(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property Organization
`International Bureau
`
`22 October 2009 (22.10.2009) (10) International Publication Number
`
`(43) International Publication Date
`
`WO 2009/129370 Al
`
`
`(51)
`
`International Patent Classification:
`AOIN 43/36 (2006.01)
`A61K 31/40 (2006.01)
`
`(21)
`
`International Application Number:
`
`PCT/US2009/040771
`
`(22)
`
`International Filing Date:
`
`(25)
`
`(26)
`
`(30)
`
`(71)
`
`(72)
`(75)
`
`Filing Language:
`
`Publication Language:
`
`16 April 2009 (16.04.2009)
`
`English
`
`English
`
`Priority Data:
`61/046,048
`
`18 April 2008 (18.04.2008)
`
`US
`
`Applicant (for all designated States except US): GLAXO
`GROUP LIMITED [US/US]; Glaxo Wellcome House,
`Berkeley Avenue, Greenford, Middlesex, UB6 ONN (US).
`
`Inventors; and
`(for US only): DENG, Jianghe
`Inventors/Applicants
`[CN/US];
`1250 South Collegeville Road, Collegeville,
`PA 19426 (US). LAINE, Dramane,
`Ibrahim [FR/US];
`709 Swedeland Road, King of Prussia, PA 19406 (US).
`MCCLELAND,
`Brent, W.
`[US/US]; 709 Swedcland
`Road, King of Prussia, PA 19406 (US). PALOVICH,
`Michael, R.
`[US/US]; 709 Swedeland Road, King of
`Prussia,
`PA
`19406
`(US).
`PETITJEAN,
`Emile,
`Veronique
`[FRVSG]; Biopolis One-north, The Helios
`
`(74)
`
`(81)
`
`(84)
`
`Block # 03-01/02,
`(SG).
`
`11 Bioplis Way,
`
`13866 Singapore
`
`Jonathan, M. et al; Glaxosmithk-
`Agents: DERMOTT,
`line, Corporate
`Intellectual
`Property, UW2220,
`709
`Swedeland Road, P.O. Box 1539, King of Prussia, PA
`19406-0939 (US).
`
`Designated States (unless otherwise indicated, for every
`kind ¢d national protection available): AE, AG, AL, AM,
`AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ,
`CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ,
`Ec, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN,
`HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR,
`KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME,
`MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO,
`NZ, OM, PG, PH, PL, PT, RO, RS, RU, SC, SD, SE, SG,
`SK, SL, SM, ST, SV, SY, TJ, TM, TN, TR, TT, TZ, UA,
`UG, US, UZ, VC, VN, ZA, 7M, ZW.
`
`Designated States (unless otherwise indicated, for every
`kind d regional protection available): ARIPO (BW, GH,
`GM, KF, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, 7M,
`ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ,
`TM), European (AT, BE, BG, CH, CY, CZ, DE, DK, EE,
`ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV,
`Mc, MK, MT, NL, NO, PL, PT, RO, SE, SI, SK, TR),
`OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, ML,
`MR, NE, SN, TD, TG).
`
`(54) Title: CATITEPSIN C INHIBITORS
`
`IN
`
`i
`
`(1)
`
`[Continued on nextpage]
`
`(57) Abstract: What is disclosed herein are compounds of the following
`formula (I); or a salt thereof wherein Ar is a monocyclic heteroaromatic
`ring, a bicyclic heteroaromatic ring or a bicyclic heterocycloalkylaromatic
`ring.
`
`
`
`
`
`wo2009/129370A1IMITINMININMTAIANAITAUATA
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`

`

`WO 2009/129370 A1 IMMINENTATTAAE AC TTANA EAUT ACAA
`
`inventorship
`of
`Declarations under Rule 4.17:
`tere
`— as to applicant's entitlement
`Bublishea:
`apatent (Rule 4.17(U))
`— as to the appticant’s entitlement to claim the priority g& ~~
`with international search 'éport Art. 2103)
`the earlier application (Rule 4.17(Hi))
`
`to apply for and be granted
`
`_
`
`(Rule 4.) 7tiv))
`
`

`

`WO 2009/129370
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`PCT/US2009/040771
`
`FIELD OF THE INVENTION
`
`Cathepsin C Inhibitors
`
`This invention relates to certain ]-cyano-3-pyrrolidinyl-benzenesulfonamides—that
`
`are cathepsin C inhibitors, and their use in the treatment of diseases mediated by the
`
`cathepsin C enzyme such as chronic obstructive pulmonary disease.
`
`BACKGROUND OF THE INVENTION
`
`Cathepsins are a family of enzymes included in the papain superfamily of cysteine
`
`proteases. Cathepsins B,C, F,H, K,L,S, V, and X have been described in the scientific
`
`10
`
`literature. Cathepsin C is also known in the literature as Dipeptidyl Peptidase I or
`
`"DPPI."
`
`A number of recently published studies have begun to describe the role cathepsin C plays
`
`in certain inflammatory processes. See E.g. Adkison et al., The Journal of Clinical
`
`Investigation 109:363-371 (2002); Tran et al., Archives of Biochemistry and Biophysics
`
`15
`
`403:160-170 (2002); Thiele et al., The Journal of Immunology 158: 5200-5210 (1997);
`
`Bidere et al., The Journal of Biological Chemistry 277: 32339-32347 (2002); Mabee et
`
`al., The Journal of Immunology 160: 5880-5885; McGuire et al., The Journal of
`
`Biological Chemistry, 268: 2458-2467; and Paris et al., FEBS Letters 369: 326-330
`
`(1995). From these studies, it appears that cathepsin C is co-expressed with certain serine
`
`20
`
`proteases, which are released from inflammatory cells recruited to cites of inflammation,
`
`and acts as a physiological activator of these proteases. Once activated, these proteases
`
`are capable of degrading various extracellular matrix components, which can lead to
`
`tissue damage and chronic inflammation.
`
`For example, Chronic Obstructive Pulmonary Disease ("COPD") is a chronic
`
`25
`
`inflammatory disease where cathepsin C appears to play arole. The American Thoracic
`
`Society defines COPD as "a disease characterized by the presence of airflow obstruction
`
`due to chronic bronchitis or emphysema; the airflow obstruction is generally progressive,
`
`may be accompanied by airway hyperreactivity, and may be partially reversible."
`
`American Journal of Respiratory and Critical Care Medicine 152: S77-S120 (1995).
`
`30
`
`Chronic bronchitis is generally characterized by a chronic productive cough, whereas
`
`emphysema is generally characterized by permanent enlargement of the airspaces distal to
`
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`

`WO 2009/129370
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`PCT/US2009/040771
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`the terminal bronchioles and airway wall destruction. Chronic bronchitis and emphysema
`
`usually occur together in COPDpatients.
`
`Cigarette smoking is a significant risk factor for developing COPD. Exposure to cigarette
`
`smoke and other noxious particles and gases may result in chornic inflammation of the
`
`lung.
`
`In response to such exposure, inflammatory cells such as CD8+ Tcells,
`
`macrophages, and neutrophils are recruited to the area. These recruited inflammatory
`
`cells release proteases, which are believed to play a major role in the disease etiology by
`
`degrading airway walls. Protcascs bclicved to be involved in this process include the
`
`serine proteases neutrophil elastase ("NE"), chymase ("CY"), cathepsin G, proteinase 3
`
`10
`
`and granzymes A and B. Cathepsin C appears to be involved in activating these enzymes.
`
`Rheumatoid arthritis ("RA") is another chronic inflammatory disease where
`
`cathepsin C appears to play arole. Neutrophils are recruited to the site ofjoint
`
`inflammation and release cathepsin G, NE, and proteinase 3, which are believd to be
`
`responsible for cartilage destruction associated with RA. Cathepsin C appears to be
`
`15
`
`involved in activating these enzymes.
`
`Other conditions where cathepsin C may play a role include osteoarthritis, asthma,
`
`and Multiple Sclerosis. See E.g. Matsui K. Yuyama N.Akaiwa M. Yoshida NL. Macda
`
`M. Sugita Y. Izuhara K., Identification of an alternative splicing variant of cathepsin
`
`C/dipeptidyl-peptidase I, Gene. 293(1-2): 1-7, 2002 Jun 26; Wolters PJ. Laig-Webster M.
`
`20
`
`Caughey GH., Dipeptidyl peptidase I cleaves matrix-associated proteins and is expressed
`
`mainly by mast cells in normal dog airways, American Journal of Respiratory Cell &
`
`Molecular Biology. 22(2): 183-90, 2000.
`
`One approach to treating these conditions is to inhibit the activity of the serine
`
`proteases involved in the inflammatory process, especially NE activity. See E.g.,
`
`25
`
`Ohbayashi, "Neutrophil elastase inhibitors as treatment for COPD", Expert Opin.
`
`Investig. Drugs 11(7): 965-980 (2002); Shapiro, "Neutrophil Elastasc: Path Clearer,
`
`Pathogen Killer, or Just Pathologic?", Am. J. Respir. Cell Mol. Biol. 26: 266-268 (2002).
`
`In light of the role cathepsin C plays in activating certain serine proteases, especially NE,
`
`it is desirable to prepare compoundsthat inhibit its activity, which thereby inhibit serine
`
`30
`
`protease activity. Thus, there is a need to identify compoundsthat inhibit cathepsin C,
`
`which can be usedin the treatment of a variety of conditions mediated by cathepsin C.
`
`

`

`WO 2009/129370
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`PCT/US2009/040771
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`SUMMARY OF THE INVENTION
`
`In a first instance, this invention relates to compounds of formula (I)
`
`SZ
`LC O
`N- S —Ar
`
`or a salt thereof wherein:
`
`Aris amonocyclic heteroaromatic ring, a bicyclic heteroaromatic ring or a
`
`bicyclic heterocycloalkylaromatic ring wherein the monocyclic ring or one or both rings
`
`of abicyclic heteroaromatic ring or bicyclic heterocycloalkylaromatic contains one or
`
`more of N, O, or S; any ring carbon being optionally substituted by at least one
`
`10
`
`substituent X which is selected from the group consisting of: Ci-Cealkyl; C,-Cealkeny];
`
`C,-Céalkynyl; halo; halo-substituted Ci-C¢alkyl; C(O)R2; amonocyclic heteroaromatic
`
`ring containing one or more of N, O or S; aryl unsubstituted or substituted by Ci-C alkyl,
`
`halo, halo-substituted Ci-C alkyl, or C(O)R2; aryl-Ci-C ¢alkyl wherein the aryl group is
`
`optionally substituted by Ci-Cgalkyl, halo, halo-substituted Ci-C alkyl or C(O)R, and the
`
`15
`
`Ci-C alkyl chain is substituted by halo; or NR3R4;
`
`R, is OH, Ci-C, alkyoxy or NR,R.; and
`
`R; or R, are independently H or Ci-Cealkyl.
`
`In a second instance, this invention relates to the use of a compound of formula (1D
`
`or a pharmaceutically acceptable salt thereof in the prevention, management or treatment
`
`20
`
`of arespiratory or inflammatory disease, such as chronic obstructive pulmonary disease
`
`or rhinitis.
`
`In a further aspect, this invention relates to a pharmaceutically acceptable
`
`formulation comprising a compound of forumula (I) or a pharmaceutically acceptable salt
`
`thereof and a pharmaceutically acceptable excipient.
`
`25
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`Terms and Definitions
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`WO 2009/129370
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`PCT/US2009/040771
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`For the avoidance of doubt, unless otherwise indicated,
`
`the term "substituted"
`
`means substituted by one or more defined groups.
`
`In the case where groups may be
`
`selected from a number of alternative groups the selected groups may be the same or
`
`different.
`
`The term “independently” means that where more than one substituent
`
`is selected
`
`from anumber of possible substituents,
`
`those substituents may be the same or different.
`
`An "effective amount" means that amount of a drug or pharmaceutical agent that
`
`will clicit the biological or medical response of atissuc, system, animal or human that is
`
`being sought, for instance, by aresearcher or clinician. Furthermore,
`
`the term
`
`10
`
`"therapeutically effective amount" means any amount which, as compared to a
`
`corresponding subject who has not received such amount, results in improved treatment,
`
`healing, prevention, or amelioration of a disease, disorder, or side effect, or a decrease in
`
`the rate of advancement of a disease or disorder. The term also includes within its scope
`
`amounts effective to enhance normal physiological
`
`function.
`
`15
`
`Asused herein the term "alkyl" refers to a saturated straight- or branched-chain
`
`hydrocarbon radical having the specified number of carbon atoms. As used herein, the
`
`terms "Ci-Cg¢ alkyl" and "Ci_Cio alkyl" refers to such a group having at least
`
`1 and up to 6
`
`or 10 carbon atoms respectively. Examples of such branched or straight-chained alkyl
`
`groups useful
`
`in the present invention include, but are not limited to, methyl, ethyl, n-
`
`20
`
`propyl,
`
`isopropyl,
`
`isobutyl, n-butyl,
`
`t-butyl, n-pentyl,
`
`isopentyl, n-hexyl, n-heptyl, n-
`
`octyl, n-nonyl, and n-decyl, and branched analogs of the latter 5 normal alkanes.
`
`The term "Ci-Cio-alkenyl" refers to straight or branched hydrocarbon chains
`
`containing the specified number of carbon atoms and at least 1, or more, carbon-carbon
`
`double bonds. Examples include ethenyl (or ethenylene) and propenyl (or propenylene).
`
`25
`
`When the term "Ci-Cioalkynyl"” (or “alkynylene")
`
`is used it refers to straight or
`
`branched hydrocarbon chains containing the specified number of carbon atoms and at
`
`least 1, or more, carbon-carbon triple bonds. Examples include ethynyl (or ethynylene)
`
`and propynyl
`
`(or propynylene).
`
`When "Cs-C 6Cycloalkyl” is used it refers to anon-aromatic,
`
`saturated, cyclic
`
`30
`
`hydrocarbon ring containing the specified number of carbon atoms. So, for example,
`
`the
`
`term "C3_C.6 cycloalkyl" refers to a non-aromatic cyclic hydrocarbon ring having from
`
`three to eight carbon atoms. Exemplary "C3-C6 cycloalkyl" groups useful in the present
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`WO 2009/129370
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`PCT/US2009/040771
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`invention include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,
`
`cyclohexyl, cycloheptyl and cyclooctyl.
`
`The term "C4-C6cycloalkenyl" refers to a non-aromatic monocyclic carboxycyclic
`
`ring having the specified number of carbon atoms and up to 3 carbon-carbon double
`
`bonds.
`
`"Cycloalkenyl" includes by way of example cyclopentenyl and cyclohexenyl.
`
`"Halo" means the halogen radical fluoro, chloro, bromo, or iodo.
`
`"Haloalkyl” means a Ci-Cioalkyl, Ci-Cio-alkenyl, or Ci-Cioalkynyl group that is
`
`substituted with one or more halo substituents. Haloalkyl includes trifluoromethyl.
`
`Where "C3-C6 heterocycloalkyl” is used, it means a non-aromatic heterocyclic
`
`10
`
`ring containing the specified number of ring atoms being, saturated or having one or more
`
`degrees of unsaturation and containing one or more heteroatom substitutions selected
`
`from O, S and/or N. Such aring may be optionally fused to one or more other
`
`“heterocyclic” ring(s) or cycloalkyl ring(s). Examples of "heterocyclic" moieties
`
`include, but are not limited to, aziridine, thiirane, oxirane, azetidine, oxetane, thietane,
`
`15
`
`tetrahydrofuran, pyran, 1,4-dioxane, 1,3-dioxane, piperidine, piperazine, 2,4-
`
`piperazinedione, pyrrolidine,
`
`imidazolidine, pyrazolidine, morpholine, thiomorpholine,
`
`tetrahydrothiopyran,
`
`tetrahydrothiophene, and the like.
`
`"Aryl" refers to optionally substituted monocyclic and polycarbocyclic unfused or
`
`fused groups having 6to 14 carbon atoms and having at least one aromatic ring that
`
`20
`
`complies with HUckel's Rule. Examples of aryl groups are phenyl, biphenyl, naphthyl,
`
`anthracenyl, phenanthrenyl
`
`andthe like.
`
`"Monocyclic heteroaromatic ring” means an optionally substituted aromatic
`
`monocyclic ring wherein the ring complies with HUckel's Rule, has the specified number
`
`of ring atoms, and that ring contains at least one heteratom selected from N, O, and/or S.
`
`25
`
`Examples of these groups include furanyl, thiophenyl, pyrrolyl, imidazolyl, pyrazolyl,
`
`triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, oxo-pyridyl,
`
`thiadiazolyl,
`
`isothiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, quinolinyl,
`
`isoquinoliny]l,
`
`benzofuranyl, benzothiophenyl,
`
`indolyl, and indazolyl.
`
`A "bicyclic heteroaromatic ring” is a polycarbocyclic fused ring system having 2
`
`30
`
`rings, both of which comply with HUckel’s Rule and at least one ring contains at least one
`
`heteratom which is N, O, and/or §. Examples of these groups include rings that have 7-9
`
`carbon atoms and at least one of N, O or S in 1 of the rings; one or both rings may have 2
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`WO 2009/129370
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`PCT/US2009/040771
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`or more of N, O or S in any combination with a concomitant reduction in carbon atoms.
`
`Examples include quinolines, benzothiadiazoles, benzothiophenes, and the like.
`
`A "bicyclic heterocycloalkylaromatic ring” is one which has 2 rings wherein 1
`
`ring is an aryl ring as defined above andthe other is a fused C3-C, heterocycloalkyl ring,
`
`5
`
`as defined above.
`
`CompoundsofParticular Interest
`
`Monocyclic or bicyclic groups of particular interest in this invention include the
`
`following rings where the floating bond onthe Icft side of the ring means the (O)2S-C
`
`bond is to any carbon in the ring, except where noted:
`
`10
`
`SLFw, KR €or A a
`
`N
`
`O
`
`
`
`
`
`O
`On (B),
`” (A),
`attachment to the sulphur is a carbon in the aromatic ring,
`
`(C) wherethe ring
`
`0}.
`
`N
`
`pn (E),
`
`Op
`
`\
`S
`
`(F) or
`
`\
`| 3),
`N
`aN
`—— 7
`N
`
`(D),
`
`15
`
`x
`
`(G) where the (O)2S-C bondis to a carbon in the cyclohexenyl ring
`()n
`and the X group(s) is likewise bonded to a carbon in the cyclohexenylring.
`
`"Enantiomerically enriched" refers to products whose enantiomeric excess is
`
`greater than zero. For example, enantiomerically enriched refers to products whose
`
`enantiomeric excess is greater than 50% ee, greater than 75% ee, and greater than 90%
`
`20
`
`ee.
`
`"Enantiomeric excess” or "ee" is the excess of one enantiomer overthe other
`
`expressed as a percentage. As aresult, since both enantiomers are present in equal
`
`amounts in aracemic mixture, the enantiomeric excess is zero (0% ee). However, if one
`
`enantiomer was enriched suchthat it constitutes 95% of the product, then the
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`WO 2009/129370
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`PCT/US2009/040771
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`enantiomeric excess would be 90% ee (the amount of the enriched enantiomer, 95%,
`
`minus the amount of the other enantiomer, 5%).
`
`"Enantiomerically pure” means products whose enantiomeric excess 1s 99% ee or
`
`greater.
`
`"Halo" means the halogen radical fluoro, chloro, bromo, or iodo.
`
`"Haloalkyl" means an alkyl group that is substituted with one or more halo substituents.
`
`Haloalkyl includes trifluoromethyl.
`
`Some compounds of formula (1) have a nitrogen which is basic enough to form
`
`pharmaceutically-acceptable acid addition salts by treatment with a suitable acid.
`
`10
`
`Suitable acids include pharmaceutically-acceptable inorganic acids amd
`
`pharmaceutically-acceptable organic acids. Representative pharmaceutically-acceptable
`
`acid addition salts include hydrochloride, hydrobromide, nitrate, methylInitrate, sulfate,
`
`bisulfate, sulfamate, phosphate, acetate, hydroxyacetate, phenylacetate, propionate,
`
`butyrate, isobutyrate, valerate, maleate, hydroxymaleate, acrylate, fumarate, malate,
`
`15
`
`tartrate, citrate, salicylate, p-aminosalicyclate, glycollate, lactate, heptanoate, phthalate,
`
`oxalate, succinate, benzoate, o-acetoxybenzoate, chlorobenzoate, methylbenzoate,
`
`dinitrobenzoate, hydroxybenzoate, methoxybenzoate, mandelate, tannate, formate,
`
`stearate, ascorbate, palmitate, oleate, pyruvate, pamoate, malonate, laurate, glutarate,
`
`glutamate, estolate, methanesulfonate (mesylate), ethanesulfonate (esylate), 2-
`
`20
`
`hydroxy ethanesulfonate, benzenesulfonate (besylate), p-aminobenzenesulfonate, p-
`
`toluenesulfonate (tosylate), and napthalene-2-sulfonate.
`
`Otheriterations of compounds of the invention have an acidic functional group,
`
`one acidic enough to form salts. Representative salts include pharmaceutically-
`
`acceptable metal salts such as sodium, potassium, lithium, calcium, magnesium,
`
`25
`
`aluminum, and zinc salts; carbonates and bicarbonates of a pharmaccutically-acceptable
`
`metal cation such as sodium, potassium, lithium, calcium, magnesium, aluminum, and
`
`zinc; pharmaceutically-acceptable organic primary, secondary, and tertiary amines
`
`including aliphatic amines, aromatic amines, aliphatic diamines, and hydroxy alkylamines
`
`such as methylamine, ethylamine, 2-hydroxyethylamine, diethylamine, triethylamine,
`
`30
`
`ethylenediamine, ethanolamine, diethanolamine, and cyclohexylamine.
`
`The compounds according to formula I may contain one or more asymmetric
`
`center, also referred to as a chiral center, and may, therefore, exist as individual
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`WO 2009/129370
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`PCT/US2009/040771
`
`enantiomers, diastereomers, or other stereoisomeric forms, or as mixtures thereof. Chiral
`
`centers may also be present in a substituent such as an alkyl group. Where the
`
`stereochemistry of a chiral center present in formula I, or in any chemical structure
`
`illustrated herein, is not specified the structure is intended to encompass any stereoisomer
`
`and all mixtures thereof. Thus, compounds according to formula I containing one or
`
`more chiral center may be used as racemic mixtures, enantiomerically enriched mixtures,
`
`or as enantiomerically pure individual stereoisomers.
`
`Individual stereoisomers of a compound according to formula I which contain one
`
`or more asymmetric center may be resolved by methods knownto those skilled in the art.
`
`10
`
`For example, such resolution may be carried out (1) by formation of diastereoisomeric
`
`salts, complexes or other derivatives; (2) by selective reaction with a stereoisomer-
`
`specific reagent, for example by enzymatic oxidation or reduction; or (3) by gas-liquid or
`
`liquid chromatography in a chiral enviornment, for example, on a chiral support such as
`
`silica with a bound chiral ligand or in the presence of a chiral solvent. The skilled artisan
`
`15
`
`will appreciate that where the desired stereoisomer is converted into another chemical
`
`entity by one of the separation procedures described above, a further step is required to
`
`liberate the desired form. Alternatively, specific stereoisomers may be synthesized by
`
`asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or
`
`by converting one enantiomerto the other by asymmetric transformation.
`
`20
`
`The compounds of the invention may exist in solid or liquid form.
`
`In the solid
`
`state, the compounds of the invention may exist in crystalline or noncrystalline form, or
`
`as amixture thereof. For compoundsof the invention that are in crystalline form, the
`
`skilled artisan will appreciate that pharmaceutically-acceptable solvates may be formed
`
`wherein solvent molecules are incorporated into the crystalline lattice during
`
`25
`
`crystallization. Solvates may involve nonaqueous solvents such as ethanol, isopropanol,
`
`DMSO, acetic acid, ethanolamine, and ethyl acetate, or they may involve wateras the
`
`solvent that is incorporated into the crystalline lattice. Solvates wherein water is the
`
`solvent that is incorporated into the crystalline lattice are typically referred to as
`
`"hydrates." Hydrates include stoichiometric hydrates as well as compositions containing
`
`30
`
`vaiable amounts of water. The invention includes all such solvates.
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`The skilled artisan will further appreciate that certain compoundsof the invention
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`that exist in crystalline form, including the various solvates thereof, may exhibit
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`polymorphism, i.e. the capacity to occur in different crystalline structures. These
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`different crystalline forms are typically known as polymorphs. The invention includesall
`
`such polymorphs. Polymorphs typically exhibit different melting points, IR spectra, and
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`X-ray powder diffraction patterns, which may be used for identification. The skilled
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`artisan will appreciate that different polymorphs may be produced, for example, by
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`changing or adjusting the reaction conditions or reagents, used in making the compound.
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`For example, changes in temperature, pressure, or solvent may result in polymophs.
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`In
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`addition, one polymorph may spontaneously convert to another polymorph undercertain
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`conditions.
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`The compoundsof the invention inhibit the cathepsin C enzyme and can be useful
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`in the treatment of conditions wherein the underlying pathology is (at least in part)
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`attributable to cathepsin C involvementor in conditions wherein cathepsin C inhibition
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`offers some clinical benefit even though the underlying pathology is not (even in part)
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`attributable to cathepsin C involvement. Examples of such conditions include COPD,
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`rheumatoid arthritis, osteoarthritis, asthma, and multiple sclerosis. Accordingly, in
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`another aspect the invention is directed to methodsof treating such conditions.
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`The methods of treatment of the invention comprise administcring a safe and
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`effective amount of a compoundof the invention to a patient in need thereof.
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`As used herein, "treatment" in reference to a condition means: (1) the amelioration
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`or prevention of the condition being treated or one or more ofthe biological
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`manifestations of the condition being treated, (2) the interference with (a) one or more
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`points in the biological cascade that leads to or is responsible for the condition being
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`treated or (b) one or more of the biological manifestations of the condition being treated,
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`or (3) the alleviation of one or more of the symptomsor effects associated with the
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`condition being treated.
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`As indicated above, "treatment" of a condition includes prevention of the
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`condition. The skilled artisan will appreciate that "prevention" is not an absolute term.
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`In
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`medicine, "prevention" is understood to refer to the prophylactic administration of a drug
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`to substantially diminish the likelihood or severity of a condition or biological
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`manifestation thereof, or to delay the onset of such condition or biological manifestation
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`thereof.
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`As usedherein, "safe and effective amount" and "therapeutically effective
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`amount” in reference to a compound of formula I, or a pharmaceutically acceptable salt of
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`il, means an amountof sufficient to significantly induce a positive modification in the
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`condition to be treated but low enoughto avoid serious side effects at a reasonable
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`benefit/risk ratio within the scope of sound medical judgment. A safe and effective
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`amount of a compound of the invention will vary with the particular compound chosen,
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`e.g. consider the potency, efficacy, and half-life of the compound; the route of
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`administration chosen; the condition being treated; the severity of the condition being
`
`treated; the age, size, weight, and physical condition of the patient being treated; the
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`medical history of the patient to be treated; the duration of the treatment; the nature of
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`concurrent therapy; the desired therapeutic effect; and like factors, but can nevertheless
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`be routinely determined by the skilled artisan.
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`As used herein, "patient" refers to a human or animal.
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`The compounds of the invention may be administered by any suitable route of
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`15
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`administration, including both systemic administration and topical administration.
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`Systemic administration includes oral administration, parenteral administration,
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`transdermal administration, rectal administration, and administration by inhalation.
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`Parenteral administration refers to routes of administration other than enteral,
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`transdermal, or by inhalation, and is typically by injection or infusion. Parenteral
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`administration includes intravenous, intramuscular, and subcutaneous injection or
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`infusion. Inhalation refers to administration into the patient's lungs whether inhaled
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`through the mouth or through the nasal passages. Topical administration includes
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`application to the skin as well as intraocular, otic, intravaginal, and intranasal
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`administration.
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`25
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`The compounds of the invention may be administered once or according to a
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`dosing regimen wherein a number of doses are administered at varying intervals of time
`
`for a given period of time. For example, doses may be administered one, two, three, or
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`four times per day. Doses may be administered until the desired therapeutic effect is
`
`achieved or indefinitely to maintain the desired therapeutic effect. Suitable dosing
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`30
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`regimens for a compound of the invention depend on the pharmacokinetic properties of
`
`that compound, such as absorption, distribution, and half-life, which can be determined
`
`by the skilled artisan.
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`In addition, suitable dosing regimens, including the amount
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`administered and the duration such regimens are administered, for a compound of the
`
`invention depend on the condition being treated, the severity of the condition being
`
`treated, the age and physical condition of the patient being treated, the medical history of
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`the patient to be treated, the nature of concurrent therapy, the particular route of
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`administration chosen, the desired therapeutic effect, and like factors within the
`
`knowledge and expertise of the skilled artisan.
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`It will be further understood by such
`
`skilled artisans that suitable dosing regimens may require adjustment given an individual
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`paticnt's responsc to the dosing regimen or over time as individual paticnt necds change.
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`Typical daily dosages range from 10 mg to 1000 mg.
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`Compositions
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`The compounds of the invention will normally, but not necessarily, be formulated
`
`into a pharmaceutical composition prior to administration to a patient. Accordingly, in
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`another aspect the invention is directed to pharmaceutical compositions comprising a
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`15
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`compound of the invention and a pharmaceutically-acceptable excipient.
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`The pharmaceutical compositions of the invention may be prepared and packaged
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`in bulk form whercin a safe and cffcctive amount of a compound of the invention can be
`
`extracted and then given to the patient such as with powders, syrups, and solutions for
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`injection. Alternatively, the pharmaceutical compositions of the invention may be
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`20
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`prepared and packaged in unit dosage form wherein each physically discrete unit contains
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`a safe and effective amount of a compound of the invention. When prepared in unit
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`dosage form, the pharmaceutical compositions of the invention typically contain from 1
`
`mg to 1000 mg.
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`The pharmaceutical compositions of the invention typically contain one
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`25
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`compound of the invention. However, in certain embodiments, the pharmaceutical
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`compositions of the invention contain more than one compound ofthe invention. For
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`example, in certain embodiments the pharmaceutical compositions of the invention
`
`contain two compoundsof the invention. In addition, the pharmaceutical compositions of
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`the invention may optionally further comprise one or more additional pharmaceutically
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`active compounds. Conversely, the pharmaceutical compositions of the invention
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`typically contain more than one pharmaceutically-acceptable excipient. However, in
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`certain embodiments, the pharmaceutical compositions of the invention contain one
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`pharmaceutically-acceptable excipient.
`
`As used herein, "pharmaceutically-acceptable excipient" means a material,
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`composition or vehicle involved in giving form or consistency to the composition and
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`which is safe when administered to a patient. Each excipient must be compatible with the
`
`other ingredients of the pharmaceutical composition when commingled such that
`
`interactions which would substantially reduce the efficacy of the compoundof the
`
`invention when administcred to a paticnt and intcractions which would result in
`
`pharmaceutical compositions that are not pharmaceutically acceptable are avoided.
`
`In
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`10
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`addition, each excipient must of course be of sufficiently high purity to render it
`
`pharmaceutically-acceptable.
`
`The compounds of the invention and the pharmaceutically-acceptable excepient or
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`excepients will typically be formulated into a dosage form adapted for administration to
`
`the patient by the desired route of administration. For example, dosage forms include
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`15
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`those adapted for (1) oral administration such as tablets, capsules, caplets, pills, troches,
`
`powders, syrups, elixers, suspensions, solutions, emulsions, sachets, and cachets; (2)
`
`parenteral administration such as sterile solutions, suspensions, and powders for
`
`reconstitution; (3) transdermal administration such as transdermal patches; (4) rectal
`
`administration such as suppositories; (5) inhalation such as aerosols and solutions; and (6)
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`20
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`topical administration such as creams, ointments, lotions, solutions, pastes, sprays, foams,
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`and gels.
`
`Suitable pharmaceutically-acceptable excipients will vary depending upon the
`
`particular dosage form chosen.
`
`In addition, suitable pharmaceutically-acceptable
`
`excipients may be chosen for a particular function that they may serve in the composition.
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`25
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`For example, certain pharmaceutically-acceptable excipients may be chosen for their
`
`ability to facilitate the production of uniform dosage forms. Ccrtain pharmaccutically-
`
`acceptable excipients may be chosenfor their ability to facilitate the production of stable
`
`dosage forms. Certain pharmaceutically-acceptable excipients may be chosen for their
`
`ability to facilitate the carrying or transporting the compound or compoundsof the
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`30
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`invention once administered to the patient from one organ, or portion of the body, to
`
`another organ, or portion of the body. Certain pharmaceutically-acceptable excipients
`
`may be chosen for their ability to enhance patient compliance.
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`Suitable pharmaceutically-acceptable excipients include the following types of
`
`excipients: Diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents,
`
`coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers,
`
`sweetners, flavoring agents, flavor masking agents, coloring agents, anticaking agents,
`
`hemectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants,
`
`preservatives, stabilizers, surfactants, and buffering agents. The skilled artisa