(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY(PCT)
`
`(19) World Intellectual Property Organization
`International Bureau
`
`(43) International Publication Date
`26 February 2009 (26.02.2009)
`
` (10) International Publication Number
`
`WO 2009/026197 Al
`
`(51) International Patent Classification:
`A61K 31/519 (2006.01)
`CO7D 471/04 (2006.01)
`
`(21) International Application Number:
`PC'1L/US2008/073425
`
`(22) International Filing Date: 18 August 2008 (18.08.2008)
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`English
`
`English
`
`(30) Priority Data:
`60/956,744
`
`20 August 2007 (20.08.2007)
`
`US
`
`(71) Applicant (for all designated States except US): GLAXO
`GROUP LIMITED [GB/GB]; Glaxo Wellcome House,
`Berkeley Avenue, Greenford, Middlesex UB6 ONN (GB).
`
`(72)
`(75)
`
`Inventors; and
`Inventors/Applicants (for US only): DENG, Jianghe
`[CN/US]; 1250 South Collegeville Road, Collegeville,
`PA 19426 (US). LAINE, Dramane, Ibrahim [FR/US];
`709 Swedeland Road, King of Prussia, PA 19406 (US).
`PALOVICH, Michael, R.
`[US/US]; 709 Swedeland
`Road, King of Prussia, PA 19406 (US). XIE, Haibo; 1250
`South Collegeville Road, Collegeville, PA 19426 (US).
`
`(81) Designated States (unless otherwise indicated, for every
`kind of 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, ZM,
`ZW.
`
`(34) Designated States (unless otherwise indicated, for every
`kind of regional protection available): ARIPO (BW, GH,
`GM, KE, LS, MW, MZ, NA, SD, SL, SZ, ‘TZ, UG, ZM,
`ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM),
`European (AT, BE, BG, CH, CY, CZ, DE, DK, LE, LS, II,
`ER, GB, GR, HR, HU, IK,IS, I'l, LE, LU, LV, MC, M'T, NL,
`NO,PL, PT, RO, SE, SI, SK, TR), OAPI (BF, BJ, CE, CG,
`CI, CM, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG).
`
`Declarations under Rule 4.17:
`
`as to applicant’s entitlement to apply for and be granted a
`patent (Rule 4.17(ii))
`as to the applicant’s entitlement to claim the priority of the
`earlier application (Rule 4.17/(iii))
`of inventorship (Rule 4.17(iv))
`
`Published:
`
`(74) Agents: KANAGY, James, M.et al.; Glaxosmithkline,
`Corporate Intellectual Property, UW 2220, 709 Swedeland
`Road, P.O. Box 1539, King of Prussia, PA 19406-0939
`(US).
`
`with international search report
`before the expiration of the time limit for amending the
`claims and to be republished in the event of receipt of
`amendments
`
`(54) Title: NOVEL CATHEPSIN C INHIBITORS AND THEIR USE
`
`‘The invention is directed to compounds
`(57) Abstract:
`according to Formula (D wherein R1, R2a, R2b, R2c, R3, and
`n are defined below, and to pharmaceutically-acceptable salts
`thereof.
`‘They are cathepsin C inhibitors and can be used in
`the treatment of diseases mediated by the cathepsin C enzyme,
`such as COPD.
`
`(R1)n
`
`N
`
`R2a
`
`R26, N
`R2c
`
`9
`i
`i
`R3
`O
`
`Formula |
`
`
`
`
`
`WO2009/026197AdTINVTMNTINEINANTINNITUMUTINYAUAA
`
`

`

`WO 2009/026197
`
`PCT/US2008/073425
`
`NOVEL CATHEPSIN C INHIBITORS AND THEIR USE
`
`FIELD OF THE INVENTION
`
`The invention is directed to novel cathepsin C inhibitors and their use in the
`
`treatment of diseases mediated by the cathepsin C enzyme.
`
`BACKGROUND OF THE INVENTION
`
`Cathepsins are a family of enzymesincluded in the papain superfamily of cysteine
`
`proteases. Cathepsins B, C, F, H, K, L, O, S, V, W, and X have been described in the
`
`10
`
`scientific literature. Cathepsin C is also Knownin the literature as Dipeptidyl Peptidase | or
`
`"DPPI."
`
`A numberof published studies have begun to describe the role cathepsin C plays
`
`in certain inflammatory processes. See E.g. Methot et al., The Journal of Biological
`
`Chemistry, 282 (29): 20836-46 (2007); Pagano et al., Proc Nat! Acad Sci USA 104 (8):
`
`15
`
`2855-60 (2007); Xuchu Que et al., The Journal of Bioogical. Chemistry, 282 (7): 4994-
`
`5003 (2007); Adkison et al., The Journal of Clinical Investigation 109: 363-371 (2002);
`
`Tran et al., Archives of Biochemistry and Biophysics 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); Mabeeet al., The Journal of Immunology 160: 5880-
`
`20
`
`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 proteases, which are released from inflammatory cells
`
`recruited to sites of inflammation, and acts as a physiological activator of these proteases.
`
`Once activated, these proteases are capable of degrading various extracellular matrix
`
`25
`
`components, which can lead to tissue damage and chronic inflammation.
`
`For example, Chronic Obstructive Pulmonary Disease ("COPD")
`
`is a chronic
`
`inflammatory disease where cathepsin C is believed to play a role. 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
`
`30
`
`progressive, may be accompanied by airway hyperreactivity, and may be partially
`
`reversible." American Journal of Respiratory and Critical Care Medicine 152: $77-S120
`
`(1995). Chronic bronchitis is generally characterized by a chronic productive cough,
`
`whereas emphysema is generally characterized by permanent enlargement of
`
`the
`
`airspaces distal
`
`to the terminal bronchioles and airway wall destruction.
`
`Chronic
`
`35
`
`bronchitis and emphysema usually occur together in COPD patients.
`
`

`

`WO 2009/026197
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`PCT/US2008/073425
`
`Cigarette smoking is a significant risk factor for developing COPD. Exposure to
`
`cigarette smoke and/or other noxious particles and gases may result
`
`in chronic
`
`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. Proteases believed to be involved in this
`
`process include the serine proteases neutrophil elastase ("NE"), chymase ("CY"),
`
`cathepsin G, proteinase 3 and granzymes A and B. Cathepsin C appears to be involved
`
`in activating these enzymes.
`
`10
`
`15
`
`Rheumatoid arthritis
`
`("RA")
`
`is another chronic inflammatory disease where
`
`cathepsin C is believed to play a role. Arthritis and Rheumatism. 52: 2553-8 (2005).
`
`Neutrophils are recruited to the site of joint inflammation and release cathepsin G, NE,
`
`and proteinase 3, which are believd to be responsible for cartilage destruction associated
`
`with RA. Cathepsin C appears also to be involved in activating these enzymes.
`
`Other conditions where cathepsin C is believed to play a role include abdominal or
`
`thoracic aortic aneurism,
`
`adult
`
`respiratory distress
`
`syndrome,
`
`acute lung injury,
`
`osteoarthritis, asthma, multiple sclerosis, sepsis, and toxoplasmosis. See E.g. Moraes,
`
`T.J., Chow, C-W., Downey, G.P. Proteases and lung injury Critical Care Medicine 31
`
`(suppl.): S189-S194 (2003); Okayama N., Kakihana Y., Setoguchi D., Matsui K. Yuyama
`
`20
`
`N. Akaiwa M. Yoshida NL. Maeda M. Sugita Y. Izuhara K., Identification of an alternative
`
`splicing variant of cathepsin C/dipeptidyl-peptidase I, Gene 293 (1-2): 1-7 (2002); Wolters
`
`PJ. Laig-Webster M. Caughey GH., Dipeptidyl peptidase | 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); Mallen-St Clair J. Pham
`
`25
`
`CT. Villalta SA. Caughey GH. Wolters PJ., Mast cell dipeptidyl peptidase | mediates
`
`survival from sepsis, Journal of Clinical Investigation 113: 628-34 (2004); Xuchu Que,
`
`Juan C. Engel, David Ferguson, Annette Wunderlich, Stanislas Tomavo, and Sharon L.
`
`Reed, Cathepsin Cs Are Key for the Intracellular Survival of the Protazoan Parasite,
`
`Toxoplasma gondii, The Journal of Biological Chemistry, 282 (7): 4994-5003 (2007).
`
`30
`
`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.q.,
`
`Ohbayashi, "Neutrophil elastase inhibitors as treatment for COPD", Expert Opin. Investig.
`
`Drugs 11 (7): 965-980 (2002); Shapiro, "Neutrophil Elastase: Path Clearer, Pathogen
`
`Killer, or Just Pathologic?", Am. J. Respir. Cell Mol. Biol. 26: 266-268 (2002); Imabayashi
`
`35
`
`T., Omae T., Matsunaga A., Kanmura Y., Clinical effects of a neutrophil elastase inhibitor,
`
`sivelestat,
`
`in patients with acute respiratory distress syndrome Journal of Anesthesia 20:
`
`2
`
`

`

`WO 2009/026197
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`PCT/US2008/073425
`
`6-70 (2006).
`
`In light of the role cathepsin C plays in activating certain serine proteases,
`
`especially NE,
`
`it is desirable to prepare compounds that inhibit its activity, which thereby
`
`inhibit serine protease activity. Thus, there is a need to identify compounds that inhibit
`
`cathepsin C, which can be usedin the treatment of a variety of conditions mediated by the
`
`cathepsin C enzyme.
`
`SUMMARYOF THE INVENTION
`
`This invention related to compounds of Formula I:
`
`N
`
`R2a
`
`(R1)n
`R2c 7] 0
`nat>/
`
`R2b
`
`N
`
`R3
`
`Ul
`O
`
`10
`
`wherein:
`
`Formula |
`
`each R1 is independently selected from the group consisting of: halo, C1-C4 alkyl,
`
`CF3, CN, NOs,
`
`-ORa,
`
`-OCF3,
`
`-C(O)NHRa,
`
`-C(OQ)ORa,
`
`-NRaRa,
`
`-NHC(O)Ra, or
`
`-
`
`NHC(O)NHRa;
`
`15
`
`n is an integer from O to 4;
`
`R2a is H, halo, -C(O)Rx, -C(OQ)ORy, -C(Q)NRaRy, -OC(O)Rx, -OC(O)NRaRy, -
`
`NRaRy, -NRaC(O)Rx, NRaC(O)R22, -NRaC(O)ORy, -NRaC(O)NRaRy, R20, R21, R22,
`
`R23, R24, -OH, -OR20, -OR21, -OR22, -OR23, or -OR24; -CN
`
`R2b is H or C1-C4 alkyl;
`
`20
`
`or R2a and R2b taken together with the carbon atom to which they are attached
`
`form a C3-C7 cycloalkyl group;
`
`R2c is H or C1-C4 alkyl;
`
`R20 is C1-C4 alkyl;
`
`wherein said R20 is optionally substituted with one or more substituents
`
`25
`
`independently selected from the group consisting of: halo, CFs, CN, NOs, R21, R22, R23,
`
`R24,
`
`-ORy,
`
`-C(O)Rx,
`
`-C(O)ORy,
`
`-C(O)NRaRy,
`
`-OC(O)Rx,
`
`-OC(O)NRaRy,
`
`-NRaRy,
`
`-
`
`NRaC(O)Rx, -NRaC(O)ORy, -NRaC(OC)NRaRy;
`
`R21 is C3-C6 cycloalkyl;
`
`wherein said R21
`
`is optionally substituted with one or more substituents
`
`30
`
`independently selected from the group consisting of: CF3, Rc, -ORa, -OCF3, and -NRaRa;
`
`

`

`WO 2009/026197
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`PCT/US2008/073425
`
`R22 is heterocycloalkyl;
`
`wherein said R22 is optionally substituted with one or more substituents
`
`independently selected from the group consisting of: CF3, Rc, -ORa, -OCF3, and -NRaRa;
`
`R23 is phenyl;
`
`wherein said R23 is optionally substituted with one or more substituents
`
`independently selected from the group consisting of: halo, CFs, CN, NOs, Re, -ORa, -
`
`OCF3,
`
`-C(O)Rb,
`
`-C(O)ORa,
`
`-C(O)NRaRa,
`
`-OC(O)Rb,
`
`-OC(O)NRaRa,
`
`-NRaRa,
`
`-
`
`NRaC(O)Rb, -NRaC(O)ORa, -NRaC(O)NRaRa;
`
`R24 is monocyclic heteroaryl;
`
`10
`
`wherein said R24 is optionally substituted with one or more substituents
`
`independently selected from the group consisting of: halo, CFs, CN, NOs, Rec, -ORa, -
`
`OCF3,
`
`-C(O)Rb,
`
`-C(O)ORa,
`
`-C(O)NRaRa,
`
`-OC(O)Rb,
`
`-OC(O)NRaRa,
`
`-NRaRa,
`
`-
`
`NRaC(O)Rb, -NRaC(O)ORa, -NRaC(O)NRaRa;
`
`R3 is H, R30, or R31;
`
`15
`
`R30 is C1-C4 alkyl, C2-C4 alkenyl, or C2-C4 alkynyl;
`
`wherein said R30 is optionally substituted with one or more substituents
`
`independently selected from the group consisting of: CF3, Re, Rf, Rg, CN, -ORa, -OCFs, -
`
`ORf, -ORg, -OR31, and -NRaRa;
`
`R31 is C3-C6 cycloalkyl;
`
`20
`
`wherein said R31
`
`is optionally substituted with one or more substituents
`
`independently selected from the group consisting of: Rb, -ORa, -OCF3, and -NRaRa;
`
`each Rais independently H or C1-C4 alkyl;
`
`each Rbis independently C1-C4 alkyl;
`
`each Rcis independently C1-C4 alkyl; wherein said C1-C4 alkyl is optionally
`
`25
`
`substituted with one or more substituents independently selected from the group
`
`consisting of: CF3, -ORa, OCF3, and -NRaRa;
`
`each Rdis independently C1-C4 alkyl; wherein said C1-C4 alkyl is optionally
`
`substituted with one or more substituents independently selected from the group
`
`consisting of: CF3, -ORa, OCF3, -NRaRa, Re, and Rf;
`
`30
`
`each Reis independently phenyl or heteroaryl optionally substituted with one or
`
`more substituents independently selected from the group consisting of: halo, NOs, CFs,
`
`Rb, R23, R24, -ORa, OCF3, and -NRaRa;
`
`each Rf is independently monocyclic heteroaryl optionally substituted with one or
`
`more substituents independently selected from the group consisting of: halo, CFs, Rb,
`
`35
`
`R23, R24, -ORa, OCF3, and —-NRaRa;
`
`

`

`WO 2009/026197
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`PCT/US2008/073425
`
`each Rgis independently napthyl optionally substituted with one or more
`
`substituents independently selected from the group consisting of: halo, CF3, Rb, -ORa,
`
`OCF3, and -NRaRa;
`
`each Rhis independently C3-C6 cycloalkyl optionally substituted with one or more
`
`substituents independently selected from the group consisting of: Rb, -ORa, -OCFs, and —
`
`NRaRa;
`
`each Rx is Rd, Re, Rf, Rg, or Rh; and
`
`each Ryis H, Rd, Re, Rf, Rg, or Rh; or
`
`a Salt thereof.
`
`10
`
`The compounds of the invention are cathepsin C inhibitors and can be used in the
`
`treatment of diseases mediated by the cathepsin C enzyme, such as COPD. Accordingly,
`
`the invention is further directed to pharmaceutical compositions comprising a compound of
`
`the invention, or pharmaceutically acceptable salt of it. The invention is still further
`
`directed to methods of inhibiting cathepsin C and treatment of conditions associated
`
`15
`
`therewith using a compound of the invention or a pharmaceutical composition comprising
`
`a compound ofthe invention, or a pharmaceutically acceptable salt it.
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`In describing the invention, chemical elements are identified in accordance with the
`
`20
`
`Periodic Table of
`
`the Elements. Abbreviations and symbols utilized herein are in
`
`accordance with the common usage of such abbreviations and symbols by thoseskilled in
`
`the chemical and biological arts.
`
`For example,
`
`the following abbreviations are used
`
`herein:
`
`“aq” is an abbreviation for aqueous
`
`25
`
`“AcCN’ is an abbreviation for acetonitrile
`
`“BOC”or “boc” is an abbreviation for tert-butyloxycarbonyl
`
`“°C” is an abbreviation for degrees Celsius
`
`“Cbz” is an abbreviation for carbobenzyloxy
`
`“CDI” is an abbreviation for carbodiimidazole
`
`30
`
`“DCM/CH2ClL“ is an abbreviation for dichloromethane
`
`“DEAD?” is an abbreviation for diethylazodicarboxylate
`
`“DMAP?” is an abbreviation for dimethylaminopyridine
`
`“DIPEA” or “DIEA”is an abbreviation for di-isopropylethylamine
`
`“DMF”is an abbreviation for dimethylformamide
`
`35
`
`“DPPA’”’is an abbreviation for diphenylphosporyl azide
`
`“EA” or “EtAc’is an abbreviation for ethyl acetate
`
`5
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`WO 2009/026197
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`PCT/US2008/073425
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`“ESI” is an abbreviation for electrospray ionization
`
`“eq” is an abbreviation for equivalent
`
`“HPLC”is an abbreviation for High Pressure Liquid Chromatography
`
`“g’ is an abbreviation for grams
`
`“h” or “hr” is an abbreviation for hour
`
`“L” is an abbreviation for liters
`
`“LC-MS”or “LC/MS”is an abbreviation for Liquid chromatography-Mass
`
`spectrometry
`
`“Me”is an abbreviation for methyl
`
`10
`
`“Ms”is an abbreviation for methanesulfonyl
`
`“mL”is an abbreviation for milliliters
`
`“min” is an abbreviation for minute or minutes
`
`“mmol” is an abbreviation for millimole or millimolar
`
`“N” is an abbreviation for Normal and refers to the number of equivalents of
`
`15
`
`reagent perliter of solution
`
`“PE”is an abbreviation for petroleum ether
`
`“Ph” is an abbreviation for phenyl
`
`“PS” is an abbreviation for polymer-supported
`
`“sat” is an abbreviation for saturated
`
`20
`
`“Si” is an abbreviation for silica
`
`“SPE”is an abbreviation for solid phase extraction
`
`“TBAF”is an abbreviation for tetra-butylammonium fluroride
`
`“TBS”is an abbreviation for t-butyldimethylsilyl
`
`“TBS-Cl” is an abbreviation for t-butyldimethyl silyl chloride
`
`25
`
`“TBTU”is an abbreviation for O-(benzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium
`
`tetrafluoroborate
`
`“TEA”is an abbreviation for triethylamine
`
`“TEMPO?”is an abbreviation for 2,2,6,6,-tetramethylpiperidine 1-oxyl
`
`“TFA” is an abbreviation for trifluoroacetic acid
`
`30
`
`“THF”is an abbreviation for tetrahydrofuran
`
`“UV”is an abbreviation for ultraviolet.
`
`“Alkyl” refers to a saturated hydrocarbon chain having the specified number of
`
`carbons. For example, C1-C8 alkyl refers to an alkyl group having from 1
`
`to 8 carbons.
`
`Alkyl groups may be optionally substituted with one or more substituents as defined
`
`35
`
`herein. Alkyl groups may be straight or branched. Representative branched alkyl groups
`
`have one,
`
`two, or three branches. Alkyl
`
`includes methyl, ethyl, propyl (n-propyl and
`
`6
`
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`WO 2009/026197
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`PCT/US2008/073425
`
`isopropyl), butyl (n-butyl, isobutyl, and t-butyl), pentyl (n-pentyl, isopentyl, and neopentyl),
`
`and hexyl.
`
`“Alkenyl” refers to an unsaturated hydrocarbon chain having the specified number
`
`of carbons and having one at least one carbon-carbon double bond. For example, C2-C6
`
`alkenyl refers to an alkenyl group having from 2 to 6 carbons. Alkenyl groups may be
`
`optionally substituted with one or more substituent as defined herein. Alkenyl groups may
`
`be straight or branched. They, may have a cis or trans configuration. Representative
`
`branched alkenyl groups have one, two, or three branches. Alkenyl includes ethylenyl,
`
`propenyl, butenyl, pentenyl, and hexenyl.
`
`10
`
`“Alkynyl” refers to an unsaturated hydrocarbon chain having the specified number
`
`carbons and having one at least one carbon-carbon triple bond. For example, C2-C6
`
`alkynyl refers to a group having from 2 to 6 carbons. Alkynyl groups may be optionally
`
`substituted with one or more substituent as defined herein. Alkynyl groups maybestraight
`
`or branched. Alkynyl includes ethylynyl, propynyl, butynyl, pentynyl, and hexynyl.
`
`15
`
`“Aryl” refers to a monovalent aromatic hydrocarbon ring.
`
`Aryl groups are
`
`monocyclic ring systems or bicyclic ring systems. Monocyclic aryl ring refers to phenyl.
`
`Bicyclic aryl ring refers to napthyl, biphenyl, and to rings wherein phenyl
`
`is fused to a
`
`cycloalkyl or cycloalkenyl ring having 5, 6, or 7 member atoms. Aryl groups may be
`
`optionally substituted with one or more substituents as defined herein.
`
`20
`
`“Cycloalkyl” or “cycloalkenyl” refers to a saturated or unsaturated hydrocarbon
`
`ring having the specified number of carbons. For example, C3-C6 cycloalkyl refers to a
`
`cycloalkyl group having from 3 to 6 carbons. And C4-C6 cycloalkyenyl refers to a ring that
`
`has 4 to 6 carbons and at least 1 double bond. These rings are not aromatic. Either
`
`group may be optionally substituted with one or more substituents as defined herein.
`
`25
`
`Cycloalkyl
`
`includes cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Cycloalkenyl
`
`includes cyclobutenyl and cyclohexenyl, for example.
`
`“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%
`ee.
`
`30
`
`"Enantiomeric excess” or
`
`"ee" is the excess of one enantiomer over the other
`
`expressed as a percentage. As a result, since both enantiomers are present in equal
`
`amounts in a racemic mixture, the enantiomeric excess is zero (0% ee). However,if one
`
`enantiomer was enriched such that
`
`it constitutes 95% of
`
`the product,
`
`then the
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`enantiomeric excess would be 90% ee (the amount of the enriched enantiomer, 95%,
`
`minus the amountof the other enantiomer, 5%).
`
`“Enantiomerically pure” refers to products whose enantiomeric excess is 99% ee
`
`or greater.
`
`“Half-life” ( or “half-lives”) refers to the time required for half of a quantity of a
`
`substance to be converted to another chemically distinct specie in vitro or in vivo.
`
`“Halo” refers to the halogen radical fluoro, chloro, bromo, or iodo.
`
`“Haloalkyl” refers to an alkyl group that
`
`is substituted with one or more halo
`
`substituents. Haloalkyl includestrifrouromethyl.
`
`10
`
`“Heteroaryl” refers to an aromatic ring containing from 1
`
`to 4 heteroatoms in the
`
`ring. Heteroaryl groups containing more than one heteroatom may contain different
`
`heteroatoms. Heteroaryl groups may be optionally substituted with one or more
`
`substituents as defined herein. Unless otherwise specificed, heteroaryl groups are
`
`monocyclic ring systems or are fused, spiro, or bridged bicyclic ring systems. Monocyclic
`
`15
`
`heteroaryl rings have 5 or 6 atoms. Bicyclic heteroaryl rings have from 7 to 11 atoms.
`
`Bicyclic heteroaryl
`
`rings
`
`include those rings wherein phenyl
`
`and a monocyclic
`
`heterocycloalkyl ring are attached forming a fused, spiro, or bridged bicyclic ring system,
`
`and those rings wherein a monocyclic heteroaryl
`
`ring and a monocyclic cycloalkyl,
`
`cycloalkenyl, heterocycloalkyl, or heteroaryl ring are attached forming a fused, spiro, or
`
`20
`
`bridged bicyclic ring system. Heteroaryl includes pyrrolyl, pyrazolyl,
`
`imidazolyl, oxazolyl,
`
`isoxazolyl, oxadiazolyl,
`
`thiazolyl,
`
`isothiazolyl,
`
`thiadiazolyl,
`
`furanyl,
`
`furazanyl,
`
`thienyl,
`
`triazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, tetrazinyl, tetrazolyl,
`
`indolyl,
`
`isoindolyl, indolizinyl, indazolyl, purinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl,
`
`pteridinyl,
`
`cinnolinyl,
`
`benzimidazolyl,
`
`benzopyranyl,
`
`benzoxazolyl,
`
`benzisoxazolyl,
`
`25
`
`benzofuranyl,
`
`isobenzofuranyl,
`
`benzothiazolyl,
`
`benzisothiazolyl,
`
`benzothienyl,
`
`furopyridinyl, and napthyridinyl.
`
`“Heteroatom”refers to a nitrogen, sulphur, or oxygen atom.
`
`“Heterocycloalkyl” or “heterocycloalkenyl” refers to a saturated or unsaturated ring
`
`containing from 1
`
`to 4 heteroatoms atoms in the ring. These rings are not aromatic. A
`
`30
`
`ring containing more than one heteroatom may contain different heteroatoms. A ring may
`
`be optionally substituted with one or more substituent as defined herein, either on a
`
`carbon or on the heteroatom. Unless otherwise specified, these rings are monocyclic or
`
`may be fused, spiro, or a bridged bicyclic ring system. Monocyclic rings have from 5 to 7
`
`member atoms. Bicyclic rings have from 7 to 11 member atoms. Theserings include, for
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`example,
`
`pyrrolidinyl,
`
`tetrahydrofuranyl,
`
`dihydrofuranyl,
`
`pyranyl,
`
`tetrahydropyranyl,
`
`dihydropyranyl,
`
`tetrahydrothienyl, pyrazolidinyl, oxazolidinyl,
`
`thiazolidinyl,
`
`piperidinyl,
`
`homopiperidinyl, piperazinyl, morpholinyl,
`
`thiamorpholinyl, azepinyl, 1,3-dioxolanyl, 1,3-
`
`dioxanyl,
`
`1,4-dioxanyl,
`
`1,3-oxathiolanyl,
`
`1,3-oxathianyl,
`
`1,3-dithianyl,
`
`azetidinyl,
`
`azabicylo[3.2.1Joctyl, azabicylo[3.3.1]Jnonyl, azabicylo[4.3.0]nonyl, oxabicylo[2.2.1]heptyl,
`
`and
`
`"Optionally substituted" indicates that a group, such as alkyl, alkenyl, alkynyl, aryl,
`
`cycloalkyl,
`
`cycloalkenyl, heterocycloalkyl, or heteroaryl, may be unsubstituted or
`
`substituted with one or more substituents as defined herein. "Substituted" in reference to
`
`10
`
`a group indicates that a hydrogen atom attached to a member atom within a group is
`
`replaced.
`
`It should be understood that
`
`the term "substituted" includes the implicit
`
`provision that such substitution be in accordance with the permitted valence of the
`
`substituted atom and the substituent and that the substitution results in a stable compound
`
`(i.e. one that does not spontaneously undergo transformation such as by rearrangement,
`
`15
`
`cyclization, or elimination).
`
`In certain embodiments, a single atom may be substituted with
`
`more than one substituent as long as such substitution is in accordance with the permitted
`
`valence of the atom. Suitable substituents are defined herein for each substituted or
`
`optionally substituted group.
`
`"Pharmaceutically
`
`acceptable"
`
`refers
`
`to
`
`those
`
`compounds, materials,
`
`20
`
`compositions, and dosage forms which are, within the scope of sound medical judgment,
`
`suitable for use in contact with the tissues of human beings and animals without excessive
`
`toxicity,
`
`irritation, or other problem or complication, commensurate with a reasonable
`
`benefit/risk ratio.
`
`25
`
`Compounds
`
`Compounds of particular interest herein include,
`
`in collectively or independently,
`
`the following groups:
`
`Compounds of Formula | where
`
`R1 is independently selected from the group consisting of: halo, C1-C4 alkyl, CFs,
`
`30
`
`CN, NOs, -ORa, and -OCF3;
`
`Ra is H or C1-C4alkyl;
`
`R2a is H, halo, -C(O)Rx, -C(O)ORy, or -C(O)NraRy; or
`
`R2a is -NRaRy, -NRaC(O)Rx, -NRaC(O)ORy, or -NRaC(O)NraRy; or
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`R2a is R20, R21, R22, R23, or R24; or
`
`R2a is -OH, -OR20, -OR21, -OR22, -OR23, or -OR24;
`
`R2b is H;
`
`R2c is H;
`
`R3 is H;
`
`Rx is Rd; and
`
`Ry is phenyl optionally substituted with one or more substituents independently
`
`selected from the group consisting of: CF3, Rb, and -ORa.
`
`The compounds according to Formula | may contain one or more asymmetric
`
`10
`
`centers (also referred to as a chiral center) and may,
`
`therefore, exist as individual
`
`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
`
`15
`
`and all mixtures thereof. Thus, compounds according to Formula | 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 | which contain one
`
`or more asymmetric center may be resolved by methods knownto thoseskilled in the art.
`
`20
`
`For example, such resolution may be carried out (1) by formation of diasterecisomeric
`
`salts, complexes or other derivatives; (2) by selective reaction with a sterecisomer-specific
`
`reagent, for example by enzamatic 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 will
`
`25
`
`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.
`
`30
`
`The compounds according to Formula | may also contain double bonds or other
`
`centers of geometric asymmetry. Where the stereochemistry of a center of geometric
`
`asymmetry present in Formula I, or in any chemical structure illustrated herein,
`
`is not
`
`specified, the structure is intended to encompass the trans (E) geometric isomer, the cis
`
`(Z) geometric isomer, and all mixtures thereof.
`10
`
`If there is a cycloalkyl or cycloalkenyl
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`

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`WO 2009/026197
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`
`group present, some substituent patterns may result
`
`in and axial or an equatorial
`
`configuration. Both forms are included, unless specified otherwise.
`
`All tautomeric forms are also included in Formula | whether such tautomers exist in
`
`equilibrium or predominately in one form.
`
`In certain embodiments, compounds according to Formula | may contain an acidic
`
`functional group and are therefore capable of forming pharmaceutically-acceptable base
`
`addition salts by treatment with a suitable base.
`
`In certain other embodiments,
`
`compounds according to Formula | may contain a basic functional group and are therefore
`
`capable of forming pharmaceutically-acceptable acid addition salts by treatment with a
`
`10
`
`suitable acid. Thus, the skilled artisan will appreciate that pharmaceutically-acceptable
`
`salts of the compounds according to Formula | may be prepared.
`
`Indeed,
`
`in certain
`
`embodiments of the invention, pharmaceutically-acceptable salts of
`
`the compounds
`
`according to Formula | may be preferred over the respective free base or free acid
`
`because such salts impart greater stability or solubility to the molecule thereby facilitating
`
`15
`
`formulation into a dosage form.
`
`Accordingly,
`
`the invention is
`
`further directed to
`
`pharmaceutically-acceptable salts of the compounds according to Formula.
`
`As used herein, the term "pharmaceutically-acceptable salts" refers to salts that
`
`retain the desired biological activity of
`
`the subject compound and exhibit minimal
`
`undesired toxicological effects.
`
`These pharmaceutically-acceptable salts may be
`
`20
`
`prepared in situ during the final
`
`isolation and purification of the compound, or by
`
`separately reacting the purified compound in its free acid or free base form with a suitable
`
`baseor acid, respectively.
`
`As used herein,
`
`the term "compounds of
`
`the invention" means both the
`
`compounds according to Formula | and the pharmaceutically-acceptable salts thereof.
`
`25
`
`The term "a compound of the invention" also appears herein and refers to both a
`
`compound according to Formula | and its pharmaceutically-acceptable salts.
`
`In the solid state, compounds of the invention can exist
`
`in crystalline, semi-
`
`crystalline and amorphous forms, as well as mixtures thereof. The skilled artisan will
`
`appreciate that pharmaceutically-acceptable solvates of a compound of the invention may
`
`30
`
`be formed wherein solvent molecules are incorporated into the solid-state structure during
`
`crystallization. Solvates may involve water or nonaqueous solvents, or mixtures thereof.
`
`In addition, the solvent content of such solvates can vary in response to environment and
`
`upon storage. For example, water may displace another solvent over time depending on
`
`relative humidity and temperature.
`
`35
`
`Solvates wherein water is the solvent
`
`that
`
`is incorporated into the solid-state
`
`structure are typically referred to as "hydrates." Solvates wherein more than one solvent
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`WO 2009/026197
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`
`is incorporated into the solid-state structure are typically referred to as “mixed solvates’.
`
`Solvates include “stoichiometric solvates” as well as compositions containing variable
`
`amounts of solvent (referred to as “non-stoichiometric solvates”). Stoichiometric solvates
`
`wherein water is the solventthat is incorporated into the solid-state structure are typically
`
`referred to as "stoichiometric hydrates", and non-stoichiometric solvates wherein wateris
`
`the solvent that is incorporated into the solid-state structure are typically referred to as
`
`"non-stoichiometric hydrates”.
`
`The invention includes both stoichiometric and non-
`
`stoichiometric solvates.
`
`In addition, crystalline forms of a compound of the invention,
`
`including solvates
`
`10
`
`thereof, may contain solvent molecules, which are not incorporated into the solid-state
`
`structure.
`
`For example, solvent molecules may become trapped in the crystals upon
`
`isolation.
`
`In addition, solvent molecules may be retained on the surface of the crystals.
`
`The invention includes such forms.
`
`The skilled artisan will
`
`further appreciate that compounds of
`
`the invention,
`
`15
`
`including solvates thereof, may exhibit polymorphism (i.e. the capacity to occur in different
`
`crystalline packing arrangements). These different crystalline forms are typically Known
`
`as "polymorphs." The invention includes all such polymorphs. Polymorphs have the
`
`same chemical composition but differ in packing, geometrical arrangement, and other
`
`descriptive properties of the crystalline solid state.
`
`Polymorphs,
`
`therefore, may have
`
`20
`
`different physical properties such as shape, density, hardness, deformability, stability, and
`
`dissolution properties. Polymorphs typically exhibit different IR spectra and X-ray powder
`
`diffraction patterns, which may be usedfor identification. Polymorphs may also exhibit
`
`different melting points, which may be used for identification. The skilled artisan will
`
`appreciate that different polymorphs may be produced, for example, by changing or
`
`25
`
`adjusting the reaction conditions or reagents, used in making the compound.
`
`For
`
`example, changes in temperature, pressure, or solvent may result in the production of
`
`different polymorphs.
`
`In addition, one polymorph may spontaneously convert to another
`
`polymorph under certain conditions.
`
`Methods of Use
`
`30
`
`The compounds of the invention inhibit the cathepsin C enzyme and ca