(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`(19) World Intellectual Property
`Organization
`International Bureau
`
`(43) International Publication Date
`7 March 2013 (07.03.2013)
`
`WIPO!IPCT
`
`\=
`
`(10) International Publication Number
`WO 2013/030218 Al
`
`GD)
`
`International Patent Classification:
`C07D 401/06 (2006.01)
`A6IP 19/00 (2006.01)
`C07D 409/14 (2006.01)
`A61P 37/00 (2006.01)
`AGLK 31/517 (2006.01)
`A6IP 9/00 (2006.01)
`A61P 35/00 (2006.01)
`A61P 31/00 (2006.01)
`A61IP 25/00 (2006.01)
`A6IP 3/00 (2006.01)
`
`(21)
`
`International Application Number:
`
`PCT/EP2012/066741
`
`(22)
`
`International Filing Date:
`
`29 August 2012 (29.08.2012)
`
`(25)
`
`(26)
`
`(30)
`
`(71)
`
`(72)
`(75)
`
`Filing Language:
`
`Publication Language:
`
`English
`
`English
`
`Priority Data:
`11306096.6
`
`2 September 2011 (02.09.2011)
`
`EP
`
`Applicant (for all designated States except US): HYBRI-
`GENICS SA [FR/FR]; 3/5 Impasse Reille, F-75014 Paris
`(FR).
`
`Inventors; and
`only): COLLAND,
`(for US
`Inventors/Applicants
`Frédéric [FR/FR]; 16 rue du Manoir, F-95380 Puiseux En
`France (FR). GOURDEL, Marie-Edith [FR/FR]; 43 rue
`Grande, F-77176 Savigny Le Temple (FR).
`
`(74)
`
`Agents: BLOT, Philippe ct al.; Cabinct Lavoix, 2, place
`d'Estienne d'Orves, F-75009 Paris (FR).
`
`(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, BN, BR, BW, BY,
`BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM,
`DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT,
`HIN, 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, NL
`NO, NZ, OM, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW,
`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.
`
`(84)
`
`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, 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,
`ML, MR,NE, SN, TD, TG).
`Published:
`
`with international search report (Art. 21(3))
`
`before the expiration ofthe time limit for amending the
`claims and to be republished in the event of receipt of
`amendments (Rule 48.2(h))
`
`with sequence listing part ofdescription (Rule 5.2(a))
`
`(54) Title: SELECTIVE AND REVERSIBLE INHIBITORS OF UBIQUITIN SPECIFIC PROTEASE 7
`
`(PR),
`
`O
`
`a
`
`—a
`N
`
`L+x
`
`a
`
`(CRPR®)
`NN,
`~(CRPR‘)
`
`.
`
`—
`
`5
`LORE
`A
`
`(I)
`
`(57) Abstract: The present invention relates to quinazolin-4-one compounds of formula(I’), their process of preparation and uses
`thereof. These compounds are useful as selective and reversible inhibitors of ubiquitin specific proteases, particularly USP7, for
`treating e.g. cancer, neurodegenerative diseases, inflammatory disorders and viral infections.
`
`
`
`wo2013/030218A1IIITINMITIMTAIMINUITVRETTTAA
`
`

`

`WO 2013/030218
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`PCT/EP2012/066741
`
`SELECTIVE AND REVERSIBLE INHIBITORS OF UBIQUITIN SPECIFIC
`PROTEASE 7
`
`The present
`
`invention concerns the discovery of new selective and reversible
`
`inhibitors of ubiquitin specific proteases, their process of preparation and their therapeutic
`use.
`
`Ubiquitin specific proteases (USP) are cysteines proteases which belong to the
`
`deubiquitinating enzymes (DUBs)family.
`
`10
`
`Deregulation of
`
`the ubiquitin-proteasome system has been implicated in
`
`the
`
`pathogenesis of many human diseases, including cancer (Hoeller et a/. Nat Rev Cancer
`
`2006,
`
`6(10),
`
`776-788), neurodegenerative disorders
`
`(Rubinsztein, Nature 2006,
`
`443(7113), 780-786) and viral diseases (Gao & Luo Can J Physiol Pharmacol! 2006, 84(1),
`5-14). The market success of the proteasome inhibitor Velcade® (bortezomib) for the
`
`15
`
`treatment of multiple myeloma and mantle cell lymphoma has established this system as
`
`a valid target for cancer treatment (Adams, Nat Rev Cancer 2004, 4(5), 349-360). A
`
`promising alternative to targeting the proteasome itself would be to interfere with the
`
`upstream ubiquitin conjugation/deconjugation machinery, to generate more specific, less
`
`toxic anticancer agents.
`
`20
`
`Mono- and polyubiquitination can be reversed by deubiquitinating enzymes, which
`
`specifically cleave the isopeptide bond at the C-terminus of ubiquitin. Ubiquitin specific
`
`proteases and ubiquitin C-terminal hydrolases (UCH) enzymesare the best characterized
`
`members of the DUB family (Komander et al. Nat. Rev. Mol. Cell Biol. 2009, 10(8), 550-
`
`63; Nijman et al. Ceff 2005, 123(5), 773-786). UCHs are thought to cleave small protein
`
`25
`
`substrates preferentially and to be involved principally in the processing and recycling of
`
`ubiquitin, but
`
`their specific functions remain poorly understood. USPs constitute the
`
`largest subfamily of DUBs, with more than 60 members. They remove ubiquitin from
`
`specific protein substrates, thus preventing their targeting to the proteasome or regulating
`
`their subcellular localization and activation (Daviet & Colland, Biochimie 2008, 90(2), 270-
`
`30
`
`83). USPs are emerging as potential targets for pharmacological interference with the
`
`ubiquitin regulation machinery, based on their protease activity and involvement in several
`
`human diseases (Colland, Biochem Soc Trans 2010, 38, 137-43).
`
`USP7 (Ubiquitin Specific Protease 7)/HAUSP (Herpes Associated Ubiquitin
`
`Specific Protease) is a 135 kDa protein of the USP family. USP7 has been shown to
`
`

`

`WO 2013/030218
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`PCT/EP2012/066741
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`2
`
`interact with viral proteins, such as ICPO (Vmw 110), a herpes simplex virus immediate-
`
`early gene stimulating initiation of the viral lytic cycle (Everett et a/., J Virol 73, 1999,
`
`417-426), and EBNA1 (Epstein-Barr Nuclear Antigen-1) (Holowaty ef a/., J Biol Chem
`
`2003, 278, 29987-29994 and 47753-47761). Human proteins, such as p53 and the
`
`major E3 ligase of p53, Mdm2, have also beenidentified as partners and substrates of
`
`USP7 (Cummins ef a/. Nature 2004, 486, Cummins & Vogelstein, Celf Cycle, 2004, 3,
`
`689-692; Li et al. Mo/ Cell 2004, 13, 879-886; Li et al. Nature 2002, 416, 648-653). More
`
`generally USP7 can deubiquitinate different targets, including Mdm2 and p53, and the
`
`net deubiquitination of these latter targets ultimately determines functional p53 levels.
`
`10
`
`Consistent with recent reports, USP7 silencing has also been shownto increase steady-
`
`state p53 levels by promoting Mdm2 degradation. Binding of USP7 to p53 was recently
`
`shownto be regulated by TSPYL5, a protein potentially involved in breast oncogenesis
`
`through a competition with p53 for binding to the same region of USP7 (Epping e¢ a/.,
`
`Nat Cell Biol. 2011, 13(1):102-8). More recently, both upregulation and downregulation
`
`15
`
`of USP7 have been shownto inhibit colon cancercell proliferation in vitro and tumor
`
`growth in vivo, by resulting in constitutively high p53 levels (Becker et a/. Cell Cycle
`
`2008, 7(9),1205-13).
`
`USP7 also alters the level of the p16™*** tumor suppressor through Bmi1/Mel18
`
`stabilization (Maertens et al., Embo J. 2010, 29, 2553-2565). Additional proteins involved
`
`20
`
`in genomic integrity/regulation such as the DNMT1 DNA methylase and the Claspin
`
`adaptor are also stabilized by USP7 (Du et al., Science Signaling 2010, 3(146):ra80;
`
`Faustrup ef a/., J. Celf Biol. 2009,184(1):13-9). Importantly, the abundance of USP7 and
`
`DNMT1, a protein involved in maintaining epigenetic methylation required to silence
`
`genesinvolved in development and cancer, correlates in human colon cancer (Du efal.,
`
`25
`
`Science Signaling, 2010, 3(146):ra80). USP7 has also been shown in human cells to
`
`deubiquitinate the well-known tumor suppressor gene PTEN, which provokesits nuclear
`
`export and henceits inactivation (Song et al/., Nature 2008, 455(7214), 813-7). More
`
`importantly, USP7 overexpression was reported for the first time in prostate cancer and
`
`this overexpression was directly associated with tumour aggressiveness (Song et al.,
`
`30
`
`Nature 2008, 455(7214), 813-7).
`
`USP7 has also been shown in human cells to deubiquitinate FOXO4, which
`
`provokes its nuclear export and hence its
`
`inactivation; consequently the oncogenic
`
`PI3K/PKB signaling pathway was activated (van der Horst ef a/., Nat Cell Biol. 2006, 8,
`
`

`

`WO 2013/030218
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`3
`1064-1073) Finally, USP7 plays an important role in p53-mediated cellular responses to
`
`various types of stress, such as DNA damage and oxidative stress (Marchenko ef ai.,
`
`Embo J. 2007 26, 923-934, Meulmeester ef a/., Mol Cell 2005, 18, 565-576., van der
`
`Horst et al., Nat Cell Biol. 2006, 8, 1064-1073).
`Synthetic inhibitors of USP7 protein binding containing the polypeptide portion P'-
`Gly-P*-Ser, where P'
`is a glutamic acid residue or an amino acid with a non polar side
`chain and P® is a glycine residue or an amino acid with non polar side chain, have been
`
`reported (WO2006072048).
`
`The phenotypes associated with USP7 silencing and the known connections
`
`10
`
`between USP7 and essential viral proteins and oncogenic pathways, such as the
`
`p53/Mdm2 and PI3K/PKB pathways,
`
`strongly suggest
`
`that
`
`targeting USP7 with
`
`small-molecule inhibitors may be beneficial in the treatment of cancers and viral diseases
`
`(Sippl et af, Future Oncology 2011, 7, 619-32). Inhibitors against USP7 were recently
`
`reported (Colland et al. Molecular Cancer Therapeutics 2009, 8, 2286-95 and EP
`
`15
`
`1 749 822 and PCT/EP2011/050523.2).
`
`However, to date, no specific and reversible USP7 small molecule inhibitors seem to
`
`have been reported.
`
`According to a first object, the present invention concerns a compoundof formula (I):
`
`(R)
`
`5
`
`O
`
`LL
`
`Re
`
`on’n’)NW) —L*—R®
`
`20
`
`25
`
`30
`
`wherein
`
`°
`
`(1)
`
`»
`
`=
`
`R’, each identical or different, is chosen from the group consisting of halogen, R,
`OR, NRR, CN, CFs, C(O)R, C(O)OR, C(O)NRR’, NOs, (C1-Ce)alkylene-OR, (C,-
`C.)alkylene-NRR’,
`(C,-C.)alkylene-CO.R,
`(C,-C.)alkylene-C(O)NRR’,
`-O-(C;-
`
`C,)alkylene-CO.R, -O-(C;-C.)alkylene-C(O)NRR’, COs-(C;-C,)alkylene-OR, CO.-
`
`C(O)NH-(C,-C,)alkylene-
`C(O)NH-(C,-C,)alkylene-OR,
`(C,-C.)alkylene-NRR’,
`NRR’, OCF, SO2R, SOsH, SO2NRR’, NHSO.R, R™°C=CR", (R1°)(R')C=C(R"")o,
`
`(C,-C,)alkylene-C(O)R, NHC(O)R, or
`
`(C,-C,)alkyl
`
`interrupted by at
`
`least one
`
`heteroatom, preferably chosen among O, N or 8S, preferably O;
`L'is linear or branched (C,-C.)alkylene optionally substituted by one or more of
`
`=O, CN, C(O)R, C(O)OR, or C(O)NRR’, or linear or branched CH,(C,-C,)alkylene,
`
`wherein the later (C,-C,)alkylene is optionally substituted by one or more of
`
`halogen, OR, NRR’ or CF3;
`
`

`

`WO 2013/030218
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`4
`X is CR*R’, NR’, aryl, heteroaryl, cycloalkyl or heterocycle, wherein the aryl,
`
`heteroaryl, cycloalkyl or heterocycle is optionally substituted by one or more of
`linear or branched C,-C,(alkyl), halogen, OR, NRR, CN, CFs, C(O)R, C(O)OR or
`
`C(O)NRR’;
`R® is a linear or branched (C,-Cz)alkylene and is linked together with R°=linear or
`branched (C;-C.)alkylene to form with —X-(CR°R*),-N-, to which they are attached,
`
`an heterocycle, preferably a heterocycle having 5 to 7 members, optionally
`substituted by one or more of OR, linear or branched (C,-Cz)alkyl, halogen, NRR,
`CN, CF3, C(O)R, C(O)OR, C(O)NRR’, or =O;
`R®, is chosen amongH and linear or branched (C,-C,)alkyl, (C;-C,)alkylene;
`R®, R*, each identical or different, are chosen in the group consisting of H, linear or
`branched (C,-C,)alkyl, halogen, OR, NRR, CN, CF3, C(O)R, C(O)OR, C(O)NRR’
`
`or =O;
`
`qis0,1,2,30r4
`
`nis 0,1,2o0r3;
`R’ is OR, H, halogen, linear or branched (C,-C.)alkyl-OR, C(O)OR, C(O)NRR’, CN,
`OR®, NRR’ or SR;
`
`iis either O or 1;
`
`A is chosen from the group consisting of:
`
`-
`
`-
`
`-
`
`linear or branched -[C,-C,(alkyl)]o4-C(O)-;
`
`linear or branched -[C,-Ce(alkyl)Jo4-C(O)NH-;
`
`linear or branched -[C,-C,(alkyl)]o-1:SOz2-; or
`
`linear or branched -[C,-C,(alkyl)]o,SO2N-;
`-
`L* is linear or branched (C,;-Cz)alkylene-O or a linear or branched (C;-Cz)alkylene
`optionally interrupted by at least one heteroatom chosen from O, NR or S$ and/or
`
`optionally substituted by: R, OR, NRR’,
`
`(C,-C,)alkyl-OR,
`
`(C,-C,)alkyl-NRR’,
`
`OC(O)R, NHC(O)R, NHC(O)NRR’, CN, G(=NH)NHOR;
`R® is chosen from the group consisting in aryl, heteroaryl, cycloalkyl, heterocycle,
`
`H, wherein the aryl, heteroaryl, cycloalkyl or heterocycle is mono or polycyclic and
`
`is optionally substituted by one or more oflinear or branched (C,-C.)alkyl, halogen,
`NRR, CN, CF;, OR, =O, C(O)R, C(O)OR, NHC(O)R, OC(O)R, linear or branched
`(C2-C,)alkenylene or C(O)NRR’;
`R°
`is chosen from the group consisting of —C(O)R,
`
`-C(O)NHR,
`
`-C(O)OR,
`
`10
`
`15
`
`20
`
`25
`
`30
`
`-C(O)GH2-NRR’, -C(O)-CHs-CH2-CO.R, -C(O)-CH2-SO3H, -C(O)-(CsH4N), -PO3Hz,
`
`35
`
`or their ionized form;
`
`

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`WO 2013/030218
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`PCT/EP2012/066741
`
`»
`
`=
`
`=
`
`5
`R"° independently identical or different is chosen from a bond, a linear or branched
`
`(C,-Ce)alkyl;
`R" independently identical or different is chosen from an hydrogen atom, a linear
`
`or branched (C,-Cz)alkyl or an aryl, the alkyl or aryl is optionally substituted by OH,
`
`NH2, C(O)OH or C(O)NH2;
`
`each R and R’,
`
`identical or different, are independently chosen from H, linear or
`
`branched (C,-C.)alkyl, cycloalkyl, aryl, aromatic or non aromatic heterocycle, linear
`
`or branched -(C,-C,)alkyl-aryl or
`
`linear or branched -(C,-C,)alkyl-heterocycle,
`
`wherein the heterocycle is aromatic or non aromatic; optionally substituted or not
`
`10
`
`by OH, CO2H, C(O)NHz, NHz
`
`or
`
`their pharmaceutically acceptable salts or
`
`their optical
`
`isomers,
`
`racemates,
`
`diastereoisomers, enantiomers or tautomers.
`
`The formula (1) of the invention refers to any of the following embodiments or any of their
`
`15
`
`combinations.
`
`Preferably, in compoundof formula (I), R', each identical or different, is chosen from the
`group consisting of linear or branched (C,-Cz)alkyl, halogen, OR, NRR, CN, CFs, C(O)R,
`C(O)OR, C(O)NRR’; NOz;
`(C1-Ce)alkylene-OR,
`(C;-C,)alkylene-NRR’,
`(C,-C,)alkylene-
`
`20
`
`COsR,
`
`(C,-C.)alkylene-C(O)NRR’,
`
`=-O-(C;-Cz)alkylene-COoR,
`
` -O-(C,;-C,)alkylene-
`
`C(O)NRR’, CO2-(C1-Cs)alkylene-OR, CO2-(Ci-Cs)alkylene-NRR’, C(O)NH-(Ci-Cz)alkylene-
`
`OR, C(O)NH-(C,-C,)alkylene-NRR’ or NHC(O)R.
`
`is linear or branched (C;-Cz)alkylene optionally
`Preferably, in compoundof formula (I), L'
`substituted by one or more of =O, CN, C(O)R, C(O)OR, or C(O)NRR’; or linear or
`
`25
`
`branched CH,(C,-C,)alkylene, wherein the later (C,;-C,)alkylene is optionally substituted
`
`by one or more of halogen, OR, NRR’ or CF3.
`
`in compound of formula (I), R? is a linear or branched (C,-Cz)alkylene and is
`Preferably,
`linked together with R®°=linear or branched (C,-Cz)alkylene to form with —X-(CR°R‘*),-N-, to
`
`30
`
`which they are attached, an heterocycle of 5 or 6 members optionally substituted by one
`or more of OR, linear or branched (C;-C.)alkyl, halogen, NRR, CN, CF3, C(O)R, C(O)OR,
`C(O)NRR’, or =O.
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`

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`WO 2013/030218
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`6
`in compound of formula (I), R’ is OR, OR®, halogen, linear or branched (C,-
`Preferably,
`C.)alkyl-OR, C(O)OR, C(O)NRR’ or CN. More preferably R’ is OR, OR®. More preferably
`R’ is OH or OR’, preferably OH.
`
`R® is chosen from the group consisting in aryl, heteroaryl, cycloalkyl, heterocycle, H,
`
`wherein the aryl, heteroaryl, cycloalkyl or heterocycle is mono or polycyclic and is
`optionally substituted by one or moreof linear or branched (C,-Cz)alkyl, halogen, NRR,
`CN, CF3, OR, C(O)R, C(O)OR, NHC(O)R, OC(O)R or C(O)NRR’.
`
`10
`
`Preferably, in compoundof formula (I), A is chosen from the group consisting of:
`
`-
`
`-
`
`-
`
`-
`
`-C(O)-;
`
`-C(O)NH-;
`
`-SOos-; or
`
`-SON-.
`
`15
`
`20
`
`25
`
`30
`
`35
`
`Preferably, in compound of formula (I), L’ is linear or branched (C;-C,)alkylene optionally
`
`interrupted by at
`
`least one heteroatom chosen from O, NR or S and/or optionally
`
`substituted by
`
`: R, OR, NAR’,
`
`(Ci-Ce)alkyl-OR,
`
`(Ci-Ce)alkyl-NRR’, OC(O)R, NHC(O)R,
`
`NHC(O)NRR’, CN, C(={NH)NHOR.
`
`Preferably, it should be understood that Lz does not represent O-(C;-C.)alkylene.
`
`Preferably, in compoundof formula (I):
`- NR?is directly bonded to at least one of C(O), C(O)N, SOz or SO2N groups; and/or
`
`- i=0, n is 1, 2 or 3 and the CR°R* linked to NR° is C(O); or i=1, A is -C(O)-, C(O)NH, SOz
`
`or SO2N; and/or
`
`-i=0, nis 1, 2 or 3 and the CR°R*linked to NR® is C(O); or i=1, A is -C(O)-, C(O)NH, SO.
`or SO.N, X is CR?R’ or NR* and R® and R’°, identical or different, are linear or branched
`(C,-C.)alkylene and form together with —X-(CR°R’%),-N-,
`to which they are attached, an
`
`heterocycle of 5 to 7 members optionally substituted by one or more of OR, linear or
`branched (C,-C,)alkyl, halogen, NRR, CN, CF3, C(O)R, C(O)OR, C(O)NRR’ and R®, R’,
`eachidentical or different, are chosen in the group consisting of H, linear or branched (C,-
`C,)alkyl, halogen, OR, NRR, CN, CF;, C(O)R, C(O)OR, C(O)NRR’; and/or
`
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`7
`-i=1 and A is —C(O)-, X is CR®R’ or NR? and R® and R’, identical or different, are linear or
`branched (C,-C.)alkylene and form together with —X-(CR°R‘),-N-,
`to which they are
`
`attached, an heterocycle of 5 to 7 members optionally substituted by one or more of OR,
`linear or branched (C,-C,)alkyl, halogen, NRR, CN, CF3, C(O)R, C(O)OR, C(O)NRR’ and
`R*, R*, each identical or different, are chosen in the group consisting of H,
`linear or
`branched (C,-Cz)alkyl, halogen, OR, NRR, CN, CF3, C(O)R, C(O)OR, C(O)NRR’; and/or
`
`- R', each identical or different, is chosen from the group consisting of linear or branched
`(C,-C,)alkyl, halogen, OR, NRR, CN, CF;, C(O)R, C(O)OR, C(O)NRR’, or NHC(O)R;
`
`10
`
`and/or
`
`- R', each identical or different, is chosen from the group consisting of linear or branched
`
`C,-C,(alkyl), halogen, OH or linear or branched -O-(C,-C,)alkyl; and or
`
`15
`
`- R', each identical or different, is chosen from the group consisting of halogen orlinear or
`
`branched -O-(C,-C,)alkyl; and/or
`
`-qis 0,
`
`1 or 2; and/or
`
`20
`
`identical or different, are linear or branched (C,-
`- X is CR?R’ or NR* and R® and R*,
`C.)alkylene and form together with —X-(CR°R*),-N-,
`to which they are attached, an
`
`heterocycle of 5 to 7 members optionally substituted by one or more of OR, linear or
`branched (C,-C.)alkyl, halogen, NRR, CN, CF3, C(O)R, C(O)OR, or C(O)NRR’.
`Preferably, the heterocycle formed by —XR*-(CR°R’),-NR°- is a non aromatic heterocycle;
`
`25
`
`and/or
`
`linear or
`- R®, R*, each identical or different, are chosen in the group consisting of H,
`branched (C,-C,)alkyl, halogen, =O, OR, NRR, CN, CF;, C(O)R, C(O)OR or C(O)NRR’;
`
`and/or
`
`30
`
`- R®, R*, each identical or different, are chosen in the group consisting of H, -O-(C,-
`C.)alkyl, OH and =O. Preferably, R°, R*, each identical or different, are chosen in the
`
`group consisting of H and OH; and/or
`
`35
`
`- X is CR°R’, or aryl and R’ is OR, OR’, linear or branched (C;-C.)alkyl-OR, halogen,
`C(O)OH, NRR’, C(O)NHz2or SR . Preferably, X is CR°R’, or aryl and R’ is OR, OR®, NRR’
`
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`WO 2013/030218
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`
`8
`or SR. More preferably, R’ is OH or OR’®, preferably OH. R® being as defined above;
`
`and/or
`
`- X is an aryl, preferably phenyl and/or
`
`- L'
`
`is linear or branched C,-C,.(alkylene) optionally substituted by one or more =O or is
`
`linear or branched CH2-C,-C,(alkylene), wherein the later alkylene is optionally substituted
`
`by one or more —OH; and/or
`
`10
`
`- L?
`
`is
`
`linear or branched C,-C,(alkylene)-O or
`
`linear or branched C,-C,(alkylene)
`
`optionally interrupted by at least one heteroatom chosen from O or S and/or optionally
`
`(C,-C.)alkyl-NRR’,
`(C,-C,)alkyl-OR,
`: R, OR, NRR’,
`substituted by one or more of
`OC(O)R, NHC(O)R, NHC(O)NRR’, CN, C(=NH)NHOR;. More preferably L’
`is linear or
`
`branched C,-C,(alkylene) or linear or branched -[C,-C,(alkylene)]-O-; and/or
`
`15
`
`- R® is chosen from the group consisting in aryl, heteroaryl, cycloalkyl or H, wherein the
`
`aryl, heteroaryl or cycloalkyl is optionally substituted by halogen, linear or branched O-(C,-
`
`Ce)alkyl; and/or
`
`20
`
`- R® is chosen from the group consisting in phenyl, thiophenyl, cyclopentyl and H, wherein
`
`the phenyl is optionally substituted by halogen, linear or branched O-(C,-Caz)alkyl.
`
`In one embodiment, in the compoundof formula (I), X is CR?R’ or NR? and R* and R° form
`together with —X-(CR°R’*),-N- to which they are attached an heterocycle of 5 to 7 members
`optionally substituted by one or more OH. Preferably, in this particular embodiment, n is 0,
`1 or 2 and/or X is CR’*R’ wherein R’ is OR, OR’, linear or branched (C,-C,)alkyl-OR,
`halogen, C(O)OH, C(O)NH2, NRR’ or SR, and/or L'
`is (CH2), wherein k is
`1 or 2,
`preferably k is 1, -C(O)-, -CH»-CH(OH)- or -CH.-C(O)-. Preferably R’ is OR, OR®, NRR’ or
`SR. Morepreferably, R’ is OH or OR’, preferably OH. R® being as defined above.
`
`In another embodiment, in the compoundof formula (I), X is aryl, heteroaryl, cycloalkyl or
`
`heterocycle, wherein the aryl, heteroaryl, cycloalkyl or heterocycle is optionally substituted
`by one or more oflinear or branched C,-C,(alkyl), halogen, OR, NRR, CN, CF3, C(O)R,
`C(O)OR or C(O)NRR’, preferably X is aryl and R® is H or linear or branched C,-C,(alkyl),
`preferably H. Preferably,in this particular embodiment, n is 0 and/or X is aryl and/or L' is —
`
`CH2-CH(OH)-.
`
`25
`
`30
`
`35
`
`

`

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`
`PCT/EP2012/066741
`
`9
`According to a particular embodiment, compoundsof the invention may beof the following
`
`formula (la)
`
`wherein
`
`(R’),
`
`oO
`
`N~
`2
`
`(CR’)
`
`p
`
`ym wk
`~(CRPR*)7 SS
`
`L2-R®
`
`(la)
`
`= R’,q, L’, L?, R° and R’ are as defined in formula(1);
`» X’is CR’ orN;
`
`=
`
`nis 0,1 or 2;
`
`= pis 1,2or3;
`»
`R®, R* and R®, each identical or different, are chosen in the group consisting of H,
`linear or branched (C,-Ce)alkyl, halogen, OH, -O-(C,-C.)alkyl, NRR, CN, CFs, OR,
`C(O)R, C(O)OR or C(O)NRR’.
`Preferably in the compound of formula (la), R®, R* and R®, each identical or different, are
`
`chosen in the group consisting of H or OH; and/or p is 1 or 2.
`
`Preferably in compoundof formula (la)
`
`oe SO Le
`
`~(CRPR’),a
`
`oSas
`a
`
`R®)
`
`L\-
`R’
`
`< \
`or
`
`)
`
`1 or 2 preferably
`tis O,
`wherein R’ is OR, halogen, linear or branched (C,;-C,)alkyl-OR, C(O)OR, C(O)NRR’, CN,
`OR®, NRR’ or SR, more preferably OR, OR®, NRR’ or SR, preferably OH or OR’, p is 1 or
`2 and R°®is chosenin the group consisting of H or OH.
`
`According to a particular embodiment, compoundsof the invention may beof the following
`
`formula (la)
`
`1
`(R ),
`
`(CR*R"),
`O a oN
`L-x'
`LN X
`Ne
`(CRPR*) 7
`
`6
`
`>
`LR
`
`(la)
`
`10
`
`15
`
`20
`
`

`

`WO 2013/030218
`
`PCT/EP2012/066741
`
`wherein
`
`10
`
`= R’,q, L’, L?, R° and R’ are as defined in formula(1);
`» X’is CR’ orN;
`
`=
`
`nis 0,1 or 2;
`
`= pis1,2or3;
`»
`R®, R*, R® and R®, each identical or different, are chosen in the group consisting of
`H, linear or branched (C,-Cez)alkyl, halogen, OH, -O-(C,-C,)alkyl, NRR, CN, CFs,
`OR, C(O)R, C(O)OR or C(O)NRR’.
`Preferably in the compound of formula (la), R®, R*, R® and R®’, each identical or different,
`
`10
`
`are chosenin the group consisting of H or OH; and/or p is 1 or 2.
`
`Preferably in compoundof formula (la)
`
`PaOe
`
`.
`*R)
`N-
`—_xX
`“(CRR*)~ aR’
`Is
`
`R®),
`N-
`
`R’),
`N—
`
`=
`
`R
`
`8
`R)
`
`N
`|
`
`or
`
`ph DB vo
`
`R°)
`ae
`\
`
`\e
`
`R®),
`
`N—
`
`N—
`
`_
`
`AD
`LO OS
`x» = oe
`
`1 or 2 preferably
`is 0,
`wherein R’ is OR, halogen, linear or branched (C;-Cz)alkyl-OR, C(O)OR, C(O)NRR’, CN,
`OR®, NRR’ or SR, more preferably OR, OR®, NRR’ or SR, preferably OH or OR’, p is 1 or
`2 and R®is chosenin the group consisting of H or OH.
`
`Jt
`
`a
`
`According to a particular embodiment, compoundsof the invention may beof the following
`
`formula (Ib)
`
`wherein
`
`(R')
`
`q
`
`r oR
`it
`yex NX
`2
`
`(Ib)
`
`= R',q, L’ and R® are as defined for compoundsof formula(I);
`
`= X is aryl, heteroaryl, cycloalkyl or heterocycle, wherein the aryl, heteroaryl,
`
`linear or
`cycloalkyl or heterocycle is optionally substituted by one or more of
`branched C,-C,(alkyl), halogen, OH, linear or branched -O-(C,-C,)alkyl, NRR, CN,
`CFs, OR, C(O)R, C(O)OR or C(O)NRR’;
`R?’is H or linear or branched (C,-Cs)alkyl;
`
`»
`
`15
`
`20
`
`25
`
`

`

`WO 2013/030218
`
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`
`11
`L'is linear or branched (C,-C,)alkyl substituted by one or more OH.
`
`=
`
`Preferably in compoundof formula (Ib), X is phenyl.
`Preferably in compound of formula (Ib), R° is H.
`
`According to a particular embodiment, compoundsof the invention may be of the following
`
`formula (I’)
`
`wherein
`
`(R’),
`
`O
`
`xy
`
`Zz
`N
`
`(CR®R®)
`
`p
`
`ay Ng
`~(CR°R*)7
`
`t= R®
`
`(I')
`
`10
`
`15
`
`= R’,q, L', A, L’, R, R’ and R® are as defined in formula(I);
`= X’is CR’;
`= R’is OR, halogen, linear or branched (C,-Cgs)alkyl-OR, C(O)OR, C(O)NRR’, CN,
`OR®, NRR’ or SR, more preferably OR, OR®, NRA’ or SR;
`R’°is as defined in formula (I);
`
`=
`
`=
`
`nis 0,1 or 2;
`
`= pis1,2or3;
`=
`R®, R*, R® and R®’, each identical or different, are chosen in the group consisting of
`H, linear or branched (C,-C,)alkyl, halogen, OH, -O-(C,-C,)alkyl, NRR, CN, CFs,
`OR, C(O)R, C(O)OR or C(O)NRR’.
`
`20
`
`Preferably, in compoundof formula (I), Ais chosen from the group consisting of:
`
`-
`
`-
`
`-
`
`-
`
`-C(O)-;
`
` -C(O)NH-;
`
` -SObs-; or
`
`-SO2N-.
`
`25
`
`30
`
`Preferably, in the compoundsof formula (I’), R°®, R*, R° and R®’, each identical or different,
`
`are chosenin the group consisting of H or OH, and/or p is 1 or 2.
`Preferably,
`in the compounds of formula (I’) R’ is OR, halogen, linear or branched (C,-
`
`C.)alkyl-OR, C(O)OR, C(O)NRR’, CN, more preferably OH.
`
`Preferably, in the compounds of formula (I’) R’ is OR, OR®, NRR’ or SR, more preferably
`R’ is OR, OR’, preferably OH or OR’, for example OH.
`
`

`

`WO 2013/030218
`
`PCT/EP2012/066741
`
`12
`Preferably, in the compounds of formula (I’) p+n = 4; more preferably p is 2 andnis 2.
`eer”,
`“(CRPR’)7 aR?
`
`Preferably in compoundof formula (I’)
`Preferably, in the compounds of formula (I’) L' is CHp.
`
`Preferably, in the compoundsof formula (I’) p is 2 and n is 2, R’ is OR, OR®, NRR’ or SR,
`more preferably R’ is OR, OR®, preferably OH or OR’, for example OH.
`
`Preferably, in the of formula (I’) p is 2 andnis 2, and L' is CHs,
`
`10
`
`is CH: and R’ is OR, OR®, NRR’ or SR,
`in the compounds of formula (I’) L'
`Preferably,
`more preferably R’ is OR, OR’®, preferably OH or OR’, for example OH.
`
`is CH2, R’ is R’ is OR,
`in the compoundsof formula (I’) p is 2 and n is 2, L'
`Preferably,
`OR®, NRR’ or SR, more preferably R’ is OR, OR’®, preferably OH or OR’, for example OH.
`
`According to a particular embodiment,
`
`in the compounds of formula (I’) A is C=O, the
`
`compound is thus of the following formula (la’)
`
`(R')
`
`q
`
`T
`N
`2
`
`N
`
`(CR*®R®)
`1 a NN LER®
`LLEX'
`3g
`4 NX
`(CR R Mn
`O
`
`15
`
`20
`
`(la’)
`wherein R', q, L', n, p, X’, R®, R*, R®, R®, L’, R® and R’ are as defined in formula(I’).
`Pace
`(GRR),
`
`7
`
`is R
`
`.
`
`Preferably in compound of formula (la’)
`
`~ 354,
`
`According to a specific embodiment, the invention relates to compounds of formula (I) as
`
`defined above with the exception of the following compound:
`- qis 0, L' is CH2, X-(CR°R*),-NR° forms a piperidine, X is CR*R’ and R’ is OH, iis 1, Ais
`
`25
`
`C=O, L? is CoH, and R°is
`
`2
`
`CH, .
`
`

`

`WO 2013/030218
`
`PCT/EP2012/066741
`
`13
`is CHs, X-(CR°R*),-NR° forms a piperidine, X is CR?R’
`-qis 1, R'is Cl at position 7, L'
`and R’ is OH, iis 1, Ais C=O, L?R® is CH(CH2CHs)>.
`
`According to a specific embodiment, the compounds of formula (lI) are chosen from:
`
`3-({4-hydroxy- 1-[3-(2-methoxyphenyl)propanoyl]piperidin-4-yl}methyl)-3,4-
`
`dihydroquinazolin-4-one
`
`7-chloro-3-{[1 -(2-ethyloutanoyl)-4-hydroxypiperidin-4-yl]methyl}-3 ,4-dihydroquinazolin-4-
`one
`
`3-({1-[2-(3-fluorophenoxy)acetyl]-4-hydroxypiperidin-4-yl}methyl)-3,4-dinydroquinazolin-4-
`one
`
`10
`
`3-{[4-hydroxy-1-(2-methylpropanoyl)piperidin-4-yl]methyl}-6 ,7-dimethoxy-3,4-
`
`dihydroquinazolin-4-one
`
`3-{[4-hydroxy-1 -(2-methylpropanoyl) piperidin-4-yl]methyl}-3 ,4-dihydroquinazolin-4-one
`
`4-hydroxy- 1-[2-methyl-3-(thiophen-2-yl)propanoyl]piperidin-4-yl}methyl)-3 ,4-
`
`15
`
`dihydroquinazolin-4-one
`
`7-chloro-3-{[1 -(3-cyclopentylpropanoyl)-4-hydroxypiperidin-4-yl]methyl}-3,4-
`
`dihydroquinazolin-4-one
`
`3-{[1-(3-cyclopentylpropanoyl)-4-hydroxypiperidin-4-yl]Jmethyl}-3,4-dihydroquinazolin-4-
`one
`
`20
`
`7-chloro-3-{[4-hydroxy-1 -(3-phenylpropanoyl)piperidin-4-yl]methyl}-3,4-dihydroquinazolin-
`
`4-one
`
`3-{[4-hydroxy-1-(3-phenylpropanoyl)piperidin-4-yl]methyl}-3,4-dihydroquinazolin-4-one
`
`7-chloro-3-({4-hydroxy- 1-[2-methyl-3-(thiophen-2-yl)propanoyl]piperidin-4-yl} methyl)-3,4-
`
`dihydroquinazolin-4-one
`
`25
`
`3-({4-hydroxy- 1-[3-(thiophen-2-yl)propanoyl]piperidin-4-yl}methyl)-3,4-dihydroquinazolin-4-
`one
`
`3-{[1-(2-benzylpropanoyl)-4-hydroxypiperidin-4-yl]methy]}-3,4-dihydroquinazolin-4-one
`
`3-{[1-(2-benzylpropanoyl)-4-hydroxypiperidin-4-yl]methy]}-7-chloro-3,4-dihydroquinazolin-
`
`4-one,
`
`30
`
`or
`
`their pharmaceutically acceptable
`
`salts or
`
`their optical
`
`isomers,
`
`racemates,
`
`diastereoisomers, enantiomers or tautomers.
`
`As used hereaboveor hereafter:
`
`"Alkyl" means an aliphatic hydrocarbon group which may be straight or branched
`
`35
`
`having 1
`
`to 6 carbon atoms in the chain. "Branched" means that one or more lower alkyl
`
`

`

`WO 2013/030218
`
`PCT/EP2012/066741
`
`14
`groups such as methyl, ethyl or propyl are attached to a linear alkyl chain. Exemplary alkyl
`
`groups include methyl, ethyl, n-propyl, -propyl, n-butyl, Hbutyl, n-pentyl, 3-pentyl.
`
`As used herein, the term “cycloalkyl” refers a non aromatic monocyclic or multicyclic
`
`hydrocarbon ring of 3 to 10 carbon atoms formed by the removal of one hydrogen atom. A
`
`designation such as "C.-C; cycloalkyl" refers to a cycloalkyl radical containing from 5 to 7
`
`carbon atoms. Examplesinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
`
`adamantyl, etc. as well as the systems formed by their condensation or by the condensation
`
`with a phenyl group.
`
`"Alken" or alkenyl means an aliphatic hydrocarbon group containing a carbon-carbon
`
`10
`
`double bond and which maybestraight or branched having 2 to 6 carbon atoms in the
`
`chain. Preferred alkenyl groups have 2 to 6 carbon atoms in the chain; and more
`
`preferably about 2 to 4 carbon atoms in the chain. Exemplary alkenyl groups include
`
`ethenyl, propenyl, n-butenyl, H-butenyl, 3-methylbut-2-enyl, n-pentenyl.
`
`"Halogen atom" refers to fluorine, chlorine, bromine or
`
`iodine atom; preferably
`
`15
`
`fluorine and chlorine atom.
`
`"Aryl" means an aromatic monocyclic or multicyclic hydrocarbon ring system of 6 to
`
`14 carbon atoms, preferably of 6 to 10 carbon atoms, substituted or not. Exemplary aryl
`
`groups include phenyl or naphthyl.
`
`As used herein, the terms “heterocycle” or “heterocyclic” refer to a saturated, partially
`
`20
`
`unsaturated or unsaturated, non aromatic stable 3 to 14, preferably 5 to 10-membered mono,
`
`bi or multicyclic rings wherein at least one memberof the ring is a hetero atom, substituted or
`
`not. Typically, heteroatoms include, but are notlimited to, oxygen, nitrogen, sulfur, selenium,
`
`and phosphorus atoms. Preferable heteroatoms are oxygen, nitrogen and sulfur.
`
`Suitable heterocycles are also disclosed in The Handbook of Chemistry and Physics,
`76" Edition, CRC Press, Inc., 1995-1996, p. 2-25 to 2-26, the disclosure of which is hereby
`
`25
`
`incorporated by reference. Example of aromatic heterocycle is thiophenyl.
`
`Preferred non aromatic heterocyclic include, but are not
`
`limited to pyrrolidinyl,
`
`pyrazolidinyl,
`
`imidazolidinyl,
`
`oxiranyl,
`
`tetrahydrofuranyl,
`
`dioxolanyl,
`
`tetrahydro-pyranyl,
`
`dioxanyl, dioxolanyl, piperidyl, piperazinyl, morpholinyl, pyranyl,
`
`imidazolinyl, pyrrolinyl,
`
`30
`
`pyrazolinyl,
`
`thiazolidinyl,
`
`tetrahydrothiopyranyl, dithianyl,
`
`thiomorpholinyl, dihydro-pyranyl,
`
`tetrahydropyranyl, dihydropyranyl,
`
`tetrahydro-pyridyl, dihydropyridyl,
`
`tetrahydropyrinidinyl,
`
`dihydrothiopyranyl, azepanyl, as well as the fused systems resulting from the condensation
`
`with a phenyl group, each substituted or not.
`
`As used herein, the term “heteroaryl” or aromatic heterocycles refers to a 5 to 14,
`
`35
`
`preferably 5 to 10-membered aromatic hetero, mono-, bi- or multicyclic ring. Examples include
`
`pyrrolyl, pyridyl, pyrazolyl, thienyl, pyrimidinyl, pyrazinyl, tetrazolyl, indolyl, quinolinyl, purinyl,
`
`

`

`WO 2013/030218
`
`PCT/EP2012/066741
`
`imidazolyl,
`
`thienyl,
`
`thiazolyl,
`
`nenzothiazolyl
`
`furanyl,
`
`benzofuranyl,
`
`1,2,4-thiadiazolyl,
`
`isothiazolyl, triazoyl, tetrazolyl, isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl, carbazolyl,
`
`benzimidazolyl, isoxazolyl, pyridyl-N-oxide , as well as the fused systems resulting from the
`
`condensation with a phenyl group.
`
`"Alkyl", "cycloalkyl", "aryl", "heteroaryl", "heterocycle" and the likes refers also to the
`
`corresponding “alkylene”, "cycloalkylene", "arylene", "heteroarylene", "heterocyclene” and the
`
`likes which are formed by the removal of two hydrogen atoms. Alkyl and alkylene are used
`
`herein interchangeably.
`
`10
`
`As used herein, the term "patient" refers to either an animal, such as a valuable animal
`
`for breeding, company or preservation purposes, or preferably a human or a humanchild,
`
`which is affl