USOO954615OB2
`
`(12)
`
`United States Patent
`Colland et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 9,546,150 B2
`Jan. 17, 2017
`
`(54) SUBSTITUTED QUINAZOLIN-4-ONES FOR
`INHIBITING UBIOUITIN SPECIFIC
`PROTEASE 7
`
`(75) Inventors: Frédéric Colland, Puiseux en France
`(FR); Marie-Edith Gourdel, Savigny le
`Temple (FR)
`
`FOREIGN PATENT DOCUMENTS
`1749 822
`8, 2005
`EP
`WO-93, 12795
`7, 1993
`WO
`WO WO-2006/O12577
`2, 2006
`WO WO 2006/072048
`T 2006
`WO WO 2011 0861.78
`T/2011
`WO WO 2013/030218
`* 3/2013
`
`(73) Assignee: HYBRIGENICSSA, Paris (FR)
`c
`- r
`(*) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`(21) Appl. No.:
`14/241,923
`
`Aug. 29, 2012
`PCT/EP2012/066741
`
`1-1.
`(22) PCT Filed:
`(86). PCT No.:
`S 371 (c)(1)
`(2), (4) Date: Jun. 16, 2014
`s
`e J. V.9
`(87) PCT Pub. No.: WO2013/030218
`PCT Pub. Date: Mar. 7, 2013
`e f 9
`O
`O
`Prior Publication Data
`US 2014/0371247 A1
`Dec. 18, 2014
`
`(65)
`
`(30)
`
`O
`O
`Foreign Application Priority Data
`
`Sep. 2, 2011
`
`(EP) ..................................... 11306096
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`
`(51) Int. Cl.
`A 6LX 3/57
`C07D 239/88
`CO7D 40/06
`CO7D 409/4
`C07D 239/91
`A6 IK 45/06
`(52) U.S. Cl.
`CPC ........... C07D 401/06 (2013.01); A61K3I/517
`(2013.01); A61K 45/06 (2013.01); C07D
`239/88 (2013.01); C07D 239/91 (2013.01);
`C07D 409/14 (2013.01)
`(58) Field of Classification Search
`CPC ............................ A61K 31/517; C07D 239/88
`USPC .......... 514/266.3; 544/287: 546/199; 549/59
`See application file for complete search history.
`
`(56)
`
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`gy,
`7, No. 5, (May 2001), pp. 619-632.
`Meulmeester, et al., “Loss of HAUSP-Mediated Deubiquitination
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`(Continued)
`
`Primary Examiner — Douglas M. Willis
`(74) Attorney, Agent, or Firm — B. Aaron Schulman,
`Esq.; Stites & Harbison, PLLC
`(57)
`ABSTRACT
`The present invention relates to quinazolin-4-one com
`pounds of formula (I), their process of preparation and uses
`thereof. These compounds are useful as selective and revers
`ible inhibitors of ubiquitin specific proteases, particularly
`USP7, for treating e.g. cancer, neurodegenerative diseases,
`inflammatory disorders and viral infections.
`
`(I)
`
`6
`2
`L.-R.
`
`CR8R8
`
`-x1 S.
`NCR-3R4)
`
`O
`
`S.
`N N1
`!
`
`2 N
`
`23 Claims, 6 Drawing Sheets
`
`Post-Grant Review Petition for US 9,840,491
`EXHIBIT 1011
`Page 1
`
`

`

`US 9,546,150 B2
`Page 2
`
`(56)
`
`References Cited
`
`OTHER PUBLICATIONS
`Van der Horst, et al. “FOXO4 transcriptional activity is regularted by
`monoubiquitination and USP7/HAUSP”, Oct. 2006, pp. 1064-1079,
`vol. 8, No. 10, Nature Cell Biology.
`Nijman, et al., “A Genomic and Functional Inventory of
`Deubiquitinating Enzymes' Dec. 2, 2005, pp. 773-786, Cell 123.
`Hoeller, et al "Ubiquitin and ubiquitin-like proteins in cancer
`pathogenesis', Oct. 2006, pp. 776-788, vol. 6, www.nature.com/
`reviews/cancer, Nature Publishing Company.
`Rubinsztein, et al. “The roles of intracellular protein-degradation
`pathways in neurodegeneration', Oct. 19, 2006, pp. 780-786, vol.
`443, Insight Review.
`Marchenko, et al. "Monoubiquitylation promotes mitochondrial p53
`translocation”, 2007, pp. 923–934, vol. 26. The EMBO Journal.
`Becker, et al., “A role of HAUSP in tumor suppression in a human
`colon carcinoma xenograft model', May 1, 2008, pp. 1205-1213,
`vol. 7, No. 9, Cell Cycle.
`Song, et al., “The deubiquitinylation and localization of PTEN are
`regulated by a HAUSP-PML network”, Oct. 9, 2008, pp. 813-818,
`vol. 455, Nature.
`Du, et al., “DNMT1 Stability is Regulated by Proteins Coordinating
`Deubiquitination and Acetylation-Driven Ubiquitination' Nov. 2,
`2010, pp. 110, vol. 3, No. 146, Science Signaling.
`Epping, et al., “TSPYL5 Suppresses p53 levels and function by
`physical interaction with USP7”. Jan. 2011, pp. 102-108, vol. 13,
`No. 1, Nature Cell Biology.
`Colland, Frederic, “The therapeutic potential of deubiquitinating
`enzyme inhibitors', 2010, pp. 137-143, vol. 38, Biochem. Soc.
`Trans.
`Gao, et al., “The ubiquitin-proteasome pathway in viral infections'.
`2006, pp. 514, vol. 84, Can. J. Physiol. Pharmacol.
`Cummins, et al., “HAUSP is Required for p53 Destabilization”. Jun.
`2004, pp. 689-692, vol. 3, No. 6, Cell Cycle.
`Adams, Julian, “The Proteasome: A Suitable antineoplastic target'.
`May 2004, pp. 349-360, vol. 4. Nature Reviews Cancer.
`Li, et al., “A Dynamic Role of HAUSP in the p53-Mdm2 Pathway”.
`Mar. 26, 2004, pp. 879-886, vol. 13, Molecular Cell.
`Daviet, et al., “Targeting ubiquitin specific proteases for drug
`discovery', 2008, pp. 270-283, vol. 90, Biochimie.
`Everett, et al., “The Ability of Herpes Simplex Virus Type 1
`Immediate-Early Protein Vmwl 10 to Bind to a Ubiquitin-Specific
`Protease Contributes to Its Roles in the Activation of Gene Expres
`sion and Stimulation of Virus Replication' Jan. 1999, pp. 417-426,
`vol. 73, No. 1, Journal of Virology.
`Li, et al., “Deubiquitination of p53 by HAUSP is an important
`pathway for p53 stabilization'. Mar. 2002, pp. 648-653, Nature.
`Holowaty, et al., “Protein Interaction Domains of the Ubiquitin
`specific Protease, USP7/HAUSP”, Nov. 28, 2003, pp. 47753-47761,
`vol. 278, No. 48, The Journal of Biological Chemistry.
`Komander, et al., “Breaking the chains: structure and function of the
`deubiquitinases” Aug. 2009, pp. 550-563, vol. 10, Nature.
`Maertens, et al., "Ubiquitin-specific proteases 7 and 11 modulate
`Polycomb regulation of the INK4a tumour Suppressor', 2010, pp.
`2553-2565, vol. 29, The EMBO Journal.
`Holowaty, et al., “Protein Profiling with Epstein-Barr Nuclear
`Antigen-1 Reveals an Interaction with the Herpesvirus-associated
`Ubiquitin-specific Protease HAUSP/USP7”, Aug. 8, 2003, pp.
`29987-29994, vol. 278, No. 32. The Journal of Biological Chem
`istry.
`Faustrup, et al., “USP7 counteracts SCFP'--but not APC--
`mediated proteolysis of Claspin' Jan. 5, 2009, pp. 133-19, JCB:
`Report.
`Colland, et al., “Small-molecule inhibitor of USP7/HAUSP
`ubiquitin protease stabilizes and activates p53 in cells' Aug. 2009,
`pp. 2286-2295, vol. 8, No. 8, Mol. Cancer Ther.
`Li, et al., “Disruption of HAUSP gene stabilizes p53', 2002, pp.
`648-653, No. 416, Nature.
`Sippl. et al., "Ubiquitin-specific proteases as cancer drug targets'.
`2011, pp. 619-632, vol. 7, No. 5, Future Oncol.
`
`Summary of Chinese Official Action in corresponding Chinese
`Application No. 20128.00541482.
`Partial European Search Report dated Jun. 12, 2012 in correspond
`ing European Application No. 11306096.
`European Search Report dated Sep. 27, 2012 in corresponding
`European Application No. 11306096.
`Zhu, et al., “Synthesis and evaluation of 4-quinazolinone com
`pounds as potential antimalarial agents”, 2010, pp. 3864-3869, 45.
`European Journal of Medicinal Chemistry.
`Hutchings, et al., “An Antimalarial Alkaloid From Hydrangea III.
`Degradation', 1952 pp. 19-34, vol. 17. No. 1, Journal of Organic
`Chemistry, American Chemical Society, Easton, US.
`Cheng, et al., “Expression of HAUSP in gliomas correlates with
`disease progression and survival of patients”, 2013, pp. 1730-1736,
`vo. 29. Oncology Reports.
`Ching, et al., “A Ubiquitin-specific Protease Possesses a Decisive
`Role for Adenovirus Replication and Oncogene-mediated Transfor
`mation'. Mar. 2013, pp. 1-18, vol. 9, No. 3, PLOS Pathogens.
`Everett, et al., “A novel ubiquitin-specific protease is dynamically
`associated with the PML nuclear domain and binds to a herpesvirus
`regulatory protein', 1997, pp. 1519-1530, vol. 16, No. 7. The
`EMBO Journal.
`Cai, et al., “Ubiquitin-Specific Protease 7 Accelerates p14“f Deg
`radation by Deubiquitinating Thyroid Hormone Receptor-Interact
`ing Protein 12 and Promotes Hepatocellular Carcinoma Progres
`sion”, May 2015, pp. 1603-1614.
`Huang, et al., “Deubiquitinase HAUSP Stabilizes Rest and Promotes
`Maintenance of Neural Progenitor Cells'. Feb. 2011, pp. 142-152,
`vol. 13, No. 2, Nat Cell Biol.
`Giovinazzi, et al., “USP7 and Daxx regulate mitosis progression and
`taxane sensitivity by affecting stability of Aurora-A kinase”, 2013,
`pp. 721-731, vol. 20, Cell Death and Differentiation.
`Hong, et al., “USP7, a Ubiquitin-Specific Protease, Interacts with
`Ataxin-1, the SCA1 Gene Product’, 2002, pp. 298-306, vol. 20,
`Molecular and Cellular Neuroscience.
`Huether, et al., “The landscape of Somatic mutations in epigenetic
`regulators across 1000 pediatric cancer genomes'. Aug. 1, 2014, pp.
`1-16, vol. 5, Nat Commun.
`Jager, et al. “The Ubiquitin-Specific Protease USP7 Modulates the
`Replication of Kaposi's Sarcoma-Associated Herpesvirus Latent
`Episomal DNA”, Jun. 2012, pp. 6745-6757, vol. 86, No. 12, Journal
`of Virology.
`Chen, et al., “The Deubiquitinating Enzyme USP7 Regulates
`Androgen Receptor Activity by Modulating Its Binding to Chro
`matin”. Jul. 14, 2015, pp. 1-29, J. Biol. Chem.
`Holowaty, et al., “Protein Profiling with Epstein-Barr Nuclear
`Antigen-1 Reveals an Interaction with the Herpesvirus-associated
`Ubiquitin-specific Protease HAUSP/USP7, 2003, pp. 29987
`2.9994, vol. 278, No. 32, Issue of Aug. 8. The Journal of Biological
`Chemistry.
`Meredith, et al., “Herpes Simplex Virus Type 1 Immediate-Early
`Protein Vmw110 Binds Strongly and Specifically to a 135-kDa
`Cellular Protein', 1994, pp. 457-469, vol. 200, Virology.
`Zhao, et al., “USP7 overexpression predicts a poor prognosis in lung
`squamous cell carcinoma and large cell carcinoma, 2015, pp.
`1721-1729, vol. 36, Tumor Biol.
`Salsman, et
`al., “Proteomic Profiling of the Human
`Cytomegalovirus UL35 Gene Products Reveals a Role for UL35 in
`the DNA Repair Response”, 2011, pp. 806-820, Journal of Virology.
`Nicholson, et al., “The Multifaceted Roles of USP7: New Thera
`peutic Opportunities”, 2011, pp. 61-68, vol. 60, Cell Biochem
`Biophys.
`Zhi, et al., “STAT3 repressed USP7 expression is crucial for colon
`cancer development”, 2012, pp. 3013-3017, FEBS Letters 586.
`Morotti, et al., “BCR-ABL disrupts PTEN nuclear-cytoplasmic
`shuttling through phosphorylation-dependent activation of
`HAUSP', 2014, pp. 1326-1333, vol. 28, Leukemia.
`Noguera, et al. "Nucleophosmin/B26 regulates PTEN through inter
`action with HAUSP in acute myeloid leukemia', 2013, pp. 1037
`1043, vol. 27. Leukemia.
`
`* cited by examiner
`
`Post-Grant Review Petition for US 9,840,491
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`U.S. Patent
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`U.S. Patent
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`Jan. 17, 2017
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`US 9,546,150 B2
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`00007
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`0000€
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`0000 $,
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`U.S. Patent
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`US 9,546,150 B2
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`U.S. Patent
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`US 9,546,150 B2
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`US 9,546,150 B2
`
`1.
`SUBSTITUTED QUINAZOLIN-4-ONES FOR
`INHIBITING UBIQUITIN SPECIFIC
`PROTEASE 7
`
`2
`recently shown to be regulated by TSPYL5, a protein
`potentially involved in breast oncogenesis through a com
`petition with p53 for binding to the same region of USP7
`(Epping et al., Nat Cell Biol. 2011, 13(1):102-8). More
`recently, both upregulation and downregulation of USP7
`have been shown to inhibit colon cancer cell proliferation in
`vitro and tumor growth in Vivo, by resulting in constitutively
`high p53 levels (Becker et al. Cell Cycle 2008, 7(9), 1205
`13).
`USP7 also alters the level of the p16'Y' tumor suppres
`sor through Bmil/Me 118 stabilization (Maertens et al.,
`Embo J. 2010, 29, 2553-2565). Additional proteins involved
`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 et al., J. Cell Biol. 2009, 184(1): 13-9). Importantly,
`the abundance of USP7 and DNMT1, a protein involved in
`maintaining epigenetic methylation required to silence
`genes involved in development and cancer, correlates in
`human colon cancer (Du et al., Science Signaling, 2010,
`3(146):ra80). USP7 has also been shown in human cells to
`deubiquitinate the well-known tumor Suppressor gene
`PTEN, which provokes its nuclear export and hence its
`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.,
`Nature 2008, 455(7214), 813-7).
`USP7 has also been shown in human cells to deubiq
`uitinate FOXO4, which provokes its nuclear export and
`hence its inactivation; consequently the oncogenic PI3K/
`PKB signaling pathway was activated (van der Horst et al.,
`Nat Cell Biol. 2006, 8, 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 et al., Embo J. 2007 26,923–934, Meulmeester
`et al., 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 gluta
`mic acid residue oran amino acid with a nonpolar side chain
`and P is a glycine residue or an amino acid with nonpolar
`side chain, have been reported (WO2006072048).
`The phenotypes associated with USP7 silencing and the
`known connections between USP7 and essential viral pro
`teins 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 al., Future
`Oncology 2011, 7, 619-32). Inhibitors against USP7 were
`recently reported (Colland et al. Molecular Cancer Thera
`peutics 2009, 8, 2286-95 and EP 1 749 822 and PCT/
`EP2011/050523.2).
`However, to date, no specific and reversible USP7 small
`molecule inhibitors seem to have been reported.
`SUMMARY OF THE INVENTION
`
`According to a first object, the present invention concerns
`a compound of formula (I):
`
`
`
`(I)
`
`FIELD OF THE INVENTION
`
`The present invention concerns the discovery of new
`selective and reversible inhibitors of ubiquitin specific pro
`teases, their process of preparation and their therapeutic use.
`
`10
`
`BACKGROUND OF THE INVENTION
`
`15
`
`25
`
`30
`
`Ubiquitin specific proteases (USP) are cysteines proteases
`which belong to the deubiquitinating enzymes (DUBs) fam
`ily.
`Deregulation of the ubiquitin-proteasome system has
`been implicated in the pathogenesis of many human dis
`eases, including cancer (Hoeller et al. 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(R) (bort
`eZomib) for the 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 protea
`some itself would be to interfere with the upstream ubiquitin
`conjugation/deconjugation machinery, to generate more spe
`cific, less toxic anticancer agents.
`Mono- and polyubiquitination can be reversed by deu
`biquitinating enzymes, which specifically cleave the isopep
`tide bond at the C-terminus of ubiquitin. Ubiquitin specific
`proteases and ubiquitin C-terminal hydrolases (UCH)
`enzymes are the best characterized members of the DUB
`family (Komander et al. Nat. Rev. Mol. Cell Biol. 2009,
`35
`10(8), 550-63; Nijman et al. Cell 2005, 123(5), 773-786).
`UCHs are thought to cleave small protein substrates pref
`erentially and to be involved principally in the processing
`and recycling of ubiquitin, but their specific functions
`remain poorly understood. USPs constitute the largest sub
`family of DUBs, with more than 60 members. They remove
`ubiquitin from specific protein Substrates, thus preventing
`their targeting to the proteasome or regulating their subcel
`lular localization and activation (Daviet & Colland, Bio
`chimie 2008, 90(2), 270-83). 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 interact with
`viral proteins, such as ICP0 (Vmw 110), a herpes simplex
`virus immediate-early gene stimulating initiation of the viral
`lytic cycle (Everett et al., J Virol 73, 1999, 417-426), and
`EBNA1 (Epstein-Barr Nuclear Antigen-1) (Holowaty et al.,
`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 been identified as partners and substrates
`of USP7 (Cummins et al. Nature 2004, 486, Cummins &
`Vogelstein, Cell Cycle, 2004, 3, 689-692; Li et al. Mol Cell
`60
`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. Consistent with recent reports, USP7 silencing has
`also been shown to increase steady-state p53 levels by
`promoting Mdm2 degradation. Binding of USP7 to p53 was
`
`40
`
`45
`
`50
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`Post-Grant Review Petition for US 9,840,491
`EXHIBIT 1011
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`5
`
`10
`
`25
`
`30
`
`35
`
`15
`
`wherein
`R", each identical or different, is chosen from the group
`consisting of halogen, R, OR, NRR', CN, CF, C(O)R.
`C(O)OR, C(O)NRR, NO, (C-C)alkylene-OR, (C-
`C.)alkylene-NRR', (C-C)alkylene-COR, (C-C)
`alkylene-C(O)NRR', —O—(C-C)alkylene-COR,
`—O—(C-C)alkylene-C(O)NRR',
`CO (C-C)
`alkylene-OR, CO (C-C)alkylene-NRR', C(O)
`NH (C-C)alkylene-OR, C(O)NH (C-C)alky
`lene-NRR, OCF, SOR, SOH, SONRR', NHSOR,
`R'C=CR'', (R')(R')C=C(R'), (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
`S. preferably O:
`L' is linear or branched (C-C)alkylene optionally sub
`stituted by one or more of—O, CN, C(O)R, C(O)OR,
`or C(O)NRR', or linear or branched CH(C-C)alky
`lene, wherein the later (C-C)alkylene is optionally
`substituted by one or more of halogen, OR, NRR' or
`CF:
`X is CRR, NR, aryl, heteroaryl, cycloalkyl or hetero
`cycle, wherein the aryl, heteroaryl, cycloalkyl or het
`erocycle is optionally substituted by one or more of
`linear or branched C-C (alkyl), halogen, OR, NRR',
`CN, CF, C(O)R, C(O)OR or C(O)NRR';
`R’ is a linear or branched (C-C)alkylene and is linked
`together with R-linear or branched (C-C)alkylene to
`form with X—(CRR), N , to which they are
`attached, an heterocycle, preferably a heterocycle hav
`ing 5 to 7 members, optionally substituted by one or
`more of OR, linear or branched (C-C)alkyl, halogen,
`NRR', CN, CF, C(O)R, C(O)OR, C(O)NRR', or —O;
`R. is chosen among H 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, halo
`gen, OR, NRR', CN, CF, C(O)R, C(O)CR, C(O)NRR
`or —O;
`q is 0, 1, 2, 3 or 4
`n is 0, 1, 2 or 3:
`R’ is OR, H, halogen, linear or branched (C-C)alkyl
`OR, C(O)OR, C(O)NRR', CN, OR, NRR' or SR;
`i is either 0 or 1;
`A is chosen from the group consisting of
`linear or branched —C-C(alkyl)--C(O)—;
`linear or branched —C-C(alkyl)--C(O)NH :
`linear or branched —C-C(alkyl). SO ; or
`linear or branched —C-C(alkyl)o-SON.—;
`L is linear or branched (C-C)alkylene-O or a 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, NRR', (C-C)alkyl
`OR, (C-C)alkyl-NRR', OC(O)R, NHC(O)R, NHC(O)
`NRR', CN, C(-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 of linear 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 (C-C)alkenylene or C(O)NRR';
`R is chosen from the group consisting of C(O)R,
`C(O)NHR,
`C(O)OR,
`C(O)CH, NRR',
`C(O)—CH2—CH2—COR, —C(O)—CH2—SOH,
`—C(O)—(CHN), —POH, or their ionized form:
`65
`R' independently identical or different is chosen from a
`bond, a linear or branched (C-C)alkyl,
`
`40
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`55
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`60
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`US 9,546,150 B2
`
`3
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`4
`R' independently identical or different is chosen from an
`hydrogen atom, a linear or branched (C-C)alkyl or an
`aryl, the alkyl or aryl is optionally substituted by OH,
`NH, C(O)CH or C(O)NH;
`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 het
`erocycle is aromatic or non aromatic; optionally Sub
`stituted or not by OH, COH, C(O)NH2, NH,
`or their pharmaceutically acceptable salts or their optical
`isomers, racemates, diastereoisomers, enantiomers or tau
`tOmerS.
`The formula (I) of the invention refers to any of the
`following embodiments or any of their combinations.
`Preferably, in compound of formula (I), 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': NO; (C-C)alkylene-OR, (C-C)
`alkylene-NRR', (C-C)alkylene-CO.R., (C-C)alkylene-C
`(O)NRR', —O (C-C)alkylene-COR,
`O—(C-C)
`alkylene-C(O)NRR', CO (C-C)alkylene-OR, CO.
`(C-C)alkylene-NRR',
`C(O)NH (C-C)alkylene-OR,
`C(O)NH-(C-C)alkylene-NRR' or NHC(O)R.
`Preferably, in compound of formula (I), 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 CF.
`Preferably, in compound of formula (I), R is a linear or
`branched (C-C)alkylene and is linked together with
`R-linear or branched (C-C)alkylene to form with X—
`(CRR), N , to 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,
`CF, C(O)R, C(O)OR, C(O)NRR', or =O.
`Preferably, in compound of formula (I), R is OR, OR,
`halogen, linear or branched (C-C)alkyl-OR, C(O)OR,
`C(O)NRR' or CN. More preferably R7 is OR, OR. More
`preferably R7 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 more of linear or branched
`(C-C)alkyl, halogen, NRR', CN, CF, OR, C(O)R, C(O)
`OR, NHC(O)R, OC(O)R or C(O)NRR".
`Preferably, in compound of formula (I), A is chosen from
`the group consisting of:
`—C(O)—;
`C(O)NH :
`—SO -, or
`—SON .
`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, NRR', (C-C)alkyl-OR, (C-C)
`alkyl-NRR', OC(O)R, NHC(O)R, NHC(O)NRR', CN,
`C(-NH)NHOR.
`Preferably, it should be understood that L does not
`represent O—(C-C)alkylene.
`Preferably, in compound of formula (I):
`NR is directly bonded to at least one of C(O), C(O)N,
`SO or SON groups; and/or
`i=0, n is 1, 2 or 3 and the CRR linked to NR is C(O);
`or i=1, A is –C(O)—, C(O)NH, SO, or SON; and/or
`
`Post-Grant Review Petition for US 9,840,491
`EXHIBIT 1011
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`US 9,546,150 B2
`
`5
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`25
`
`30
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`45
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`60
`
`5
`i=0, n is 1, 2 or 3 and the CRR linked to NR is C(O);
`or i=1, A is –C(O)—, C(O)NH, SO, or SON, X is
`CRR or NR and RandR, identical or different, are
`linear or branched (C-C)alkylene and form together
`with
`X—(CRR), 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, CF, 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-C)alkyl, halogen, OR, NRR', CN, CF,
`C(O)R, C(O)OR, C(O)NRR'; and/or
`i=1 and Ais-C(O) , X is CRR or NR and RandR,
`identical or different, are linear or branched (C-C)
`alkylene and form together with X—(CRR),
`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, CF, 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-C)alkyl, halogen, OR,
`NRR', CN, CF, 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; 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
`R', each identical or different, is chosen from the group
`consisting of halogen or linear or branched —O—(C-
`C.)alkyl, and/or
`q is 0, 1 or 2; and/or
`X is CRR or NR and Rand R, identical or different,
`are linear or branched (C-C)alkylene and form
`together with X—(CRR), 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, CF, C(O)R, C(O)
`OR, or C(O)NRR'. Preferably, the heterocycle formed
`by XR (CRR), NR is a non aromatic het
`erocycle; and/or
`R. R', each identical or different, are chosen in the group
`consisting of H. linear or branched (C-C)alkyl, halo
`gen, —O, OR, NRR', CN, CF, C(O)R, C(O)OR or
`C(O)NRR'; and/or
`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
`50
`chosen in the group consisting of H and OH; and/or
`X is CRR", or aryland R7 is OR, OR, linear or branched
`(C-C)alkyl-OR, halogen, C(O)OH, NRR', C(O)NH
`or SR. Preferably, X is CRR", or aryl and R7 is OR,
`OR, NRR' or SR. More preferably, R7 is OH or OR,
`55
`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 sub
`stituted by one or more =O or is linear or branched
`CH C-C (alkylene), wherein the later alkylene is
`optionally substituted by one or more OH; and/or
`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 option
`ally substituted by one or more of R, OR, NRR',
`65
`(C-C)alkyl-OR, (C-C)alkyl-NRR', OC(O)R, NHC
`(O)R, NHC(O)NRR', CN, C(-NH)NHOR. More pref
`
`6
`erably L is linear or branched C-C(alkylene) or
`linear or branched —C-C (alkylene)—O—; and/or
`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-C)alkyl; and/or
`R is chosen from the group consisting in phenyl, thio
`phenyl, cyclopenty1 and H, wherein the phenyl is
`optionally Substituted by halogen, linear or branched
`O—(C-C)alkyl.
`In one embodiment, in the compound of formula (I), X is
`CR'R' or NR and R and R form together with
`X—(CRR), N to which they are attached an hetero
`cycle 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 CRR wherein R7 is OR, OR, linear or
`branched (C-C)alkyl-OR, halogen, C(O)OH, C(O)NH2,
`NRR' or SR, and/or L' is (CH), wherein k is 1 or 2.
`preferably k is 1,
`C(O)—, CH-CH(OH)– or
`CH, C(O) . Preferably R7 is OR, OR, NRR' or SR.
`More preferably, R is OH or OR, preferably OH. R being
`as defined above.
`In another embodiment, in the compound of formula (I),
`X is 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, CF, 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
`—CH-CH(OH)—.
`DETAILED DESCRIPTION OF THE
`PREFERRED EMBODIMENTS
`
`According to a particular embodiment, compounds of the
`invention may be of the following formula (Ia)
`
`(Ia)
`
`wherein
`R', q, L', L, R and R are as defined in formula (I);
`X is CR7 or N:
`n is 0, 1 or 2:
`p is 1, 2 or 3:
`R. RandR, 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, CF,
`OR, C(O)R, C(O)OR or C(O)NRR".
`Preferably in the compound of formula (Ia), 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 compound of formula (Ia)
`
`-x-1 Sy
`
`CR8
`
`Post-Grant Review Petition for US 9,840,491
`EXHIBIT 1011
`Page 11
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`

`7
`-continued
`(R),
`
`(R),
`
`|\
`
`N-
`
`|\
`
`N
`
`R7
`
`R7
`
`(R),
`
`(R),
`
`–C) -()-
`
`t is 0, 1 or 2 preferably
`
`(R),
`
`–C) -O-
`
`wherein R is OR, halogen, linear or branched (C-C)
`alkyl-OR, C(O)OR, C(O)NRR', CN, OR, NRR' or SR,
`30
`more preferably OR, OR, NRR' or SR, preferably OH or
`OR, p is 1 or 2 and R is chosen in the group consisting of
`H or OH.
`According to a particular embodiment, compounds of the
`invention may be of the following formula (Ia)
`
`35
`
`O
`
`(CRRS)
`L-X 1. S.
`y
`N N1
`Y(CR-3R4),
`
`2
`
`2 N
`
`(Ia)
`
`2
`6
`L.-R
`
`40
`
`O
`
`wherein
`R", q, L. L. R and R7 are as defined in formula (I);
`X is CR 7 or N:
`n is 0, 1 or 2:
`p is 1, 2 or 3:
`R. R. Rand R, each identical or different, are chosen
`in the group consisting of H. linear or branched (C-
`C.)alkyl, halogen, OH, - O