WO2007135427A1 - 1,4-disubstituées pipérazine et 1,4-disubstituées azépane inhibitrices de la 11 -béta-hydroxystéroid déshydrogénase 1 - Google Patents

1,4-disubstituées pipérazine et 1,4-disubstituées azépane inhibitrices de la 11 -béta-hydroxystéroid déshydrogénase 1 Download PDF

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Publication number
WO2007135427A1
WO2007135427A1 PCT/GB2007/001902 GB2007001902W WO2007135427A1 WO 2007135427 A1 WO2007135427 A1 WO 2007135427A1 GB 2007001902 W GB2007001902 W GB 2007001902W WO 2007135427 A1 WO2007135427 A1 WO 2007135427A1
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Prior art keywords
trifluoromethyl
piperazine
methylsulfonyl
pyridin
compound
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PCT/GB2007/001902
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English (en)
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Peter William Rodney Caulkett
William Mccoull
Martin Packer
Paul Robert Owen Whittamore
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Astrazeneca Ab
Astrazeneca Uk Limited
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Publication of WO2007135427A1 publication Critical patent/WO2007135427A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/84—Nitriles
    • C07D213/85—Nitriles in position 3

Definitions

  • This invention relates to chemical compounds, or pharmaceutically acceptable salts thereof. These compounds possess human 11- ⁇ -hydroxysteroid dehydrogenase type 1 enzyme s (11 ⁇ HSDl) inhibitory activity and accordingly have value in the treatment of disease states including metabolic syndrome and are useful in methods of treatment of a warm-blooded animal, such as man.
  • the invention also relates to processes for the manufacture of said compounds, to pharmaceutical compositions containing them and to their use in the manufacture of medicaments to inhibit 11 ⁇ HSDl in a warm-blooded animal, such as man.
  • Q Glucocorticoids Cortisol in man, corticosterone in rodents
  • Glucocorticoids are also important in the differentiation of pre-adipocytes into mature adipocytes which are able to store triglycerides (Bujalska IJ et al. 1999; Endocrinology 140, 3188-3196).
  • mice show attenuated glucocorticoid-induced activation of gluconeogenic enzymes in response to fasting and lower plasma glucose levels in response to stress or obesity (Kotelevtsev Y et al. 1997; Proc. Natl. Acad. Sci USA 94, 14924-14929) indicating the utility of inhibition of 1 l ⁇ HSDl in lowering of plasma glucose and hepatic glucose output in type 2 diabetes. Furthermore, these mice express an anti-atherogenic lipoprotein profile, having low triglycerides, increased HDL cholesterol and increased apo-lipoprotein AI levels.
  • ll ⁇ HSDl transgenic mice When expressed under the control of an adipose specific promoter, ll ⁇ HSDl transgenic mice have high adipose levels of corticosterone, central obesity, insulin resistant diabetes, hyperlipidaemia and hyperphagia. Most importantly, the increased levels of ll ⁇ HSDl activity in the fat of these mice are similar to those seen in obese subjects. Hepatic 11 ⁇ HSDl activity and plasma corticosterone levels were normal, however, hepatic portal vein levels of corticosterone were increased 3 fold and it is thought that this is the cause of the metabolic effects in liver.
  • Glucocorticoids also decrease insulin secretion and this could exacerbate the effects of glucocorticoid induced insulin resistance.
  • Pancreatic islets express ll ⁇ HSDl and carbenoxolone can inhibit the effects of 11-dehydocorticosterone on insulin release (Davani B et al. 2000; J. Biol. Chem. 275, 34841 -34844).
  • 11 ⁇ HSD 1 inhibitors may not only act at the tissue level on insulin resistance but also increase insulin secretion itself.
  • Skeletal development and bone function is also regulated by glucocorticoid action.
  • I l ⁇ HSDl is present in human bone osteoclasts and osteoblasts and treatment of healthy volunteers with carbenoxolone showed a decrease in bone resorption markers with no change in bone formation markers (Cooper MS et al 2000; Bone 27, 375-381). Inhibition of
  • I 1 ⁇ HSDl activity in bone could be used as a protective mechanism in treatment of osteoporosis.
  • Glucocorticoids may also be involved in diseases of the eye such as glaucoma.
  • 11 ⁇ HSDl has been shown to affect intraocular pressure in man and inhibition of 11 ⁇ HSD 1 may be expected to alleviate the increased intraocular pressure associated with glaucoma (Rauz S et al. 2001; Investigative Opthalmology & Visual Science 42, 2037-2042).
  • the WHO consultation has recommended the following definition which does not imply causal relationships and is suggested as a working definition to be improved upon in due course: > ⁇
  • the patient has at least one of the following conditions: glucose intolerance, impaired glucose tolerance (IGT) or diabetes mellitus and/or insulin resistance; together with two or more of the following:
  • Ring A is phenyl, optionally substituted by 1, 2 or 3 substituents independently selected from
  • R 1 is selected from hydroxy, nitro, halo, trifluoromethyl, Ci -4 alkyl, hydroxyC 1-4 alkyl,
  • Ring B is pyridyl, optionally substituted in the 2-, 2'-, 3- or 3'- positions (relative to the point of attachment) (where available) by 1 or 2 substituents independently selected from R 2 , and/or substituted on the 4-position (relative to the point of attachment) (where available) with a substituent selected from R 3 ;
  • R 2 is selected from halo, cyano, trifluoromethyl, d ⁇ alkyl and Ci -4 alkoxy;
  • R 3 is selected from halo, cyano, Ci -3 alkylsulfonyl and -CONR 4 R 5 ;
  • R 4 and R 5 are independently selected from hydrogen and C 1-4 alkyl; or R 4 and R 5 together with the nitrogen to which they are attached form an azetidinyl or pyrrolidinyl ring; n is O, 1 or 2;
  • R 6 is selected from methyl and hydroxymethyl
  • each R 6 group may be attached to any carbon atom in the piperazine or homopiperazine ring, including gem di-s ⁇ bstitution.
  • alkyl includes both straight and branched chain alkyl groups but references to individual alkyl groups such as “propyl” are specific for the straight chain version only.
  • “Ci-ealkyl” and “C 1-4 alkyl” includes propyl, isopropyl and t-butyl.
  • references to individual alkyl groups such as 'propyl' are specific for the straight chained version only and references to individual branched chain alkyl groups such as 'isopropyl' are specific for the branched chain version only.
  • references to individual alkyl groups such as 'propyl' are specific for the straight chained version only and references to individual branched chain alkyl groups such as 'isopropyl' are specific for the branched chain version only.
  • references to other radicals therefore "Ci ⁇ alkylcarbonyl” would include prop-1-ylcarbonyl, but-3- ylcarbonyl.
  • halo refers to fluoro, chloro, bromo and iodo.
  • Examples of “C 1-4 alkoxy” include methoxy, ethoxy andpropoxy.
  • Examples of “C 1 -4alkylcarbonylamino” include formamido, acetamido and propionylamino.
  • Examples of “C 1-3 alkylsulphonyl” include mesyl and ethylsulphonyl.
  • Examples of “C M alkanoyl” include propionyl and acetyl.
  • Examples of “C ⁇ aalkyl” include methyl, ethyl, propyl andisopropyl.
  • Examples of “C ⁇ aUcyl” include the examples of “C ⁇ aUcyl” as well as butyl and tert-butyl.
  • hydroxy C 1 _ 4 alkyl examples include hydroxymethyl, hydroxyethyl, l-hydroxyprop-2-yl and l-hydroxyprop-3-yl.
  • Examples of "Ci -4 alkylcarbonyl” include methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl and tert-butylcarbonyl.
  • the present invention relates to the compounds of formula (1) as hereinbefore defined as well as to the salts thereof.
  • Salts for use in pharmaceutical compositions will be pharmaceutically acceptable salts, but other salts may be useful in the production of the compounds of formula (1) and their pharmaceutically acceptable salts.
  • a suitable pharmaceutically acceptable salt of a compound of the invention is, for example, an acid-addition salt of a compound of the invention which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulphuric, phosphoric, trifluoroacetic, citric or maleic acid.
  • a suitable pharmaceutically acceptable salt of a compound of the invention which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a physiologically-acceptable cation, for example a salt with o methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
  • an alkali metal salt for example a sodium or potassium salt
  • an alkaline earth metal salt for example a calcium or magnesium salt
  • an ammonium salt or a salt with an organic base which affords a physiologically-acceptable cation
  • a salt with o methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine for example a salt with o methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tri
  • Some compounds of the formula (1) may have chiral centres and/or geometric isomeric centres (E- and Z- isomers), and it is to be understood that the invention encompasses all such optical, diastereoisomers and geometric isomers that possess ll ⁇ HSDl s inhibitory activity.
  • the invention relates to any and all tautomeric forms of the compounds of the formula
  • compounds of formula (1) in one embodiment of the invention are provided compounds of formula (1); in an alternative embodiment are provided pharmaceutically-acceptable salts of compounds of formula (1).
  • Particular values of variable groups are as follows. Such values may be used where appropriate with any of the definitions, claims or embodiments defined hereinbefore or hereinafter, for compounds of formula (1), (IA) and/or (IB).
  • Ring A is phenyl, substituted by 1 or 2 substituents independently selected from R 1
  • R 1 is selected from hydroxy, nitro, fluoro, chloro, trifluoromethyl, C 1-4 alkyl, 0 hydroxyC 1-4 alkyl, CF 3 C(OH)(Me)-, cyano, methylcarbonyl, methylsulfonyl
  • R 1 is selected from fluoro, chloro, trifluoromethyl, methyl, hydroxyethyl, cyano, methylcarbonyl, methylsulfonyl and CF 3 C(OH)(Me)- 4)
  • R 1 is selected from fluoro, chloro, trifluoromethyl, methyl, hydroxyethyl, cyano, methylcarbonyl and methylsulfonyl
  • R 1 is selected from fluoro, chloro, trifluoromethyl, C]. 4 alkyl and CF 3 C(OH)(Me)-
  • R 1 is selected from fluoro, chloro, trifluoromethyl and C ⁇ 4 alkyl 7) R 1 is CF 3 C(OH)(Me)-
  • Ring B is 2-pyridyl or 4-pyridyl
  • Ring B is substituted in the 2- and/or 2'- positions (relative to the point of attachment) by one or two, as appropriate, substituents independently selected from R 2 , particularly wherein R 2 is selected from chloro, fluoro and trifluoromethyl 10) Ring B is substituted on the 4- position (relative to the point of attachment) (where available) with a substituent selected from R 3
  • R 2 is selected from fluoro, chloro, cyano, trifluoromethyl, C 1-4 alkyl and C 1-4 alkoxy
  • R 2 is selected from fluoro, chloro, cyano, trifluoromethyl, C 1-4 alkyl and methoxy
  • R 2 is selected from chloro, fluoro and trifluoromethyl 14) R 2 is 3-trifluoromethylpyrid-2-yl or 3,5-dichloro ⁇ yrid-4-yl
  • R 3 is selected from fluoro, chloro, cyano, d-salkylsulfonyl, -CONHMe and -CONMe 2
  • R 3 is -CONR 4 R 5 wherein R 4 and R 5 together with the nitrogen to which they are attached form an azetidinyl or pyrrolidinyl ring
  • n 0 or 1 18) n is O
  • R 6 is methyl
  • R 6 is hydroxymethyl
  • L 1 is -CH 2 - or -CH 2 CH 2 , particularly -CH 2 -
  • L 1 is -CH(Me)- 23)
  • L 1 is -CMe 2 -
  • suitable compounds of the invention are any one or more of the Examples or a salt thereof.
  • suitable compounds of the invention are any one or more of the following or a salt thereof:
  • Another aspect of the present invention provides a process for preparing a compound of formula (1) or a pharmaceutically acceptable salt thereof which process (wherein variable groups are, unless otherwise specified, as defined in formula (I)) comprises of: a) reaction of a compound of Formula (2) with a compound of Formula (3):
  • Examples of conversions of a compound of Formula (1) into another compound of Formula (1) include functional group interconversions such as hydrolysis, hydrogenation, hydrogenolysis, oxidation or reduction, and/or further functionalisation by standard reactions such as amide or metal-catalysed coupling, or nucleophilic displacement reactions.
  • Suitable conditions for the above processes a) to c) are as follows.
  • a) Process a) may be carried out in a suitable solvent such as DCM, DMF, pyridine or water, typically with the addition of a base such as triethylamine, DIPEA, pyridine, or aqueous sodium hydroxide.
  • Process b) may be carried out without solvent, or in a suitable solvent such as DMA, DMF or xylene; typically the reaction is carried out without solvent at elevated temperature, using Microwave or conventional heating.
  • X 4 is a leaving group and R is hydrogen or a suitable protecting group, followed by removal of said protecting group if appropriate.
  • Process c) is typically carried out in an anhydrous aprotic solvent such as THF or diethyl ether; examples of suitable organometallic reagents for process c) are alkyl or aryl magnesium halides (Grignard reagent), alkyl or aryl lithium, or trimethyl (trifluoromethyl) silane (Ruppert's reagent).
  • Suitable examples of leaving groups for processes a) to c) are: fluoro, chloro, bromo, iodo, mesylate, tosylate or triflate.
  • Suitable examples of protecting groups for processes a) to c) are: tert-butyl oxycarbonyl (Boc), benzyloxycarbonyl (Z), acetyl or trifluoracetyl.
  • aromatic substitution reactions include the introduction of a nitro group using concentrated nitric acid, the introduction of an acyl group using, for example, an acyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; the introduction of an alkyl group using an alkyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; and the introduction of a halogeno group.
  • modifications include the reduction of a nitro group to an amino group by for example, catalytic hydrogenation with a nickel catalyst or treatment with iron in the presence of hydrochloric acid with heating; oxidation of alkylthio to alkylsulphinyl or alkylsulphonyl.
  • a suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or ⁇ -butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl.
  • the deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group.
  • an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • an acyl group such as a /-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulphuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate).
  • a suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example hydroxylamine, or with hydrazine.
  • a suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl.
  • the deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group.
  • an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide.
  • an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
  • a suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a ⁇ -butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifiuoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
  • a base such as sodium hydroxide
  • a ⁇ -butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifiuoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
  • the protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the chemical art.
  • cortisone to the active steroid Cortisol by 11 ⁇ HSDl oxo-reductase activity can be measured using a competitive homogeneous time resolved fluorescence assay (HTRF) (CisBio International, R&D, Administration and Europe Office, In Vitro Technologies — HTRF® / Bioassays BP 84175, 30204 Bagnols/Ceze Cedex, France.
  • HTRF time resolved fluorescence assay
  • DMSO dimethyl sulphoxide
  • the assay was carried out in a total volume of 20 ⁇ l consisting of cortisone (Sigma, Poole, Dorset, UK, 16OnM), glucose-6-phosphate (Roche Diagnostics, ImM), NADPH (Roche Diagnostics, lOO ⁇ M), glucose-6-phos ⁇ hate dehydrogenase (Roche Diagnostics, 12.5 ⁇ g/ml), EDTA (Sigma, Poole, Dorset, UK, ImM), assay buffer (K 2 HPO 4 ZKH 2 PO 4 , 10OmM) pH 7.5, recombinant 1 i ⁇ HSDl (1.5 ⁇ g/ml) plus test compound.
  • cortisone Sigma, Poole, Dorset, UK, 16OnM
  • glucose-6-phosphate Roche Diagnostics, ImM
  • NADPH Roche Diagnostics, lOO ⁇ M
  • glucose-6-phos ⁇ hate dehydrogenase Roche Diagnostics, 12.5 ⁇ g/ml
  • EDTA Sigma, Poole, Dorset, UK, Im
  • the assay plates were incubated for 25 minutes at 37°C after which time the reaction was stopped by the addition of lO ⁇ l of 0.5mM glycerrhetinic acid plus cortisol-XL665. lO ⁇ l of anti-cortisol Cryptate was then added and the plates sealed and incubated for 6 hours at room temperature. Fluorescence at 665nm and 620nm was measured and the 665nm:620nm ratio calculated using an Envision plate reader.
  • Compounds of the present invention typically show an IC 5 0 of less than 30 ⁇ M, and preferably less than 5 uM. For example, the following results were obtained:
  • compositions of the invention which comprises a compound of the Examples, or a pharmaceutically acceptable salt thereof, as defined hereinbefore in association with a pharmaceutically-acceptable diluent or carrier.
  • the compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intramuscular dosing or as a suppository for rectal dos
  • inhalation for example as
  • compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art.
  • compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents.
  • Suitable pharmaceutically acceptable excipients for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as corn starch or algenic acid; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservative agents such as ethyl or propyl p_-hydroxybenzoate, and anti-oxidants, such as ascorbic acid.
  • Tablet formulations may be uncoated or coated either to modify their disintegration and the subsequent absorption of the active ingredient within the gastrointestinal tract, or to improve their stability and/or appearance, in either case, using conventional coating agents and procedures well known in the art.
  • Compositions for oral use may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water or an oil such as peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions generally contain the active ingredient in finely powdered form together with one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as lecithin or condensation products of an alkylene oxide with fatty acids (for example polyoxethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol
  • the aqueous suspensions may also contain one or more preservatives (such as ethyl or propyl p_-hydroxybenzoate, anti-oxidants (such as ascorbic acid), colouring agents, flavouring agents, and/or sweetening agents (such as sucrose, saccharine or aspartame).
  • preservatives such as ethyl or propyl p_-hydroxybenzoate, anti-oxidants (such as ascorbic acid), colouring agents, flavouring agents, and/or sweetening agents (such as sucrose, saccharine or aspartame).
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil (such as arachis oil, olive oil, sesame oil or coconut oil) or in a mineral oil (such as liquid paraffin).
  • the oily suspensions may also contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set out above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water generally contain the active ingredient together with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients such as sweetening, flavouring and colouring agents, may also be present.
  • the pharmaceutical compositions of the invention may also be in the form of oil-in- water emulsions.
  • the oily phase may be a vegetable oil, such as olive oil or arachis oil, or a mineral oil, such as for example liquid paraffin or a mixture of any of these.
  • Suitable emulsifying agents may be, for example, naturally-occurring gums such as gum acacia or gum tragacanth, naturally-occurring phosphatides such as soya bean, lecithin, an esters or partial esters derived from fatty acids and hexitol anhydrides (for example sorbitan monooleate) and condensation products of the said partial esters with ethylene oxide such as polyoxy ethylene sorbitan monooleate.
  • the emulsions may also contain sweetening, flavouring and preservative agents.
  • Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also contain a demulcent, preservative, flavouring and/or colouring agent.
  • sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also contain a demulcent, preservative, flavouring and/or colouring agent.
  • compositions may also be in the form of a sterile injectable aqueous or oily suspension, which may be formulated according to known procedures using one or more of the appropriate dispersing or wetting agents and suspending agents, which have been mentioned above.
  • a sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example a solution in 1,3-butanediol.
  • Compositions for administration by inhalation may be in the form of a conventional pressurised aerosol arranged to dispense the active ingredient either as an aerosol containing finely divided solid or liquid droplets.
  • Conventional aerosol propellants such as volatile fluorinated hydrocarbons or hydrocarbons may be used and the aerosol device is conveniently arranged to dispense a metere'd quantity of active ingredient.
  • the amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration.
  • a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 2 g of active agent compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.
  • Dosage unit forms will generally contain about 1 mg to about 500 mg of an active ingredient.
  • the compounds defined in the present invention are effective 11 ⁇ HSD 1 inhibitors, and accordingly have value in the treatment of disease states associated with metabolic syndrome.
  • metabolic syndrome relates to metabolic syndrome as defined in 1) and/or 2) or any other recognised definition of this syndrome.
  • Synonyms for "metabolic syndrome” used in the art include Reaven's Syndrome, Insulin Resistance Syndrome and Syndrome X. It is to be understood that where the term “metabolic syndrome” is used herein it also refers to Reaven's Syndrome, Insulin Resistance Syndrome and Syndrome X.
  • a compound of formula (1), or a pharmaceutically acceptable salt thereof, as defined hereinbefore for use in a method of prophylactic or therapeutic treatment of a warm-blooded animal, such as man.
  • production of or producing an 1 l ⁇ HSDl inhibitory effect is referred to suitably this refers to the treatment of metabolic syndrome.
  • production of an 1 l ⁇ HSDl inhibitory effect is referred to this refers to the treatment of diabetes, obesity, hyperlipidaemia, hyperglycaemia, hyperinsulinemia or hypertension, particularly diabetes and 5 obesity.
  • production of an 11 ⁇ HSDl inhibitory effect is referred to this refers to the treatment of glaucoma, osteoporosis, tuberculosis, dementia, cognitive disorders or depression.
  • an 1 l ⁇ HSDl inhibitory effect refers to the treatment of cognitive disorders, such as improving the cognitive ability of an io individual, for example by improvement of verbal fluency, verbal memory or logical memory, or for treatment of mild cognitive disorders.
  • cognitive disorders such as improving the cognitive ability of an io individual, for example by improvement of verbal fluency, verbal memory or logical memory, or for treatment of mild cognitive disorders.
  • PNAS National Academy of Sciences
  • I 5 refers to the treatment of, delaying the onset of and/or reducing the risk of atherosclerosis - see for example J. Experimental Medicine, 2005, 202(4), 517-527.
  • a 2 o method for producing an 1 l ⁇ HSDl inhibitory effect in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of formula (1), or a pharmaceutically acceptable salt thereof.
  • the compounds of formula formula (1), or a pharmaceutically acceptable salt thereof are also useful as pharmacological tools in 25 the development and standardisation of in vitro and in vivo test systems for the evaluation of the effects of inhibitors of 1 l ⁇ HSDl in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part of the search for new therapeutic agents.
  • the inhibition of 1 l ⁇ HSDl described herein may be applied as a sole therapy or may involve, in addition to the subject of the present invention, one or more other substances 30 and/or treatments. Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate administration of the individual components of the treatment. Simultaneous treatment may be in a single tablet or in separate tablets.
  • agents than might be co-administered with 11 ⁇ HSD 1 inhibitors, particularly those of the present invention may include the following main categories of treatment:
  • Insulin and insulin analogues 1) Insulin and insulin analogues; 2) Insulin secretagogues including sulphonylureas (for example glibenclamide, glipizide), prandial glucose regulators (for example repaglinide, nateglinide), glucagon-like peptide 1 agonist (GLPl agonist) (for example exenatide, liraglutide) and dipeptidyl peptidase IV inhibitors (DPP-IV inhibitors);
  • sulphonylureas for example glibenclamide, glipizide
  • prandial glucose regulators for example repaglinide, nateglinide
  • GLPl agonist glucagon-like peptide 1 agonist
  • DPP-IV inhibitors dipeptidyl peptidase IV inhibitors
  • Insulin sensitising agents including PPAR ⁇ agonists (for example pioglitazone and rosiglitazone);
  • Anti-diabetic agents including phosotyrosine phosphatase inhibitors, glucose 6 - phosphatase inhibitors, glucagon receptor antagonists, glucokinase activators, glycogen phosphorylase inhibitors, fructose 1,6 bisphosphastase inhibitors, glutamine:fructose -6-phosphate amidotransferase inhibitors 8) Anti-obesity agents (for example sibutramine and orlistat);
  • Anti- dyslipidaemia agents such as, HMG-CoA reductase inhibitors (statins, eg pravastatin); PP ARa agonists (fibrates, eg gemfibrozil); bile acid sequestrants (cholestyramine); cholesterol absorption inhibitors (plant stanols, synthetic inhibitors); ileal bile acid absorption inhibitors (IBATi), cholesterol ester transfer protein inhibitors and nicotinic acid and analogues (niacin and slow release formulations);
  • Antihypertensive agents such as, ⁇ blockers (eg atenolol, inderal); ACE inhibitors (eg lisinopril); calcium antagonists (eg. nifedipine); angiotensin receptor antagonists (eg candesartan), ⁇ antagonists and diuretic agents (eg. furosemide, benzthiazide); l l)Haemostasis modulators such as, antithrombotics, activators of fibrinolysis and antiplatelet agents; thrombin antagonists; factor Xa inhibitors; factor Vila inhibitors; antiplatelet agents (eg. aspirin, clopidogrel); anticoagulants (heparin and Low molecular weight analogues, hirudin) and warfarin; and
  • ⁇ blockers eg atenolol, inderal
  • ACE inhibitors eg lisinopril
  • calcium antagonists eg. nifedipine
  • Anti-inflammatory agents such as non-steroidal anti-inflammatory drugs (eg. aspirin) and steroidal anti-inflammatory agents (eg. cortisone).
  • non-steroidal anti-inflammatory drugs eg. aspirin
  • steroidal anti-inflammatory agents eg. cortisone
  • an Isolute SCX-2 column is referred to, this means an "ion exchange" extraction cartridge for adsorption of basic compounds, i.e. a polypropylene tube containing a benzenesulphonic acid based strong cation exchange sorbent, used according to the manufacturers instructions obtained from International Sorbent Technologies Limited, Dyffryn Business Park, Hengeod, Mid Glamorgan, UK, CF82 7RJ; viii) where an Isolute-NH2 column is referred to, this means an "ion exchange" extraction cartridge for adsorption of acidic compounds, i.e.
  • a polypropylene tube containing a amino silane covalently bonded to a silica particle used according to the manufacturers instructions obtained from International Sorbent Technologies Limited, Dyffryn Business Park, Hengeod, Mid Glamorgan, UK, CF82 7RJ; ix) where as Isco CombiFlash Optix-10 parallel flash chromatography system is referred to this means an automated chromatography workstation capable of carrying out up to 10 purifications in parallel via flash chromatography using pre packed silica cartridges; x) where a "Biotage 9Og silica column” is referred to this means an automated chromatography workstation capable of carrying out up to 4 purifications in parallel via flash chromatography using pre packed silica cartridges, eg Si 12+M available from Biotage Inc.
  • Example 2 l-benzylsulfonyl-4-(3,5-dichloropyridin-4-yl)-2-methyl-piperazine
  • Example 3 l-(3,5-dichloropyridin-4-yl)-4-[[3-(trifluoromethyl)phenyl] methylsulfonyl]piperazine
  • Example 4 l-[(3,4-dichlorophenyl)methylsulfonyl]-4-(3,5-dichloropyridin-4-yl)piperazme
  • Example 5 1 -(3 , 5-dichloropyridin-4-y l)-4- [(3 -methyl ⁇ henyl)methylsulfonyl]piperazine
  • Example 6 1 -(3,5-dichloropyridin-4-yl)-4-[(2-fluorophenyl)methylsulfonyl]piperazine
  • Example 7 l-(3,5-dichloropyridin-4
  • Example 10 l-[(2,4-dichlorophenyl)metliylsulfonyl]-4-(3,5-dichloropyridin-4-yl)piperazine
  • Example 11 l-(3,5-dichloropyridin-4-yl)-4-[(3-nitrophenyl)methylsulfonyl]piperazine
  • Example 12 1 -[(2-fluorophenyl)methy lsulfonyl] -4- [3 -(trifluoromethyl)pyridin-2- yljpiperazine s
  • Example 13 l-[(2-fluorophenyl)methylsulfonyl]-2-methyl-4-[3-(trifluorometliyl)pyridin-2- yljpiperazine
  • Example 14 1- [(2-fluorophenyl)methylsulfonyl]-4- [3-(trifluoromethyl)pyridin-2-yl] - 1 ,4- diazepane
  • Example 15 2-[4-[(2-fluorophenyl)methylsulfonyl]-3-methyl-pi ⁇ erazin-l-yl]pyridine-3- Q carbonitrile
  • Example 16 1 -[(2-fluorophenyl)methylsulfonyl]-2,2-dimethyl-4-[3-(trifluoromethyl)pyridin-
  • Example 17 [l-[(2-fluorophenyl)methylsulfonyl]-4-[3-(trifluoromethyl)pyridin-2- yl]piperazin-2-yl]methanol
  • Example 18 l-[[4-(trifluoromethyl)phenyl]methylsulfonyl]-4-[3-(trifluoromethyl)pyridin-2- yljpiperazine
  • Example 20 1 -[(4-fluorophenyl)methylsulfonyl]-4-[3-(trifluoromethyl) ⁇ yridin-2- yl]piperazine
  • Example 22 1 -[(2-chlorophenyl)methylsulfonyl] -4- [3 -(trifluoromethy l)pyridin-2- yl]piperazine
  • Example 23 l-[(3-chlorophenyl)methylsulfonyl]-4-[3-(trifluoromethyl)pyridin-2- yl]piperazine
  • Example 25 l-[(2,6-difluoro ⁇ henyl)methylsulfonyl]-4-[3-(trifluoromethyl)pyridin-2- yljpiperazine
  • Examples 16 and 17 were prepared by reacting the appropriate piperazine with n-butyl litium in THF at -65 0 C to -55 0 C under an atmosphere of argon, and adding the sulfonyl chloride to the anion thus generated.
  • Piperazine (10.11 g, 117.58) and 2-chloro-3-(trifluoromethyl)pyridine (3.0 g, 23.51 mmol) were weighed into a round-bottomed flask and DMF (3 ml) was added. The mixture was heated to 90 0 C until the solid piperazine had melted and then stirred at 90 0 C for 1 A hour and then 70 0 C for a further hour. The reaction mixture was cooled to ambient temperature and EtOAc (150 ml) was added; the resulting solution was washed with water (150 ml) and then brine (100 ml).
  • Example 28 l-f3-ff4-f3-(trifluoromethyl)pyridin-2-yllpiperazin-l-vnsulfonylmethyl1 phenyl] ethanone
  • Example 29 l-[4-[[443-(trifluoromethylWridin-2-yl1piperazin-l- yli sulf onylmethyll phenyl] ethanone
  • Example 30 lJ,l-Trifluoro-2-f3-fr4-r3-(trifluoromethvI)pyridin-2-yllpiperazm-l- yllsuIfonylmethyIlphenyllpropan-2-ol
  • reaction mixture was then concentrated in vacuo to give a yellow oil which was purified by flash column chromatography (12g silica cartridge, eluting sequentially with neat isohexane, isohexane containing 40% v/v of ethyl acetate, then isohexane containing 80% v/v of ethyl acetate).
  • Example 31 l,l,l-trifluoro-2-f4-[f4-f3-(trifluoromethyl)pyridin-2-yl1piperazin-l- yll sulfonylmethyll phenyll propan-2-ol
  • Example 32 l-[3-[[4-f3-(trifluoromethvDpyridin-2-yllpiperazin-l- yll sulf onylmethyll phenyl] ethanol

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Abstract

L'invention porte sur des composés de formule (I) dans laquelle les groupes variables sont définis dans la description, sur leur utilisation comme inhibiteurs de la 11βHSD1, sur leurs procédés d'obtention, et sur des préparations pharmaceutiques les comprenant.
PCT/GB2007/001902 2006-05-23 2007-05-23 1,4-disubstituées pipérazine et 1,4-disubstituées azépane inhibitrices de la 11 -béta-hydroxystéroid déshydrogénase 1 WO2007135427A1 (fr)

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Cited By (16)

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WO2009021740A2 (fr) 2007-08-15 2009-02-19 Sanofis-Aventis Nouvelles tétrahydronaphtalines substituées, leurs procédés de préparation et leur utilisation comme médicaments
WO2010041054A1 (fr) * 2008-10-06 2010-04-15 Cancer Research Technology Limited Composés à base de pyridine et de pyrimidine en tant qu’inhibiteurs de la voie de signalisation wnt pour le traitement du cancer
WO2011107494A1 (fr) 2010-03-03 2011-09-09 Sanofi Nouveaux dérivés aromatiques de glycoside, médicaments contenants ces composés, et leur utilisation
WO2011157827A1 (fr) 2010-06-18 2011-12-22 Sanofi Dérivés d'azolopyridin-3-one en tant qu'inhibiteurs de lipases et de phospholipases
WO2011161030A1 (fr) 2010-06-21 2011-12-29 Sanofi Dérivés de méthoxyphényle à substitution hétérocyclique par un groupe oxo, leur procédé de production et leur utilisation comme modulateurs du récepteur gpr40
WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation et utilisation comme médicament
WO2012004269A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés d'acide ( 2 -aryloxy -acétylamino) - phényl - propionique, procédé de production et utilisation comme médicament
WO2012010413A1 (fr) 2010-07-05 2012-01-26 Sanofi Acides hydroxy-phényl-hexiniques substitués par aryloxy-alkylène, procédé de production et utilisation comme médicament
WO2012120053A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine ramifiés, procédé pour leur préparation, utilisation en tant que médicament, agents pharmaceutiques contenant ces dérivés et leur utilisation
WO2012120054A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine di- et tri-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120055A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine di- et tri-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120052A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés d'oxathiazine substitués par des carbocycles ou des hétérocycles, leur procédé de préparation, médicaments contenant ces composés et leur utilisation
WO2012120056A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine tétra-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
WO2013045413A1 (fr) 2011-09-27 2013-04-04 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b] pyridine-4-carboxylique utilisés comme inhibiteurs de kinase
US10364228B2 (en) * 2013-11-14 2019-07-30 Novira Therapeutics, Inc. Azepane derivatives and methods of treating hepatitis B infections

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WO2007092435A2 (fr) * 2006-02-07 2007-08-16 Wyeth Inhibiteurs 11-beta hsd1

Cited By (22)

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Publication number Priority date Publication date Assignee Title
WO2009021740A2 (fr) 2007-08-15 2009-02-19 Sanofis-Aventis Nouvelles tétrahydronaphtalines substituées, leurs procédés de préparation et leur utilisation comme médicaments
JP2012504592A (ja) * 2008-10-06 2012-02-23 キャンサー・リサーチ・テクノロジー・リミテッド がんの治療のためのＷｎｔシグナル伝達経路阻害剤としてのピリジン系及びピリミジン系の化合物
KR20110118611A (ko) * 2008-10-06 2011-10-31 캔써 리서치 테크놀로지 리미티드 암의 치료를 위한 ｗｎｔ 신호전달 경로 억제제로서의 피리딘계 및 피리미딘계 화합물
US8778925B2 (en) 2008-10-06 2014-07-15 Cancer Research Technology Ltd. Pyridine and pyrimidine based compounds as Wnt signaling pathway inhibitors for the treatment of cancer
WO2010041054A1 (fr) * 2008-10-06 2010-04-15 Cancer Research Technology Limited Composés à base de pyridine et de pyrimidine en tant qu’inhibiteurs de la voie de signalisation wnt pour le traitement du cancer
KR101666517B1 (ko) 2008-10-06 2016-10-14 캔써 리서치 테크놀로지 리미티드 암의 치료를 위한 ｗｎｔ 신호전달 경로 억제제로서의 피리딘계 및 피리미딘계 화합물
EA021828B1 (ru) * 2008-10-06 2015-09-30 Кэнсэр Ресерч Текнолоджи Лимитед Соединения на основе пиридина и пиримидина в качестве ингибиторов сигнального пути wnt для лечения рака
AU2009300869B2 (en) * 2008-10-06 2014-11-20 Cancer Research Technology Limited Pyridine and pyrimidine based compounds as Wnt signaling pathway inhibitors for the treatment of cancer
WO2011107494A1 (fr) 2010-03-03 2011-09-09 Sanofi Nouveaux dérivés aromatiques de glycoside, médicaments contenants ces composés, et leur utilisation
WO2011157827A1 (fr) 2010-06-18 2011-12-22 Sanofi Dérivés d'azolopyridin-3-one en tant qu'inhibiteurs de lipases et de phospholipases
WO2011161030A1 (fr) 2010-06-21 2011-12-29 Sanofi Dérivés de méthoxyphényle à substitution hétérocyclique par un groupe oxo, leur procédé de production et leur utilisation comme modulateurs du récepteur gpr40
WO2012004270A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés 1,3-propanedioxyde à substitution spirocyclique, procédé de préparation et utilisation comme médicament
WO2012004269A1 (fr) 2010-07-05 2012-01-12 Sanofi Dérivés d'acide ( 2 -aryloxy -acétylamino) - phényl - propionique, procédé de production et utilisation comme médicament
WO2012010413A1 (fr) 2010-07-05 2012-01-26 Sanofi Acides hydroxy-phényl-hexiniques substitués par aryloxy-alkylène, procédé de production et utilisation comme médicament
WO2012120053A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine ramifiés, procédé pour leur préparation, utilisation en tant que médicament, agents pharmaceutiques contenant ces dérivés et leur utilisation
WO2012120056A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine tétra-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120052A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés d'oxathiazine substitués par des carbocycles ou des hétérocycles, leur procédé de préparation, médicaments contenant ces composés et leur utilisation
WO2012120055A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine di- et tri-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2012120054A1 (fr) 2011-03-08 2012-09-13 Sanofi Dérivés oxathiazine di- et tri-substitués, procédé pour leur préparation, utilisation en tant que médicament, agent pharmaceutique contenant ces dérivés et utilisation
WO2013037390A1 (fr) 2011-09-12 2013-03-21 Sanofi Dérivés amides d'acide 6-(4-hydroxyphényl)-3-styryl-1h-pyrazolo[3,4-b]pyridine-4-carboxylique en tant qu'inhibiteurs de kinase
WO2013045413A1 (fr) 2011-09-27 2013-04-04 Sanofi Dérivés d'amide d'acide 6-(4-hydroxyphényl)-3-alkyl-1h-pyrazolo[3,4-b] pyridine-4-carboxylique utilisés comme inhibiteurs de kinase
US10364228B2 (en) * 2013-11-14 2019-07-30 Novira Therapeutics, Inc. Azepane derivatives and methods of treating hepatitis B infections

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