(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(ARYA TAAA
`
`(10) International Publication Number
`WO 2019/192992 Al
`
`= =
`
`WIPO! PCT
`
`(19) World Intellectual Property
`Organization
`International Bureau
`
`(43) International Publication Date
`10 October 2019 (10.10.2019)
`
`(51) International Patent Classification:
`CO7D 239/22 (2006.01)
`CO7D 413/14 (2006.01)
`CO7D 405/04 (2006.01)
`CO7D 471/04 (2000.01)
`CO7D 401/12 (2006.01)
`CO7D 493/08 (2006.01)
`CO7D 403/12 (2006.01)
`A61IP 33/06 (2006.01)
`CO7D 405/06 (2006.01)
`A61K 31/513 (2006.01)
`CO7D 405/14 (2006.01)
`
`(21)
`
`International Application Number:
`
`PCT/EP2019/058249
`
`(84)
`
`OM,PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW,SA,
`SC, SD, SE, SG, SK, SL, SM,ST, SV, SY, TH, TJ, TM, TN,
`TR, TT. TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW.
`
`Designated States (unless otherwise indicated, for every
`kind of regional protection available); ARIPO (BW, GH,
`GM,KE, LR, LS, MW, MZ, NA, RW,SD, SL, ST, SZ, TZ,
`UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ,
`TM), European (AL, 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, RS, SE, SI, SK, SM,
`TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW,
`KM,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))
`of inventorship (Rule 4.17(iv))
`Published:
`with international search report (Art. 21(3))
`
`G4) Title: ANTIMALARIAL HEXAHYDROPYRIMIDINE ANALOGUES
`
` (57) Abstract: The application relates to a series of 2-imino-6-methylhexahydropyrimidin-4-one
`
`derivatives and 3-imino-5-methy]-l,2,4-thiadiazinane 1,1-dioxide derivatives of formula (D, sub-
`stituted by an arylaminopheny! or heteroarylaminophenyl moiety. The compounds are potent in-
`hibitors of the growth and propagation of the Plasmodium falciparum parasite in human blood and
`thus useful as pharmaceutical agents for the treatment of malaria.
`
`(22)
`
`International Filing Date:
`
`(25)
`
`Filing Language:
`
`Publication Language:
`
`02 April 2019 (02.04.2019)
`
`English
`
`English
`
`Priority Data:
`1805816.4
`
`06 April 2018 (06.04.2018)
`
`GB
`
`Applicant: UCB BIOPHARMA SPRL [BE/BE]; 60, Al-
`lée de la Recherche, 1070 Brussels (BE).
`
`Inventors: DE HARO GARCIA,Teresa; c/o IPD, UCB
`Biopharma SPRL, 60 Allee de la Recherche, 1070 Brus-
`sels (BE). KING, Lloyd Malcolm; c/o IPD, UCB Cell-
`tech, 208 Bath Road, Slough Berkshire SLI 3WE (GB).
`LOWE,Martin Alexander; c/o IPD, UCB Celltech, 208
`Bath Road, Slough Berkshire SLI 3 WE (GB). MACCOSS,
`Maleolm; c/o Bohickct Pharma Consulting LLC, 2556
`Seabrook Island Road, Seabrook Island, South Carolina
`29455 (US). TAYLOR, Richard David; c/o TPD, UCB
`Celltech, 208 Bath Road, Slough Berkshire SL1 3WE (GB).
`ZHU, Zhaoning; c/o IPD, UCB Celltech, 208 Bath Road,
`Slough Berkshire SL1 3WE (GB).
`
`Agent: UCB INTELLECTUAL PROPERTY; c/o UCB
`Celltech, 208 Bath Road, Slough Berkshire SL1 3WE (GB).
`
`Designated States (unless otherwise indicated, for every
`kind of national protection available): AE, AG, AL, AM,
`AO,AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ,
`CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO,
`DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN,
`HR, HU, ID, IL, IN,IR,IS, JO, JP, KE, KG, KH, KN, KP,
`KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME,
`MG, MK, MN, MW, MX, MY, MZ, NA, NG, NL NO, NZ,
`
`(26)
`
`(30)
`
`(71)
`
`(72)
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`(74)
`
`(81)
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`
`
`
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`wo2019/192992Ad.ITNIMITTIITITTYAA
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`

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`WO 2019/192992
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`PCT/EP2019/058249
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`-l-
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`ANTIMALARIAL HEXAHYDROPYRIMIDINE ANALOGUES
`
`The present invention relates to a class of heterocyclic compounds,and to their use
`
`in therapy. More particularly, this invention is concerned with pharmacologically active
`
`substituted hexahydropyrimidinederivatives, and analogues thereof. These compounds
`
`are potent inhibitors of the growth and propagation of the Plasmodiumfalciparumparasite
`
`in human blood, and are accordingly of benefit as pharmaceutical agents, especially in the
`
`treatment of malaria.
`
`Malaria is a mosquito-borne infectious disease, caused by a parasite of the genus
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`10
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`Plasmodium, which has devastating consequences. In 2010, an estimated 225 million
`
`cases were reported, with 610,000 to 971,000 deaths, approximately 80% of which
`
`occurred in sub-Saharan Africa, mostly in young children (aged 5 yearsorless).
`
`The compoundsin accordance with the present invention, being potent inhibitors
`
`of the growth and propagation of the P. falciparumparasite in human blood, are therefore
`
`15
`
`beneficial in the treatment of malaria.
`
`In addition, the compoundsin accordance with the present invention may be
`
`beneficial as pharmacological standards for use in the development of new biologicaltests
`
`and in the search for new pharmacological agents. Thus, the compoundsof this invention
`
`may be useful as radioligands in assays for detecting pharmacologically active
`
`20
`
`compounds.
`
`WO 2017/142825 describes a family of heterocyclic compounds whichare stated
`
`to be potent inhibitors of P. falciparum growth in vitro that may be useful for the treatment
`
`of malaria.
`
`WO 2017/089453 and WO 2017/144517 describe heterocyclic compounds which
`
`25
`
`are stated to be potent and selective inhibitors of plasmepsin V activity that are beneficial
`
`in the treatment of malaria.
`
`WO 2016/172255, WO 2016/118404 and WO 2011/044181 describe certain
`
`classes of heterocyclic compounds whichare stated to be BACEinhibitors that may be
`
`useful for treating AB-related pathologies including Alzheimer’s disease.
`
`30
`
`WO 2008/103351, WO 2006/065277 and WO 2005/058311 describe a family of
`
`heterocyclic compounds that are stated to be aspartyl protease inhibitors. The compounds
`
`described in those publications are also stated to be effective in a methodof inhibiting
`
`inter alia plasmepsins(specifically plasmepsins I and IJ) for treatment of malaria.
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`

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`WO 2019/192992
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`PCT/EP2019/058249
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`-2-
`
`The present invention provides a compoundof formula (J) or a pharmaceutically
`
`acceptable salt thereof:
`
`
`
`wherein
`
`W represents C(O) or S(O)2;
`
`Z represents aryl or heteroaryl, either of which groups may beoptionally
`
`substituted by one or more substituents;
`
`10
`
`R! represents C26 alkyl, optionally substituted by hydroxy; or R! represents C3-7
`
`cycloalkyl, C3-7 cycloalkyl(C1-6)alkyl, aryl(Ci-s)alkyl, C3-7 heterocycloalkyl, C3-7
`
`heterocycloalkyl(Ci-s)alkyl, Cao heterobicycloalkyl, C4 spiroheterocycloalkyl or
`
`heteroaryl(Ci-6)alkyl, any of which groups may be optionally substituted by one or more
`
`substituents; and
`
`15
`
`R’, R? and R* independently represent hydrogen, halogenortrifluoromethyl.
`
`The compoundsin accordance with the present invention are encompassed within
`
`the broadest generic scope of WO 2016/172255, WO 2016/118404, WO 2011/044181,
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`WO 2008/103351, WO 2006/065277 and WO 2005/058311. There is, however, no
`
`specific disclosure in any of those publications of a compoundof formula (I) as defined
`
`20
`
`above, or a pharmaceutically acceptable salt thereof.
`
`The present invention also provides a compound of formula(I) as defined above, or
`
`a pharmaceutically acceptable salt thereof, for use in therapy.
`
`The present invention also provides a compoundof formula (1Das defined above,or
`
`a pharmaceutically acceptable salt thereof, for use in the treatment and/or prevention of
`
`25
`
`malaria.
`
`The present invention also provides a mcthod for the treatment and/or prevention
`
`of malaria which comprises administering to a patient in need of such treatment an
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`WO 2019/192992
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`PCT/EP2019/058249
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`-3-
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`effective amount of a compoundof formula (1) as defined above, or a pharmaceutically
`
`acceptable salt thereof.
`
`The present invention also provides the use of a compoundof formula (1) as
`
`defined above, or a pharmaceutically acceptable salt thereof, for the manufacture of a
`
`medicamentfor the treatment and/or prevention of malaria.
`
`Whereany of the groups in the compounds of formula (1) aboveis stated to be
`
`optionally substituted, this group may be unsubstituted, or substituted by one or more
`
`substituents. Typically, such groups will be unsubstituted, or substituted by one, two or
`
`three substituents, generally by one or two substituents.
`
`10
`
`For use in medicine, the salts of the compounds of formula (1) will be
`
`pharmaccutically acceptable salts. Other salts may, however, be uscful in the preparation
`
`of the compoundsof use in the invention or of their pharmaceutically acceptable salts.
`
`Standard principles underlying the selection and preparation of pharmaceutically
`
`acceptable salts are described, for example, in Handbook ofPharmaceutical Salts:
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`15
`
`Properties, Selection and Use, ed. P.H. Stahl & C.G. Wermuth, Wiley-VCH,2002.
`
`Suitable alkyl groups which may be present on the compoundsof use in the
`
`invention include straight-chained and branched C1alkyl groups, for example C1-4 alkyl
`
`groups. Typical examples include methyl and ethyl groups, and straight-chained or
`
`branched propyl, butyl and pentyl groups. Particular alkyl groups include methyl, ethyl, 7-
`
`20
`
`propyl, isopropyl, #-butyl, sec-butyl, isobutyl, tert-butyl, 2,2-dimcthylpropyl and 3-
`
`methylbutyl. Derived expressions such as “C1-6 alkoxy”, “Cialkylthio”, “Ci-6
`
`alkylsulfonyl” and “C16 alkylamino” are to be construed accordingly.
`
`The term “C37 cycloalkyl” as used herein refers to monovalent groupsof 3 to 7
`
`carbon atoms derived from a saturated monocyclic hydrocarbon, and may comprise benzo-
`
`25
`
`fused analogues thereof. Suitable C3-7 cycloalkyl groups include cyclopropyl, cyclobutyl,
`
`benzocyclobutenyl, cyclopentyl, indanyl, cyclohexyl and cycloheptyl.
`
`The term “aryl” as used herein refers to monovalent carbocyclic aromatic groups
`
`derived from a single aromatic ring or multiple condensed aromatic rings. Suitable aryl
`
`groups include phenyl and naphthyl, preferably phenyl.
`
`Suitable aryl(Ci-6)alkyl groups include benzyl, phenylethyl, phenylpropyl and
`
`naphthylmethy]1.
`
`The term “C37 heterocycloalkyl” as used herein refers to saturated monocyclic
`
`rings containing 3 to 7 carbon atomsandat least one heteroatom selected from oxygen,
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`WO 2019/192992
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`PCT/EP2019/058249
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`-4-
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`sulphur and nitrogen, and may comprise benzo-fused analogues thereof. Suitable
`
`heterocycloalkyl groups include oxetanyl, azetidinyl, tetrahydrofuranyl, dihydrobenzo-
`
`furanyl, dihydrobenzothienyl, pyrrolidinyl, indolinyl, isoindolinyl, oxazolidinyl,
`
`thiazolidinyl, isothiazolidinyl, tmidazolidinyl, tetrahydropyranyl, chromanyl, dioxanyl,
`
`tetrahydrothiopyranyl, piperidinyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydro-
`
`isoquinolinyl, piperazinyl, 1,2,3,4-tetrahydroquinoxalinyl, hexahydro-[1,2,5]thiadiazolo-
`
`[2,3-a]pyrazinyl, homopiperazinyl, morpholinyl, benzoxazinyl, thiomorpholinyl, azepanyl,
`
`oxazepanyl, diazepanyl, thiadiazepanyl and azocanyl.
`
`The term “C49 heterobicycloalkyl” as used herein refers to monovalent groups of 4
`
`10
`
`to 9 carbon atomsderived from a saturated bicyclic hydrocarbon, comprising one or more
`
`hetcroatomsselected from oxygen, sulphur and nitrogen. Typical hctcrobicycloalkyl
`
`groupsinclude 3-azabicyclo[3.1.0]hexanyl, 2-oxa-5-azabicyclo|[2.2.1 |heptanyl, 7-oxa-
`
`bicyclo[2.2.1]hexanyl, 6-azabicyclo[3.2.0|heptanyl, 3-azabicyclo[3.1.1]heptanyl, 6-oxa-3-
`
`azabicyclo[3.1.1]heptanyl, 3-azabicyclo[4.1.0]heptanyl, 2-oxabicyclo[2.2.2]octanyl,
`
`15
`
`quinuclidinyl, 2-oxa-5-azabicyclo[2.2.2]octanyl, 3-azabicyclo[3.2.1]octanyl, 8-oxabicyclo-
`
`[3.2.1 ]octanyl, 8-azabicyclo[3.2.1 ]octanyl, 3-oxa-8-azabicyclo[3.2.1]octanyl, 3,8-diaza-
`
`bicyclo[3.2.1 Joctanyl, 3,6-diazabicyclo[3.2.2]nonanyl, 3-oxa-7-azabicyclo[3.3.1]nonanyl,
`
`3,7-dioxa-9-azabicyclo[3.3.1]nonanyl and 3,9-diazabicyclo[4.2.1]nonanyl.
`
`The term “C49 spiroheterocycloalkyl” as used herein refers to saturated bicyclic
`
`20
`
`ring systems containing 4 to 9 carbon atomsandat Icast one hetcroatom sclected from
`
`oxygen, sulphur and nitrogen, in which the two rings are linked by a common atom.
`
`Suitable spiroheterocycloalkyl groups include 5-azaspiro[2.3]hexanyl, 5-azaspiro[2.4]-
`
`heptanyl, 2-oxaspiro[3.3]heptanyl, 2-azaspiro[3.3 ]heptanyl, 2-oxa-6-azaspiro[3.3]-
`
`heptanyl, 3-oxa-6-azaspiro[3.3 ]heptanyl, 6-thia-2-azaspiro[3.3]heptanyl, 2-oxa-6-azaspiro-
`
`25
`
`[3.4]Joctanyl, 2-oxa-6-azaspiro[3.5 |Jnonanyl, 7-oxa-2-azaspiro[3.5 |nonanyl, 2-oxa-7-aza-
`
`spiro[3.5}]nonanyl and 2,4,8-triazaspiro[4.5 ]decanyl.
`
`The term “heteroaryl” as used herein refers to monovalent aromatic groups
`
`containing at least five atoms derived from a single ring or multiple condensedrings,
`
`wherein one or more carbon atoms have been replaced by one or more heteroatoms
`
`selected from oxygen, sulfur and nitrogen. Suitable heteroaryl groupsincludefury],
`
`benzofuryl, dibenzofuryl, thienyl, benzothienyl, thieno[2,3-c]pyrazolyl, thieno[3,2-c]-
`
`pyridinyl, dibenzothienyl, pyrrolyl, indolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,2-c]-
`
`pyridinyl, pyrrolo[3,4-b]pyridinyl, pyrazolyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[3,4-d]-
`
`

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`WO 2019/192992
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`PCT/EP2019/058249
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`-5-
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`pyrimidinyl, indazolyl, 4,5,6,7-tetrahydroindazolyl, oxazolyl, benzoxazolyl, isoxazolyl,
`
`thiazolyl, benzothiazolyl, isothiazolyl, imidazolyl, benzimidazolyl, imidazo[2, 1-b]-
`
`thiazolyl, imidazo[1,2-a|pyridinyl, imidazo[4,5-b]pyridinyl, purinyl, imidazo[1,2-a]-
`
`pyrimidinyl, imidazo[1,2-a]pyrazinyl, oxadiazolyl, thiadiazolyl, triazolyl, [1,2,4]triazolo-
`
`[1,5-a]pyrimidinyl, benzotriazolyl, tetrazolyl, pyridinyl, quinolinyl, isoquinolinyl,
`
`naphthyridinyl, pyridazinyl, cinnolinyl, phthalazinyl, pyrimidinyl, quinazolinyl, pyrazinyl,
`
`quinoxalinyl, pteridinyl, triazinyl and chromenyl groups. Additional groups include
`
`pyrazolo[3,4-b]pyridinyl, imidazo[1,5-a]pyridinyl and [1,2,4]triazolo[1,5-a]pyridinyl.
`
`The term “halogen” as used herein is intended to includefluorine, chlorine,
`
`10
`
`bromine and iodine atoms, typically fluorine, chlorine or bromine.
`
`The absolute stercochemical configuration of the chiral carbon atom in the W-
`
`containing six-membered ring of the compoundsaccordingto the invention is as depicted
`
`in formula (1) above. Generally, the compounds in accordance with the invention are at
`
`least 51% enantiomerically pure (by whichit is meant that a sample thereof comprises a
`
`15
`
`mixture of enantiomers containing 51% or more of the enantiomerdepicted in formula(1)
`
`and 49% or less of the opposite antipode). Typically, the compoundsin accordance with
`
`the invention are at least 60% enantiomerically pure. Appositely, the compounds in
`
`accordance with the invention are at least 75% enantiomerically pure. Suitably, the
`
`compounds in accordance with the invention are at least 80% enantiomerically pure. More
`
`20
`
`suitably, the compoundsin accordance with the invention are at Icast 85%
`
`enantiomerically pure. Still more suitably, the compounds in accordance with the
`
`invention are at least 90% enantiomerically pure. Even more suitably, the compounds in
`
`accordance with the invention are at least 95% enantiomerically pure. Preferably, the
`
`compoundsin accordance with the invention are at least 99% enantiomerically pure.
`
`25
`
`Ideally, the compoundsin accordance with the inventionare at least 99.9%
`
`enantiomerically pure.
`
`Where the compounds of formula (1) have one or more additional asymmetric
`
`centres, they may accordingly exist as enantiomers. Where the compounds in accordance
`
`with the invention possess one or more additional asymmetric centres, they may also exist
`
`as diastereomers. The invention is to be understood to extend to the use of all such
`
`enantiomers and diastereomers, and to mixtures thereof in any proportion, including
`
`racemates. Formula (1) and the formulae depicted hereinafter are intended to representall
`
`individual stereoisomers andall possible mixtures thereof, unless stated or shown
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`WO 2019/192992
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`PCT/EP2019/058249
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`-6-
`
`otherwise. In addition, compounds of formula (1) may exist as tautomers, for example
`
`keto (CH2C=O)enol (CH=CHOH)tautomers or amide (NHC=O)<hydroxyimine
`
`(N=COB)tautomers or imide (NHC=NH)<aminoimine (N=CNHz2) tautomers. Formula
`
`(I) and the formulae depicted hereinafter are intended to representall individual tautomers
`
`and all possible mixtures thereof, unless stated or shown otherwise. In addition, under
`certain circumstances, e.g. where R? represents halogen, compoundsof formula (I) may
`
`exist as atropisomers. Formula (1) and the formulae depicted hereinafter are intended to
`
`representall individual atropisomcrsandall possible mixtures thercof, unless stated or
`
`shownotherwise.
`
`10
`
`It is to be understood that each individual atom present in formula (1), or in the
`
`formulae depicted hereinafter, may in fact be present in the form of any ofits naturally
`
`occurring isotopes, with the most abundant isotope(s) being preferred. Thus, by way of
`
`example, each individual hydrogen atom present in formula(1), or in the formulae depicted
`hereinafter, may be present as a 'H, 7H (deuterium; D) or 3H (tritium; T) atom, preferably
`'H. Similarly, by way of example, each individual carbon atom present in formula(1), or
`
`15
`
`in the formulae depicted hereinafter, may be present as a !2C, °C or 4C atom, preferably
`
`20.
`
`S(O)z.
`
`In a first embodiment, W represents C(O).
`
`In a second embodiment, W represents
`
`20
`
`In a first embodiment, the present invention provides a compoundof formula (IA)
`
`or a pharmaceutically acceptable salt thereof:
`
`
`
`25
`
`wherein
`
`Z, R', R’, R3 and R4 are as defined above.
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`

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`WO 2019/192992
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`PCT/EP2019/058249
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`-7-
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`In a second embodiment, the present invention provides a compound of formula
`
`(IB) or a pharmaceutically acceptable salt thereof:
`
`
`
`wherein
`
`Z, R', R?, R° and R‘ are as defined above.
`
`In a first embodiment, Z represents aryl, which group maybe optionally
`
`substituted by one or more substituents. In a second embodiment, Z represents
`
`10
`
`heteroaryl, which group may be optionally substituted by one or more substituents.
`
`Typically, Z represents phenyl, naphthyl, furyl, benzofuryl, dibenzofuryl, thienyl,
`
`benzothienyl, thieno[2,3-c]pyrazolyl, thieno[3,2-c]pyridinyl, dibenzothienyl, pyrrolyl,
`
`indolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,2-c]pyridinyl, pyrrolo[3,4-b]pyridinyl,
`
`pyrazolyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[3,4-d]pyrimidinyl, indazolyl, 4,5,6,7-
`
`15
`
`tetrahydroindazolyl, oxazolyl, benzoxazolyl, isoxazolyl, thiazolyl, benzothiazolyl,
`
`isothiazolyl, imidazolyl, benzimidazolyl, imidazo[2,1-b]thiazolyl, imidazo[1,2-a]-
`
`pyridinyl, imidazo[4,5-b]|pyridinyl, purinyl, imidazo[1,2-a]pyrimidinyl, imidazo[1,2-a]-
`
`pyrazinyl, oxadiazolyl, thiadiazolyl, triazolyl, [1,2,4]triazolo[1,5-a]pyrimidinyl,
`
`benzotriazolyl, tetrazolyl, pyridinyl, quinolinyl, isoquinolinyl, naphthyridinyl,
`
`20
`
`pyridazinyl, cinnolinyl, phthalazinyl, pyrimidinyl, quinazolinyl, pyrazinyl, quinoxalinyl,
`
`pteridinyl, triazinyl or chromenyl, any of which groups may be optionally substituted by
`
`one or more substituents. Additionally, Z may represent 2,3-dihydroindolyl, 2,3-dihydro-
`
`benzoxazinyl, pyrazolo[3,4-b]pyridinyl, imidazo[1,5-a]pyridinyl or [1,2,4]triazolo[ 1,5-a]-
`
`pyridinyl, any of which groups may be optionally substituted by one or more substituents.
`
`25
`
`Appositely, Z represents phenyl, naphthyl, 2,3-dihydroindolyl, 2,3-dihydro-
`
`benzoxazinyl, pyrazolyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[3,4-b]pyridinyl, indazolyl,
`
`imidazo[1,2-a]pyridinyl, imidazo[1,5-a]pyridinyl, imidazo[4,5-b]pyridinyl, [1,2,4]-
`
`

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`WO 2019/192992
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`PCT/EP2019/058249
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`-8-
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`triazolo[1,5-a]pyridinyl, pyridinyl, quinolinyl, isoquinolinyl, pyridazinyl, pyrimidinyl or
`
`pyrazinyl, any of which groups may be optionally substituted by one or moresubstituents.
`
`Moreparticularly, Z represents phenyl, pyridinyl, pyridazinyl, pyrimidinyl or
`
`pyrazinyl, any of which groups may be optionally substituted by one or more substituents.
`
`Suitably, Z represents phenylor pyridinyl, either of which groups may be
`
`optionally substituted by one or more substituents.
`
`In a first embodiment, Z represents phenyl, which group maybe optionally
`
`substituted by one or more substituents. In a second embodiment, Z represents pyridinyl,
`
`which group may be optionally substituted by one or more substituents. In a third
`
`10
`
`embodiment, Z represents pyridazinyl, which group may be optionally substituted by one
`
`or more substituents. In a fourth embodiment, Z represents pyrimidinyl, which group
`
`may be optionally substituted by one or more substituents. In a fifth embodiment, Z
`
`represents pyrazinyl, which group may be optionally substituted by one or more
`
`substituents.
`
`15
`
`Typical examples of optional substituents on Z include one, two or three
`
`substituents independently selected from halogen, cyano, nitro, C16 alkyl, difluoromethyl,
`
`trifluoromethyl, hydroxy, hydroxy(Ci-6)alkyl, oxo, Cialkoxy, difluoromethoxy,
`
`trifluoromethoxy, C1-6 alkylthio, C1-6 alkylsulfinyl, Cialkylsulfonyl, amino, C1-6
`
`alkylamino, di(Ci-c)alkylamino, amino(C1-6)alkyl, di(Ci-c)alkylamino(C1-s)alkyl, C2-6
`
`20
`
`alkylcarbonylamino, C2-6 alkoxycarbonylamino, Cialkylsulfonylamino, formyl, C2
`
`alkylcarbonyl, carboxy, C2alkoxycarbonyl, aminocarbonyl, Ci-6 alkylaminocarbonyl,
`
`di(C1-6)alkylaminocarbonyl, aminosulfonyl, Cialkylaminosulfonyl and di(C1-6)alkyl-
`
`aminosulfonyl. Additional examples includetrifluoroethyl, cyclopropyl, cyclobutyl,
`
`cyanocyclobutyl, phenyl, azetidinyl, oxopyrrolidinyl, morpholinyl, oxazolyl, methyl-
`
`25
`
`oxadiazolyl, triazolyl, methyltetrazolyl, difluoroethoxy,trifluoroethoxy, phenoxy,
`
`methylenedioxy, difluoromethylenedioxy and di(Ci-6)alkylsulfoximino.
`
`Selected examples of optional substituents on Z include one, two orthree
`
`substituents independently selected from halogen, cyano, C1- alkyl, difluoromethyl,
`
`trifluoromethyl, trifluoroethyl, cyclopropyl, cyclobutyl, cyanocyclobutyl, phenyl,
`
`azetidinyl, oxopyrrolidinyl, morpholinyl, oxazolyl, methyloxadiazolyl, triazolyl,
`
`methyltetrazolyl, oxo, Cialkoxy, difluoromethoxy, trifluoromethoxy, difluoroethoxy,
`
`trifluoroethoxy, phenoxy, methylenedioxy, difluoromethylenedioxy, C16 alkylsulfonyl,
`
`di(C1-6)alkylamino, C26 alkylcarbonyl, C26 alkoxycarbonyl and di(C1-6)alkylsulfoximino.
`
`

`

`WO 2019/192992
`
`PCT/EP2019/058249
`
`-9-
`
`Suitable examples of optional substituents on Z include one, twoor three
`
`substituents independently selected from halogen, cyano, Cialkyl andtrifluoromethyl.
`
`Typical examples of particular substituents on Z include one, twoorthree
`
`substituents independently selected from fluoro, chloro, bromo, cyano, nitro, methyl,
`
`ethyl, isopropyl, difluoromethyl, trifluoromethyl, hydroxy, hydroxymethyl, hydroxyethyl,
`
`hydroxyisopropyl, oxo, methoxy, difluoromethoxy, trifluoromethoxy, methylthio,
`
`methylsulfinyl, methylsulfonyl, amino, methylamino, dimethylamino, aminomethyl,
`
`dimethylaminomethyl, acetylamino, methoxycarbonylamino, methylsulfonylamino,
`
`formyl, acetyl, carboxy, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, methyl-
`
`10
`
`aminocarbonyl, dimethylaminocarbonyl, aminosulfonyl, methylaminosulfonyl and
`
`dimcthylaminosulfonyl. Additional examples include tert-butyl, trifluorocthyl,
`
`cyclopropyl, cyclobutyl, cyanocyclobutyl, phenyl, azetidinyl, oxopyrrolidinyl,
`
`morpholinyl, oxazolyl, methyloxadiazolyl, triazolyl, methyltetrazolyl, isopropoxy,
`
`difluoroethoxy,trifluoroethoxy, phenoxy, methylenedioxy, difluoromethylenedioxy and
`
`15
`
`dimethylsulfoximino.
`
`Selected examplesof particular substituents on Z include one, twoor three
`
`substituents independently selected from fluoro, chloro, cyano, methyl, ethyl, tert-butyl,
`
`difluoromethyl, trifluoromethyl,trifluoroethyl, cyclopropyl, cyclobutyl, cyanocyclobutyl,
`
`phenyl, azetidinyl, oxopyrrolidinyl, morpholinyl, oxazolyl, methyloxadiazolyl, triazolyl,
`
`20
`
`methyltctrazolyl, oxo, methoxy, isopropoxy, difluoromcthoxy,trifluoromcthoxy,
`
`difluoroethoxy, trifluoroethoxy, phenoxy, methylenedioxy, difluoromethylenedioxy,
`
`methylsulfonyl, dimethylamino, acetyl, methoxycarbony] and dimethylsulfoximino.
`
`Representative examples of particular substituents on Z include one, two or three
`
`substituents independently selected from methyl, cyclopropyl, difluoromethoxy and
`
`25
`
`difluoroethoxy.
`
`Suitable examplesof particular substituents on Z include one, twoorthree
`
`substituents independently selected from fluoro, chloro, cyano, methyl and trifluoro-
`
`methyl.
`
`Selected values of Z include phenyl, fluorophenyl, chlorophenyl, cyanophenyl,
`
`methylphenyl, tert-butylphenyl, trifluoromethylphenyl, biphenylyl, oxopyrrolidinyl-
`
`phenyl, oxazolylphenyl, methyloxadiazolylphenyl, methoxyphenyl, isopropoxyphenyl,
`
`difluoromethoxyphenyl, trifluoromethoxyphenyl, phenoxyphenyl, methylenedioxyphenyl,
`
`difluoromethylenedioxyphenyl, methylsulfonylphenyl, methoxycarbonylphenyl,
`
`

`

`WO 2019/192992
`
`PCT/EP2019/058249
`
`-10-
`
`dimethylsulfoximinophenyl, difluorophenyl, (chloro)(fluoro)phenyl, (cyano)(fluoro)-
`
`phenyl, (fluoro)(methyl)phenyl, (fluoro)(methoxy)phenyl, (fluoro)(difluoromethoxy)-
`
`phenyl, (fluoro)(trifluoromethoxy)phenyl, (fluoro)(methylsulfonyl)phenyl, (chloro)-
`
`(cyano)phenyl, (chloro)(methylsulfonyl)phenyl, (cyano)(trifluoromethyl)phenyl,
`
`(cyano)(methoxy)phenyl, (cyano)(difluoromethoxy)phenyl, dimethylphenyl, dimethoxy-
`
`phenyl, trifluorophenyl, naphthyl, acetyl-2,3-dihydroindolyl, methy|-2,3-dihydro-
`
`benzoxazinyl, (dimethyl)(phenyl)pyrazolyl, pyrazolo[1,5-a]pyridinyl, fluoropyrazolo[1,5-
`
`alpyridinyl, methylpyrazolo[3,4-b|pyridinyl, methylindazolyl, imidazo[1,2-a]pyridinyl,
`
`imidazo[1,5-a]pyridinyl, methylimidazo[4,5-b]pyridinyl, [1,2,4]triazolo[1,5-a]pyridinyl,
`
`10
`
`pyridinyl, fluoropyridinyl, chloropyridinyl, cyanopyridinyl, methylpyridinyl, ethyl-
`
`pyridinyl, tert-butylpyridinyl, difluoromcthylpyridinyl, trifluoromcthylpyridinyl,
`
`trifluoroecthylpyridinyl, cyclopropylpyridinyl, cyclobutylpyridinyl, cyanocyclobutyl-
`
`pyridinyl, azetidinylpyridinyl, morpholinylpyridinyl, triazolylpyridinyl, methyltetrazolyl-
`
`pyridinyl, methoxypyridinyl, difluoromethoxypyridinyl, trifluoromethoxypyridinyl,
`
`15
`
`difluoroethoxypyridinyl, trifluoroethoxypyridinyl, dimethylaminopyridinyl, (fluoro)-
`
`(methoxy)pyridinyl, (chloro)(methyl)pyridinyl, (chloro)(trifluoromethyl)pyridinyl,
`
`(cyano)(methyl)pyridinyl, (cyano)(difluoromethyl)pyridinyl, (methyl)(trifluoromethyl)-
`
`pyridinyl, (methyl)(oxo)pyridinyl, (cyclopropyl)(oxo)pyridinyl, (methoxy)(methyl)-
`
`pyridinyl, (difluoromethoxy)(methyl)pyridinyl, quinolinyl, cyanoquinolinyl, difluoro-
`
`20
`
`methoxyquinolinyl, isoquinolinyl, mcthylisoquinolinyl, difluoromcthoxyisoquinolinyl,
`
`methylpyridazinyl, cyclopropylpyridazinyl, trifluorocthoxypyridazinyl, methyl-
`
`pyrimidinyl, tert-butylpyrimidiny], trifluoromethylpyrimidinyl, cyclopropylpyrimidinyl,
`
`methylpyrazinyl, tert-butylpyrazinyl, cyclopropylpyrazinyl and difluoromethoxy-
`
`pyrazinyl.
`
`25
`
`Representative values of Z include methylpyridinyl, cyclopropylpyridinyl,
`
`difluoromethoxypyridinyl, difluoroethoxypyridinyl, (difluoromethoxy)(methyl)pyridinyl,
`
`cyclopropylpyridazinyl, cyclopropylpyrimidinyl and difluoromethoxypyrazinyl.
`
`Typical values of Z include phenyl, fluorophenyl, chlorophenyl, cyanophenyl,
`
`methylphenyl, trifluoromethylphenyl, (fluoro)(methyl)phenyl and methylpyridinyl.
`
`Appositely, R! represents C3-7 cycloalkyl, C3-7 cycloalkyl(C1-6)alkyl, aryl(C1-6)-
`
`alkyl, C3-7 heterocycloalkyl, Cs-7 heterocycloalkyl(C1-6)alkyl, Cao heterobicycloalkyl, C4-9
`
`spiroheterocycloalkyl or heteroaryl(C1-6)alkyl, any of which groups may be optionally
`
`substituted by one or more substituents.
`
`

`

`WO 2019/192992
`
`PCT/EP2019/058249
`
`-ll-
`
`Generally, R! represents C26 alkyl, optionally substituted by hydroxy; or R!
`
`represents C3-7 cycloalkyl, Ca-7 cycloalkyl(Ci«)alkyl, aryl(Ci+«)alkyl, C3-7
`
`heterocycloalkyl, C3-7 heterocycloalkyl(Ci-6)alkyl or heteroaryl(Ci-s)alkyl, any of which
`
`groups may be optionally substituted by one or more substituents.
`
`Moreparticularly, R' represents C3-7 cycloalkyl, C3-7 cycloalkyl(Ci-6)alkyl, aryl-
`
`(C16)alkyl, C37 heterocycloalkyl, C37 heterocycloalkyl(Ci-6)alkyl or heteroaryl(C1-6)-
`
`alkyl, any of which groups may be optionally substituted by one or more substituents.
`Suitably, R! represents C3-7 cycloalkyl, C3-7 cycloalkyl(C1-6)alkyl, C3-7
`
`heterocycloalkyl, C3-7 heterocycloalkyl(Ci-6)alkyl, C4 heterobicycloalkyl or C4-9
`
`10
`
`spiroheterocycloalkyl, any of which groups may be optionally substituted by one or more
`
`substituents.
`
`Typically, R' represents C3-7 cycloalkyl, C37 cycloalkyl(Ci-s)alkyl, C3-7
`
`heterocycloalkyl or C3-7 heterocycloalkyl(Ci-6)alkyl, any of which groups may be
`
`optionally substituted by one or more substituents.
`Suitable values of R! include cyclobutyl, cyclohexyl, cyclopropylmethy]l,
`
`15
`
`tetrahydrofuranyl, tetrahydropyranyl, oxetanylmethyl, tetrahydropyranylmethyl, 7-
`
`oxabicyclo[2.2.1]heptanyl, 8-oxabicyclo[3.2.1]octanyl and 2-oxaspiro[3.3 |heptanyl, any
`
`of which groups may be optionally substituted by one or more substituents.
`Typical values of R! include cyclobutyl, cyclohexyl, cyclopropylmethyl,
`
`20
`
`tetrahydrofuranyl, tetrahydropyranyl and tctrahydropyranylmcthyl, any of which groups
`
`may be optionally substituted by one or more substituents.
`
`A particular value of R! is tetrahydropyranyl, which group may be optionally
`
`substituted by one or more substituents.
`Typical examples of optional substituents on R! include one, two or three
`
`25
`
`substituents independently selected from halogen, cyano, nitro, C16 alkyl, difluoromethyl,
`
`trifluoromethyl, hydroxy, hydroxy(Ci-6)alkyl, oxo, Cialkoxy, difluoromethoxy,
`
`trifluoromethoxy, C1-6 alkylthio, C1-6 alkylsulfinyl, Cialkylsulfonyl, amino, C1-6
`
`alkylamino, di(Ci-c)alkylamino, amino(C1-6)alkyl, di(Ci-c)alkylamino(C1-s)alkyl, C2-6
`
`alkylcarbonylamino, C2-6 alkoxycarbonylamino, Cialkylsulfonylamino, formyl, C2
`
`alkylcarbonyl, carboxy, C2-6 alkoxycarbonyl, aminocarbonyl, Ci-6 alkylaminocarbonyl,
`
`di(Ci-6)alkylaminocarbonyl, aminosulfonyl, Ci alkylaminosulfonyl and di(C1-6)alkyl-
`
`aminosulfony].
`
`

`

`WO 2019/192992
`
`PCT/EP2019/058249
`
`-12-
`
`Selected examples of optional substituents on R! include one, twoorthree
`
`substituents independently selected from halogen, cyano, C1-alkyl, trifluoromethyl and
`
`hydroxy.
`Suitable examples of optional substituents on R! include one, two or three
`
`substituents independently selected from Ci-6 alkyl and hydroxy.
`Typical examples of particular substituents on R! include one, two or three
`
`substituents independently selected from fluoro, chloro, bromo, cyano, nitro, methyl,
`
`ethyl, isopropyl, difluoromethyl, trifluoromethyl, hydroxy, hydroxymethyl, hydroxyethyl,
`
`hydroxyisopropyl, oxo, methoxy, difluoromethoxy,trifluoromethoxy, methylthio,
`
`10
`
`methylsulfinyl, methylsulfonyl, amino, methylamino, dimethylamino, aminomethyl,
`
`dimecthylaminomcthyl, acctylamino, mcthoxycarbonylamino, methylsulfonylamino,
`
`formyl, acetyl, carboxy, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, methyl-
`
`aminocarbonyl, dimethylaminocarbonyl, aminosulfonyl, methylaminosulfonyl and
`
`dimethylaminosulfonyl.
`Selected examples of particular substituents on R! include one, two orthree
`
`15
`
`substituents independently selected from fluoro, cyano, methyl, ethyl, isopropyl,
`
`trifluoromethyl and hydroxy.
`
`Suitable examples ofparticular substituents on R! include one, twoorthree
`
`substituents independently selected from methyl and hydroxy.
`Selected valucs of R! include (cyano)(mcthyl)cyclobutyl, (hydroxy)(mcthyl)-
`
`20
`
`cyclobutyl, (ethyl)(hydroxy)cyclobutyl, (hydroxy)(isopropyl)cyclobutyl, (hydroxy)-
`
`(trifluoromethyl)cyclobutyl, cyclohexyl, difluorocyclohexyl, hydroxycyclopropylmethyl,
`
`tetrahydrofuranyl, tetrahydropyranyl, methyltetrahydropyranyl, dimethyltetrahydro-
`
`pyranyl, methyloxetanylmethyl, tetrahydropyranylmethyl, 7-oxabicyclo[2.2.1]heptanyl,
`
`25
`
`8-oxabicyclo[3.2.1 ]octanyl and 2-oxaspiro[3.3 ]heptanyl.
`
`Particular values of R! include tetrahydropyranyl, methyltetrahydropyranyl and
`dimethyltetrahydropyranyl. In a first embodiment, R! represents tetrahydropyranyl. In a
`second embodiment, R! represents methyltetrahydropyranyl. In a third embodiment, R!
`
`represents dimethyltetrahydropyranyl.
`
`Suitable values of R! include (hydroxy)(methyl)cyclobutyl, cyclohexyl,
`
`hydroxycyclopropylmethyl, tetrahydrofuranyl, tetrahydropyranyl and tetrahydro-
`
`pyranylmethyl.
`Generally, R’, R? and R* independently represent hydrogen or halogen.
`
`

`

`WO 2019/192992
`
`PCT/EP2019/058249
`
`-13-
`
`Generally, R? represents hydrogen or halogen.
`In a first embodiment, R? represents hydrogen. In a second embodiment, R?
`represents halogen, especially fluoro or chloro. In one aspect of that embodiment, R?
`represents fluoro.
`In another aspect of that embodiment, R? represents chloro. In a third
`
`embodiment, R’ representstrifluoromethyl.
`Selected values of R? include hydrogen, fluoro and chloro.
`Suitably, R? represents chloro.
`Generally, R? represents hydrogenor halogen.
`In a first embodiment, R* represents hydrogen. In a second em