WO2017063757A1 - Composés macrocycliques à conformation limitée - Google Patents

Composés macrocycliques à conformation limitée Download PDF

Info

Publication number
WO2017063757A1
WO2017063757A1 PCT/EP2016/025114 EP2016025114W WO2017063757A1 WO 2017063757 A1 WO2017063757 A1 WO 2017063757A1 EP 2016025114 W EP2016025114 W EP 2016025114W WO 2017063757 A1 WO2017063757 A1 WO 2017063757A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
mmol
soln
diseases
ocf
Prior art date
Application number
PCT/EP2016/025114
Other languages
English (en)
Inventor
Daniel Obrecht
Original Assignee
Polyphor Ag
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Polyphor Ag filed Critical Polyphor Ag
Publication of WO2017063757A1 publication Critical patent/WO2017063757A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/18—Bridged systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention provides novel, conformationally constrained macrocyclic compounds of formula (I), as described herein below, having a substituent E that contains at least one ester moiety.
  • These conformationally constrained macrocyclic compounds exhibit antiproliferative activity on various cancer cell lines.
  • they can be metabolized to compounds with modulating activity on the peptidyl-prolyl cis/trans isomerase Pin1 and may thus be useful in the treatment or prevention of a variety of diseases, conditions and disorders mediated by or sustained through the activity of Pin1 , or in the support of therapeutic treatments of specific disease conditions of primarily different cause.
  • the present invention relates to methods of using these compounds in the treatment of various diseases and disorders, and to pharmaceutical compositions and forms comprising these compounds.
  • PPIases Peptidyl-prolyl cis/trans isomerases
  • the peptidyl-prolyl isomerase Pin1 (protein interacting with NIMA 1 (K. P. Lu et al., Nature 1996, 380(6574), 544-547)), belonging to the parvulin class of PPIase, is a phosphorylation-dependent peptidyl-prolyl isomerase that shows a unique substrate specificity for phosphorylated Ser/Thr-Pro motif(s).
  • This conformational isomerization by Pin1 has been reported to be critically involved in diverse regulatory processes (K. P. Lu et a/., Nat. Chem Biol. 2007, 3(10), 619-629), affecting the function, protein- protein interactions, subcellular localization, protein phosphorylation, and stability of corresponding substrate proteins (Y.-C.
  • Human Pin1 is a small protein of 163 amino acids, comprising an N-terminal WW domain for substrate recognition, a flexible linker, and a C-terminal catalytic peptidyl- prolyl isomerase (PPI) domain (P.-J. Lu et al, J. Biol. Chem. 2002, 277(4), 2381 - 2384).
  • PPI catalytic peptidyl- prolyl isomerase
  • Pin1 inhibitors comprising peptidic and non-peptidic compounds.
  • Pin1 was identified as target of all- trans retinoic acid (S. Wei eta/., Nat. Med. 2015, 21 (5), 457-466) which is used in the therapy for acute promyelotic leukemia and was also applied in clinical trials for treatment of advanced breast cancer.
  • Other known Pin1 inhibitors are less advanced.
  • potential liabilities concerning selectivity and/or stability and/or potency and/or activity on whole cells were reported (J. D. Moore, A. Potter, Bioorg. Med. Chem. Lett. 2013, 23, 4283-4291 and literature cited therein).
  • peptidic Pin1 inhibitors comprise elements that mimic the phospho-Ser/Thr and/or proline moieties of the phosphorylated Ser/Thr-Pro motif in Pin1 substrates. Mimicry of the phospho-Ser/Thr moiety was mainly achieved by phosphonic or phosphoric acid-bearing residues, and corresponding peptidic inhibitors of Pin1 were frequently reported to be inactive or only weakly active in whole cell experiments. This issue was addressed by a combination strategy based on cell-penetrating peptides (W. Lian eta/., J. Am. Chem. Soc. 2014, 136(28), 9830-9833; T. Liu eta/., J. Med. Chem. 2010, 53(6), 2494-2501 ) or masking the acidic moiety by a prodrug-type ester (WO2006/124494 A1 ).
  • Pin1 inhibitors have been published in addition to the above- mentioned a ⁇ -trans retinoic acid, including, naphthoquinone juglone, a non-reversible Pin1 inhibitor (L. Hennig et a/., Biochemistry 1998, 37, 5953-5960), hydroxy- naphthoquinone buparvaquone, used for treatment of certain parasitic infections in animals (J. Masolier et a/, Nature 2015, 520, 378-382), compounds comprising various acidic functional groups to mimic the phosphate group of the substrate (C. Guo et a/., Bioorg. Med. Chem. Lett.
  • Pin1 modulators may be useful in the treatment or prevention of other diseases and conditions related to abnormal cell growth (Z. Lu, T. Hunter, Cell Res. 2014, 24, 1033-1049 and literature cited therein; E. S. Yeh, A. R. Means, Nat. Rev.
  • Pin1 has been reported to control normal and cancer stem cells in the human breast (Rustighi A. et a!, Mol. Med. 2014, 6(1), 99- 1 19), including effects mediated through the p53 pathway (J. E. Giardini et a!, Cancer Cell 2011 , 12, 79-91 ; F. Mantovani et a/., Biochim. Biophys. Acta 2015, 1850(10), 2048-2060).
  • Evidence on the role of Pin1 in tumorigenesis of breast cancer has also been obtained from studies in in vivo models (G. Wulf eta/., EMBO J. 2004, 23, 3397-3407).
  • Pin1 inhibitors may be useful for the treatment and/or prevention of other diseases or conditions, including asthma (P. Anders, Nat. Immunol. 2005, 6, 121 1-1212), allergic pulmonary eosinophilia (S. Esnaut etai, J. Allergy Clin. Immunol. 2007, 120, 1082-1088), pulmonary fibrosis, for example caused by chronic asthma (Z.-J. Shen et ai, J. Clin. Invest. 2008, 118(2), 479-490), stroke (S. H. Baik et ai, Ann. Neurol. 2015, 77(3), 504-517), viral infections, for example HIV/AIDS (H.
  • Pin1 is also suggested to be involved in other neurodegenerative diseases, including Huntington's disease (M. T. Lin, M. F. Beal, Nature 2006, 443, 787-795; A. Grison et al., /VAS 2011 , 108(44), 17979-17984) and frontotemporal dementia that is associated with a mutation in the tau gene (J. Lim et al, J. Clin. Invest. 2008, 118(5), 1877-1889).
  • Pin1 inhibitors may also be useful for the treatment or prevention of certain parasite infections in animals, including infections of cattle with Theileria parasites (J. Masolier et al., Nature 2015, 520, 378-382). Importantly, the homologue of Pin1 in Theileria annulata was demonstrated to play a key role in maintaining bovine leukocyte transformation, and Pin1 inhibitor buparvaquone was able to reverse transformed phenotypes.
  • the compounds of the invention show antiproliferative activity on various cancer cell lines, including THP-1 , MHHES1 , A673, and BT20 cells.
  • the THP-1 cell line has been used for the study of anticancer compounds, including antileukemic drugs (P. W. Hollenbach et al., PLoS CWE2010, 5(2); doi:10.1371/journal.pone.0009001 ), and has been reported as model for immune modulation studies (W. Chanput et ai, Int. Immunopharmacol. 2014, 23(1), 37-45).
  • results from experiments using THP-1 cells suggested a role of Pin1 in nonalcoholic steatohepatitis (Y. Nakatsu et al., J. Biol. Chem.
  • the breast cancer cell line BT20, and Ewing's sarcoma cell lines MHHES1 and A673 have been applied in cancer research, including studies based on BT20 cells (A. D. Hughes et ai, Cancer Letters 2014, 352, 28-35; A. A. Pritsa et ai, Anticancer Drugs 2001 , 12(2), 137-142), studies based on MHHES1 cells (D. G. Gimenez et ai, Planta Med.
  • the present invention provides new chemical entities which contain a macrocyclic backbone with appended substituents, including E, G, and Q.
  • Substituent E comprises at least one ester moiety, that can be metabolized to liberate the corresponding acid moiety, which is involved in the mimicry of the phospho-Ser/Thr moiety of Pin1 substrates. Additionally, it is essential that compounds of the invention comprise an aromatic group in substituents G and/or Q, as described herein below.
  • Compounds based on macrocyclic scaffolds and modular approaches for their synthesis have been described in the literature and also in patent applications WO201 1/014973 A2, WO201 1/015241 A1 and WO2013/139697 A1 .
  • the three latter publications contain versatile methods to generate macrocyclic compounds using combinatorial and parallel synthesis strategies.
  • the present invention relates to compounds of formula (I)
  • L is -C(O)-; or -S(0) 2 -;
  • V is -OC(O)-; -NR 7 C(0)-; -SC(O)-; -OS(0) 2 -; or -NR 7 S(0) 2 -; r is an integer of 1-2;
  • t is an integer of 0-1;
  • i and p are independently an integer of 0-3 with the proviso that 1 ⁇ i+p ⁇ 3;
  • R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are independently H; F; or CH 3 ;
  • R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are F; or CH 3 ;
  • R 7 is H; Ci-3 alkyl; or cyclopropyl;
  • R 8 is H; or F
  • R 9 is H; F; CF 3 ; orCi-3-alkyl
  • R 10 , R 11 , R 12 , R 3 , and R 14 are independently H; F; or C1-3 alkyl;
  • R 10 , R 11 , R 12 , R 13 , and R 14 are F; or Ci -3 alkyl; R 15 is H; or Ci- 3 alkyl;
  • R 6 is H; F;orCH 3 ; E is a group of one of the formulae
  • R 17 is -C(0)OR 18a ; or -P(0)(OR 18a )(OR 18b );
  • R 18a is Ci-4-alkyl; C3-4-cycloalkyl; benzyl; phenyl; or a group of formula
  • R 8b is F1 ;
  • R 19 is Ci-4-alkyl; -CHR 20 R 21 ; oxetan-2-yl; oxetan-3-yl; or -(CH 2 )jCH 2 OH;
  • R 20 and R 21 are independently H; or Ci-4-alkyl
  • R 20 and R 21 together with the carbon atom to which they are connected can form C3-6-cycloalkyl moieties
  • R 22 is H; Ci-2-alkyl; -(CHR 23 ) 0 C(0)OR 8a ; -(CHR 23 ) 0 P(0)(OR 8a )(OR 8b );
  • R 23 is H; F; or CH 3 ;
  • R 24a and R 24b are independently H; or CH 3 ;
  • Z is -C(O)-; -S(0) 2 -; -OC(O)-; -OS(0) 2 -; -NR 24 C(0)-; or -NR 24 S(0) 2 -;
  • Z 2 is -C(O)-; -S(0) 2 -; -(CHR 23 )-; -OC(O)-; -OS(0) 2 -; -NR 2 C(0)-;
  • d is an integer of 0-1 ;
  • j is an integer of 0-3;
  • E is E3; E4; E5; or E6; o is an integer of 0-1 ; with the proviso that
  • G is H; Ci-6-alkyl; C2-6-alkenyl; C3-6-cycloalkyl; C3-6-heterocyclyl; C6-io-aryl;
  • R 25 is H; F; CH 3 ; CF 3 ; OCH 3 ; OCF 3 ; or OCHF 2 ;
  • R 26 is H; F; CI; CF 3 ; OCF 3 ; OCHF 2 ; Ci -2 -alkyl; Ci -2 -alkoxy; or Ci -2 -thioalkoxy;
  • R 27 is H; F; CI; CF 3 ; OCF 3 ; OCHF 2 ; CN; Ci -3 -alkyl; Ci -3 -alkoxy;
  • Ci- 3 -thioalkoxy -C(0)NR 3 R 32 ; or -S(0) 2 NR 3 R 32 ;
  • R 28 is H; F; CI; CF 3 ; CN; OCF 3 ; OCHF 2 ; Ci -3 -alkyl; Ci -3 -alkoxy; or
  • R 29 is H; F; CF 3 ; OCF 3 ; OCHF 2 ; Ci -3 -alkyl; Ci -3 -alkoxy; or Ci -3 -thioalkoxy;
  • R 30 is H; F; CI; CF 3 ; OH; OCF 3 ; OCHF 2 ; N0 2 ; Ci -3 -alkyl; Ci -3 -alkoxy;
  • Ci- 3 -thioalkoxy or -NR 3 R 32 ;
  • R 31 and R 32 are independently H; or CH 3 ;
  • R 33 is H; Ci-3-alkyl; or -C(0)-Ci -3 -alkyl;
  • T is N; or CR 25 ;
  • M is 0; S; or NR 33 ; with the proviso that
  • R 34 in Q1 is H ; F; CF 3 ; OH ; SH ; Ci -8 -alkyl; C 2 - 8 -alkenyl; C 2-8 -alkynyl; Ci-8-alkoxy; Ci-e-thioalkoxy; C 3- 8-cycloalkyl; C 3- 8-heterocyclyl; or
  • G is C6-io-aryl; Cs-io-heteroaryl; or a group of one of the formulae G1 to G14;
  • Q is O; S; -S(O)-; -S(0) 2 -; or a group of one of the formulae
  • Z 3 is -(CHR 47 )-; O; -C(O)-; -C(0)NR 48 -; -NR 48 C(0)-; -NR 48 C(0)NR 48 -;
  • R 34 is H; F; CF 3 ; OH; SH; Ci -8 -alkyl; C 2-8 -alkenyl; C 2-8 -alkynyl; Ci -8 -alkoxy;
  • Ci-e-thioalkoxy C 3- 8-cycloalkyl; C 3- 8-heterocyclyl; C6-io-aryl;
  • R 35 is H; or CH 3 ;
  • R 36 is a group of one of the formulae
  • R 37 is H; F; CI; CH 3 ; OCH 3 ; CF 3 ; OCF 3 ; or OCHF 2 ;
  • R 38 is H; F; CI; CF 3 ; OCF 3 ; OCHF 2 ; Ci-4-alkyl; C 2-4 -alkenyl; Ci -4 -alkoxy;
  • Ci -4 -thioalkoxy or C 3-4 -cycloalkyl
  • R 39 is H; F; CI; Br; I; CF 3 ; OH; OCF 3 ; OCHF 2 ; N0 2 ; CN; Ci -6 -alkyl; Ci -6 -alkoxy;
  • Ci-6-thioalkoxy C 3-6 -cycloalkyl; C 3-6 -heterocyclyl; -C(0)OR 18a ;
  • R 40 and R 41 are independently H; or Ci -3 -alkyl
  • R 42 is C6-aryl-Ci- 4 -alkyl; C5-6-heteroaryl-Ci -4 -alkyl; or a group of formula
  • R 43 is C6-aryl; Cs-6-heteroaryl; or a group of one of the formulae
  • R is H; F; CI; CF 3 ; OH; OCF 3 ; OCHF 2 ; N0 2 ; CN; Ci-4-alkyl; Ci-4-alkoxy;
  • Ci -4 -thioalkoxy or C 3-4 -cycloalkyl
  • R 45 is H; F; CI; CF 3 ; OCF 3 ; OCHF 2 ; Ci-4-alkyl; Ci-4-alkoxy; or Ci -4 -thioalkoxy;
  • R 46 is H; Ci-e-alkyl; -C(0)-Ci -6 -alkyl; or -C(0)-C 3 - 6 -cycloalkyl;
  • R 7 is H; F; CI; CH 3 ; or CF 3 ;
  • R 8 is H; or Ci -3 alkyl
  • M' is O; S; or NR 46 ;
  • T' is N; or CR 37 ;
  • e is an integer of 0-1 ;
  • g is an integer of 0-2; with the proviso that,
  • G is H; Ci-6-alkyl; C2-6-alkenyl; C 3- 6-cycloalkyl; or C 3- 6-heterocyclyl;
  • Q is Q1 ; or Q2; R 34 in Q1 is C6-io-aryl; or Cs-io-heteroaryl; and with the proviso that,
  • Q is Q1 ; or Q2;
  • G is H; C1-6 alkyl; C2-6-alkenyl; C 3- 6-cycloalkyl; or C 3- 6-heterocyclyl;
  • R 34 in Q1 is C6-io-aryl; or Cs-io-heteroaryl; and with the proviso that
  • Y is CR 49 ; NR 55 ; N; O; or S;
  • Y 2 is CR 50 ; NR 55 ; N; O; or S;
  • Y 3 is CR 51 ; NR 55 ; N; O; or S; with the proviso that
  • the aromatic 5-membered ring system is a group of one of the formulae
  • Y 1 is CR 49 ; or N
  • Y 2 is CR 50 ; or N
  • Y 3 is CR 51 ; orN
  • Y 4 is CR 52 ; or N with the proviso that
  • aromatic 6-membered rin s stem is a rou of one of the formulae
  • R 49 and R 50 are independently H; F; CI; CH 3 ; CH 2 CH 3 ; CF 3 ; OCH 3 ; OCF 3 ; or
  • R 51 is H; F; CI; CF 3 ; OCF 3 ; OCHF 2 ; N0 2 ; NH 2 ; OH; CN; Ci-4-alkyl; C 2-4 -alkenyl;
  • R 52 is H; F; CI; CH 3 ; CF 3 ; OCF 3 ; OCHF 2 ; or OCH 3 ;
  • R 53 and R 54 are independently H; or Ci -2 -alkyl
  • R 53 and R 54 together with the nitrogen atom to which they are connected can form C 3- 5-heterocyclyl moieties
  • R 55 is H; or CH 3 ; and wherein
  • each such compound at most 12 halogen substituents are present; or stereoisomers; or tautomers or rotamers thereof; or a salts; or a pharmaceutically acceptable salts; or a solvates thereof.
  • a bond drawn as dotted line indicates the point of attachment of the corresponding radical or substituent.
  • substituents for example, but not limited to, R 3 , R 4 , R 10 , R 11 , R 12 , R 13 , R 8a , R 8b , R 19 , R 20 , R 21 , R 23 , R 47 , and R 48 ; as well as some of the indices (for example o, and g) may occur several times within the same molecular entity. In such a case each of them shall be selected independently from others specified by the same symbol, unless otherwise indicated.
  • Salts as understood herein are especially, but not limited to, the pharmaceutically acceptable salts of compounds of formula (I). Such salts are formed, for example, as acid addition salts with organic or inorganic acids, from macrocyclic compounds of the invention with a basic nitrogen atom. Suitable inorganic acids are, for example, halogen acids, such as hydrochloric acid, sulfuric acid, or phosphoric acid.
  • Suitable organic acids are, for example, carboxylic, phosphonic, sulfonic or sulfamic acids; like acetic acid, propionic acid, octanoic acid, decanoic acid, dodecanoic acid, glycolic acid, lactic acid, fumaric acid, succinic acid, adipic acid, pimelic acid, suberic acid, azelaic acid, malic acid, tartaric acid, citric acid, amino acids, such as glutamic acid or aspartic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, cyclohexanecarboxylic acid, adamantine-carboxylic acid, benzoic acid, salicylic acid, 4 aminosalicylic acid, phthalic acid, phenylacetic acid, mandelic acid, cinnamic acid, methane- or ethane-sulfonic acid, 2-hydroxy-ethanesulfonic acid, ethane-1 ,2- dis
  • alkyl taken alone or in combinations (i.e. as part of another group, such as “aryl-Ci-6-alkyl”), designates saturated, straight-chain or branched hydrocarbon radicals and, unless otherwise indicated, may be optionally substituted with at most 2 substituents selected from the group of F and CI.
  • Cx-y-alkyl (x and y each being an integer) refers to an alkyl group as defined above containing x to y carbon atoms. For example a Ci-6-alkyl group contains one to six carbon atoms.
  • alkyl groups include methyl, ethyl, n- propyl, /so-propyl, /7-butyl, /so-butyl, sec-butyl, fe -butyl, /7-pentyl, /7-hexyl and the like.
  • alkenyl taken alone or in combinations, designates straight chain or branched hydrocarbon radicals containing at least one or, depending on the chain length, up to four olefinic double bonds. Such alkenyl moieties, unless otherwise indicated, may be optionally substituted with at most 2 substituents selected from the group of F and CI, and can independently exist as E or Z configurations per double bond, which are all part of the invention.
  • C x - y -alkenyl (x and y each being an integer) refers to an alkenyl group as defined above, containing x to y carbon atoms. Examples of this moiety include, but are not limited to, vinyl, prop-1-en-1-yl, 2- methylprop-1 -en-1 -yl, and allyl.
  • alkynyl designates straight chain or branched hydrocarbon radicals containing at least one or, depending on the chain length, up to four triple bonds.
  • C x - y -alkynyl (x and y each being an integer) refers to an alkynyl group as defined above, containing x to y carbon atoms. Examples of this moiety include, but are not limited to, prop-2-yn-1 -yl.
  • cycloalkyi refers to a saturated or partially unsaturated alicyclic moiety having from three to eight carbon atoms and, unless otherwise indicated, may be optionally substituted with at most 2 substituents selected from the group of F and CI.
  • C x-y -cycloalkyl (x and y each being an integer) refers to a cycloalkyi group as defined above, containing x to y carbon atoms. Examples of this moiety include, but are not limited to, cyclobutyl, cyclohexyl, norbornyl and the like.
  • heterocyclyl describes a saturated or partially unsaturated mono- or bicyclic moiety having from one to seven ring carbon atoms and one or more ring heteroatoms selected from oxygen, sulphur or nitrogen, provided the nitrogen is forming an aromatic amino group, or is part of an amide, urea, urethane, or sulfonamide group within the heterocyclyl moiety.
  • C x - y -heterocyclyl (x and y each being an integer) refers to a heterocyclyl group as defined above, containing x to y ring atoms. Examples of this moiety include, but are not limited to, morpholino, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, and the like.
  • aryl taken alone or in combinations, designates aromatic carbocyclic hydrocarbon radicals containing one or two six-membered rings.
  • C6-aryl refers to phenyl.
  • C6-io-aryl refers to phenyl or naphthyl, which, unless otherwise indicated, may be optionally substituted with at most 3 substituents selected from the group of F, CI, CF3, OCF3, and OCF2.
  • heteroaryl taken alone or in combinations, designates aromatic heterocyclic radicals containing one or two five- and/or six-membered rings, at least one of them containing up to four heteroatoms selected from the group consisting of O, S and N and whereby the heteroaryl radicals or tautomeric forms thereof may be attached via any suitable atom.
  • C x-y -heteroaryl (x and y each being an integer) refers to a heteraryl group as defined above, containing x to y ring atoms. Said heteroaryl ring(s) are optionally substituted, e.g. as indicated above for "aryl".
  • C5-6-heteroaryl examples include, but are not limited to, furanyl, oxazolyl, isoxazolyl, thiophenyl, thiazolyl, isothiazolyl, pyrrolyl, pyrimidinyl, pyridyl and the like.
  • Cs-io-heteroaryl examples include, but are not limited to, furanyl, oxazolyl, isoxazolyl, thiophenyl, thiazolyl, isothiazolyl, pyrrolyl, pyrimidinyl, pyridyl, quinolinyl, benzothiofuranyl and the like.
  • -C(0)-C x - y -alkyl refers to an C x-y -alkyl group as defined above, connected to a carbonyl group.
  • Representative examples of -C(0)-C x-y -alkyl moieties include, but are not limited to, acetyl, propanoyl, /so-butanoyl and the like.
  • -C(0)-C3-6-cycloalkyl refers to an C x-y -cycloalkyl group as defined above, connected to a carbonyl group.
  • C6-aryl-C x-y -alkyl refers to an C x-y -alkyl group as defined above, substituted by an C6-aryl group, as defined above.
  • Representative examples of C6-aryl-C x-y -alkyl moieties include, but are not limited to, benzyl, 1-phenylethyl, 2- phenylethyl, 3-phenylpropyl, 2-phenylpropyl and the like.
  • C5-6-heteroaryl-C x-y -alkyl refers to an C x-y -alkyl group as defined above, substituted by a Cs-6-heteroaryl group, as defined above.
  • Examples of C5-6-heteroaryl-C x-y -alkyl groups include pyridin-3-ylmethyl, (1 H-pyrrol-2- yl)ethyl and the like.
  • alkoxy and "aryloxy”, taken alone or in combinations, refer to the groups of -O-alkyl and -O-aryl respectively, wherein an alkyl group or an aryl group is as defined above.
  • C x-y -alkoxy refers to an -O- alkyl group as defined above containing x to y carbon atoms attached to an oxygen atom.
  • alkoxy groups include methoxy, ethoxy, n- propoxy, /so-propoxy, /7-butoxy, fe -butoxy and the like.
  • aryloxy include e.g. phenoxy.
  • thioalkoxy taken alone or in combinations, refers to an -S-alkyl group, wherein an alkyl group is as defined above.
  • C x-y -thioalkoxy refers to an -S-alkyl group as defined above containing x to y carbon atoms attached to an sulfur atom.
  • Representative examples of thioalkoxy groups include methlythio, ethylthio and the like.
  • halogen refers to a fluorine substituent (F), a chlorine substituent (CI), a bromine substituent (Br) or an iodine substituent (I).
  • Amino designates primary, secondary or tertiary amine groups. Particular secondary and tertiary amine groups are alkylamine, dialkylamine, arylamine, diarylamine, arylalkylamine and diarylamine groups wherein the alkyl or aryl is as herein defined and optionally substituted.
  • heteroatom refers to any atom that is not carbon or hydrogen.
  • a further embodiment (2) of the invention relates to compounds of formula (I) according to embodiment (1 ),
  • a further embodiment (3) of the invention relates to compounds of formula (I) according to embodiment (2),
  • L is -C(O)-
  • X is O
  • V is -OC(O)-; r is 1;
  • R 1 to R 16 , and R 35 are H; Eis E1;E2;orE3;
  • R 18a is Ci-3-alkyl; orF1;
  • R 19 is Ci-4-alkyl
  • R 20 is H
  • R 21 is H; orCi-3-alkyl
  • R22 is H; -(CHR 23 ) 0 C(0)OR 18a ; or -(CHR 23 ) 0 P(0)(OR 18a )(OR 18b );
  • R 23 , R24a, and R 24b are H;
  • Z is -C(O)-
  • Z 2 is -C(0)NH-; d is 0;
  • E E2
  • o is an integer of 0-1 ;
  • G is Ci-3-alkyl; G5; G13;
  • R 25 is H
  • R 26 , R 27 , and R 28 are independently H; F; CI; CH 3 ; CF 3 ; OCH 3 ; OCF 3 ; or OCHF 2 ;
  • R 29 is H; F; CH 3 ; or CF 3 ;
  • R 3 ° is H; OH; or NH 2 ; Tis N; orCH; with the proviso that
  • G13 is a group of one of the formulae
  • R 34 in Q1 is H; F; CF 3 ; OH; Ci-4-alkyl; C 2- -alkenyl; or Ci-4-alkoxy;
  • Z 3 is -NR 48 C(0)-; -NR 48 C(0)NR 48 -; or -NR 8 S(0) 2 -;
  • R 34 is H; F; CF 3 ; OH; Ci -4 -alkyl; C 2 - 4 -alkenyl; or Ci -4 -alkoxy;
  • R 37 is H; F; CI; CH 3 ; OCH 3 ; CF 3 ; OCF 3 ; or OCHF 2 ;
  • R 38 is H; F; CI; CF 3 ; OCF 3 ; OCHF 2 ; Ci-*-alkyl; C 2-4 -alkenyl; Ci- 4 -alkoxy;
  • Ci -4 -thioalkoxy or C 3-4 -cycloalkyl
  • R 39 is H; F; CI; Br; I; CF 3 ; OH; OCF 3 ; OCHF 2 ; CN; Ci- 6 -alkyl; Ci- 6 -alkoxy;
  • Ci-6-thioalkoxy C 3 -6-cycloalkyl; or C 3- 6-heterocyclyl;
  • R 3 is H13
  • R 44 is H; F; CI; CF 3 ; OCF 3 ; OCHF 2 ; Ci--alkyl; or
  • R 5 is H; F; CI; or CH 3 ;
  • R 47 and R 48 are H; m and n are 0;
  • g is 0;or1;
  • Q is Q1 ; or Q2;
  • R 49 , R 50 and R 52 are independently H; F; CI; CH 3 ; CF 3 ; OCH 3 ; OCF 3 ; or OCHF 2 ;
  • R 51 is H; F; CI; CF 3 ; OCF 3 ; OCHF 2 ; NH 2 ; Ci -3 -alkyl; or Ci -3 -alkoxy; with the proviso that in H24 two of the substituents are H; or tautomers or rotamers thereof; or salts; or pharmaceutically acceptable salts; solvates thereof.
  • a further embodiment (4) of the invention relates to compounds of formula (I) according to embodiment (3),
  • R 17 is -C(0)OR 18a ;
  • R 22 is H; or -(CHR 23 ) 0 C(0)OR 18a ; in substituent Q
  • R 34 is H; F; CF 3 ; OH; Ci -4 -alkyl; or Ci-4-alkoxy;
  • R 36 is is a group of one of the formulae
  • R 37 and R 38 are H; F; CI; CH 3 ; OCH 3 ; CF 3 ; OCF 3 ; or OCHF 2 ;
  • R 39 is H; F; CI; CF 3 ; OH; OCF 3 ; OCHF 2 ; Ci-4-alkyl; Ci-4-alkoxy;
  • M' is 0; or S; or tautomers or rotamers thereof; or salts; or pharmaceutically acceptable salts; solvates thereof.
  • a further embodiment (5) of the invention relates to compounds of formula (I) according to embodiment (3),
  • G is phenyl; 1-naphthyl; 2-naphthyl; G5'; G5"; G5 m ; G5 IV ; G5 V ; G5 VI ; G5 VM ;
  • Z 3 is -NHC(O)-; or -NHC(0)NH-;
  • R 34 is H;OH;orOCH 3 ; 3 6 is a group of one of the formulae
  • Q is Q1 ; or Q2;
  • Q is O; or Q1 ; R 34 in Q1 is H; in H29 positioned between functional moieties L and X
  • R 49 , R 50 , R 51 , and R 52 are H; or
  • R 49 is F
  • R 50 is H
  • R 51 is H
  • R 52 is F
  • R 49 is F, R 50 is F, R 51 is H, and R 52 is H; or
  • R 49 is H, R 50 is H, R 51 is H, and R 52 is CI; or
  • R 49 is CI, R 50 is H, R 51 is H, and R 52 is H; or
  • R 49 is OCHs, R 50 is H, R 51 is H, and R 52 is H; or
  • R 49 is H, R 50 is H, R 51 is H, and R 52 is OCH 3 ; or
  • R 49 is H, R 50 is H, R 51 is NH 2 , and R 52 is H; or tautomers or rotamers thereof; or salts; or pharmaceutically acceptable salts; solvates thereof.
  • a further embodiment (6) of the invention relates to compounds of formula (I) according to embodiment (5),
  • E is a group of one of the formulae E1 1 ; E1"; E1 m ; E3'; or E3";
  • G is phenyl; 1-naphthyl; 2-naphthyl; or a group of one of the formulae G5";
  • G5' ; G5 VI ; orG13 lv ;
  • Z 3 is -NHC(O)-
  • R 34 is H;orOCH 3 ;
  • R 36 is a group of one of the formulae H2 m ; H2 IX ; or H2 XI ; with the proviso that,
  • Q is O; or Q1 ; R 34 in Q1 is H; in H24 positioned between functional moieties L and X
  • R 49 , R 50 , R5 i , and R 52 are H; or tautomers or rotamers thereof; or salts; or pharmaceutically acceptable salts; or solvates thereof.
  • a further embodiment (7) of the invention relates to compounds of formula (I) according to embodiment (6),
  • R 18a and R 18b areF1; or tautomers or rotamers thereof; or salts; or pharmaceutically acceptable salts; or solvates thereof.
  • a further embodiment (8) of the invention relates to compounds of formula (I) according to embodiment (6),
  • E is E1 1 ; E3 1 ; or E3";
  • R 18a is CH 3 ; or CH 2 CH 3 ; or tautomers or rotamers thereof; or salts; or pharmaceutically acceptable salts; or solvates thereof.
  • a further embodiment (9) of the invention relates to compounds of formula (I) according to embodiment (6),
  • E is E3';
  • R 18a is CH 2 CH 3 ; or tautomers or rotamers thereof; or salts; or pharmaceutically acceptable salts; or solvates thereof.
  • a further embodiment (10) of the present invention may also include compounds, which are identical to the compounds of formula (I), except that one or more atoms are replaced by an atom having an atomic mass number or mass different from the atomic mass number or mass usually found in nature, e.g. compounds enriched in 2 H (D), 3 H, 11 C, 14 C, 127 l etc.
  • isotopic analogs and their pharmaceutical salts and formulations are considered useful agents in the therapy and/or diagnostic, for example, but not limited to, where a fine-tuning of in vivo half-life time could lead to an optimized dosage regimen.
  • a further embodiment (1 1) of the invention relates to compounds of formula (I) according to embodiment (1 ) which are selected from the group consisting of Ex.1 to Ex.8, the lUPAC names of which are shown in Table 01 b; or tautomers or rotamers thereof; or salts; or pharmaceutically acceptable salts; or solvates thereof.
  • Table 01 b the group consisting of Ex.1 to Ex.8, the lUPAC names of which are shown in Table 01 b; or tautomers or rotamers thereof; or salts; or pharmaceutically acceptable salts; or solvates thereof.
  • the macrocyclic compounds of the invention can formally be dissected into building blocks A, B, and C. Additionally, building block C can be divided into two appropriately substituted subunits c1 and c2.
  • Building block A is based on appropriately substituted and protected divalent phenol or thiophenol derivatives.
  • Building block B is corresponding to appropriately substituted and protected secondary aminoalcohols.
  • appropriately substituted subunits c1 and c2 are derived from suitably substituted and protected precursors, like, but not limited to, appropriately substituted and protected amino acids derivatives.
  • pyrrolidine derivatives comprising a carboxy group in alpha-position to the cyclic amine can be accessed through commercially available building blocks or from building blocks that are accessible through well established synthesis strategies.
  • Piperidine derivatives comprising a carboxy group in alpha position to the cyclic amine can be prepared by various routes.
  • Efficient approaches for 3-hydroxypipecolic acid derivatives include a reaction sequence starting from 1 ,5-pentandiol (B. B. Ahuja, A. Sudalai, Tetrahedron Asymmetry 2015, 26(1), 24-28), use of readily available L-(+)-tartaric acid as starting material (S. P. Chavan eta!, Tetrahedron Lett. 2013 , 54(36), 4851 -4853), or reduction of appropriately substituted pyridine compounds (J. Drummond eta/., J. Med. Chem. 1989, 32(9), 21 16-2128).
  • the macrocydic compounds of the invention can be obtained by cyclization of suitable linear precursors which are derived from optionally substituted bifunctional phenols or thiophenols A, substituted amino alcohols B, and two building blocks forming C. If needed, further transformations can be performed.
  • Variable substituents can be introduced by pre- or postcyclative derivatization of one or more orthogonally protected attachment points (e.g. amino groups, carboxyl groups, hydroxyl groups) on B, C or A.
  • Variable R-groups may also be introduced as side chain motifs of the subunits of building block C.
  • the macrocydic products of the invention can be prepared either in solution or on solid support.
  • the essential ring closure reaction may be performed between any of the building blocks; for example, macrocycles of formula (I) may be obtained by
  • the macrocyclic compounds of the invention exhibit antiproliferative activity on various cancers cell lines.
  • they can be metabolized to modulators of Pin1 and thus may be used in a wide range of applications in order to modulate Pin1 activity, leading to the desired therapeutic effect in man or in other mammals.
  • prodrugs can be used as prodrugs, the term "prodrug” referring to a compound that can be converted in vivo into the parent active form.
  • a prodrug may be favorable, and a prodrug-type approach, for example, can be utilized for acid-bearing compounds to mask the corresponding acid moiety, including carboxylic and phosphonic acids.
  • a prodrug would be a compound that is administered as an ester (representing the "prodrug") to improve cell-permeability. Inside the cell, the ester would then be metabolically hydrolyzed to the respective acid, representing the active entity.
  • ester representing the "prodrug”
  • Conventional procedures for the selection and preparation of prodrug derivatives are described, for example, in H.
  • the compounds of the invention can be used as agents for treating and/or preventing and/or delaying the onset of diseases, disorders or conditions related to abnormal cell growth, such as various cancers, such as breast cancer, prostate cancer, cervical cancer, lung cancer, liver cancer, esophageal cancer, and gastric cancer; or sarcoma, such as Ewing's sarcoma; or lymphoma, such as non-Hodgkin lymphoma; or leukemia, such as promyelotic leukemia or acute myeloid leukemia; inflammatory diseases, such as asthma, allergic pulmonary eosinophilia, acute respiratory distress syndrome, rheumatoid arthritis or inflammatory bowel diseases; or acute neurological disorders, such as stroke; or neurodegenerative diseases, such as Huntington's disease and frontotemporal dementia; or viral infections, such as HIV/AIDS; or infection with intracellular and extracellular pathogens, such as infections by Chlamydia trachomatis; or osteolytic bone diseases, such as period
  • macrocyclic compounds of the invention can be administered singly, as mixtures of several macrocyclic compounds of the invention, in combination with other anti cancer agents, or antiviral (e.g. anti-HIV) agents, or in combination with other pharmaceutically active agents.
  • the macrocyclic compounds can be administered per se or as pharmaceutical compositions.
  • the macrocyclic compounds of the invention may be administered per se or may be applied as an appropriate formulation together with carriers, diluents or excipients well known in the art.
  • compositions comprising macrocyclic compounds of the invention may be manufactured by means of conventional mixing, dissolving, granulating, coated tablet making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.
  • Pharmaceutical compositions may be formulated in conventional manner using one or more physiologically acceptable carriers, diluents, excipients or auxiliaries which facilitate processing of the macrocyclic compounds into preparations which can be used pharmaceutically. Proper formulation depends upon the method of administration chosen.
  • the macrocyclic compounds of the invention may be formulated as solutions, gels, ointments, creams, suspensions, etc. as are well known in the art.
  • Systemic formulations include those designed for administration by injection, e.g. subcutaneous, intravenous, intramuscular, intrathecal or intraperitoneal injection, as well as those designed for transdermal, transmucosal, oral or pulmonary administration.
  • the macrocyclic compounds of the invention may be formulated in adequate solutions, preferably in physiologically compatible buffers such as Hink's solution, Ringer's solution, or physiological saline buffer.
  • the solutions may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • the macrocyclic compounds of the invention may be in powder form for combination with a suitable vehicle, e.g., sterile pyrogen free water, before use.
  • a suitable vehicle e.g., sterile pyrogen free water
  • penetrants appropriate to the barrier to be permeated are used in the formulation as known in the art.
  • the compounds can be readily formulated by combining the active macrocyclic compounds of the invention with pharmaceutically acceptable carriers well known in the art.
  • Such carriers enable the ester compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions etc., for oral ingestion by a patient to be treated.
  • suitable excipients include fillers such as sugars, such as lactose, sucrose, mannitol and sorbitol; cellulose preparations such as maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP); granulating agents; and binding agents.
  • desintegrating agents may be added, such as cross linked polyvinylpyrrolidones, agar, or alginic acid or a salt thereof, such as sodium alginate.
  • solid dosage forms may be sugar coated or enteric coated using standard techniques.
  • suitable carriers, excipients or diluents include water, glycols, oils, alcohols, etc.
  • flavoring agents, preservatives, coloring agents and the like may be added.
  • the composition may take the form of tablets, lozenges, etc. formulated as usual.
  • the macrocyclic compounds of the invention are conveniently delivered in form of an aerosol spray from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluromethane, carbon dioxide or another suitable gas.
  • a suitable propellant e.g. dichlorodifluoromethane, trichlorofluromethane, carbon dioxide or another suitable gas.
  • the dose unit may be determined by providing a valve to deliver a metered amount.
  • Capsules and cartridges of e.g. gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the macrocyclic compounds of the invention and a suitable powder base such as lactose or starch.
  • the compounds may also be formulated in rectal or vaginal compositions such as suppositories together with appropriate suppository bases such as cocoa butter or other glycerides.
  • the macrocyclic compounds of the invention may also be formulated as depot preparations. Such long acting formulations may be administered by implantation (e.g. subcutaneously or intramuscularly) or by intramuscular injection.
  • the macrocyclic compounds of the invention may be formulated with suitable polymeric or hydrophobic materials (e.g. as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble salts.
  • the macrocyclic compounds of the invention may be delivered using a sustained release system, such as semipermeable matrices of solid polymers containing the therapeutic agent (e.g. for coated stents).
  • sustained release materials have been established and are well known by those skilled in the art.
  • Sustained release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days.
  • additional strategies for protein stabilization may be employed.
  • the macrocyclic compounds of the invention may contain charged residues, they may be included in any of the above described formulations as such or as pharmaceutically acceptable salts.
  • Pharmaceutically acceptable salts tend to be more soluble in aqueous and other protic solvents than are the corresponding free forms.
  • the compounds of the present invention and their pharmaceutical acceptable salts may be used per se or in any appropriate formulation in morphological different solid state forms, which may or may not contain different amounts of solvent, e.g. hydrate.
  • the macrocyclic compounds of the invention, or compositions thereof, will generally be used in an amount effective to achieve the intended purpose. It is to be understood that the amount used will depend on a particular application.
  • the macrocyclic compounds of the invention or compositions thereof are administered or applied in a therapeutically effective amount. Determination of a therapeutically effective amount is well within the capacities of those skilled in the art, especially in view of the detailed disclosure provided herein.
  • a therapeutically effective dose can be estimated initially from in vitro assays.
  • a dose can be formulated in animal models to achieve a circulating macrocyclic compounds concentration range that includes the GI50 (or IC50) as determined in an cell-based assay.
  • GI50 or IC50
  • Initial dosages can also be determined from in vivo data, e.g. animal models, using techniques that are well known in the art. One having ordinary skill in the art could readily optimize administration to humans based on animal data.
  • Dosage amounts for applications as compounds that can be metabolized to agents for Pin1 modulation may be adjusted individually to provide plasma levels of the macrocyclic compounds of the invention which are sufficient to maintain the therapeutic effect.
  • Therapeutically effective serum levels may be achieved by administering multiple doses each day.
  • the effective local concentration of the macrocyclic compounds of the invention may not be related to plasma concentration.
  • One having the ordinary skill in the art will be able to optimize therapeutically effective local dosages without undue experimentation.
  • the amount of macrocyclic compounds of the invention administered will, of course, be dependent on the subject being treated, on the subject's weight, the severity of the affliction, the manner of administration and the judgement of the prescribing physician.
  • a therapeutically effective dose of the macrocyclic compounds of the invention described herein will provide therapeutic benefit without causing substantial toxicity.
  • Toxicity of the macrocyclic compounds of the invention can be determined by standard pharmaceutical procedures in experimental animals, e.g., by determining the LD50 (the dose lethal to 50% of the population) or the LD100 (the dose lethal to 100% of the population).
  • the dose ratio between toxic and therapeutic effect is the therapeutic index. Compounds which exhibit high therapeutic indices are preferred.
  • the data obtained from these animal studies can be used in formulating a dosage range that is not toxic for use in humans.
  • the dosage of the macrocyclic compounds of the invention lies preferably within a range of circulating concentrations that include the effective dose with little or no toxicity. The dosage may vary within the range depending upon the dosage form employed and the route of administration utilized.
  • the exact formulation, route of administration and dose can be chosen by the individual physician in view of the patient's condition (see, e.g. E. Fingl etal. 1975, In: The Pharmacological Basis of Therapeutics, Ch.1 , p.1 ).
  • the effective dosage of the compounds of the invention employed may vary depending on the particular compound or pharmaceutical preparation employed, the mode of administration and the severity and type of the condition treated. Thus, the dosage regimen is selected in accordance with factors including the route of administration and the clearance pathway, e.g. the renal and hepatic function of the patient.
  • a physician, clinician or veterinarian skilled in the art can readily determine and prescribe the amount of the single compound of the invention required to prevent, ameliorate or arrest the progress of the condition or disease.
  • Optimal precision in achieving concentrations of the compounds without toxicity requires a regimen based on the kinetics of the compounds' availability to the target sites. This involves a consideration of the distribution, equilibrium, and elimination of the compounds of the invention.
  • ADDP 1 ,1 '-(azodicarbonyl)dipiperidine
  • Boc 2 0 di-tert. -butyl pyrocarbonate; Boc anhydride, di-tert. -butyl dicarbonate br.: broad
  • HATU C ⁇ (7-azabenzotriazol-1-yl)-A,A,A ',/V-tetramethyluronium hexa- fluorophosphate
  • Pd(PPh3) 4 tetrakis(triphenylphosphine)palladium(0)
  • i-Pr 2 NEt Nethyl-A/,/V-diisopropylamine
  • TMSCI trimethylsilyl chloride, trimethylchlorosilane
  • Tris-HCI tris(hydroxymethyl)aminomethane hydrochloride
  • Flash chromatography Fluka silica gel 60 (0.04-0.063 mm) and Interchim Puriflash IR 60 silica gel (0.04-0.063 mm).
  • Method 1a m/z 95 - 1800, 2 sec; centroid mode, positive mode 40V
  • Method 1 b m/z 95 - 1800, 2 sec; profile mode, positive mode 80V
  • Method 1d m/z 95 - 1800, 2 sec; profile mode, positive mode 40V
  • Method 1e m/z 95 - 1800, 2 sec; profile mode, positive mode 20V
  • Method 2a m/z 95 - 1800, 2 sec; profile mode, positive mode 40V
  • Method 2b m/z 95 - 1800, 2 sec; centroid mode, negative mode 40V
  • Method 3a m/z 95 - 1800, 2 sec; centroid mode, positive mode 40V
  • Method 3b m/z 95 - 1800, 2 sec; profile mode, positive mode 40V Method 4
  • Method 4a m/z 95 - 1800, 2 sec; profile mode, positive mode 40V Method 5
  • Method 5a m/z 95 - 1800, 1.5 sec; centroid mode, positive mode 40V
  • Method 5b m/z 95 - 1800, 1.5 sec; profile mode, positive mode 40V Method 6
  • Method 6a m/z 95 - 1800, 2 sec; profile mode, positive mode 40V
  • Method 7a m/z 95 - 2000, 2 sec; profile mode, positive mode 40V
  • Method 7b m/z 95 - 2000, 2 sec; profile mode, positive mode 60V
  • Method 7c m/z 95 - 2000, 2 sec; centroid mode, positive mode 40V
  • Method 9a m/z 95 - 1800 Da, 2 sec; centroid mode, positive mode 40V
  • Methyl 4-hydroxybenzoate (1 ) is commercially available.
  • tert.-butyldimethylsilyl chloride (4.45 g, 28.6 mmol) was added in portions to a soln of 4 (5.0 g, 17.9 mmol) and imidazole (3.65 g, 53.7 mmol) in DMF (50 mL). The mixture was allowed to warm to rt and stirred for 7 h. Aq. workup (Et.20, 1 M aq. NaH 2 P0 4 soln, sat. aq. NaHCOs soln; Na 2 S0 4 ) and FC (hexane / EtOAc) afforded 5 (7.4 g).
  • (2S,3S)-1-(Tert.-butoxycarbonyl)-3-hydroxypyrrolidine-2-carboxylic acid was prepared by Boc protection of the secondary amino group of 13 by di-tert. -butyl dicarbonate in dioxane in the presence of aq. Na2CC>3 soln applying standard conditions.
  • EDC HCI (1 .38 g, 7.2 mmol) was added at 0°C to a solution of 15 (1.28 g, 5.5 mmol) and 17 TFA (2.4 g, ca 6.1 mmol) in pyridine (20 mL). The mixture was stirred at rt for 15 h. Aq. workup (EtOAc, 1 M aq. HCI soln, half-sat. aq. NaHC0 3 soln, H 2 0, sat. aq. NaCI soln; Na 2 S0 4 ) and purification by FC (hexane / EtOAc) afforded 18 (1 .45 g, 63%).
  • 22b (7.6 g, 73%) was obtained from allyl chloroacetate (5.0 mL, 43.1 mmol), 1-naphthylamine (21 b; 15.0 g, 104.7 mmol) and tetrabutylammonium iodide (16 g, 43.3 mmol) applying the procedure described for the synthesis of 22a.
  • 22c (0.54 g, 73%) was obtained from allyl chloroacetate (0.355 mL, 3.1 mmol), 2-naphthylamine (21c; 0.87 g, 6.1 mmol) and tetrabutylammonium iodide (1.1 g, 3.1 mmol) applying the procedure described for the synthesis of 22a.
  • the aminoacetate 22f (0.97 g, 94%) was obtained from allyl chloroacetate (0.57 ml_, 4.9 mmol), 4-fluoroaniline (21f; 1 .1 g, 9.9 mmol) and tetrabutylammonium iodide (1.83 g, 4.9 mmol) applying the procedure described for the synthesis of 22a.
  • ADDP (3.2 g, 12.56 mmol) was added at 0°C to a soln of 6-aminonaphthalen-1-ol (20, 1 .0 g, 6.28 mmol), benzyl alcohol (1 .0 ml_, 9.66 mmol) and PPh 3 (3.5 g, 12.56 mmol) in CHCI3 (30 ml_). The mixture was stirred at rt for 16 h and concentrated. FC (hexane / EtOAc) and precipitation with EtOAc / hexane 1 :3 afforded 21g (1.09 g, 70%).
  • ADDP (3.78 g, 15 mmol) in CHCI 3 (10 mL) was added drop by drop to a soln of methyl 4-hydroxybenzoate (1 ; 1 .82 g, 12 mmol), alcohol 2 (3.0 g, 10 mmol) and PPh 3 (3.93 g, 15 mmol) in CHC (60 mL).
  • the mixture was stirred at rt for 2 h followed by aq. workup (CH2CI2, sat. aq. NaHCC>3 soln; Na2S0 4 ).
  • CH2CI2 / hexane 2:8 was filtered.
  • the filtrate was concentrated and purified by FC (hexane / EtOAc) to afford 23 (4.28 g, 98%).
  • 29b (26 mg, 20%) was obtained from 28b (132 mg, 0.19 mmol) applying the procedure described for the synthesis of 29a.
  • 29c 43 mg, 35%) was obtained from 28c (125 mg, 0.18 mmol) applying the procedure described for the synthesis of 29a.
  • TFA (0.1 mL) was added at 0°C to a soln of 29b (45 mg, 0.067 mmol) in CH 2 CI 2 (2 mL). Stirring was continued at 0°C to rt for 2.5 h. More TFA (0.2 mL) was added at 0°C and stirring was continued at 0°C to rt for 2 h, followed by an aq. workup (CH2CI2, sat. aq. NaHCOs soln; Na 2 S0 4 ) to yield 30b (40 mg, quant, yield).
  • 31 b (42 mg, 93%; purification by prep. TLC (EtOAc)) was obtained from 30b (36 mg, 0.063 mmol) applying the procedure described for the synthesis of 31a.
  • Data of 31 b CssHssCIISUOs (71 1.2).
  • LC-MS (method 1 d): Rt 2.21 (99%), 71 1 .2 ([M+H] + ).
  • 32b 38 mg, 95%) was obtained from 31 b (41 mg, 0.058 mmol) applying the procedure described for the synthesis of 32a.
  • i-Pr 2 NEt (0.021 mL, 0.13 mmol) was added to a soln of HATU (38 mg, 0.1 mmol) and HOAt (14 mg, 0.10 mmol), 32a (18 mg, 0.028 mmol) and ⁇ -alanine methyl ester hydrochloride (12 mg, 0.083 mmol) in DMF (2 mL).
  • Stirring at 0°C was continued for 4.5 h followed by an aq. workup (EtOAc, 1 M aq. HCI soln, H2O; Na 2 S0 4 ) and purification by prep. TLC (EtOAc) to afford 33a (12.5 mg, 62%).
  • i-Pr 2 NEt (0.016 mL, 0.095 mmol) was added to a soln of HATU (25 mg, 0.66 mmol) and HOAt (10 mg, 0.073 mmol), 32b (15 mg, 0.022 mmol) and ⁇ -alanine methyl ester hydrochloride (9 mg, 0.064 mmol) in DMF (1 mL).
  • Stirring at 0°C was continued for 2 h followed by an aq. workup (EtOAc, 1 M aq. HCI soln, H2O; Na2S0 4 ) and purification by prep. TLC (EtOAc) to afford 33b (12 mg, 71 %).
  • i-Pr 2 NEt (0.014 mL, 0.08 mmol) was added to a soln of HATU (19.4 mg, 0.05 mmol) and HOAt (7.2 mg, 0.05 mmol), 32c (13 mg, 0.019 mmol) and ⁇ -alanine methyl ester hydrochloride (7.1 mg, 0.051 mmol) in DMF (1 mL).
  • Stirring at 0°C was continued for 2 h followed by an aq. workup (EtOAc, 1 M aq. HCI soln, H2O; Na2S0 4 ) and purification by prep. TLC (EtOAc) to afford 33c (12 mg, 82%).
  • i-Pr 2 NEt (0.042 mL, 0.25 mmol) was added to a soln of HATU (67 mg, 0.18 mmol) and HOAt (26 mg, 0.19 mmol), 34 (41 mg, 0.067 mmol) and ⁇ -alanine methyl ester hydrochloride (24 mg, 0.17 mmol) in DMF (3 mL).
  • Stirring at 0°C was continued for 4 h followed by an aq. workup (EtOAc, 1 M aq. HCI soln, H 2 0; Na 2 S0 4 ) and purification by FC (hexane / EtOAc) to afford 35 (34 mg, 73%).
  • i-Pr 2 NEt 0.054 mL, 0.31 mmol was added to a soln of HATU (96 mg, 0.25 mmol) and HOAt (33 mg, 0.24 mmol), 46d (58 mg, ca 0.07 mmol) and ⁇ -alanine methyl ester hydrochloride (31 mg, 0.22 mmol) in DMF (4 mL).
  • Stirring at 0°C was continued for 4.5 h followed by an aq. workup (EtOAc, H2O) and purification by FC (hexane / EtOAc) to afford 47 (53 mg, 82%).
  • i-Pr 2 NEt (0.05 mL, 0.29 mmol) was added to a soln of HATU (42 mg, 0.1 1 mmol) and HOAt (15 mg, 0.1 1 mmol), 48 (30 mg, 0.038 mmol) and ammonium chloride (9.7 mg, 0.18 mmol) in DMF (1 mL).
  • Stirring at 0°C was continued for 2.5 h, followed by an aq. workup (EtOAc, H 2 0; Na2S0 4 ) and purification by FC (CH2CI2 / MeOH) to afford 49 (26 mg, 57%).
  • i-Pr 2 NEt (0.056 mL, 0.33 mmol) was added to a soln of HATU (88 mg, 0.23 mmol) and HOAt (32 mg, 0.23 mmol), 46e (50 mg, 0.066 mmol) and ⁇ -alanine methyl ester hydrochloride (28 mg, 0.20 mmol) in DMF (6 mL).
  • Stirring at 0°C was continued for 5 h followed by an aq. workup (EtOAc, 1 M aq. HCI soln, aq. NaCI soln) and purification by FC (EtOAc) to afford 50 (46 mg, 83%).
  • Ester 51 (55 mg, 89%; purification by FC (EtOAc)) was obtained from 46e (55 mg, 0.073 mmol) and methyl azetidine-3-carboxylate hydrochloride (33 mg, 0.22 mmol) applying the conditions outlined for the synthesis of 50.
  • 52b (18.5 mg, 47%; purification by prep. HPLC (method 1 a)) was obtained from 46e (35 mg, 0.047 mmol) and (aminomethyl)phosphonic acid (26 mg, 0.23 mmol) following the procedure outlined for the synthesis of 52a.
  • i-Pr 2 NEt (1.0 mL, 5.84 mmol) was added to a soln of HATU (0.852 g, 2.24 mmol), 41 (0.857 g, 1 .86 mmol) and 19 CF 3 C0 2 H (0.80 g, 1.86 mmol) in DMF (16 mL).
  • Stirring was continued at rt for 20 h followed by an aq. workup (EtOAc, 1 M aq. HCI soln, sat. aq. NaHCC>3 soln, H 2 0, sat. aq. NaCI soln; Na2S0 4 ) and purification by FC (hexane / EtOAc then EtOAc / MeOH) to afford 53 (1.18 g, 84%; used without further purification).
  • 55h (142 mg, 77%; purification by FC (CH2CI2 / MeOH)) was obtained from 54h (210 mg, 0.20 mmol) applying the procedure outlined for the synthesis of 55e.
  • ADDP (4.09 g, 16.2 mmol) in CHCI 3 (10 mL) was added drop by drop at 0°C to a soln of methyl 4-hydroxybenzoate (1 ; 1.97 g, 13 mmol), alcohol 3 (2.0 g, 10.8 mmol) and PP i3 (4.25 g, 16.2 mmol) in degassed CHCI3 (30 mL).
  • the mixture was stirred at rt for 16 h followed by aq. workup (CH2CI2, sat. aq. NaHCC soln; Na2S0 4 ).
  • the resulting crude product was suspended in CH2CI2 / hexane 2:8 and filtered. The filtrate was concentrated and purified by FC (hexane / EtOAc) to afford 57 (3.84 g, contaminated with ca 18% of 1 ; used without further purification).
  • i-Pr 2 NEt (2.4 mL, 14 mmol) was added to a soln of HATU (2.1 g, 5.55 mmol), 58 (1.41 g, 4.62 mmol) and 19 CF 3 C0 2 H (2.2 g, 4.62 mmol) in DMF (40 mL).
  • Stirring was continued at rt for 3 h followed by an aq. workup (EtOAc, 1 M aq. HCI soln, sat. aq. NaHCOs soln, H2O, sat. aq. NaCI soln; Na2S0 4 ) and purification by FC (hexane / EtOAc then EtOAc / MeOH) to afford 59 (2.4 g, 86%).
  • Amino acid 61e (182 mg, 100%; purified by FC (CH2CI2 / MeOH) was obtained from 60e (210 mg, 0.23 mmol) by following the procedure described for the synthesis of 61a.
  • Amino acid 61f (129 mg, 84%; purified by FC (CH2CI2 / MeOH)) was obtained from 60f (180 mg, 0.22 mmol) by following the procedure described for the synthesis of 61a.
  • ADDP (3.24 g, 12.8 mmol) in CHCI 3 (15 mL) was added drop by drop at 0°C to a soln of methyl 4-hydroxybenzoate (1 ; 1.56 g, 10.3 mmol), alcohol 8 (2.7 g, 8.56 mmol) and PPh 3 (3.37 g, 12.8 mmol) in degassed CHCI3 (35 mL).
  • the mixture was stirred at rt for 16 h followed by aq. workup (CH 2 CI 2 , sat. aq. NaHC0 3 soln; Na 2 S0 4 ).
  • the resulting crude product was suspended in CH2CI2 / hexane 2:8 and filtered. The filtrate was concentrated and purified by FC (hexane / EtOAc) to afford 64 (3.82 g, 99%).
  • LiOH H2O (0.43 g, 10.2 mmol) was added to a soln of 64 (2.3 g, 5.1 mmol) in THF (40 mL), MeOH (10 mL) and H 2 0 (10 mL). The mixture was stirred at 0°C to rt for 3 h. More LiOH H2O (0.215 g, 5.2 mmol) was added and stirring was continued for 4 h, followed by a further addn of LiOH H2O (0.1 1 g, 2.6 mmol). The mixture was stirred for addn 2 h, cooled to 0°C, diluted with 1 M aq. HCI soln (50 mL) and extracted with CHCI3.
  • i-Pr 2 NEt (1.6 mL, 9.35 mmol) was added to a soln of HATU (1 .28 g, 3.36 mmol), 65 (0.98 g, 2.24 mmol) and 19 CF 3 C0 2 H (80%; 1.2 g, 2.24 mmol) in DMF (30 mL).
  • Stirring was continued at rt for 16 h followed by an aq. workup (EtOAc, sat. aq. NaHCC>3 soln, H2O, sat. aq. NaCI soln; Na2S0 4 ) and purification by FC (hexane / EtOAc / MeOH) to afford 66 (1.64 g, ca 80%; used without further purification).
  • TBAF soln (1 M in THF; 0.87 mL, 0.87 mmol) was added at 0°C to a soln of 64 (325 mg, 0.723 mmol) in THF (30 mL). The mixture was stirred at 0°C for 2.5 h, followed by an aq. workup (EtOAc, sat. aq. NH 4 CI soln, H2O, sat. aq. NaCI soln; Na2S0 4 ) and purification by FC (hexane / EtOAc) to afford 72 (245 mg, 100%).
  • i-Pr 2 NEt (0.55 mL, 3.2 mmol) was added to a soln of HATU (0.408 g, 1 .07 mmol), 74 (0.24 g, 0.716 mmol) and 19 CF 3 C0 2 H (80%; 0.383 g, 0.716 mmol) in DMF (6 mL).
  • Stirring was continued at rt for 3 h followed by an aq. workup (EtOAc, 1 M aq. HCI soln, sat. aq. NaHCC>3 soln, H 2 0, sat. aq. NaCI soln; Na 2 S0 4 ) and purification by FC (hexane / EtOAc then EtOAc / MeOH) to afford 75 (0.38 g, 84%).
  • ADDP (4.41 g, 17.46 mmol) was added to a soln of methyl 4-hydroxybenzoate (1 ; 2.125 g, 14.0 mmol), alcohol 11 (2.32 g, 1 1 .6 mmol) and PPh 3 (4.58 g, 17.46 mmol) in degassed CHCI3 (50 mL).
  • the mixture was diluted with CHCI3 (20 mL) and stirred at rt for 20 h followed by evaporation of the volatiles.
  • the resulting crude product was purified by FC (hexane / EtOAc) to afford pure 79 (0.36 g, 9%) and 79 (1 .7 g, ca 35%, purity ca 80%; used without further purification).
  • Ester 80 (2.87 g, 96%, purified by FC (hexane / EtOAc) was obtained from methyl 4- hydroxybenzoate (1 ; 1 .63 g, 10.7 mmol), alcohol 12 (1.8 g, 8.95 mmol) by applying the procedure outlined for the synthesis of 79.
  • Acid 82 (2.51 g, 95%) was obtained from 80 (2.76 g, 8.25 mmol) by following the procedure described for the synthesis of 81.
  • the macrocyclic diester 90 (7 mg, 12%) was obtained from 88 (62 mg, 0.076 mmol) by following the procedure outlined for the synthesis of 89.
  • Macrocyclic diacid 92 (0.7 mg, 16%, purification by prep. HPLC (method 2a)) was obtained from 90 (4.6 mg) by following the procedure outlined for the synthesis of macrocyclic diacid 91 .
  • E.coli BL21 pLysE(DE3) cells (New England BioLabs, Ipswich, USA) were transformed with pET14b vector (Merck Millipore, Darmstadt, Germany) encoding for full length Pin1 (amino acids 1-163) with a stabilizing mutation in position 14 (arginine to alanine replacement; Y. Zhang et a/., ACS Chem Biol.
  • IPTG isopropyl-3-D- thiogalactopyranosid
  • the clarified supernatant was loaded onto a 5 mL Ni-NTA column at 2.5 mL/minute.
  • the column was washed with 50 mL buffer A.
  • a step gradient was applied at 2.5 mL/minute from 100% buffer A to 100 % buffer B (25 mM Tris-HCI (pH 8.0), 0.5 M NaCI, 10 mM 2-mercaptoethanol and 1 % Tween 20 ⁇ ⁇ / ⁇ , 500 mM imidazole).
  • Fractions of 5 mL were collected and analyzed by SDS-PAGE (4-12%). The fractions containing 6xHis Pin1 were collected and pooled.
  • thrombin (1 U thrombin/mg protein; Sigma-Aldrich) during dialysis for 16 hours at 4°C (molecular weight cut-off: 3 kDa; dialysis buffer: 50 mM Tris-HCI (pH 8.0), 0.15 M NaCI, 5 mM MgCI 2 , 2.5 mM CaCI 2 , 1 mM DTT, 10% glycerol ⁇ ⁇ / ⁇ ).
  • the overnight solution was passed through a Ni-NTA column (5 mL). The flow through was collected and concentrated to a volume of 2 mL for final size exclusion chromatography. The concentrate was loaded on a Superdex 75 column (90 ml.) with 2 mL/minute and eluted with buffer S (10 mM Hepes (pH 7.5), 0.1 M NaCI, 1 mM DTT). The fractions containing monomeric Pin1 were collected and pooled. Pooled Pin1 was concentrated to about 20 mg/mL for further studies (see below).
  • THP-1 cells were tested in a cell viability assay on THP-1 cells (obtained from ATCC). The cell line was grown as recommended by the supplier. THP-1 cells were then seeded on 96-well plate with RPMI 1640 medium (Sigma Aldrich) containing 10% fetal bovine serum ( 1 /1/) (Gibco), 0.05 mM 2-mercaptoethanol and 100 U ⁇ g penicillin and streptomycin (Thermo Fisher Scientific), at a density of 300 ⁇ 00 cells/mL in 75 uL. Serial dilutions of compounds were added to the cells (25 uL/well, 0.5% DMSO final, v/V) and were incubated at 37°C and 5% C0 2 for 72 hours.
  • Ex.1 - Ex.8 are inactive on Pin1 and comprise at least one ester moiety in substituent E, as described herein above. Respective acids obtained from hydrolysis of Ex.1 - Ex.8 show activity on Pin1.
  • Table 03 IC50 values from the cell viability assay on THP-1 cells *)
  • Ex.7 was tested in proliferation assays on MHHES1 cells (obtained from DSMZ cell line collection), A673 cells (obtained from ECACC cell line collection), and BT20 cells (obtained from ATTC cell line collections) applying the methodology described by E. Prinz et al. (Supplementary Information S18-S21. In: J. Med. Chem. 2011 , 54, 4247- 4263). Briefly, the cell lines were grown as recommended by the suppliers. Cells were then treated for 72 hours with Ex.7 at a maximum concentration of 25 ⁇ and in serial 10-fold dilutions. Subsequently, cell proliferation was determined by means of sulforhodamine B staining, and GI50 values were calculated.

Abstract

L'invention concerne des composés macrocycliques à conformation limitée de formule (I), y compris les substituants E avec au moins une fraction ester, G et Q, tels que définis dans la description et les revendications, et leurs sels, lesdits composés pouvant être métabolisés en composés ayant la propriété de moduler l'activité des peptidyl-prolyl cis/trans isomérases Pin1. Ils présentent par ailleurs une activité anti-proliférative sur diverses lignées de cellules cancéreuses. Ces composés et ces compositions pharmaceutiques contenant lesdits composés peuvent être utiles pour traiter et/ou prévenir les maladies ou les pathologies relevant du domaine des affections et des maladies prolifératives, comme le cancer, les maladies inflammatoires, le rejet de greffe, les infections virales, les maladies osseuses ostéolytiques, les maladies cardiaques, les maladies cardiovasculaires, les maladies respiratoires, les maladies neurologiques aiguës, les maladies neurodégénératives, les maladies immunitaires et la theilériose lymphoproliférative.
PCT/EP2016/025114 2015-10-12 2016-10-12 Composés macrocycliques à conformation limitée WO2017063757A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP15002906 2015-10-12
EP15002906.4 2015-10-12

Publications (1)

Publication Number Publication Date
WO2017063757A1 true WO2017063757A1 (fr) 2017-04-20

Family

ID=54293017

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2016/025114 WO2017063757A1 (fr) 2015-10-12 2016-10-12 Composés macrocycliques à conformation limitée

Country Status (1)

Country Link
WO (1) WO2017063757A1 (fr)

Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004005315A2 (fr) 2002-07-09 2004-01-15 Pfizer Inc. Polypeptides isomerase peptidyl-prolyl pin1, leurs structures cristallines, et leur utilisation dans la conception de medicament
WO2004087720A1 (fr) 2003-03-10 2004-10-14 Pfizer Inc. Composes a base d'esters de sulfate/phosphate et compositions pharmaceutiques inhibant l'activite de nima interagissant avec des proteines (pin1)
WO2006019982A2 (fr) 2004-07-15 2006-02-23 Vernalis Plc Composes modulateurs de pin1 et leurs procedes d'utilisation
WO2006040646A1 (fr) 2004-10-14 2006-04-20 Pfizer, Inc. Amides de benzimidazole ou d'indole en tant qu'inhibiteurs de pin1
WO2006124494A1 (fr) 2005-05-13 2006-11-23 Virginia Tech Intellectual Properties, Inc. Inhibiteurs d'etat de transition de pin1, constitues par des composes peptidomimetiques contenant un $g(a)-cetoamide, et synthese de ceux-ci
WO2009069100A1 (fr) 2007-11-29 2009-06-04 Actelion Pharmaceuticals Ltd Dérivés d'acide phosphonique et leur utilisation en tant qu'antagonistes du récepteur p2y12
WO2011014973A2 (fr) 2009-08-05 2011-02-10 Polyphor Ag Composés macrocycliques entièrement synthétiques présentant des contraintes conformationnelles
WO2013139697A1 (fr) 2012-03-17 2013-09-26 Polyphor Ag Composés macrocycliques entièrement synthétiques et à conformation contrainte
WO2015032998A1 (fr) 2013-09-09 2015-03-12 Centre National De La Recherche Scientifique (Cnrs) Inhibiteurs de pin1 utilisés dans la prévention et/ou le traitement de la theilériose, et applications s'y rapportant
WO2015089137A1 (fr) 2013-12-11 2015-06-18 Karos Pharmaceuticals, Inc. Acylguanidines comme inhibiteurs de la tryptophan hydroxylase

Patent Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004005315A2 (fr) 2002-07-09 2004-01-15 Pfizer Inc. Polypeptides isomerase peptidyl-prolyl pin1, leurs structures cristallines, et leur utilisation dans la conception de medicament
WO2004087720A1 (fr) 2003-03-10 2004-10-14 Pfizer Inc. Composes a base d'esters de sulfate/phosphate et compositions pharmaceutiques inhibant l'activite de nima interagissant avec des proteines (pin1)
WO2006019982A2 (fr) 2004-07-15 2006-02-23 Vernalis Plc Composes modulateurs de pin1 et leurs procedes d'utilisation
WO2006040646A1 (fr) 2004-10-14 2006-04-20 Pfizer, Inc. Amides de benzimidazole ou d'indole en tant qu'inhibiteurs de pin1
WO2006124494A1 (fr) 2005-05-13 2006-11-23 Virginia Tech Intellectual Properties, Inc. Inhibiteurs d'etat de transition de pin1, constitues par des composes peptidomimetiques contenant un $g(a)-cetoamide, et synthese de ceux-ci
WO2009069100A1 (fr) 2007-11-29 2009-06-04 Actelion Pharmaceuticals Ltd Dérivés d'acide phosphonique et leur utilisation en tant qu'antagonistes du récepteur p2y12
WO2011014973A2 (fr) 2009-08-05 2011-02-10 Polyphor Ag Composés macrocycliques entièrement synthétiques présentant des contraintes conformationnelles
WO2011015241A1 (fr) 2009-08-05 2011-02-10 Polyphor Ag Composés macrocycliques entièrement synthétiques, à conformation contrainte
WO2013139697A1 (fr) 2012-03-17 2013-09-26 Polyphor Ag Composés macrocycliques entièrement synthétiques et à conformation contrainte
WO2015032998A1 (fr) 2013-09-09 2015-03-12 Centre National De La Recherche Scientifique (Cnrs) Inhibiteurs de pin1 utilisés dans la prévention et/ou le traitement de la theilériose, et applications s'y rapportant
WO2015089137A1 (fr) 2013-12-11 2015-06-18 Karos Pharmaceuticals, Inc. Acylguanidines comme inhibiteurs de la tryptophan hydroxylase

Non-Patent Citations (95)

* Cited by examiner, † Cited by third party
Title
A. A. PRITSA ET AL., ANTICANCER DRUGS, vol. 12, no. 2, 2001, pages 137 - 142
A. D. HUGHES ET AL., CANCER LETTERS, vol. 352, 2014, pages 28 - 35
A. GRISON ET AL., PNAS, vol. 108, no. 44, 2011, pages 17979 - 17984
A. POTTER, BIOORG. MED. CHEM. LETT, vol. 20, 2010, pages 6483 - 6488
A. R. KATRITZKY ET AL.: "Comprehensive Functional Group Transformations", 1995, PERGAMON
A. RYO ET AL., CLIN. CANCER RES., vol. 11, no. 20, 2005, pages 7523 - 7531
A. TUN-KYI, NAT. IMMUNOL., vol. 12, no. 8, 2011, pages 733 - 741
A.J. OLIVE, CELL HOST MICROB, vol. 15, no. 1, 2014, pages 113 - 124
B. B. AHUJA; A. SUDALAI, TETRAHEDRON ASYMMETRY, vol. 26, no. 1, 2015, pages 24 - 28
B. TESTA; J. M. MAYER: "Hydrolysis in Drug and Prodrug Metabolism: Chemistry, Biochemistry, and Enyzmology", 2003, VERLAG HELVETICA CHIMICA ACTA, article "The Hydrolysis of Carboxylic Acid Ester Prodrugs"
C. GUO ET AL., BIOORG. MED. CHEM. LETT., vol. 24, no. 17, 2014, pages 4187 - 4191
C. J. WIM ET AL., WORLD J. GASTROENTEROL, vol. 11, no. 32, 2005, pages 5006 - 5009
C. L. CUBITT, SARCOMA, 2013
C. LIU ET AL., BIOORG. MED. CHEM. LETT., vol. 20, 2012, pages 2992 - 2999
D. BALDWIN, EUR. J. MED. CHEM., vol. 17, no. 4, 1982, pages 297 - 300
D. G. GIMENEZ ET AL., PLANTA MED., vol. 76, no. 2, 2010, pages 133 - 136
D. OBRECHT, J.M. VILLALGORDO: "Solid-Supported Combinatorial and Parallel Synthesis of Small-Molecular-Weight Compound Libraries", 1998, PERGAMON
D. WILDEMANN, J. MED. CHEM., vol. 49, no. 7, 2006, pages 2147 - 2150
DONG L ET AL: "Structure-based design of novel human Pin1 inhibitors (II)", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, PERGAMON, AMSTERDAM, NL, vol. 20, no. 7, 1 April 2010 (2010-04-01), pages 2210 - 2214, XP002717452, ISSN: 0960-894X, [retrieved on 20100214], DOI: 10.1016/J.BMCL.2010.02.033 *
E. DEFOSSA ET AL.: "Liebigs Annales", vol. 11, 1996, pages: 1743 - 1749
E. FINGL ET AL.: "The Pharmacological Basis of Therapeutics", 1975, article "Ch.1.", pages: 1
E. PRINZ ET AL., SUPPLEMENTARY INFORMATION, pages S18 - S21
E. S. YEH; A. R. MEANS, NAT. REV. CANCER, vol. 7, 2007, pages 381 - 387
F. MANTOVANI ET AL., BIOCHIM. BIOPHYS. ACTA, vol. 1850, no. 10, 2015, pages 2048 - 2060
F. PANENI ET AL., EUR. HEART J., vol. 36, no. 13, 2015, pages 817 - 828
G. FAN ET AL., CANCER RES., vol. 69, no. 11, 2009, pages 4589 - 4597
G. KIM ET AL., BIOL. PHARM. BULL., vol. 38, no. 7, 2015, pages 975 - 979
G. WULF ET AL., EMBO J., vol. 23, 2004, pages 3397 - 3407
H. BUNDGAARD: "Design of Prodrugs", 1985, ELSEVIER
H. HOU ET AL., GENE, vol. 656, no. 1, 2015, pages 9 - 14
H. JIN ET AL., ONCOL. LETT., vol. 2, no. 6, 2011, pages 1191 - 1196
H. LI ET AL., ONCOL. REP, vol. 16, 2006, pages 491 - 496
H. T. SERAFINOWSKA ET AL., J. MED. CHEM., vol. 38, 1995, pages 1372 - 1379
H. TOKO ET AL., CIRC. RES., vol. 112, no. 9, 2013, pages 1244 - 1252
J. A. DRIVER ET AL., BIOCHIM BIPHYS. ACTA, vol. 1850, no. 10, 2015, pages 2069 - 2076
J. A. DRIVER ET AL., DISCOV. MED, vol. 17, no. 92, 2014, pages 93 - 99
J. D. MOORE; A. POTTER, BIOORG. MED. CHEM. LETT, vol. 23, 2013, pages 4283 - 4291
J. DRUMMOND ET AL., J. MED. CHEM., vol. 32, no. 9, 1989, pages 2116 - 2128
J. E. GIARDINI ET AL., CANCER CELL, vol. 12, 2011, pages 79 - 91
J. K. DICKSON ET AL., J. MED. CHEM., vol. 39, 1996, pages 661 - 664
J. LIM, J. CLIN. INVEST., vol. 118, no. 5, 2008, pages 1877 - 1889
J. MARCH: "Advanced Organic Chemistry, 4 ed.,", 1992, WILEY
J. MASOLIER ET AL., NATURE, vol. 520, 2015, pages 378 - 382
J. MASOLIER, NATURE, vol. 520, 2015, pages 378 - 382
J. MED. CHEM., vol. 54, 2011, pages 4247 - 4263
J. Z. WANG ET AL., PHARMACOL. RES, vol. 93, 2015, pages 28 - 35
K. E. DUNCON ET AL., J. MED. CHEM., vol. 54, no. 11, 2011, pages 3854 - 3865
K. P. LU ET AL., NAT CHEM BIOL., vol. 3, no. 10, 2007, pages 619 - 629
K. P. LU ET AL., TRENDS CELL. BIOL, vol. 12, 2002, pages 164 - 172
K. P. LU, NATURE, vol. 380, no. 6574, 1996, pages 544 - 547
L. BAO, AM. J. PATHOL., vol. 164, 2004, pages 1727 - 1737
L. HENNIG ET AL., BIOCHEMISTRY, vol. 37, 1998, pages 5953 - 5960
L. LV, J. CELL MOL. MED., vol. 17, no. 8, 2013, pages 989 - 1005
M. GOODMAN: "Methods of Organic Chemistry (Houben-Weyi)", vol. E22A, 2004, GEORG THIEME VERLAG, article "Synthesis of Peptides and Peptidomimetics"
M. SHI ET AL., CELL BIOCHEM. BIOPHYS, vol. 71, no. 2, 2015, pages 857 - 864
M. T. LIN; M. F. BEAL, NATURE, vol. 443, 2006, pages 787 - 795
P. ANDERS, NAT. IMMUNOL., vol. 6, 2005, pages 1211 - 1212
P.G.M. WUTS; T.W. GREENE: "Greene's Protective Groups in Organic Synthesis, 4th Edition,", 2006, JOHN WILEY AND SONS
P.J. KONCIENSKI: "Protecting Groups,3rd ed.", 2005, GEORG THIEME VERLAG
P.-J. LU ET AL., J. BIOL. CHEM., vol. 277, no. 4, 2002, pages 2381 - 2384
P.-J. LU ET AL., SCIENCE, vol. 283, 1999, pages 1325
R. B. BAUDY ET AL., J. MED. CHEM., vol. 52, no. 3, 2009, pages 771 - 778
R. RANGANATHAN ET AL., CELL, vol. 89, no. 6, 1997, pages 875 - 886
R. W. PANG ET AL., J. PATHOL, vol. 210, 2006, pages 19 - 25
RUSTIGHI A ET AL., MOL. MED., vol. 6, no. 1, 2014, pages 99 - 119
S. B. SINGH ET AL., J. MED. CHEM., vol. 57, no. 20, 2014, pages 8421 - 8444
S. D. HANES ET AL., YEAST, vol. 5, no. 1, 1989, pages 55 - 72
S. D. HANES, BIOCHIM. BIOPHYS. ACTA, vol. 1850, no. 10, 2015, pages 2017 - 2034
S. DE LOMBAERT ET AL., J. MED. CHEM., vol. 37, 1994, pages 498 - 511
S. ESNAULT, PLOS ONE, vol. 2, 2007, pages E226
S. ESNAUT ET AL., J. ALLERGY CLIN. IMMUNOL., vol. 120, 2007, pages 1082 - 1088
S. H. BAIK, ANN. NEUROL., vol. 77, no. 3, 2015, pages 504 - 517
S. P. CHAVAN ET AL., TETRAHEDRON LETT., vol. 54, no. 36, 2013, pages 4851 - 4853
S. PATAI, Z. RAPPOPORT: "Chemistry of Functional Groups", 1999, WILEY
S. R. AMBATI, MOL. ONCOL., vol. 8, no. 2, 2014, pages 323 - 336
S. SAKAI ET AL., LIFE SCI., vol. 102, no. 2, 2014, pages 98 - 104
S. WEI, NAT. MED, vol. 21, no. 5, 2015, pages 457 - 466
S. ZHAO; F. A. ETZKORN, BIOORG. MED. CHEM. LETT., vol. 17, no. 23, 2007, pages 6615 - 6618
S.-Y. CHEN, MOL. CELL. BIOL., vol. 26, no. 3, 2006, pages 929 - 939
T. BOUSSETTA, BLOOD, vol. 116, no. 25, 2010, pages 5795 - 5802
T. HSU ET AL., NAT. CELL BIOL, vol. 3, 2001, pages 538 - 543
T. LIU ET AL., J. MED. CHEM., vol. 53, no. 6, 2010, pages 2494 - 250
T. LIU, J. MED. CHEM., vol. 53, no. 6, 2010, pages 2494 - 2501
W. BANNWARTH ET AL.: "Combinatorial Chemistry: From Theory to Application", 2006, WILEY-VCH
W. CHANPUT ET AL., INT. IMMUNOPHARMACOL, vol. 23, no. 1, 2014, pages 37 - 45
W. LIAN, J. AM. CHEM. SOC., vol. 136, no. 28, 2014, pages 9830 - 9833
X. TAN ET AL., CANCER BIOL. THER., vol. 9, no. 2, 2010, pages 111 - 119
Y. NAKATSU ET AL., J. BIOL. CHEM., vol. 287, no. 53, 2012, pages 44526 - 44535
Y. ZHANG ET AL., ACS CHEM BIOL., vol. 2, no. 5, 2007, pages 320 - 328
Y. ZHANG ET AL., ACS CHEM. BIOL, vol. 2, no. 5, 2007, pages 320 - 328
Y.-A. CHO, J. DENT. RES., vol. 94, no. 2, 2015, pages 371 - 380
Y.-C. LIOU ET AL., TRENDS BIOCHEM. SCI., vol. 36, no. 10, 2011, pages 501 - 514
Z. LU; T. HUNTER, CELL RES., vol. 24, 2014, pages 1033 - 1049
Z.-H. SHEN; J. S. MALTER, BIOMOLECULES, vol. 5, 2015, pages 412 - 434
Z.-J. SHEN ET AL., J. CLIN. INVEST., vol. 118, no. 2, 2008, pages 479 - 490

Similar Documents

Publication Publication Date Title
CN110312719B (zh) 作为jak家族激酶抑制剂的咪唑并吡咯并吡啶
CN107148417B (zh) 苯并氮杂*磺酰胺化合物
KR101344989B1 (ko) Ｐｐａｒ 작용제 활성을 갖는 유도체
ES2684776T3 (es) Ftalazinonas e isoquinolinonas como inhibidores de ROCK
AU2016382372B2 (en) Sulfonamide derivative and preparation method and use thereof
WO2013083991A1 (fr) Nouveaux composés et leur utilisation en thérapie
JP2018522863A (ja) Ｎａｄｐｈオキシダーゼ４阻害剤
CN110099898A (zh) 化合物及其用途
TW202031659A (zh) 具抗b型肝炎病毒（hbv）活性之新穎6,7-二氫-4h-吡唑并[1,5-a]吡嗪吲哚-2-羧醯胺
KR20230142745A (ko) Cdk2 억제제 및 그의 사용 방법
CN116438160A (zh) 用于治疗病毒感染的氨基氨基甲酰基化合物
MX2011005124A (es) Derivados de carbamatos de alquil-heterociclos, preparacion y su aplicacion en terapeutica.
AU2022260554A9 (en) Modulators of sortilin activity
US20080221063A1 (en) Heterocyclic Sulfonamide Derivatives As Inhibitors Of Factor Xa
US20160194313A1 (en) Indole amide compound as inhibitor of necrosis
CN109641909B (zh) 雷帕霉素信号通路抑制剂的机理靶标及其治疗应用
CN110028508B (zh) 一种抗肿瘤的重氮双环类细胞凋亡蛋白抑制剂
KR102537615B1 (ko) 히스톤 탈아세틸화효소 6 억제제로서의 1,3,4-옥사다이아졸 유도체 화합물 및 이를 포함하는 약제학적 조성물
WO2008038011A1 (fr) DÉrivÉs de la pyrimidine servant d'inhibiteurs de l'aurora A et de l'aurora B
CN113767102A (zh) 具有抗乙型肝炎病毒(hbv)活性的新的苯基和吡啶基脲类化合物
KR100814092B1 (ko) 히스톤 디아세틸라제 저해활성을 갖는 알킬카바모일나프탈렌일옥시 옥테노일 하이드록시아마이드 유도체, 이의제조방법 및 이를 유효성분으로 하는 항암제용 약학조성물
WO2017063757A1 (fr) Composés macrocycliques à conformation limitée
TW202330537A (zh) Wee1抑制劑及其製備和用途
WO2017063755A1 (fr) Composés macrocycliques à conformation limitée
WO2017063756A1 (fr) Utilisation de composés macrocycliques à conformation limitée comme modulateurs de pin1

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 16785354

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 16785354

Country of ref document: EP

Kind code of ref document: A1