preferably if a specific stereoisomer is desired, said compound may be synthesized by stereospecific 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 which 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, JV-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, valopicitabine, PSI-6130, XTL-2125, NM-107, R7128 (R4048), GSK625433, R803, R-1626, BILB-1941, HCV- 796, JTK-109 and JTK-003, benzimidazole derivatives, benzo-l,2,4-thiadiazine derivatives, phenylalanine derivatives, A-831 and A-689; 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, BILN-2065, BMS-605339, 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 such as rIFN-α 2b , rIFN-α 2ba, consensus IFN-α (infergen), feron, reaferon, intermax α, rIFN-β, infergen + actimmune, IFN-omega with DUROS, albuferon, locteron, Rebif, Oral IFN-α, IFN-α 2b XL, AVI-005, pegylated- infergen, pegylated derivatized interferon-α compounds such as pegylated rIFN-α 2b, pegylated rIFN-α 2a, pegylated IFN- β, 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, ribavirin analogs such as rebetol, copegus and viramidine (taribavirin), amantadine, and telbivudine, inhibitors of internal ribosome entry, alpha-glucosidase 1 inhibitors such as MX-3253 (celgosivir) and UT-231B, hepatoprotectants such as IDN-6556, ME-3738, LB-84451 and MitoQ, 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, mycophenolic acid and derivatives thereof, and including, but not limited to VX-497, VX-148, and/or VX-944); and other drugs for treating HCV such as zadaxin, nitazoxanide, BIVN-401 (virostat), PYN-17 (altirex), KPE02003002, actilon (CPG-10101), KRN-7000, civacir, GI-5005, ANA-975, XTL-6865, ANA-971, NOV-205, tarvacin, EHC-18, NIM811, DEBIO-025, VGX-410C, EMZ-702, AVI 4065, Bavituximab, and Oglufanide; 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. ritonavir (RTV), saquinavir (SQV), lopinavir (ABT-378 or LPV), indinavir (IDV), amprenavir (VX-478), TMC 126, nelfmavir (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 which 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 : 1 l-(3-chlorophenyl)-6-hydroxy-3,3-dimethyl-2,3,4,5,10,l 1-hexahydro- dibenzo|"&, e]\\ ,41diazepin- 1 -one (6).
Step l
Figure imgf000050_0001
A mixture of 2-amino-3-nitrophenol (10.0 g, 64.9 mmol), 10% Pd/C in ethanol (150 mL), was hydrogenated at room temperature for 12 h. Then, the reaction mixture was degassed with nitrogen. The catalyst was removed by filtration and washed extensively with ethanol. The filtrate was evaporated to give 8.0 g (99%) of the desired product as a black solid.
Figure imgf000051_0001
A solution of dimedone (9.0 g, 64.4 mmol) and the 2,4-diaminophenol (8.0 g, 64.4 mmol) in dry toluene (300 mL) was refluxed overnight in a Dean-Stark. Then, the reaction mixture was cooled down to room temperature and concentrated under vacuum. LCMS (liquid chromatography-mass spectrometry) analysis of the reaction mixture showed a major product 4 and a minor regioisomer 5. The residue was triturated in boiling ethyl acetate and ethanol (9:1). The precipitate was filtered off to give 14.3 g (90%) of the desired product 4 contaminated with 5. Recrystalization from isopropanol afforded 4.8 g of the desired product 4: m/z = 247 (M+H)+.
Figure imgf000051_0002
A solution of the enamine 4 (500 mg, 2.03 mmol) and 3-chlorobenzaldehyde (229 μL, 2.03 mmol) in acetic acid (1 mL) and absolute ethanol (10 mL) was heated at reflux for 12h. Then, the reaction mixture was cooled down to room temperature and concentrated under vacuum. The residue was triturated in a mixture of ethyl acetate and a diluted aqueous solution of NaHCOs, then filtered off. The precipitate was successively washed with water and ethyl acetate to give 700 mg (93%) of the desired product 6 as a white solid: m/z = 369 (M+H)+, mp (melting point) > 287°C. Example 2: 10-acetyl-l l-(3-chlorophenyl)-6-hydroxy-3,3-dimethyl-2,3,4,5,10,l 1-hexa- hvdro-dibenzor&,eiπ,41diazepin-l-one (8).
Figure imgf000052_0001
A solution of the benzodiazepine 6 (200 mg, 0.54 mmol) and acetic anhydride (0.5 mL) in pyridine (5 mL) was heated at 500C. After 12h, the reaction mixture was allowed to cool down at room temperature, then diluted with water (100 mL). The precipitate was successively filtered and washed with water to give the intermediate 7 as a white powder, which was re-dissolved in THF (5 mL). Then, a solution OfLiOH1H2O (67 mg, 1.62 mmol) in water (5 mL) was added. The resulting solution was stirred at room temperature. After 2h, the pH of the reaction mixture was adjusted to 3 with a 1 N solution of HCl. The precipitate was collected by filtration to give 158 mg (71%) of the target product 8 as a white powder: m/z = 411 (M+H)+, mp = 281-284°C.
Example 3: 1 l-(2,4-dichlorobenzyl)-6-hydroxy-3, 3-dimethyl-2, 3,4,5, 10,11-hexahydro- dibenzo[b,el [1 ,41diazepin- 1 -one (9).
Figure imgf000052_0002
The title compound 9 was prepared from the enamine 4 and 2,4-dichlorophenyl- acetaldehyde following the procedure reported for the preparation of compound 6: m/z = 417 (M+H)+, mp > 2650C.
Example 4: 1 l-(4-benzyloxy-2-chlorophenyl)-6-hydroxy-3,3-dimethyl- 2.3.4.5.10.1 l-hexahvdro-dibenzorb.eiπ.41diazepin-l-one (13).
Step 1 : synthesis of 4-benzyloxy-2-chlorobenzaldehyde (11). Method A
Figure imgf000053_0001
A mixture of 2-chloro-4-hydroxybenzaldehyde 10 (457 mg, 2.92 mmol), benzylbromide (534 μL, 4.38 mmol) and Cs2CO3 (1.14 g, 3.50 mmol) in dry DMF (10 mL) 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 630 mg (87%) of the desired product 11 as a white solid.
Method B
Figure imgf000053_0002
A IM solution of DiBALH in hexanes (diisobutylaluminium hydride; 23.5 mL,
23.1 mmol) was added at 00C under argon to a stirred solution of the nitrile 12 (5.44 g, 22.3 mmol) in dry THF (100 mL). After 2h at 00C, the reaction mixture was allowed to warm up to room temperature. Then, additional DiBALH (7.36 mL, 0.33 eq) was added dropwise at 00C. The reaction mixture was allowed to warm up to room temperature. After 24h, the reaction mixture was successively poured dropwise into 5 N HCl (100 mL) and heated at 500C. After Ih, the solution was cooled down to room temperature and the pH was adjusted to 7 with K2CO3. The resulting solution was successively diluted with water, extracted with diethylether, washed with brine, dried (Na2SO4) and evaporated to give 5.56 g of the desired product 11: m/z = 247 (M+H)+.
Step 2: Synthesis of l l-(4-benzyloxy-2-chlorophenyl)-6-hydroxy-3,3-dimethyl- 2,3,4,5,10,1 l-hexahydro-dibenzo[δ,e][l,4]diazepin-l-one (13).
The title compound 13 was prepared from the enamine 4 and 4-benzyloxy- 2-chlorobenzaldehyde (11) following the procedure reported for the preparation of compound 6: m/z = 475 (M+H)+.
Example 5: 10-acetyl-l l-(4-benzyloxy-2-chlorophenyl)-6-hydroxy-3,3-dimethyl- 2,3,4,5,10,1 l-hexahydro-dibenzorb,eiri,41diazepin-l-one (14).
Figure imgf000054_0001
The title compound 14 was prepared from compound 13 following the procedure reported for the preparation of compound 8: m/z = 517 (M+H)+.
Example 6: l l-(2,4-dichlorophenethyl)-6-hydroxy-3,3-dimethyl- 2,3,4,5,10,1 l-hexahydro-dibenzo|"b,e"||"l,4"|diazepin-l-one (17).
Step l
Figure imgf000054_0002
A IM solution of DiBALH in hexanes (12.9 mL, 12.9 mmol) was added under argon at -78°C to a stirred solution of 3-(2,4-dichlorophenyl)propionyl ethyl ester (15; 3.0 g, 12.9 mmol) in dry CH2Cl2 (100 mL). After 2h, the reaction mixture was allowed to warm up to room temperature. Then, a saturated solution of NaHCO3 (100 mL) was added and the organic layer was successively washed with brine, dried (Na2SO4) and evaporated to give 2.75 g of the desired aldehyde 16: m/z = 203 (M+H)+. Step 2.
Figure imgf000055_0001
The title compound 17 was prepared from the enamine 4 and 2,4-dichlorophenyl- propionaldehyde (16) following the procedure reported for the preparation of compound 6: m/z = 431 (M+H)+, mp > 24FC.
Example 7: 10-acetyl-l l-(2,4-dichlorophenethyl)-6-hydroxy-3,3-dimethyl- 2,3,4,5,10,1 l-hexahvdro-dibenzorb,eiri,41diazepin-l-one (18).
Figure imgf000055_0002
The title compound 18 was prepared from compound 17 following the procedure reported for the preparation of compound 8: m/z = 473 (M+H)+, mp 230-2350C.
Example 8: {[1 l-(4-Benzyloxy-2-chlorophenyl)-6-hydroxy-3,3-dimethyl-l-oxo-
1,2,3,4,5,1 l-hexahydrodibenzorb^iriΛldiazepine-lO-carbonyllaminolacetic acid (21).
Step 1.
Figure imgf000055_0003
Potassium tert-butoxidc (1.42 g, 11.6 mmol) was added at 00C under nitrogen to a solution of compound 13 in dry THF (150 mL), and after 1 minute, a yellow precipitate of the phenolate was formed. Fifteen minutes later, a solution of triisopropylsilyl chloride (2.5 mL, 11.6 mmol) was added dropwise. After 10 min, the reaction mixture was allowed to warm up to room temperature for Ih. Then, the solution was partitioned between ethyl acetate and a saturated solution OfNH4Cl. The organic layer was successively washed with brine, dried (Na2SO4) and evaporated. The residue was triturated in heptane, then filtered off and washed with small portions of heptane to give 6.1 g (92%) of the desired silyl protected derivative 19: m/z = 631 (M+H)+.
Step 2.
Figure imgf000056_0001
A solution of the silyl 19 (2.0 g, 3.17 mmol) in ethyl isocyanatoacetate (2 mL, 17.8 mmol) was stirred at room temperature under nitrogen for 72h. Then, the reaction mixture was diluted with heptane. The precipitate was filtered and subsequently washed with heptane. Purification by column chromatography (ethyl acetate/heptane, 1 :1) afforded 1.65g (68%) of the desired product 20: m/z = 760 (M+H)+.
Step 3.
Figure imgf000056_0002
A IM solution of LiOH in water (1 mL) was added to a stirred solution of the silyl 20 (223 mg, 0.29 mmol) in THF (2 mL). After 6h, the reaction mixture was diluted with water (20 mL) and the pH of the resulting solution was adjusted to 3 with diluted HCl. The precipitate was collected by filtration, then washed with water and dried under vacuum to give 160 mg (96%) of the desired product 21: m/z = 576 (M+H)+, mp > 2700C (decomposition). Example 9: 3-{[l l-(4-Benzyloxy-2-chlorophenyl)-6-hydroxy-3,3-dimethyl-l-oxo- 1,2,3,4,5,1 l-hexahydrodibenzoFb, el ri^idiazepine-lO-carbonyliaminolpropionic acid
(21).
Figure imgf000057_0001
The title compound 22 was prepared from the silyl 19 and isocyanatopropionate following the procedure reported for the preparation of compound 21: m/z = 590 (M+H)+, mp 216°C (decomposition).
Example 10: {[1 l-(4-Benzyloxy-2-chlorophenyl)-6-hydroxy-3,3-dimethyl-l-oxo- 1,2,3,4,5,1 l-hexahydrodibenzofb^lfl^ldiazepine-lO-carbonyllaminolacetic acid ethyl ester (23).
Figure imgf000057_0002
A solution of the silyl 20 (100 mg, 0.13 mmol) and dimethylamine (2M in THF, 2 mL) was stirred in a closed vessel for 12h. The precipitate was collected by filtration, washed with ether and dried under vacuum to give 76 mg of the ester 23: m/z = 604 (M+H)+, mp: 254°C (decomposition).
Example 11 : 1 l-(4-benzyloxy-2-chlorophenyl)-6-hydroxy-3,3-dimethyl-l-oxo- 1,2,3,4,5,1 l-hexahydrodibenzo|"b,el[l,4"|diazepine-10-carboxyric acid (2-oxo- 2-pyrrolidin- 1 -yl-ethvDamide (24).
Figure imgf000058_0001
A solution of compound 21 (100 mg, 0.17 mmol), pyrrolidine (22 μL, 0.26 mmol) EDCLHCl (Λ/-(3-dimethylaminopropyl)-Λ/-ethylcarbodiimide hydrochloride, 50 mg, 0.26 mmol), HOAT (l-hydroxy-7-azabenzotriazole; 35 mg, 0.26 mmol) and DIPEA (Λ/,Λ/"-diisopropylethylamine; 60 μL, 0.34 mmol) in dry DMF (2 mL) was stirred at room temperature under nitrogen. After 12h, the reaction mixture was diluted with water (30 mL). The pH of the resulting solution was adjusted to 6-7 with NH4Cl. The resulting suspension was successively extracted with ethyl acetate and washed with brine. A precipitate in the ethyl acetate layer was filtered off. This material was purified by preparative TLC (thin layer chromatography) to give 59 mg of the title product as a white powder: m/z = 629 (M+H)+, mp: 244°C.
Example 12: 1 l-(4-benzyloxy-2-chlorophenyl)-6-hydroxy-3,3-dimethyl-l-oxo- 1,2,3,4,5,1 l-hexahydrodibenzo|"b,el[l,4"|diazepine-10-carboxyric acid (2-oxo- 2-morpholin-4-yl-ethyl)amide (25).
Figure imgf000058_0002
The title compound 25 was prepared from acid 21 and morpholine following the procedure reported for the preparation of compound 24: m/z = 645 (M+H)+, mp 233°C (decomposition).
Example 13: {[1 l-(4-Benzyloxy-2-chlorophenyl)-6-hydroxy-3,3-dimethyl-l-oxo- 1,2,3,4,5,1 l-hexahydrodibenzoTb, el ri,41diazepine-10-carbonyllamino|acetamide (26).
Figure imgf000059_0001
A solution of the silyl 20 (100 mg, 0.13 mmol), NH3 (7N in methanol, 0.5 mL) in 0.5 mL of methanol was stirred at room temperature for 4 days. Then, the reaction mixture was successively evaporated under vacuum and sonicated in ether. The precipitate was collected by filtration, then washed with additional ether to give 68 mg of the title product as a white powder: m/z = 575 (M+H)+, mp 277°C (decomposition).
Example 14: 2-{[l l-(4-Benzyloxy-2-chlorophenyl)-6-hydroxy-3,3-dimethyl-l-oxo- 1,2,3,4,5,11 -hexahydrodibenzo|"b,el [ 1 ,4"|diazepine- 1 Q-carbonyl]amino| -iV-methyl- acetamide (27).
Figure imgf000059_0002
The title compound 27 was prepared from the silyl 20 and methylamine following the procedure reported for the preparation of compound 26: m/z = 589 (M+H)+, mp 256°C (decomposition).
Example 15: 2-{[l l-(4-Benzyloxy-2-chlorophenyl)-6-hydroxy-3,3-dimethyl-l-oxo- 1,2,3,4,5,1 l-hexahydrodibenzo[b,el[l,41diazepine-10-carbonyllamino|-Λ/-(3-hydroxy- pror>l-yl)acetamide (28).
Figure imgf000060_0001
The title compound 28 was prepared from compound 21 and 3-hydroxypropylamine following the procedure reported for the preparation of compound 25: m/z = 633 (M+H)+.
Example 16: 4-(2-{[l l-(4-Benzyloxy-2-chloro-phenyl)-6-hydroxy-3,3-dimethyl-l-oxo- 1,2,3,4,5,1 l-hexahydrodibenzo[b,el[l,41diazepine-10-carbonyllamino|acetyl)- piperazine-1-carboxylic acid tert-butyl ester (29).
Figure imgf000060_0002
The title compound 29 was prepared from compound 21 and mono-BOC piperazine following the procedure reported for the preparation of compound 25: m/z = 744 (M+H)+.
Example 17: 1 l-(4-benzyloxy-2-chlorophenyl)-6-hydroxy-3,3-dimethyl-l-oxo- 1,2,3,4,5,1 l-hexahydrodibenzo|"b,el[l,4"|diazepine-10-carboxyric acid (2-oxo- 2-piperazin- 1 -ylethvDamide (30).
Figure imgf000060_0003
A solution of compound 29 (100 mg) and HCl (IM in diethylether, 0.6 mL) in CH2Cl2 (9 mL) and methanol (1 mL) was stirred at room temperature under nitrogen for 18h. Then, additional HCl (IM, 0.6 mL) was added. After 4Oh, the reaction mixture was evaporated. The residue was dissolved in TFA (trifluoroacetic acid; 1 mL). After 12h, the reaction mixture was concentrated under vacuum. The residue was successively neutralized with an aqueous solution OfNH4Cl, extracted with ethyl acetate, dried (Na2SO4) and evaporated. Purification by preparative TLC provided 20 mg of the title product 30: m/z = 644 (M+H)+.
Example 18: 1 l-(4-benzyloxy-2-chlorophenyl)-6-hydroxy-3,3-dimethyl-l-oxo- 1,2,3,4,5,1 l-hexahydrodibenzo|"b,el[l,4"|diazepine-10-carboxylic acid [2-oxo- 2-(4-methylpiperazin-l-yl)ethyl"|amide (31).
Figure imgf000061_0001
The title compound 31 was prepared from compound 21 and 1-methylpiperazine following the procedure reported for the preparation of compound 25: m/z = 658 (M+H)+, mp: 225 (decomposition).
Example 19: 1 l-(4-Benzyloxy-2-chloro-phenyl)-6-hydroxy-3,3-dimethyl-l-oxo- 1,2,3,4,5,1 l-hexahydro-dibenzo|"b,e"||"l,4"|diazepine-10-carboxyric acid [(2-hydroxy- ethylcarbamoyD-methyl] -amide (32) .
Figure imgf000061_0002
The title compound 32 was prepared from compound 21 and 2-hydroxyethylamine following the procedure reported for the preparation of compound 25: m/z = 619 (M+H)+. Example 20: ([I l-(4-benzyloxy-2-chlorophenyl)-6-hydroxy-3,3-dimethyl-l-oxo- 1,2,3,4,5,1 l-hexahvdrodibenzorb,eiri,41diazepine-10-carbonylloxy| acetic acid ethyl ester (34).
Figure imgf000062_0001
A dispersion of NaH in mineral oil (60%, 96 mg) was added to a solution of the silyl 19 (500 mg, 0.792 mmol) and the ester 33 (550 μL) in dry THF (15 mL). After 72h at room temperature, the reaction mixture was successively diluted with ethyl acetate, washed with diluted NH4Cl, dried (Na2SO4) and evaporated. The residue was triturated in isopropyl ether, then filtered to give 491 mg (75%) of the target product 34: m/z = 605 (M+H)+.
Example 21 : 1 l-(4-benzyloxy-2-chlorophenyl)-6-hydroxy-3,3-dimethyl-l-oxo- 1,2,3,4,5,1 l-hexahydrodibenzo|"&,e"||"l,4]diazepine-10-carboxyric acid 2-pyrrolidin- 1-yl-ethyl ester (36).
Step l
Figure imgf000062_0002
The intermediate 35 was prepared in 75% overall yield from silyl derivative 19 and 2-chloroethylchloro formate following the procedure reported for the preparation of {[11 -(4-benzyloxy-2-chlorophenyl)-6-hydroxy-3 ,3 -dimethyl- 1 -oxo- 1,2,3,4,5,1 l-hexahydrodibenzo[b,e][l,4]diazepine-10-carbonyl]oxy} acetic acid ethyl ester (34): m/z = 737 (M+H)+. Step 2.
Figure imgf000063_0001
A solution of the silyl 35 (88 mg, 0.12 mmol), pyrrolidine (98 μL, 0.12 mmol) and potassium iodide (20 mg) in CH3CN (3 mL) was stirred at room temperature for 72h. Then, the reaction mixture was stirred at 500C. After 5h, the solution was allowed to cool down to room temperature. Then, the reaction mixture was concentrated under vacuum. The residue was purified by preparative TLC to afford the target product 36: m/z = 616 (M+H)+.
Example 22: 1 l-(4-benzyloxy-2-chlorophenyl)-6-hydroxy-3,3-dimethyl-l-oxo- 1,2,3,4,5,1 l-hexahydrodibenzo[&,e"||"l,4"|diazepine-10-carboxyric acid methyl ester (38).
Step 1.
Figure imgf000063_0002
A dispersion of NaH in mineral oil (60%, 32 mg) was added to a solution of the silyl 19 (100 mg, 0.158 mmol) and methylchloro formate (61 μL) in dry THF (5 mL). After 12 h at room temperature, additional methylchloro formate (61 μL) was added. After 24h, the reaction mixture was successively diluted with ethyl acetate, washed with diluted NH4CI and brine, dried (Na2SO4) and evaporated. The residue was triturated in isopropyl ether, then filtered off. The isopropyl ether solution was concentrated until crystals start to appear. The desired product 37 was collected by filtration and directly engaged in the next step: m/z = 689 (M+H)+. Step 2.
Figure imgf000064_0001
A IM solution of TBAF in THF (tetra-n-butylammonium fluoride; 80 μL, 0.080 mmol) was added to a stirred solution of the silyl 37 in THF (1 rnL). After 15 minutes, the reaction mixture was diluted with water (5 mL) and ethyl acetate (3 mL). The precipitate formed was filtered off, then successively washed with water and ethyl acetate and dried to give 33 mg (78%) of the title product 38: m/z = 533 (M+H)+, mp: 275 (decomposition).
Example 23: 1 l-(4-benzyloxy-2-chlorophenyl)-6-hydroxy-3,3-dimethyl-l-oxo- 1,2,3,4,5,1 l-hexahvdrodibenzor&,eiri,41diazepine-10-carboxylic acid isopropyl ester
39).
Figure imgf000064_0002
The title product 39 was prepared from the silyl 19 and isopropylchloroformate following the procedure reported for the preparation of compound 38: m/z = 561 (M+H)+, mp: 274-278°C. Example 24: 1 l-(4-benzyloxy-2-chlorophenyl)-6-hydroxy-3,3-dimethyl-l-oxo- 1,2,3,4,5,1 l-hexahydrodibenzo[^e"||"l,4]diazepine-10-carboxyric acid 2-(morpholin- 4-vQethyl ester (40).
Figure imgf000065_0001
The title product 40 was prepared from the silyl 35 and morpholine, following the procedure reported for the preparation of compound 36: m/z = 632 (M+H)+, mp: 215°C (decomposition).
Example 25: {[1 l-(4-benzyloxy-2-chlorophenyl)-6-hydroxy-3,3-dimethyl-l-oxo-
1,2,3,4,5,1 l-hexahydrodibenzorb^iriΛldiazepine-lO-carbonylloxylacetic acid (41).
Figure imgf000065_0002
The title product 41 was prepared from compound 34 following the procedure (Step 3) reported for the preparation of compound 21: m/z = 577 (M+H)+.
Example 26: 1 l-(4-benzyloxy-2-chlorophenyl)-6-hydroxy-3,3-dimethyl-l-oxo- 1,2,3,4,5,1 l-hexahydrodibenzo[ά,el[l,41diazepine-10-carboxylic acid benzyl ester (42).
Figure imgf000065_0003
The title product 42 was prepared from the silyl 19 and benzylchloro formate following the procedure reported for the preparation of compound 38: m/z = 609 (M+H)+, mp: 2500C (decomposition).
Example 27: 1 l-(4-benzyloxy-2-chlorophenyl)-6-hydroxy-3,3-dimethyl-l-oxo-
1,2,3,4,5,1 l-hexahydrodibenzo|"&,e"||"l,4]diazepine-10-carboxyric acid 2-methoxyethyl ester (43).
Figure imgf000066_0001
The title product 43 was prepared from the silyl 19 and 2-methoxyethylchloro formate following the procedure reported for the preparation of compound 38: m/z = 577 (M+H)+, mp: 2000C (decomposition).
Example 28: {[1 l-(4-benzyloxy-2-chlorophenyl)-6-hydroxy-3,3-dimethyl-l-oxo- 1,2,3,4,5,11 -hexahydrodibenzo|"&, e] \ 1 ,4]diazepine- 10-carbonylloxyl acetamide (44).
Figure imgf000066_0002
The title product 44 was prepared from compound 34 following the procedure reported for the preparation of compound 26: m/z = 576 (M+H)+. Example 29: 2-{[l l-(4-benzyloxy-2-chlorophenyl)-6-hydroxy-3,3-dimethyl-l-oxo- 1,2,3,4,5,11 -hexahydrodibenzo|"&, e] \ 1 ,4"|diazepine- 10-carbonylloxy I -iV-methyl- acetamide (45).
Figure imgf000067_0001
The title product 45 was prepared from compound 34 and methylamine following the procedure reported for the preparation of compound 26: m/z = 590 (M+H)+, mp: 185°C (decomposition).
Example 30: 2-{[l l-(4-benzyloxy-2-chlorophenyl)-6-hydroxy-3,3-dimethyl-l-oxo- 1,2,3,4,5,11 -hexahydrodibenzo|"&, e] \ 1 ,4]diazepine- 10-carbonylloxy I -iV-(methyl- sulfonvDacetamide (46).
Figure imgf000067_0002
Carbonyldiimidazole (56 mg, 0.34 mmol) was added at 00C under nitrogen to a stirred solution of compound 41 (100 mg, 0.17 mmol) in dry DMF (5 mL). After 5 min, the reaction mixture was allowed to warm up to room temperature for 4h. Then, methansulfonamide (66 mg, 0.692 mmol) and DBU (l,8-diazabicyclo[5.4.0]undec- 7-ene; 103 μL, 0.692 mmol) were added. After 48h, the reaction mixture was diluted with water and neutralized with diluted HCl. The precipitate was filtered off, then washed with water. The crude material was purified by preparative TLC to give 87 mg (75%) of the title product 46 as a white powder: m/z = 654 (M+H)+, mp: 2200C (decomposition). Example 31 : 1 l-(4-benzyloxy-2-chlorophenyl)-6-hydroxy-3,3-dimethyl-l-oxo- 1,2,3,4,5,1 l-hexahydrodibenzor&,eiri,41diazepine-10-carboxylic acid 2-(2-methoxy- ethoxy)ethyl ester (47).
Figure imgf000068_0001
The title product 47 was prepared from the silyl 19 and 2-(2-methoxyethoxy)ethyl- chloroformate following the procedure reported for the preparation of compound 38: m/z = 621 (M+H)+.
Example 32: 3-{[l l-(4-benzyloxy-2-chlorophenyl)-6-hydroxy-3,3-dimethyl-l-oxo- 1,2,3,4,5,1 l-hexahydrodibenzorb^iri^ldiazepine-lO-carbonylloxylpropionic acid
48).
Figure imgf000068_0002
The title product 48 was prepared from the silyl 19 and S-ethoxy-S-oxopropylchloro- formate following the procedure reported for the preparation of compound 41: m/z = 591 (M+H)+, mp = 225°C (decomposition).
Example 33: 1 l-(4-benzyloxy-2-chlorophenyl)-6-hydroxy-3,3-dimethyl-l-oxo- 1,2,3,4,5,1 l-hexahvdrodibenzor^eiri,41diazepine-10-carboxylic acid phenethyl ester
49)
Figure imgf000069_0001
The title product 49 was prepared from the silyl 19 and phenethylchloro formate following the procedure reported for the preparation of compound 38: m/z = 623 (M+H)+, mp: 245-247°C.
Example 34: 2-{[l l-(4-benzyloxy-2-chlorophenyl)-6-hydroxy-3,3-dimethyl-l-oxo- 1,2,3,4,5,11 -hexahydrodibenzo|"&, e] \ 1 ,4]diazepine- 10-carbonylloxy I -Af.JV-dimethyl- acetamide (50).
Figure imgf000069_0002
A solution of compound 41 (100 mg, 0.173 mmol), dimethylamine (2 M in THF, 433 μL, 0.866 mmol), and HATU (126 mg, 0.332 mmol) in DMF (4 mL) was stirred at room temperature for 72h. Then, the reaction mixture was diluted with water and neutralized with diluted KHSO4. The precipitate was collected by filtration, then successively washed with water and ethyl acetate. The crude material was purified by preparative TLC. Trituration in diisopropyl ether afforded 36 mg of the title product 50 as a white powder: m/z = 604 (M+H)+, mp: 270-2730C. Example 35: 2-{[l l-(4-benzyloxy-2-chlorophenyl)-6-hydroxy-3,3-dimethyl-l-oxo- 1,2,3,4,5,11 -hexahydrodibenzo|"b,e] [ 1 ,4"|diazepine- 10-carbonylloxy I -3-methylbutyric acid (51 and 52).
Figure imgf000070_0001
The title products 51 and 52 were prepared from the silyl 19 following the procedure reported for the preparation of compound 21: m/z = 618 (M+H)+.
Example 36: 1 l-[4-(2-bromophenoxy)-2-chlorophenyll-6-hydroxy-3,3-dimethyl- 2,3.4,5.10.1 l-hexahvdro-dibenzorb.eiπ,41diazepin-l-one (56).
Figure imgf000070_0002
A mixture of 2-chloro-4-fluorobenzaldehyde 54 (4.96 g, 31.3 mmol), 2-bromophenol (5.57 g, 32.2 mmol) and Cs2CO3 (11.3 g, 34.7 mmol) in dry DMF (51 mL) was heated at 75°C under nitrogen. After 12h, the reaction mixture was successively allowed to cool down to room temperature, diluted with water (510 mL) and extracted with ether. The organic layer was dried (Na2SO4) and evaporated to afford 9.74 g (97%) of the aldehyde 55 as a yellow oil: m/z = 312 (M+H)+. Step 2.
Figure imgf000071_0001
The title product 56 was prepared from the aldehyde 55 and the enamine 4 following the procedure reported for the preparation of compound 6: m/z = 540 (M+H)+.
Example 37: 10-isobutyryl-l l-[4-(2-bromophenoxy)-2-chlorophenyll-6-hydroxy- 3,3-dimethyl-2,3,4,5J0J l-hexahvdro-dibenzor^,eiri,41diazepin-l-one (57).
Figure imgf000071_0002
A solution of compound 56 (415 mg, 768 mmol) in 2-methylpropionic anhydride (6 mL) was heated at 155°C for 2h. Then, the reaction mixture was allowed to cool down at room temperature. The yellow solid formed was filtered off, then redissolved in THF (15 mL) and water (15 mL). Next, a solution of LiOFLH2O (99 mg,
2.31 mmol) in water (5 mL) was added. After 1 h at room temperature, the pH of the reaction mixture was adjusted to 5 with diluted HCl. The resulting solution was concentrated under vacuum. Then, CH2Cl2 was added and the solid material was collected by filtration, successively washed with water and isopropyl ether to afford 65 mg (14%) of the title product 57 as a yellowish powder: m/z = 610 (M+H)+.
Example 38: 1 l-[4-(2-phenylphenoxy)-2-chlorophenyll-6-hydroxy-3,3-dimethyl- 2,3,4,5,10,1 l-hexahvdro-dibenzorb,eiri,41diazepin-l-one (58).
Figure imgf000072_0001
The title product 58 was prepared from 2-chloro-4-fluorobenzaldehyde, 2-phenylphenol and the enamine 4 following the procedure reported for the preparation of compound 56: m/z = 537 (M+H)+.
Example 39: 1 l-[4-(2-bromo-6-fluorophenoxy)-2-chlorophenyll-6-hydroxy- 3,3-dimethyl-2,3,4,5J0J l-hexahvdro-dibenzorb,eiπ,41diazepin-l-one (60).
Figure imgf000072_0002
The title product 60 was prepared from the aldehyde 59 and the enamine 4 following the procedure reported for the preparation of compound 56: m/z = 558 (M+H)+.
Example 40: 10-acetyl-l l-[4-(2-phenylphenoxy)-2-chlorophenyll-6-hydroxy- 3,3-dimethyl-2,3,4,5J0J l-hexahvdro-dibenzorb,eiπ,41diazepin-l-one (61).
Figure imgf000072_0003
A solution of compound 58 (203 mg, 0.378 mmol) in acetic anhydride (4 rnL) was heated at 1100C for 2h. Then, the reaction mixture was allowed to cool down at room temperature. The excess of acetic anhydride was evaporated under vacuum. The residue was redissolved in THF (10 mL) and water (8 mL). Then, a solution of LiOH1H2O (130 mg) in water (2 mL) was added. After Ih at room temperature, the pH of the reaction mixture was adjusted to 5 with diluted HCl. The precipitate was collected by filtration, then successively washed with water, isopropanol and isopropyl ether to afford 199 mg (91%) of the title product 61 as a yellowish powder: m/z = 579 (M+H)+.
Example 41 : 10-acetyl-l l-[4-(2-bromo-6-fluorophenoxy)-2-chlorophenyll-6-hydroxy- 3,3-dimethyl-2,3,4,5J0J l-hexahvdro-dibenzor&,eiπ,41diazepin-l-one (62).
Figure imgf000073_0001
The title product 62 was prepared from compound 60 and acetic anhydride following the procedure reported for the preparation of compound 61: m/z = 600 (M+H)+.
Example 42: 10-(2-cyanoacetyl)-l l-[4-(2-bromophenoxy)-2-chlorophenyll-6-hydroxy- 3,3-dimethyl-2,3,4,5J0J l-hexahvdro-dibenzor^,eiri,41diazepin-l-one (63).
Figure imgf000073_0002
A solution of compound 56 (152 mg, 0.283 mmol), hydroxybenzotriazole (12.0 mg, 0.088 mmol), Λ/-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (128 mg, 0.66 mmol) and cyanacetic acid (62 mg, 0.369 mmol) in dry DMF (1 mL) and THF (2 mL) was stirred at room temperature for 3h. Then, the reaction mixture was diluted with CH2Cl2, and evaporated. The residue was purified by column chromato- graphy (ethyl acetate/CH2Cl2, 15:85) to give 142 mg (83%) of the title product 63 as a white powder: m/z = 607 (M+H)+.
Example 43: 10-(3-oxo-3-methoxypropionyl)-l l-[4-(2-bromophenoxy)-2-chloro- phenyll-6-hydroxy-3,3-dimethyl-2,3,4,5J0,l l-hexahydro-dibenzo[&,el[l,41diazepin-l- one (64).
Figure imgf000074_0001
3-Methoxy-3-oxopropionyl chloride (657 mg, 4.81 mmol) was added dropwise to a solution of compound 56 (1.01 g, 1.88 mmol) and pyridine (378 mg, 4.78 mmol) in CH2Cl2 (30 mL). After 1.5h, the reaction mixture was concentrated under vacuum. The residue was redissolved in THF (20 mL) and water (20 mL). Then, a solution of LiOH.H2O (321 mg, 7.50 mmol) in water (2 mL) was added. After 10 min, the reaction mixture was successively diluted with water and the pH was adjusted to 4 with diluted HCl. The resulting solution was extracted with CH2Cl2 and the organic layer was dried (Na2SO4) and evaporated. The residue was purified by column chromatography (CH2Cl2/methanol/acetic acid, 90:9.9:0.1) to give the target product, which was recrystallized from isopropanol and isopropyl ether to give 1.02 g (86%) of the title product 64 as a yellowish solid: m/z = 640 (M+H)+.
Example 44: 3-{l l-[4-(2-bromophenoxy)-2-chlorophenyl]-6-hydroxy-3,3-dimethyl- 1 -oxo- 1,2,3,4,5,11 -hexahydrodibenzo \b, e] \ 1 ,41 diazepin- 10-ylj -3 -oxopropionic acid (65).
Figure imgf000074_0002
A solution of compound 64 (725 mg, 1.13 mmol) and lithium hydroxy de monohydrate in THF (20 mL) and water (10 mL) was stirred at room temperature for 72h. Then, the reaction mixture was diluted with water (20 mL), and the pH of the solution was adjusted to 2 with diluted HCl. The resulting suspension was concentrated under vacuum, then filtered to provide the title product 65 as a white powder: m/z = 626 (M+H)+.
Example 45: 10-(2-cyanoacetyl)-l l-[4-(2-bromo-6-fluorophenoxy)-2-chlorophenyll- 6-hydroxy-3 ,3-dimethyl-2,3 ,4,5 , 10,11 -hexahydro-dibenzo|"&, e] \ 1 ,4"|diazepin- 1 -one (66).
Figure imgf000075_0001
The title product 66 was prepared from compound 60 and cyanacetic acid following the procedure reported for the preparation of compound 63: m/z = 625 (M+H)+.
Example 46: 10-(2-cyanoacetyl)-l l-(4-benzyloxy-2-chlorophenyl)-6-hydroxy- 3.3-dimethyl-2,3.4,5.10.11-hexahvdro-dibenzor^.eiri,41diazepin-l-one (67).
Figure imgf000075_0002
The title product 67 was prepared from compound 13 and cyanacetic acid following the procedure reported for the preparation of compound 63: m/z = 542 (M+H)+.
Example 47: 1 l-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl- 2,3,4,5,10,1 l-hexahvdro-dibenzor&,e"iri,41diazepin-l-one (69).
Step 1 : synthesis of 4-benzyloxy-2-fluorobenzaldehyde (68).
Figure imgf000076_0001
The title product 68 was prepared in 94.4% yield from 2-fluoro-4-hydroxybenz- aldehyde and benzylbromide following the procedure (Method A) reported for the preparation of compound 11: m/z = 231 (M+H)+.
Step 2: Synthesis of l l-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl- 2,3,4,5,10,1 l-hexahydro-dibenzo[δ,e][l,4]diazepin-l-one (69).
Figure imgf000076_0002
The title product 69 was prepared in 62% yield from the enamine 4 and compound 68 following the procedure reported for the preparation of compound 6: m/z = 459 (M+H)+.
Example 48: (1 li?)-10-(2-cyanoacetyl)-l l-(4-benzyloxy-2-chlorophenyl)-6-hydroxy- 3.3-dimetfayl-2.3.4.5.10.11-hexahvdro-dibenzor6.eiri.41diazepin-l-one (70) and (115)- 10-(2-cyanoacetyl)-l l-(4-benzyloxy-2-chlorophenyl)-6-hydroxy-3,3-dimethyl- 2,3,4,5,10,1 l-hexahydro-dibenzor&.eiri/πdiazepin-l-one (71).
Figure imgf000076_0003
The 2 enantiomers of 10-(2-cyanoacetyl)-l l-(4-benzyloxy-2-chlorophenyl)-6-hydroxy- 3, 3-dimethyl-2, 3,4,5, 10,1 l-hexahydro-dibenzo[δ,e][l,4]diazepin-l-one (67) were purified by SFC (supercritical fluid chromatography) with a chiral column (eluent: CCVisopropanol). Two fractions were collected and the solvent was evaporated to give ( 1 Ii?)- 10-(2-cyanoacetyl)- 11 -(-(4-benzyloxy-2-chlorophenyl)-6-hydroxy-3 ,3-dimethyl- 2,3,4,5,10,1 l-hexahydro-dibenzo[δ,e][l,4]diazepin-l-one (70): retention time 2.0 min; m/z = 542 (M+H)+, and (115)-10-(2-cyanoacetyl)-l l-(4-benzyloxy-2-chlorophenyl)- 6-hydroxy-3 ,3-dimethyl-2,3 ,4,5 , 10,11 -hexahydro-dibenzo[δ, e] [ 1 ,4]diazepin- 1 -one (71): retention time 1.6 min; m/z = 542 (M+H)+.
Example 49: (1 IR)-I l-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl- 2.3.4.5.10.1 l-hexahvdro-dibenzor6.eiri.41diazepin-l-one (72) and (US)-I l- (4-benzyloxy-2-fluorophenyl)-6-hydroxy-3 ,3-dimethyl-2,3 ,4,5 , 10,11 -hexahydro- dibenzor&,eiri,41diazepin-l-one (73).
Figure imgf000077_0001
The 2 enantiomers of 1 l-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl-
2,3,4,5,10,1 l-hexahydro-dibenzo[δ,e][l,4]diazepin-l-one (69) were purified by SFC with a chiral column (eluent: CCVisopropanol). Two fractions were collected and the solvent was evaporated to give (1 Ii?)- 1 l-(4-benzyloxy-2-fluorophenyl)-6-hydroxy- 3, 3-dimethyl-2, 3,4,5, 10,1 l-hexahydro-dibenzo[δ,e][l,4]diazepin-l-one (72): retention time 3.2 min; m/z = 459 (M+H)+, and (1 IS)- 11 -(4-benzyloxy-2-fluorophenyl)-
6-hydroxy-3 ,3-dimethyl-2,3 ,4,5 , 10,11 -hexahydro-dibenzo[δ, e] [ 1 ,4]diazepin- 1 -one (73): retention time 2.4 min; m/z = 459 (M+H)+.
Example 50: 10-(2-methylpropionyl)-l l-(4-benzyloxy-2-fluorophenyl)-6-hydroxy- 3.3-dimethyl-2.3.4.5.10.11-hexahvdro-dibenzor^.eiri.41diazepin-l-one (74).
Figure imgf000077_0002
The title product 74 was prepared in 78% yield from compound 69 following the procedure reported for the preparation of compound 57: m/z = 529 (M+H)+.
Example 51 : (1 li?)-10-(2-methylpropionyl)-l l-(4-benzyloxy-2-fluorophenyD- 6-hydroxy-3 ,3-dimethyl-2,3 ,4,5 , 10,11 -hexahydro-dibenzo|"&, e] \ 1 ,4"|diazepin- 1 -one (75) and (1161-10-(2-methylpropionyl)-l l-(4-benzyloxy-2-fluorophenyl)-6-hydroxy- 3,3-dimethyl-2,3,4,5,10,l l-hexahvdro-dibenzor^,eiri,41diazepin-l-one (76).
Figure imgf000078_0001
The 2 enantiomers of 10-(2-methylpropionyl)- 11 -(4-benzyloxy-2-fluorophenyl)-
6-hydroxy-3 ,3-dimethyl-2,3 ,4,5 , 10,11 -hexahydro-dibenzo[δ, e] [ 1 ,4]diazepin- 1 -one (74) were purified by SFC with a chiral column (eluent: CCVisopropanol). Two fractions were collected and the solvent was evaporated to give (1 li?)-10-(2-methylpropionyl)- 11 -(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3 ,3-dimethyl-2,3 ,4,5 , 10,11 -hexahydro- dibenzo[δ,e][l,4]diazepin-l-one (75): retention time 3.55 min; m/z = 529 (M+H)+, and ( 1 IS)- 10-(2-methylpropionyl)- 11 -(4-benzyloxy-2-fluorophenyl)-6-hydroxy- 3, 3-dimethyl-2, 3,4,5, 10,1 l-hexahydro-dibenzo[δ,e][l,4]diazepin-l-one (76): retention time 3.33 min; m/z = 529 (M+H)+.
Example 52: 10-(quinolin-2-ylcarbonyl)-l l-(4-benzyloxy-2-fluorophenyl)-6-hydroxy- 3,3-dimethyl-2,3,4,5,10,l l-hexahvdro-dibenzor^,eiri,41diazepin-l-one (77).
Figure imgf000078_0002
Diisopropylethylamine (250 μL, 1.51 mmol) was added under nitrogen to a stirred solution of compound 69 (127 mg, 0.28 mmol) and quinaldyl chloride (182 mg,
0.95 mmol) in dry CH2Cl2 (8 mL). After 12h at room temperature, the reaction mixture was concentrated under reduced pressure. The residue was re-dissolved in methanol (7 mL), then NaOH (1.12 g, 28 mmol) in water (4 mL) was added. After 3h, the reaction mixture was concentrated under vacuum. The residue was diluted with water (10 mL) and the pH of the solution was adjusted to 1-2 with concentrated HCl. Then, the pH was adjusted to 7.5-8 with a saturated solution of NaHCOs. The reaction mixture was successively extracted with ethyl acetate, dried (Na2SO4) and evaporated. Purification by column chromatography (gradient of ethyl acetate/Heptane/CH2Cl2, 1 : 1 :2 to 1 :0:0) provided the desired product, which was triturated in ether, filtered and dried to give 120 mg (70%) of the title product 77 as a yellowish powder: m/z = 614 (M+H)+.
Example 53: 10-acetyl-l l-[4-(2-bromophenoxy)-2-chlorophenyll-6-hydroxy- 3.3-dimethyl-2.3.4.5J0J l-hexahvdro-dibenzorά.eiπ.41diazepin-l-one (78).
Figure imgf000079_0001
The title product 78 was prepared from compound 56 and acetic anhydride following the procedure reported for the preparation of compound 61: m/z = 582 (M+H)+.
Example 54: 10-(3-cyclopropylsulfonylamino-3-oxopropionyl)-l l-[4-(2-bromo- phenoxy)-2-chlorophenyll-6-hydroxy-3,3-dimethyl-2,3,4,5J0,l l-hexahydro- dibenzor&.eiπ.41diazepin-l-one (80).
Figure imgf000079_0002
The title product 80 was prepared in 33% yield from compound 56 and acid 79 following the procedure reported for the preparation of compound 63: m/z = 729 (M+H)+. Example 55: 10-acetyl-l l-[4-(4-bromobenzyloxy)-2-chlorophenyl]-6-hydroxy- 3,3-dimethyl-2,3,4,5J0J l-hexahydro-dibenzo[ά,el[l,41diazepin-l-one (84). Step 1. Synthesis of l l-[4-(4-methoxybenzyloxy)-2-chlorophenyl]-6-hydroxy- 3,3-dimethyl-2,3,4,5,10,l l-hexahydro-dibenzo[δ,e][l,4]diazepin-l-one (81).
Figure imgf000080_0001
The title product 81 was prepared from the enamine 4 and 2-chloro-4-(4-methoxy- benzyl)benzaldehyde following the procedure reported for the preparation of compound 13: m/z = 505 (M+H)+.
Step 2. Synthesis of 10-acetyl-l 1 -[4-(4-methoxybenzylo xy)-2-chlorophenyl]- 6-acetoxy-3,3-dimethyl-2,3,4,5,10,l l-hexahydro-dibenzo[δ,e][l,4]diazepin-l-one (82).
Figure imgf000080_0002
A solution of compound 81 (315 mg, 0.624 mmol) in acetic anhydride (2 mL) was heated at reflux for 2h. Then, the reaction mixture was successively cooled down to room temperature and evaporated to give the title product 82 as an orange sticky oil: m/z = 589 (M+H)+.
Step 3. Synthesis of 10-acetyl-l l-(4-hydroxy-2-chlorophenyl)-6-acetoxy-3, 3-dimethyl- 2,3,4,5,10,1 l-hexahydro-dibenzo[ό,e][l,4]diazepin-l-one (83).
Figure imgf000081_0001
DDQ (2,3-dicyano-5,6-dichloro-parabenzoquinone; 148 mg, 0.652 mmol) was added to a solution of compound 82 (320 mg, 0.543 mmol) in a mixture Of CH2Cl2 and water. After 72h, the reaction mixture was successively diluted with water, extracted with CH2Cl2, washed with brine, dried (Na2SO4) and evaporated to give 45 mg of the title product 83 (Fractionl). The brine solution was extracted with ethyl acetate, dried (Na2SO4) and evaporated to give 45 mg of the title product 83 (Fraction 2). Fractions 1 and 2 were mixed to give 90 mg (35%) of a single batch of 83: m/z = 469 (M+H)+.
Step 4. Synthesis of 10-acetyl-l l-[4-(4-bromobenzyloxy)-2-chlorophenyl]-6-hydroxy- 3,3-dimethyl-2,3,4,5,10,l l-hexahydro-dibenzo[δ,e][l,4]diazepin-l-one (84).
Figure imgf000081_0002
A solution of compound 83 (40 mg, 0.085 mmol), 4-bromobenzylbromide (21 mg, 0.085 mmol) and cesiumcarbonate (28 mg, 0.085 mmol) in dry DMF (2 mL) was stirred at room temperature for 30 min. Then, the reaction mixture was successively diluted with water, extracted with ethyl acetate, dried (Na2SO4) and evaporated. The residue was redissolved in THF (2 mL) and methanol (2 mL), then LiOH (100 mg in 1 mL of water) was added. After Ih, the pH of the reaction mixture was adjusted to 6 with diluted HCl. The resulting solution was extracted with ethyl acetate, dried (Na2SO4) and evaporated. The crude material was purified by column chromatography (CH2Cl2/methanol, 98:2) to give 10 mg (20%) of the target product 84 as a white powder: m/z = 596 (M+H)+. Example 56: 1 l-[5-(2-bromophenoxy)thienyl]-6-hydroxy-3,3-dimethyl- 2,3,4,5,10,1 l-hexahydro-dibenzor&,eiri,41diazepin-l-one (86).
Step 1.
Figure imgf000082_0001
A mixture of 5-chlorothiophene-2-carboxaldehyde (500 mg, 3.41 mmol), cesium carbonate (1.11 g, 3.41 mmol) and 2-bromophenol (590 mg, 3.41 mmol) in dry DMF (5 mL) was heated at 800C under nitrogen. After 5h, the reaction mixture was allowed to cool down at room temperature. Then, water (100 mL) was added and the resulting solution was successively extracted with ethyl acetate, washed with brine, dried (Na2SO4) and evaporated. Purification by column chromatography (CF^CVheptane, 50:50) provided 400 mg (41%) of the target product 85 as a colorless oil: m/z = 284 (M+H)+.
Step 2.
Figure imgf000082_0002
The title product 86 was prepared from the enamine 4 and the aldehyde 85 following the procedure reported for the preparation of compound 6: m/z = 512 (M+H)+.
Example 57: 10-acetyl-l l-[5-(2-bromophenoxy)thienyll-6-hydroxy-3,3-dimethyl- 2.3.4.5.10.1 l-hexahvdro-dibenzor6.eiπ.41diazepin-l-one (87).
Figure imgf000082_0003
The title product 87 was prepared from compound 86 following the procedure reported for the preparation of compound 61: m/z = 554 (M+H)+.
Example 58: 10-acetyl-l l-[4-(4-fluorobenzyloxy)-2-chlorophenyl]-6-hydroxy- 3.3-dimethyl-2.3.4.5J0J l-hexahvdro-dibenzorά.eiπ.41diazepin-l-one (88).
Figure imgf000083_0001
The title product 88 was prepared from intermediate 83 and 4-fluorobenzylbromide following the procedure reported for the preparation of compound 81: m/z = 535 (M+H)+.
Example 59: (R)-3-{l l-[4-(2-bromophenoxy)-2-chlorophenyll-6-hydroxy- 3,3-dimethyl-l-oxo-l,2,3,4,5J l-hexahydrodibenzo[ά,el[l,41diazepin-10-yU-3-oxo- propionic acid (89) and (61-3-{l l-[4-(2-bromophenoxy)-2-chlorophenyll-6-hydroxy- 3,3-dimethyl-l-oxo-l,2,3,4,5J l-hexahydrodibenzo[ά,el[l,41diazepin-10-yU-3- oxopropionic acid (90).
Figure imgf000083_0002
The 2 enantiomers of 3-{l l-[4-(2-bromophenoxy)-2-chlorophenyl]-6-hydroxy- 3,3-dimethyl-l-oxo-l,2,3,4,5,l l-hexahydrodibenzo[δ,e][l,4]diazepin-10-yl}- 3-oxopropionic acid (65) were purified by SFC with a chiral column (eluent: CCVisopropanol). Two fractions were collected and the solvent was evaporated to give (i?)-3- { 11 -[4-(2-bromophenoxy)-2-chlorophenyl]-6-hydroxy-3,3-dimethyl- 1 -oxo- 1,2,3,4,5,1 l-hexahydrodibenzo[δ,e][l,4]diazepin-10-yl}-3-oxopropionic acid (89): m/z = 526 (M+H)+, and (5)-3-{l l-[4-(2-bromophenoxy)-2-chlorophenyl]-6-hydroxy- 3,3-dimethyl-l-oxo-l,2,3,4,5,l l-hexahydrodibenzo[^e][l,4]diazepin-10-yl}- 3-oxopropionic acid (90): m/z = 526 (M+H)+.
Example 60: 1 l-[4-(3-nitrobenzyloxy)-2-chlorophenyll-6-hydroxy-3,3-dimethyl- 2.3.4.5.10.1 l-hexahvdro-dibenzor6.eiπ.41diazepin-l-one (92).
Figure imgf000084_0001
The title product 92 was prepared from 2-chloro-4-(3-nitrobenzyloxy)benzaldehyde (91), which was obtained in 91% yield from 3-nitrobenzylbromide following the procedure (Method A) reported for the synthesis of compound 11. Aldehyde 91 was condensed (74% yield) with the enamine 4 following the procedure reported for the synthesis of compound 6: m/z = 520 (M+H)+.
Example 61 : 10-acetyl-l l-[4-(3-nitrobenzyloxy)-2-chlorophenyll-6-hydroxy- 3,3-dimethyl-2,3,4,5,10,l l-hexahvdro-dibenzorά,eiπ,41diazepin-l-one (93).
Figure imgf000084_0002
The title product 93 was prepared from compound 92 following the procedure reported for the preparation of compound 61: m/z = 562 (M+H)+.
Example 62: 1 l-[5-(benzyloxy)thienyll-6-hydroxy-3,3-dimethyl-2,3,4,5,10,l 1-hexa- hydro-dibenzorά, e\ W ,41diazepin- 1 -one (94).
Figure imgf000085_0001
The title product 94 was prepared from the enamine 4 and 4-benzyloxythiophene- 2-carboxaldehyde (obtained via the procedure reported for 85) following the procedure reported for the preparation of compound 6: m/z = 447 (M+H)+.
Example 63: 10-acetyl-l l-[4-(3-aminobenzyloxy)-2-chlorophenyl]-6-hydroxy- 3,3-dimethyl-2,3,4,5, 10,11 -hexahvdro-dibenzorά, e] [ 1 ,41diazepin- 1 -one (95).
Figure imgf000085_0002
A solution of compound 94 (100 mg, 0.178 mmol) and SnCl2-H2O (148 mg, 0.712 mmol) in ethanol (10 mL) and concentrated HCl (3 mL) was stirred at room temperature for 78h. Then, the reaction mixture was successively neutralized with a saturated solution of NaHCOs, extracted with CH2Cl2, washed with brine, dried (Na2SO4) and concentrated. Crystallization from CH2Cl2 and isopropyl ether gave 50 mg (53%) of the target product 95 as a white powder: m/z = 532 (M+H)+.
Example 64: 10-acetyl-l l-[5-(benzyloxy)thienyll-6-hydroxy-3,3-dimethyl- 2.3.4.5.10.1 l-hexahvdro-dibenzor6.eiπ.41diazepin-l-one (96).
Figure imgf000085_0003
The title product 96 was prepared from compound 94 following the procedure reported for the preparation of compound 61: m/z = 489 (M+H)+.
Example 65: 4-[l l-(4-benzyloxy-2-chlorophenyl)-6-hydroxy-3,3-dimethyl-l-oxo- 1,2,3,4,5,1 l-hexahvdrodibenzor&,eiri,41diazepin-10-vH-4-oxobutyric acid (97).
Figure imgf000086_0001
Method A.
Into a 1 x 9 cm round bottom tube equipped with a magnetic stir bar was placed compound 13 (30 mg, 63 μmol), succinic anhydride (6.3 mg, 63 μmol), pyridine
(100 μL), and THF (6 mL). The resulting mixture was stirred at 900C for 20 minutes, reducing the volume to about 1 mL. The vial was sealed and heated to 900C for 24h. Then, solvents were removed under reduced pressure, reconstituted in CH2Cl2 and purified via silica plug, eluding with 10% methanol in ethylacetate. Evaporation afforded 19 mg (52%) of the target product 97 as a brown solid: m/z = 575 (M+H)+.
Method B.
Into a 100 mL round bottom flask equipped with a magnetic stir bar and reflux condensor was placed compound 13 (2000 mg, 4.2 mmol), THF (40 mL), pyridine (3 mL). The vessel was cooled to 00C in an ice-water bath. Then, methyl 4-chloro- 4-oxobutyrate (1331 mg, 8.8 mmol) as a solution in THF (10 mL) was added slowly. The reaction mixture was stirred at reflux for 6h. LCMS showed complete conversion to the diacylated product. Then, the solvents were removed under reduced pressure and the compound was filtered through silica with ethyl acetate. The solvents were removed under reduced pressure and the residue was reconstitued in THF (50 mL) in a 500 mL round bottom flask. Water (200 mL) and a solution of lithium hydroxide (720 mg, 16.8 mmol) in water (50 mL) were added. The resulting solution was stirred at 200C for 15h. LCMS showed complete conversion to the desired product 97. The reaction mixture was successively brought to pH 3 via concentrated HCl addition and extracted with ethyl acetate (3 x 100 mL). The organic layers were combined, dried (sodium sulfate), solids removed by filtration, and the solvents were removed under reduced pressure to afford 2.4 g (97%) of the title product 97 as a white solid: m/z = 575 (M+H)+.
Example 66: 10-[3-(cyclopropylsulfonylamino)-3-oxopropionyll-l l-(4-benzyloxy- 2-chlorophenyl)-6-hydroxy-3, 3-dimethyl-2, 3,4,5, 10,l l-hexahydro-dibenzo[ά,el [1,41- diazepin-1-one (100).
Step 1.
Figure imgf000087_0001
Into a 250 mL round bottom flask equipped with a magnetic stir bar was placed cyclopropane sulfonamide (6000 mg, 49.5 mmol), potassium carbonate (1.25 g), benzyltriethylammonium chloride (1545 mg, 5.0 mmol), and acetonitrile (75 mL). The flask was sealed, equipped with a nitrogen balloon and allowed to stir at 45°C. A solution of methyl malonyl chloride (8790 mg, 64.4 mmol) in acetonitrile (40 mL) was added dropwise via addition funnel. When addition was complete, the heating was removed and the reaction stirred at room temperature for Ih. LCMS showed product formed. Then, the reaction mixture was diluted with water (100 mL) and the aqueous layer was separated with ethyl acetate (3 x 100 mL). The organic layers were combined, dried (sodium sulfate), solids removed by filtration, and the solvents removed under reduced pressure to give the target product 98: m/z = 222 (M+H)+.
Step 2.
Figure imgf000087_0002
Into a 250 mL round bottom flask equipped with a magnetic stir bar was placed the ester 98 (4000 mg, 18.1 mmol), THF (50 mL), and lithium hydroxide (1546 mg, 36.2 mmol) in water (30 mL). The resulting mixture was stirred at 200C for 24h. LCMS showed complete conversion. Then, the reaction mixture was brought to pH 6 via addition of concentrated HCl. The aqueous layer was separated with ethyl acetate (3 x 100 niL). The organic layers were combined, dried (sodium sulfate), solids removed by filtration, and the solvents removed under reduced pressure to afford the target product 99: m/z = 208 (M+H)+.
Step 3.
Figure imgf000088_0001
Into a 1 x 9 cm round bottom tube equipped with a magnetic stir bar was placed acid 99
(44 mg, 211 μmol), EDC (40 mg, 211 μmol), DMF (2 mL) and DIPEA (41 mg,
316 μmol). After 10 minutes, compound 13 (50 mg, 105 μmol) was added. After 2Oh, LCMS analysis showed partial conversion. Then, more of the acid 99 (44 mg,
211 μmol) and EDC (40 mg, 211 μmol) were added. After 24 h, the reaction mixture was diluted with water (10 mL). The aqueous layer was separated with ethyl acetate (3 x 25 mL). The organic layers were combined, dried (sodium sulfate), solids removed by filtration, and the solvents removed under reduced pressure. The crude material was purified by silica column chromatography using CH2Cl2 to 40% ethylacetate in CH2Cl2 to afford 10 mg (14%) of the title product 100: m/z = 664 (M+H)+.
Example 67: 10-[4-(phenylsulfonylamino)-4-oxobutyryll-l l-(4-benzyloxy-2-chloro- phenyl)-6-hydroxy-3, 3-dimethyl-2, 3,4,5, 10,l l-hexahydro-dibenzo|"&,e"||"l,4]diazepin-l- one (102).
Figure imgf000088_0002
Into a 10 niL vial equipped with a magnetic stir bar was placed compound 97 (100 mg, 174 μmol), EDC (100 mg, 522 μmol), DMF (2 mL), DMAP (21.2 mg, 174 μmol), and phenylsulfonamide (137 mg, 869 μmol). The reaction mixture was stirred at 400C under nitrogen for 4h. Then, the reaction mixture was partitioned between water and ethyl acetate. The organic layers were combined, dried (sodium sulfate), solids removed by filtration, and the solvents removed under reduced pressure. The residue was purified by silica column chromatography (C^C^/ethylacetate and 1% methanol) to give 22 mg (18%) of the title product 102 as a white solid: m/z = 714 (M+H)+.
Example 68: 4-[l l-(4-benzyloxy-2-chlorophenyl)-6-hydroxy-3,3-dimethyl-l-oxo- 1,2,3,4,5,1 l-hexahydrodibenzo|"&,e"||"l,41diazepine-10-carbonyl]benzoic acid (103).
Figure imgf000089_0001
Into a 10 mL vial equipped with a magnetic stir bar was placed compound 13 (30 mg, 63 μmol), terathalyl chloride (28 mg, 139 μmol), THF (1 mL), and pyridine (250 mg, 3158 μmol). The resulting solution was stirred at 500C for 15h. Then, the solvents were removed under reduced pressure. The residue was reconstituted in THF (20 mL), and water (20 mL) and LiOH (2 mL of IM aqueous solution) were added. After 4h, the reaction mixture was succesively brought to pH 3 via HCl and extracted with ethyl acetate (3 x 30 mL). The organic layers were combined, dried (sodium sulfate), solids removed by filtration, and the solvents evaporated under reduced pressure. The residue was purified by silica column chromatography (gradient of heptane/ethyl acetate/methanol, 2: 1 :0 to 1 :9: 1). The compound was further purified by reverse phase separation to give 70 mg (52%) of the title product 103 as a white solid: m/z = 623 (M+H)+.
Example 69: 10-[4-(4-methylpiperazin-l-yl)-4-oxobutyryll-l l-(4-benzyloxy-2-chloro- phenyl)-6-hydroxy-3, 3-dimethyl-2, 3,4,5, 10,l l-hexahydro-dibenzo|"&,e"||"l,4]diazepin-l- one (104).
Figure imgf000090_0001
A 0.5 M solution of HATU (19 mg, 0.050 mmol) in DMF was added to a 0.25 M solution of compound 97 (29 mg, 0.050 mmol) in DMF. Then, a 1 M solution of DIPEA in DMF was added, followed by a 0.5 M solution of 4-methylpiperazine
(0.050 mmol). The resulting solution was stirred at room temperature for 15h. Next, the reaction mixture was successively diluted with water (4 mL), extracted with ethyl acetate (3x2 mL), washed with 7M ammonia in methanol (1 mL), dried (MgSO4) and evaporated under vacuum. The residue was filtered through silica gel to give 11 mg (31%) of the target product 104: m/z = 657 (M+H)+.
Example 70: (1 li?)-4-[l l-(4-benzyloxy-2-chlorophenyl)-6-hydroxy-3,3-dimethyl- l-oxo-1,2,3,4,5,1 l-hexahydrodibenzo[ά,el[l,41diazepin-10-yll-4-oxobutyric acid (105) and (1151-4-[I l-(4-benzyloxy-2-chlorophenyl)-6-hydroxy-3,3-dimethyl-l-oxo- 1,2,3,4,5,1 l-hexahvdrodibenzor&,eiri,41diazepin-10-yl1-4-oxobutyric acid (106).
Figure imgf000090_0002
The 2 enantiomers of 4-[l l-(4-benzyloxy-2-chlorophenyl)-6-hydroxy-3,3-dimethyl- l-oxo-1,2,3,4,5,1 l-hexahydrodibenzo[δ,e][l,4]diazepin-10-yl]-4-oxobutyric acid (97) were purified by SFC with a chiral column (eluent: CCVisopropanol). Two fractions were collected and the solvent was evaporated to give (1 Ii?)- 4-[l l-(4-benzyloxy- 2-chlorophenyl)-6-hydroxy-3 ,3-dimethyl- 1 -oxo- 1,2,3,4,5,11 -hexahydrodibenzo- [6,e][l,4]diazepin-10-yl]-4-oxobutyric acid (105): m/z = 575 (M+H)+, and (1 IS)A-[I l- (4-benzyloxy-2-chlorophenyl)-6-hydroxy-3 ,3-dimethyl- 1 -oxo- 1 ,2,3 ,4,5 , 11 -hexahydro- dibenzo[ό,e][l,4]diazepin-10-yl]-4-oxobutyric acid (106): m/z = 575 (M+H)+.
Example 71 : [1 l-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl-l-oxo- 1,2,3,4,5,1 l-hexahvdrodibenzor&,eiri,41diazepin-10-vHoxoacetic acid (107).
Figure imgf000091_0001
The title product 107 was prepared from compound 69 and oxalylchloride mo no methyl ester following the procedure (Method B) reported for the preparation of compound 97: m/z = 531 (M+H)+.
Example 72: 4-[l l-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl-l-oxo- 1,2,3,4,5,1 l-hexahvdrodibenzor&,eiri,41diazemn-10-vH-4-oxobutyric acid (108).
Figure imgf000091_0002
The title product 108 was prepared from compound 69 following the procedure reported for the preparation of compound 97: m/z = 559 (M+H)+.
Examples 73-103:
The Compounds in Table 1 were synthesized starting from 1 l-(4-benzyloxy-2-fluoro- phenyl)-6-hydroxy-3, 3-dimethyl-2, 3,4,5, 10, l l-hexahydro-dibenzo[δ,e][l,4]diazepin-l- one (69) and the corresponding acylchloride following the procedure reported for the preparation of 10-(quinolin-2-ylcarbonyl)-l l-(4-benzyloxy-2-fluorophenyl)-6-hydroxy- 3,3-dimethyl-2,3,4,5,10,l l-hexahydro-dibenzo[δ,e][l,4]diazepin-l-one (77).
Table 1.
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0001
Figure imgf000097_0001
Figure imgf000098_0001
Examples 104-105:
The compounds in Table 2 were synthesized starting from 1 l-(4-benzyloxy-2-chloro- phenyl)-6-hydroxy-3, 3-dimethyl-2, 3,4,5, 10, l l-hexahydro-dibenzo[δ,e][l,4]diazepin-l- one (13) and the corresponding acylchloride following the procedure reported for the preparation of 10-(quinolin-2-ylcarbonyl)-l l-(4-benzyloxy-2-fluorophenyl)-6-hydroxy- 3,3-dimethyl-2,3,4,5,10,l l-hexahydro-dibenzo[δ,e][l,4]diazepin-l-one (77). Table 2.
Figure imgf000099_0002
Example 106: (1 li?)-l l-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl- 10-(5-methylisoxazole-3-carbonyl)-2,3,4,5J0J l-hexahydrodibenzo[ά,el[l,41diazepin- 1-one (142) and (1161-1 l-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3, 3-dimethyl- 10-(5-methylisoxazole-3-carbonyl)-2,3,4,5J0J l-hexahydrodibenzo[6,e1[l,41diazepin- 1-one (143).
Figure imgf000099_0001
The 2 enantiomers of 1 l-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl- 10-(5-methylisoxazole-3-carbonyl)-2,3,4,5,10,l l-hexahydrodibenzo[^e][l,4]diazepin- 1-one (114) were purified by SFC with a chiral column (eluent: CCVisopropanol). Two fractions were collected and the solvent was evaporated to give (l li?)-l l-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl-10-(5-methyl- isoxazo le-3-carbonyl)-2, 3,4,5, 10,l l-hexahydrodibenzo[δ,e][l,4]diazepin-l -one (142): m/z = 568 (M+H)+, RT : 5.60 min and (1 IS)-I l-(4-benzyloxy-2-fluorophenyl)-6- hydroxy-3, 3-dimethyl-10-(5-methylisoxazole-3-carbonyl)-2, 3,4,5, 10,11- hexahydrodibenzo[6,e][l,4]diazepin-l-one (143): m/z = 568 (M+H)+, RT = 4.25 min.
Example 107: (i?)-{[l l-(4-benzyloxy-2-chlorophenyl)-6-hydroxy-3,3-dimethyl-l-oxo- 1,2,3,4,5,11 -hexahydrodibenzo[&, e] [ 1 ,4"|diazepine- 10-carbonylloxy I acetamide (144) and (S)- {[11 -(4-benzyloxy-2-chlorophenyl)-6-hydroxy-3 ,3-dimethyl- 1 -oxo- 1,2,3,4,5,11 -hexahydrodibenzo[&, e\ [ 1 ,41diazepine- 10-carbonylloxyl acetamide (145).
Figure imgf000100_0001
The 2 enantiomers of {[1 l-(4-benzyloxy-2-chlorophenyl)-6-hydroxy-3,3-dimethyl- 1 -oxo-1, 2,3,4,5, l l-hexahydrodibenzo[δ,e][l,4]diazepine-10-carbonyl]oxy} acetamide (44) were purified by SFC with a chiral column (eluent: CCVisopropanol). Two fractions were collected and the solvent was evaporated to give (i?)-{[l l-(4-benzyloxy- 2-chlorophenyl)-6-hydroxy-3 ,3-dimethyl- 1 -oxo- 1,2,3,4,5,11 -hexahydrodibenzo[δ, e]- [l,4]diazepine-10-carbonyl]oxy}acetamide (144): m/z = 576 (M+H)+, RT : 5.60 min and (S)- {[11 -(4-benzyloxy-2-chlorophenyl)-6-hydroxy-3 ,3-dimethyl- 1 -oxo- 1,2,3,4,5,1 l-hexahydrodibenzo[δ,e][l,4]diazepine-10-carbonyl]oxy} acetamide (145): m/z = 576 (M+H)+, RT = 4.25 min.
Example 108: (1 IR)-I l-(4-benzyloxy-2-fluorophenyl)-10-(2,5-dimethyloxazole- 4-carbonyl)-6-hydroxy-3,3-dimethyl-2,3,4,5,10,l l-hexahydrodibenzo[^e"||"l,4"|- diazepin-1-one (146) and (l iy)-l l-(4-benzyloxy-2-fluorophenyl)-10-(2,5- dimethyloxazole-4-carbonyl)-6-hydroxy-3,3-dimethyl-2, 3,4,5, 10,11 -hexahydro- dibenzor&,eiri,41diazepin-l-one (147).
Figure imgf000101_0001
The 2 enantiomers of 1 l-(4-benzyloxy-2-fluorophenyl)-10-(2,5-dimethyloxazole- 4-carbonyl)-6-hydroxy-3 ,3-dimethyl-2,3 ,4,5 , 10, 11 -hexahydrodibenzo[δ, e] [ 1 ,4]- diazepin-1-one (112) were purified by SFC with a chiral column (eluent:
CCVisopropanol). Two fractions were collected and the solvent was evaporated to give (1 Ii?)- 11 -(4-benzyloxy-2-fluorophenyl)- 10-(2,5-dimethyloxazole-4-carbonyl)-6- hydroxy-3 ,3-dimethyl-2,3 ,4,5 ,10,11 -hexahydrodibenzo[δ, e] [ 1 ,4]diazepin- 1 -one (146) : m/z = 582 (M+H)+, RT : 1.39 min and (1 IS)-I l-(4-benzyloxy-2-fiuorophenyl)-10-(2,5- dimethyloxazo le-4-carbonyl)-6-hydroxy-3,3-dimethyl-2, 3,4,5, 10, 11-hexahydrodi- benzo[6,e][l,4]diazepin-l-one (147): m/z = 582 (M+H)+, RT = 1.08 min.
Examples 109-137:
The compounds in Table 3 were synthesized starting from the enamine 4 and the corresponding aldehyde following the procedure (step 3) reported for the preparation of compound 6. Table 3.
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
Figure imgf000105_0001
Figure imgf000106_0002
Example 138: 10-acetyl-l l-(2,4-dichlorophenyl)-6-hydroxy-3,3-dimethyl- 2,3,4,5,10,1 l-hexahydro-dibenzor&,eiri,41diazepin-l-one (177).
Figure imgf000106_0001
A mixture of 1 l-(2,4-dichlorophenyl)-6-hydroxy-3,3-dimethyl-2, 3,4,5, 10,11-hexa- hydrodibenzo[δ,e][l,4]diazepin-l-one (176, 0.0019 mol) in acetic anhydride (5 mL) was stirred and refluxed for 2 hours, then concentrated under reduced pressure. The residue was dissolved in THF (40 mL), after which LiOH1H2O (0.006 mol) in water (40 mL) was added. The mixture was successively stirred at room temperature for 1 hour and concentrated under reduced pressure. The pH of the resulting solution was adjusted to 4 with diluted HCl and extracted with CH2Cl2. The organic layer was separated, dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography over silica gel (CH2C12/CH3OH/NH4OH 96:4:0.4 to 90:10:1). The target product was triturated in 2-propanone, then filtered off and dried to give: 0.45 g (53%) of 177: m/z = 445 (M+H)+, mp > 2500C. Example 139: (1 lift- 10-acetyl-l l-(2.4-dichlorophenyl)-6-hvdroxy-3.3-dimethyl- 2,3.4,5.10.1 l-hexahvdro-dibenzor&.eiri,41diazepin-l-one (178) and (1 IS)-10-acetyl- l l-(2,4-dichlorophenyl)-6-hydroxy-3,3-dimethyl-2,3,4,5,10,l l-hexahydro- dibenzor&,eiπ,41diazepin-l-one (179).
Figure imgf000107_0001
The racemic mixture of 10-acetyl-l l-(2,4-dichlorophenyl)-6-hydroxy-3,3-dimethyl- 2,3,4,5,10,1 l-hexahydrodibenzo[δ,e][l,4]diazepin-l-one (177) was purified by SFC chiral column OD-H (eluent: CO2/CH3OH/2-propanol 87:13:0.5) to give (1 li?)-10-acetyll l-(2,4-dichlorophenyl)-6-hydroxy-3,3-dimethyl-2,3,4,5,10,l 1-hexa- hydrodibenzo[6,e][l,4]diazepin-l-one (178): m/z = 445 (M+H)+, mp > 2500C and (115)- 10-acetyl-l l-(2,4-dichlorophenyl)-6-hydroxy-3,3-dimethyl-2,3,4,5,10,l 1- hexahydro-dibenzo[ό,e][l,4]diazepin-l-one (179): m/z = 445 (M+H)+, mp > 2500C.
Example 140: (1 Ii?)- 10-acetyl-l l-(4-benzyloxy-2-chlorophenyl)-6-hydroxy- 3, 3-dimethyl-2, 3,4,5, 10,1 l-hexahydro-dibenzo|"b,e1[l,4]diazepin-l-one (180) and (1 IS)- 10-acetyl-l l-(4-benzylo xy-2-chlorophenyl)-6-hydroxy-3, 3-dimethyl- 2,3,4,5,10,1 l-hexahydro-dibenzorb,eiri,41diazepin-l-one (181).
Figure imgf000107_0002
The racemic mixture of 10-acetyl-l l-(4-benzylo xy-2-chlorophenyl)-6-hydroxy- 3, 3-dimethyl-2, 3,4,5, 10,1 l-hexahydro-dibenzo[b,e][l,4]diazepin-l-one (14) was purified by SFC chiral column over Chiracel OD-H (eluent: CO2/CH3OH/2-propanol/- isopropylamine 75:12.5:12.5:0.3). Two fractions were collected and the solvent was evaporated to give (1 Ii?)- 10-acetyl-l l-(4-benzyloxy-2-chlorophenyl)-6-hydroxy-3,3- dimethyl-2,3,4,5,10,l l-hexahydro-dibenzo[b,e][l,4]diazepin-l-one (180): m/z = 517 (M+H)+, mp > 2500C, and (115)-10-acetyl-l l-(4-benzyloxy-2-chlorophenyl)-6- hydroxy-3, 3-dimethyl-2, 3,4,5, 10, l l-hexahydro-dibenzo[b,e][l,4]diazepin-l-one (181): m/z = 517 (M+H)+, mp > 2500C.
Example 141 : 3-[l l-(2,4-dichlorophenyl)-6-hydroxy-3,3-dimethyl-l-oxo- 1,2,3,4,5,1 l-hexahvdrodibenzorά,eiri,41diazepin-10-yll-3-oxopropionic acid (183).
Figure imgf000108_0001
Chlorocarbonylacetic acid ethyl ester (0.104 rnL) was added drop wise to a solution of compound 176 (0.30 mmol) and triethylamine (0.40 mmol) in THF (3 rnL). The mixture was stirred and refluxed for 12 h. Then, additional chlorocarbonylacetic acid ethyl ester (0.057 mL) was added and the resulting solution was stirred at reflux. After 6h, the reaction was cooled down to room temperature. The precipitate was collected by filtration, rinsed with THF and dried to give 0.35 g of intermediate 182, which was used directly in the next reaction without further purification.
Figure imgf000108_0002
A mixture of diacylated intermediate 182 (0.50 mmol) and LiOH/H2O (2.2 mmol) in THF (10 mL) and H2O (10 mL) was stirred at room temperature for 12h. THF was evaporated. H2O was added and the aqueous layer was acidified with HCl. The precipitate was filtered off, successively washed with water and diisopropyl ethyl ether and dried to give 0.094 g (35%) of the title product 183: m/z = 489 (M+H)+, mp > 2600C. Example 142: 3-[l l-(2,4-dichlorophenyl)-6-hydroxy-3,3-dimethyl-l-oxo- 1,2,3,4,5,1 l-hexahydrodibenzoF^ el ri,41diazepm-10-yl1-3-oxopropionamide (184).
Figure imgf000109_0001
A mixture of diacylated intermediate 182 (0.80 mol) in a 7N methanolic solution of NH3 (10 mL) was stirred in a sealed vessel at 8O0C. After 12h, 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 over silica gel (gradient CH2CI2/CH3OH/NH4OH, 95:5:0.5 to 90:10:0.5), then was crystallized from CHsCN/diisopropyl ether and recrystallized from 2-propanone/diisopropyl ether to give 101 mg (26%) of the title product 184: m/z = 488 (M+H)+, mp: 2200C.
Example 143: 1 l-(2,4-dichlorophenyl)-6-hydroxy-3,3-dimethyl-l-oxo- 1,2,3,4,5,1 l-hexahvdrodibenzor&,eiri,41diazepine-10-carboxyric acid methylamide
Figure imgf000109_0002
A mixture of compound 176 (0.20 mmol) and isopropylisocyanate (1.2 mmol) in THF (5 mL) was stirred and refluxed for 12h. Then, more of isopropylisocyanate (0.2 mL) was added. After Ih, the reaction mixture was allowed to cool down at room temperature and the reaction mixture was evaporated. The residue was partitioned between water and CH2Cl2. The organic layer was separated, dried (MgSO4), filtered and evaporated until dryness. The residue again partitioned between water and CH2Cl2. The aqueous layer was saturated with K2CO3 (powder) and extracted with CH2Cl2. The combined organic layer were separated and mixed, dried (MgSO4), filtered and evaporated until dryness. The residue (0.12 g) was crystallized from CHsCN/diisopropylether. The precipitate was filtered off and dried to give 74 mg (61%) of the title product 185: m/z = 460 (M+H)+, mp > 2600C.
Example 144: 1 l-[2-chloro-4-(pyridin-3-ylmethoxy)phenyll-6-hydroxy-3,3-dimethyl- 2.3.4.5.10.1 l-hexahvdrodibenzor6.eiri.41diazepin-l-one (200).
Figure imgf000110_0001
A mixture of 2-(chloromethyl)pyridine (6.3 mmol), 3-chloro-4-(hydroxymethyl)phenol (6.3 mmol) and CS2CO3 (13.9 mmol) in DMF (25 mL) was stirred for 24h at room temperature. The precipitate was removed by filtration. Then, the filtrate was concentrated under reduced pressure and the residue was successively partitioned between water and ethyl acetate, filtered and evaporated to give 1.42 g (90%) of the target product 198.
Figure imgf000110_0002
MnO2 (7 g) was added portion wise to a solution of alcohol 198 (5.6 mmol) in CH2Cl2 (50 mL). The mixture was stirred at room temperature for 2h, and then filtered over celite. The celite was washed with CH2Cl2. The filtrate was concentrated under reduced pressure to give 1.15 g (82%) of the target product 199.
Step 3.
Figure imgf000111_0001
A mixture of aldehyde 199 (0.6 mol) and the enamine 4 (0.6 mmol) in ethanol (2 rnL) and acetic acid (0.15 rnL) was stirred at 75°C for 12h. The precipitate was filtered off and dried. The residue was crystallized from 2-propanone to give 168 mg (29%) of the title product 200.
Example 145: 10-acetyl-l l-[2-chloro-4-(pyridin-3-ylmethoxy)phenyll-6-hydroxy- 3.3-dimetfayl-2.3.4.5.10.11-hexahvdrodibenzor6.eiri.41diazepin-l-one (20iy
Figure imgf000111_0002
A mixture of compound 200 (0.30 mmol) in acetic anhydride (4 mL) was heated to reflux. After 12h, acetic anhydride was evaporated and the residue was reconstituted in THF (2 mL) and H2O (2 mL). Then, a solution LiOH/H2O (1.4 mmol) was added and the mixture was stirred at room temperature. After Ih, the pH was adjusted to 7 with diluted HCl. The resulting solution was successively extracted with ethyl acetate, dried (MgSO4), and evaporated. The residue (0.17 g) was purified by column chromatography (CH2CI2/CH3OH/NH4OH, 95:5:0.5), then crystallized from 2-propanone to give 76 mg (42%) of the target product 201 : m/z = 518 (M+H)+, mp > 2500C.
Examples 146-169: The compounds in Table 4 were synthesized starting from the starting materials indicated in the table and the corresponding anhydride following the procedure (step 3) reported for the preparation of compound 61.
Table 4.
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0001
Figure imgf000116_0002
Example 170: 3-[l l-(4-benzyloxy-2-methylphenyl)-6-hydroxy-3,3-dimethyl-l-oxo- 1,2,3,4,5,1 l-hexahvdrodibenzorά,eiri,41diazepin-10-yll-3-oxopropionitrile (226).
Figure imgf000116_0001
The title product 226 was prepared from 1 l-(4-benzyloxy-2-methylphenyl)-6-hydroxy- 3, 3-dimethyl-2, 3,4,5, 10,1 l-hexahydrodibenzo[δ,e][l,4]diazepin-l-one 174 following the procedure reported for the preparation of compound 63: m/z = 522 (M+H)+.
Example 171 : 4-[l l-(4-benzyloxy-2-methylphenyl)-6-hydroxy-3,3-dimethyl-l-oxo- 1,2,3,4,5,1 l-hexahydrodibenzor&,eiri,41diazemn-10-vH-4-oxobutyric acid (227).
Figure imgf000117_0001
The title product 227 was prepared from compound 174 following the procedure reported for the preparation of compound 97: m/z = 555 (M+H)+.
Examples 172-228:
The compounds in Table 5 were synthesized starting from the starting material indicated in the table and the corresponding amine following the procedure reported for the preparation of compound 104.
Table 5.
Figure imgf000117_0002
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_0003
Example 229: 1 l-(2,4-dichlorophenyl)-10-(2,5-dimethyloxazole-4-carbonyl)- 6-hydroxy-3 ,3-dimethyl-2,3 ,4,5 , 10,11 -hexatiydrodibenzoT^, e\ \ 1 ,41diazepin- 1 -one
Figure imgf000131_0002
The title product 285 was prepared from compound 176 following the procedure reported for the preparation of compound 77: m/z = 526 (M+H)+.
Example 230: 2-{4-[l l-(4-benzyloxy-2-chlorophenyl)-6-hydroxy-3,3-dimethyl-l-oxo- 1 ,2,3,4,5, 11 -hexahydro-dibenzo|"&, e] [1 ,4]diazepin- 10-yll-4-oxobutyrylamino| - 3-(lH-imidazol-4-yl)propionic acid (286).
Figure imgf000131_0001
The title product 286 was prepared from 2-{4-[l l-(4-benzyloxy-2-chlorophenyl)- 6-hydroxy-3 ,3-dimethyl- 1 -oxo- 1,2,3,4,5,11 -hexahydro-dibenzo[δ, e] [ 1 ,4]diazepin- 10-yl]-4-oxobutyrylamino}-3-(lH-imidazol-4-yl)propionic acid methyl ester (232) following the procedure reported for the preparation of compound 65: m/z = 712 (M+H)+.
Example 231 : (7?)-4-[l l-(4-benzyloxy-2-chlorophenyl)-6-hydroxy-3,3-dimethyl-l-oxo- 1,2,3,4,5,11 -hexahydrodibenzo|"&, e] \ 1 ,4"|diazepin- 10-yl]-4-oxo-N-(4-pyrrol- 1 -yl- phenyPbutyramide (287) and (5V4-[l l-(4-benzyloxy-2-chlorophenyl)-6-hydroxy-3,3- dimethyl- 1 -oxo- 1,2,3,4,5,11 -hexahydrodibenzo|"&, e] \ 1 ,4"|diazepin- 10-yl"|-4-oxo-N-(4- pyrrol-l-vbhenvDbutyramide (288).
Figure imgf000132_0001
The title products 287 and 288 were prepared by chiral HPLC separation of the 2 enantiomers of 4-[ 11 -(4-benzyloxy-2-chlorophenyl)-6-hydroxy-3,3-dimethyl- 1 -oxo- 1,2,3,4,5,11 -hexahydrodibenzo[δ, e] [ 1 ,4]diazepin- 10-yl]-4-oxo-N-(4-pyrrol- 1 -yl- phenyl)butyramide (258) following the procedure reported for the preparation of compounds 180 and 181: m/z = 715 (M+H)+ for both 287 and 288.
Example 232: (i?)-l-[l l-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl-l-oxo- 1,2,3,4,5,1 l-hexahydrodibenzo[ά,el[l,41diazepin-10-yll-4-(4-morpholin-4-yl-piperidin- l-yl)butane-l,4-dione (289) and (61-l-[l l-(4-benzyloxy-2-fluorophenyl)-6-hydroxy- 3,3-dimethyl-l-oxo-l,2,3,4,5,l l-hexahydrodibenzo[ά,el[l,41diazepin-10-yll- 4-(4-morpholin-4-yl-prperidin- 1 -vDbutane- 1 ,4-dione (290).
Figure imgf000133_0001
The title products 289 and 290 were prepared by chiral HPLC separation of the 2 enantiomers of 1-[1 l-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl-l-oxo- 1,2,3,4,5,11 -hexahydrodibenzo[δ, e] [ 1 ,4]diazepin- 10-yl]-4-(4-morpholin-4-yl-piperidin- l-yl)butane-l,4-dione (281) following the procedure reported for the preparation of compounds 180 and 181: m/z = 711 (M+H)+ for both 287 and 288.
Example 233: Synthesis of 292.
Figure imgf000133_0002
The title product 292 was prepared from 2 and 291 following the procedure reported for the preparation of compound 6: m/z = 443 (M+H)+.
Examples 234-397: synthesis of compounds 293-456
Compounds 293-456 were synthesized from the starting reagents described in table 6, following the indicated protocol.
Protocol A: generic acylation method using an anhydride The benzodiazepine indicated in table 6 was acylated following the procedures described for the preparation of compound 8 or compound 57, using the anhydride indicated in the table.
Protocol B: generic acylation method using an acid chloride The benzodiazepine indicated in the table was acylated using the acid chloride indicated in the table, following the procedure described for the preparation of compound 64 or 77. Protocol C: generic method for enantiomer separation
The two enantiomers (R) and (S) of the racemic mixture indicated in the table were separated by SFC with a chiral column (eluent: CCVisopropanol) as described for example for compound 67.
Protocol D: generic acylation method using coupling reagents The benzodiazepine indicated in the table was acylated using the carboxylic acid indicated in the table and coupling reagents as described for example for the preparation of compound 63.
Protocol E: generic method for urea formation
The benzodiazepine indicated in the table was reacted with the isocyanate indicated in the table to form the corresponding urea, following the 3 -step procedure described for the preparation of compound 21.
Protocol F:
To the starting material indicated in the table (30 mg, 0.049 mmol) dissolved in acetonitrile/water 1 :1 (2 mL) was added palladium(II) chloride (0.88 mg, 0.1 eq) at room temperature. After 15h, the reaction mixture was concentrated under reduced pressure and the crude was purified by flash chromatography using a gradient of ethyl acetate in heptane, to give 3 mg (10% yield) of the desired product as a tan solid.
Protocol G: generic method for carbamate formation The benzodiazepine indicated in the table was reacted as its silyl-protected phenol with the chloroformate indicated in the table to form the corresponding carbamate, following the procedure described for the preparation of compound 34.
Protocol H: The PMB-protecting group of the tetrazole moiety and the trityl-protecting group on the phenol of the benzodiazepine 520 were simultaneously deprotected in TFA at 500C during 48h. After cooling down to 00C, water was added to the reaction mixture, which was subsequently neutralized by addition of potassium carbonate, then extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, concentrated, and the crude was purified by flash chromatography to give 60 mg (15% yield) of the desired product as a solid, which was recrystallized from acetone; mp > 2600C. Protocol I:
The indicated product dissolved in THF was reacted with LiOH IM in water to hydro lize the ester to a carboxylic acid moiety, as described for the preparation of compound 21.
Table 6.
Figure imgf000135_0001
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
Figure imgf000152_0001
Figure imgf000153_0001
Figure imgf000154_0001
Figure imgf000155_0001
Figure imgf000156_0001
Figure imgf000157_0001
Figure imgf000158_0001
Figure imgf000159_0001
Figure imgf000160_0001
Figure imgf000161_0001
Figure imgf000162_0001
Figure imgf000163_0001
Figure imgf000164_0001
Figure imgf000165_0001
Figure imgf000166_0001
Figure imgf000167_0001
Figure imgf000168_0001
Figure imgf000169_0001
Figure imgf000170_0001
Figure imgf000171_0001
Figure imgf000172_0001
Figure imgf000173_0001
Figure imgf000174_0001
Figure imgf000175_0001
Example 398: 1 l-(4-Benzyloxy-2-fluoro-phenyl)-6-hydroxy-3,3-dimethyl-
10-(2-morpholin-4-yl-acetyl)-2,3 ,4,5 ,10,11 -hexahydro-dibenzo|"b,e] [ 1 ,4]diazepin- 1 -one
(458)
Figure imgf000176_0001
To a suspension of compound 69 (200 mg, 0.437 mmol) and sodium bicarbonate (184 mg, 5 eq) in THF was added chloroacetylchloride (101 mg, 2.05 eq) dropwise at room temperature. After Ih, the reaction mixture was diluted with water and lithium hydroxide (11.5 mg, 1.1 eq) was added. The organic layer was separated, washed with brine, dried over magnesium sulfate, filtered and concentrated to give the desired compound 11 -(4-Benzyloxy-2-fluoro-phenyl)- 10-(2-chloro-acetyl)-6-hydroxy- 3, 3-dimethyl-2, 3,4,5, 10,1 l-hexahydro-dibenzo[b,e][l,4]diazepin-l-one (457), which was used without further purification in the next step; m/z = 536 (M+H)+.
Figure imgf000176_0002
A mixture of compound 457 (31 mg, 0.058 mmol), morpholine (25 mg, 5 eq) and sodium iodide (8.7 mg, 1 eq) in THF/ethanol (2 mL/4 mL) was stirred at 600C during 16h. The reaction mixture was then evaporated on silica and filtered through a silica pad with ClHkCk/methanol 95:5 as eluent to give 12 mg (35% yield) of the desired compound 458; m/z = 586 (M+H)+.
Examples 399-450: synthesis of compounds 459-510
The examples 399-450 described in table 7 were prepared following the procedure reported for the preparation of compound 6, from the enamine 4 and the appropriate aldehyde indicated in the table, instead of 3-chlorobenzaldehyde.
Table 7.
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
Figure imgf000187_0001
Figure imgf000188_0001
Figure imgf000189_0001
Figure imgf000190_0002
Example 451 : synthesis of l l-(4-Benzyloxy-2-fluoro-phenyl)-6-hydroxy-3,3-dimethyl- 10-[2-(3-oxo-piperazin-l-yl)-acetyll-2, 3,4, 5, 10,11 -hexahydro-dibenzo[b,el [1,41- diazepin- 1 -one (511)
Figure imgf000190_0001
Compound 511 was prepared in 42% yield following the procedure reported for the preparation of 458, using piperazinone instead of morpholine in step 2, and was obtained as a slightly brown solid; m/z = 599 (M+H)+. Example 452: synthesis of l l-(2-Fluoro-4-phenethyl-phenyl)-6-hydroxy-10-isobutyryl- 3,3-dimethyl-2,3,4,5J0J l-hexahvdro-dibenzorb,eiπ,41diazepin-l-one (514)
Figure imgf000191_0001
Compound 512 was prepared in 46% yield (132 mg) following the procedure reported for the preparation of 6, from the enamine 4 (150 mg, 0.61 mmol) and 2-fluoro- 4-styryl-benzaldehyde (138 mg, 1 eq) instead of 3-chlorobenzaldehyde; m/z = 455 (M+H)+.
Figure imgf000191_0002
Compound 513 was prepared in 60% yield (92 mg) following the procedure reported for the preparation of 77, from 512 (132 mg, 0.29 mmol) and isobutyryl chloride (155 mg, 5 eq) instead of quinaldyl chloride; m/z = 525 (M+H)+. Step 3
Figure imgf000192_0001
The title compound 514 was prepared in 73% yield (70 mg) from compound 513 (92 mg, 0.175 mmol) by catalytic hydrogenation using Pd/C 10% in methanol; m/z : 527 (M+H)+.
Example 453: synthesis of l l-(2,4-Dichloro-phenyl)-10-{3-[l-(4-methoxy-benzyl)- lH-tetrazol-5-yll-propionyl|-3,3-dimethyl-6-trityloxy-2,3,4,5J0,l l-hexahydro- dibenzoRxel [ 1 ,41diazepin- 1 -one (520)
Figure imgf000192_0002
To a solution of 3-cyano-propionic acid methyl ester (5 g, 44.2 mmol) in DMF (30 mL) were added ammonium chloride (3.5 g, 1.5 eq) and sodium azide (4.3 g, 1.5 eq). The reaction mixture was heated at 1200C during 24h. After cooling down to room temperature, the reaction mixture was diluted with water (25 mL) and concentrated HCl (7 mL), then extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford 4.3 g (62% yield) of the desired product 3-(lH-tetrazol-5-yl)-propionic acid methyl ester (515) which was used in the next step without further purification.
Figure imgf000193_0001
A mixture of compound 515 (4.3 g, 27.5 mmol), 4-methoxybenzyl bromide (3.3 mL, 1 eq) and cesium carbonate (10.7 g, 1.2 eq) in DMF (50 mL) was heated at 1000C during 12h. After cooling down to room temperature, the precipitate was filtered off and the filtrate was concentrated. The residue was diluted with CH2Cl2, washed with water, dried over magnesium sulfate, filtered and concentrated to give 4.8 g (63% yield) of the alkylated starting material (515), as a mixture of the regioisomers (516): 3-[l-(4-methoxy-benzyl)-lH-tetrazol-5-yl]-propionic acid methyl ester and 3 -[2-(4-methoxy-benzyl)-2H-tetrazol-5-yl] -propionic acid methyl ester.
Figure imgf000193_0002
To a solution of the regioisomers 516 (0.5 g, 1.8 mmol) in THF (5 mL) was added lithium hydroxide (0.23 g, 3 eq) in water (5 mL). After stirring during 4h at room temperature, the reaction mixture was concentrated under reduced pressure and the aqueous layer was acidified with HCl 3N, then extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated to give 0.4 g (85% yield) of the carboxylic acid derivative (517) as a mixture of regioisomers.
Figure imgf000193_0003
The two regioisomers 517 (0.4 g, 1.52 mmol) were heated in refluxing thionyl chloride (2 rnL) during 2h. After concentration under reduced pressure, the obtained acid chloride regioisomers (518) were used without further purification in the next step.
Figure imgf000194_0001
To a solution of the benzodiazepine 176 (4 g, 2.48 mmol) and triethylamine (0.52 mL, 1.5 eq) in CH2Cl2 (10 mL) was added trityl chloride (0.76 g, 1.1 eq) portionwise at 00C. After stirring for 4h at room temperature, the reaction mixture was diluted with water, the organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated to give 1.5 g (94% yield) of the desired product 1 l-(2,4-dichloro-phenyl)- 3 ,3-dimethyl-6-trityloxy-2,3 ,4,5 ,10,11 -hexahydro-dibenzo[b,e] [ 1 ,4]diazepin- 1 -one (519); m/z = 646 (M+H)+.
Figure imgf000194_0002
To a solution of the trityl-protected benzodiazepine 519 (1.5 g, 2.32 mmol) and triethylamine (1.6 niL, 5 eq) in THF (15 niL) was added the mixture of regio isomers (518) (2 g, 3 eq). The reaction mixture was heated at 800C during 24h, then concentrated. The residue was redissolved in CH2Cl2, washed with water, dried over magnesium sulfate, filtered, concentrated and purified by flash chromatography on silica gel (eluent CH2Cl2/methanol 99:1) to give 0.7 g (34% yield) of the desired product (520) as a mixture of regio isomers; m/z = 890 (M+H)+.
Example 454: synthesis of 5-Ethyl-5-methyl-cyclohexane-l,3-dione (524)
Figure imgf000195_0001
A solution of 3-ethyl-3-methyl-pentanedioic acid (5 g, 28.7 mmol, commercially available) in acetic anhydride (150 mL) was refluxed during 2h. The reaction mixture was then concentrated under reduced pressure, and the brown residue was stripped with toluene (200 mL), then redissolved in ethyl acetate, washed with saturated aqueous sodium bicarbonate, then brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was stripped with toluene to remove the residual acetic anhydride and to afford a quantitative yield of the desired product (521) 4-ethyl- 4-methyl-dihydro-pyran-2,6-dione.
Figure imgf000195_0002
To a mixture of the cyclic anhydride 521 (4.48 g, 28.7 mmol) and copper iodide (550 mg, 0.1 eq) in THF (150 mL), at -15°C, was added methyl magnesium bromide 3M in diethyl ether (9.6 mL, 1 eq) dropwise. The reaction mixture was allowed to warm up to room temperature and was stirred during 16h. Since the reaction was not complete after this time, the reaction mixture was cooled down to 00C and more methyl magnesium bromide (1 rnL, 0.1 eq) was added. After 3h, the reaction mixture was quenched with water and acidified until pH 2 with 2N HCl. The aqueous mixture was filtered off and the filtrate was extracted with diethylether (3 times). The combined organic layers were dried over sodium sulfate, filtered and concentrated to give 5.02 g of the desired product 3-ethyl-3-methyl-5-oxo-hexanoic acid (522), which was used without further purification in the next step.
Figure imgf000196_0001
Acetyl chloride (10.7 mL, 150 mmol) was added to methanol (150 mL) over 30 minutes, at 00C, under N2 atmosphere. This solution was then added to the intermediate 522 (4.94 g, 28.7 mmol) and the reaction mixture was refluxed during 6h. After concentration, the reaction mixture was diluted with water and extracted with diethylether. The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (eluent: ethyl acetate/heptane 1 :9) to give 775 mg (15% yield) of the desired product 3-ethyl- 3-methyl-5-oxo-hexanoic acid methyl ester (523) as a colorless oil; m/z = 187 (M+H)+.
Figure imgf000196_0002
To a solution of intermediate 523 (0.775 g, 4.16 mmol) in THF (50 mL) was added sodium hydride 60% dispersion in mineral oil (0.2 g, 1.2 eq) at room temperature. After stirring during 4h at room temperature, the reaction mixture was quenched with water (50 mL), acidified to pH 2 with IN HCl and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was stripped with diisopropylether to afford 0.656 g of the desired product (524); m/z = 155 (M+H)+. Example 455: synthesis of 3-Isopropyl-3-methyl-pentanedioic acid (527)
Figure imgf000197_0001
A mixture of 3-methyl-2-butanone (525) (19 g, 0.221 mol), cyanoethylacetate (50 g, 2 eq) and ammonium acetate (220 mg) in 88 mL of a 5.88 M solution OfNH3 in absolute ethanol was kept in the fridge at 5°C during 16h. An extra catalytic amount of ammonium acetate was then added and the reaction mixture was kept in the fridge for another 24h. The resulting precipitate was filtered off, washed with diethylether and dried to afford 26.62 g of the desired product 4-isopropyl-4-methyl-2,6-dioxo- piperidine-3,5-dicarbonitrile (526) as an ammonium salt. Another crop (1.52 g) was obtained and combined with the first crop, resulting in a 54% yield.
Figure imgf000197_0002
A mixture of the imide 526 (26.7 g, 0.113 mol, ammonium salt) in 65% (w/w) H2SO4 was heated at 1600C during 16h. The clear yellowish solution was then allowed to cool down to 50C and the resulting white solid was collected, washed with water and dried overnight at 400C in a vacuum oven, to afford 4.94 g (18%) of the dicarboxylic acid product 527.
Example 456: synthesis of 5-isopropyl-5-methyl-cyclohexane-l,3-dione (528)
Figure imgf000197_0003
The title compound 528 was synthesized following the 4-step procedure reported for the preparation of compound 524, starting from compound 527 instead of 3-ethyl- 3-methyl-pentanedioic acid.
Example 457: synthesis of 3-methyl-3-propyl-pentanedioic acid (529)
Figure imgf000198_0001
The title compound 529 was synthesized in 31% overall yield following the 2-step procedure reported for the preparation of compound 527, starting from 2-pentanone instead of 3-methyl-2-butanone.
Example 458: synthesis of 5-Methyl-5-propyl-cyclohexane-l,3-dione (530)
Figure imgf000198_0002
The title compound 530 was synthesized following the 4-step procedure reported for the preparation of compound 524, starting from compound 529 instead of 3-ethyl- 3-methyl-pentanedioic acid.
Example 459: synthesis of l l-(4-benzyloxy-2-fluoro-phenyl)-3-ethyl-6-hydroxy- 3-methyl-2.3.4.5.10.1 l-hexahvdro-dibenzorb.eiπ.41diazepin-l-one (531)
Figure imgf000198_0003
The title product 531 was prepared in 31% overall yield from compounds 2 and 524 following the procedure reported for the preparation of compound 6: m/z = 473 (M+H)+.
Example 460: synthesis of l l-(4-benzyloxy-2-fluoro-phenyl)-6-hydroxy-3-isopropyl-3- methyl-2,3,4,5,10,l l-hexahvdro-dibenzorb,eiri,41diazepin-l-one (532)
Figure imgf000199_0001
The title product 532 was prepared in 40% overall yield from compounds 2 and 528 following the procedure reported for the preparation of compound 6: m/z = 487 (M+H)+.
Example 461 : synthesis of l l-(4-Benzyloxy-2-fluoro-phenyl)-6-hydroxy-3-methyl- 3-propyl-2, 3,4,5, 10, l l-hexahvdro-dibenzorb,eiri,41diazepin-l-one (533)
Figure imgf000199_0002
The title product 533 was prepared from compounds 2 and 530 following the procedure reported for the preparation of compound 6: m/z = 487 (M+H)+. Example 462: Activity of compounds of formula (I) Replicon assay
The compounds of formula (I) were examined for activity in the inhibition 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 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 various 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 compound 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 milliliters 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 30,000x 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.
Table 9.
Figure imgf000202_0001
Figure imgf000203_0002
The following Table 10 lists compounds that were prepared according to any one of the above examples. The activities of the compounds tested are also depicted in Table 10.
Table 10.
Figure imgf000203_0001
Figure imgf000204_0001
Figure imgf000205_0001
Figure imgf000206_0001
Figure imgf000207_0001
Figure imgf000208_0001
Figure imgf000209_0001
Figure imgf000210_0001
Figure imgf000211_0001
Figure imgf000212_0001
Figure imgf000213_0001
Figure imgf000214_0001
Figure imgf000215_0001
Figure imgf000216_0001

Claims

Claims
1. A compound having the formula
Figure imgf000217_0001
and the stereoisomers, prodrugs, tautomers, racemics, salts, hydrates or solvates thereof, wherein
R1 is hydrogen, 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 R ,4a and R ,4b is, independently, C1-6alkyl, or both R 4a and R ,4b together with the carbon atom of the 6-hydroxy-dibenzodiazepinone 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, -S(=O)2-aryl, -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 R ,7aa and R ,7b 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 selected from halo, hydroxy, Ci_6alkoxy, C3_7Cycloalkenyl, phenyl, and Het, wherein the phenyl may optionally be substituted with halo, hydroxy, Ci_6alkoxy, nitro, or amino; C2_6alkenyl; C2_6alkynyl; C3_7Cycloalkenyl; indanyl; or phenyl optionally substituted with one or two substituents selected from halo, hydroxy, 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 or three substituents each independently selected from the group consisting of halo; phenyl; polyhaloCi-βalkyl; cyano; Ci_6alkyl optionally substituted with -OR9 or phenyl; polyhaloCi-βalkoxy; polyhaloCi-βalkylphenyl; polyhaloCi-βalkylthienyl; -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 halo, -OR9, -CN, -NR10aR10b, or phenyl;-C(=O)-NH2; -C(=O)-phenyl; -C(=O)-OH; -C(=O)-Ci_6alkyl; Ci_6alkylthio; C3-7cycloalkyl; phenyl optionally substituted with Ci_6alkoxy; morpholinyl; C2_6alkynyl; pyrrolidinyl; pyrrolyl; furanyl; pyridinyl, tetrazolyl; 1,3-dioxolanyl; and thiophenyl; and each R1Oa andR1Ob is, independently, hydrogen, d_6alkyl, arylCi_6alkyl, aryl, or R1Oa and R1Ob, 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
R1 is hydrogen, 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 6-hydroxy-dibenzodiazepinone 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 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-βalkyl, cyano, Ci_6alkyl, 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; 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 R10aandR10b 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.
3. A compound according to claim 1 or 2, having one of the structural Formula (II) or (III)
Figure imgf000220_0001
wherein R1, R2, R3, R4a and R4b are as specified in any one of claims 1 or 2.
4. A compound according to any one of claims 1 or 3, wherein: R1 is hydrogen, 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 aryl; 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 6-hydroxy-dibenzodiazepinone 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, -OR9, -C(=O)-Het, -C(=O)-OR6, -C(=O)-OH, -C(=O)-NR7aR7b, -C(=O)-NH-S(=O)2-R8, -S(=O)2-aryl, 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-hydroxyCi_6alkyl, -C(=O)-Het, aryl and Het; C2.6alkenyl; C3-7cycloalkyl optionally substituted with hydroxy; aryl; or Het; R8 is Ci_6alkyl, C3_7Cycloalkyl, or aryl;
R9 is hydrogen; Ci_6alkyl optionally substituted with one, two, or three substitutents selected from halo, Ci_6alkoxy, phenyl, and 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, Ci_6alkyl, and phenyl; aryl as a group or part of a group is phenyl optionally substituted with one, two or three substituents each independently selected from the group consisting of halo; phenyl; polyhaloCi-βalkyl; cyano; Ci_6alkyl optionally substituted with -OR9 or phenyl; polyhaloCi_6alkoxy; -OR9; -C(=O)OH; Ci_6alkylcarbonyl; Ci_6alkylthio;
Ci_6alkylsulfonyl; -S(=O)2NH2; and pyrrolyl; and
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 halo, -NR10aR10b, -OR9 or phenyl;-C(=O)-NH2; -C(=O)-phenyl; -C(=O)-OH;
-C(=O)-Ci_6alkyl; Ci_6alkylthio; C2-6alkynyl; phenyl optionally substituted with
Ci_6alkoxy; morpholinyl; pyrrolidinyl; pyrrolyl; furanyl; pyridinyl; tetrazolyl; and thiophenyl; each R10aandR10b is, independently, hydrogen, Ci_6alkyl, arylCi-βalkyl, or aryl.
5. A compound according to any one of claims 1, 3-4, wherein R1 is hydrogen;
R2 is -C(=O)-R5, -C(=O)-OR6, or -C(=O)-NR7aR7b; R3 is aryl or Het; each R4a and R4b is, independently, Ci_6alkyl, or both R4a and R4b together with the carbon atom of the 6-hydroxy-dibenzodiazepinone 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,
-OR9, -C(=O)-Het, -C(=O)-OR6, -C(=O)-OH, -C(=O)-NR7aR7b, -C(=O)-NH- S(=O)2-R8, -S(=O)2-aryl, 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 mono- or diCi_6alkylamino, -C(=O)-OR9,
-C(=O)-NH2, -C(=O)-Het, aryl and Het; C2-6alkenyl; C3-7cycloalkyl optionally substituted with hydroxyl; aryl; or Het; R8 is Ci_6alkyl, C3-7Cy cloalkyl, or aryl;
R9 is hydrogen; Ci_6alkyl optionally substituted with halo, 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 halo; aryl as a group or part of a group is phenyl optionally substituted with one, two or three substituents each independently selected from the group consisting of halo; phenyl; polyhaloCi-βalkyl; cyano; Ci_6alkyl optionally substituted with -OR9 or phenyl; polyhaloCi_6alkoxy; -OR9; -C(=O)OH; Ci_6alkylthio; -S(=O)2NH2; and pyrrolyl; and
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 halo, -NR10aR10b, -OR9; -C(=O)-phenyl; -C(=O)-OH; -C(=O)-Ci_6alkyl;
Ci_6alkylthio; C2-6alkynyl; phenyl optionally substituted with Ci_6alkoxy; morpholinyl; pyrrolidinyl; pyrrolyl; furanyl; pyridinyl; tetrazolyl; and thiophenyl; each R10aandR10b is, independently, hydrogen, d^alkyl, arylCi-βalkyl, or aryl.
6. A compound according to any one of claims 1, 3-5, wherein R1 is hydrogen;
R2 is -C(=O)-R5, -C(=O)-OR6, or -C(=O)-NR7aR7b; R is aryl or Het; each R4a and R4b is, independently, C1-6alkyl, or both R4a and R4b together with the carbon atom of the 6-hydroxy-dibenzodiazepinone 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, -OR9, -C(=O)-Het, -C(=O)-OR6, -C(=O)-OH, aryl, Het, and -C(=O)-NR7aR7b; polyhaloCi-βalkyl; C3_7Cycloalkyl; aryl; or Het; R6 is Ci_6alkyl optionally substituted with -C(=O)-OR9, or -C(=O)-NR7aR7b; each R7a and R7b is, independently, hydrogen; Ci_6alkyl optionally substituted with one or two substituents selected from mono- or diCi_6alkylamino, -C(=O)-OR9, and -C(=O)-Het; aryl; or Het;
R9 is hydrogen; Ci_6alkyl optionally substituted with halo, Ci_6alkoxy, phenyl or Het, wherein the phenyl may optionally be substituted with halo, nitro, or amino; or phenyl optionally substituted with one or two halo; 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; phenyl; polyhaloCi-βalkyl; Ci_6alkyl optionally substituted with -OR9 or phenyl; polyhaloCi_6alkoxy; -OR9; -C(=O)OH; Ci_6alkylthio; -S(=O)2NH2; and pyrrolyl; and
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 halo, -NR10aR10b, -OR9; -C(=O)-OH; -C(=O)-Ci_6alkyl; Ci_6alkylthio;
C2-βalkynyl; phenyl; morpholinyl; pyridinyl;pyrrolidinyl; pyrrolyl; furanyl; tetrazolyl; and thiophenyl; each R10aandR10b is, independently, hydrogen, Ci_6alkyl, arylCi-βalkyl, or aryl.
7. A compound according to any one of claims 1-6 wherein the compound has the formula (I-a)
Figure imgf000223_0001
wherein R2 and R3 are as specified in any one of claims 1-6.
8. A compound according to any one of claims 1-6 wherein the compound has the formula (I-b)
Figure imgf000223_0002
R1 ! represents -R5, -OR6, -NR7aR7b; and R3, R4a and R4b, R5, R6, R7a and R7b are as specified are as specified in any one of claims 1-6.
9. A compound according to any one of claims 1-6 wherein the compound has the formula (I-c)
Figure imgf000224_0001
wherein
R i l1 l1 repres „en Ats., - rR> 5\ - /O~vrR> 60, - -NvrRr> 7/aa-Rr> 7/bB;. and j r R> 33, τ R-, 5\ τ R-, 60, τ R-, 7/aa and R7b are as specified in any one of claims 1-6.
10. A compound according to any one of claims 1-6 wherein the compound has the formula (I-d)
Figure imgf000224_0002
wherein R11 represents -R5, -OR6, -NR7aR7b; and R4a, R4b, R5, R6, R7a and R7b are as specified in any one of claims 1-6.
11. 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 1-10.
12. A pharmaceutical composition according to claim 11, further comprising at least one other anti HCV compound.
13. A pharmaceutical composition according to claim 11, further comprising at least one anti HIV compound.
14. A compound according to any of claims 1-10, or a pharmaceutical composition according to any of claims 11-13, for use as a medicament.
15. A compound according to any of claims 1-10, or a pharmaceutical composition according to any of claims 11-13, for inhibiting HCV replication.
16. A compound according to any of claims 1-10 or a pharmaceutical composition according to any of claims 11-13, for treating hepatitis C.
17. A pharmaceutical composition according to claim 13, for inhibiting HCV and HIV replication.
18. Use of a compound according to any of claims 1-10, for the manufacture of a medicament for inhibiting HCV replication.
19. 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 1-10 or a pharmaceutical composition according to any of claims 11-13.
20. A combination comprising a compound according to any one of claims 1-10, and at least one other anti-HCV compound.
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US10246464B2 (en) 2014-09-09 2019-04-02 The Regents Of The University Of Michigan Thienopyrimidine and thienopyridine compounds and methods of use thereof
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