WO2019072978A1 - Mitochondrial inhibitors for the treatment of proliferation disorders - Google Patents

Mitochondrial inhibitors for the treatment of proliferation disorders Download PDF

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WO2019072978A1
WO2019072978A1 PCT/EP2018/077752 EP2018077752W WO2019072978A1 WO 2019072978 A1 WO2019072978 A1 WO 2019072978A1 EP 2018077752 W EP2018077752 W EP 2018077752W WO 2019072978 A1 WO2019072978 A1 WO 2019072978A1
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pharmaceutically acceptable
acceptable salt
ring
compound
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Florian Richalet
Sven Weiler
Mahmoud EL SHEMERLY
Heidi Lane
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Basilea Pharmaceutica International AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • 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
    • C07D498/02—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 two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • Mitochondrial inhibitors for the treatment of proliferation disorders are Mitochondrial inhibitors for the treatment of proliferation disorders
  • the present invention relates to mitochondrial inhibitors and their use in the treatment of proliferation disorders, in particular cancer.
  • Mitochondria are the power house of the cell because they generate most of the adenosine triphosphate (ATP), used as a source of chemical energy (Campbell, N.A., Williamson B., Heyden, R.J. Biology: Exploring Life 2006 th Edition, Publisher: Pearson Prentice Hall, 2006).
  • mitochondria are involved in other functions, such as cellular signaling, differentiation and death, as well as maintaining control of the cell cycle and cell growth (McBride H.M. et.al., Curr. Biol., vol. 16, no.14, R551-60, 2006). Cancer cells reprogram their metabolism in favour of glycolysis, regardless of oxygen presence, according to a phenomenon known as aerobic glycolysis.
  • Warburg phenotype involves high glucose uptake and a high glycolytic activity (Warburg O., Science, vol. 123, no. 3191, pages 309- 314, 1956). Nevertheless, cancer cells are also dependent on mitochondria for ATP production through oxidative phosphorylation (OXPHOS) (Marchetti P. et al., International Journal of Cell Biology, vol. 2015, pages 1-17, 2015 and Solaini G. et al., Biochim. Biophys. Acta,, vol. 2, page: 314-323, 2010). Mitochondrial metabolism is now recognized as a potential target for anticancer agents due to the metabolic characteristic of cancer cells.
  • human cancer is associated with mitochondrial dysregulation, which promotes cancer cell survival, tumor progression and metastases as well as resistance to current anticancer drugs (Marchetti P. et al., International Journal of Cell Biology, vol. 2015, pages 1-17, 2015, Boland M.L. et al., Frontieres in Oncology, vol. 3, Article 292, pages 1-28, 2013 and Solaini G. et al., Biochim. Biophys. Acta, vol. 1797, pages 1171-1177, 2010).
  • Metabolic reprogramming in cancer cells results in the maintenance of energy (ATP) production even under stressed conditions, contributing to tumor growth and survival through (for example) mitochondrial utilization of alternative carbon sources such as glutamine and fatty acids to generate ATP (Solaini G.
  • mitochondrial glutaminolysis is preferentially used to produce ATP and, therefore, contribute to cancer cell survival (DeBerardinis R.J. et al., PNAS, vol. 104, no. 49, pages 19345-19350, 2007) being crucial for the development (Strohecker A.M. et al., Cancer Discovery, vol. 3, no. 11, pages 1272-1285, 2013) and anchorage-independent growth (Weinberg F. et al., PNAS, vol. 107, no. 19, pages 8788-8793, 2010) of certain tumor types.
  • mitochondrial activity has also been associated with the development of drug resistance.
  • chemotherapeutic and targeted drugs e.g. BRAF inhibitors
  • BRAF inhibitors have been shown to induce a shift in cancer metabolism leading to mitochondrial dependency (addiction) characterized for example by upregulation of OXPHOS and mitochondrial biogenesis in surviving cells
  • WO2010/054763 Hence, targeting mitochondrial metabolism is of great interest for the development of novel therapeutic approaches for cancer treatment.
  • the present invention provides compounds of formula I and pharmaceutically acce table salts thereof
  • ring A represents group A-I, A-II or A-III
  • A8 represents -C(R4a)(R4a)-, -N(R4b)-, -O- or -S-;
  • A9 represents -C(R4c)(R4c)- or -0-;
  • A10 represents -C(R4c)(R4c)- or -0-;
  • Al 1 represents -C(R4c)(R4c)- or -0-;
  • A12 represents -C(R4a)(R4a)-, -O- or -S-;
  • group A-I, group A-II and group A- III do not contain adjacent oxygen atoms, adjacent oxygen and sulfur atoms or adjacent oxygen and nitrogen atoms or a moiety selected from the group consisting of N-C-N, N-C-S, S-C-S, O-C-N, O-C-0 and O-C-S, wherein in each case the carbon atom in the N-C-N, N- C-S, S-C-S, O-C-N, O-C-0 and O-C-S moiety is saturated;
  • Bl, B2, B3 and B4 represent independently C(R3) or N, wherein no more than two of Bl, B2, B3 and B4 represent N;
  • Rl represents independently at each occurrence Cl-C6alkyl, Cl-C6haloalkyl or Cl-C6alkyl wherein one or two carbon atoms are independently replaced by -O- and wherein the alkyl moiety is optionally substituted by one or more halogen (when two carbon atoms are replaced by -0-, the oxygen atoms are not adjacent);
  • R2 represents halogen, cyano, hydroxyl, mercapto, Cl-C6alkyl optionally substituted by one to five R7,
  • Cl-C6alkoxy optionally substituted by one to five R7, -N(R6a)(R6b) or -Cl-C6alkylene-N(R6a)(R6b);
  • R3 represents independently at each occurrence hydrogen, halogen, cyano or Cl-C4alkyl
  • R4a and R4b represent independently at each occurrence hydrogen or Cl-C3alkyl
  • R4c represents independently at each occurrence hydrogen, Cl-C6alkyl optionally substituted by Rl 1, or
  • Cl-C6alkyl in which one carbon atom is replaced by oxygen and which is additionally optionally substituted by Rl 1 , providing that when R4c is alkoxy the oxygen atom of R4c does not form with two ring atoms a moiety selected from the group consisting of O-C-N, O-C-0 and O-C-S, wherein in each case the carbon atom in the O-C-N, O-C-0 and O-C-S moiety is saturated;
  • R5 represents hydrogen or C 1 -C4alkyl
  • R6a represents hydrogen, Cl-C6alkyl optionally substituted by one to five R7, -Cl-C6alkylene-Cycle-
  • R6b represents hydrogen or Cl-C6alkyl
  • R7 represents independently at each occurrence halogen, cyano, hydroxyl, Cl-C6alkoxy, Cl- C3alkylsulfonyl, amino, -NH(C1-C4alkyl) or -N(Cl-C4alkyl) 2 ;
  • Cycle-P represents independently at each occurrence a saturated or partially unsaturated 3- to 8- membered carbocyclic ring optionally substituted by 1 to 3 R9, or a saturated or partially unsaturated 3- to 8-membered heterocyclic ring optionally substituted by 1 to 3 R9 containing carbon atoms as ring members and one or two ring members independently selected from N and O, wherein N optionally may bear R8;
  • Cycle-Q represents independently at each occurrence phenyl optionally substituted by 1 to 3 RI O or a 5- to 6-membered heteroaryl ring containing one to four heteroatoms selected from O, S and N, optionally substituted by 1 to 3 RI O;
  • R8 represents independently at each occurrence hydrogen or Cl -C4alkyl
  • R9 and RI O represent independently at each occurrence cyano, Cl -C4alkyl, Cl -C4haloalkyl, Cl - C4alkoxy or Cl -C4haloalkoxy;
  • Rl 1 represents hydroxyl or cyano
  • n 1 or 2;
  • q 0, 1 , 2, 3 or 4.
  • the invention provides compounds of formula I and pharmaceutically acceptable salts thereof for use in the treatment of proliferation diseases and disorders, in particular cancer, in a subject selected from a mammal, in particular in a human.
  • the invention provides use of compounds of formula I and pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of proliferation diseases and disorders, in particular cancer, in a subject selected from a mammal, in particular in a human.
  • the invention provides methods of treating proliferation diseases and disorders, in particular cancer, in a subject selected from a mammal, in particular in a human, comprising
  • compositions comprising a compound of formula I or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
  • Each alkyl moiety either alone or as part of a larger group such as alkoxy is a straight or branched chain and is preferably Cl -C6alkyl, more preferably Cl -C4alkyl.
  • Examples include methyl, ethyl, « -propyl, prop-2-yl, « -butyl, but-2-yl, 2-methyl-prop-l -yl or 2-methyl-prop-2-yl.
  • Each alkylene moiety is a straight or branched chain and is, for example, -CH 2 -, -CH 2 -CH 2 -, -CH(CH 3 )-, - CH 2 -CH 2 -CH 2 -, -CH(CH 3 )-CH 2 -, or -CH(CH 2 CH 3 )-.
  • Each alkenyl moiety either alone or as part of a larger group such as alkenyloxy is a straight or branched chain and is preferably C2-C6alkenyl, more preferably C2-C4alkenyl.
  • Each moiety can be of either the (E)- or (Z)-configuration. Examples include vinyl and allyl.
  • Each alkynyl moiety either alone or as part of a larger group such as alkynyloxy is a straight or branched chain and is preferably C2-C6alkynyl, more preferably C2-C4alkynyl. Examples are ethynyl and propargyl.
  • Each haloalkyl moiety either alone or as part of a larger group such as haloalkoxy is an alkyl group substituted by one or more of the same or different halogen atoms. Examples include difluoromethyl, trifluoromethyl, chlorodifluoromethyl and 2,2,2-trifluoro-ethyl.
  • Haloalkyl moieties include for example 1 to 5 halo substituents, or 1 to 3 halo substituents.
  • Each haloalkenyl moiety either alone or as part of a larger group such as haloalkenyloxy is an alkenyl group substituted by one or more of the same or different halogen atoms.
  • Examples include 2-difluoro- vinyl and 1 ,2-dichloro-2-fluoro-vinyl.
  • Haloalkenyl moieties include for example 1 to 5 halo substituents, or 1 to 3 halo substituents.
  • Each cycloalkyl moiety can be in mono- or bi-cyclic form and preferably contains 3 to 8 carbon atoms, more preferably 3 to 6 carbon atoms.
  • monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • An example of a bicyclic cycloalkyl group is
  • Halogen is fluorine, chlorine, bromine, or iodine.
  • amino refers to -NH 2 .
  • mercapto refers to -SH.
  • alkylsulfonyl means -S(0)2-alkyl.
  • alkoxyalkyl means -alkyl-O-alkyl.
  • heteroaryl refers to an aromatic ring system containing at least one heteroatom, and preferably up to four, for example up to three, heteroatoms selected from nitrogen, oxygen and sulfur as ring members. Heteroaryl rings do not contain adjacent oxygen atoms, adjacent sulfur atoms, or adjacent oxygen and sulfur atoms within the ring.
  • Examples include pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, tetrazolyl, furanyl and thiophenyl.
  • heterocyclic ring refers to a saturated or partially unsaturated carbocyclic ring containing one to four heteroatoms selected from nitrogen, oxygen and sulfur as ring members. Such rings do not contain adjacent oxygen atoms, adjacent sulfur atoms, or adjacent oxygen and sulfur atoms within the ring.
  • Examples include tetrahydro furanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, dioxanyl and morpholinyl.
  • a group is said to be optionally substituted, it may be substituted or unsubstituted, for example optionally with 1-5 substituents, for example optionally with 1-3 substituents.
  • Certain compounds of formula I may contain one or two or more centers of chirality and such compounds may be provided as pure enantiomers or pure diastereoisomers as well as mixtures thereof in any ratio.
  • the H on the carbon atom connected to X by the dotted line may be in the axial or equatorial configuration and the invention includes both isomers in any ratio.
  • the compounds of the invention also include all cis/trans-isomers (for example where the dotted line is a double bond) as well as mixtures thereof in any ratio.
  • the compounds of the invention also include all tautomeric forms of the compounds of formula I.
  • the compounds of formula I may also be solvated, especially hydrated, which are also included in the compounds of formula I. Solvation and hydration may take place during the preparation process.
  • Reference to compounds of the invention includes pharmaceutically acceptable salts of said compounds. Such salts may also exist as hydrates and solvates.
  • pharmacologically acceptable salts of the compounds of formula (I) are salts of physiologically acceptable mineral acids, such as hydrochloric acid, sulfuric acid and phosphoric acid, or salts of organic acids, such as methane-sulfonic acid, p- toluenesulfonic acid, lactic acid, acetic acid, trifluoroacetic acid, citric acid, succinic acid, fumaric acid, maleic acid and salicylic acid.
  • pharmacologically acceptable salts of the compounds of formula (I) are alkali metal and alkaline earth metal salts such as, for example, sodium, potassium, lithium, calcium or magnesium salts, ammonium salts or salts of organic bases such as, for example, methylamine, dimethylamine, triethylamine, piperidine, ethylenediamine, lysine, choline hydroxide, meglumine, morpholine or arginine salts.
  • alkali metal and alkaline earth metal salts such as, for example, sodium, potassium, lithium, calcium or magnesium salts, ammonium salts or salts of organic bases such as, for example, methylamine, dimethylamine, triethylamine, piperidine, ethylenediamine, lysine, choline hydroxide, meglumine, morpholine or arginine salts.
  • substituent definitions may be combined in any combination.
  • Al represents -C(R4a)(R4a)-, -N(R4b)-, -O- or -S-;
  • A2 represents -C(R4c)(R4c);
  • A3 represents -C(R4c)(R4c)-
  • A4 represents -C(R4a)(R4a)- , -O- or -S-; or
  • Al represents -C(R4a)(R4a)-;
  • A2 represents -C(R4c)(R4c) or -0-;
  • A3 represents -C(R4c)(R4c)- or -0-, wherein both A2 and A3 do not represent -0-;
  • A4 represents -C(R4a)(R4a)-;
  • group A-I may represent group A-Ia, group A-Ib, group A-Ic, group A-Id or group A-Ie:
  • Ala represents -C(R4a)(R4a)-, -N(R4b)-, -O- or -S-;
  • A4a represents -C(R4a)(R4a)-, -O- or -S-;
  • A2 represents -C(R4c)(R4c)- or -0-;
  • Ala represents -CH(R4a)-, -N(R4b)- or -O- or -S-;
  • A4a represents -CH(R4a)-, -O- or -S-;
  • A2 represents -CH(R4c) or -0-;
  • Al a represents -CH(R4a)-, -N(R4b)- or -0-;
  • A4a represents -CH(R4a)- or -0-;
  • A2 represents -CH(R4c) or -0-;
  • A3 represents -CH(R4c)- or -0-, wherein both A2 and A3 do not represent -0-;
  • group A-I may represent group A-If
  • A2 and A3 represents independently -C(R4c)(R4c)-.
  • A5 represents -C(R4a)(R4a)-, -N(R4b)-, -O- or -S-;
  • A6 represents -C(R4c)(R4c)-
  • A7 represents -C(R4a)(R4a)-, -O- or -S-; or
  • A5 represents -C(R4a)(R4a)-, -N(R4b)-, or -0-;
  • group A-II may represent group A-IIa, group A-IIb or group A-IIc;
  • A5a represents -C(R4a)(R4a)-, -N(R4b)-, -O- or -S-;
  • A7a represents -C(R4a)(R4a)-, -O- or -S-, wherein at least one of A5a and A7a represents -C(R4a)(R4a)-;
  • A7b represents -O- or -S-;
  • A5c represents -N(R4b)-, -O- or -S-;
  • A5a represents -CH(R4a)-, -N(R4b)-, -O- or -S-;
  • A7a represents -CH(R4a)-, -O- or -S-, wherein at least one of A5a and A7a is -CH(R4a)-;
  • A7b represents -O- or -S-;
  • A5a represents -CH(R4a)-
  • A7a represents -CH(R4a)- or -0-;
  • A7b represents -O- or -S-;
  • A5c presents -0-
  • A8 represents -C(R4a)(R4a)- or -0-;
  • A9 represents -C(R4c)(R4c)-
  • A10 represents -C(R4c)(R4c)-;
  • Al l represents -C(R4c)(R4c)-;
  • A12 represents -C(R4a)(R4a)- or -0-.
  • group A-III may present group A-IIIa
  • A8 represents -C(R4a)(R4a)- or -0-;
  • A12 represents -C(R4a)(R4a)- or -0-;
  • A8 represents -CH(R4a)- or -0-;
  • A12 represents -CH(R4a)- or -0-.
  • group A-III may present group A-IIIb, A-IIIc
  • A9, A10 and Al 1 represent independently -C(R4c)(R4c)-, in particular A-IIId.
  • ring A preferably no more than two of the substituents R4a, R4b and R4c are other than hydrogen and in some cases no more than one of the substituents R4a, R4b and R4c are other than hydrogen.
  • Bl, B2, B3 and B4 preferably represent independently C(R3) or N, wherein no more than one of Bl, B2, B3 and B4 represents N.
  • Bl, B2, B3 and B4 represent independently C(R3a), C(R3b) or N wherein no more than two of Bl, B2, B3 and B4 represent C(R3a), wherein no more than one of Bl, B2, B3 and B4 represents N, wherein each R3a is independently R3 and each R3b represents hydrogen.
  • Structural examples of the ring comprising Bl, B2, B3 and B4 as ring members are represented by group B-I group B-II, group B-III and roup B-IV:
  • B-IV Further structural examples of the ring comprising Bl, B2, B3 and B4 as ring members are represented by group B-la, group B-Ib, group B-IIa, group B-IIIa and B-IVa, wherein B-la is of particular interest:
  • R3a is R3a*, wherein R3a* is as defined for R3a but is other than hydrogen
  • structural examples of the ring comprising Bl, B2, B3 and B4 as ring members include group B-Ia-1, group B-Ia-2, group B-Ia- 3, group B-Ib-1, group B-Ib-2, group B-IIa-1, group B-IIa-2, group B-IIIa-1 and group B-IIIa-2:
  • B-Ia-1 B-Ia-2 and B-Ia-3 are of particular interest.
  • Examples of the ring comprising B 1 , B2, B3 and B4 as ring members include include the following groups:
  • Rl preferably represents independently at each occurrence Cl-C4alkyl, Cl-C4alkoxy or Cl-C3alkoxy- Cl-C3alkyl, even more preferably methyl, ethyl, propyl, methoxy, ethoxy, methoxymethyl or methoxyethyl, and in particular methyl, ethyl, propyl or methoxy.
  • Rl does not attach to the carbon atom bonded to X.
  • R2 represents halogen, cyano, hydroxyl, Cl-C6alkyl, Cl-C6haloalkyl, Cl-C6alkyl wherein one or two non-adjacent carbon atoms in the alkyl other than the connecting carbon atom are replaced independently by -0-, -OH, -NH-, -NH 2 , -N(CH 3 )-, -NH(CH 3 ), -N(CH 3 ) 2 or -CN, or Cl-C6haloalkyl wherein one or two non-adjacent carbon atoms in the haloalkyl other than the connecting carbon atom are replaced independently by -0-, -OH, -NH-, -NH 2 , -N(CH 3 )-, -NH(CH 3 ), -N(CH 3 ) 2 or -CN, or Cl-
  • R2 represents fluoro, chloro, bromo, cyano, hydroxyl, Cl-C6alkyl, Cl-C6haloalkyl, Cl-C6alkoxy, Cl-C6haloalkoxy, -Cl-C4alkylene-methoxy, -N(R6b)-Cl-C4alkylene- Rl 1, -N(R6b)-Cl-C4alkylene-Cycle-P or -N(R6b)-Cycle-P, wherein Cycle-P represents
  • R6b represents hydrogen, methyl or ethyl
  • R8 represents independently at each occurrence hydrogen or methyl
  • Rl 1 represents -OH, -OCH 3 , -CN, -NH 3 ⁇ 4 -NH(CH 3 ), or - N(CH 3 ) 2 .
  • R2 is halogen, cyano, methoxy or trifluoromethyl, in particular halogen (e.g. chloro) or cyano.
  • R2 include fluoro, chloro, bromo, cyano, amino, hydroxyl, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, methoxymethyl, trifluromethyl, trifluoromethoxy, -N(CH 3 ) 2 , -NH(CH 3 ), -NHCH 2 CH 2 NH 2 , -NHCH 2 CH 2 CH 2 NH 2 , -N(CH 3 )CH 2 CH 2 OH, - N(CH 3 )CH 2 CH 2 OCH 3 , -N(CH 3 )CH 2 CN, -N(CH 3 )CH 2 (l-methylazetidinyl) (e.g.
  • Preferred specific examples are fluoro, chloro, bromo, cyano, methyl, trifluromethyl, N(CH 3 ) 2 , methoxy, methoxymethyl, -N(CH 3 )CH 2 CH 2 OH, -N(CH 3 )CH 2 CH 2 OCH 3 , -N(CH 3 )CH 2 CN, - N(CH 3 )CH 2 (l-methylazetidinyl) (e.g. -N(CH 3 )CH 2 (l-methylazetidin-3-yl) and -N(CH 3 )CH 2 CN, e.g. fluoro, chloro, cyano, trifluoromethyl or methoxy, in particular chloro and cyano.
  • R3 preferably represents independently at each occurrence hydrogen, halogen, cyano or methyl, more preferably hydrogen, fluoro, chloro, bromo, cyano, methyl, even more preferably hydrogen, fluoro, choro or methyl, e.g. hydrogen or fluoro.
  • each R3 on Bl, B2, B3 and B4 is hydrogen, or each R3 on Bl, B2 and B4 is hydrogen and R3 on B3 is halogen, in particular fluoro, or each R3 on Bl and B4 is hydrogen and each R3 on B2 and B3 is independently halogen, e.g. fluoro.
  • R4a represents independently at each occurrence hydrogen or Cl-C3alkyl. Preferably, no more than one R4a on a given carbon atom is other than hydrogen. More preferably no more than one R4a may be other than hydrogen. A specific example of R4a is hydrogen.
  • R4b represents independently at each occurrence hydrogen or Cl-C3alkyl. Preferably no more than one R4b is other than hydrogen. Specific examples of R4b are hydrogen and methyl.
  • R4c preferably represents independently at each occurrence hydrogen, Cl-C6alkyl -Cl-C6alkyl-cyano, - Cl-C6alkyl-hydroxy or -C0-C2alkyl-Cl-C4alkoxy, more preferably hydrogen, Cl-C4alkyl, -Cl-C4alkyl- cyano, -Cl-C4alkyl-hydroxy or -C0-C2alkyl-Cl-C3alkoxy.
  • Specific examples of R4c are hydrogen, methyl, cyanomethyl, hydroxymethyl, methoxy and methoxymethyl. In some embodiments no more than two R4c are other than hydrogen.
  • R4c is alkoxy the oxygen atom of R4c does not form with two ring atoms a moiety selected from the group consisting of O-C-N, O-C-0 and O-C-S, wherein in each case the carbon atom in the O-C-N, O-C-0 or O-C-S moiety is saturated.
  • R5 preferably represents hydrogen or methyl.
  • R6a preferably represents hydrogen or Cl-C6alkyl optionally substituted by one to five R7, more preferably hydrogen or Cl-C6alkyl wherein one or two non-adjacent carbon atoms in the alkyl are replaced independently by -0-, -OH, -NH-, -NH 2 , -N(CH 3 )-, -NH(CH 3 ), -N(CH 3 ) 2 or -CN, or R6a represents -Cl-C6-alkylene-Cycle-P or Cycle-P, wherein Cycle-P preferably represents a saturated 4- to 6-membered heterocyclic ring containing one or two heteroatoms selected from O and N(R8), wherein the heterocyclic ring is optionally substituted by one to three substituents selected from methyl, and R8 represents independently at each occurrence hydrogen or methyl, more preferably R6a represents -Cl- C4alkylene-Rl 1, -Cl-C4alkylene-Cycle-
  • R6b preferably represents hydrogen, methyl or ethyl, e.g. hydrogen or methyl.
  • R7 preferably represents independently at each occurrence halogen, cyano, hydroxyl or Cl-C4alkoxy.
  • Cycle-P preferably represents independently at each occurrence a saturated 4- to 6-membered carbocyclic ring or a saturated or partially unsaturated 5- to -6-membered heterocyclic ring wherein the carbocyclic ring and heterocyclic ring are optionally substituted by 1 to 3 R9 containing carbon atoms as ring members and one or two ring members independently selected from N and O, wherein N optionally may bear R8.
  • Cycle-P represents a saturated 4- to 6-membered heterocyclic ring containing one or two heteroatoms selected from O and N(R8), wherein the heterocyclic ring is optionally substituted by one to three substituents selected from methyl, and R8 represents independently at each occurrence hydrogen or methyl, even more preferably Cycle-P represents tetrahydrofuranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, dioxanyl or morpholinyl wherein N is substituted by R8 in each case and wherein R8 represents independently at each occurrence hydrogen or methyl.
  • Cycle-Q preferably represents independently at each occurrence a 5- to 6-membered heteroaryl ring containing one to four heteroatoms selected from O, S and N, optionally substituted by 1 to 3 RIO.
  • oxadiazolyl in particular 3-methyl-oxadiazolyl.
  • R8 preferably represents independently at each occurrence hydrogen or methyl.
  • R9 represents independently at each occurrence cyano, Cl-C4alkyl, Cl-C4haloalkyl, Cl-C4alkoxy or Cl- C4haloalkoxy, preferably cyano, methyl, halomethyl, methoxy or halomethoxy, even more preferably cyano, methyl, trifluoromethyl or methoxy.
  • RIO represents independently at each occurrence cyano, Cl-C4alkyl, Cl-C4haloalkyl, Cl-C4alkoxy or Cl-C4haloalkoxy, preferably cyano, methyl, halomethyl, methoxy or halomethoxy, even more preferably cyano, methyl, trifluoromethyl or methoxy.
  • q is preferably 0, 1 or 2, and preferably when q is 2 the Rl substituents are on the same carbon atom, more preferably q is 0 or 1.
  • X represents -CH(R5)-.
  • X represents -C(O)-.
  • X represents -0-.
  • ring ; A represents group A-I.
  • ring ; A represents group A-II.
  • ring ; A represents group A-III.
  • ring ; A represents group A-Ia.
  • ring ; A represents group A-Ib.
  • ring ; A represents group A-Ic.
  • ring ; A represents group A-Id.
  • ring ; A represents group A-Ie.
  • ring ; A represents group A-If.
  • ring ; A represents group A-IIa. In another embodiment ring A represents group A- lib.
  • ring A represents group A- He.
  • ring A represents group A- Ilia.
  • ring A represents group A- Illb.
  • ring A represents group A- [f or group A-IIIb.
  • ring A represents group A- [ and X presents -CH 2 -.
  • ring A represents group A- [I and X represents -CH 2 -.
  • ring A represents group A- [II and X represents -CH 2 -.
  • ring A represents group A- [ and X presents -C(O)-.
  • ring A represents group A- [I and X represents -C(O)-.
  • ring A represents group A- [II and X represents -C(O)-.
  • ring A represents group A- [ and X presents -0-.
  • ring A represents group A- [I and X represents -0-.
  • ring A represents group A- [II and X represents -0-.
  • ring A represents group A- [a and X represents -CH 2 -.
  • ring A represents group A- [b and X presents -CH 2 -.
  • ring A represents group A- [c and X represents -CH 2 -.
  • ring A represents group A- Id and X represents -CH 2 -.
  • ring A represents group A- [e and X represents -CH 2 -.
  • ring A represents group A- [f and X represents -CH 2 -.
  • ring A represents group A- [Ia and X represents -CH 2 -.
  • ring A represents group A- [Ib and X represents -CH 2 -.
  • ring A represents group A- [Ic and X represents -CH 2 -. In another embodiment ring A represents group A -Ilia and X represents -CH 2 -.
  • ring A represents group A -Illb and X represents -CH 2 -.
  • ring A represents group A -Ia and X represents -C(O)-.
  • ring A represents group A -Ib and X represents -C(O)-.
  • ring A represents group A -Ic and X represents -C(O)-.
  • ring A represents group A -Id and X represents -C(O)-.
  • ring A represents group A -Ie and X represents -C(O)-.
  • ring A represents group A -If and X represents -C(O)-.
  • ring A represents group A -Ila and X represents -C(O)-.
  • ring A represents group A -lib and X represents -C(O)-.
  • ring A represents group A -lie and X represents -C(O)-.
  • ring A represents group A -Ilia and X represents -C(O)-.
  • ring A represents group A -Illb and X represents -C(O)-.
  • ring A represents group A -Ia and X represents -0-.
  • ring A represents group A -Ib and X represents -0-.
  • ring A represents group A -Ic and X represents -0-.
  • ring A represents group A -Id and X represents -0-.
  • ring A represents group A -Ie and X represents -0-.
  • ring A represents group A -If and X represents -0-.
  • ring A represents group A -Ila and X represents -0-.
  • ring A represents group A -lib and X represents -0-.
  • ring A represents group A -lie and X represents -0-.
  • ring A represents group A -Ilia and X represents -0-.
  • ring A represents group A -Illb and X represents -0-.
  • n 1
  • n is 2.
  • q is 1.
  • q is 2.
  • q is 1 or 2.
  • ring A is ring A-I, A-II or A-III and the bridge in ring A formed by the A moieties is saturated, e.g.
  • Al represents -C(R4a)(R4a)-, -N(R4b)-, -O- or -S-;
  • A2 represents -C(R4c)(R4c)- or -0-;
  • A3 represents -C(R4c)(R4c)- or -0-;
  • A4 represents -C(R4a)(R4a)-, -O- or -S-;
  • A5 represents -C(R4a)(R4a)-, -N(R4b)-, -O- or -S-;
  • A6 represents -C(R4c)(R4c)-;
  • A7 represents -C(R4a)(R4a)-, -O- or -S-;
  • A8 represents -C(R4a)(R4a)-, -N(R4b)-, -O- or -S-;
  • A9 represents -C(R4c)(R4c)- or -0-;
  • A10 represents -C(R4c)(R4c)- or -0-;
  • Al 1 represents -C(R4c)(R4c)- or -0-;
  • A12 represents -C(R4a)(R4a)-, -O- or -S-.
  • Groups A-Ia, A-Ib, A-Id, A-Ie, A- If, A-IIa, A- Ilia and A-IIIb represent examples wherein ring A formed by the A moieties is saturated.
  • ring A is group A-I or A-II and the bridge in ring A formed by the A moieties is unsaturated (e.g. aromatic), e.g.
  • Groups A-Ic, A-IIb and A-IIc represent examples wherein ring A formed by the A moieties is unsaturated.
  • R4a, R4b and R4c substituents are other than hydrogen. In another embodiment no more than one of the R4a, R4b and R4c substituents are other than hydrogen.
  • ring A represents group A-I or group A-III and Al, A4, A8 and A12 represent -O- and A2, A3, A9, A10 and Al 1 represent independently -C(R4c)(R4c)-.
  • ring A represents group A-I or group A-III and Al and A8 represent -O- and A2, A3, A4, A9, A10, Al land A12 represent independently -C(R4c)(R4c)-.
  • ring A represents group A-Ia, A-Id, A-Ie or A-IIIa and Ala
  • A4a, A8 and A12 represent -O- and A2,
  • A3, A9, A10 and Al 1 represent independently -C(R4c)(R4c)-.
  • ring A represents group A-Ia, A-Id, A-Ie or A-IIIa and Ala and A8 represent -O- and A2, A3, A4a, A9, A 10, Al land A12 represent independently -C(R4c)(R4c)-.
  • ring A represents group A-I, A-II or A- III
  • A8 represents -C(R4a)(R4a)-, -N(R4b)-, -O- or -S-;
  • A9 represents -C(R4c)(R4c)- or -0-;
  • A10 represents -C(R4c)(R4c)- or -0-;
  • Al 1 represents -C(R4c)(R4c)- or -0-;
  • A12 represents -C(R4a)(R4a)-, -O- or -S-;
  • group A-I, group A-II and group A-III do not contain adjacent oxygen atoms, adjacent oxygen and sulfur atoms or adjacent oxygen and nitrogen atoms or a moiety selected from the group consisting of
  • Rl represents independently at each occurrence Cl-C4alkyl, Cl-C4alkoxy or Cl-C3alkoxy-Cl-C3alkyl;
  • R2 represents halogen, cyano, methoxy or trifluoromethyl (e.g. halogen or cyano);
  • R3 represents independently at each occurrence hydrogen or halogen
  • R4a and R4b represent independently at each occurrence hydrogen or Cl-C3alkyl
  • R4c represents independently at each occurrence hydrogen, Cl-C6alkyl optionally substituted by Rl 1, or Cl-C6alkyl in which one carbon atom is replaced by oxygen and optionally substituted by Rl 1, providing that when R4c is alkoxy the oxygen atom of R4c does not form with two ring atoms a moiety selected from the group consisting of O-C-N, O-C-0 and O-C-S, wherein in each case the carbon atom in the O- C-N, O-C-0 or O-C-S moiety is saturated;
  • Rl 1 represents hydroxyl or cyano
  • n 1 or 2;
  • q 0, 1 or 2.
  • ring A represents group A-Ia, A-Ib, A-Ic, A-Id, A-Ie, A-IIa, A- lib, AIIc or A-IIIa:
  • Ala represents -CH(R4a)-, -N(R4b)- or -O- or -S-;
  • A4a represents -CH(R4a)-, -O- or -S-;
  • A2 represents -CH(R4c) or -0-;
  • A3 represents -CH(R4c)- or -0-, wherein both A2 and A3 do not represent -0-;
  • A5a represents -CH(R4a)-, -N(R4b)-, -O- or -S-;
  • A7a represents -CH(R4a)-, -O- or -S-, wherein at least one of A5a and A7a is -CH(R4a)-;
  • A7b represents -O- or -S-;
  • A5c represents -N(R4b)-, -O- or -S-;
  • A8 represents -CH(R4a)- or -0-;
  • A12 represents -CH(R4a)- or -0-;
  • Rl represents independently at each occurrence methyl, ethyl, propyl, methoxy, ethoxy, methoxymethyl or methoxyethyl;
  • R2 represents halogen, cyano, methoxy or trifluoromethyl (e.g. halogen or cyano);
  • R3 represents independently at each occurrence hydrogen or halogen
  • R4a and R4b represent independently at each occurrence hydrogen or Cl-C3alkyl
  • R4c represents independently at each occurrence hydrogen, Cl-C4alkyl -Cl-C4alkyl-cyano, -Cl-C4alkyl- hydroxy or -C0-C2alkyl-Cl-C3alkoxy, providing that when R4c is alkoxy, the oxygen atom of R4c does not form with two ring atoms a moiety selected from the group consisting of O-C-N, O-C-0 and O-C-S, wherein in each case the carbon atom in the O-C-N, O-C-0 or O-C-S moiety is saturated;
  • n 1 or 2;
  • q 0, 1 or 2.
  • the compound of formula I is as defined in Embodiment 2 wherein ring A represents group A- la, A-Ib or A-Ic.
  • the compound of formula I is as defined in Embodiment 2 wherein ring A represents group A- la or A-Ib.
  • the compound of formula I is as defined in Embodiment 2 wherein ring A represents group A-Ic.
  • the compound of formula I is as defined in Embodiment 2 wherein ring A represents group A-IIa, A-IIb or A-IIc.
  • the compound of formula I is as defined in Embodiment 2 wherein ring A represents group A-IIa.
  • the compound of formula I is as defined in Embodiment 2 wherein ring A represents group A- lib or A-IIc.
  • the compound of formula I is as defined in Embodiment 2 wherein ring A represents group A- Ilia.
  • ring A represents group A-Ia, A-Ib, A-Ic, A-Id, A-Ie, A-IIa, A- Ilb, A-IIc or A-IIIa:
  • Ala represents -CH(R4a)-, -N(R4b)- or -0-;
  • A4a represents -CH(R4a)- or -0-;
  • A2 represents -CH(R4c) or -0-;
  • A3 represents -CH(R4c)- or -0-, wherein both A2 and A3 do not represent -0-;
  • A5a represents -CH(R4a)-
  • A7a represents -CH(R4a)- or -0-, wherein at least one of A5a and A7a is -CH(R4a)-;
  • A7b represents -O- or -S-;
  • A5c represents -0-
  • A8 represents -CH(R4a)- or -0-;
  • A12 represents -CH(R4a)- or -0-;
  • Rl represents independently at each occurrence methyl, ethyl, propyl or methoxy
  • R2 represents halogen or cyano, methoxy or trifluoromethyl (e.g. halogen or cyano);
  • R3 represents independently at each occurrence hydrogen or halogen
  • R4a and R4b represent independently at each occurrence hydrogen or Cl-C3alkyl
  • R4c represents independently at each occurrence hydrogen, Cl-C4alkyl, -Cl-C4alkyl-cyano, -Cl-
  • R4c when R4c is alkoxy the oxygen atom of R4c does not form with two ring atoms a moiety selected from the group consisting of O-C-N, O-C-0 and O-C-S, wherein in each case the carbon atom in the O-C-N, O-C-0 or O-C-S moiety is saturated;
  • n 1 or 2;
  • q 0, 1 or 2.
  • the compound of formula I is as defined in embodiment 3 wherein ring A represents group A- la, A-Ib or A-Ic.
  • the compound of formula I is as defined in embodiment 3 wherein ring A represents group A- la or A-Ib.
  • the compound of formula I is as defined in embodiment 3 wherein ring A represents group A-Ic.
  • the compound of formula I is as defined in embodiment 3 wherein ring A represents group A-IIa, A-IIb or A-IIc.
  • the compound of formula I is as defined in embodiment 3 wherein ring A represents group A-IIa.
  • the compound of formula I is as defined in embodiment 3 wherein ring A represents group A- lib or A-IIc.
  • the compound of formula I is as defined in embodiment 3 wherein ring A represents group A- Ilia.
  • ring A represents one of the following groups:
  • ring A represents one of the groups defined in embodiment 4 and X, Rl, R2, R3, R4c, n and q are as defined in Embodiment 2.
  • ring A represents one of the groups defined in embodiment 4 and X, Rl, R2, R3, R4c, n and q are as defined in Embodiment 3.
  • ring A represents group A-If or A-IIIb, wherein
  • A2 and A3 represent independently -C(R4c)(R4c)-
  • A9, A10 and Al 1 represent independently - C(R4c)(R4c)-
  • Rl, R2, R3, R4c, n and q (and preferably X) are as defined in Embodiment 1.
  • ring A represents group A-If or A-IIIb, wherein
  • A2 and A3 represent independently -C(R4c)(R4c)-
  • A9, A10 and Al 1 represent independently - C(R4c)(R4c)-
  • Rl, R2, R3, R4c, n and q (and preferably X) are as defined in Embodiment 2.
  • ring A represents group A-If or A-IIIb
  • A9, A10 and Al 1 represent independently -C(R4c)(R4c)- and A2 and A3 represent
  • ring A represents one of the following groups:
  • X CH- or -C(O)-
  • R2 represents fluoro, chloro, cyano, trifluoromethyl or methoxy
  • each R3 represents independently fluoro or hydrogen
  • n land q is 0.
  • Al, A2, A3, A4, R2 and R3 are as defined for the compound of formula I, including preferred definitions thereof.
  • Al, A2, A3, A4, R2 and R3 may be as defined in Embodiment 1, or for example Al, A2, A3, A4, R2 and R3 may be as defined in Embodiment 2, or for example Al, A2, A3, A4, R2 and R3 may be as defined in Embodiment 3.
  • the compound of formula I is a compound of formula la, wherein Al and A4 represent -0-, A2 and A3 represent independently -C(R4c)(R4c)- and R2, R3 and R4c are as defined for the compound of formula I, including preferred definitions thereof.
  • the compound of formula I is a compound of formula la, wherein Al represents -0-, A2 and A3 independently represent -C(R4c)(R4c)-, A4 represents CH 2 and R2, R3 and R4c are as defined for the compound of formula I, including preferred definitions thereof.
  • R2, R3 and R4c may be as defined in Embodiment 1 , or for example R2, R3 and R4c may be as defined in Embodiment 2, or for example R2, R3 and R4c may be as defined in Embodiment 3.
  • Al, A2, A3, A4, R2 and R3 are as defined for the compound of formula I, including preferred definitions thereof.
  • Al, A2, A3, A4, R2 and R3 may be as defined in Embodiment 1, or for example Al, A2, A3, A4, R2 and R3 may be as defined in Embodiment 2, or for example Al, A2, A3, A4, R2 and R3 may be as defined in Embodiment 3.
  • the compound of formula I is a compound of formula lb, wherein Al and A4 represent -0-, A2 and A3 represent independently -C(R4c)(R4c)- and R2, R3 and R4c are as defined for the compound of formula I, including preferred definitions thereof.
  • the compound of formula I is a compound of formula la, wherein Al represents -0-, A2 and A3 independently represent -C(R4c)(R4c)-, A4 represents CH 2 and R2, R3 and R4c are as defined for the compound of formula I, including preferred definitions thereof.
  • R2, R3 and R4c may be as defined in Embodiment 1 , or for example R2, R3 and R4c may be as defined in Embodiment 2, or for example R2, R3 and R4c may be as defined in Embodiment 3.
  • Al, A2, A3, A4, Rl, R2, R3 and q are as defined for the compound of formula I, including preferred definitions thereof.
  • Al, A2, A3, A4, Rl, R2, R3 and q may be as defined in Embodiment 1, or for example Al , A2, A3, A4, Rl, R2, R3 and q may be as defined in Embodiment 2 or for example Al, A2, A3, A4, Rl, R2, R3 and q may be as defined in Embodiment 3.
  • the compound of formula I is a compound of formula Ic, wherein Al and A4 represent -0-, A2 and A3 represent independently -C(R4c)(R4c)- and R2, R3, R4c and q are as defined for the compound of formula I, including preferred definitions thereof.
  • the compound of formula I is a compound of formula la, wherein Al represents -0-, A2 and A3
  • R2 independently represent -C(R4c)(R4c)-
  • A4 represents CH 2 and R2, R3, R4c and q are as defined for the compound of formula I, including preferred definitions thereof.
  • R2, R3 and R4c may be as defined in Embodiment 1, or for example R2, R3, R4c and q may be as defined in Embodiment 2, or for example R2, R3, R4c and q may be as defined in Embodiment 3.
  • Al, A2, A3, A4, R2 and R3 are as defined for the compound of formula I, including preferred definitions thereof.
  • Al, A2, A3, A4, R2 and R3 may be as defined in Embodiment 1, or for example Al, A2, A3, A4, R2 and R3 may be as defined in Embodiment 2 or for example Al, A2, A3, A4, R2 and R3 may be as defined in Embodiment 3.
  • the compound of formula I is a compound of formula Ic-i, wherein Al and A4 represent -0-, A2 and A3 represent independently -C(R4c)(R4c)- and R2, R3 and R4c are as defined for the compound of formula I, including preferred definitions thereof.
  • the compound of formula I is a compound of formula la, wherein Al represents -0-, A2 and A3 independently represent -C(R4c)(R4c)-, A4 represents CH 2 and R2, R3 and R4c are as defined for the compound of formula I, including preferred definitions thereof.
  • R2, R3 and R4c may be as defined in Embodiment 1 , or for example R2, R3 and R4c may be as defined in Embodiment 2, or for example R2, R3 and R4c may be as defined in Embodiment 3.
  • Al, A2, A3, A4, R2 and R3 are as defined for the compound of formula I, including preferred definitions thereof.
  • Al, A2, A3, A4, R2 and R3 may be as defined in Embodiment 1, or for example Al, A2, A3, A4, R2 and R3 may be as defined in Embodiment 2 or for example Al, A2, A3, A4, R2 and R3 may be as defined in Embodiment 3.
  • the compound of formula I is a compound of formula Id, wherein Al and A4 represent -0-, A2 and A3 represent independently -C(R4c)(R4c)- and R2, R3 and R4c are as defined for the compound of formula I, including preferred definitions thereof.
  • the compound of formula I is a compound of formula la, wherein Al represents -0-, A2 and A3 independently represent -C(R4c)(R4c)-, A4 represents CH 2 and R2, R3 and R4c are as defined for the compound of formula I, including preferred definitions thereof.
  • R2, R3 and R4c may be as defined in Embodiment 1 , or for example R2, R3 and R4c may be as defined in Embodiment 2, or for example R2, R3 and R4c may be as defined in Embodiment 3.
  • A5, A6, A7, R2 and R3 are as defined for the compound of formula I, including preferred definitions thereof.
  • A5, A6, A7, R2 and R3 may be as defined in Embodiment 1, or for example A5, A6, A7, R2 and R3 may be as defined in Embodiment 2, or for example A5, A6, A7, R2 and R3 may be as defined in Embodiment 3.
  • A5, A6, A7, R2 and R3 are as defined for the compound of formula I, including preferred definitions thereof.
  • Al, A2, A3, A4, R2 and R3 may be as defined in Embodiment 1, or for example A5, A6, A7, R2 and R3 may be as defined in Embodiment 2 or for example A5, A6, A7, R2 and R3 may be as defined in Embodiment 3.
  • A8, A9, A10, Al 1, A12, R2 and R3 are as defined for the compound of formula I, including preferred definitions thereof.
  • A8, A9, A10, Al 1, A12, R2 and R3 may be as defined in Embodiment 1, or for example A8, A9, A10, Al 1, A12, R2 and R3 may be as defined in Embodiment 2, or for example A8, A9, A10, Al 1, A12, R2 and R3 may be as defined in Embodiment 3.
  • the compound of formula I is a compound of formula Ig wherein A8 and A12 represent -0-, A9, AlO and Al 1 represent independently -C(R4c)(R4c)- and R2, R3 and R4c are as defined for the compound of formula I, including preferred definitions thereof.
  • R2, R3 and R4c may be as defined in Embodiment 1, or for example R2, R3 and R4c may be as defined in
  • Embodiment 2 or for example R2, R3 and R4c may be as defined in Embodiment 3.
  • A8, A9, AlO, Al 1, A12, R2 and R3 are as defined for the compound of formula I, including preferred definitions thereof.
  • A8, A9, AlO, Al 1, A12, R2 and R3 may be as defined in Embodiment 1, or for example A8, A9, AlO, Al 1, A12, R2 and R3 may be as defined in Embodiment 2, or for example A8, A9, AlO, Al 1, A12, R2 and R3 may be as defined in Embodiment 3.
  • the compound of formula I is a compound of formula Ih wherein A8 and A12 represent -0-, A9, AlO and Al 1 represent independently -C(R4c)(R4c)- and R2, R3 and R4c are as defined for the compound of formula I, including preferred definitions thereof.
  • R2, R3 and R4c may be as defined in Embodiment 1, or for example R2, R3 and R4c may be as defined in
  • Embodiment 2 or for example R2, R3 and R4c may be as defined in Embodiment 3.
  • A8, A9, AlO, Al 1, A12, R2 and R3 are as defined for the compound of formula I, including preferred definitions thereof.
  • A8, A9, AlO, Al 1, A12, R2 and R3 may be as defined in Embodiment 1, or for example A8, A9, AlO, Al 1, A12, R2 and R3 may be as defined in Embodiment 2, or for example A8, A9, AlO, Al 1, A12, R2 and R3 may be as defined in Embodiment 3.
  • the compound of formula I is a compound of formula Ii wherein A8 and A12 represent -0-, A9, AlO and Al 1 represent independently -C(R4c)(R4c)- and R2, R3 and R4c are as defined for the compound of formula I, including preferred definitions thereof.
  • R2, R3 and R4c may be as defined in Embodiment 1, or for example R2, R3 and R4c may be as defined in
  • Embodiment 2 or for example R2, R3 and R4c may be as defined in Embodiment 3.
  • A8, A9, AlO, Al 1, A12, R2 and R3 are as defined for the compound of formula I, including preferred definitions thereof.
  • A8, A9, AlO, Al 1, A12, R2 and R3 may be as defined in Embodiment 1, or for example A8, A9, AlO, Al 1, A12, R2 and R3 may be as defined in Embodiment 2, or for example A8, A9, AlO, Al 1, A12, R2 and R3 may be as defined in Embodiment 3.
  • the compound of formula I is a compound of formula Ij wherein A8 and A12 represent -0-, A9, AlO and Al 1 represent independently -C(R4c)(R4c)-, and R2, R3 and R4c are as defined for the compound of formula I, including preferred definitions thereof.
  • R2, R3 and R4c may be as defined in Embodiment 1, or for example R2, R3 and R4c may be as defined in
  • Embodiment 2 or for example R2, R3 and R4c may be as defined in Embodiment 3.
  • A8, A9, AlO, Al 1, A12 and R2 are as defined for the compound of formula I, including preferred definitions thereof.
  • A8, A9, AlO, Al 1, A12 and R2 may be as defined in Embodiment 1, or for example A8, A9, AlO, Al 1, A12 and R2 may be as defined in Embodiment 2, or for example A8, A9, AlO, Al 1, A12 and R2 may be as defined in Embodiment 3.
  • A8, A9, AlO, Al 1, A12, R2 and R3 are as defined for the compound of formula I, including preferred definitions thereof.
  • A8, A9, AlO, Al 1, A12, R2 and R3 may be as defined in
  • Embodiment 1 or for example A8, A9, AlO, Al 1, A12, R2 and R3 may be as defined in Embodiment 2, or for example A8, A9, AlO, Al 1, A12, R2 and R3 may be as defined in Embodiment 3.
  • the invention provides the following compounds and pharmaceutically acceptable salts thereof:
  • the present invention relates also to pharmaceutical compositions that comprise a compound of formula I as active ingredient or or pharmaceutically acceptable salt thereof, e.g. present in a therapeutically- effective amount, which can be used especially in the treatment of the proliferation disorders, in particular cancer, as described herein.
  • compositions may be formulated for non-parenteral administration, such as nasal, buccal, rectal, pulmonary, vaginal, sublingual, topical, transdermal, ophthalmic, otic or, especially, for oral administration, e.g. in the form of oral solid dosage forms, e.g. granules, pellets, powders, tablets, coated tablets (e.g. film or sugar coated), effervescent tablets, hard and soft gelatin or HPMC capsules, coated as applicable, orally disintegrating tablets, solutions, emulsions (e.g.
  • compositions may comprise the active ingredient alone or, preferably, together with a pharmaceutically acceptable excipient.
  • the compounds of formula I or pharmaceutically acceptable salt, solvate or hydrate thereof can be processed with pharmaceutically inert, inorganic or organic excipients for the production of oral solid dosage forms, e.g. granules, pellets, powders, tablets, coated tablets (e.g. film or sugar coated), effervescent tablets and hard gelatin or HPMC capsules or orally disintegrating tablets.
  • Fillers e.g.
  • lactose cellulose, mannitol, sorbitol, calcium phosphate, starch (e.g. corn starch) or derivatives thereof, binders e.g. cellulose, starch, polyvinylpyrrolidone, or derivatives thereof, glidants e.g. talcum, stearic acid or its salts, flowing agents e.g. fumed silica, can be used as such excipients e.g. for formulating and manufacturing of oral solid dosage forms, such as granules, pellets, powders, tablets, film or sugar coated tablets, effervescent tablets, hard gelatine or HPMC capsules, or orally disintegrating tablets.
  • oral solid dosage forms such as granules, pellets, powders, tablets, film or sugar coated tablets, effervescent tablets, hard gelatine or HPMC capsules, or orally disintegrating tablets.
  • Suitable excipients for soft gelatin capsules are e.g. vegetable oils, waxes, fats, semisolid and liquid polyols etc.
  • Suitable excipients for the manufacture of solutions e.g. oral solutions
  • lipid emulsions or suspensions are e.g. water, alcohols, polyols, saccharose, invert sugar, glucose etc.
  • Suitable excipients for parenteral formulations are e.g. water, alcohols, polyols, glycerol, vegetable oils, lecithin, surfactants etc..
  • the pharmaceutical preparations can contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
  • the dosage can vary within wide limits and will, of course, be fitted to the individual requirements in each particular case. In general, a daily dosage of about 1 to 1000 mg, e.g. 10 to 1000 mg per person of a compound of general formula I should be appropriate, although the above upper limit (and likewise the lower limit) can also be exceeded when necessary.
  • the compounds of formula I can also be used in combination with one or more other pharmaceutically active compounds, which are either effective against the same disease, preferably using a different mode of action, or which reduce or prevent possible undesired side effects of the compounds of formula I.
  • the combination partners can be administered in such a treatment either simultaneously, e.g. by incorporating them into a single pharmaceutical formulation, or consecutively by administration of two or more different dosage forms, each containing one or more than one of the combination partners.
  • Compounds of formula I according to the invention as described above or pharmaceutically acceptable salts thereof are particularly useful for the treatment of proliferation disorders and/or diseases such as cancer, in particular carcinoma, sarcoma, leukemia, myeloma and lymphoma and cancers of the brain and spinal cord, e.g. when administered in therapeutically effective amounts.
  • proliferation disorders and/or diseases such as cancer, in particular carcinoma, sarcoma, leukemia, myeloma and lymphoma and cancers of the brain and spinal cord, e.g. when administered in therapeutically effective amounts.
  • proliferation disorders and diseases include, but are not limited to, epithelial neoplasms, squamous cell neoplasms, basal cell neoplasms, transitional cell papillomas and carcinomas, adenomas and adenocarcinomas, adnexal and skin appendage neoplasms, mucoepidermoid neoplasms, cystic neoplasms, mucinous and serous neoplasms, ducal-, lobular and medullary neoplasms, acinar cell neoplasms, complex epithelial neoplasms, specialized gonadal neoplasms, paragangliomas and glomus tumours, naevi and melanomas, soft tissue tumours and sarcomas, fibromatous neoplasms, myxomatous neoplasms, lipomatous neoplasms, myomatous
  • cancers in terms of the organs and parts of the body affected include, but are not limited to, the breast, cervix, ovaries, colon, rectum (including colon and rectum i.e. colorectal cancer), lung (including small cell lung cancer, non-small cell lung cancer, large cell lung cancer and mesothelioma), endocrine system, bone, adrenal gland, thymus, liver, stomach (gastric cancer), intestine, pancreas, bone marrow, hematological malignancies (such as lymphoma, leukemia, myeloma or lymphoid malignancies), bladder, urinary tract, kidneys, skin, thyroid, brain, head, neck, prostate and testis.
  • lung including small cell lung cancer, non-small cell lung cancer, large cell lung cancer and mesothelioma
  • endocrine system bone, adrenal gland, thymus, liver, stomach (gastric cancer), intestine, pancreas, bone marrow, hematological
  • the cancer is selected from the group consisting of breast cancer, prostate cancer, cervical cancer, ovarian cancer, gastric cancer, colorectal cancer, pancreatic cancer, liver cancer, brain cancer, neuroendocrine cancer, lung cancer, kidney cancer, hematological malignancies, melanoma and sarcomas.
  • treatment or “treating” as used herein in the context of treating a disease or disorder, pertains generally to treatment and therapy, whether of a human or an animal (e.g., in veterinary applications), in which some desired therapeutic effect is achieved, for example, the inhibition of the progress of the disease or disorder, and includes a reduction in the rate of progress, a halt in the rate of progress, alleviation of symptoms of the disease or disorder, amelioration of the disease or disorder, and cure of the disease or disorder.
  • Treatment as a prophylactic measure i.e., prophylaxis
  • prophylaxis is also included.
  • treatment includes the prophylaxis of cancer, reducing the incidence of cancer, alleviating the symptoms of cancer, etc..
  • terapéuticaally-effective amount refers to that amount of a compound, or a material, composition or dosage form comprising a compound, which is effective for producing some desired therapeutic effect, commensurate with a reasonable benefit/risk ratio, when administered in accordance with a desired treatment regimen.
  • the compounds of formula I can be synthesized by methods given below, by methods given in the experimental part below or by analogous methods.
  • the schemes described herein are not intended to present an exhaustive list of methods for preparing the compounds of formula (I); rather, additional techniques of which the skilled chemist is aware may be also used for the compound synthesis.
  • protecting groups may be used in accordance with standard practice, well known in the art (for illustration see Greene T.W., Wuts P.G.M., Protective Groups in Organic Synthesis, 5th Edition, Publisher: John Wiley & Sons, 2014).
  • the protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the art, or they may be removed during a later reaction step or work-up.
  • manipulations may include, but are not limited to, reduction, oxidation, alkylation, acylation, substitution, coupling, including transition-metal catalyzed coupling and hydrolysis reactions which are commonly known by those skilled in the art;
  • compounds of formula (I) can be obtained by the coupling reaction of a compound of formula (3) and a compound of formula (4), wherein E2 is a halogen or a leaving group such as imidazole, phenol, 4-nitrophenol, 2,2,2-trifluoro-ethanol or l-hydroxypyrrolidine-2,5-dione (Scheme 1).
  • the coupling reaction between a compound of formula (3) and a compound of formula (4) is generally performed in a variety of organic solvents such as tetrahydofuran, dichloromethane, 1 ,2-dichloroethane, diethylether, ethyl acetate, dimethylsulfoxide, N,N-dimethylformamide, and acetonitrile, aqueous solvents and a mixture of theses solvents under biphasic conditions (more frequently in N,N-dimethylformamide) in a presence of an inorganic base such as sodium hydride, sodium carbonate or sodium hydrogen carbonate or in the presence of an organic base such as triethylamine, pyridine or alike (more frequently triethylamine).
  • organic solvents such as tetrahydofuran, dichloromethane, 1 ,2-dichloroethane, diethylether, ethyl acetate, dimethylsulfoxide, N,N
  • the compounds of formula (4), wherein E2 is a leaving group such as imidazole (which can be activated by methylation prior to the reaction), phenol, 4-nitrophenol, 2,2,2-trifluoro-ethanol or 1 - hydroxypyrrolidine-2,5-dione, are typically obtained by the coupling reaction of a compound of formula (2) and 1 , ⁇ -carbonyldiimidazole, phenyl chloro formate, 4-nitrophenyl chloro formate, 2,2,2-trifluoroethyl chloroformate or N,N'-Disuccinimidyl carbonate, respectively, in presence of a base, such as sodium hydride, triethylamine, pyridine (diluted or neat), 4-(dimethylamino)pyridine in aprotic solvents such as dichloromethane, chloroform, acetonitrile, tetrahydrofuran, ethyl acetate. Reactions are typically run from -10 °C to 80
  • the compounds of formula (4), for which E2 is a chlorine are generally prepared in situ by the reaction of a compound of formula (2) and phosgene or more frequently a phosgene analogue (such as
  • reaction is typically performed in aprotic and inert solvents such as dichloromethane, chloroform, acetonitrile, tetrahydrofuran, ethyl acetate (more frequently dichloromethane) in presence of a base such as triethylamine, 4-(dimethylamino)- pyridine or N,N-diisopropylethylamine.
  • a base such as triethylamine, 4-(dimethylamino)- pyridine or N,N-diisopropylethylamine.
  • Reactions are typically run from -40 °C to 50 °C, generally 0 °C. The low stability of such intermediates does often not allow isolation and they are generally prepared in situ.
  • a compound of Formula (3) is allowed to react subsequently with a compound of formula (4) to generate the corresponding compound of Formula (I).
  • compounds of formula (I) can be prepared from a compound of formula (5), wherein E3 is a leaving group such as chlorine, imidazole, phenol, 4-nitrophenol, 2,2,2- trifluoro-ethanol or l-hydroxypyrrolidine-2,5-dione, more preferably a phenol or 4-nitrophenol and a compound of formula (2) by a coupling reaction, following similar procedures previously described.
  • E3 is a leaving group such as chlorine, imidazole, phenol, 4-nitrophenol, 2,2,2- trifluoro-ethanol or l-hydroxypyrrolidine-2,5-dione, more preferably a phenol or 4-nitrophenol and a compound of formula (2) by a coupling reaction, following similar procedures previously described.
  • Compounds of formula (5) can be prepared from a compound of formula (3) by a coupling reaction following similar procedures as described above.
  • compounds of formula (I) can be generated from a compound of formula (6) and a compound of formula (7), wherein E4 is a halogen or a leaving group such as a triflate, via a transition- metal catalyst reaction coupling (Scheme 3).
  • Typical catalysts include palladium(II) acetate, tris- (dibenzylideneacetone)dipalladium(O) or alike. The reaction is typically run at a temperature from 0 °C to 150 °C, more frequently from 100 °C to 120 °C.
  • reaction is performed in the presence of a ligand such as di-teri-butyl-[3,6-dimethoxy-2-(2,4,6-triisopropylphenyl)phenyl]phosphane, di-teri-butyl- [2,3,4,5-tetramethyl-6-(2,4,6-triisopropylphenyl)phenyl]phosphane, 2-(dicyclohexylphosphino)biphenyl or the like and a base such as sodium fert-butylate, cesium carbonate, potassium carbonate, more frequently cesium carbonate in a large variety of inert solvents such as toluene, tetrahydrofuran, dioxane, 1 ,2-dichloroethane, N,N-dimethylformamide, dimethylsulfoxide, water and acetonitrile, or a mixture of solvents, more frequently in dioxane.
  • a ligand such as di-ter
  • a compound of formula (6) can be obtained from compounds of formula (3) following procedures described in literature, or by procedures known by a person skilled in the art.
  • a compound of formula (6) can be prepared by the reaction of a compound of formula (3) with isocyanatotrimethylsilane in aprotic solvents such as acetonitrile, ethyl acetate, chloroform and more frequently in dichloromethane in a presence of an organic base such as triethylamine, 4-(dimethylamino)pyridine, N,N-diisopropylethyl- amine or alike.
  • the reaction can be run at a temperature from 0 °C to 50 °C, generally at room
  • the Boc group is removed under acidic conditions such as hydrochloric acid in an organic solvent such as methanol, dioxane or ethyl acetate, or trifluoroacetic acid neat or diluted in a solvent such as dichloromethane.
  • the Alloc group is removed in presence of a palladium salt such as palladium acetate or tetrakis(triphenylphosphine)palladium(0) and an allyl cation scavenger such as morpholine, pyrrolidine, dimedone or tributylstannane generally at temperatures from 0 °C to 70 °C in a solvent such as tetrahydrofuran.
  • the N-benzyl protected amines are deprotected by hydrogenolysis over a noble metal catalyst (e.g. palladium hydroxide on activated carbon) or other suitable catalyst e.g. Raney-Ni.
  • a noble metal catalyst e.g. palladium hydroxide on activated carbon
  • suitable catalyst e.g. Raney-Ni.
  • the Fmoc protecting group is removed under mild basic conditions such as diluted morpholine or piperidine in N,N-dimethylformamide or acetonitrile.
  • the N- acetyl protected amines are deprotected by hydrolysis using either acidic or basic aqueous solution at temperatures from 0 °C to 100 °C.
  • the Wittig reaction is the reaction of an aldehyde or ketone with a triphenyl phosphonium ylide to afford an alkene and triphenylphosphine oxide.
  • the Wittig reagent is usually prepared from a phosphonium salt. To form the Wittig reagent, the phosphonium salt is suspended in a solvent such as diethyl ether or tetrahydroiuran and a strong base such as n-butyl lithium or lithium bis(trimethylsilyl)amide is added. With simple ylides, the product is usually mainly the Z-isomer, although a lesser amount of the E-isomer also is often formed.
  • the Schlosser modification may be used.
  • the Horner- Wadsworth-Emmons reaction produces predominantly E-alkenes.
  • the Horner- Wadsworth-Emmons reaction is the condensation of stabilized phosphonate carbanions with aldehydes or ketones in presence of a base such as sodium hydride or lithium bis(trimethylsilyl)amide in a solvent such as tetrahydroiuran or N,N-dimethylformamide, generally at temperatures from 0 °C to 80 °C.
  • phosphonate-stabilized carbanions are more nucleophilic and more basic.
  • a compound of formula (9) can be for example obtained by alkylation of triphenylphosphine and a compound of formula (8), wherein E5 is a halogen, following well-known procedures.
  • a compound of formula (9) can be obtained by the reaction of triethylphosphite and a compound of formula (8), wherein E5 is a halogen, following well-known procedures.
  • the amino protecting groups (PG) can be present in the starting material or introduced by reacting the corresponding free amine with allyl, fluorenylmethyl or benzyl chloroformate, or with di-tert-butyl dicarbonate in presence of a base such as sodium hydroxide, sodium hydrogen carbonate, triethylamine, 4- dimethylaminopyridine or imidazole.
  • a base such as sodium hydroxide, sodium hydrogen carbonate, triethylamine, 4- dimethylaminopyridine or imidazole.
  • the free amine can also be protected as N-benzyl derivatives by reaction with benzyl bromide or chloride in presence of a base such as sodium carbonate or triethylamine.
  • N-benzyl derivatives can be obtained through reductive amination in presence of benzaldehyde.
  • the free amine can also be protected as N-acetyl derivatives by reaction with acetyl chloride or acetic anhydride in presence of a base such as sodium carbonate or trimethylamine.
  • a base such as sodium carbonate or trimethylamine.
  • compounds of formula (11-a) can be prepared from a compound of formula (14) and a compound of formula (15), wherein E10 is a halogen or a leaving group such as triflate via cross-coupling reaction (i.e. Suzuki, Stille, Negishi, etc), as outlined in scheme 5.
  • E10 is a halogen or a leaving group such as triflate via cross-coupling reaction (i.e. Suzuki, Stille, Negishi, etc), as outlined in scheme 5.
  • E9 is a boronic acid or a boronic ester
  • a compound of formula (14) can react with a compound of formula (15) to form a compound of formula (1 1-a) via Suzuki cross-coupling reaction.
  • the Suzuki reaction is a palladium- catalyzed cross-coupling reaction between organoboronic acids or esters and aryl or vinyl halides or triflates.
  • Typical catalysts include palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), tris(dibenzylideneacetone)dipalladium(0), bis(triphenylphosphine)palladium(II) dichloride and
  • reaction can be carried out in a variety of organic solvents including toluene, tetrahydrofuran, dioxane, 1 ,2-dichloroethane, N,N-dimethyl- formamide, dimethylsulfoxide and acetonitrile, aqueous solvents and under biphasic conditions.
  • Reactions are typically run under inert atmosphere from room temperature to 150 °C, more frequently from 90 °C to 120 °C.
  • Additives such as cesium fluoride, potassium fluoride, potassium hydroxide, potassium carbonate, potassium acetate, potassium phosphate or sodium ethylate frequently accelerate the coupling.
  • Potassium trifluorob orates and organoboranes or boronate esters may be used in place of boronic acids.
  • the Suzuki reaction such as the particular palladium catalyst, the ligand, additives, solvent, temperature, numerous protocols have been identified. One skilled in the art will be able to identify a satisfactory protocol without undue experimentation.
  • Organoboronic acids or esters of formula (14) are generally obtained from diboron reagents (such as bis(pinacolato)diboron or bis-boronic acid) and a compound of Formula (13), wherein E8 is halogen, via Miyaura borylation (Ishiyama T. et al., J. Org. Chem., vol.
  • a palladium catalyst such as tris(dibenzylideneacetone)dipalladium(0) or chloro(2-dicyclohexylphosphino- 2',4',6'-triisopropyl-l, -biphenyl)[2-(2'-amino-l, -biphenyl)]palladium(II) and a ligand such as triphenylphosphine or 2-(dicyclohexylphosphino)-2',4',6'-tri-isopropyl-l, -biphenyl.
  • a palladium catalyst such as tris(dibenzylideneacetone)dipalladium(0) or chloro(2-dicyclohexylphosphino- 2',4',6'-triisopropyl-l, -biphenyl)[2-(2'-amino-l, -biphenyl)]palladium(II)
  • the reaction can be carried out in a variety of organic solvents including toluene, tetrahydrofuran, dioxane, 1,2-dichloro- ethane, N,N-dimethylformamide, dimethylsulfoxide and acetonitrile, aqueous solvents and under biphasic conditions. Reactions are typically run from room temperature to 150 °C (more frequently at 100 °C). Crucial for the success of the borylation reaction is the choice of an appropriate base, as strong activation of the product enables the competing Suzuki coupling.
  • Vinyl halides of formula (13) used for the preparation of organoboronic acids or esters (14) can be prepared via a Wittig reaction between a compound of formula (10) and a compound of formula (12), wherein E7 is a triphenylphosphonium salt and E8 is a halogen, following procedures previously described.
  • compounds of formula (3) can be obtained from a compound of formula (11-c) as outlined in scheme 6, by removal of the amino protecting group (PG), following procedure previously described.
  • Compounds of formula (11-c) can be obtained from a compound of formula (15), wherein E10 is a halogen, via Weinreb Ketone Synthesis with a compound of formula (16).
  • the reaction takes place in the presence of a strong base such as n-butyl lithium or /-butyl lithium under anhydrous conditions in an organic solvent such as tetrahydrofuran and at temperatures from -78 °C to 60 °C (around 0 °C is preferred).
  • compounds of formula (1 lc) can be obtained from a compound of formula (15), wherein El 0 is a halogen, via Grignard reaction with a corresponding acyl halogenide (e.g. a compound of formula (18)).
  • the Grignard reaction is typically performed under anhydrous conditions in an organic solvent such as tetrahydrofuran. The reaction are usually run from -78 °C to 60 °C (0 °C preferably).
  • the Grignard reagent is generally obtained from the reaction of an aryl halide of formula (15) and magnesium metal using classical methods widely described in literature (Rogers H.R. et al., J. Am Chem. Soc, vol. 102, no. 1, pages 217-226, 1980) or by magnesium-halide exchange reaction using isopropylmagnesium chloride.
  • compounds of formula (11-c) can be obtained from a compound of formula (17) and a compound of formula (18) by Friedel-Crafts acylation (Scheme 7).
  • the amino protecting group (PG) is preferentially a N-acetyl group.
  • Friedel-Crafts acylation is the acylation of aromatic rings with an acyl chloride using a strong Lewis acid catalyst such as ferric chloride or aluminium chloride (more frequently aluminium chloride). Friedel-Crafts acylation is also possible with acid anhydrides. Normally, a stoichiometric amount of the Lewis acid catalyst is required, because both the substrate and the product form complexes.
  • the reaction is generally performed under anhydrous conditions in an inert solvent such as acetonitrile, tetrahydrofuran, dichloromethane, 1,2-dichloroethane or in neat mixture at a wide range of temperatures (e.g. from -20 °C to 100 °C).
  • an inert solvent such as acetonitrile, tetrahydrofuran, dichloromethane, 1,2-dichloroethane or in neat mixture at a wide range of temperatures (e.g. from -20 °C to 100 °C).
  • compounds of formula (3) can be obtained from a compound of formula (11-d) as outlined in scheme 8, by removal of the amino protecting group (PG), following procedure previously described.
  • compounds of formula (11-d) can be obtained from commercial sources, or are prepared following procedures described in literature, or by procedures known by a person skilled in the art.
  • compounds of formula (11-d) can be from a compound of formula (19) and a compound of formula (20) via a Mitsunobu coupling (as reviewed in O. Mitsunobu, Synthesis, Vol. 1, pages 1-28, 1981).
  • the reaction is performed in the presence of diethyl or diisopropyl azodicarboxylate and triphenylphosphine, in a wide range of solvents such as N,N-dimethylformamide, tetrahydrofuran, 1 ,2-dimethoxyethane or dichloromethane and within a wide range of temperatures (e.g. between -20 °C and 60 °C).
  • solvents such as N,N-dimethylformamide, tetrahydrofuran, 1 ,2-dimethoxyethane or dichloromethane
  • temperatures e.g. between -20 °C and 60 °C.
  • the reaction might also be performed using polymer-supported triphenylphosphine.
  • An alternative route to form compounds of formula 11-d consists of reacting a compound of formula (19) with a compound of formula (20) for which the hydroxyl group needs to be activated prior to the reaction by substitution reaction.
  • the substitution reaction can be performed in presence of an inorganic base such as sodium hydride, potassium carbonate, cesium carbonate or the like or an organic base such as triethylamine or the like in a wide variety of solvents such as acetonitrile, tetrahydrofuran or N,N- dimethylformamide e.g. at a temperature from -20 °C to 120 °C.
  • Hydroxyl group of a compound of formula (20) can be activated to a mesylate, a tosylate or a triflate groups by reacting the corresponding alcohol with methanesulfonyl chloride or methanesulfonic anhydride, / toluenesulfonyl chloride, trifluoromethanesulfonyl chloride or trifluoromethanesulfonic anhydride, respectively, in presence of a base such as triethylamine or the like in a dry aprotic solvent such as pyridine, acetonitrile,
  • tetrahydrofuran or dichloromethane e.g. at a temperature from -30 °C to 80 °C.
  • substituents Rl, R2, R3, R4a, R4b, R4c and / or Rl 1 can be present as precursors in the starting material, and/or can be transformed by additional routine transformations during the synthetic pathways described herein. These transformations might be carried out at any convenient stage during the synthesis and may include, but are not limited to the following lists of reactions, which are commonly known by those skilled in the art:
  • nitro group can also be reduced via catalytic hydrogenolysis over a noble metal catalyst (such as palladium on activated carbon) or other suitable hydrogenation catalyst.
  • a noble metal catalyst such as palladium on activated carbon
  • R2 is a nitro group
  • Suitable coupling agents may be utilized such as, 0-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, 2-ethoxy- 1 -ethoxycarbonyl- 1 ,2-dihydroquinoline, carbonyldiimidazole or diethylphosphorylcyanide.
  • a base like triethylamine, N,N-diisopropylethylamine or pyridine can be added to perform the coupling.
  • the amide coupling is conducted at a temperature e.g.
  • the carboxylic acid can be activated by conversion into its corresponding acid chloride or its corresponding activated ester, such as the N- hydroxysuccinimidyl ester (Singh J., et al., Org. Process Res. & Dev., vol. 6, no. 6, pages 863-868, 2002) or the benzothiazolyl thioester (Ishikawa T. et al., J. Antibiotics, vol. 53, no. 10, pages 1071-1085, 2000).
  • an inert solvent preferably a dry aprotic solvent like dichloromethane, acetonitrile or N,N- dimethylformamide and chloroform.
  • the carboxylic acid can be activated by conversion into its corresponding acid chloride or its corresponding activated ester, such as the N- hydroxysuccinimidyl ester (Singh J., et al., Org. Process Res. & Dev., vol. 6, no. 6, pages 863-868
  • the generated activated entity can react e.g. at a temperature from -20 °C to 80 °C with the amine reagent in an aprotic solvent like dichloromethane, chloroform, acetonitrile, N,N-dimethylformamide and tetrahydrofuran.
  • an aprotic solvent like dichloromethane, chloroform, acetonitrile, N,N-dimethylformamide and tetrahydrofuran.
  • a base like triethylamine, N,N-diisopropylethylamine, pyridine, sodium hydroxide, sodium carbonate, potassium carbonate can be added to perform the coupling.
  • the reductive amination reaction between an amine and an aldehyde or a ketone is conducted in a solvent system allowing the removal of the formed water through physical or chemical means (e.g. distillation of the solvent-water azeotrope or presence of drying agents such as molecular sieves, magnesium sulfate or sodium sulfate).
  • Such solvent is typically toluene, n-hexane, tetrahydrofuran, dichloromethane N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, 1 ,2-dichloroethane or mixture of solvents such as methanol or 1,2-dichloroethane.
  • the reaction can be catalyzed by traces of acid (usually acetic acid).
  • the intermediate imine is reduced subsequently or simultaneously with a suitable reducing agent (e.g. sodium borohydride, sodium cyanoborohydride, sodium
  • reaction is usually carried out from -10 °C to 110 °C, preferably from 0 °C to 60 °C.
  • the reaction can also be carried out in one pot. It can also be performed in protic solvents such as methanol or water in presence of a picoline-borane complex (Sato S. et al., Tetrahedron, vol. 60, pages 7899-7906, 2004).
  • substitution reaction can be performed in presence of an inorganic base such as sodium hydride, potassium carbonate, cesium carbonate or the like or an organic base such as triethylamine or the like in a wide variety of solvents such as acetonitrile, tetrahydrofuran or N,N- dimethylformamide at a temperature e.g. from -20 °C to 120 °C.
  • an inorganic base such as sodium hydride, potassium carbonate, cesium carbonate or the like
  • organic base such as triethylamine or the like
  • solvents such as acetonitrile, tetrahydrofuran or N,N- dimethylformamide at a temperature e.g. from -20 °C to 120 °C.
  • substitution reaction between a compound of formula (I), wherein R 2 is -Cl-C6alkylene-OH (which needs to be activated prior to the reaction), and a compound of formula HN(R6a)(R6b) leads to a compound of formula (I), wherein R2 is -Cl-C6alkylene-N(R6a)(R6b) and R6a and R6b are as defined by the claims.
  • Hydroxyl group can be transformed to a mesylate, a tosylate or a triflate by reacting the corresponding alcohol with methanesulfonyl chloride or methanesulfonic anhydride, p-toluenesulfonyl chloride, trifluoromethanesulfonyl chloride or
  • trifluoromethanesulfonic anhydride in presence of a base such as triethylamine or the like in a dry aprotic solvent such as pyridine, acetonitrile, tetrahydrofuran or dichloromethane e.g. at a temperature from -30 °C to 80 °C.
  • a base such as triethylamine or the like
  • a dry aprotic solvent such as pyridine, acetonitrile, tetrahydrofuran or dichloromethane e.g. at a temperature from -30 °C to 80 °C.
  • alkyl ester typically methyl or ethyl esters
  • This reduction is performed with a reducing agent like boron or aluminium hydride, lithium aluminium hydride, lithium borohydride, sodium borohydride in a solvent such as tetrahydrofuran, methanol or ethanol e.g. at a temperature from -20 °C to 80 °C.
  • a reducing agent like boron or aluminium hydride, lithium aluminium hydride, lithium borohydride, sodium borohydride in a solvent such as tetrahydrofuran, methanol or ethanol e.g. at a temperature from -20 °C to 80 °C.
  • the ester function is hydrolyzed into its corresponding carboxylic acid using an alkali hydroxide such as sodium hydroxide, potassium hydroxide or lithium hydroxide in water or in a mixture of water with polar protic or aprotic organic solvents such as dioxane, tetrahydrofuran or methanol e.g. at a temperature from -10 °C to 80 °C or the ester function is hydrolyzed using aqueous acidic solution.
  • the resulting carboxylic acid is further reduced into the corresponding alcohol using a borane derivative such as borane -tetrahydrofuran complex in a solvent such as tetrahydrofuran e.g. at a temperature from -10 °C to 80 °C.
  • a compound of formula (I), wherein R2 is -CH 2 OH can be converted to a compound of formula (I), wherein R2 is -CHO by oxidation using Dess-Martin reagent.
  • the reaction is typically run in an aprotic solvent such as dichloromethane e.g. at a temperature from 0 °C to 50 °C, more frequently at room temperature.
  • the Buchwald-Hartwig amination reaction (Surry D.S. and Buchwald S.L., Chem. Sci., vol. 2, pages 27-50, 2011) is a palladium-catalyzed cross-coupling reaction of amines and aryl halides or triflates.
  • Typical catalysts include palladium(II) acetate, or
  • reaction is typically run at a temperature from 0 °C to 150 °C.
  • a ligand such as di-tert-butyl- [3,6-dimethoxy-2-(2,4,6-triisopropylphenyl)phenyl]-'phosphane, 2-(dicyclohexylphosphino)biphenyl or the like and a base such as sodium tert-butylate, cesium carbonate, potassium carbonate in a large variety of inert solvents such as toluene, tetrahydrofuran, dioxane, 1 ,2-dichloroethane, N,N-dimethylformamide, dimethylsulfoxide and acetonitrile, aqueous solvents and under biphasic conditions.
  • the nitration of aromatic compounds is the chemical process for the introduction of a nitro group into an organic compound. In the case of the nitration of aromatic compounds, this process is one example of the electrophilic aromatic substitution.
  • the reaction is typically run in a mixture of acids, usually nitric acid and another strong acid, such as sulfuric acid or trifluoroacetic acid.
  • the reaction can be performed in a wide range of temperature (e.g. from 0 °C to 100 °C).
  • an optically active form of a compound of the invention may be obtained by carrying out one of the above procedures using a pure enantiomer or diastereomer as a starting material, or by resolution of a mixture of the enantiomers or diastereomers of the final product or intermediate using a standard procedure.
  • the resolution of enantiomers may be achieved by chromatography on a chiral stationary phase, such as for example REGIS PIRKLE COVALENT (R-R) WHELK-02, 10 ⁇ , 100 A, 250 x 21.1 mm column.
  • resolution of stereoisomers may be obtained by preparation and selective crystallization of a diastereomeric salt of a chiral intermediate or chiral product with a chiral acid, such as camphorsulfonic acid or with a chiral base such as phenylethylamine.
  • a method of stereoselective synthesis may be employed, for example by using a chiral variant of a protecting group, a chiral catalyst or a chiral reagent where appropriate in the reaction sequence.
  • Enzymatic techniques may also be used for the preparation of optically active compounds and/or intermediates.
  • Figure 1 shows the results of the cell growth assays (crystal violet) in HeLa galactose and HeLa glucose cells treated with mitochondrial inhibitors Antimycin A ( Figure la) and Example 5 ( Figure lb) or the cytotoxic drug Paclitaxel ( Figure lc).
  • evaporations are carried out by rotary evaporation under reduced pressure and work-up procedures are carried out after removal of residual solids by filtration;
  • hydrogenation or hydrogenolysis reactions can be performed using hydrogen gas in balloon or using Parr-apparatus system or other suitable hydrogenation equipment;
  • each intermediate is purified to the standard required for the subsequent stage and is characterized in sufficient detail to confirm that the assigned structure is correct;
  • Example numbers used in the leftmost column are used in the application text for identifying the respective compounds.
  • Example 2 4-[(4-chloro-2,6-difluorophenyl)methylene]-A r -(6,7-dihydro-5H- cyclopenta[b]pyridin-4-yl)piperidine-l-carboxamide:
  • Step 1-a Preparation of ferf -butyl 4-(bromomethylene)piperidine-l-carboxylate:
  • reaction mixture was deactivated with a saturated aqueous solution of NH 4 C1 and then partitioned between EA and brine. The organic layer was separated, washed with brine, dried over MgSO i, filtered and concentrated to dryness. The residue was purified by column chromatography (silica gel; c-Hex : EA; 1 :0 to 4:1 ; v/v) to afford teri-butyl 4-(bromomethylene)- piperidine-l-carboxylate (960 mg) as a colorless oil.
  • Step 1-b Preparation of ferf-butyl 4-r(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)methylene1piperidine- 1-carboxylate:
  • a sealable tube was charged with teri-butyl 4-(bromomethylene)piperidine-l-carboxylate (700 mg; 2.51 mmol), potassium acetate (620 mg; 6.27 mmol), bis(pinacolato)diboron (1040 mg; 4.01 mmol) and dioxane (20 mL) at rt.
  • Argon was bubbled in the reaction mixture for 10 min and triphenylphosphine (70 mg; 0.25 mmol) and Pd 2 dba 3 (160 mg; 0.15 mmol) were added.
  • the tube was flushed with argon and sealed.
  • the reaction mixture was then heated to 100 °C and stirred for 4 h.
  • Step 1-c Preparation of fer/-butyl 4-r(4-chloro-2,6-difluorophenyl)methylene1piperidine-l-carboxylate: Under argon atmosphere, a mixture of X-Phos (745 mg; 1.53 mmol), 2-bromo-5-chloro-l,3-difluoro- benzene (3518 mg; 15.31 mmol), teri-butyl 4-[(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)methylene]- piperidine-l-carboxylate (5500 mg;, 15.31 mmol), Pd 2 dba 3 (708 mg; 0.76 mmol) and K3PO4 (4975 mg; 22.97 mmol) in a mixture of H 2 0 (5 mL) and dioxane (100 mL) was heated to 100 °C and stirred for 2 h.
  • X-Phos 7
  • Step 1-d Preparation of 4-[(4-chloro-2,6-difluorophenyl methylenelpiperidine, hydrochloride:
  • Step 2-a Preparation of 6,7-dihvdro-5H-cvclopentarb1pyridine-l -oxide:
  • Step 2-b Preparation of 4-nitro-6J-dihvdro-5H-cvclopentarb1pyridine-l-oxide:
  • Nitric acid, fuming (3.99 mL; 86.09 mmol) was added dropwise to a solution of sulfuric acid, 96 % (4.01 mL; 71.94 mmol).
  • the reaction solution was then heated to 50 °C and 6,7-dihydro-5H- cyclopenta[b]pyridine-l -oxide (1610 mg; 11.79 mmol) was added as solid.
  • the reaction mixture was heated to 70 - 80 °C for 15 min.
  • the reaction solution was then poured out into a mixture of ice - H 2 0 (100 mL).
  • the product was extracted with DCM (100 mL).
  • Step 2-c Preparation of 6,7-dihydro-5H-cvclopentarb1pyridin-4-amine:
  • Step 3-a Preparation of phenyl N-(6,7-dihvdro-5H-cvclopentarb1pyridin-4-yl)carbamate:
  • Step 3-b Preparation of 4-[(4-chloro-2,6-difluorophenyl)methylenel-N-(6,7-dihydro-5H- cvclopentarb1pyridin-4-yl)piperidine- 1 -carboxamide:
  • Example 3 4-[(4-cyano-2,6-difluoro-phenyl)methylene]-A r -(5,6,7,8- tetrahydroquinolin-4-yl)piperidine-l-carboxamide:
  • Step 1 Preparation of 3,5-difluoro-4-(4-piperidylidenemethyl)benzonitrile, hydrochloride:
  • Step 2 Preparation of 4-[(4-cyano-2,6-difluorophenyl methylenel-N-(5,6,7,8-tetrahydroquinolin-4- yPpiperidine- 1 -carboxamide:
  • Example 5 4-[(4-chloro-2,6-difluoro-phenyl)methylene]-A r -(2,3-dihydro- [l,4]dioxino[2,3-b]pyridin-8-yl)piperidine-l-carboxamide:
  • Step 1-a Preparation of 2,3-dihvdro-ri,41dioxinor2,3-b1pyridin-5-oxide:
  • Step 1-b Preparation of 8-nitro-2,3-dihvdro-ri,41dioxinor2,3-b1pyridine:
  • Step 2 Preparation of 4-r(4-cvano-2,6-difluorophenyl)methylene1-N-(5,6,7,8-tetrahvdroquinolin-4- vDpiperidine- 1 -carboxamide:
  • the title compound was prepared as a white solid following scheme 1 and in analogy to Example 2 (steps 3-a and 3-b) using 2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-8-amine and 4-[(4-chloro-2,6-difluoro- phenyl)methylene]piperidine, hydrochloride as starting materials and after purification by preparative HPLC.
  • Example 6 4-[(4-chloro-2,6-difluorophenyl)methylene]-A r -(2,3-dihydrofuro[2,3- b] pyridin-4-yl)piperidine- 1 -carboxamide :
  • Step 1-a Preparation of 2-(2-fluoro-4-iodo-3-pyridyl)ethanol:
  • Step 2-a Preparation of 4-r(4-chloro-2,6-difluorophenyl)methylene1piperidine-l-carboxamide:
  • Step 2-b Preparation of 4-r(4-chloro-2,6-difluorophenyl)methylene1-N-(2 ,3-dihvdrofuror2,3-b1pyridin-4- vDpiperidine- 1 -carboxamide:
  • Example 7 4-[(4-chloro-2,6-difluorophenyl)methylene]-A r -(3,4-dihydro-2H- pyrano[2,3-b]pyridin-5-yl)piperidine-l-carboxamide: Step 1-a: Preparation of 3-allyl-2-fluoro-4-iodopyridine:
  • Step 1-b Preparation of 3-(2-fluoro-4-iodo-3-pyridyl)propan-l-ol:
  • Step 1-c Preparation of 5-iodo-3,4-dihvdro-2H-pyranor2,3-b1pyridine:
  • step 1-b The title compound was prepared as a white solid following the procedure described in Example 6 (step 1-b) using 3-(2-fluoro-4-iodo-3-pyridyl)propan-l-ol as starting material and after purification by column chromatography (silica gel; PE : EA; 10: 1 ; v/v).
  • Step 2 Preparation of 4-r(4-chloro-2,6-difluorophenyl)methylene1-N-(3,4-dihvdro-2H-pyranor2,3- b1pyridin-5-yl)piperidine-l-carboxamide:
  • Step 2 Preparation of 4-r(4-chloro-2-fluorophenyl methylene1-N-(l,8-naphthyridin-4-yl piperidine-l- carboxamide:
  • Example 9 4-[(4-cyano-2,6-difluorophenyl)methylene]-A r -(5,6,7,8-tetrahydro-l,5- naphthyridin-4-yl)piperidine-l-carboxamide, formic acid:
  • Step 1-a Preparation of l-(3,4-dihvdro-2H-L5-naphthyridin-l-yl)-2,2,2-trifluoroethanone:
  • Step 1-b Preparation of 2,2,2-trifluoro-l-(5-oxido-3,4-dihvdro-2H-L5-naphthyridin-5-ium-l- vDethanone:
  • Step 1-c Preparation of 2,2,2-trifluoro-l-(8-nitro-5-oxido-3,4-dihydro-2H-l,5-naphthyridin-5-ium-l- vPethanone:
  • Step 1-f Preparation of ferf-butyl 8-amino-3,4-dihvdro-2H-l,5-naphthyridine-l-carboxylate:
  • Step 2-a Preparation of ferf-butyl 8-(phenoxycarbonylamino)-3,4-dihvdro-2H-l,5-naphthyridine-l- carboxylate:
  • Step 2-b Preparation of ferf-butyl 8-rr4-r(4-cvano-2,6-difluorophenyl)methylene1piperidine-l- carbonyl1amino1-3,4-dihvdro-2H-L5-naphthyridine-l-carboxylate:
  • the title compound was prepared as a light yellow solid following scheme 1 and in analogy to Example 2 (step 3-b) using tert-butyl 8-(phenoxycarbonylamino)-3,4-dihydro-2H-l,5-naphthyridine-l-carboxylate and 3,5-difluoro-4-(4-piperidylidenemethyl)benzonitrile as starting materials, and after purification by column chromatography (silica gel; DCM : MeOH; 20: 1 ; v/v).
  • Step 2-c Preparation of 4-r(4-cvano-2,6-difluorophenyl)methylene1-N-(5,6,7,8-tetrahvdro-L5- naphthyridin-4-yl)piperidine-l-carboxamide, formic acid:
  • Example 10 4-[(4-cyano-2,6-difluorophenyl)methylene]-A r -(5-methyl-7,8-dihydro- 6H-l,5-naphthyridin-4-yl)piperidine-l-carboxamide, formic acid:
  • Step 1-a Preparation of 2-bromo-3-(oxiran-2-ylmethoxy)pyridine:
  • Step 1-c Preparation of 3-(methoxymethyl)-2,3-dihvdro-rL41dioxinor2,3-b1pyridine and 2- (methoxymethyl)-2,3 -dihydro- ⁇ 1 ,41 dioxino ⁇ 2.3 -blpyridine :
  • Step 1-d Preparation of 3-(methoxymethyl)- 2,3-dihvdro-rL41dioxino[2,3-b1pyridine-5-oxide and 2- (methoxymethyl)- 2,3-dihvdro-rL41dioxino[2,3-b1pyridine-5-oxide:
  • Step 1-e Preparation of 3-(methoxymethyl -8-nitro-2,3-dihydro-ri,41dioxinor2,3-b1pyridine-5-oxide and
  • Step 1-f Preparation of 3-(methoxymethyl)-2,3-dihvdro-rL41dioxinor2,3-b1pyridin-8-amine and 2- (methoxymethyl)-2,3-dihvdro-rL41dioxinor2,3-b1pyridin-8-amine:
  • Step 2 Preparation of 4-r(4-chloro-2-fluorophenyl)methylene1-N-r3-(methoxymethyl)-2,3-dihvdro- ri,41dioxinor2,3-b1pyridin-8-vHpiperidine-l-carboxamide and 4-r(4-chloro-2-fluorophenyl)methylene1- N-r2-(methoxymethyl)-2,3-dihvdro-ri,41dioxinor2,3-b1pyridin-8-vHpiperidine-l-carboxamide:
  • Example 13 4-[(4-cyano-2,6-difluorophenyl)methylene]-A r -[3-(methoxymethyl)-2,3- dihydro-[l,4]dioxino[2,3-b]pyridin-8-yl]piperidine-l-carboxamide:
  • Example 19 4-[(4-chloro-2,6-difluorophenyl)methyl]-A r -(2,3-dihydro- [l,4]dioxino[2,3-b]pyridin-8-yl)piperidine-l-carboxamide, trifluoroacetic acid:
  • Step 1 Preparation of 4-[(4-chloro-2,6-difluorophenyl methyll-N-(2,3-dihydro-[l,41dioxinor2,3- blpyridin-8-yl piperidine-l-carboxamide, trifluoroacetic acid:
  • Example 20 4-(4-chlorobenzoyl)-A r -(2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-8- yl)piperidine-l-carboxamide: Step 1-a: Preparation of ferf -butyl 4-(4-chlorobenzoyl)piperidine-l-carboxylate:
  • Step 1-b Preparation of (4-chlorophenyl)-(4-piperidyl)methanone hydrochloride:
  • Step 3 Preparation of 4-(4-chlorobenzoyl)-N-(2 -dihydro-[l ⁇ ldioxinor2 -blpyridin-8-yl)piperidine-l- carboxamide:
  • Example 21 4-[(4-cyano-2,6-difluoro-phenyl)methyl]-A r -(2,3-dihydro- [l,4]dioxino[2,3-b]pyridin-8-yl)piperidine-l-carboxamide:
  • Step 1-a Preparation of ferf-butyl 4-r(4-ethoxycarbonyl-2,6-difluorophenyl)methylene1piperidine-l - carboxylate:
  • the title compound was prepared as a light yellow solid following scheme 5 and in analogy to Example 2 (step 1-c) using ethyl 4-bromo-3,5-difluorobenzoate and tert-butyl 4-[(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)methylene]piperidine-l-carboxylate as starting material and after purification by column chromatography (silica gel; PE : EA; 50:1 to 30:1 ; v/v).
  • Step 1-c Preparation of ferf-butyl 4-r(4-carbamoyl-2,6-difluorophenyl)methyl1piperidine-l-carboxylate: In a sealable tube was dissolved teri-butyl 4-[(4-ethoxycarbonyl-2,6-difluorophenyl)methyl]piperidine-l - carboxylate (500 mg; 1.28 mmol) in NH 3 solution, 2N in MeOH (10 mL). The tube was sealed and the reaction solution was heated to 70 °C and stirred for 18 h.
  • Step 1-d Preparation of ferf-butyl 4-r(4-cvano-2,6-difluorophenyl)methyl1piperidine-l-carboxylate: To a stirred solution of teri-butyl 4-[(4-carbamoyl-2,6-difluorophenyl)methyl]piperidine-l-carboxylate (450 mg; 1.22 mmol) in DCM (10 mL) was added TEA (0.42 mL; 3.06 mmol). The reaction mixture was cooled to 0 °C, and TFAA (0.42 mL; 3.06 mmol) was added. After stirring for 2 h, the reaction mixture was concentrated to dryness.
  • Step 1-e Preparation of 3,5-difluoro-4-(4-piperidylmethyl)benzonitrile, hydrochloride:
  • Step 2 Preparation of 4-r(4-cyano-2,6-difluorophenyl methyl1-N-(2,3-dihvdro-ri ,41dioxinor2,3- b1pyridin-8-yl)piperidine-l -carboxamide:
  • the title compound was prepared as a white solid following scheme 3 and in analogy to Example 6 (steps 2-a and 2-b) using 3,5-difluoro-4-(4-piperidylmethyl)benzonitrile hydrochloride and 8-bromo-2,3- dihydro-[l ,4]dioxino[2,3-b]pyridine as starting materials and after purification by preparative HPLC.
  • Step 1-a Preparation of 2-(2-bromo-4-chloro-3-pyridyl)ethanol:
  • Step 1-b Preparation of 2-(2-bromo-4-chloro-3-pyridyl ethoxy-fer?-butyl-dimethyl-silane:
  • Step 1-c Preparation of fer?-butyl-r2-(4-chloro-2-methyl-3-pyridyl)ethoxy1dimethylsilane:
  • Step 1-e Preparation of 4-chloro-3-(2-chloroethyl)-2-methylpyridine-l-oxide:
  • Step 1-f Preparation of r4-chloro-3-(2-chloroethyl)-2-pyridyl1methyl acetate:
  • Step 1-g Preparation of 4-chloro-6,8-dihvdro-5H-pyranor3,4-b1pyridine:
  • Step 1-a Preparation of r2-r(2-cMoro-3-pyridyl oxy1-l -methylethvH hydrogen sulfate:
  • Step 1-b Preparation of l -[(2-chloro-3-pyridyl)oxylpropan-2-ol:
  • Step 1-c Preparation of 3-methyl-2,3-dihvdro-rL41dioxinor2,3-b1pyridine and 2-methyl-2,3-dihydro- rL41dioxinor2,3-b1pyridine:
  • Step 1-d Preparation of 3-methyl-2,3-dihydro-[l,41dioxinor2,3-blpyridin-5-oxide and 2-methyl-2,3- dihvdro-ri,41dioxinor2,3-b1pyridin-5-oxide:
  • Step 1-e Preparation of 3-methyl-8-nitro-2,3-dihvdro-ri,41dioxinor2,3-b1pyridine and 2-methyl-8-nitro- 2,3-dihydro-[l,41dioxino[2,3-b1pyridine:
  • Step 1-f Preparation of 3-methyl-2,3-dihvdro-rL41dioxinor2,3-b1pyridin-8-amine and 2-methyl-2,3- dihvdro-rL41dioxinor2,3-b1pyridin-8-amine:
  • Step 2 4-[(4-cyano-2,6-difluorophenyl methylene1-N-(3 ⁇
  • Example 29 4-[(4-cyano-2,6-difluorophenyl)methylene]-A r -(2,2-dimethyl-3H- [l,4]dioxino[2,3-b]pyridin-8-yl)piperidine-l-carboxamide, trifluoroacetic acid:
  • Step 1-a Preparation of ethyl 2-r(2-chloro-3-pyridyl)oxy1acetate:
  • Step 1-b Preparation of l-r(2-chloro-3-pyridyl)oxy1-2-methylpropan-2-ol:
  • Step 1-c Preparation of 2,2-dimethyl-3H-ri ,41dioxinor2,3-b1pyridine:
  • Step 2 Preparation of 4-r(4-cvano-2,6-difluorophenyl methylene1-N-(2,2-dimethyl-3H-ri ,41dioxinor2,3- b1pyridin-8-yl)piperidine-l -carboxamide, trifluoroacetic acid:
  • the title compound was prepared as a yellow solid following scheme 1 and in analogy to Examples 27 15 and 28 (steps 1 -d, 1 -e, 1 -f and 2) using 2,2-dimethyl-3H-[l ,4]dioxino[2,3-b]pyridine and 3,5-difluoro-4- (4-piperidylidenemethyl)benzonitrile, hydrochloride as starting materials, and after purification by preparative HPLC.

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Abstract

The invention provides compounds of formula (I) or pharmaceutically acceptable salt thereof wherein ring A represents group A-I, A-II or A-III. Al represents -C(R4a)(R4a)-, -C(R4a)= -N(R4b)-, -N= -O- or -S-; A2 represents -C(R4c)(R4c)-, -C(R4c)= or -0-; A3 represents -C(R4c)(R4c)-, -C(R4c)= or -0-; A4 represents -C(R4a)(R4a)-, -C(R4a)= -N= -O- or -S-; A5 represents -C(R4a)(R4a)-, -C(R4a)= -N(R4b)-, -N= -O- or -S-; A6 represents -C(R4c)(R4c)- or -C(R4c)=; A7 represents -C(R4a)(R4a)-, -C(R4a)= -N= -O- or -S-; A8 represents -C(R4a)(R4a)-, -N(R4b)-, -O- or -S-; A9 represents -C(R4c)(R4c)- or -0-; A10 represents -C(R4c)(R4c)- or -0-; A11 represents -C(R4c)(R4c)- or -0-; A12 represents -C(R4a)(R4a)-, -O- or -S-; wherein group A-I, group A-II and group A-III de not contain adjacent oxygen atoms, adjacent oxygen and sulfur atoms or adjacent oxygen and nitrogen atoms or a moiety selected from the group consisting of N-C-N, N-C-S, S-C-S, O-C-N, O-C-O and O-C-S, wherein in each case the carbon atom in the N-C-N, N-C-S, S-C-S, O-C-N, O-C-O and O-C-S moiety is saturated; B1, B2, B3 and B4 represent independently C(R3) or N, wherein no more than two of B1, B2, B3 and B4 represent N; n is 1 or 2; and R1, R2, R3, R4a, R4b and R4c are as defined in the claims, as well as methods of using the compounds to treat proliferation diseases, in particular cancer.

Description

Mitochondrial inhibitors for the treatment of proliferation disorders
The present invention relates to mitochondrial inhibitors and their use in the treatment of proliferation disorders, in particular cancer.
Mitochondria are the power house of the cell because they generate most of the adenosine triphosphate (ATP), used as a source of chemical energy (Campbell, N.A., Williamson B., Heyden, R.J. Biology: Exploring Life 2006th Edition, Publisher: Pearson Prentice Hall, 2006). In addition, mitochondria are involved in other functions, such as cellular signaling, differentiation and death, as well as maintaining control of the cell cycle and cell growth (McBride H.M. et.al., Curr. Biol., vol. 16, no.14, R551-60, 2006). Cancer cells reprogram their metabolism in favour of glycolysis, regardless of oxygen presence, according to a phenomenon known as aerobic glycolysis. This so-called "Warburg phenotype" involves high glucose uptake and a high glycolytic activity (Warburg O., Science, vol. 123, no. 3191, pages 309- 314, 1956). Nevertheless, cancer cells are also dependent on mitochondria for ATP production through oxidative phosphorylation (OXPHOS) (Marchetti P. et al., International Journal of Cell Biology, vol. 2015, pages 1-17, 2015 and Solaini G. et al., Biochim. Biophys. Acta,, vol. 2, page: 314-323, 2010). Mitochondrial metabolism is now recognized as a potential target for anticancer agents due to the metabolic characteristic of cancer cells. Indeed, human cancer is associated with mitochondrial dysregulation, which promotes cancer cell survival, tumor progression and metastases as well as resistance to current anticancer drugs (Marchetti P. et al., International Journal of Cell Biology, vol. 2015, pages 1-17, 2015, Boland M.L. et al., Frontieres in Oncology, vol. 3, Article 292, pages 1-28, 2013 and Solaini G. et al., Biochim. Biophys. Acta, vol. 1797, pages 1171-1177, 2010). Metabolic reprogramming in cancer cells results in the maintenance of energy (ATP) production even under stressed conditions, contributing to tumor growth and survival through (for example) mitochondrial utilization of alternative carbon sources such as glutamine and fatty acids to generate ATP (Solaini G. et al., Biochim. Biophys. Acta, vol. 1797, pages 1171-1177, 2010). Indeed, as a result of the separation of glycolytic flux from mitochondria, mitochondrial glutaminolysis is preferentially used to produce ATP and, therefore, contribute to cancer cell survival (DeBerardinis R.J. et al., PNAS, vol. 104, no. 49, pages 19345-19350, 2007) being crucial for the development (Strohecker A.M. et al., Cancer Discovery, vol. 3, no. 11, pages 1272-1285, 2013) and anchorage-independent growth (Weinberg F. et al., PNAS, vol. 107, no. 19, pages 8788-8793, 2010) of certain tumor types.
Moreover, mitochondrial activity has also been associated with the development of drug resistance. For example, chemotherapeutic and targeted drugs (e.g. BRAF inhibitors) have been shown to induce a shift in cancer metabolism leading to mitochondrial dependency (addiction) characterized for example by upregulation of OXPHOS and mitochondrial biogenesis in surviving cells (Marchetti P. et al.,
International Journal of Cell Biology, vol. 2015, pages 1-17, 2015; and Vellinga T. T. et al., Clinical Cancer Research, vol. 21, no. 12, pages 2870-2879, 2015). In the case of BRAF inhibitors, acquired resistance was associated with maintenance of an OXPHOS phenotype regardless of the underlying resistance mechanism (Corazao-Rozas P. et al., Oncotarget, vol. 4, no. 11, pages 1986-1998, 2013), suggesting a potential metabolic arena that could be exploited on a therapeutic level. Hence, taken together, accumulating data provide convincing evidence supporting the involvement of mitochondria in cancer development and a strong rationale for developing mitochondrial targeted agents to fight cancer. Based on growing interest in mitochondria as therapeutic targets for cancer, in recent years a number of mitochondrial-targeting investigational agents have entered clinical development. For example, the antidiabetic medication metformin, which inhibits OXPHOS through inhibition of complex I of the mitochondrial respiratory chain (El-Mir et al., J. Biol. Chem. vol. 275, pages 223-228, 2000, and Wheaton W.W. et al., eLife vol. 3, 2014) is currently being investigated in a number of clinical trials in cancer patients (Chae Y.K. et al., Oncotarget, March 19, 2016). These trials were stimulated by preclinical data in tumor models (Chae Y.K. et al., Oncotarget, March 19, 2016) and the observation that type 2 diabetics treated with metformin had a decreased risk of developing various types of cancer (Quinn B.J., Kitagawa H., Memmott R.M., et al. Trends Endocrinol. Metab. vol. 24, pages 469-80, 2000 and Chae Y.K. et al., Oncotarget, March 19, 2016). Subsequently, increased interest in this therapeutic approach has led to other complex 1 inhibitor classes being investigated (WO2014/031928,
WO2014/031936, Ziegelbauer et al., Cancer Medicine, vol. 2 no. 5, pages 611-624, 2013 and
WO2010/054763). Hence, targeting mitochondrial metabolism is of great interest for the development of novel therapeutic approaches for cancer treatment.
Accordingly in a first aspect the present invention provides compounds of formula I and pharmaceutically acce table salts thereof
Figure imgf000004_0001
wherein
ring A represents group A-I, A-II or A-III
Figure imgf000004_0002
(A-I) (A-II) (A-III)
Al represents -C(R4a)(R4a)-, -C(R4a)=, -N(R4b)-, -N= -O- or -S-;
A2 represents -C(R4c)(R4c)-, -C(R4c)= or -0-;
A3 represents -C(R4c)(R4c)-, -C(R4c)= or -0-;
A4 represents -C(R4a)(R4a)-, -C(R4a)= -N= -O- or -S-;
A5 represents -C(R4a)(R4a)-, -C(R4a)=, -N(R4b)-, -N= -O- or -S-; A6 represents -C(R4c)(R4c)- or -C(R4c)=;
A7 represents -C(R4a)(R4a)-, -C(R4a)= -N= -O- or -S-;
A8 represents -C(R4a)(R4a)-, -N(R4b)-, -O- or -S-;
A9 represents -C(R4c)(R4c)- or -0-;
A10 represents -C(R4c)(R4c)- or -0-;
Al 1 represents -C(R4c)(R4c)- or -0-;
A12 represents -C(R4a)(R4a)-, -O- or -S-;
wherein group A-I, group A-II and group A- III do not contain adjacent oxygen atoms, adjacent oxygen and sulfur atoms or adjacent oxygen and nitrogen atoms or a moiety selected from the group consisting of N-C-N, N-C-S, S-C-S, O-C-N, O-C-0 and O-C-S, wherein in each case the carbon atom in the N-C-N, N- C-S, S-C-S, O-C-N, O-C-0 and O-C-S moiety is saturated;
Bl, B2, B3 and B4 represent independently C(R3) or N, wherein no more than two of Bl, B2, B3 and B4 represent N;
X represents -CH(R5)-, -C(R5)= -C(O)- or -0-, and wherein when X represents -CH(R5) , -C(O)- or -O- the dotted line represents a single bond, and when X represents -C(R5)= the dotted line represents a double bond;
Rl represents independently at each occurrence Cl-C6alkyl, Cl-C6haloalkyl or Cl-C6alkyl wherein one or two carbon atoms are independently replaced by -O- and wherein the alkyl moiety is optionally substituted by one or more halogen (when two carbon atoms are replaced by -0-, the oxygen atoms are not adjacent);
R2 represents halogen, cyano, hydroxyl, mercapto, Cl-C6alkyl optionally substituted by one to five R7,
Cl-C6alkoxy optionally substituted by one to five R7, -N(R6a)(R6b) or -Cl-C6alkylene-N(R6a)(R6b);
R3 represents independently at each occurrence hydrogen, halogen, cyano or Cl-C4alkyl;
R4a and R4b represent independently at each occurrence hydrogen or Cl-C3alkyl;
R4c represents independently at each occurrence hydrogen, Cl-C6alkyl optionally substituted by Rl 1, or
Cl-C6alkyl in which one carbon atom is replaced by oxygen and which is additionally optionally substituted by Rl 1 , providing that when R4c is alkoxy the oxygen atom of R4c does not form with two ring atoms a moiety selected from the group consisting of O-C-N, O-C-0 and O-C-S, wherein in each case the carbon atom in the O-C-N, O-C-0 and O-C-S moiety is saturated;
R5 represents hydrogen or C 1 -C4alkyl;
R6a represents hydrogen, Cl-C6alkyl optionally substituted by one to five R7, -Cl-C6alkylene-Cycle-
P, -Cl-C6alkylene-Cycle-Q, Cycle-P or Cycle-Q;
R6b represents hydrogen or Cl-C6alkyl;
R7 represents independently at each occurrence halogen, cyano, hydroxyl, Cl-C6alkoxy, Cl- C3alkylsulfonyl, amino, -NH(C1-C4alkyl) or -N(Cl-C4alkyl)2;
Cycle-P represents independently at each occurrence a saturated or partially unsaturated 3- to 8- membered carbocyclic ring optionally substituted by 1 to 3 R9, or a saturated or partially unsaturated 3- to 8-membered heterocyclic ring optionally substituted by 1 to 3 R9 containing carbon atoms as ring members and one or two ring members independently selected from N and O, wherein N optionally may bear R8;
Cycle-Q represents independently at each occurrence phenyl optionally substituted by 1 to 3 RI O or a 5- to 6-membered heteroaryl ring containing one to four heteroatoms selected from O, S and N, optionally substituted by 1 to 3 RI O;
R8 represents independently at each occurrence hydrogen or Cl -C4alkyl;
R9 and RI O represent independently at each occurrence cyano, Cl -C4alkyl, Cl -C4haloalkyl, Cl - C4alkoxy or Cl -C4haloalkoxy;
Rl 1 represents hydroxyl or cyano;
n is 1 or 2; and
q is 0, 1 , 2, 3 or 4.
In a further aspect the invention provides compounds of formula I and pharmaceutically acceptable salts thereof for use in the treatment of proliferation diseases and disorders, in particular cancer, in a subject selected from a mammal, in particular in a human.
In a further aspect the invention provides use of compounds of formula I and pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of proliferation diseases and disorders, in particular cancer, in a subject selected from a mammal, in particular in a human.
In a further aspect the invention provides methods of treating proliferation diseases and disorders, in particular cancer, in a subject selected from a mammal, in particular in a human, comprising
administering the compound of formula I or pharmaceutically acceptable salt thereof to said subject. In a further aspect the invention provides pharmaceutical compositions comprising a compound of formula I or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
Each alkyl moiety either alone or as part of a larger group such as alkoxy is a straight or branched chain and is preferably Cl -C6alkyl, more preferably Cl -C4alkyl. Examples include methyl, ethyl, « -propyl, prop-2-yl, « -butyl, but-2-yl, 2-methyl-prop-l -yl or 2-methyl-prop-2-yl.
Each alkylene moiety is a straight or branched chain and is, for example, -CH2-, -CH2-CH2-, -CH(CH3)-, - CH2-CH2-CH2-, -CH(CH3)-CH2-, or -CH(CH2CH3)-.
Each alkenyl moiety either alone or as part of a larger group such as alkenyloxy is a straight or branched chain and is preferably C2-C6alkenyl, more preferably C2-C4alkenyl. Each moiety can be of either the (E)- or (Z)-configuration. Examples include vinyl and allyl.
Each alkynyl moiety either alone or as part of a larger group such as alkynyloxy is a straight or branched chain and is preferably C2-C6alkynyl, more preferably C2-C4alkynyl. Examples are ethynyl and propargyl. Each haloalkyl moiety either alone or as part of a larger group such as haloalkoxy is an alkyl group substituted by one or more of the same or different halogen atoms. Examples include difluoromethyl, trifluoromethyl, chlorodifluoromethyl and 2,2,2-trifluoro-ethyl. Haloalkyl moieties include for example 1 to 5 halo substituents, or 1 to 3 halo substituents.
Each haloalkenyl moiety either alone or as part of a larger group such as haloalkenyloxy is an alkenyl group substituted by one or more of the same or different halogen atoms. Examples include 2-difluoro- vinyl and 1 ,2-dichloro-2-fluoro-vinyl. Haloalkenyl moieties include for example 1 to 5 halo substituents, or 1 to 3 halo substituents.
Each cycloalkyl moiety can be in mono- or bi-cyclic form and preferably contains 3 to 8 carbon atoms, more preferably 3 to 6 carbon atoms. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. An example of a bicyclic cycloalkyl group is
bicyclo[2.2.1]heptan-2-yl.
Halogen is fluorine, chlorine, bromine, or iodine.
The term "amino" refers to -NH2.
The term "mercapto" refers to -SH.
The term "alkylsulfonyl" means -S(0)2-alkyl.
The term "alkoxyalkyl" means -alkyl-O-alkyl.
The term "heteroaryl" refers to an aromatic ring system containing at least one heteroatom, and preferably up to four, for example up to three, heteroatoms selected from nitrogen, oxygen and sulfur as ring members. Heteroaryl rings do not contain adjacent oxygen atoms, adjacent sulfur atoms, or adjacent oxygen and sulfur atoms within the ring. Examples include pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, tetrazolyl, furanyl and thiophenyl.
The term "heterocyclic ring" refers to a saturated or partially unsaturated carbocyclic ring containing one to four heteroatoms selected from nitrogen, oxygen and sulfur as ring members. Such rings do not contain adjacent oxygen atoms, adjacent sulfur atoms, or adjacent oxygen and sulfur atoms within the ring.
Examples include tetrahydro furanyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, dioxanyl and morpholinyl.
Where a group is said to be optionally substituted, it may be substituted or unsubstituted, for example optionally with 1-5 substituents, for example optionally with 1-3 substituents.
Certain compounds of formula I may contain one or two or more centers of chirality and such compounds may be provided as pure enantiomers or pure diastereoisomers as well as mixtures thereof in any ratio.
For example, when X represents -CH(R5) - or -C(O)- or-O- and n is 2, or n is 1 and at least one Rl is different than H, the H on the carbon atom connected to X by the dotted line may be in the axial or equatorial configuration and the invention includes both isomers in any ratio. The compounds of the invention also include all cis/trans-isomers (for example where the dotted line is a double bond) as well as mixtures thereof in any ratio. The compounds of the invention also include all tautomeric forms of the compounds of formula I.
The compounds of formula I may also be solvated, especially hydrated, which are also included in the compounds of formula I. Solvation and hydration may take place during the preparation process.
Reference to compounds of the invention includes pharmaceutically acceptable salts of said compounds. Such salts may also exist as hydrates and solvates. Examples of pharmacologically acceptable salts of the compounds of formula (I) are salts of physiologically acceptable mineral acids, such as hydrochloric acid, sulfuric acid and phosphoric acid, or salts of organic acids, such as methane-sulfonic acid, p- toluenesulfonic acid, lactic acid, acetic acid, trifluoroacetic acid, citric acid, succinic acid, fumaric acid, maleic acid and salicylic acid. Further examples of pharmacologically acceptable salts of the compounds of formula (I) are alkali metal and alkaline earth metal salts such as, for example, sodium, potassium, lithium, calcium or magnesium salts, ammonium salts or salts of organic bases such as, for example, methylamine, dimethylamine, triethylamine, piperidine, ethylenediamine, lysine, choline hydroxide, meglumine, morpholine or arginine salts. The following examples of substituent definitions may be combined in any combination.
When ring A represents group A-I then preferably
Al represents -C(R4a)(R4a)-, -N(R4b)-, -O- or -S-;
A2 represents -C(R4c)(R4c);
A3 represents -C(R4c)(R4c)-; and
A4 represents -C(R4a)(R4a)- , -O- or -S-; or
Al represents -C(R4a)(R4a)-;
A2 represents -C(R4c)(R4c) or -0-;
A3 represents -C(R4c)(R4c)- or -0-, wherein both A2 and A3 do not represent -0-; and
A4 represents -C(R4a)(R4a)-; or
Al represents -C(R4a)= or -N=;
A2 represents -C(R4c)=;
A3 represents -C(R4c)=; and
A4 represents -C(R4a)= or -N=.
For example, group A-I may represent group A-Ia, group A-Ib, group A-Ic, group A-Id or group A-Ie:
Figure imgf000008_0001
(A-Ia) (A-Ib) (A-Ic)
Figure imgf000009_0001
(A-Id) (A-Ie)
wherein
Ala represents -C(R4a)(R4a)-, -N(R4b)-, -O- or -S-;
A4a represents -C(R4a)(R4a)-, -O- or -S-;
A2 represents -C(R4c)(R4c)- or -0-;
A3 represents -C(R4c)(R4c)- or -0-, wherein both A2 and A3 do not represent -0-; Alb represents -C(R4a)= or -N=; and
A4b represents -C(R4a)= or -N=;
preferably wherein
Ala represents -CH(R4a)-, -N(R4b)- or -O- or -S-;
A4a represents -CH(R4a)-, -O- or -S-;
A2 represents -CH(R4c) or -0-;
A3 represents -CH(R4c)- or -0-, wherein both A2 and A3 do not represent -0-; Alb represents -C(R4a)= or -N=; and
A4b represents -C(R4a)= or -N=;
more preferably wherein
Al a represents -CH(R4a)-, -N(R4b)- or -0-;
A4a represents -CH(R4a)- or -0-;
A2 represents -CH(R4c) or -0-;
A3 represents -CH(R4c)- or -0-, wherein both A2 and A3 do not represent -0-;
Alb represents -C(R4a)= or -N=; and
A4b represents -C(R4a)= or -N=.
For example, group A-I may represent group A-If
Figure imgf000009_0002
wherein A2 and A3 represents independently -C(R4c)(R4c)-.
Specific examples of group A-I are as follows: 
Figure imgf000010_0001
Figure imgf000011_0001
When ring A represents group A-II then preferably
A5 represents -C(R4a)(R4a)-, -N(R4b)-, -O- or -S-;
A6 represents -C(R4c)(R4c)-; and
A7 represents -C(R4a)(R4a)-,-0- or -S-, wherein at least one of A5 and A7 represents -C(R4a)(R4a)-; or A5 represents -C(R4a)= or -N=;
A6 represents -C(R4c)=; and
A7 represents -C(R4a)(R4a)-, -O- or -S-; or
A5 represents -C(R4a)(R4a)-, -N(R4b)-, or -0-;
A6 represents -C(R4c)=; and
A7 represents -C(R4a)= or -N=.
For example, group A-II may represent group A-IIa, group A-IIb or group A-IIc;
Figure imgf000011_0002
(A-IIa) (A-IIb) (A-IIc)
wherein
A5a represents -C(R4a)(R4a)-, -N(R4b)-, -O- or -S-;
A7a represents -C(R4a)(R4a)-, -O- or -S-, wherein at least one of A5a and A7a represents -C(R4a)(R4a)-; A5b represents -C(R4a)= or -N=;
A7b represents -O- or -S-;
A5c represents -N(R4b)-, -O- or -S-; and
A7c represents -C(R4a)= or -N=;
preferably wherein
A5a represents -CH(R4a)-, -N(R4b)-, -O- or -S-;
A7a represents -CH(R4a)-, -O- or -S-, wherein at least one of A5a and A7a is -CH(R4a)-;
A5b represents -C(R4a)= or -N=;
A7b represents -O- or -S-;
A5c represents -N(R4b)-, -O- or -S-; and A7c represents -C(R4a)= or -N=;
more preferably wherein
A5a represents -CH(R4a)-;
A7a represents -CH(R4a)- or -0-;
A5b represents -C(R4a)=;
A7b represents -O- or -S-;
A5c presents -0-; and
A7c presents -C(R4a)=.
Specific examples of group A-II are as follows:
Figure imgf000012_0001
When ring A represents group A-III then preferably A8 represents -C(R4a)(R4a)- or -0-;
A9 represents -C(R4c)(R4c)-;
A10 represents -C(R4c)(R4c)-;
Al l represents -C(R4c)(R4c)-;
A12 represents -C(R4a)(R4a)- or -0-.
For example group A-III may present group A-IIIa
Figure imgf000012_0002
wherein
A8 represents -C(R4a)(R4a)- or -0-; and
A12 represents -C(R4a)(R4a)- or -0-;
more preferably wherein
A8 represents -CH(R4a)- or -0-; and
A12 represents -CH(R4a)- or -0-.
For example group A-III may present group A-IIIb, A-IIIc
Figure imgf000013_0001
(A-IIIb) A-IIIc o A-IIId
wherein A9, A10 and Al 1 represent independently -C(R4c)(R4c)-, in particular A-IIId.
Specific examples of group A- III are as follows:
Figure imgf000013_0002
Further specific examples of group A-III are:
Figure imgf000013_0003
Generally, on ring A preferably no more than two of the substituents R4a, R4b and R4c are other than hydrogen and in some cases no more than one of the substituents R4a, R4b and R4c are other than hydrogen.
Bl, B2, B3 and B4 preferably represent independently C(R3) or N, wherein no more than one of Bl, B2, B3 and B4 represents N. For example Bl, B2, B3 and B4 represent independently C(R3a), C(R3b) or N wherein no more than two of Bl, B2, B3 and B4 represent C(R3a), wherein no more than one of Bl, B2, B3 and B4 represents N, wherein each R3a is independently R3 and each R3b represents hydrogen. Structural examples of the ring comprising Bl, B2, B3 and B4 as ring members are represented by group B-I group B-II, group B-III and roup B-IV:
Figure imgf000013_0004
(B-IV) Further structural examples of the ring comprising Bl, B2, B3 and B4 as ring members are represented by group B-la, group B-Ib, group B-IIa, group B-IIIa and B-IVa, wherein B-la is of particular interest:
Figure imgf000014_0001
(B-la) (B-Ib) (B-IIa) (B-IIIa)
When R3a is R3a*, wherein R3a* is as defined for R3a but is other than hydrogen, structural examples of the ring comprising Bl, B2, B3 and B4 as ring members include group B-Ia-1, group B-Ia-2, group B-Ia- 3, group B-Ib-1, group B-Ib-2, group B-IIa-1, group B-IIa-2, group B-IIIa-1 and group B-IIIa-2:
Figure imgf000014_0002
(B-IIa-2) (B-IIIa- 1) (B-IIIa-2)
Of these B-Ia-1, B-Ia-2 and B-Ia-3 are of particular interest.
Examples of the ring comprising B 1 , B2, B3 and B4 as ring members include include the following groups:
Figure imgf000014_0003
Figure imgf000015_0001
X preferably represents -CH=, -CH2-, -C(O)- or -0-.
Rl preferably represents independently at each occurrence Cl-C4alkyl, Cl-C4alkoxy or Cl-C3alkoxy- Cl-C3alkyl, even more preferably methyl, ethyl, propyl, methoxy, ethoxy, methoxymethyl or methoxyethyl, and in particular methyl, ethyl, propyl or methoxy. For the avoidance of doubt, Rl does not attach to the carbon atom bonded to X.
Preferably R2 represents halogen, cyano, hydroxyl, Cl-C6alkyl, Cl-C6haloalkyl, Cl-C6alkyl wherein one or two non-adjacent carbon atoms in the alkyl other than the connecting carbon atom are replaced independently by -0-, -OH, -NH-, -NH2, -N(CH3)-, -NH(CH3), -N(CH3)2 or -CN, or Cl-C6haloalkyl wherein one or two non-adjacent carbon atoms in the haloalkyl other than the connecting carbon atom are replaced independently by -0-, -OH, -NH-, -NH2, -N(CH3)-, -NH(CH3), -N(CH3)2 or -CN, or Cl-
C6alkoxy, Cl-C6alkoxy wherein one carbon atom in the alkoxy other than the carbon atom connected to the oxygen is replaced by -0-, -OH, -NH-, -NH2, -N(CH3)- or -CN, or -N(R6a)(R6b) or -Cl-C6alkylene- N(R6a)(R6b) and wherein R6a represents hydrogen, Cl-C6alkyl wherein one or two non-adjacent carbon atoms in the alkyl, preferably other than the carbon atom connected to the nitrogen atom, are replaced independently by -0-, -OH, -NH-, -NH2, -N(CH3)-, -NH(CH3), -N(CH3)2 or -CN, or R6a represents -Cl- C6-alkylene-Cycle-P or Cycle-P, wherein Cycle-P preferably represents a saturated 4- to 6- membered heterocyclic ring containing one or two heteroatoms selected from O and N(R8), wherein the heterocyclic ring is optionally substituted by one to three substituents selected from methyl, R6b represents hydrogen, methyl or ethyl, preferably hydrogen or methyl, and R8 represents independently at each occurrence hydrogen or methyl. More preferably R2 represents fluoro, chloro, bromo, cyano, hydroxyl, Cl-C6alkyl, Cl-C6haloalkyl, Cl-C6alkoxy, Cl-C6haloalkoxy, -Cl-C4alkylene-methoxy, -N(R6b)-Cl-C4alkylene- Rl 1, -N(R6b)-Cl-C4alkylene-Cycle-P or -N(R6b)-Cycle-P, wherein Cycle-P represents
tetrahydrofuranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, dioxanyl or morpholinyl wherein N is substituted by R8 in each case, R6b represents hydrogen, methyl or ethyl, R8 represents independently at each occurrence hydrogen or methyl, and Rl 1 represents -OH, -OCH3, -CN, -NH¾ -NH(CH3), or - N(CH3)2. Most preferably R2 is halogen, cyano, methoxy or trifluoromethyl, in particular halogen (e.g. chloro) or cyano. Specific examples of R2 include fluoro, chloro, bromo, cyano, amino, hydroxyl, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, methoxymethyl, trifluromethyl, trifluoromethoxy, -N(CH3)2, -NH(CH3), -NHCH2CH2NH2, -NHCH2CH2CH2NH2, -N(CH3)CH2CH2OH, - N(CH3)CH2CH2OCH3, -N(CH3)CH2CN, -N(CH3)CH2(l-methylazetidinyl) (e.g. -N(CH3)CH2(1- methylazetidin-3-yl)), -N(CH3)-tetrahydrofuran (e.g. N(CH3)-3-tetrahydrofuran), -N(CH3)(CH2)3NH2, - NHCH2CH3, -NH-tetrahydrofuran (e.g. NH-3-tetrahydrofuran), -N(CH3)CH2CH2NH2, -N(CH2CH3)2, and -N(CH3)(CH2)4NH2. Preferred specific examples are fluoro, chloro, bromo, cyano, methyl, trifluromethyl, N(CH3)2, methoxy, methoxymethyl, -N(CH3)CH2CH2OH, -N(CH3)CH2CH2OCH3, -N(CH3)CH2CN, - N(CH3)CH2(l-methylazetidinyl) (e.g. -N(CH3)CH2(l-methylazetidin-3-yl) and -N(CH3)CH2CN, e.g. fluoro, chloro, cyano, trifluoromethyl or methoxy, in particular chloro and cyano. R3 preferably represents independently at each occurrence hydrogen, halogen, cyano or methyl, more preferably hydrogen, fluoro, chloro, bromo, cyano, methyl, even more preferably hydrogen, fluoro, choro or methyl, e.g. hydrogen or fluoro. Preferably no more than two R3 are other than hydrogen. Particularly preferably each R3 on Bl, B2, B3 and B4 is hydrogen, or each R3 on Bl, B2 and B4 is hydrogen and R3 on B3 is halogen, in particular fluoro, or each R3 on Bl and B4 is hydrogen and each R3 on B2 and B3 is independently halogen, e.g. fluoro.
R4a represents independently at each occurrence hydrogen or Cl-C3alkyl. Preferably, no more than one R4a on a given carbon atom is other than hydrogen. More preferably no more than one R4a may be other than hydrogen. A specific example of R4a is hydrogen.
R4b represents independently at each occurrence hydrogen or Cl-C3alkyl. Preferably no more than one R4b is other than hydrogen. Specific examples of R4b are hydrogen and methyl.
R4c preferably represents independently at each occurrence hydrogen, Cl-C6alkyl -Cl-C6alkyl-cyano, - Cl-C6alkyl-hydroxy or -C0-C2alkyl-Cl-C4alkoxy, more preferably hydrogen, Cl-C4alkyl, -Cl-C4alkyl- cyano, -Cl-C4alkyl-hydroxy or -C0-C2alkyl-Cl-C3alkoxy. Specific examples of R4c are hydrogen, methyl, cyanomethyl, hydroxymethyl, methoxy and methoxymethyl. In some embodiments no more than two R4c are other than hydrogen.
When R4c is alkoxy the oxygen atom of R4c does not form with two ring atoms a moiety selected from the group consisting of O-C-N, O-C-0 and O-C-S, wherein in each case the carbon atom in the O-C-N, O-C-0 or O-C-S moiety is saturated.
R5 preferably represents hydrogen or methyl.
R6a preferably represents hydrogen or Cl-C6alkyl optionally substituted by one to five R7, more preferably hydrogen or Cl-C6alkyl wherein one or two non-adjacent carbon atoms in the alkyl are replaced independently by -0-, -OH, -NH-, -NH2, -N(CH3)-, -NH(CH3), -N(CH3)2 or -CN, or R6a represents -Cl-C6-alkylene-Cycle-P or Cycle-P, wherein Cycle-P preferably represents a saturated 4- to 6-membered heterocyclic ring containing one or two heteroatoms selected from O and N(R8), wherein the heterocyclic ring is optionally substituted by one to three substituents selected from methyl, and R8 represents independently at each occurrence hydrogen or methyl, more preferably R6a represents -Cl- C4alkylene-Rl 1, -Cl-C4alkylene-Cycle-P or Cycle-P, wherein Cycle-P represents tetrahydrofuranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, dioxanyl or morpholinyl wherein N is substituted by R8 in each case and R8 represents independently at each occurrence hydrogen or methyl, and wherein Rl 1 represents -OH, -OCH3, -CN, -NH¾ -NH(CH3), or -N(CH3)2.
R6b preferably represents hydrogen, methyl or ethyl, e.g. hydrogen or methyl.
R7 preferably represents independently at each occurrence halogen, cyano, hydroxyl or Cl-C4alkoxy. Cycle-P preferably represents independently at each occurrence a saturated 4- to 6-membered carbocyclic ring or a saturated or partially unsaturated 5- to -6-membered heterocyclic ring wherein the carbocyclic ring and heterocyclic ring are optionally substituted by 1 to 3 R9 containing carbon atoms as ring members and one or two ring members independently selected from N and O, wherein N optionally may bear R8. More preferably Cycle-P represents a saturated 4- to 6-membered heterocyclic ring containing one or two heteroatoms selected from O and N(R8), wherein the heterocyclic ring is optionally substituted by one to three substituents selected from methyl, and R8 represents independently at each occurrence hydrogen or methyl, even more preferably Cycle-P represents tetrahydrofuranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, dioxanyl or morpholinyl wherein N is substituted by R8 in each case and wherein R8 represents independently at each occurrence hydrogen or methyl. Specific examples include morpholinyl and pyrrolidinyl, tetrahydrofuranyl, 1 -methylazetidinyl (e.g. l-methylazetidin-3-yl). Cycle-Q preferably represents independently at each occurrence a 5- to 6-membered heteroaryl ring containing one to four heteroatoms selected from O, S and N, optionally substituted by 1 to 3 RIO.
Specific examples include oxadiazolyl, in particular 3-methyl-oxadiazolyl.
R8 preferably represents independently at each occurrence hydrogen or methyl.
R9 represents independently at each occurrence cyano, Cl-C4alkyl, Cl-C4haloalkyl, Cl-C4alkoxy or Cl- C4haloalkoxy, preferably cyano, methyl, halomethyl, methoxy or halomethoxy, even more preferably cyano, methyl, trifluoromethyl or methoxy.
RIO represents independently at each occurrence cyano, Cl-C4alkyl, Cl-C4haloalkyl, Cl-C4alkoxy or Cl-C4haloalkoxy, preferably cyano, methyl, halomethyl, methoxy or halomethoxy, even more preferably cyano, methyl, trifluoromethyl or methoxy.
q is preferably 0, 1 or 2, and preferably when q is 2 the Rl substituents are on the same carbon atom, more preferably q is 0 or 1.
Any embodiment relating to the chemical structure of the compounds of the invention may be combined with any other embodiment where possible, including with any of the examples of substituent definitions given above.
In one embodiment X represents -C(R5)=.
In another embodiment X represents -CH(R5)-.
In another embodiment X represents -C(O)-.
In another embodiment X represents -0-.
In another embodiment ring ; A represents group A-I.
In another embodiment ring ; A represents group A-II.
In another embodiment ring ; A represents group A-III.
In another embodiment ring ; A represents group A-Ia.
In another embodiment ring ; A represents group A-Ib.
In another embodiment ring ; A represents group A-Ic.
In another embodiment ring ; A represents group A-Id.
In another embodiment ring ; A represents group A-Ie.
In another embodiment ring ; A represents group A-If.
In another embodiment ring ; A represents group A-IIa. In another embodiment ring A represents group A- lib.
In another embodiment ring A represents group A- He.
In another embodiment ring A represents group A- Ilia.
In another embodiment ring A represents group A- Illb.
In another embodiment ring A represents group A- [f or group A-IIIb.
In another embodiment ring A represents group A- [ and X represents -CH=.
In another embodiment ring A represents group A- [I and X represents -CH=.
In another embodiment ring A represents group A- [II and X represents -CH=.
In another embodiment ring A represents group A- [ and X presents -CH2-.
In another embodiment ring A represents group A- [I and X represents -CH2-.
In another embodiment ring A represents group A- [II and X represents -CH2-.
In another embodiment ring A represents group A- [ and X presents -C(O)-.
In another embodiment ring A represents group A- [I and X represents -C(O)-.
In another embodiment ring A represents group A- [II and X represents -C(O)-.
In another embodiment ring A represents group A- [ and X presents -0-.
In another embodiment ring A represents group A- [I and X represents -0-.
In another embodiment ring A represents group A- [II and X represents -0-.
In another embodiment ring A represents group A- [a and X represents -CH=.
In another embodiment ring A represents group A- [b and X presents -CH=.
In another embodiment ring A represents group A- [c and X represents -CH=.
In another embodiment ring A represents group A- Id and X represents -CH=.
In another embodiment ring A represents group A- [e and X represents -CH=.
In another embodiment ring A represents group A- [f and X represents -CH=.
In another embodiment ring A represents group A- [Ia and X represents -CH=.
In another embodiment ring A represents group A- [Ib and X represents -CH=.
In another embodiment ring A represents group A- [Ic and X represents -CH=.
In another embodiment ring A represents group A- [Ila and X represents -CH=
In another embodiment ring A represents group A- [lib and X represents -CH=
In another embodiment ring A represents group A- [a and X represents -CH2-.
In another embodiment ring A represents group A- [b and X presents -CH2-.
In another embodiment ring A represents group A- [c and X represents -CH2-.
In another embodiment ring A represents group A- Id and X represents -CH2-.
In another embodiment ring A represents group A- [e and X represents -CH2-.
In another embodiment ring A represents group A- [f and X represents -CH2-.
In another embodiment ring A represents group A- [Ia and X represents -CH2-.
In another embodiment ring A represents group A- [Ib and X represents -CH2-.
In another embodiment ring A represents group A- [Ic and X represents -CH2-. In another embodiment ring A represents group A -Ilia and X represents -CH2-.
In another embodiment ring A represents group A -Illb and X represents -CH2-.
In another embodiment ring A represents group A -Ia and X represents -C(O)-.
In another embodiment ring A represents group A -Ib and X represents -C(O)-.
In another embodiment ring A represents group A -Ic and X represents -C(O)-.
In another embodiment ring A represents group A -Id and X represents -C(O)-.
In another embodiment ring A represents group A -Ie and X represents -C(O)-.
In another embodiment ring A represents group A -If and X represents -C(O)-.
In another embodiment ring A represents group A -Ila and X represents -C(O)-.
In another embodiment ring A represents group A -lib and X represents -C(O)-.
In another embodiment ring A represents group A -lie and X represents -C(O)-.
In another embodiment ring A represents group A -Ilia and X represents -C(O)-.
In another embodiment ring A represents group A -Illb and X represents -C(O)-.
In another embodiment ring A represents group A -Ia and X represents -0-.
In another embodiment ring A represents group A -Ib and X represents -0-.
In another embodiment ring A represents group A -Ic and X represents -0-.
In another embodiment ring A represents group A -Id and X represents -0-.
In another embodiment ring A represents group A -Ie and X represents -0-.
In another embodiment ring A represents group A -If and X represents -0-.
In another embodiment ring A represents group A -Ila and X represents -0-.
In another embodiment ring A represents group A -lib and X represents -0-.
In another embodiment ring A represents group A -lie and X represents -0-.
In another embodiment ring A represents group A -Ilia and X represents -0-.
In another embodiment ring A represents group A -Illb and X represents -0-.
In another embodiment n is 1.
In another embodiment n is 2.
In another embodiment q is 0.
In another embodiment q is 1.
In another embodiment q is 2.
In another embodiment q is 1 or 2.
In another embodiment ring A is ring A-I, A-II or A-III and the bridge in ring A formed by the A moieties is saturated, e.g.
Al represents -C(R4a)(R4a)-, -N(R4b)-, -O- or -S-;
A2 represents -C(R4c)(R4c)- or -0-;
A3 represents -C(R4c)(R4c)- or -0-;
A4 represents -C(R4a)(R4a)-, -O- or -S-;
A5 represents -C(R4a)(R4a)-, -N(R4b)-, -O- or -S-; A6 represents -C(R4c)(R4c)-;
A7 represents -C(R4a)(R4a)-, -O- or -S-;
A8 represents -C(R4a)(R4a)-, -N(R4b)-, -O- or -S-;
A9 represents -C(R4c)(R4c)- or -0-;
A10 represents -C(R4c)(R4c)- or -0-;
Al 1 represents -C(R4c)(R4c)- or -0-;
A12 represents -C(R4a)(R4a)-, -O- or -S-.
Groups A-Ia, A-Ib, A-Id, A-Ie, A- If, A-IIa, A- Ilia and A-IIIb represent examples wherein ring A formed by the A moieties is saturated.
In another embodiment ring A is group A-I or A-II and the bridge in ring A formed by the A moieties is unsaturated (e.g. aromatic), e.g.
Al represents -C(R4a)= or -N=;
A2 represents -C(R4c)=;
A3 represents -C(R4c)=;
A4 represents -C(R4a)= -N=;
A5 represents -C(R4a)=, -N(R4b)-, -N= -O- or -S-;
A6 represents -C(R4c)=;
A7 represents -C(R4a)= -N= -O- or -S-.
Groups A-Ic, A-IIb and A-IIc represent examples wherein ring A formed by the A moieties is unsaturated.
In another embodiment no more than two of the R4a, R4b and R4c substituents are other than hydrogen. In another embodiment no more than one of the R4a, R4b and R4c substituents are other than hydrogen. In another embodiment ring A represents group A-I or group A-III and Al, A4, A8 and A12 represent -O- and A2, A3, A9, A10 and Al 1 represent independently -C(R4c)(R4c)-.
In another embodiment ring A represents group A-I or group A-III and Al and A8 represent -O- and A2, A3, A4, A9, A10, Al land A12 represent independently -C(R4c)(R4c)-.
In another embodiment ring A represents group A-Ia, A-Id, A-Ie or A-IIIa and Ala, A4a, A8 and A12 represent -O- and A2, A3, A9, A10 and Al 1 represent independently -C(R4c)(R4c)-.
In another embodiment ring A represents group A-Ia, A-Id, A-Ie or A-IIIa and Ala and A8 represent -O- and A2, A3, A4a, A9, A 10, Al land A12 represent independently -C(R4c)(R4c)-.
In another embodiment ring A represents one of the following groups:
Figure imgf000021_0001
Figure imgf000022_0001
In another embodiment ring A represents one of the following groups
Figure imgf000022_0002
In another embodiment ring A represents one of the following groups
Figure imgf000022_0003
In another embodiment ring A represents one of the following groups
Figure imgf000022_0004
In another embodiment (Embodiment 1) ring A represents group A-I, A-II or A- III
Figure imgf000023_0001
(A-I) (A-II) (A-III)
Al represents -C(R4a)(R4a)-, -C(R4a)=, -N(R4b)-, -N= -O- or -S-;
A2 represents -C(R4c)(R4c)-, -C(R4c)= or -0-;
A3 represents -C(R4c)(R4c)-, -C(R4c)= or -0-;
A4 represents -C(R4a)(R4a)-, -C(R4a)= -N= -O- or -S-;
A5 represents -C(R4a)(R4a)-, -C(R4a)=, -N(R4b)-, -N= -O- or -S-;
A6 represents -C(R4c)(R4c)- or -C(R4c)=;
A7 represents -C(R4a)(R4a)-, -C(R4a)= -N= -O- or -S-;
A8 represents -C(R4a)(R4a)-, -N(R4b)-, -O- or -S-;
A9 represents -C(R4c)(R4c)- or -0-;
A10 represents -C(R4c)(R4c)- or -0-;
Al 1 represents -C(R4c)(R4c)- or -0-;
A12 represents -C(R4a)(R4a)-, -O- or -S-;
wherein group A-I, group A-II and group A-III do not contain adjacent oxygen atoms, adjacent oxygen and sulfur atoms or adjacent oxygen and nitrogen atoms or a moiety selected from the group consisting of
N-C-N, N-C-S, S-C-S, O-C-N, O-C-0 and O-C-S, wherein in each case the carbon atom in the N-C-N, N-
C-S, S-C-S, O-C-N, O-C-0 and O-C-S moiety is saturated;
the ring formed by Bl, B2, B3 and B4 is represented by group B-Ia:
Figure imgf000023_0002
(B-Ia);
X represents -CH2-, -CH=, -C(O)- or -0-, and wherein when X represents -CH(R5)-, -C(O)- or -O- the dotted line represents a single bond, and when X represents -C(R5)= the dotted line represents a double bond;
Rl represents independently at each occurrence Cl-C4alkyl, Cl-C4alkoxy or Cl-C3alkoxy-Cl-C3alkyl; R2 represents halogen, cyano, methoxy or trifluoromethyl (e.g. halogen or cyano);
R3 represents independently at each occurrence hydrogen or halogen;
R4a and R4b represent independently at each occurrence hydrogen or Cl-C3alkyl;
R4c represents independently at each occurrence hydrogen, Cl-C6alkyl optionally substituted by Rl 1, or Cl-C6alkyl in which one carbon atom is replaced by oxygen and optionally substituted by Rl 1, providing that when R4c is alkoxy the oxygen atom of R4c does not form with two ring atoms a moiety selected from the group consisting of O-C-N, O-C-0 and O-C-S, wherein in each case the carbon atom in the O- C-N, O-C-0 or O-C-S moiety is saturated;
Rl 1 represents hydroxyl or cyano;
n is 1 or 2; and
q is 0, 1 or 2.
In another embodiment (Embodiment la) the compound of formula I is as defined in embodiment 1 wherein ring A represents group A-I.
In another embodiment (Embodiment lb) the compound of formula I is as defined in embodiment 1 wherein ring A represents group A-II.
In another embodiment (Embodiment lc) the compound of formula I is as defined in embodiment 1 wherein ring A represents group A- III.
In another embodiment (Embodiment 2) ring A represents group A-Ia, A-Ib, A-Ic, A-Id, A-Ie, A-IIa, A- lib, AIIc or A-IIIa:
Figure imgf000024_0001
(A-Ia) (A-Ib) (A-Ic)
Figure imgf000024_0002
(A-Id) (A-Ie)
Figure imgf000024_0003
(A-IIa) (A-IIb) (A-IIc) (A-IIIa)
Ala represents -CH(R4a)-, -N(R4b)- or -O- or -S-; A4a represents -CH(R4a)-, -O- or -S-;
A2 represents -CH(R4c) or -0-;
A3 represents -CH(R4c)- or -0-, wherein both A2 and A3 do not represent -0-;
Alb represents -C(R4a)= or -N=;
A4b represents -C(R4a)= or -N=;
A5a represents -CH(R4a)-, -N(R4b)-, -O- or -S-;
A7a represents -CH(R4a)-, -O- or -S-, wherein at least one of A5a and A7a is -CH(R4a)-;
A5b represents -C(R4a)= or -N=;
A7b represents -O- or -S-;
A5c represents -N(R4b)-, -O- or -S-;
A7c represents -C(R4a)= or -N=;
A8 represents -CH(R4a)- or -0-; and
A12 represents -CH(R4a)- or -0-;
X represents =CH-, -CH2-, -C(O)- or -0-;
the ring formed by B 1 , B2, B3 and B4 is represented by group B-Ia:
Figure imgf000025_0001
Rl represents independently at each occurrence methyl, ethyl, propyl, methoxy, ethoxy, methoxymethyl or methoxyethyl;
R2 represents halogen, cyano, methoxy or trifluoromethyl (e.g. halogen or cyano);
R3 represents independently at each occurrence hydrogen or halogen;
R4a and R4b represent independently at each occurrence hydrogen or Cl-C3alkyl;
R4c represents independently at each occurrence hydrogen, Cl-C4alkyl -Cl-C4alkyl-cyano, -Cl-C4alkyl- hydroxy or -C0-C2alkyl-Cl-C3alkoxy, providing that when R4c is alkoxy, the oxygen atom of R4c does not form with two ring atoms a moiety selected from the group consisting of O-C-N, O-C-0 and O-C-S, wherein in each case the carbon atom in the O-C-N, O-C-0 or O-C-S moiety is saturated;
n is 1 or 2; and
q is 0, 1 or 2.
In another embodiment (Embodiment 2a) the compound of formula I is as defined in Embodiment 2 wherein ring A represents group A- la, A-Ib or A-Ic.
In another embodiment (Embodiment 2b) the compound of formula I is as defined in Embodiment 2 wherein ring A represents group A- la or A-Ib.
In another embodiment (Embodiment 2c) the compound of formula I is as defined in Embodiment 2 wherein ring A represents group A-Ic. In another embodiment (Embodiment 2d) the compound of formula I is as defined in Embodiment 2 wherein ring A represents group A-IIa, A-IIb or A-IIc.
In another embodiment (Embodiment 2e) the compound of formula I is as defined in Embodiment 2 wherein ring A represents group A-IIa.
In another embodiment (Embodiment 2f) the compound of formula I is as defined in Embodiment 2 wherein ring A represents group A- lib or A-IIc.
In another embodiment (Embodiment 2g) the compound of formula I is as defined in Embodiment 2 wherein ring A represents group A- Ilia. In another embodiment (Embodiment 3) ring A represents group A-Ia, A-Ib, A-Ic, A-Id, A-Ie, A-IIa, A- Ilb, A-IIc or A-IIIa:
Figure imgf000026_0001
Figure imgf000026_0002
(A-IIa) (A-IIb) (A-IIc)
Ala represents -CH(R4a)-, -N(R4b)- or -0-;
A4a represents -CH(R4a)- or -0-;
A2 represents -CH(R4c) or -0-;
A3 represents -CH(R4c)- or -0-, wherein both A2 and A3 do not represent -0-;
Alb represents -C(R4a)= or -N=; A4b represents -C(R4a)= or -N=;
A5a represents -CH(R4a)-;
A7a represents -CH(R4a)- or -0-, wherein at least one of A5a and A7a is -CH(R4a)-;
A5b represents -C(R4a)=;
A7b represents -O- or -S-;
A5c represents -0-;
A7c represents -C(R4a)=;
A8 represents -CH(R4a)- or -0-;
A12 represents -CH(R4a)- or -0-;
preferably X represents =CH-, -CH2-, -C(O)- or -0-;
the ring formed by Bl, B2, B3 and B4 is represented by group B-Ia:
Figure imgf000027_0001
Rl represents independently at each occurrence methyl, ethyl, propyl or methoxy;
R2 represents halogen or cyano, methoxy or trifluoromethyl (e.g. halogen or cyano);
R3 represents independently at each occurrence hydrogen or halogen;
R4a and R4b represent independently at each occurrence hydrogen or Cl-C3alkyl;
R4c represents independently at each occurrence hydrogen, Cl-C4alkyl, -Cl-C4alkyl-cyano, -Cl-
C4alkyl-hydroxy or -C0-C2alkyl-Cl-C3alkoxy,
providing that when R4c is alkoxy the oxygen atom of R4c does not form with two ring atoms a moiety selected from the group consisting of O-C-N, O-C-0 and O-C-S, wherein in each case the carbon atom in the O-C-N, O-C-0 or O-C-S moiety is saturated;
n is 1 or 2; and
q is 0, 1 or 2.
In another embodiment (Embodiment 3a) the compound of formula I is as defined in embodiment 3 wherein ring A represents group A- la, A-Ib or A-Ic.
In another embodiment (Embodiment 3b) the compound of formula I is as defined in embodiment 3 wherein ring A represents group A- la or A-Ib.
In another embodiment (Embodiment 3c) the compound of formula I is as defined in embodiment 3 wherein ring A represents group A-Ic.
In another embodiment (Embodiment 3d) the compound of formula I is as defined in embodiment 3 wherein ring A represents group A-IIa, A-IIb or A-IIc.
In another embodiment (Embodiment 3e) the compound of formula I is as defined in embodiment 3 wherein ring A represents group A-IIa. In another embodiment (Embodiment 3f) the compound of formula I is as defined in embodiment 3 wherein ring A represents group A- lib or A-IIc.
In another embodiment (Embodiment 3g) the compound of formula I is as defined in embodiment 3 wherein ring A represents group A- Ilia.
In another embodiment (Embodiment 4) ring A represents one of the following groups:
Figure imgf000028_0001
and X, Rl , R2, R3, R4c, n and q are as defined in Embodiment 1.
In another embodiment (Embodiment 5) ring A represents one of the groups defined in embodiment 4 and X, Rl, R2, R3, R4c, n and q are as defined in Embodiment 2.
In another embodiment (Embodiment 6) ring A represents one of the groups defined in embodiment 4 and X, Rl, R2, R3, R4c, n and q are as defined in Embodiment 3.
In another embodiment (Embodiment 7) ring A represents group A-If or A-IIIb, wherein
A2 and A3 represent independently -C(R4c)(R4c)-, A9, A10 and Al 1 represent independently - C(R4c)(R4c)-, and Rl, R2, R3, R4c, n and q (and preferably X) are as defined in Embodiment 1.
In another embodiment (Embodiment 8) ring A represents group A-If or A-IIIb, wherein
A2 and A3 represent independently -C(R4c)(R4c)-, A9, A10 and Al 1 represent independently - C(R4c)(R4c)-, and Rl, R2, R3, R4c, n and q (and preferably X) are as defined in Embodiment 2.
In another embodiment (Embodiment 9) ring A represents group A-If or A-IIIb,
wherein A9, A10 and Al 1 represent independently -C(R4c)(R4c)- and A2 and A3 represent
independently -C(R4c)(R4c)- and Rl, R2, R3, R4c, n and q (and preferably X) are as defined in
Embodiment 3. In another embodiment (Embodiment 10) ring A represents one of the following groups:
Figure imgf000029_0001
X represents =CH- or -C(O)-, R2 represents fluoro, chloro, cyano, trifluoromethyl or methoxy, each R3 represents independently fluoro or hydrogen, n is land q is 0.
In another embodiment the compound of formula I is a compound of formula la
Figure imgf000029_0002
wherein Al, A2, A3, A4, R2 and R3 are as defined for the compound of formula I, including preferred definitions thereof. For example, Al, A2, A3, A4, R2 and R3 may be as defined in Embodiment 1, or for example Al, A2, A3, A4, R2 and R3 may be as defined in Embodiment 2, or for example Al, A2, A3, A4, R2 and R3 may be as defined in Embodiment 3.
In another embodiment the compound of formula I is a compound of formula la, wherein Al and A4 represent -0-, A2 and A3 represent independently -C(R4c)(R4c)- and R2, R3 and R4c are as defined for the compound of formula I, including preferred definitions thereof. In another embodiment the compound of formula I is a compound of formula la, wherein Al represents -0-, A2 and A3 independently represent -C(R4c)(R4c)-, A4 represents CH2 and R2, R3 and R4c are as defined for the compound of formula I, including preferred definitions thereof. For example, R2, R3 and R4c may be as defined in Embodiment 1 , or for example R2, R3 and R4c may be as defined in Embodiment 2, or for example R2, R3 and R4c may be as defined in Embodiment 3.
In another embodiment the compound of formula I is a compound of formula lb
Figure imgf000029_0003
wherein Al, A2, A3, A4, R2 and R3 are as defined for the compound of formula I, including preferred definitions thereof. For example Al, A2, A3, A4, R2 and R3 may be as defined in Embodiment 1, or for example Al, A2, A3, A4, R2 and R3 may be as defined in Embodiment 2, or for example Al, A2, A3, A4, R2 and R3 may be as defined in Embodiment 3. In another embodiment the compound of formula I is a compound of formula lb, wherein Al and A4 represent -0-, A2 and A3 represent independently -C(R4c)(R4c)- and R2, R3 and R4c are as defined for the compound of formula I, including preferred definitions thereof. In another embodiment the compound of formula I is a compound of formula la, wherein Al represents -0-, A2 and A3 independently represent -C(R4c)(R4c)-, A4 represents CH2 and R2, R3 and R4c are as defined for the compound of formula I, including preferred definitions thereof. For example, R2, R3 and R4c may be as defined in Embodiment 1 , or for example R2, R3 and R4c may be as defined in Embodiment 2, or for example R2, R3 and R4c may be as defined in Embodiment 3.
In another embodiment the compound of formula I is a compound of formula Ic
Figure imgf000030_0001
wherein Al, A2, A3, A4, Rl, R2, R3 and q are as defined for the compound of formula I, including preferred definitions thereof. For example Al, A2, A3, A4, Rl, R2, R3 and q may be as defined in Embodiment 1, or for example Al , A2, A3, A4, Rl, R2, R3 and q may be as defined in Embodiment 2 or for example Al, A2, A3, A4, Rl, R2, R3 and q may be as defined in Embodiment 3.
In another embodiment the compound of formula I is a compound of formula Ic, wherein Al and A4 represent -0-, A2 and A3 represent independently -C(R4c)(R4c)- and R2, R3, R4c and q are as defined for the compound of formula I, including preferred definitions thereof. In another embodiment the compound of formula I is a compound of formula la, wherein Al represents -0-, A2 and A3
independently represent -C(R4c)(R4c)-, A4 represents CH2 and R2, R3, R4c and q are as defined for the compound of formula I, including preferred definitions thereof. For example, R2, R3 and R4c may be as defined in Embodiment 1, or for example R2, R3, R4c and q may be as defined in Embodiment 2, or for example R2, R3, R4c and q may be as defined in Embodiment 3.
In another embodiment the compound of formula I is a compound of formula Ic-i
Figure imgf000030_0002
wherein Al, A2, A3, A4, R2 and R3 are as defined for the compound of formula I, including preferred definitions thereof. For example Al, A2, A3, A4, R2 and R3 may be as defined in Embodiment 1, or for example Al, A2, A3, A4, R2 and R3 may be as defined in Embodiment 2 or for example Al, A2, A3, A4, R2 and R3 may be as defined in Embodiment 3.
In another embodiment the compound of formula I is a compound of formula Ic-i, wherein Al and A4 represent -0-, A2 and A3 represent independently -C(R4c)(R4c)- and R2, R3 and R4c are as defined for the compound of formula I, including preferred definitions thereof. In another embodiment the compound of formula I is a compound of formula la, wherein Al represents -0-, A2 and A3 independently represent -C(R4c)(R4c)-, A4 represents CH2 and R2, R3 and R4c are as defined for the compound of formula I, including preferred definitions thereof. For example, R2, R3 and R4c may be as defined in Embodiment 1 , or for example R2, R3 and R4c may be as defined in Embodiment 2, or for example R2, R3 and R4c may be as defined in Embodiment 3.
In another embodiment the compound of formula I is a compound of formula Id
Figure imgf000031_0001
wherein Al, A2, A3, A4, R2 and R3 are as defined for the compound of formula I, including preferred definitions thereof. For example Al, A2, A3, A4, R2 and R3 may be as defined in Embodiment 1, or for example Al, A2, A3, A4, R2 and R3 may be as defined in Embodiment 2 or for example Al, A2, A3, A4, R2 and R3 may be as defined in Embodiment 3.
In another embodiment the compound of formula I is a compound of formula Id, wherein Al and A4 represent -0-, A2 and A3 represent independently -C(R4c)(R4c)- and R2, R3 and R4c are as defined for the compound of formula I, including preferred definitions thereof. In another embodiment the compound of formula I is a compound of formula la, wherein Al represents -0-, A2 and A3 independently represent -C(R4c)(R4c)-, A4 represents CH2 and R2, R3 and R4c are as defined for the compound of formula I, including preferred definitions thereof. For example, R2, R3 and R4c may be as defined in Embodiment 1 , or for example R2, R3 and R4c may be as defined in Embodiment 2, or for example R2, R3 and R4c may be as defined in Embodiment 3.
In another embodiment the compound of formula I is a compound of formula Ie
Figure imgf000031_0002
(Ie) wherein A5, A6, A7, R2 and R3 are as defined for the compound of formula I, including preferred definitions thereof. For example A5, A6, A7, R2 and R3 may be as defined in Embodiment 1, or for example A5, A6, A7, R2 and R3 may be as defined in Embodiment 2, or for example A5, A6, A7, R2 and R3 may be as defined in Embodiment 3.
In another embodiment the compound of formula I is a compound of formula If
Figure imgf000032_0001
wherein A5, A6, A7, R2 and R3 are as defined for the compound of formula I, including preferred definitions thereof. For example Al, A2, A3, A4, R2 and R3 may be as defined in Embodiment 1, or for example A5, A6, A7, R2 and R3 may be as defined in Embodiment 2 or for example A5, A6, A7, R2 and R3 may be as defined in Embodiment 3.
In another embodiment the compound of formula I is a compound of formula Ig
Figure imgf000032_0002
wherein A8, A9, A10, Al 1, A12, R2 and R3 are as defined for the compound of formula I, including preferred definitions thereof. For example A8, A9, A10, Al 1, A12, R2 and R3 may be as defined in Embodiment 1, or for example A8, A9, A10, Al 1, A12, R2 and R3 may be as defined in Embodiment 2, or for example A8, A9, A10, Al 1, A12, R2 and R3 may be as defined in Embodiment 3.
In another embodiment the compound of formula I is a compound of formula Ig wherein A8 and A12 represent -0-, A9, AlO and Al 1 represent independently -C(R4c)(R4c)- and R2, R3 and R4c are as defined for the compound of formula I, including preferred definitions thereof. For example, R2, R3 and R4c may be as defined in Embodiment 1, or for example R2, R3 and R4c may be as defined in
Embodiment 2, or for example R2, R3 and R4c may be as defined in Embodiment 3.
In another embodiment the compound of formula I is a compound of formula Ih
Figure imgf000033_0001
wherein A8, A9, AlO, Al 1, A12, R2 and R3 are as defined for the compound of formula I, including preferred definitions thereof. For example A8, A9, AlO, Al 1, A12, R2 and R3 may be as defined in Embodiment 1, or for example A8, A9, AlO, Al 1, A12, R2 and R3 may be as defined in Embodiment 2, or for example A8, A9, AlO, Al 1, A12, R2 and R3 may be as defined in Embodiment 3.
In another embodiment the compound of formula I is a compound of formula Ih wherein A8 and A12 represent -0-, A9, AlO and Al 1 represent independently -C(R4c)(R4c)- and R2, R3 and R4c are as defined for the compound of formula I, including preferred definitions thereof. For example, R2, R3 and R4c may be as defined in Embodiment 1, or for example R2, R3 and R4c may be as defined in
Embodiment 2, or for example R2, R3 and R4c may be as defined in Embodiment 3.
In another embodiment the compound of formula I is a compound of formula Ii
Figure imgf000033_0002
wherein A8, A9, AlO, Al 1, A12, R2 and R3 are as defined for the compound of formula I, including preferred definitions thereof. For example A8, A9, AlO, Al 1, A12, R2 and R3 may be as defined in Embodiment 1, or for example A8, A9, AlO, Al 1, A12, R2 and R3 may be as defined in Embodiment 2, or for example A8, A9, AlO, Al 1, A12, R2 and R3 may be as defined in Embodiment 3.
In another embodiment the compound of formula I is a compound of formula Ii wherein A8 and A12 represent -0-, A9, AlO and Al 1 represent independently -C(R4c)(R4c)- and R2, R3 and R4c are as defined for the compound of formula I, including preferred definitions thereof. For example, R2, R3 and R4c may be as defined in Embodiment 1, or for example R2, R3 and R4c may be as defined in
Embodiment 2, or for example R2, R3 and R4c may be as defined in Embodiment 3.
In another embodiment the compound of formula I is a compound of formula Ij
Figure imgf000034_0001
wherein A8, A9, AlO, Al 1, A12, R2 and R3 are as defined for the compound of formula I, including preferred definitions thereof. For example A8, A9, AlO, Al 1, A12, R2 and R3 may be as defined in Embodiment 1, or for example A8, A9, AlO, Al 1, A12, R2 and R3 may be as defined in Embodiment 2, or for example A8, A9, AlO, Al 1, A12, R2 and R3 may be as defined in Embodiment 3.
In another embodiment the compound of formula I is a compound of formula Ij wherein A8 and A12 represent -0-, A9, AlO and Al 1 represent independently -C(R4c)(R4c)-, and R2, R3 and R4c are as defined for the compound of formula I, including preferred definitions thereof. For example, R2, R3 and R4c may be as defined in Embodiment 1, or for example R2, R3 and R4c may be as defined in
Embodiment 2, or for example R2, R3 and R4c may be as defined in Embodiment 3.
In another embodiment the compound of formula I is a compound of formula Ik
Figure imgf000034_0002
wherein A8, A9, AlO, Al 1, A12 and R2 are as defined for the compound of formula I, including preferred definitions thereof. For example A8, A9, AlO, Al 1, A12 and R2 may be as defined in Embodiment 1, or for example A8, A9, AlO, Al 1, A12 and R2 may be as defined in Embodiment 2, or for example A8, A9, AlO, Al 1, A12 and R2 may be as defined in Embodiment 3.
In another embodiment the compound of formula I is a compound of formula II
Figure imgf000034_0003
wherein A8, A9, AlO, Al 1, A12, R2 and R3 are as defined for the compound of formula I, including preferred definitions thereof. For example A8, A9, AlO, Al 1, A12, R2 and R3 may be as defined in
Embodiment 1, or for example A8, A9, AlO, Al 1, A12, R2 and R3 may be as defined in Embodiment 2, or for example A8, A9, AlO, Al 1, A12, R2 and R3 may be as defined in Embodiment 3. In further embodiments the invention provides the following compounds and pharmaceutically acceptable salts thereof:
4-[(4-chloro-2,6-difluorophenyl)methylene]-N-(4-quinolyl)piperidine-l-carboxamide;
4-[(4-chloro-2,6-difluorophenyl)methylene]-N-(6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)piperidine-l- carboxamide;
4-[(4-cyano-2,6-difluorophenyl)methylene]-N-(5,6,7,8-tetrahydroquinolin-4-yl)piperidine-l - carboxamide;
4-[(4-cyano-2,6-difluorophenyl)methylene]-N-(3,4-dihydro-2H-pyrano[3,2-b]pyridin-8-yl)piperidine-l- carboxamide;
4-[(4-chloro-2,6-difluorophenyl)methylene]-N-(2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-8-yl)piperidine- carboxamide;
4-[(4-chloro-2,6-difluorophenyl)methylene]-N-(2,3-dihydrofuro[2,3-b]pyridin-4-yl)piperidine-l- carboxamide;
4-[(4-chloro-2,6-difluorophenyl)methylene]-N-(3,4-dihydro-2H-pyrano[2,3-b]pyridin-5-yl)piperidine-l- carboxamide;
4-[(4-chloro-2-fluorophenyl)methylene]-N-(l,8-naphthyridin-4-yl)piperidine-l -carboxamide;
4-[(4-cyano-2,6-difluorophenyl)methylene]-N-(5,6,7,8 etrahydro-l,5-naphthyridin-4-yl)piperidine-l- carboxamide;
4-[(4-cyano-2,6-difluorophenyl)methylene]-N-(5-methyl-7,8-dihydro-6H-l,5-naphthyridin-4- yl)piperidine-l -carboxamide;
4-[(4-chloro-2-fluorophenyl)methylene]-N-[3-(methoxymethyl)-2,3-dihydro-[l,4]dioxino[2,3-b]pyridin- 8-yl]piperidine- 1 -carboxamide;
4-[(4-chloro-2-fluorophenyl)methylene]-N-[2-(methoxymethyl)-2,3-dihydro-[l,4]dioxino[2,3-b]pyridin- 8-yl]piperidine- 1 -carboxamide;
4-[(4-cyano-2,6-difluorophenyl)methylene]-N-[3-(methoxymethyl)-2,3-dihydro-[l,4]dioxino[2,3- b]pyridin-8-yl]piperidine-l -carboxamide;
4-[(4-cyano-2,6-difluorophenyl)methylene]-N-(7-methoxy-4-quinolyl)piperidine-l -carboxamide;
4-[(4-cyano-2,6-difluorophenyl)methylene]-N-(2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-8-yl)piperidine-l- carboxamide;
4-[(4-cyano-2,6-difluorophenyl)methylene]-N-(6-methoxy-4-quinolyl)piperidine-l -carboxamide;
4-[(4-cyano-2,6-difluorophenyl)methylene]-N-(l,5-naphthyridin-4-yl)piperidine-l -carboxamide;
4-[(4-cyano-2,6-difluorophenyl)methylene]-N-(l,8-naphthyridin-4-yl)piperidine-l -carboxamide;
4-[(4-chloro-2,6-difluorophenyl)methyl]-N-(2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-8-yl)piperidine-l- carboxamide;
4-(4-chlorobenzoyl)-N-(2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-8-yl)piperidine-l -carboxamide;
4-[(4-cyano-2,6-difluorophenyl)methyl]-N-(2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-8-yl)piperidine-l- carboxamide; 4-[(4-chloro-2,6-difluorophenyl)methylen^
carboxamide;
4-[(4-cyano-2,6-difluorophenyl)methylene]-N- 4-[(4-cyano-2,6-difluorophenyl)methylene]-N- 4-[(4-cyano-2,6-difluorophenyl)methylene]-N^
carboxamide;
4-[(4-cyano-2,6-difluorophenyl)methylene]-N hieno[2,3-b]pyridin-4-yl-piperidine-l-carboxa
4-[(4-cyano-2,6-difluorophenyl)methylene]-N-(3-methyl-2,3-dihydro-[l,4]dioxino[2,3-b]pyri yl)piperidine- 1 -carboxamide;
4-[(4-cyano-2,6-difluorophenyl)methylene]-N-(2-methyl-2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-8- yl)piperidine- 1 -carboxamide;
4-[(4-cyano-2,6-difluorophenyl)methylene]-N-(3,3-dimethyl-2H-[l,4]dioxino[2,3-b]pyridin-8- yl)piperidine- 1 -carboxamide;
4-[(4-cyano-2,6-difluorophenyl)methylene]-N-(3,3-dimethyl-2H-[l,4]dioxino[2,3-b]pyridin-8- yl)piperidine-l -carboxamide;
4-[(4-cyano-2,6-difluorophenyl)methylene]-N-(2,3-dimethyl-2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-8- yl)piperidine- 1 -carboxamide;
4-[(4-cyano-2,6-difluorophenyl)methylene]-N-[3-(hydroxymethyl)-2,3-dihydro-[l,4]dioxino[2,3- b]pyridin-8-yl]piperidine-l -carboxamide;
4-[(4-chloro-2,6-difluorophenyl)methylene]-N-[3-(hydroxymethyl)-2,3-dihydro-[l,4]dioxinoP b]pyridin-8-yl]piperidine-l -carboxamide;
4- [(4-chloro-2,6-difluorophenyl)methylene] -N- [2-(hydroxymethyl)-2,3 -dihydro- [ 1 ,4] dioxino [2,3- b]pyridin-8-yl]piperidine-l -carboxamide;
4-[(4-chloro-2,6-difluorophenyl)methylene]-N-[3-(cyanomethyl)-2,3-dihydro-[l,4]dioxino[2,3-b]pyridm^ 8-yl]piperidine-l -carboxamide;
4-[(4-cyano-2,6-difluorophenyl)methylene]-N-(3,4-dihydro-2H-[l,4]dioxepino[2,3-b]pyridin-9- yl)piperidine- 1 -carboxamide;
4-(4-chlorophenoxy)-N-(3,4-dihydro-2H-[l,4]dioxepino[2,3-b]pyridin-9-yl)piperidine-l-carboxami
4-(4-chlorobenzoyl)-N-thieno[2,3-b]pyridin-4-yl-piperidine-l -carboxamide;
4-(2,4-difluorobenzoyl)-N-(2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-8-yl)piperidine-l-carboxami
4-(4-cyanobenzoyl)-N-(2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-8-yl)piperidine-l -carboxamide;
4- [[2,6-difluoro-4- [methyl- [( 1 -methylazetidin-3 -yl)methyl] amino]phenyl]methylene] -N-(2,3 -dihydro-
[l,4]dioxino[2,3-b]pyridin-8-yl)piperidine-l -carboxamide;
4-[[2,6-difluoro-4-[2-hydroxyethyl(methyl)^
b]pyridin-8-yl)piperidine-l -carboxamide;
(4E)-4-[(4-chloro-2-fluorophenyl)methylene]-N-(2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-8-yl)-3,3- dimethyl-piperidine- 1 -carboxamide; (4E)-4-[[2,6-difluoro-4-(trifluoromethyl^
yl)-2-methyl-piperidine- 1 -carboxamide;
4-[[2,6-difluoro-4-(trifluoromethyl)phenyl]m
2-methyl-piperidine-l-carboxamide;4-[(2,6-diflu^
[l,4]dioxino[2,3-b]pyridin-8-yl)azepane-l -carboxamide;
4-[(4-cyano-2,6-difluorophenyl)methylene]-N-[2-(hydroxymethyl)thieno[2,3-b]pyridin-4-yl]piperi carboxamide;
4-[(4-cyano-2,6-difluorophenyl)methylene]-N^
1 -carboxamide;
4-[(4-cyano-2,6-difluorophenyl)methylene]-N^
carboxamide;
4-[(4-chloro-2,6-difluorophenyl)methylene]-N-(7,8-dihydro-5H-pyrano[4,3-b]pyridin-4-yl)piperidine carboxamide;
4-(4-chloro-2-fluorobenzoyl)-N-(2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-8-yl)piperidine-l-carbox 4-(4-cyano-2-fluorobenzoyl)-N-(2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-8-yl)piperidine-l-carboxamide N-(2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-8-yl)-4^
carboxamide;
4-(4-chloro-2,6-difluorobenzoyl)-N-(2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-8-yl)piperidine-l- carboxamide;
4-(4-cyano-2,6-difluorobenzoyl)-N-(2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-8-yl)piperidine-l- carboxamide;
4-[2,6-difluoro-4-(trifluoromethyl)benzoyl]-N-(2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-8-yl)pi^ carboxamide;
4-(4-chlorophenoxy)-N-(2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-8-yl)piperidine-l -carboxamide;
4-(2,4-difluorobenzoyl)-N-(3,4-dihydro-2H-[l,4]dioxepino[2,3-b]pyridin-9-yl)piperidine-l^
4-[(4-chloro-2-fluorophenyl)methyl]-N-(3,4-dm^
carboxamide;
4-(4-chlorobenzoyl)-N-(2,3-dihydro-[l,4]diox
carboxamide;
4-[(4-fluoro-6-methoxy-3-pyridyl)methylene]-N-(2,3,4,5-tetrahydrooxepino[2,3-b]pyridin-6- yl)piperidine- 1 -carboxamide;
4-[(5-methoxypyrazin-2-yl)methylene]-N-(6,7,8,9-tetrahydrooxepino[3,2-b]pyridin-4-yl)piperidine-l- carboxamide;
4-(4-chloro-2-fluorobenzoyl)-N-(3-methyl-3,4-dm^
1 -carboxamide;
4-(4-chlorobenzoyl)-N-(3,4-dihydro-2H-pyrano[3,2-b]pyridin-8-yl)piperidine-l-carboxamide; and 4-(4-chloro-2-fluorobenzoyl)-N-(3,4-dihydro-2H-pyrano[3,2-b]pyridin-8-yl)piperidine-l -carboxamide. The present invention relates also to pharmaceutical compositions that comprise a compound of formula I as active ingredient or or pharmaceutically acceptable salt thereof, e.g. present in a therapeutically- effective amount, which can be used especially in the treatment of the proliferation disorders, in particular cancer, as described herein. Compositions may be formulated for non-parenteral administration, such as nasal, buccal, rectal, pulmonary, vaginal, sublingual, topical, transdermal, ophthalmic, otic or, especially, for oral administration, e.g. in the form of oral solid dosage forms, e.g. granules, pellets, powders, tablets, coated tablets (e.g. film or sugar coated), effervescent tablets, hard and soft gelatin or HPMC capsules, coated as applicable, orally disintegrating tablets, solutions, emulsions (e.g. lipid emulsions) or suspensions, or for parenteral administration, such as intravenous, intramuscular or subcutaneous, intrathecal, intradermal or epidural administration, to mammals, especially humans, e.g. in the form of solutions, lipid emulsions or suspensions containing microparticles or nanoparticles. The compositions may comprise the active ingredient alone or, preferably, together with a pharmaceutically acceptable excipient.
The compounds of formula I or pharmaceutically acceptable salt, solvate or hydrate thereof can be processed with pharmaceutically inert, inorganic or organic excipients for the production of oral solid dosage forms, e.g. granules, pellets, powders, tablets, coated tablets (e.g. film or sugar coated), effervescent tablets and hard gelatin or HPMC capsules or orally disintegrating tablets. Fillers e.g.
lactose, cellulose, mannitol, sorbitol, calcium phosphate, starch (e.g. corn starch) or derivatives thereof, binders e.g. cellulose, starch, polyvinylpyrrolidone, or derivatives thereof, glidants e.g. talcum, stearic acid or its salts, flowing agents e.g. fumed silica, can be used as such excipients e.g. for formulating and manufacturing of oral solid dosage forms, such as granules, pellets, powders, tablets, film or sugar coated tablets, effervescent tablets, hard gelatine or HPMC capsules, or orally disintegrating tablets. Suitable excipients for soft gelatin capsules are e.g. vegetable oils, waxes, fats, semisolid and liquid polyols etc. Suitable excipients for the manufacture of solutions (e.g. oral solutions), lipid emulsions or suspensions are e.g. water, alcohols, polyols, saccharose, invert sugar, glucose etc.
Suitable excipients for parenteral formulations (e.g. injection solutions) are e.g. water, alcohols, polyols, glycerol, vegetable oils, lecithin, surfactants etc..
Moreover, the pharmaceutical preparations can contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances. The dosage can vary within wide limits and will, of course, be fitted to the individual requirements in each particular case. In general, a daily dosage of about 1 to 1000 mg, e.g. 10 to 1000 mg per person of a compound of general formula I should be appropriate, although the above upper limit (and likewise the lower limit) can also be exceeded when necessary.
The compounds of formula I can also be used in combination with one or more other pharmaceutically active compounds, which are either effective against the same disease, preferably using a different mode of action, or which reduce or prevent possible undesired side effects of the compounds of formula I. The combination partners can be administered in such a treatment either simultaneously, e.g. by incorporating them into a single pharmaceutical formulation, or consecutively by administration of two or more different dosage forms, each containing one or more than one of the combination partners.
Compounds of formula I according to the invention as described above or pharmaceutically acceptable salts thereof are particularly useful for the treatment of proliferation disorders and/or diseases such as cancer, in particular carcinoma, sarcoma, leukemia, myeloma and lymphoma and cancers of the brain and spinal cord, e.g. when administered in therapeutically effective amounts.
Examples of such proliferation disorders and diseases include, but are not limited to, epithelial neoplasms, squamous cell neoplasms, basal cell neoplasms, transitional cell papillomas and carcinomas, adenomas and adenocarcinomas, adnexal and skin appendage neoplasms, mucoepidermoid neoplasms, cystic neoplasms, mucinous and serous neoplasms, ducal-, lobular and medullary neoplasms, acinar cell neoplasms, complex epithelial neoplasms, specialized gonadal neoplasms, paragangliomas and glomus tumours, naevi and melanomas, soft tissue tumours and sarcomas, fibromatous neoplasms, myxomatous neoplasms, lipomatous neoplasms, myomatous neoplasms, complex mixed and stromal neoplasms, fibroepithelial neoplasms, synovial like neoplasms, mesothelial neoplasms, germ cell neoplasms, trophoblastic neoplasms, mesonephromas, blood vessel tumours, lymphatic vessel tumours, osseous and chondromatous neoplasms, giant cell tumours, miscellaneous bone tumours, odontogenic tumours, gliomas, neuroepitheliomatous and neuroendocrine neoplasms, meningiomas, nerve sheath tumours, granular cell tumours and alveolar soft part sarcomas, Hodgkin's and non-Hodgkin's lymphomas, B-cell lymphoma, T-cell lymphoma, hairy cell lymphoma, Burkitts lymphoma and other lymphoreticular neoplasms, plasma cell tumours, mast cell tumours, immunoproliferative diseases, leukemias, miscellaneous myeloproliferative disorders, lymphoproliferative disorders and myelodysplasia syndromes.
Examples of cancers in terms of the organs and parts of the body affected include, but are not limited to, the breast, cervix, ovaries, colon, rectum (including colon and rectum i.e. colorectal cancer), lung (including small cell lung cancer, non-small cell lung cancer, large cell lung cancer and mesothelioma), endocrine system, bone, adrenal gland, thymus, liver, stomach (gastric cancer), intestine, pancreas, bone marrow, hematological malignancies (such as lymphoma, leukemia, myeloma or lymphoid malignancies), bladder, urinary tract, kidneys, skin, thyroid, brain, head, neck, prostate and testis. Preferably the cancer is selected from the group consisting of breast cancer, prostate cancer, cervical cancer, ovarian cancer, gastric cancer, colorectal cancer, pancreatic cancer, liver cancer, brain cancer, neuroendocrine cancer, lung cancer, kidney cancer, hematological malignancies, melanoma and sarcomas.
The term "treatment" or "treating" as used herein in the context of treating a disease or disorder, pertains generally to treatment and therapy, whether of a human or an animal (e.g., in veterinary applications), in which some desired therapeutic effect is achieved, for example, the inhibition of the progress of the disease or disorder, and includes a reduction in the rate of progress, a halt in the rate of progress, alleviation of symptoms of the disease or disorder, amelioration of the disease or disorder, and cure of the disease or disorder. Treatment as a prophylactic measure (i.e., prophylaxis) is also included. For example, use with patients who have not yet developed the disease or disorder, but who are at risk of developing the disease or disorder, is encompassed by the term "treatment." For example, treatment includes the prophylaxis of cancer, reducing the incidence of cancer, alleviating the symptoms of cancer, etc..
The term "therapeutically-effective amount," as used herein, pertains to that amount of a compound, or a material, composition or dosage form comprising a compound, which is effective for producing some desired therapeutic effect, commensurate with a reasonable benefit/risk ratio, when administered in accordance with a desired treatment regimen.
The compounds of formula I can be synthesized by methods given below, by methods given in the experimental part below or by analogous methods. The schemes described herein are not intended to present an exhaustive list of methods for preparing the compounds of formula (I); rather, additional techniques of which the skilled chemist is aware may be also used for the compound synthesis.
It is understood by one skilled in the art of organic synthesis that optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by routine optimization procedures. In some cases, the order of performing the following reaction schemes, and/or reaction steps, may be varied to facilitate the reaction or to avoid the formation of unwanted side products. In addition, the functionality present at various positions of the molecule must be compatible with the reagents and reactions proposed. Such restrictions to the substituents, which are compatible with the reaction conditions, will be readily apparent to one skilled in the art and alternate methods must then be used. Furthermore in some of the reactions mentioned herein it may be necessary or desirable to protect any sensitive groups in compounds and it will be assumed that such protecting groups (PG) as necessary are in place. Conventional protecting groups may be used in accordance with standard practice, well known in the art (for illustration see Greene T.W., Wuts P.G.M., Protective Groups in Organic Synthesis, 5th Edition, Publisher: John Wiley & Sons, 2014). The protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the art, or they may be removed during a later reaction step or work-up.
In the general sequence of reactions outlined below, the abbreviations X, n, q, the dotted line and the generic groups B 1 -4, Rl , R2, R5 and ring A are as defined for formula (I), unless otherwise specified. Other abbreviations used herein are explicitly defined, or are as defined in the experimental section.
The necessary starting materials for the synthetic methods as described herein, if not commercially available, may be made by procedures which are described in the scientific literature, or may be made from commercially available compounds using adaptations of processes reported in the scientific literature. The reader is further referred to March J., Smith M., Advanced Organic Chemistry, 7th Edition Publisher: John Wiley & Sons, 2013 for general guidance on reaction conditions and reagents. The compounds according to the present invention, pharmaceutically acceptable salts, solvates, and hydrates thereof can be prepared according to the general sequence of reactions outlined below, followed, if necessary, by:
manipulation of substituents to give a new final product. These manipulations may include, but are not limited to, reduction, oxidation, alkylation, acylation, substitution, coupling, including transition-metal catalyzed coupling and hydrolysis reactions which are commonly known by those skilled in the art;
removing any protecting groups;
forming a pharmaceutically acceptable salt; or
forming a pharmaceutically acceptable solvate or hydrate. Generally, compounds of formula (I) can be obtained by the coupling reaction of a compound of formula (3) and a compound of formula (4), wherein E2 is a halogen or a leaving group such as imidazole, phenol, 4-nitrophenol, 2,2,2-trifluoro-ethanol or l-hydroxypyrrolidine-2,5-dione (Scheme 1).
When E2 is a leaving group such as imidazole, phenol, 4-nitrophenol, 2,2,2-trifluoro-ethanol or 1 - hydroxypyrrolidine-2,5-dione, more preferably a phenol or 4-nitrophenol, the coupling reaction between a compound of formula (3) and a compound of formula (4) is generally performed in a variety of organic solvents such as tetrahydofuran, dichloromethane, 1 ,2-dichloroethane, diethylether, ethyl acetate, dimethylsulfoxide, N,N-dimethylformamide, and acetonitrile, aqueous solvents and a mixture of theses solvents under biphasic conditions (more frequently in N,N-dimethylformamide) in a presence of an inorganic base such as sodium hydride, sodium carbonate or sodium hydrogen carbonate or in the presence of an organic base such as triethylamine, pyridine or alike (more frequently triethylamine). Reactions are typically run from -20 °C to 80 °C (generally at room temperature).
The compounds of formula (4), wherein E2 is a leaving group such as imidazole (which can be activated by methylation prior to the reaction), phenol, 4-nitrophenol, 2,2,2-trifluoro-ethanol or 1 - hydroxypyrrolidine-2,5-dione, are typically obtained by the coupling reaction of a compound of formula (2) and 1 , Γ-carbonyldiimidazole, phenyl chloro formate, 4-nitrophenyl chloro formate, 2,2,2-trifluoroethyl chloroformate or N,N'-Disuccinimidyl carbonate, respectively, in presence of a base, such as sodium hydride, triethylamine, pyridine (diluted or neat), 4-(dimethylamino)pyridine in aprotic solvents such as dichloromethane, chloroform, acetonitrile, tetrahydrofuran, ethyl acetate. Reactions are typically run from -10 °C to 80 °C.
The compounds of formula (4), for which E2 is a chlorine are generally prepared in situ by the reaction of a compound of formula (2) and phosgene or more frequently a phosgene analogue (such as
bis(trichloromethyl) carbonate or trichloromethyl chloroformate). The reaction is typically performed in aprotic and inert solvents such as dichloromethane, chloroform, acetonitrile, tetrahydrofuran, ethyl acetate (more frequently dichloromethane) in presence of a base such as triethylamine, 4-(dimethylamino)- pyridine or N,N-diisopropylethylamine. Reactions are typically run from -40 °C to 50 °C, generally 0 °C. The low stability of such intermediates does often not allow isolation and they are generally prepared in situ. A compound of Formula (3) is allowed to react subsequently with a compound of formula (4) to generate the corresponding compound of Formula (I).
Compounds of formula (2) can be obtained from commercial sources, or are prepared following p dures known by a person skilled in the art.
Figure imgf000042_0001
(2) (4)
Figure imgf000042_0002
Scheme 1
Similarly, as outlined in scheme 2, compounds of formula (I) can be prepared from a compound of formula (5), wherein E3 is a leaving group such as chlorine, imidazole, phenol, 4-nitrophenol, 2,2,2- trifluoro-ethanol or l-hydroxypyrrolidine-2,5-dione, more preferably a phenol or 4-nitrophenol and a compound of formula (2) by a coupling reaction, following similar procedures previously described. Compounds of formula (5) can be prepared from a compound of formula (3) by a coupling reaction following similar procedures as described above.
Figure imgf000043_0001
Figure imgf000043_0002
(I)
Scheme 2
Alternatively, compounds of formula (I) can be generated from a compound of formula (6) and a compound of formula (7), wherein E4 is a halogen or a leaving group such as a triflate, via a transition- metal catalyst reaction coupling (Scheme 3). Typical catalysts include palladium(II) acetate, tris- (dibenzylideneacetone)dipalladium(O) or alike. The reaction is typically run at a temperature from 0 °C to 150 °C, more frequently from 100 °C to 120 °C. Usually the reaction is performed in the presence of a ligand such as di-teri-butyl-[3,6-dimethoxy-2-(2,4,6-triisopropylphenyl)phenyl]phosphane, di-teri-butyl- [2,3,4,5-tetramethyl-6-(2,4,6-triisopropylphenyl)phenyl]phosphane, 2-(dicyclohexylphosphino)biphenyl or the like and a base such as sodium fert-butylate, cesium carbonate, potassium carbonate, more frequently cesium carbonate in a large variety of inert solvents such as toluene, tetrahydrofuran, dioxane, 1 ,2-dichloroethane, N,N-dimethylformamide, dimethylsulfoxide, water and acetonitrile, or a mixture of solvents, more frequently in dioxane.
Compounds of formula (6) can be obtained from compounds of formula (3) following procedures described in literature, or by procedures known by a person skilled in the art. For example, a compound of formula (6) can be prepared by the reaction of a compound of formula (3) with isocyanatotrimethylsilane in aprotic solvents such as acetonitrile, ethyl acetate, chloroform and more frequently in dichloromethane in a presence of an organic base such as triethylamine, 4-(dimethylamino)pyridine, N,N-diisopropylethyl- amine or alike. The reaction can be run at a temperature from 0 °C to 50 °C, generally at room
temperature.
Compounds of formula (7) can be obtained from commercial sources, or are prepared following procedures described in literature, or by procedures known by a person skilled in the art.
Figure imgf000044_0001
(3) (6) (7)
Figure imgf000044_0002
(I)
Scheme 3
Compounds of formula (3) are generally obtained from commercial sources, or prepared following procedures described in literature, or by procedures known by a person skilled in the art. For example, when X is -C(R5)= (double bond Z, E or Z/E), in which formulae R5 is a hydrogen or a Cl-C4alkyl substituent, compounds of formula (3) can be prepared from a compound of formula (11-a), wherein PG is an amino protecting group, by deprotection of the amino protecting group, as outlined in scheme 4. The amino protecting group can be removed under standard conditions. For example the benzyl carbamates are deprotected by hydrogenolysis over a noble metal catalyst (e.g. palladium or palladium hydroxide on activated carbon) or other suitable catalyst e.g. Raney-Ni. The Boc group is removed under acidic conditions such as hydrochloric acid in an organic solvent such as methanol, dioxane or ethyl acetate, or trifluoroacetic acid neat or diluted in a solvent such as dichloromethane. The Alloc group is removed in presence of a palladium salt such as palladium acetate or tetrakis(triphenylphosphine)palladium(0) and an allyl cation scavenger such as morpholine, pyrrolidine, dimedone or tributylstannane generally at temperatures from 0 °C to 70 °C in a solvent such as tetrahydrofuran. The N-benzyl protected amines are deprotected by hydrogenolysis over a noble metal catalyst (e.g. palladium hydroxide on activated carbon) or other suitable catalyst e.g. Raney-Ni. The Fmoc protecting group is removed under mild basic conditions such as diluted morpholine or piperidine in N,N-dimethylformamide or acetonitrile. The N- acetyl protected amines are deprotected by hydrolysis using either acidic or basic aqueous solution at temperatures from 0 °C to 100 °C. Further general methods to remove amine protecting groups have been described in Greene T.W., Wuts P.G.M., Protective Groups in Organic Synthesis, 5th Edition, Publisher: John Wiley & Sons, 2014. Compounds of formula (11-a) are generally obtained from commercial sources, or prepared following procedures described in literature, or by procedures known by a person skilled in the art. Generally, compounds of formula (11-a) can be prepared from a compound of formula (10) and a compound of formula (9), wherein E6 is a phosphonium salt (typically triphenylphosphonium salt) or a phosphonate (typically diethyl phosphonate) via a Wittig or Horner- Wadsworth-Emmons reaction, respectively. The Wittig reaction is the reaction of an aldehyde or ketone with a triphenyl phosphonium ylide to afford an alkene and triphenylphosphine oxide. The Wittig reagent is usually prepared from a phosphonium salt. To form the Wittig reagent, the phosphonium salt is suspended in a solvent such as diethyl ether or tetrahydroiuran and a strong base such as n-butyl lithium or lithium bis(trimethylsilyl)amide is added. With simple ylides, the product is usually mainly the Z-isomer, although a lesser amount of the E-isomer also is often formed. If the E-isomer is the desired product, the Schlosser modification may be used. Alternatively the Horner- Wadsworth-Emmons reaction produces predominantly E-alkenes. The Horner- Wadsworth-Emmons reaction is the condensation of stabilized phosphonate carbanions with aldehydes or ketones in presence of a base such as sodium hydride or lithium bis(trimethylsilyl)amide in a solvent such as tetrahydroiuran or N,N-dimethylformamide, generally at temperatures from 0 °C to 80 °C. In contrast to phosphonium ylides used in the Wittig reaction, phosphonate-stabilized carbanions are more nucleophilic and more basic. When E6 is a phosphonium salt group, a compound of formula (9) can be for example obtained by alkylation of triphenylphosphine and a compound of formula (8), wherein E5 is a halogen, following well-known procedures.
When E6 is a diethyl phosphonate group, a compound of formula (9) can be obtained by the reaction of triethylphosphite and a compound of formula (8), wherein E5 is a halogen, following well-known procedures.
Compounds of formula (8) can be obtained from commercial sources, or are prepared following procedures described in literature, or by procedures known by a person skilled in the art.
Compounds of formula (10) are generally obtained from commercial sources, or prepared following procedures described in literature, or by procedures known by a person skilled in the art. The amino protecting groups (PG) can be present in the starting material or introduced by reacting the corresponding free amine with allyl, fluorenylmethyl or benzyl chloroformate, or with di-tert-butyl dicarbonate in presence of a base such as sodium hydroxide, sodium hydrogen carbonate, triethylamine, 4- dimethylaminopyridine or imidazole. The free amine can also be protected as N-benzyl derivatives by reaction with benzyl bromide or chloride in presence of a base such as sodium carbonate or triethylamine. Alternatively, N-benzyl derivatives can be obtained through reductive amination in presence of benzaldehyde. The free amine can also be protected as N-acetyl derivatives by reaction with acetyl chloride or acetic anhydride in presence of a base such as sodium carbonate or trimethylamine. Further strategies to introduce other amino protecting groups have been described in Greene T.W, Wuts P.G.M, Protective Groups in Organic Synthesis, 5th Edition, Publisher: John Wiley & Sons, 2014.
Figure imgf000046_0001
(8) (9) (10)
Figure imgf000046_0002
(1 1 -a) (3)
Scheme 4 Alternatively, compounds of formula (11-a) can be prepared from a compound of formula (14) and a compound of formula (15), wherein E10 is a halogen or a leaving group such as triflate via cross-coupling reaction (i.e. Suzuki, Stille, Negishi, etc), as outlined in scheme 5. For example, when E9 is a boronic acid or a boronic ester, a compound of formula (14) can react with a compound of formula (15) to form a compound of formula (1 1-a) via Suzuki cross-coupling reaction. The Suzuki reaction is a palladium- catalyzed cross-coupling reaction between organoboronic acids or esters and aryl or vinyl halides or triflates. Typical catalysts include palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0), tris(dibenzylideneacetone)dipalladium(0), bis(triphenylphosphine)palladium(II) dichloride and
[l,rbis(diphenylphosphino)ferrocene]dichloropalladium(II). The reaction can be carried out in a variety of organic solvents including toluene, tetrahydrofuran, dioxane, 1 ,2-dichloroethane, N,N-dimethyl- formamide, dimethylsulfoxide and acetonitrile, aqueous solvents and under biphasic conditions.
Reactions are typically run under inert atmosphere from room temperature to 150 °C, more frequently from 90 °C to 120 °C. Additives such as cesium fluoride, potassium fluoride, potassium hydroxide, potassium carbonate, potassium acetate, potassium phosphate or sodium ethylate frequently accelerate the coupling. Potassium trifluorob orates and organoboranes or boronate esters may be used in place of boronic acids. As there are numerous components in the Suzuki reaction such as the particular palladium catalyst, the ligand, additives, solvent, temperature, numerous protocols have been identified. One skilled in the art will be able to identify a satisfactory protocol without undue experimentation.
Compounds of formula (15) can be obtained from commercial sources, or are prepared following procedures described in literature, or by procedures known by a person skilled in the art. Organoboronic acids or esters of formula (14) are generally obtained from diboron reagents (such as bis(pinacolato)diboron or bis-boronic acid) and a compound of Formula (13), wherein E8 is halogen, via Miyaura borylation (Ishiyama T. et al., J. Org. Chem., vol. 60, pages 7508-7510, 1995) in presence of a palladium catalyst such as tris(dibenzylideneacetone)dipalladium(0) or chloro(2-dicyclohexylphosphino- 2',4',6'-triisopropyl-l, -biphenyl)[2-(2'-amino-l, -biphenyl)]palladium(II) and a ligand such as triphenylphosphine or 2-(dicyclohexylphosphino)-2',4',6'-tri-isopropyl-l, -biphenyl. The reaction can be carried out in a variety of organic solvents including toluene, tetrahydrofuran, dioxane, 1,2-dichloro- ethane, N,N-dimethylformamide, dimethylsulfoxide and acetonitrile, aqueous solvents and under biphasic conditions. Reactions are typically run from room temperature to 150 °C (more frequently at 100 °C). Crucial for the success of the borylation reaction is the choice of an appropriate base, as strong activation of the product enables the competing Suzuki coupling. The use of potassium acetate (Ishiyama et al., J. Org. Chem, vol. 60, pages 7508-7510, 1995) and potassium phenolate (Takagi J. et al., J. Am. Chem. Soc, vol. 27, no. 27, pages 8001-8006, 2002) is actually the result of a screening of different reaction conditions by the Miyaura group. Other bases such as potassium hydroxide, cesium carbonate, potassium carbonate, potassium phosphate or sodium ethylate are frequently used as well. As for the Suzuki reaction, there are numerous components in the Miyaura borylation reaction such as the particular palladium catalyst, the ligand, additives, solvent, temperature and numerous protocols have been identified. One skilled in the art will be able to identify a satisfactory protocol without undue experimentation.
Vinyl halides of formula (13) used for the preparation of organoboronic acids or esters (14) can be prepared via a Wittig reaction between a compound of formula (10) and a compound of formula (12), wherein E7 is a triphenylphosphonium salt and E8 is a halogen, following procedures previously described.
Figure imgf000047_0001
(10) (12) (13)
Figure imgf000047_0002
Scheme 5 In addition, the compounds of formulae (11-a), (3) and (I), wherein X is -C(R5)= (double bond Z, E or Z/E), can further be reduced to generate compounds of formulae (11-b), (3) and (I), respectively, wherein X is -CH(R5)-, in which formulae R5 is a hydrogen or a Cl-C4alkyl substituent. The reduction reaction is usually performed by hydrogenation over a noble metal catalyst (e.g. palladium, palladium hydroxide on activated carbon (Trost B.M. et al., Chem Eur. J., vol. 5, no. 3, page 1055-1069, platinum dioxide) or other suitable catalysts. This hydrogenation step can be performed at any convenient stage during the synthesis.
Figure imgf000048_0001
(11 -b) (3)
When X is -C(O)-, compounds of formula (3) can be obtained from a compound of formula (11-c) as outlined in scheme 6, by removal of the amino protecting group (PG), following procedure previously described.
Compounds of formula (11-c) can be obtained from a compound of formula (15), wherein E10 is a halogen, via Weinreb Ketone Synthesis with a compound of formula (16). The reaction takes place in the presence of a strong base such as n-butyl lithium or /-butyl lithium under anhydrous conditions in an organic solvent such as tetrahydrofuran and at temperatures from -78 °C to 60 °C (around 0 °C is preferred).
Compounds of formulae (15) and (16) can be obtained from commercial sources, or are prepared following procedures described in literature, or by procedures known by a person skilled in the art. For example, compounds of formula (16) can be prepared from the corresponding carboxylic acid and N,0- dimethylhydroxylamine via amide coupling reaction using methods well known in the art.
Alternatively, compounds of formula (1 lc) can be obtained from a compound of formula (15), wherein El 0 is a halogen, via Grignard reaction with a corresponding acyl halogenide (e.g. a compound of formula (18)). The Grignard reaction is typically performed under anhydrous conditions in an organic solvent such as tetrahydrofuran. The reaction are usually run from -78 °C to 60 °C (0 °C preferably). The Grignard reagent is generally obtained from the reaction of an aryl halide of formula (15) and magnesium metal using classical methods widely described in literature (Rogers H.R. et al., J. Am Chem. Soc, vol. 102, no. 1, pages 217-226, 1980) or by magnesium-halide exchange reaction using isopropylmagnesium chloride.
Figure imgf000049_0001
Figure imgf000049_0002
Alternatively, compounds of formula (11-c) can be obtained from a compound of formula (17) and a compound of formula (18) by Friedel-Crafts acylation (Scheme 7). The amino protecting group (PG) is preferentially a N-acetyl group. Friedel-Crafts acylation is the acylation of aromatic rings with an acyl chloride using a strong Lewis acid catalyst such as ferric chloride or aluminium chloride (more frequently aluminium chloride). Friedel-Crafts acylation is also possible with acid anhydrides. Normally, a stoichiometric amount of the Lewis acid catalyst is required, because both the substrate and the product form complexes. The reaction is generally performed under anhydrous conditions in an inert solvent such as acetonitrile, tetrahydrofuran, dichloromethane, 1,2-dichloroethane or in neat mixture at a wide range of temperatures (e.g. from -20 °C to 100 °C).
Compounds of formulae (17) and (18) can be obtained from commercial sources, or are prepared following procedures described in literature, or by procedures known by a person skilled in the art.
Figure imgf000049_0003
(17) (18)
Scheme 7
When X is -0-, compounds of formula (3) can be obtained from a compound of formula (11-d) as outlined in scheme 8, by removal of the amino protecting group (PG), following procedure previously described.
Compounds of formula (11-d) can be obtained from commercial sources, or are prepared following procedures described in literature, or by procedures known by a person skilled in the art. For example, compounds of formula (11-d) can be from a compound of formula (19) and a compound of formula (20) via a Mitsunobu coupling (as reviewed in O. Mitsunobu, Synthesis, Vol. 1, pages 1-28, 1981). The reaction is performed in the presence of diethyl or diisopropyl azodicarboxylate and triphenylphosphine, in a wide range of solvents such as N,N-dimethylformamide, tetrahydrofuran, 1 ,2-dimethoxyethane or dichloromethane and within a wide range of temperatures (e.g. between -20 °C and 60 °C). The reaction might also be performed using polymer-supported triphenylphosphine.
An alternative route to form compounds of formula 11-d consists of reacting a compound of formula (19) with a compound of formula (20) for which the hydroxyl group needs to be activated prior to the reaction by substitution reaction. The substitution reaction can be performed in presence of an inorganic base such as sodium hydride, potassium carbonate, cesium carbonate or the like or an organic base such as triethylamine or the like in a wide variety of solvents such as acetonitrile, tetrahydrofuran or N,N- dimethylformamide e.g. at a temperature from -20 °C to 120 °C. Hydroxyl group of a compound of formula (20) can be activated to a mesylate, a tosylate or a triflate groups by reacting the corresponding alcohol with methanesulfonyl chloride or methanesulfonic anhydride, / toluenesulfonyl chloride, trifluoromethanesulfonyl chloride or trifluoromethanesulfonic anhydride, respectively, in presence of a base such as triethylamine or the like in a dry aprotic solvent such as pyridine, acetonitrile,
tetrahydrofuran or dichloromethane e.g. at a temperature from -30 °C to 80 °C.
Compounds of formulae (19) and (20) can be obtained from commercial sources, or are prepared following procedures described in literature, or by procedures known by a person skilled in the art.
Figure imgf000050_0001
(19) (20) (1 1 -d)
Figure imgf000050_0002
(3)
Scheme 8
Whenever required, the substituents Rl, R2, R3, R4a, R4b, R4c and / or Rl 1 can be present as precursors in the starting material, and/or can be transformed by additional routine transformations during the synthetic pathways described herein. These transformations might be carried out at any convenient stage during the synthesis and may include, but are not limited to the following lists of reactions, which are commonly known by those skilled in the art:
- Selective reduction of the aryl-nitro group (Bechamp reduction) using iron powder in the presence of aqueous acidic solution. The nitro group can also be reduced via catalytic hydrogenolysis over a noble metal catalyst (such as palladium on activated carbon) or other suitable hydrogenation catalyst. For example, when R2 is a nitro group, reduction of the nitro group to R2 is an amino group can be selectively achieved by Bechamp reduction without affecting the double bond, when X is -C(R5)=.
- Dealkylation of aromatic ether using boron tribromide or alike in an organic solvent such as dichloromethane (Ilhyong R. et al., J. Am. Chem. Soc, vol. 124, no. 44, pages 12946-12947, 2002). The reaction can also be performed using trimethylsilyl bromide or iodide in an organic solvent such as acetonitrile and at a temperature e.g. from 0 °C to 90 °C. Optionally, sodium iodide can be used to support the reaction. For example, a compound of formula (I), wherein R2 is a methoxy group can be converted to a compound of formula (I), wherein R2 is a hydroxyl group.
- Amide coupling reaction between a carboxylic acid and an amine. The reaction takes place in the presence of an activating agent such as N,N-dicyclohexylcarbodiimide or N-(3-dimethylaminopropyl)- N'-ethylcarbodiimide hydrochloride, with the optional addition of 1-hydroxybenzotriazole. Other suitable coupling agents may be utilized such as, 0-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, 2-ethoxy- 1 -ethoxycarbonyl- 1 ,2-dihydroquinoline, carbonyldiimidazole or diethylphosphorylcyanide. Optionally, a base like triethylamine, N,N-diisopropylethylamine or pyridine can be added to perform the coupling. The amide coupling is conducted at a temperature e.g. from -20 °C to 80 °C, in an inert solvent, preferably a dry aprotic solvent like dichloromethane, acetonitrile or N,N- dimethylformamide and chloroform. Alternatively, the carboxylic acid can be activated by conversion into its corresponding acid chloride or its corresponding activated ester, such as the N- hydroxysuccinimidyl ester (Singh J., et al., Org. Process Res. & Dev., vol. 6, no. 6, pages 863-868, 2002) or the benzothiazolyl thioester (Ishikawa T. et al., J. Antibiotics, vol. 53, no. 10, pages 1071-1085, 2000). The generated activated entity can react e.g. at a temperature from -20 °C to 80 °C with the amine reagent in an aprotic solvent like dichloromethane, chloroform, acetonitrile, N,N-dimethylformamide and tetrahydrofuran. Optionally, a base like triethylamine, N,N-diisopropylethylamine, pyridine, sodium hydroxide, sodium carbonate, potassium carbonate can be added to perform the coupling.
- Reductive amination reaction between an amine and an aldehyde or a ketone. The reductive amination reaction between the amine and the aldehyde or the ketone to form an intermediate imine is conducted in a solvent system allowing the removal of the formed water through physical or chemical means (e.g. distillation of the solvent-water azeotrope or presence of drying agents such as molecular sieves, magnesium sulfate or sodium sulfate). Such solvent is typically toluene, n-hexane, tetrahydrofuran, dichloromethane N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, 1 ,2-dichloroethane or mixture of solvents such as methanol or 1,2-dichloroethane. The reaction can be catalyzed by traces of acid (usually acetic acid). The intermediate imine is reduced subsequently or simultaneously with a suitable reducing agent (e.g. sodium borohydride, sodium cyanoborohydride, sodium
triacetoxyborohydride; Hutchins M.K., Comprehensive Organic Synthesis, Publisher: Fleming, Eds; Pergamon Press, vol. 8, pages. 25-78, 1991) or through hydrogenation over a suitable catalyst such as palladium on activated carbon. The reaction is usually carried out from -10 °C to 110 °C, preferably from 0 °C to 60 °C. The reaction can also be carried out in one pot. It can also be performed in protic solvents such as methanol or water in presence of a picoline-borane complex (Sato S. et al., Tetrahedron, vol. 60, pages 7899-7906, 2004). For example, the reductive amination reduction between a compound of formula (I), wherein R2 is -CHO and a compound of formula HN(R6a)(R6b) leads to a compound of formula (I), wherein R2 is -CH2-N(R6a)(R6b) and R6a and R6b are as defined by the claims.
- Substitution reaction. The substitution reaction can be performed in presence of an inorganic base such as sodium hydride, potassium carbonate, cesium carbonate or the like or an organic base such as triethylamine or the like in a wide variety of solvents such as acetonitrile, tetrahydrofuran or N,N- dimethylformamide at a temperature e.g. from -20 °C to 120 °C. For example, the substitution reaction between a compound of formula (I), wherein R2 is -Cl-C6alkylene-OH (which needs to be activated prior to the reaction), and a compound of formula HN(R6a)(R6b) leads to a compound of formula (I), wherein R2 is -Cl-C6alkylene-N(R6a)(R6b) and R6a and R6b are as defined by the claims.
- Activation of the hydroxyl group prior to substitution reaction. Hydroxyl group can be transformed to a mesylate, a tosylate or a triflate by reacting the corresponding alcohol with methanesulfonyl chloride or methanesulfonic anhydride, p-toluenesulfonyl chloride, trifluoromethanesulfonyl chloride or
trifluoromethanesulfonic anhydride, respectively, in presence of a base such as triethylamine or the like in a dry aprotic solvent such as pyridine, acetonitrile, tetrahydrofuran or dichloromethane e.g. at a temperature from -30 °C to 80 °C.
- Reduction of alkyl ester (typically methyl or ethyl esters) into their corresponding alcohols. This reduction is performed with a reducing agent like boron or aluminium hydride, lithium aluminium hydride, lithium borohydride, sodium borohydride in a solvent such as tetrahydrofuran, methanol or ethanol e.g. at a temperature from -20 °C to 80 °C. Alternatively, the ester function is hydrolyzed into its corresponding carboxylic acid using an alkali hydroxide such as sodium hydroxide, potassium hydroxide or lithium hydroxide in water or in a mixture of water with polar protic or aprotic organic solvents such as dioxane, tetrahydrofuran or methanol e.g. at a temperature from -10 °C to 80 °C or the ester function is hydrolyzed using aqueous acidic solution. The resulting carboxylic acid is further reduced into the corresponding alcohol using a borane derivative such as borane -tetrahydrofuran complex in a solvent such as tetrahydrofuran e.g. at a temperature from -10 °C to 80 °C.
- Oxidation of hydroxyl group to ketone or aldehyde. The alcohol is transformed into its corresponding aldehyde or ketone through oxidation under Swern, Dess-Martin, Sarett or Corey-Kim conditions respectively, or via NaOCl oxidation. Further methods are described in Larock R.C., Comprehensive Organic Transformations. A guide to functional Group Preparation, 2nd Edition, Publisher: Wiley-VC; New York, Chichester, Weinheim, Brisbane, Singapore, Toronto, 1999. Section aldehydes and ketones, p.1235-1236 and 1238-1246. For example, a compound of formula (I), wherein R2 is -CH2OH can be converted to a compound of formula (I), wherein R2 is -CHO by oxidation using Dess-Martin reagent. The reaction is typically run in an aprotic solvent such as dichloromethane e.g. at a temperature from 0 °C to 50 °C, more frequently at room temperature.
- Buchwald-Hartwig animation. The Buchwald-Hartwig amination reaction (Surry D.S. and Buchwald S.L., Chem. Sci., vol. 2, pages 27-50, 2011) is a palladium-catalyzed cross-coupling reaction of amines and aryl halides or triflates. Typical catalysts include palladium(II) acetate, or
tris(dibenzylideneacetone)dipalladium chloroform complex. The reaction is typically run at a temperature from 0 °C to 150 °C. Usually the reaction is performed in the presence of a ligand such as di-tert-butyl- [3,6-dimethoxy-2-(2,4,6-triisopropylphenyl)phenyl]-'phosphane, 2-(dicyclohexylphosphino)biphenyl or the like and a base such as sodium tert-butylate, cesium carbonate, potassium carbonate in a large variety of inert solvents such as toluene, tetrahydrofuran, dioxane, 1 ,2-dichloroethane, N,N-dimethylformamide, dimethylsulfoxide and acetonitrile, aqueous solvents and under biphasic conditions. Several versions of the reaction, employing complexes of copper and nickel rather than palladium, have also been developed (Hartwig J.F., Angew. Chem. Int. Ed., vol. 37, no. 15, pages 2046-2067, 1998). The reaction can be performed using microwave irradiation. For example, the reaction between a compound of formula (I), wherein R2 is a halogen (more frequently a chlorine) and a compound of formula HN(R6a)(R6b) via Buchwald-Hartwig amination leads to a compound of formula (I), wherein R2 is -N(R6a)(R6b) and R6a and R6b are as defined by the claims.
- Nitration of aromatic compounds. The nitration of aromatic compounds is the chemical process for the introduction of a nitro group into an organic compound. In the case of the nitration of aromatic compounds, this process is one example of the electrophilic aromatic substitution. The reaction is typically run in a mixture of acids, usually nitric acid and another strong acid, such as sulfuric acid or trifluoroacetic acid. The reaction can be performed in a wide range of temperature (e.g. from 0 °C to 100 °C).
Whenever an optically active form of a compound of the invention is required, it may be obtained by carrying out one of the above procedures using a pure enantiomer or diastereomer as a starting material, or by resolution of a mixture of the enantiomers or diastereomers of the final product or intermediate using a standard procedure. The resolution of enantiomers may be achieved by chromatography on a chiral stationary phase, such as for example REGIS PIRKLE COVALENT (R-R) WHELK-02, 10 μιη, 100 A, 250 x 21.1 mm column. Alternatively, resolution of stereoisomers may be obtained by preparation and selective crystallization of a diastereomeric salt of a chiral intermediate or chiral product with a chiral acid, such as camphorsulfonic acid or with a chiral base such as phenylethylamine. Alternatively a method of stereoselective synthesis may be employed, for example by using a chiral variant of a protecting group, a chiral catalyst or a chiral reagent where appropriate in the reaction sequence. Enzymatic techniques may also be used for the preparation of optically active compounds and/or intermediates.
The schemes and processes described herein are not intended to present an exhaustive list of methods for preparing the compounds of formula I; rather, additional techniques of which the skilled chemist is aware of may be also used for the compound synthesis.
All aspects and embodiments of the invention described herein may be combined in any combination where possible.
A number of publications are cited herein in order to more fully describe and disclose the invention and the state of the art to which the invention pertains. Each of these references is incorporated herein by reference in its entirety into the present disclosure, to the same extent as if each individual reference was specifically and individually indicated to be incorporated by reference.
Particular embodiments of the invention are described in the following Examples, which serve to illustrate the invention in more detail and should not be construed as limiting the invention in any way.
Figures
Figure 1 shows the results of the cell growth assays (crystal violet) in HeLa galactose and HeLa glucose cells treated with mitochondrial inhibitors Antimycin A (Figure la) and Example 5 (Figure lb) or the cytotoxic drug Paclitaxel (Figure lc).
Examples
Preparation Examples
All reagents and solvents are generally used as received from the commercial supplier;
reactions are routinely performed with anhydrous solvents in well-dried glassware under nitrogen atmosphere;
evaporations are carried out by rotary evaporation under reduced pressure and work-up procedures are carried out after removal of residual solids by filtration;
all temperatures are given in degree Celcius (°C) and are approximate temperatures; unless otherwise noted, operations are carried out at room temperature (rt), that is typically in the range 18 - 25 °C;
column chromatography (by the flash procedure) is used to purify compounds and is performed using Merck silica gel 60 (70-230 mesh ASTM) unless otherwise stated;
classical flash chromatography is often replaced by automated systems. This does not change the separation process per se. A person skilled in the art will be able to replace a classical flash
chromatography process by an automated one, and vice versa. Typical automated systems can be used, as they are provided by Buchi or Isco (combiflash) for instance; reaction mixture can often be separated by preparative HPLC. A person skilled in the art will find suitable conditions for each separation; in some cases the compounds are isolated after purification in a form of the corresponding trifluoroacetic salt (*1), or the respective formic acid salt (*2); such compounds are marked accordingly;
reactions, which required higher temperature, are usually performed using classical heating instruments; but can also be performed using microwave apparatus (CEM Explorer) at a power of 250 W, unless otherwise noted;
hydrogenation or hydrogenolysis reactions can be performed using hydrogen gas in balloon or using Parr-apparatus system or other suitable hydrogenation equipment;
concentration of solutions and drying of solids was performed under reduced pressure unless otherwise stated;
in general, the course of reactions is followed by TLC, HPLC, or LC/MS and reaction times are given for illustration only; yields are given for illustration only and are not necessarily the maximum attainable; the structure of the final products of the invention is generally confirmed by NMR and mass spectral techniques.
Proton NMR spectra are recorded on a Bruker 400 MHz spectrometer. Chemical shifts (δ) are reported in ppm relative to Me4Si as internal standard, and NMR coupling constants (J values) are in Hertz (Hz). Each peak is denoted as a broad singlet (br), singlet (s), doublet (d), triplet (t), quadruplet (q), doublet of doublets (dd), triplet of doublets (td) or multiplet (m). Mass spectra are generated using a Q-Tof Ultima (Waters AG or Thermo Scientific MSQ Plus) mass spectrometer in the positive ESI mode. The system is equipped with the standard Lockspray interface;
each intermediate is purified to the standard required for the subsequent stage and is characterized in sufficient detail to confirm that the assigned structure is correct;
analytical and preparative HPLC on non-chiral phases are performed using RP-C18 based columns; the following abbreviations may be used (reference can also be made to The Journal of Organic
Chemistry Guidelines for Authors, 2017 for a comprehensive list of standard abbreviations):
ACN Acetonitrile
Boc tert-butoxy carbonyl group
BTC Bis(trichloromethyl)carbonate
Cat. no. Catalog number
CDC13 Deuterated chloroform
DCM Dichloromethane
DMAP 4-Dimethylaminopyridine
DMF Dimethylformamide
DMSO-d6 Deuterated dimethyl sulfoxide EA Ethyl acetate
ELSD Evaporative light scattering detection
Ex. Example
HATU 0-(7-azabenzotriazol- 1 -yl)-N,N,N' ,Ν' -tetramethyluronium hexafluorophosphate c-Hex Cyclohexane
n-Hex n-Hexane
LAH Lithium aluminum hydride
LC/MS Liquid chromatography coupled to mass spectroscopy
LHMDS Lithium bis(trimethylsilyl)amide
Me4Si Tetramethylsilane
MCI Mitsubishi gel with high porous polymer for reverse phase column
chromatography
MeOH Methanol
nt Not Tested
PE Petroleum Ether
Pd2dba3 Tris(dib enzylideneacetone)dipalladium(O)
i-BuOH tert-butanol
TEA Triethylamine
TFAA Trifluoroacetic anhydride
THF Tetrahydrofuran
W Watt
X-Phos 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl
The following Examples refer to the compounds of formula (I) as indicated in Table 1.
The Examples listed in the following table can be prepared using procedures described above, and detailed synthesis methodology is described in detail below. The Example numbers used in the leftmost column are used in the application text for identifying the respective compounds.
Table 1: Exemplified compounds
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Preparation of Example 2: 4-[(4-chloro-2,6-difluorophenyl)methylene]-Ar-(6,7-dihydro-5H- cyclopenta[b]pyridin-4-yl)piperidine-l-carboxamide:
Step 1-a: Preparation of ferf -butyl 4-(bromomethylene)piperidine-l-carboxylate:
To a stirred suspension of (bromomethyl)triphenylphosphonium bromide (2000 mg; 4.47 mmol) in THF (45 mL) cooled to -15 °C was added dropwise LHMDS solution, 1M in THF (5.82 mL; 5.82 mmol) over 5 min. The reaction mixture was stirred for 15 min at -15 °C and then treated with a solution of teri-butyl 4-oxopiperidine-l-carboxylate (1000 mg; 4.92 mmol) in THF (5 mL). The mixture was allowed to warm up gradually to rt and further stirred for 2 h. The reaction mixture was deactivated with a saturated aqueous solution of NH4C1 and then partitioned between EA and brine. The organic layer was separated, washed with brine, dried over MgSO i, filtered and concentrated to dryness. The residue was purified by column chromatography (silica gel; c-Hex : EA; 1 :0 to 4:1 ; v/v) to afford teri-butyl 4-(bromomethylene)- piperidine-l-carboxylate (960 mg) as a colorless oil.
'H-NMR (400 MHz, CDC13) δ ppm: 6.02 (s, 1H), 3.48 - 3.42 (m, 4H), 2.42 (m, 2H), 2.27 (m, 2H), 1.49 (s, 9H).
Step 1-b: Preparation of ferf-butyl 4-r(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)methylene1piperidine- 1-carboxylate:
A sealable tube was charged with teri-butyl 4-(bromomethylene)piperidine-l-carboxylate (700 mg; 2.51 mmol), potassium acetate (620 mg; 6.27 mmol), bis(pinacolato)diboron (1040 mg; 4.01 mmol) and dioxane (20 mL) at rt. Argon was bubbled in the reaction mixture for 10 min and triphenylphosphine (70 mg; 0.25 mmol) and Pd2dba3 (160 mg; 0.15 mmol) were added. The tube was flushed with argon and sealed. The reaction mixture was then heated to 100 °C and stirred for 4 h. After cooling to rt, the reaction mixture was filtered and the cake was washed with EA. The filtrate was finally concentrated to dryness. The residue was then purified by column chromatography (silica gel; c-Hex : EA; 1 :0 to 4:1 ; v/v) to afford teri-butyl 4-[(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)methylene]piperidine-l -carboxylate (720 mg) as a light yellow solid.
'H-NMR (400 MHz, CDCI3) δ ppm: 5.17 (s, 1H), 3.48 - 3.42 (m, 4H), 2.62 (m, 2H), 2.28 (m, 2H), 1.49 (s, 9H), 1.28 (s, 12H).
Step 1-c: Preparation of fer/-butyl 4-r(4-chloro-2,6-difluorophenyl)methylene1piperidine-l-carboxylate: Under argon atmosphere, a mixture of X-Phos (745 mg; 1.53 mmol), 2-bromo-5-chloro-l,3-difluoro- benzene (3518 mg; 15.31 mmol), teri-butyl 4-[(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)methylene]- piperidine-l-carboxylate (5500 mg;, 15.31 mmol), Pd2dba3 (708 mg; 0.76 mmol) and K3PO4 (4975 mg; 22.97 mmol) in a mixture of H20 (5 mL) and dioxane (100 mL) was heated to 100 °C and stirred for 2 h. After cooling down to rt, H20 and EA were added. The organic layer was separated, washed with brine, dried over MgSO i, filtered and concentrated to dryness. The residue was purified by column chromatography (silica gel; PE : EA; 40: 1 ; v/v) to afford feri-butyl 4-[(4-chloro-2,6-difluorophenyl)- methylene]piperidine-l-carboxylate (4000 mg) as a light yellow solid.
MS m/z (+ESI): 288.0, 290.0 [M-i-Bu+H]+.
'H-NMR (400 MHz, CDC13) δ ppm: 6.96 - 6.91 (m, 2H), 5.93 (s, 1H), 3.53 (t, J= 5.6 Hz, 2H), 3.43 (t, J = 5.6 Hz, 2H), 2.38 (t, J= 5.6 Hz, 2H), 2.13 (t, J= 5.6 Hz, 2H), 1.48 (s, 9H).
Step 1-d: Preparation of 4-[(4-chloro-2,6-difluorophenyl methylenelpiperidine, hydrochloride:
To a stirred solution of teri-butyl 4-[(4-chloro-2,6-difluorophenyl)methylene]piperidine-l-carboxylate (11560 mg; 33.29 mmol) in EA (20 mL) was added dropwise HC1 solution, 2N in EA (80 mL). The reaction mixture was stirred for 3 h and then concentrated to dryness to afford 4-[(4-chloro-2,6-difluoro- phenyl)methylene]piperidine, hydrochloride (8300 mg) as a white solid.
MS m/z (+ESI): 244.3, 246.2 [M+H]+.
'H-NMR (400 MHz, DMSO-i¾ δ ppm: 9.07 (br, 2H), 7.44 - 7.38 (m, 2H), 6.11 (s, 1H), 3.15 (t, J= 5.6 Hz, 2H), 3.03 (t, J= 5.6 Hz, 2H), 2.61 (t, J= 5.6 Hz, 2H), 2.29 (t, J= 5.6 Hz, 2H),
Step 2-a: Preparation of 6,7-dihvdro-5H-cvclopentarb1pyridine-l -oxide:
3-Chloroperbenzoic acid, technical grade ~ 70 % (6740 mg; 27.34 mmol) was dissolved in EA (40 mL) and the solution was treated dropwise with a solution of 2,3-cyclopentenopyridine (2036 mg; 17.09 mmol) in EA (10 mL) over 10 min. The reaction solution was stirred for 4 h. The reaction solution was successively washed with a solution of NaHSC>3 (700 mg) in H20 (10 mL) twice and with H20 (10 mL). The aqueous layers were combined and then neutralized with Na2C03 until pH about 8. The product was finally extracted with DCM (5 x 20 mL). The combined organic layers were dried over MgSO i, filtered and concentrated to dryness to afford 6,7-dihydro-5H-cyclopenta[b]pyridine-l-oxide (1610 mg) as an off- white solid.
MS m/z (+ESI): 136.2 [M+H]+.
Step 2-b: Preparation of 4-nitro-6J-dihvdro-5H-cvclopentarb1pyridine-l-oxide:
Nitric acid, fuming (3.99 mL; 86.09 mmol) was added dropwise to a solution of sulfuric acid, 96 % (4.01 mL; 71.94 mmol). The reaction solution was then heated to 50 °C and 6,7-dihydro-5H- cyclopenta[b]pyridine-l -oxide (1610 mg; 11.79 mmol) was added as solid. The reaction mixture was heated to 70 - 80 °C for 15 min. The reaction solution was then poured out into a mixture of ice - H20 (100 mL). The product was extracted with DCM (100 mL). The organic layer was washed with water (3 x 50 mL), dried over MgSO i, filtered and concentrated to dryness. The residue was purified by column chromatography (silica gel; DCM : 20% MeOH in DCM; 1 :0 to 4: 1; v/v) to afford 4-nitro-6,7- dihydro-5H-cyclopenta[b]pyridine-l -oxide (940 mg) as a light brown solid.
MS m/z (+ESI): 181.4 [M+H]+. 'H-NMR (400 MHz, DMSO-i¼) δ ppm: 8.26 (d, J = 7.2 Hz, 1H), 8.02 (d, J= 7.2 Hz, 1H), 3.50 - 3.37 (m, 2H), 3.08 - 2.97 (m, 2H), 2.23 - 2.08 (m, 2H).
Step 2-c: Preparation of 6,7-dihydro-5H-cvclopentarb1pyridin-4-amine:
To a stirred solution of 4-nitro-6,7-dihydro-5H-cyclopenta[b]pyridine-l -oxide (640 mg; 3.37 mmol) in MeOH (20 mL) was added 10% palladium on activated carbon (359 mg; 0.34 mmol). The reaction solution was stirred under hydrogen atmosphere (2 bars) for 24 h. Insolubles were removed by filtration and the cake was washed with MeOH. The combined filtrate was concentrated to dryness to afford 6,7- dihydro-5H-cyclopenta[b]pyridin-4-amine (380 mg) as a light brown solid.
MS m/z (+ESI): 135.2 [M+H]+.
'H-NMR (400 MHz, DMSO-i¾ δ ppm: 7.77 (d, J = 5.5 Hz, 1H), 6.27 (d, J= 5.5 Hz, 1H), 5.71 (s, 2H), 2.73 (t, J= 7.7 Hz, 2H), 2.64 (t, J = 7.4 Hz, 2H), 1.99 - 1.92 (m, 2H).
Step 3-a: Preparation of phenyl N-(6,7-dihvdro-5H-cvclopentarb1pyridin-4-yl)carbamate:
To a solution of 6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine (1000 mg; 7.08 mmol) in DCM (60 mL) was added TEA (2.98 mL; 21.24 mmol) and phenyl chloroformate (1.35 mL; 10.62 mmol). The reaction mixture was stirred for 2 h and was then concentrated to dryness to afford crude phenyl N-(6,7- dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamate (2400 mg; 70% purity) as a yellow solid, which was used in the next step without purification.
MS m/z (+ESI): 255.1 [M+H]+.
Step 3-b: Preparation of 4-[(4-chloro-2,6-difluorophenyl)methylenel-N-(6,7-dihydro-5H- cvclopentarb1pyridin-4-yl)piperidine- 1 -carboxamide:
To a stirred solution of 4-[(4-chloro-2,6-difluorophenyl)methylene]piperidine, hydrochloride (70 mg; 0.25 mmol) in DMF (5 mL) were successively added TEA (0.07 mL; 0.52 mmol) and crude phenyl N- (6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)carbamate (103 mg; 0.28 mmol; 70%> purity). The reaction mixture was stirred for 18 h and then concentrated to dryness. The residue was purified by preparative HPLC to afford 4-[(4-chloro-2,6-difluorophenyl)methylene]-N-(6,7-dihydro-5H-cyclopenta[b]pyridin-4- yl)piperidine-l -carboxamide (70 mg) as a white powder.
Preparation of Example 3: 4-[(4-cyano-2,6-difluoro-phenyl)methylene]-Ar-(5,6,7,8- tetrahydroquinolin-4-yl)piperidine-l-carboxamide:
Step 1 : Preparation of 3,5-difluoro-4-(4-piperidylidenemethyl)benzonitrile, hydrochloride:
The title compound was prepared as a white solid following schemes 5 and 4 and in analogy to procedures described in Example 2 (step 1 -c and 1 -d) using tert-butyl 4-[(4,4,5,5-tetramethyl-l ,3,2- dioxaborolan-2-yl)methylene]piperidine-l-carboxylate and 4-bromo-3,5-difluorobenzonitrile as starting materials.
MS m/z (+ESI): 235.2 [M+H]+.
'H-NMR (400 MHz, DMSO-ί/ί) δ ppm: 8.70 (br, 2H), 7.87 - 7.82 (m, 2H), 6.20 (s, 1H), 3.20 (m, 2H), 3.07 (m, 2H), 2.61 (t, J= 5.6 Hz, 2H), 2.28 (t, J= 5.6 Hz, 2H).
Step 2: Preparation of 4-[(4-cyano-2,6-difluorophenyl methylenel-N-(5,6,7,8-tetrahydroquinolin-4- yPpiperidine- 1 -carboxamide:
The title compound was prepared as a white solid following scheme 1 and in analogy to Example 2 (steps 3-a and 3-b) using 5-methyl-7,8-dihydro-6H-l,5-naphthyridin-4-amine and 3,5-difluoro-4-(4- piperidylidenemethyl)benzonitrile hydrochloride as starting materials and after purification by preparative HPLC.
Preparation of Example 5: 4-[(4-chloro-2,6-difluoro-phenyl)methylene]-Ar-(2,3-dihydro- [l,4]dioxino[2,3-b]pyridin-8-yl)piperidine-l-carboxamide:
Step 1-a: Preparation of 2,3-dihvdro-ri,41dioxinor2,3-b1pyridin-5-oxide:
To a stirred solution of 2,3-dihydro-[l,4]dioxino[2,3-b]pyridine (500 mg; 3.46 mmol) in EA (30 mL) was added 3-chloroperbenzoic acid, technical grade ~ 70 % (1240 mg; 5.54 mmol). The reaction solution was stirred for 24 h. The solution was washed with distilled water (2 x 20 mL) and the combined aqueous layers were concentrated to dryness to afford 2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-5-oxide (530 mg) as a white solid.
MS m/z (+ESI): 154.0 [M+H]+. Step 1-b: Preparation of 8-nitro-2,3-dihvdro-ri,41dioxinor2,3-b1pyridine:
In a sealable tube, 2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-5-oxide (530 mg; 3.43 mmol) was dissolved in TFA (2.5 mL) and nitric acid, fuming (2.5 mL) was added. The tube was sealed and the reaction solution was heated to 90 °C and stirred for 18 h. The tube was then placed in an ice-bath and a mixture of ice - water (20 mL) was cautiously added thereto. The product was extracted with DCM (3 x 20 mL) and the combined organic layers were concentrated. The residue was treated with NaHCC>3 solution, 8% in H20 (20 mL) and the resulting mixture was stirred for 0.5 h. The product was extracted back with DCM (3 x 20 mL) and the combined organic layers were dried over MgSO i, filtered and concentrated. The residue was purified by column chromatography (silica gel; DCM : 20% MeOH in DCM; 1 :0 to 9: 1 ; v/v) to afford 8-nitro-2,3-dihydro-[l,4]dioxino[2,3-b]pyridine (373 mg) as a yellow solid.
MS m/z (+ESI): 183.3 [M+H]+.
'H-NMR (400 MHz, DMSO-i¼) δ ppm: 7.93 (d, J= 5.4 Hz, 1H), 7.51 (d, J= 5.4 Hz, 1H), 4.62 - 4.52 (m, 2H), 4.50 - 4.42 (m, 2H). Step 1-c: Preparation of 2,3-dihvdro-ri,41dioxinor2,3-b1pyridin-8-amine:
To a stirred solution of 8-nitro-2,3-dihydro-[l,4]dioxino[2,3-b]pyridine (370 mg; 1.93 mmol) in MeOH (15 mL) was added 10% palladium on activated carbon (41 mg; 0.04 mmol). The reaction solution was stirred under hydrogen atmosphere (1.5 bars) for 1 h. Insolubles were removed by filtration and the cake was washed with MeOH. The combined filtrate was concentrated to dryness to afford 2,3-dihydro- [l,4]dioxino[2,3-b]pyridin-8-amine (305 mg) as an off-white solid.
MS m/z (+ESI): 153.1 [M+H]+.
'H-NMR (400 MHz, DMSO-i¾ δ ppm: 7.29 (d, J= 5.4 Hz, 1H), 6.26 (d, J= 5.4 Hz, 1H), 5.65 (s, 2H), 4.34 - 4.25 (m, 2H), 4.24 - 4.13 (m, 2H).
Step 2: Preparation of 4-r(4-cvano-2,6-difluorophenyl)methylene1-N-(5,6,7,8-tetrahvdroquinolin-4- vDpiperidine- 1 -carboxamide:
The title compound was prepared as a white solid following scheme 1 and in analogy to Example 2 (steps 3-a and 3-b) using 2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-8-amine and 4-[(4-chloro-2,6-difluoro- phenyl)methylene]piperidine, hydrochloride as starting materials and after purification by preparative HPLC.
Preparation of Example 6: 4-[(4-chloro-2,6-difluorophenyl)methylene]-Ar-(2,3-dihydrofuro[2,3- b] pyridin-4-yl)piperidine- 1 -carboxamide :
Step 1-a: Preparation of 2-(2-fluoro-4-iodo-3-pyridyl)ethanol:
A solution of LDA, 2M in n-heptane / THF / ethylbenzene (5.3 mL; 10.6 mmol) was added to a solution of 2-fluoro-4-iodopyridine (2000 mg; 8.79 mmol) in THF (40 mL) at -78 °C. The reaction mixture was stirred at -78 °C for 1.5 h. With the temperature maintained at -78 °C, a solution of 1,3,2-dioxathiolane 2,2-dioxide (1450 mg; 11.4 mmol) in THF (20 mL) was added slowly over a period of 20 min. The solution was further stirred at -78 °C for 20 min, then allowed to warm to rt and stirred for additional 2 h. The mixture was then cooled to 0 °C, and 12 M aqueous HC1 (3.3 mL) was added. The reaction mixture was allowed to warm to rt and stirred for 3 h. Saturated aqueous solution of NaHCC>3 (200 mL) was added and the product was extracted with EA (3 x 150 mL). The combined extracts were washed with brine (250 mL), dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel; n-Hex : EA; 1 :0 to 0: 1 ; v/v) to afford 2-(2-fluoro-4-iodo- 3-pyridyl)ethanol (1950 mg) as a white solid.
MS m/z (+ESI): 268.0 [M+H]+.
'H-NMR (400 MHz, DMSO-ί/ί + D20) δ ppm: 7.77 (d, J= 5.2 Hz, 1H), 7.72 (d, J= 5.2 Hz, 1H), 3.52 (t, J= 7.2 Hz, 2H), 2.88 (t, J= 7.2 Hz, 2H). Step 1-b: Preparation of 4-iodo-2,3-dihydrofuror2,3-b1pyridine:
To a stirred solution of 2-(2-fluoro-4-iodo-3-pyridyl)ethanol (1800 mg; 6.1 mmol) in dioxane (80 mL) was added K3PO4 (5260 mg; 24.3 mmol). The reaction mixture was heated to reflux and stirred for 72 h. After cooling down to rt, insolubles were removed by filtration and the filtrate was concentrated to dryness. The residue was purified by column chromatography (silica gel; PE : EA; 8:1 ; v/v) to afford 4- iodo-2,3-dihydrofuro[2,3-b]pyridine (1300 mg) as a white solid.
MS m/z (+ESI): 248.0 [M+H]+.
'H-NMR (400 MHz, DMSO-i¾ δ ppm: 7.58 - 7.57 (m, 1H), 7.23 (d, J= 5.6 Hz, 1H), 4.57 (t, J= 8.4 Hz, 2H), 3.14 (t, J= 8.4 Hz, 2H).
Step 2-a: Preparation of 4-r(4-chloro-2,6-difluorophenyl)methylene1piperidine-l-carboxamide:
To a stirred solution of 4-[(4-chloro-2,6-difluorophenyl)methylene]piperidine, hydrochloride (100 mg; 0.36 mmol) in DCM (5 mL) were successively added TEA (0.28 mL; 1.94 mmol) and
trimethylsilylisocyanate (55 mg; 0.47 mmol). Then, the reaction mixture was stirred for 16 h. Saturated aqueous solution of NaHCC>3 (10 mL) was added and the product was extracted with DCM (2 x 20 mL). The combined extracts were washed with brine (10 mL), dried over Na2S04, filtered and concentrated to dryness. The residue was purified by column chromatography (silica gel; DCM : MeOH; 20:1 ; v/v) to afford 4- [(4-chloro-2,6-difluorophenyl)methylene]piperidine-l-carboxamide (100 mg) as a white solid. MS m/z (+ESI): 287.1, 289.0 [M+H]+.
'H-NMR (400 MHz, OMSO-d6 + D20) δ ppm: 7.36 - 7.31 (m, 2H), 5.96 (s, 1H), 3.37 (t, J= 5.6 Hz, 2H), 3.27 (t, J= 5.6 Hz, 2H), 2.29 (t, J= 5.8 Hz, 2H), 1.98 (br, 2H).
Step 2-b: Preparation of 4-r(4-chloro-2,6-difluorophenyl)methylene1-N-(2 ,3-dihvdrofuror2,3-b1pyridin-4- vDpiperidine- 1 -carboxamide:
Under argon atmosphere, to a stirred solution of 4-iodo-2,3-dihydrofuro[2,3-b]pyridine (150 mg; 0.58 mmol) in dioxane (5 mL) were added 4-[(4-chloro-2,6-difluorophenyl)methylene]piperidine-l- carboxamide (209 mg; 0.69 mmol), Cs2C03 (230 mg; 0.69 mmol), Pd2dba3 (12 mg; 0.01 mmol) and X- Phos (17 mg; 0.03 mmol). The reaction mixture was heated to 110 °C and stirred for 16 h. After cooling to rt, insolubles were removed by filtration and the filtrate was concentrated to dryness. The residue was purified by preparative HPLC to afford 4-[(4-chloro-2,6-difluorophenyl)methylene]-N-(2,3- dihydrofuro [2,3 -b]pyridin-4-yl)piperidine-l -carboxamide (50 mg) as a white solid.
Preparation of Example 7: 4-[(4-chloro-2,6-difluorophenyl)methylene]-Ar-(3,4-dihydro-2H- pyrano[2,3-b]pyridin-5-yl)piperidine-l-carboxamide: Step 1-a: Preparation of 3-allyl-2-fluoro-4-iodopyridine:
The title compound was prepared as a white solid following the procedure described in Example 6 (step
1- a) using 2-fluoro-4-iodopyridine and allyl bromide as starting materials and after purification by column chromatography (silica gel; n-Hex : EA; 9:1 ; v/v).
MS m/z (+ESI): 264.0 [M+H]+.
'H-NMR (400 MHz, DMSO-i¾ δ ppm: 7.84 - 7.78 (m, 2H), 5.90 - 5.84 (m, 1H), 5.12 - 5.08 (m, 1H), 4.96 (dd, J= 1.2, 17.2 Hz, 1H), 3.49 (dd, J= 1.2, 6.0 Hz, 2H).
Step 1-b: Preparation of 3-(2-fluoro-4-iodo-3-pyridyl)propan-l-ol:
To a stirred solution of 3-allyl-2-fluoro-4-iodo-pyridine (300 mg; 1.08 mmol) in THF (5 mL) was added boron trifluoride diethyl etherate (0.16 mL; 1.19 mmol) at 0 °C. The reaction mixture was allowed to warm to rt and then treated with 9-borabicyclo[3.3.1]nonane, 0.5M in THF (5.4 mL; 2.7 mmol). After stirring for 16 h, the reaction mixture was successively treated with tetramethylethylenediamine (70 mg;
0.59 mmol), NaOH solution, 2.5M in H20 (2.8 mL) and H202 solution, 30% in H20 (2.8 mL). The mixture was stirred for additional 0.5 h. H20 (5 mL) and EA (30 mL) were added. The organic layer was washed with water, brine, dried over Na2SC>4, filtered and concentrated to dryness. The residue was purified by column chromatography (silica gel; PE : EA; 2: 1 ; v/v) to afford 3-(2-fluoro-4-iodo-3- pyridyl)propan-l-ol (140 mg) as a white solid.
MS m/z (+ESI): 282.0 [M+H]+.
'H-NMR (400 MHz, DMSO-i/6 + D20) δ ppm: 7.78 (d, J= 5.2 Hz, 1H), 7.72 (d, J= 5.2 Hz, 1H), 3.45 (t,
J= 6.4 Hz, 2H), 2.73 (t, J= 8.0 Hz, 2H), 1.64 - 1.57 (m, 2H).
Step 1-c: Preparation of 5-iodo-3,4-dihvdro-2H-pyranor2,3-b1pyridine:
The title compound was prepared as a white solid following the procedure described in Example 6 (step 1-b) using 3-(2-fluoro-4-iodo-3-pyridyl)propan-l-ol as starting material and after purification by column chromatography (silica gel; PE : EA; 10: 1 ; v/v).
MS m/z (+ESI): 261.7 [M+H]+.
'H-NMR (400 MHz, DMSO-i¾ δ ppm: 7.65 (d, J= 5.2 Hz, 1H), 7.44 (d, J= 5.2 Hz, 1H), 4.22 (t, J= 5.2 Hz, 2H), 2.63 (t, J= 6.4 Hz, 2H), 1.99 - 1.91 (m, 2H).
Step 2: Preparation of 4-r(4-chloro-2,6-difluorophenyl)methylene1-N-(3,4-dihvdro-2H-pyranor2,3- b1pyridin-5-yl)piperidine-l-carboxamide:
The title compound was prepared as a white solid following scheme 3 and in analogy to Example 6 (step
2- b) using 5-iodo-3,4-dihydro-2H-pyrano[2,3-b]pyridine and 4-[(4-chloro-2,6-difluorophenyl)- methylene]piperidine-l-carboxamide as starting materials and after purification by preparative HPLC. Preparation of Example 8: 4-[(4-chloro-2-fluorophenyl)methylene]-Ar-(l,8-naphthyridin-4- yl)piperidine-l-carboxamide:
Step 1: Preparation of 4 (4-chloro-2-fluorophenyl)methylene1piperidine, hydrochloride:
The title compound was prepared as a white solid following scheme 5 and in analogy to Example 2 (steps 1-c and 1-d) using l-bromo-4-chloro-2-fluorobenzene and teri-butyl 4-[(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)methylene]piperidine-l-carboxylate as starting materials.
MS m/z (+ESI): 226.2, 228.2 [M+H]+.
'H-NMR (400 MHz, DMSO-i¾ δ ppm: 9.10 (br, 2H), 7.47 (dd, J= 10.0, 2.1 Hz, 1H), 7.42 - 7.24 (m, 2H), 6.35 (s, 1H), 3.16 (t, J= 6.0 Hz, 2H), 3.08 (t, J= 6.0 Hz, 2H), 2.63 - 2.56 (m, 2H), 2.51 - 2.46 (m, 2H).
Step 2: Preparation of 4-r(4-chloro-2-fluorophenyl methylene1-N-(l,8-naphthyridin-4-yl piperidine-l- carboxamide:
To a cooled (-10°C) solution of l,8-naphthyridin-4-amine (100 mg; 0.69 mmol) and TEA (0.12 mL; 0.83 mmol) in dry ACN (2 mL) was added 2,2,2-trifluoroethyl chloro formate (118 mg; 0.72 mmol). Upon addition, the reaction mixture was allowed to warm to rt and stirred for 24 h. 4-[(4-chloro-2-fluoro- phenyl)methylene]piperidine hydrochloride (181 mg; 0.69 mmol) and TEA (0.24 mL; 1.66 mmol) were added and the reaction mixture was heated to 70 °C. The reaction mixture was concentrated to dryness and the residue was purified by preparative HPLC to afford 4-[(4-chloro-2-fluorophenyl)methylene]-N- (l,8-naphthyridin-4-yl)piperidine-l-carboxamide (93 mg) as a light brown solid.
Preparation of Example 9: 4-[(4-cyano-2,6-difluorophenyl)methylene]-Ar-(5,6,7,8-tetrahydro-l,5- naphthyridin-4-yl)piperidine-l-carboxamide, formic acid:
Step 1-a: Preparation of l-(3,4-dihvdro-2H-L5-naphthyridin-l-yl)-2,2,2-trifluoroethanone:
To a stirred solution of l,2,3,4-tetrahydro-l,5-naphthyridine (1000 mg; 7.08 mmol) in DCM (100 mL) were successively added pyridine (0.74 mL; 9.20 mmol) and TFAA (1.18 mL; 8.50 mmol). After stirring for 6 h, the reaction solution was washed with water and brine, dried over Na2S04, filtered and concentrated to dryness to afford l-(3,4-dihydro-2H-l,5-naphthyridin-l-yl)-2,2,2-trifluoroethanone (1800 mg; 90% purity) as a light yellow solid.
MS m/z (+ESI): 231.1 [M+H]+.
Step 1-b: Preparation of 2,2,2-trifluoro-l-(5-oxido-3,4-dihvdro-2H-L5-naphthyridin-5-ium-l- vDethanone:
To a stirred solution of l-(3,4-dihydro-2H-l,5-naphthyridin-l-yl)-2,2,2-trifluoroethanone (3250 mg; 14.12 mmol) in DCM (60 mL) was added 3-chloroperbenzoic acid, technical grade ~ 70 % (5200 mg; 21.18 mmol). The reaction solution was heated to 50 °C and stirred for 5 h. The reaction solution was concentrated to dryness and the residue was purified by column chromatography (silica gel; DCM :
MeOH; 15: 1 ; v/v) to afford 2,2,2-trifluoro-l-(5-oxido-3,4-dihydro-2H-l,5-naphthyridin-5-ium-l- yl)ethanone (3340 mg) as a grey solid.
'H-NMR (400 MHz, CDC13) δ ppm: 8.21 (d, J= 6.4 Hz, 1H), 7.84 (d, J= 8.0 Hz, 1H), 7.22 (dd, J = 6.4, 8.0 Hz, 1H), 3.88 - 3.82 (m, 2H), 3.11 (t, J= 6.8 Hz, 2H), 2.25 - 2.17 (m, 2H).
Step 1-c: Preparation of 2,2,2-trifluoro-l-(8-nitro-5-oxido-3,4-dihydro-2H-l,5-naphthyridin-5-ium-l- vPethanone:
2,2,2-Trifluoro-l-(5-oxido-3,4-dihydro-2H-l,5-naphthyridin-5-ium-l-yl)ethanone (1900 mg; 7.72 mmol) was dissolved in nitric acid, fuming (15 mL) and the solution was heated to 50°C for 16 h. Volatiles were removed under reduced pressure and the residue was successively purified by column chromatography (silica gel; DCM : MeOH; 20: 1 ; v/v) and by a second column chromatography (silica gel; PE : EA; 3:2 to 1 :3; v/v) to afford 2,2,2-trifluoro- 1 -(8-nitro-5-oxido-3,4-dihy dro-2H-l, 5-naphthyridin-5-ium- 1- yl)ethanone (260 mg) as a yellow solid.
MS m/z (+ESI): 292.1 [M+H]+.
'H-NMR (400 MHz, CDC13) δ ppm: 8.26 (d, J= 7.2 Hz, 1H), 7.86 (d, J= 7.2 Hz, 1H), 3.13 (t, J= 7.2 Hz, 2H), 2.28 (br, 2H), 1.66 (br, 2H). Step 1-d: Preparation of 8-nitro-l,2,3,4-tetrahydro-l,5-naphthyridin-5-oxide:
To a stirred solution of 2,2,2-trifluoro-l-(8-nitro-5-oxido-3,4-dihydro-2H-l,5-naphthyridin-5-ium-l- yl)ethanone (820 mg; 2.73 mmol) in MeOH (5mL) was added K2C03 (584 mg; 4.10 mmol). After stirring for 0.5 h, the reaction mixture was concentrated to dryness. The residue was purified by column chromatography (silica gel; DCM : MeOH; 20:1 ; v/v) to afford 8-nitro-l,2,3,4-tetrahydro-l,5- naphthyridin-5-oxide (530 mg) as a yellow solid.
MS m/z (+ESI): 196.1 [M+H]+.
'H-NMR (400 MHz, DMSO-i¾ δ ppm: 8.65 (br, 1H), 7.85 (d, J= 7.2 Hz, 1H), 7.46 (d, J= 7.6 Hz, 1H), 3.41 - 3.36 (m, 2H), 2.83 (t, J= 6.4 Hz, 2H), 1.91 - 1.84 (m, 2H). Step 1-e: Preparation of ferf-butyl 8-nitro-5-oxido-3,4-dihvdro-2H-l,5-naphthyridin-5-ium-l- carboxylate:
To a stirred suspension of 8-nitro-l,2,3,4-tetrahydro-l,5-naphthyridin-5-oxide (250 mg; 1.24 mmol) in THF (10 mL) were added DMAP (228 mg; 1.86 mmol) and (Boc)20 (856 mg; 3.73 mmol). The resulting solution was heated to 45 °C and stirred for 16 h. Volatiles were removed under reduced pressure and the residue was purified by column chromatography (silica gel; PE : EA; 1 : 1 ; v/v) to afford tert-butyl 8-nitro- 5-oxido-3,4-dihydro-2H-l,5-naphthyridin-5-ium-l-carboxylate (154 mg) as a light yellow oil.
MS m/z (+ESI): 296.1 [M+H]+. 'H-NMR (400 MHz, CDC13) δ ppm: 8.10 (d, J= 7.2 Hz, 1H), 7.74 (d, J= 7.2 Hz, 1H), 4.58 (br, 1H), 3.84 (br, 1H), 3.05 (t, J= 6.8 Hz, 2H), 2.08 (br, 2H), 1.43 (br, 9H).
Step 1-f: Preparation of ferf-butyl 8-amino-3,4-dihvdro-2H-l,5-naphthyridine-l-carboxylate:
To a stirred solution of tert-butyl 8-nitro-5-oxido-3,4-dihydro-2H-l,5-naphthyridin-5-ium-l-carboxylate (150 mg; 0.49 mmol) in MeOH (10 mL) was added 10% palladium on activated carbon (50 mg; 0.05 mmol). The reaction solution was stirred under hydrogen atmosphere (1 bar) for 16 h. The mixture was heated to 50 °C and further stirred for 16 h. After cooling to rt, insolubles were removed by filtration and the cake was washed with MeOH. The combined filtrate was concentrated to dryness to afford tert-butyl 8-amino-3,4-dihydro-2H-l,5-naphthyridine-l-carboxylate (120 mg) as a colorless oil.
MS m/z (+ESI): 250.1 [M+H]+.
Step 2-a: Preparation of ferf-butyl 8-(phenoxycarbonylamino)-3,4-dihvdro-2H-l,5-naphthyridine-l- carboxylate:
To a stirred solution of tert-butyl 8-amino-3,4-dihydro-2H-l,5-naphthyridine-l-carboxylate (120 mg; 0.48 mmol) in ACN (5 mL) were added TEA (0.1 mL; 0.72 mmol) and phenyl chloroformate (0.07 mL; 0.51 mmol) at 0 °C. After stirring for 2 h, volatiles were removed under reduced pressure and the residue was purified by column chromatography (silica gel; PE : EA; 1 :1 ; v/v) to afford of tert-butyl 8- (phenoxycarbonylamino)-3,4-dihydro-2H-l,5-naphthyridine-l-carboxylate (93 mg) as a grey semisolid mass.
MS m/z (+ESI): 370.1 [M+H]+.
Step 2-b: Preparation of ferf-butyl 8-rr4-r(4-cvano-2,6-difluorophenyl)methylene1piperidine-l- carbonyl1amino1-3,4-dihvdro-2H-L5-naphthyridine-l-carboxylate:
The title compound was prepared as a light yellow solid following scheme 1 and in analogy to Example 2 (step 3-b) using tert-butyl 8-(phenoxycarbonylamino)-3,4-dihydro-2H-l,5-naphthyridine-l-carboxylate and 3,5-difluoro-4-(4-piperidylidenemethyl)benzonitrile as starting materials, and after purification by column chromatography (silica gel; DCM : MeOH; 20: 1 ; v/v).
MS m/z (+ESI): 510.3 [M+H]+.
Step 2-c: Preparation of 4-r(4-cvano-2,6-difluorophenyl)methylene1-N-(5,6,7,8-tetrahvdro-L5- naphthyridin-4-yl)piperidine-l-carboxamide, formic acid:
tert-butyl 8-[[4-[(4-cyano-2,6-difluorophenyl)methylene]piperidine-l-carbonyl]amino]-3,4-dihydro-2H- 1,5-naphthyridine-l-carboxylate (110 mg; 0.19 mmol) was dissolved in HC1 solution, 4N in dioxane (6 mL) and the solution was stirred for 3 h. The reaction solution was concentrated to dryness and the residue was purified by preparative HPLC to afford 4-[(4-cyano-2,6-difluorophenyl)methylene]-N- (5,6,7,8-tetrahydro-l,5-naphthyridin-4-yl)piperidine-l-carboxamide, formic acid (69 mg) as an off-white powder.
Preparation of Example 10: 4-[(4-cyano-2,6-difluorophenyl)methylene]-Ar-(5-methyl-7,8-dihydro- 6H-l,5-naphthyridin-4-yl)piperidine-l-carboxamide, formic acid:
Preparation of 5-methyl-7,8-dihydro-6H-l,5-naphthyridin-4-amine:
To a stirred solution of teri-butyl 8-amino-3,4-dihydro-2H-l,5-naphthyridine-l-carboxylate (100 mg; 0.36 mmol; intermediate of Example 9 - step 1-f) in THF (5 mL) was added LAH solution, 1M in THF (1.8 mL, 1.80 mmol). The reaction mixture was stirred for 18 h. The reaction mixture was deactivated by the addition of Na2SO4.10H2O and insolubles were removed by filtration. The filtrate was concentrated to dryness and the residue was purified by column chromatography (silica gel; DCM : MeOH; 40: 1 to 15:1 ; v/v) to afford 5-methyl-7,8-dihydro-6H-l,5-naphthyridin-4-amine (30 mg) as an off-white solid.
MS m/z (+ESI): 164.2 [M+H]+.
Preparation of 4-r(4-cvano-2,6-difluorophenyl)methylene1-N-(5-methyl-7,8-dihvdro-6H-L5- naphthyridin-4-yl)piperidine-l-carboxamide, formic acid:
The title compound was prepared as an off-white solid following scheme 1 and in analogy to Example 2 (steps 3-a and 3-b) using 5-methyl-7,8-dihydro-6H-l,5-naphthyridin-4-amine and 3,5-difluoro-4-(4- piperidylidenemethyl)benzonitrile as starting materials and after purification by preparative HPLC.
Preparation of Examples 11 and 12: 4-[(4-chloro-2-fluorophenyl)methylene]-Ar-[3- (methoxymethyl)-2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-8-yl]piperidine-l-carboxamide and 4-[(4- chloro^-fluorophenylJmethylenel-A^^-^ethoxymethylJ^^-dihydro-Il^ldioxino^^-blpyridin-S- yl]piperidine-l-carboxamide:
Step 1-a: Preparation of 2-bromo-3-(oxiran-2-ylmethoxy)pyridine:
To a slurry of NaH (520 mg; 20.48 mmol) in dry DMF (30 mL) was added a solution of 2-bromo-3- pyridinol (3000 mg; 17.07 mmol) in dry DMF (10 mL). The reaction mixture, which became dark yellow, was stirred for 0.5 h. A solution of 2-(bromomethyl)oxirane (1.86 mL; 21.34 mmol) in dry DMF (10 mL) was added dropwise and the reaction mixture was heated to 60 °C. After 3 h, the reaction solution was placed in an ice-bath and then cautiously deactivated with water. Ethyl acetate was added and the mixture was decanted. The organic layer was washed with water and brine, dried over MgSO i, filtered and concentrated to dryness to afford 2-bromo-3-(oxiran-2-ylmethoxy)pyridine (3430 mg) as a light yellow oil, which solidified upon ageing.
MS m/z (+ESI): 230.1, 232.1 [M+H]+. 'H-NMR (400 MHz, DMSO-i¼) δ ppm: 8.00 (dd, J= 4.6, 1.5 Hz, 1H), 7.56 (dd, J= 8.2, 1.6 Hz, 1H), 7.42 (dd, J= 8.2, 4.6 Hz, 1H), 4.51 (dd, J= 11.6, 2.5 Hz, 1H), 4.04 (dd, J= 11.6, 6.2 Hz, 1H), 3.39 (ddt, J = 6.2, 4.2, 2.6 Hz, 1H), 2.88 (dd, J= 5.1 , 4.2 Hz, 1H), 2.78 (dd, J= 5.1, 2.6 Hz, 1H). Step 1-b: Preparation of l-r(2-bromo-3-pyridyl)oxy1-3-methoxypropan-2-ol:
To a stirred solution of MeOH (50 mL) was added dropwise trifluoromethanesulfonic acid (0.13 mL; 1.42 mmol) at 0 °C. After 5 min, the reaction solution was treated with a solution of 2-bromo-3-(oxiran-2- ylmethoxy)pyridine (3430 mg; 14.2 mmol) in MeOH (50 mL) at 0 °C. The reaction solution was then stirred for 20 h at rt and then concentrated to dryness to afford l-[(2-bromo-3-pyridyl)oxy]-3-methoxy- propan-2-ol as a light yellow oil in quantitative yield.
MS m/z (+ESI): 262.0, 264.0 [M+H]+.
Step 1-c: Preparation of 3-(methoxymethyl)-2,3-dihvdro-rL41dioxinor2,3-b1pyridine and 2- (methoxymethyl)-2,3 -dihydro- Γ 1 ,41 dioxino Γ2.3 -blpyridine :
To a stirred solution l-[(2-bromo-3-pyridyl)oxy]-3-methoxypropan-2-ol (4270 mg; 14.7 mmol) in t- BuOH (100 mL) was added potassium tert-butoxide (4200 mg; 36.7 mmol). The reaction mixture was heated to 80 °C and stirred for 20 h. After cooling to rt, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over MgSO i, filtered and concentrated to dryness. The residue was purified by column chromatography (silica gel; DCM : 20% MeOH in DCM; 1 : 0 to 3 : 1 ; v/v) to afford a mixture of 3 -(methoxymethyl)-2,3 -dihydro- [ 1 ,4] dioxino [2,3 - b]pyridine and 2-(methoxymethyl)-2,3-dihydro-[l,4]dioxino[2,3-b]pyridine (1640 mg) in a 4/1 ratio respectively and as a colorless viscous oil.
MS m/z (+ESI): 182.3 [M+H]+ for both isomers.
'H-NMR (400 MHz, DMSO-i¾ δ ppm: 7.77 - 7.74 (m, 1H), 7.35 - 7.28 (m, 1H), 6.97 - 6.93 (m, 1H), 4.55 - 4.46 (m,lH), 4.37 - 4.32 (m, 1H), 4.05 - 4.00 (m, 1H), 3.68 - 3.58 (m, 2H), 3.33 (s, 2.4H), 3.32 (s, 0.6H).
Step 1-d: Preparation of 3-(methoxymethyl)- 2,3-dihvdro-rL41dioxino[2,3-b1pyridine-5-oxide and 2- (methoxymethyl)- 2,3-dihvdro-rL41dioxino[2,3-b1pyridine-5-oxide:
To a stirred solution of a mixture of 3-(methoxymethyl)-2,3-dihydro-[l,4]dioxino[2,3-b]pyridine and 2- (methoxymethyl)-2,3-dihydro-[l,4]dioxino[2,3-b]pyridine (1640 mg; 8.60 mmol; ratio 4/1) in EA (80 mL) was added 3-chloroperbenzoic acid, technical -70% (3392 mg, 13.8 mmol) and the reaction solution was stirred for 24 h. Water (50 mL) was added and the organic layer was extracted with water (30 mL). The aqueous layers were combined and concentrated to dryness. The oily residue was dissolved in acetone (10 mL) and an abundant precipitation occurred. The suspension was diluted with ethyl acetate (5 mL) and filtered. The solid was washed with ethyl acetate and dried under reduced pressure to afford 3- (methoxymethyl)- 2,3-dihydro-[l,4]dioxino[2,3-b]pyridine-5-oxide (305 mg) as a light brown powder. The mother liquid was concentrated to dryness to afford a mixture of 3-(methoxymethyl)- 2,3-dihydro- [l,4]dioxino[2,3-b]pyridine-5-oxide and 2-(methoxymethyl)-2,3-dihydro-[l,4]dioxino[2,3-b]pyridine-5- oxide (890 mg) in a 7/3 ratio as a light brown solid.
For 3-(methoxymethyl)-2,3-dihydro-[l,4]dioxino[2,3-b]pyridine-5-oxide:
MS m/z (+ESI): 198.3 [M+H]+.
'H-NMR (400 MHz, DMSO-i¼) δ ppm: 7.88 (dd, J= 6.5, 1.5 Hz, 1H), 6.97 (dd, J= 8.5, 1.5 Hz, 1H), 6.89 (dd, J= 8.5, 6.5 Hz, 1H), 4.69 - 4.64 (m, 1H), 4.45 (dd, J= 11.8, 2.5 Hz, 1H), 4.11 (dd, J= 11.8, 7.6 Hz, 1H), 3.69 (d, J= 4.6 Hz, 2H), 3.35 (s, 3H).
For the mixture of 3-(methoxymethyl)-2,3-dihydro-[l,4]dioxino[2,3-b]pyridine-5-oxide and 2- (methoxymethyl)-2,3-dihydro-[l ,4]dioxino[2,3-b]pyridine-5-oxide:
MS m/z (+ESI): 198.3 [M+H]+ for both isomers.
'H-NMR (400 MHz, DMSO-i¾ δ ppm: 7.89 - 7.85 (m, 1H), 7.01 - 6.96 (m, 1H), 6.92 - 6.88 (m, 1H), 4.70 - 4.61 (m, 1H), 4.52 - 4.47 (m, 0.3H), 4.45 (dd, J= 11.8, 2.5 Hz, 0.7H), 4.32 - 4.21 (m, 0.3H), 4.11 (dd, J= 11.8, 7.6 Hz, 0.7H), 3.68 (d, J= 4.7 Hz, 1.4H), 3.63 (d, J= 4.8 Hz, 0.6H), 3.37 (s, 0.9H), 3.35 (s, 2.1H).
Step 1-e: Preparation of 3-(methoxymethyl -8-nitro-2,3-dihydro-ri,41dioxinor2,3-b1pyridine-5-oxide and
2-(methoxymethyl -8-nitro-2,3-dihydro-[l,41dioxinor2,3-blpyridine-5-oxide:
A mixture of 3-(methoxymethyl)- 2,3-dihydro-[l,4]dioxino[2,3-b]pyridine-5-oxide and 2- (methoxymethyl)- 2,3-dihydro-[l,4]dioxino[2,3-b]pyridine-5-oxide (610 mg; 2.94 mmol; ratio 7/3) was dissolved in TFA (1.76 mL; 23.5 mmol). Nitric acid, fuming (1.64 mL; 35.3 mmol) was added. The reaction mixture was heated to 60 °C and stirred for 4 h. The reaction mixture was then placed in an ice- bath and a mixture of ice - H20 (20 mL) was added. The product was extracted with DCM (2 x 20 mL), the combined extracts were dried over MgSO i, filtered and concentrated to dryness. The residue was purified by column chromatography (silica gel; DCM : 20% MeOH in DCM; 1 :0 to 7:3; v/v) to afford a mixture of 3-(methoxymethyl)-8-nitro-2,3-dihydro-[l,4]dioxino[2,3-b]pyridine-5-oxide and 2- (methoxymethyl)-8-nitro-2,3-dihydro-[l,4]dioxino[2,3-b]pyridine-5-oxide (700 mg) in a 7/3 ratio and as a yellow solid.
MS m/z (+ESI): 243.2 [M+H]+ for both isomers.
'H-NMR (400 MHz, DMSO-i¾ δ ppm: 8.01 (m, 1H), 7.72 - 7.68 (m, 1H), 4.86 - 4.75 (m, 1H), 4.67 (dd, J= 11.7, 2.6 Hz, 1H), 4.43 (dd, J= 11.6, 7.6 Hz, 0.3H), 4.29 (dd, J= 11.8, 7.8 Hz, 0.7H), 3.77 - 3.69 (m, 2H), 3.36 and 3.35 (2s, 3H).
Step 1-f: Preparation of 3-(methoxymethyl)-2,3-dihvdro-rL41dioxinor2,3-b1pyridin-8-amine and 2- (methoxymethyl)-2,3-dihvdro-rL41dioxinor2,3-b1pyridin-8-amine:
To a stirred solution of mixture of 3-(methoxymethyl)-8-nitro-2,3-dihydro-[l,4]dioxino[2,3-b]pyridine-5- oxide and 2-(methoxymethyl)-8-nitro-2,3-dihydro-[l,4]dioxino[2,3-b]pyridine-5-oxide (740 mg; 2.90 mmol, ratio 7/3) in MeOH (20 mL) was added 10% palladium on activated carbon (310 mg; 0.29 mmol). The reaction mixture was stirred under hydrogen atmosphere (2.5 bars) for 16 h, filtered through a plug of celite and the cake was washed with methanol. The combined filtrate was concentrated to dryness. The residue was purified by column chromatography (silica gel; DCM : 20% MeOH in DCM; 1 :0 to 0: 1 ; v/v) to afford a mixture of 3-(methoxymethyl)-2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-8-amine and 2-
(methoxymethyl)-2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-8-amine (361 mg) in a 7/3 ratio and as a brown viscous oil.
MS m/z (+ESI): 197.3 [M+H]+ for both isomers.
'H-NMR (400 MHz, DMSO-i¼) δ ppm: 7.50 (m, 1H), 7.00 - 6.73 (m, 2H), 6.45 (m, 1H), 4.68 (m, 0.7H), 4.56 (dd, J= 11.5, 2.4 Hz, 0.3H), 4.44 (dd, J= 11.6, 2.4 Hz, 1H), 4.28 (dd, J = 11.5, 7.3 Hz, 0.3H), 4.09 (dd, J= 11.7, 7.3 Hz, 0.7H), 3.68 - 3.61 (m, 2H), 3.34 (s, 3H).
Step 2: Preparation of 4-r(4-chloro-2-fluorophenyl)methylene1-N-r3-(methoxymethyl)-2,3-dihvdro- ri,41dioxinor2,3-b1pyridin-8-vHpiperidine-l-carboxamide and 4-r(4-chloro-2-fluorophenyl)methylene1- N-r2-(methoxymethyl)-2,3-dihvdro-ri,41dioxinor2,3-b1pyridin-8-vHpiperidine-l-carboxamide:
To a stirred solution of a mixture 3-(methoxymethyl)-2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-8-amine and 2-(methoxymethyl)-2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-8-amine (207 mg; 1.00 mmol; ratio 7/3) in DCM (8 mL) cooled to 0 °C was added TEA (0.23 mL; 1.67 mmol) and BTC (100 mg; 0.33 mmol) and the reaction solution was stirred for 20 min. Then, a solution of 4-[(4-chloro-2-fluorophenyl)methylene]- piperidine (190 mg; 0.83 mmol) and TEA (0.23 mL; 1.67 mmol) in DCM (8 mL) was added and the reaction solution was further stirred for 15 min at 0 °C. The ice-bath was removed and the reaction solution was further stirred for 1 h. MeOH (1 mL) was added to the reaction solution and volatiles were removed under reduced pressure. The residue was partitioned between ethyl acetate and brine and the organic layer was separated, dried over MgSO i, filtered and concentrated to dryness. The residue was purified by column chromatography (silica gel; "Gold Isco Column"; DCM : 20% MeOH in DCM; 1 :0 to 4: 1; v/v) to afford respectively 4- [(4-chloro-2-fluorophenyl)methylene]-N- [3 -(methoxymethyl)-2,3- dihydro-[l,4]dioxino[2,3-b]pyridin-8-yl]piperidine-l-carboxamide (78 mg) as a white powder and 4-[(4- chloro-2-fluorophenyl)methylene] -N- [2-(methoxymethyl)-2,3 -dihydro- [ 1 ,4] dioxino [2,3 -b]pyridin-8- yl]piperidine-l-carboxamide (45 mg) as a light brown solid.
Preparation of Example 13: 4-[(4-cyano-2,6-difluorophenyl)methylene]-Ar-[3-(methoxymethyl)-2,3- dihydro-[l,4]dioxino[2,3-b]pyridin-8-yl]piperidine-l-carboxamide:
Preparation of 4- r(4-cyano-2,6-difluorophenyl)methylene1 -N- Γ3 -(methoxymethyl)-2,3 -dihydro- rL41dioxinor2,3-b1pyridin-8-vHpiperidine-l-carboxamide:
The title compound was prepared as a white solid following scheme 1 and in analogy to Example 11 (steps 1-e, 1-f and 2) using 3-(methoxymethyl)-2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-5-oxide and 3,5- difluoro-4-(4-piperidylidenemethyl)benzonitrile hydrochloride as starting materials and after purification by column chromatography (silica gel; DCM : 20% MeOH in DCM; 1 :0 to 9: 1 ; v/v).
Preparation of Example 19: 4-[(4-chloro-2,6-difluorophenyl)methyl]-Ar-(2,3-dihydro- [l,4]dioxino[2,3-b]pyridin-8-yl)piperidine-l-carboxamide, trifluoroacetic acid:
Step 1: Preparation of 4-[(4-chloro-2,6-difluorophenyl methyll-N-(2,3-dihydro-[l,41dioxinor2,3- blpyridin-8-yl piperidine-l-carboxamide, trifluoroacetic acid:
To a stirred solution of 4-[(4-chloro-2,6-difluorophenyl)methylene]-N-(2,3-dihydro-[l,4]dioxino[2,3- b]pyridin-8-yl)piperidine-l-carboxamide (100 mg; 0.23 mmol) (Example 5) in EA (10 mL) was added Pt02 (26 mg; 0.11 mmol). The reaction mixture was stirred under hydrogen atmosphere (1 bar) for 3 h. Insolubles were removed by filtration and the filtrate was concentrated to dryness. The residue was purified by preparative HPLC to afford 4-[(4-chloro-2,6-difluorophenyl)methyl]-N-(2,3-dihydro- [l,4]dioxino[2,3-b]pyridin-8-yl)piperidine-l-carboxamide, trifluoroacetic acid (65 mg) as a white powder.
Preparation of Example 20: 4-(4-chlorobenzoyl)-Ar-(2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-8- yl)piperidine-l-carboxamide: Step 1-a: Preparation of ferf -butyl 4-(4-chlorobenzoyl)piperidine-l-carboxylate:
To a stirred isopropylmagnesium chloride solution, 2N in THF (8.25 mL; 16.5 mmol) was added a solution of l-chloro-4-iodobenzene (3580 mg; 14.9 mmol) in THF (20 mL) over 5 min. After stirring for 2 h, a solution of tert-butyl 4-[methoxy(methyl)carbamoyl]piperidine-l-carboxylate (4540 mg; 16.3 mmol) in THF (15 mL) was added and the reaction mixture was further stirred for 3 h. Volatiles were removed under reduced pressure and the residue was dissolved in EA (100 mL). The solution was successively washed with a saturated aqueous solution of NH4C1 (3 x 30 mL) and brine (2 x 30 mL), dried over Na2S04, filtered and concentrated to dryness. The residue was purified by column
chromatography (silica gel; PE : EA; 20: 1 to 10: 1 ; v/v) to afford tert-butyl 4-(4-chlorobenzoyl)piperidine- 1 -carboxylate (3340 mg) as a white solid.
MS m/z (+ESI): 324.1, 326.1 [M+H]+.
'H-NMR (400 MHz, DMSO-i¼) δ ppm: 8.00 (d, J = 8.8 Hz, 2H), 7.60 (d, J = 8.8 Hz, 2H), 3.98 - 3.94 (m, 2H), 3.65 - 3.55 (m, 1H), 2.95 - 2.82 (m., 2H), 1.77 - 1.73 (m, 2H), 1.46-1.36 (m, 11H).
Step 1-b: Preparation of (4-chlorophenyl)-(4-piperidyl)methanone hydrochloride:
To a stirred solution of tert-butyl 4-(4-chlorobenzoyl)piperidine-l -carboxylate (4150 mg; 12.7 mmol) in DCM (40 mL) was added HCl solution, 2N in EA (40 mL) and the reaction mixture was stirred for 5 h. The reaction mixture was then concentrated to dryness to afford (4-chlorophenyl)-(4-piperidyl)- methanone, hydrochloride in quantitative yield and as a white solid.
MS m/z (+ESI): 224.1, 226.0 [M+H]+. Step 2: Preparation of 8-bromo-2,3-dihvdro-ri,41dioxinor2,3-b1pyridine:
To a stirred solution of 2,3-dihydro-[l,4]dioxino[2,3-b]pyridine (2000 mg; 14.3 mmol) in THF (15 mL) was added n-butyllithium solution, 1.6N in n-Hex (17.9 mL; 28.6 mmol) at -78 °C. After 0.5 h, a solution of 1 ,2-dibromotetrafluoroethane (1.74 mL; 14.3 mmol) in THF (5 mL) was added dropwise over 5 min at -78 °C. The reaction mixture was further stirred for 0.5 h. A saturated aqueous solution of NH4C1 (10 mL) was cautiously added, followed by the addition of EA (50 mL). The organic layer was successively washed with water and brine, dried over Na2S04, filtered and concentrated to dryness. The residue was purified by column chromatography (silica gel; 2-methylpentane : EA; 7:3; v/v) to afford 8-bromo-2,3- dihydro-[l,4]dioxino[2,3-b]pyridine (1000 mg) as a white solid.
MS m/z (+ESI): 216.1, 218.1 [M+H]+.
'H-NMR (400 MHz, DMSO-i¾ δ ppm: 7.61 (d, J = 5.2 Hz, 1H), 7.24 (d, J = 5.2 Hz, 1H), 4.45 - 4.42 (m, 2H), 4.36 - 4.34 (m, 2H).
Step 3: Preparation of 4-(4-chlorobenzoyl)-N-(2 -dihydro-[l^ldioxinor2 -blpyridin-8-yl)piperidine-l- carboxamide:
The title compound was prepared as a white solid following scheme 3 and in analogy to Example 6 (steps 2-a and 2-b) using (4-chlorophenyl)-(4-piperidyl)methanone hydrochloride and 8-bromo-2,3-dihydro- [l,4]dioxino[2,3-b]pyridine as starting materials and after purification by preparative HPLC.
Preparation of Example 21: 4-[(4-cyano-2,6-difluoro-phenyl)methyl]-Ar-(2,3-dihydro- [l,4]dioxino[2,3-b]pyridin-8-yl)piperidine-l-carboxamide:
Step 1-a: Preparation of ferf-butyl 4-r(4-ethoxycarbonyl-2,6-difluorophenyl)methylene1piperidine-l - carboxylate:
The title compound was prepared as a light yellow solid following scheme 5 and in analogy to Example 2 (step 1-c) using ethyl 4-bromo-3,5-difluorobenzoate and tert-butyl 4-[(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)methylene]piperidine-l-carboxylate as starting material and after purification by column chromatography (silica gel; PE : EA; 50:1 to 30:1 ; v/v).
MS m/z (+ESI): 326.1 [M-i-Bu+H]+.
'H-NMR (400 MHz, CDC13) δ ppm: 7.58 - 7.55 (m, 2H), 6.03 (s, 1H), 4.39 (q, J= 7.2 Hz, 2H), 3.55 (t, J = 5.6 Hz, 2H), 3.44 (t, J= 5.6 Hz, 2H), 2.41 (t, J= 5.2 Hz, 2H), 2.15 (t, J= 5.2 Hz, 2H), 1.49 (s, 9H), 1.40 (t, J= 7.2 Hz, 3H). Step 1-b: Preparation of ferf-butyl 4-r(4-ethoxycarbonyl-2,6-difluorophenyl methyl1piperidine-l- carboxylate:
To the solution of teri-butyl 4-[(4-ethoxycarbonyl-2,6-difluorophenyl)methylene]piperidine-l- carboxylate (520 mg; 1.30 mmol) in MeOH (10 niL) was added 10% palladium on activated carbon (276 mg; 0.26 mmol). The reaction solution was stirred under hydrogen atmosphere (1 bar) for 18 h. The reaction mixture was then filtered through a plug of celite and the cake was washed with methanol. The combined filtrate was concentrated to dryness to afford teri-butyl 4-[(4-ethoxycarbonyl-2,6-difluoro- phenyl)methyl]piperidine-l-carboxylate (500 mg) as a colorless oil.
MS m/z (+ESI): 328.1 [M-i-Bu+H]+.
Step 1-c: Preparation of ferf-butyl 4-r(4-carbamoyl-2,6-difluorophenyl)methyl1piperidine-l-carboxylate: In a sealable tube was dissolved teri-butyl 4-[(4-ethoxycarbonyl-2,6-difluorophenyl)methyl]piperidine-l - carboxylate (500 mg; 1.28 mmol) in NH3 solution, 2N in MeOH (10 mL). The tube was sealed and the reaction solution was heated to 70 °C and stirred for 18 h. The reaction solution was finally concentrated to dryness to afford teri-butyl 4-[(4-carbamoyl-2,6-difluoro-phenyl)methyl]piperidine-l-carboxylate (450 mg) as an off-white solid.
MS m/z (+ESI): 299.1 [M-/-Bu+H]+.
Step 1-d: Preparation of ferf-butyl 4-r(4-cvano-2,6-difluorophenyl)methyl1piperidine-l-carboxylate: To a stirred solution of teri-butyl 4-[(4-carbamoyl-2,6-difluorophenyl)methyl]piperidine-l-carboxylate (450 mg; 1.22 mmol) in DCM (10 mL) was added TEA (0.42 mL; 3.06 mmol). The reaction mixture was cooled to 0 °C, and TFAA (0.42 mL; 3.06 mmol) was added. After stirring for 2 h, the reaction mixture was concentrated to dryness. The residue was purified by column chromatography (silica gel; PE : EA; 20:1 ; v/v) to afford teri-butyl 4-[(4-cyano-2,6-difluorophenyl)methyl]piperidine-l-carboxylate (400 mg) as a colorless oil.
MS m/z (+ESI): 281.1 [M-i-Bu+H]+.
Step 1-e: Preparation of 3,5-difluoro-4-(4-piperidylmethyl)benzonitrile, hydrochloride:
The title compound was prepared as an off-white solid following scheme 5 and in analogy to Example 2 (step 1-d) using teri-butyl 4-[(4-cyano-2,6-difluoro-phenyl)methyl]piperidine-l -carboxylate as starting material.
MS m/z (+ESI): 237.2 [M+H]+. Step 2: Preparation of 4-r(4-cyano-2,6-difluorophenyl methyl1-N-(2,3-dihvdro-ri ,41dioxinor2,3- b1pyridin-8-yl)piperidine-l -carboxamide:
The title compound was prepared as a white solid following scheme 3 and in analogy to Example 6 (steps 2-a and 2-b) using 3,5-difluoro-4-(4-piperidylmethyl)benzonitrile hydrochloride and 8-bromo-2,3- dihydro-[l ,4]dioxino[2,3-b]pyridine as starting materials and after purification by preparative HPLC.
Preparation of Example 22: 4-[(4-chloro-2,6-difluorophenyl)methylene]-Ar-(6,8-dihydro-5H- pyrano[3,4-b]pyridin-4-yl)piperidine-l-carboxamide, trifluoroacetic acid: Step 1-a: Preparation of 2-(2-bromo-4-chloro-3-pyridyl)ethanol:
The title compound was prepared as a yellow oil following the procedure described in Example 6 (step 1 - a) using 2-bromo-4-chloropyridine as starting material and after purification by column chromatography
(silica gel; PE : EA; 2: 1 ; v/v).
MS m/z (+ESI): 235.9, 237.9, 240.0 [M+H]+.
'H-NMR (400 MHz, CDC13) δ ppm: 8.17 - 8.10 (m, 1H), 7.29 - 7.26 (m, 1H), 4.13 - 4.08 (m, 2H), 3.27 -
3.21 (m, 2H), 2.30 (br, 1H).
Step 1-b: Preparation of 2-(2-bromo-4-chloro-3-pyridyl ethoxy-fer?-butyl-dimethyl-silane:
To a stirred solution of 2-(2-bromo-4-chloro-3-pyridyl)ethanol (5000 mg; 19.0 mmol) in DMF (50 mL) were added imidazole (1980 mg; 28.5 mmol) and tert-butyldimethylsilyl chloride (3510 mg; 22.8 mmol). After stirring for 16 h, EA (100 mL) was added and the organic layer was successively washed with water (3 x 20 mL) and brine (10 mL), dried over MgSO i, filtered and concentrated to dryness. The residue was purified by column chromatography (silica gel; n-Hex : EA; 9: 1 ; v/v) to afford 2-(2-bromo-4-chloro-3- pyridyl)ethoxy-tert-butyl-dimethyl-silane (5550 mg) as a white solid.
MS m/z (+ESI): 350.0, 352.0, 354.0 [M+H]+.
Step 1-c: Preparation of fer?-butyl-r2-(4-chloro-2-methyl-3-pyridyl)ethoxy1dimethylsilane:
To a stirred solution of 2-(2-bromo-4-chloro-3-pyridyl)ethoxy-tert-butyldimethylsilane (10.0 g; 25.7 mmol) in dioxane (200 mL) were added trimethylboroxine (32.9 g; 25.7 mmol), 1 ,1 '- bis(diphenylphosphino)ferrocene-palladium(II) dichloride, dichloromethane complex (64.2 g; 7.7 mmol) and CS2CO3 (25.6 g, 77.0 mmol). The reaction mixture was heated to 80 °C and stirred for 18 h.
Insolubles were removed by filtration and the filtrate was concentrated to dryness. The residue was purified by column chromatography (silica gel; PE : EA; 85: 15; v/v) to afford tert-butyl-[2-(4-chloro-2- methyl-3-pyridyl)ethoxy]dimethylsilane (5.2 g) as a yellow oil.
MS m/z (+ESI): 286.2, 288.2 [M+H]+.
'H-NMR (400 MHz, CDCI3) δ ppm: 8.22 (d, J= 5.2 Hz, 1H), 7.15 (d, J= 5.2 Hz, 1H), 3.83 (t, J= 6.8 Hz, 2H), 3.06 (t, J= 6.8 Hz, 2H), 2.65 (s, 3H), 0.86 (s, 9H), 0.00 (s, 6H). Step 1-d: Preparation of 4-chloro-3-(2-chloroethyl)-2-methylpyridine:
To a stirred solution of teri-butyl-[2-(4-chloro-2-methyl-3-pyridyl)ethoxy]dimethylsilane (5000 mg; 15.7 mmol) in chloroform (50 mL) was added thionyl chloride (2.33 mL; 31.5 mmol). The reaction mixture was then heated to 70 °C and stirred for 16 h. After cooling to rt, a saturated aqueous solution of NaHCC>3 (100 mL) was added. The aqueous layer was was extracted with DCM (2 x 20 mL). The combined organic extracts were washed with brine, dried over MgSO i, filtered and concentrated to dryness. The residue was purified by column chromatography (silica gel; PE : EA; 9: 1 ; v/v) to afford 4-chloro-3-(2- chloroethyl)-2-methylpyridine (2800 mg) as a yellow oil.
MS m/z (+ESI): 190.1, 192.1 [M+H]+.
'H-NMR (400 MHz, CDC13) δ ppm: 8.27 (d, J= 5.2 Hz, 1H), 7.18 (d, J= 5.2 Hz, 1H), 3.70 (t, J= 6.8 Hz, 2H), 3.29 (t, J= 6.8 Hz, 2H), 2.65 (s, 3H).
Step 1-e: Preparation of 4-chloro-3-(2-chloroethyl)-2-methylpyridine-l-oxide:
To a stirred solution of 4-chloro-3-(2-chloroethyl)-2-methylpyridine (2700 mg; 12.8 mmol) in DCM (50 mL) was added 3-chloroperbenzoic acid, 85% (5190 mg; 25.6 mmol). After stirring for 16 h, the reaction solution was successively washed with a saturated aqueous solution of NaHC03 (50 mL), water (10 mL) and brine (10 mL). The organic solution was finally dried over MgSO i, filtered and concentrated to dryness to afford 4-chloro-3-(2-chloroethyl)-2-methylpyridine-l-oxide (2500 mg) as a yellow solid. MS m/z (+ESI): 206.1, 208.1 [M+H]+.
Step 1-f: Preparation of r4-chloro-3-(2-chloroethyl)-2-pyridyl1methyl acetate:
A solution of 4-chloro-3-(2-chloroethyl)-2-methylpyridine-l-oxide (2400 mg; 10.5 mmol) in acetic anhydride (20 mL) was heated at 140 °C for 2 h. The reaction solution was concentrated to dryness to afford [4-chloro-3-(2-chloroethyl)-2-pyridyl]methyl acetate (2000 mg) as a yellow oil, used in the next step without further purification.
MS m/z (+ESI): 248.0, 250.1 [M+H]+.
Step 1-g: Preparation of 4-chloro-6,8-dihvdro-5H-pyranor3,4-b1pyridine:
[4-Chloro-3-(2-chloroethyl)-2-pyridyl]methyl acetate (2000 mg; 7.25 mmol) was dissolved in a KOH solution, IN in MeOH (50 mL) and the reaction solution was heated to 70 °C and stirred for 0.5 h.
Volatiles were removed under reduced pressure and the residue was suspended in water (20 mL). The product was extracted with DCM (2 x 20 mL) and the combined organic extracts were dried over Na2S04, filtered and concentrated to dryness. The residue was purified by column chromatography (silica gel; PE : EA; 7:3; v/v) to afford 4-chloro-6,8-dihydro-5H-pyrano[3,4-b]pyridine (1000 mg) as a white solid.
MS m/z (+ESI): 170.1, 172.1 [M+H]+.
'H-NMR (400 MHz, DMSO-i¾ δ ppm: 8.33 (d, J= 5.2 Hz, 1H), 7.42 (d, J= 5.2 Hz, 1H), 4.65 (s, 2H), 3.94 (t, J= 5.6 Hz, 2H), 2.79 (t, J= 5.6 Hz, 2H). Step 2: Preparation of 4-r(4-chloro-2,6-difluorophenyl methylene1-N-(6,8-dihvdro-5H-pyranor3,4- b1pyridin-4-yl)piperidine-l -carboxamide, trifluoroacetic acid:
The title compound was prepared as a white solid following scheme 3 and in analogy to Example 6 (step 2-b) using 4-chloro-6,8-dihydro-5H-pyrano[3,4-b]pyridine and 4-[(4-chloro-2,6-difluorophenyl)- methylene]piperidine-l -carboxamide as starting materials and after purification by preparative HPLC.
Preparation of Examples 27 and 28 : 4-[(4-cyano-2,6-difluorophenyl)methylene]-Ar-(3-methyl-2,3- dihydro-[l,4]dioxino[2,3-b]pyridin-8-yl)piperidine-l-carboxamide, formic acid and 4-[(4-cyano-2,6- difluoro-phenyl)methylene]-Ar-(2-methyl-2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-8-yl)piperidine-l- carboxamide, formic acid:
Step 1-a: Preparation of r2-r(2-cMoro-3-pyridyl oxy1-l -methylethvH hydrogen sulfate:
To a solution of 2-chloro-3 -pyridinol (500 mg; 3.82 mmol) in THF (20 mL) was added 4-methyl- 1 ,3,2- dioxathiolane 2,2-dioxide (0.76 mL; 7.64 mmol) and NaH, 55% (491 mg; 1 1.46 mmol). The mixture was heated to 100 °C and stirred for 6 h. The mixture was then concentrated to dryness and the residue was triturated in diethyl ether and filtered to afford [2-[(2-chloro-3-pyridyl)oxy]-l-methyl-ethyl] hydrogen sulfate (1200 mg) as a brown solid.
MS m/z (+ESI): 268.0, 270.0 [M+H]+.
Step 1-b: Preparation of l -[(2-chloro-3-pyridyl)oxylpropan-2-ol:
A mixture of [2-[(2-chloro-3-pyridyl)oxy]-l -methylethyl]hydrogensulfate (1200 mg; 3.59 mmol) in H2SO4, 20% in water (18 mL) was heated to 60 °C and stirred for 18 h. After cooling to rt, the mixture was cautiously basified to pH about 10 using solid Na2C03. The product was extracted with diethyl ether and the organic layer was dried over Na2S04, filtered and concentrated. The residue was purified by column chromatography (silica gel; diethyl ether) to afford l -[(2-chloro-3-pyridyl)oxy]propan-2-ol (610 mg) as a yellow oil.
MS m/z (+ESI): 188.1 , 190.1 [M+H]+.
'H-NMR (400 MHz, CDCI3) δ ppm: 8.03 (d, J= 2.0 Hz, 1H), 7.24 - 7.20 (m, 2H), 4.32 - 4.24 (m, 1H), 4.06 - 4.03 (dd, J = 9.2, 3.2 Hz, 1H), 3.90 - 3.85 (m, 1H), 1.36 - 1.33 (m, 3H).
Step 1-c: Preparation of 3-methyl-2,3-dihvdro-rL41dioxinor2,3-b1pyridine and 2-methyl-2,3-dihydro- rL41dioxinor2,3-b1pyridine:
To a solution of l -[(2-chloro-3-pyridyl)oxy]propan-2-ol (590 mg; 2.99 mmol) in i-BuOH (15 mL) was added potassium tert-butoxide (1016 mg; 8.96 mmol). The mixture was heated to 90 °C and stirred for 6 h. After cooling to rt, insolubles were removed by filtration and the filtrate was concentrated. The residue was purified by column chromatography (silica gel; diethyl ether) to afford a mixture of 3-methyl-2,3- dihydro-[l,4]dioxino[2,3-b]pyridine and 2-methyl-2,3-dihydro-[l,4]dioxino[2,3-b]pyridine (370 mg) as a colorless oil.
MS m/z (+ESI): 152.1 [M+H]+.
'H-NMR (400 MHz, CDC13) δ ppm: 7.83 - 7.82 (m, 1H), 7.22 - 7.18 (m, 1H), 6.90 - 6.86 (m, 1H), 4.50 - 4.40 (m, 1H), 4.35 - 4.22 (m, 1H), 4.06 - 4.01 (m, 0.55H), 3.88 - 3.83 (m, 0.45H), 1.45 (d, J= 6.4 Hz, 1.35H), 1.39 (d, J= 6.4 Hz, 1.65H).
Step 1-d: Preparation of 3-methyl-2,3-dihydro-[l,41dioxinor2,3-blpyridin-5-oxide and 2-methyl-2,3- dihvdro-ri,41dioxinor2,3-b1pyridin-5-oxide:
To a solution of a mixture of 3-methyl-2,3-dihydro-[l,4]dioxino[2,3-b]pyridine and 2-methyl-2,3- dihydro-[l,4]dioxino[2,3-b]pyridine (370 mg; 2.33 mmol) in DCM (10 mL) was added 3- chloroperbenzoic acid, technical -70% (1216 mg). The solution was stirred for 5 h and concentrated. The residue was purified by column chromatography (silica gel; diethyl ether : MeOH; 1 :0 to 0: 1 ; v/v) to afford a mixture of 3-methyl-2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-5-oxide and 2-methyl-2,3-dihydro- [l,4]dioxino[2,3-b]pyridin-5-oxide (370 mg) as a white semisolid.
MS m/z (+ESI): 168.1 [M+H]+.
'H-NMR (400 MHz, CDCI3) δ ppm: 7.93 - 7.91 (m, 1H), 6.92 - 6.88 (m, 1H), 6.82 - 6.77 (m, 1H), 4.66 - 4.59 (m, 1H), 4.40 - 4.30 (m, 1H), 4.15 - 4.10 (m, 0.55H), 3.96 - 3.91 (m, 0.45H), 1.57 (d, J= 6.4 Hz, 1.35H), 1.44 (d, J= 6.4 Hz, 1.65H).
Step 1-e: Preparation of 3-methyl-8-nitro-2,3-dihvdro-ri,41dioxinor2,3-b1pyridine and 2-methyl-8-nitro- 2,3-dihydro-[l,41dioxino[2,3-b1pyridine:
A mixture of 3-methyl-2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-5-oxide and 2-methyl-2,3-dihydro- [l,4]dioxino[2,3-b]pyridin-5-oxide (370 mg; 2.10 mmol) was dissolved in TFA (2 mL). Nitric acid, fuming (1 mL) was added dropwise. The solution was heated to 80 °C and stirred for 3 h. The solution was cooled to rt, poured into ice and the mixture was basified to pH about 14 using NaOH solution, 10N in water. The product was extracted with DCM and the organic layer was dried over Na2S04, filtered and concentrated to dryness to afford a mixture of 3-methyl-8-nitro-2,3-dihydro-[l,4]dioxino[2,3-b]pyridine and 2-methyl-8-nitro-2,3-dihydro-[l,4]dioxino[2,3-b]pyridine (270 mg) as a yellow oil.
MS m/z (+ESI): 197.1 [M+H]+.
Step 1-f: Preparation of 3-methyl-2,3-dihvdro-rL41dioxinor2,3-b1pyridin-8-amine and 2-methyl-2,3- dihvdro-rL41dioxinor2,3-b1pyridin-8-amine:
To a solution of a mixture of 3-methyl-8-nitro-2,3-dihydro-[l,4]dioxino[2,3-b]pyridine and 2-methyl-8- nitro-2,3-dihydro-[l,4]dioxino[2,3-b]pyridine (270 mg; 1.31 mmol) in EtOH (15 mL) and H20 (5 mL) was added iron powder (370 mg; 6.54 mmol) and NH4C1 (353 mg; 6.54 mmol). The mixture was heated to 90 °C and stirred for 3 h. The hot mixture was filtered through a plug of celite and the filtrate was concentrated. The residue was basified to pH about 12 using NaOH solution, ION in water. The product was extracted with DCM and the organic layer was dried over Na2S04, filtered and concentrated to dryness to afford a mixture of 3-methyl-2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-8-amine and 2-methyl- 2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-8-amine (220 mg) as a yellow oil.
MS m/z (+ESI): 167.1 [M+H]+.
Step 2: 4-[(4-cyano-2,6-difluorophenyl methylene1-N-(3^
8-yl)piperidine-l-carboxamide, formic acid and 4-[(4-cyano-2,6-difluorophenyl methylenel-N-(2-methyl- 2 -dihvdro-ri,41dioxinor2,3-b1pyridin-8-yl piperidine-l-carboxamide, formic acid:
The title compounds were prepared both as a white solid following scheme 1 and in analogy to Example 2 (steps 3-a and 3-b) using a mixture of 3-methyl-2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-8-amine and 2- methyl-2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-8-amine and 3,5-difluoro-4-(4- piperidylidenemethyl)benzonitrile hydrochloride as starting materials and phenyl chloroformate, and after purification by preparative HPLC (i.e. separation of the 2 compounds was carried out at the last stage).
Preparation of Example 29: 4-[(4-cyano-2,6-difluorophenyl)methylene]-Ar-(2,2-dimethyl-3H- [l,4]dioxino[2,3-b]pyridin-8-yl)piperidine-l-carboxamide, trifluoroacetic acid:
Step 1-a: Preparation of ethyl 2-r(2-chloro-3-pyridyl)oxy1acetate:
To a solution of 2-chloro-3 -pyridinol (1.00 g; 7.64 mmol) in DMF (20 mL) was added NaH, 55% (492 mg; 11.5 mmol). After stirring for 10 min, ethyl bromoacetate (1.28 mL; 11.5 mmol) was added and the mixture was stirred for 3 h. The reaction was deactivated with brine and the mixture was extracted with diethyl ether. The organic layer was dried over Na2S04, filtered and concentrated. The residue was purified by column chromatography (silica gel; PE : diethyl ether; 1 :1, v/v) to afford ethyl 2-[(2-chloro-3- pyridyl)oxy] acetate (1800 mg) as a white semisolid mass.
MS m/z (+ESI): 216.1, 218.1 [M+H]+.
'H-NMR (400 MHz, CDC13) δ ppm: 8.07 (dd, J= 4.4, 1.6 Hz, 1H), 7.22 - 7.14 (m, 2H), 4.73 (s, 2H), 4.31 - 4.21 (m, 2H), 1.32 - 1.28 (m, 3H). Step 1-b: Preparation of l-r(2-chloro-3-pyridyl)oxy1-2-methylpropan-2-ol:
To a solution of ethyl 2-[(2-chloro-3-pyridyl)oxy]acetate (1.80 g; 7.51 mmol) in THF (30 mL) was added dropwise methylmagnesium iodide solution, 3N in THF (7.51 mL; 22.5 mmol). After stirring for 3 h, the reaction was deactivated using a saturated aqueous solution of NH4C1. The product was then extracted with diethyl ether and the organic layer was separated, drier over Na2S04, filtered and concentrated. The residue was purified by column chromatography (silica gel; diethyl ether) to afford l-[(2-chloro-3- pyridyl)oxy]-2-methylpropan-2-ol (1150 mg) as a yellow oil.
MS m/z (+ESI): 202.1, 204.1 [M+H]+. 'H-NMR (400 MHz, CDC13) δ ppm: 8.03 (t, J= 3.2 Hz, 1H), 7.22 (d, J= 2.8 Hz, 2H), 3.88 (s, 2H), 1.41 (s, 6H).
Step 1-c: Preparation of 2,2-dimethyl-3H-ri ,41dioxinor2,3-b1pyridine:
5 The title compound was prepared as a yellow oil following procedure described in Examples 27 and 28 (step 1-c) using l -[(2-chloro-3-pyridyl)oxy]-2-methyl-propan-2-ol as starting material and after purification by column chromatography (silica gel; EA).
MS m/z (+ESI): 166.1 [M+H]+.
'H-NMR (400 MHz, CDCI3) δ ppm: 7.83 (dd, J= 5.2, 1.6 Hz, 1H), 7.20 (dd, J = 8.0, 1.6 Hz, 1H), 6.91 10 (dd, J = 8.0, 5.2 Hz, 1H), 4.10 (s, 2H), 1.39 (s, 6H).
Step 2: Preparation of 4-r(4-cvano-2,6-difluorophenyl methylene1-N-(2,2-dimethyl-3H-ri ,41dioxinor2,3- b1pyridin-8-yl)piperidine-l -carboxamide, trifluoroacetic acid:
The title compound was prepared as a yellow solid following scheme 1 and in analogy to Examples 27 15 and 28 (steps 1 -d, 1 -e, 1 -f and 2) using 2,2-dimethyl-3H-[l ,4]dioxino[2,3-b]pyridine and 3,5-difluoro-4- (4-piperidylidenemethyl)benzonitrile, hydrochloride as starting materials, and after purification by preparative HPLC.
Preparation of Example 30: 4-[(4-cyano-2,6-difluorophenyl)methylene]-Ar-(3,3-dimethyl-2H- 20 [l,4]dioxino[2,3-b]pyridin-8-yl)piperidine-l-carboxamide:
Step 1 : Preparation of 3,3-dimethyl-2H-[l ,41dioxino[2,3-b1pyridine:
To a solution of l -[(2-chloro-3-pyridyl)oxy]-2-methyl-propan-2-ol (2.32 g; 10.9 mmol) in THF (20 mL) was added NaH, 55% (1.31 mg; 32.7 mmol). The reaction mixture was heated to 90 °C and stirred for 18 25 h. EA and brine were added and the organic layer was separated, drier over Na2S04, filtered and
concentrated. The residue was purified by preparative HPLC to afford 3,3-dimethyl-2H-[l ,4]dioxino[2,3- b]pyridine (470 mg) as a yellow oil.
MS m/z (+ESI): 166.1 [M+H]+.
'H-NMR (400 MHz, CDCI3) δ ppm: 7.84 (dd, J= 5.2, 1.6 Hz, 1H), 7.20 (dd, J = 8.0, 1.6 Hz, 1H), 6.85 30 (dd, J = 8.0, 5.2 Hz, 1H), 3.90 (s, 2H), 1.42 (s, 6H).
Step 2: Preparation of 4-r(4-cvano-2,6-difluorophenyl)methylene1-N-(3,3-dimethyl-2H-ri ,41dioxinor2,3- b1pyridin-8-yl)piperidine-l -carboxamide:
The title compound was prepared as a white solid following scheme 1 and in analogy to Examples 27 and 35 28 (steps 1 -d, 1-e, 1 -f and 2) using 3,3-dimethyl-2H-[l ,4]dioxino[2,3-b]pyridine and 3,5-difluoro-4-(4- piperidylidenemethyl)benzonitrile, hydrochloride as starting materials, and after purification by preparative HPLC. Preparation of Example 31: 4-[(4-cyano-2,6-difluorophenyl)methylene]-Ar-(2,3-dimethyl-2,3- dihydro-[l,4]dioxino[2,3-b]pyridin-8-yl)piperidine-l-carboxamide, trifluoroacetic acid:
Step 1: Preparation of 2,3-dimethyl-2,3-dihvdro-ri,41dioxinor2,3-b1pyridine:
To a solution of 2-chloro-3 -pyridinol (3.00 g; 22.9 mmol) in DMF (80 mL) was added NaH, 55% (1.50 g; 34.4 mmol) and 2,3-butylene oxide (2.1 mL; 22.9 mmol). The reaction mixture was heated to 120 °C and stirred for 72 h. After cooling to rt, the reaction mixture was deactivated using H20 and then
concentrated. The residue was purified by preparative HPLC to afford 2,3-dimethyl-2,3-dihydro- [l,4]dioxino[2,3-b]pyridine (400 mg) as a yellow oil.
MS m/z (+ESI): 166.2 [M+H]+.
'H-NMR (400 MHz, CDC13) δ ppm: 7.83 - 7.80 (m, 1H), 7.17 - 7.15 (m, 1H), 6.87 - 6.84 (m, 1H), 4.50 - 4.45 (m, 0.75H), 4.37 - 4.28 (m, 0.75H), 4.06 - 4.04 (m, 0.25H), 3.90 - 3.88 (m, 0.25H), 1.44 - 1.30 (m, 6H). Step 2: Preparation of 4-r(4-cvano-2,6-difluorophenyl)methylene1-N-(2,3-dimethyl-2,3-dihvdro- rL41dioxinor2,3-b1pyridin-8-yl)piperidine-l-carboxamide, trifluoroacetic acid:
The title compound was prepared as a white solid following scheme 1 and in analogy to Examples 27 and 28 (steps 1-d, 1-e, 1-f and 2) using 2,3-dimethyl-2,3-dihydro-[l,4]dioxino[2,3-b]pyridine and 3,5- difluoro-4-(4-piperidylidenemethyl)benzonitrile, hydrochloride as starting materials, and after purification by preparative HPLC.
Preparation of Example 32: 4-[(4-cyano-2,6-difluorophenyl)methylene]-Ar-[3-(hydroxymethyl)-2,3- dihydro-[l,4]dioxino[2,3-b]pyridin-8-yl]piperidine-l-carboxamide: Step 1: Preparation of 4-r(4-cvano-2,6-difluorophenyl)methylene1-N-r3-(hvdroxymethyl)-2,3-dihvdro- rL41dioxinor2,3-b1pyridin-8-vHpiperidine-l-carboxamide:
To a stirred solution of 4-[(4-cyano-2,6-difluorophenyl)methylene]-N-[3-(methoxymethyl)-2,3-dihydro- [l,4]dioxino[2,3-b]pyridin-8-yl]piperidine-l-carboxamide (100 mg; 0.20 mmol) (Example 13) in DCM (3 mL) was added dropwise BBr3 solution, 1M in DCM (0.61 mL; 0.61 mmol). The reaction mixture was stirred for 1.5 h. MeOH (2 mL) was added to deactivate excess of reagent and the solution was washed with brine, dried over MgSO i, filtered and concentrated to dryness to afford 4-[(4-cyano-2,6-difluoro- phenyl)methylene] -N- [3 -(hydroxymethyl)-2,3 -dihydro- [ 1 ,4] dioxino[2,3 -b]pyridin- 8-yl]pip eridine- 1 - carboxamide (100 mg) as a white solid. Preparation of Examples 33 and 34: 4-[(4-chloro-2,6-difluorophenyl)methylene]-Ar-[3- (hydroxymethyl)-2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-8-yl]piperidine-l-carboxamide and 4-[(4- chloro- ^-difluorophenylJmethylenel-A^^-^ydroxymethylJ- ^-dihydro-Il^ldioxino [2,3- b] pyridin-8-yl] piperidine- 1 -carboxamide :
Step 1-a: Preparation of 3-(methoxymethyl -8-nitro-2,3-dihydro-ri,41dioxinor2,3-b1pyridine and 2- (methoxymethyl)-8 -nitro-2,3 -dihydro- [ 1 ,41 dioxino [2,3 -blpyridine:
In a sealable tube, a mixture of 3-(methoxymethyl)- 2,3-dihydro-[l,4]dioxino[2,3-b]pyridine-5-oxide and 2-(methoxymethyl)- 2,3-dihydro-[l,4]dioxino[2,3-b]pyridine-5-oxide (1.32 g; 6.36 mmol) (intermediate examples 11 and 12 step 1-d) was dissolved in TFA (3.8 mL) and nitric acid, fuming (3.7 mL) was added. The tube was sealed and the reaction solution was heated to 90 °C and stirred for 24 h. The solution was placed in an ice-bath and a mixture of ice and water (50 mL) was added. The product was extracted with DCM (3 x 20 mL) and the combined organic layers were concentrated. The residue was suspended in 8% NaHC03 aqueous solution (20 mL). The product was extracted with DCM (3 x 20 mL) and the combined organic layers were dried over MgSO i, filtered and concentrated to dryness. The residue was purified by column chromatography (silica gel; DCM : 20% MeOH in DCM; 1 :0 to 7:3; v/v) to afford a mixture of 3- (methoxymethyl)-8 -nitro-2,3 -dihydro- [ 1 ,4] dioxino [2,3 -b]pyridine and 2-(methoxymethyl)- 8-nitro-2,3 - dihydro-[l,4]dioxino[2,3-b]pyridine (710 mg) as a yellow solid.
MS m/z (+ESI): 227.1 [M+H]+ for both isomers.
'H-NMR (400 MHz, DMSO-i¾ δ ppm: 7.96 - 7.93 (m, 1H), 7.54 - 7.52 (m, 1H), 4.77 - 4.69 (m, 0.75H), 4.66 - 4.61 (m, 0.5H), 4.56 (dd, J= 11.6, 2.6 Hz, 0.75H), 4.41 - 4.34 (m, 0.25H), 4.21 (dd, J = 11.6, 7.7 Hz, 0.75H), 3.69 - 3.65 (m, 2H), 3.35 (s, 2.25H), 3.33 (s, 0.75H).
Step 1-b: Preparation of (8-nitro-2,3-dihvdro-ri,41dioxinor2,3-blpyridin-3-yl)methanol and (8-nitro-2,3- dihvdro-ri,41dioxinor2,3-blpyridin-2-yl)methanol:
To an ice-cold solution of a mixture 3-(methoxymethyl)-8-nitro-2,3-dihydro-[l,4]dioxino[2,3-b]pyridine and 2-(methoxymethyl)-8-nitro-2,3-dihydro-[l,4]dioxino[2,3-b]pyridine (700 mg; 2.79 mmol) in DCM (25 mL) was added dropwise BBr3 solution, 1M in DCM (8.36 mL; 8.36 mmol). The reaction mixture was stirred for 0.5 h at 0 °C. The ice-bath was removed and the reaction mixture was further stirred for 1 h. MeOH (2 mL) was added to deactivate excess of reagent and the mixture was partitioned between DCM and 8% NaHC03 aqueous solution. The layers were separated and the aqueous layer was washed with DCM (2 x 10 mL). The combined organic layers were dried over MgSO i, filtered and concentrated to dryness to afford a mixture of (8-nitro-2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-3-yl)methanol and (8- nitro-2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-2-yl)methanol (560 mg) as a yellow oil.
MS m/z (+ESI): 213.1 [M+H]+ for both isomers. Step 1-c: Preparation of (8-nitro-2,3-dihvdro-ri,41dioxinor2,3-b1pyridin-3-yl methyl acetate and (8-nitro- 2,3-dihvdro-ri,41dioxinor2,3-b1pyridin-2-yl methyl acetate:
To a stirred solution of a mixture of (8-nitro-2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-3-yl)methanol and (8-nitro-2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-2-yl)methanol (493 mg; 2.30 mmol) in DCM (4 mL) were added TEA (0.91 mL; 6.44 mmol) and acetyl chloride (0.25 mL; 3.45 mmol). The reaction solution was stirred for 0.5 h, diluted with DCM (10 mL) and then washed with brine, dried over MgSO i, filtered and concentrated to dryness to afford a mixture of (8-nitro-2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-3- yl)methyl acetate and (8-nitro-2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-2-yl)methyl acetate (577 mg) as a yellow oil.
MS m/z (+ESI): 255.1 [M+H]+ for both isomers.
Step 1-d: Preparation of (8-amino-2,3-dihvdro-rL41dioxinor2,3-b1pyridin-3-yl)methyl acetate and (8- amino-2,3-dihvdro-rL41dioxinor2,3-b1pyridin-2-yl)methyl acetate:
To a stirred solution of (8-nitro-2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-3-yl)methyl acetate (580 mg; 2.21 mmol) in MeOH (20 mL) was added 10% palladium on activated carbon (120 mg; 0.12 mmol). The reaction solution was stirred under hydrogen atmosphere (1 bar) for 0.5 h. The reaction mixture was then filtered through a plug of celite and the cake was washed with methanol. The combined filtrate was concentrated to dryness to afford a mixture of (8-amino-2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-3- yl)methyl acetate and (8-amino-2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-2-yl)methyl acetate (500 mg) as a light yellow solid.
MS m/z (+ESI): 225.1 [M+H]+ for both isomers.
Step 2-a: Preparation of r8-rr4-r(4-chloro-2,6-difluorophenyl)methylene1piperidine-l-carbonyl1amino1- 2,3-dihvdro-rL41dioxinor2,3-b1pyridin-3-yl1methyl acetate and r8-rr4-r(4-chloro-2,6-difluoro- phenvDmethylenelpiperidine- 1 -carbonyll aminol -2,3 -dihydro- Γ 1 ,41 dioxino r2,3-b1pyridin-2-yl1methyl acetate:
A mixture of title compounds was prepared as a light yellow foam following procedure described in Examples 11 and 12 (step 2) using a mixture of (8-amino-2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-3- yl)methyl acetate and (8-amino-2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-2-yl)methyl acetate and 4-[(4- chloro-2,6-difluorophenyl)methylene]piperidine, hydrochloride as starting materials.
MS m/z (+ESI): 494.1, 496.1 [M+H]+ for both isomers. Step 2-b: Preparation of 4-r(4-chloro-2,6-difluorophenyl methylene1-N-r3-(hvdroxymethyl -2,3-dihvdro- ri,41dioxinor2,3-b1pyridin-8-yl1piperidine-l-carboxamide and 4-r(4-chloro-2,6-difluoro- phenvDmethylenel -N- r2-(hvdroxymethyl)-2,3 -dihydro- Γ 1 ,41 άίοχίηοΓ2,3 -blpyridin- 8-vHpip eridine- 1 - carboxamide:
A mixture of [8-[[4-[(4-chloro-2,6-difluorophenyl)methylene]piperidine-l-carbonyl]amino]-2,3-dihydro- [l,4]dioxino[2,3-b]pyridin-3-yl]methyl acetate and [8-[[4-[(4-chloro-2,6-difluoro- phenyl)methylene]piperidine- 1 -carbonyl] amino] -2,3 -dihydro- [ 1 ,4] dioxino [2,3-b]pyridin-2-yl]methyl acetate (900 mg; 1.28 mmol) in MeOH (15 mL) was treated with K2C03 (712 mg; 5.10 mmol). The reaction mixture was stirred for 0.5 h. EA and water were added and the organic layer was separated, washed with brine, dried over MgSO i, filtered and concentrated. The residue was purified by column chromatography (silica gel; DCM : 20% MeOH in DCM; 1 :0 to 7:3; v/v) to afford 4-[(4-chloro-2,6- difluoro-phenyl)methylene] -N- [3 -(hydroxymethyl)-2,3 -dihydro- [ 1 ,4] dioxino [2,3 -b]pyridin-8- yl]piperidine-l -carboxamide (273 mg) as an off-white solid and 4-[(4-chloro-2,6-difluoro- phenyl)methylene] -N- [2-(hydroxymethyl)-2,3 -dihydro- [ 1 ,4] dioxino[2,3 -b]pyridin- 8-yl]pip eridine- 1 - carboxamide (115 mg) as a white foam.
Preparation of Example 35: 4-[(4-chloro-2,6-difluorophenyl)methylene]-Ar-[3-(cyanomethyl)-2,3- dihydro-[l,4]dioxino[2,3-b]pyridin-8-yl]piperidine-l-carboxamide: Step 1: Preparation of 4-[(4-chloro-2,6-difluorophenyl)methylenel-N-r3-(cyanomethyl)-2,3-dihydro- ri,41dioxinor2,3-b1pyridin-8-vHpiperidine-l -carboxamide:
To an ice-cold solution of 4-[(4-chloro-2,6-difluorophenyl)methylene]-N-[3-(hydroxymethyl)-2,3- dihydro-[l,4]dioxino[2,3-b]pyridin-8-yl]piperidine-l-carboxamide (85 mg; 0.19 mmol) (Example 33) in dry THF (2 mL) was added triphenylphosphine (107 mg; 0.39 mmol) and acetone cyanohydrin (0.044 mL; 0.48 mmol). After 5 min, diethyl azodicarboxylate (0.061 mL; 0.37 mmol) was added dropwise and the reaction soluton was stirred for additional 10 min at 0 °C. The ice-bath was removed. After stirring for 20 h, the reaction solution was concentrated. The residue was purified by column chromatography (silica gel; DCM : 20% MeOH in DCM; 1 :0 to 7:3; v/v) to afford 4-[(4-chloro-2,6-difluorophenyl)methylene]- N-[3-(cyanomethyl)-2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-8-yl]piperidine-l-carboxamide (43 mg) as a white solid.
Preparation of Example 36: 4-[(4-cyano-2,6-difluorophenyl)methylene]-Ar-(3,4-dihydro-2H- [l,4]dioxepino[2,3-b]pyridin-9-yl)piperidine-l-carboxamide: Step 1-a: Preparation of 3,4-dihvdro-2H-rL41dioxepinor2,3-b1pyridin-6-oxide:
The title compound was prepared as a yellow oil following procedure described in Example 5 (step 1-a) using 3,4-dihydro-2H-[l,4]dioxepino[2,3-b]pyridine as starting material. MS m/z (+ESI): 167.9 [M+H]
Step 1-b: Preparation of 9-nitro-3,4-dihvdro-2H-ri,41dioxepinor2,3-b1pyridine:
The title compound was prepared as a yellow solid following procedure described in Example 5 (step 1-b) using 3,4-dihydro-2H-[l,4]dioxepino[2,3-b]pyridin-6-oxide as starting material and after purification by column chromatography (silica gel; DCM : 20% MeOH in DCM; 1 :0 to 4: 1 ; v/v).
MS m/z (+ESI): 197.3 [M+H]+.
'H-NMR (400 MHz, DMSO-i¾ δ ppm: 8.07 (d, J= 5.2 Hz, 1H), 7.57 (d, J= 5.2 Hz, 1H), 4.42 (t, J= 5.6 Hz, 2H), 4.37 (t, J= 5.8 Hz, 2H), 2.24 (dt, J= 5.6, 5.8 Hz, 2H).
Step 1-c: Preparation of 9-amino-3,4-dihvdro-2H-ri,41dioxepinor2,3-b1pyridine:
The title compound was prepared as a white solid following procedure described in Example 5 (step 1-c) using 9-nitro-3,4-dihydro-2H-[l,4]diox ino[2,3-b]pyridine as starting material.
MS m/z (+ESI): 166.9 [M+H]+.
'H-NMR (400 MHz, DMSO-i¾ δ ppm: 7.37 (d, J= 5.4 Hz, 1H), 6.35 (d, J= 5.4 Hz, 1H), 5.78 (s, 2H), 4.12 (t, J= 5.6 Hz, 2H), 4.05 (t, J= 5.6 Hz, 2H), 2.12 - 2.04 (m, 2H).
Step 2: Preparation of 4-[(4-cyano-2,6-difluorophenyl)methylenel-N-(3,4-dihydro-2H- Γ1 ,41dioxepinor2,3-b1pyridin-9-yl)piperidine- 1 -carboxamide:
The title compound was prepared as a white solid following procedure described in Examples 11 and 12 (step 2) using 9-amino-3,4-dihydro-2H-[l,4]diox ino[2,3-b]pyridine and 3,5-difluoro-4-(4- piperidylidenemethyl)benzonitrile as starting materials and after purification by column chromatography (silica gel; DCM : 20% MeOH in DCM; 1 :0 to 7:3; v/v). Preparation of Example 37: 4-(4-chlorophenoxy)-Ar-(3,4-dihydro-2H-[l,4]dioxepino[2,3-b]pyridin- 9-yl)piperidine-l-carboxamide:
Step 1: Preparation of 4-(4-chlorophenoxy)-N-(3,4-dihvdro-2H-ri,41dioxepinor2,3-b1pyridin-9- vDpiperidine- 1 -carboxamide:
The title compound was prepared as a white solid following procedure described in Examples 11 and 12 (step 2) using 9-amino-3,4-dihydro-2H-[l,4]diox ino[2,3-b]pyridine and 4-(4-chlorophenoxy)piperidine hydrochloride as starting materials and after purification by column chromatography (silica gel; DCM : 20% MeOH in DCM; 1 :0 to 7:3; v/v). Preparation of Example 41: 4- [[2,6-difluoro-4- [methyl- [(1 -met hylazetidin-3- yl)methyl]amino]phenyl]methylene]-Ar-(2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-8-yl)piperidine-l- carboxamide, formic acid: Step 1: Preparation of ferf-butyl 3-rr3,5-difluoro-4-(4-piperidylidenemethyl anilino1methyl1azetidine-l- carboxylate:
To a solution of 4-[(4-chloro-2,6-difluorophenyl)methylene]piperidine hydrochloride (300 mg; 1.07 mmol) in dioxane (12 mL) were added tris(dibenzylideneacetone)dipalladium (224 mg; 0.21 mmol), 1- Boc-3-(aminomethyl)azetidine (302 mg; 1.61 mmol), CS2CO3 (1057 mg; 3.21 mmol) and X-Phos (206 mg; 0.43 mmol). The reaction mixture was heated to 100 °C and stirred for 16 h. After cooling to rt, water and EA were added and the organic layer was separated, dried over MgSO i, filtered and concentrated. The residue was purified by preparative HPLC to afford teri-butyl 3-[[3,5-difluoro-4-(4- piperidylidenemethyl)anilino]methyl]azetidine-l -carboxylate (100 mg) as a brown oil.
MS m/z (+ESI): 394.0 [M+H]+.
Step 2-a: Preparation of ferz-butyl 3-rr4-rri-(2,3-dihvdro-ri,41dioxinor2,3-b1pyridin-8-ylcarbamoyl)-4- piperidylidenelmethyll -3 ,5-difluoroanilinolmethyll azetidine- 1 -carboxylate :
The title compound was prepared as a yellow solid following scheme 1 and in analogy to Example 2 (step 3-b) using teri-butyl 3-[[3,5-difluoro-4-(4-piperidylidenemethyl)anilino]methyl]azetidine- 1 -carboxylate and phenyl N-(2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-8-yl)carbamate as starting materials and after purification by preparative HPLC.
MS m/z (+ESI): 572.1 [M+H]+. Step 2-b: Preparation of 4-[[4-(azetidin-3-ylmethylamino)-2,6-difluorophenyllmethylenel-N-(2,3- dihvdro-rL41dioxinor2,3-b1pyridin-8-yl)piperidine-l-carboxamide, trifluoroacetic acid:
To a solution of teri-butyl 3-[[4-[[l-(2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-8-ylcarbamoyl)-4- piperidylidene]methyl]-3,5-difluoroanilino]methyl]azetidine-l-carboxylate (110 mg; 0.19 mmol) in DCM (5 mL) was added TFA (1 mL). The reaction was stirred for 1 h and then concentrated to dryness to afford 4- [ [4-(azetidin-3 -ylmethylamino)-2,6-difluorophenyl]methylene] -N-(2,3 -dihydro- [ 1 ,4] dioxino[2,3 - b]pyridin-8-yl)piperidine-l-carboxamide, trifluoroacetic acid (89 mg) as a brown oil.
MS m/z (+ESI): 471.9 [M+H]+.
Step 2-c: Preparation of 4-rr2,6-difluoro-4-rmethyl-r(l-methylazetidin-3- yl)methyl1amino1phenyl1methylene1-N-(2 -dihvdro-ri^1dioxinor2 -b1pyridin-8-yl)piperidine-l - carboxamide, formic acid:
To a solution of 4-[[4-(azetidin-3-ylmethylamino)-2,6-difluorophenyl]methylene]-N-(2,3-dihydro- [l,4]dioxino[2,3-b]pyridin-8-yl)piperidine-l-carboxamide (100 mg; 0.21 mmol) in MeOH (3 mL) were added formaldehyde solution, 36% in water (0.08 mL; 1.05 mmol) and NaBH3CN (40 mg; 0.63 mmol). The mixture was stirred for 18 h and then purified by preparative HPLC to afford of 4-[[2,6-difluoro-4- [methyl- [(1 -methylazetidin-3 -yl)methyl] amino]phenyl]methylene] -N-(2,3 -dihydro- [ 1 ,4] dioxino [2,3 - b]pyridin-8-yl)piperidine-l-carboxamide, formic acid (32 mg) as a white solid. Preparation of Example 45: 4-[(2,6-difluoro-4-methoxyphenyl)methyl]-Ar-(2,3-dihydro- [l,4]dioxino[2,3-b]pyridin-8-yl)azepane-l-carboxamide, trifluoroacetic acid:
Step 1-a: Preparation of 2-(diethoxyphosphorylmethyl -l ,3-difluoro-5-methoxybenzene:
In a re-sealable tube was charged triethyl phosphite (3.54 mL; 20.46 mmol) and 2-(bromomethyl)-l ,3- difluoro-5-methoxybenzene (5.00 g; 20.46 mmol). The tube was sealed and the mixture was heated to 140 °C and stirred for 6 h. After cooling to rt, the mixture was purified by column chromatography (silica gel; PE : EA; 2: 1 ; v/v) to afford 2-(diethoxyphosphorylmethyl)-l ,3-difluoro-5-methoxy-benzene (5.40 g) as a colorless oil.
MS m/z (+ESI): 295.1 [M+H]+.
Step 1-b: Preparation of ferf-butyl 4-Γ 2,6-difluoro-4-methoxyphenyl)methylene^azφane- l -carboxylate: To a solution of 2-(diethoxyphosphorylmethyl)- l ,3-difluoro-5-methoxy-benzene (3.00 mg; 10.1 mmol) in THF (60 mL) was added NaH, 55% (600 mg; 15.1 mmol). The mixture was stirred for 0.5 h and tert- butyl 4-oxoazepane- l-carboxylate (2.18 mg; 10.1 mmol) was added. The reaction mixture was stirred for 16 h. Saturated aqueous solution of NH4CI and EA were added and the organic layer was separated, washed with water and brine, dried over MgSO i, filtered and concentrated. The residue was purified by column chromatography (silica gel; PE : EA; 10: 1 to 5: 1 ; v/v) to afford tert-butyl 4-[(2,6-difluoro-4- methoxy-phenyl)methylene]azepane-l -carboxylate (1.00 mg) as a colorless oil.
MS m/z (+ESI): 354.0 [M+H]+.
Step 1-c: Preparation of ferf-butyl 4-[(2,6-difluoro-4-methoxyphenyl)methyllazφane-l -carboxylate: To a stirred solution of tert-butyl 4-[(2,6-difluoro-4-methoxyphenyl)methylene]azepane- l-carboxylate (550 mg; 1.54 mmol) in MeOH (30 mL) was added 10% palladium on activated carbon (160 mg; 0.15 mmol). The reaction solution was stirred under hydrogen atmosphere (1 bar) for 16 h. The reaction mixture was then filtered through a plug of celite and the cake was washed with methanol. The combined filtrate was concentrated to dryness to afford tert-butyl 4-[(2,6-difluoro-4-methoxyphenyl)methyl]- azepane-l -carboxylate (526 mg) as a colorless oil.
MS m/z (+ESI): 356.0 [M+H]+.
Step 2: Preparation of 4-r(2,6-difluoro-4-methoxyphenyl)methyl1-N-(2,3-dihvdro-rL41dioxinor2,3- b1pyridin-8-yl)azepane-l -carboxamide, trifluoroacetic acid:
The title compound was prepared as a white solid following scheme 1 and in analogy to Example 2 (steps 1 -d and 3-b) using tert-butyl 4-[(2,6-difluoro-4-methoxyphenyl)methyl]azepane- l -carboxylate and phenyl N-(2,3-dihydro-[l ,4]dioxino[2,3-b]pyridin-8-yl)carbamate as starting materials, and after purification by preparative HPLC. Preparation of Example 46: 4-[(4-cyano-2,6-difluorophenyl)methylene]-Ar-[2- (hydroxymethyl)thieno[2,3-b]pyridin-4-yl]piperidine-l-carboxamide:
Step 1: Preparation of 4-chlorothienor2,3-b1pyridine-2-carbaldehyde:
To a solution of 4-chloro-thieno[2,3-b]pyridine (107 mg; 0.62 mmol) in THF (8 mL) was added lithium diisopropylamide (0.078 mL; 0.62 mmol) at -78 °C. The mixture was stirred for 1 h and DMF (0.051 mL; 0.65 mmol) was added. After stirring for 1 h at -78 °C, water (1 mL) was cautiously added and the mixture was concentrated. The residue was purified by column chromatography (silica gel; PE : EA; 10:1 ; v/v) to afford 4-chlorothieno[2,3-b]pyridine-2-carbaldehyde (86 mg) as a yellow solid.
MS m/z (+ESI): 198.0, 200.0 [M+H]+.
'H-NMR (400 MHz, DMSO-i¼) δ ppm: 10.19 (s, 1H), 8.72 (d, J= 5.2 Hz, 1H), 8.55 (s, 1H), 7.77 (d, J= 5.2 Hz, 1H).
Step 2-a: Preparation of 4-r(4-cvano-2,6-difluorophenyl)methylene1-N-(2-formylthienor2,3-b1pyridin-4- vDpiperidine- 1 -carboxamide:
The title compound was prepared as a yellow solid following scheme 3 and in analogy to Example 6 (steps 2-a and 2-b) using 4-chlorothieno[2,3-b]pyridine-2-carbaldehyde and 4-[(4-cyano-2,6-difluoro- phenyl)methylene]piperidine hydrochloride as starting materials, and after purification by column chromatography (silica gel; DCM : EA; 3:2; v/v).
MS m/z (+ESI): 439.0 [M+H]+.
Step 2-b: Preparation of 4-[(4-cyano-2,6-difluorophenyl)methylenel-N-r2-(hydroxymethyl)thienor2,3- blpyridin-4-vHpiperidine-l -carboxamide:
To a solution solution of 4-[(4-cyano-2,6-difluoro-phenyl)methylene]-N-(2-formylthieno[2,3-b]pyridin-4- yl)piperidine-l -carboxamide (153 mg; 0.34 mmol) in MeOH (15 mL) was added NaBH4 (26 mg; 0.68 mmol). The mixture was stirred for 2 h and then concentrated. The residue was purified by preparative HPLC to afford 4- [(4-cyano-2,6-difluorophenyl)methylene] -N- [2-(hydroxymethyl)thieno [2,3 -b]pyridin-4- yl]piperidine-l -carboxamide (97 mg) as a white solid. Preparation of Example 47: 4-[(4-cyano-2,6-difluorophenyl)methylene]-Ar-(2,3-dihydro-lH- pyrido[2,3-b] [l,4]oxazin-8-yl)piperidine-l-carboxamide:
Step 1-a: Preparation of 2-r(2-chloro-4-nitro-3-pyridyl)amino1ethanol:
A solution of 2-aminoethanol (0.67 mL; 11 mmol) cooled to 0 °C was treated with 2-chloro-3-fluoro-4- nitropyridine (2.00 g; 11 mmol) and stirred for 0.5 h. A solid was formed, which was then purified by column chromatography (silica gel; PE : EA; 1 :1 to 0:1 ; v/v) to afford 2-[(2-chloro-4-nitro-3- pyridyl)amino]ethanol (1.68 g) as an orange solid. 'H-NMR (400 MHz, CDC13) δ ppm: 7.85 (d, J= 5.6 Hz, 1H), 7.68 (d, J= 5.6 Hz, 1H), 3.89 - 3.85 (m, 2H), 3.56 - 3.52 (m, 2H).
Step 1-b: Preparation of 2 (4-amino-2-chloro-3-pyridyl)amino1ethanol:
To a stirred solution of 2-[(2-chloro-4-nitro-3-pyridyl)amino]ethanol (1.68 g; 7.64 mmol) in EtOH (90 mL) and H20 (30 mL) was added iron powder (2.18 g; 38.2 mmol) and NH4Cl (2.07 mg; 38.2 mmol). The mixture was heated to 80 °C and stirred for 2 h. The hot mixture was filtered through a plug of celite and the filtrate was concentrated under reduced pressure. The residue was basified to pH 12 using NaOH solution, 6N in H20. The product was extracted with a mixture of DCM and z'PrOH (2 x 50 mL; 3: 1 ; v/v). The combined organic layers were dried over Na2S04, filtered and concentrated to dryness to afford 2- [(4-amino-2-chloro-3-pyridyl)amino]ethanol (1.10 g) as a yellow solid.
MS m/z (+ESI): 188.1, 190.1 [M+H]+.
Step 1-c: Preparation of 2,3-dihvdro-lH-pyridor2,3-bi ri,41oxazin-8-amine:
To a solution of 2-[(4-amino-2-chloro-3-pyridyl)amino]ethanol (1.00 g; 4.80 mmol) in i-BuOH (20 mL) was added potassium tert-butoxide (1.63 g; 14.4 mmol). The mixture was heated to 100 °C and stirred for
3 h. The mixture was cooled down to rt and filtered through a plug of celite. The filtrate was concentrated and the residue was purified by column chromatography (silica gel; EA : MeOH; 1 :0 to 2: 1 ; v/v) to afford
2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-8-amine (455 mg) as a yellow solid.
MS m/z (+ESI): 152.1 [M+H]+.
'H-NMR (400 MHz, DMSO-i¾ δ ppm: 7.15 (d, J= 5.6 Hz, 1 H), 6.18 (d, J= 5.6 Hz, 1 H), 5.34 (s, 2 H),
4.56 (br, 1 H), 4.16 - 4.13 (m, 2 H), 3.25 - 3.21 (m, 2 H).
Step 1-d: Preparation of (8-amino-2,3-dihvdropyridor2,3-birL41oxazin-l-yl)phenylmethanone:
To a solution of 2,3-dihydro-lH-pyrido[2,3-b][l,4]oxazin-8-amine (450 mg; 2.83 mmol) in ACN (30 mL) was added benzoyl chloride (0.33 mL; 2.83 mmol) at 0 °C. The cooling bath was removed and the reaction solution was stirred for 18 h. Volatiles were removed under reduced pressure and the residue was triturated in Et20, filtered and dried under vacuum to afford (8-amino-2,3-dihydropyrido[2,3- b][l,4]oxazin-l-yl)phenylmethanone (510 mg) as a yellow solid.
MS m/z (+ESI): 256.2 [M+H]+.
Step 1-e: Preparation of phenyl N-(l-benzoyl-2,3-dihvdropyridor2,3-birL41oxazin-8-yl)carbamate: The title compound was prepared as a white foam following scheme 1 and in analogy to procedure described in Example 2 (step 3-a) using (8-amino-2,3-dihydropyrido[2,3-b][l,4]oxazin-l-yl)phenyl- methanone and phenyl chloroformate as starting materials and after purification by column
chromatography (silica gel; PE : EA; 3: 1 to 1 : 1 ; v/v).
MS m/z (+ESI): 376.1 [M+H]+. Step 2-a: Preparation ofN-(l-benzoyl-2,3-dihydropyridor2,3-birL41oxazin-8-yl -4-r(4-cvano-2,6- difluoro-phenvPmethylenelpiperidine- 1 -carboxamide:
The title compound was prepared as a white gum following scheme 1 and in analogy to procedure described in Example 2 (step 3-b) using phenyl N-(l-benzoyl-2,3-dihydropyrido[2,3-b][l,4]oxazin-8- yl)carbamate and 3,5-difluoro-4-(4-piperidylidenemethyl)benzonitrile hydrochloride as starting materials and after purification by column chromatography (silica gel; PE : EA; 1 : 1 to 0: 1 ; v/v).
MS m/z (+ESI): 516.2 [M+H]+.
Step 2-b: Preparation of 4-r(4-cvano-2,6-difluorophenyl methylene1-N-(2,3-dihvdro-lH-pyridor2,3- bl Γ1 ,41oxazin-8-yl piperidine-l -carboxamide:
To a solution of N-(l-benzoyl-2,3-dihydropyrido[2,3-b][l,4]oxazin-8-yl)-4-[(4-cyano-2,6-difluoro- phenyl)methylene]piperidine-l -carboxamide (120 mg; 0.22 mmol) in MeOH (3 mL) was added KOH (63 mg; 1.11 mmol). The mixture was heated to 60 °C and stirred for 0.5 h. After cooling, the mixture was purified by preparative HPLC to afford 4-[(4-cyano-2,6-difluoro-phenyl)methylene]-N-(2,3-dihydro-lH- pyrido[2,3-b][l,4]oxazin-8-yl)piperidine-l-carboxamide as a yellow solid.
Preparation of Example 59: 4-(4-chlorobenzoyl)-Ar-(2,3-dihydro-[l,4]dioxino[2,3-b]pyridin-8-yl)- 3,5-dimethylpiperidine-l-carboxamide: Step 1-a: Preparation of ferf-butyl 4-(methoxymethylene)-3,5-dimethylpiperidine-l-carboxylate:
To a suspension of (methoxymethyl)triphenylphosphonium chloride (2.92 g; 8.36 mmol) in THF (10 mL) was added a solution of potassium tert-butoxide (1.44 g; 12.5 mmol) in THF (15 mL) at 0 °C. The mixture was stirred for 1 h and a solution of tert-butyl 3,5-dimethyl-4-oxopiperidine-l-carboxylate (1.00 g; 4.18 mmol) in THF (15 mL) was added at 0 °C. The mixture was allowed to warm up to rt and stirred for 16 h. Saturated aqueous solution of NH4C1 (20 mL) was added and THF was removed under reduced pressure. The product was extracted with EA (2 x 20 mL) and the combined organic layers were dried over Na2S04, filtered and concentrated. The residue was purified by column chromatography (silica gel; PE : EA; 10:1 ; v/v) to afford tert-butyl 4-(methoxymethylene)-3,5-dimethyl-piperidine-l -carboxylate (880 mg) as a colorless oil.
MS m/z (+ESI): 200.2 [M-i-Bu+H]+.
Step 1-b: Preparation of ferf-butyl 4-formyl-3,5-dimethylpiperidine-l-carboxylate:
To a solution of tert-butyl 4-(methoxymethylene)-3,5-dimethylpiperidine-l-carboxylate (600 mg; 2.30 mmol) in ACN (30 mL) was added CeCl3 (1.14 g; 4.61 mmol) and Nal (115 mg; 0.76 mmol) at 40 °C. The mixture was stirred for 18 h. The solvent was removed under reduced pressure and the residue was dissolved in EA (15 mL). The solution was then successively washed with HC1 solution, 1 N in H20, saturated aqueous solution of NaHCC>3 and brine. The organic layer was dried over Na2S04, filtered and concentrated. The residue was purified by column chromatography (silica gel; PE : EA; 1 :0 to 7:3; v/v) to afford teri-butyl 4-formyl-3,5-dimethylpiperidine- l-carboxylate (550 mg) as a colorless oil.
MS m/z (+ESI): 186.2 [M-/-Bu+H]+. Step 1-c: Preparation of ferf-butyl 4-r(4-chlorophenyl hvdroxymethyl1-3,5-dimethylpiperidine-l - carboxylate:
To a solution of teri-butyl 4-formyl-3,5-dimethylpiperidine-l -carboxylate (405 mg; 1.65 mmol) in THF (15 mL) was added 4-chlorophenylmagnesium bromide (0.61 mL; 2.47 mmol) at -20 °C. The mixture was stirred for 1 hour and then deactivated using saturated aqueous solution of NH4C1. EA and H20 were added and the organic layer was separated, washed with brine, dried over MgSO i, filtered and concentrated to afford crude teri-butyl 4-[(4-chlorophenyl)hydroxymethyl]-3,5-dimethylpiperidine-l - carboxylate (580 mg) as a colorless oil.
MS m/z (+ESI): 354.2, 356.1 [M+H]+. Step 1-d: Preparation of ferf-butyl 4-(4-chlorobenzoyl)-3,5-dimethylpiperidine- l -carboxylate:
To a solution of teri-butyl 4-[(4-chlorophenyl)hydroxymethyl]-3,5-dimethylpiperidine-l -carboxylate (190 mg; 0.430 mmol) in DMSO (1 mL) was added 2-iodoxybenzoic Acid (380 mg; 1.29 mmol). The mixture was stirred for 16 h and H20 (50 mL) was added. The product was extracted with EA (3 x 25 mL) and the combined organic layers were dried over MgSO i, filtered and concentrated. The residue was purified by column chromatography (silica gel; PE : EA; 8.5: 1.5; v/v) to afford teri-butyl 4-(4-chlorobenzoyl)-3,5- dimethylpiperidine-l -carboxylate (127 mg) as a colorless oil.
MS m/z (+ESI): 352.1 , 354.1 [M+H]+.
'H-NMR (400 MHz, CDC13) δ ppm: 7.92 - 7.89 (m, 2H), 7.47 - 7.44 (m, 2H), 3.86 - 3.80 (m, 3H), 3.17 - 3.10 (m, 2H), 2.06 - 2.00 (m, 2H), 1.51 and 1.49 (2s, 9H), 0.84 - 0.81 (m, 6H).
Step 1-e: Preparation of (4-chlorophenyl)-(3,5-dimethyl-4-piperidyl)methanone, hydrochloride:
teri-Butyl 4-(4-chlorobenzoyl)-3,5-dimethylpiperidine-l -carboxylate (430 mg; 1.10 mmol) was dissolved in HC1 solution, 4N in dioxane (10 mL) and the mixture was stirred for 2 h. Volatiles were removed under reduced pressure to afford (4-chlorophenyl)-(3,5-dimethyl-4-piperidyl)methanone hydrochloride (350 mg) as a white solid.
MS m/z (+ESI): 252.2, 254.2 [M+H]+.
Step 2: Preparation of 4-(4-chlorobenzoyl)-N-(2,3-dihvdro-rL41dioxinor2,3-b1pyridin-8-yl)-3,5- dimethylpiperidine- 1 -carboxamide:
The tile compound was prepared as a white solid following scheme 1 and in analogy to Example 2 (step 3-b) using (4-chlorophenyl)-(3,5-dimethyl-4-piperidyl)methanone, hydrochloride and phenyl N-(2,3- dihydro-[l ,4]dioxino[2,3-b]pyridin-8-yl)carbamate as starting materials and after purification by preparative HPLC.
Preparation of Example 60: 4-[(4-fluoro-6-methoxy-3-pyridyl)methylene]-Ar-(2,3,4,5- tetrahydrooxepino [2,3-b] pyridin-6-yl)piperidine-l-carboxamide :
Step 1-a: Preparation of 4-(2-fluoro-3-pyridyl)butan-l -ol:
To a stirred solution of 4-(2-fluoro-3-pyridyl)but-3-yn-l -ol (1.83 g; 9.97 mmol) in MeOH (77 mL) was added 10% palladium on activated carbon (200 mg). The reaction solution was stirred under hydrogen atmosphere (1 bar) for 5 h. Insolubles were removed by filtration and the cake was washed with MeOH. The combined filtrate was concentrated to dryness. The residue was purified by column chromatography (silica gel; PE:EA; 1 : 1 ; v/v) to afford 4-(2-fluoro-3-pyridyl)butan-l -ol (1.68 g) as a colorless oil.
MS m/z (+ESI): 170.1 [M+H]+.
Step 1-b: Preparation of 2,3,4,5-ί6^^(1τοοχφίηοΓ2,3^1ρντίάίη6:
To an ice-cold solution of 4-(2-fluoro-3-pyridyl)butan-l -ol (483 mg; 2.71 mmol) in DMF (5 mL) was added in portions NaH, 55% (325 mg; 8.14 mmol) and the reaction mixture was stirred for 0.5 h at 0°C. The mixture was then heated to 100°C and stirred for 1.5 h. EA (20 mL) and water (10 mL) were added and the organic layer was separated, dried over MgSO i, filtered and concentrated. The residue was purified by column chromatography (silica gel; PE:EA; 1 : 1 ; v/v) to afford 2,3,4,5-tetrahydrooxepino[2,3- b]pyridine (406 mg) as a yellow oil.
MS m/z (+ESI): 150.2 [M+H]+.
'H-NMR (400 MHz, CDC13) δ ppm: 8.12 - 8.10 (m, 1H), 7.51 - 7.48 (m, 1H), 6.98 - 6.94 (m, 1H), 4.17 - 4.14 (m, 2H), 2.80 - 2.78 (m, 2H), 2.04 - 1.98 (m, 2H), 1.81 - 1.74 (m, 2H).
Step 1-c: Preparation of phenyl N-(2,3,4,5-tetrahvdrooxepinor2,3-b1pyridin-6-yl)carbamate:
The tile compound was prepared as a yellow oil following scheme 1 and in analogy to Example 2 (steps 2-a to 2-c and 3-b) using 2,3,4,5-tetrahydrooxepino[2,3-b]pyridine as starting material.
MS m/z (+ESI): 285.2 [M+H]+.
Step 2-a: Preparation of 4-fluoro-2-methoxy-5-(4-piperidylidenemethyl)pyridine hydrochloride:
The tile compound was prepared as a yellow solid following scheme 5 and in analogy to Example 2 (steps 1 -c to 1 -d) using tert-butyl 4-[(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)methylene]piperidine-l - carboxylate and 5-bromo-4-fluoro-2-methoxy-pyridine as starting materials.
MS m/z (+ESI): 285.2 [M+H]+. Step 2-b: Preparation of 4-r(4-fluoro-6-methoxy-3-pyridyl methylene1-N-(2,3,4,5-tetrahvdrooxepinor2,3- b1pyridin-6-yl piperidine-l-carboxamide:
The tile compound was prepared as a yellow solid following scheme 1 and in analogy to Example 2 (step 3-b) using phenyl N-(2,3,4,5-tetrahydrooxepino[2,3-b]pyridin-6-yl)carbamate and 4-fluoro-2-methoxy-5- (4-piperidylidenemethyl)pyridine, hydrochloride as starting materials and after purification by preparative HPLC.
Preparation of Example 61: 4-[(5-methoxypyrazin-2-yl)methylene]-Ar-(6,7,8,9- tetrahydrooxepino [3,2-b] pyridin-4-yl)piperidine-l-carboxamide :
Step 1-a: Preparation of 4-(3-fluoro-2-pyridyl)butan-l-ol:
The title compound was prepared as a yellow oil in analogy to Example 60 (step 1-a) using 4-(3-fluoro-2- pyridyl)but-3-yn-l-ol as starting material.
MS m/z (+ESI): 170.1 [M+H]+.
Step 1-b: Preparation of 6,7,8, 9-ί6^^(1τοοχφίηοΓ3,2^1ρντίάίη6:
To a solution of 4-(3-fluoro-2-pyridyl)butan-l-ol (520 mg; 2.92 mmol) in DMF (15 mL) was added in portions NaH, 55% (584 mg; 14.6 mmol). The reaction mixture was then irradiated for 0.5 h at 100°C. EA (30 mL) and water (10 mL) were added and the organic layer was separated, dried over MgSO i, filtered and concentrated. The residue was purified by column chromatography (silica gel; PE:EA; 1 : 1; v/v) to afford 6,7,8, 9-tetrahydrooxepino[3,2-b]pyridine (407 mg) as a yellow oil.
MS m/z (+ESI): 150.1 [M+H]+.
'H-NMR (400 MHz, CDC13) δ ppm: 8.19 - 8.17 (m, 1H), 7.27 - 7.24 (m, 1H), 7.08 - 7.04 (m, 1H), 4.04 - 4.01 (m, 2H), 3.09 - 3.05 (m, 2H), 2.02 - 1.96 (m, 2H), 1.84 - 1.75 (m, 2H).
Step 1-c: Preparation of phenyl N-(6,7,8,9-tetrahvdrooxepinor3,2-b1pyridin-4-yl)carbamate:
The tile compound was prepared as a yellow oil following scheme 1 and in analogy to Example 2 (steps
2-a to 2-c and 3-b) using 6,7,8,9-tetrahydrooxepino[3,2-b]pyridine as starting material.
MS m/z (+ESI): 285.1 [M+H]+.
Step 2-a: Preparation of 2-methoxy-5-(4-piperidylidenemethyl)pyrazine hydrochloride:
The tile compound was prepared as a yellow solid following scheme 5 and in analogy to Example 2 (steps 1-c to 1-d) using tert-butyl 4-[(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)methylene]piperidine-l - carboxylate and 2-bromo-5-methoxypyrazine as starting materials.
MS m/z (+ESI): 206.1 [M+H]+. Step 2-b: Preparation of 4-r(5-methoxypyrazin-2-yl methylene1-N-(6,7,8,9-tetrahvdrooxepinor3,2- b1pyridin-4-yl)piperidine-l-carboxamide:
The tile compound was prepared as a yellow solid following scheme 1 and in analogy to Example 2 (step 3-b) using phenyl N-(6,7,8,9-tetrahydrooxepino[3,2-b]pyridin-4-yl)carbamate and 2-methoxy-5-(4- 5 piperidylidenemethyl)pyrazine hydrochloride as starting materials and after purification by preparative HPLC.
Biological Examples
Cell culture
10 The cervical tumor cell line HeLa (ATCC, CCL-2) was cultivated in DMEM medium (Invitrogen cat. no.11971, 4.5 g/L high glucose) containing 10% fetal calf serum (Sigma cat. no. F9665) and 1%
Penicillin/Streptomycin (Sigma cat. no. P0781) at 37 °C in 5% CO2. HeLa galactose cells (i.e. HeLa cells that grow in high concentrations of galactose) were generated from HeLa glucose cells (i.e. HeLa cells that grow in high concentrations of glucose) by gradually changing the amount of glucose in the media to
15 zero glucose in the presence of galactose as a sugar source (50% galactose /50% glucose media for one week, then 75% galactose /25% glucose media for one week, to 100% galactose media in the third week). Galactose media (Invitrogen cat. no. 11966) was supplemented with 10 mM galactose (Sigma cat. no. G5388).
20 Cell growth and proliferation assay of HeLa Galactose and Glucose Cells
HeLa galactose cells and HeLa glucose cells were seeded in 96 well plates (TPP, cat.no 92696) at 2000 and 1500 cells/well, respectively, in 100 of complete medium. After overnight incubation the cells were incubated for 72 hours in complete medium containing 0.001 ) DMSO or compounds (final concentration of DMSO 0.001%). After the medium was removed, cells were fixed and stained by adding
25 50 \L crystal violet staining (0.2 % crystal violet (Sigma- Aldrich cat. no. C0775) in 50% methanol) per well. The plates were incubated for 1 hour at room temperature. Subsequently the stain was decanted and plates were washed 4 times with de-mineralized water. Plates were air-dried for 2 hours. The stain was dissolved by adding 100 i buffer (0.1 M Tris pH 7.5, 0.2% SDS, 20% ethanol) per well and shaking the plates. Absorbance at 590 nm was measured using a SpectraMax® 250 plate reader (Molecular Devices).
30 Antiproliferative / growth inhibition IC50s were calculated from concentration-response curves using GraphPad Prism software.
Oxygen consumption assay
Oxygen consumption is one of the most informative and direct measures of mitochondrial function and 35 can be measured, for example, by using the MitoXpress® assay (Luxcel MX-2001, Luxcel Biosciences).
The MitoXpress® probe is one of a family of phosphorescent oxygen sensitive probes. The assay exploits the ability of oxygen to quench the excited state of the MitoXpress® probe. As the test material respires (i.e. the cells), oxygen is depleted in the surrounding solution/environment, which increases the probe phosphorescence signal. Changes in oxygen consumption reflecting changes in mitochondrial activity are seen as changes in the MitoXpress® probe signal over time.
Cells were seeded in 96 well black plates with transparent bottoms (Greiner Bio-One cat. no. 655090) at a 5 density of 50Ό00 cells/well in a final volume of 100 μL·. After 24 hours the incubation media was removed and 150 μL· of fresh media containing inhibitors at different concentrations was added to each well. Then, 10 μΐ^ of MitoXpress® and 150 μΐ^ mineral oil were added per well. Reading from the top of the plate, kinetic analysis was performed at 37 °C for 5 hours using a Synergy 4 plate reader (BioTek) and Time-resolved Fluoresence (TRF) wavelengths of 380/11 nm excitation and 650/20 nm emission or 10 665/40 emission (30 microsecond delay time, 100 microsecond integration time, gain or sensitivity
settings set at either medium or high). IC50s were calculated as the concentration that inhibits 50% of the phosphorescent oxygen sensitive probe signal (MitoXpress®) as compared to untreated cells.
Galactose cells are highly dependent on OXPHOS and more sensitive to mitochondrial inhibitors than 15 glucose cells (Gohil V.M. et al., Nat. Biotechnol., vol. 28, no. 3, pages 249-255, 2010). For example, a differential sensitivity in HeLa glucose versus HeLa galactose cell growth is exhibited by Antimycin A (Sigma- Aldrich cat. no. A8674), an inhibitor of complex III of the electron transport chain of the mitochondria (Figure la), but not by a cytotoxic compound such as Paclitaxel (CAS 33069-62-4) Figure lc). Compounds of the invention also exhibit differential sensitivity in HeLa glucose versus HeLa 20 galactose cell growth assays as shown by Figure lb, which shows the HeLa glucose versus HeLa
galactose cell growth for Example 5. As such HeLa galactose cells can be used to screen for
mitochondrial inhibitors. Moreover, compounds with activity in HeLa galactose cells can be confirmed as true mitochondrial inhibitors by testing Oxygen consumption inhibition as shown in Table 2. Biological data are given below in Table 2.
25
Table 2:
IC50 Oxygen
IC50 HeLa
Example Consumption
Galactose (nM)
(nM)
1 5 12
2 < 2 < 9
3 6 15
4 5 17
5 < 2 < 9
6 12 < 9 7 <2 <9
8 9 24
9 18 48
10 22 63
11 16 21
12 37 33
13 18 30
14 29 94
15 5 <9
16 20 49
17 32 59
18 18 38
19 <2 <9
20 3 <9
21 4 <9
22 6 20
23 40 122
24 23 82
25 45 58
26 6 <9
27 5 11
28 3 <9
29 28 73
30 13 64
31 7 21
32 49 123
33 7 23
34 6 <9
35 53 97 36 3 <9
37 3 <9
38 6 10
39 4 <9
40 19 19
41 16 15
42 17 27
43 9 18
44 4 11
45 3 <9
46 46 104
47 18 65
48 10 58
49 2 13
50 <2 <9
51 4 <9
52 <2 <9
53 <2 <9
54 5 <9
55 <2 <9
56 3 12
57 <2 <9
58 <2 <9
59 <4 <9
60 11 27
61 6 23
62 5 15
63 <4 <9
64 <4 <9 In vivo efficacy studies
MCF7 tumor xenograft study
NOD/SCID mice were implanted with estrogen pellets (0.36mg, 17P-estradiol, Innovative Research of America, Sarasota, Florida, USA) at the right flank one day before the tumor inoculation. All animals were randomly allocated lxlO7 of MCF7 cells injected in the right mammary fat pad. The mean tumor size at randomization was approximately 121.68 mm3. Randomization was performed based on "Matched distribution" randomization method using multi-task method (StudyDirector™ software, version 3.1.399.19). Tumor volumes were measured twice weekly in two dimensions using a caliper and the volume was calculated using the formula: V = (L x W x W)/2, where V is tumor volume, L is tumor length (the longest tumor dimension) and W is tumor width (the longest tumor dimension perpendicular to L). Animals were dosed daily orally with either 2.5 mg/kg of the compound of Example 4 or 0.25 mg/kg of the compound of Example 5. Doses were reduced to 2.0 mg/kg and 0.2 mg/kg, respectively, 9 days after treatment start. The vehicle control was administered with the same schedule. Statistical analysis of the results was performed using the One-Way-ANOVA (Tukey test).
An anti-tumor response was observed with a ΔΤ/C of 56 and 74 % (*p< 0.0001 and *p= 0.0067 vs vehicle controls) for Example 4 and Example 5, respectively, at day 23 of treatment when the study was terminated. This indicates that Example 4 and 5 are able to elicit an anti-tumor response in the MCF7 tumor xenograft model. *p = statistically significant. ΔΤ/C = the difference between the starting and the final mean tumor size of the drug-treated/vehicle control- treated mice, expressed as a %.
BT474 xenograft study
Female CB.17 SCID mice were inoculated with BT474 tumor fragments subcutaneously in the flank. Treatment commenced when tumors reached an average size of 100-150 mm3.
Tumor volumes were measured twice weekly as described in the MCF7 xenograft study. Animals were dosed daily orally with either 2 mg/kg Example 4, 2 mg/kg Example 15 or 0.4 mg/kg Example 5. No doses were administered from day 12 to day 16 and thereafter doses were reduced to 1.5, 1.5 and 0.3 mg/kg, respectively. The vehicle control was administered with the same schedule. Statistical analysis of the results was performed using the One-Way-ANOVA (Tukey test).
Examples 4, 5 and 15 elicited an anti-tumor response with a final ΔΤ/C of 29, 55 and 47 %, respectively, on day 32 when the study was terminated (*p= 0.0041, p= 0.07 and *p= 0.0082 vs vehicle controls). This indicates that Examples 4, 5 and 15 are also able to elicit an anti-tumor response in the BT474 tumor xenograft model. *p = statistically significant. ΔΤ/C = the difference between the starting and the final mean tumor size of the drug-treated/vehicle control-treated mice, expressed as a %.

Claims

Claims
1. A com ound of formula I or pharmaceutically acceptable salt thereof
Figure imgf000118_0001
wherein
ring A represents group A-I, A-II or A-III
Figure imgf000118_0002
(A-I) (Α-Π) (Α-ΠΙ)
Al represents -C(R4a)(R4a)-, -C(R4a)= -N(R4b)-, -N= -O- or -S-;
A2 represents -C(R4c)(R4c)-, -C(R4c)= or -0-;
A3 represents -C(R4c)(R4c)-, -C(R4c)= or -0-;
A4 represents -C(R4a)(R4a)-, -C(R4a)= -N= -O- or -S-;
A5 represents -C(R4a)(R4a)-, -C(R4a)= -N(R4b)-, -N= -O- or -S-;
A6 represents -C(R4c)(R4c)- or -C(R4c)=;
A7 represents -C(R4a)(R4a)-, -C(R4a)= -N= -O- or -S-;
A8 represents -C(R4a)(R4a)-, -N(R4b)-, -O- or -S-;
A9 represents -C(R4c)(R4c)- or -0-;
A10 represents -C(R4c)(R4c)- or -0-;
Al 1 represents -C(R4c)(R4c)- or -0-;
A12 represents -C(R4a)(R4a)-, -O- or -S-;
wherein group A-I, group A-II and group A-III do not contain adjacent oxygen atoms, adjacent oxygen and sulfur atoms or adjacent oxygen and nitrogen atoms or a moiety selected from the group consisting of
N-C-N, N-C-S, S-C-S, O-C-N, O-C-0 and O-C-S, wherein in each case the carbon atom in the N-C-N, INT- OS, S-C-S, O-C-N, O-C-0 and O-C-S moiety is saturated;
Bl, B2, B3 and B4 represent independently C(R3) or N, wherein no more than two of Bl, B2, B3 and B4 represent N;
X represents -CH(R5)-, -C(R5)= -C(O)- or -0-, and wherein when X represents -CH(R5) , -C(O)- or -O- the dotted line represents a single bond, and when X represents -C(R5)= the dotted line represents a double bond; Rl represents independently at each occurrence Cl-C6alkyl, Cl-C6haloalkyl or Cl-C6alkyl wherein one or two carbon atoms are independently replaced by -O- and wherein the alkyl moiety is optionally substituted by one or more halogen;
R2 represents halogen, cyano, hydroxyl, mercapto, Cl-C6alkyl optionally substituted by one to five R7, C 1 -C6alkoxy optionally substituted by one to five R7, -N(R6a)(R6b) or -C 1 -C6alkylene-N(R6a)(R6b); R3 represents independently at each occurrence hydrogen, halogen, cyano or Cl-C4alkyl;
R4a and R4b represent independently at each occurrence hydrogen or Cl-C3alkyl;
R4c represents independently at each occurrence hydrogen, Cl-C6alkyl optionally substituted by Rl 1, or Cl-C6alkyl in which one carbon atom is replaced by oxygen and which is additionally optionally substituted by Rl 1 , providing that when R4c is alkoxy the oxygen atom of R4c does not form with two ring atoms a moiety selected from the group consisting of O-C-N, O-C-0 and O-C-S, wherein in each case the carbon atom in the O-C-N, O-C-0 and O-C-S moiety is saturated;
R5 represents hydrogen or Cl-C4alkyl;
R6a represents hydrogen, Cl-C6alkyl optionally substituted by one to five R7, -Cl-C6alkylene-Cycle- P, -Cl-C6alkylene-Cycle-Q, Cycle-P or Cycle-Q;
R6b represents hydrogen or Cl-C6alkyl;
R7 represents independently at each occurrence halogen, cyano, hydroxyl, Cl-C6alkoxy, Cl- C3alkylsulfonyl, amino, -NH(C1-C4alkyl) or -N(Cl-C4alkyl)2;
Cycle-P represents independently at each occurrence a saturated or partially unsaturated 3- to 8- membered carbocyclic ring optionally substituted by 1 to 3 R9, or a saturated or partially unsaturated 3- to 8-membered heterocyclic ring optionally substituted by 1 to 3 R9 containing carbon atoms as ring members and one or two ring members independently selected from N and O, wherein N optionally may bear R8;
Cycle-Q represents independently at each occurrence phenyl optionally substituted by 1 to 3 RIO or a 5- to 6-membered heteroaryl ring containing one to four heteroatoms selected from O, S and N, optionally substituted by 1 to 3 RIO;
R8 represents independently at each occurrence hydrogen or Cl-C4alkyl;
R9 and RIO represent independently at each occurrence cyano, Cl-C4alkyl, Cl-C4haloalkyl, Cl- C4alkoxy or Cl-C4haloalkoxy;
Rl 1 represents hydroxyl or cyano;
n is 1 or 2; and
q is 0, 1, 2, 3 or 4.
2. A compound according to claim 1 or pharmaceutically acceptable salt thereof, wherein ring A represents group A-I.
3. A compound according to claim 1 or claim 2 or pharmaceutically acceptable salt thereof, wherein group A-I represents group A-Ia, group A-Ib, group A-Ic, group A-Id or group A-Ie:
Figure imgf000120_0001
(A-Ia) (A-Ib) (A-Ic)
Figure imgf000120_0002
(A-Id) (A-Ie)
wherein
Ala represents -C(R4a)(R4a)-, -N(R4b)-, -O- or -S-;
A4a represents -C(R4a)(R4a)-, -O- or -S-;
A2 represents -C(R4c)(R4c) or -0-;
A3 represents -C(R4c)(R4c)- or -0-, wherein both A2 and A3 do not represent -0-;
Alb represents -C(R4a)= or -N=; and
A4b represents -C(R4a)= or -N=.
4. A compound according to claim 3 or pharmaceutically acceptable salt thereof, wherein group A-I represents group A-Ia, group A-Id or group A-Ie.
5. A compound according to claim 3 or pharmaceutically acceptable salt thereof, wherein group A-I represents group A-Ib.
6. A compound according to claim 3 or pharmaceutically acceptable salt thereof, wherein group A-I represents group A-Ic.
7. A compound according to claim 1 or pharmaceutically acceptable salt thereof, wherein ring A represents group A-II.
8. A compound according to claim 1 or claim 7 or pharmaceutically acceptable salt thereof, wherein group A-II represents A-IIa, group A- lib or group A- lie:
Figure imgf000121_0001
(A-IIa) (A-IIb) (A-IIc)
5 wherein
A5a represents -C(R4a)(R4a)-, -N(R4b)-, -O- or -S-;
A7a represents -C(R4a)(R4a)-, -O- or -S-, wherein at least one of A5a and A7a represents -C(R4a)(R4a)-; A5b represents -C(R4a)= or -N=;
A7b represents -O- or -S-;
10 A5c represents -N(R4b)-, -O- or -S-; and
A7c represents -C(R4a)= or -N=.
9. A compound according to claim 8 or pharmaceutically acceptable salt thereof, wherein group A- II represents group A-IIa.
15
10. A compound according to claim 8 or pharmaceutically acceptable salt thereof, wherein group A- II represents group A-IIb.
11. A compound according to claim 8 or pharmaceutically acceptable salt thereof, wherein group A- 20 II represents group A-IIc.
12. A compound according to claim 1 or pharmaceutically acceptable salt thereof, wherein ring A represents group A-III.
25 13. A compound according to claim 1 or claim 12 or pharmaceutically acceptable salt thereof,
wherein ring A represents group A- Ilia.
Figure imgf000121_0002
wherein A8 represents -C(R4a)(R4a)- or -0-; and
A12 represents -C(R4a)(R4a)- or -0-.
14. A compound according to any one of claims 1 to 4, 12 and 13 or pharmaceutically acceptable salt thereof, wherein Al, Ala, A4, A4a, A8 and A12 represent -O- and A2, A3, A9, AlO and Al 1 represent independently -C(R4c)(R4c)-, or wherein Al, Ala and A8 represent -O- and A2, A3, A4, A4a, A9, AlO, Al land A12 represent independently -C(R4c)(R4c)-.
15. A compound according to claim 1 or pharmaceutically acceptable salt thereof, wherein ring A represents one of the following groups:
Figure imgf000122_0001
Figure imgf000122_0002
Figure imgf000123_0001
16. A compound according to claim 15 or pharmaceutically acceptable salt thereof, wherein represents one of the following groups:
Figure imgf000123_0002
17. A compound according to any one of claims 1 to 5, 7 to 9 and 12 to 15 or pharmaceutically acceptable salt thereof, wherein ring A is ring A-I, A-II or A-III and the bridge in ring A formed by the A moieties is saturated.
18. A compound according to any one of claims 1 to 3, 6 to 8, 10, 11 and 15 or pharmaceutically acceptable salt thereof, wherein ring A is ring A-I or A-II and the bridge in ring A formed by the A moieties is unsaturated.
A compound according to any one of claims 1 to 18 or pharmaceutically acceptable salt thereof,
20. A compound according to any one of claims 1 to 18 or pharmaceutically acceptable salt thereof, wherein n is 2.
21. A compound according to any one of claims 1 to 20 or pharmaceutically acceptable salt thereof, 5 wherein X represents -CH=.
22. A compound according to any one of claims 1 to 20 or pharmaceutically acceptable salt thereof, wherein X represents -CH2-.
10 23. A compound according to any one of claims 1 to 20 or pharmaceutically acceptable salt thereof, wherein X represents -C(O)-.
24. A compound according to any one of claims 1 to 20 or pharmaceutically acceptable salt thereof, wherein X represents -0-.
15
25. A compound according to any one of claims 1 to 24 or pharmaceutically acceptable salt thereof, wherein the ring formed by Bl, B2, B3 and B4 is represented by group B-Ia:
Figure imgf000124_0001
20 26. A compound according to claim 25 or pharmaceutically acceptable salt thereof, wherein the ring formed by Bl, B2, B3 and B4 is represented by group B-la-1, B-la-2 or B-la-3:
Figure imgf000124_0002
(B-la-1) (B-la-2) (B-la-3);
wherein R3a* represents independently at each occurrence halogen, cyano or Cl-C4alkyl.
27. A compound according to any one of claims 1 to 26 or pharmaceutically acceptable salt thereof, wherein R2 represents halogen, cyano, methoxy or trifluoromethyl.
28. A compound according to any one of claims 1 to 27 or pharmaceutically acceptable salt thereof, wherein R3 represents independently at each occurrence hydrogen, fluoro, chloro, bromo, cyano, methyl and R3a* represents independently at each occurrence fluoro, chloro, bromo, cyano, methyl.
29. A compound according to any one of claims 1 to 28 or pharmaceutically acceptable salt thereof, wherein R4c represents indendently at each occurrence hydrogen, Cl-C4alkyl, -Cl-C4alkyl-cyano, -Cl- C4alkyl-hydroxy or -C0-C2alkyl-Cl-C3alkoxy.
30. A compound according to claim 1 or pharmaceutically acceptable salt thereof,
wherein ring A represents group A- la, A- lb, A-Ic, A-Id, A-Ie, A-IIa, A- lib, A-IIc or A- Ilia:
Figure imgf000125_0001
(A-Id) (A-Ie)
Figure imgf000125_0002
Ala represents -CH(R4a)-, -N(R4b)- or -O- or -S-;
A4a represents -CH(R4a)-, -O- or -S-;
A2 represents -CH(R4c) or -0-;
A3 represents -CH(R4c)- or -0-, wherein both A2 and A3 do not represent -0-;
Alb represents -C(R4a)= or -N=;
A4b represents -C(R4a)= or -N=;
A5a represents -CH(R4a)-, -N(R4b)-, -O- or -S-; A7a represents -CH(R4a)-, -O- or -S-, wherein at least one of A5a and A7a represents -CH(R4a)-;
A5b represents -C(R4a)= or -N=;
A7b represents -O- or -S-;
A5c represents -N(R4b)-, -O- or -S-;
A7c represents -C(R4a)= or -N=;
A8 represents -CH(R4a)- or -0-; and
A12 represents -CH(R4a)- or -0-;
X represents =CH-, -CH2-, -C(O)- or -0-;
the ring formed by Bl, B2, B3 and B4 is represented by group B-Ia:
Figure imgf000126_0001
Rl represents independently at each occurrence methyl, ethyl, propyl, methoxy, ethoxy, methoxymethyl or methoxyethyl;
R2 represents halogen, cyano, methoxy or trifluoromethyl;
R3 represents independently at each occurrence hydrogen or halogen;
R4a and R4b represent independently at each occurrence hydrogen or Cl-C3alkyl;
R4c represents independently at each occurrence hydrogen, Cl-C4alkyl -Cl-C4alkyl-cyano, -Cl-C4alkyl- hydroxy or -C0-C2alkyl-Cl-C3alkoxy, providing that when Rc is alkoxy, the oxygen atom of R4c does not form with two ring atoms a moiety selected from the group consisting of O-C-N, O-C-0 and O-C-S, wherein in each case the carbon atom in the O-C-N, O-C-0 or O-C-S moiety is saturated;
n is 1 or 2; and
q is 0, 1 or 2.
31. A compound according to claim 30 or pharmaceutically acceptable salt thereof, wherein ring A one of the following groups:
Figure imgf000126_0002
Figure imgf000127_0001
32. A compound of formula I or pharmaceutically acceptable salt for use in the treatment of a proliferation disease or disorder, wherein the compound of formula I is as defined in any one of claims 1 to 31.
33. Use of a compound of formula I as defined in any one of claims 1 to 31 or pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a proliferation disease or disorder.
34. A method of treating a proliferation disease or disorder in a subject comprising administering a pharmaceutically effective amount of the compound of formula I as defined in any one of claims 1 to 31 or pharmaceutically acceptable salt thereof to said subject.
35. A compound for use according to claim 32 or pharmaceutically acceptable salt thereof , use of a compound according to claim 33 or pharmaceutically acceptable salt thereof , or a method of treating a proliferation disease or disorder according to claim 34, wherein the proliferation disorder or disease is selected from the group consisting of epithelial neoplasms, squamous cell neoplasms, basal cell neoplasms, transitional cell papillomas and carcinomas, adenomas and adenocarcinomas, adnexal and skin appendage neoplasms, mucoepidermoid neoplasms, cystic neoplasms, mucinous and serous neoplasms, ducal-, lobular and medullary neoplasms, acinar cell neoplasms, complex epithelial neoplasms, specialized gonadal neoplasms, paragangliomas and glomus tumours, naevi and melanomas, soft tissue tumours and sarcomas, fibromatous neoplasms, myxomatous neoplasms, lipomatous neoplasms, myomatous neoplasms, complex mixed and stromal neoplasms, fibroepithelial neoplasms, synovial like neoplasms, mesothelial neoplasms, germ cell neoplasms, trophoblastic neoplasms, mesonephromas, blood vessel tumours, lymphatic vessel tumours, osseous and chondromatous neoplasms, giant cell tumours, miscellaneous bone tumours, odontogenic tumours, gliomas, neuroepitheliomatous and neuroendocrine neoplasms, meningiomas, nerve sheath tumours, granular cell tumours and alveolar soft part sarcomas, Hodgkin's and non-Hodgkin's lymphomas, B-cell lymphoma, T- cell lymphoma, hairy cell lymphoma, Burkitts lymphoma and other lymphoreticular neoplasms, plasma cell tumours, mast cell tumours, immunoproliferative diseases, leukemias, miscellaneous
myeloproliferative disorders, lymphoproliferative disorders and myelodysplastic syndromes.
36. A compound for use according to claim 35 or pharmaceutically acceptable salt thereof, use of a compound according to claim 35 or pharmaceutically acceptable salt thereof, or a method of treating a proliferation disease or disorder according to claim 35, wherein proliferation disease or disorder is a cancer.
37. A compound for use according to claim 36 or pharmaceutically acceptable salt thereof, use of a compound according to claim 36 or pharmaceutically acceptable salt thereof, or a method of treating a proliferation disease or disorder according to claim 36, wherein the cancer is selected from the group consisting of breast cancer, prostate cancer, cervical cancer, ovarian cancer, gastric cancer, colorectal cancer, pancreatic cancer, liver cancer, brain cancer, neuroendocrine cancer, lung cancer, kidney cancer, hematological malignancies, melanoma and sarcomas.
38. A compound for use according to claim 32 or 35 to 37 or pharmaceutically acceptable salt thereof, use of a compound according to claim 33 or 35 to 37 or pharmaceutically acceptable salt thereof, or a method of treating a proliferation disease or disorder according to claim 34 or 35 to 37, wherein the subject is a human.
39. A pharmaceutical composition comprising a compound of formula I as defined in any one of claims 1 to 31 , or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20190142810A1 (en) * 2016-06-30 2019-05-16 Basilea Pharmaceutica International AG Mitochondrial inhibitors for the treatment of proliferation disorders
CN112830933A (en) * 2021-02-04 2021-05-25 康化（上海）新药研发有限公司 Synthetic method of 3, 4-dihydro-2H-pyrano [2,3-b ] pyridine

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110604314A (en) * 2019-10-15 2019-12-24 大连工业大学 TPP mitochondrion targeted astaxanthin emulsion and preparation method thereof

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040209821A1 (en) * 2003-04-18 2004-10-21 Hamann Lawrence G. N-substituted phenylurea inhibitors of mitochondrial F1F0 ATP hydrolase
WO2006074025A1 (en) * 2004-12-30 2006-07-13 Janssen Pharmaceutica N.V. Piperazinyl and piperidinyl ureas as modulators of fatty acid amide hydrolase
WO2010054763A1 (en) 2008-11-14 2010-05-20 Bayer Schering Pharma Aktiengesellschaft Heterocyclically substituted aryl compounds as hif inhibitors
WO2014031928A2 (en) 2012-08-24 2014-02-27 Philip Jones Heterocyclic modulators of hif activity for treatment of disease
WO2014031936A2 (en) 2012-08-24 2014-02-27 Philip Jones Heterocyclic modulators of hif activity for treatment of disease

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040209821A1 (en) * 2003-04-18 2004-10-21 Hamann Lawrence G. N-substituted phenylurea inhibitors of mitochondrial F1F0 ATP hydrolase
WO2006074025A1 (en) * 2004-12-30 2006-07-13 Janssen Pharmaceutica N.V. Piperazinyl and piperidinyl ureas as modulators of fatty acid amide hydrolase
WO2010054763A1 (en) 2008-11-14 2010-05-20 Bayer Schering Pharma Aktiengesellschaft Heterocyclically substituted aryl compounds as hif inhibitors
WO2014031928A2 (en) 2012-08-24 2014-02-27 Philip Jones Heterocyclic modulators of hif activity for treatment of disease
WO2014031936A2 (en) 2012-08-24 2014-02-27 Philip Jones Heterocyclic modulators of hif activity for treatment of disease

Non-Patent Citations (37)

* Cited by examiner, † Cited by third party
Title
BOLAND M.L. ET AL., FRONTIERES IN ONCOLOGY, vol. 3, 2013, pages 1 - 28
CAMPBELL, N.A.; WILLIAMSON B.; HEYDEN, R.J.: "Biology: Exploring Life", 2006, PEARSON PRENTICE HALL
CHAE Y.K. ET AL., ONCOTARGET, 19 March 2016 (2016-03-19)
CHEMICAL ABSTRACTS, Columbus, Ohio, US; abstract no. 33069-62-4
CORAZAO-ROZAS P. ET AL., ONCOTARGET, vol. 4, no. 11, 2013, pages 1986 - 1998
DEBERARDINIS R.J. ET AL., PNAS, vol. 104, no. 49, 2007, pages 19345 - 19350
EL-MIR ET AL., J. BIOL. CHEM., vol. 275, 2000, pages 223 - 228
GOHIL V.M. ET AL., NAT. BIOTECHNOL., vol. 28, no. 3, 2010, pages 249 - 255
GREENE T.W.; WUTS P.G.M.: "Protective Groups in Organic Synthesis", 2014, JOHN WILEY & SONS
GREENE T.W; WUTS P.G.M: "Protective Groups in Organic Synthesis", 2014, JOHN WILEY & SONS
HARTWIG J.F., ANGEW. CHEM. INT. ED., vol. 37, no. 15, 1998, pages 2046 - 2067
HUTCHINS M.K.: "Comprehensive Organic Synthesis", vol. 8, 1991, PERGAMON PRESS, pages: 25 - 78
ILHYONG R. ET AL., J. AM. CHEM. SOC., vol. 124, no. 44, 2002, pages 12946 - 12947
ISHIKAWA T. ET AL., J. ANTIBIOTICS, vol. 53, no. 10, 2000, pages 1071 - 1085
ISHIYAMA ET AL., J. ORG. CHEM., vol. 60, 1995, pages 7508 - 7510
ISHIYAMA T. ET AL., J. ORG. CHEM., vol. 60, 1995, pages 7508 - 7510
LAROCK R.C.: "A guide to functional Group Preparation", 1999, WILEY-VC, article "Comprehensive Organic Transformations", pages: 1235 - 1236,1238-1246
MARCH J.; SMITH M.: "Advanced Organic Chemistry", 2013, JOHN WILEY & SONS
MARCHETTI P. ET AL., INTERNATIONAL JOURNAL OF CELL BIOLOGY, vol. 2015, 2015, pages 1 - 17
MCBRIDE H.M., CURR. BIOL., vol. 16, no. 14, 2006, pages R551 - 60
O. MITSUNOBU, SYNTHESIS, vol. 1, 1981, pages 1 - 28
QUINN B.J.; KITAGAWA H.; MEMMOTT R.M. ET AL., TRENDS ENDOCRINOL. METAB., vol. 24, 2000, pages 469 - 80
ROGERS H.R. ET AL., J. AM CHEM. SOC., vol. 102, no. 1, 1980, pages 217 - 226
SATO S. ET AL., TETRAHEDRON, vol. 60, 2004, pages 7899 - 7906
SINGH J. ET AL., ORG. PROCESS RES. & DEV., vol. 6, no. 6, 2002, pages 863 - 868
SOLAINI G. ET AL., BIOCHIM. BIOPHYS. ACTA, vol. 1797, 2010, pages 1171 - 1177
SOLAINI G. ET AL., BIOCHIM. BIOPHYS. ACTA, vol. 2, 2010, pages 314 - 323
STROHECKER A.M. ET AL., CANCER DISCOVERY, vol. 3, no. 11, 2013, pages 1272 - 1285
SURRY D.S.; BUCHWALD S.L., CHEM. SCI., vol. 2, 2011, pages 27 - 50
TAKAGI J. ET AL., J. AM. CHEM. SOC., vol. 27, no. 27, 2002, pages 8001 - 8006
THE JOURNAL OF ORGANIC CHEMISTRY GUIDELINES FOR AUTHORS, 2017
TROST B.M. ET AL., CHEM. EUR. J., vol. 5, no. 3, pages 1055 - 1069
VELLINGA T. T. ET AL., CLINICAL CANCER RESEARCH, vol. 21, no. 12, 2015, pages 2870 - 2879
WARBURG O., SCIENCE, vol. 123, no. 3191, 1956, pages 309 - 314
WEINBERG F. ET AL., PNAS, vol. 107, no. 19, 2010, pages 8788 - 8793
WHEATON W. W. ET AL., ELIFE, vol. 3, 2014
ZIEGELBAUER ET AL., CANCER MEDICINE, vol. 2, no. 5, 2013, pages 611 - 624

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20190142810A1 (en) * 2016-06-30 2019-05-16 Basilea Pharmaceutica International AG Mitochondrial inhibitors for the treatment of proliferation disorders
CN112830933A (en) * 2021-02-04 2021-05-25 康化（上海）新药研发有限公司 Synthetic method of 3, 4-dihydro-2H-pyrano [2,3-b ] pyridine

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